DRUG INTERACTIONS
Abacavir; Dolutegravir; Lamivudine: Concurrent administration of dolutegravir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated dolutegravir plasma concentrations. Dolutegravir is a substrate of uridine glucuronyltransferase (UGT) and the hepatic isoenzyme CYP3A4. Ritonavir is a potent inhibitor of CYP3A4 and dasabuvir, ombitasvir, and paritaprevir are all UGT1A1 inhibitors. Additionally, dolutegravir is a substrate of the breast cancer resistance protein (BCRP); dasabuvir, ritonavir, and paritaprevir are BCRP inhibitors. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of dolutegravir with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated dolutegravir plasma concentrations. Dolutegravir is a substrate of uridine glucuronyltransferase (UGT) and the hepatic isoenzyme CYP3A4. Ritonavir is a potent inhibitor of CYP3A4 and dasabuvir, ombitasvir, and paritaprevir are all UGT1A1 inhibitors. Additionally, dolutegravir is a substrate of the breast cancer resistance protein (BCRP); dasabuvir, ritonavir, and paritaprevir are BCRP inhibitors. Caution and close monitoring are advised if these drugs are administered together.
Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: Since ritonavir induces glucuronidation, there is the potential for reduction in zidovudine, ZDV plasma concentrations during concurrent therapy with ritonavir. When coadministered with ritonavir, the AUC and Cmax of zidovudine, ZDV are decreased by 12% and 27%. The clinical significance of this interaction is unknown.
Acarbose: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors.
Acebutolol: Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
Acetaminophen: Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Acetaminophen; Aspirin, ASA; Caffeine: Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Acetaminophen; Butalbital: Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Acetaminophen; Butalbital; Caffeine: Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Acetaminophen; Butalbital; Caffeine; Codeine: Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
Acetaminophen; Caffeine; Dihydrocodeine: Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of dihydrocodeine with ritonavir may result in elevated plasma concentrations of dihydrocodeine. Ritonavir is a substrate and inhibitor of the hepatic isoenzyme CYP2D6. Dihydrocodeine is metabolized by CYP2D6. Caution and close monitoring are advised if these drugs are administered together.
Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together. Concurrent administration of dextromethorphan with ritonavir may result in elevated dextromethorphan plasma concentrations. Dextromethorphan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together. Concurrent administration of dextromethorphan with ritonavir may result in elevated dextromethorphan plasma concentrations. Dextromethorphan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together.
Acetaminophen; Codeine: Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
Acetaminophen; Dextromethorphan: Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of dextromethorphan with ritonavir may result in elevated dextromethorphan plasma concentrations. Dextromethorphan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Acetaminophen; Dextromethorphan; Doxylamine: Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of dextromethorphan with ritonavir may result in elevated dextromethorphan plasma concentrations. Dextromethorphan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of dextromethorphan with ritonavir may result in elevated dextromethorphan plasma concentrations. Dextromethorphan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Acetaminophen; Dextromethorphan; Phenylephrine: Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of dextromethorphan with ritonavir may result in elevated dextromethorphan plasma concentrations. Dextromethorphan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Acetaminophen; Dextromethorphan; Pseudoephedrine: Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of dextromethorphan with ritonavir may result in elevated dextromethorphan plasma concentrations. Dextromethorphan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Acetaminophen; Dichloralphenazone; Isometheptene: Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Acetaminophen; Diphenhydramine: Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of diphenhydramine with ritonavir may result in elevated plasma concentrations of diphenhydramine. Diphenhydramine is a CYP2D6 substrate, and ritonavir is a CYP2D6 inhibitor. Caution and close monitoring are advised if these drugs are administered together.
Acetaminophen; Guaifenesin; Phenylephrine: Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Acetaminophen; Hydrocodone: Concurrent administration of hydrocodone with ritonavir may result in elevated hydrocodone plasma concentrations and subsequent adverse events, such as sedation and respiratory depression. If these drugs are given together, a 50% reduction in the dose of hydrocodone may be needed, and monitoring for respiratory depression and sedation at regular intervals is recommended. Hydrocodone is metabolized by the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is an inhibitor of these enzymes. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ritonavir may reduce the efficacy of hydrocodone. Caution and close monitoring for both efficacy and adverse reactions are advised if these drugs are administered together; a hydrocodone dosage adjustment may be necessary. Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Acetaminophen; Oxycodone: Oxycodone is metabolized by CYP3A4. Concomitant administration of ritonavir, a CYP3A4 inhibitor, may cause an increase in oxycodone plasma concentrations, which could increase or prolong adverse effects and may cause potentially fatal respiratory depression. If coadministration of these agents is necessary, patients should be monitored for an extended period and dosage adjustments made if warranted. In addition, oxycodone is metabolized in part by CYP2D6 to oxymorphone, which represents less than 15% of the total administered dose. Concurrent use of some agents that inhibit CYP2D6 has not been shown to result in clinically significant interactions. However, potent inhibitors of CYP2D6, such as ritonavir, may potentially increase the effects of oxycodone. Caution and close monitoring are advised if these drugs are administered together. Initiate oxycodone at low dosages and titrate carefully. Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Acetaminophen; Pentazocine: Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Acetaminophen; Propoxyphene: Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Due to effects on microsomal isoenzymes responsible for hepatic metabolism, ritonavir may alter the response and/or increase the AUC of opiate analgesics. Concurrent use of ritonavir and propoxyphene is not recommended, due the increased formation of the neurotoxic metabolites of propoxyphene. Also, propoxyphene is a substrate/inhibitor of CYP3A4. Increased serum concentrations of propoxyphene can occur from concurrent use of ritonavir, a CYP3A4 inhibitor. A reduced dosage of propoxyphene may be needed. Monitor for CNS and respiratory depression.
Acetaminophen; Pseudoephedrine: Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Acetaminophen; Tramadol: Tramadol is primarily metabolized by CYP2D6 and CYP3A4; drugs that inhibit these enzymes, such as ritonavir, may decrease the metabolism of tramadol. This may result in a decreased concentration of the active metabolite (O-desmethyltramadol) leading to decreased analgesic effects and possibly increased side effects (seizures and serotonin syndrome) due to higher tramadol concentrations. Concurrent administration of acetaminophen with ritonavir may result in elevated acetaminophen plasma concentrations and subsequent adverse events. Acetaminophen is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Adefovir: Patients who are concurrently taking adefovir with antiretrovirals like the protease inhibitors, are at risk of developing lactic acidosis and severe hepatomegaly with steatosis. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with antiretrovirals. A majority of these cases have been in women; obesity and prolonged nucleoside exposure may also be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for hepatic disease; however, cases have also been reported in patients with no known risk factors. Suspend adefovir in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).
Ado-Trastuzumab emtansine: Ritonavir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use ritonavir concomitantly with ado-trastuzumab emtansine. Ritonavir is a strong CYP3A4 inhibitor. Although formal drug interactions have not been completed, the cytotoxic small molecule of ado-trastuzumab emtansine, DM1, is primarily metabolized by CYP3A4 (and to a lesser extent, CYP3A5) in vitro, and has been associated with hepatotoxicity, interstitial lung disease (ILD) / pneumonitis, and severe bleeding events. Treatment with ado-trastuzumab emtansine should be delayed until ritonavir is cleared from the circulation (approximately 3 elimination half-lives) or an alternate medication with less potential to inhibit CYP3A4 should be considered.
Afatinib: If the concomitant use of ritonavir and afatinib is necessary, consider reducing the afatinib dose by 10 mg per day if the original dose is not tolerated; resume the previous dose of afatinib as tolerated after discontinuation of ritonavir. Afatinib is a P-glycoprotein (P-gp) substrate and inhibitor in vitro, and ritonavir is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration of ritonavir (200 mg twice daily for 3 days) 1 hour before afatinib (single dose) increased the afatinib AUC and Cmax by 48% and 39%, respectively; there was no change in the afatinib AUC when ritonavir was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with ritonavir, and 111% and 105% when ritonavir was administered 6 hours after afatinib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day, but does not address a minimum dose otherwise. Concomitant use of afatinib with ombitasvir; paritaprevir; ritonavir or dasabuvir; ombitasvir; paritaprevir; ritonavir may increase afatinib plasma concentrations. Afatinib is a P-gp substrate, and ritonavir and paritaprevir are P-gp inhibitors. In a single dose study, when ritonavir was co-administered with afatinib or administered 6 hours after afatinib, the relative AUC and Cmax were minimally affected. However, in another study, ritonavir was administered 1 hour before a single dose of afatinib, resulting in an AUC increased by 48% and Cmax increased by 39%. If the use of both agents is necessary, consider reducing the afatinib dose to 30 mg/day if the original dose is not tolerated. Resume the previous dose if ombitasvir; paritaprevir; ritonavir or is discontinued.
Albuterol: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir, include beta-agonists.
Albuterol; Ipratropium: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir, include beta-agonists.
Aldesleukin, IL-2: Concurrent administration of aldesleukin, IL-2 with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in increased plasma concentrations of paritaprevir, ritonavir and dasabuvir. Aldesleukin, IL-2 increases IL-6 concentrations, and IL-6 is an inhibitor of the hepatic isoenzyme CYP3A4; paritaprevir, ritonavir and dasabuvir (minor) are substrates of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of aldesleukin, IL-2 with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in increased plasma concentrations of paritaprevir, ritonavir and dasabuvir. Aldesleukin, IL-2 increases IL-6 concentrations, and IL-6 is an inhibitor of the hepatic isoenzyme CYP3A4; paritaprevir, ritonavir and dasabuvir (minor) are substrates of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of aldesleukin, IL-2 with ritonavir may result in increased plasma concentrations of ritonavir. Aldesleukin, IL-2 increases IL-6 concentrations, and IL-6 is an inhibitor of the hepatic isoenzyme CYP3A4; ritonavir is a substrate of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Alfentanil: Alfentanil is metabolized by the hepatic isoenzyme CYP3A4. Drugs that inhibit this enzyme, such as protease inhibitors, may alter responses to alfentanil. A dose reduction of one or both drugs may be warranted. Monitor closely for oversedation and respiratory depression.
Alfuzosin: Alfuzosin is contraindicated for use with anti-retroviral protease inhibitors due to the potential for serious/life-threatening reactions, including hypotension. Alfuzosin is primarily metabolized by CYP3A4 hepatic enzymes; potent inhibitors of CYP3A4, such as anti-retroviral protease inhibitors, block the metabolism of alfuzosin and increase systemic exposure to alfuzosin. Additionally, ritonavir, saquinavir boosted with ritonavir and lopinavir; ritonavir cause dose-dependent QT and PR prolongation; the risk of QT interval prolongation may be increased if these drugs are used with alfuzosin.
Aliskiren: The plasma concentrations of aliskiren may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Ritonavir is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of both CYP3A4 and P-gp.
Aliskiren; Amlodipine: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. The plasma concentrations of aliskiren may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Ritonavir is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of both CYP3A4 and P-gp.
Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. The plasma concentrations of aliskiren may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Ritonavir is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of both CYP3A4 and P-gp.
Aliskiren; Hydrochlorothiazide, HCTZ: The plasma concentrations of aliskiren may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Ritonavir is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of both CYP3A4 and P-gp.
Aliskiren; Valsartan: Coadministration of valsartan and regimens containing paritaprevir may result in elevated valsartan plasma concentrations. A valsartan dose reduction, and close monitoring for adverse events (i.e., hypotension and worsening renal function) are advised during coadministration. If adverse events are observed, consider further reductions in valsartan dose or an alternative to the angiotensin receptor blocker. Valsartan is a substrate of the organic anion transporting polypeptides (OATP) and paritaprevir is an OATP1B1 and OATP1B3 inhibitor. The plasma concentrations of aliskiren may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Ritonavir is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Aliskiren is a substrate of both CYP3A4 and P-gp. Valsartan is a substrate of the hepatic efflux transporter MRP2 and ritonavir is an inhibitor of MRP2. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan during coadministration.
Almotriptan: Ombitasvir; paritaprevir; ritonavir may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and ritonavir is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure. Ritonavir may increase the systemic exposure of almotriptan. If coadministered, the recommended starting dose of almotriptan is 6.25 mg; do not exceed 12.5 mg within a 24-hour period. Avoid coadministration in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and ritonavir is a potent CYP3A4 inhibitor. In a drug interaction study, coadministration of almotriptan and ketoconazole, another potent CYP3A4 inhibitor, resulted in an approximately 60% increase in almotriptan exposure.
Alogliptin: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Alogliptin; Metformin: The manufacturer recommends against concurrent administration of ombitasvir; paritaprevir; ritonavir and metformin in patients with hepatic or renal impairment. If these drugs are given together, closely monitor blood glucose concentrations and for signs of lactic acidosis (i.e., abdominal or respiratory distress, worsening renal function, somnolence). New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Alogliptin; Pioglitazone: Concurrent administration of pioglitazone with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated pioglitazone plasma concentrations and decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Pioglitazone is an inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. In addition, pioglitazone is metabolized by CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Alosetron: Concurrent administration of alosetron with ritonavir may alter alosetron plasma concentrations; however, the precise effect is undefined. Alosetron is metabolized by the hepatic isoenzymes CYP3A4, CYP2C9, and CYP1A2; ritonavir is an inhibitor of CYP3A4 and an inducer of CYP1A2 and possibly CYP2C9. Caution and close monitoring are advised if these drugs are administered together.
Alpha-glucosidase Inhibitors: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors.
Alprazolam: Coadministration of alprazolam and ritonavir or lopinavir; ritonavir is not recommended. If coadministration cannot be avoided, a dosage reduction of alprazolam should be considered. Lopinavir and ritonavir are potent CYP3A4 inhibitors. The initial step in alprazolam metabolism is hydroxylation catalyzed by cytochrome CYP3A. Drugs that inhibit this metabolic pathway may profoundly decrease alprazolam clearance, resulting in increased potential for serious alprazolam-related adverse events, such as respiratory depression and prolonged sedation. Consequently, alprazolam should be avoided in patients receiving very potent inhibitors of CYP3A isoenzymes.
Ambrisentan: Concurrent administration can result in elevated ambrisentan plasma concentrations, which may increase the risk for adverse effects. Ambrisentan is metabolized by CYP3A4. Although data are lacking, significant CYP3A4 inhibitors, such as ritonavir, could potentially increase ambrisentan plasma concentrations via CYP3A4 inhibition. In addition, ritonavir also inhibits P-glycoprotein further increasing the risk for ambrisentan toxicity. Monitor for increased toxicity as well as increased therapeutic effect during times of coadministration. Concurrent administration of ambrisentan with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir can result in elevated ambrisentan plasma concentrations, which may increase the risk for adverse effects. Ambrisentan is a substrate of the hepatic isoenzyme CYP3A4, P-glycoprotein (P-gp), and the organic anion transporting polypeptides (OATP). Ritonavir inhibits CYP3A4 and P-gp, and paritaprevir is an OATP1B1 OATP1B3, and P-gp inhibitor. Caution and close monitoring are advised if these drugs are administered together.
Amiodarone: Coadministration of HIV treatment doses of ritonavir and amiodarone is contraindicated due to the potential for serious or life-threatening reactions, such as cardiac arrhythmias. Cautious consideration may be given to administering amiodarone with boosting doses of ritonavir. Ritonavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, such as amiodarone, should be expected with concurrent use. In addition, both ritonavir and amiodarone are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
Amitriptyline: Concurrent administration of amitriptyline with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated amitriptyline plasma concentrations; however, the clinical implications of this interaction have not been clearly defined. Amitriptyline is a substrate of the hepatic isoenzymes CYP3A4 and CYP2D6 and uridine glucuronyltransferase (UGT). Ritonavir inhibits CYP3A4 and CYP2D6, while dasabuvir, ombitasvir and paritaprevir are UGT1A1 inhibitors. Hepatic isoenzymes CYP1A2, CYP2C9, and CYP2C19 also contribute to amitriptyline's metabolism, and these isoenzymes do not appear to be inhibited by the 4-drug regimen. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of amitriptyline with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated amitriptyline plasma concentrations; however, the clinical implications of this interaction have not been clearly defined. Amitriptyline is a substrate of the hepatic isoenzymes CYP3A4 and CYP2D6 and uridine glucuronyltransferase (UGT). Ritonavir inhibits CYP3A4 and CYP2D6, while dasabuvir, ombitasvir and paritaprevir are UGT1A1 inhibitors. Hepatic isoenzymes CYP1A2, CYP2C9, and CYP2C19 also contribute to amitriptyline's metabolism, and these isoenzymes do not appear to be inhibited by the 4-drug regimen. Caution and close monitoring are advised if these drugs are administered together. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Ritonavir has a possible risk for QT prolongation and torsade de pointes (TdP) and should be used cautiously and with close monitoring with doxepin. In addition, ritonavir potently inhibits CYP2D6 and CYP3A4, and thus may inhibit the metabolism of the tricyclic antidepressants (TCAs). A significant effect of ritonavir on desipramine clearance has been reported. Since the magnitude of the interaction with the TCAs is difficult to predict but may be significant, closely monitor patients receiving ritonavir and TCAs concurrently. Adjust the dosage of the coadministered drug based on therapeutic response. TCA serum concentration monitoring may be useful to guide adjustments and prevent toxicity.
Amitriptyline; Chlordiazepoxide: Concurrent administration of amitriptyline with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated amitriptyline plasma concentrations; however, the clinical implications of this interaction have not been clearly defined. Amitriptyline is a substrate of the hepatic isoenzymes CYP3A4 and CYP2D6 and uridine glucuronyltransferase (UGT). Ritonavir inhibits CYP3A4 and CYP2D6, while dasabuvir, ombitasvir and paritaprevir are UGT1A1 inhibitors. Hepatic isoenzymes CYP1A2, CYP2C9, and CYP2C19 also contribute to amitriptyline's metabolism, and these isoenzymes do not appear to be inhibited by the 4-drug regimen. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of amitriptyline with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated amitriptyline plasma concentrations; however, the clinical implications of this interaction have not been clearly defined. Amitriptyline is a substrate of the hepatic isoenzymes CYP3A4 and CYP2D6 and uridine glucuronyltransferase (UGT). Ritonavir inhibits CYP3A4 and CYP2D6, while dasabuvir, ombitasvir and paritaprevir are UGT1A1 inhibitors. Hepatic isoenzymes CYP1A2, CYP2C9, and CYP2C19 also contribute to amitriptyline's metabolism, and these isoenzymes do not appear to be inhibited by the 4-drug regimen. Caution and close monitoring are advised if these drugs are administered together. CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Ritonavir has a possible risk for QT prolongation and torsade de pointes (TdP) and should be used cautiously and with close monitoring with doxepin. In addition, ritonavir potently inhibits CYP2D6 and CYP3A4, and thus may inhibit the metabolism of the tricyclic antidepressants (TCAs). A significant effect of ritonavir on desipramine clearance has been reported. Since the magnitude of the interaction with the TCAs is difficult to predict but may be significant, closely monitor patients receiving ritonavir and TCAs concurrently. Adjust the dosage of the coadministered drug based on therapeutic response. TCA serum concentration monitoring may be useful to guide adjustments and prevent toxicity.
Amlodipine: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
Amlodipine; Atorvastatin: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with atorvastatin is contraindicated due to the potential for severe adverse reactions, including myopathy and rhabdomyolysis. Coadministration may result in elevated atorvastatin systemic concentrations. Atorvastatin is a substrate of the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this isoenzyme. In addition, atorvastatin may inhibit P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with lopinavir; ritonavir. The risk of developing myopathy/rhabdomyolysis increases when atorvastatin is used concomitantly with lopinavir; ritonavir. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and lopinavir; ritonavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
Amlodipine; Benazepril: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. Coadministration of valsartan and regimens containing paritaprevir may result in elevated valsartan plasma concentrations. A valsartan dose reduction, and close monitoring for adverse events (i.e., hypotension and worsening renal function) are advised during coadministration. If adverse events are observed, consider further reductions in valsartan dose or an alternative to the angiotensin receptor blocker. Valsartan is a substrate of the organic anion transporting polypeptides (OATP) and paritaprevir is an OATP1B1 and OATP1B3 inhibitor. Valsartan is a substrate of the hepatic efflux transporter MRP2 and ritonavir is an inhibitor of MRP2. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan during coadministration.
Amlodipine; Olmesartan: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
Amlodipine; Telmisartan: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
Amlodipine; Valsartan: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. Coadministration of valsartan and regimens containing paritaprevir may result in elevated valsartan plasma concentrations. A valsartan dose reduction, and close monitoring for adverse events (i.e., hypotension and worsening renal function) are advised during coadministration. If adverse events are observed, consider further reductions in valsartan dose or an alternative to the angiotensin receptor blocker. Valsartan is a substrate of the organic anion transporting polypeptides (OATP) and paritaprevir is an OATP1B1 and OATP1B3 inhibitor. Valsartan is a substrate of the hepatic efflux transporter MRP2 and ritonavir is an inhibitor of MRP2. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan during coadministration.
Amobarbital: Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required.
Amoxapine: Ritonavir potently inhibits CYP2D6, and may inhibit the metabolism of amoxapine. Since the magnitude of the interaction with the amoxapine is difficult to predict but may be significant, monitor patients receiving ritonavir and amoxapine concurrently closely. Adjust the dosage of the coadministered drug based on therapeutic response. Amoxapine serum concentration monitoring may be useful to guide adjustments and prevent toxicity.
Amoxicillin; Clarithromycin; Lansoprazole: Caution is advised when administering clarithromycin concurrently with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir. Use of these drugs together may result in elevated concentrations of clarithromycin, paritaprevir, ritonavir, dasabuvir and ombitasvir. Predications regarding this interaction can be made based on the drugs metabolic pathways. Clarithromycin is a substrate/inhibitor of CYP3A4 and an inhibitor of P-glycoprotein (P-gp). Ritonavir is an inhibitor/substrate of CYP3A4 and a P-gp substrate. Paritaprevir and dasabuvir are substrates of CYP3A4 and P-gp. Ombitasvir is a substrate of P-gp. Monitor for adverse reactions. Caution is advised when administering clarithromycin concurrently with dasabuvir; ombitasvir; paritaprevir; ritonavir. Use of these drugs together may result in elevated concentrations of clarithromycin, paritaprevir, ritonavir, dasabuvir and ombitasvir. Predications regarding this interaction can be made based on the drugs metabolic pathways. Clarithromycin is a substrate/inhibitor of CYP3A4 and an inhibitor of P-glycoprotein (P-gp). Ritonavir is an inhibitor/substrate of CYP3A4 and a P-gp substrate. Paritaprevir and dasabuvir are substrates of CYP3A4 and P-gp. Ombitasvir is a substrate of P-gp. Monitor for adverse reactions. Concomitant administration of ritonavir and clarithromycin results in 77% increases in clarithromycin AUC. Clarithromycin dosage adjustments are recommended in patients with renal impairment who are receiving ritonavir concurrently. For patients with creatinine clearance 60 to 30 ml/min, the dose of clarithromycin should be reduced by 50%. For patients with creatinine clearance < 30 ml/min, the dose of clarithromycin should be reduced by 75%. No dosage adjustment of clarithromycin is required for patients with normal renal function who are also receiving ritonavir. Increases in erythromycin concentrations may also be noted, although the necessity of dosage adjustments has not been determined. In addition, ritonavir, clarithromycin, and erythromycin are associated with QT prolongation; concomitant use increases the risk of QT prolongation. Caution is advised when administering lansoprazole concurrently with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir. Use of these drugs together may result elevated concentrations lansoprazole, paritaprevir, ritonavir, dasabuvir and ombitasvir. Predications regarding this interaction can be made based on the drugs metabolic pathways. Lansoprazole is a substrate of CYP3A4 and a substrate/inhibitor of P-glycoprotein (P-gp). Ritonavir is an inhibitor/substrate of CYP3A4 and a P-gp substrate. Paritaprevir, dasabuvir, and ombitasvir are substrates of P-gp. Monitor for adverse reactions. Caution is advised when administering lansoprazole concurrently with dasabuvir; ombitasvir; paritaprevir; ritonavir. Use of these drugs together may result elevated concentrations of lansoprazole, paritaprevir, ritonavir, dasabuvir and ombitasvir. Predications regarding this interaction can be made based on the drugs metabolic pathways. Lansoprazole is a substrate of CYP3A4 and a substrate/inhibitor of P-glycoprotein (P-gp). Ritonavir is an inhibitor/substrate of CYP3A4 and a P-gp substrate. Paritaprevir, dasabuvir, and ombitasvir are substrates of P-gp. Monitor for adverse reactions. Use caution when administering ritonavir and lansoprazole concurrently. Ritonavir is an inhibitor of CYP3A and P-glycoprotein (P-gp). Coadministration of ritonavir with CYP3A and P-gp substrates, such as lansoprazole, can increase lansoprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Amoxicillin; Clarithromycin; Omeprazole: Caution is advised when administering clarithromycin concurrently with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir. Use of these drugs together may result in elevated concentrations of clarithromycin, paritaprevir, ritonavir, dasabuvir and ombitasvir. Predications regarding this interaction can be made based on the drugs metabolic pathways. Clarithromycin is a substrate/inhibitor of CYP3A4 and an inhibitor of P-glycoprotein (P-gp). Ritonavir is an inhibitor/substrate of CYP3A4 and a P-gp substrate. Paritaprevir and dasabuvir are substrates of CYP3A4 and P-gp. Ombitasvir is a substrate of P-gp. Monitor for adverse reactions. Caution is advised when administering clarithromycin concurrently with dasabuvir; ombitasvir; paritaprevir; ritonavir. Use of these drugs together may result in elevated concentrations of clarithromycin, paritaprevir, ritonavir, dasabuvir and ombitasvir. Predications regarding this interaction can be made based on the drugs metabolic pathways. Clarithromycin is a substrate/inhibitor of CYP3A4 and an inhibitor of P-glycoprotein (P-gp). Ritonavir is an inhibitor/substrate of CYP3A4 and a P-gp substrate. Paritaprevir and dasabuvir are substrates of CYP3A4 and P-gp. Ombitasvir is a substrate of P-gp. Monitor for adverse reactions. Concomitant administration of ritonavir and clarithromycin results in 77% increases in clarithromycin AUC. Clarithromycin dosage adjustments are recommended in patients with renal impairment who are receiving ritonavir concurrently. For patients with creatinine clearance 60 to 30 ml/min, the dose of clarithromycin should be reduced by 50%. For patients with creatinine clearance < 30 ml/min, the dose of clarithromycin should be reduced by 75%. No dosage adjustment of clarithromycin is required for patients with normal renal function who are also receiving ritonavir. Increases in erythromycin concentrations may also be noted, although the necessity of dosage adjustments has not been determined. In addition, ritonavir, clarithromycin, and erythromycin are associated with QT prolongation; concomitant use increases the risk of QT prolongation. Dosage adjustments of omeprazole may be required during concomitant administration with dasabuvir; ombitasvir; paritaprevir; ritonavir. Use of these drugs together results in decreased omeprazole serum concentrations. Monitor for decreasing efficacy and consider increasing the omeprazole dose if needed; however, adult doses should be limited to no more than 40 mg/day. The dose should be re-adjusted after completion of the 4-drug hepatitis C treatment regimen. Use caution when administering ritonavir and omeprazole concurrently. Ritonavir is an inhibitor of CYP3A and P-glycoprotein (P-gp), while omeprazole is a CYP3A and P-gp substrate. Coadministration may increase omeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Amphetamine: Patients receiving amphetamines may experience prolonged effects if receiving ritonavir concurrently. A case report describes a patient who was treated with ritonavir and saquinavir and then experienced a prolonged effect from a small dose of methylene-dioxy-methamphetamine (MDMA or ecstasy) and a near fatal reaction from a small dose of gamma-hydroxybutyrate (GHB). The effects in this patient suggests that the prolonged effects of MDMA were due to ritonavir-induced inhibition of CYP2D6 metabolism. The GHB toxicity in this patient may have been due to ritonavir-induced inhibition of first pass metabolism, leading to increased levels of GHB. Patients receiving other amphetamine drugs, such as amphetamine, amphetamine; dextroamphetamine mixed salts, lisdexamfetamine, or methamphetamine may experience prolonged effects if receiving ritonavir concurrently. Patients should be warned that there are potentially serious drug interactions between ritonavir and illicit drugs, such as ecstasy.
Amphetamine; Dextroamphetamine: Patients receiving amphetamines may experience prolonged effects if receiving ritonavir concurrently. A case report describes a patient who was treated with ritonavir and saquinavir and then experienced a prolonged effect from a small dose of methylene-dioxy-methamphetamine (MDMA or ecstasy) and a near fatal reaction from a small dose of gamma-hydroxybutyrate (GHB). The effects in this patient suggests that the prolonged effects of MDMA were due to ritonavir-induced inhibition of CYP2D6 metabolism. The GHB toxicity in this patient may have been due to ritonavir-induced inhibition of first pass metabolism, leading to increased levels of GHB. Patients receiving other amphetamine drugs, such as amphetamine, amphetamine; dextroamphetamine mixed salts, lisdexamfetamine, or methamphetamine may experience prolonged effects if receiving ritonavir concurrently. Patients should be warned that there are potentially serious drug interactions between ritonavir and illicit drugs, such as ecstasy.
Amphetamines: Patients receiving amphetamines may experience prolonged effects if receiving ritonavir concurrently. A case report describes a patient who was treated with ritonavir and saquinavir and then experienced a prolonged effect from a small dose of methylene-dioxy-methamphetamine (MDMA or ecstasy) and a near fatal reaction from a small dose of gamma-hydroxybutyrate (GHB). The effects in this patient suggests that the prolonged effects of MDMA were due to ritonavir-induced inhibition of CYP2D6 metabolism. The GHB toxicity in this patient may have been due to ritonavir-induced inhibition of first pass metabolism, leading to increased levels of GHB. Patients receiving other amphetamine drugs, such as amphetamine, amphetamine; dextroamphetamine mixed salts, lisdexamfetamine, or methamphetamine may experience prolonged effects if receiving ritonavir concurrently. Patients should be warned that there are potentially serious drug interactions between ritonavir and illicit drugs, such as ecstasy.
Anagrelide: Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with anagrelide include ritonavir
Apixaban: Concurrent administration of apixaban with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir requires a dosage adjustment for apixaban. For patients receiving more than 2.5 mg PO twice daily of apixaban, reduce the apixaban dosage by 50%. For patients receiving apixaban 2.5 mg PO twice daily, avoid coadministration with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir. Apixaban is a substrate of both CYP3A4 and P-glycoprotein (P-gp); ritonavir inhibits both CYP3A4 and P-gp and paritaprevir inhibits P-gp. Coadministration of these agents increases apixaban plasma concentrations and risk of adverse events such as bleeding. Reduce the apixaban dose to 2.5 mg twice daily when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as ritonavir. Concomitant administration of ritonavir and apixaban results in increased exposure to apixaban and an increase in the risk of bleeding. If patients are already receiving the reduced dose of 2.5 mg twice daily, avoid concomitant administration of apixaban and ritonavir.
Apomorphine: Coadministration of ritonavir and apomorphine may result in increased risk of QT prolongation. The use of ritonavir could result in QT prolongation. Limited data indicate that QT prolongation is possible with apomorphine; however, the change in QTc interval is not significant in most patients receiving dosages within the manufacturer's guidelines.
Aprepitant, Fosaprepitant: Avoid the concomitant use of ritonavir with aprepitant, fosaprepitant due to substantially increased exposure of aprepitant; increased ritonavir exposure may also occur. If coadministration cannot be avoided, use caution and monitor for an increase in ritonavir- and aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. Ritonavir is a strong CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of a single oral dose of aprepitant (125 mg) on day 5 of a 10-day ketoconazole regimen (strong CYP3A4 inhibitor) increased the aprepitant AUC approximately 5-fold, and increased the mean terminal half-life by approximately 3-fold. Ritonavir is also a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may additionally increase plasma concentrations of ritonavir. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Avoid the concomitant use of ombitasvir; paritaprevir; ritonavir with aprepitant due to substantially increased exposure of aprepitant; increased paritaprevir and ritonavir exposure may also occur. If coadministration cannot be avoided, use caution and monitor for an increase in paritaprevir-, ritonavir-, and aprepitant-related adverse effects for several days after administration of a multi-day aprepitant regimen. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. Ritonavir is a strong CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of a single oral dose of aprepitant (125 mg) on day 5 of a 10-day ketoconazole regimen (strong CYP3A4 inhibitor) increased the aprepitant AUC approximately 5-fold, and increased the mean terminal half-life by approximately 3-fold. Paritaprevir and ritonavir are also CYP3A4 substrates. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer; substitution of fosaprepitant 115 mg IV on day 1 of the 3-day regimen may lessen the inhibitory effects of CYP3A4. The AUC of a single dose of another CYP3A4 substrate, midazolam, increased by 2.3-fold and 3.3-fold on days 1 and 5, respectively, when coadministered with a 5-day oral aprepitant regimen. After a 3-day oral aprepitant regimen, the AUC of midazolam increased by 25% on day 4, and decreased by 19% and 4% on days 8 and 15, respectively, when given on days 1, 4, 8, and 15. As a single 40-mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.2-fold; the midazolam AUC increased by 1.5-fold after a single 125-mg dose of oral aprepitant. After single doses of IV fosaprepitant, the midazolam AUC increased by 1.8-fold (150 mg) and 1.6-fold (100 mg); less than a 2-fold increase in the midazolam AUC is not considered clinically important. Concurrent administration of aprepitant, fosaprepitant with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated aprepitant, fosaprepitant plasma concentrations, and altered concentrations of paritaprevir, ritonavir, and dasabuvir. The clinical consequences of the potential interaction are not known. Aprepitant, fosaprepitant, paritaprevir, ritonavir, and dasabuvir (minor) are all CYP3A4 substrates. Ritonavir is a potent inhibitor of CYP3A4. Aprepitant is a moderate inhibitor of CYP3A4 at doses of 80 to 125 mg, but it has also been found to be an inducer of CYP3A4 as well. The use of fosaprepitant may affect the plasma concentrations of paritaprevir, ritonavir, and dasabuvir to a lesser degree than oral aprepitant (125 mg). Caution and close monitoring are advised if these drugs are administered together.
Arformoterol: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir, include beta-agonists.
Aripiprazole: Because ritonavir (including lopinavir; ritonavir) and aripiprazole are associated with a possible risk for QT prolongation and torsade de pointes (TdP), these combinations should be used cautiously and with close monitoring. In addition, because aripiprazole is metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the oral aripiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving inhibitors of both CYP3A4 and CYP2D6 such as ritonavir. Patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor, such as ritonavir, should have a dose reduction to 200 mg/month IM. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated.
Armodafinil: Concurrent administration of armodafinil with dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in decreased plasma concentrations of paritaprevir, ritonavir, and dasabuvir, which may affect antiviral efficacy. Armodafinil is an inducer of the hepatic isoenzyme CYP3A4; paritaprevir, ritonavir and dasabuvir (minor) are substrates of this enzyme. Concurrent administration of armodafinil with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in decreased plasma concentrations of paritaprevir, ritonavir, and dasabuvir, which may affect antiviral efficacy. Armodafinil is an inducer of the hepatic isoenzyme CYP3A4; paritaprevir, ritonavir and dasabuvir (minor) are substrates of this enzyme. Coadministration of ritonavir with armodafinil may result in elevated armodafinil concentrations and decreased ritonavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Armodafinil is a substrate and inducer of CYP3A4, and a P-glycoprotein (P-gp) substrate. Ritonavir is a substrate of CYP3A4 and an inhibitor of P-gp. Ritonavir is also a potent inhibitor of CYP3A4.
Arsenic Trioxide: Avoid coadministration of ritonavir and arsenic trioxide. The use of ritonavir could result in QT prolongation. If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. If concomitant drug use is unavoidable, frequently monitor electrocardiograms. QT prolongation should be expected with the administration of arsenic trioxide.
Artemether; Lumefantrine: Ritonavir is a substrate, potent inhibitor, and inducer of the CYP3A4 isoenzyme, depending on the activity of the coadministered drug. Both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased or decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation due to increased drug concentrations, or loss of antimalarial activity depending on the artemether; lumefantrine concentrations. Consider ECG monitoring if ritonavir must be used with or after artemether; lumefantrine treatment. Ritonavir is a substrate, potent inhibitor, and inducer of the CYP3A4 isoenzyme, depending on the activity of the coadministered drug. Both components of artemether; lumefantrine are substrates of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased or decreased artemether; lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation due to increased drug concentrations, or loss of antimalarial activity depending on the artemether; lumefantrine concentrations. Consider ECG monitoring if ritonavir must be used with or after artemether; lumefantrine treatment.
Asenapine: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include asenapine. In addition, coadministration can result in increased plasma concentrations of both asenapine and ritonavir. The enzymes CYP3A4 and CYP2D6 contribute to asenapine's metabolism. Ritonavir inhibits both CYP3A4 and CYP2D6. Asenapine is also a mild inhibitor of CYP2D6. The manufacturer of asenapine recommends caution when coadministering drugs that are both substrates and inhibitors of CYP2D6, such as ritonavir.
Aspirin, ASA; Butalbital; Caffeine: Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required.
Aspirin, ASA; Butalbital; Caffeine; Codeine: Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
Aspirin, ASA; Caffeine; Dihydrocodeine: Concurrent administration of dihydrocodeine with ritonavir may result in elevated plasma concentrations of dihydrocodeine. Ritonavir is a substrate and inhibitor of the hepatic isoenzyme CYP2D6. Dihydrocodeine is metabolized by CYP2D6. Caution and close monitoring are advised if these drugs are administered together.
Aspirin, ASA; Carisoprodol: Systemic exposure and the maximum serum concentration of carisoprodol were decreased when a single 250 mg dose was administered concurrently with ombitasvir; paritaprevir; ritonavir. If these drugs are given together, monitor for reduced carisoprodol efficacy; consider increasing the carisoprodol dose if clinically needed.
Aspirin, ASA; Carisoprodol; Codeine: Systemic exposure and the maximum serum concentration of carisoprodol were decreased when a single 250 mg dose was administered concurrently with ombitasvir; paritaprevir; ritonavir. If these drugs are given together, monitor for reduced carisoprodol efficacy; consider increasing the carisoprodol dose if clinically needed. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
Aspirin, ASA; Omeprazole: Dosage adjustments of omeprazole may be required during concomitant administration with dasabuvir; ombitasvir; paritaprevir; ritonavir. Use of these drugs together results in decreased omeprazole serum concentrations. Monitor for decreasing efficacy and consider increasing the omeprazole dose if needed; however, adult doses should be limited to no more than 40 mg/day. The dose should be re-adjusted after completion of the 4-drug hepatitis C treatment regimen. Use caution when administering ritonavir and omeprazole concurrently. Ritonavir is an inhibitor of CYP3A and P-glycoprotein (P-gp), while omeprazole is a CYP3A and P-gp substrate. Coadministration may increase omeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Aspirin, ASA; Oxycodone: Oxycodone is metabolized by CYP3A4. Concomitant administration of ritonavir, a CYP3A4 inhibitor, may cause an increase in oxycodone plasma concentrations, which could increase or prolong adverse effects and may cause potentially fatal respiratory depression. If coadministration of these agents is necessary, patients should be monitored for an extended period and dosage adjustments made if warranted. In addition, oxycodone is metabolized in part by CYP2D6 to oxymorphone, which represents less than 15% of the total administered dose. Concurrent use of some agents that inhibit CYP2D6 has not been shown to result in clinically significant interactions. However, potent inhibitors of CYP2D6, such as ritonavir, may potentially increase the effects of oxycodone. Caution and close monitoring are advised if these drugs are administered together. Initiate oxycodone at low dosages and titrate carefully.
Aspirin, ASA; Pravastatin: Dosage adjustments of pravastatin may be required during concomitant administration with dasabuvir; ombitasvir; paritaprevir; ritonavir. Use of these drugs together results in elevated pravastatin serum concentrations. Adult doses of pravastatin must be limited to no more than 40 mg/day when administered with dasabuvir; ombitasvir; paritaprevir; ritonavir. The dose should be re-adjusted after completion of the 4-drug hepatitis C treatment regimen. Dosage adjustments of pravastatin may be required during concomitant administration with ritonavir. Use of these drugs together results in elevated pravastatin serum concentrations. Adult doses of pravastatin must be limited to no more than 40 mg/day when administered with ritonavir.
Atazanavir: Administering atazanavir (boosted with ritonavir) concurrently with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir has resulted in elevated paritaprevir serum concentrations. Coadministration of ombitasvir; paritaprevir; ritonavir and atazanavir is not recommended. If dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with atazanavir, change the atazanavir regimen to atazanavir 300 mg administered only in the morning and given WITHOUT the ritonavir booster. The dose should be re-adjusted after completion of dasabuvir; ombitasvir; paritaprevir; ritonavir. Ritonavir is a substrate and inhibitor of CYP3A4. Coadministration of atazanavir (300 mg daily) with ritonavir (100 mg daily) results in a higher Cmax, Cmin and AUC compared to atazanavir given alone (at 400 mg daily); reduced adult doses of atazanavir 300 mg once daily are recommended when ritonavir (100 mg once daily) is given concomitantly. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including atazanavir) has not been evaluated.
Atazanavir; Cobicistat: Use of ritonavir with cobicistat is not recommended, because of similar effects on CYP3A. Both ritonavir and cobicistat are potent inhibitors of CYP3A4. Administering atazanavir (boosted with ritonavir) concurrently with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir has resulted in elevated paritaprevir serum concentrations. Coadministration of ombitasvir; paritaprevir; ritonavir and atazanavir is not recommended. If dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with atazanavir, change the atazanavir regimen to atazanavir 300 mg administered only in the morning and given WITHOUT the ritonavir booster. The dose should be re-adjusted after completion of dasabuvir; ombitasvir; paritaprevir; ritonavir. Ritonavir is a substrate and inhibitor of CYP3A4. Coadministration of atazanavir (300 mg daily) with ritonavir (100 mg daily) results in a higher Cmax, Cmin and AUC compared to atazanavir given alone (at 400 mg daily); reduced adult doses of atazanavir 300 mg once daily are recommended when ritonavir (100 mg once daily) is given concomitantly. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including atazanavir) has not been evaluated.
Atenolol: Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
Atenolol; Chlorthalidone: Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
Atomoxetine: QT prolongation has occurred during therapeutic use of atomoxetine and following overdose. Both atomoxetine and ritonavir are considered drugs with a possible risk of torsade de pointes (TdP); therefore, the combination should be used cautiously and with close monitoring. In addition, because atomoxetine is primarily metabolized by CYP2D6, concurrent use of CYP2D6 inhibitors such as ritonavir may theoretically increase the risk of atomoxetine-induced adverse effects. Monitor for adverse effects, such as dizziness, drowsiness, nervousness, insomnia, and cardiac effects (e.g., hypertension, increased pulse rate, QT prolongation).
Atorvastatin: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with atorvastatin is contraindicated due to the potential for severe adverse reactions, including myopathy and rhabdomyolysis. Coadministration may result in elevated atorvastatin systemic concentrations. Atorvastatin is a substrate of the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this isoenzyme. In addition, atorvastatin may inhibit P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with lopinavir; ritonavir. The risk of developing myopathy/rhabdomyolysis increases when atorvastatin is used concomitantly with lopinavir; ritonavir. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and lopinavir; ritonavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
Atorvastatin; Ezetimibe: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with atorvastatin is contraindicated due to the potential for severe adverse reactions, including myopathy and rhabdomyolysis. Coadministration may result in elevated atorvastatin systemic concentrations. Atorvastatin is a substrate of the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this isoenzyme. In addition, atorvastatin may inhibit P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with lopinavir; ritonavir. The risk of developing myopathy/rhabdomyolysis increases when atorvastatin is used concomitantly with lopinavir; ritonavir. Monitor patients for any signs or symptoms of muscle pain, weakness, or tenderness especially in the initial months of therapy and any time the dosage of either drug is titrated upward. Protease inhibitors inhibit the CYP3A4 metabolism of atorvastatin. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined 'statin' and lopinavir; ritonavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage.
Atovaquone: The concurrent administration of ritonavir with atovaquone may result in decreased plasma levels of atovaquone. The clinical significance and mechanism of this potential interaction are unknown; the manufacturer states that an increase in atovaquone doses may be needed.
Atovaquone; Proguanil: The concurrent administration of ritonavir with atovaquone may result in decreased plasma levels of atovaquone. The clinical significance and mechanism of this potential interaction are unknown; the manufacturer states that an increase in atovaquone doses may be needed.
Atropine; Hyoscyamine; Phenobarbital; Scopolamine: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with phenobarbital is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir and ritonavir. Phenobarbital is a potent inducer of the hepatic isoenzyme CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. In addition, phenobarbital may induce P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with phenobarbital is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir and ritonavir. Phenobarbital is a potent inducer of the hepatic isoenzyme CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. In addition, phenobarbital may induce P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required.
Avanafil: Avanafil is a substrate of and primarily metabolized by CYP3A4. Studies have shown that drugs that inhibit CYP3A4 can increase avanafil exposure. Patients taking strong CYP3A4 inhibitors such as ritonavir, should not take avanafil. For example, ketoconazole increased avanafil AUC and Cmax equal to 13-fold and 3-fold, respectively and prolonged the half-life of avanafil to approximately 9 hours. Likewise, coadministration of ritonavir with avanafil resulted in an approximate 13-fold increase in AUC and 2.4-fold increase in Cmax of avanafil. Therefore, concomitant use with strong CYP3A4 inhibitors is not recommended.
Axitinib: Avoid coadministration of axitinib with ritonavir due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately 50%; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after ritonavir is discontinued. Axitinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor, ketoconazole, significantly increased the plasma exposure of axitinib in healthy volunteers. Ritonavir is also a CYP1A2 inducer, which theoretically could decrease exposure to axitinib; however, the effects of ritonavir on CYP1A2 are not expected to overcome its effects on CYP3A4, as CYP3A4 is the major route of metabolism for axitinib. Monitor patients for increased axitinib-related adverse events if coadministration with dasabuvir occurs. Axitinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Dasabuvir is a UGT1A1 inhibitor. Theoretically, exposure to axitinib may be increased. Monitor patients for increased axitinib-related adverse events if coadministration with ombitasvir occurs. Axitinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Ombitasvir is a UGT1A1 inhibitor. Theoretically, exposure to axitinib may be increased. Monitor patients for increased axitinib-related adverse events if coadministration with paritaprevir occurs. Axitinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2, CYP2C19, and UGT1A1. Paritaprevir is a UGT1A1 inhibitor. Theoretically, exposure to axitinib may be increased.
Azelastine; Fluticasone: Ritonavir significantly increases plasma fluticasone exposure via inhibition of CYP3A4, resulting in significantly reduced serum cortisol concentrations. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving inhaled or intranasally administered fluticasone with ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Therefore, coadministration of fluticasone (or fluticasone-containing products), including intranasal fluticasone formulations, and ritonavir (or ritonavir-containing products or treatment regimens) is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Azithromycin: Both ritonavir and azithromycin are P-glycoprotein (P-gp) inhibitors and substrates, so coadministration may lead to increased concentrations of either agent. Monitor patients for increased side effects if these drugs are given together. In addition, the use of ritonavir could result in QT prolongation; QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. Concurrent use may result in additive risk of QT prolongation. Concurrent administration of azithromycin with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of all 5 drugs. Increased plasma concentrations increases the risk of adverse effects, some of which may be serious; azithromycin and ritonavir both have been associated with QT-prolongation. Azithromycin and ritonavir are inhibitors of the drug transporter P-glycoprotein (P-gp), and all 5 drugs are P-gp substrates. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of azithromycin with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of azithromycin and the components of the hepatitis C regimen. Increased plasma concentrations increases the risk of adverse effects, some of which may be serious; azithromycin and ritonavir both have been associated with QT-prolongation. Azithromycin and ritonavir are inhibitors of the drug transporter P-glycoprotein (P-gp), and azithromycin, dasabuvir, ombitasvir, paritaprevir, and ritonavir are P-gp substrates. Caution and close monitoring are advised if these drugs are administered together.
Barbiturates: Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required.
Basiliximab: Concurrent administration of basiliximab with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in increased plasma concentrations of paritaprevir, ritonavir, and dasabuvir. Basiliximab may cause a down-regulation of CYP3A4 activity by increasing IL-2 binding to the IL-2 receptors on hepatic and intestinal cells; paritaprevir, ritonavir, and dasabuvir (minor) are substrates of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of basiliximab with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in increased plasma concentrations of paritaprevir, ritonavir, and dasabuvir. Basiliximab may cause a down-regulation of CYP3A4 activity by increasing IL-2 binding to the IL-2 receptors on hepatic and intestinal cells; paritaprevir, ritonavir, and dasabuvir (minor) are substrates of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of basiliximab with ritonavir may result in increased plasma concentrations of ritonavir. Basiliximab may cause a down-regulation of CYP3A4 activity by increasing IL-2 binding to the IL-2 receptors on hepatic and intestinal cells; ritonavir is a substrate of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Bedaquiline: Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as ritonavir, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, ritonavir may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions, such as QT prolongation and hepatotoxicity. In addition, ritonavir has a possible risk of QT prolongation.
Belladonna Alkaloids; Ergotamine; Phenobarbital: Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with phenobarbital is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir and ritonavir. Phenobarbital is a potent inducer of the hepatic isoenzyme CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. In addition, phenobarbital may induce P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with phenobarbital is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir and ritonavir. Phenobarbital is a potent inducer of the hepatic isoenzyme CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. In addition, phenobarbital may induce P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required.
Belladonna; Opium: Ritonavir is an inhibitor of the cytochrome P450 3A4 isoenzyme and may decrease the metabolism of opium if the two drugs are coadministered.
Bendroflumethiazide; Nadolol: Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
Benzphetamine: Patients receiving amphetamines may experience prolonged effects if receiving ritonavir concurrently. A case report describes a patient who was treated with ritonavir and saquinavir and then experienced a prolonged effect from a small dose of methylene-dioxy-methamphetamine (MDMA or ecstasy) and a near fatal reaction from a small dose of gamma-hydroxybutyrate (GHB). The effects in this patient suggests that the prolonged effects of MDMA were due to ritonavir-induced inhibition of CYP2D6 metabolism. The GHB toxicity in this patient may have been due to ritonavir-induced inhibition of first pass metabolism, leading to increased levels of GHB. Patients receiving other amphetamine drugs, such as amphetamine, amphetamine; dextroamphetamine mixed salts, lisdexamfetamine, or methamphetamine may experience prolonged effects if receiving ritonavir concurrently. Patients should be warned that there are potentially serious drug interactions between ritonavir and illicit drugs, such as ecstasy.
Bepridil: Ritonavir can produce large increases in plasma concentrations of certain drugs metabolized by cytochrome P450 3A4. The concurrent use of ritonavir is contraindicated with bepridil.
Betamethasone: Coadministration of betamethasone with ritonavir (a strong CYP3A4 inhibitor) may cause betamethasone serum concentrations to increase, potentially resulting in Cushing's syndrome and adrenal suppression. Consider use of an alternative corticosteroid whose concentrations are less affected by strong CYP3A4 inhibitors, such as beclomethasone and prednisolone, especially during long-term treatment.
Betaxolol: Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
Bexarotene: Concurrent administration of bexarotene with dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in elevated bexarotene plasma concentrations and decreased concentrations of paritaprevir, ritonavir, and dasabuvir, which may affect antiviral efficacy. Bexarotene is a substrate and inducer of the hepatic isoenzyme CYP3A4; ritonavir inhibits the enzyme. In addition, paritaprevir, ritonavir, and dasabuvir (minor) are substrates of CYP3A4. Concurrent administration of bexarotene with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in elevated bexarotene plasma concentrations and decreased concentrations of paritaprevir, ritonavir, and dasabuvir, which may affect antiviral efficacy. Bexarotene is a substrate and inducer of the hepatic isoenzyme CYP3A4; ritonavir inhibits the enzyme. In addition, paritaprevir, ritonavir, and dasabuvir (minor) are substrates of CYP3A4. Bexarotene is a substrate and inducer of the hepatic isoenzyme CYP3A4; protease inhibitors are CYP3A4 substrates/inhibitors. Coadministration may increase bexarotene plasma concentrations and decrease concentrations of the protease inhibitor.
Bicalutamide: Bicalutamide is metabolized by cytochrome P450 3A4. Substances that are potent inhibitors of CYP3A4 activity, such as protease inhibitors, decrease the metabolism of bicalutamide and increase bicalutamide concentrations. This increase may be clinically relevant as adverse reactions to bicalutamide are related to dose and exposure.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Oral solutions of ritonavir contain ethanol. Administration of ritonavir oral solution to patients receiving or who have recently received disulfiram or metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations. Addtionally, potential QT prolongation has been reported in limited case reports with metronidazole; therefore, it should be used cautiously and with close monitoring when administered with ritonavir, which has a possible risk for QT prolongation and TdP.
Bismuth Subsalicylate; Metronidazole; Tetracycline: Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Oral solutions of ritonavir contain ethanol. Administration of ritonavir oral solution to patients receiving or who have recently received disulfiram or metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations. Addtionally, potential QT prolongation has been reported in limited case reports with metronidazole; therefore, it should be used cautiously and with close monitoring when administered with ritonavir, which has a possible risk for QT prolongation and TdP.
