Viekira

NS3/4A Protease Inhibitor Antivirals in Combination with NS5A Protein Inhibitor Antivirals and NS5B RNA Polymerase Inhibitor Antivirals for Hepatitis C

Oral Administration Oral Solid Formulations

Administer with a meal, regardless of fat or caloric content.

Severe

angioedema / Rapid / Incidence not known
erythema multiforme / Delayed / Incidence not known
serious hypersensitivity reactions or anaphylaxis / Rapid / Incidence not known
hepatic failure / Delayed / Incidence not known
hepatitis B exacerbation / Delayed / Incidence not known

Moderate

anemia / Delayed / 0-29.0
contact dermatitis / Delayed / Incidence not known
skin ulcer / Delayed / Incidence not known
erythema / Early / Incidence not known
psoriasis / Delayed / Incidence not known
elevated hepatic enzymes / Delayed / Incidence not known
hyperbilirubinemia / Delayed / Incidence not known

Mild

fatigue / Early / 13.0-50.0
headache / Early / 16.0-44.0
cough / Delayed / 11.0-32.0
insomnia / Early / 5.0-26.0
diarrhea / Early / 26.0-26.0
asthenia / Delayed / 4.0-24.0
nausea / Early / 8.0-24.0
pruritus / Rapid / 7.0-18.0
irritability / Delayed / 10.0-10.0
maculopapular rash / Early / Incidence not known
rash / Early / Incidence not known
photosensitivity / Delayed / Incidence not known

Hepatitis B exacerbation

Use of direct-acting antivirals (DAA), such as dasabuvir, ombitasvir, and paritaprevir, to treat hepatitis C virus (HCV) infection in patients currently or previously infected with hepatitis B virus (HBV) has been associated with reactivation and hepatitis B exacerbation. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Hepatitis B reactivation has also occurred in patients receiving certain immunosuppressive or chemotherapeutic medications; the risk of HBV reactivation associated with DAA treatment may be increased in these patients. HBV reactivation is characterized as an abrupt increase in viral replication manifesting as a rapid increase in serum HBV DNA concentration. In patients with resolved HBV infection, the reappearance of HBsAg can occur. Reactivation of HBV replication may be accompanied by hepatitis (i.e., increases in aminotransferase concentrations) and, in severe cases, increases in bilirubin concentrations, liver failure, and death can occur. To decrease the risk of reactivating an HBV infection, screen all potential drug recipients for evidence of current or prior HBV infection by measuring the hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc). For those patients whose screening reveals serologic evidence of HBV infection, a baseline HBV DNA concentration should be obtained prior to starting dasabuvir; ombitasvir; paritaprevir; ritonavir. Continue to monitor coinfected patients during and after treatment for clinical and laboratory signs of hepatitis B exacerbation (i.e., HBsAg, HBV DNA, hepatic enzymes, bilirubin). In addition, instruct patients to immediately report any signs of liver toxicity (e.g., yellow eyes or skin, fatigue, weakness, loss of appetite, nausea, vomiting, or light-colored stools) to their health care provider. If a dasabuvir; ombitasvir; paritaprevir; ritonavir recipient develops signs of HBV reactivation, initiate appropriate treatment for HBV infection as clinically indicated.

Viekira

Rx

Combination oral product containing 3 antivirals with activity against HCV and a pharmacokinetic enhancer
For HCV genotype 1a and 1b, including patients with and without compensated cirrhosis
Contraindicated in patients with moderate to severe hepatic disease (Child-Pugh Class B and C)

For the treatment of chronic hepatitis C infection.
NOTE: Viekira Pak contains dasabuvir tablets packaged with ombitasvir; paritaprevir; ritonavir fixed-dose combination tablets.
NOTE: Not recommended for use in patients with decompensated liver disease. Assess hepatic function prior to treatment initiation. For the treatment of chronic hepatitis C infection, genotype 1a, in patients without cirrhosis. Oral dosage (Viekira Pak) Adults weighing 75 kg or more

Two fixed-dose combination tablets containing ombitasvir; paritaprevir; ritonavir (12.5/75/50 mg per tablet) PO once daily in the morning with dasabuvir 250 mg PO twice daily and ribavirin 600 mg PO twice daily. Administer for 12 weeks. For liver transplant recipients with normal hepatic function and mild fibrosis (Metavir fibrosis score of 2 or less), increase treatment duration to 24 weeks.

Adults weighing less than 75 kg

Two fixed-dose combination tablets containing ombitasvir; paritaprevir; ritonavir (12.5/75/50 mg per tablet) PO once daily in the morning with dasabuvir 250 mg PO twice daily and ribavirin 500 mg PO twice daily. Administer for 12 weeks. For liver transplant recipients with normal hepatic function and mild fibrosis (Metavir fibrosis score of 2 or less), increase treatment duration to 24 weeks.

For the treatment of chronic hepatitis C infection, genotype 1a, in patients with compensated cirrhosis (Child-Pugh A). Oral dosage (Viekira Pak) Adults weighing 75 kg or more

Two fixed-dose combination tablets containing ombitasvir; paritaprevir; ritonavir (12.5/75/50 mg per tablet) PO once daily in the morning with dasabuvir 250 mg PO twice daily and ribavirin 600 mg PO twice daily. Administer for 24 weeks. In some patients, the treatment duration may be reduced to 12 weeks; base decision regarding duration of treatment on the patient's prior treatment history.

Adults weighing less than 75 kg

Two fixed-dose combination tablets containing ombitasvir; paritaprevir; ritonavir (12.5/75/50 mg per tablet) PO once daily in the morning with dasabuvir 250 mg PO twice daily and ribavirin 500 mg PO twice daily. Administer for 24 weeks. In some patients, the treatment duration may be reduced to 12 weeks; base decision regarding duration of treatment on the patient's prior treatment history.

For the treatment of chronic hepatitis C infection, genotype 1b, in patients with or without compensated cirrhosis (Child-Pugh A). Oral dosage (Viekira Pak) Adults

Two fixed-dose combination tablets containing ombitasvir; paritaprevir; ritonavir (12.5/75/50 mg per tablet) PO once daily in the morning with dasabuvir 250 mg PO twice daily. Administer for 12 weeks. For liver transplant recipients with normal hepatic function and mild fibrosis (Metavir fibrosis score of 2 or less), add ribavirin (600 mg/dose if weight is 75 kg or more or 500 mg/dose if weight is less than 75 kg) PO twice daily, and increase treatment duration to 24 weeks.

Hepatic Impairment

Use is contraindicated in patients with moderate to severe hepatic impairment (Child-Pugh Class B and C). In addition, the manufacturer recommends treatment be avoided in patients with decompensated liver disease. No dosage adjustments are needed for mild hepatic impairment (Child-Pugh Class A).

Renal Impairment

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. Guidelines recommend use of dasabuvir; ombitasvir; paritaprevir; ritonavir as an alternative direct acting antiviral regimen for treatment of HCV genotypes 1a and 1b in patients with chronic kidney disease (i.e., GFR less than 30 mL/min/1.73 m2), including kidney transplant recipients.

Abacavir: (Moderate) Caution is advised when administering abacavir and ritonavir concurrently. Ritonavir appears to induce glucuronosyl transferase, and therefore, has the potential to reduce plasma concentrations of drugs that undergo glucuronidation, such as abacavir. The clinical significance of the potential for this interaction is unknown.
Abacavir; Dolutegravir; Lamivudine: (Moderate) Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of dolutegravir with dasabuvir may result in elevated dolutegravir plasma concentrations. Dolutegravir is a substrate of uridine glucuronyltransferase (UGT) and the breast cancer resistance protein (BCRP). Dasabuvir is a UGT1A1 inhibitor and BCRP inhibitor. (Moderate) Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of dolutegravir with ombitasvir may result in elevated dolutegravir plasma concentrations. Dolutegravir is a substrate of uridine glucuronyltransferase (UGT). Ombitasvir inhibits UGT1A1. (Moderate) Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of dolutegravir with paritaprevir may result in elevated dolutegravir plasma concentrations. Dolutegravir is a substrate of uridine glucuronyltransferase (UGT) and the breast cancer resistance protein (BCRP). Paritaprevir inhibits UGT1A1 and BCRP. (Moderate) Caution is advised when administering abacavir and ritonavir concurrently. Ritonavir appears to induce glucuronosyl transferase, and therefore, has the potential to reduce plasma concentrations of drugs that undergo glucuronidation, such as abacavir. The clinical significance of the potential for this interaction is unknown.
Abacavir; Lamivudine, 3TC: (Moderate) Caution is advised when administering abacavir and ritonavir concurrently. Ritonavir appears to induce glucuronosyl transferase, and therefore, has the potential to reduce plasma concentrations of drugs that undergo glucuronidation, such as abacavir. The clinical significance of the potential for this interaction is unknown.
Abacavir; Lamivudine, 3TC; Zidovudine, ZDV: (Moderate) Caution is advised when administering abacavir and ritonavir concurrently. Ritonavir appears to induce glucuronosyl transferase, and therefore, has the potential to reduce plasma concentrations of drugs that undergo glucuronidation, such as abacavir. The clinical significance of the potential for this interaction is unknown. (Minor) 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.
Abemaciclib: (Major) If coadministration with ritonavir is necessary, reduce the dose of abemaciclib to 100 mg PO twice daily in patients on either of the recommended starting doses of either 200 mg or 150 mg twice daily. In patients who have had already had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the dose of abemaciclib to 50 mg PO twice daily. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. If ritonavir is discontinued, increase the dose of abemaciclib to the original dose after 3 to 5 half-lives of ritonavir. Abemaciclib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 2.5-fold in cancer patients.
Abrocitinib: (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with abrocitinib is necessary. Concurrent use may increase ombitasvir exposure. Ombitasvir is a P-gp substrate and abrocitinib is a P-gp inhibitor. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with abrocitinib is necessary. Concurrent use may increase paritaprevir exposure. Paritaprevir is a P-gp substrate and abrocitinib is a P-gp inhibitor. (Moderate) Monitor for increased dasabuvir-related adverse reactions, including QT prolongation, if coadministered with abrocitinib. Concurrent use may increase dasabuvir exposure. Dasabuvir is a P-gp substrate and abrocitinib is a P-gp inhibitor.
Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and ritonavir; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days. (Moderate) Coadministration of acalabrutinib and dasabuvir may increase dasabuvir exposure and increase the risk of dasabuvir toxicity. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Dasabuvir is a substrate and inhibitor of BCRP. (Moderate) Coadministration of acalabrutinib and ombitasvir, paritaprevir, ritonavir may increase the exposure and the risk of toxicity of ombitasvir, paritaprevir, ritonavir. Acalabrutinib is a substrate and inhibitor of the breast cancer resistance protein (BCRP) transporter in vitro; it may inhibit intestinal BCRP. Ombitasvir is a BCRP transporter substrate and paritaprevir is a substrate and inhibitor of BCRP.
Acarbose: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) 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: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
Acetaminophen: (Moderate) 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: (Moderate) 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: (Moderate) 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; Diphenhydramine: (Moderate) 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. (Moderate) 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; Caffeine: (Moderate) 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; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with ritonavir may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of ritonavir could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ritonavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Ritonavir is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) 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; Pyrilamine: (Moderate) 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: (Moderate) 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. (Moderate) 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; Chlorpheniramine; Dextromethorphan: (Moderate) 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. (Moderate) 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; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) 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. (Moderate) 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; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) 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. (Moderate) 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; Chlorpheniramine; Phenylephrine : (Moderate) 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. (Moderate) 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: (Moderate) Concomitant use of codeine with ritonavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of ritonavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ritonavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ritonavir is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. (Moderate) 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; Dextromethorphan: (Moderate) 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; Dextromethorphan; Doxylamine: (Moderate) 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; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) 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; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) 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; Dextromethorphan; Phenylephrine: (Moderate) 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; Dextromethorphan; Pseudoephedrine: (Moderate) 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; Dichloralphenazone; Isometheptene: (Moderate) 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: (Moderate) 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. (Moderate) 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: (Moderate) 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: (Moderate) 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. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ritonavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ritonavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Ibuprofen: (Moderate) 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: (Moderate) 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. (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. If ritonavir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like ritonavir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ritonavir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Acetaminophen; Pamabrom; Pyrilamine: (Moderate) 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: (Moderate) 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; Pseudoephedrine: (Moderate) 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.
Acetohexamide: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Adagrasib: (Moderate) Monitor for an increase in adagrasib-related adverse effects during concomitant use of ritonavir. Avoid concomitant use during adagrasib therapy initiation (approximately 8 days); concomitant use before steady state is achieved may increase adagrasib exposure and the risk for adagrasib-related adverse reactions. Adagrasib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use of a single 200 mg dose of adagrasib with another strong CYP3A inhibitor increased adagrasib exposure by approximately 4-fold, however, no clinically significant differences in pharmacokinetics are predicted at steady state. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with adagrasib is necessary. Paritaprevir is a CYP3A and P-gp substrate and adagrasib is a strong CYP3A and P-gp inhibitor. Coadministration with other strong CYP3A inhibitors increased paritaprevir exposure by 2.2- to 2.9-fold.
Adefovir: (Major) 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: (Major) Avoid coadministration of ritonavir with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until ritonavir has cleared from the circulation (approximately 3 half-lives of ritonavir) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; ritonavir is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
Afatinib: (Moderate) If the concomitant use of paritaprevir and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of paritaprevir. 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. Afatinib is a P-glycoprotein (P-gp) substrate and paritaprevir is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor 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 the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib. (Moderate) If the concomitant use of ritonavir and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of ritonavir. 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. Afatinib is a P-glycoprotein (P-gp) substrate and ritonavir is a P-gp inhibitor; coadministration may increase plasma concentrations of afatinib. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor 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 the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
Albiglutide: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Aldesleukin, IL-2: (Moderate) 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. (Moderate) 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. (Moderate) 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: (Moderate) 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: (Contraindicated) Coadministration of alfuzosin with protease inhibitors is contraindicated as potentially increased alfuzosin concentrations can result in hypotension, and potentially life-threatening cardiac arrhythmia. Alfuzosin is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors.
Aliskiren: (Moderate) 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: (Moderate) 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.
Almotriptan: (Major) 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. (Major) 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: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) 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: (Major) While no dosage adjustment of metformin is recommended in patients with normal hepatic or renal function, careful patient monitoring and dose adjustment of metformin and/or the potentially interfering drug is recommended with concurrent use. Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Do not use metformin with paritaprevir in patients with renal insufficiency or hepatic impairment. Drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Paritaprevir is an inhibitor of the organic anion transporters OATP1B1 and OATP1B3. While initial drug-drug interaction studies of paritaprevir-containing hepatitis treatments have not noted an effect on metformin concentrations, more study is needed. (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) 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. (Moderate) 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: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) 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: (Major) 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.
Alpelisib: (Major) Avoid coadministration of alpelisib with dasabuvir due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and dasabuvir is a BCRP inhibitor. (Major) Avoid coadministration of alpelisib with paritaprevir due to increased exposure to alpelisib and the risk of alpelisib-related toxicity. If concomitant use is unavoidable, closely monitor for alpelisib-related adverse reactions. Alpelisib is a BCRP substrate and paritaprevir is a BCRP inhibitor.
Alpha-glucosidase Inhibitors: (Moderate) 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: (Major) Avoid coadministration of alprazolam and ritonavir due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. If coadministration of alprazolam and ritonavir is necessary, reduce alprazolam to half of the recommended dosage when a patient is started on ritonavir and alprazolam together, or when ritonavir administered to a patient treated with alprazolam. Increase the alprazolam dosage to the target dose after 10 to 14 days of dosing ritonavir and alprazolam together. It is not necessary to reduce alprazolam dose in patients who have been taking ritonavir for more than 10 to 14 days. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with ritonavir, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Short-term low doses of ritonavir (4 doses of 200 mg) increased mean AUC of alprazolam by about 2.5-fold, and did not significantly affect Cmax of alprazolam. The elimination half-life of alprazolam was prolonged (30 hours vs. 13 hours). Upon extended exposure to ritonavir (500 mg, twice daily for 10 days), CYP3A induction offset this inhibition. Alprazolam AUC and Cmax was reduced by 12% and 16%, respectively, in the presence of ritonavir. The elimination half-life of alprazolam was not significantly changed.
Amiodarone: (Major) 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.
Amitriptyline: (Major) 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. (Major) 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. (Moderate) A dose reduction of the tricyclic antidepressant (TCA) may be necessary when coadministered with ritonavir. Concurrent use may result in elevated TCA plasma concentrations.
Amlodipine: (Moderate) 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: (Contraindicated) Concomitant use of dasabuvir; 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. (Contraindicated) Concomitant use of 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. (Major) Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with ritonavir. The risk of developing myopathy/rhabdomyolysis increases when atorvastatin is used concomitantly with 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. (Moderate) 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: (Moderate) 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; Celecoxib: (Moderate) 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; Olmesartan: (Moderate) 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: (Moderate) 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. (Moderate) 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. (Minor) 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; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) 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. (Moderate) 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. (Minor) 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: (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers.
Amoxapine: (Major) 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; Omeprazole: (Major) Because the exposure to 14-OH clarithromycin is significantly decreased by ritonavir, consider alternative antibiotic therapy for indications other than Mycobacterium avium. Clarithromycin doses above 1000 mg should not be administered with ritonavir. If coadministration cannot be avoided, clarithromycin dosage reductions are recommended in patients with renal impairment (CrCl 30 to 60 mL/minute, decrease clarithromycin by 50%; CrCl less than 30 mL/minute, decrease clarithromycin by 75%). Concomitant administration of ritonavir and clarithromycin resulted in a 77% increase in clarithromycin exposure and a 100% decrease in 14-OH clarithromycin exposure. The microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria. (Moderate) Caution is advised when administering clarithromycin concurrently with dasabuvir. Use of these drugs together may result in elevated concentrations of dasabuvir. Clarithromycin is an inhibitor of P-glycoprotein (P-gp). Dasabuvir is a substrate of P-gp. (Moderate) Caution is advised when administering clarithromycin concurrently with ombitasvir. Use of these drugs together may result in elevated concentrations of ombitasvir. Clarithromycin is an inhibitor of P-glycoprotein (P-gp). Ombitasvir is a substrate of P-gp. (Moderate) Caution is advised when administering clarithromycin concurrently with paritaprevir. Use of these drugs together may result in elevated concentrations of paritaprevir. Clarithromycin is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Paritaprevir is a substrate of CYP3A4 and P-gp. (Moderate) 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. (Moderate) Increased exposure to omeprazole may occur during concurrent administration of ritonavir. Although dosage adjustment of omeprazole is not normally required, dosage reduction may be considered in patients receiving higher omeprazole doses (e.g., those with Zollinger-Ellison syndrome). Ritonavir is a strong CYP3A4 inhibitor. Omeprazole is a CYP2C19 and CYP3A4 substrate. Coadministration of a dual CYP2C19/strong CYP3A4 inhibitor increased the omeprazole AUC by an average of 4-times.
Amphetamine: (Moderate) Warn patients that the risk of amphetamine toxicity may be increased during concurrent use of ritonavir, a strong CYP2D6 inhibitor. Amphetamines are partially metabolized by CYP2D6 and have serotonergic properties; inhibition of amphetamine metabolism may increase the risk of serotonin syndrome or other toxicity. If serotonin syndrome occurs, both the amphetamine and CYP2D6 inhibitor should be discontinued and appropriate medical treatment should be implemented.
Amphetamine; Dextroamphetamine: (Moderate) Warn patients that the risk of amphetamine toxicity may be increased during concurrent use of ritonavir, a strong CYP2D6 inhibitor. Amphetamines are partially metabolized by CYP2D6 and have serotonergic properties; inhibition of amphetamine metabolism may increase the risk of serotonin syndrome or other toxicity. If serotonin syndrome occurs, both the amphetamine and CYP2D6 inhibitor should be discontinued and appropriate medical treatment should be implemented.
Amphetamines: (Moderate) Warn patients that the risk of amphetamine toxicity may be increased during concurrent use of ritonavir, a strong CYP2D6 inhibitor. Amphetamines are partially metabolized by CYP2D6 and have serotonergic properties; inhibition of amphetamine metabolism may increase the risk of serotonin syndrome or other toxicity. If serotonin syndrome occurs, both the amphetamine and CYP2D6 inhibitor should be discontinued and appropriate medical treatment should be implemented.
Antidiabetic Agents: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Apalutamide: (Contraindicated) Coadministration of paritaprevir with apalutamide is contraindicated due to the potential for decreased paritaprevir concentrations and the potential development of viral resistance. Paritaprevir is metabolized by CYP3A4 and apalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased paritaprevir exposure by 70%. (Contraindicated) Coadministration of ritonavir with apalutamide is contraindicated as there is a potential for decreased ritonavir concentrations which may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance; exposure to apalutamide may also increase. Ritonavir is a CYP3A4 substrate and strong inhibitor. Apalutamide is a CYP3A4 substrate and strong inducer.
Apixaban: (Major) 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. (Major) Reduce the apixaban dose by 50% when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as ritonavir. If patients are already receiving the reduced dose of 2.5 mg twice daily, avoid concomitant administration of apixaban and ritonavir. Concomitant administration of ritonavir and apixaban results in increased exposure to apixaban and an increase in the risk of bleeding.
Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use of ritonavir with aprepitant, fosaprepitant due to substantially increased exposure of aprepitant; after administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. 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 with another strong CYP3A4 inhibitor increased the AUC of aprepitant by approximately 5-fold, and the mean terminal half-life by approximately 3-fold. Ritonavir is also a 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. When administered as a single oral or single intravenous dose, the inhibitory effect of aprepitant on CYP3A4 is weak and does not result in a clinically significant increase in the AUC of a sensitive substrate. (Moderate) 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. (Moderate) 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 a