Bisoprolol: Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
Bisoprolol; Hydrochlorothiazide, HCTZ: Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
Boceprevir: Concurrent administration of ritonavir with boceprevir is not recommended due to the potential for HIV and hepatitis C treatment failures. This combination has resulted in decreased serum concentrations of both medications. Ritonavir is an inhibitor, inducer, and substrate of the hepatic isoenzyme CYP3A4; boceprevir is an inhibitor and substrate of this isoenzyme. Additionally, both drugs are substrates and inhibitors of the drug efflux transporter P-glycoprotein (PGP). If these drugs are coadministered, health care providers are advised to closely monitor for decreased treatment response and virologic rebound. Health care providers are also encouraged to report any drug-related adverse reactions to the FDA MedWatch Program.
Bortezomib: In vitro studies with human liver microsomes indicate that bortezomib is a significant substrate for CYP3A4. Agents that inhibit CYP3A4, such ritonavir, may increase the exposure to bortezomib and increase the risk for toxicity. The manufacturer warns that patients who are receiving bortezomib concurrently with potent CYP3A4 inhibitors should be closely monitored for potential toxicity. Additionally, ritonavir can cause peripheral neuropathy. It may be prudent to monitor patients for signs and symptoms of neuropathy.
Bosentan: Concurrent administration of bosentan with dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in elevated bosentan plasma concentrations and decreased concentrations of paritaprevir, ritonavir, and dasabuvir, which may affect antiviral efficacy. Bosentan is a substrate and inducer of the hepatic isoenzymes CYP2C9 and CYP3A4 and a substrate of the organic anion transporting polypeptide (OATP). Ritonavir inhibits CYP3A4 and OATP; paritaprevir is also an OATP inhibitor. In addition, paritaprevir, ritonavir, and dasabuvir (minor) are substrates of CYP3A4. Concurrent administration of bosentan with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in elevated bosentan plasma concentrations and decreased concentrations of paritaprevir, ritonavir, and dasabuvir, which may affect antiviral efficacy. Bosentan is a substrate and inducer of the hepatic isoenzymes CYP2C9 and CYP3A4 and a substrate of the organic anion transporting polypeptide (OATP). Ritonavir inhibits CYP3A4 and OATP; paritaprevir is also an OATP inhibitor. In addition, paritaprevir, ritonavir, and dasabuvir (minor) are substrates of CYP3A4. Do not administer bosentan with anti-retroviral protease inhibitors that are not boosted with ritonavir as decreased protease inhibitor concentrations are expected. In addition, administration of anti-retroviral protease inhibitors with bosentan may increase bosentan serum concentrations due to the inhibition of the CYP3A4 isoenzyme. In patients who have been receiving protease inhibitor therapy for at least 10 days, initiate bosentan at 62.5 mg daily or every other day based on tolerability. For patients on bosentan who need protease inhibitor therapy, discontinue use of bosentan at least 36 hours prior to starting protease inhibitor therapy. After 10 days of the protease inhibitor therapy, bosentan may be restarted at 62.5 mg daily or every other day based on tolerability. Bosentan is a substrate for organic anion transport protein (OATP), CYP3A, and CYP2C9. In healthy subjects, initial and steady state trough plasma concentrations of bosentan were approximately 48-fold and 5-fold higher, respectively, after coadministration of bosentan 125 mg twice daily PO and lopinavir; ritonavir 400/100 mg twice daily PO compared to those measured after bosentan alone. This is most likely explained by inhibition by lopinavir of OATP-mediated uptake into hepatocytes; toxicity of bosentan is possible. Monitor for potential adverse effects of bosentan during coadministration with CYP2C9 or CYP3A4 inhibitors; excessive bosentan dosage may result in hypotension or elevated hepatic enzyme. Additionally, bosentan is a significant inducer of CYP3A4 and CYP2C9 hepatic enzymes. Theoretically, bosentan may increase the clearance of the protease inhibitors and potentially lead to a reduction of anti-retroviral efficacy. However, this interaction has not been studied.
Bosutinib: Avoid concomitant use of bosutinib and ritonavir or lopinavir; ritonavir as bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. In a cross-over trial in 24 healthy volunteers, the Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor. Avoid concurrent administration of bosutinib with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir; coadministration is expected to result in elevated bosutinib concentrations and increased risk of adverse events. Bosutinib is metabolized by the hepatic isoenzyme CYP3A4, and is an inhibitor of the drug transporter P-glycoprotein (P-gp). Ritonavir is a potent CYP3A4 inhibitor. In addition, dasabuvir, ombitasvir, paritaprevir, and ritonavir are P-gp substrates, which suggests elevated plasma concentrations of the antivirals may also occur. Avoid concurrent administration of bosutinib with dasabuvir; ombitasvir; paritaprevir; ritonavir; coadministration is expected to result in elevated bosutinib concentrations and increased risk of adverse events. Bosutinib is metabolized by the hepatic isoenzyme CYP3A4, and is an inhibitor of the drug transporter P-glycoprotein (P-gp). Ritonavir is a potent CYP3A4 inhibitor. In addition, dasabuvir, ombitasvir, paritaprevir, and ritonavir are P-gp substrates, which suggests elevated plasma concentrations of the antivirals may also occur.
Brentuximab vedotin: Concomitant administration of brentuximab vedotin and ritonavir may increase the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. The manufacturer suggests that potent CYP3A4 inhibitors, such as ritonavir, may alter MMAE exposure as MMAE is a CYP3A4 substrate. Monitor patients for adverse reactions.
Brexpiprazole: Because brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the brexpiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving a moderate to strong inhibitor of CYP3A4 inhibitor in combination with a moderate to strong inhibitor of CYP2D6. Ritonavir (including lopinavir; ritonavir) is a strong inhibitor of CYP3A4 and a moderate inhibitor of CYP2D6. If these agents are used in combination, the patient should be carefully monitored for brexpiprazole-related adverse reactions. If the co-administered CYP inhibitor is discontinued, adjust the brexpiprazole dose to its original level.
Brigatinib: Avoid coadministration of brigatinib with ritonavir if possible due to increased plasma exposure of brigatinib and decreased exposure to ritonavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. If concomitant use is unavoidable, closely monitor for changes in the clinical efficacy of the antiretroviral regimen and reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of ritonavir, resume the brigatinib dose that was tolerated prior to initiation of ritonavir. Brigatinib is a CYP3A4 substrate and inducer; ritonavir is a CYP3A4 substrate and strong inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively. A strong CYP3A4 inducer decreased the AUC and Cmax of ritonavir by 35% and 25%, respectively. Monitor for decreased efficacy of paritaprevir if coadministration with brigatinib is necessary. Paritaprevir is a CYP3A substrate and brigatinib induces CYP3A in vitro; plasma concentrations of paritaprevir may decrease. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance.
Brimonidine; Timolol: Timolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as ritonavir, may impair timolol metabolism; the clinical significance of such interactions is unknown.
Bromocriptine: When bromocriptine is used for diabetes, avoid coadministration with ritonavir ensuring adequate washout before initiating bromocriptine. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may significantly increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; ritonavir is a strong inhibitor of CYP3A4.
Brompheniramine; Dextromethorphan; Guaifenesin: Concurrent administration of dextromethorphan with ritonavir may result in elevated dextromethorphan plasma concentrations. Dextromethorphan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Brompheniramine; Guaifenesin; Hydrocodone: Concurrent administration of hydrocodone with ritonavir may result in elevated hydrocodone plasma concentrations and subsequent adverse events, such as sedation and respiratory depression. If these drugs are given together, a 50% reduction in the dose of hydrocodone may be needed, and monitoring for respiratory depression and sedation at regular intervals is recommended. Hydrocodone is metabolized by the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is an inhibitor of these enzymes. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ritonavir may reduce the efficacy of hydrocodone. Caution and close monitoring for both efficacy and adverse reactions are advised if these drugs are administered together; a hydrocodone dosage adjustment may be necessary.
Brompheniramine; Hydrocodone; Pseudoephedrine: Concurrent administration of hydrocodone with ritonavir may result in elevated hydrocodone plasma concentrations and subsequent adverse events, such as sedation and respiratory depression. If these drugs are given together, a 50% reduction in the dose of hydrocodone may be needed, and monitoring for respiratory depression and sedation at regular intervals is recommended. Hydrocodone is metabolized by the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is an inhibitor of these enzymes. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ritonavir may reduce the efficacy of hydrocodone. Caution and close monitoring for both efficacy and adverse reactions are advised if these drugs are administered together; a hydrocodone dosage adjustment may be necessary.
Budesonide: Via inhibition of CYP3A4, ritonavir significantly increases plasma concentrations of budesonide, resulting in significantly reduced serum cortisol concentrations. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving budesonide with ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Therefore, coadministration of budesonide and ritonavir (or ritonavir-containing products or treatment regimens) is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Budesonide; Formoterol: Via inhibition of CYP3A4, ritonavir significantly increases plasma concentrations of budesonide, resulting in significantly reduced serum cortisol concentrations. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving budesonide with ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Therefore, coadministration of budesonide and ritonavir (or ritonavir-containing products or treatment regimens) is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir, include beta-agonists.
Bupivacaine Liposomal: Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed.
Bupivacaine: Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed.
Bupivacaine; Lidocaine: Anti-retroviral protease inhibitors can inhibit hepatic cytochrome P450 3A4, an isoenzyme that is partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and anti-retroviral protease inhibitors should be carefully monitored due to the potential for serious toxicity. Bupivacaine is metabolized by cytochrome P450 (CYP) 3A4 isoenzymes. Known inhibitors of CYP 3A4, such as anti-retroviral protease inhibitors, may result in increased systemic levels of bupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of bupivacaine may be needed.
Buprenorphine: Concurrent use of buprenorphine and ritonavir is considered contraindicated. Buprenorphine, a CYP3A4 substrate, and ritonavir, a CYP3A4 inhibitor, are both associated with a risk for QT prolongation and torsade de pointes (TdP). The combined use of two drugs that can cause QT prolongation and TdP, along with a possible increased risk for these effects due to elevated plasma concentrations of buprenorphine via CYP3A4 inhibition by ritonavir, warrants a contraindication for concurrent use.
Buprenorphine; Naloxone: Concurrent use of buprenorphine and ritonavir is considered contraindicated. Buprenorphine, a CYP3A4 substrate, and ritonavir, a CYP3A4 inhibitor, are both associated with a risk for QT prolongation and torsade de pointes (TdP). The combined use of two drugs that can cause QT prolongation and TdP, along with a possible increased risk for these effects due to elevated plasma concentrations of buprenorphine via CYP3A4 inhibition by ritonavir, warrants a contraindication for concurrent use.
Bupropion: Concurrent administration of bupropion with ritonavir results in decreased concentrations of bupropion and its active metabolite. According to the manufacturers of bupropion, increased doses of bupropion may be necessary during concurrent therapy; however, the maximum recommended dose of bupropion should not be exceeded. Closely monitor bupropion efficacy if these drugs are given together. Ritonavir induces CYP2B6, which is responsible for bupropion's metabolism. In one study, ritonavir 100 mg twice daily reduced the AUC and Cmax of bupropion by 22% and 21%, respectively. In addition, exposure to the active metabolite of bupropion (hydroxybupropion) was decreased by 23%. When given with ritonavir 600 mg twice daily, the AUC and Cmax of bupropion decreased by 66% and 63% respectively and exposure to hydroxybupropion decreased by 78%.
Bupropion; Naltrexone: Concurrent administration of bupropion with ritonavir results in decreased concentrations of bupropion and its active metabolite. According to the manufacturers of bupropion, increased doses of bupropion may be necessary during concurrent therapy; however, the maximum recommended dose of bupropion should not be exceeded. Closely monitor bupropion efficacy if these drugs are given together. Ritonavir induces CYP2B6, which is responsible for bupropion's metabolism. In one study, ritonavir 100 mg twice daily reduced the AUC and Cmax of bupropion by 22% and 21%, respectively. In addition, exposure to the active metabolite of bupropion (hydroxybupropion) was decreased by 23%. When given with ritonavir 600 mg twice daily, the AUC and Cmax of bupropion decreased by 66% and 63% respectively and exposure to hydroxybupropion decreased by 78%.
Buspirone: When buspirone is administered with a potent inhibitor of CYP3A4 like ritonavir, a low dose of buspirone used cautiously is recommended. Some patients receiving drugs that are potent inhibitors of CYP3A4 with buspirone have reported lightheadedness, asthenia, dizziness, and drowsiness. If the two drugs are to be used in combination, a low dose of buspirone (e.g., 2.5 mg PO twice daily) is recommended. Subsequent dose adjustment of either drug should be based on clinical assessment. Several other anti-retroviral protease inhibitors also inhibit CYP3A4, and these may interact with buspirone in a similar manner.
Butabarbital: Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required.
Cabazitaxel: Avoid coadministration of cabazitaxel with ritonavir if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and ritonavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Cabozantinib: Cabozantinib is a P-glycoprotein (P-gp) inhibitor and ombitasvir is a P-gp substrate. The clinical relevance of this finding is unknown; however, plasma concentrations of ombitasvir may be increased. Because ombitasvir is only available in products containing ritonavir, coadministration with cabozantinib is contraindicated due to the potential for ritonavir to increase cabozantinib concentrations. Cabozantinib is a P-glycoprotein (P-gp) inhibitor and paritaprevir is a P-gp substrate. The clinical relevance of this finding is unknown; however, plasma concentrations of paritaprevir may be increased. Because paritaprevir is only available in products containing ritonavir, coadministration with cabozantinib is contraindicated due to the potential for ritonavir to increase cabozantinib concentrations. Ritonavir is contraindicated for use with medications are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events; do not use ritonavir concomitantly with cabozantinib. Ritonavir is a strong CYP3A4 inhibitor. Cabozantinib is primarily metabolized by CYP3A4 and has been associated with serious and sometimes fatal bleeding, reversible posterior leukoencephalopathy syndrome (RPLS), palmar-plantar erythrodysesthesia (hand and foot syndrome), GI perforation and fistula, cytopenias, and other serious toxicities. Coadministration with another strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days), increased cabozantinib (single dose) exposure by 38%. Cabozantinib is also a P-glycoprotein (P-gp) inhibitor and Multidrug Resistance Protein 2 (MRP2) substrate; ritonavir is an MRP2 inhibitor and P-gp substrate. The clinical relevance of this finding is unknown; however, plasma concentrations of ritonavir may be increased and concentrations of cabozantinib further increased.
Caffeine; Ergotamine: Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
Calcifediol: Dose adjustment of calcifediol may be necessary during coadministration with ritonavir. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with ritonavir. Ritonavir, which is a cytochrome P450 inhibitor, may inhibit enzymes involved in vitamin D metabolism (CYP24A1 and CYP27B1) and may alter serum concentrations of calcifediol.
Canagliflozin: Concurrent administration of canagliflozin with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in altered concentrations of any of the 5 drugs. For patients with an GFR >= 60 ml/min/1.73m2 receiving canagliflozin 100 mg once daily, canagliflozin's product labeling recommends considering increasing the dosage to canagliflozin 300 mg PO once daily when coadministered with ritonavir. For patients with an eGFR < 60 ml/min/1.73m2, consider an alternate antihyperglycemic agent. Canagliflozin is a substrate of uridine glucuronyltransferase (UGT), and ritonavir is a UGT inducer. In addition, canagliflozin is an inhibitor of the drug transporter P-glycoprotein (P-gp), and all 4 antiviral agents are P-gp substrates. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of canagliflozin with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in altered concentrations of canagliflozin or the components of the hepatitis C regimen. For patients with an GFR >= 60 ml/min/1.73m2 receiving canagliflozin 100 mg once daily, canagliflozin's product labeling recommends considering increasing the dosage to canagliflozin 300 mg PO once daily when coadministered with ritonavir. For patients with an eGFR < 60 ml/min/1.73m2, consider an alternate antihyperglycemic agent. Canagliflozin is a substrate of uridine glucuronyltransferase (UGT), and ritonavir is a UGT inducer. In addition, canagliflozin is an inhibitor of the drug transporter P-glycoprotein (P-gp), and dasabuvir, ombitasvir, paritaprevir, and ritonavir are P-gp substrates. Caution and close monitoring are advised if these drugs are administered together. In patients taking canagliflozin (UGT substrate) concomitantly with ritonavir (UGT enzyme inducer), consider increasing the dosage of canagliflozin to 300 mg once daily in patients currently tolerating canagliflozin 100 mg once daily who have an eGFR >= 60 ml/min/1.73 m2 and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR of 45 to 59 ml/min/1.73 m2 receiving concurrent therapy with a UGT inducer and require additional glycemic control. In addition, new onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Canagliflozin; Metformin: Concurrent administration of canagliflozin with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in altered concentrations of any of the 5 drugs. For patients with an GFR >= 60 ml/min/1.73m2 receiving canagliflozin 100 mg once daily, canagliflozin's product labeling recommends considering increasing the dosage to canagliflozin 300 mg PO once daily when coadministered with ritonavir. For patients with an eGFR < 60 ml/min/1.73m2, consider an alternate antihyperglycemic agent. Canagliflozin is a substrate of uridine glucuronyltransferase (UGT), and ritonavir is a UGT inducer. In addition, canagliflozin is an inhibitor of the drug transporter P-glycoprotein (P-gp), and all 4 antiviral agents are P-gp substrates. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of canagliflozin with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in altered concentrations of canagliflozin or the components of the hepatitis C regimen. For patients with an GFR >= 60 ml/min/1.73m2 receiving canagliflozin 100 mg once daily, canagliflozin's product labeling recommends considering increasing the dosage to canagliflozin 300 mg PO once daily when coadministered with ritonavir. For patients with an eGFR < 60 ml/min/1.73m2, consider an alternate antihyperglycemic agent. Canagliflozin is a substrate of uridine glucuronyltransferase (UGT), and ritonavir is a UGT inducer. In addition, canagliflozin is an inhibitor of the drug transporter P-glycoprotein (P-gp), and dasabuvir, ombitasvir, paritaprevir, and ritonavir are P-gp substrates. Caution and close monitoring are advised if these drugs are administered together. In patients taking canagliflozin (UGT substrate) concomitantly with ritonavir (UGT enzyme inducer), consider increasing the dosage of canagliflozin to 300 mg once daily in patients currently tolerating canagliflozin 100 mg once daily who have an eGFR >= 60 ml/min/1.73 m2 and require additional glycemic control. Consider other antihyperglycemic therapy in patients with an eGFR of 45 to 59 ml/min/1.73 m2 receiving concurrent therapy with a UGT inducer and require additional glycemic control. In addition, new onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. The manufacturer recommends against concurrent administration of ombitasvir; paritaprevir; ritonavir and metformin in patients with hepatic or renal impairment. If these drugs are given together, closely monitor blood glucose concentrations and for signs of lactic acidosis (i.e., abdominal or respiratory distress, worsening renal function, somnolence). New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Candesartan: Concurrent administration of candesartan; hydrochlorothiazide, HCTZ with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated candesartan plasma concentrations. A candesartan dose reduction, and close monitoring for adverse events (i.e., hypotension and worsening renal function) are advised during coadministration. If adverse events are observed, consider further reductions in candesartan dose or an alternative to the angiotensin receptor blocker. Concurrent administration of candesartan; hydrochlorothiazide, HCTZ with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated candesartan plasma concentrations. A candesartan dose reduction, and close monitoring for adverse events (i.e., hypotension and worsening renal function) are advised during coadministration. If adverse events are observed, consider further reductions in candesartan dose or an alternative to the angiotensin receptor blocker.
Candesartan; Hydrochlorothiazide, HCTZ: Concurrent administration of candesartan; hydrochlorothiazide, HCTZ with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated candesartan plasma concentrations. A candesartan dose reduction, and close monitoring for adverse events (i.e., hypotension and worsening renal function) are advised during coadministration. If adverse events are observed, consider further reductions in candesartan dose or an alternative to the angiotensin receptor blocker. Concurrent administration of candesartan; hydrochlorothiazide, HCTZ with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated candesartan plasma concentrations. A candesartan dose reduction, and close monitoring for adverse events (i.e., hypotension and worsening renal function) are advised during coadministration. If adverse events are observed, consider further reductions in candesartan dose or an alternative to the angiotensin receptor blocker.
Carbamazepine: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with carbamazepine is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir and ritonavir. Carbamazepine is a potent inducer and substrate of the hepatic isoenzyme CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. In addition, carbamazepine induces P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with carbamazepine is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir and ritonavir. Carbamazepine is a potent inducer and substrate of the hepatic isoenzyme CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. In addition, carbamazepine induces P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Ritonavir decreases the hepatic CYP metabolism of carbamazepine, resulting in increased carbamazepine concentrations. In addition, carbamazepine increases the metabolism of the protease inhibitors and may lead to decreased efficacy of these medications. Carbamazepine is a potent inducer and substrate of the hepatic isoenzyme CYP3A4; ritonavir is a substrate and inhibitor of this isoenzyme. In addition, carbamazepine induces P-glycoprotein (P-gp), a drug efflux transporter for which ritonavir is a substrate. Treatment failures have been reported with protease inhibitors when carbamazepine is used concomitantly. The appropriate drug-dose adjustments necessary to ensure optimum levels of both antiretroviral drugs and carbamazepine are unknown. If used concomitantly, the patient should be observed for changes in the clinical efficacy of the antiretroviral regimen or for carbamazepine toxicity.
Carbetapentane; Chlorpheniramine: Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together.
Carbetapentane; Chlorpheniramine; Phenylephrine: Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together.
Carbetapentane; Diphenhydramine; Phenylephrine: Concurrent administration of diphenhydramine with ritonavir may result in elevated plasma concentrations of diphenhydramine. Diphenhydramine is a CYP2D6 substrate, and ritonavir is a CYP2D6 inhibitor. Caution and close monitoring are advised if these drugs are administered together.
Carbinoxamine; Dextromethorphan; Pseudoephedrine: Concurrent administration of dextromethorphan with ritonavir may result in elevated dextromethorphan plasma concentrations. Dextromethorphan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Carbinoxamine; Hydrocodone; Phenylephrine: Concurrent administration of hydrocodone with ritonavir may result in elevated hydrocodone plasma concentrations and subsequent adverse events, such as sedation and respiratory depression. If these drugs are given together, a 50% reduction in the dose of hydrocodone may be needed, and monitoring for respiratory depression and sedation at regular intervals is recommended. Hydrocodone is metabolized by the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is an inhibitor of these enzymes. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ritonavir may reduce the efficacy of hydrocodone. Caution and close monitoring for both efficacy and adverse reactions are advised if these drugs are administered together; a hydrocodone dosage adjustment may be necessary.
Carbinoxamine; Hydrocodone; Pseudoephedrine: Concurrent administration of hydrocodone with ritonavir may result in elevated hydrocodone plasma concentrations and subsequent adverse events, such as sedation and respiratory depression. If these drugs are given together, a 50% reduction in the dose of hydrocodone may be needed, and monitoring for respiratory depression and sedation at regular intervals is recommended. Hydrocodone is metabolized by the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is an inhibitor of these enzymes. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ritonavir may reduce the efficacy of hydrocodone. Caution and close monitoring for both efficacy and adverse reactions are advised if these drugs are administered together; a hydrocodone dosage adjustment may be necessary.
Cariprazine: Cariprazine and its active metabolites are extensively metabolized by CYP3A4. When a strong CYP3A4 inhibitor, such as ritonavir, is initiated in a patient who is on a stable dose of cariprazine, reduce the cariprazine dosage by half. For adult patients taking cariprazine 4.5 mg daily, the dosage should be reduced to 1.5 mg or 3 mg daily. For patients taking cariprazine 1.5 mg daily, the dosing frequency should be adjusted to every other day. When the CYP3A4 inhibitor is withdrawn, the cariprazine dosage may need to be increased. When initiating cariprazine in a patient who is stable on a strong CYP3A4 inhibitor, the patient should be administered 1.5 mg of cariprazine on Day 1 and on Day 3 with no dose administered on Day 2. From Day 4 onward, the dose should be administered at 1.5 mg daily, then increased to a maximum dose of 3 mg daily. When the CYP3A4 inhibitor is withdrawn, the cariprazine dosage may need to be increased.
Carisoprodol: Systemic exposure and the maximum serum concentration of carisoprodol were decreased when a single 250 mg dose was administered concurrently with ombitasvir; paritaprevir; ritonavir. If these drugs are given together, monitor for reduced carisoprodol efficacy; consider increasing the carisoprodol dose if clinically needed.
Carteolol: Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
Carvedilol: Concurrent administration of carvedilol with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of carvedilol and all 4 antiviral drugs. Carvedilol is a substrate of the hepatic isoenzyme CYP2D6 and a substrate and inhibitor of the drug transporter P-glycoprotein (P-gp). Ritonavir inhibits CYP2D6 and P-gp. In addition, dasabuvir, ombitasvir, paritaprevir, and ritonavir are all P-gp substrates. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of carvedilol with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of carvedilol and the components of the hepatitis C regimen. Carvedilol is a substrate of the hepatic isoenzyme CYP2D6 and a substrate and inhibitor of the drug transporter P-glycoprotein (P-gp). Ritonavir inhibits CYP2D6 and P-gp. In addition, dasabuvir, ombitasvir, paritaprevir, and ritonavir are all P-gp substrates. Caution and close monitoring are advised if these drugs are administered together. Inhibitors of the hepatic CYP450 isozyme CYP2D6, such as ritonavir, may inhibit the hepatic oxidative metabolism of carvedilol. In addition, both drugs are inhibitors and subtrates for P-glycoprotein (P-gp). Close monitoring of serum drug concentrations and/or therapeutic and adverse effects is required when carvedilol is coadministered with ritonavir.
Ceritinib: Ritonavir is a strong inhibitor of CYP3A4 and is a substrate and inhibitor of P-glycoprotein (P-gp). Ceritinib is a substrate of CYP3A4 and P-gp, and is associated with QT prolongation. Ceritinib should not be given with a strong CYP3A4 inhibitor such as ritonavir (or lopinavir; ritonavir). If co-administration is necessary, decrease the ceritinib dose by approximately one-third, rounded to the nearest 150 mg. Periodically monitor electrocardiograms (EGCs) and electrolytes; therapy interruption, dose reduction, or discontinuation may be required. Additionally, monitor the patient for other ceritinib toxicities. If ritonavir is discontinued, resume the recommended ceritinib dose after a washout period based on the half-life of ritonavir.
Cetirizine: Coadministration of cetirizine and ritonavir resulted in a 42% increase in the AUC, 53% increase in half-life, and 29% decrease in clearance of cetirizine. Cetirizine did not alter ritonavir disposition.
Cetirizine; Pseudoephedrine: Coadministration of cetirizine and ritonavir resulted in a 42% increase in the AUC, 53% increase in half-life, and 29% decrease in clearance of cetirizine. Cetirizine did not alter ritonavir disposition.
Cevimeline: Cevimeline is metabolized by CYP3A4 and CYP2D6. Anti-retroviral protease inhibitors inhibit one or both of these isoenzymes and are expected to lead to an increase in cevimeline plasma concentrations.
Chloramphenicol: Concurrent administration of chloramphenicol with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of paritaprevir, ritonavir, and dasabuvir and subsequent adverse events. Chloramphenicol is an inhibitor of the hepatic isoenzyme CYP3A4; paritaprevir, ritonavir, and dasabuvir (minor) are substrates of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of chloramphenicol with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of paritaprevir, ritonavir, and dasabuvir and subsequent adverse events. Chloramphenicol is an inhibitor of the hepatic isoenzyme CYP3A4; paritaprevir, ritonavir, and dasabuvir (minor) are substrates of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of chloramphenicol with ritonavir may result in elevated plasma concentrations of ritonavir, and subsequent adverse events. Chloramphenicol is an inhibitor of the hepatic isoenzyme CYP3A4; ritonavir is a substrate of this enzyme. Monitor patient for ritonavir-related adverse events.
Chlordiazepoxide: CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed.
Chlordiazepoxide; Clidinium: CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed.
Chloroquine: Concurrent administration of chloroquine with ritonavir may result in elevated plasma concentrations of chloroquine, which may increase the risk of adverse events such as QT prolongation. Chloroquine is partially metabolized by CYP3A4 and CYP2D6; ritonavir inhibits both isoenzymes. However, most of each chloroquine dose is excreted unchanged in the urine; therefore, the clinical significance of this enzyme inhibition is not clear. Monitor patient for chloroquine-related adverse events.
Chlorpheniramine: Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together.
Chlorpheniramine; Codeine: Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
Chlorpheniramine; Dextromethorphan: Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together. Concurrent administration of dextromethorphan with ritonavir may result in elevated dextromethorphan plasma concentrations. Dextromethorphan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Chlorpheniramine; Dextromethorphan; Phenylephrine: Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together. Concurrent administration of dextromethorphan with ritonavir may result in elevated dextromethorphan plasma concentrations. Dextromethorphan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together. Concurrent administration of dihydrocodeine with ritonavir may result in elevated plasma concentrations of dihydrocodeine. Ritonavir is a substrate and inhibitor of the hepatic isoenzyme CYP2D6. Dihydrocodeine is metabolized by CYP2D6. Caution and close monitoring are advised if these drugs are administered together.
Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together. Concurrent administration of dihydrocodeine with ritonavir may result in elevated plasma concentrations of dihydrocodeine. Ritonavir is a substrate and inhibitor of the hepatic isoenzyme CYP2D6. Dihydrocodeine is metabolized by CYP2D6. Caution and close monitoring are advised if these drugs are administered together.
Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: Concurrent administration of hydrocodone with ritonavir may result in elevated hydrocodone plasma concentrations and subsequent adverse events, such as sedation and respiratory depression. If these drugs are given together, a 50% reduction in the dose of hydrocodone may be needed, and monitoring for respiratory depression and sedation at regular intervals is recommended. Hydrocodone is metabolized by the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is an inhibitor of these enzymes. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ritonavir may reduce the efficacy of hydrocodone. Caution and close monitoring for both efficacy and adverse reactions are advised if these drugs are administered together; a hydrocodone dosage adjustment may be necessary. Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together.
Chlorpheniramine; Hydrocodone: Concurrent administration of hydrocodone with ritonavir may result in elevated hydrocodone plasma concentrations and subsequent adverse events, such as sedation and respiratory depression. If these drugs are given together, a 50% reduction in the dose of hydrocodone may be needed, and monitoring for respiratory depression and sedation at regular intervals is recommended. Hydrocodone is metabolized by the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is an inhibitor of these enzymes. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ritonavir may reduce the efficacy of hydrocodone. Caution and close monitoring for both efficacy and adverse reactions are advised if these drugs are administered together; a hydrocodone dosage adjustment may be necessary. Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together.
Chlorpheniramine; Hydrocodone; Phenylephrine: Concurrent administration of hydrocodone with ritonavir may result in elevated hydrocodone plasma concentrations and subsequent adverse events, such as sedation and respiratory depression. If these drugs are given together, a 50% reduction in the dose of hydrocodone may be needed, and monitoring for respiratory depression and sedation at regular intervals is recommended. Hydrocodone is metabolized by the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is an inhibitor of these enzymes. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ritonavir may reduce the efficacy of hydrocodone. Caution and close monitoring for both efficacy and adverse reactions are advised if these drugs are administered together; a hydrocodone dosage adjustment may be necessary. Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together.
Chlorpheniramine; Hydrocodone; Pseudoephedrine: Concurrent administration of hydrocodone with ritonavir may result in elevated hydrocodone plasma concentrations and subsequent adverse events, such as sedation and respiratory depression. If these drugs are given together, a 50% reduction in the dose of hydrocodone may be needed, and monitoring for respiratory depression and sedation at regular intervals is recommended. Hydrocodone is metabolized by the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is an inhibitor of these enzymes. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ritonavir may reduce the efficacy of hydrocodone. Caution and close monitoring for both efficacy and adverse reactions are advised if these drugs are administered together; a hydrocodone dosage adjustment may be necessary. Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together.
Chlorpheniramine; Phenylephrine: Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together.
Chlorpheniramine; Pseudoephedrine: Concurrent administration of chlorpheniramine with ritonavir may result in elevated plasma concentrations of chlorpheniramine. Chlorpheniramine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Monitor for adverse effects if these drugs are administered together.
Chlorpromazine: Phenothiazines have been associated with a risk of QT prolongation and/or torsade de pointes (TdP). This risk is generally higher at elevated drugs concentrations of phenothiazines. Chlorpromazine is specifically associated with an established risk of QT prolongation and TdP; case reports have included patients receiving therapeutic doses of chlorpromazine. Agents that prolong the QT interval, such as ritonavir or lopinavir; ritonavir, could lead to torsade de pointes when combined with chlorpromazine, and therefore are generally not recommended for combined use.
Ciclesonide: Coadministration of ciclesonide with ritonavir may cause elevated ciclesonide serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Ciclesonide is a CYP3A4 substrate; ritonavir is a strong inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use.
Cidofovir: Additive adverse effects may be seen when cidofovir is given with other agents that cause neutropenia. Patients receiving anti-retroviral protease inhibitors in combination with cidofovir may have an increased risk of iritis or uveitis.
Cilostazol: Concurrent administration of cilostazol with protease inhibitors can result in elevated cilostazol plasma concentrations; the manufacturer recommends prescribers consider up to a 50% reduction in cilostazol dosage during concurrent administration. Cilostazol is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Cimetidine: Concurrent administration of cimetidine with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of paritaprevir, ritonavir, and dasabuvir. Cimetidine is an inhibitor of the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is partially metabolized by both of these enzymes. In addition, paritaprevir and dasabuvir (minor) are substrates of CYP3A4. Monitor for adverse events if these drugs are administered together. Concurrent administration of cimetidine with ritonavir may result in elevated plasma concentrations of ritonavir. Cimetidine is an inhibitor of the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is partially metabolized by both of these enzymes. Monitor for adverse events if these drugs are administered together.
Cinacalcet: Concurrent administration of cinacalcet with ritonavir may result in elevated plasma concentrations of cinacalcet. Cinacalcet is a substrate of CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Ciprofloxacin: Ritonavir has been associated with dose-related QT prolongation in other trials. Rare cases of QT prolongation and torsade de pointe (TdP) have been reported with ciprofloxacin during post-marketing surveillance. Ciprofloxacin should be used cautiously and with close monitoring with ritonavir.
Cisapride: Concurrent use of cisapride with anti-retroviral protease inhibitors (PI) is contraindicated due to the risk of life threatening cardiac arrhythmias such as torsade de pointes (TdP). Cisapride is metabolized by CYP3A4, and all PIs inhibit this enzyme; thus, coadministration may increases cisapride plasma concentrations and increase the risk of adverse events. Cases of QT prolongation and ventricular arrhythmias, including TdP and death, have been observed during post-marketing surveillance when cisapride is administered with potent CYP3A4 inhibitors. Additionally, saquinavir boosted with ritonavir and lopinavir; ritonavir causes QT prolongation, which could further increase the risk for TdP if coadministered with cisapride.
Citalopram: Because ritonavir and SSRIs including citalopram and escitalopram are associated with a possible risk for QT prolongation and torsade de pointes (TdP), these combinations should be used cautiously and with close monitoring. According to the manufacturer, concurrent use of citalopram with other drugs that prolong the QT interval is not recommended. If concurrent therapy is considered essential, ECG monitoring is recommended. In addition, ritonavir inhibits CYP3A metabolism and, therefore, should be used cautiously with SSRIs metabolized by CYP3A4 including escitalopram and citalopram. Close monitoring for adverse effects is prudent.
Clarithromycin: Caution is advised when administering clarithromycin concurrently with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir. Use of these drugs together may result in elevated concentrations of clarithromycin, paritaprevir, ritonavir, dasabuvir and ombitasvir. Predications regarding this interaction can be made based on the drugs metabolic pathways. Clarithromycin is a substrate/inhibitor of CYP3A4 and an inhibitor of P-glycoprotein (P-gp). Ritonavir is an inhibitor/substrate of CYP3A4 and a P-gp substrate. Paritaprevir and dasabuvir are substrates of CYP3A4 and P-gp. Ombitasvir is a substrate of P-gp. Monitor for adverse reactions. Caution is advised when administering clarithromycin concurrently with dasabuvir; ombitasvir; paritaprevir; ritonavir. Use of these drugs together may result in elevated concentrations of clarithromycin, paritaprevir, ritonavir, dasabuvir and ombitasvir. Predications regarding this interaction can be made based on the drugs metabolic pathways. Clarithromycin is a substrate/inhibitor of CYP3A4 and an inhibitor of P-glycoprotein (P-gp). Ritonavir is an inhibitor/substrate of CYP3A4 and a P-gp substrate. Paritaprevir and dasabuvir are substrates of CYP3A4 and P-gp. Ombitasvir is a substrate of P-gp. Monitor for adverse reactions. Concomitant administration of ritonavir and clarithromycin results in 77% increases in clarithromycin AUC. Clarithromycin dosage adjustments are recommended in patients with renal impairment who are receiving ritonavir concurrently. For patients with creatinine clearance 60 to 30 ml/min, the dose of clarithromycin should be reduced by 50%. For patients with creatinine clearance < 30 ml/min, the dose of clarithromycin should be reduced by 75%. No dosage adjustment of clarithromycin is required for patients with normal renal function who are also receiving ritonavir. Increases in erythromycin concentrations may also be noted, although the necessity of dosage adjustments has not been determined. In addition, ritonavir, clarithromycin, and erythromycin are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
Clevidipine: Ritonavir is expected to decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
Clindamycin: Concomitant use of clindamycin and ritonavir may decrease clindamycin clearance and increase the risk of adverse reactions. Clindamycin is a CYP3A4 substrate; ritonavir is a strong inhibitor of CYP3A4. Caution and close monitoring are advised if these drugs are used together.
Clobazam: Concurrent administration of clobazam with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of clobazam and altered concentrations of paritaprevir, dasabuvir, and ritonavir. Because of the complex interactions with hepatic isoenzymes and P-glycoprotein (P-gp), the final effect on drug concentrations is not clear. Clobazam is a CYP3A4 and P-gp substrate, and ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor. Paritaprevir is a P-gp inhibitor. Ritonavir is a CYP2D6 substrate, and clobazam is a CYP2D6 inhibitor. Ritonavir, paritaprevir, and dasabuvir (minor) are all CYP3A4 substrates, and clobazam is a CYP3A4 inducer. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of clobazam with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of clobazam and altered concentrations of paritaprevir, dasabuvir, and ritonavir. Because of the complex interactions with hepatic isoenzymes and P-glycoprotein (P-gp), the final effect on drug concentrations is not clear. Clobazam is an inhibitor of CYP2D6, a substrate for P-gp, and a substrate/inducer of CYP3A4. Ritonavir is a substrate/inhibitor of both CYP3A4 and P-gp, as well as a CYP2D6 substrate. Paritaprevir is a P-gp inhibitor. In addition, paritaprevir and dasabuvir (minor) are all CYP3A4 substrates. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of clobazam with ritonavir may result in elevated plasma concentrations of clobazam and altered concentrations of ritonavir. Clobazam is a substrate of CYP3A4 and P-glycoprotein (P-gp), weak inducer of CYP3A4, and an inhibitor of CYP2D6. Ritonavir is a substrate of CYP3A4, CYP2D6, and P-gp inhibitor. Ritonavir is also a potent inhibitor of CYP3A4 and P-gp. Caution and close monitoring are advised if these drugs are administered together.
Clofarabine: Concomitant use of clofarabine, a substrate of OCT1, and ritonavir, an inhibitor of OCT1, may result in increased clofarabine levels. Therefore, monitor for signs of clofarabine toxicity such as gastrointestinal toxicity (e.g., nausea, vomiting, diarrhea, mucosal inflammation), hematologic toxicity, and skin toxicity (e.g. hand and foot syndrome, rash, pruritus) in patients also receiving OCT1 inhibitors.
Clomipramine: Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Ritonavir has a possible risk for QT prolongation and torsade de pointes (TdP) and should be used cautiously and with close monitoring with doxepin. In addition, ritonavir potently inhibits CYP2D6 and CYP3A4, and thus may inhibit the metabolism of the tricyclic antidepressants (TCAs). A significant effect of ritonavir on desipramine clearance has been reported. Since the magnitude of the interaction with the TCAs is difficult to predict but may be significant, closely monitor patients receiving ritonavir and TCAs concurrently. Adjust the dosage of the coadministered drug based on therapeutic response. TCA serum concentration monitoring may be useful to guide adjustments and prevent toxicity.
Clonazepam: CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of clonazepam and increase the potential for benzodiazepine toxicity. A decrease in the clonazepam dose may be needed.
Clopidogrel: According to the manufacturer, concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with stong CYP2C8 inhibitors is contraindicated due to the potential for dasabuvir-induced QT prolongation. Clopidogrel is a potent inhibitor of the hepatic isoenzyme CYP2C8; dasabuvir is primarily metabolized by CYP2C8. In addition, use of these drugs may alter plasma concentrations and/or biotransformation of clopidogrel. Clopidogrel requires hepatic biotransformation to an active metabolite; the activation is thought to be mediated, in part, by the CYP3A4 isoenzyme. Ritonavir is an inhibitor of this enzyme. It is not clear whether clopidogrel's effectivenss would beis altered during coadministration.
Clorazepate: CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of N-desmethyldiazepam, the active metabolite of clorazepate, and increase the potential for benzodiazepine toxicity. Monitor patients closely who receive concurrent therapy.
Clozapine: Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. The manufacturer of clozapine recommends caution during concurrent use with medications known to cause QT prolongation such as lopinavir; ritonavir. In addition, ritonavir is an inhibitor of CYP2D6 and CYP3A4, two of the isoenzymes responsible for the metabolism of clozapine. Ritonavir may also have inducing effects on CYP3A4 and CYP1A2. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias or other adverse effects. Use with a CYP inducer may result in loss of effectiveness of clozapine. According to the manufacturer, patients receiving clozapine in combination with inhibitors or inducers of CYP2D6, CYP3A4, or CYP1A2 should be monitored for adverse reactions or loss of effectiveness. Consideration should be given to adjusting the clozapine dose if clinically warranted.
Cobicistat: Use of ritonavir with cobicistat is not recommended, because of similar effects on CYP3A. Both ritonavir and cobicistat are potent inhibitors of CYP3A4.
Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: Use of ritonavir with cobicistat is not recommended, because of similar effects on CYP3A. Both ritonavir and cobicistat are potent inhibitors of CYP3A4. Concurrent administration of elvitegravir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated elvitegravir plasma concentrations. Elvitegravir is a substrate of uridine glucuronyltransferase (UGT1A1/3) and the hepatic isoenzyme CYP3A4. Ritonavir inhibits the CYP3A4 enzyme, while dasabuvir, ombitasvir, and paritaprevir are UGT1A1 inhibitors. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of elvitegravir with ritonavir may result in elevated elvitegravir plasma concentrations. Elvitegravir is a substrate of the hepatic isoenzyme CYP3A4. Ritonavir inhibits the CYP3A4 enzyme. Caution and close monitoring are advised if these drugs are administered together.
Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: Use of ritonavir with cobicistat is not recommended, because of similar effects on CYP3A. Both ritonavir and cobicistat are potent inhibitors of CYP3A4. Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, concurrently with inhibitors of P-gp and BCRP, such as ritonavir. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. Concurrent administration of elvitegravir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated elvitegravir plasma concentrations. Elvitegravir is a substrate of uridine glucuronyltransferase (UGT1A1/3) and the hepatic isoenzyme CYP3A4. Ritonavir inhibits the CYP3A4 enzyme, while dasabuvir, ombitasvir, and paritaprevir are UGT1A1 inhibitors. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of elvitegravir with ritonavir may result in elevated elvitegravir plasma concentrations. Elvitegravir is a substrate of the hepatic isoenzyme CYP3A4. Ritonavir inhibits the CYP3A4 enzyme. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of tenofovir, PMPA with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated tenofovir plasma concentrations. Tenofovir is a substrate for the breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp). Dasabuvir, paritaprevir, and ritonavir are BCRP inhibitors, and ritonavir inhibits P-gp. Caution and close monitoring are advised if these drugs are administered together.
Cobimetinib: Avoid the concurrent use of cobimetinib with paritaprevir due to the risk of cobimetinib toxicity. Cobimetinib is a P-glycoprotein (P-gp) substrate; paritaprevir is a P-gp inhibitor. Coadministration may increase cobimetinib serum concentrations. Avoid the concurrent use of cobimetinib with ritonavir due to the risk of cobimetinib toxicity. Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; ritonavir is a P-gp inhibitor as well as a strong CYP3A inhibitor. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), another strong CYP3A4 inhibitor, increased the mean cobimetinib AUC by 6.7-fold (90% CI, 5.6 to 8) and the mean Cmax by 3.2-fold (90% CI, 2.7 to 3.7).
Codeine: The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
Codeine; Guaifenesin: The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
Codeine; Phenylephrine; Promethazine: Concurrent administration of promethazine with ritonavir may result in elevated plasma concentrations of promethazine and increased risk of adverse events. Promethazine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. In addition, rarely promethazine has been associated with QT prolongation. Caution and close monitoring are advised if these drugs are administered together. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
Codeine; Promethazine: Concurrent administration of promethazine with ritonavir may result in elevated plasma concentrations of promethazine and increased risk of adverse events. Promethazine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. In addition, rarely promethazine has been associated with QT prolongation. Caution and close monitoring are advised if these drugs are administered together. The CYP3A4 pathway is an important metabolic clearance route for codeine, and inhibition of this metabolic pathway by strong CYP3A4 inhibitors such as the anti-retroviral protease inhibitors may lead to elevated codeine concentrations that are available for conversion to morphine by CYP2D6. Codeine should be used with caution in those patients receiving inhibitors of CYP3A4, or those who have increased endogenous CYP2D6 activity. Conduct regular patient observation, particularly during times of drug initiation, drug discontinuation, or dose adjustment. Monitor for altered pain response to codeine, and for excessive CNS sedation and respiratory depression. Perform dose adjustments as necessary to achieve stable patient response.
Colchicine: Coadministration of colchicine and dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir is contraindicated due to the potential for serious and life-threatening toxicity. Colchicine is a P-glycoprotein (P-gp) and CYP3A4 substrate, and ritonavir is a P-gp inhibitor and strong CYP3A4 inhibitor. Paritaprevir is also a P-gp inhibitor. When coadministered with P-gp/CYP3A4 inhibitors, patients with renal or hepatic impairment may experience a significant increase in colchicine serum concentration; thereby, increasing the risk for seroius toxicity. Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and ritonavir in patients with normal renal and hepatic function unless the use of both agents is imperative. Coadministration is contraindicated in patients with renal or hepatic impairment because colchicine accumulation may be greater in these populations. Ritonavir can inhibit colchicine's metabolism via P-glycoprotein (P-gp) and CYP3A4, resulting in increased colchicine exposure. If coadministration in patients with normal renal and hepatic function cannot be avoided, adjust the dose of colchicine by either reducing the daily dose or the dosage frequency, and carefully monitor for colchicine toxicity. Specific dosage adjustment recommendations are available for the Colcrys product for patients who have taken ritonavir in the past 14 days or require concurrent use: for prophylaxis of gout flares, if the original dose is 0.6 mg twice daily, decrease to 0.3 mg once daily or if the original dose is 0.6 mg once daily, decrease to 0.3 mg once every other day; for treatment of gout flares, give 0.6 mg as a single dose, then 0.3 mg 1 hour later, and do not repeat for at least 3 days; for familial Mediterranean fever, do not exceed a 0.6 mg/day.
Conivaptan: Coadministration of conivaptan with strong CYP3A4 inhibitors like ritonavir is contraindicated. The plasma concentrations of both drugs may be elevated during concurrent use. Coadministration of conivaptan with ketoconazole, a potent CYP3A4 inhibitor, results in 4- and 11- fold increase in conivaptan Cmax and AUC, respectively; similar pharmacokinetic effects could be seen with the coadministration of conivaptan and ritonavir. In addition, conivaptan inhibits both CYP3A4 and P-glycoprotein (P-gp); ritonavir is a substrate of both CYP3A4 and P-gp. Per the manufacturer of conivaptan, concomitant use of conivaptan with CYP3A4 substrates should be avoided. Subsequent treatment with CYP3A substrates may be initiated no sooner than 1 week after completion of conivaptan therapy.
Conjugated Estrogens: In vitro and in vivo studies have shown that estrogens are metabolized partially by CYP3A4. Inhibitors of CYP3A4, such as ritonavir, may increase the exposure of conjugated estrogens resulting in an increased risk of estrogen-related side effects or endometrial hyperplasia. Therefore, when chronically coadministering ritonavir (more than 30 days) with conjugated estrogens, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. Patients should report any breakthrough bleeding or adverse events to their prescribers.
Conjugated Estrogens; Bazedoxifene: In vitro and in vivo studies have shown that estrogens are metabolized partially by CYP3A4. Inhibitors of CYP3A4, such as ritonavir, may increase the exposure of conjugated estrogens resulting in an increased risk of estrogen-related side effects or endometrial hyperplasia. Therefore, when chronically coadministering ritonavir (more than 30 days) with conjugated estrogens, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. Patients should report any breakthrough bleeding or adverse events to their prescribers.
Conjugated Estrogens; Medroxyprogesterone: Coadministration of medroxyprogesterone, a CYP3A substrate with ritonavir, a strong CYP3A inhibitor should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is metabolized primarily by hydroxylation via the CYP3A4 in vitro. In vitro and in vivo studies have shown that estrogens are metabolized partially by CYP3A4. Inhibitors of CYP3A4, such as ritonavir, may increase the exposure of conjugated estrogens resulting in an increased risk of estrogen-related side effects or endometrial hyperplasia. Therefore, when chronically coadministering ritonavir (more than 30 days) with conjugated estrogens, adequate diagnostic measures, including directed or random endometrial sampling when indicated by signs and symptoms of endometrial hyperplasia, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding. Patients should report any breakthrough bleeding or adverse events to their prescribers.
Crizotinib: Coadministration of ritonavir with crizotinib is contraindicated, as increased serum concentrations may lead to serious adverse effects including QT prolongation. Both drugs have been associated with QT prolongation. Additionally, crizotinib is primarily metabolized by CYP3A4/5 and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of crizotinib (single dose) by 3.2-fold and 1.4-fold, respectively; the effect of CYP3A4 inhibitors on steady-state crizotinib exposure has not been evaluated. Finally, crizotinib is a moderate CYP3A4 inhibitor and ritonavir is a CYP3A4 substrate; exposure to ritonavir may increase. According to the manufacturer, the use of potent CYP3A4 inhibitors, such as ritonavir, with crizotinib should be avoided. Concurrent administration of crizotinib with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of all 5 drugs. Crizotinib is a substrate/inhibitor of CYP3A4 and the drug transporter P-glycoprotein (P-gp). Ritonavir is also a substrate and inhibitor of CYP3A4, while paritaprevir and dasabuvir (minor) are CYP3A4 substrates. In addition, ritonavir, paritaprevir, ombitasvir, and dasabuvir are all P-gp substrates. Furthermore, both ritonavir and crizitonib are associated with QT prolongation; coadministration increases the risk of QT prolongation. If coadministration cannot be avoided, caution and close monitoring are advised.
Cyclobenzaprine: Systemic exposure and the maximum serum concentration (Cmax) of cyclobenzaprine were decreased when a single 5 mg dose was administered concurrently with ombitasvir; paritaprevir; ritonavir. If these drugs are given together, monitor for reduced cyclobenzaprine efficacy; consider increasing the cyclobenzaprine dose if clinically needed. In addition, monitor for signs of QT prolongation. Cyclobenzaprine has been associated with a possible risk for QT prolongation. While ombitasvir; paritaprevir; ritonavir did not prolong the QT interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with dose-related QT prolongation in other trials. The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include cyclobenzaprine. In addition, cyclobenzaprine is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme.
Cyclophosphamide: Use caution if cyclophosphamide is used concomitantly with ritonavir, and monitor for possible changes in the efficacy or toxicity profile of cyclophosphamide. The clinical significance of this interaction is unknown. Cyclophosphamide is a prodrug that is hydroxylated and activated primarily by CYP2B6; the contribution of CYP3A4 to the activation of cyclophosphamide is variable. Additional isoenzymes involved in the activation of cyclophosphamide include CYP2A6, 2C9, 2C18, and 2C19. N-dechloroethylation to therapeutically inactive but neurotoxic metabolites occurs primarily via CYP3A4. The active metabolites, 4-hydroxycyclophosphamide and aldophosphamide, are then inactivated by aldehyde dehydrogenase-mediated oxidation. Ritonavir is a strong CYP3A4 inhibitor as well as a moderate inhibitor of CYP2C9; conversion of cyclophosphamide to its active metabolites may be affected. The use of protease inhibitor-based regimens was found to be associated with a higher incidence of infections and neutropenia in patients receiving cyclophosphamide, doxorubicin, and etoposide (CDE) than use of a non-nucleoside reverse transcriptase inhibitor-based regimen. In vitro, coadministration with troleandomycin, a CYP3A4 inhibitor, had little-to-no effect on cyclophosphamide metabolism. However, concurrent use of cyclophosphamide conditioning therapy with itraconazole (a strong CYP3A4 inhibitor) and fluconazole (a moderate CYP3A4 inhibitor) in a randomized trial resulted in increases in serum bilirubin and creatinine, along with increased exposure to toxic cyclophosphamide metabolites (n = 197).