re advised if these drugs are administered together.
Arformoterol: (Moderate) 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: (Major) Recommendations for managing aripiprazole and ritonavir vary by aripiprazole dosage form. For aripiprazole oral dosage forms, administer a quarter of the usual dose. For monthly extended-release aripiprazole injections (Abilify Maintena), reduce the dosage from 400 mg to 200 mg/month or from 300 mg to 160 mg/month. For extended-release aripiprazole injections given once every 2 months (Abilify Asimtufii), reduce the dosage from 960 mg to 720 mg; avoid use in patients known to be poor metabolizers of CYP2D6. Further dosage reductions may be required in patients who are also receiving a strong CYP2D6 inhibitor; see individual product prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is CYP2D6 and CYP3A substrate; ritonavir is a weak CYP2D6 and strong CYP3A inhibitor. (Major) Recommendations for managing aripiprazole and ritonavir vary by aripiprazole dosage form. For extended-release aripiprazole lauroxil injections (Aristada), reduce the dose to the next lowest strength; no dosage adjustment is required for patients tolerating 441 mg. For extended-release aripiprazole lauroxil injections (Aristada) in patients who are known to be poor metabolizers of CYP2D6, reduce the dose to 441 mg; no dosage adjustment is necessary for patients already tolerating 441 mg. For fixed dose extended-release aripiprazole lauroxil injections (Aristada Initio), avoid concomitant use because the dose cannot be modified. Further dosage reductions may be required in patients who are also receiving a strong CYP2D6 inhibitor; see individual product prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is CYP2D6 and CYP3A substrate; ritonavir is a weak CYP2D6 and strong CYP3A inhibitor.
Armodafinil: (Contraindicated) 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. (Contraindicated) 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. (Major) 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.
Artemether; Lumefantrine: (Major) 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. (Major) 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.
Artesunate: (Moderate) Monitor for a decrease in antimalarial efficacy if artesunate is coadministered with ritonavir. Coadministration of oral artesunate with ritonavir resulted in a decrease in the AUC of the active metabolite of artesunate, dihydroartemisinin, by 38%.
Asciminib: (Moderate) Closely monitor for asciminib-related adverse reactions if concurrent use of asciminib 200 mg twice daily with ritonavir is necessary as asciminib exposure may increase. Asciminib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor.
Aspirin, ASA; Butalbital; Caffeine: (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers.
Aspirin, ASA; Carisoprodol: (Moderate) 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: (Moderate) Concomitant use of codeine with ritonavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of ritonavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ritonavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ritonavir is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. (Moderate) 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; Citric Acid; Sodium Bicarbonate: (Moderate) 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.
Aspirin, ASA; Omeprazole: (Moderate) 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. (Moderate) Increased exposure to omeprazole may occur during concurrent administration of ritonavir. Although dosage adjustment of omeprazole is not normally required, dosage reduction may be considered in patients receiving higher omeprazole doses (e.g., those with Zollinger-Ellison syndrome). Ritonavir is a strong CYP3A4 inhibitor. Omeprazole is a CYP2C19 and CYP3A4 substrate. Coadministration of a dual CYP2C19/strong CYP3A4 inhibitor increased the omeprazole AUC by an average of 4-times.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. If ritonavir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like ritonavir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ritonavir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Aspirin, ASA; Pravastatin: (Major) Adult doses of pravastatin must be limited to no more than 40 mg/day when administered with paritaprevir-containing regimens. The dose should be re-adjusted after completion of the hepatitis C treatment regimen. Monitor for pravastatin related adverse events, such as myopathy or rhabdomyolysis. Use of these drugs together results in elevated pravastatin serum concentrations.
Atazanavir: (Major) 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. (Minor) Coadministration of atazanavir with ritonavir results in higher atazanavir concentrations; 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 is a CYP3A4 substrate; ritonavir is a strong inhibitor of CYP3A4.
Atazanavir; Cobicistat: (Contraindicated) Use of ritonavir with cobicistat is not recommended, because of similar effects on CYP3A. Both ritonavir and cobicistat are potent inhibitors of CYP3A4. (Major) 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. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with cobicistat is necessary. Paritaprevir is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased paritaprevir exposure by 2.2-fold to 2.9-fold. (Minor) Coadministration of atazanavir with ritonavir results in higher atazanavir concentrations; 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 is a CYP3A4 substrate; ritonavir is a strong inhibitor of CYP3A4.
Atenolol: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
Atenolol; Chlorthalidone: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
Atogepant: (Major) Avoid use of atogepant and ritonavir when atogepant is used for chronic migraine. Limit the dose of atogepant to 10 mg PO once daily for episodic migraine if coadministered with ritonavir. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of CYP3A and ritonavir is a strong CYP3A inhibitor. Coadministration with a strong CYP3A inhibitor resulted in a 5.5-fold increase in atogepant overall exposure and a 2.15-fold increase in atogepant peak concentration. (Major) Limit the dose of atogepant to 10 or 30 mg PO once daily for episodic migraine or 30 mg PO once daily for chronic migraine if coadministered with paritaprevir. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of OATP1B1 and OATP1B3 and paritaprevir is an OATP inhibitor. Coadministration with an OATP1B1/3 inhibitor resulted in a 2.85-fold increase in atogepant overall exposure and a 2.23-fold increase in atogepant peak concentration.
Atorvastatin: (Contraindicated) Concomitant use of dasabuvir; 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. (Contraindicated) Concomitant use of 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. (Major) Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with ritonavir. The risk of developing myopathy/rhabdomyolysis increases when atorvastatin is used concomitantly with 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: (Contraindicated) Concomitant use of dasabuvir; 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. (Contraindicated) Concomitant use of 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. (Major) Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with ritonavir. The risk of developing myopathy/rhabdomyolysis increases when atorvastatin is used concomitantly with 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: (Minor) 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: (Minor) 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.
Avacopan: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of ritonavir is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Avanafil: (Major) 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.
Avapritinib: (Major) Avoid coadministration of avapritinib with ritonavir due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Avatrombopag: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with ritonavir. In patients starting ritonavir while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as ritonavir decrease avatrombopag exposure, which may reduce efficacy.
Axitinib: (Major) 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 half; 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 a CYP3A4/5 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Azelastine; Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and ritonavir is not recommended; use caution with inhaled fluticasone furoate. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving inhaled fluticasone propionate with ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Fluticasone is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with ritonavir increased plasma fluticasone propionate exposure resulting in an 86% decrease in serum cortisol AUC. Another strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Barbiturates: (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers.
Bedaquiline: (Major) Concurrent use of bedaquiline and ritonavir should be avoided due to the potential risk of adverse reactions to bedaquiline because of increased systemic exposure. Bedaquiline is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased bedaquiline exposure by 22%.
Belladonna; Opium: (Moderate) Ritonavir is an inhibitor of the cytochrome P450 3A4 isoenzyme and may decrease the metabolism of opium if the two drugs are coadministered.
Belzutifan: (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with belzutifan. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and belzutifan is a weak CYP3A inducer.
Bendamustine: (Major) Consider the use of an alternative therapy if ritonavir treatment is needed in patients receiving bendamustine. Ritonavir may decrease bendamustine exposure, which may result in decreased efficacy. Bendamustine is a CYP1A2 substrate and ritonavir is a CYP1A2 inducer.
Bendroflumethiazide; Nadolol: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
Benzhydrocodone; Acetaminophen: (Moderate) 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. (Moderate) Concurrent use of benzhydrocodone with ritonavir may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. Consider a dose reduction of benzhydrocodone until stable drug effects are achieved. Monitor patients for respiratory depression and sedation at frequent intervals. Discontinuation of ritonavir in a patient taking benzhydrocodone may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If ritonavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a substrate for CYP3A4 and CYP2D6. Ritonavir is a strong inhibitor of CYP3A4 and a weak in vitro inhibitor of CYP2D6.
Benzphetamine: (Moderate) Warn patients that the risk of amphetamine toxicity may be increased during concurrent use of ritonavir, a strong CYP2D6 inhibitor. Amphetamines are partially metabolized by CYP2D6 and have serotonergic properties; inhibition of amphetamine metabolism may increase the risk of serotonin syndrome or other toxicity. If serotonin syndrome occurs, both the amphetamine and CYP2D6 inhibitor should be discontinued and appropriate medical treatment should be implemented.
Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking dasabuvir. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Additionally, monitor for an increase in dasabuvir-related adverse reactions, including QT prolongation, as concurrent use may also increase dasabuvir exposure. Berotralstat is a BCRP substrate and P-gp inhibitor; dasabuvir is a P-gp substrate and BCRP inhibitor. Coadministration with another BCRP inhibitor increased berotralstat exposure by 69%. (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking paritaprevir. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Additionally, monitor for increased toxicity of paritaprevir as concurrent use may also increase the exposure of paritaprevir. Berotralstat is a BCRP substrate and P-gp inhibitor; paritaprevir is a P-gp substrate and BCRP inhibitor. Coadministration with another BCRP inhibitor increased berotralstat exposure by 69%. (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking ritonavir. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Additionally, monitor for ritonavir-related adverse effects as concurrent use may increase the exposure of ritonavir. Berotralstat is a P-gp substrate and moderate CYP3A4 inhibitor; ritonavir is a CYP3A4 substrate and P-gp inhibitor. Coadministration with another P-gp inhibitor increased berotralstat exposure by 69%. (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with berotralstat is necessary. Concurrent use may increase ombitasvir exposure. Ombitasvir is a P-gp substrate and berotralstat is a P-gp inhibitor.
Betamethasone: (Moderate) Consider an alternative corticosteroid that is less affected by CYP3A4 (i.e., beclomethasone or prednisolone), particularly for long-term use, in patients receiving ritonavir. Coadministration may significantly increase betamethasone exposure increasing the risk for Cushing's syndrome and adrenal suppression. Ritonavir is a strong CYP3A4 inhibitor and betamethasone is a CYP3A4 substrate. Another strong CYP3A4 inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%.
Betaxolol: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving ritonavir. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving ritonavir. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; ritonavir inhibits P-gp.
Bexarotene: (Contraindicated) Concurrent administration of bexarotene with paritaprevir is contraindicated. Taking these drugs together may result in decreased concentrations of paritaprevir which may affect antiviral efficacy. Bexarotene is a moderate CYP3A4 inducer; paritaprevir is a CYP3A4 substrate. (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with bexarotene. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and bexarotene is a moderate CYP3A inducer.
Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Ritonavir oral solution and capsules contain ethanol. Administration of ritonavir oral solution or capsules 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 of ritonavir (e.g., tablets, oral powder).
Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Ritonavir oral solution and capsules contain ethanol. Administration of ritonavir oral solution or capsules 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 of ritonavir (e.g., tablets, oral powder).
Bisoprolol: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
Bortezomib: (Moderate) 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: (Contraindicated) 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. (Major) 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 the recommended initial dose once 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 the recommended initial dose once 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: (Major) 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.
Brentuximab vedotin: (Minor) 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: (Major) 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: (Major) Avoid coadministration of brigatinib with ritonavir if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, 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; ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively. (Moderate) Monitor for an increase in dasabuvir-related adverse reactions if coadministration with brigatinib is necessary. Dasabuvir is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters. (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with brigatinib is necessary. Ombitasvir is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with brigatinib is necessary. Paritaprevir is a substrate of P-glycoprotein (P-gp) and BCRP. Brigatinib inhibits both P-gp and BCRP in vitro and may have the potential to increase concentrations of substrates of these transporters.
Brimonidine; Timolol: (Moderate) Timolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as ritonavir, may impair timolol metabolism; the clinical significance of such interactions is unknown.
Brincidofovir: (Moderate) Postpone the administration of paritaprevir for at least three hours after brincidofovir administration and increase monitoring for brincidofovir-related adverse reactions (i.e., elevated hepatic enzymes and bilirubin, diarrhea, other gastrointestinal adverse events) if concomitant use of brincidofovir and paritaprevir is necessary. Brincidofovir is an OATP1B1/3 substrate and paritaprevir is an OATP1B1/3 inhibitor. In a drug interaction study, the mean AUC and Cmax of brincidofovir increased by 374% and 269%, respectively, when administered with another OATP1B1/3 inhibitor.
Bromocriptine: (Major) 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.
Budesonide: (Major) Avoid coadministration of oral budesonide and ritonavir due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
Budesonide; Formoterol: (Major) Avoid coadministration of oral budesonide and ritonavir due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
Budesonide; Glycopyrrolate; Formoterol: (Major) Avoid coadministration of oral budesonide and ritonavir due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
Bupivacaine Liposomal: (Minor) 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: (Minor) 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; Epinephrine: (Minor) 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: (Moderate) 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. (Minor) 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; Meloxicam: (Moderate) 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. (Minor) 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: (Moderate) Concomitant use of buprenorphine and ritonavir can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when ritonavir is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping ritonavir, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If ritonavir is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and ritonavir is a strong CYP3A4 inhibitor.
Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine and ritonavir can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when ritonavir is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping ritonavir, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If ritonavir is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and ritonavir is a strong CYP3A4 inhibitor.
Bupropion: (Moderate) 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: (Moderate) 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: (Major) 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: (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers.
Butalbital; Acetaminophen: (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers. (Moderate) 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.
Butalbital; Acetaminophen; Caffeine: (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers. (Moderate) 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.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers. (Moderate) Concomitant use of codeine with ritonavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of ritonavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ritonavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ritonavir is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. (Moderate) 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.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers. (Moderate) Concomitant use of codeine with ritonavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of ritonavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ritonavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ritonavir is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Cabazitaxel: (Major) 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%.
Cabotegravir: (Contraindicated) Coadministration of cabotegravir and ritonavir is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; ritonavir is an inducer of UGT. Coadministration with another UGT inducer decreased cabotegravir exposure by 59%.
Cabotegravir; Rilpivirine: (Contraindicated) Coadministration of cabotegravir and ritonavir is contraindicated due to the potential for significant decreases in the plasma concentrations of cabotegravir, which may result in potential loss of virologic response and development of resistance. Cabotegravir is a substrate for UGT1A1 and UGT1A9; ritonavir is an inducer of UGT. Coadministration with another UGT inducer decreased cabotegravir exposure by 59%.
Cabozantinib: (Major) Avoid concomitant use of cabozantinib and ritonavir due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with ritonavir 2 to 3 days after discontinuation of ritonavir. Cabozantinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%. (Minor) Monitor for an increase in dasabuvir-related adverse reactions if coadministration with cabozantinib is necessary. Dasabuvir is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown. (Minor) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with cabozantinib is necessary; a dose adjustment of ombitasvir may be necessary. Ombitasvir is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown. (Minor) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with cabozantinib is necessary; a dose adjustment of paritaprevir may be necessary. Paritaprevir is a P-glycoprotein (P-gp) substrate. Cabozantinib is a P-gp inhibitor and has the potential to increase plasma concentrations of P-gp substrates; however, the clinical relevance of this finding is unknown.
Calcifediol: (Moderate) 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.
Calcium, Magnesium, Potassium, Sodium Oxybates: (Major) 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.
Canagliflozin: (Major) Increase the canagliflozin dose to 200 mg/day in persons who are tolerating canagliflozin 100 mg/day and receiving concomitant ritonavir. The canagliflozin dose may be further increased to 300 mg/day for persons with an eGFR of 60 mL/minute/1.73 m2 or more who require additional glycemic control; consider adding another antihyperglycemic agent for persons with an eGFR less than 60 mL/minute/1.73 m2 who require additional glycemic control. Canagliflozin is an UGT1A9 and UGT2B4 substrate, and ritonavir is an UGT inducer. Coadministration with a nonselective inducer of several UGT enzymes decreased canagliflozin exposure by 51%. This decrease in exposure may decrease canagliflozin efficacy. (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Canagliflozin; Metformin: (Major) Increase the canagliflozin dose to 200 mg/day in persons who are tolerating canagliflozin 100 mg/day and receiving concomitant ritonavir. The canagliflozin dose may be further increased to 300 mg/day for persons with an eGFR of 60 mL/minute/1.73 m2 or more who require additional glycemic control; consider adding another antihyperglycemic agent for persons with an eGFR less than 60 mL/minute/1.73 m2 who require additional glycemic control. Canagliflozin is an UGT1A9 and UGT2B4 substrate, and ritonavir is an UGT inducer. Coadministration with a nonselective inducer of several UGT enzymes decreased canagliflozin exposure by 51%. This decrease in exposure may decrease canagliflozin efficacy. (Major) While no dosage adjustment of metformin is recommended in patients with normal hepatic or renal function, careful patient monitoring and dose adjustment of metformin and/or the potentially interfering drug is recommended with concurrent use. Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Do not use metformin with paritaprevir in patients with renal insufficiency or hepatic impairment. Drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Paritaprevir is an inhibitor of the organic anion transporters OATP1B1 and OATP1B3. While initial drug-drug interaction studies of paritaprevir-containing hepatitis treatments have not noted an effect on metformin concentrations, more study is needed. (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) 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: (Moderate) 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. (Moderate) 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: (Moderate) 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. (Moderate) 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.