Cyclosporine: An interaction is anticipated to occur with all anti-retroviral protease inhibitors and cyclosporine, as all protease inhibitors inhibit CYP3A4. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. Prior to beginning saquinavir the patient had been receiving stable doses of cyclosporine resulting in trough concentrations of 150 to 200 mcg/ml. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased to 580 mcg/ml. Dosages of both agents were decreased by 50% leading to resolution of symptoms. This interaction is probably due to CYP3A4 inhibition by saquinavir. Another possible mechanism is that both drugs have a high affinity for the drug efflux protein, P-glycoprotein, which may increase the absorption or decrease the clearance of the other drug. Reduce cyclosporine dose to one-fifth (1/5th) of the patients current cyclosporine dose when initiating treatment with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir, as coadministration results in elevated cyclosporine blood concentrations. With subsequent doses, monitor cyclosporine blood concentrations to determine further dose adjustments. After completion of the 4-drug hepatitis C treatment regimen, the dose should be re-adjusted based on measured blood concentrations. Monitor for renal function and cyclosporine associated adverse reactions. Reduce cyclosporine dose to one-fifth (1/5th) of the patients current cyclosporine dose when initiating treatment with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir, as coadministration results in elevated cyclosporine blood concentrations. With subsequent doses, monitor cyclosporine blood concentrations to determine further dose adjustments. After completion of thehepatitis C treatment regimen, the dose should be re-adjusted based on measured blood concentrations. Monitor for renal function and cyclosporine associated adverse reactions Reduce cyclosporine dose to one-fifth (1/5th) of the patients current cyclosporine dose when initiating treatment with dasabuvir; ombitasvir; paritaprevir; ritonavir, as coadministration results in elevated cyclosporine blood concentrations. With subsequent doses, monitor cyclosporine blood concentrations to determine further dose adjustments. After completion of the 4-drug hepatitis C treatment regimen, the dose should be re-adjusted based on measured blood concentrations. Monitor for renal function and cyclosporine associated adverse reactions.
Dabigatran: Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with dasabuvir; ombitasvir; paritaprevir; ritonavir as ritonavir and paritaprevir are P-gp inhibitors. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE), avoid coadministration with P-gp inhibitors like ritonavir in patients with CrCl less than 50 mL/min. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/min), avoid coadministration with ritonavir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran. Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir, as ritonavir and paritaprevir are P-gp inhibitors. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like ritonavir in patients with CrCl less than 50 mL/min. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/min), avoid coadministration with ritonavir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran. Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir, as ritonavir and paritaprevir are P-gp inhibitors. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE), avoid coadministration with P-gp inhibitors like ritonavir in patients with CrCl less than 50 mL/min. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/min), avoid coadministration with ritonavir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran. Increased serum concentrations of dabigatran are possible when dabigatran, a P-glycoprotein (P-gp) substrate, is coadministered with ritonavir, a P-gp inhibitor. Patients should be monitored for increased adverse effects of dabigatran. When dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE), or prophylaxis of DVT or PE following hip replacement surgery, avoid coadministration with P-gp inhibitors like ritonavir in patients with CrCl less than 50 mL/minute. When dabigatran is used in patients with non-valvular atrial fibrillation and severe renal impairment (CrCl less than 30 mL/minute), avoid coadministration with ritonavir, as serum concentrations of dabigatran are expected to be higher than when administered to patients with normal renal function. P-gp inhibition and renal impairment are the major independent factors that result in increased exposure to dabigatran.
Dabrafenib: Concurrent administration of dabrafenib with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated dabrafenib plasma concentrations and decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Dabrafenib's product labeling recommends avoidance of coadministration with strong CYP3A4 inhibitors if possible. Dabrafenib is a CYP3A4 substrate, and ritonavir is a potent inhibitor of this enzyme. In addition, ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. Dabrafenib is a CYP3A4 inducer, which could increase the metabolism of the antivirals. If these drugs must be administered together, caution and close monitoring are advised. The concomitant use of dabrafenib, a CYP3A4 substrate and a moderate CYP3A4 inducer, and ritonavir, a strong CYP3A4 inhibitor and a CYP3A4 substrate and inducer, may result in altered levels of either agent; avoid concomitant use if possible. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for dabrafenib or ritonavir adverse effects and/or reduced efficacy.
Daclatasvir: Taking daclatasvir with dasabuvir may increase serum concentrations of dasabuvir, and potentially increase the risk for adverse effects. Dasabuvir is a P-glycoprotein (P-gp) substrates; daclatasvir is a P-gp inhibitor. Taking daclatasvir with ombitasvir may increase serum concentrations of ombitasvir, and potentially increase the risk for adverse effects. Ombitasvir is a P-glycoprotein (P-gp) substrates; daclatasvir is a P-gp inhibitor. Taking daclatasvir with paritaprevir may increase serum concentrations of paritaprevir, and potentially increase the risk for adverse effects. Paritaprevir is a P-glycoprotein (P-gp) substrates; daclatasvir is a P-gp inhibitor. The dose of daclatasvir, a CYP3A4 substrate, must be reduced to 30 mg PO once daily when administered in combination with strong CYP3A4 inhibitors, such as ritonavir. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects. In addition, the therapeutic effects of ritonavir, a P-glycoprotein (P-gp) substrate, may be increased by daclatasvir, a P-gp inhibitor.
Dalfopristin; Quinupristin: Dalfopristin; quinupristin is a major inhibitor of cytochrome P450 3A4 and may decrease the elimination of drugs metabolized by this enzyme, including ritonavir. Per the manufacturer of dalfopristin; quinupristin, concomitant use with CYP3A4 substrates that may prolong the QT interval should be avoided; ritonavir has been associated with dose-related QT prolongation. Concurrent administration of dalfopristin; quinupristin with dasabuvir; ombitasvir; paritaprevir; ritonavir is expected to result in elevated plasma concentrations of dasabuvir, paritaprevir, and ritonavir. According to the manufacturer of dalfopristin; quinupristin, concomitant use with CYP3A4 substrates that may prolong the QT interval should be avoided. While dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QT interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with dose-related QT prolongation in other trials. Quinupristin is a potent inhibitor of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of dalfopristin; quinupristin with dasabuvir; ombitasvir; paritaprevir; ritonavir is expected to result in elevated plasma concentrations of dasabuvir, paritaprevir, and ritonavir. According to the manufacturer of dalfopristin;quinupristin, concomitant use with CYP3A4 substrates that may prolong the QT interval should be avoided. While dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QT interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with dose-related QT prolongation in other trials. Quinupristin is a potent inhibitor of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. Caution and close monitoring are advised if these drugs are administered together.
Danazol: Concurrent administration of danazol with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of dasabuvir, paritaprevir, and ritonavir. Danazol is an inhibitor of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir and dasabuvir (minor) are substrates of this enzyme. Although therapy with dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QTc interval to a clinical relevant extent in healthy subjects, ritonavir has been associated with concentration-dependent QT prolongation in other trials. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of danazol with ritonavir may result in elevated plasma concentrations of ritonavir. Danazol is an inhibitor of the hepatic isoenzyme CYP3A4; ritonavir is a substrate of this enzyme. Ritonavir has been associated with concentration-dependent QT prolongation in trials. Caution and close monitoring are advised if these drugs are administered together.
Dapagliflozin: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Dapagliflozin; Metformin: The manufacturer recommends against concurrent administration of ombitasvir; paritaprevir; ritonavir and metformin in patients with hepatic or renal impairment. If these drugs are given together, closely monitor blood glucose concentrations and for signs of lactic acidosis (i.e., abdominal or respiratory distress, worsening renal function, somnolence). New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Dapsone: Concurrent administration of dapsone with ritonavir may result in elevated dapsone plasma concentrations. Dapsone is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Darifenacin: Concurrent administration of darifenacin with ritonavir may result in elevated darifenacin plasma concentrations. If these drugs are coadministered, do not exceed a darifenacin dose of 7.5 mg daily and closely monitor the patient for increased anticholinergic effects. Darifenacin is CYP3A4 and CYP2D6 substrate; ritonavir is a potent CYP3A4 inhibitor and a CYP2D6 inhibitor.
Darunavir: Darunavir trough concentrations (Cmin) are reduced when darunavir (boosted with ritonavir) is administered with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir. Avoid concurrent use of these drugs in treatment experienced patients with 1 or more darunavir-associated mutations or with no baseline resistance data. However, for treatment-naive and treatment-experienced patients with no darunavir-associated mutations, darunavir may be administered with the 3- or 4-drug hepatitis C treatment regimens if: darunavir is dosed at 800 mg daily; darunavir is given WITHOUT ritonavir; darunavir is given at the same time as the hepatitis C treatment regimen. The darunavir dose should be re-adjusted after completion of the hepatitis C treatment regimen.
Darunavir; Cobicistat: Use of ritonavir with cobicistat is not recommended, because of similar effects on CYP3A. Both ritonavir and cobicistat are potent inhibitors of CYP3A4. Darunavir trough concentrations (Cmin) are reduced when darunavir (boosted with ritonavir) is administered with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir. Avoid concurrent use of these drugs in treatment experienced patients with 1 or more darunavir-associated mutations or with no baseline resistance data. However, for treatment-naive and treatment-experienced patients with no darunavir-associated mutations, darunavir may be administered with the 3- or 4-drug hepatitis C treatment regimens if: darunavir is dosed at 800 mg daily; darunavir is given WITHOUT ritonavir; darunavir is given at the same time as the hepatitis C treatment regimen. The darunavir dose should be re-adjusted after completion of the hepatitis C treatment regimen.
Dasatinib: If possible, avoid the concurrent use of dasatinib and dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir. Coadministration is expected to result in an increased risk of serious adverse events, including QT prolongation, and elevated concentrations of dasatinib, dasabuvir, paritaprevir, and ritonavir. If concurrent use cannot be avoided, the dasatinib dose must be significantly decreased (from 100 mg/day to 20 mg/day OR from 140 mg/day to 40 mg/day) with careful patient monitoring for dasatinib toxicity; if the reduced dose is not tolerated, either dasatinib or the hepatitis C regimen must be discontinued. While dasabuvir; ombitasvir; paritaprevir; ritonavir and ombitasvir; paritaprevir; ritonavir did not prolong the QTc interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with QT prolongation in other trials. Dasatinib has the potential to prolong the QT interval, in vitro, and should be used cautiously with other drugs that could also cause QT prolongation. Additionally, because concentrations of both ritonavir and dasatinib can be increased with coadministration, the risk of QT prolongation may be further increased. Dasatinib is a CYP3A4 substrate and inhibitor; ritonavir is a CYP3A4 substrate and potent inhibitor; and dasabuvir and paritaprevir are CYP3A4 substrates. If possible, avoid the concurrent use of dasatinib and dasabuvir; ombitasvir; paritaprevir; ritonavir. Coadministration is expected to result in an increased risk of serious adverse events, including QT prolongation, and elevated concentrations of dasatinib, dasabuvir, paritaprevir, and ritonavir. If concurrent use cannot be avoided, the dasatinib dose must be significantly decreased (from 100 mg/day to 20 mg/day OR from 140 mg/day to 40 mg/day) with careful patient monitoring for dasatinib toxicity; if the reduced dose is not tolerated, either dasatinib or dasabuvir; ombitasvir; paritaprevir; ritonavir must be discontinued. While dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QTc interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with QT prolongation in other trials. Dasatinib has the potential to prolong the QT interval, in vitro, and should be used cautiously with other drugs that could also cause QT prolongation. Additionally, because concentrations of both ritonavir and dasatinib can be increased with coadministration, the risk of QT prolongation may be further increased. Dasatinib is a CYP3A4 substrate and inhibitor; ritonavir is a CYP3A4 substrate and potent inhibitor; and dasabuvir and paritaprevir are CYP3A4 substrates. Ritonavir is a strong inhibitor, and a substrate, of CYP3A4. Dasatinib is also a substrate and inhibitor of CYP3A4. If possible, avoid concomitant use as it may result in elevated serum concentrations of both medications. If concurrent use cannot be avoided, the dasatinib dose must be significantly decreased (from 100 mg/day to 20 mg/day OR from 140 mg/day to 40 mg/day) with careful patient monitoring for dasatinib toxicity; if the reduced dose is not tolerated, either dasatinib or ritonavir must be discontinued. Closely monitor the patient for adverse events. In addition, both ritonavir and dasatanib are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
Daunorubicin: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with daunorubicin may increase the risk for QT prolongation and torsade de pointes (TdP). Daunorubicin is known to increase the QT interval. While dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QT interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with dose-related QT prolongation in other trials. In addition, daunorubicin is a substrate of the drug transporter P-glycoprotein (P-gp), and ritonavir and paritaprevir are P-gp inhibitorsis a P-gp inhibitor. Caution and close monitoring is advised if these drugs are administered together. The use of ritonavir could result in QT prolongation. Use ritonavir cautiously in patients taking other drugs known to prolong the QT interval. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported. In addition, daunorubicin is a substrate of the drug transporter P-glycoprotein (P-gp), and ritonavir is a P-gp inhibitor. Caution and close monitoring is advised if these drugs are administered together.
Deferasirox: Concurrent administration of deferasirox with dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in altered deferasirox plasma concentrations and decreased concentrations of paritaprevir, ritonavir, and dasabuvir, which may affect antiviral efficacy. Deferasirox is an inducer of CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. In addition, deferasirox is a substrate for uridine glucuronyltransferase (UGT); dasabuvir, ombitasvir and paritaprevir are UGT1A1 inhibitors. In addition, ritonavir may induce UGT. Concurrent administration of deferasirox with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in altered deferasirox plasma concentrations. Deferasirox is a substrate for uridine glucuronyltransferase (UGT); dasabuvir, ombitasvir and paritaprevir are UGT1A1 inhibitors. In addition, ritonavir may induce UGT. Caution and close monitoring are advised if these drugs are administered together. Deferasirox undergoes UGT metabolism, and ritonavir is a potent inducer of this enzyme system. The concomitant administration of deferasirox (single dose of 30 mg/kg) and the potent UGT inducer rifampin (i.e., rifampicin 600 mg/day for 9 days) resulted in a decrease in deferasirox AUC by 44%. Although specific drug interaction studies of deferasirox and ritonavir are not available, a similar interaction may occur. Avoid the concomitant use of ritonavir and deferasirox if possible. If ritonavir and deferasirox coadministration is necessary, consider increasing the initial dose of deferasirox. Monitor serum ferritin concentrations and clinical response for further modifications.
Deflazacort: Decrease deflazacort dose to one third of the recommended dosage when coadministered with ritonavir. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; ritonavir is a strong inhibitor of CYP3A4. Administration of deflazacort with clarithromycin, a strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
Degarelix: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include degarelix.
Delavirdine: Concurrent administration of delavirdine with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of delavirdine, dasabuvir, paritaprevir, and ritonavir. During concurrent administration of delavirdine with ritonavir, increased ritonavir AUC (70%) has been noted. Appropriate doses of ritonavir in combination with delavirdine in regard to safety, efficacy, and pharmacokinetics have not been established. Both delavirdine and ritonavir are CYP3A4 potent inhibitors and substrates as well as CYP2D6 inhibitors and substrates. Paritaprevir and dasabuvir (minor) are CYP3A4 substrates. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of delavirdine with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of delavirdine, dasabuvir, paritaprevir, and ritonavir. During concurrent administration of delavirdine with ritonavir, increased ritonavir AUC (70%) has been noted. Appropriate doses of ritonavir in combination with delavirdine in regard to safety, efficacy, and pharmacokinetics have not been established. Both delavirdine and ritonavir CYP3A4 potent inhibitors and substrates as well as CYP2D6 inhibitors and substrates. Paritaprevir and dasabuvir (minor) are CYP3A4 substrates. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of delavirdine with ritonavir, increased AUC of ritonavir. During concurrent administration of delavirdine with ritonavir, increased ritonavir AUC (70%) has been noted. Appropriate doses of ritonavir in combination with delavirdine in regard to safety, efficacy, and pharmacokinetics have not been established. Both delavirdine and ritonavir CYP3A4 potent inhibitors and substrates as well as CYP2D6 inhibitors and substrates.
Desflurane: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include halogenated anesthetics.
Desipramine: Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Ritonavir has a possible risk for QT prolongation and torsade de pointes (TdP) and should be used cautiously and with close monitoring with doxepin. In addition, ritonavir potently inhibits CYP2D6 and CYP3A4, and thus may inhibit the metabolism of the tricyclic antidepressants (TCAs). A significant effect of ritonavir on desipramine clearance has been reported. Since the magnitude of the interaction with the TCAs is difficult to predict but may be significant, closely monitor patients receiving ritonavir and TCAs concurrently. Adjust the dosage of the coadministered drug based on therapeutic response. TCA serum concentration monitoring may be useful to guide adjustments and prevent toxicity.
Desloratadine: The plasma concentrations of desloratadine may be elevated when administered concurrently with dasabuvir; ombitasvir; paritaprevir; ritonavir. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Ritonavir and paritaprevir are P-glycoprotein (P-gp) inhibitorsis a P-glycoprotein (P-gp) inhibitor, while desloratidine is a P-gp substrate. The plasma concentrations of desloratadine may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Ritonavir is a P-glycoprotein (P-gp) inhibitor, while desloratadine is a P-gp substrate.
Desloratadine; Pseudoephedrine: The plasma concentrations of desloratadine may be elevated when administered concurrently with dasabuvir; ombitasvir; paritaprevir; ritonavir. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Ritonavir and paritaprevir are P-glycoprotein (P-gp) inhibitorsis a P-glycoprotein (P-gp) inhibitor, while desloratidine is a P-gp substrate. The plasma concentrations of desloratadine may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Ritonavir is a P-glycoprotein (P-gp) inhibitor, while desloratadine is a P-gp substrate.
Deutetrabenazine: Avoid coadministration of deutetrabenazine with ritonavir. Clinically relevant QT prolongation may occur with deutetrabenazine. The use of ritonavir could result in QT prolongation.
Dexamethasone: Concurrent administration of dexamethasone with dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in elevated dexamethasone plasma concentrations and decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Antiviral efficacy could be affected. Dexamethasone is a P-glycoprotein (P-gp) substrate and a CYP3A4 substrate/inducer. Ritonavir is a P-gp inhibitor and a CYP3A4 substrate/potent inhibitor. Both paritaprevir and dasabuvir (minor) are CYP3A4 substrates. Concurrent administration of dexamethasone with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in elevated dexamethasone plasma concentrations and decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Antiviral efficacy could be affected. Dexamethasone is a P-glycoprotein (P-gp) substrate and a CYP3A4 substrate/inducer. Ritonavir is a P-gp inhibitor and a CYP3A4 substrate/potent inhibitor. Both paritaprevir and dasabuvir (minor) are CYP3A4 substrates. Close monitoring of therapeutic and adverse effects is required when dexamethasone is coadministered with ritonavir. Ritonavir inhibits CYP3A4 and dexamethasone is a CYP3A4 substrate.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: Concurrent administration of dextromethorphan with ritonavir may result in elevated dextromethorphan plasma concentrations. Dextromethorphan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Dexlansoprazole: Concurrent administration of dexlansoprazole with ritonavir may result in elevated dexlansoprazole plasma concentrations. Dexlansoprazole is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and monitoring for adverse effects are advised if these drugs are administered together.
Dextroamphetamine: Patients receiving amphetamines may experience prolonged effects if receiving ritonavir concurrently. A case report describes a patient who was treated with ritonavir and saquinavir and then experienced a prolonged effect from a small dose of methylene-dioxy-methamphetamine (MDMA or ecstasy) and a near fatal reaction from a small dose of gamma-hydroxybutyrate (GHB). The effects in this patient suggests that the prolonged effects of MDMA were due to ritonavir-induced inhibition of CYP2D6 metabolism. The GHB toxicity in this patient may have been due to ritonavir-induced inhibition of first pass metabolism, leading to increased levels of GHB. Patients receiving other amphetamine drugs, such as amphetamine, amphetamine; dextroamphetamine mixed salts, lisdexamfetamine, or methamphetamine may experience prolonged effects if receiving ritonavir concurrently. Patients should be warned that there are potentially serious drug interactions between ritonavir and illicit drugs, such as ecstasy.
Dextromethorphan: Concurrent administration of dextromethorphan with ritonavir may result in elevated dextromethorphan plasma concentrations. Dextromethorphan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Dextromethorphan; Diphenhydramine; Phenylephrine: Concurrent administration of dextromethorphan with ritonavir may result in elevated dextromethorphan plasma concentrations. Dextromethorphan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of diphenhydramine with ritonavir may result in elevated plasma concentrations of diphenhydramine. Diphenhydramine is a CYP2D6 substrate, and ritonavir is a CYP2D6 inhibitor. Caution and close monitoring are advised if these drugs are administered together.
Dextromethorphan; Guaifenesin: Concurrent administration of dextromethorphan with ritonavir may result in elevated dextromethorphan plasma concentrations. Dextromethorphan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Dextromethorphan; Guaifenesin; Phenylephrine: Concurrent administration of dextromethorphan with ritonavir may result in elevated dextromethorphan plasma concentrations. Dextromethorphan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: Concurrent administration of dextromethorphan with ritonavir may result in elevated dextromethorphan plasma concentrations. Dextromethorphan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Dextromethorphan; Guaifenesin; Pseudoephedrine: Concurrent administration of dextromethorphan with ritonavir may result in elevated dextromethorphan plasma concentrations. Dextromethorphan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Dextromethorphan; Promethazine: Concurrent administration of promethazine with ritonavir may result in elevated plasma concentrations of promethazine and increased risk of adverse events. Promethazine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. In addition, rarely promethazine has been associated with QT prolongation. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of dextromethorphan with ritonavir may result in elevated dextromethorphan plasma concentrations. Dextromethorphan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Dextromethorphan; Quinidine: The manufacturer of ombitasvir; paritaprevir; ritonavir recommends caution and therapeutic drug monitoring (when available) if administered concurrently with quinidine. However, since one of the components of the 3-drug combination is ritonavir, use of these drugs together is contraindicated. Both ritonavir and quinidine are associated with QT prolongation; concomitant use increases the risk for developing Torsade de Pointes (TdP). In addition, ritonavir is a potent CYP3A4 inhibitor, an enzyme partially responsible for the metabolism of quinidine. If administered together, serum concentration of quinidine may increase. Coadministration of HIV treatment doses of ritonavir and quinidine is contraindicated due to the potential for serious or life-threatening reactions, such as cardiac arrhythmias. Cautious consideration may be given to administering quinidine with boosting doses of ritonavir. Ritonavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, such as quinidine, should be expected with concurrent use. In addition, ritonavir is associated with QT prolongation and quinidine is associated with QT prolongation and torsade de pointes (TdP); concomitant use increases the risk of QT prolongation. Concurrent administration of dextromethorphan with ritonavir may result in elevated dextromethorphan plasma concentrations. Dextromethorphan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Diazepam: CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of diazepam and increase the potential for benzodiazepine toxicity. Prolonged sedation and respiratory depression can occur. A decrease in the diazepam dose may be needed Systemic exposure of diazepam and its metabolite, nordiazepam, were decreased when a single 2 mg dose was administered concurrently with ombitasvir; paritaprevir; ritonavir. If these drugs are given together, monitor for reduced diazepam efficacy; consider increasing the diazepam dose if clinically needed.
Diclofenac: Concurrent administration of diclofenac with ritonavir may result in elevated diclofenac plasma concentrations. Diclofenac is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring for adverse effects are advised if these drugs are administered together.
Diclofenac; Misoprostol: Concurrent administration of diclofenac with ritonavir may result in elevated diclofenac plasma concentrations. Diclofenac is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring for adverse effects are advised if these drugs are administered together.
Didanosine, ddI: Administration of didanosine, ddI and dasabuvir; ombitasvir; paritaprevir; ritonavir should be separated by at least 2.5 hours to avoid formulation incompatibilities. Didanosine is given on an empty stomach, and the 4-drug hepatitis regimen must be given with food. Coadministration of ritonavir and didanosine resulted in decreases in the AUC and Cmax of didanosine by 13% and 16%, respectively, in pharmacokinetic trials. Dosage adjustments might be required when didanosine is administered with ritonavir. Coadministration of ritonavir and didanosine, resulted in decreases in the AUC and Cmax of didanosine by 13% and 16%, respectively. Dosage adjustments might be required when didanosine is administered with ritonavir. The administration of didanosine and ritonavir should be separated by at least 2.5 hours to avoid formulation incompatibilities.
Dienogest; Estradiol valerate: Ritonavir has been shown to increase the metabolism of ethinyl estradiol. Ritonavir is a substrate and inhibitor of CYP3A4. It is not known if the effects of protease inhibitors are similar on estradiol; however, estradiol is metabolized by CYP3A4, similar to ethinyl estradiol.
Digoxin: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with digoxin is expected to increase digoxin serum concentrations. Digoxin's product labeling recommends a digoxin dosage reduction of 30 to 50%. Measure digoxin serum concentration before initiating dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir, and then as clinically appropriate during coadministration to ensure appropriate digoxin dosage titration. Monitor for therapeutic and adverse effects. Digoxin is a P-glycoprotein (P-gp) substrate, and ritonavir and paritaprevir are a P-gp inhibitors. In a pharmacokinetic study of 11 healthy men, increases in digoxin AUC (86%), volume of distribution, and half-life were seen, while renal and non-renal clearance decreased, when coadministered with ritonavir. It appears that this interaction is mediated by ritonavir's inhibition or P-glycoprotein-mediated renal tubular secretion of digoxin. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including digoxin) has not been evaluated. Measure serum digoxin concentrations before initiating ritonavir or lopinavir; ritonavir. Reduce digoxin concentrations by decreasing the digoxin dose by approximately 30 to 50% or by modifying the dosing frequency and continue monitoring.
Dihydrocodeine; Guaifenesin; Pseudoephedrine: Concurrent administration of dihydrocodeine with ritonavir may result in elevated plasma concentrations of dihydrocodeine. Ritonavir is a substrate and inhibitor of the hepatic isoenzyme CYP2D6. Dihydrocodeine is metabolized by CYP2D6. Caution and close monitoring are advised if these drugs are administered together.
Dihydroergotamine: Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
Diltiazem: Elevated plasma concentrations and an increased risk of serious adverse events may occur with coadministration of diltiazem and dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir. If these drugs are to be coadministered, carefully monitor the patient for adverse reactions and diltiazem toxicity. Ritonavir and diltiazem both prolong the PR interval and caution for increased risk is recommended with coadministration. Ritonavir (CYP3A4 substrate/potent inhibitor, P-glycoprotein (P-gp) substrate/inhibitor), may competitively inhibit diltiazem (CYP3A4 substrate/inhibitor, P-gp substrate/inhibitor) metabolism, and could increase the diltiazem AUC by up to three-fold with the potential for diltiazem toxicity. Paritaprevir is also a P-gp inhibitor. Ritonavir concentrations could also be increased. The manufacturer for ritonavir recommends caution when coadministering with diltiazem. Additionally, diltiazem can increase paritaprevir, ombitasvir and dasabuvir concentrations by inhibiting CYP3A4 metabolism (paritaprevir and dasabuvir, minor) and P-gp (all 3 drugs). Elevated plasma concentrations and an increased risk of serious adverse events may occur with coadministration of diltiazem and dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir. If these drugs are to be coadministered, carefully monitor the patient for adverse reactions. Ritonavir (CYP3A4 substrate/potent inhibitor, P-glycoprotein (P-gp) substrate/inhibitor), may competitively inhibit diltiazem (CYP3A4 substrate/inhibitor, P-gp substrate/inhibitor) metabolism, and could increase the diltiazem AUC by up to three-fold with the potential for diltiazem toxicity. Ritonavir concentrations could also be increased. The manufacturer for ritonavir recommends caution when coadministering with diltiazem. Additionally, diltiazem can increase paritaprevir, ombitasvir and dasabuvir concentrations by inhibiting CYP3A4 metabolism (paritaprevir and dasabuvir, minor) and P-gp (all 3 drugs). Further, ritonavir and diltiazem both prolong the PR interval and caution for increased risk is recommended with coadministration. Elevated plasma concentrations and an increased risk of serious adverse events may occur with coadministration of diltiazem and dasabuvir; ombitasvir; paritaprevir; ritonavir. If these drugs are to be coadministered, carefully monitor the patient for adverse reactions. Ritonavir (CYP3A4 substrate/potent inhibitor, P-glycoprotein (P-gp) substrate/inhibitor), may competitively inhibit diltiazem (CYP3A4 substrate/inhibitor, P-gp substrate/inhibitor) metabolism, and could increase the diltiazem AUC by up to three-fold with the potential for diltiazem toxicity. Ritonavir concentrations could also be increased. The manufacturer for ritonavir recommends caution when coadministering with diltiazem. Additionally, diltiazem can increase paritaprevir, ombitasvir and dasabuvir concentrations by inhibiting CYP3A4 metabolism (paritaprevir and dasabuvir, minor) and P-gp (all 3 drugs). Further, ritonavir and diltiazem both prolong the PR interval and caution for increased risk is recommended with coadministration. Ritonavir is expected to decreases the hepatic CYP metabolism of diltiazem, resulting in increased diltiazem concentrations. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased diltiazem may be warranted. In addition, ritonavir and diltiazem both prolong the PR interval and caution for increased risk is recommended with coadministration.
Diphenhydramine: Concurrent administration of diphenhydramine with ritonavir may result in elevated plasma concentrations of diphenhydramine. Diphenhydramine is a CYP2D6 substrate, and ritonavir is a CYP2D6 inhibitor. Caution and close monitoring are advised if these drugs are administered together.
Diphenhydramine; Hydrocodone; Phenylephrine: Concurrent administration of hydrocodone with ritonavir may result in elevated hydrocodone plasma concentrations and subsequent adverse events, such as sedation and respiratory depression. If these drugs are given together, a 50% reduction in the dose of hydrocodone may be needed, and monitoring for respiratory depression and sedation at regular intervals is recommended. Hydrocodone is metabolized by the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is an inhibitor of these enzymes. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ritonavir may reduce the efficacy of hydrocodone. Caution and close monitoring for both efficacy and adverse reactions are advised if these drugs are administered together; a hydrocodone dosage adjustment may be necessary. Concurrent administration of diphenhydramine with ritonavir may result in elevated plasma concentrations of diphenhydramine. Diphenhydramine is a CYP2D6 substrate, and ritonavir is a CYP2D6 inhibitor. Caution and close monitoring are advised if these drugs are administered together.
Diphenhydramine; Ibuprofen: Concurrent administration of diphenhydramine with ritonavir may result in elevated plasma concentrations of diphenhydramine. Diphenhydramine is a CYP2D6 substrate, and ritonavir is a CYP2D6 inhibitor. Caution and close monitoring are advised if these drugs are administered together.
Diphenhydramine; Naproxen: Concurrent administration of diphenhydramine with ritonavir may result in elevated plasma concentrations of diphenhydramine. Diphenhydramine is a CYP2D6 substrate, and ritonavir is a CYP2D6 inhibitor. Caution and close monitoring are advised if these drugs are administered together.
Diphenhydramine; Phenylephrine: Concurrent administration of diphenhydramine with ritonavir may result in elevated plasma concentrations of diphenhydramine. Diphenhydramine is a CYP2D6 substrate, and ritonavir is a CYP2D6 inhibitor. Caution and close monitoring are advised if these drugs are administered together.
Disopyramide: Caution is warranted when ritonavir is coadministered with antiarrhythmics, including disopyramide. Ritonavir is an inhibitor of CYP3A4, and increased concentrations of disopyramide may be expected during coadministration. Therapeutic antiarrhythmic concentration monitoring is suggested when available. Monitor therapeutic response closely; dosage reduction may be needed. In some cases, the drug interaction may require more than 50% dosage reduction due to potent inhibitory effects and drug accumulation. Cardiac and neurologic events have been reported when ritonavir was concurrently administered with disopyramide.
Disulfiram: Oral solutions of ritonavir contain ethanol. Administration of ritonavir oral solution to patients receiving or who have recently received disulfiram may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations.
Docetaxel: Docetaxel is metabolized by CYP3A4 enzymes. In vitro studies have shown drugs that inhibit, induce, or are also metabolized by CYP3A enzymes can significantly affect the metabolism of docetaxel. Potential CYP3A inhibition interactions may occur with docetaxel and ritonavir. Coadminister these drugs cautiously
Dofetilide: Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP); therefore, use with drugs having a possible risk of QT prolongation and TdP, such as ritonavir, is contraindicated. In addition, ritonavir, a CYP3A4 inhibitor, may decrease the metabolism of dofetilide, thereby increasing the potential for QT prolongation.
Dolasetron: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include dolasetron.
Dolutegravir: Concurrent administration of dolutegravir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated dolutegravir plasma concentrations. Dolutegravir is a substrate of uridine glucuronyltransferase (UGT) and the hepatic isoenzyme CYP3A4. Ritonavir is a potent inhibitor of CYP3A4 and dasabuvir, ombitasvir, and paritaprevir are all UGT1A1 inhibitors. Additionally, dolutegravir is a substrate of the breast cancer resistance protein (BCRP); dasabuvir, ritonavir, and paritaprevir are BCRP inhibitors. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of dolutegravir with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated dolutegravir plasma concentrations. Dolutegravir is a substrate of uridine glucuronyltransferase (UGT) and the hepatic isoenzyme CYP3A4. Ritonavir is a potent inhibitor of CYP3A4 and dasabuvir, ombitasvir, and paritaprevir are all UGT1A1 inhibitors. Additionally, dolutegravir is a substrate of the breast cancer resistance protein (BCRP); dasabuvir, ritonavir, and paritaprevir are BCRP inhibitors. Caution and close monitoring are advised if these drugs are administered together.
Donepezil: Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Ritonavir has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, ritonavir may inhibit the metabolism of donepezil by inhibiting CYP3A4 and CYP2D6. Close monitoring of serum drug concentrations and/or therapeutic and adverse effects is required when donepezil is coadministered with ritonavir or combinations containing ritonavir such as lopinavir; ritonavir. Dosage reduction may be needed.
Donepezil; Memantine: Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. Donepezil is considered a drug with a known risk of TdP. Ritonavir has a possible risk for QT prolongation and TdP and should be used cautiously and with close monitoring with donepezil. In addition, ritonavir may inhibit the metabolism of donepezil by inhibiting CYP3A4 and CYP2D6. Close monitoring of serum drug concentrations and/or therapeutic and adverse effects is required when donepezil is coadministered with ritonavir or combinations containing ritonavir such as lopinavir; ritonavir. Dosage reduction may be needed.
Dorzolamide; Timolol: Timolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as ritonavir, may impair timolol metabolism; the clinical significance of such interactions is unknown.
Doxepin: Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Ritonavir has a possible risk for QT prolongation and torsade de pointes (TdP) and should be used cautiously and with close monitoring with doxepin. In addition, ritonavir potently inhibits CYP2D6 and CYP3A4, and thus may inhibit the metabolism of the tricyclic antidepressants (TCAs). A significant effect of ritonavir on desipramine clearance has been reported. Since the magnitude of the interaction with the TCAs is difficult to predict but may be significant, closely monitor patients receiving ritonavir and TCAs concurrently. Adjust the dosage of the coadministered drug based on therapeutic response. TCA serum concentration monitoring may be useful to guide adjustments and prevent toxicity.
Doxercalciferol: Protease inhibitors may decrease efficacy of doxercalciferol. Doxercalciferol is converted in the liver to 1,25-dihydroxyergocalciferol, the major active metabolite, and 1-alpha, 24-dihydroxyvitamin D2, a minor metabolite. Although not specifically studied, cytochrome P450 enzyme inhibitors, including protease inhibitors, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if these drugs are administered together.
Doxorubicin Liposomal: Avoid coadministration doxorubicin (including doxorubicin liposomal) and dasabuvir; ombitasvir; paritaprevir; ritonavir if possible. Giving these drugs together increases the risk of serious adverse events including myelosuppression, cardiotoxicity, and QT prolongation. If both of these drugs must be used, carefully monitor the patient for doxorubicin toxicity and efficacy. Ritonavir is expected to inhibit the CYP3A4, CYP2D6, and of P-glycoprotein (P-gp) metabolism of doxorubicin. Additionally, while dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QTc interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with QT prolongation in other trials. Acute cardiotoxicity can occur during the administration of doxorubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
Doxorubicin: Avoid coadministration of ritonavir and doxorubicin if possible. If avoidance is not possible, closely monitor for doxorubicin efficacy and increased side effects of doxorubicin including myelosuppression and cardiotoxicity. Ritonavir is a potent inhibitor of CYP3A4, a moderate inhibitor of P-glycoprotein (P-gp) and CYP2D6 (in vitro). Doxorubicin is a major CYP2D6, CYP3A4, and P-gp substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, CYP2D6, and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin. Ritonavir has a possible risk for QT prolongation and torsades de pointes (TdP). Additionally, acute cardiotoxicity can occur during the administration of doxorubicin; although, the incidence is rare. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
Dronabinol, THC: Use caution if coadministration of dronabinol with ritonavir is necessary, and closely monitor for an increase in dronabinol-related adverse reactions (e.g., cognitive impairment, psychosis, seizures, and hemodynamic instability, as well as feeling high, dizziness, confusion, somnolence). Ritonavir is a strong inhibitor of CYP3A4 and a moderate CYP2C9 inducer; it is contraindicated with sensitive drugs that are highly dependent on CYP3A4/5 for clearance. Dronabinol is a CYP2C9 and 3A4 substrate; concomitant use may result in elevated plasma concentrations of dronabinol.
Dronedarone: The concomitant use of dronedarone and dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated. Dronedarone use is contraindicated with other drugs that prolong the QTc and may induce Torsade de Pointes (TdP), such as ritonavir. Furthermore, no data exist for the safe administration of dronedarone (CYP3A substrate/moderate inhibitor) with strong CYP3A4 inhibitors, such as ritonavir, and concomitant use is contraindicated. Elevated concentrations of each drug can be expected, followed by further risk of serious adverse reactions. Dronedarone is also a P-glycoprotein (P-gp) inhibitor. Ritonavir, paritaprevir, and dasabuvir are CYP3A and P-gp substrates; ombitasvir is also a P-gp substrate. The concomitant use of dronedarone and ritonavir is contraindicated. Dronedarone is metabolized by CYP3A, is a moderate inhibitor of CYP3A, and is an inhibitor of P-gp. Ritonavir is a strong inhibitor of CYP3A4, is an inducer of CYP3A, and is a substrate of CYP3A and P-gp. Repeated doses of ketoconazole, also a strong CYP3A4 inhibitor, increased dronedarone exposure 17-fold and increased dronedarone Cmax 9-fold. Furthermore, coadministration of dronedarone and ritonavir may, theoretically, result in decreased concentrations of dronedarone due to CYP3A induction by ritonavir; the net effect on dronedarone plasma concentrations is not known. However, no data exist regarding the safe administration of dronedarone with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated. Also, the effects of dronedarone on the pharmacokinetics of ritonavir have not been described, although an increase in ritonavir serum concentrations is possible.
Droperidol: An increased risk of adverse events, including QT prolongation, and elevated droperidol plasma concentrations may result if droperidol is coadministered with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir. Droperidol should be administered with extreme caution to any patient who is receiving other drugs that may prolong the QT interval. While dasabuvir; ombitasvir; paritaprevir; ritonavir and ombitasvir; paritaprevir; ritonavir did not prolong the QTc interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with QT prolongation in other trials. If these drugs must be used together, initiate droperidol at the lowest dose with cautious upward dosage adjustments, if needed, to achieve the desired effect. Further caution is warranted as droperidol is a substrate of CYP3A4 and P-glycoprotein (P-gp). Ritonavir is a potent inhibitor of CYP3A4 and an inhibitor of P-gp. Paritaprevir is also a P-gp inhibitor. Increased droperidol concentrations would be expected, along with an increased risk of serious adverse effects. The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include droperidol. If these drugs must be used together, initiate droperidol at the lowest dose with cautious upward dosage adjustments, if needed, to achieve the desired effect. Further caution is warranted as droperidol is a substrate of CYP3A4 and P-glycoprotein (P-gp). Ritonavir is a potent inhibitor of CYP3A4 and an inhibitor of P-gp. Increased droperidol concentrations would be expected, along with an increased risk of serious adverse effects.
Drospirenone; Estradiol: Ritonavir has been shown to increase the metabolism of ethinyl estradiol. Ritonavir is a substrate and inhibitor of CYP3A4. It is not known if the effects of protease inhibitors are similar on estradiol; however, estradiol is metabolized by CYP3A4, similar to ethinyl estradiol.
Drospirenone; Ethinyl Estradiol: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting the hepatitis C regimen, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with the hepatitis C regimen. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting dasabuvir; ombitasvir; paritaprevir; ritonavir, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with dasabuvir; ombitasvir; paritaprevir; ritonavir. Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Drospirenone; Ethinyl Estradiol; Levomefolate: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting the hepatitis C regimen, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with the hepatitis C regimen. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting dasabuvir; ombitasvir; paritaprevir; ritonavir, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with dasabuvir; ombitasvir; paritaprevir; ritonavir. Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Dutasteride: Concurrent administration of dutasteride with protease inhibitors may result in elevated dutasteride plasma concentrations. Dutasteride is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitors of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Dutasteride; Tamsulosin: Plasma concentrations of tamsulosin may be increased with concomitant use of anti-retroviral protease inhibitors. Tamsulosin is extensively metabolized by CYP3A4 and CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension. Therefore, concomitant use of tamsulosin with a strong CYP3A4 inhibitor, or an agent with both CYP3A4 and CYP2D6 inhibitor activity, should be avoided. Concurrent administration of dutasteride with protease inhibitors may result in elevated dutasteride plasma concentrations. Dutasteride is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitors of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Echinacea: Use Echinacea sp. with caution in patients taking medications for human immunodeficiency virus (HIV) infection. Some experts have suggested that Echinacea's effects on the immune system might cause problems for patients with HIV infection, particularly with long-term use. There may be less risk with short-term use (less than 2 weeks). A few pharmacokinetic studies have shown reductions in blood levels of some antiretroviral medications when Echinacea was given, presumably due to CYP induction. However, more study is needed for various HIV treatment regimens. Of the agents studied, the interactions do not appear to be significant or to require dose adjustments at the time of use. Although no dose adjustments are required, monitoring drug concentrations may give reassurance during co-administration. Monitor viral load and other parameters carefully during therapy.
Edoxaban: Coadministration of edoxaban and ritonavir may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and ritonavir is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of ritonavir; monitor for increased adverse effects of edoxaban. Dosage reduction may be considered for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism.
Efavirenz: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with efavirenz is contraindicated. The use of this drug combination was pooly tolerated by recipients and resulted in hepatic enzyme elevations. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with efavirenz is contraindicated. The use of this drug combination was pooly tolerated by recipients and resulted in hepatic enzyme elevations. Coadministration of ritonavir with efavirenz may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with both drugs. In addition, coadministration of ritonavir (500 mg every 12 hours) and efavirenz (600 mg once daily) has been associated with a higher frequency of other adverse reactions (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Giving these drugs together is expected to result in increased concentrations of both drugs.
Efavirenz; Emtricitabine; Tenofovir: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with efavirenz is contraindicated. The use of this drug combination was pooly tolerated by recipients and resulted in hepatic enzyme elevations. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with efavirenz is contraindicated. The use of this drug combination was pooly tolerated by recipients and resulted in hepatic enzyme elevations. Coadministration of ritonavir with efavirenz may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has been observed with both drugs. In addition, coadministration of ritonavir (500 mg every 12 hours) and efavirenz (600 mg once daily) has been associated with a higher frequency of other adverse reactions (e.g., dizziness, nausea, paresthesia) and laboratory abnormalities (elevated liver enzymes). Giving these drugs together is expected to result in increased concentrations of both drugs. Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, concurrently with inhibitors of P-gp and BCRP, such as ritonavir. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. Concurrent administration of tenofovir, PMPA with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated tenofovir plasma concentrations. Tenofovir is a substrate for the breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp). Dasabuvir, paritaprevir, and ritonavir are BCRP inhibitors, and ritonavir inhibits P-gp. Caution and close monitoring are advised if these drugs are administered together.
Elbasvir; Grazoprevir: Concurrent administration of grazoprevir with paritaprevir is contraindicated. Use of these drugs together is expected to significantly increase grazoprevir plasma concentrations, and may result in adverse effects (i.e., elevated ALT concentrations). Paritaprevir is an inhibitor of the organic anion transporting polypeptide (OATP); grazoprevir is a substrate of OATP1B1/3. Concurrent administration of elbasvir with ritonavir should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ritonavir is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. Concurrent administration of grazoprevir with ritonavir should be avoided if possible. Use of these drugs together is expected to significantly increase the plasma concentrations of grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations and hepatotoxicity). Ritonavir is a strong inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A. In addition, concentrations of ritonavir (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
Eletriptan: Eletriptan is contraindicated for use within 72 hours of using any drug that is a potent CYP3A4 inhibitor as described in the prescribing information of the interacting drug including protease inhibitors. Eletriptan is metabolized via CYP3A4, and coadministration with protease inhibitors may cause increased eletriptan concentrations and thus toxicity.
Eliglustat: Coadministration of dasabuvir; ombitasvir; paritaprevir; ritonavir and eliglustat is contraindicated. Ritonavir is a substrate/inhibitor of both CYP3A4 and CYP2D6. Eliglustat is a CYP3A and CYP2D6 substrate, and a P-gp inhibitor; ritonavir, paritaprevir, ombitasvir and dasabuvir are all P-gp substrates. In addition, eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Use of these drugs together may result in additive effects on the QT interval and, potentially, increased plasma concentrations of eliglustat and/or ritonavir, further increasing the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias). Coadministration of eliglustat with both a moderate or strong CYP3A inhibitor and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients because it inhibit eliglustat's metabolic clearance through both pathways. Coadministration of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir and eliglustat is contraindicated. Ritonavir is a substrate/inhibitor of both CYP3A4 and CYP2D6. Eliglustat is a CYP3A and CYP2D6 substrate, and a P-gp inhibitor; ritonavir, paritaprevir, ombitasvir and dasabuvir are all P-gp substrates In addition, eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Use of these drugs together may result in additive effects on the QT interval and, potentially, increased plasma concentrations of eliglustat and/or ritonavir, further increasing the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias). Coadministration of eliglustat with both a moderate or strong CYP3A inhibitor and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients because it inhibit eliglustat's metabolic clearance through both pathways. Coadministration of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir and eliglustat is contraindicated. Ritonavir is a substrate/inhibitor of both CYP3A4 and CYP2D6. Eliglustat is a CYP3A and CYP2D6 substrate, and a P-gp inhibitor; ritonavir, paritaprevir, ombitasvir and dasabuvir are all P-gp substrates. In addition, eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Use of these drugs together may result in additive effects on the QT interval and, potentially, increased plasma concentrations of eliglustat and/or ritonavir, further increasing the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias). Coadministration of eliglustat with both a moderate or strong CYP3A inhibitor and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients because it inhibit eliglustat's metabolic clearance through both pathways. Coadministration of ritonavir and eliglustat is contraindicated. Ritonavir is strong CYP3A inhibitor, moderate CYP26 inhibitor, and a P-glycoprotein (P-gp) substrate that may cause QT prolongation; its use is contraindicated with drugs that are highly dependent on CYP3A for metabolic clearance and for which increased plasma concentrations may result in serious reactions. Eliglustat is a CYP3A and CYP2D6 substrate and P-gp inhibitor that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Coadministration of ritonavir and eliglustat may result in additive effects on the QT interval and, potentially, increased plasma concentrations of one or both drugs, further increasing the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias).
Eltrombopag: Eltrombopag is metabolized by CYP1A2. The significance of administering inducers of CYP1A2, such as ritonavir, on the systemic exposure of eltrombopag has not been established. Monitor patients for a decrease in the efficacy of eltrombopag if these drugs are coadministered.
Eluxadoline: When administered concurrently with paritaprevir, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for adverse effects. Both eluxadoline and paritaprevir are substrates and inhibitors of the organic anion-transporting peptide (OATP1B1). In addition, eluxadoline may inhibit the breast cancer resistance protein (BCRP); paritaprevir is a substrate of this transporter. This specific interaction has not been evaluated; however, administration of eluxadoline with another OATP and BCRP substrate (rosuvastatin) resulted in an increase in the exposure (AUC) and maximum plasma concentration (Cmax) of rosuvastatin by 40% and 18%, respectively. In another study, coadministration of eluxadoline with an OATP inhibitor (cyclosporine) resulted in elevated AUC and Cmax of eluxadoline by 4.4- and 6.2-fold, respectively. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
Elvitegravir: Concurrent administration of elvitegravir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated elvitegravir plasma concentrations. Elvitegravir is a substrate of uridine glucuronyltransferase (UGT1A1/3) and the hepatic isoenzyme CYP3A4. Ritonavir inhibits the CYP3A4 enzyme, while dasabuvir, ombitasvir, and paritaprevir are UGT1A1 inhibitors. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of elvitegravir with ritonavir may result in elevated elvitegravir plasma concentrations. Elvitegravir is a substrate of the hepatic isoenzyme CYP3A4. Ritonavir inhibits the CYP3A4 enzyme. Caution and close monitoring are advised if these drugs are administered together.
Empagliflozin: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Empagliflozin; Linagliptin: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, inducers of CYP3A4 (e.g., ritonavir) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Empagliflozin; Metformin: The manufacturer recommends against concurrent administration of ombitasvir; paritaprevir; ritonavir and metformin in patients with hepatic or renal impairment. If these drugs are given together, closely monitor blood glucose concentrations and for signs of lactic acidosis (i.e., abdominal or respiratory distress, worsening renal function, somnolence). New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: Close clinical monitoring is advised when administering ritonavir with rilpivirine due an increased potential for rilpivirine-related adverse events. Dosage adjustments are not recommended. Predictions about the interaction can be made based on metabolic pathways. Ritonavir is an inhibitor and inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. In addition, ritonavir has a possible risk of QT prolongation.
Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: Close clinical monitoring is advised when administering ritonavir with rilpivirine due an increased potential for rilpivirine-related adverse events. Dosage adjustments are not recommended. Predictions about the interaction can be made based on metabolic pathways. Ritonavir is an inhibitor and inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. In addition, ritonavir has a possible risk of QT prolongation. Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, concurrently with inhibitors of P-gp and BCRP, such as ritonavir. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. Concurrent administration of tenofovir, PMPA with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated tenofovir plasma concentrations. Tenofovir is a substrate for the breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp). Dasabuvir, paritaprevir, and ritonavir are BCRP inhibitors, and ritonavir inhibits P-gp. Caution and close monitoring are advised if these drugs are administered together.
Emtricitabine; Tenofovir disoproxil fumarate: Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, concurrently with inhibitors of P-gp and BCRP, such as ritonavir. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. Concurrent administration of tenofovir, PMPA with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated tenofovir plasma concentrations. Tenofovir is a substrate for the breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp). Dasabuvir, paritaprevir, and ritonavir are BCRP inhibitors, and ritonavir inhibits P-gp. Caution and close monitoring are advised if these drugs are administered together.
Enalapril; Felodipine: Concurrent administration of felodipine with protease inhibitors may result in elevated felodipine plasma concentrations. This increase in felodipine concentration may lead to increased therapeutic and adverse effects, such as lower blood pressure, dizziness, and headache. Felodipine is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitors of this enzyme. In addition, ritonavir prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring.
Encainide: Concurrent administration of encainide with ritonavir may result in elevated encainide plasma concentrations. Encainide is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme and may increase serum encainide concentrations by as much as 2-fold. Because encainide has a narrow therapeutic index and adverse events may be severe, close monitoring and dose adjustment are advised if these drugs are administered together.
Enflurane: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include halogenated anesthetics.
Enzalutamide: Concurrent administration of enzalutamide with dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in elevated enzalutamide and ombitasvir plasma concentrations, as well as altered concentrations of dasabuvir, paritaprevir, and ritonavir, which may decrease antiviral activity. Enzalutamide is metabolized by the hepatic isoenzyme CYP3A4. Enzalutamide is also an inducer of CYP3A4, and an inhibitor of CYP2C8, CYP2D6, and the drug transporter P-glycoprotein (P-gp). Ritonavir is a CYP3A4 and CYP2D6 substrate/inhibitor, while dasabuvir is a substrate of CYP2C8 and CYP3A4 (minor), and paritaprevir is a CYP3A4 substrate. In addition, dasabuvir, ombitasvir, paritaprevir, and ritonavir are all P-gp substrates. Concurrent administration of enzalutamide with ritonavir may result in elevated enzalutamide plasma concentrations, as well as altered concentrations of ritonavir. Enzalutamide is metabolized by the hepatic isoenzyme CYP3A4. Enzalutamide is also an inducer of CYP3A4, and an inhibitor of CYP2C8, CYP2D6, and the drug transporter P-glycoprotein (P-gp). Ritonavir is a CYP3A4 and CYP2D6 substrate/inhibitor. In addition, ritonavir is a P-gp substrate. Caution and close monitoring are advised if these drugs are administered together.
Epirubicin: The use of ritonavir could result in QT prolongation. Use ritonavir cautiously in patients taking other drugs known to prolong the QT interval. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
Eplerenone: Coadministration of ritonavir and eplerenone is contraindicated. Ritonavir potently inhibits the hepatic CYP3A4 isoenzyme and can increase the serum concentrations of eplerenone. Increased eplerenone concentrations may lead to a risk of developing hyperkalemia and hypotension.
Ergoloid Mesylates: Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
Ergonovine: Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
Ergot alkaloids: Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
Ergotamine: Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
Eribulin: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include eribulin.