Cannabidiol: (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with cannabidiol is necessary. Concurrent use may increase ombitasvir exposure. Ombitasvir is a P-gp substrate and cannabidiol is a P-gp inhibitor. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with cannabidiol is necessary. Concurrent use may increase paritaprevir exposure. Paritaprevir is a P-gp substrate and cannabidiol is a P-gp inhibitor. (Moderate) Monitor for increased dasabuvir-related adverse reactions, including QT prolongation, if coadministered with cannabidiol. Consider a dose reduction of dasabuvir as clinically appropriate, if adverse reactions occur. Increased dasabuvir exposure is possible which may result in QT prolongation. Dasabuvir is a CYP2C8 and P-gp substrate and cannabidiol is a CYP2C8 and P-gp inhibitor.
Capmatinib: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with ritonavir is necessary. Capmatinib is a CYP3A substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%. (Moderate) Monitor for an increase in dasabuvir-related adverse reactions if coadministration with capmatinib is necessary. Dasabuvir is a subst rate of BCRP and P-glycoprotein (P-gp). Capmatinib is a BCRP and P-gp inhibitor. Concomitant use may increase dasabuvir plasma concentrations. (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with capmatinib is necessary. Ombitasvir is a P-glycoprotein (P-gp) and BCRP substrate. Capmatinib is a P-gp and BCRP inhibitor. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with capmatinib is necessary. Paritaprevir is a P-glycoprotein (P-gp) and BCRP substrate. Capmatinib is a P-gp and BCRP inhibitor. Concomitant use may increase paritaprevir exposure.
Carbamazepine: (Contraindicated) 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. (Contraindicated) 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. (Major) Avoid concomitant use of ritonavir and carbamazepine. Concomitant use may increase carbamazepine exposure, resulting in toxicity and/or decrease ritonavir exposure, resulting in reduced efficacy. If concomitant use is necessary, monitor for reduced virologic response and for carbamazepine toxicity; a carbamazepine dose reduction may be needed. Ritonavir is a CYP3A and P-gp substrate and CYP3A inducer; carbamazepine is a CYP3A and P-gp inducer.
Cariprazine: (Major) 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: (Moderate) 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: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
Carvedilol: (Moderate) 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. (Moderate) 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. (Moderate) 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. (Moderate) 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.
Celecoxib; Tramadol: (Major) 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.
Cenobamate: (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with cenobamate. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and cenobamate is a moderate CYP3A inducer.
Ceritinib: (Major) Avoid concomitant use of ceritinib with ritonavir due to increased ceritinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is necessary, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg and monitor for ceritinib-related adverse reactions. After ritonavir is discontinued, resume the dose of ceritinib taken prior to initiating ritonavir. Ceritinib is a CYP3A substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A inhibitor increased ceritinib exposure by 2.9-fold. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with ceritinib is necessary. Paritaprevir is a CYP3A4 substrate and ceritinib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased paritaprevir exposure by 2.2- to 2.9-fold.
Cetirizine: (Moderate) 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: (Moderate) 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.
Chloramphenicol: (Moderate) 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. (Moderate) 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. (Moderate) 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: (Major) 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; Amitriptyline: (Major) 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. (Major) 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. (Major) 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. (Moderate) A dose reduction of the tricyclic antidepressant (TCA) may be necessary when coadministered with ritonavir. Concurrent use may result in elevated TCA plasma concentrations.
Chlordiazepoxide; Clidinium: (Major) 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.
Chlorpheniramine: (Moderate) 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: (Moderate) Concomitant use of codeine with ritonavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of ritonavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ritonavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ritonavir is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy. (Moderate) 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; Dextromethorphan: (Moderate) 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; Dextromethorphan; Phenylephrine: (Moderate) 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; Dextromethorphan; Pseudoephedrine: (Moderate) 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; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of dihydrocodeine with ritonavir may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of dihydrocodeine until stable drug effects are achieved. Discontinuation of ritonavir could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If ritonavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Ritonavir is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) 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: (Moderate) 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. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ritonavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ritonavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) 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: (Moderate) 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: (Moderate) 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.
Chlorpropamide: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Ciclesonide: (Moderate) 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: (Moderate) 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: (Major) 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: (Moderate) 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. (Moderate) 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: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of ritonavir and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Cisapride: (Contraindicated) 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.
Clarithromycin: (Major) Because the exposure to 14-OH clarithromycin is significantly decreased by ritonavir, consider alternative antibiotic therapy for indications other than Mycobacterium avium. Clarithromycin doses above 1000 mg should not be administered with ritonavir. If coadministration cannot be avoided, clarithromycin dosage reductions are recommended in patients with renal impairment (CrCl 30 to 60 mL/minute, decrease clarithromycin by 50%; CrCl less than 30 mL/minute, decrease clarithromycin by 75%). Concomitant administration of ritonavir and clarithromycin resulted in a 77% increase in clarithromycin exposure and a 100% decrease in 14-OH clarithromycin exposure. The microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria. (Moderate) Caution is advised when administering clarithromycin concurrently with dasabuvir. Use of these drugs together may result in elevated concentrations of dasabuvir. Clarithromycin is an inhibitor of P-glycoprotein (P-gp). Dasabuvir is a substrate of P-gp. (Moderate) Caution is advised when administering clarithromycin concurrently with ombitasvir. Use of these drugs together may result in elevated concentrations of ombitasvir. Clarithromycin is an inhibitor of P-glycoprotein (P-gp). Ombitasvir is a substrate of P-gp. (Moderate) Caution is advised when administering clarithromycin concurrently with paritaprevir. Use of these drugs together may result in elevated concentrations of paritaprevir. Clarithromycin is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Paritaprevir is a substrate of CYP3A4 and P-gp.
Clevidipine: (Moderate) 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: (Moderate) Monitor for an increase in clindamycin-related adverse reactions with coadministration of ritonavir as concurrent use may increase clindamycin exposure. Clindamycin is a CYP3A4 substrate; ritonavir is a strong inhibitor of CYP3A4.
Clobazam: (Moderate) Monitor for reduced response to ritonavir and increased adverse effects from both clobazam and ritonavir during concurrent use. Coadministration may result in elevated plasma concentrations of clobazam and altered concentrations of ritonavir. Clobazam is a substrate of CYP3A4, weak inducer of CYP3A4, and an inhibitor of CYP2D6. Ritonavir is a substrate of CYP3A4 and CYP2D6. Ritonavir is also a strong inhibitor of CYP3A4.
Clofarabine: (Moderate) 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: (Moderate) A dose reduction of the tricyclic antidepressant (TCA) may be necessary when coadministered with ritonavir. Concurrent use may result in elevated TCA plasma concentrations.
Clonazepam: (Moderate) Use protease inhibitors cautiously and carefully monitor patients receiving concurrent clonazepam due to impaired metabolism of clonazepam leading to exaggerated concentrations and adverse effects, such as CNS and/or respiratory depression. Clonazepam is a CYP3A4 substrate. Protease inhibitors are CYP3A4 inhibitors.
Clopidogrel: (Major) Avoid concomitant use of clopidogrel and ritonavir due to the risk for decreased clopidogrel efficacy. Consider the use of an alternative antiplatelet agent such as prasugrel. Ritonavir has been observed to decrease the concentration of clopidogrel's active metabolite by 69% and significantly reduce clopidogrel's antiplatelet activity as measured by the VerifyNow P2Y12 assay. Clopidogrel may be converted to its active metabolite partially via CYP3A; ritonavir is a strong CYP3A inhibitor. (Moderate) Monitor for increased dasabuvir-related adverse reactions, including QT prolongation, if coadministered with clopidogrel. Concurrent use may increase dasabuvir exposure. Dasabuvir is a CYP2C8 substrate and clopidogrel is a moderate CYP2C8 inhibitor.
Clorazepate: (Major) 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: (Major) Consider a clozapine dose adjustment if coadministered with ritonavir and monitor for efficacy and adverse reactions. If ritonavir is discontinued, monitor for lack of clozapine effect and adverse effects and adjust dose if necessary. A clinically relevant increase or decrease in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4, CYP2D6, and CYP1A2. Ritonavir is a strong CYP3A4 and weak CYP2D6 inhibitor and a moderate inducer of CYP1A2.
Cobicistat: (Contraindicated) Use of ritonavir with cobicistat is not recommended, because of similar effects on CYP3A. Both ritonavir and cobicistat are potent inhibitors of CYP3A4. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with cobicistat is necessary. Paritaprevir is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased paritaprevir exposure by 2.2-fold to 2.9-fold.
Cobimetinib: (Major) 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. (Major) 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).
Cocaine: (Moderate) Concurrent use of cocaine with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of cocaine, dasabuvir, paritaprevir, and ritonavir. Cocaine is a substrate/inhibitor of CYP3A4 and an inhibitor of CYP2D6; ritonavir is a substrate/inhibitor of both these enzymes. In addition, paritaprevir and dasabuvir (minor) are CYP3A4 substrates. While single uses of topical cocaine for local anethesia would not be expected to have clinically significant interactions, users of systemic cocaine could experience adverse events. (Moderate) Concurrent use of cocaine with ritonavir may result in elevated plasma concentrations of cocaine and ritonavir. Cocaine is a substrate/inhibitor of CYP3A4 and an inhibitor of CYP2D6; ritonavir is a substrate/inhibitor of both these enzymes. While single uses of topical cocaine for local anethesia would not be expected to have clinically significant interactions, users of systemic cocaine could experience adverse events.
Codeine: (Moderate) Concomitant use of codeine with ritonavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of ritonavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ritonavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ritonavir is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with ritonavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of ritonavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ritonavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ritonavir is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with ritonavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of ritonavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ritonavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ritonavir is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with ritonavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of ritonavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ritonavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ritonavir is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with ritonavir may alter codeine plasma concentrations, resulting in an unpredictable effect such as reduced efficacy or symptoms of opioid withdrawal or prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage adjustment of codeine until stable drug effects are achieved. Discontinuation of ritonavir could alter codeine plasma concentrations, resulting in an unpredictable effect such as prolonged opioid adverse reactions or decreased opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If ritonavir is discontinued, monitor the patient carefully and consider adjusting the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Ritonavir is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. CYP3A4 inhibitors may increase codeine-related adverse effects while CYP2D6 inhibitors may reduce efficacy.
Colchicine: (Contraindicated) 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. (Major) 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: (Contraindicated) Coadministration of conivaptan and ritonavir is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a CYP3A substrate; ritonavir is a strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
Conjugated Estrogens: (Moderate) 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: (Moderate) 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: (Major) 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. (Moderate) 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.
Copanlisib: (Major) Avoid the concomitant use of copanlisib and ritonavir if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; ritonavir is a strong CYP3A inhibitor.
Crizotinib: (Major) Avoid concomitant use of ritonavir and crizotinib due to increased plasma concentrations of crizotinib, which may increase the incidence and severity of adverse reactions. If concomitant use is necessary for adults with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), reduce the dose of crizotinib to 250 mg PO once daily. If concomitant use is necessary for young adult or pediatric patients with anaplastic large cell lymphoma or pediatric patients with IMT, reduce the dose of crizotinib to 250 mg PO twice daily for BSA of 1.7 m2 or more; 200 mg PO twice daily for BSA of 1.17 to 1.69 m2; and 250 mg PO once daily for BSA of 0.81 to 1.16 m2; do not use this combination in patients with a BSA of 0.6 to 0.8 m2. Resume the original crizotinib dose after discontinuation of ritonavir. Crizotinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with one strong CYP3A inhibitor increased the AUC of single-dose crizotinib by 216%. Concomitant use with another strong CYP3A inhibitor increased the steady-state AUC of crizotinib by 57% compared to crizotinib alone.
Cyclobenzaprine: (Moderate) 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.
Cyclophosphamide: (Moderate) Monitor for an increase in cyclophosphamide-related adverse reactions if coadministration with protease inhibitors is necessary. 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 the use of a Non-Nucleoside Reverse Transcriptase Inhibitor-based regimen. Concomitant use of protease inhibitors may increase the concentration of cytotoxic metabolites.
Cyclosporine: (Major) An interaction is anticipated to occur with protease inhibitors and cyclosporine, as CYP3A4 is inhibited by protease inhibitors and cyclosporine is a CYP3A4 substrate. Closely monitor cyclosporine concentrations and adjust the dose of cyclosporine as appropriate if coadministration with an anti-retroviral protease inhibitor is necessary. In a study of 18 HIV-infected patients who underwent renal or hepatic transplant and received concomitant therapy with protease inhibitors and cyclosporine, there was a 3-fold increase in cyclosporine AUC resulting in an 85% reduction in cyclosporine dose over a 2-year period. In another study, HIV-infected, liver and kidney transplant patients required 4- to 5-fold reductions in cyclosporine dose and approximate 50% increases in dosing interval when cyclosporine was coadministered with protease inhibitors. Consider a reduction in cyclosporine dose to 25 mg every 1 to 2 days when coadministered with a boosted protease inhibitor. Cyclosporine toxicity, consisting of fatigue, headache, and GI distress, has been reported by a patient receiving cyclosporine and saquinavir. After receiving saquinavir for 3 days, the cyclosporine trough concentration increased from 150 to 200 mcg/mL up to 580 mcg/mL. Dosages of both agents were decreased by 50% leading to resolution of symptoms. (Major) 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. (Major) 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 (Major) 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: (Moderate) 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. (Moderate) 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. (Moderate) 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. (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with ritonavir is necessary in patients with creatinine clearance (CrCl) greater than 50 mL/minute. Avoid coadministration in patients with CrCl less than 50 mL/minute 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 in patients with CrCl less than 30 mL/minute in patients with non-valvular atrial fibrillation. Serum concentrations of dabigatran are expected to be higher in patients with renal impairment compared to patients with normal renal function. Dabigatran is a P-gp substrate and ritonavir is a P-gp inhibitor.
Dabrafenib: (Major) 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. (Major) 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: (Major) 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. (Major) 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. (Major) 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. (Major) 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: (Moderate) 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: (Moderate) 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.
Dapagliflozin: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) 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: (Major) While no dosage adjustment of metformin is recommended in patients with normal hepatic or renal function, careful patient monitoring and dose adjustment of metformin and/or the potentially interfering drug is recommended with concurrent use. Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Do not use metformin with paritaprevir in patients with renal insufficiency or hepatic impairment. Drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Paritaprevir is an inhibitor of the organic anion transporters OATP1B1 and OATP1B3. While initial drug-drug interaction studies of paritaprevir-containing hepatitis treatments have not noted an effect on metformin concentrations, more study is needed. (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) 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. (Moderate) 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.
Dapagliflozin; Saxagliptin: (Major) 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. (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) 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.
Dapsone: (Moderate) 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.
Daridorexant: (Major) Avoid concomitant use of daridorexant and ritonavir. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Darifenacin: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with ritonavir due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor.
Darolutamide: (Moderate) Monitor for an increase in dasabuvir-related adverse reactions if coadministration with darolutamide is necessary. Dasabuvir is a BCRP substrate and darolutamide is a BCRP inhibitor. (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with darolutamide is necessary. Concomitant use may increase plasma concentrations of ombitasvir. Ombitasvir is a BCRP substrate. Darolutamide is a BCRP inhibitor. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with darolutamide is necessary. Concomitant use may increase plasma concentrations of paritaprevir. Paritaprevir is a BCRP and OATP1B1/1B3 substrate. Darolutamide is a BCRP and OATP1B1/1B3 inhibitor. (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with ritonavir is necessary due to the risk of increased darolutamide exposure; decrease the dose of darolutamide for grade 3 or 4 adverse reactions or for otherwise intolerable adverse reactions. Ritonavir is a P-glycoprotein (P-gp) inhibitor and a strong CYP3A4 inhibitor; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp inhibitor and strong CYP3A4 inhibitor increased the mean AUC and Cmax of darolutamide by 1.7-fold and 1.4-fold, respectively.
Darunavir: (Major) 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: (Contraindicated) Use of ritonavir with cobicistat is not recommended, because of similar effects on CYP3A. Both ritonavir and cobicistat are potent inhibitors of CYP3A4. (Major) 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. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with cobicistat is necessary. Paritaprevir is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased paritaprevir exposure by 2.2-fold to 2.9-fold.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Contraindicated) Use of ritonavir with cobicistat is not recommended, because of similar effects on CYP3A. Both ritonavir and cobicistat are potent inhibitors of CYP3A4. (Major) 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. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with cobicistat is necessary. Paritaprevir is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased paritaprevir exposure by 2.2-fold to 2.9-fold.
Dasatinib: (Major) Avoid coadministration of dasatinib and ritonavir due to the potential for increased dasatinib exposure and subsequent toxicity including QT prolongation and torsade de pointes (TdP). An alternative to ritonavir with no or minimal enzyme inhibition potential is recommended if possible. If coadministration cannot be avoided, consider a dasatinib dose reduction to 40 mg PO daily if original dose was 140 mg daily, 20 mg PO daily if original dose was 100 mg daily, or 20 mg PO daily if original dose was 70 mg daily. Concomitant use of ritonavir is not recommended in patients receiving dasatinib 60 mg or 40 mg daily. If dasatinib is not tolerated after dose reduction, consider alternative therapies. If ritonavir is stopped, allow a washout of approximately 1 week before increasing the dasatinib dose. Dasatinib is a CYP3A4 substrate that has the potential to prolong the QT interval; ritonavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the mean Cmax and AUC of dasatinib by 4-fold and 5-fold, respectively.
Deferasirox: (Contraindicated) 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. (Major) 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. (Major) 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: (Major) 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.
Delavirdine: (Moderate) 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. (Moderate) 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. (Moderate) Monitor for increased toxicity of ritonavir during coadministration of delavirdine. Appropriate doses of ritonavir in combination with delavirdine with respect to safety and efficacy have not been established. The exposure to ritonavir has been increased by 70% during concurrent administration of delavirdine.
Desipramine: (Moderate) A dose reduction of the tricyclic antidepressant (TCA) may be necessary when coadministered with ritonavir. Concurrent use may result in elevated TCA plasma concentrations.
Desogestrel; Ethinyl Estradiol: (Contraindicated) 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. (Contraindicated) 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. (Major) 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.
Dexamethasone: (Contraindicated) 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. (Contraindicated) 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. (Moderate) Close monitoring of therapeutic and adverse effects is required when dexamethasone is coadministered with ritonavir. Ritonavir inhibits CYP3A4 and dexamethasone is a CYP3A4 substrate.
Dexlansoprazole: (Moderate) 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.
Dexmedetomidine: (Moderate) Use caution if ritonavir is coadministered with dexmedetomidine due to the potential for decreased dexmedetomidine exposure which may decrease its efficacy. Limited data suggests that dexmedetomidine is metabolized by several enzymes, including CYP2C19. Ritonavir is an inducer of CYP2C19.
Dextroamphetamine: (Moderate) Warn patients that the risk of amphetamine toxicity may be increased during concurrent use of ritonavir, a strong CYP2D6 inhibitor. Amphetamines are partially metabolized by CYP2D6 and have serotonergic properties; inhibition of amphetamine metabolism may increase the risk of serotonin syndrome or other toxicity. If serotonin syndrome occurs, both the amphetamine and CYP2D6 inhibitor should be discontinued and appropriate medical treatment should be implemented.
Dextromethorphan; Bupropion: (Moderate) 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%.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) 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; Quinidine: (Contraindicated) 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. (Major) 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.
Diazepam: (Major) 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 (Moderate) 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: (Moderate) 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: (Moderate) 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: (Major) 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.
Dienogest; Estradiol valerate: (Moderate) 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: (Major) 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. (Major) 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.
Dihydroergotamine: (Contraindicated) 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: (Moderate) Ritonavir is expected to decrease 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. A decreased diltiazem dose may be warranted. In addition, ritonavir and diltiazem both prolong the PR interval and caution for increased risk is recommended with coadministration.
Diphenhydramine: (Moderate) 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: (Moderate) 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: (Moderate) 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: (Moderate) 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: (Major) 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: (Major) 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: (Major) Avoid coadministration of docetaxel with ritonavir if possible due to increased plasma concentrations of docetaxel. If concomitant use is unavoidable, closely monitor for docetaxel-related adverse reactions and consider a 50% dose reduction of docetaxel. Docetaxel is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased docetaxel exposure by 2.2-fold.
Dofetilide: (Moderate) Concomitant use of dofetilide and ritonavir may increase the risk of QT prolongation and torsade de pointes (TdP) due to increased dofetilide exposure. Dofetilide is metabolized to a small degree by CYP3A4; ritonavir is a potent inhibitor of CYP3A4.
Dolutegravir: (Moderate) Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of dolutegravir with dasabuvir may result in elevated dolutegravir plasma concentrations. Dolutegravir is a substrate of uridine glucuronyltransferase (UGT) and the breast cancer resistance protein (BCRP). Dasabuvir is a UGT1A1 inhibitor and BCRP inhibitor. (Moderate) Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of dolutegravir with ombitasvir may result in elevated dolutegravir plasma concentrations. Dolutegravir is a substrate of uridine glucuronyltransferase (UGT). Ombitasvir inhibits UGT1A1. (Moderate) Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of dolutegravir with paritaprevir may result in elevated dolutegravir plasma concentrations. Dolutegravir is a substrate of uridine glucuronyltransferase (UGT) and the breast cancer resistance protein (BCRP). Paritaprevir inhibits UGT1A1 and BCRP.
Dolutegravir; Lamivudine: (Moderate) Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of dolutegravir with dasabuvir may result in elevated dolutegravir plasma concentrations. Dolutegravir is a substrate of uridine glucuronyltransferase (UGT) and the breast cancer resistance protein (BCRP). Dasabuvir is a UGT1A1 inhibitor and BCRP inhibitor. (Moderate) Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of dolutegravir with ombitasvir may result in elevated dolutegravir plasma concentrations. Dolutegravir is a substrate of uridine glucuronyltransferase (UGT). Ombitasvir inhibits UGT1A1. (Moderate) Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of dolutegravir with paritaprevir may result in elevated dolutegravir plasma concentrations. Dolutegravir is a substrate of uridine glucuronyltransferase (UGT) and the breast cancer resistance protein (BCRP). Paritaprevir inhibits UGT1A1 and BCRP.
Dolutegravir; Rilpivirine: (Moderate) Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of dolutegravir with dasabuvir may result in elevated dolutegravir plasma concentrations. Dolutegravir is a substrate of uridine glucuronyltransferase (UGT) and the breast cancer resistance protein (BCRP). Dasabuvir is a UGT1A1 inhibitor and BCRP inhibitor. (Moderate) Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of dolutegravir with ombitasvir may result in elevated dolutegravir plasma concentrations. Dolutegravir is a substrate of uridine glucuronyltransferase (UGT). Ombitasvir inhibits UGT1A1. (Moderate) Caution and close monitoring are advised if these drugs are administered together. Concurrent administration of dolutegravir with paritaprevir may result in elevated dolutegravir plasma concentrations. Dolutegravir is a substrate of uridine glucuronyltransferase (UGT) and the breast cancer resistance protein (BCRP). Paritaprevir inhibits UGT1A1 and BCRP.
Donepezil: (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Ritonavir is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
Donepezil; Memantine: (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Ritonavir is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
Doravirine: (Minor) Coadministration of doravirine and ritonavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; ritonavir is a strong inhibitor. In a drug interaction study, concurrent use of ritonavir increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) 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. (Moderate) 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. (Minor) Coadministration of doravirine and ritonavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; ritonavir is a strong inhibitor. In a drug interaction study, concurrent use of ritonavir increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Dorzolamide; Timolol: (Moderate) Timolol is significantly metabolized by CYP2D6 isoenzymes. CYP2D6 inhibitors, such as ritonavir, may impair timolol metabolism; the clinical significance of such interactions is unknown.
Doxazosin: (Moderate) Monitor blood pressure and for signs of hypotension during coadministration. The plasma concentrations of doxazosin may be elevated when administered concurrently with ritonavir. Ritonavir is a strong CYP3A4 inhibitor; doxazosin is a CYP3A4 substrate. Coadministration of doxazosin with a moderate CYP3A4 inhibitor resulted in a 10% increase in mean AUC and an insignificant increase in mean Cmax and mean half-life of doxazosin. Although not studied in combination with doxazosin, strong CYP3A4 inhibitors may have a larger impact on doxazosin concentrations and therefore should be used with caution.
Doxepin: (Moderate) A dose reduction of the tricyclic antidepressant (TCA) may be necessary when coadministered with ritonavir. Concurrent use may result in elevated TCA plasma concentrations.
Doxercalciferol: (Moderate) 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: (Major) Avoid coadministration of ritonavir with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Ritonavir is a strong CYP3A4 inhibitor and a P-gp inhibitor; doxorubicin is a CYP3A4 and P-gp substrate. Concurrent use of CYP3A4 and/or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of ritonavir with doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Ritonavir is a strong CYP3A4 inhibitor and a P-gp inhibitor; doxorubicin is a CYP3A4 and P-gp substrate. Concurrent use of CYP3A4 and/or P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Dronabinol: (Major) 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: (Contraindicated) 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. (Contraindicated) 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: (Major) 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.
Drospirenone; Estradiol: (Moderate) 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: (Contraindicated) 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. (Contraindicated) 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. (Major) 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: (Contraindicated) 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. (Contraindicated) 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. (Major) 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.
Dulaglutide: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Dutasteride: (Moderate) 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: (Major) 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. (Moderate) 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.
Duvelisib: (Major) Reduce duvelisib dose to 15 mg PO twice daily and monitor for increased toxicity when coadministered with ritonavir. Coadministration may increase the exposure of duvelisib. Duvelisib is a CYP3A substrate; ritonavir is a strong CYP3A inhibitor. The increase in exposure to duvelisib is estimated to be approximately 2-fold when used concomitantly with strong CYP3A inhibitors such as ritonavir.
Echinacea: (Moderate) 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: (Moderate) 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: (Contraindicated) 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. (Contraindicated) 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. (Contraindicated) 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. (Moderate) Monitor for elevation of liver enzymes and for adverse clinical experiences (e.g., dizziness, nausea, paresthesia) when efavirenz is coadministered with ritonavir. Concurrent use is is expected to result in increased concentrations of both drugs.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Contraindicated) 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. (Contraindicated) 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. (Contraindicated) 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. (Moderate) 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. (Moderate) 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. (Moderate) Monitor for elevation of liver enzymes and for adverse clinical experiences (e.g., dizziness, nausea, paresthesia) when efavirenz is coadministered with ritonavir. Concurrent use is is expected to result in increased concentrations of both drugs.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Contraindicated) 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. (Contraindicated) 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. (Contraindicated) 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. (Moderate) 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. (Moderate) 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. (Moderate) Monitor for elevation of liver enzymes and for adverse clinical experiences (e.g., dizziness, nausea, paresthesia) when efavirenz is coadministered with ritonavir. Concurrent use is is expected to result in increased concentrations of both drugs.
Elacestrant: (Major) Avoid concomitant use of elacestrant and ritonavir due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. Elacestrant is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased elacestrant overall exposure by 5.3-fold. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with elacestrant is necessary. Concurrent use may increase paritaprevir exposure. Paritaprevir is a substrate of BCRP and P-gp; elacestrant is an inhibitor of BCRP and P-gp.
Elagolix: (Contraindicated) Concomitant use of elagolix and strong organic anion transporting polypeptide (OATP) 1B1 inhibitors such as paritaprevir is contraindicated. Use of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Elagolix is a substrate of CYP3A, P-gp, and OATP1B1. Paritaprevir is an inhibitor of OATP1B1. Another OATP1B1 potent inhibitor increased elagolix AUC in the range of 2- to 5.58-fold. Increased elagolix concentrations increase the risk for dose-related side effects, including loss of bone mineral density. (Major) Concomitant use of elagolix 200 mg twice daily and ritonavir for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and ritonavir to 6 months. Monitor for elagolix-related side effects and reduced response to ritonavir. Elagolix is a CYP3A substrate and a weak to moderate CYP3A4 inducer; ritonavir is a strong inhibitor of CYP3A and a CYP3A4 substrate. Coadministration may increase elagolix plasma concentrations and decrease ritonavir concentrations. In drug interaction studies, coadministration of elagolix with another strong CYP3A inhibitor increased the Cmax and AUC of elagolix by 77% and 120%, respectively.
Elagolix; Estradiol; Norethindrone acetate: (Contraindicated) Concomitant use of elagolix and strong organic anion transporting polypeptide (OATP) 1B1 inhibitors such as paritaprevir is contraindicated. Use of elagolix with drugs that inhibit OATP1B1 may increase elagolix plasma concentrations. Elagolix is a substrate of CYP3A, P-gp, and OATP1B1. Paritaprevir is an inhibitor of OATP1B1. Another OATP1B1 potent inhibitor increased elagolix AUC in the range of 2- to 5.58-fold. Increased elagolix concentrations increase the risk for dose-related side effects, including loss of bone mineral density. (Major) Concomitant use of elagolix 200 mg twice daily and ritonavir for more than 1 month is not recommended. Limit concomitant use of elagolix 150 mg once daily and ritonavir to 6 months. Monitor for elagolix-related side effects and reduced response to ritonavir. Elagolix is a CYP3A substrate and a weak to moderate CYP3A4 inducer; ritonavir is a strong inhibitor of CYP3A and a CYP3A4 substrate. Coadministration may increase elagolix plasma concentrations and decrease ritonavir concentrations. In drug interaction studies, coadministration of elagolix with another strong CYP3A inhibitor increased the Cmax and AUC of elagolix by 77% and 120%, respectively. (Moderate) 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. (Moderate) 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.
Elbasvir; Grazoprevir: (Contraindicated) 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. (Major) 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. (Major) 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: (Contraindicated) 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.
Elexacaftor; tezacaftor; ivacaftor: (Major) If ritonavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor to twice a week in the morning, approximately 3 to 4 days apart (i.e., Day 1 and Day 4) when coadministered with ritonavir; omit the evening dose of ivacaftor. Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; ritonavir is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased elexacaftor exposure by 2.8- fold, tezacaftor exposure by 4.5-fold, and ivacaftor exposure by 15.6-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with ritonavir; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, dose 1 tezacaftor; ivacaftor combination tablet twice a week, approximately 3 to 4 days apart (i.e., Day 1 and Day 4). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); ritonavir is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with elexacaftor is necessary. Concurrent use may increase paritaprevir exposure. Paritaprevir is an OATP1B1 substrate and elexacaftor is an OATP1B1 inhibitor.
Eliglustat: (Contraindicated) 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. (Contraindicated) 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. (Contraindicated) 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. (Major) Coadministration of eliglustat and ritonavir is contraindicated in intermediate or poor CYP2D6 metabolizers (IMs or PMs). In extensive CYP2D6 metabolizers (EMs), coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. The coadministration of eliglustat with ritonavir and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients. Eliglustat is a CYP3A and CYP2D6 substrate. Coadministration of eliglustat with CYP3A inhibitors, such as ritonavir, increases eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); this risk is the highest in CYP2D6 IMs and PMs because a larger portion of the eliglustat dose is metabolized via CYP3A.
Eltrombopag: (Moderate) 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: (Major) 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. (Major) When administered concurrently with ritonavir, the dose of eluxadoline must be reduced to 75 mg PO twice daily, and the patient should be closely monitored for eluxadoline-related adverse effects (i.e., decreased mental and physical acuity). Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known. Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); ritonavir is an OATP1B1 inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Contraindicated) Use of ritonavir with cobicistat is not recommended, because of similar effects on CYP3A. Both ritonavir and cobicistat are potent inhibitors of CYP3A4. (Moderate) 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. (Moderate) 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. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with cobicistat is necessary. Paritaprevir is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased paritaprevir exposure by 2.2-fold to 2.9-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofo vir Disoproxil Fumarate: (Contraindicated) Use of ritonavir with cobicistat is not recommended, because of similar effects on CYP3A. Both ritonavir and cobicistat are potent inhibitors of CYP3A4. (Moderate) 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. (Moderate) 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. (Moderate) 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. (Moderate) 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. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with cobicistat is necessary. Paritaprevir is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased paritaprevir exposure by 2.2-fold to 2.9-fold.
Empagliflozin: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) 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: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) Monitor for changes in glycemic control, specifically hyperglycemia, if ritonavir is administered concurrently with 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. (Moderate) 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; Metformin: (Major) While no dosage adjustment of metformin is recommended in patients with normal hepatic or renal function, careful patient monitoring and dose adjustment of metformin and/or the potentially interfering drug is recommended with concurrent use. Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Do not use metformin with paritaprevir in patients with renal insufficiency or hepatic impairment. Drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Paritaprevir is an inhibitor of the organic anion transporters OATP1B1 and OATP1B3. While initial drug-drug interaction studies of paritaprevir-containing hepatitis treatments have not noted an effect on metformin concentrations, more study is needed. (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) Monitor for changes in glycemic control, specifically hyperglycemia, if ritonavir is administered concurrently with 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. (Moderate) 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. (Moderate) 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.
Empagliflozin; Metformin: (Major) While no dosage adjustment of metformin is recommended in patients with normal hepatic or renal function, careful patient monitoring and dose adjustment of metformin and/or the potentially interfering drug is recommended with concurrent use. Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Do not use metformin with paritaprevir in patients with renal insufficiency or hepatic impairment. Drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Paritaprevir is an inhibitor of the organic anion transporters OATP1B1 and OATP1B3. While initial drug-drug interaction studies of paritaprevir-containing hepatitis treatments have not noted an effect on metformin concentrations, more study is needed. (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) 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. (Moderate) 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 Disoproxil Fumarate: (Moderate) 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. (Moderate) 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: (Moderate) 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. (Moderate) 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.
Enasidenib: (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with enasidenib is necessary. Concurrent use may increase ombitasvir exposure. Ombitasvir is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with enasidenib is necessary. Concurrent use may increase paritaprevir exposure. Paritaprevir is a P-gp, BCRP, and OATP1B1/3 substrate and enasidenib is a P-gp, BCRP, OATP1B1/3 inhibitor. (Moderate) Monitor for increased dasabuvir-related adverse reactions, including QT prolongation, if coadministered with enasidenib. Concurrent use may increase dasabuvir exposure. Dasabuvir is a P-gp and BCRP substrate and enasidenib is a P-gp and BCRP inhibitor.
Encainide: (Major) 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.
Encorafenib: (Major) Avoid coadministration of encorafenib and ritonavir due to increased encorafenib exposure. If concurrent use cannot be avoided, reduce the encorafenib dose to one-third of the dose used prior to the addition of ritonavir. If ritonavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of ritonavir. Encorafenib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 50 mg dose of encorafenib (0.1 times the recommended dose) increased the encorafenib AUC and Cmax by 3-fold and 68%, respectively. (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with encorafenib is necessary. Concurrent use may increase ombitasvir exposure. Ombitasvir is a BCRP substrate and encorafenib is a BCRP inhibitor. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with encorafenib is necessary. Concurrent use may increase paritaprevir exposure. Paritaprevir is a BCRP substrate and encorafenib is a BCRP inhibitor. (Moderate) Monitor for increased dasabuvir-related adverse reactions, including QT prolongation, if coadministered with encorafenib. Concurrent use may increase dasabuvir exposure. Dasabuvir is a BCRP substrate and encorafenib is a BCRP inhibitor.