Erlotinib: Avoid the coadministration of erlotinib with ritonavir due to the risk of increased erlotinib-related adverse reactions and possibly decreased efficacy of erlotinib; if concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is primarily metabolized by CYP3A4, and to a lesser extent by CYP1A2. Ritonavir is a strong CYP3A4 inhibitor, and may also induce CYP1A2. Coadministration of erlotinib with ketoconazole, another strong CYP3A4 inhibitor, increased the erlotinib AUC by 67%. In a single-dose pharmacokinetics trial in healthy volunteers, cigarette smoking (moderate CYP1A2 inducer) decreased the AUC of erlotinib by 64% (95% CI, 46% to 76%) in current smokers compared with former/never smokers. Steady-state trough concentrations of erlotinib were approximately 2-fold less in current smokers compared with former/never smokers in a separate study of patients with NSCLC.
Erythromycin: Concomitant administration of ritonavir and clarithromycin results in 77% increases in clarithromycin AUC. Clarithromycin dosage adjustments are recommended in patients with renal impairment who are receiving ritonavir concurrently. For patients with creatinine clearance 60 to 30 ml/min, the dose of clarithromycin should be reduced by 50%. For patients with creatinine clearance < 30 ml/min, the dose of clarithromycin should be reduced by 75%. No dosage adjustment of clarithromycin is required for patients with normal renal function who are also receiving ritonavir. Increases in erythromycin concentrations may also be noted, although the necessity of dosage adjustments has not been determined. In addition, ritonavir, clarithromycin, and erythromycin are associated with QT prolongation; concomitant use increases the risk of QT prolongation. Concurrent administration of erythromycin with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of all 5 drugs. Erythromycin is a substrate/inhibitor of the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp). Ritonavir is also a CYP3A4 substrate/inhibitor, while paritaprevir and dasabuvir (minor) are substrates of CYP3A4. In addition, dasabuvir, ombitasvir, paritaprevir, and ritonavir are all P-gp substrates. Both erythromycin and ritonavir have been associated with a dose-related QT prolongation, and coadministration can result in elevated concentrations of both ritonavir and erythromycin. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of erythromycin with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of both drugs. Erythromycin is a substrate/inhibitor of the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp). Ritonavir is also a CYP3A4 substrate/inhibitor, while paritaprevir and dasabuvir (minor) are substrates of CYP3A4. In addition, dasabuvir, ombitasvir, paritaprevir, and ritonavir are all P-gp substrates. Both erythromycin and ritonavir have been associated with a dose-related QT prolongation, and coadministration can result in elevated concentrations of both ritonavir and erythromycin. Caution and close monitoring are advised if these drugs are administered together.
Erythromycin; Sulfisoxazole: Concomitant administration of ritonavir and clarithromycin results in 77% increases in clarithromycin AUC. Clarithromycin dosage adjustments are recommended in patients with renal impairment who are receiving ritonavir concurrently. For patients with creatinine clearance 60 to 30 ml/min, the dose of clarithromycin should be reduced by 50%. For patients with creatinine clearance < 30 ml/min, the dose of clarithromycin should be reduced by 75%. No dosage adjustment of clarithromycin is required for patients with normal renal function who are also receiving ritonavir. Increases in erythromycin concentrations may also be noted, although the necessity of dosage adjustments has not been determined. In addition, ritonavir, clarithromycin, and erythromycin are associated with QT prolongation; concomitant use increases the risk of QT prolongation. Concurrent administration of erythromycin with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of all 5 drugs. Erythromycin is a substrate/inhibitor of the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp). Ritonavir is also a CYP3A4 substrate/inhibitor, while paritaprevir and dasabuvir (minor) are substrates of CYP3A4. In addition, dasabuvir, ombitasvir, paritaprevir, and ritonavir are all P-gp substrates. Both erythromycin and ritonavir have been associated with a dose-related QT prolongation, and coadministration can result in elevated concentrations of both ritonavir and erythromycin. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of erythromycin with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of both drugs. Erythromycin is a substrate/inhibitor of the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp). Ritonavir is also a CYP3A4 substrate/inhibitor, while paritaprevir and dasabuvir (minor) are substrates of CYP3A4. In addition, dasabuvir, ombitasvir, paritaprevir, and ritonavir are all P-gp substrates. Both erythromycin and ritonavir have been associated with a dose-related QT prolongation, and coadministration can result in elevated concentrations of both ritonavir and erythromycin. Caution and close monitoring are advised if these drugs are administered together.
Escitalopram: Although not studied, anti-retroviral protease inhibitors might theoretically impair the metabolism of escitalopram when administered concomitantly. In addition, escitalopram has been associated with QT prolongation. Coadministration with other drugs that have a possible risk for QT prolongation and torsade de pointes (TdP), such as saquinavir and lopinavir; ritonavir, should be done with caution and close monitoring. Escitalopram is metabolized by CYP3A4 and CYP2C19. Several drugs can inhibit the metabolism of CYP 450 isoenzymes, including those that are responsible for the metabolism of escitalopram. Although clinical studies have not been done to determine the clinical significance of such an interaction, the potential for increased adverse effects and toxicity associated with elevated plasma levels of escitalopram theoretically exists. In clinical trial subjects, combined administration of cimetidine and citalopram for 8 days resulted in an increase in citalopram AUC and Cmax of 43% and 39%, respectively. The clinical relevance of these findings is unknown as the combination was not associated with significant adverse effects. Because escitalopram is metabolized by multiple enzyme systems, inhibition of one pathway may not appreciably decrease drug clearance.
Eslicarbazepine: Concurrent administration of eslicarbazepine with dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in decreased plasma concentrations of dasabuvir, paritaprevir, and ritonavir, which may result in decreased antiviral activity. Eslicarbazepine is an inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir and dasabuvir (minor) are metabolized by this enzyme. Concurrent administration of eslicarbazepine with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in decreased plasma concentrations of dasabuvir, paritaprevir, and ritonavir, which may result in decreased antiviral activity. Eslicarbazepine is an inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir and dasabuvir (minor) are metabolized by this enzyme. Concurrent administration of eslicarbazepine with ritonavir may result in decreased plasma concentrations of ritonavir. Eslicarbazepine is an inducer of the hepatic isoenzyme CYP3A4; ritonavir is metabolized by this enzyme. Caution and close monitoring for decreased antiviral efficacy are advised if these drugs are administered together.
Esmolol: Ritonavir is expected to decrease the hepatic CYP metabolism of beta-blockers, resulting in increased beta-blocker concentrations. Cardiac and neurologic events have been reported when ritonavir is concurrently administered with beta-blockers. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including beta-blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased beta-blocker doses may be warranted.
Esomeprazole: Concurrent administration of esomeprazole with ritonavir may result in elevated esomeprazole plasma concentrations. Esomeprazole is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Monitor patients for increased side effects if these drugs are administered together.
Esomeprazole; Naproxen: Concurrent administration of esomeprazole with ritonavir may result in elevated esomeprazole plasma concentrations. Esomeprazole is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Monitor patients for increased side effects if these drugs are administered together.
Estazolam: In vitro studies with human liver microsomes indicate that the biotransformation of estazolam to the major circulating metabolite 4-hydroxy-estazolam is mediated by CYP3A. In theory, CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of estazolam and increase the potential for benzodiazepine toxicity (i.e., prolonged sedation and respiratory depression)
Esterified Estrogens: Ritonavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers.
Esterified Estrogens; Methyltestosterone: Ritonavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers.
Estradiol Cypionate; Medroxyprogesterone: Coadministration of medroxyprogesterone, a CYP3A substrate with ritonavir, a strong CYP3A inhibitor should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is metabolized primarily by hydroxylation via the CYP3A4 in vitro. Ritonavir has been shown to increase the metabolism of ethinyl estradiol. Ritonavir is a substrate and inhibitor of CYP3A4. It is not known if the effects of protease inhibitors are similar on estradiol; however, estradiol is metabolized by CYP3A4, similar to ethinyl estradiol.
Estradiol: Ritonavir has been shown to increase the metabolism of ethinyl estradiol. Ritonavir is a substrate and inhibitor of CYP3A4. It is not known if the effects of protease inhibitors are similar on estradiol; however, estradiol is metabolized by CYP3A4, similar to ethinyl estradiol.
Estradiol; Levonorgestrel: Data on the effects that protease inhibitors have on the serum concentrations of estrogens and progestins are complex. Some protease inhibitors increase (i.e., ritonavir, lopinavir; ritonavir, nelfinavir, tipranavir) and others decrease (i.e., atazanavir, indinavir) the metabolism of hormonal contraceptives. The safety and efficacy of hormonal contraceptives may be affected if coadministered with protease inhibitors. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors concurrently should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with protease inhibitors to use an additional method of contraception to protect against unwanted pregnancy, unless other drug-specific recommendations are made by the manufacturer of the protease inhibitor. Furthermore, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with protease inhibitors should use an additional barrier method of contraception such as condoms. Ritonavir has been shown to increase the metabolism of ethinyl estradiol. Ritonavir is a substrate and inhibitor of CYP3A4. It is not known if the effects of protease inhibitors are similar on estradiol; however, estradiol is metabolized by CYP3A4, similar to ethinyl estradiol.
Estradiol; Norethindrone: Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. For example, ritonavir (also found in combinations like lopinavir; ritonavir, and used as a booster in many HIV treatment regimens) may decrease the metabolism of norethindrone, raising norethindrone concentrations. Women receiving norethindrone for hormone replacement or contraception should report potential hormonal adverse effects (e.g., bleeding pattern changes, acne, emotional lability) or any changes in efficacy (e.g., noted changes in bleeding patterns) to their prescribers. Because norethindrone-containing contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive norethindrone contraception concurrently with ritonavir should use an additional barrier method of contraception such as condoms. Ritonavir has been shown to increase the metabolism of ethinyl estradiol. Ritonavir is a substrate and inhibitor of CYP3A4. It is not known if the effects of protease inhibitors are similar on estradiol; however, estradiol is metabolized by CYP3A4, similar to ethinyl estradiol.
Estradiol; Norgestimate: Ritonavir has been shown to increase the metabolism of ethinyl estradiol. Ritonavir is a substrate and inhibitor of CYP3A4. It is not known if the effects of protease inhibitors are similar on estradiol; however, estradiol is metabolized by CYP3A4, similar to ethinyl estradiol.
Estropipate: Ritonavir has been shown to increase the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should report any breakthrough bleeding or adverse events to their prescribers.
Eszopiclone: The adult dose of eszopiclone should not exceed 2 mg/day during co-administration of potent CYP3A4 inhibitors, such as anti-retroviral protease inhibitors. CYP3A4 is a primary metabolic pathway for eszopiclone, and increased systemic exposure to eszopiclone increases the risk of next-day psychomotor or memory impairment, which may decrease the ability to perform tasks requiring full mental alertness such as driving.
Ethanol: Concurrent administration of ethanol with dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated or ombitasvir; paritaprevir; ritonavir. Taking these drugs together could result in decreased plasma concentrations of paritaprevir, ritonavir and dasabuvir, which may affect antiviral efficacy. Ethanol is an inducer of the hepatic isoenzyme CYP3A4; paritaprevir, ritonavir and dasabuvir (minor) are substrates of this enzyme. Concurrent administration of ethanol with dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in decreased plasma concentrations of paritaprevir, ritonavir and dasabuvir, which may affect antiviral efficacy. Ethanol is an inducer of the hepatic isoenzyme CYP3A4; paritaprevir, ritonavir and dasabuvir (minor) are substrates of this enzyme. Additionally, use of ethanol within 4 hours of Viekira XR may interfere with the optimal release of dasabuvir. Concurrent administration of ethanol with dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in decreased plasma concentrations of paritaprevir, ritonavir, and dasabuvir, which may affect antiviral efficacy. Ethanol is an inducer of the hepatic isoenzyme CYP3A4; paritaprevir, ritonavir and dasabuvir (minor) are substrates of this enzyme. Additionally, use of ethanol within 4 hours of Viekira XR may interfere with the optimal release of dasabuvir. Concurrent administration of ethanol with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in decreased plasma concentrations of dasabuvir, paritaprevir and ritonavir, which may affect antiviral efficacy. Ethanol is an inducer of the hepatic isoenzyme CYP3A4; paritaprevir and ritonavir are substrates of this enzyme. Concurrent administration of ethanol with ritonavir may result in decreased plasma concentrations of ritonavir, which may affect antiviral efficacy. Ethanol is an inducer of the hepatic isoenzyme CYP3A4; ritonavir is a substrate of this enzyme. Caution and close monitoring are advised if ethanol and ritonavir are administered together.
Ethinyl Estradiol: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting the hepatitis C regimen, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with the hepatitis C regimen. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting dasabuvir; ombitasvir; paritaprevir; ritonavir, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with dasabuvir; ombitasvir; paritaprevir; ritonavir. Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Ethinyl Estradiol; Desogestrel: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting the hepatitis C regimen, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with the hepatitis C regimen. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting dasabuvir; ombitasvir; paritaprevir; ritonavir, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with dasabuvir; ombitasvir; paritaprevir; ritonavir. Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Ethinyl Estradiol; Ethynodiol Diacetate: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting the hepatitis C regimen, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with the hepatitis C regimen. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting dasabuvir; ombitasvir; paritaprevir; ritonavir, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with dasabuvir; ombitasvir; paritaprevir; ritonavir. Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Ethinyl Estradiol; Etonogestrel: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting the hepatitis C regimen, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with the hepatitis C regimen. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting dasabuvir; ombitasvir; paritaprevir; ritonavir, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with dasabuvir; ombitasvir; paritaprevir; ritonavir. Coadministration may result in an increased or decreased effect of etonogestrel. Contraceptive efficacy may be reduced. Etonogestrel is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor and CYP3A4 inducer. Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Ethinyl Estradiol; Levonorgestrel: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting the hepatitis C regimen, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with the hepatitis C regimen. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting dasabuvir; ombitasvir; paritaprevir; ritonavir, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with dasabuvir; ombitasvir; paritaprevir; ritonavir. Data on the effects that protease inhibitors have on the serum concentrations of estrogens and progestins are complex. Some protease inhibitors increase (i.e., ritonavir, lopinavir; ritonavir, nelfinavir, tipranavir) and others decrease (i.e., atazanavir, indinavir) the metabolism of hormonal contraceptives. The safety and efficacy of hormonal contraceptives may be affected if coadministered with protease inhibitors. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors concurrently should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with protease inhibitors to use an additional method of contraception to protect against unwanted pregnancy, unless other drug-specific recommendations are made by the manufacturer of the protease inhibitor. Furthermore, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with protease inhibitors should use an additional barrier method of contraception such as condoms. Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting the hepatitis C regimen, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with the hepatitis C regimen. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting dasabuvir; ombitasvir; paritaprevir; ritonavir, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with dasabuvir; ombitasvir; paritaprevir; ritonavir. Data on the effects that protease inhibitors have on the serum concentrations of estrogens and progestins are complex. Some protease inhibitors increase (i.e., ritonavir, lopinavir; ritonavir, nelfinavir, tipranavir) and others decrease (i.e., atazanavir, indinavir) the metabolism of hormonal contraceptives. The safety and efficacy of hormonal contraceptives may be affected if coadministered with protease inhibitors. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors concurrently should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with protease inhibitors to use an additional method of contraception to protect against unwanted pregnancy, unless other drug-specific recommendations are made by the manufacturer of the protease inhibitor. Furthermore, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with protease inhibitors should use an additional barrier method of contraception such as condoms. Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Ethinyl Estradiol; Norelgestromin: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting the hepatitis C regimen, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with the hepatitis C regimen. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting dasabuvir; ombitasvir; paritaprevir; ritonavir, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with dasabuvir; ombitasvir; paritaprevir; ritonavir. Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Ethinyl Estradiol; Norethindrone Acetate: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting the hepatitis C regimen, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with the hepatitis C regimen. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting dasabuvir; ombitasvir; paritaprevir; ritonavir, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with dasabuvir; ombitasvir; paritaprevir; ritonavir. Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. For example, ritonavir (also found in combinations like lopinavir; ritonavir, and used as a booster in many HIV treatment regimens) may decrease the metabolism of norethindrone, raising norethindrone concentrations. Women receiving norethindrone for hormone replacement or contraception should report potential hormonal adverse effects (e.g., bleeding pattern changes, acne, emotional lability) or any changes in efficacy (e.g., noted changes in bleeding patterns) to their prescribers. Because norethindrone-containing contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive norethindrone contraception concurrently with ritonavir should use an additional barrier method of contraception such as condoms.
Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting the hepatitis C regimen, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with the hepatitis C regimen. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting dasabuvir; ombitasvir; paritaprevir; ritonavir, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with dasabuvir; ombitasvir; paritaprevir; ritonavir. Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. For example, ritonavir (also found in combinations like lopinavir; ritonavir, and used as a booster in many HIV treatment regimens) may decrease the metabolism of norethindrone, raising norethindrone concentrations. Women receiving norethindrone for hormone replacement or contraception should report potential hormonal adverse effects (e.g., bleeding pattern changes, acne, emotional lability) or any changes in efficacy (e.g., noted changes in bleeding patterns) to their prescribers. Because norethindrone-containing contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive norethindrone contraception concurrently with ritonavir should use an additional barrier method of contraception such as condoms.
Ethinyl Estradiol; Norethindrone: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting the hepatitis C regimen, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with the hepatitis C regimen. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting dasabuvir; ombitasvir; paritaprevir; ritonavir, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with dasabuvir; ombitasvir; paritaprevir; ritonavir. Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. For example, ritonavir (also found in combinations like lopinavir; ritonavir, and used as a booster in many HIV treatment regimens) may decrease the metabolism of norethindrone, raising norethindrone concentrations. Women receiving norethindrone for hormone replacement or contraception should report potential hormonal adverse effects (e.g., bleeding pattern changes, acne, emotional lability) or any changes in efficacy (e.g., noted changes in bleeding patterns) to their prescribers. Because norethindrone-containing contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive norethindrone contraception concurrently with ritonavir should use an additional barrier method of contraception such as condoms.
Ethinyl Estradiol; Norethindrone; Ferrous fumarate: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting the hepatitis C regimen, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with the hepatitis C regimen. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting dasabuvir; ombitasvir; paritaprevir; ritonavir, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with dasabuvir; ombitasvir; paritaprevir; ritonavir. Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms. Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. For example, ritonavir (also found in combinations like lopinavir; ritonavir, and used as a booster in many HIV treatment regimens) may decrease the metabolism of norethindrone, raising norethindrone concentrations. Women receiving norethindrone for hormone replacement or contraception should report potential hormonal adverse effects (e.g., bleeding pattern changes, acne, emotional lability) or any changes in efficacy (e.g., noted changes in bleeding patterns) to their prescribers. Because norethindrone-containing contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive norethindrone contraception concurrently with ritonavir should use an additional barrier method of contraception such as condoms.
Ethinyl Estradiol; Norgestimate: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting the hepatitis C regimen, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with the hepatitis C regimen. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting dasabuvir; ombitasvir; paritaprevir; ritonavir, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with dasabuvir; ombitasvir; paritaprevir; ritonavir. Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Ethinyl Estradiol; Norgestrel: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting the hepatitis C regimen, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with the hepatitis C regimen. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with ethinyl estradiol is contraindicated due to the potential for elevated liver function tests (LFTs). Ethinyl estradiol-containing medications must be discontinued prior to starting dasabuvir; ombitasvir; paritaprevir; ritonavir, and restarted no sooner than 2 weeks following completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving these drugs in combination experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with dasabuvir; ombitasvir; paritaprevir; ritonavir. Ritonavir increases the metabolism of oral contraceptives and non-oral combination contraceptives; coadministration decreases ethinyl estradiol AUC by 40% and Cmax by 32%. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors (PIs), such as ritonavir, should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with PIs to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with PIs should use an additional barrier method of contraception such as condoms.
Ethosuximide: Ritonavir decreases the hepatic CYP metabolism of ethosuximide, resulting in increased ethosuximide concentrations. If coadministration is warranted, do so with caution and careful monitoring of ethosuximide concentrations. A 50% dose reduction of ethosuximide may be needed.
Ethotoin: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with ethotoin should be undertaken with extreme caution due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposure to dasabuvir, ombitasvir, paritaprevir and ritonavir. Although specific data are unavailable regarding cytochrome P450 enzyme involvement with ethotoin metabolism or enzyme induction, interactions that are documented with phenytoin may theoretically occur with ethotoin. Phenytoin is a potent inducer and substrate of the hepatic isoenzyme CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. In addition, phenytoin may induce P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Concurrent use of ritonavir with ethotoin, phenytoin, or fosphenytoin should be avoided when possible. Increased doses of anticonvulsants may be required due to metabolism induction by ritonavir. Additionally, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required.
Etonogestrel: Coadministration may result in an increased or decreased effect of etonogestrel. Contraceptive efficacy may be reduced. Etonogestrel is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor and CYP3A4 inducer.
Etoposide, VP-16: Monitor for an increased incidence of etoposide-related adverse effects if used concomitantly with ritonavir. Ritonavir is a strong inhibitor of CYP3A4 as well as a P-glycoprotein (P-gp) inhibitor; etoposide, VP-16 is a CYP3A4 and P-gp substrate. Coadministration may cause accumulation of etoposide and decreased metabolism, resulting in increased etoposide concentrations.
Etravirine: Concurrent administration of etravirine with dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could may result in increased etravirine plasma concentrations and decreased concentrations of paritaprevir, ritonavir, and dasabuvir, which may affect antiviral efficacy. Etravirine is partially metabolized by CYP3A4 (in addition to CYP2C9 and CYP2C19). Ritonavir potently inhibits CYP3A4, which may reduce etravirine's metabolism. Etravirine is also a CYP3A4 inducer and P-glycoprotein (P-gp) inhibitor; ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates and all 4 antiviral drugs are all P-gp substrates. Concurrent administration of etravirine with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in increased etravirine plasma concentrations and altered antiviral concentrations. Etravirine is partially metabolized by CYP3A4 (in addition to CYP2C9 and CYP2C19). Ritonavir potently inhibits CYP3A4, which may reduce etravirine's metabolism. While coadministration with full-dose ritonavir (600 mg twice daily) is not recommended; etravirine can be administered with lower ritonavir doses such as those used for boosting other protease inhibitors. Etravirine is a CYP3A4 and P-glycoprotein (P-gp) inhibitor; ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates and all 4 antiviral drugs are all P-gp substrates. Caution and close monitoring are advised if these drugs are administered together. Concomitant use of etravirine with full-dose ritonavir (i.e., 600 mg twice daily) may cause a significant decrease in etravirine plasma concentration and, thus, a loss of therapeutic effect. Etravirine and full-dose ritonavir should not be coadministered.
Everolimus: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with everolimus is contraindicated due to the potential for severe immunosuppressant-associated adverse events. When administered concurrently with ombitasvir; paritaprevir; ritonavir, the maximum plasma concentration (peak), minimum plasma concentration (trough), and systemic exposure of everolimus are significantly increased. Avoid concurrent use of Afinitor (CYP3A4 substrate) and strong CYP3A4 inhibitors such as ritonavir. For Zortress, coadministration with strong inhibitors of CYP3A4 is not recommended, as patients may experience an increase in systemic exposure to everolimus if these drugs are coadministered. If Zortress and ritonavir are coadministered, close monitoring of everolimus whole blood trough concentrations and consideration of Zortress dose adjustment are recommended.
Ezetimibe; Simvastatin: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with simvastatin is contraindicated due to the potential for severe adverse reactions, including myopathy and rhabdomyolysis. Coadministration may result in elevated simvastatin systemic concentrations. Simvastatin is a substrate of the hepatic isoenzyme CYP3A4 and OATP1B1; ritonavir is a potent inhibitor of CYP3A4 and paritaprevir inhibits OATP1B1. In addition, simvastatin may inhibit P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with simvastatin is contraindicated due to the potential for severe adverse reactions, including myopathy and rhabdomyolysis. Coadministration may result in elevated simvastatin systemic concentrations. Simvastatin is a substrate of the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this isoenzyme. In addition, simvastatin may inhibit P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Ezogabine: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include ezogabine.
Felbamate: Concurrent administration of felbamate with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in decreased plasma concentrations of dasabuvir, paritaprevir, and ritonavir. Felbamate is a mild inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir, and dasabuvir (minor) are metabolized by this enzyme. Monitor for antiviral efficacy if these drugs are administered together. Concurrent administration of felbamate with ritonavir may result in decreased plasma concentrations of ritonavir. Felbamate is a mild inducer of the hepatic isoenzyme CYP3A4; ritonavir is metabolized by this enzyme. Monitor for antiviral efficacy if these drugs are administered together.
Felodipine: Concurrent administration of felodipine with protease inhibitors may result in elevated felodipine plasma concentrations. This increase in felodipine concentration may lead to increased therapeutic and adverse effects, such as lower blood pressure, dizziness, and headache. Felodipine is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitors of this enzyme. In addition, ritonavir prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring.
Fenofibrate: Concurrent administration of fenofibrate with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in increased dasabuvir plasma concentrations. Fenofibrate is a mild inhibitor of the hepatic isoenzyme CYP2C8; dasabuvir is metabolized by this enzyme. Monitor for adverse effects if these drugs are administered together.
Fentanyl: Use fentanyl in combination with ritonavir with extreme caution; ritonavir can significantly inhibit fentanyl's metabolism. The fentanyl dose may need to be very conservative, and the patient should be carefully monitored for signs of excessive fentanyl exposure such as oversedation, respiratory depression, and hypotension. Fentanyl is metabolized mainly by the cytochrome P450 (CYP) 3A4 isoenzyme and is a P-glycoprotein (P-gp) substrate. Ritonavir is a potent CYP3A4 inhibitor, and also inhibits P-gp. Clinical investigations have suggested that ritonavir may decrease the clearance of fentanyl by 67%, increase the elimination half-life from 9.4 to 20.1 hours, and increase the systemic exposure of fentanyl by 174% (range: 52 to 420%).
Fesoterodine: Fesoterodine is rapidly hydrolyzed to its active metabolite, 5-hydroxymethyltolterodine, which is metabolized via hepatic CYP3A4 and 2D6. In theory, the CYP3A4 inhibitory effects of anti-retroviral protease inhibitors may result in an increase in plasma concentrations of 5-hydroxymethyltolterodine. Anti-retroviral protease inhibitors which also inhibit 2D6, such as ritonavir, may impair both CYP metabolic pathways of 5-hydroxymethyltolterodine. Fesoterodine doses greater than 4 mg/day are not recommended during concurrent use of potent 3A4 inhibitors.
Fexofenadine: The plasma concentrations of fexofenadine may be elevated when administered concurrently with dasabuvir; ombitasvir; paritaprevir; ritonavir. Clinical monitoring for adverse effects, such as drowsiness, is recommended during coadministration. Ritonavir and paritaprevir are P-glycoprotein (P-gp) inhibitors, while fexofenadine is a P-gp substrate. The plasma concentrations of fexofenadine may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as drowsiness, is recommended during coadministration. Ritonavir is a P-glycoprotein (P-gp) inhibitor, while fexofenadine is a P-gp substrate.
Fexofenadine; Pseudoephedrine: The plasma concentrations of fexofenadine may be elevated when administered concurrently with dasabuvir; ombitasvir; paritaprevir; ritonavir. Clinical monitoring for adverse effects, such as drowsiness, is recommended during coadministration. Ritonavir and paritaprevir are P-glycoprotein (P-gp) inhibitors, while fexofenadine is a P-gp substrate. The plasma concentrations of fexofenadine may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as drowsiness, is recommended during coadministration. Ritonavir is a P-glycoprotein (P-gp) inhibitor, while fexofenadine is a P-gp substrate.
Fingolimod: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include fingolimod.
Flecainide: Concurrent use of HIV treatment doses of ritonavir with flecainide is contraindicated. Cautious consideration may be given to administering amiodarone with boosting doses of ritonavir. The potential increase in plasma concentrations of flecainide could result in significant adverse effects. Ritonavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme should be expected with concurrent use. Additionally, ritonavir is associated with QT prolongation. Flecainide is a Class IC antiarrhythmic also associated with a possible risk for QT prolongation and/or torsade de pointes. Patients receiving these drugs may have an increased risk of developing proarrhythmias.
Flibanserin: The concomitant use of flibanserin and strong CYP3A4 inhibitors, such as ritonavir, is contraindicated. Strong CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a strong CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a strong CYP3A4 inhibitor following flibanserin use, start the strong CYP3A4 inhibitor at least 2 days after the last dose of flibanserin.
Fluconazole: The coadministration of fluconazole and ritonavir is contraindicated. Fluconazole has been associated with QT prolongation and rare cases of torsade de pointes (TdP). The concurrent use of fluconazole and other drugs that prolong the QT and are CYP3A4 substrates, such as ritonavir, is contraindicated due to the risk of increased plasma concentrations and adverse effects of ritonavir, including life-threatening arrhythmias such as TdP. Avoid concurrent administration of fluconazole with dasabuvir; ombitasvir; paritaprevir; ritonavir due to an increased risk of QT prolongation. Although therapy with dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QTc interval to a clinical relevant extent in healthy subjects, ritonavir has been associated with concentration-dependent QT prolongation in other trials. Concurrent use of fluconazole with other agents known to prolong the QT interval and which are metabolized by CYP3A4 is contraindicated. Fluconazole is an inhibitor of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir, and dasabuvir (minor) are metabolized by this enzyme.
Fluoxetine: Because both ritonavir and fluoxetine are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. A dose reduction of fluoxetine may be necessary during co-administration of ritonavir. Concurrent use of CYP2D6 substrates, such as fluoxetine, with ritonavir could result in increases (up to 2-fold) in the AUC of fluoxetine. Close monitoring for adverse effects is prudent. Coadministration of dasabuvir; ombitasvir; paritaprevir; ritonavir and fluoxetine should be undertaken cautiously and with careful monitoring; a dose reduction of fluoxetine may be necessary. Both fluoxetine and ritonavir have been associated with dose-related QT prolongation, and coadministration can result in elevated concentrations of both fluoxetine and ritonavir. Neurologic adverse events have also been reported when ritonavir was concurrently administered with fluoxetine. Fluoxetine is primarily metabolized by CYP2D6; ritonavir is a CYP2D6 inhibitor. Ritonavir is a substrate for CYP2D6 and CYP3A4; fluoxetine potently inhibits CYP2D6 and CYP3A4 to a lesser degree. In addition, paritaprevir and dasabuvir (minor) are metabolized by CYP3A4; therefore, their concentrations may also be affected by coadministration. Coadministration of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir and fluoxetine should be undertaken cautiously and with careful monitoring; a dose reduction of fluoxetine may be necessary. Both fluoxetine and ritonavir have been associated with dose-related QT prolongation, and coadministration can result in elevated concentrations of both fluoxetine and ritonavir. Neurologic adverse events have also been reported when ritonavir was concurrently administered with fluoxetine. Fluoxetine is primarily metabolized by CYP2D6; ritonavir is a CYP2D6 inhibitor. Ritonavir is a substrate for CYP2D6 and CYP3A4; fluoxetine potently inhibits CYP2D6 and CYP3A4 to a lesser degree. In addition, paritaprevir and dasabuvir (minor) are metabolized by CYP3A4; therefore, their concentrations may also be affected by coadministration.
Fluoxetine; Olanzapine: Because both ritonavir and fluoxetine are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. A dose reduction of fluoxetine may be necessary during co-administration of ritonavir. Concurrent use of CYP2D6 substrates, such as fluoxetine, with ritonavir could result in increases (up to 2-fold) in the AUC of fluoxetine. Close monitoring for adverse effects is prudent. Coadministration of dasabuvir; ombitasvir; paritaprevir; ritonavir and fluoxetine should be undertaken cautiously and with careful monitoring; a dose reduction of fluoxetine may be necessary. Both fluoxetine and ritonavir have been associated with dose-related QT prolongation, and coadministration can result in elevated concentrations of both fluoxetine and ritonavir. Neurologic adverse events have also been reported when ritonavir was concurrently administered with fluoxetine. Fluoxetine is primarily metabolized by CYP2D6; ritonavir is a CYP2D6 inhibitor. Ritonavir is a substrate for CYP2D6 and CYP3A4; fluoxetine potently inhibits CYP2D6 and CYP3A4 to a lesser degree. In addition, paritaprevir and dasabuvir (minor) are metabolized by CYP3A4; therefore, their concentrations may also be affected by coadministration. Coadministration of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir and fluoxetine should be undertaken cautiously and with careful monitoring; a dose reduction of fluoxetine may be necessary. Both fluoxetine and ritonavir have been associated with dose-related QT prolongation, and coadministration can result in elevated concentrations of both fluoxetine and ritonavir. Neurologic adverse events have also been reported when ritonavir was concurrently administered with fluoxetine. Fluoxetine is primarily metabolized by CYP2D6; ritonavir is a CYP2D6 inhibitor. Ritonavir is a substrate for CYP2D6 and CYP3A4; fluoxetine potently inhibits CYP2D6 and CYP3A4 to a lesser degree. In addition, paritaprevir and dasabuvir (minor) are metabolized by CYP3A4; therefore, their concentrations may also be affected by coadministration. Ritonavir may reduce olanzapine serum concentrations by approximately 50%; how this affects olanzapine efficacy, however, is not known. Ritonavir appears to induce olanzapine's metabolism by either CYP1A2 or glucuronide conjugation. If ritonavir and olanzapine are used concurrently, monitor for reduced olanzapine effect and adjust olanzapine dose as needed. In addition, both ritonavir and olanzapine are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
Fluphenazine: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation that should be used cautiously and with close monitoring with ritonavir include fluphenazine.
Flurazepam: CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of flurazepam and increase the potential for benzodiazepine toxicity. A decrease in the flurazepam dose may be needed.
Fluticasone: Ritonavir significantly increases plasma fluticasone exposure via inhibition of CYP3A4, resulting in significantly reduced serum cortisol concentrations. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving inhaled or intranasally administered fluticasone with ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Therefore, coadministration of fluticasone (or fluticasone-containing products), including intranasal fluticasone formulations, and ritonavir (or ritonavir-containing products or treatment regimens) is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Fluticasone; Salmeterol: Avoid coadministration of salmeterol with ritonavir. The coadministration of salmeterol with CYP3A4 inhibitors can result in elevated salmeterol plasma concentrations and increased risk for adverse reactions, particularly cardiovascular effects. Ritonavir significantly increases plasma fluticasone exposure via inhibition of CYP3A4, resulting in significantly reduced serum cortisol concentrations. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving inhaled or intranasally administered fluticasone with ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Therefore, coadministration of fluticasone (or fluticasone-containing products), including intranasal fluticasone formulations, and ritonavir (or ritonavir-containing products or treatment regimens) is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects.
Fluticasone; Vilanterol: Ritonavir significantly increases plasma fluticasone exposure via inhibition of CYP3A4, resulting in significantly reduced serum cortisol concentrations. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving inhaled or intranasally administered fluticasone with ritonavir, resulting in systemic corticosteroid effects including Cushing syndrome and adrenal suppression. Therefore, coadministration of fluticasone (or fluticasone-containing products), including intranasal fluticasone formulations, and ritonavir (or ritonavir-containing products or treatment regimens) is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir, include beta-agonists.
Fluvastatin: Ritonavir is an inhibitor of CYP3A4 and may increase exposure to drugs metabolized by this enzyme, such as fluvastatin. Because fluvastatin does not rely exclusively on CYP3A4 for its metabolism (approximately 20%), ritonavir may not interact to the same extent as expected with other HMG-CoA reductase inhibitors. Elevated serum concentrations of fluvastatin may increase the risk for adverse reactions, such as myopathy.
Fluvoxamine: Concurrent administration of fluvoxamine with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in increased plasma concentrations of fluvoxamine, dasabuvir, paritaprevir, and ritonavir. Fluvoxamine is partially metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of CYP2D6. In addition, ritonavir, paritaprevir, and dasabuvir (minor) are metabolized by CYP3A4, and fluvoxamine is a CYP3A4 inhibitor. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of fluvoxamine with ritonavir may result in increased plasma concentrations of both drugs. Fluvoxamine is partially metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of CYP2D6. In addition, ritonavir is metabolized by CYP3A4, and fluvoxamine is a CYP3A4 inhibitor. Caution and close monitoring are advised if these drugs are administered together.
Food: The pharmacokinetic parameters of anti-retroviral medications (anti-retroviral non-nucleoside reverse transcriptase inhibitors (NNRTIs), anti-retroviral nucleoside reverse transcriptase inhibitors (NRTIs), anti-retroviral nucleotide reverse transcriptase inhibitors, and anti-retroviral protease inhibitors) metabolized through the CYP isoenzyme system are slightly altered by smoked and oral marijuana. Despite this interaction, marijuana is not expected to adversely affect anti-retroviral efficacy. However, the incidence of marijuana associated adverse effects may change following coadministration with anti-retroviral drugs. Many anti-retrovirals are inhibitors of CYP3A4, an isoenzyme partially responsible for the metabolism of marijuana's most psychoactive compound, delta-9-tetrahydrocannabinol (Delta-9-THC). When given concurrently with anti-retrovirals, the amount of Delta-9-THC converted to the active metabolite 11-hydroxy-delta-9-tetrahydrocannabinol (11-OH-THC) may be reduced. These changes in Delta-9-THC and 11-OH-THC plasma concentrations may result in an altered marijuana adverse event profile.
Formoterol: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir, include beta-agonists.
Formoterol; Mometasone: Coadministration of mometasone with ritonavir (a strong CYP3A4 inhibitor) may cause mometasone serum concentrations to increase, potentially resulting in Cushing's syndrome and adrenal suppression. Consider use of an alternative corticosteroid whose concentrations are less affected by strong CYP3A4 inhibitors, such as beclomethasone and prednisolone, especially during long-term treatment. The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir, include beta-agonists.
Fosamprenavir: Concurrent administration of fosamprenavir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in increased plasma concentrations of amprenavir, dasabuvir, paritaprevir, and ritonavir. Fosamprenavir is the prodrug of amprenavir. Amprenavir is a substrate of CYP2C9, CYP3A4, CYP2D6, and P-glycoprotein (P-gp); ritonavir inhibits CYP3A4, CYP2D6, and P-gp. When boosted with ritonavir, the recommended dosage of fosamprenavir is 700 mg PO twice daily (with ritonavir 100 mg twice daily) or 1400 mg PO once daily (with ritonavir 100 mg or 200 mg once daily). In addition to the effects on amprenavir concentrations, concurrent use may increase ritonavir, paritaprevir, and dasabuvir concentrations through amprenavir's CYP3A4 inhibition. Caution and close monitoring are advised if these drugs are administered together.
Foscarnet: When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as ritonavir. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). The use of ritonavir could also result in QT prolongation. Also abnormal renal function has been observed in clinical practice during the use of foscarnet in combination with ritonavir. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.
Fosphenytoin: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with fosphenytoin is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir and ritonavir. Phenytoin is a potent inducer and substrate of the hepatic isoenzyme CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. In addition, phenytoin may induce P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with phenytoin or fosphenytoin is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir and ritonavir. Phenytoin is a potent inducer and substrate of the hepatic isoenzyme CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. In addition, phenytoin may induce P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Concurrent use of ritonavir with ethotoin, phenytoin, or fosphenytoin should be avoided when possible. Increased doses of anticonvulsants may be required due to metabolism induction by ritonavir. Additionally, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required.
Furosemide: The manufacturer of dasabuvir; ombitasvir; paritaprevir; ritonavir and ombitasvir; paritaprevir; ritonavir recommends caution and clinical monitoring if administered concurrently with furosemide. Use of these drugs in combination has resulted in elevated furosemide maximum plasma concentrations (Cmax). Individualize the dose of furosemide based on the patient's clinical response. The dose should be re-adjusted after completion of the hepatitis C treatment regimen. The manufacturer of dasabuvir; ombitasvir; paritaprevir; ritonavir recommends caution and clinical monitoring if administered concurrently with furosemide. Use of these drugs in combination has resulted in elevated furosemide maximum plasma concentrations (Cmax). Individualize the dose of furosemide based on the patient's clinical response. The dose should be re-adjusted after completion of the 4-drug hepatitis C treatment regimen.
Galantamine: Galantamine is a substrate for CYP3A4 and CYP2D6. The bioavailability of galantamine is increased when coadministered with CYP3A4 inhibitors, such as ritonavir. An increase in cholinergic side effects may occur, particularly nausea and vomiting.
Gefitinib: Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib is used concomitantly with either lopinavir or ritonavir. Gefitinib is metabolized significantly by CYP3A4 and both lopinavir and ritonavir are strong CYP3A4 inhibitors; gefitinib is metabolized to a lesser extent by CYP2D6, and ritonavir inhibits CYP2D6 in vitro. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. Administration of a single 250 mg gefitinib dose with another strong CYP3A4 inhibitor (itraconazole) increased the mean AUC of gefitinib by 80%. In patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated.
Gemfibrozil: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with gemfibrozil is contraindicated due to the potential for dasabuvir-induced QT prolongation. Coadministration increases dasabuvir exposures by 10-fold. Gemfibrozil is an inhibitor of the hepatic isoenzyme CYP2C8; dasabuvir is a substrate of this isoenzyme.
Gemifloxacin: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include gemifloxacin.
Glimepiride; Pioglitazone: Concurrent administration of pioglitazone with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated pioglitazone plasma concentrations and decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Pioglitazone is an inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. In addition, pioglitazone is metabolized by CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Glipizide; Metformin: The manufacturer recommends against concurrent administration of ombitasvir; paritaprevir; ritonavir and metformin in patients with hepatic or renal impairment. If these drugs are given together, closely monitor blood glucose concentrations and for signs of lactic acidosis (i.e., abdominal or respiratory distress, worsening renal function, somnolence). New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Glyburide; Metformin: The manufacturer recommends against concurrent administration of ombitasvir; paritaprevir; ritonavir and metformin in patients with hepatic or renal impairment. If these drugs are given together, closely monitor blood glucose concentrations and for signs of lactic acidosis (i.e., abdominal or respiratory distress, worsening renal function, somnolence). New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Glycopyrrolate; Formoterol: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir, include beta-agonists.
Goserelin: Ritonavir should be used cautiously and with close monitoring with goserelin. The use of ritonavir could result in QT prolongation. Androgen deprivation therapy (e.g., goserelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval.
Granisetron: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include granisetron. In addition, concurrent administration may result in elevated granisetron plasma concentrations. Granisetron is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme.
Grapefruit juice: Concurrent administration of dasabuvir; ombitasvir; paritaprevir; ritonavir with grapefruit juice may result in elevated plasma concentrations of all 4 antiviral medications. Grapefruit juice is an inhibitor of the hepatic isoenzymes CYP3A4 and CYP2D6, and an inhibitor of the drug transporter P-glycoprotein (P-gp). Ritonavir, paritaprevir, and dasabuvir (minor) are metabolized by CYP3A4. In addition, dasabuvir, ombitasvir, paritaprevir, and ritonavir are all substrates for P-gp. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of ritonavir with grapefruit juice may result in elevated ritonavir concentrations. Grapefruit juice is an inhibitor of the hepatic isoenzymes CYP3A4 and CYP2D6, and an inhibitor of the drug transporter P-glycoprotein (P-gp). Ritonavir is metabolized by both enzymes and is a substrate for P-gp. Caution and close monitoring are advised if these drugs are administered together.
Griseofulvin: Concurrent administration of griseofulvin with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in decreased plasma concentrations of dasabuvir, paritaprevir, and ritonavir. Griseofulvin is an inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir and dasabuvir (minor) are metabolized by this enzyme. Monitor for antiviral efficacy if these drugs are administered together. Concurrent administration of griseofulvin with ritonavir may result in decreased plasma concentrations of ritonavir. Griseofulvin is an inducer of the hepatic isoenzyme CYP3A4; ritonavir is metabolized by this enzyme. Monitor for antiviral efficacy if these drugs are administered together.
Guaifenesin; Hydrocodone: Concurrent administration of hydrocodone with ritonavir may result in elevated hydrocodone plasma concentrations and subsequent adverse events, such as sedation and respiratory depression. If these drugs are given together, a 50% reduction in the dose of hydrocodone may be needed, and monitoring for respiratory depression and sedation at regular intervals is recommended. Hydrocodone is metabolized by the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is an inhibitor of these enzymes. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ritonavir may reduce the efficacy of hydrocodone. Caution and close monitoring for both efficacy and adverse reactions are advised if these drugs are administered together; a hydrocodone dosage adjustment may be necessary.
Guaifenesin; Hydrocodone; Pseudoephedrine: Concurrent administration of hydrocodone with ritonavir may result in elevated hydrocodone plasma concentrations and subsequent adverse events, such as sedation and respiratory depression. If these drugs are given together, a 50% reduction in the dose of hydrocodone may be needed, and monitoring for respiratory depression and sedation at regular intervals is recommended. Hydrocodone is metabolized by the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is an inhibitor of these enzymes. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ritonavir may reduce the efficacy of hydrocodone. Caution and close monitoring for both efficacy and adverse reactions are advised if these drugs are administered together; a hydrocodone dosage adjustment may be necessary.
Guanfacine: Ritonavir may significantly alter guanfacine plasma concentrations. Guanfacine is primarily metabolized by CYP3A4. Ritonavir is a potent CYP3A4 inhibitor; moderate CYP3A4 induction has been reported with concomitant use of voriconazole. The net effect of this potential interaction is unclear, but guanfacine dosage adjustments, most likely a dose decrease, may be required. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if used with a moderate to strong CYP3A4 inhibitor, the guanfacine dosage should be decreased to half of the recommended dose and the patient should be closely monitored for alpha-adrenergic effects (e.g., hypotension, drowsiness, bradycardia). However, if used with a moderate to strong CYP3A4 inducer, labeling recommends to consider doubling the recommended dose of guanfacine ER; if the inducer is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If the inducer or inhibitor is discontinued, guanfacine ER should return to its recommended dose (with downward titration occurring over 1 to 2 weeks). Specific recommendations for immediate-release (IR) guanfacine are not available.
Halofantrine: Protease Inhibitors significantly inhibit cytochrome CYP3A4,and may lead to an inhibition of halofantrine metabolism, placing the patient at risk for halofantrine cardiac toxicity.
Halogenated Anesthetics: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include halogenated anesthetics.
Haloperidol: Ritonavir is an inhibitor of CYP2D6 and CYP3A4, the isoenzymes responsible for the metabolism of haloperidol. Mild to moderate increases in haloperidol plasma concentrations have been reported during concurrent use of haloperidol and inhibitors of CYP3A4 or CYP2D6. Elevated haloperidol concentrations occurring through inhibition of CYP2D6 or CYP3A4 may increase the risk of adverse effects, including QT prolongation. In addition, ritonavir also is associated with QT prolongation; concomitant use increases the risk of QT prolongation. Until more data are available, it is advisable to closely monitor for adverse events when these medications are co-administered.
Halothane: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include halogenated anesthetics.
Homatropine; Hydrocodone: Concurrent administration of hydrocodone with ritonavir may result in elevated hydrocodone plasma concentrations and subsequent adverse events, such as sedation and respiratory depression. If these drugs are given together, a 50% reduction in the dose of hydrocodone may be needed, and monitoring for respiratory depression and sedation at regular intervals is recommended. Hydrocodone is metabolized by the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is an inhibitor of these enzymes. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ritonavir may reduce the efficacy of hydrocodone. Caution and close monitoring for both efficacy and adverse reactions are advised if these drugs are administered together; a hydrocodone dosage adjustment may be necessary.
Hydantoins: Concurrent use of ritonavir with ethotoin, phenytoin, or fosphenytoin should be avoided when possible. Increased doses of anticonvulsants may be required due to metabolism induction by ritonavir. Additionally, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required.
Hydrochlorothiazide, HCTZ; Losartan: Concurrent administration of losartan with ritonavir may result in elevated losartan plasma concentrations. Losartan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Hydrochlorothiazide, HCTZ; Metoprolol: Metoprolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as ritonavir, may impair metoprolol metabolism. Clinicians should be alert to exaggerated beta-blocker effects if metoprolol is given with these drugs.
Hydrochlorothiazide, HCTZ; Propranolol: Concurrent administration of propranolol with ritonavir may result in elevated propranolol plasma concentrations. Cardiac and neurologic events have been reported when ritonavir is concurrently administered with beta-blockers. Propranolol is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Decreased beta-blocker dosage may be needed.
Hydrochlorothiazide, HCTZ; Valsartan: Coadministration of valsartan and regimens containing paritaprevir may result in elevated valsartan plasma concentrations. A valsartan dose reduction, and close monitoring for adverse events (i.e., hypotension and worsening renal function) are advised during coadministration. If adverse events are observed, consider further reductions in valsartan dose or an alternative to the angiotensin receptor blocker. Valsartan is a substrate of the organic anion transporting polypeptides (OATP) and paritaprevir is an OATP1B1 and OATP1B3 inhibitor. Valsartan is a substrate of the hepatic efflux transporter MRP2 and ritonavir is an inhibitor of MRP2. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan during coadministration.
Hydrocodone: Concurrent administration of hydrocodone with ritonavir may result in elevated hydrocodone plasma concentrations and subsequent adverse events, such as sedation and respiratory depression. If these drugs are given together, a 50% reduction in the dose of hydrocodone may be needed, and monitoring for respiratory depression and sedation at regular intervals is recommended. Hydrocodone is metabolized by the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is an inhibitor of these enzymes. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ritonavir may reduce the efficacy of hydrocodone. Caution and close monitoring for both efficacy and adverse reactions are advised if these drugs are administered together; a hydrocodone dosage adjustment may be necessary.
Hydrocodone; Ibuprofen: Concurrent administration of hydrocodone with ritonavir may result in elevated hydrocodone plasma concentrations and subsequent adverse events, such as sedation and respiratory depression. If these drugs are given together, a 50% reduction in the dose of hydrocodone may be needed, and monitoring for respiratory depression and sedation at regular intervals is recommended. Hydrocodone is metabolized by the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is an inhibitor of these enzymes. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ritonavir may reduce the efficacy of hydrocodone. Caution and close monitoring for both efficacy and adverse reactions are advised if these drugs are administered together; a hydrocodone dosage adjustment may be necessary.
Hydrocodone; Phenylephrine: Concurrent administration of hydrocodone with ritonavir may result in elevated hydrocodone plasma concentrations and subsequent adverse events, such as sedation and respiratory depression. If these drugs are given together, a 50% reduction in the dose of hydrocodone may be needed, and monitoring for respiratory depression and sedation at regular intervals is recommended. Hydrocodone is metabolized by the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is an inhibitor of these enzymes. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ritonavir may reduce the efficacy of hydrocodone. Caution and close monitoring for both efficacy and adverse reactions are advised if these drugs are administered together; a hydrocodone dosage adjustment may be necessary.
Hydrocodone; Potassium Guaiacolsulfonate: Concurrent administration of hydrocodone with ritonavir may result in elevated hydrocodone plasma concentrations and subsequent adverse events, such as sedation and respiratory depression. If these drugs are given together, a 50% reduction in the dose of hydrocodone may be needed, and monitoring for respiratory depression and sedation at regular intervals is recommended. Hydrocodone is metabolized by the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is an inhibitor of these enzymes. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ritonavir may reduce the efficacy of hydrocodone. Caution and close monitoring for both efficacy and adverse reactions are advised if these drugs are administered together; a hydrocodone dosage adjustment may be necessary.
Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: Concurrent administration of hydrocodone with ritonavir may result in elevated hydrocodone plasma concentrations and subsequent adverse events, such as sedation and respiratory depression. If these drugs are given together, a 50% reduction in the dose of hydrocodone may be needed, and monitoring for respiratory depression and sedation at regular intervals is recommended. Hydrocodone is metabolized by the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is an inhibitor of these enzymes. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ritonavir may reduce the efficacy of hydrocodone. Caution and close monitoring for both efficacy and adverse reactions are advised if these drugs are administered together; a hydrocodone dosage adjustment may be necessary.
Hydrocodone; Pseudoephedrine: Concurrent administration of hydrocodone with ritonavir may result in elevated hydrocodone plasma concentrations and subsequent adverse events, such as sedation and respiratory depression. If these drugs are given together, a 50% reduction in the dose of hydrocodone may be needed, and monitoring for respiratory depression and sedation at regular intervals is recommended. Hydrocodone is metabolized by the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is an inhibitor of these enzymes. In addition, the metabolism of hydrocodone to its active metabolite, hydromorphone, is dependent on CYP2D6. Theoretically, coadministration of hydrocodone and a CYP2D6 inhibitor, such as ritonavir may reduce the efficacy of hydrocodone. Caution and close monitoring for both efficacy and adverse reactions are advised if these drugs are administered together; a hydrocodone dosage adjustment may be necessary.
Hydromorphone: Ritonavir is an inhibitor of the cytochrome P450 3A4 isoenzyme and may decrease the metabolism of hydromorphone if the two drugs are coadministered.
Hydroxychloroquine: Avoid coadministration of hydroxychloroquine and ritonavir. Hydroxychloroquine increases the QT interval and should not be administered with other drugs known to prolong the QT interval. Ventricular arrhythmias and torsade de pointes have been reported with the use of hydroxychloroquine. The use of ritonavir could result in QT prolongation.
Hydroxyprogesterone: Concurrent administration of hydroxyprogesterone with ritonavir may result in elevated hydroxyprogesterone plasma concentrations. Hydroxyprogesterone is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Hydroxyzine: Post-marketing data indicate that hydroxyzine causes QT prolongation and Torsade de Pointes (TdP). Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with hydroxyzine include ritonavir.