Enfortumab vedotin: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with ritonavir is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; ritonavir is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Entrectinib: (Major) Avoid coadministration of entrectinib with ritonavir due to increased entrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided in adults and pediatric patients 12 years and older with BSA greater than 1.5 m2, reduce the entrectinib dose to 100 mg PO once daily. If ritonavir is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of ritonavir. Entrectinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study.
Enzalutamide: (Contraindicated) Coadministration of paritaprevir with enzalutamide is contraindicated due to the potential for decreased paritaprevir concentrations and the potential development of viral resistance. Paritaprevir is metabolized by CYP3A4 and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased paritaprevir exposure by 70%. (Contraindicated) Coadministration of ritonavir with enzalutamide is contraindicated as there is a potential for decreased ritonavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is metabolized by CYP3A4; enzalutamide is a strong CYP3A4 inducer.
Eplerenone: (Contraindicated) 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.
Erdafitinib: (Major) Avoid coadministration of erdafitinib and ritonavir due to the risk of increased plasma concentrations of erdafitinib. If concomitant use is unavoidable, closely monitor for erdafitinib-related adverse reactions and consider dose modifications as clinically appropriate. If ritonavir is discontinued, the dose of erdafitinib may be increased in the absence of drug-related toxicity. Erdafitinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. The mean ratios for the Cmax and AUC of erdafitinib were 105% and 134%, respectively, when coadministered with another strong CYP3A4 inhibitor.
Ergoloid Mesylates: (Contraindicated) 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: (Contraindicated) 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: (Contraindicated) 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: (Contraindicated) 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; Caffeine: (Contraindicated) 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.
Erlotinib: (Major) Avoid coadministration of erlotinib with ritonavir if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
Ertugliflozin: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Ertugliflozin; Metformin: (Major) While no dosage adjustment of metformin is recommended in patients with normal hepatic or renal function, careful patient monitoring and dose adjustment of metformin and/or the potentially interfering drug is recommended with concurrent use. Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Do not use metformin with paritaprevir in patients with renal insufficiency or hepatic impairment. Drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Paritaprevir is an inhibitor of the organic anion transporters OATP1B1 and OATP1B3. While initial drug-drug interaction studies of paritaprevir-containing hepatitis treatments have not noted an effect on metformin concentrations, more study is needed. (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) 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.
Ertugliflozin; Sitagliptin: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) 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.
Erythromycin: (Moderate) Caution is warranted with the use of erythromycin and dasabuvir as concurrent administration may result in elevated plasma concentrations of dasabuvir. Monitor for adverse events such as gastrointestinal and skin reactions. Erythromycin is an inhibitor of P-glycoprotein (P-gp) and dasabuvir is a P-gp substrate. (Moderate) Caution is warranted with the use of erythromycin and ombitasvir as concurrent administration may result in elevated plasma concentrations of ombitasvir. Monitor for adverse events such as gastrointestinal and skin reactions. Erythromycin is an inhibitor of P-glycoprotein (P-gp) and ombitasvir is a P-gp substrate. (Moderate) Caution is warranted with the use of erythromycin and paritaprevir as concurrent administration may result in elevated plasma concentrations of paritaprevir. Monitor for adverse events such as gastrointestinal and skin reactions. Erythromycin is an inhibitor of CYP3A4 and P-glycoprotein (P-gp), while paritaprevir is a CYP3A4 and P-gp substrate. (Moderate) Caution is warranted with the use of erythromycin and ritonavir as erythromycin may increase ritonavir serum concentrations resulting in increased treatment-related adverse effects. Erythromycin inhibits CYP3A4 and P-glycoprotein (P-gp), while ritonavir is a substrate of both CYP3A4 and P-gp.
Eslicarbazepine: (Contraindicated) 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. (Contraindicated) 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. (Major) 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: (Moderate) 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: (Moderate) 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: (Moderate) 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: (Moderate) 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: (Moderate) 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: (Major) 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. (Moderate) 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: (Moderate) 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: (Major) 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. (Moderate) 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: (Moderate) 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. (Moderate) 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: (Moderate) 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; Progesterone: (Moderate) 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. (Moderate) Use caution if coadministration of ritonavir with progesterone is necessary, as the systemic exposure of progesterone may be increased resulting in an increase in treatment-related adverse reactions. Ritonavir is a strong CYP3A4 inhibitor. Progesterone is metabolized primarily by hydroxylation via a CYP3A4. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Estropipate: (Moderate) 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: (Major) 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: (Major) Concurrent administration of alcohol with ritonavir may result in decreased plasma concentrations of ritonavir, which may affect antiviral efficacy. Alcohol is an inducer of the hepatic isoenzyme CYP3A4; ritonavir is a substrate of this enzyme. Caution and close monitoring are advised if alcohol and ritonavir are administered together. (Major) Inform patients to swallow tablets whole and not to consume alcohol within 4 hours of taking dasabuvir-containing extended-release products, such as Viekira XR. Taking alcohol can interfere with the optimal release of dasabuvir, which can compromise efficacy.
Ethinyl Estradiol: (Contraindicated) 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. (Contraindicated) 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. (Major) 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: (Contraindicated) 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. (Contraindicated) 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. (Major) 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. (Major) 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: (Contraindicated) 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. (Contraindicated) 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. (Major) 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: (Contraindicated) 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. (Contraindicated) 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. (Major) 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. (Moderate) 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; Norgestrel: (Contraindicated) 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. (Contraindicated) 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. (Major) 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: (Moderate) 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: (Major) Avoid concomitant use of ritonavir and hydantoins. Concomitant use may decrease the exposure of ritonavir and hydantoins, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the hydantoin. A dose increase of the hydantoin may be necessary. Ritonavir is a CYP3A substrate and inducer and hydantoins are CYP3A inducers. (Major) 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.
Ethynodiol Diacetate; Ethinyl Estradiol: (Contraindicated) 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. (Contraindicated) 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. (Major) 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.
Etonogestrel: (Major) 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.
Etonogestrel; Ethinyl Estradiol: (Contraindicated) 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. (Contraindicated) 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. (Major) 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. (Major) 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.
Etravirine: (Major) Do not coadminister etravirine and dasabuvir; ombitasvir; paritaprevir; ritonavir due to potential loss of direct acting antiviral efficacy. (Moderate) 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: (Major) Avoid coadministration of everolimus with ritonavir due to the risk of increased everolimus-related adverse reactions. If concomitant use is unavoidable in patients receiving everolimus for either kidney or liver transplant, closely monitor everolimus whole blood trough concentrations. Everolimus is a sensitive CYP3A4 substrate and a P-glycoprotein (P-gp) substrate. Ritonavir is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
Exenatide: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Ezetimibe; Simvastatin: (Contraindicated) Coadministration of paritaprevir may increase simvastatin exposure. Paritaprevir is an inhibitor of OATP1B1/3; simvastatin is a substrate of OATP1B1/3. (Contraindicated) 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.
Fedratinib: (Major) Avoid coadministration of fedratinib with ritonavir as concurrent use may increase fedratinib exposure. If concurrent use cannot be avoided, reduce the dose of fedratinib to 200 mg PO once daily. If ritonavir is discontinued, increase the fedratinib dose as follows: 300 mg PO once daily for 2 weeks and then 400 mg PO once daily thereafter as tolerated. Fedratinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
Felbamate: (Major) 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. (Major) 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: (Moderate) 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: (Moderate) 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: (Major) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. If ritonavir is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ritonavir can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If ritonavir is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl. 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: (Major) Limit the dose of fesoterodine to 4 mg once daily in adults and pediatric patients weighing more than 35 kg if coadministered with anti-retroviral protease inhibitors. Avoid use of fesoterodine and protease inhibitors in pediatric patients weighing 25 to 35 kg. Concurrent use may increase fesoterodine exposure. Fesoterodine is a CYP3A4 substrate and protease inhibitors are strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor led to approximately a doubling of the overall exposure of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine.
Fexofenadine: (Minor) 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.
Fexofenadine; Pseudoephedrine: (Minor) 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.
Finasteride; Tadalafil: (Major) 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.
Finerenone: (Contraindicated) Concomitant use of finerenone and ritonavir is contraindicated. Concomitant use may increase finerenone exposure and the risk for finerenone-related adverse reactions. Finerenone is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased overall exposure to finerenone by more than 400%.
Flecainide: (Major) 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.
Flibanserin: (Contraindicated) 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: (Major) 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. (Moderate) Caution is warranted with the use of fluconazole and ritonavir as ritonavir serum concentrations may be increased resulting in increased treatment-related adverse effects. Fluconazole is a moderate CYP3A4 inhibitor, while ritonavir is a substrate of CYP3A4.
Fluoxetine: (Major) 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. (Major) 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. (Moderate) A dose reduction of fluoxetine may ne necessary if coadministered with ritonavir. Increased fluoxetine exposure may occur. Cardiac and neurologic events have been reported when ritonavir has been administered with fluoxetine.
Flurazepam: (Major) 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: (Major) Coadministration of inhaled fluticasone propionate and ritonavir is not recommended; use caution with inhaled fluticasone furoate. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving inhaled fluticasone propionate with ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Fluticasone is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with ritonavir increased plasma fluticasone propionate exposure resulting in an 86% decrease in serum cortisol AUC. Another strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluticasone; Salmeterol: (Major) Avoid concomitant use of salmeterol with ritonavir. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose. (Major) Coadministration of inhaled fluticasone propionate and ritonavir is not recommended; use caution with inhaled fluticasone furoate. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving inhaled fluticasone propionate with ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Fluticasone is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with ritonavir increased plasma fluticasone propionate exposure resulting in an 86% decrease in serum cortisol AUC. Another strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluticasone; Umeclidinium; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and ritonavir is not recommended; use caution with inhaled fluticasone furoate. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving inhaled fluticasone propionate with ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Fluticasone is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with ritonavir increased plasma fluticasone propionate exposure resulting in an 86% decrease in serum cortisol AUC. Another strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluticasone; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and ritonavir is not recommended; use caution with inhaled fluticasone furoate. During post-marketing use, there have been reports of clinically significant drug interactions in patients receiving inhaled fluticasone propionate with ritonavir, resulting in systemic corticosteroid effects including Cushing's syndrome and adrenal suppression. Fluticasone is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with ritonavir increased plasma fluticasone propionate exposure resulting in an 86% decrease in serum cortisol AUC. Another strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluvastatin: (Moderate) 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: (Major) 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. (Moderate) Concurrent administration of fluvoxamine with ritonavir may result in increased plasma concentrations of one or both drugs. Fluvoxamine is partially metabolized by CYP2D6 and ritonavir is a weak CYP2D6 inhibitor. In addition, ritonavir is metabolized by CYP3A4, and fluvoxamine is a moderate CYP3A4 inhibitor. Caution and close monitoring are advised if these drugs are administered together.
Food: (Major) Advise patients to avoid cannabis use during protease inhibitor treatment. Concomitant use may alter the exposure of some cannabinoids and increase the risk for adverse reactions. The cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP3A substrates and protease inhibitors are strong CYP3A inhibitors. Concomitant use of a cannabinoid product containing THC and CBD at an approximate 1:1 ratio with another strong CYP3A inhibitor increased THC, 11-OH-THC, and CBD peak exposures by 1.3-, 3-, and 1.9-fold respectively.
Formoterol; Mometasone: (Moderate) 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.
Fosamprenavir: (Major) 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: (Moderate) Abnormal renal function has been observed in clinical practice during the use of foscarnet in combination with ritonavir. If these drugs are administered together, monitor kidney function.
Fosphenytoin: (Contraindicated) 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. (Contraindicated) 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. (Major) Avoid concomitant use of ritonavir and hydantoins. Concomitant use may decrease the exposure of ritonavir and hydantoins, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the hydantoin. A dose increase of the hydantoin may be necessary. Ritonavir is a CYP3A substrate and inducer and hydantoins are CYP3A inducers.
Fostamatinib: (Moderate) Monitor for dasabuvir toxicities that may require dasabuvir dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a BCRP or P-gp substrate may increase the concentration of the BCRP or P-gp substrate. Fostamatinib is a P-gp inhibitor, and the active metabolite of fostamatinib, R406, is a BCRP inhibitor; dasabuvir is a substrate for BCRP and P-gp. Coadministration of fostamatinib with another BCRP substrate increased the substrate AUC by 95% and Cmax by 88%. Coadministration of fostamatinib with another P-gp substrate increased the substrate AUC by 37% and Cmax by 70%. (Moderate) Monitor for fostamatinib toxicities that may require fostamatinib dose reduction (i.e., elevated hepatic enzymes, neutropenia, high blood pressure, severe diarrhea) if given concurrently with a strong CYP3A4 inhibitor. Concomitant use of fostamatinib with a strong CYP3A4 inhibitor increases exposure to the major active metabolite, R406, which may increase the risk of adverse reactions. R406 is extensively metabolized by CYP3A4; ritonavir is a strong CYP3A4 inhibitor. Coadministration of fostamatinib with another strong CYP3A4 inhibitor increased R406 AUC by 102% and Cmax by 37%. (Moderate) Monitor for ombitasvir toxicities that may require ombitasvir dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a BCRP or P-gp substrate may increase the concentration of the BCRP or P-gp substrate. Fostamatinib is a P-gp inhibitor, and the active metabolite of fostamatinib, R406, is a BCRP inhibitor; ombitasvir is a substrate for BCRP and P-gp. Coadministration of fostamatinib with another BCRP substrate increased the substrate AUC by 95% and Cmax by 88%. Coadministration of fostamatinib with another P-gp substrate increased the substrate AUC by 37% and Cmax by 70%. (Moderate) Monitor for paritaprevir toxicities that may require paritaprevir dose reduction if given concurrently with fostamatinib. Concomitant use of fostamatinib with a BCRP or P-gp substrate may increase the concentration of the BCRP or P-gp substrate. Fostamatinib is a P-gp inhibitor, and the active metabolite of fostamatinib, R406, is a BCRP inhibitor; paritaprevir is a substrate for BCRP and P-gp. Coadministration of fostamatinib with another BCRP substrate increased the substrate AUC by 95% and Cmax by 88%. Coadministration of fostamatinib with another P-gp substrate increased the substrate AUC by 37% and Cmax by 70%.
Fostemsavir: (Moderate) Monitor for increased dasabuvir-related adverse reactions if coadministered with fostemsavir. Concurrent use may increase dasabuvir exposure. Dasabuvir is a substrate of BCRP and fostemsavir is a BCRP inhibitor. (Moderate) Monitor for increased ombitasvir-related adverse reactions if coadministered with fostemsavir. Concurrent use may increase ombitasvir exposure. Ombitasvir is a substrate of BCRP and fostemsavir is a BCRP inhibitor. (Moderate) Monitor for increased paritaprevir-related adverse reactions if coadministered with fostemsavir. Concurrent use may increase paritaprevir exposure. Paritaprevir is a substrate of BCRP and OATP1B1/3; fostemsavir is a BCRP and OATP1B1/3 inhibitor.
Furosemide: (Moderate) 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. (Moderate) 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.
Futibatinib: (Major) Avoid concurrent use of futibatinib and ritonavir. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; ritonavir is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%. (Moderate) Monitor for increased dasabuvir-related adverse reactions if coadministered with futibatinib. Concurrent use may increase dasabuvir exposure. Dasabuvir is a P-gp and BCRP substrate and futibatinib is a P-gp and BCRP inhibitor.
Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with ritonavir is necessary. Gefitinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Gemfibrozil: (Contraindicated) 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.
Gilteritinib: (Major) Consider an alternative to ritonavir during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with gilteritinib is necessary. Concurrent use may increase ombitasvir exposure. Ombitasvir is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with gilteritinib is necessary. Concurrent use may increase paritaprevir exposure. Paritaprevir is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor. (Moderate) Monitor for increased dasabuvir-related adverse reactions, including QT prolongation, if coadministered with gilteritinib. Concurrent use may increase dasabuvir exposure. Dasabuvir is a substrate of P-gp and BCRP and gilteritinib is a P-gp and BCRP inhibitor.
Glasdegib: (Major) Consider an alternative to ritonavir during treatment with glasdegib. Concurrent use may increase glasdegib exposure resulting in treatment-related adverse events including QT prolongation. If coadministration cannot be avoided, monitor for increased adverse events; more frequent ECG monitoring is recommended. Glasdegib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
Glecaprevir; Pibrentasvir: (Major) Coadministration of glecaprevir with ritonavir is not recommended as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of CYP3A4 and P-glycoprotein (P-gp); ritonavir is an inhibitor of CYP3A4 and P-gp. Additionally, ritonavir is a P-gp substrate and glecaprevir is a P-gp inhibitor; concentrations of ritonavir may also be increased. (Major) Coadministration of pibrentasvir with ritonavir is not recommended as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of the drug transporter P-glycoprotein (P-gp); ritonavir is an inhibitor of P-gp. Additionally, ritonavir is a P-gp substrate and pibrentasvir is a P-gp inhibitor; concentrations of ritonavir may also be increased. (Moderate) Caution is advised with the coadministration of glecaprevir and dasabuvir as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Dasabuvir is a substrate of P-glycoprotein (P-gp) and a substrate and inhibitor of breast cancer resistance protein (BCRP); glecaprevir is a substrate and inhibitor of P-gp and BCRP. (Moderate) Caution is advised with the coadministration of glecaprevir and ombitasvir as coadministration may increase serum concentrations of ombitasvir and increase the risk of adverse effects. Ombitasvir is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); glecaprevir is an inhibitor of P-gp and BCRP. (Moderate) Caution is advised with the coadministration of glecaprevir and paritaprevir as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Glecaprevir and paritaprevir are both substrates and inhibitors of organic anion transporting polypeptide (OATP) 1B1/3. Additionally, paritaprevir is a substrate of P-glycoprotein (P-gp) and substrate and inhibitor of breast cancer resistance protein (BCRP); glecaprevir is a P-gp inhibitor and a substrate and inhibitor of BCRP. (Moderate) Caution is advised with the coadministration of pibrentasvir and dasabuvir as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Dasabuvir is a substrate of P-glycoprotein (P-gp) and a substrate and inhibitor of breast cancer resistance protein (BCRP); pibrentasvir is an inhibitor of P-gp and a substrate and inhbitor of BCRP. (Moderate) Caution is advised with the coadministration of pibrentasvir and ombitasvir as coadministration may increase serum concentrations of ombitasvir and increase the risk of adverse effects. Ombitasvir is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); pibrentasvir is an inhibitor of P-gp and BCRP. (Moderate) Caution is advised with the coadministration of pibrentasvir and paritaprevir as coadministration may increase serum concentrations of both drugs and increase the risk of adverse effects. Paritaprevir is a substrate of of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and organic anion transporting polypeptide (OATP)1B1/3; pibrentasvir is an inhibitor of all these drug transporters. Additionally, pibrentasvir is a substrate of BCRP while paritaprevir is an inhibitor of BCRP.
Glimepiride: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Glimepiride; Rosiglitazone: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Glipizide: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Glipizide; Metformin: (Major) While no dosage adjustment of metformin is recommended in patients with normal hepatic or renal function, careful patient monitoring and dose adjustment of metformin and/or the potentially interfering drug is recommended with concurrent use. Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Do not use metformin with paritaprevir in patients with renal insufficiency or hepatic impairment. Drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Paritaprevir is an inhibitor of the organic anion transporters OATP1B1 and OATP1B3. While initial drug-drug interaction studies of paritaprevir-containing hepatitis treatments have not noted an effect on metformin concentrations, more study is needed. (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) 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: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Glyburide; Metformin: (Major) While no dosage adjustment of metformin is recommended in patients with normal hepatic or renal function, careful patient monitoring and dose adjustment of metformin and/or the potentially interfering drug is recommended with concurrent use. Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Do not use metformin with paritaprevir in patients with renal insufficiency or hepatic impairment. Drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Paritaprevir is an inhibitor of the organic anion transporters OATP1B1 and OATP1B3. While initial drug-drug interaction studies of paritaprevir-containing hepatitis treatments have not noted an effect on metformin concentrations, more study is needed. (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) 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.
Glycerol Phenylbutyrate: (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with glycerol phenylbutyrate. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and glycerol phenylbutyrate is a weak CYP3A inducer.
Granisetron: (Minor) Plasma concentrations of granisetron may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as gastrointestinal or CNS effects, is recommended during coadministration. Ritonavir is a CYP3A4 inhibitor; granisetron is a CYP3A4 substrate.
Grapefruit juice: (Moderate) 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. (Moderate) 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: (Major) Ritonavir oral solution and capsules contain ethanol. Administration of ritonavir oral solution and capsules to patients receiving or who have recently received griseofulvin may result in disulfiram-like reactions (e.g., abdominal cramps, nausea/vomiting, headaches, and flushing). A disulfiram reaction would not be expected to occur with non-ethanol containing formulations of ritonavir (e.g., tablets or oral powder).
Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ritonavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ritonavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ritonavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ritonavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Guanfacine: (Major) 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.
Haloperidol: (Moderate) Mild to moderate increases in haloperidol plasma concentrations have been reported during concurrent use of haloperidol and inhibitors of CYP3A4 or CYP2D6, such as ritonavir. Elevated haloperidol concentrations may increase the risk of adverse effects. Closely monitor for adverse events when these medications are coadministered.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ritonavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ritonavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydantoins: (Major) Avoid concomitant use of ritonavir and hydantoins. Concomitant use may decrease the exposure of ritonavir and hydantoins, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the hydantoin. A dose increase of the hydantoin may be necessary. Ritonavir is a CYP3A substrate and inducer and hydantoins are CYP3A inducers.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ritonavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ritonavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ritonavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ritonavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like ritonavir can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If ritonavir is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Ibrexafungerp: (Major) Decrease the ibrexafungerp dose to 150 mg PO every 12 hours for 1 day if administered concurrently with ritonavir. Coadministration may result in increased ibrexafungerp exposure and toxicity. Ibrexafungerp is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of ibrexafungerp by 5.8-fold and 2.5-fold, respectively.
Ibrutinib: (Major) Avoid concomitant use of ibrutinib and ritonavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. If ritonavir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like ritonavir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ritonavir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Idelalisib: (Contraindicated) 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. (Major) 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: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with ritonavir is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Ritonavir is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
Iloperidone: (Major) Reduce the iloperidone dose by one-half if coadministered with ritonavir. If ritonavir is discontinued, increase the iloperidone dose to the previous level. Increased iloperidone exposure may occur with concurrent use. Iloperidone is a CYP3A4 substrate. Ritonavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of iloperidone and its metabolites P88 and P95 by 57%, 55% and 35%, respectively.
Imatinib: (Major) Coadministration of dasabuvir and imatinib may result in increased plasma concentrations of dasabuvir and/or imatinib. Dasabuvir is a CYP3A substrate and a BCRP inhibitor; imatinib is a moderate CYP3A4 inhibitor and a BCRP substrate. (Major) 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. (Moderate) Coadministration of paritaprevir and imatinib may result in increased plasma concentrations of paritaprevir and/or imatinib. Paritaprevir is a CYP3A substrate and a BCRP inhibitor; imatinib is a moderate CYP3A4 inhibitor and a BCRP substrate.
Imipramine: (Moderate) A dose reduction of the tricyclic antidepressant (TCA) may be necessary when coadministered with ritonavir. Concurrent use may result in elevated TCA plasma concentrations.
Incretin Mimetics: (Moderate) 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: (Moderate) 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. (Moderate) Although no dosage adjustment of the 75 mcg indacaterol daily dose is needed, use caution if indacaterol and ritonavir are used concurrently. Monitor the patient clinically for beta-agonist side effects like tremor, nervousness, or fast, irregular heart rate. In addition, both ritonavir and long-acting beta agonists (LABAs) are associated with QT prolongation; concomitant use may increase the risk of QT prolongation. 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 exposure (AUC) whereas indacaterol maximal concentration (Cmax) was unaffected.
Indacaterol; Glycopyrrolate: (Moderate) 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. (Moderate) Although no dosage adjustment of the 75 mcg indacaterol daily dose is needed, use caution if indacaterol and ritonavir are used concurrently. Monitor the patient clinically for beta-agonist side effects like tremor, nervousness, or fast, irregular heart rate. In addition, both ritonavir and long-acting beta agonists (LABAs) are associated with QT prolongation; concomitant use may increase the risk of QT prolongation. 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 exposure (AUC) whereas indacaterol maximal concentration (Cmax) was unaffected.
Indinavir: (Minor) 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. (Minor) 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. (Minor) 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.
Infigratinib: (Major) Avoid concomitant use of infigratinib and ritonavir. Coadministration may increase infigratinib exposure, increasing the risk for adverse effects. Infigratinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC of infigratinib by 622%.
Insulin Aspart: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Insulin Aspart; Insulin Aspart Protamine: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Insulin Degludec; Liraglutide: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Insulin Detemir: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Insulin Glargine: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Insulin Glargine; Lixisenatide: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Insulin Glulisine: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Insulin Lispro: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Insulin Lispro; Insulin Lispro Protamine: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Insulin, Inhaled: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Insulins: (Moderate) 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.
Interferons: (Moderate) The concomitant use of interferons and anti-retroviral protease inhibitors should be done with caution as both can cause hepatotoxicity. Closely monitor patients for treatment-associated toxicities, especially hepatic decompensation. Most protease inhibitors have been associated with episodes of liver toxicity. Cirrhotic chronic HCV infected patients co-infected with HIV receiving HAART and alpha interferons appear to be at increased risk for hepatic decompensation (e.g., Childs-Pugh score 6 or more) compared to patients not receiving HAART. 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.
Irinotecan Liposomal: (Major) Avoid administration of dasabuvir during treatment with irinotecan unless there are no therapeutic alternatives. The active metabolite of irinotecan, SN-38, is a UGT1A1 substrate; dasabuvir is a UGT1A1 inhibitor. Concomitant use of UGT1A1 inhibitors may increase systemic exposure to SN-38. (Major) Avoid administration of ombitasvir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are UGT1A1 substrates. Ombitasvir is a UGT1A1 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38. (Major) Avoid administration of paritaprevir during treatment with irinotecan unless there are no therapeutic alternatives. The active metabolite of irinotecan, SN-38, is a UGT1A1 substrate; paritaprevir is a UGT1A1 inhibitor. Concomitant use with UGT1A1 inhibitors may increase systemic exposure to SN-38. (Major) Avoid administration of ritonavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Ritonavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Irinotecan: (Major) Avoid administration of dasabuvir during treatment with irinotecan unless there are no therapeutic alternatives. The active metabolite of irinotecan, SN-38, is a UGT1A1 substrate; dasabuvir is a UGT1A1 inhibitor. Concomitant use of UGT1A1 inhibitors may increase systemic exposure to SN-38. (Major) Avoid administration of ombitasvir d uring treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are UGT1A1 substrates. Ombitasvir is a UGT1A1 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38. (Major) Avoid administration of paritaprevir during treatment with irinotecan unless there are no therapeutic alternatives. The active metabolite of irinotecan, SN-38, is a UGT1A1 substrate; paritaprevir is a UGT1A1 inhibitor. Concomitant use with UGT1A1 inhibitors may increase systemic exposure to SN-38. (Major) Avoid administration of ritonavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. Ritonavir is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Isavuconazonium: (Contraindicated) 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). (Moderate) 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. (Moderate) 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. (Moderate) 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.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Contraindicated) 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. (Contraindicated) 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. (Contraindicated) 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: (Contraindicated) 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. (Contraindicated) 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. (Contraindicated) 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.
Isophane Insulin (NPH): (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Isradipine: (Moderate) 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.
Istradefylline: (Major) Do not exceed 20 mg once daily of istradefylline if administered with ritonavir as istradefylline exposure and adverse effects may increase. Ritonavir is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Itraconazole: (Major) Concurrent administration of itraconazole with dasabuvir is expected to result in elevated dasabuvir plasma concentrations, which increases the risk of adverse events. Itraconazole is an inhibitor of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Dasabuvir is a substrate for P-gp and BCRP. (Major) Concurrent administration of itraconazole with ombitasvir is expected to result in elevated ombitasvir plasma concentrations, which increases the risk of adverse events. Itraconazole is an inhibitor of the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Ombitasvir is a substrate for P-gp and BCRP. (Major) Concurrent administration of itraconazole with paritaprevir is expected to result in elevated paritaprevir plasma concentrations, which increases the risk of adverse events. Itraconazole is a strong inhibitor of the enzyme CYP3A4 and the drug transporters P-glycoprotein (P-gp) and breast cancer resistance protein. Paritaprevir is a substrate for CYP3A4, P-gp, and BCRP. (Major) When administering itraconazole with ritonavir or ritonavir-containing drugs, do not exceed the maximum recommended itraconazole dose of 200 mg per day. Concurrent administration may result in increased exposure to both drugs. Monitor patients for itraconazole and ritonavir-associated adverse effects. Both itraconazole and ritonavir are strong CYP3A4 inhibitors and substrates.
Ivabradine: (Contraindicated) 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: (Major) If ritonavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with ritonavir due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If ritonavir is discontinued, wait at least 5 half-lives of ritonavir before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Ixabepilone: (Major) Avoid concurrent use of ixabepilone and ritonavir due to increased ixabepilone exposure, which may increase the risk of adverse reactions. If concomitant use is unavoidable, reduce the dose of ixabepilone to 20 mg/m2. Ixabepilone is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ixabepilone exposure by 79%.
Ketamine: (Moderate) Use caution if ritonavir is coadministered with ketamine due to the potential for increased ketamine exposure which may increase the risk of toxicity. Ketamine is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor.
Ketoconazole: (Major) Avoid ritonavir for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of ketoconazole and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for ketoconazole-related adverse reactions; a ketoconazole dose reduction may be necessary. Ketoconazole is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor.
Labetalol: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
Lacosamide: (Moderate) 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: (Minor) 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.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) 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. (Moderate) 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.
Lamotrigine: (Major) 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%. (Moderate) 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.
Lansoprazole: (Moderate) Increased exposure to lansoprazole may occur during concurrent administration of ritonavir. Although dosage adjustment of lansoprazole is not normally required, dosage reduction may be considered in patients receiving higher lansoprazole doses (e.g., those with Zollinger-Ellison syndrome). Ritonavir is a strong CYP3A4 inhibitor. Lansoprazole is a CYP2C19 and CYP3A4 substrate. Coadministration of a dual CYP2C19/strong CYP3A4 inhibitor increased the lansoprazole AUC by an average of 4-times.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Because the exposure to 14-OH clarithromycin is significantly decreased by ritonavir, consider alternative antibiotic therapy for indications other than Mycobacterium avium. Clarithromycin doses above 1000 mg should not be administered with ritonavir. If coadministration cannot be avoided, clarithromycin dosage reductions are recommended in patients with renal impairment (CrCl 30 to 60 mL/minute, decrease clarithromycin by 50%; CrCl less than 30 mL/minute, decrease clarithromycin by 75%). Concomitant administration of ritonavir and clarithromycin resulted in a 77% increase in clarithromycin exposure and a 100% decrease in 14-OH clarithromycin exposure. The microbiological activities of clarithromycin and 14-OH-clarithromycin are different for different bacteria. (Moderate) Caution is advised when administering clarithromycin concurrently with dasabuvir. Use of these drugs together may result in elevated concentrations of dasabuvir. Clarithromycin is an inhibitor of P-glycoprotein (P-gp). Dasabuvir is a substrate of P-gp. (Moderate) Caution is advised when administering clarithromycin concurrently with ombitasvir. Use of these drugs together may result in elevated concentrations of ombitasvir. Clarithromycin is an inhibitor of P-glycoprotein (P-gp). Ombitasvir is a substrate of P-gp. (Moderate) Caution is advised when administering clarithromycin concurrently with paritaprevir. Use of these drugs together may result in elevated concentrations of paritaprevir. Clarithromycin is an inhibitor of CYP3A4 and P-glycoprotein (P-gp). Paritaprevir is a substrate of CYP3A4 and P-gp. (Moderate) Increased exposure to lansoprazole may occur during concurrent administration of ritonavir. Although dosage adjustment of lansoprazole is not normally required, dosage reduction may be considered in patients receiving higher lansoprazole doses (e.g., those with Zollinger-Ellison syndrome). Ritonavir is a strong CYP3A4 inhibitor. Lansoprazole is a CYP2C19 and CYP3A4 substrate. Coadministration of a dual CYP2C19/strong CYP3A4 inhibitor increased the lansoprazole AUC by an average of 4-times.
Lansoprazole; Naproxen: (Moderate) Increased exposure to lansoprazole may occur during concurrent administration of ritonavir. Although dosage adjustment of lansoprazole is not normally required, dosage reduction may be considered in patients receiving higher lansoprazole doses (e.g., those with Zollinger-Ellison syndrome). Ritonavir is a strong CYP3A4 inhibitor. Lansoprazole is a CYP2C19 and CYP3A4 substrate. Coadministration of a dual CYP2C19/strong CYP3A4 inhibitor increased the lansoprazole AUC by an average of 4-times.
Lanthanum Carbonate: (Major) 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: (Major) Avoid coadministration of lapatinib with ritonavir due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If ritonavir is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased lapatinib exposure by 3.6-fold and increased the half-life of lapatinib by 1.7-fold. (Major) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with lapatinib is necessary. Ombitasvir is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. (Moderate) Monitor for an increase in dasabuvir-related adverse reactions if coadministration with lapatinib is necessary. Dasabuvir is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor. Increased plasma concentrations of dasabuvir may occur. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with lapatinib is necessary. Paritaprevir is a P-glycoprotein (P-gp) substrate and lapatinib is a P-gp inhibitor.
Larotrectinib: (Major) Avoid coadministration of larotrectinib with ritonavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If ritonavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of ritonavir. Larotrectinib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of larotrectinib by 4.3-fold in a drug interaction study.
Lasmiditan: (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with lasmiditan is necessary. Concurrent use may increase paritaprevir exposure. Paritaprevir is a P-gp substrate and lasmiditan is a P-gp inhibitor.
Ledipasvir; Sofosbuvir: (Moderate) 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. (Moderate) 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. (Moderate) 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.
Lefamulin: (Major) Avoid coadministration of ritonavir with oral lefamulin due to increased lefamulin exposure; ritonavir may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate and ritonavir is a P-gp and strong CYP3A4 inhibitor. Coadministration of a combined P-gp and strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively.
Lemborexant: (Major) Avoid coadministration of lemborexant and ritonavir as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse CNS effects. Lemborexant is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of lemborexant with another strong CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold.
Lenacapavir: (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with lenacapavir is necessary. Concurrent use may increase paritaprevir exposure. Paritaprevir is a P-gp and BCRP substrate and lenacapavir is a P-gp and BCRP inhibitor.
Leniolisib: (Major) Avoid concomitant use of leniolisib and ritonavir due to the risk for increased leniolisib exposure which may increase the risk for adverse effects. Leniolisib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased leniolisib overall exposure by 2-fold. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with leniolisib is necessary. Concurrent use may increase paritaprevir exposure. Paritaprevir is a substrate of BCRP and OATP1B1/3 and leniolisib is an inhibitor of BCRP and OATP1B1/3.
Lente Insulin: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Lesinurad: (Moderate) 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.
Lesinurad; Allopurinol: (Moderate) 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.
Letermovir: (Moderate) A clinically relevant increase in the plasma concentration of ritonavir may occur if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. Ritonavir is primarily metabolized by CYP3A. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. (Moderate) Administering paritaprevir concurrently with letermovir may result in elevated concentrations of both drugs. The magnitude of this interaction may be increased in patients who are also receiving cyclosporine. Closely monitor for adverse events, including tachycardia, atrial fibrillation, hepatotoxicity, and gastrointestinal events. Both paritaprevir and letermovir are substrates and inhibitors of the organic anion-transporting polypeptides (OATP1B1/3). Paritaprevir is also primarily metabolized by CYP3A4. Letermovir is a moderate CYP3A4 inhibitor; however, when given with cyclosporine, the combined effect on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. In addition, cyclosporine is an OATP1B1 inhibitor, which could further amplify this interaction. (Moderate) Plasma concentrations of dasabuvir could be increased when administered concurrently with letermovir. If these drugs are given together, closely monitor for dasabuvir-related adverse events. Letermovir is an inhibitor of CYP2C8; dasabuvir is primarily metabolized by CYP2C8.