Ibrutinib: Do not use ibrutinib concomitantly with ritonavir; ritonavir is contraindicated for use with medications that are highly dependent on CYP3A4 for clearance and are associated with serious and/or life-threatening events. Significantly increased ibrutinib levels may occur. Consider the use of alternate agents. Ibrutinib is a CYP3A4 substrate; ritonavir is a strong CYP3A inhibitor. In a drug interaction study, the ibrutinib Cmax and AUC values increased by 29-fold and 24-fold, respectively, when ibrutinib was administered with a strong CYP3A4 inhibitor in healthy volunteers.
Ibuprofen; Oxycodone: Oxycodone is metabolized by CYP3A4. Concomitant administration of ritonavir, a CYP3A4 inhibitor, may cause an increase in oxycodone plasma concentrations, which could increase or prolong adverse effects and may cause potentially fatal respiratory depression. If coadministration of these agents is necessary, patients should be monitored for an extended period and dosage adjustments made if warranted. In addition, oxycodone is metabolized in part by CYP2D6 to oxymorphone, which represents less than 15% of the total administered dose. Concurrent use of some agents that inhibit CYP2D6 has not been shown to result in clinically significant interactions. However, potent inhibitors of CYP2D6, such as ritonavir, may potentially increase the effects of oxycodone. Caution and close monitoring are advised if these drugs are administered together. Initiate oxycodone at low dosages and titrate carefully.
Ibutilide: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include ibutilide.
Idarubicin: The use of ritonavir could result in QT prolongation. Use ritonavir cautiously in patients taking other drugs known to prolong the QT interval. Acute cardiotoxicity can occur during administration of daunorubicin, doxorubicin, epirubicin, or idarubicin; cumulative, dose-dependent cardiomyopathy may also occur. Acute ECG changes during anthracycline therapy are usually transient and include ST-T wave changes, QT prolongation, and changes in QRS voltage. Sinus tachycardia is the most common arrhythmia, but other arrhythmias such as supraventricular tachycardia (SVT), ventricular tachycardia, heart block, and premature ventricular contractions (PVCs) have been reported.
Idelalisib: Concomitant use of idelalisib, a CYP3A4 substrate, and ritonavir, a strong CYP3A4 inhibitor, may increase the exposure of idelalisib. Additionally, idelalisib is a strong CYP3A inhibitor while ritonavir is a CYP3A substrate. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib. Avoid concomitant use of idelalisib and ritonavir. Avoid concurrent administration of idelalisib with dasabuvir; ombitasvir; paritaprevir; ritonavir. Coadministration is expected to result in elevated plasma concentrations idelalisib, ritonavir, dasabuvir, and paritaprevir and increased risk of serious adverse events, such as hepatotoxicity. Idelalisib and ritonavir are both substrates and potent inhibitors of the hepatic isoenzyme CYP3A4; paritaprevir and dasabuvir (minor) are also metabolized by this enzyme. If coadministration is unavoidable, extreme caution and close monitoring are advised.
Ifosfamide: The concomitant use of ifosfamide, a CYP3A4 substrate, and ritonavir, a CYP3A4 inhibitor (strong), substrate, and inducer, may decrease the metabolism of ifosfamide to its active metabolite, 4-hydroxy-ifosfamide. As a result of this interaction, ifosfamide treatment effectiveness may be reduced. Caution and close monitoring are advised if these drugs are administered together.
Iloperidone: Avoid concurrent administration of iloperidone with dasabuvir; ombitasvir; paritaprevir; ritonavir. Coadministration may result in elevated plasma concentrations of all 5 drugs and subsequent adverse events such as QT prolongation. While dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QT interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with QT prolongation in other trials. According to iloperidine's manufacturer, the drug should be avoided in combination with other agents known to prolong the QT interval. If coadministration cannot be avoided, the manufacturer recommends a reduction in the iloperidone dose by one-half during co-administration with strong inhibitors of CYP 3A4; caution and careful montioring are advised. Iloperidone is a substrate for the hepatic isoenzymes CYP3A4 and CYP2D6, and an inhibitor of the drug transporter P-glycoprotein (P-gp). Ritonavir is a strong CYP3A4 inhibitor and also inhibits CYP2D6 and P-gp. In addition, dasabuvir, ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp. Avoid concurrent administration of iloperidone with dasabuvir; ombitasvir; paritaprevir; ritonavir. Coadministration may result in elevated plasma concentrations of all 5 drugs and subsequent adverse events such as QT prolongation. While dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QT interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with QT prolongation in other trials. According to iloperidine's manufacturer, the drug should be avoided in combination with other agents known to prolong the QT interval. If coadministration cannot be avoided, the manufacturer recommends a reduction in the iloperidone dose by one-half during co-administration with strong inhibitors of CYP3A4; caution and careful montioring are advised. Iloperidone is a substrate for the hepatic isoenzymes CYP3A4 and CYP2D6, and an inhibitor of the drug transporter P-glycoprotein (P-gp). Ritonavir is a strong CYP3A4 inhibitor and also inhibits CYP2D6 and P-gp. In addition, dasabuvir, ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp. In vitro studies indicate that CYP3A4 is involved in the metabolism of iloperidone. In theory, potent inhibitors of CYP3A4 such as ritonavir may decrease the elimination of iloperidone. The manufacturer recommends a reduction in the iloperidone dose by one-half during co-administration with strong inhibitors of CYP3A4. In addition, both ritonavir and iloperidone are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
Imatinib, STI-571: Concurrent administration of imatinib, STI-571 with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of imatinib, dasabuvir, paritaprevir, and ritonavir. Due to the complex interaction that may occur between ritonavir and imatinib, close monitoring of the antiviral and antineoplastic responses are recommended. Imatinib is a substrate and inhibitor of CYP3A4, and an inhibitor of CYP2D6; ritonavir is a substrate/inhibitor of both these enzymes. In addition, paritaprevir and dasabuvir (minor) are metabolized by CYP3A4. Additionally, imatinib is a substrate for P-glycoprotein (P-gp) while ritonavir is a P-gp inhibitor adding an additional mechanism by which imatinib concentrations may be increased. Caution and close monitoring are advised if these drugs are administered together. Protease Inhibitors inhibit cytochrome P450 CYP3A4 and may decrease the metabolism of imatinib and increase imatinib concentrations leading to an increased incidence of adverse reactions. In addition, because imatinib inhibits CYP2C9, CYP2D6, and CYP3A4/5, the metabolism of protease inhibitors may be decreased by imatinib. Close monitoring of the antiviral and antineoplastic responses is recommended.
Imipramine: Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Ritonavir has a possible risk for QT prolongation and torsade de pointes (TdP) and should be used cautiously and with close monitoring with doxepin. In addition, ritonavir potently inhibits CYP2D6 and CYP3A4, and thus may inhibit the metabolism of the tricyclic antidepressants (TCAs). A significant effect of ritonavir on desipramine clearance has been reported. Since the magnitude of the interaction with the TCAs is difficult to predict but may be significant, closely monitor patients receiving ritonavir and TCAs concurrently. Adjust the dosage of the coadministered drug based on therapeutic response. TCA serum concentration monitoring may be useful to guide adjustments and prevent toxicity.
Incretin Mimetics: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Indacaterol: Although no dosage adjustment of the 75 mcg indacaterol daily dose is needed, use caution if coadministered with dasabuvir; ombitasvir; paritaprevir; ritonavir. By inhibiting CYP3A4 and CYP2D6, ritonavir alters indacaterol metabolism. In drug interaction studies, coadministration of indacaterol 300 mcg (single dose) with ritonavir (300 mg bid for 7.5 days) resulted in a 1.7-fold increase in indacaterol AUC(0 to 24) whereas indacaterol Cmax was unaffected. In addition, indaceterol is a substrate for uridine glucuronyltransferase (UGT) 1A1 and P-glycoprotein (P-gp). Ombitasvir, dasabuvir, and paritaprevir are UGT1A1 inhibitors, while ritonavir and paritaprevir are P-gp inhibitors. Monitor the patient clinically for tremor, palpitations, or increased heart rate. Although no dosage adjustment of the 75 mcg indacaterol daily dose is needed, use caution if indacaterol and ritonavir are used concurrently. By inhibiting CYP3A4, CYP2D6, and P-glycoprotein, ritonavir reduces indacaterol metabolism. In drug interaction studies, coadministration of indacaterol 300 mcg (single dose) with ritonavir (300 mg twice daily for 7.5 days) resulted in a 1.7-fold increase in indacaterol AUC (0 to 24) whereas indacaterol Cmax was unaffected. Monitor the patient clinically for tremor, palpitations, or increased heart rate. Concurrent administration of indacaterol with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated indacaterol plasma concentrations. Indacaterol is metabolized by the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is an inhibitor of both enzymes. In addition, indaceterol is a substrate for uridine glucuronyltransferase (UGT ) 1A1 and P-glycoprotein (P-gp). Dasabuvir, ombitasvir, and paritaprevir are UGT1A1 inhibitors, and ritonavir is a P-gp inhibitor. The manufacturer of indacaterol states that no dosage adjustment of the 75 mcg indacaterol daily dose is needed. However, caution and monitoring (for side effects such as tremor, palpitations, or increased heart rate) are advised if these drugs are administered together.
Indacaterol; Glycopyrrolate: Although no dosage adjustment of the 75 mcg indacaterol daily dose is needed, use caution if coadministered with dasabuvir; ombitasvir; paritaprevir; ritonavir. By inhibiting CYP3A4 and CYP2D6, ritonavir alters indacaterol metabolism. In drug interaction studies, coadministration of indacaterol 300 mcg (single dose) with ritonavir (300 mg bid for 7.5 days) resulted in a 1.7-fold increase in indacaterol AUC(0 to 24) whereas indacaterol Cmax was unaffected. In addition, indaceterol is a substrate for uridine glucuronyltransferase (UGT) 1A1 and P-glycoprotein (P-gp). Ombitasvir, dasabuvir, and paritaprevir are UGT1A1 inhibitors, while ritonavir and paritaprevir are P-gp inhibitors. Monitor the patient clinically for tremor, palpitations, or increased heart rate. Although no dosage adjustment of the 75 mcg indacaterol daily dose is needed, use caution if indacaterol and ritonavir are used concurrently. By inhibiting CYP3A4, CYP2D6, and P-glycoprotein, ritonavir reduces indacaterol metabolism. In drug interaction studies, coadministration of indacaterol 300 mcg (single dose) with ritonavir (300 mg twice daily for 7.5 days) resulted in a 1.7-fold increase in indacaterol AUC (0 to 24) whereas indacaterol Cmax was unaffected. Monitor the patient clinically for tremor, palpitations, or increased heart rate. Concurrent administration of indacaterol with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated indacaterol plasma concentrations. Indacaterol is metabolized by the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is an inhibitor of both enzymes. In addition, indaceterol is a substrate for uridine glucuronyltransferase (UGT ) 1A1 and P-glycoprotein (P-gp). Dasabuvir, ombitasvir, and paritaprevir are UGT1A1 inhibitors, and ritonavir is a P-gp inhibitor. The manufacturer of indacaterol states that no dosage adjustment of the 75 mcg indacaterol daily dose is needed. However, caution and monitoring (for side effects such as tremor, palpitations, or increased heart rate) are advised if these drugs are administered together.
Indinavir: Concurrent administration of indinavir with dasabuvir; ombitasvir; paritaprevir; ritonavir is expected to result in increased plasma concentrations of indinavir, dasabuvir, paritaprevir, and ritonavir. Indinavir is a substrate of CYP3A4 and P-glycoprotein (P-gp); ritonavir inhibits both CYP3A4 and P-gp. Paritaprevir also inhibits P-gp. Ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates, and indinavir in a potent CYP3A4 inhibitor. Patients should be closely monitored for possible indinavir toxicity during concurrent administration; indinavir dosage reductions may be necessary. In general when ritonavir and indinavir are used together, the recommended dosage regimen is indinavir 800 mg twice daily plus ritonavir 100 or 200 mg twice daily; however, additional dosage adjustments may be necessary for certain additional interacting drugs. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of indinavir with dasabuvir; ombitasvir; paritaprevir; ritonavir is expected to result in increased plasma concentrations of indinavir, dasabuvir, paritaprevir, and ritonavir. Indinavir is a substrate of CYP3A4 and P-glycoprotein (P-gp); ritonavir inhibits both CYP3A4 and P-gp. Ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates, and indinavir in a potent CYP3A4 inhibitor. Patients should be closely monitored for possible indinavir toxicity during concurrent administration; indinavir dosage reductions may be necessary. In general when ritonavir and indinavir are used together, the recommended dosage regimen is indinavir 800 mg twice daily plus ritonavir 100 or 200 mg twice daily; however, additional dosage adjustments may be necessary for certain additional interacting drugs. Caution and close monitoring are advised if these drugs are administered together. Ritonavir inhibits the clearance of indinavir, and increased indinavir serum concentrations are seen with concurrent administration. In a pharmacokinetic study in healthy volunteers, the AUC of single indinavir dose increased 185 to 475% during concurrent ritonavir dosing; the mean indinavir half-life increased from 1.2 to 2.7 hours. In an observational study of HIV-infected patients, the combination of indinavir 1200 mg and ritonavir 100 mg, both twice daily, led to high systemic exposure to indinavir and was not well tolerated. The combination of indinavir 800 mg and ritonavir 100 mg twice daily resulted in therapeutic indinavir serum concentrations with improved tolerability and similar maximum serum concentrations as the approved indinavir dosage of 800 mg three times a day. Patients should be closely monitored for possible indinavir toxicity during concurrent administration; indinavir dosage reductions may be necessary. The recommended dosing regimen for this combination is indinavir 800 mg twice daily plus ritonavir 100 or 200 mg twice daily.
Insulins: Monitor patients receiving insulin closely for changes in diabetic control, specifically hyperglycemia, when anti-retroviral protease inhibitors are instituted. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment.
Interferon Alfa-2b; Ribavirin: The concomitant use of ribavirin and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
Interferons: The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
Irinotecan Liposomal: If possible, avoid concomitant use of irinotecan liposomal with ritonavir, a strong CYP3A4 inhibitor, due to increased risk of irinotecan-related toxicity. Discontinue ritonavir at least 1 week prior to initiation of liposomal irinotecan therapy. The metabolism of liposomal irinotecan has not been evaluated; however, coadministration of ketoconazole, a strong CYP3A4 and UGT1A1 inhibitor, with non-liposomal irinotecan HCl resulted in increased exposure to both irinotecan and its active metabolite, SN-38.
Irinotecan: Ritonavir is a strong CYP3A4 inhibitor, moderate P-glycoprotein inhibitor, and moderate CYP3A4 inducer. Irinotecan is a CYP3A4 and P-gp substrate. Exposure to irinotecan and to the active metabolite, SN-38, will increase when the drugs are used together. Do not administer ritonavir concurrently with irinotecan unless there are no therapeutic alternatives; discontinue ritonavir at least 1 week before starting irinotecan. If concomitant use is necessary, monitor for increased irinotecan side effects, including diarrhea, nausea, vomiting, and myelosuppression.
Isavuconazonium: Concomitant use of isavuconazonium with high-dose ritonavir (i.e., 400 mg every 12 hours) is contraindicated due to the risk for increased isavuconazole serum concentrations and serious adverse reactions, such as hepatic toxicity. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of hepatic isoenzyme CYP3A4; ritonavir is a strong inhibitor of this enzyme. According to the manufacturer, coadministration of isavuconazole with strong CYP3A4 inhibitors is contraindicated. Isavuconazole serum concentrations were increased 5-fold when coadministered with ketoconazole, another strong CYP3A4 inhibitor. Elevated ritonavir concentrations may also be seen with coadministration, as ritonavir is a substrate and isavuconazole is an inhibitor of CYP3A4 and the drug transporter P-glycoprotein (P-gp). Concomitant use of isavuconazonium with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in increased serum concentrations of all 5 drugs. Dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-glycoprotein (P-gp); additionally, paritaprevir is a substrate of CYP3A4, ritonavir is a substrate and potent inhibitor of CYP3A4, and dasabuvir is a substrate of CYP3A4. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of CYP3A4 and an inhibitor of P-gp. Caution and close monitoring are advised if these drugs are used together. Concomitant use of isavuconazonium with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in increased serum concentrations of both drugs. Dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-glycoprotein (P-gp); additionally, paritaprevir is a substrate of CYP3A4, ritonavir is a substrate and potent inhibitor of CYP3A4, and dasabuvir is a substrate of CYP3A4. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of CYP3A4 and an inhibitor of P-gp. Caution and close monitoring are advised if these drugs are used together.
Isoflurane: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include halogenated anesthetics.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: Coadministration of rifampin and ritonavir results in markedly decreased ritonavir concentrations; HIV treatment failure and virologic resistance would be expected. Rifampin (300 or 600 mg daily for 10 days) decreases the AUC and Cmax of ritonavir (500 mg every 12 hours for 20 days) by 35% and 25%, respectively. Coadministration may lead to loss of virologic response if ritonavir is the sole protease inhibitor and increase the risk of hepatotoxicity. The DHHS/NIH HIV Treatment Guidelines recommend ritonavir and rifampin should not be coadministered and suggest the consideration of alternative antimycobacterial agents, such as rifabutin. However, CDC guidelines suggest no change in ritonavir or rifampin dose when the drugs are coadministered, but this appears to only be in the setting of low-dose ritonavir (i.e., 100 mg or 200 mg twice daily) used to 'boost' concentrations of other protease inhibitors. In this setting it would be less likely to produce adverse events than higher ritonavir doses; however, a net CYP3A4 induction still results when used with rifampin. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with rifampin is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir and ritonavir. Rifampin is a potent inducer of the hepatic isoenzyme CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. Rifampin also induces CYP2D6 and CYP2C8, enzymes partially responsible for the metabolism of ritonavir and dasabuvir, respectively. In addition, rifampin induces the drug transporter proteins P-glycoprotein (P-gp) and UGT; dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates for P-gp, while dasabuvir, ombitasvir and paritaprevir are also substrates of UGT. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with rifampin is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir and ritonavir. Rifampin is a potent inducer of the hepatic isoenzyme CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. Rifampin also induces CYP2D6 and CYP2C8, enzymes partially responsible for the metabolism of ritonavir and dasabuvir, respectively. In addition, rifampin induces the drug transporter proteins P-glycoprotein (P-gp) and UGT; dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates for P-gp, while dasabuvir, ombitasvir and paritaprevir are also substrates of UGT.
Isoniazid, INH; Rifampin: Coadministration of rifampin and ritonavir results in markedly decreased ritonavir concentrations; HIV treatment failure and virologic resistance would be expected. Rifampin (300 or 600 mg daily for 10 days) decreases the AUC and Cmax of ritonavir (500 mg every 12 hours for 20 days) by 35% and 25%, respectively. Coadministration may lead to loss of virologic response if ritonavir is the sole protease inhibitor and increase the risk of hepatotoxicity. The DHHS/NIH HIV Treatment Guidelines recommend ritonavir and rifampin should not be coadministered and suggest the consideration of alternative antimycobacterial agents, such as rifabutin. However, CDC guidelines suggest no change in ritonavir or rifampin dose when the drugs are coadministered, but this appears to only be in the setting of low-dose ritonavir (i.e., 100 mg or 200 mg twice daily) used to 'boost' concentrations of other protease inhibitors. In this setting it would be less likely to produce adverse events than higher ritonavir doses; however, a net CYP3A4 induction still results when used with rifampin. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with rifampin is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir and ritonavir. Rifampin is a potent inducer of the hepatic isoenzyme CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. Rifampin also induces CYP2D6 and CYP2C8, enzymes partially responsible for the metabolism of ritonavir and dasabuvir, respectively. In addition, rifampin induces the drug transporter proteins P-glycoprotein (P-gp) and UGT; dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates for P-gp, while dasabuvir, ombitasvir and paritaprevir are also substrates of UGT. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with rifampin is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir and ritonavir. Rifampin is a potent inducer of the hepatic isoenzyme CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. Rifampin also induces CYP2D6 and CYP2C8, enzymes partially responsible for the metabolism of ritonavir and dasabuvir, respectively. In addition, rifampin induces the drug transporter proteins P-glycoprotein (P-gp) and UGT; dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates for P-gp, while dasabuvir, ombitasvir and paritaprevir are also substrates of UGT.
Isradipine: Concurrent administration of isradipine with protease inhibitors may result in elevated isradipine plasma concentrations and increased hypotensive effects. Isradipine is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitors of this enzyme. In addition, ritonavir prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
Itraconazole: Concurrent administration of itraconazole with dasabuvir; ombitasvir; paritaprevir; ritonavir is expected to result in elevated plasma concentrations of all 5 drugs, which increases the risk of serious adverse events such as QT prolongation. While dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QT interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with QT prolongation in other trials, especially at increased concentrations. Itraconazole is contraindicated for concurrent use with other drugs that are CYP3A4 inhibitors and known to increase the QT interval. As a result of recommendations regarding use of other azole antifungals with ritonavir, it would be prudent to avoid ritonavir use for up to 2 weeks after discontinuation of itraconazole unless benefits of treatment outweigh the increased risk of side effects. Itraconazole and ritonavir are both substrates and potent inhibitors of CYP3A4. In addition, both drugs are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). Paritaprevir and dasabuvir (minor) are CYP3A4 substrates, and dasabuvir, ombitasvir, and paritaprevir are P-gp substrates. If coadministration is unavoidable, careful monotoring of therapeutic and adverse effects is recommended. High doses of itraconazole (i.e., >200 mg per day) are not recommended. When administering itraconazole with ritonavir or ritonavir-containing drugs, do not exceed the maximum recommended itraconazole dose of 200 mg per day. Concurrent administration of ritonavir (a potent CYP3A4 inhibitor) with itraconazole (a CYP3A4 substrate) significantly increases itraconazole systemic concentrations. In addition, because both drugs are associated with prolongation of the QT interval, coadministration may increase the risk for developing QT prolongation. If these drugs are given together, closely monitor patients for itraconazole-associated adverse effects, including QT prolongation. If itraconazole therapy is stopped, it may be prudent to continue close monitoring for up to 2 weeks after discontinuing itraconazole. Once discontinued, the plasma concentration of itraconazole decreases to almost undetectable concentrations within 7 to 14 days. The decline in plasma concentrations may be even more gradual in patients with hepatic cirrhosis or who are receiving concurrent CYP3A4 inhibitors.
Ivabradine: Coadministration of ivabradine and ritonavir is contraindicated. Ivabradine is primarily metabolized by CYP3A4; ritonavir is a strong CYP3A4 inhibitor. Coadministration will increase the plasma concentrations of ivabradine. Increased ivabradine concentrations may result in bradycardia exacerbation and conduction disturbances.
Ivacaftor: Concurrent administration of ivacaftor with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of all 5 drugs. If these drugs are taken concurrently, reduce the ivacaftor dose to 150 mg twice weekly and monitor of adverse effects associated with any of the drugs. Ivacaftor is a substrate and inhibitor of CYP3A4, and an inhibitor of the drug transporter P-glycoprotein (P-gp). Ritonavir is an inhibitor of CYP3A4, and ritonavir, paritaprevir and dasabuvir (minor) are CYP3A4 substrates. In addition, dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-gp. Caution and close monitoring are advised if these drugs are administered together. If ritonavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg twice weekly). Ivacaftor is a CYP3A substrate and ritonavir is a CYP3A inhibitor. Coadministration with ketoconazole, another strong CYP3A inhibitor, increased ivacaftor exposure by 8.5-fold. Ivacaftor is also an inhibitor of CYP3A and P-glycoprotein (P-gp); ritonavir is metabolized by CYP3A and is a substrate of P-gp. Coadministration may increase ritonavir exposure leading to increased or prolonged therapeutic effects and adverse events.
Ixabepilone: If possible, avoid coadministration of ixabepilone with ritonavir; concurrent use is expected to result in increased ixabepilone plasma concentrations and risk of adverse events. Consider alternative therapies before using ixabepilone with ritonavir. If coadministration of ixabepilone with ritonavir cannot be avoided, consider an ixabepilone dosage reduction to 20 mg/m2 IV over 3 hours given every 3 weeks, as this dose is predicted to adjust the ixabepilone AUC to the range observed without inhibitors. Carefully monitor for adverse events. If a patient is already receiving ritonavir, a washout period of approximately 1 week is recommended before starting ixabepilone. Ixabepilone is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme.
Ketoconazole: When administering ketoconazole with ritonavir or ritonavir-containing drugs, do not exceed the maximum recommended ketoconazole dose of 200 mg per day. Concurrent administration of ritonavir (a potent CYP3A4 inhibitor) with ketoconazole (a CYP3A4 substrate) significantly increases ketoconazole systemic concentrations. In one drug interaction study, ketoconazole exposure was increased by 3.4-fold when given concurrently with ritonavir (500 mg twice daily). In addition, because both drugs are associated with prolongation of the QT interval, coadministration may increase the risk for developing QT prolongation. If these drugs are given together, closely monitor patients for ketoconazole-associated adverse effects, including QT prolongation.
Labetalol: Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
Lacosamide: Use caution during concurrent use of lacosamide and ritonavir, particularly in patients with renal or hepatic impairment. Lacosamide is a CYP3A4 substrate; ritonavir is a potent inhibitor of CYP3A4. Patients with renal or hepatic impairment may have significantly increased exposure to lacosamide if coadministered with a strong CYP3A4 inhibitor. Dosage reduction of lacosamide may be necessary in this population.
Lamivudine, 3TC; Zidovudine, ZDV: Since ritonavir induces glucuronidation, there is the potential for reduction in zidovudine, ZDV plasma concentrations during concurrent therapy with ritonavir. When coadministered with ritonavir, the AUC and Cmax of zidovudine, ZDV are decreased by 12% and 27%. The clinical significance of this interaction is unknown.
Lamotrigine: Adjustments in lamotrigine escalation and maintenance dose regimens are necessary with concomitant lopinavir; ritonavir use. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and lopinavir; ritonavir induces glucuronidation. During concurrent use of lamotrigine with lopinavir; ritonavir in 18 healthy subjects, induction of glucuronidation by lopinavir (400 mg twice daily); ritonavir (100 mg twice daily) decreased lamotrigine AUC, Cmax, and half-life by approximately 50% to 55.4%. If coadministration of lamotrigine and dasabuvir; ombitasvir; paritaprevir; ritonavir is warranted, use caution and carefully monitor lamotrigine concentrations; lamotrigine dosage adjustments may be needed. Ritoanvir may increase the hepatic metabolism of lamotrigine via glucuronidation, resulting in decreased lamotrigine concentrations. Additionally, lamotrigine interactions are thought to be mediated by uridine diphosphate glucuronyltransferase (UGT), and dasabuvir, ombitasvir, and paritaprevir are UGT1A1 inhibitors. Further alterations to lamotrigine concentrations could occur.
Lanreotide: Concurrent administration of lanreotide with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of dasabuvir, paritaprevir, and ritonavir. Limited data suggest somatostatin analogs may decrease the metabolic clearance of drugs metabolized by CYP3A4. Ritonavir, paritaprevir, and dasabuvir (minor) are metabolized by this enzyme. Monitor for adverse events if these drugs are administered together. Concurrent administration of lanreotide with ritonavir may result in elevated plasma concentrations of ritonavir. Limited data suggest somatostatin analogs may decrease the metabolic clearance of drugs metabolized by CYP3A4. Ritonavir is metabolized by this enzyme. Monitor for adverse events if these drugs are administered together.
Lansoprazole: Caution is advised when administering lansoprazole concurrently with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir. Use of these drugs together may result elevated concentrations lansoprazole, paritaprevir, ritonavir, dasabuvir and ombitasvir. Predications regarding this interaction can be made based on the drugs metabolic pathways. Lansoprazole is a substrate of CYP3A4 and a substrate/inhibitor of P-glycoprotein (P-gp). Ritonavir is an inhibitor/substrate of CYP3A4 and a P-gp substrate. Paritaprevir, dasabuvir, and ombitasvir are substrates of P-gp. Monitor for adverse reactions. Caution is advised when administering lansoprazole concurrently with dasabuvir; ombitasvir; paritaprevir; ritonavir. Use of these drugs together may result elevated concentrations of lansoprazole, paritaprevir, ritonavir, dasabuvir and ombitasvir. Predications regarding this interaction can be made based on the drugs metabolic pathways. Lansoprazole is a substrate of CYP3A4 and a substrate/inhibitor of P-glycoprotein (P-gp). Ritonavir is an inhibitor/substrate of CYP3A4 and a P-gp substrate. Paritaprevir, dasabuvir, and ombitasvir are substrates of P-gp. Monitor for adverse reactions. Use caution when administering ritonavir and lansoprazole concurrently. Ritonavir is an inhibitor of CYP3A and P-glycoprotein (P-gp). Coadministration of ritonavir with CYP3A and P-gp substrates, such as lansoprazole, can increase lansoprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Lansoprazole; Naproxen: Caution is advised when administering lansoprazole concurrently with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir. Use of these drugs together may result elevated concentrations lansoprazole, paritaprevir, ritonavir, dasabuvir and ombitasvir. Predications regarding this interaction can be made based on the drugs metabolic pathways. Lansoprazole is a substrate of CYP3A4 and a substrate/inhibitor of P-glycoprotein (P-gp). Ritonavir is an inhibitor/substrate of CYP3A4 and a P-gp substrate. Paritaprevir, dasabuvir, and ombitasvir are substrates of P-gp. Monitor for adverse reactions. Caution is advised when administering lansoprazole concurrently with dasabuvir; ombitasvir; paritaprevir; ritonavir. Use of these drugs together may result elevated concentrations of lansoprazole, paritaprevir, ritonavir, dasabuvir and ombitasvir. Predications regarding this interaction can be made based on the drugs metabolic pathways. Lansoprazole is a substrate of CYP3A4 and a substrate/inhibitor of P-glycoprotein (P-gp). Ritonavir is an inhibitor/substrate of CYP3A4 and a P-gp substrate. Paritaprevir, dasabuvir, and ombitasvir are substrates of P-gp. Monitor for adverse reactions. Use caution when administering ritonavir and lansoprazole concurrently. Ritonavir is an inhibitor of CYP3A and P-glycoprotein (P-gp). Coadministration of ritonavir with CYP3A and P-gp substrates, such as lansoprazole, can increase lansoprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Lanthanum Carbonate: Oral compounds known to interact with antacids, like protease inhibitors, should not be taken within 2 hours of dosing with lanthanum carbonate. If these agents are used concomitantly, space the dosing intervals appropriately. Monitor serum concentrations and clinical condition.
Lapatinib: Concurrent administration of lapatinib with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of all 5 drugs. If coadministration is necessary, consider a lapatinib dosage reduction. Both lapatinib and ritonavir have been associated with QT prolongation; concomitant use increases the risk for developing Torsade de Pointed (TdP). Both ritonavir and lapatinib are substrates and inhibitors of the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp). Lapatinib is also an inhibitor of CYP2C8. Dasabuvir is primarily metabolized by CYP2C8, while lapatinib, ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. In addition, dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates of P-gp. Caution and close monitoring are advised if these drugs are administered together. Lapatinib is a CYP3A4 substrate, and concomitant use of lapatinib with strong CYP3A4 inhibitors, such as ritonavir, should generally be avoided. In addition, coadministration increases the risk for QT prolongation and torsade de pointes. If concurrent treatment with ritonavir is necessary, strongly consider a lapatinib dose reduction. If ritonavir is discontinued, allow 7 days to elapse before increasing the lapatinib dose.
Ledipasvir; Sofosbuvir: Caution is warranted when ritonavir is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Ritonavir is an inhibitor of the transporter P-glycoprotein (P-gp). Both ledipasvir and sofosbuvir are substrates of P-gp. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects. Caution is warranted when ritonavir is administered with sofosbuvir as there is a potential for elevated concentrations of sofosbuvir. Ritonvir is an inhibitor of the transporter P-glycoprotein (P-gp). Sofosbuvir is a substrate of P-gp. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects. Concurrent administration of ledipasvir; sofosbuvir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of ledipasvir, sofosbuvir, dasabuvir, ombitasvir, paritaprevir and ritonavir. Ledipasvir is an inhibitor of the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-gp. In addition, ritonavir is an inhibitor of the breast cancer resistance protein (BCRP); ledipasvir, dasabuvir and paritaprevir are substrates/inhibitors of BCRP, while sofosbuvir is a BCRP substrate. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of sofosbuvir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of sofosbuvir. Ritonavir is an inhibitor of the breast cancer resistance protein (BCRP); dasabuvir and paritaprevir are substrates/inhibitors of BCRP, while sofosbuvir is a BCRP substrate. Caution and close monitoring are advised if these drugs are administered together Concurrent administration of sofosbuvir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of sofosbuvir. Ritonavir is an inhibitor of the breast cancer resistance protein (BCRP); dasabuvir and paritaprevir are substrates/inhibitors of BCRP, while sofosbuvir is a BCRP substrate. Caution and close monitoring are advised if these drugs are administered together.
Lenvatinib: Ritonavir should be used cautiously and with close monitoring with lenvatinib as the risk of QT prolongation may be increased. The use of ritonavir could result in QT prolongation. QT prolongation was also reported in patients with radioactive iodine-refractory differentiated thyroid cancer (RAI-refractory DTC) in a double-blind, randomized, placebo-controlled clinical trial after receiving lenvatinib daily at the recommended dose; the QT/QTc interval was not prolonged, however, after a single 32 mg dose (1.3 times the recommended daily dose) in healthy subjects.
Lesinurad: Ritonavir may decrease the systemic exposure and therapeutic effect of lesinurad; monitor for potential reduction in efficacy. Ritonavir is a CYP2C9 inducer, and lesinurad is a CYP2C9 substrate.
Leuprolide: Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include ritonavir.
Leuprolide; Norethindrone: Androgen deprivation therapy (e.g., leuprolide) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with leuprolide include ritonavir. Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. For example, ritonavir (also found in combinations like lopinavir; ritonavir, and used as a booster in many HIV treatment regimens) may decrease the metabolism of norethindrone, raising norethindrone concentrations. Women receiving norethindrone for hormone replacement or contraception should report potential hormonal adverse effects (e.g., bleeding pattern changes, acne, emotional lability) or any changes in efficacy (e.g., noted changes in bleeding patterns) to their prescribers. Because norethindrone-containing contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive norethindrone contraception concurrently with ritonavir should use an additional barrier method of contraception such as condoms.
Levalbuterol: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir, include beta-agonists.
Levobupivacaine: Levobupivacaine is metabolized by CYP3A4 and CYP1A2. Known inhibitors of CYP3A4, such as ritonavir, may result in increased systemic levels of levobupivacaine when given concurrently, with potential for toxicity. Although not studied, dosage adjustments of levobupivacaine may be needed.
Levocetirizine: Coadministration of cetirizine and ritonavir resulted in a 42% increase in the AUC, 53% increase in half-life, and 29% decrease in clearance of cetirizine. Cetirizine did not alter ritonavir disposition.
Levofloxacin: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include levofloxacin.
Levomethadyl: Agents that inhibit hepatic cytochrome P450 CYP 3A4, including ritonavir, may decrease the metabolism of levomethadyl, increase levomethadyl levels, and may precipitate severe arrhythmias including torsade de pointes.
Levomilnacipran: The adult dose of levomilnacipran should not exceed 80 mg/day during concurrent use of strong CYP3A4 inhibitors such as ritonavir. Levomilnacipran is partially metabolized by CYP3A4, and decreased metabolism of the drug can lead to an increased risk of adverse effects such as urinary retention. Additionally, ritonavir could further increase levomilnacipran concentrations by inhibiting its P-glycoprotein (P-gp) metabolism.
Levonorgestrel: Data on the effects that protease inhibitors have on the serum concentrations of estrogens and progestins are complex. Some protease inhibitors increase (i.e., ritonavir, lopinavir; ritonavir, nelfinavir, tipranavir) and others decrease (i.e., atazanavir, indinavir) the metabolism of hormonal contraceptives. The safety and efficacy of hormonal contraceptives may be affected if coadministered with protease inhibitors. Women receiving hormonal contraceptives and anti-retroviral protease inhibitors concurrently should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with protease inhibitors to use an additional method of contraception to protect against unwanted pregnancy, unless other drug-specific recommendations are made by the manufacturer of the protease inhibitor. Furthermore, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with protease inhibitors should use an additional barrier method of contraception such as condoms.
Levorphanol: Ritonavir is an inhibitor of the cytochrome P450 3A4 isoenzyme and may decrease the metabolism of levorphanol if the two drugs are coadministered.
Lidocaine: Anti-retroviral protease inhibitors can inhibit hepatic cytochrome P450 3A4, an isoenzyme that is partially responsible for the metabolism of lidocaine. The concurrent use of systemic lidocaine and anti-retroviral protease inhibitors should be carefully monitored due to the potential for serious toxicity.
Linagliptin: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, inducers of CYP3A4 (e.g., ritonavir) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended.
Linagliptin; Metformin: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, inducers of CYP3A4 (e.g., ritonavir) can decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations. For patients requiring use of such drugs, an alternative to linagliptin is strongly recommended. The manufacturer recommends against concurrent administration of ombitasvir; paritaprevir; ritonavir and metformin in patients with hepatic or renal impairment. If these drugs are given together, closely monitor blood glucose concentrations and for signs of lactic acidosis (i.e., abdominal or respiratory distress, worsening renal function, somnolence). New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Lisdexamfetamine: Patients receiving amphetamines may experience prolonged effects if receiving ritonavir concurrently. A case report describes a patient who was treated with ritonavir and saquinavir and then experienced a prolonged effect from a small dose of methylene-dioxy-methamphetamine (MDMA or ecstasy) and a near fatal reaction from a small dose of gamma-hydroxybutyrate (GHB). The effects in this patient suggests that the prolonged effects of MDMA were due to ritonavir-induced inhibition of CYP2D6 metabolism. The GHB toxicity in this patient may have been due to ritonavir-induced inhibition of first pass metabolism, leading to increased levels of GHB. Patients receiving other amphetamine drugs, such as amphetamine, amphetamine; dextroamphetamine mixed salts, lisdexamfetamine, or methamphetamine may experience prolonged effects if receiving ritonavir concurrently. Patients should be warned that there are potentially serious drug interactions between ritonavir and illicit drugs, such as ecstasy.
Lithium: Lithium should be used cautiously and with close monitoring with ritonavir. Both lithium and ritonavir may cause QT prolongation. Coadministration increases the risk for QT prolongation.
Lomitapide: Concomitant use of ritonavir and lomitapide is contraindicated. If treatment with ritonavir is unavoidable, lomitapide should be stopped during the course of treatment. Ritonavir is a strong CYP3A4 inhibitor. The exposure to lomitapide was increased 27-fold in the presence of ketoconazole, a strong CYP3A4 inhibitor.
Loperamide: Concurrent administration of loperamide and ritonavir may increase the risk for adverse reactions, such as CNS events and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest). At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest. Ritonavir is also associated with QT prolongation. In addition, loperamide is a substrate for the enzymes CYP3A4, CYP2D6, and the drug transporter P-glycoprotein (P-gp); ritonavir is an inhibitor of both enzymes and P-gp. When these drugs were administered together, an increase was seen in loperamide's Cmax (17%), Tmax (56%), AUC (223%), and amount excreted in the urine (118%). There was also a decrease in loperamide's oral clearance (70%). No CNS opioid effects (e.g., changes in pupil diameter, changes in pO2 or pCO2) were observed in this study, but it should be noted that because ritonavir is a potent P-gp inhibitor, it has the potential to hinder transport of loperamide out of the CNS and thereby depress respiratory ventilation. Monitor for depressed respiratory ventilation and adverse cardiac effects if these drugs are to be coadministered.
Loperamide; Simethicone: Concurrent administration of loperamide and ritonavir may increase the risk for adverse reactions, such as CNS events and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest). At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, TdP, and cardiac arrest. Ritonavir is also associated with QT prolongation. In addition, loperamide is a substrate for the enzymes CYP3A4, CYP2D6, and the drug transporter P-glycoprotein (P-gp); ritonavir is an inhibitor of both enzymes and P-gp. When these drugs were administered together, an increase was seen in loperamide's Cmax (17%), Tmax (56%), AUC (223%), and amount excreted in the urine (118%). There was also a decrease in loperamide's oral clearance (70%). No CNS opioid effects (e.g., changes in pupil diameter, changes in pO2 or pCO2) were observed in this study, but it should be noted that because ritonavir is a potent P-gp inhibitor, it has the potential to hinder transport of loperamide out of the CNS and thereby depress respiratory ventilation. Monitor for depressed respiratory ventilation and adverse cardiac effects if these drugs are to be coadministered.
Lopinavir; Ritonavir: Avoid coadministration of lopinavir with paritaprevir. Use of these drugs in combination has resulted in elevated paritaprevir serum concentrations. Paritaprevir is a substrate of the drugs transporter organic anion transporting polypeptide (OATP1B1); lopinavir is an OATP1B1 inhibitor.
Loratadine: Theoretically, anti-retroviral protease inhibitors could lead to elevated loratadine concentrations due to inhibition of CYP3A4, CYP2D6 and/or P-glycoprotein (P-gp). Elevated loratadine serum concentrations do not result in clinically significant QT prolongation, ECG changes, or any significant differences in adverse reactions compared to control patients. However, caution should be exercised with using this drug combination in a patient with concurrent risk factors for arrhythmogenic events. Although significant drug interactions have not been confirmed between loratadine and other agents that inhibit cytochrome P-450, like protease inhibitors, caution should be used during coadministration due to the serious nature of interactions between these drugs and certain other H1-antagonists.
Loratadine; Pseudoephedrine: Theoretically, anti-retroviral protease inhibitors could lead to elevated loratadine concentrations due to inhibition of CYP3A4, CYP2D6 and/or P-glycoprotein (P-gp). Elevated loratadine serum concentrations do not result in clinically significant QT prolongation, ECG changes, or any significant differences in adverse reactions compared to control patients. However, caution should be exercised with using this drug combination in a patient with concurrent risk factors for arrhythmogenic events. Although significant drug interactions have not been confirmed between loratadine and other agents that inhibit cytochrome P-450, like protease inhibitors, caution should be used during coadministration due to the serious nature of interactions between these drugs and certain other H1-antagonists.
Losartan: Concurrent administration of losartan with ritonavir may result in elevated losartan plasma concentrations. Losartan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Lovastatin: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with lovastatin is contraindicated due to the potential for severe adverse reactions, including myopathy and rhabdomyolysis. Coadministration may result in elevated lovastatin systemic concentrations. Lovastatin is a substrate of the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this isoenzyme. In addition, lovastatin may inhibit P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with lovastatin is contraindicated due to the potential for severe adverse reactions, including myopathy and rhabdomyolysis. Coadministration may result in elevated lovastatin systemic concentrations. Lovastatin is a substrate of the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this isoenzyme. In addition, lovastatin may inhibit P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Concurrent use of lovastatin and anti-retroviral protease inhibitors is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is substantially increased if lovastatin is administered concomitantly with anti-retroviral protease inhibitors. Lovastatin is a substrate of CYP3A4 and anti-retroviral protease inhibitors are strong inhibitors of CYP3A4; therefore, coadministration may result in substantial increases in plasma concentrations of lovastatin.
Lovastatin; Niacin: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with lovastatin is contraindicated due to the potential for severe adverse reactions, including myopathy and rhabdomyolysis. Coadministration may result in elevated lovastatin systemic concentrations. Lovastatin is a substrate of the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this isoenzyme. In addition, lovastatin may inhibit P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with lovastatin is contraindicated due to the potential for severe adverse reactions, including myopathy and rhabdomyolysis. Coadministration may result in elevated lovastatin systemic concentrations. Lovastatin is a substrate of the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this isoenzyme. In addition, lovastatin may inhibit P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Concurrent use of lovastatin and anti-retroviral protease inhibitors is contraindicated. The risk of developing myopathy, rhabdomyolysis, and acute renal failure is substantially increased if lovastatin is administered concomitantly with anti-retroviral protease inhibitors. Lovastatin is a substrate of CYP3A4 and anti-retroviral protease inhibitors are strong inhibitors of CYP3A4; therefore, coadministration may result in substantial increases in plasma concentrations of lovastatin.
Lumacaftor; Ivacaftor: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir and lumacaftor; ivacaftor is contraindicated due to the potential for hepatitis C treatment failure. Dasabuvir is a 2C8 and 3A (minor) substrate; ombitasvir is a P-gp substrate; paritaprevir is a 3A4 substrate and P-gp substrate; ritonavir is a substrate of CYP3A4 and P-gp. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce and/or inhibit CYP2C8 and P-gp. Lumacaftor; ivacaftor may decrease the therapeutic efficacy of ritonavir; avoid concurrent use if possible. If concomitant use of ritonavir is necessary, monitor antiretroviral efficacy and adjust therapy as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when ritonavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking ritonavir, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking ritonavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Ritonavir is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of ritonavir and decrease its therapeutic efficacy. Although ritonavir is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor, itraconazole, increased ivacaftor exposure by 4.3-fold. Lastly, ritonavir is also a substrate of the drug transporter P-glycoprotein (P-gp), and lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect on P-gp substrates is not clear, but their exposure may be affected.
Lumacaftor; Ivacaftor: Concurrent administration of ivacaftor with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of all 5 drugs. If these drugs are taken concurrently, reduce the ivacaftor dose to 150 mg twice weekly and monitor of adverse effects associated with any of the drugs. Ivacaftor is a substrate and inhibitor of CYP3A4, and an inhibitor of the drug transporter P-glycoprotein (P-gp). Ritonavir is an inhibitor of CYP3A4, and ritonavir, paritaprevir and dasabuvir (minor) are CYP3A4 substrates. In addition, dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-gp. Caution and close monitoring are advised if these drugs are administered together. If ritonavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly (e.g., if the usual dosage is 150 mg twice daily, reduce to 150 mg twice weekly). Ivacaftor is a CYP3A substrate and ritonavir is a CYP3A inhibitor. Coadministration with ketoconazole, another strong CYP3A inhibitor, increased ivacaftor exposure by 8.5-fold. Ivacaftor is also an inhibitor of CYP3A and P-glycoprotein (P-gp); ritonavir is metabolized by CYP3A and is a substrate of P-gp. Coadministration may increase ritonavir exposure leading to increased or prolonged therapeutic effects and adverse events. Lumacaftor; ivacaftor may decrease the therapeutic efficacy of ritonavir; avoid concurrent use if possible. If concomitant use of ritonavir is necessary, monitor antiretroviral efficacy and adjust therapy as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when ritonavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking ritonavir, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking ritonavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Ritonavir is a substrate and strong inhibitor of CYP3A. Ivacaftor is a CYP3A substrate, and lumacaftor is a strong CYP3A inducer. Lumacaftor's induction of CYP3A may decrease the systemic exposure of ritonavir and decrease its therapeutic efficacy. Although ritonavir is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy (i.e., 150 mg PO every 12 hours) because of lumacaftor's CYP3A induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor, itraconazole, increased ivacaftor exposure by 4.3-fold. Lastly, ritonavir is also a substrate of the drug transporter P-glycoprotein (P-gp), and lumacaftor; ivacaftor has the potential to both induce and inhibit P-gp. The net effect on P-gp substrates is not clear, but their exposure may be affected.
Lurasidone: Concurrent use of lurasidone with strong CYP3A4 inhibitors, such as ritonavir, is contraindicated. Lurasidone is primarily metabolized by CYP3A4. Increased lurasidone plasma concentrations are expected when the drug is co-administered with inhibitors of CYP3A4.
Macitentan: Avoid concurrent use of macitentan and ritonavir. Ritonavir is a strong inhibitor of CYP3A4. Coadministration of macitentan with another strong CYP3A4 inhibitor approximately doubled macitentan exposure. Consider alternative treatment options for pulmonary hypertension if treatment with ritonavir is necessary.
Maprotiline: Ritonavir potently inhibits the CYP2D6 and CYP3A4 isozymes, and thus may inhibit the metabolism of maprotiline. Since the magnitude of the interaction with the maprotiline is difficult to predict but may be significant, monitor patients receiving ritonavir and maprotiline concurrently closely. In addition, coadministration increases the risk for QT prolongation and torsade de pointes. Adjust the dosage of maprotiline based on therapeutic response. Maprotiline serum concentration monitoring may be useful to guide adjustments and prevent toxicity.
Maraviroc: Coadministration of maraviroc, a CYP3A/P-gp substrate, with ritonavir, a strong CYP3A4 inhibitor and P-gp inhibitor, has been reported to significantly increase maraviroc concentrations. Reduce the dose of maraviroc when coadministered with strong CYP3A inhibitors; coadministration of maraviroc with strong CYP3A inhibitors is contraindicated in patients with CrCl less than 30 mL/min. Adjust the maraviroc dosage as follows when administered with ritonavir (with or without a concomitant CYP3A inducer): adults and children weighing 40 kg or more: 150 mg PO twice daily; children weighing 30 to 39 kg: 100 mg PO twice daily; children weighing 20 to 29 kg: 75 mg PO twice daily (or 80 mg PO twice daily for solution); children weighing 10 to 19 kg: 50 mg PO twice daily.
Meclizine: Concurrent administration of meclizine with ritonavir may result in elevated meclizine plasma concentrations. Meclizine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Medroxyprogesterone: Coadministration of medroxyprogesterone, a CYP3A substrate with ritonavir, a strong CYP3A inhibitor should be avoided since it is expected to increase concentrations of medroxyprogesterone acetate. Formal drug interaction studies have not been conducted; however, medroxyprogesterone is metabolized primarily by hydroxylation via the CYP3A4 in vitro.
Mefloquine: Concurrent administration of mefloquine with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of all 5 drugs and susequent adverse effects such as QT prolongation. Mefloquine is a substrate of the hepatic isoenzyme CYP3A4, and a substrate and inhibitor of the drug transporter P-glycoprotein (P-gp). Ritonavir is a potent inhibitor of CYP3A4 and also inhibits P-gp. In addition, dasabuvir, ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp. Mefloquine alone has not been reported to cause QT prolongation. However, due to the lack of clinical data, mefloquine should be used with caution and careful monitoring in patients receiving drugs that prolong the QT interval, such as ritonavir. Mefloquine is metabolized by CYP3A4. Ritonavir is an inhibitor of this enzyme and may decrease the clearance of mefloquine and increase mefloquine systemic exposure. In addition, coadministration increases the risk for QT prolongation and torsade de pointes.
Meloxicam: Concurrent administration of meloxicam with ritonavir may result in elevated meloxicam plasma concentrations. Meloxicam is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Meperidine: Concomitant use of high-dose, long-term meperidine therapy with ritonavir is not recommended due the increased concentration of the neurotoxic metabolite of meperidine, normeperidine. Ritonavir is associated with a 62% decrease in meperidine AUC thought to be due to increased meperidine metabolism. The AUC and Cmax of normeperidine, the toxic metabolite of meperidine, increased 47% and 87%, respectively, with concurrent administration of ritonavir.
Meperidine; Promethazine: Concomitant use of high-dose, long-term meperidine therapy with ritonavir is not recommended due the increased concentration of the neurotoxic metabolite of meperidine, normeperidine. Ritonavir is associated with a 62% decrease in meperidine AUC thought to be due to increased meperidine metabolism. The AUC and Cmax of normeperidine, the toxic metabolite of meperidine, increased 47% and 87%, respectively, with concurrent administration of ritonavir. Concurrent administration of promethazine with ritonavir may result in elevated plasma concentrations of promethazine and increased risk of adverse events. Promethazine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. In addition, rarely promethazine has been associated with QT prolongation. Caution and close monitoring are advised if these drugs are administered together.
Mephobarbital: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with mephobarbital is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir, and ritonavir. Mephobarbital is converted to phenobarbital in vivo, and phenobarbital is a potent inducer of the hepatic isoenzyme CYP3A4. Dasabuvir (minor), paritaprevir, and ritonavir are substrates of this isoenzyme. In addition, phenobarbital may induce P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir, and ritonavir are substrates. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with mephobarbital is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir, and ritonavir. Mephobarbital is converted to phenobarbital in vivo, and phenobarbital is a potent inducer of the hepatic isoenzyme CYP3A4. Dasabuvir (minor), paritaprevir, and ritonavir are substrates of this isoenzyme. In addition, phenobarbital may induce P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir, and ritonavir are substrates. Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required.
Mestranol; Norethindrone: Because mestranol is converted to ethinyl estradiol in the body, comcomitant use of mestranol; norethindrone with dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated due to the potential for elevated liver function tests (LFTs). Mestranol; norethindrone must be discontinued prior to starting dasabuvir; ombitasvir; paritaprevir; ritonavir, and restarted no sooner than 2 weeks after completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving ethinyl estradiol with dasabuvir; ombitasvir; paritaprevir; ritonavir experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with dasabuvir; ombitasvir; paritaprevir; ritonavir. Because mestranol is converted to ethinyl estradiol in the body, comcomitant use of mestranol; norethindrone with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir is contraindicated due to the potential for elevated liver function tests (LFTs). Mestranol; norethindrone must be discontinued prior to starting the hepatitis C regimen, and restarted no sooner than 2 weeks after completion of the hepatitis C regimen. Alternate forms of contraception should be employed at this time. During clinical studies, female patients receiving ethinyl estradiol with dasabuvir; ombitasvir; paritaprevir; ritonavir experienced significantly higher rates of ALT elevations. Health care providers are advised that estrogens other than ethinyl estradiol did not show the same increase in ALT; however, due to the limited number of study subjects, the manufacturer recommends these estrogens be used with caution when administered with the hepatitis C regimen. Ritonavir increases the metabolism of mestranol. Women receiving hormonal contraceptives and ritonavir should be instructed to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives concurrently with ritonavir to use an additional method of contraception to protect against unwanted pregnancy. Additionally, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive hormonal contraceptives concurrently with ritonavir should use an additional barrier method of contraception such as condoms. Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. For example, ritonavir (also found in combinations like lopinavir; ritonavir, and used as a booster in many HIV treatment regimens) may decrease the metabolism of norethindrone, raising norethindrone concentrations. Women receiving norethindrone for hormone replacement or contraception should report potential hormonal adverse effects (e.g., bleeding pattern changes, acne, emotional lability) or any changes in efficacy (e.g., noted changes in bleeding patterns) to their prescribers. Because norethindrone-containing contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive norethindrone contraception concurrently with ritonavir should use an additional barrier method of contraception such as condoms.