Leuprolide; Norethindrone: (Moderate) 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.
Levamlodipine: (Moderate) 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.
Levocetirizine: (Moderate) 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.
Levoketoconazole: (Major) Avoid ritonavir for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of ketoconazole and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for ketoconazole-related adverse reactions; a ketoconazole dose reduction may be necessary. Ketoconazole is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor.
Levomilnacipran: (Major) 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: (Major) 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.
Levonorgestrel; Ethinyl Estradiol: (Contraindicated) 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. (Contraindicated) 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. (Major) 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. (Major) 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.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Contraindicated) 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. (Contraindicated) 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. (Major) 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. (Major) 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.
Levorphanol: (Moderate) Ritonavir is an inhibitor of the cytochrome P450 3A4 isoenzyme and may decrease the metabolism of levorphanol if the two drugs are coadministered.
Lidocaine: (Moderate) 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.
Lidocaine; Epinephrine: (Moderate) 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.
Lidocaine; Prilocaine: (Moderate) 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: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) Monitor for changes in glycemic control, specifically hyperglycemia, if ritonavir is administered concurrently with 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.
Linagliptin; Metformin: (Major) While no dosage adjustment of metformin is recommended in patients with normal hepatic or renal function, careful patient monitoring and dose adjustment of metformin and/or the potentially interfering drug is recommended with concurrent use. Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Do not use metformin with paritaprevir in patients with renal insufficiency or hepatic impairment. Drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Paritaprevir is an inhibitor of the organic anion transporters OATP1B1 and OATP1B3. While initial drug-drug interaction studies of paritaprevir-containing hepatitis treatments have not noted an effect on metformin concentrations, more study is needed. (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) Monitor for changes in glycemic control, specifically hyperglycemia, if ritonavir is administered concurrently with 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. (Moderate) 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.
Liraglutide: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Lisdexamfetamine: (Moderate) Warn patients that the risk of amphetamine toxicity may be increased during concurrent use of ritonavir, a strong CYP2D6 inhibitor. Amphetamines are partially metabolized by CYP2D6 and have serotonergic properties; inhibition of amphetamine metabolism may increase the risk of serotonin syndrome or other toxicity. If serotonin syndrome occurs, both the amphetamine and CYP2D6 inhibitor should be discontinued and appropriate medical treatment should be implemented.
Lixisenatide: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Lomitapide: (Contraindicated) 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.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and ritonavir is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; ritonavir is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%. (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with lonafarnib is necessary. Concurrent use may increase ombitasvir exposure. Ombitasvir is a P-gp substrate and lonafarnib is a P-gp inhibitor. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with lonafarnib is necessary. Paritaprevir is a CYP3A4 and P-gp substrate and lonafarnib is a P-gp and strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased paritaprevir exposure by 2.2- to 2.9-fold. (Moderate) Monitor for increased dasabuvir-related adverse reactions, including QT prolongation, if coadministered with lonafarnib. Concurrent use may increase dasabuvir exposure. Dasabuvir is a P-gp substrate and lonafarnib is a P-gp inhibitor.
Loperamide: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with ritonavir. Concurrent use may increase loperamide exposure. Loperamide is a CYP3A4 and P-gp substrate and ritonavir is a strong CYP3A4 and P-gp inhibitor. Coadministration with ritonavir increased loperamide plasma concentrations by 2- to 3-fold.
Loperamide; Simethicone: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with ritonavir. Concurrent use may increase loperamide exposure. Loperamide is a CYP3A4 and P-gp substrate and ritonavir is a strong CYP3A4 and P-gp inhibitor. Coadministration with ritonavir increased loperamide plasma concentrations by 2- to 3-fold.
Lopinavir; Ritonavir: (Major) 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.
Lorazepam: (Moderate) Monitor for an increase in lorazepam-related adverse reactions and consider reducing the dose of lorazepam if concomitant use of lorazepam and dasabuvir is necessary. Avoid lorazepam extended-release capsules and utilize lorazepam immediate-release dosage forms that can be easily titrated. Lorazepam is an UGT substrate and dasabuvir is an UGT inhibitor. (Moderate) Monitor for an increase in lorazepam-related adverse reactions and consider reducing the dose of lorazepam if concomitant use of lorazepam and ombitasvir is necessary. Avoid lorazepam extended-release capsules and utilize lorazepam immediate-release dosage forms that can be easily titrated. Lorazepam is an UGT substrate and ombitasvir is an UGT inhibitor. (Moderate) Monitor for an increase in lorazepam-related adverse reactions and consider reducing the dose of lorazepam if concomitant use of lorazepam and paritaprevir is necessary. Avoid lorazepam extended-release capsules and utilize lorazepam immediate-release dosage forms that can be easily titrated. Lorazepam is an UGT substrate and paritaprevir is an UGT inhibitor.
Lorlatinib: (Major) Avoid coadministration of lorlatinib with ritonavir due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions. Ritonavir plasma concentrations may also decrease, leading to reduced efficacy and increasing the potential for viral resistance. If concomitant use is unavoidable, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. If ritonavir is discontinued, resume the original dose of lorlatinib after 3 half-lives of ritonavir. Lorlatinib is a CYP3A substrate and moderate inducer. Ritonavir is a CYP3A4 substrate and strong inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
Losartan: (Moderate) 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.
Losartan; Hydrochlorothiazide, HCTZ: (Moderate) 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: (Contraindicated) 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: (Contraindicated) 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: (Contraindicated) 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. (Major) 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 or 1 packet of oral granules every other day 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 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: (Major) If ritonavir and ivacaftor are taken together, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly. Coadministration is not recommended in patients younger than 6 months. Ivacaftor is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) 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 or 1 packet of oral granules every other day 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 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.
Lumateperone: (Major) Avoid coadministration of lumateperone and dasabuvir as concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a UGT1A1 substrate; dasabuvir is a UGT1A1 inhibitor. (Major) Avoid coadministration of lumateperone and ombitasvir as concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a UGT1A1 substrate; ombitasvir is a UGT1A1 inhibitor. (Major) Reduce the dose of lumateperone to 10.5 mg once daily if concomitant use of ritonavir is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor increased lumateperone exposure by approximately 4-fold.
Lurasidone: (Contraindicated) 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.
Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and ritonavir due to the risk of increased lurbinectedin exposure which may increase the incidence of lurbinectedin-related adverse reactions. Lurbinectedin is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor.
Macitentan: (Major) 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: (Moderate) 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. Adjust the dosage of maprotiline based on therapeutic response. Maprotiline serum concentration monitoring may be useful to guide adjustments and prevent toxicity.
Maraviroc: (Major) Coadministration of maraviroc (a substrate of CYP3A, P-gp, MRP2) with ritonavir (a strong CYP3A4 inhibitor and P-gp/MRP2 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; children weighing 2 to 9 kg: use not recommended. (Moderate) Use caution and closely monitor for increased adverse effects during concurrent administration of maraviroc and paritaprevir as increased maraviroc concentrations may occur. Maraviroc is a substrate of organic anion-transporting polypeptide (OATP1B1); paritaprevir is an inhibitor of OATP1B1. The effects of this transporter on the concentrations of maraviroc are unknown, although an increase in concentrations and thus, toxicity, are possible.
Maribavir: (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with maribavir is necessary. Concurrent use may increase ombitasvir exposure. Ombitasvir is a P-gp and BCRP substrate and maribavir is a P-gp and BCRP inhibitor. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with maribavir is necessary. Concurrent use may increase paritaprevir exposure. Paritaprevir is a P-gp and BCRP substrate and maribavir is a P-gp and BCRP inhibitor. (Moderate) Monitor for increased dasabuvir-related adverse reactions, including QT prolongation, if coadministered with maribavir. Concurrent use may increase dasabuvir exposure. Dasabuvir is a P-gp and BCRP substrate and maribavir is a P-gp and BCRP inhibitor.
Mavacamten: (Contraindicated ) Coadministration of paritaprevir with mavacamten is contraindicated due to the potential for decreased paritaprevir concentrations and the potential development of viral resistance. Paritaprevir is metabolized by CYP3A and mavacamten is a moderate CYP3A inducer. (Contraindicated) Mavacamten is contraindicated for use with ritonavir due to risk of heart failure due to systolic dysfunction. Concomitant use increases mavacamten exposure and may decrease plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mavacamten is a substrate and moderate inducer of CYP3A and ritonavir is a substrate and strong inhibitor of CYP3A. Concomitant use with a strong CYP3A inhibitor is predicted to increase mavacamten overall exposure up to 130%.
Meclizine: (Moderate) 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: (Major) 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: (Major) 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. (Moderate) The plasma concentrations of mefloquine may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as GI or neuropsychiatric effects, is recommended during coadministration. Ritonavir is a strong inhibitor of CYP3A4 and P-glycoprotein (P-gp) inhibitor, while mefloquine is a CYP3A4 and P-gp substrate.
Meloxicam: (Moderate) 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: (Contraindicated) 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: (Contraindicated) 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.
Mestranol; Norethindrone: (Contraindicated) 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. (Contraindicated) 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. (Major) 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. (Moderate) 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.
Metformin: (Major) While no dosage adjustment of metformin is recommended in patients with normal hepatic or renal function, careful patient monitoring and dose adjustment of metformin and/or the potentially interfering drug is recommended with concurrent use. Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Do not use metformin with paritaprevir in patients with renal insufficiency or hepatic impairment. Drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Paritaprevir is an inhibitor of the organic anion transporters OATP1B1 and OATP1B3. While initial drug-drug interaction studies of paritaprevir-containing hepatitis treatments have not noted an effect on metformin concentrations, more study is needed. (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) 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: (Major) While no dosage adjustment of metformin is recommended in patients with normal hepatic or renal function, careful patient monitoring and dose adjustment of metformin and/or the potentially interfering drug is recommended with concurrent use. Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Do not use metformin with paritaprevir in patients with renal insufficiency or hepatic impairment. Drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Paritaprevir is an inhibitor of the organic anion transporters OATP1B1 and OATP1B3. While initial drug-drug interaction studies of paritaprevir-containing hepatitis treatments have not noted an effect on metformin concentrations, more study is needed. (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) Coadministration of repaglinide and protease inhibitors may increase or decrease glucose concentrations and increase repaglinide AUC; if coadministration is necessary, repaglinide dosage adjustment may be necessary and increased frequency of glucose monitoring is 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. In addition, repaglinide is a substrate of the hepatic isoenzyme CYP3A4 and the drug transporter organic anion transporting polypeptide (OATP1B1); protease inhibitors are potent CYP3A4 inhibitors and inhibitors of OATP. (Moderate) 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. (Moderate) 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; Rosiglitazone: (Major) While no dosage adjustment of metformin is recommended in patients with normal hepatic or renal function, careful patient monitoring and dose adjustment of metformin and/or the potentially interfering drug is recommended with concurrent use. Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Do not use metformin with paritaprevir in patients with renal insufficiency or hepatic impairment. Drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Paritaprevir is an inhibitor of the organic anion transporters OATP1B1 and OATP1B3. While initial drug-drug interaction studies of paritaprevir-containing hepatitis treatments have not noted an effect on metformin concentrations, more study is needed. (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) 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: (Major) 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. (Major) While no dosage adjustment of metformin is recommended in patients with normal hepatic or renal function, careful patient monitoring and dose adjustment of metformin and/or the potentially interfering drug is recommended with concurrent use. Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Do not use metformin with paritaprevir in patients with renal insufficiency or hepatic impairment. Drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Paritaprevir is an inhibitor of the organic anion transporters OATP1B1 and OATP1B3. While initial drug-drug interaction studies of paritaprevir-containing hepatitis treatments have not noted an effect on metformin concentrations, more study is needed. (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) 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: (Major) While no dosage adjustment of metformin is recommended in patients with normal hepatic or renal function, careful patient monitoring and dose adjustment of metformin and/or the potentially interfering drug is recommended with concurrent use. Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Do not use metformin with paritaprevir in patients with renal insufficiency or hepatic impairment. Drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Paritaprevir is an inhibitor of the organic anion transporters OATP1B1 and OATP1B3. While initial drug-drug interaction studies of paritaprevir-containing hepatitis treatments have not noted an effect on metformin concentrations, more study is needed. (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) 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. (Moderate) 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: (Moderate) Coadministration of ritonavir with methadone has resulted in decreased methadone plasma concentrations. However, because methadone is metabolized by multiple CYP450 enzymes, including CYP3A4, CYP2C19, CYP2C9, and CYP2D6, and ritonavir is known to inhibit CYP3A4 and CYP2D6 and induce CYP2C19 and CYP2C9, the potential for increased methadone exposure should also be considered with concomitant administration. Therefore, concurrent use may increase or prolong opioid effects, resulting in fatal overdose or may decrease methadone efficacy or produce onset of withdrawal symptoms in patients physically dependent on methadone. Monitor for respiratory depression, sedation, and signs of opioid withdrawal. Consider adjusting the methadone dose until stable drug effects are achieved. If ritonavir is discontinued, and its CYP450 effects decline, methadone plasma concentrations may increase or decrease. Closely monitor for increased opioid adverse effects and for evidence of withdrawal and adjust the methadone dose as necessary when ritonavir is discontinued.
Methamphetamine: (Moderate) Warn patients that the risk of amphetamine toxicity may be increased during concurrent use of ritonavir, a strong CYP2D6 inhibitor. Amphetamines are partially metabolized by CYP2D6 and have serotonergic properties; inhibition of amphetamine metabolism may increase the risk of serotonin syndrome or other toxicity. If serotonin syndrome occurs, both the amphetamine and CYP2D6 inhibitor should be discontinued and appropriate medical treatment should be implemented.
Methohexital: (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers.
Methylergonovine: (Contraindicated) 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: (Moderate) Monitor for corticosteroid-related adverse events if methylprednisolone is used with ritonavir. Concurrent use may increase the exposure of methylprednisolone. Methylprednisolone is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Other strong CYP3A4 inhibitors have been reported to decrease the metabolism of certain corticosteroids by up to 60%.
Metoclopramide: (Moderate) 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: (Moderate) 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.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) 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: (Major) Medications with significant alcohol content should not be ingested during therapy with metronidazole and should be avoided for 3 days after therapy is discontinued. Ritonavir oral solution and capsules contain ethanol. Administration of ritonavir oral solution or capsules 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 of ritonavir (e.g., tablets, oral powder).
Mexiletine: (Major) 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: (Major) The use of oral midazolam and anti-retroviral protease inhibitors is contraindicated due to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression. 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. Lorazepam, oxazepam, or temazepam may be safer alternatives, as these benzodiazepines are not oxidatively metabolized. Midazolam is metabolized by hepatic isozyme CYP3A4. Protease inhibitors have been shown to increase oral midazolam AUCs by up to 3-fold, resulting in clinically significant potentiation of sedation.
Midostaurin: (Major) Avoid the concomitant use of midostaurin and ritonavir due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone. (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with midostaurin is necessary. Concurrent use may increase ombitasvir exposure. Ombitasvir is a BCRP substrate and midostaurin is a BCRP inhibitor. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with midostaurin is necessary. Concurrent use may increase paritaprevir exposure. Paritaprevir is a BCRP and OATP1B1 substrate and midostaurin is a BCRP and OATP1B1 inhibitor. (Moderate) Monitor for increased dasabuvir-related adverse reactions, including QT prolongation, if coadministered with midostaurin. Concurrent use may increase dasabuvir exposure. Dasabuvir is a BCRP substrate and midostaurin is a BCRP inhibitor.
Mifepristone: (Major) Caution is advised when administering ritonavir with mifepristone because increased serum concentrations of either drug may occur. When mifepristone is used in the treatment of Cushing's syndrome, coadministration with ritonavir should be done only when necessary, and in such cases the dose of mifepristone should be limited to a maximum dose of 900 mg per day. In a patient already receiving ritonavir, initiate mifepristone at a dose of 300 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with ritonavir is initiated in a patient already receiving mifepristone 300 mg, 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 900 mg, reduce dose of mifepristone to 600 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with ritonavir is initiated in a patient already receiving 1,200 mg, reduce the mifepristone dose to 900 mg. Both mifepristone and ritonavir are substrates and strong inhibitors of CYP3A4. (Major) Elevated ombitasvir concentrations may result if mifepristone is coadministered chronically. If these drugs must be used together, closely monitor the patient for antiviral-related adverse events. Because ombitasvir is used in drug regimens that may reduce the clearance of mifepristone and increase the risk for QT prolongation, dosage reduction of mifepristone is necessary with certain medications. The response to mifepristone, when used chronically for hormonal conditions like Cushing's syndrome, requires careful monitoring. Consult the mifepristone package insert/product labeling for appropriate dose reduction. Mifepristone is a CYP3A4 inhibitor and substrate and may be a P-glycoprotein (P-gp) inhibitor. Ombitasvir is a P-gp substrate. Inhibition of P-gp may increase the plasma concentrations of ombitasvir. (Major) Elevated paritaprevir concentrations may result if mifepristone is coadministered chronically. If these drugs must be used together, closely monitor the patient for antiviral-related adverse events. Because paritaprevir is used in drug regimens that may reduce the clearance of mifepristone and increase the risk for QT prolongation, dosage reduction of mifepristone is necessary with certain medications. The response to mifepristone, when used chronically for hormonal conditions like Cushing's syndrome, requires careful monitoring. Consult the mifepristone package insert/product labeling for appropriate dose reduction. Mifepristone is a CYP3A4 inhibitor and may inhibit P-glycoprotein (P-gp). Paritaprevir is a CYP3A4 and P-gp substrate. (Major) Use is not recommended. Dasabuvir is primarily metabolized by CYP2C8 and mifepristone may significantly inhibit CYP2C8 and may increase dasabuvir plasma concentrations and risk for adverse effects, including QT prolongation. Dasabuvir is primarily metabolized by CYP2C8 enzymes and is contraindicated with drugs that are strong inhibitors of CYP2C8. Consider alternatives to chronic mifepristone therapy in patients receiving dasabuvir. Due to the slow elimination of mifepristone from the body, interactions that occur may be prolonged. If use together cannot be avoided, patients should be closely monitored for dasabuvir-related adverse effects, such as nausea, liver problems, skin rash, trouble sleeping, unusual tiredness or weakness, and QT prolongation.