Metaproterenol: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir, include beta-agonists.
Metformin: The manufacturer recommends against concurrent administration of ombitasvir; paritaprevir; ritonavir and metformin in patients with hepatic or renal impairment. If these drugs are given together, closely monitor blood glucose concentrations and for signs of lactic acidosis (i.e., abdominal or respiratory distress, worsening renal function, somnolence). New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Metformin; Pioglitazone: Concurrent administration of pioglitazone with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated pioglitazone plasma concentrations and decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Pioglitazone is an inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. In addition, pioglitazone is metabolized by CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. The manufacturer recommends against concurrent administration of ombitasvir; paritaprevir; ritonavir and metformin in patients with hepatic or renal impairment. If these drugs are given together, closely monitor blood glucose concentrations and for signs of lactic acidosis (i.e., abdominal or respiratory distress, worsening renal function, somnolence). New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Metformin; Repaglinide: The manufacturer recommends against concurrent administration of ombitasvir; paritaprevir; ritonavir and metformin in patients with hepatic or renal impairment. If these drugs are given together, closely monitor blood glucose concentrations and for signs of lactic acidosis (i.e., abdominal or respiratory distress, worsening renal function, somnolence). Concurrent administration of repaglinide with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated repaglinide plasma concentrations. Monitor blood glucose concentrations closely; a repaglinide dosage reduction may be necessary. Repaglinide is a substrate of the hepatic isoenzyme CYP3A4 and the organic anion transporting polypeptides (OATP). Ritonavir inhibits CYP3A4, and paritaprevir is an OATP1B1 and OATP1B3 inhibitor. Caution and close monitoring are advised if these drugs are administered together. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, repaglinide is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1), protease inhibitors inhibit CYP3A4 and OATP.
Metformin; Rosiglitazone: The manufacturer recommends against concurrent administration of ombitasvir; paritaprevir; ritonavir and metformin in patients with hepatic or renal impairment. If these drugs are given together, closely monitor blood glucose concentrations and for signs of lactic acidosis (i.e., abdominal or respiratory distress, worsening renal function, somnolence). New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Metformin; Saxagliptin: The manufacturer recommends against concurrent administration of ombitasvir; paritaprevir; ritonavir and metformin in patients with hepatic or renal impairment. If these drugs are given together, closely monitor blood glucose concentrations and for signs of lactic acidosis (i.e., abdominal or respiratory distress, worsening renal function, somnolence). The metabolism of saxagliptin is primarily mediated by CYP3A4/5. The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP3A4/5 inhibitor such as ritonavir. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have also been reported with use of anti-retroviral protease inhibitors, such as ritonavir. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Metformin; Sitagliptin: The manufacturer recommends against concurrent administration of ombitasvir; paritaprevir; ritonavir and metformin in patients with hepatic or renal impairment. If these drugs are given together, closely monitor blood glucose concentrations and for signs of lactic acidosis (i.e., abdominal or respiratory distress, worsening renal function, somnolence). New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Methadone: Ritonavir may result in QT prolongation and the effect may be additive to the QT prolongation risk from methadone. Additionally, due to effects on CYP enzymes responsible for hepatic metabolism, ritonavir may alter the response to various opioid agonists. Administration of methadone and ritonavir has resulted in a 36% decrease in methadone AUC and 38% decrease in methadone Cmax in some reports; increased methadone doses may be required. However, any methadone dose increase should be approached with caution.
Methamphetamine: Patients receiving amphetamines may experience prolonged effects if receiving ritonavir concurrently. A case report describes a patient who was treated with ritonavir and saquinavir and then experienced a prolonged effect from a small dose of methylene-dioxy-methamphetamine (MDMA or ecstasy) and a near fatal reaction from a small dose of gamma-hydroxybutyrate (GHB). The effects in this patient suggests that the prolonged effects of MDMA were due to ritonavir-induced inhibition of CYP2D6 metabolism. The GHB toxicity in this patient may have been due to ritonavir-induced inhibition of first pass metabolism, leading to increased levels of GHB. Patients receiving other amphetamine drugs, such as amphetamine, amphetamine; dextroamphetamine mixed salts, lisdexamfetamine, or methamphetamine may experience prolonged effects if receiving ritonavir concurrently. Patients should be warned that there are potentially serious drug interactions between ritonavir and illicit drugs, such as ecstasy.
Methohexital: Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required.
Methylergonovine: Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
Methylprednisolone: Concurrent administration of methylprednisolone with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated methylprednisolone plasma concentrations. Methylprednisolone is metabolized by the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp); ritonavir is an inhibitor of this enzyme and drug transporter. Paritaprevir also inhibits P-gp. Use caution and monitor for corticosteroid-related side effects if these drugs are administered together. Concurrent administration of methylprednisolone with ritonavir may result in elevated methylprednisolone plasma concentrations. Methylprednisolone is metabolized by the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp); ritonavir is an inhibitor of this enzyme and transporter. Use caution and monitor for corticosteroid-related side effects if these drugs are administered together.
Methysergide: Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
Metoclopramide: Concurrent administration of metoclopramide with ritonavir may result in elevated plasma concentrations of metoclopramide. Metoclopromide is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Metoprolol: Metoprolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as ritonavir, may impair metoprolol metabolism. Clinicians should be alert to exaggerated beta-blocker effects if metoprolol is given with these drugs.
Metronidazole: Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Oral solutions of ritonavir contain ethanol. Administration of ritonavir oral solution to patients receiving or who have recently received disulfiram or metronidazole may result in disulfiram-like reactions. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations. Addtionally, potential QT prolongation has been reported in limited case reports with metronidazole; therefore, it should be used cautiously and with close monitoring when administered with ritonavir, which has a possible risk for QT prolongation and TdP.
Metyrapone: Concurrent administration of metyrapone with dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in decreased plasma concentrations of dasabuvir, paritaprevir, and ritonavir, which may affect antiviral efficacy. Metyrapone is an inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. Concurrent administration of metyrapone with ritonavir may result in decreased plasma concentrations of ritonavir. Metyrapone is an inducer of the hepatic isoenzyme CYP3A4; ritonavir is a CYP3A4 substrate. If metyrapone is used chronically, monitor for antiviral efficacy.
Mexiletine: Ritonavir is an inhibitor of CYP3A4 and CYP2D6 (in vitro), and may increase exposure to drugs metabolized by these enzymes, such as mexiletine. Increased mexiletine serum concentrations may increase the risk for adverse reactions.
Midazolam: The use of oral midazolam and anti-retroviral protease inhibitors is contraindicated. Midazolam is metabolized by hepatic isozyme CYP3A4; inhibitors of this pathway can potentiate the clinical effects of midazolam. Protease inhibitors have been shown to increase oral midazolam AUCs by up to 3-fold, resulting in clinically significant potentiation of sedation. Lorazepam, oxazepam, or temazepam may be safer alternatives, as these benzodiazepines are not oxidatively metabolized. Parenteral midazolam can be used with protease inhibitors in a setting that allows for close clinical monitoring with the ability to manage respiratory depression or sedation should they occur; a reduction in the dose of parenteral midazolam may be warranted.
Midostaurin: Concomitant use of midostaurin and ritonavir is contraindicated, as significantly increased exposure of midostaurin and its active metabolites may occur resulting in serious adverse effects, including QT prolongation. Both midostaurin and ritonavir have been associated with QT prolongation. Additionally, midostaurin is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. The AUC values of midostaurin and its metabolites CGP62221 and CGP52421 increased by 10.4-fold, 3.5-fold, and 1.2-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor in a drug interaction study. The Cmin (trough) levels of midostaurin and its metabolites CGP62221 and CGP52421 on day 28 increased by 2.1-fold, 1.2-fold, and 1.3-fold, respectively, when midostaurin was administered with another strong CYP3A4 inhibitor compared with day 21 Cmin levels with midostaurin alone in another drug interaction study.
Mifepristone, RU-486: An increased risk of adverse events, including QT prolongation, and elevated plasma concentrations of all 5 drugs may result if mifepristone, RU-486 is coadministered with dasabuvir; ombitasvir; paritaprevir; ritonavir. If these drugs must be used together, closely monitor the patient for adverse events. Mifepristone has been associated with dose-dependent prolongation of the QT interval; the lowest effective dose should always be used to decrease risk and it should be used cautiously with other drugs that may prolong the QT interval. While dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QTc interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with QT prolongation in other trials. Further caution is warranted as increased concentrations of mifepristone, ritonavir, dasabuvir, ombitasvir, and paritaprevir are expected due to metabolic interactions, along with an increased risk of serious adverse effects. Mifepristone is a CYP3A4 substrate/inhibitor and a P-glycoprotein (P-gp) inhibitor. Ritonavir is CYP3A4 substrate/potent inhibitor and a P-gp substrate. Paritaprevir and dasabuvir (minor) are CYP3A4 and P-gp substrates, and ombitasvir is a P-gp substrate. Also of note, in patients receiving mifepristone for endogenous Cushing's syndrome, the dosage should not exceed 300 mg once daily if a potent CYP3A4 inhibitor, such as ritonavir, is also used. Avoid coadministration of ritonavir with mifepristone if possible because increased serum concentrations of either drug and an increased risk of QT prolongation may result. The benefit of concomitant use of these agents should be carefully weighed against the potential risks. Both mifepristone and ritonavir have been associated with QT prolongation. The CYP3A4 metabolism of mifepristone may be inhibited by ritonavir, a strong CYP3A4 inhibitor. In addition, mifepristone is a strong CYP3A4 inhibitor and may lead to an increase in serum concentrations of CYP3A4 substrates, such as ritonavir. When mifepristone is used in the treatment of Cushing's syndrome, coadministration with strong CYP3A inhibitors should be done only when necessary, and in such cases the dose of mifepristone should be limited to 600 mg per day. In a patient already receiving ritonavir, initiate mifepristone at a dose of 300 mg and titrate to a maximum of 600 mg if clinically indicated. If therapy with ritonavir is initiated in a patient already receiving mifepristone 300 mg, mifepristone dosage adjustments are not required. If therapy with ritonavir is initiated in a patient already receiving mifepristone 600 mg, reduce dose of mifepristone to 300 mg and titrate to a maximum of 600 mg if clinically indicated. If therapy with ritonavir is initiated in a patient already receiving mifepristone 900 mg or 1200 mg, reduce the mifepristone dose to 600 mg.
Miglitol: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors.
Mirabegron: Concurrent administration of mirabegron with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of mirabegron, dasabuvir, paritaprevir and ritonavir. Both ritonavir and mirabegron are substrates and inhibitors of the hepatic isoenzymes CYP3A4 and CYP2D6, while paritaprevir and dasabuvir (minor) are CYP3A4 substrates. In addition mirabegron is a substrate for uridine glucuronyltransferase (UGT ) and P-glycoprotein (P-gp); dasabuvir, ombitasvir and paritaprevir are UGT1A1 inhibitors and ritonavir is a P-gp inhibitor. Caution and close monitoring for adverse effects, such as increased blood pressure, are advised if these drugs are administered together. Concurrent administration of mirabegron with ritonavir may result in elevated plasma concentrations of both drugs. Both ritonavir and mirabegron are substrates and inhibitors of the hepatic isoenzymes CYP3A4 and CYP2D6. In addition, mirabegron is a substrate for P-glycoprotein (P-gp); ritonavir is a P-gp inhibitor. Caution and close monitoring for adverse effects, such as increased blood pressure, are advised if these drugs are administered together.
Mirtazapine: Concurrent administration of mirtazapine with protease inhibitors may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine and decrease the dose if necessary. Mirtazapine is metabolized by the hepatic isoenzymes CYP3A4 and CYP2D6; protease inhibitors block the actions of both these enzymes.
Mitomycin: The plasma concentrations of mitomycin may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as myelosuppression and pulmonary toxicity, is recommended during coadministration. Ritonavir is a P-glycoprotein (P-gp) inhibitor, while mitomycin is a P-gp substrate.
Mitotane: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with mitotane is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposure to dasabuvir, ombitasvir, paritaprevir and ritonavir. Mitotane is a strong inducer of CYP3A4; dasabuvir (minor), paritaprevir, and ritonavir are substrates of this isoenzyme. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with mitotane is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposure to dasabuvir, ombitasvir, paritaprevir and ritonavir. Mitotane is a strong inducer of CYP3A4; dasabuvir (minor), paritaprevir, and ritonavir are substrates of this isoenzyme. Avoid the concomitant use of mitotane with ritonavir due to the potential for reduced antiretroviral efficacy and the potential development of viral resistance. If coadministration cannot be avoided, monitor for decreased efficacy of ritonavir. Mitotane is a strong CYP3A4 inducer and ritonavir is a CYP3A4 substrates; coadministration may result in decreased plasma concentrations of ritonavir. Another strong CYP3A inducer, rifampin (300 or 600 mg daily for 10 days), decreased the AUC and Cmax of ritonavir (500 mg every 12 hours for 20 days) by 35% and 25%, respectively.
Modafinil: Concurrent administration of modafinil with dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in elevated plasma concentrations of modafinil and decreased concentrations of dasabuvir, paritaprevir, and ritonavir, which may affect antiviral efficacy. Modafinil is a substrate and inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. In addition, ritonavir is a potent CYP3A4 inhibitor. Concurrent administration of modafinil with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in elevated plasma concentrations of modafinil and decreased concentrations of dasabuvir, paritaprevir, and ritonavir, which may affect antiviral efficacy. Modafinil is a substrate and inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. In addition, ritonavir is a potent CYP3A4 inhibitor. Concurrent administration of modafinil with ritonavir may result in elevated plasma concentrations of modafinil and decreased concentrations of ritonavir. Modafinil is a substrate and inducer of the hepatic isoenzyme CYP3A4; ritonavir is a CYP3A4 substrate. In addition, ritonavir is a potent CYP3A4 inhibitor. Because the resultant effect of coadministration of a CYP3A4 inducer (modafinil) and inhibitor (ritonavir) on the plasma concentrations of these drugs is not defined, caution and close monitoring are advised if these drugs are administered together.
Mometasone: Coadministration of mometasone with ritonavir (a strong CYP3A4 inhibitor) may cause mometasone serum concentrations to increase, potentially resulting in Cushing's syndrome and adrenal suppression. Consider use of an alternative corticosteroid whose concentrations are less affected by strong CYP3A4 inhibitors, such as beclomethasone and prednisolone, especially during long-term treatment.
Montelukast: Concurrent administration of montelukast with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in increased plasma concentrations of montelukast and dasabuvir. Montelukast is a substrate for the hepatic isoenzymes CYP2C8 (primary), CYP2C9, and CYP3A4; ritonavir is a potent CYP3A4 inhibitor. It is unclear whether the inhibition of only one of the involved enzymes would lead to a clinically significant interaction. In addition, in vitro data suggests montelukast is a potent inhibitor of CYP2C8; however, in vivo data do not substantiate a clinically relevant interaction with CYP2C8 substrates. Dasabuvir is primarily metabolized by CYP2C8. Monitor for adverse effects if these drugs are administered together. Concurrent administration of montelukast with ritonavir may result in increased plasma concentrations of montelukast. Montelukast is a substrate for the hepatic isoenzymes CYP2C8 (primary), CYP2C9, and CYP3A4; ritonavir is a potent CYP3A4 inhibitor. It is unclear whether the inhibition of only one of the involved enzymes would lead to a clinically significant interaction. Monitor for adverse effects if these drugs are administered together.
Morphine: Close clinical monitoring is advised when administering morphine with ritonavir due to an increased potential for morphine-related adverse events, including hypotension, respiratory depression, profound sedation, coma, and death. Dosage reductions of morphine and/or ritonavir may be required. Morphine is a substrate of the drug efflux transporter P-glycoprotein (P-gp); ritonavir is an inhibitor of this efflux protein. Coadministration may cause an approximate 2-fold increase in morphine exposure.
Morphine; Naltrexone: Close clinical monitoring is advised when administering morphine with ritonavir due to an increased potential for morphine-related adverse events, including hypotension, respiratory depression, profound sedation, coma, and death. Dosage reductions of morphine and/or ritonavir may be required. Morphine is a substrate of the drug efflux transporter P-glycoprotein (P-gp); ritonavir is an inhibitor of this efflux protein. Coadministration may cause an approximate 2-fold increase in morphine exposure.
Moxifloxacin: Concomitant use of ritonavir with moxifloxacin may theoretically increase the risk of QT prolongation. Additionally, other ritonavir adverse effects may be increased. Ritonavir was evaluated for QT prolongation in a randomized, placebo and moxifloxacin (400 mg once-daily) controlled, crossover study in 45 healthy adults; QT intervals were measured on the third day. All patients took ritonavir 400 mg twice daily; the maximum mean (95% upper confidence bound) difference in QT interval in patients on moxifloxacin versus placebo after baseline correction was 5.5 (7.6) milliseconds. Additionally, after 3 days of ritonavir 400 mg twice daily plus moxifloxacin, ritonavir exposure was approximately 1.5 times higher than exposure that has been observed with ritonavir 600 mg twice-daily alone. Caution and close monitoring is advised if these drugs are administered together.
Nabilone: Coadministration of ritonavir and oral THC results in increased THC concentrations. A decreased dose of nabilone may be needed if these drugs are coadministered with ritonavir.
Nadolol: Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
Nafcillin: Concurrent administration of nafcillin with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in decreased plasma concentrations of dasabuvir, paritaprevir, and ritonavir, which may affect antiviral efficacy. Nafcillin is an inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir and dasabuvir (minor) are CYP3A4 substrates. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of nafcillin with ritonavir may result in decreased plasma concentrations of ritonavir, which may affect antiviral efficacy. Nafcillin is an inducer of the hepatic isoenzyme CYP3A4; ritonavir is a CYP3A4 substrate. Caution and close monitoring are advised if these drugs are administered together.
Nanoparticle Albumin-Bound Paclitaxel: Concurrent administration of paclitaxel (or nanoparticle albumin-bound paclitaxel) with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in increased paclitaxel plasma concentrations and risk for toxicity. Caution and close monitoring are advised if these drugs are administered together. Paclitaxel is metabolized by the hepatic isoenzymes CYP2C8 and CYP3A4; ritonavir is a potent CYP3A4 inhibitor. In addition, paclitaxel is a substrate of the drug transporter P-glycoprotein (P-gp), and ritonavir also inhibits P-gp. Paritaprevir also inhibits P-gp. Concurrent administration of paclitaxel (or nanoparticle albumin-bound paclitaxel) with protease inhibitors may result in increased paclitaxel plasma concentrations and risk for toxicity. Caution and close monitoring are advised if these drugs are administered together. Paclitaxel is metabolized by the hepatic isoenzymes CYP2C8 and CYP3A4; protease inhibits are potent CYP3A4 inhibitors. In addition, paclitaxel is a substrate of the drug transporter P-glycoprotein (P-gp); some protease inhibitors also inhibit P-gp. Several case reports describe potential interactions between anti-retroviral protease inhibitors and paclitaxel. In one report, two patients on combined therapy with delavirdine, didanosine, and saquinavir developed unexpectedly severe paclitaxel toxicity, including mucositis and neutropenia, but a causal relationship was not established. These patients were previously treated with paclitaxel with only mild toxicity (i.e., nausea and alopecia). In another case, paclitaxel was given concomitantly with antiretroviral agents and no dosage adjustments of paclitaxel, indinavir, ritonavir, saquinavir or nevirapine were required.
Nateglinide: Concurrent administration of nateglinide with protease inhibitors may result in elevated nateglinide plasma concentrations. Monitor blood glucose concentrations during coadministration as hypoglycemia could occur. Nateglinide is partially metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors are potent inhibitor of this enzyme. However, new onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Monitor blood glucose concentrations during coadministration. Caution and close monitoring are advised if these drugs are administered together.
Nebivolol: Ritonavir is expected to decrease the hepatic CYP metabolism of beta-blockers like nebivolol, resulting in increased beta-blocker concentrations. Cardiac and neurologic events have been reported when ritonavir is concurrently administered with beta-blockers. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including beta-blockers) has not been evaluated. If coadministration of nebivolol and ritonavir is warranted, do so with caution and careful monitoring. Decreased beta-blocker doses may be warranted.
Nebivolol; Valsartan: Coadministration of valsartan and regimens containing paritaprevir may result in elevated valsartan plasma concentrations. A valsartan dose reduction, and close monitoring for adverse events (i.e., hypotension and worsening renal function) are advised during coadministration. If adverse events are observed, consider further reductions in valsartan dose or an alternative to the angiotensin receptor blocker. Valsartan is a substrate of the organic anion transporting polypeptides (OATP) and paritaprevir is an OATP1B1 and OATP1B3 inhibitor. Ritonavir is expected to decrease the hepatic CYP metabolism of beta-blockers like nebivolol, resulting in increased beta-blocker concentrations. Cardiac and neurologic events have been reported when ritonavir is concurrently administered with beta-blockers. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including beta-blockers) has not been evaluated. If coadministration of nebivolol and ritonavir is warranted, do so with caution and careful monitoring. Decreased beta-blocker doses may be warranted. Valsartan is a substrate of the hepatic efflux transporter MRP2 and ritonavir is an inhibitor of MRP2. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan during coadministration.
Nefazodone: Elevated plasma concentrations of nefazodone and ritonavir may occur. Both ritonavir and nefazodone are CYP3A4 substrates/potent inhibitors. Cardiac and neurologic events have been reported when ritonavir was concurrently administered with nefazodone. If coadministration of these drugs is warranted, do so with caution and careful monitoring. A 50% reduction in the nefazodone dose may be warranted. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs with potential bradycardic effects has not been evaluated. If coadministration of nefazodone and dasabuvir; ombitasvir; paritaprevir; ritonavir is warranted, do so with caution and careful monitoring. Cardiac and neurological events have been reported when ritonavir has been coadministered with nefazodone. Ritonavir prolongs the PR interval in some; the impact on the PR interval during coadministration with drugs that posess bradycardic effects, such as nefazodone, has not been specifically evaluated. Elevated plasma concentrations of nefazodone, dasabuvir, paritaprevir, and ritonavir may occur. Both ritonavir and nefazodone are CYP3A4 substrates/potent inhibitors, and paritaprevir and dasabuvir (minor) are CYP3A4 substrates.
Nelfinavir: Concurrent administration of nelfinavir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of nelfinavir, dasabuvir, ombitasvir, paritaprevir and ritonavir. When nelfinavir and ritonavir are coadministered, the nelfinavir AUC increases 1.5-fold; dosage recommendations for coadministration are given in the HIV treatment guidelines that cannot be met with the combination product (ritonavir 400 mg twice daily plus nelfinavir 500 to 750 mg twice daily). If these drugs are given together, closely monitor patients for adverse events. Both ritonavir and nelfinavir are potent inhibitors and substrates of CYP3A4; paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. In addition, nelfinavir is a substrate and inhibitor of the drug transporter P-glycoprotein (P-gp); ritonavir is a subsrate and inhibitor of P-gp; and dasabuvir, ombitasvir, and paritaprevir are all substrates of P-gp. Concurrent administration of nelfinavir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of nelfinavir, dasabuvir, ombitasvir, paritaprevir and ritonavir. When nelfinavir and ritonavir are coadministered, the nelfinavir AUC increases 1.5-fold; dosage recommendations for coadministration are given in the HIV treatment guidelines that cannot be met with the combination product (ritonavir 400 mg twice daily plus nelfinavir 500 to 750 mg twice daily). If these drugs are given together, closely monitor patients for adverse events. Both ritonavir and nelfinavir are potent inhibitors and substrates of CYP3A4; paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. In addition, nelfinavir is a substrate and inhibitor of the drug transporter P-glycoprotein (P-gp); ritonavir is a subsrate and inhibitor of P-gp; paritaprevir inhibits P-gp; and dasabuvir, ombitasvir, and paritaprevir are all substrates of P-gp. Concurrent administration of ritonavir and nelfinavir results in a 1.5-fold increase of nelfinavir AUC. Dosage recommendations for coadministration from HIV treatment guidelines are ritonavir 400 mg twice daily plus nelfinavir 500 to 750 mg twice daily. Both ritonavir and nelfinavir are potent inhibitors and substrates of CYP3A4 and P-glycoprotein (P-gp).
Netupitant; Palonosetron: Concurrent administration of netupitant; palonosetron with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of netupitant, palonosetron, dasabuvir, paritaprevir and ritonavir. Both ritonavir and netupitant are substrates and inhibitors of CYP3A4; palonosetron, paritaprevir and dasabuvir (minor) are metabolized by CYP3A4. Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are metabolized through CYP3A4 such as ritonavir; the inhibitory effect of CYP3A4 can last for multiple days. Increased ritonavir concentrations may lead to ritonavir-induced side effects, including a possible risk for QT prolongation. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor such as ritonavir can significantly increase the systemic exposure to netupitant. No dosage adjustment is necessary for single dose adminstration of netupitant; palonosetron. In addition, palonosetron is metabolized by the hepatic isoenzymes CYP2D6; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are metabolized through CYP3A4 such as ritonavir; the inhibitory effect on CYP3A4 can last for multiple days. Increased ritonavir concentrations may lead to ritonavir-induced side effects, including a possible risk for QT prolongation. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor such as ritonavir can significantly increase the systemic exposure to netupitant. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron.
Nevirapine: Concurrent administration of nevirapine with dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in elevated nevirapine plasma concentrations and decreased plasma concentrations of paritaprevir, ritonavir, and dasabuvir, which may affect antiviral efficacy. Nevirapine is a substrate and inducer of the hepatic isoenzyme CYP3A4; ritonavir is a substrate and potent inhibitor of this enzyme. Paritaprevir and dasabuvir (minor) are also metabolized by CYP3A4. Concurrent administration of nevirapine with ritonavir may result in elevated nevirapine plasma concentrations and decreased concentrations of ritonavir. Nevirapine is a substrate and inducer of the hepatic isoenzyme CYP3A4; ritonavir is a substrate and potent inhibitor of this enzyme. Caution and close monitoring for antiviral efficacy and adverse effects are advised if these drugs are administered together.
Niacin; Simvastatin: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with simvastatin is contraindicated due to the potential for severe adverse reactions, including myopathy and rhabdomyolysis. Coadministration may result in elevated simvastatin systemic concentrations. Simvastatin is a substrate of the hepatic isoenzyme CYP3A4 and OATP1B1; ritonavir is a potent inhibitor of CYP3A4 and paritaprevir inhibits OATP1B1. In addition, simvastatin may inhibit P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with simvastatin is contraindicated due to the potential for severe adverse reactions, including myopathy and rhabdomyolysis. Coadministration may result in elevated simvastatin systemic concentrations. Simvastatin is a substrate of the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this isoenzyme. In addition, simvastatin may inhibit P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Nicardipine: Elevated plasma concentrations and an increased risk of serious adverse events may occur with coadministration of nicardipine and dasabuvir; ombitasvir; paritaprevir; ritonavir. Ritonavir and nicardipine both prolong the PR interval and the manufacturer for ritonavir recommends caution during coadministration. The metabolic interactions that may occur are complex, with increased plasma concentrations and, thus, adverse reactions of all 5 drugs anticipated. Nicardipine is a CYP2C8 inhibitor, a CYP2D6 potent inhibitor, a CYP3A4 substrate/ inhibitor, and a P-glycoprotein (P-gp) transport substrate/potent inhibitor. Ritonavir is a CYP2D6 substrate/inhibitor, a CYP3A4 substrate/potent inhibitor, and a P-gp substrate/inhibitor. Paritaprevir is a substrate of CYP3A4 and P-gp. Dasabuvir is a substrate of CYP2C8, CYP3A4, and P-gp. Ombitasvir is a P-gp substrate. Caution and close monitoring are advised if these drugs are administered together. Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
Nifedipine: According to the manufacturer of nifedipine, coadministration with ritonavir may result in increased exposure to nifedipine, and initiation of nifedipine should begin with the lowest available dose. Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted. Elevated plasma concentrations and an increased risk of serious adverse events may occur with coadministration of nifedipine and dasabuvir; ombitasvir; paritaprevir; ritonavir. A nifedipine dose reduction and close monitoring for adverse events (i.e., hypotension and edema) are advised during coadministration. If adverse events are observed, consider further nifedipine dose reductions or an alternative to the calcium channel blocker. Ritonavir and nifedipine both prolong the PR interval and caution for increased risk is recommended with coadministration. Ritonavir (potent CYP3A4 inhibitor) may inhibit nifedipine (CYP3A4 substrate) metabolism, resulting in increased exposure to nifedipine. The manufacturers of both ritonavir and nifedipine recommend caution, careful monitoring, and possible nifedipine dose adjustment during coadministration; the lowest available nifedipine dose should be used if nifedipine is initiated. Additionally, nifedipine may increase dasabuvir, ombitasvir, paritaprevir, and ritonavir concentrations as it is a mild inhibitor of the P-glycoprotein (P-gp) drug transporter.
Nilotinib: Avoid the concomitant use of nilotinib and dasabuvir; ombitasvir; paritaprevir; ritonavir. Nilotinib should be avoided in patients receiving strong CYP3A4 inhibitors. Nilotinib should also be avoided in patients receiving drugs that prolong the QT interval. Ritonavir is a strong CYP3A4 inhibitor and has also been associated with QT prolongation in clinical trials. If use of dasabuvir; ombitasvir; paritaprevir; ritonavir is necessary, hold nilotinib therapy. If the use of nilotinib and dasabuvir; ombitasvir; paritaprevir; ritonavir cannot be avoided, closely monitor the QT interval and consider a nilotinib dose reduction (to nilotinib 200 mg PO once daily in adult patients with newly diagnosed Ph+ CML or to nilotinib 300 mg PO once daily in adult patients with resistant or intolerant Ph+ CML). In addition to an increased risk of serious adverse events, such as QT prolongation, elevated plasma concentrations of all 5 drugs may result due to complex drug interactions. Nilotinib is a CYP2D6 inhibitor, a CYP3A4 substrate/inhibitor, a CYP2C8 inhibitor/inducer, and a P-glycoprotein (P-gp) drug transporter substrate/inhibitor. Ritonavir is a CYP3A4 substrate/potent inhibitor, CYP2D6 substrate, and a P-gp substrate/inhibitor. Paritaprevir is a substrate of CYP3A4 and P-gp. Dasabuvir is a substrate of CYP2C8, CYP3A4, and P-gp. Ombitasvir is a P-gp substrate. Avoid the concomitant use of nilotinib, a substrate and inhibitor of CYP3A4 and P-glycoprotein (P-gp), with ritonavir, a substrate and strong inhibitor of CYP3A4 and a substrate and inhibitor of P-gp; levels of both drugs may increase. If the use of a strong CYP3A4 inhibitor is necessary, hold nilotinib therapy. If the use of nilotinib and ritonavir cannot be avoided, consider a nilotinib dose reduction (to nilotinib 200 mg PO once daily in adult patients with newly diagnosed Ph+ CML or to nilotinib 300 mg PO once daily in adult patients with resistant or intolerant Ph+ CML); close monitoring of the QT interval is recommended. If the strong CYP3A4 inhibitor is discontinued, titrate the nilotinib dose upward to the recommended dose following a washout period.
Nimodipine: Anti-retroviral protease inhibitors are CYP3A4 inhibitors and may decrease the hepatic metabolism of nimodipine, leading to increased plasma concentrations of nimodipine. In addition, ritonavir and calcium channel blockers both prolong the PR interval and the manufacturer for ritonavir recommends caution during coadministration. Monitor therapeutic response and for adverse effects, such as hypotension. Decreased calcium-channel blocker doses may be warranted.
Nintedanib: Concurrent administration of nintedanib with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated nintedanib plasma concentrations. Closely monitor the patient for nintedanib adverse effects, including gastrointestinal toxicity, elevated liver enzymes, and hypertension; a dose reduction, interruption of therapy, or discontinuation of therapy may be necessary. Nintedanib is a substrate of CYP3A4 and P-glycoprotein (P-gp). Ritonavir can increase nintedanib concentrations as it is a potent CYP3A4 inhibitor and a P-gp inhibitor. Paritaprevir also inhibits P-gp. Concurrent administration of nintedanib with ritonavir may result in elevated nintedanib plasma concentrations. Closely monitor the patient for nintedanib adverse effects, including gastrointestinal toxicity, elevated liver enzymes, and hypertension; a dose reduction, interruption of therapy, or discontinuation of therapy may be necessary. Nintedanib is a substrate of CYP3A4 and P-glycoprotein (P-gp). Ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor.
Nisoldipine: Anti-retroviral protease inhibitors may decrease the hepatic CYP metabolism of calcium-channel blockers (mainly through CYP3A4 inhibition) resulting in increased calcium-channel blocker concentrations. In addition, ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
Norethindrone: Many anti-retroviral protease inhibitors may interact with hormonal agents like norethindrone, due to their actions on CYP metabolism, particularly CYP3A4. Data on the effects that protease inhibitors have on the serum concentrations of norethindrone are complex and are based mostly off of data with norethindrone-containing contraceptives. For example, ritonavir (also found in combinations like lopinavir; ritonavir, and used as a booster in many HIV treatment regimens) may decrease the metabolism of norethindrone, raising norethindrone concentrations. Women receiving norethindrone for hormone replacement or contraception should report potential hormonal adverse effects (e.g., bleeding pattern changes, acne, emotional lability) or any changes in efficacy (e.g., noted changes in bleeding patterns) to their prescribers. Because norethindrone-containing contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive norethindrone contraception concurrently with ritonavir should use an additional barrier method of contraception such as condoms.
Norfloxacin: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include norfloxacin.
Nortriptyline: Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Ritonavir has a possible risk for QT prolongation and torsade de pointes (TdP) and should be used cautiously and with close monitoring with doxepin. In addition, ritonavir potently inhibits CYP2D6 and CYP3A4, and thus may inhibit the metabolism of the tricyclic antidepressants (TCAs). A significant effect of ritonavir on desipramine clearance has been reported. Since the magnitude of the interaction with the TCAs is difficult to predict but may be significant, closely monitor patients receiving ritonavir and TCAs concurrently. Adjust the dosage of the coadministered drug based on therapeutic response. TCA serum concentration monitoring may be useful to guide adjustments and prevent toxicity.
Obeticholic Acid: Obeticholic acid may increase the exposure to paritaprevir. Paritaprevir is a substrate of OATP1B1 and OATP1B3 and obeticholic acid inhibits OAT1B1 and OATP1B3 in vitro. Caution and close monitoring is advised if obeticholic acid is administered with products containing paritaprevir.
Octreotide: An increased risk of adverse events, including torsade de pointes (TdP), and elevated plasma concentrations of dasabuvir, paritaprevir, and ritonavir may occur if octreotide and dasabuvir; ombitasvir; paritaprevir; ritonavir are used concomitantly. Caution is warranted, along with careful monitoring of patients for adverse events. While dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QTc interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with QT prolongation in other trials. Bradycardia is a risk factor for development of torsade de pointes (TdP), and sinus bradycardia has occurred during octreotide therapy. The potential for bradycardia during octreotide administration theoretically increases the risk of TdP in patients receiving drugs that prolong the QT interval, such as ritonavir. There is also the potential for elevated ritonavir concentrations, further increasing the risk for serious adverse events, as octreotide is expected to inhibit the CYP3A4 metabolism of ritonavir. Paritaprevir and dasabuvir (minor) are also CYP3A4 substrates; elevated concentrations may be seen. The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include octreotide. There is also the potential for elevated ritonavir concentrations, further increasing the risk for serious adverse events, as octreotide is expected to inhibit the CYP3A4 metabolism of ritonavir.
Ofloxacin: Concomitant use of ritonavir with ofloxacin may theoretically increase the risk for QT prolongation. Fluoroquinolones, including ofloxacin, have been associated with QT prolongation and cases of torsade de pointes (TdP). Ritonavir has been associated with dose-related QT prolongation. Caution and close monitoring is advised if these drugs are administered together.
Olanzapine: Ritonavir may reduce olanzapine serum concentrations by approximately 50%; how this affects olanzapine efficacy, however, is not known. Ritonavir appears to induce olanzapine's metabolism by either CYP1A2 or glucuronide conjugation. If ritonavir and olanzapine are used concurrently, monitor for reduced olanzapine effect and adjust olanzapine dose as needed. In addition, both ritonavir and olanzapine are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
Olaparib: Avoid the coadministration of olaparib with ritonavir due to the risk of increased olaparib- and ritonavir-related adverse reactions; if concomitant use is necessary, decrease the dose of olaparib to 150 mg by mouth twice daily. Olaparib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Additionally, ritonavir is a P-glycoprotein (P-gp) substrate / inhibitor; olaparib is also an in vitro P-gp substrate / inhibitor, although the clinical relevance of this finding is unknown. Coadministration with itraconazole, another strong CYP3A4 inhibitor, increased the AUC and Cmax of olaparib by 2.7-fold and 1.4-fold, respectively; ritonavir may also increase olaparib exposure. Use caution if coadministration of olaparib with ombitasvir is necessary, due to an increased risk of ombitasvir-related adverse reactions. Ombitasvir is a P-glycoprotein (P-gp) and BCRP substrate. Olaparib is an in vitro P-gp and BCRP inhibitor, although the clinical relevance is unknown. Use caution if coadministration of olaparib with paritaprevir is necessary, due to an increased risk of paritaprevir-related adverse reactions. Paritaprevir is a substrate of P-glycoprotein (P-gp), BCRP, and OATP1B1. Olaparib is an in vitro inhibitor of these isoenzymes and drug transporters, although the clinical relevance is unknown.
Olodaterol: Beta-agonists, such as olodaterol, may be associated with adverse cardiovascular effects including QT interval prolongation. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with olodaterol include ritonavir.
Omeprazole: Dosage adjustments of omeprazole may be required during concomitant administration with dasabuvir; ombitasvir; paritaprevir; ritonavir. Use of these drugs together results in decreased omeprazole serum concentrations. Monitor for decreasing efficacy and consider increasing the omeprazole dose if needed; however, adult doses should be limited to no more than 40 mg/day. The dose should be re-adjusted after completion of the 4-drug hepatitis C treatment regimen. Use caution when administering ritonavir and omeprazole concurrently. Ritonavir is an inhibitor of CYP3A and P-glycoprotein (P-gp), while omeprazole is a CYP3A and P-gp substrate. Coadministration may increase omeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Omeprazole; Sodium Bicarbonate: Concurrent administration of tipranavir and ritonavir with antacids results in decreased tipranavir concentrations. Administer tipranavir and ritonavir 2 hours before or 1 hour after antacids. Dosage adjustments of omeprazole may be required during concomitant administration with dasabuvir; ombitasvir; paritaprevir; ritonavir. Use of these drugs together results in decreased omeprazole serum concentrations. Monitor for decreasing efficacy and consider increasing the omeprazole dose if needed; however, adult doses should be limited to no more than 40 mg/day. The dose should be re-adjusted after completion of the 4-drug hepatitis C treatment regimen. Use caution when administering ritonavir and omeprazole concurrently. Ritonavir is an inhibitor of CYP3A and P-glycoprotein (P-gp), while omeprazole is a CYP3A and P-gp substrate. Coadministration may increase omeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Ondansetron: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include ondansetron. The manufacturer of ondansetron recommends ECG monitoring if it is coadministered with other drugs that are known to prolong the QT interval. Ondansetron is metabolized by the hepatic isoenzymes CYP3A4, CYP2D6, and CYP1A2; ritonavir inhibits 2 of these enzymes (CYP3A4 and CYP2D6). In addition, ondansetron is a substrate of the drug transporter P-glycoprotein (P-gp), which ritonavir and paritaprevir also inhibit. Caution and close monitoring are advised if these drugs are administered together.
Oritavancin: Concurrent administration of oritavancin with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in decreased plasma concentrations of dasabuvir, paritaprevir, and ritonavir. Oritavancin is an inducer of the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir, paritaprevir, and dasabuvir (minor) are substrates of CYP3A4. Ritonavir is also partially metabolized by CYP2D6. Monitor for antiviral efficacy if these drugs are administered together. Ritonavir is metabolized by CYP3A4 and CYP2D6 (minor); oritavancin is a weak CYP3A4 and CYP2D6 inducer. Plasma concentrations and efficacy of ritonavir may be reduced if these drugs are administered concurrently.
Orlistat: According to the manufacturer of orlistat, HIV RNA levels should be frequently monitored in patients receiving orlistat while being treated for HIV infection with anti-retroviral protease inhibitors. Loss of virological control has been reported in HIV-infected patients taking orlistat with atazanavir, ritonavir, tenofovir disoproxil fumarate, emtricitabine, lopinavir; ritonavir, and emtricitabine; efavirenz; tenofovir disoproxil fumarate. The exact mechanism for this interaction is not known, but may involve inhibition of systemic absorption of the anti-retroviral agent. If an increased HIV viral load is confirmed, orlistat should be discontinued.
Osimertinib: Periodically monitor ECGs and electrolytes if coadministration of osimertinib with ritonavir is necessary due to the risk of QT prolongation and torsade de pointes (TdP). Concentration-dependent QTc prolongation has been suggested at the recommended dosing of osimertinib in a pharmacokinetic/pharmacodynamic analysis. The use of ritonavir could also result in QT prolongation. Concomitant use may increase the risk of QT prolongation. Use caution if coadministration of osimertinib with ombitasvir; paritaprevir; ritonavir is necessary, and closely monitor for possible QT prolongation and an increase in osimertinib- or ombitasvir; paritaprevir; ritonavir-related adverse reactions. Osimertinib causes concentration dependent prolongation of the QT interval at recommended dosing. Ritonavir is associated with a possible risk for QT prolongation and torsade de pointes (TdP). Additive QT prolongation is possible. Additionally, ritonavir is a P-glycoprotein (P-gp) inhibitor. Paritaprevir and ombitasvir are both substrates of BCRP; paritaprevir also inhibits BCRP. Osimertinib is an in vitro P-gp substrate, as well as a BCRP substrate/inhibitor in vitro. P-gp and BCRP inhibition by ombitasvir; paritaprevir; ritonavir may result in increased osimertinib exposure. Similarly, BRCP inhibition by osimertinib may increase exposure to paritaprevir and ombitasvir. Monitor for an increase in dasabuvir-related adverse reactions during coadministration of osimertinib. Dasabuvir exposure may be increased. Dasabuvir is a substrate of BCRP. Osimertinib is a BCRP inhibitor.
Ospemifene: Coadministration of ritonavir and ospemifene may be inappropriate, as concurrent use may increase ospemifene systemic concentrations and, thus, increase the risk of ospemifene-related adverse reactions. Ritonavir is a strong CYP3A4 inhibitor and a CYP2C9 inhibitor, and ospemifene is a CYP3A4 and CYP2C9 substrate. In addition, ospemifene is a weak inhibitor of CYP2D6 and CYP3A4; ritonavir is a CYP3A4 and CYP2D6 substrate. Concurrent administration of ospemifene with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in increased plasma concentrations of ospemifene, dasabuvir, paritaprevir, and ritonavir; although the extent of these increases is not known. Ospemifene is primarily metabolized by CYP3A4 and CYP2C9, but other pathways also contribute to its metabolism. Ritonavir is a potent CYP3A4 inhibitor. In addition, ospemifene is a weak inhibitor of CYP2D6, CYP3A4, and CYP2C8. Paritaprevir and dasabuvir (minor) are metabolized by CYP3A4, and ritonavir is a CYP3A4 and CYP2D6 substrate. Dasabuvir is primarily metabolized by CYP2C8. Caution and close monitoring are advised if these drugs are administered together.
Oxaliplatin: QT prolongation and ventricular arrhythmias including fatal Torsade de Pointes have been reported with oxaliplatin use in post-marketing experience. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with oxaliplatin include ritonavir.
Oxcarbazepine: Concurrent administration of oxcarbazepine with dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in decreased plasma concentrations of paritaprevir, ritonavir, and dasabuvir, which may affect antiviral efficacy. Oxcarbazepine is a moderate inducer of the hepatic isoenzyme CYP3A4, and ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. Concurrent administration of oxcarbazepine with ritonavir should be undertaken with caution and careful monitoring of antiviral efficacy. Oxcarbazepine is a moderate inducer of the hepatic isoenzyme CYP3A4, and ritonavir is a CYP3A4 substrate.
Oxybutynin: Oxybutynin is metabolized by CYP3A4. Caution should be used when oxybutynin is given in combination with inhibitors of CYP3A4, such as protease inhibitors. Monitor for adverse effects if these drugs are administered together.
Oxycodone: Oxycodone is metabolized by CYP3A4. Concomitant administration of ritonavir, a CYP3A4 inhibitor, may cause an increase in oxycodone plasma concentrations, which could increase or prolong adverse effects and may cause potentially fatal respiratory depression. If coadministration of these agents is necessary, patients should be monitored for an extended period and dosage adjustments made if warranted. In addition, oxycodone is metabolized in part by CYP2D6 to oxymorphone, which represents less than 15% of the total administered dose. Concurrent use of some agents that inhibit CYP2D6 has not been shown to result in clinically significant interactions. However, potent inhibitors of CYP2D6, such as ritonavir, may potentially increase the effects of oxycodone. Caution and close monitoring are advised if these drugs are administered together. Initiate oxycodone at low dosages and titrate carefully.
Oxymorphone: Ritonavir is an inhibitor of the cytochrome P450 3A4 isoenzyme and may decrease the metabolism of oxymorphone if the two drugs are coadministered.
Paclitaxel: Concurrent administration of paclitaxel (or nanoparticle albumin-bound paclitaxel) with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in increased paclitaxel plasma concentrations and risk for toxicity. Caution and close monitoring are advised if these drugs are administered together. Paclitaxel is metabolized by the hepatic isoenzymes CYP2C8 and CYP3A4; ritonavir is a potent CYP3A4 inhibitor. In addition, paclitaxel is a substrate of the drug transporter P-glycoprotein (P-gp), and ritonavir also inhibits P-gp. Paritaprevir also inhibits P-gp. Due to ritonavir's potential inhibitory effects on various hepatic isoenzymes, numerous drug interactions may occur with ritonavir. Close monitoring of serum drug concentrations and/or therapeutic and adverse effects is required when paclitaxel (a CYP2C8 and CYP3A4 substrate) is coadministered with ritonavir (a CYP3A4 inhibitor). In addition, paclitaxel is a substrate of the drug transporter P-glycoprotein (P-gp), and ritonavir also inhibits P-gp.
Palbociclib: Avoid coadministration of ritonavir with palbociclib; significantly increased plasma exposure of palbociclib may occur. If concomitant use cannot be avoided, reduce the dose of palbociclib to 75 mg PO once daily and monitor for increased adverse reactions. If ritonavir is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of ritonavir) to the dose used before initiation of ritonavir. Palbociclib is primarily metabolized by CYP3A4 and ritonavir is a strong CYP3A4 inhibitor. In a drug interaction trial, coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of palbociclib by 87% and 34%, respectively.
Paliperidone: Concurrent administration of paliperidone with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in increased plasma concentrations of all 5 drugs; however, the clinical significance of potential alterations in drug exposure is not clear. In addition, there may be an increased risk for QT prolongation if these drugs are coadministered. Paliperidone causes a modest increase in the QT interval and should not be coadministered with other drugs known to prolong the QT interval. While dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QTc interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with QT prolongation in other trials. If coadministration cannot be avoided, caution and close monitoring are advised. Paliperidone is a substrate of CYP3A4, CYP2D6, and P-glycoprotein (P-gp); ritonavir inhibits both enzymes and P-pg. In vivo data indicate that hepatic metabolism plays a relatively minor role in overall paliperidone clearance; therefore, the clinical significance of ritonavir's CYP inhibition is unclear. In addition, paliperidone inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp. The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include paliperidone. Paliperidone causes a modest increase in the QT interval. In addition, paliperidone is a substrate of CYP3A4 and CYP2D6; ritonavir inhibits both enzymes. Both paliperidone and ritonavir are also substrates/inhibitors of P-glycoprotein (P-gp).
Panobinostat: The co-administration of panobinostat with ritonavir or lopinavir; ritonavir is not recommended; QT prolongation has been reported with these agents. If concomitant use cannot be avoided, reduce the panobinostat dose from 20 mg PO to 10 mg PO and closely monitor electrocardiograms during treatment. Hold panobinostat if the QTcF increases to >= 480 milliseconds during therapy; permanently discontinue if QT prolongation does not resolve. Ritonavir and lopinavir/ritonavir are strong CYP3A4 inhibitors and panobinostat is a CYP3A4 substrate. The panobinostat Cmax and AUC (0-48hr) values were increased by 62% and 73%, respectively, in patients with advanced cancer who received a single 20 mg-dose of panobinostat after taking 14 days of a strong CYP3A4 inhibitor.
Pantoprazole: Concurrent administration of pantoprazole with dasabuvir may result in increased plasma concentrations of dasabuvir; monitor for adverse effects if these drugs are administered together. Dasabuvir is a P-glycoprotein (P-gp) substrate and pantoprazole inhibits P-gp. Concurrent administration of pantoprazole with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in increased plasma concentrations of all 5 drugs; monitor for adverse effects if these drugs are administered together. While CYP2C19 plays the primary role in pantoprazole's hepatic metabolism, CYP3A4 is also involved; pantoprazole is also a P-glycoprotein (P-gp) substrate. Ritonavir is an inhibitor of both CYP3A4 and P-gp. Paritaprevir also inhibits P-gp. In addition, dasabuvir, ombitasvir, paritaprevir, and ritonavir are all P-gp substrates. Pantoprazole inhibits P-gp. Concurrent administration of pantoprazole with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in increased plasma concentrations of all 5 drugs; monitor for adverse effects if these drugs are administered together. While CYP2C19 plays the primary role in pantoprazole's hepatic metabolism, CYP3A4 is also involved; pantoprazole is also a P-glycoprotein (P-gp) substrate. Ritonavir is an inhibitor of both CYP3A4 and P-gp. Paritaprevir also inhibits P-gp. In addition, dasabuvir, ombitasvir, paritaprevir, and ritonavir are all P-gp substrates. Pantoprazole inhibits P-gp. Use caution when administering ritonavir and pantoprazole concurrently. Ritonavir is an inhibitor of CYP3A and P-glycoprotein (P-gp), while pantoprazole is a CYP3A and P-gp substrate. Coadministration may increase pantoprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Paricalcitol: Paricalcitol is partially metabolized by CYP3A4. Care should be taken when dosing paricalcitol with strong CYP3A4 inhibitors, such as protease inhibitors. Dose adjustments of paricalcitol may be required. Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with this combination.
Paroxetine: A dose reduction of paroxetine may be necessary during co-administration of ritonavir. Concurrent use of CYP2D6 substrates, such as paroxetine, with ritonavir could result in increases (up to 2-fold) in the AUC of paroxetine. Paroxetine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Pasireotide: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include pasireotide.
Pazopanib: Avoid administering pazopanib with strong CYP3A4 inhibitors, such as ritonavir. If co-administration with a strong CYP3A4 inhibitor is unavoidable, reduce the pazopanib dose to 400 mg PO once daily; further dose adjustments may be necessary if adverse effects occur. The concomitant use of pazopanib, a weak CYP3A4 inhibitor and a CYP3A4 and P-glycoprotein (P-gp) substrate, and ritonavir, a CYP3A4 and P-gp inhibitor, a CYP3A4 inducer, and a CYP3A4 and P-gp substrate, may result in altered pazopanib and/or ritonavir concentrations. In addition, ritonavir has a possible risk of QT prolongation. Avoid concurrent administration of pazopanib with dasabuvir; ombitasvir; paritaprevir; ritonavir if possibile. Complex metabolic interactions may occur resulting in elevated plasma concentrations of all 5 drugs. If coadministration is unavoidable, reduce the pazopanib dosage to 400 mg PO once daily, and monitor for adverse effects. Further dosage adjustments may be necessary depending on tolerability. Both pazopanib and ritonavir are substrates and inhibitors of the hepatic isoenzyme CYP3A4. Paritaprevir and dasabuvir (minor) are also CYP3A4 substrates. Pazopanib inhibits CYP2D6 and CYP2C8; dasabuvir is primarily metabolized by CYP2C8 and CYP2D6 is partially responsible for the metabolism of ritonavir. Pazopanib is a substrate for the breast cancer resistance protein (BCRP); ritonavir, dasabuvir, paritaprevir are BCRP inhibitors. Finally, pazopanib is a substrate and inhibitor of the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-gp. Ritonavir is also a P-gp inhibitor.
Penbutolol: Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
Pentamidine: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include pentamidine.
Pentobarbital: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with pentobarbital should be undertaken with great caution due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir, and ritonavir. Barbituates are known to induce hepatic CYP isoenzymes; phenobarbital, a potent inducer of CYP3A4, is contraindicated for use with dasabuvir; ombitasvir; paritaprevir; ritonavir and ombitasvir; paritaprevir; ritonavir. Dasabuvir (minor), paritaprevir, and ritonavir are substrates of CYP3A4. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with pentobarbital should be undertaken with great caution due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir, and ritonavir. Barbituates are known to induce hepatic CYP isoenzymes; phenobarbital, a potent inducer of CYP3A4, is contraindicated for use with dasabuvir; ombitasvir; paritaprevir; ritonavir and ombitasvir; paritaprevir; ritonavir. Dasabuvir (minor), paritaprevir, and ritonavir are substrates of CYP3A4. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with pentobarbital should be undertaken with great caution due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, paritaprevir, and ritonavir. Barbituates are known to induce hepatic CYP isoenzymes; phenobarbital, a potent inducer of CYP3A4, is contraindicated for use with dasabuvir; ombitasvir; paritaprevir; ritonavir. Dasabuvir (minor), paritaprevir, and ritonavir are substrates of CYP3A4. Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required.
Perampanel: Concurrent administration of perampanel with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated perampanel plasma concentrations and decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Perampanel is a weak inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. In addition, perampanel is a CYP3A4 substrate; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Concurrent use of perampanel with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated perampanel plasma concentrations and decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Perampanel is a weak inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. In addition, perampanel is a CYP3A4 substrate; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Concurrent use of perampanel with ritonavir may decrease ritonavir concentrations and increase perampanel concentrations. Both drugs are metabolized by CYP3A4. Ritonavir is also a CYP3A4 inhibitor, while perampanel is a weak inducer of CYP3A4. Monitor patients for increases in adverse effects such as anger, anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required.
Pergolide: Coadministration of ergot alkaloids with potent inhibitors of CYP3A4, like anti-retroviral protease inhibitors is considered contraindicated due to the risk of acute ergot toxicity (e.g., vasospasm leading to cerebral ischemia, peripheral ischemia and/or other serious effects). Several case reports have established the clinical significance of this interaction in the medical literature. In some cases, fatal interactions have occurred.
Perindopril; Amlodipine: Amlodipine is a CYP3A4 substrate. Theoretically, CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, may increase the plasma concentration of amlodipine via CYP3A4 inhibition; this effect might lead to hypotension in some individuals. Caution should be used when anti-retroviral protease inhibitors are coadministered with amlodipine; therapeutic response should be monitored. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
Perphenazine: Ritonavir is expected to decrease the hepatic CYP metabolism of perphenazine, resulting in increased neuroleptic concentrations. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased perphenazine doses may be required. In addition, both ritonavir and perphenazine are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
Perphenazine; Amitriptyline: Concurrent administration of amitriptyline with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated amitriptyline plasma concentrations; however, the clinical implications of this interaction have not been clearly defined. Amitriptyline is a substrate of the hepatic isoenzymes CYP3A4 and CYP2D6 and uridine glucuronyltransferase (UGT). Ritonavir inhibits CYP3A4 and CYP2D6, while dasabuvir, ombitasvir and paritaprevir are UGT1A1 inhibitors. Hepatic isoenzymes CYP1A2, CYP2C9, and CYP2C19 also contribute to amitriptyline's metabolism, and these isoenzymes do not appear to be inhibited by the 4-drug regimen. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of amitriptyline with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated amitriptyline plasma concentrations; however, the clinical implications of this interaction have not been clearly defined. Amitriptyline is a substrate of the hepatic isoenzymes CYP3A4 and CYP2D6 and uridine glucuronyltransferase (UGT). Ritonavir inhibits CYP3A4 and CYP2D6, while dasabuvir, ombitasvir and paritaprevir are UGT1A1 inhibitors. Hepatic isoenzymes CYP1A2, CYP2C9, and CYP2C19 also contribute to amitriptyline's metabolism, and these isoenzymes do not appear to be inhibited by the 4-drug regimen. Caution and close monitoring are advised if these drugs are administered together. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Ritonavir has a possible risk for QT prolongation and torsade de pointes (TdP) and should be used cautiously and with close monitoring with doxepin. In addition, ritonavir potently inhibits CYP2D6 and CYP3A4, and thus may inhibit the metabolism of the tricyclic antidepressants (TCAs). A significant effect of ritonavir on desipramine clearance has been reported. Since the magnitude of the interaction with the TCAs is difficult to predict but may be significant, closely monitor patients receiving ritonavir and TCAs concurrently. Adjust the dosage of the coadministered drug based on therapeutic response. TCA serum concentration monitoring may be useful to guide adjustments and prevent toxicity. Ritonavir is expected to decrease the hepatic CYP metabolism of perphenazine, resulting in increased neuroleptic concentrations. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased perphenazine doses may be required. In addition, both ritonavir and perphenazine are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
Phenobarbital: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with phenobarbital is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir and ritonavir. Phenobarbital is a potent inducer of the hepatic isoenzyme CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. In addition, phenobarbital may induce P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with phenobarbital is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir and ritonavir. Phenobarbital is a potent inducer of the hepatic isoenzyme CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. In addition, phenobarbital may induce P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required.
Phentermine; Topiramate: Concurrent administration of topiramate with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir, paritaprevir, and dasabuvir (minor) are all metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of topiramate with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir, paritaprevir, and dasabuvir (minor) are all metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of topiramate with ritonavir may result in decreased concentrations of ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir is metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Phenylephrine; Promethazine: Concurrent administration of promethazine with ritonavir may result in elevated plasma concentrations of promethazine and increased risk of adverse events. Promethazine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. In addition, rarely promethazine has been associated with QT prolongation. Caution and close monitoring are advised if these drugs are administered together.
Phenytoin: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with phenytoin is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir and ritonavir. Phenytoin is a potent inducer and substrate of the hepatic isoenzyme CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. In addition, phenytoin may induce P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with phenytoin or fosphenytoin is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir and ritonavir. Phenytoin is a potent inducer and substrate of the hepatic isoenzyme CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. In addition, phenytoin may induce P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Concurrent use of ritonavir with ethotoin, phenytoin, or fosphenytoin should be avoided when possible. Increased doses of anticonvulsants may be required due to metabolism induction by ritonavir. Additionally, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required.
Pimavanserin: Ritonavir is a strong CYP3A4 inhibitor and may cause QT prolongation and torsade de pointes. Concurrent use of ritonavir with CYP3A4 substrates that may prolong the QT interval, such as pimavanserin, is contraindicated. If an alternative to ritonavir is not available and coadministration is unavoidable, the manufacturer recommends that the pimavanserin dose be reduced to 17 mg/day PO in patients receiving strong inhibitors of CYP3A4 such as ritonavir.
Pimozide: Coadministration of pimozide with protease inhibitors is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Pimozide is thought to be metabolized through CYP3A4, and to a lesser extent CYP1A2 and CYP2D6. Elevated pimozide plasma levels are probable when coadministered with CYP3A4 inhibitors, such as the protease inhibitors. Similarly, concurrent use of pimozide and potent CYP2D6 inhibitors, such as tipranavir, may elevated pimozide concentrations. Increased plasma concentrations of pimozide have been associated with QT prolongation and serious cardiovascular adverse events including death due to TdP. Saquinavir boosted with ritonavir and lopinavir; ritonavir may also cause QT prolongation, which could further increase the risk for TdP if coadministered with pimozide.
Pindolol: Ritonavir is expected to decrease the hepatic CYP metabolism of pindolol, resulting in increased beta-blocker concentrations. Cardiac and neurologic events have been reported when ritonavir is concurrently administered with beta-blockers. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including beta-blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased beta-blocker doses may be warranted.
Pioglitazone: Concurrent administration of pioglitazone with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated pioglitazone plasma concentrations and decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Pioglitazone is an inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. In addition, pioglitazone is metabolized by CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Pirbuterol: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir, include beta-agonists.
Pirfenidone: Concurrent administration of pirfenidone with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of dasabuvir, ombitasvir, paritaprevir, and ritonavir. Pirfenidone is a mild inhibitor of CYP3A4; an enzyme for which ritonavir, paritaprevir, and dasabuvir (minor) are substrates. In addition, pirfenidone is a mild inhibitor of the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp. Monitor for antiviral adverse effects if these drugs are administered together. Concurrent administration of pirfenidone with ritonavir may result in elevated plasma concentrations of ritonavir. Pirfenidone is a mild inhibitor of CYP3A4 and the drug transporter P-glycoprotein (P-gp); ritonavir is a substrate of both CYP3A4 and P-gp. Monitor for antiviral adverse effects if these drugs are administered together.
Pitavastatin: Concurrent administration of pitavastatin with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in altered pitavastatin and ritonavir plasma concentrations; the drug interaction is complex and the ultimate effect on concentrations is undefined. Pitavastatin is a substrate of the organic anion transporting polypeptide (OATP) 1B1. Paritaprevir inhibits OATP1B1; therefore, coadministration may result in increased pitavastatin concentrations. In contrast, pharmacokinetic studies of ritonavir-boosted regimens in combination with pitavastatin showed a reduction in pitavastatin exposure when the drugs were coadministered. Caution and close monitoring is advised if these drugs are administered together.
Pomalidomide: Use pomalidomide and ritonavir together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and ritonavir is a CYP1A2 inducer.
Ponatinib: Concomitant use of ponatinib and dasabuvir; ombitasvir; paritaprevir; ritonavir may increase systemic exposures of all 5 drugs. Ponatinib is a CYP3A4 substrate, and ritonavir is a strong CYP3A4 inhibitor. If use of ponatinib and a ritonavir-containing medication is necessary, reduce the starting ponatinib dose to 30 mg/day. Additionally, ponatinib is a P-gp inhibitor, while dasabuvir, paritaprevir, ombitasvir and ritonavir are all P-gp substrates. Concomitant use of ponatinib, a CYP3A4 substrate, and ritonavir, a strong CYP3A4 inhibitor, may increase the exposure of ponatinib. If the use of both agents is necessary, reduce the starting ponatinib dose to 30 mg/day. Additionally, ponatinib is a P-gp inhibitor and may increase the plasma concentration of a P-gp substrate such as, ritonavir.
Posaconazole: The concurrent use of posaconazole and ritonavir is contraindicated due to the risk of life threatening arrhythmias such as torsade de pointes (TdP). Posaconazole is an inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of ritonavir. These drugs used in combination may result in elevated ritonavir plasma concentrations, causing an increased risk for ritonavir-related adverse events, such as QT prolongation. Data from one study found the Cmax and AUC of ritonavir increased by 49% and 80%, respectively, when administered with posaconazole. Additionally, posaconazole has been associated with prolongation of the QT interval as well as rare cases of TdP; avoid use with other drugs that may prolong the QT interval and are metabolized through CYP3A4, such as ritonavir. Concurrent administration of posaconazole with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in increased plasma concentrations of both drugs, which increases the risk of serious adverse events such as QT prolongation. Posaconazole is a potent inhibitor of the hepatic isoenzyme CYP3A4; an enzyme for which ritonavir, paritaprevir, and dasabuvir (minor) are substrates. In one study, coadministration of posaconazole (400 mg PO twice daily) with ritonavir (100 mg PO daily) resulted in significant increases in ritonavir Cmax (49% increase) and AUC (80% increase). While dasabuvir; ombitasvir; paritaprevir; ritonavir and ombitasvir; paritaprevir; ritonavir did not prolong the QT interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with dose-related QT prolongation in other trials. Posaconazole has been associated with QT prolongation and torsade de pointes. In addition, posaconazole inhibits the drug transporter P-glycoprotein (P-gp); all 4 antiviral drugs are P-gp substrates. Similarly, posaconazole is a P-gp substrate, and ritonavir and paritaprevir are P-gp inhibitors. If coadministration is unavoidable, careful monotoring of therapeutic and adverse effects is recommended.
Pramlintide: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors.
Pravastatin: Dosage adjustments of pravastatin may be required during concomitant administration with dasabuvir; ombitasvir; paritaprevir; ritonavir. Use of these drugs together results in elevated pravastatin serum concentrations. Adult doses of pravastatin must be limited to no more than 40 mg/day when administered with dasabuvir; ombitasvir; paritaprevir; ritonavir. The dose should be re-adjusted after completion of the 4-drug hepatitis C treatment regimen. Dosage adjustments of pravastatin may be required during concomitant administration with ritonavir. Use of these drugs together results in elevated pravastatin serum concentrations. Adult doses of pravastatin must be limited to no more than 40 mg/day when administered with ritonavir.
Praziquantel: Monitor for increased side effects of praziquantel if administered with ritonavir. Concurrent administration may result in elevated praziquantel plasma concentrations. Praziquantel is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme.
Prednisolone: Ritonavir inhibits CYP3A4, and prednisolone is a CYP3A4 substrate. Monitor patients for corticosteroid-related side effects if prednisone or prednisolone and ritonavir are taken.
Prednisone: Coadministration of prednisone with ritonavir (a strong CYP3A4 inhibitor) may cause prednisone serum concentrations to increase, potentially resulting in Cushing's syndrome and adrenal suppression. Consider use of an alternative corticosteroid whose concentrations are less affected by strong CYP3A4 inhibitors, such as beclomethasone and prednisolone, especially during long-term treatment.
Primaquine: Due to the potential for QT interval prolongation with primaquine, caution is advised with other drugs that prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with primaquine include ritonavir.
Primidone: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with primidone is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir, and ritonavir. Primidone is converted to phenobarbital in vivo, and phenobarbital is a potent inducer of the hepatic isoenzyme CYP3A4. Dasabuvir (minor), paritaprevir, and ritonavir are substrates of this isoenzyme. In addition, phenobarbital may induce P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir, and ritonavir are substrates. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with primidone is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir, and ritonavir. Primidone is converted to phenobarbital in vivo, and phenobarbital is a potent inducer of the hepatic isoenzyme CYP3A4. Dasabuvir (minor), paritaprevir, and ritonavir are substrates of this isoenzyme. In addition, phenobarbital may induce P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir, and ritonavir are substrates. Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required.
Procainamide: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include procainamide.
Prochlorperazine: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include prochlorperazine. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation.
Promethazine: Concurrent administration of promethazine with ritonavir may result in elevated plasma concentrations of promethazine and increased risk of adverse events. Promethazine is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. In addition, rarely promethazine has been associated with QT prolongation. Caution and close monitoring are advised if these drugs are administered together.
Propafenone: The manufacturer of ombitasvir; paritaprevir; ritonavir recommends caution and therapeutic drug monitoring (when available) if administered concurrently with propafenone. However, since one of the components of the 3-drug combination is ritonavir, use of these drugs together is contraindicated. Both ritonavir and propafenone are associated with QT prolongation; concomitant use increases the risk for developing Torsade de Pointes (TdP). In addition, ritonavir is a potent CYP3A4 inhibitor, an enzyme partially responsible for the metabolism of propafenone. If administered together, serum concentration of propafenone may increase. Coadministration of HIV treatment doses of ritonavir and propafenone is contraindicated due to the potential for serious or life-threatening reactions, such as cardiac arrhythmias. However, propafenone may be administered with caution to patients receiving lower doses of ritonavir for use as a boosting agent. Ritonavir inhibits both CYP3A4 and CYP2D6. Drugs that inhibit both pathways are expected to increase propafenone serum concentrations. In addition, both ritonavir and amiodarone are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
Propoxyphene: Due to effects on microsomal isoenzymes responsible for hepatic metabolism, ritonavir may alter the response and/or increase the AUC of opiate analgesics. Concurrent use of ritonavir and propoxyphene is not recommended, due the increased formation of the neurotoxic metabolites of propoxyphene. Also, propoxyphene is a substrate/inhibitor of CYP3A4. Increased serum concentrations of propoxyphene can occur from concurrent use of ritonavir, a CYP3A4 inhibitor. A reduced dosage of propoxyphene may be needed. Monitor for CNS and respiratory depression.
Propranolol: Concurrent administration of propranolol with ritonavir may result in elevated propranolol plasma concentrations. Cardiac and neurologic events have been reported when ritonavir is concurrently administered with beta-blockers. Propranolol is metabolized by the hepatic isoenzyme CYP2D6; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. Decreased beta-blocker dosage may be needed.
Protriptyline: Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Ritonavir has a possible risk for QT prolongation and torsade de pointes (TdP) and should be used cautiously and with close monitoring with doxepin. In addition, ritonavir potently inhibits CYP2D6 and CYP3A4, and thus may inhibit the metabolism of the tricyclic antidepressants (TCAs). A significant effect of ritonavir on desipramine clearance has been reported. Since the magnitude of the interaction with the TCAs is difficult to predict but may be significant, closely monitor patients receiving ritonavir and TCAs concurrently. Adjust the dosage of the coadministered drug based on therapeutic response. TCA serum concentration monitoring may be useful to guide adjustments and prevent toxicity.
Quazepam: CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of quazepam and increase the potential for benzodiazepine toxicity. A decrease in the quazepam dose may be needed.
Quetiapine: Avoid concurrent use of quetiapine and ritonavir due to the potential for additive effects on the QT interval and torsade de pointes. Ritonavir may be associated with QT prolongation. Limited data, including some case reports, suggest that quetiapine may also be associated with a significant prolongation of the QTc interval in rare instances. Ritonavir may also inhibit the CYP3A4 metabolism of quetiapine, resulting in elevated quetiapine plasma concentrations. If administration of ritonavir is required in a patient taking quetiapine, reduce the quetiapine dose to one sixth of the current dose. If ritonavir is discontinued, increase the quetiapine dose by 6-fold.
Quinidine: The manufacturer of ombitasvir; paritaprevir; ritonavir recommends caution and therapeutic drug monitoring (when available) if administered concurrently with quinidine. However, since one of the components of the 3-drug combination is ritonavir, use of these drugs together is contraindicated. Both ritonavir and quinidine are associated with QT prolongation; concomitant use increases the risk for developing Torsade de Pointes (TdP). In addition, ritonavir is a potent CYP3A4 inhibitor, an enzyme partially responsible for the metabolism of quinidine. If administered together, serum concentration of quinidine may increase. Coadministration of HIV treatment doses of ritonavir and quinidine is contraindicated due to the potential for serious or life-threatening reactions, such as cardiac arrhythmias. Cautious consideration may be given to administering quinidine with boosting doses of ritonavir. Ritonavir is an inhibitor of CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, such as quinidine, should be expected with concurrent use. In addition, ritonavir is associated with QT prolongation and quinidine is associated with QT prolongation and torsade de pointes (TdP); concomitant use increases the risk of QT prolongation.
Quinine: Concomitant use of quinine and ritonavir should be avoided due to increased quinine concentrations. In a study of healthy patients who received a single oral 600 mg dose of quinine with the 15th dose of ritonavir (200 mg PO Q12h for 9 days), there was a 4-fold increase in the mean quinine AUC and Cmax and an increase in the mean quinine elimination half-life (13.4 h vs. 11.2 h) when compared to quinine administered alone. There were no significant changes in the ritonavir pharmacokinetics. Ritonavir is a potent CYP3A4 inhibitor and quinine is a CYP3A4 substrate. Concurrent administration of quinine with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir is expected to result in elevated quinine plasma concentrations and altered concentrations of dasabuvir, paritaprevir, and ritonavir. Quinine's product labeling recommends avoiding concomitant use with ritonavir due to increased quinine concentrations and risk for toxicity. In a study of healthy patients who received a single oral 600 mg dose of quinine with the 15th dose of ritonavir (200 mg PO q12h for 9 days), there was a 4-fold increase in the mean quinine AUC and Cmax and an increase in the mean quinine elimination half-life compared to when quinine was administered alone. The dosage of ritonavir in dasabuvir; ombitasvir; paritaprevir; ritonavir is lower than that studied; therefore, the degree of increase in quinine plasma concentrations with coadministration of these specific products in not known. Both ritonavir and quinine are substrates and inhibitors of the hepatic isoenzymes CYP3A4 and CYP2D. Paritaprevir and dasabuvir (minor) are also substrates of CYP3A4. Quinine is a P-glycoprotein (P-gp) substrate, and ritonavir and paritaprevir inhibit P-gp. Both ritonavir and quinine have been shown to prolong the QT interval in a concentration-dependent fashion. Caution and close monitoring are advised if these drugs are administered together.
Rabeprazole: Concurrent administration of rabeprazole with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in increased rabeprazole plasma concentrations; however, the clinical significance of this interaction is unclear. Rabeprazole is metabolized by the hepatic isoenzymes CYP2C19 and CYP3A4; ritonavir is a potent inhibitor of CYP3A4. Monitor for rabeprazole-associated adverse events if these drugs are administered together. Concurrent administration of rabeprazole with ritonavir may result in increased rabeprazole plasma concentrations; however, the clinical significance of this interaction is unclear. Rabeprazole is metabolized by the hepatic isoenzymes CYP2C19 and CYP3A4; ritonavir is a potent inhibitor of CYP3A4. Monitor for rabeprazole-associated adverse events if these drugs are administered together.
Ramelteon: The serum concentrations of ramelteon may increase when ramelteon is administered with strong CYP3A4 inhibitors like the anti-retroviral protease inhibitors. Because there is the potential for multiple CYPP450 enzyme inhibition interactions between protease inhibitors and ramelteon, caution should be used if these 2 drugs are coadministered. The patient should be monitored closely for toxicity even though ramelteon has a wide therapeutic index.
Ranolazine: Coadministration of ranolazine with strong CYP3A inhibitors, such as ritonavir-containing regimens, is contraindicated. Concurrent administration of ranolazine with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir is expected to result in elevated plasma concentrations of ranolazine, dasabuvir, ombitasvir, paritaprevir, and ritonavir. Both ritonavir and ranolazine are substrates and inhibitors of CYP3A4, CYP2D6, and P-glycoprotein (P-gp); both drugs are also associated with concentration-dependent QT prolongation. Paritaprevir also inhibits P-gp. Increased plasma concentrations of ranolazine and ritonavir increase the risk of drug toxicity and proarrhythmic effects. Plasma concentrations of the other antiviral agents may also be affected. Paritaprevir and dasabuvir (minor) are metabolized by CYP3A4, and dasabuvir, ombitasvir, and paritaprevir, are all substrates of P-gp. Ranolazine is primarily metabolized by CYP3A, but it is also a substrate of P-glycoprotein. Ranolazine is contraindicated for use with moderate or potent inhibitors of CYP3A isoenzymes, including the anti-retroviral protease inhibitors. Ranolazine is associated with dose and plasma concentration-related increases in the QTc interval. Coadministration with anti-retroviral protease inhibitors may increase the plasma concentrations of ranolazine, thus increasing the risk of drug toxicity and proarrhythmic effects. In addition, ritonavir and several other anti-retroviral protease inhibitors can increase the absorption of ranolazine via inhibition of P-glycoprotein transport. Furthermore, ritonavir also is associated with QT prolongation; concomitant use increases the risk of QT prolongation.
Red Yeast Rice: The risk of myopathy, including rhabdomyolysis, may be increased when anti-retroviral protease inhibitors are given in combination with most HMG-CoA reductase inhibitors. Since compounds in red yeast rice claim to have HMG-CoA reductase inhibitor activity, coadministration of red yeast rice with anti-retroviral protease inhibitors is not recommended.
Regadenoson: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include regadenoson.
Regorafenib: Avoid coadministration of regorafenib with ritonavir, due to increased regorafenib exposure; coadministration may also result in elevated plasma concentrations of ritonavir. Ritonavir is a strong CYP3A4 inhibitor and regorafenib is a CYP3A4 substrate. Ketoconazole, another strong CYP3A4 inhibitor, increased the mean AUC of regorafenib by 33%, and decreased the mean AUC of active metabolites M-2 and M-5 by 93%; concomitant use with other strong CYP3A4 inhibitors may lead to an increase in regorafenib-related adverse reactions. In addition, regorafenib is a mild in vitro inhibitor of CYP2D6, while ritonavir is partially metabolized via CYP2D6. Coadministration of ritonavir with another CYP2D6 inhibitor, fluoxetine, increased the ritonavir AUC by 19%.
Remifentanil: Ritonavir is an inhibitor of the cytochrome P450 3A4 isoenzyme and may decrease the metabolism of remifentanil if the two drugs are coadministered.
Repaglinide: Concurrent administration of repaglinide with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated repaglinide plasma concentrations. Monitor blood glucose concentrations closely; a repaglinide dosage reduction may be necessary. Repaglinide is a substrate of the hepatic isoenzyme CYP3A4 and the organic anion transporting polypeptides (OATP). Ritonavir inhibits CYP3A4, and paritaprevir is an OATP1B1 and OATP1B3 inhibitor. Caution and close monitoring are advised if these drugs are administered together. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, repaglinide is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1), protease inhibitors inhibit CYP3A4 and OATP.
Ribavirin: The concomitant use of ribavirin and anti-retroviral protease inhibitors should be done with caution as both can cause hepatic damage. Most protease inhibitors have been associated with episodes of liver toxicity, with lopinavir/low-dose ritonavir, fosamprenavir/low-dose ritonavir, and nelfinavir being less hepatotoxic and tipranavir/low-dose ritonavir being the most hepatotoxic. Hyperbilirubinemia is often associated with atazanavir and/or indinavir therapy but does not reflect liver damage and is related to the inhibition of UDP glucuronosyltransferase. Overall, the HCV-HIV International Panel recommends the management of hepatotoxicity should be based on the knowledge of the mechanisms involved for each drug. Furthermore, they state that there are lower rates of liver-related mortality in coinfected patients taking HAART, even in those with end-stage liver disease, compared with patients not receiving HAART. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation.
Ribociclib: Coadministration of ribociclib with ritonavir is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to ritonavir may also increase. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Ritonavir has also been associated with QT prolongation. Ribociclib is also extensively metabolized by CYP3A4 and ritonavir is a strong CYP3A4 inhibitor; exposure to ribociclib may be increased. Coadministration with ritonavir, a strong CYP3A4 inhibitor increased the ribociclib AUC and Cmax by 3.2-fold and 1.7-fold, respectively, in healthy volunteers. Additionally, ribociclib is a moderate CYP3A4 inhibitor and ritonavir is a CYP3A4 substrate. Use caution if coadministration of ribociclib with paritaprevir is necessary, as the systemic exposure of paritaprevir may be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and paritaprevir is a CYP3A4 substrate.
Ribociclib; Letrozole: Coadministration of ribociclib with ritonavir is contraindicated, as elevated plasma concentrations of ribociclib may be associated with QT prolongation; exposure to ritonavir may also increase. Ribociclib has been shown to prolong the QT interval in a concentration-dependent manner. Ritonavir has also been associated with QT prolongation. Ribociclib is also extensively metabolized by CYP3A4 and ritonavir is a strong CYP3A4 inhibitor; exposure to ribociclib may be increased. Coadministration with ritonavir, a strong CYP3A4 inhibitor increased the ribociclib AUC and Cmax by 3.2-fold and 1.7-fold, respectively, in healthy volunteers. Additionally, ribociclib is a moderate CYP3A4 inhibitor and ritonavir is a CYP3A4 substrate. Use caution if coadministration of ribociclib with paritaprevir is necessary, as the systemic exposure of paritaprevir may be increased resulting in increase in treatment-related adverse reactions. Ribociclib is a moderate CYP3A4 inhibitor and paritaprevir is a CYP3A4 substrate.
Rifabutin: Concurrent administration of rifabutin with dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in elevated rifabutin plasma concentrations and decreased concentrations of paritaprevir, ritonavir, and dasabuvir, which may affect antiviral efficacy. Rifabutin is a CYP3A4 substrate, and ritonavir is a potent CYP3A4 inhibitor. In addition, rifabutin is an inducer of CYP3A4, and ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. Although rifabutin appears to induce the enzyme to a lesser degree than rifampin, the plasma concentrations of ritonavir, paritaprevir, and dasabuvir may be reduced. Concurrent administration of rifabutin with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in elevated rifabutin plasma concentrations and decreased concentrations of paritaprevir, ritonavir, and dasabuvir, which may affect antiviral efficacy. Rifabutin is a CYP3A4 substrate, and ritonavir is a potent CYP3A4 inhibitor. In addition, rifabutin is an inducer of CYP3A4, and ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. Although rifabutin appears to induce the enzyme to a lesser degree than rifampin, the plasma concentrations of ritonavir, paritaprevir, and dasabuvir may be reduced. Coadministration of ritonavir and rifabutin results in clinically significant alterations of rifabutin pharmacokinetic parameters, with the rifabutin AUC being increased by 430%. In patients receiving any dosage of ritonavir, the dose of rifabutin should always be decreased to 150 mg every day or 300 mg three times per week.
Rifampin: Coadministration of rifampin and ritonavir results in markedly decreased ritonavir concentrations; HIV treatment failure and virologic resistance would be expected. Rifampin (300 or 600 mg daily for 10 days) decreases the AUC and Cmax of ritonavir (500 mg every 12 hours for 20 days) by 35% and 25%, respectively. Coadministration may lead to loss of virologic response if ritonavir is the sole protease inhibitor and increase the risk of hepatotoxicity. The DHHS/NIH HIV Treatment Guidelines recommend ritonavir and rifampin should not be coadministered and suggest the consideration of alternative antimycobacterial agents, such as rifabutin. However, CDC guidelines suggest no change in ritonavir or rifampin dose when the drugs are coadministered, but this appears to only be in the setting of low-dose ritonavir (i.e., 100 mg or 200 mg twice daily) used to 'boost' concentrations of other protease inhibitors. In this setting it would be less likely to produce adverse events than higher ritonavir doses; however, a net CYP3A4 induction still results when used with rifampin. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with rifampin is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir and ritonavir. Rifampin is a potent inducer of the hepatic isoenzyme CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. Rifampin also induces CYP2D6 and CYP2C8, enzymes partially responsible for the metabolism of ritonavir and dasabuvir, respectively. In addition, rifampin induces the drug transporter proteins P-glycoprotein (P-gp) and UGT; dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates for P-gp, while dasabuvir, ombitasvir and paritaprevir are also substrates of UGT. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with rifampin is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir and ritonavir. Rifampin is a potent inducer of the hepatic isoenzyme CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. Rifampin also induces CYP2D6 and CYP2C8, enzymes partially responsible for the metabolism of ritonavir and dasabuvir, respectively. In addition, rifampin induces the drug transporter proteins P-glycoprotein (P-gp) and UGT; dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates for P-gp, while dasabuvir, ombitasvir and paritaprevir are also substrates of UGT.
Rifapentine: Concurrent use of rifapentine and dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in decreased concentrations of paritaprevir, ritonavir, and dasabuvir, which may affect antiviral efficacy. Rifapentine is expected to induce the CYP2C8 and CYP3A4 metabolism of dasbuvir and the CYP3A4 metabolism of paritaprevir and ritonavir. Rifapentine is an inducer of CYP3A4 and CYP2C8/9, and should not be coadministered with protease inhibitors as complex interactions may lead to decreased plasma concentrations of the anti-retroviral agents. In one study, indinavir Cmax and AUC were reduced by 55% and 70%, respectively. The clearance of indinavir was increased 3-fold in the presence of rifapentine while half-life did not change. Additionally, HIV patients treated with rifapentine have a higher rate of TB relapse than those treated with other rifamycin-based regimens; an alternative agent is recommended.
Rifaximin: Although the clinical significance of this interaction is unknown, concurrent use of rifaximin, a P-glycoprotein (P-gp) substrate, and ritonavir, a P-gp inhibitor, may substantially increase the systemic exposure to rifaximin; caution is advised if these drugs must be administered together. During one in vitro study, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in the mean Cmax and AUC of rifaximin, respectively. In patients with hepatic impairment, the effects of reduced metabolism and P-gp inhibition may further increase exposure to rifaximin. Concurrent administration of rifaximin with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated rifaximin and ombitasvir plasma concentrations and altered concentrations of dasabuvir, paritaprevir, and ritonavir. Rifaximin is a substrate and inhibitor of the drug transporter P-glycoprotein (P-gp); ritonavir is a P-gp inhibitor. Although ritonavir's effect on rifaximin clearance is not defined, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in rifaximin Cmax and AUC, respectively. In patients with hepatic impairment, the reduced metabolism and P-gp inhibition may further increase rifaximin exposure. Dasabuvir, ombitasvir, paritaprevir, and ritonavir are also P-gp substrates. In addition, ritonavir, paritaprevir, and dasabuvir (minor) are substrates of the hepatic isoenzyme CYP3A4. Rifaximin has been shown to be an inducer of CYP3A4, but enzyme induction is not expected when rifaximin is given at FDA-approved dosages in patients with normal liver function. It is not known whether rifaximin has a significant effect on the pharmacokinetics of CYP3A4 substrates in patients with hepatic impairment. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of rifaximin with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated rifaximin and ombitasvir plasma concentrations and altered concentrations of dasabuvir, paritaprevir, and ritonavir. Rifaximin is a substrate and inhibitor of the drug transporter P-glycoprotein (P-gp); ritonavir and paritaprevir are P-gp inhibitors. Although ritonavir's effect on rifaximin clearance is not defined, coadministration with cyclosporine, a potent P-gp inhibitor, resulted in an 83-fold and 124-fold increase in rifaximin Cmax and AUC, respectively. In patients with hepatic impairment, the reduced metabolism and P-gp inhibition may further increase rifaximin exposure. Dasabuvir, ombitasvir, paritaprevir, and ritonavir are also P-gp substrates. In addition, ritonavir, paritaprevir, and dasabuvir (minor) are substrates of the hepatic isoenzyme CYP3A4. Rifaximin has been shown to be an inducer of CYP3A4, but enzyme induction is not expected when rifaximin is given at FDA-approved dosages in patients with normal liver function. It is not known whether rifaximin has a significant effect on the pharmacokinetics of CYP3A4 substrates in patients with hepatic impairment. Caution and close monitoring are advised if these drugs are administered together.
Rilpivirine: Close clinical monitoring is advised when administering ritonavir with rilpivirine due an increased potential for rilpivirine-related adverse events. Dosage adjustments are not recommended. Predictions about the interaction can be made based on metabolic pathways. Ritonavir is an inhibitor and inducer of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. In addition, ritonavir has a possible risk of QT prolongation.
Riociguat: Concomitant use of riociguat with dasabuvir; ombitasvir; paritaprevir; ritonavir may increase riociguat exposure and result in hypotension. Ritonavir inhibits isoenzymes and drug transporters that metabolize riociguat, specifically CYP3A4, P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP). In addition, dasabuvir and paritaprevir are also BCRP inhibitors. If these drugs are to be coadministered, consider an initial riociguat dose of 0.5 mg PO three times a day, monitor patients for hypotension, and decrease the riociguat dose in patients who do not tolerate the hypotensive effects. Concomitant use of riociguat with strong cytochrome CYP inhibitors and P-glycoprotein (P-gp)/breast cancer resistance protein (BCRP) inhibitors, such as ritonavir, increases riociguat exposure and may result in hypotension. Consider a starting adult dose of 0.5 mg PO three times a day when initiating riociguat in patients receiving strong CYP and P-gp/BCRP inhibitors. Monitor for signs and symptoms of hypotension on initiation and on treatment with strong CYP and P-gp/BCRP inhibitors. A dose reduction should be considered in patients who may not tolerate the hypotensive effect of riociguat.
Risperidone: Concurrent administration of risperidone with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of risperidone and ritonavir and increased risk of adverse events. Both ritonavir and risperidone are substrates and inhibitors of the hepatic isoenzyme CYP2D6. In addition, risperidone is a substrate for CYP3A4 and P-glycoprotein (P-gp); ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor. Paritaprevir also inhibits P-gp. While dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QTc interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with QT prolongation in other trials. Risperidone has been associated with QT prolongation in post-marketing trials. Concurrent use of risperidone and dasabuvir; ombitasvir; paritaprevir; ritonavir may the increase the risk of QT prolongation. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of risperidone with ritonavir may result in elevated plasma concentrations of both drugs and increased risk of adverse events. Both ritonavir and risperidone are substrates and inhibitors of the hepatic isoenzyme CYP2D6. In addition, risperidone is a substrate for CYP3A4 and P-glycoprotein (P-gp); ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased risperidone doses may be required. In addition, both ritonavir and risperidone are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
Rivaroxaban: Avoid concomitant administration of rivaroxaban and ritonavir; significant increases in rivaroxaban exposure may increase bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter. Concurrent use of a single dose of rivaroxaban and ritonavir, a combined P-gp and strong CYP3A4 inhibitor, led to an increase in the rivaroxaban AUC by 150% and Cmax by 60%. Similar increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed.
Roflumilast: Patients receiving roflumilast may have altered serum concentrations if coadministered with ritonavir. Ritonavir is a potent inhibitor and an inducer of CYP3A4, and roflumilast is a CYP3A4 substrate. Specific pharmacokinetic study of this potential interaction has not been conducted.
Romidepsin: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with romidepsin may increase romidepsin concentrations and the risk for QT prolongation and torsade de pointes (TdP). Romidepsin is known to increase the QT interval. While dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QT interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with dose-related QT prolongation in other trials. In addition, romidepsin is a CYP3A4 substrate and a P-glycoprotein (P-gp) substrate, while ritonavir is a strong inhibitor of CYP3A4 and P-gp. Paritaprevir is also a P-gp inhibitor. Therefore, coadministration may increase romidepsin plasma concentrations and further increase the risk of QT prolongation and romidepsin toxicity; dosage adjustments may be necessary. Caution and close monitoring is advised if these drugs are administered together. The concomitant use of romidepsin, a CYP3A4 substrate and a P-glycoprotein (P-gp) substrate, and ritonavir, a strong CYP3A4 inhibitor and a P-gp substrate and inhibitor, may increase romidepsin plasma exposure. If these agents are used together, monitor patients for signs and symptoms of romidepsin toxicity including hematologic toxicity, infection, and electrocardiogram changes; therapy interruption or discontinuation or a dosage reduction may be required if toxicity develops. In addition, both ritonavir and romidepsin are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
Rosuvastatin: Dosage adjustments of rosuvastatin may be required during concomitant administration with dasabuvir; ombitasvir; paritaprevir; ritonavir. Use of these drugs together results in elevated rosuvastatin serum concentrations. Adult doses of rosuvastatin must be limited to no more than 10 mg/day when administered with dasabuvir; ombitasvir; paritaprevir; ritonavir. The dose should be re-adjusted after completion of the 4-drug hepatitis C treatment regimen. Due to CYP3A4 inhibition by ritonavir, the risk of myopathy (including rhabdomyolysis) may be increased when ritonavir is given in combination with rosuvastatin. If coadministration is necessary, use the lowest possible dose of rosuvastatin. Alternatively, consider using pravastatin or fluvastatin; however, fluvastatin is partially metabolized (about 20%) by CYP3A4 and is generally recommended to be used cautiously with protease inhibitors.
Ruxolitinib: Concurrent administration of ruxolitinib with ritonavir is expected to result in elevated ruxolitinib plasma concentrations, increasing the risk for adverse events such as thrombocytopenia, anemia, neutropenia, and infection. Patients who are stable on a ruxolitinib dose of 5 mg once daily should avoid concomitant use of ritonavir; other patients taking ritonavir will require a ruxolitinib dose reduction. Additional dose modifications should be made only after close monitoring of ruxolitinib's safety and efficacy. Ruxolitinib is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Sacubitril; Valsartan: Coadministration of valsartan and regimens containing paritaprevir may result in elevated valsartan plasma concentrations. A valsartan dose reduction, and close monitoring for adverse events (i.e., hypotension and worsening renal function) are advised during coadministration. If adverse events are observed, consider further reductions in valsartan dose or an alternative to the angiotensin receptor blocker. Valsartan is a substrate of the organic anion transporting polypeptides (OATP) and paritaprevir is an OATP1B1 and OATP1B3 inhibitor. Valsartan is a substrate of the hepatic efflux transporter MRP2 and ritonavir is an inhibitor of MRP2. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan during coadministration.
Salmeterol: Avoid coadministration of salmeterol with ritonavir. The coadministration of salmeterol with CYP3A4 inhibitors can result in elevated salmeterol plasma concentrations and increased risk for adverse reactions, particularly cardiovascular effects.
Sapropterin: Caution is advised with the concomitant use of sapropterin and dasabuvir as coadministration may result in increased systemic exposure of dasabuvir. Dasabuvir is a substrate for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side effects of dasabuvir. Caution is advised with the concomitant use of sapropterin and ombitasvir; paritaprevir; ritonavir as coadministration may result in increased systemic exposure of ombitasvir; paritaprevir; ritonavir. All 3 drugs are substrates for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side effects of ombitasvir; paritaprevir; ritonavir. Caution is advised with the concomitant use of sapropterin and ritonavir as coadministration may result in increased systemic exposure of ritonavir. Ritonavir is a substrate for the drug transporter P-glycoprotein (P-gp); in vitro data show that sapropterin may inhibit P-gp. If these drugs are used together, closely monitor for increased side effects of ritonavir.
Saquinavir: Concurrent administration of saquinavir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of saquinavir, dasabuvir, ombitasvir, paritaprevir, and ritonavir and subsequent adverse effects such as QT prolongation. Both saquinavir and ritonavir are substrates and inhibitors of the hepatic isoenzyme CYP3A4; paritaprevir and dasabuvir (minor) are partially metabolized by CYP3A4. In addition, saquinavir inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp. Saquinavir and ritonavir have both been associated with QT prolongation; caution and close monitoring are advised if these drugs are administered together. Although often administered together, ritonavir increases saquinavir plasma concentrations by two mechanisms: 1) the inhibition of GI cytochrome P450 during absorption and 2) metabolic inhibition of hepatic CYP450. Clinically, the interaction is used to therapeutic benefit. The combination allows for less frequent saquinavir dosing, while reducing the likelihood of developing saquinavir-resistant HIV strains. Saquinavir (Invirase) should only be used in combination with ritonavir. The use of saquinavir 'boosted' with ritonavir is contraindicated in patients with severe hepatic impairment. Saquinavir boosted with ritonavir has been found to increase the risk of QT prolongation and PR prolongation in a dose-dependent fashion. The manufacturer of saquinavir recommends that saquinavir boosted with ritonavir not be used in combination with other drugs that may prolong the QT or PR interval. Examples of general risk factors for TdP include congenital long QT syndrome, female sex, older age (i.e., elderly), significant bradycardia, hypokalemia, hypomagnesemia, and underlying cardiac disease (e.g., arrhythmias, cardiomyopathy, acute myocardial ischemia).
Saxagliptin: The metabolism of saxagliptin is primarily mediated by CYP3A4/5. The saxagliptin dose is limited to 2.5 mg once daily when coadministered with a strong CYP3A4/5 inhibitor such as ritonavir. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have also been reported with use of anti-retroviral protease inhibitors, such as ritonavir. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Secobarbital: Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required.
Selegiline: Concurrent administration of selegiline with ritonavir may result in elevated selegiline plasma concentrations. Selegiline is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Sertraline: An increased risk of serious adverse events, including QT prolongation, and elevated plasma concentrations of both sertraline and ritonavir may result if sertraline is coadministered with ritonavir. Ritonavir has been associated with QT prolongation. There have been post-marketing reports of QT prolongation and Torsade de Pointes (TdP) with sertraline; caution is advisable if used concurrently with other agents that may prolong the QT interval. Sertraline is a CYP2D6 substrate/inhibitor and a CYP3A4 substrate; ritonavir is a CYP2D6 substrate/inhibitor and a potent CYP3A4 inhibitor. Caution and close monitoring are advised if these drugs are used together.
Sevoflurane: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include halogenated anesthetics.
Sibutramine: Due to ritonavir's potential inhibitory effects on various hepatic isoenzymes, close monitoring of serum drug concentrations and/or therapeutic and adverse effects is required when sibutramine is coadministered with ritonavir; dosage reduction may be needed.
Sildenafil: When sildenafil is used for the treatment of pulmonary arterial hypertension (PAH), the use of ritonavir is contraindicated because a safe and effective dose has not been established. In patients with erectile dysfunction, particular caution should be used when prescribing phosphodiesterase type 5 (PDE5) inhibitors to patients receiving ritonavir. If coadministered when sildenafil is used for erectile dysfunction, a reduced dose of sildenafil 25 mg every 48 hours with increased monitoring for adverse reactions is recommended. Coadministration of ritonavir with sildenafil results in an 11-fold increase of sildenafil AUC; one death has been reported in a patient who received sildenafil in combination with ritonavir and Fortovase. Substantially increased sildenafil plasma concentrations may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Silodosin: Coadministration of silodosin and ombitasvir; paritaprevir; ritonavir or dasabuvir; ombitasvir; paritaprevir; ritonavir is contraindicated. Silodosin is extensively metabolized by CYP3A4 and the manufacturer contraindicates concurrent use with potent CYP3A4 inhibitors, including ritonavir. Also of note, silodosin is a P-glycoprotein (P-gp) substrate and ritonavir and paritaprevir are P-gp inhibitors. Coadministration would be expected to cause significant increases in silodosin plasma concentrations. Concurrent use of silodosin and ritonavir is contraindicated. Silodosin is extensively metabolized by CYP3A4; ritonavir is a potent inhibitor of this enzyme. Also of note, silodosin is a P-glycoprotein (P-gp) substrate and ritonavir is a P-gp inhibitor. Coadministration may cause significant increases in silodosin plasma concentrations, potentially resulting in adverse events.
Simeprevir: Avoid concurrent use of simeprevir and ritonavir. Inhibition of CYP3A4 and P-glycoprotein (P-gp) by ritonavir causes significantly increased plasma concentrations of simeprevir, potentially resulting in adverse effects. Avoid the coadministration of simeprevir and dasabuvir; ombitasvir; paritaprevir; ritonavir. The FDA-approved labeling for simeprevir, a CYP3A4 substrate, states that coadministration with strong CYP3A4 inhibitors, including ritonavir, is not recommended as significant increases in simeprevir could result. Additional metabolic interactions are expected which would lead to elevated plasma concentrations of simeprevir, dasabuvir, ombitasvir, paritaprevir, and ritonavir. Simeprevir is a P-glycoprotein (P-gp) substrate/inhibitor, ritonavir is a P-gp substrate/inhibitor, and dasabuvir, ombitasvir, and paritaprevir are P-gp substrates. Simeprevir and paritaprevir are both OATP1B1/3 substrate/inhibitors. Finally, simeprevir is a mild CYP3A4 inhibitor and dasabuvir, paritaprevir, and ritonavir are CYP3A4 substrates. Avoid the coadministration of simeprevir and dasabuvir; ombitasvir; paritaprevir; ritonavir. The FDA-approved labeling for simeprevir, a CYP3A4 substrate, states that coadministration with strong CYP3A4 inhibitors, including ritonavir, is not recommended as significant increases in simeprevir could result. Additional metabolic interactions are expected which would lead to elevated plasma concentrations of simeprevir, dasabuvir, ombitasvir, paritaprevir, and ritonavir. Simeprevir is a P-glycoprotein (P-gp) substrate/inhibitor, ritonavir is a P-gp substrate/inhibitor, dasabuvir, ombitasvir, and paritaprevir are P-gp substrates, and paritaprevir is a P-gp inhibitor. Simeprevir and paritaprevir are both OATP1B1/3 substrate/inhibitors. Finally, simeprevir is a mild CYP3A4 inhibitor and dasabuvir, paritaprevir, and ritonavir are CYP3A4 substrates.
Simvastatin: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with simvastatin is contraindicated due to the potential for severe adverse reactions, including myopathy and rhabdomyolysis. Coadministration may result in elevated simvastatin systemic concentrations. Simvastatin is a substrate of the hepatic isoenzyme CYP3A4 and OATP1B1; ritonavir is a potent inhibitor of CYP3A4 and paritaprevir inhibits OATP1B1. In addition, simvastatin may inhibit P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with simvastatin is contraindicated due to the potential for severe adverse reactions, including myopathy and rhabdomyolysis. Coadministration may result in elevated simvastatin systemic concentrations. Simvastatin is a substrate of the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this isoenzyme. In addition, simvastatin may inhibit P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors.
Simvastatin; Sitagliptin: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with simvastatin is contraindicated due to the potential for severe adverse reactions, including myopathy and rhabdomyolysis. Coadministration may result in elevated simvastatin systemic concentrations. Simvastatin is a substrate of the hepatic isoenzyme CYP3A4 and OATP1B1; ritonavir is a potent inhibitor of CYP3A4 and paritaprevir inhibits OATP1B1. In addition, simvastatin may inhibit P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with simvastatin is contraindicated due to the potential for severe adverse reactions, including myopathy and rhabdomyolysis. Coadministration may result in elevated simvastatin systemic concentrations. Simvastatin is a substrate of the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this isoenzyme. In addition, simvastatin may inhibit P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. The coadministration of anti-retroviral protease inhibitors with simvastatin is contraindicated. Taking these drugs together may significantly increase the serum concentration of simvastatin; thereby increasing the risk of myopathy and rhabdomyolysis. One report has demonstrated that ritonavir plus saquinavir therapy markedly increases the AUC for simvastatin by 3059%. Simvastatin is a substrate for CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are CYP3A4 and OATP inhibitors. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Sirolimus: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with sirolimus is contraindicated due to the potential for severe immunosuppressant-associated adverse events. When administered concurrently with ombitasvir; paritaprevir; ritonavir, the maximum plasma concentration (peak), minimum plasma concentration (trough), and systemic exposure of sirolimus are significantly increased. Avoid the use of sirolimus with potent CYP3A4 inhibitors, such as protease inhibitors. Protease inhibitors may affect absorption and elimination of sirolimus leading to increased blood concentrations. Sirolimus is extensively metabolized by CYP3A4 in the gut and liver and undergoes counter-transport from enterocytes of the small intestine into the gut lumen by the P-glycoprotein drug efflux pump. Sirolimus is potentially recycled between enterocytes and the gut lumen to allow continued metabolism by CYP3A4.
Sitagliptin: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Another possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients taking antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Sodium Bicarbonate: Concurrent administration of tipranavir and ritonavir with antacids results in decreased tipranavir concentrations. Administer tipranavir and ritonavir 2 hours before or 1 hour after antacids.
Sodium Oxybate: One case report describes a possible interaction between sodium oxybate and ritonavir and saquinavir, leading to repetitive, clonic contractions. The patient also experienced shallow respirations, a heart rate of 40 beats per min, and was responsive only to painful stimuli. The exact contribution of ritonavir and saquinavir to this reaction cannot be determined since several other compounds were detected through a urinary toxin screen.
Sofosbuvir: Caution is warranted when ritonavir is administered with sofosbuvir as there is a potential for elevated concentrations of sofosbuvir. Ritonvir is an inhibitor of the transporter P-glycoprotein (P-gp). Sofosbuvir is a substrate of P-gp. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects. Concurrent administration of sofosbuvir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of sofosbuvir. Ritonavir is an inhibitor of the breast cancer resistance protein (BCRP); dasabuvir and paritaprevir are substrates/inhibitors of BCRP, while sofosbuvir is a BCRP substrate. Caution and close monitoring are advised if these drugs are administered together Concurrent administration of sofosbuvir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of sofosbuvir. Ritonavir is an inhibitor of the breast cancer resistance protein (BCRP); dasabuvir and paritaprevir are substrates/inhibitors of BCRP, while sofosbuvir is a BCRP substrate. Caution and close monitoring are advised if these drugs are administered together.
Sofosbuvir; Velpatasvir: Avoid coadministration of velpatasvir with ritonavir. Taking these drugs together may significantly alter the plasma concentrations of velpatasvir, and increase the concentrations of ritonavir. Velpatasvir is a CYP3A4 substrate. Ritonavir is a mixed inducer/inhibitor of CYP3A4. In addition, both ritonavir and velpatasvir are substrates and inhibitors of the drug transporter P-glycoprotein (P-gp). If these drugs are administered together, monitor for loss of antiviral efficacy and adverse effects. Caution is warranted when ritonavir is administered with sofosbuvir as there is a potential for elevated concentrations of sofosbuvir. Ritonvir is an inhibitor of the transporter P-glycoprotein (P-gp). Sofosbuvir is a substrate of P-gp. According to the manufacturer, no dosage adjustments are required when sofosbuvir is administered concurrently with P-gp inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effects. Concurrent administration of sofosbuvir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of sofosbuvir. Ritonavir is an inhibitor of the breast cancer resistance protein (BCRP); dasabuvir and paritaprevir are substrates/inhibitors of BCRP, while sofosbuvir is a BCRP substrate. Caution and close monitoring are advised if these drugs are administered together Concurrent administration of sofosbuvir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of sofosbuvir. Ritonavir is an inhibitor of the breast cancer resistance protein (BCRP); dasabuvir and paritaprevir are substrates/inhibitors of BCRP, while sofosbuvir is a BCRP substrate. Caution and close monitoring are advised if these drugs are administered together.
Solifenacin: Solifenacin is significantly metabolized via the CYP3A4 pathway. Patients receiving CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, should not receive solifenacin doses greater than 5 mg per day. Pharmacokinetic studies of the use of solifenacin concomitantly with all CYP3A4 inhibitors have not been performed. The interaction between solifenacin and ketoconazole has been studied. Following the administration of solifenacin 10 mg and ketoconazole 400 mg PO, the peak concentration and AUC increased 150% and 270%, respectively. In addition, both ritonavir and solifenacin are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
Somatropin, rh-GH: When somatropin, an inducer of CYP3A4, and anti-retroviral protease inhibitors, a CYP3A4 substrate, are coadministered, patients should be monitored for changes in anti-retroviral efficacy. Published data indicate that in HIV-infected patients receiving somatropin for wasting or HIV-associated adipose redistribution syndrome (HARS), somatropin did not adversely affect antiretroviral effectiveness as indicated by no change in the concentration of circulating CD4 counts or viral load.
Sonidegib: Avoid the concomitant use of sonidegib and ritonavir or lopinavir; ritonavir as sonidegib levels may be significantly increased resulting in an increased risk of adverse events, particularly musculoskeletal toxicity. Sonidegib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. The sonidegib geometric mean Cmax and AUC (0-10 days) values were increased 2.2-fold and 1.5-fold, respectively, in healthy subjects who received a single 800-mg dose of sonidegib after taking 14 days of a strong CYP3A4 inhibitor. Physiologic-based pharmacokinetics simulations indicate that the sonidegib geometric mean steady-state AUC (0-24 hours) would be increased to a similar extent in cancer patients who received 14 days of sonidegib 200 mg/day with a strong CYP3A inhibitor.
Sorafenib: Coadministration may result in increased plasma concentrations of dasabuvir, although the clinical significance is unclear. Sorafenib inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir is a substrate of P-gp. Caution and close monitoring are advised if these drugs are administered together. Coadministration may result in increased plasma concentrations of ombitasvir. Sorafenib inhibits the drug transporter P-glycoprotein (P-gp); ombitasvir is a substrate of P-gp. Caution and close monitoring are advised if these drugs are administered together. Coadministration may result in increased plasma concentrations of paritaprevir. Sorafenib inhibits the drug transporter P-glycoprotein (P-gp); paritaprevir is a substrate of P-gp. Caution and close monitoring are advised if these drugs are administered together. The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include sorafenib. Sorafenib is associated with QT prolongation; electrolyte and ECG monitoring are recommended when sorafenib is coadministered with other drugs known to prolong the QT interval. Interrupt sorafenib therapy if the QTc interval is longer than 500 milliseconds or if there is an increase of 60 milliseconds or more from baseline. In addition, coadministration may result in increased plasma concentrations of ritonavir, although the clinical significance is unclear. Sorafenib is an inhibitor of the drug transporter P-glycoprotein (P-gp); however, potency of the inhibition is not known. Ritonavir is a substrate for P-gp. Caution and close monitoring are advised if these drugs are administered together
Sotalol: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include sotalol.
St. John's Wort, Hypericum perforatum: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with St. John's Wort, Hypericum perforatum is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir and ritonavir. St. John's Wort is a potent inducer of the hepatic isoenzyme CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. In addition, St. John's Wort may induce P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with St. John's Wort, Hypericum perforatum is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to dasabuvir, ombitasvir, paritaprevir and ritonavir. St. John's Wort is a potent inducer of the hepatic isoenzyme CYP3A4; dasabuvir (minor), paritaprevir and ritonavir are substrates of this isoenzyme. In addition, St. John's Wort may induce P-glycoprotein (P-gp), a drug efflux transporter for which dasabuvir, ombitasvir, paritaprevir and ritonavir are substrates. Use of St. John's wort with protease inhibitors is contraindicated. St. John's wort is an inducer of CYP3A and is expected to significantly decrease the plasma concentrations of all currently marketed protease inhibitors. Reductions in plasma concentrations of these drugs could lead to HIV treatment failures or the development of viral-resistance. St. John's wort in all forms, including teas, should be avoided in HIV patients treated with these agents.
Streptogramins: Dalfopristin; quinupristin is a major inhibitor of cytochrome P450 3A4 and may decrease the elimination of drugs metabolized by this enzyme, including ritonavir. Per the manufacturer of dalfopristin; quinupristin, concomitant use with CYP3A4 substrates that may prolong the QT interval should be avoided; ritonavir has been associated with dose-related QT prolongation. Concurrent administration of dalfopristin; quinupristin with dasabuvir; ombitasvir; paritaprevir; ritonavir is expected to result in elevated plasma concentrations of dasabuvir, paritaprevir, and ritonavir. According to the manufacturer of dalfopristin; quinupristin, concomitant use with CYP3A4 substrates that may prolong the QT interval should be avoided. While dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QT interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with dose-related QT prolongation in other trials. Quinupristin is a potent inhibitor of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of dalfopristin; quinupristin with dasabuvir; ombitasvir; paritaprevir; ritonavir is expected to result in elevated plasma concentrations of dasabuvir, paritaprevir, and ritonavir. According to the manufacturer of dalfopristin;quinupristin, concomitant use with CYP3A4 substrates that may prolong the QT interval should be avoided. While dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QT interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with dose-related QT prolongation in other trials. Quinupristin is a potent inhibitor of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. Caution and close monitoring are advised if these drugs are administered together.
Sufentanil: Sufentanil is metabolized by the hepatic isoenzyme CYP3A4. Agents that inhibit CYP3A4 activity, such as protease inhibitors may decrease systemic clearance of sufentanil leading to increased or prolonged effects. Initiate sufentanil at a conservative dosage and carefully monitor for signs of excessive exposure such as oversedation, respiratory depression, and hypotension.
Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: Ritonavir can increase the AUC of trimethoprim by 20%. Conversely, ritonavir can decrease the AUC of sulfamethoxazole by 20%. However, the Cmax of trimethoprim and sulfamethoxazole was not affected. In addition, both ritonavir and sulfamethoxazole; trimethoprim are associated with QT prolongation; concomitant use increases the risk of QT prolongation. According to the manufacturer, no dosage adjustments are required when trimethoprim is administered with dasabuvir; ombitasvir; paritaprevir; ritonavir; however, use of these drugs together may result in elevated dasabuvir plasma concentrations. Trimethoprim inhibits CYP2C8, an enzyme primarily responsible for the metabolism of dasabuvir. Caution and close monitoring are advised if these drugs are administered together. Ritonavir can increase the AUC of trimethoprim by 20%. Conversely, ritonavir can decrease the AUC of sulfamethoxazole by 20%. However, the Cmax of trimethoprim and sulfamethoxazole was not affected.
Sulfonylureas: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Sunitinib: Concurrent administration of sunitinib with ritonavir may result in elevated plasma concentrations of sunitinib and its primary active metabolite. Sunitinib is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is a potent inhibitor of this enzyme. Whenever possible, selection of an alternative concomitant medication with no or minimal enzyme inhibition potential is recommended; otherwise, a reduction in the sunitinib dosage is recommended. In addition, both ritonavir and sunitinib are associated with QT prolongation; concomitant use may increase the risk of QT prolongation. Caution and close monitoring are advised if these drugs are administered together.
Suvorexant: Coadministration of suvorexant and dasabuvir; ombitasvir; paritaprevir; ritonavir should be avoided. The manufacturer of suvorexant, a CYP3A substrate, recommends against concurrent use with strong CYP3A inhibitors, such as ritonavir, as significantly increased suvorexant exposure (AUC) occurs. Additionally, suvorexant inhibits P-glycoprotein (P-gp) and could increase the concentrations of P-gp substrates such as each component of dasabuvir; ombitasvir; paritaprevir; ritonavir. Coadministration of suvorexant and dasabuvir; ombitasvir; paritaprevir; ritonavir should be avoided. The manufacturer of suvorexant, a CYP3A substrate, recommends against concurrent use with strong CYP3A inhibitors, such as ritonavir, as significantly increased suvorexant exposure (AUC) occurs. Additionally, suvorexant inhibits P-glycoprotein (P-gp) and could increase the concentrations of P-gp substrates such as each component of dasabuvir; ombitasvir; paritaprevir; ritonavir. Suvorexant is primarily metabolized by CYP3A, and the manufacturer recommends against concurrent use of suvorexant with strong CYP3A inhibitors such as ritonavir. Strong inhibitors of CYP3A significantly increase suvorexant exposure (AUC).
Tacrolimus: Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir with tacrolimus is contraindicated due to the potential for severe immunosuppressant-associated adverse events. When administered concurrently with ombitasvir; paritaprevir; ritonavir, the maximum plasma concentration (peak), minimum plasma concentration (trough), and systemic exposure of tacrolimus are significantly increased. Ritonavir inhibits CYP3A4, increasing whole blood concentrations of tacrolimus and leading to the potential for nephrotoxicity or other tacrolimus-related side effects. Extreme caution must be used when administering tacrolimus concomitantly with any anti-retroviral protease inhibitor. Tacrolimus concentrations can be maintained with appropriate monitoring and dosage adjustment. In addition, both ritonavir and tacrolimus are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
Tadalafil: For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of ritonavir for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Avoid the use of tadalafil for pulmonary hypertension during the initiation of ritonavir therapy. Stop tadalafil at least 24 hours prior to starting ritonavir. After at least 1 week of ritonavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Coadministration of ritonavir with tadalafil results in a 124% increase in tadalafil AUC. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. It should be noted that during once daily administration of tadalafil, the presence of continuous plasma tadalafil concentrations may change the potential for interactions with potent inhibitors of CYP3A4.
Tamoxifen: Caution is advised with the concomitant use of tamoxifen and ritonavir due to an increased risk of QT prolongation; reduced tamoxifen efficacy and/or increased tamoxifen toxicity is also possible. Monitor for evidence of QT prolongation, altered tamoxifen efficacy, and increased tamoxifen adverse effects if coadministration needed. Tamoxifen has been reported to prolong the QT interval, usually in overdose or when used in high doses. Rare case reports of QT prolongation have also been described when tamoxifen is used at lower doses. Ritonavir is also associated with QT prolongation. Ritonavir may reduce the conversion of tamoxifen to other potent active metabolites via inhibition of CYP3A4. Concurrent administration of tamoxifen with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in in increased antiviral exposure and decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. Consider avoiding concomitant use of ritonavir and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for increased antiviral side effects, as well as changes in the therapeutic efficacy of tamoxifen. Both ritonavir and tamoxifen are substrates and inhibitors of the hepatic isoenzyme CYP3A4; paritaprevir and dasabuvir (minor) are CYP3A4 substrates. Tamoxifen is also a substrate for CYP2D6; ritonavir is a CYP2D6 inhibitor. In addition, tamoxifen inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp. Concurrent administration of tamoxifen with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in in increased antiviral exposure and decreased concentrations of the active metabolites of tamoxifen, which can compromise efficacy. Consider avoiding concomitant use of ritonavir and tamoxifen; if it is not possible to avoid concomitant use, monitor patients for increased antiviral side effects, as well as changes in the therapeutic efficacy of tamoxifen. Both ritonavir and tamoxifen are substrates and inhibitors of the hepatic isoenzyme CYP3A4; paritaprevir and dasabuvir (minor) are CYP3A4 substrates. Tamoxifen is also a substrate for CYP2D6; ritonavir is a CYP2D6 inhibitor. In addition, tamoxifen inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp.
Tamsulosin: Plasma concentrations of tamsulosin may be increased with concomitant use of anti-retroviral protease inhibitors. Tamsulosin is extensively metabolized by CYP3A4 and CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP3A4 inhibitor resulted in significant increases in tamsulosin exposure. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension. Therefore, concomitant use of tamsulosin with a strong CYP3A4 inhibitor, or an agent with both CYP3A4 and CYP2D6 inhibitor activity, should be avoided.
Tasimelteon: Concurrent use of tasimelteon and strong inhibitors of CYP3A4, such as ritonavir, should be avoided if possible. Because tasimelteon is partially metabolized via CYP3A4, a large increase in exposure of tasimelteon with the potential for adverse reactions is possible if these drugs are coadministered. During administration of tasimelteon and another potent CYP3A4 inhibitor, tasimelteon exposure increased by about 50%.
Telaprevir: Concurrent administration of telaprevir with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of both drugs. Both ritonavir and telaprevir are substrates and inhibitors of the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp). Paritaprevir and dasabuvir (minor) are CYP3A4 substrates. In addition, dasabuvir, ombitasvir, and paritaprevir are all substrates of P-gp. Telaprevir also inhibits the organic anion transporting polypeptides (OATP) 1B1. Paritaprevir is a substrate of OATP1B1. Caution and close monitoring is advised if these drugs are administered together.
Telavancin: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include telavancin.
Telithromycin: Both telithromycin and ritonavir are substrates and inhibitors of CYP3A4. In addition, telithromycin inhibits the drug transporter P-glycoprotein (P-gp); ritonavir is a substrate of this transporter. Coadministration may result in increased plasma concentrations of both drugs, which may increase or prolong both the therapeutic and adverse effects. In addition, both ritonavir and telithromycin are associated with QT prolongation; concomitant use increases the risk of QT prolongation. Concurrent administration of telithromycin with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of all 5 drugs and subsequent adverse effects. There may be a risk of QT prolongation when these drugs are administered together. While dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QT interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with dose-related QT prolongation in other trials. Telithromycin also has the potential to cause QT prolongation. Both ritonavir and telithromycin are substrates and potent inhibitors of the hepatic isoenzyme CYP3A4; paritaprevir and dasabuvir (minor) are CYP3A4 substrates. In addition, telithromycin inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-gp. Telithromycin also inhibits the organic anion transporting polypeptides (OATP). Paritaprevir is a substrate of OATP1B1 and OATP1B3. Caution and close monitoring is advised if these drugs are administered together. Concurrent administration of telithromycin with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of both drugs and subsequent adverse effects. There may be a risk of QT prolongation when these drugs are administered together. While dasabuvir; ombitasvir; paritaprevir; ritonavir and ombitasvir; paritaprevir; ritonavir did not prolong the QT interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with dose-related QT prolongation in other trials. Telithromycin also has the potential to cause QT prolongation. Both ritonavir and telithromycin are substrates and potent inhibitors of the hepatic isoenzyme CYP3A4; paritaprevir and dasabuvir (minor) are CYP3A4 substrates. In addition, telithromycin inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-gp. Telithromycin also inhibits the organic anion transporting polypeptides (OATP). Paritaprevir is a substrate of OATP1B1 and OATP1B3. Caution and close monitoring is advised if these drugs are administered together.
Telotristat Ethyl: The use of ombitasvir; paritaprevir; ritonavir is contraindicated with telotristat ethyl, due to reduced systemic exposure resulting in reduced efficacy. Paritaprevir is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. The Cmax and AUC ratio of paritaprevir was 0.34 and 0.3, respectively, after carbamazepine adminsitration compared with paritaprevir alone. Use caution if coadministration of telotristat ethyl and ritonavir is necessary, as the systemic exposure of ritonavir may be decreased resulting in reduced efficacy; exposure to telotristat ethyl may also be increased. If these drugs are used together, monitor patients for suboptimal efficacy of ritonavir as well as an increase in adverse reactions related to telotristat ethyl. Ritonavir is a CYP3A4 substrate. The mean Cmax and AUC of another sensitive CYP3A4 substrate was decreased by 25% and 48%, respectively, when coadministered with telotristat ethyl; the mechanism of this interaction appears to be that telotristat ethyl increases the glucuronidation of the CYP3A4 substrate. Coadministration with a strong CYP3A4 inducer decreased the ritonavir AUC and Cmax by 35% and 25%, respectively. Additionally, the active metabolite of telotristat ethyl, telotristat, is a substrate of P-glycoprotein (P-gp) and ritonavir is a P-gp inhibitor. Exposure to telotristat ethyl may increase.
Temsirolimus: Avoid coadministration of temsirolimus with ritonavir due to the risk of an increase in temsirolimus- and ritonavir-related adverse events. If concomitant use cannot be avoided, consider a temsirolimus dose reduction to 12.5 mg per week. If ritonavir is discontinued, allow a washout period of approximately 1 week before the temsirolimus dose is increased to the dose used before initiation of ritonavir. Temsirolimus is a CYP3A4 substrate and ritonavir is a strong inhibitor of CYP3A4. Coadministration of temsirolimus with ketoconazole, a strong CYP3A4 inhibitor, had no significant effect on the AUC or Cmax of temsirolimus, but increased the sirolimus AUC and Cmax by 3.1-fold and 2.2-fold, respectively. Additionally, temsirolimus is P-glycoprotein (P-gp) substrate/inhibitor in vitro, while ritonavir is also a P-gp substrate/inhibitor. Concomitant use may result in increased plasma concentrations of both ritonavir and temsirolimus (and active metabolite, sirolimus).
Teniposide: Concurrent administration of teniposide with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated teniposide plasma concentrations. Teniposide is a substrate for CYP3A4 and P-glycoprotein (P-gp); ritonavir is inhibits both CYP3A44 and P-gp. Paritaprevir also inhibits P-gp. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of teniposide with ritonavir may result in elevated teniposide plasma concentrations. Teniposide is a substrate for CYP3A4 and P-glycoprotein (P-gp); ritonavir inhibits both CYP3A44 and P-gp. Caution and close monitoring are advised if these drugs are administered together.
Tenofovir, PMPA: Caution is advised when administering tenofovir, PMPA, a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate, concurrently with inhibitors of P-gp and BCRP, such as ritonavir. Coadministration may result in increased absorption of tenofovir. Monitor for tenofovir-associated adverse reactions. Concurrent administration of tenofovir, PMPA with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated tenofovir plasma concentrations. Tenofovir is a substrate for the breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp). Dasabuvir, paritaprevir, and ritonavir are BCRP inhibitors, and ritonavir inhibits P-gp. Caution and close monitoring are advised if these drugs are administered together.
Terbinafine: Caution is advised when administering terbinafine with ritonavir. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may alter the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP1A2, CYP2C9, and CYP3A4; ritonavir is an inducer of CYP1A2 and CYP2C9, and an inhibitor/inducer of CYP3A4. Monitor patients for adverse reactions and breakthrough fungal infections if these drugs are coadministered.
Terbutaline: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir, include beta-agonists.
Terfenadine: Caution should be used in patients receiving protease inhibitors concurrently with drugs metabolized via CYP3A4 and known to cause QT prolongation. Protease inhibitors inhibit the CYP3A4 isoenzyme at clinically relevant concentrations, which may lead to increased serum concentrations of terfenadine and an increased potential for QT prolongation or other adverse effects. Serious and/or life-threatening drug interactions could potentially occur between protease inhibitors and terfenadine.
Teriflunomide: Concurrent administration of teriflunomide with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations dasabuvir, ombitasvir, and paritaprevir. Dasabuvir, ombitasvir, and paritaprevir are substrates of BCRP, and teriflunomide is a BRCP inhibitor. Teriflunomide also inhibits the hepatic isoenzyme CYP2C8, the enzyme primarily responsible for dasabuvir's metabolism. In addition, paritaprevir is a substrate of the organic anion transporting polypeptides (OATP1B1 and OATP1B3), and teriflunomide is an OATP inhibitor. When these drugs are coadministered, the degree of increase in the plasma concentrations of the antivirals has not been defined. Coadministration of dasabuvir; ombitasvir; paritaprevir; ritonavir with potent CYP2C8 inhibitors is contraindicated due to the increased risk for QT prolongation associated with elevated dasabuvir concentrations. Caution and close monitoring is advised if these drugs are administered together.
Tesamorelin: Use caution when coadministering tesamorelin with ritonavir as their concurrent use may alter ritonavir plasma concentrations. In a pharmacokinetic study, multiple 2 mg doses of tesamorelin administered with ritonavir resulted in a 9% decrease in ritonavir AUC and an 11% decrease in ritonavir Cmax. The clinical impact of these pharmacokinetic changes is unknown; however, patients should be monitored for decreased ritonavir efficacy.
Testosterone: Concurrent administration of testosterone with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of testosterone, dasabuvir, ombitasvir, paritaprevir, and ritonavir. Testosterone is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp). Ritonavir is a potent CYP3A4 inhibitor; it also inhibits P-gp. In addition, testosterone inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-gp. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of testosterone with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of testosterone, dasabuvir, ombitasvir, paritaprevir, and ritonavir. Testosterone is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp). Ritonavir is a potent CYP3A4 inhibitor; it also inhibits P-gp. Paritaprevir also inhibits P-gp. In addition, testosterone inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-gp. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of testosterone with ritonavir may result in elevated plasma concentrations of testosterone and ritonavir. Testosterone is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter P-glycoprotein (P-gp). Ritonavir is a CYP3A4 and P-gp inhibitor. In addition, testosterone inhibits P-gp; ritonavir is a substrate of P-gp. Caution and close monitoring are advised if these drugs are administered together.
Tetrabenazine: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include tetrabenazine.
Theophylline, Aminophylline: Ritonavir decreased theophylline AUC and Cmax by 43% and 52%, respectively, when the two drugs were coadministered. Higher dosages of aminophylline might be required. Ritonavir decreased theophylline AUC and Cmax by 43% and 52%, respectively, when the two drugs were coadministered. If these drugs are used together, therapeutic drug monitoring should be considered. Higher dosages of theophylline might be required.
Thiazolidinediones: New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of anti-retroviral protease inhibitors. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic agents should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. In addition, coadministration of atazanavir with rosiglitazone may result in elevated rosiglitazone plasma concentrations. Rosiglitazone is a substrate for CYP2C8; atazanavir is a weak inhibitor of CYP2C8.
Thiopental: Concurrent use of ritonavir with phenobarbital or other barbiturates should be done cautiously. Increased doses of anticonvulsants may be required due metabolism induction by ritonavir. However, since these anticonvulsants are hepatic enzyme inducing drugs, increased metabolism of protease inhibitors may occur, leading to decreased antiretroviral efficacy. Close monitoring of drug concentrations and/or therapeutic and adverse effects is required.
Thioridazine: Concurrent administration of thioridazine with ritonavir is contraindicated; coadministration is expected to result in elevated plasma concentrations of thioridazine, which can increase the risk of QT prolongation. Thioridazine is metabolized by the hepatic isoenzyme CYP2D6 and ritonavir is an inhibitor of this enzyme; both drugs are associated with concentration-dependent QT prolongation.
Tiagabine: Concurrent administration of tiagabine with ritonavir may result in elevated tiagabine plasma concentrations. Tiagabine is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Ticagrelor: Avoid the concomitant use of ticagrelor and dasabuvir; ombitasvir; paritaprevir; ritonavir. Ticagrelor is a substrate of CYP3A4/5 and P-glycoprotein (P-gp), and ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor. Concomitant use is expected to increase ticagrelor exposure, which may increase bleeding risk. Ticagrelor is also a mild CYP3A4 inhibitor and P-gp inhibitor. Ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates, and dasabuvir, ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp. Avoid the concomitant use of ticagrelor and ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir. Ticagrelor is a substrate of CYP3A4/5 and P-glycoprotein (P-gp), and ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor. Paritaprevir also inhibits P-gp. Concomitant use is expected to increase ticagrelor exposure, which may increase bleeding risk. Ticagrelor is also a mild CYP3A4 inhibitor and P-gp inhibitor. Ritonavir and paritaprevir are CYP3A4 substrates, and ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp. Avoid the concomitant use of ticagrelor and ritonavir. Ticagrelor is a substrate of CYP3A4/5 and P-glycoprotein (P-gp), and ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor. Concomitant use with ritonavir substantially increases ticagrelor exposure which may increase the bleeding risk. In addition, ticagrelor is also a mild CYP3A4 inhibitor and P-gp inhibitor. Ritonavir is a substrate of both CYP3A4 and P-gp.
Tigecycline: Coadministration of P-glycoprotein (P-gp) inhibitors, such as ritonavir, may increase tigecycline serum concentrations. Based on an in vitro study, tigecycline is a P-gp substrate; however, the potential contribution of P-gp-mediated transport to the in vivo disposition of tigecycline is not known.
Timolol: Timolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as ritonavir, may impair timolol metabolism; the clinical significance of such interactions is unknown.
Tinidazole: Alcoholic beverages and preparations containing ethanol, such as ritonavir oral solution, should be avoided during tinidazole therapy and for three days after stopping therapy. Formulations containing a high-percentage of alcohol, although infrequent, may cause disulfiram-like reactions in patients taking tinidazole concurrently. A disulfiram reaction would not be expected to occur with non-ethanol containing formulations of ritonavir. In addition, tinidazole is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Tiotropium; Olodaterol: Beta-agonists, such as olodaterol, may be associated with adverse cardiovascular effects including QT interval prolongation. Beta-agonists should be administered with extreme caution to patients being treated with drugs known to prolong the QT interval because the action of beta-agonists on the cardiovascular system may be potentiated. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with olodaterol include ritonavir.
Tipranavir: Concurrent administration of tipranavir with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir will result in increased tipranavir plasma concentrations. Tipranavir is only indicated for use in combination with ritonavir boosting; carefully account for all sources of ritonavir to ensure proper dosing and avoid serious toxicity (e.g., hepatotoxicity). Tipranavir is a substrate/inhibitor of CYP3A4 and an inhibitor of CYP2D6, while ritonavir is a substrate/inhibitor of both enzymes. In addition to altered tipranavir concentrations, decreased ombitasvir concentrations and altered concentrations of dasabuvir, paritaprevir, and ritonavir may also occur. Paritaprevir and dasabuvir (minor) are CYP3A4 substrates, and their metabolism may be reduced by tipranavir. Tipranavir is also an inducer of the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-gp. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of tipranavir with dasabuvir; ombitasvir; paritaprevir; ritonavir will result in increased tipranavir plasma concentrations. Tipranavir is only indicated for use in combination with ritonavir boosting; carefully account for all sources of ritonavir to ensure proper dosing and avoid serious toxicity (e.g., hepatotoxicity). Tipranavir is a substrate/inhibitor of CYP3A4 and an inhibitor of CYP2D6, while ritonavir is a substrate/inhibitor of both enzymes. In addition to altered tipranavir concentrations, decreased ombitasvir concentrations and altered concentrations of dasabuvir, paritaprevir, and ritonavir may also occur. Paritaprevir and dasabuvir (minor) are CYP3A4 substrates, and their metabolism may be reduced by tipranavir. Tipranavir is also an inducer of the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-gp. Caution and close monitoring are advised if these drugs are administered together.
Tizanidine: Ritonavir should be used cautiously and with close monitoring with tizanidine. Tizanidine administration may result in QT prolongation. The use of ritonavir could result in QT prolongation. Coadministration increases the risk for QT prolongation and torsade de pointes.
Tofacitinib: Tofacitinib exposure is increased when coadministered with potent inhibitors of cytochrome P450 (CYP) 3A4 such as ritonavir. Reduce the tofacitinib dose to 5 mg once daily when used with a potent CYP3A4 inhibitor.
Tolterodine: In a small portion of patients who poorly metabolize tolterodine via CYP2D6, the CYP3A4 pathway becomes important in tolterodine elimination. Pharmacokinetic studies of the use of tolterodine concomitantly with CYP3A4 inhibitors have not been performed. CYP3A4 inhibitors include anti-retroviral protease inhibitors. In addition, ritonavir and delavirdine inhibit CYP2D6. Because it is difficult to assess which patients will be poor metabolizers of tolterodine via CYP2D6, those patients receiving CYP3A4 inhibitors should not receive > 2 mg/day of tolterodine. In addition, both ritonavir and tolterodine are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
Tolvaptan: The concomitant use of tolvaptan and strong CYP3A4 inhibitors, such as ritonavir, is contraindicated. Tolvaptan is metabolized by CYP3A4 and is a substrate for P-gp. Ritonavir is a strong inhibitor of CYP3A4 and P-gp. Ketoconazole 200 mg, also a strong CYP3A4 inhibitor, increased tolvaptan exposure 5-fold; larger ketoconazole doses are expected to produce larger increases in tolvaptan exposure. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors; therefore, concomitant use is contraindicated.
Topiramate: Concurrent administration of topiramate with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir, paritaprevir, and dasabuvir (minor) are all metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of topiramate with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir, paritaprevir, and dasabuvir (minor) are all metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of topiramate with ritonavir may result in decreased concentrations of ritonavir. Topiramate is not extensively metabolized, but is a mild CYP3A4 inducer. Ritonavir is metabolized by this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Topotecan: Avoid the concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with oral topotecan, a P-glycoprotein (P-gp) substrate. Ritonavir is a strong P-gp inhibitor, paritaprevir is a P-gp inhibitor, and dasabuvir, paritaprevir, and ritonavir all inhibit Breast Cancer Resistance Protein (BCRP); topotecan is a P-gp and BCRP substrate. P-gp inhibitors have less of an effect on intravenous topotecan and these may be coadministered with caution. If coadministration of lopinavir or ritonavir and oral topotecan is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea; this also applies to the combination of lopinavir; ritonavir. In a pharmacokinetic cohort study, coadministration of oral topotecan with elacradir, a potent P-gp and BCRP inhibitor, (n = 8) increased the Cmax and AUC of topotecan by 2 to 3 fold (p = 0.008); coadministration with intravenous topotecan (n = 8) increased total topotecan exposure by 1.2-fold (p = 0.02) and topotecan lactone by 1.1-fold (not significant). In a separate study, when oral topotecan was administered concomitantly with escalating doses of a dual BCRP and P-gp inhibitor, exposure to both total topotecan and topotecan lactone increased by approximately 2.5-fold compared with control. Avoid the concomitant use of ritonavir, P-glycoprotein (P-gp) inhibitor, with oral topotecan, a P-gp substrate; P-gp inhibitors have less of an effect on intravenous topotecan and these may be coadministered with caution. If coadministration of ritonavir and oral topotecan is necessary, carefully monitor for increased toxicity of topotecan, including severe myelosuppression and diarrhea; this also applies to the combination of lopinavir; ritonavir. In a pharmacokinetic cohort study, coadministration of oral topotecan with a potent P-gp inhibitor (n = 8) increased the Cmax and AUC of topotecan by 2 to 3 fold (p = 0.008); coadministration with intravenous topotecan (n = 8) increased total topotecan exposure by 1.2-fold (p = 0.02) and topotecan lactone by 1.1-fold (not significant). Concomitant use of dasabuvir; ombitasvir; paritaprevir; ritonavir with topotecan may result in elevated serum concentrations of topotecan and increased toxicity. Topotecan is a P-glycoprotein (P-gp) substrate, and ritonavir is a strong inhibitor of P-gp. Topotecan is also a substrate of breast cancer resistance protein (BCRP). Dasabuvir, paritaprevir, and ritonavir are all BCRP inhibitors. The manufacturer recommends avoiding concomitant use of P-gp inhibitors with topotecan capsules. However, if topotecan capsules are administered with a drug known to inhibit P-gp, carefully monitor patients for topotecan-related adverse reactions. Caution and close monitoring is advised if any formulation of topotecan is administered with dasabuvir; ombitasvir; paritaprevir; ritonavir.
Toremifene: Metabolism of toremifene may be inhibited by drugs known to inhibit CYP3A4 hepatic enzymes, such as ritonavir. Formal interaction studies with toremifene have not been performed, and the clinical relevance of potential interactions is uncertain. In addition, both ritonavir and toremifene are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
Trabectedin: Avoid the concomitant use of trabectedin with ritonavir due to significantly increased trabectedin exposure. If short-term ritonavir (less than 14 days) cannot be avoided, begin administration 1 week after the trabectedin infusion and discontinue it the day prior to the next trabectedin infusion. Trabectedin is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with ketoconazole (200 mg twice daily for 7.5 days), another strong CYP3A inhibitor, increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% and the Cmax by 22% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Tramadol: Tramadol is primarily metabolized by CYP2D6 and CYP3A4; drugs that inhibit these enzymes, such as ritonavir, may decrease the metabolism of tramadol. This may result in a decreased concentration of the active metabolite (O-desmethyltramadol) leading to decreased analgesic effects and possibly increased side effects (seizures and serotonin syndrome) due to higher tramadol concentrations.
Trametinib: Concurrent administration of trametinib with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated dasabuvir plasma concentrations. Trametinib inhibits CYP2C8, an enzyme primarily responsible for the metabolism of dasabuvir. Caution and close monitoring are advised if these drugs are administered together.
Trandolapril; Verapamil: Concurrent administration of verapamil with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of all 5 drugs. A verapamil dose reduction and close monitoring for adverse events (i.e., hypotension and edema) are advised during coadministration. If adverse events are observed, consider further verapamil dose reductions or an alternative to the calcium channel blocker. Both verapamil and ritonavir are substrates and inhibitors of CYP3A4; paritaprevir and dasabuvir (minor) are partially metabolized by CYP3A4. Verapamil also inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-gp. Concurrent administration of verapamil with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of both drugs. A verapamil dose reduction and close monitoring for adverse events (i.e., hypotension and edema) are advised during coadministration. If adverse events are observed, consider further verapamil dose reductions or an alternative to the calcium channel blocker. Both verapamil and ritonavir are substrates and inhibitors of CYP3A4; paritaprevir and dasabuvir (minor) are partially metabolized by CYP3A4. Verapamil also inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-gp. Concurrent administration of verapamil with ritonavir may result in elevated plasma concentrations of both drugs. Both verapamil and ritonavir are substrates and inhibitors of CYP3A4. Verapamil also inhibits the drug transporter P-glycoprotein (P-gp); ritonavir is a substrate of P-gp. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
Trazodone: The manufacturer of trazodone recommends avoiding trazodone in patients receiving other drugs that increase the QT interval. Trazodone can prolong the QT/QTc interval at therapeutic doses. In addition, there are post-marketing reports of torsade de pointes (TdP). Ritonavir has a possible risk for QT prolongation and TdP. In addition, ritonavir may decrease the hepatic CYP metabolism of trazodone, resulting in increased trazodone concentrations. Adverse events of nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone and ritonavir.
Triamcinolone: Coadministration of triamcinolone with ritonavir may cause elevated triamcinolone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Triamcinolone is a CYP3A4 substrate; ritonavir is a strong inhibitor of CYP3A4. Corticosteroids, such as beclomethasone and prednisolone) whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use.
Triazolam: In general, the concurrent use of triazolam and anti-retroviral protease inhibitors is contraindicated. Anti-retroviral protease inhibitors have been shown to increase triazolam concentrations, resulting in prolonged sedation and respiratory depression. Lorazepam, oxazepam, or temazepam may be safer alternatives, as these benzodiazepines are not oxidatively metabolized.
Tricyclic antidepressants: Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Ritonavir has a possible risk for QT prolongation and torsade de pointes (TdP) and should be used cautiously and with close monitoring with doxepin. In addition, ritonavir potently inhibits CYP2D6 and CYP3A4, and thus may inhibit the metabolism of the tricyclic antidepressants (TCAs). A significant effect of ritonavir on desipramine clearance has been reported. Since the magnitude of the interaction with the TCAs is difficult to predict but may be significant, closely monitor patients receiving ritonavir and TCAs concurrently. Adjust the dosage of the coadministered drug based on therapeutic response. TCA serum concentration monitoring may be useful to guide adjustments and prevent toxicity.
Trifluoperazine: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include trifluoperazine. Theoretically, trifluoperazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation.
Trimethoprim: According to the manufacturer, no dosage adjustments are required when trimethoprim is administered with dasabuvir; ombitasvir; paritaprevir; ritonavir; however, use of these drugs together may result in elevated dasabuvir plasma concentrations. Trimethoprim inhibits CYP2C8, an enzyme primarily responsible for the metabolism of dasabuvir. Caution and close monitoring are advised if these drugs are administered together. Ritonavir can increase the AUC of trimethoprim by 20%. Conversely, ritonavir can decrease the AUC of sulfamethoxazole by 20%. However, the Cmax of trimethoprim and sulfamethoxazole was not affected.
Trimetrexate: Protease inhibitors inhibit the cytochrome P450 3A4 isoenzyme. Concurrent administration of trimetrexate with protease inhibitors may result in increased trimetrexate levels. Monitor patients closely.
Trimipramine: Concurrent administration of trimipramine with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated trimipramine plasma concentrations and subsequent adverse effects such as QT prolongation. Trimipramine is a substrate for the hepatic isoenzyme CYP2D6 and for uridine glucuronyltransferase (UGT ). Ritonavir is an inhibitor of CYP2D6, and dasabuvir, ombitasvir and paritaprevir are UGT1A1 inhibitors. Tricyclic antidepressants and ritonavir have both been associated with QT prolongation; caution and close monitoring are advised if these drugs are administered together. Tricyclic antidepressants (TCAs) share pharmacologic properties similar to the Class IA antiarrhythmic agents and may prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Ritonavir has a possible risk for QT prolongation and torsade de pointes (TdP) and should be used cautiously and with close monitoring with doxepin. In addition, ritonavir potently inhibits CYP2D6 and CYP3A4, and thus may inhibit the metabolism of the tricyclic antidepressants (TCAs). A significant effect of ritonavir on desipramine clearance has been reported. Since the magnitude of the interaction with the TCAs is difficult to predict but may be significant, closely monitor patients receiving ritonavir and TCAs concurrently. Adjust the dosage of the coadministered drug based on therapeutic response. TCA serum concentration monitoring may be useful to guide adjustments and prevent toxicity.
Triptorelin: Androgen deprivation therapy (e.g., triptorelin) prolongs the QT interval; the risk may be increased with the concurrent use of drugs that may prolong the QT interval. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with triptorelin include ritonavir.
Ulipristal: Concurrent administration of ulipristal with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of ulipristal, dasabuvir, ombitasvir, paritaprevir, and ritonavir. Ulipristal is a CYP3A4 substrate; ritonavir is a potent inhibitor of this enzyme. In addition, ulipristal inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp. Caution and close monitoring are advised if these drugs are administered together. Ulipristal is a substrate of CYP3A4 and ritonavir is a CYP3A4 inhibitor and inducer. In addition, ulipristal inhibits the drug transporter P-glycoprotein (P-gp); ritonavir is a substrate of P-gp. Concomitant use may increase or decrease the plasma concentration of ulipristal and increased ritonavir concentrations resulting in an increased risk for adverse events or decrease in efficacy.
Umeclidinium; Vilanterol: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir, include beta-agonists.
Valbenazine: The dose of valbenazine should be reduced to 40 mg once daily during co-administration with a strong CYP3A4 inhibitor, such as ritonavir. QT prolongation is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant.
Valproic Acid, Divalproex Sodium: Concurrent administration of valproic acid with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in altered valproic acid plasma concentrations and decreased concentrations of dasabuvir, ombitasvir, paritaprevir, and ritonavir. Valproic acid is an inducer of the drug transporter P-glycoprotein (P-gp) and an inhibitor/inducer of CYP3A4. Dasabuvir, ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp, while ritonavir, paritaprevir, and dasabuvir (minor) are partially metabolized by CYP3A4. In addition, in a case report, possible ritonavir-mediated induction of valproic acid glucuronidation resulted in a decrease in valproic acid concentrations and efficacy. Caution and close monitoring are advised if these drugs are administered together. In a single case report, possible ritonavir-mediated induction of valproic acid glucuronidation resulted in a decrease in valproic acid concentrations and efficacy. A man with bipolar disorder and HIV was stabilized on valproic acid 250 mg PO three times daily. Treatment was started with lopinavir; ritonavir and lamivudine, 3TC; zidovudine, ZDV in addition to the valproic acid. Three weeks after starting the antiretroviral medication, his manic symptoms worsened. Upon hospital admission due to the mania, his valproic acid concentration had decreased 48% (from 495 to 238 micromol/l). His valproic acid dose was increased to 1500 mg and olanzapine was introduced. The valproic acid concentration following this dose escalation was 392 micromol/l, and the patient improved clinically. Of note, the patient had also received paroxetine for treatment of comorbid depression when the antiretrovirals were initiated, but the SSRI was discontinued by the patient after 5 days. The SSRI may have contributed to the initial hypomanic episode. Clinicians should be aware of this potential interaction and closely monitor valproic acid concentrations and efficacy. A valproic acid dose increase may be needed. In addition, valproic acid is an inducer of P-glycoprotein (P-gp) and an inhibitor/inducer of CYP3A4; ritonavir is a substrate of both CYP3A4 and P-gp.
Valsartan: Coadministration of valsartan and regimens containing paritaprevir may result in elevated valsartan plasma concentrations. A valsartan dose reduction, and close monitoring for adverse events (i.e., hypotension and worsening renal function) are advised during coadministration. If adverse events are observed, consider further reductions in valsartan dose or an alternative to the angiotensin receptor blocker. Valsartan is a substrate of the organic anion transporting polypeptides (OATP) and paritaprevir is an OATP1B1 and OATP1B3 inhibitor. Valsartan is a substrate of the hepatic efflux transporter MRP2 and ritonavir is an inhibitor of MRP2. Coadministration may increase systemic exposure to valsartan. Patients should be monitored for adverse effects of valsartan during coadministration.
Vandetanib: The manufacturer of vandetanib recommends avoiding coadministration with other drugs that prolong the QT interval due to an increased risk of QT prolongation and torsade de pointes (TdP); there is also a risk of increased ritonavir-related adverse reactions. Vandetanib can prolong the QT interval in a concentration-dependent manner. TdP and sudden death have been reported in patients receiving vandetanib; ritonavir also has a possible risk for QT prolongation. If ritonavir is given to a patient already taking vandetanib and no alternative therapy exists, an ECG is needed, as well as more frequent monitoring of the QT interval. If QTcF is greater than 500 msec, interrupt vandetanib dosing until the QTcF is less than 450 msec - vandetanib may be resumed at a reduced dose. Additionally, ritonavir is a substrate of P-glycoprotein (P-gp). Coadministration with vandetanib increased the Cmax and AUC of another P-gp substrate by 29% and 23%, respectively.
Vardenafil: Coadministration of ritonavir with vardenafil results in a 20% decrease in ritonavir AUC and a 49-fold increase in vardenafil AUC. Substantially increased vardenafil plasma concentrations may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. If coadministered, use vardenafil at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions. Vardenafil orally disintegrating tablets provide increased exposure as compared to the regular tablets; therefore, use of the orally disintegrating tablets with ritonavir is not recommended. No change in ritonavir dose is required. In addition, both ritonavir and vardenafil are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
Vemurafenib: Concurrent administration of vemurafenib with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir is contraindicated. Taking these drugs together could result in elevated vemurafenib and ombitasvir plasma concentrations and decreased concentrations of paritaprevir, ritonavir, and dasabuvir, which may affect antiviral efficacy. Additionally, vemurafenib has been associated with QT prolongation, and while dasabuvir; ombitasvir; paritaprevir; ritonavir did not prolong the QT interval to a clinically relevant extent in healthy subjects, ritonavir has been associated with dose-related QT prolongation in other trials. Vemurafenib is a substrate/inducer of CYP3A4, a substrate/inhibitor of P-glycoprotein (P-gp), and an inhibitor of CYP2D6. Ritonavir is a potent inhibitor of CYP3A4 and is metabolized by both CYP3A4 and CYP2D6. Paritaprevir and dasabuvir (minor) are substrates of CYP3A4. Paritaprevir is also a P-gp inhibitor. In addition, dasabuvir, ombitasvir, paritaprevir, and ritonavir are all substrates of P-gp. Concomitant administration of ritonavir and vemurafenib may increase vemurafenib concentrations and may alter ritonavir concentrations. Ritonavir is a CYP3A4 substrate and strong inhibitor as well as a P-glycoprotein (P-gp) substrate/inhibitor, while vemurafenib is a CYP3A4 substrate/inducer and a P-gp substrate/inhibitor. In addition, both ritonavir and vemurafenib are associated with QT prolongation; concomitant use increases the risk of QT prolongation. Avoid using these agents together if possible.
Venetoclax: Avoid the concomitant use of venetoclax and lopinavir; ritonavir or ritonavir; venetoclax is a substrate of CYP3A4 and P-glycoprotein (P-gp) and ritonavir is a strong CYP3A4 and P-gp inhibitor. The concomitant use of these agents together is contraindicated during the initial and dose titration phase of venetoclax. If concomitant use of these drugs is required when the patient is on a steady venetoclax dose (after the titration phase), reduce the venetoclax dosage by at least 75% (maximum dose of 100 mg/day). If the strong CYP3A4 inhibitor is discontinued, wait 2 to 3 days and then resume the recommended venetoclax dosage (or prior dosage if less). Monitor patients for signs and symptoms of venetoclax toxicity such as hematologic toxicity, GI toxicity, and tumor lysis syndrome. In a drug interaction study, the venetoclax Cmax and AUC values were increased by 2.3-fold and 6.4-fold, respectively, when a strong CYP3A4 inhibitor was co-administered in NHL patients.
Venlafaxine: Ritonavir may be expected to decrease the metabolism of venlafaxine; ritonavir is a potent inhibitor of CYP3A4 and 2D6, and venlafaxine is a substrate for both of these enzymes. In addition, venlafaxine can inhibit the CYP2D6 metabolism of ritonavir. The risk of elevated plasma concentrations and toxicity may be greater when ritonavir is given with venlafaxine. In addition, both ritonavir and venlafaxine are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
Verapamil: Concurrent administration of verapamil with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of all 5 drugs. A verapamil dose reduction and close monitoring for adverse events (i.e., hypotension and edema) are advised during coadministration. If adverse events are observed, consider further verapamil dose reductions or an alternative to the calcium channel blocker. Both verapamil and ritonavir are substrates and inhibitors of CYP3A4; paritaprevir and dasabuvir (minor) are partially metabolized by CYP3A4. Verapamil also inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-gp. Concurrent administration of verapamil with dasabuvir; ombitasvir; paritaprevir; ritonavir or ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of both drugs. A verapamil dose reduction and close monitoring for adverse events (i.e., hypotension and edema) are advised during coadministration. If adverse events are observed, consider further verapamil dose reductions or an alternative to the calcium channel blocker. Both verapamil and ritonavir are substrates and inhibitors of CYP3A4; paritaprevir and dasabuvir (minor) are partially metabolized by CYP3A4. Verapamil also inhibits the drug transporter P-glycoprotein (P-gp); dasabuvir, ombitasvir, paritaprevir and ritonavir are all substrates of P-gp. Concurrent administration of verapamil with ritonavir may result in elevated plasma concentrations of both drugs. Both verapamil and ritonavir are substrates and inhibitors of CYP3A4. Verapamil also inhibits the drug transporter P-glycoprotein (P-gp); ritonavir is a substrate of P-gp. Ritonavir also prolongs the PR interval in some patients; however, the impact on the PR interval of coadministration of ritonavir with other drugs that prolong the PR interval (including calcium channel blockers) has not been evaluated. If coadministration of these drugs is warranted, do so with caution and careful monitoring. Decreased calcium-channel blocker doses may be warranted.
Vilazodone: Concurrent administration of vilazodone with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of vilazodone, dasabuvir and ritonavir. Because CYP3A4 is the primary isoenzyme involved in the metabolism of vilazodone, the manufacturer recommends that the daily dose be reduced to 20 mg in patients receiving strong inhibitors of CYP3A4 such as ritonavir. Both ritonavir and vilazodone are substrates and inhibitors of the hepatic isoenzyme CYP2D6. Vilazodone also inhibits CYP2C8, an enzyme primarily responsible for the metabolism of dasabuvir. Caution and close monitoring are advised if these drugs are administered together. CYP3A4 is the primary isoenzyme involved in the metabolism of vilazodone and ritonavir is a strong CYP3A4 inhibitor. Concurrent use of vilazodone and ritonavir may lead to an increased risk of vilazodone-related adverse reactions. The manufacturer recommends a reduction in vilazodone dose to 20 mg/day in patients receiving a strong CYP3A4 inhibitor. When the inhibitor is discontinued, resume the previous vilazodone dose.
Vinblastine: Ritonavir is an inhibitor of the efflux transporter P-glycoprotein (P-gp, ABCB1) and an inhibitor of cytochrome P450 (CYP) isoenzyme 3A4. Vinblastine is a P-gp and CYP3A4 substrate. Increased concentrations of vinblastine are likely if it is coadministered with ritonavir; exercise caution.
Vincristine Liposomal: The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a CYP3A4 and P-gp inhibitor.
Vincristine: The plasma concentrations of vincristine may be significantly elevated when administered concurrently with protease inhibitors. Consideration should be given to temporarily withholding the regimen in patients who develop significant hematological or gastrointestinal toxicity when protease inhibitors are coadministered with vincristine. Vincristine is a CYP3A4 and P-glycoprotein (P-gp) substrate; protease inhibitors are CYP3A4 inhibitors and some also inhibit P-gp. If the antiretroviral regimen needs to be withheld for a prolonged period, consider use of a revised regimen that does not include a CYP3A4 and P-gp inhibitor.
Vinorelbine: Use caution and monitor patients for an earlier onset and/or an increased severity of adverse effects, including neurotoxicity and myelosuppression, if ritonavir is used concomitantly with vinorelbine. Ritonavir is a CYP3A4 and P-glycoprotein (P-gp) inhibitor, and vinorelbine is a CYP3A4 and P-gp substrate; coadministration may cause the metabolism of vinorelbine to be decreased. This may also apply to combination products containing ritonavir such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Vorapaxar: Avoid coadministration of vorapaxar and ritonavir. Increased serum concentrations of vorapaxar are possible when vorapaxar, a CYP3A4 substrate, is coadministered with ritonavir, a strong CYP3A inhibitor. Increased exposure to vorapaxar may increase the risk of bleeding complications.
Voriconazole: Coadministration of voriconazole and ritonavir at doses of 400 mg every 12 hours is contraindicated, and coadministration of voriconazole with ritonavir at doses of 100 mg should be avoided unless an assessment of the benefit to risk ratio justifies concurrent use. In one study, concurrent administration of voriconazole (400 mg every 12 hours for 1 day, then 200 mg every 12 hours for 8 days) and ritonavir (400 mg every 12 hours for 9 days) resulted in a 66% and 82% decrease in voriconazole Cmax and AUC, respectively. Low dose ritonavir (100 mg every 12 hours) decreased voriconazole Cmax and AUC concentrations by 24% and 39%, respectively. In addition, both ritonavir and voriconazole are associated with QT prolongation; concomitant use increases the risk of QT prolongation.
Vorinostat: The use of ritonavir could result in QT prolongation. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with ritonavir include vorinostat.
Warfarin: Many antiretroviral agents may interact with warfarin. Agents that inhibit cytochrome P450 (CYP) isoenzymes 3A4, 1A2, or 2C9 may decrease the metabolism of warfarin leading to increased anticoagulation effects. Ritonavir may have induction or inhibition effects on warfarin metabolism. When warfarin (single dose of 5 mg) is administered with ritonavir (400 mg every 12 hours) a 9% increase in warfarin AUC and a 9% decrease in warfarin Cmax is seen. The high vitamin E content in amprenavir formulations may exacerbate the effects of warfarin. Patients should be carefully monitored for changes in INR, with the potential need for warfarin dosage adjustments, if warfarin and antiretroviral agents are coadministered.
Yohimbine: Concurrent administration of yohimbine with ritonavir may result in elevated yohimbine plasma concentrations. Yohimbine is metabolized by the hepatic isoenzymes CYP3A4 and CYP2D6; ritonavir is an inhibitor of these enzymes. Caution and close monitoring are advised if these drugs are administered together.
Zafirlukast: Concurrent administration of zafirlukast with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of dasabuvir, paritaprevir, and ritonavir. In vitro, zafirlukast is an inhibitor of the hepatic isoenzymes CYP3A4 and CYP2C8; however, in vivo data do not substantiate clinically relevant CYP2C8 inhibition. Ritonavir and paritaprevir are substrates for CYP3A4, and dasabuvir is metabolized by both CYP2C8 and CYP3A4 (minor). Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of zafirlukast with ritonavir may result in elevated plasma concentrations of ritonavir. In vitro, zafirlukast is an inhibitor of the hepatic isoenzyme CYP3A4. Ritonavir is a substrate for CYP3A4. Caution and close monitoring are advised if these drugs are administered together.
Zalcitabine, ddC: Zalcitabine may cause peripheral neuropathy and coadministration with other drugs associated with peripheral neuropathy, such as ritonavir, should be avoided when possible.
Zidovudine, ZDV: Since ritonavir induces glucuronidation, there is the potential for reduction in zidovudine, ZDV plasma concentrations during concurrent therapy with ritonavir. When coadministered with ritonavir, the AUC and Cmax of zidovudine, ZDV are decreased by 12% and 27%. The clinical significance of this interaction is unknown.
Zileuton: Concurrent administration of zileuton with protease inhibitors may result in elevated zileuton plasma concentrations. Zileuton is metabolized by the hepatic isoenzyme CYP3A4; protease inhibitors block this enzyme. Caution and close monitoring are advised if these drugs are administered together
Ziprasidone: Concurrent use of ziprasidone and ritonavir is contraindicated due to the risk of QT prolongation. Ritonavir has been associated with QT prolongation. Ziprasidone has also been associated with a possible risk for QT prolongation and/or torsade de pointes. Per the manufacturer of ziprasidone, the drug is contraindicated with any drug that lists QT prolongation as a pharmacodynamic effect when this effect has been described within the contraindications or bolded or boxed warnings of the official labeling for such drugs.
Zolmitriptan: Concurrent administration of zolmitriptan with ritonavir may result in elevated zolmitriptan plasma concentrations. Zolmitriptan is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together.
Zolpidem: It is advisable to closely monitor zolpidem tolerability and safety during co-administration of potent CYP3A4 inhibitors, such as anti-retroviral protease inhibitors, and consider using a lower dose of zolpidem to minimize the potential for adverse CNS effects. CYP3A4 is the primary isoenzyme responsible for zolpidem metabolism, and there is evidence of an increase in pharmacodynamics effects and systemic exposure of zolpidem during co-administration with some potent inhibitors of CYP3A4, such as azole antifungals.
Zonisamide: Concurrent administration of zonisamide with ritonavir may result in elevated plasma concentrations of both zonisamide and ritonavir. Zonisamide is metabolized by the hepatic isoenzyme CYP3A4; ritonavir is an inhibitor of this enzyme. Additionally, zonisamide is a weak inhibitor of P-gp, and ritonavir is a substrate of P-gp. There is theoretical potential for zonisamide to affect the pharmacokinetics of drugs that are P-gp substrates. Use caution when starting or stopping zonisamide or changing the zonisamide dosage in patients also receiving drugs which are P-gp substrates. Caution and close monitoring are advised if these drugs are administered together.