Miglitol: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) 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: (Moderate) Concurrent administration of mirabegron with ritonavir may result in elevated plasma concentrations of ritonavir. Mirabegron is a moderate inhibitor of CYP2D6. Ritonavir is a CYP2D6 substrate. Caution and close monitoring are advised if these drugs are administered together.
Mirtazapine: (Moderate) The plasma concentrations of mirtazapine may be elevated when administered concurrently with ritonavir. Clinical monitoring for adverse effects, such as CNS or GI effects, is recommended during coadministration. Ritonavir is a strong CYP3A4 inhibitor, while mirtazapine is a CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased mirtazapine exposure by approximately 50%.
Mirvetuximab Soravtansine: (Moderate) Closely monitor for mirvetuximab soravtansine-related adverse reactions if concomitant use of ritonavir is necessary. DM4, the cytotoxic component of mirvetuximab soravtansine, is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant use may increase unconjugated DM4 exposure.
Mitapivat: (Major) Avoid coadministration of mitapivat with ritonavir due to increased risk of adverse reactions from mitapivat. Coadministration increases mitapivat concentrations and may decrease ritonavir concentrations leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mitapivat is a CYP3A substrate and weak inducer and ritonavir is a CYP3A substrate and strong inhibitor. Concomitant use with other strong CYP3A inhibitors increased mitapivat overall exposure by 3.6 to 4.9-fold. (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with mitapivat is necessary. Concurrent use may increase ombitasvir exposure. Ombitasvir is a P-gp substrate and mitapivat is a P-gp inhibitor. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with mitapivat is necessary. Concurrent use may increase paritaprevir exposure. Paritaprevir is a P-gp substrate and mitapivat is a P-gp inhibitor. (Moderate) Monitor for increased dasabuvir-related adverse reactions, including QT prolongation, if coadministered with mitapivat. Concurrent use may increase dasabuvir exposure. Dasabuvir is a P-gp substrate and mitapivat is a P-gp inhibitor.
Mitotane: (Contraindicated) 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. (Contraindicated) 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. (Major) 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.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and ritonavir. Concomitant use may increase mobocertinib exposure and the risk for adverse reactions such as QT prolongation. Mobocertinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Use of a strong CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 374% to 419%.
Modafinil: (Contraindicated) 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. (Contraindicated) 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. (Major) 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: (Moderate) 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.
Morphine: (Moderate) 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: (Moderate) 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: (Moderate) Concomitant use of ritonavir with moxifloxacin may increase ritonavir adverse effects. After 3 days of ritonavir 400 mg twice daily plus moxifloxacin (400 mg once daily), 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: (Moderate) 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: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
Nafcillin: (Major) 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. (Major) 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.
Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with ritonavir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a substrate of CYP3A4 and P-gp; ritonavir is a moderate P-gp inhibitor and a strong CYP3A4 inhibitor.
Naloxegol: (Contraindicated) Concomitant use of naloxegol with ritonavir is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as ritonavir, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with ritonavir is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
Nanoparticle Albumin-Bound Sirolimus: (Contraindicated) 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. (Major) 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.
Naproxen; Esomeprazole: (Moderate) 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.
Nateglinide: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) Concurrent administration of nateglinide with some protease inhibitors may result in elevated nateglinide plasma concentrations via inhibition of CYP2C9. Ritonavir may induce CYP2C9 leading to a reduction of nateglinide concentrations. Monitor blood glucose concentrations during coadministration as hypoglycemia or hyperglycemia could occur. 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: (Moderate) 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: (Moderate) 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. (Moderate) 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. (Minor) 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: (Major) 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. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with nefazodone is necessary. Paritaprevir is a CYP3A substrate and nefazodone is a strong CYP3A inhibitor. Coadministration with other strong CYP3A inhibitors increased paritaprevir exposure by 2.2- to 2.9-fold.
Nelfinavir: (Moderate) Concurrent administration of nelfinavir with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated plasma concentrations of nelfinavir, dasabuvir, ombitasvir, paritaprevir and ritonavir. If these drugs are given together, closely monitor patients for adverse effects. Both ritonavir and nelfinavir are potent inhibitors and substrates of CYP3A4; paritaprevir and dasabuvir (minor) are CYP3A4 substrates. In addition, dasabuvir, ombitasvir paritaprevir, and ritonavir are all P-gp substrates while nelfinavir and ritonavir are P-gp inhibitors. (Moderate) 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. (Moderate) 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).
Neratinib: (Major) Avoid concomitant use of ritonavir with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations. (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with neratinib is necessary. Concurrent use may increase ombitasvir exposure. Ombitasvir is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with neratinib is necessary. Paritaprevir is a P-glycoprotein (P-gp) substrate. Neratinib is a P-gp inhibitor. (Moderate) Monitor for increased dasabuvir-related adverse reactions, including QT prolongation, if coadministered with neratinib. Concurrent use may increase dasabuvir exposure. Dasabuvir is a P-glycoprotein (P-gp) substrate and neratinib is a P-gp inhibitor.
Netupitant, Fosnetupitant; Palonosetron: (Major) 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. (Moderate) Coadministration may result in increased netupitant and ritonavir exposure. Netupitant is a CYP3A4 substrate and moderate inhibitor of CYP3A4; the inhibitory effect on CYP3A4 can last for multiple days. Ritonavir is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased netupitant exposure by 140%. No dosage adjustment is necessary.
Nevirapine: (Major) Avoid concurrent use of nevirapine and dasabuvir; ombitasvir; paritaprevir; ritonavir. Concomitant use may 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 weak inducer of CYP3A; ritonavir is a substrate and potent inhibitor of this enzyme. Paritaprevir and dasabuvir (minor) are also metabolized by CYP3A. (Major) Avoid concurrent use of nevirapine and dasabuvir; ombitasvir; paritaprevir; ritonavir. Concomitant use may 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 weak inducer of CYP3A; ritonavir is a substrate and potent inhibitor of this enzyme. Paritaprevir and dasabuvir (minor) are also metabolized by CYP3A. (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with nevirapine. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Additionally, monitor for an increase in nevirapine-related adverse reactions if coadministration with ritonavir is necessary. Ritonavir is a CYP3A substrate and strong CYP3A inhibitor; nevirapine is a CYP3A substrate and weak CYP3A inducer. Coadministration with a moderate CYP3A4 inhibitor increased nevirapine exposure by 100%; concomitant use with a strong CYP3A4 inhibitor may also increase nevirapine exposure.
Niacin; Simvastatin: (Contraindicated) Coadministration of paritaprevir may increase simvastatin exposure. Paritaprevir is an inhibitor of OATP1B1/3; simvastatin is a substrate of OATP1B1/3. (Contraindicated) 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: (Moderate) 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: (Major) 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.
Nilotinib: (Major) Avoid the concomitant use of nilotinib and ritonavir. If coadministration is required, monitor patients closely for prolongation of the QT interval and reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML. If ritonavir is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate and moderate inhibitor of CYP3A4 and ritonavir is a substrate and a strong inhibitor of CYP3A4.
Nimodipine: (Moderate) 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: (Moderate) Dual inhibitors of P-glycoprotein (P-gp) and CYP3A4, such as ritonavir, are expected to increase the exposure and clinical effect of nintedanib. If use together is necessary, closely monitor for increased nintedanib side effects including gastrointestinal toxicity (nausea, vomiting, diarrhea, abdominal pain, loss of appetite), headache, elevated liver enzymes, and hypertension. A dose reduction, interruption of therapy, or discontinuation of nintedanib therapy may be necessary. Ritonavir is a potent CYP3A4 inhibitor and a P-gp inhibitor; nintedanib is a P-gp substrate and a minor CYP3A4 substrate. In drug interactions studies, administration of nintedanib with a dual P-gp and CYP3A4 inhibitor increased nintedanib AUC by 60%.
Nisoldipine: (Moderate) 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 Acetate; Ethinyl Estradiol; Ferrous fumarate: (Contraindicated) 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. (Contraindicated) 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. (Major) 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. (Moderate) 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.
Norethindrone: (Moderate) 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 concen trations. 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.
Norethindrone; Ethinyl Estradiol: (Contraindicated) 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. (Contraindicated) 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. (Major) 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. (Moderate) 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.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Contraindicated) 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. (Contraindicated) 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. (Major) 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. (Moderate) 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.
Norgestimate; Ethinyl Estradiol: (Contraindicated) 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. (Contraindicated) 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. (Major) 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.
Nortriptyline: (Moderate) A dose reduction of the tricyclic antidepressant (TCA) may be necessary when coadministered with ritonavir. Concurrent use may result in elevated TCA plasma concentrations.
Odevixibat: (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with odevixibat. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and odevixibat is a weak CYP3A inducer.
Olanzapine: (Moderate) 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.
Olanzapine; Fluoxetine: (Major) 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. (Major) 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. (Moderate) A dose reduction of fluoxetine may ne necessary if coadministered with ritonavir. Increased fluoxetine exposure may occur. Cardiac and neurologic events have been reported when ritonavir has been administered with fluoxetine. (Moderate) 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.
Olanzapine; Samidorphan: (Moderate) 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.
Olaparib: (Major) Avoid coadministration of olaparib with ritonavir due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 100 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after ritonavir is discontinued. Olaparib is a CYP3A substrate and ritonavir is a strong CYP3A4 inhibitor; concomitant use may increase olaparib exposure. Coadministration with another strong CYP3A inhibitor increased the olaparib Cmax by 42% and the AUC by 170%.
Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and ritonavir is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and ritonavir may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If ritonavir is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) 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.
Olodaterol: (Moderate) 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.
Olopatadine; Mometasone: (Moderate) 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.
Olutasidenib: (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with olutasidenib. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and olutasidenib is a weak CYP3A inducer.
Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and ritonavir. If concomitant use is necessary, decrease omaveloxolone dose to 50 mg once daily. Concomitant use may increase omaveloxolone exposure and the risk for omaveloxolone-related adverse effects. Additionally, monitor for decreased efficacy of ritonavir as concomitant use may decrease ritonavir exposure. Omaveloxolone is a CYP3A substrate and weak CYP3A inducer and ritonavir is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased omaveloxolone overall exposure by 4-fold.
Omeprazole: (Moderate) 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. (Moderate) Increased exposure to omeprazole may occur during concurrent administration of ritonavir. Although dosage adjustment of omeprazole is not normally required, dosage reduction may be considered in patients receiving higher omeprazole doses (e.g., those with Zollinger-Ellison syndrome). Ritonavir is a strong CYP3A4 inhibitor. Omeprazole is a CYP2C19 and CYP3A4 substrate. Coadministration of a dual CYP2C19/strong CYP3A4 inhibitor increased the omeprazole AUC by an average of 4-times.
Omeprazole; Amoxicillin; Rifabutin: (Contraindicated) 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. (Contraindicated) 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. (Major) 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. (Moderate) 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. (Moderate) Increased exposure to omeprazole may occur during concurrent administration of ritonavir. Although dosage adjustment of omeprazole is not normally required, dosage reduction may be considered in patients receiving higher omeprazole doses (e.g., those with Zollinger-Ellison syndrome). Ritonavir is a strong CYP3A4 inhibitor. Omeprazole is a CYP2C19 and CYP3A4 substrate. Coadministration of a dual CYP2C19/strong CYP3A4 inhibitor increased the omeprazole AUC by an average of 4-times.
Omeprazole; Sodium Bicarbonate: (Moderate) 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. (Moderate) 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. (Moderate) Increased exposure to omeprazole may occur during concurrent administration of ritonavir. Although dosage adjustment of omeprazole is not normally required, dosage reduction may be considered in patients receiving higher omeprazole doses (e.g., those with Zollinger-Ellison syndrome). Ritonavir is a strong CYP3A4 inhibitor. Omeprazole is a CYP2C19 and CYP3A4 substrate. Coadministration of a dual CYP2C19/strong CYP3A4 inhibitor increased the omeprazole AUC by an average of 4-times.
Ondansetron: (Moderate) Caution and close monitoring are advised if these drugs are administered together. Ondansetron exposure may be altered resulting in increased adverse effects or decreased efficacy. Ondansetron is metabolized by the hepatic isoenzymes CYP3A4, CYP2D6, and CYP1A2; ritonavir inhibits CYP3A4 and CYP2D6 and induces CYP1A2.
Oritavancin: (Major) 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. (Major) 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: (Major) 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.
Osilodrostat: (Major) Reduce the dose of osilodrostat by one-half during coadministration of ritonavir; concurrent use may increase osilodrostat exposure and the risk of osilodrostat-related adverse reactions. Osilodrostat is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor.
Osimertinib: (Moderate) Monitor for an increase in dasabuvir-related adverse reactions during coadministration of osimertinib. Dasabuvir exposure may be increased. Dasabuvir is a substrate of BCRP and P-glycoprotein (P-gp). Osimertinib is a BCRP and P-gp inhibitor. (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with osimertinib is necessary. Concomitant use may increase plasma concentrations of ombitasvir. Ombitasvir is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with osimertinib is necessary. Concomitant use may increase plasma concentrations of paritaprevir. Paritaprevir is a BCRP and P-glycoprotein (P-gp) substrate. Osimertinib is a BCRP and P-gp inhibitor.
Ospemifene: (Major) Use caution when administering ospemifene to a patient taking ritonavir, as concurrent use may increase ospemifene systemic exposure and increase the risk of ospemifene-related adverse reactions. Consider if alternative therapy is appropriate. Ritonavir is a strong CYP3A4 inhibitor and a CYP2C9 inhibitor, and ospemifene is a CYP3A4 and CYP2C9 substrate. Co-administration of ospemifene with a drug known to inhibit CYP3A4 and CYP2C9 isoenzymes increased the ospemifene exposure 2.7-fold.
Oteseconazole: (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with oteseconazole is necessary. Concurrent use may increase ombitasvir exposure. Ombitasvir is a BCRP substrate and oteseconazole is a BCRP inhibitor. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with oteseconazole is necessary. Concurrent use may increase paritaprevir exposure. Paritaprevir is a BCRP substrate and oteseconazole is a BCRP inhibitor. (Moderate) Monitor for increased dasabuvir-related adverse reactions, including QT prolongation, if coadministered with oteseconazole. Concurrent use may increase dasabuvir exposure. Dasabuvir is a BCRP substrate and oteseconazole is a BCRP inhibitor.
Oxcarbazepine: (Contraindicated) 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. (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with oxcarbazepine. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and oxcarbazepine is a weak CYP3A inducer.
Oxybutynin: (Moderate) 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: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of ritonavir is necessary. If ritonavir is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like ritonavir can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If ritonavir is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Oxymorphone: (Moderate) Ritonavir is an inhibitor of the cytochrome P450 3A4 isoenzyme and may decrease the metabolism of oxymorphone if the two drugs are coadministered.
Paclitaxel: (Minor) 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. (Minor) 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.
Pacritinib: (Contraindicated) Concurrent use of pacritinib with ritonavir is contraindicated due to increased pacritinib exposure which increases the risk of adverse reactions. Pacritinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. (Moderate) Monitor for an increase in ombitasvir-related adverse reactions if coadministration with pacritinib is necessary. Concurrent use may increase ombitasvir exposure. Ombitasvir is a P-gp and BCRP substrate; pacritinib is a P-gp and BCRP inhibitor. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with pacritinib is necessary. Concurrent use may increase paritaprevir exposure. Paritaprevir is a P-gp and BCRP substrate; pacritinib is a P-gp and BCRP inhibitor. (Moderate) Monitor for increased dasabuvir-related adverse reactions, including QT prolongation, if coadministered with pacritinib. Concurrent use may increase dasabuvir exposure. Dasabuvir is a BCRP and P-gp substrate; pacritinib is a BCRP and P-gp inhibitor.
Palbociclib: (Major) 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: (Major) 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. (Major) 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 has also been associated with QT prolongation; TdP and ventricular fibrillation have been reported in the setting of overdose. 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. (Major) 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 has been associated with QT prolongation; torsade de pointes (TdP) and ventricular fibrillation have been reported in the setting of overdose. 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.
Panobinostat: (Major) Reduce the starting dose of panobinostat to10 mg when coadministered with ritonavir. Concurrent use may increase systemic exposure of panobinostat. Panobinostat is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of panobinostat by 73%.
Paricalcitol: (Moderate) 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: (Moderate) Monitor for an increase in paroxetine-related adverse reactions, including serotonin syndrome, if concomitant use with ritonavir is necessary. Concomitant use may increase paroxetine exposure. Paroxetine is a CYP2D6 substrate and ritonavir is a weak CYP2D6 inhibitor.
Pazopanib: (Major) Avoid coadministration of pazopanib and ritonavir due to the potential for increased pazopanib exposure. If concurrent use is unavoidable, reduce the pazopanib dose to 400 mg PO once daily; further dose adjustments may be necessary if adverse effects occur. Pazopanib is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased the Cmax and AUC of pazopanib by 1.5-fold and 1.7-fold, respectively. (Major) 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.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and ritonavir due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If ritonavir is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of ritonavir. Pemigatinib is a CYP3A4 substrate and ritonavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased pemigatinib exposure by 88%.
Penbutolol: (Moderate) Cardiac and neurologic events have been reported when ritonavir was concurrently administered with beta-blockers.
Pentobarbital: (Contraindicated) 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. (Contraindicated) 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. (Contraindicated) 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. (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers.
Perampanel: (Moderate) 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. (Moderate) 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. (Moderate) 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.
Perindopril; Amlodipine: (Moderate) 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; Amitriptyline: (Major) 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. (Major) 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. (Moderate) A dose reduction of the tricyclic antidepressant (TCA) may be necessary when coadministered with ritonavir. Concurrent use may result in elevated TCA plasma concentrations.
Pexidartinib: (Contraindicated) Concurrent use of paritaprevir and pexidartinib is contraindicated due to the risk of decreased paritaprevir exposure which may reduce its efficacy. Concomitant use may also increase pexidartinib exposure and the risk for pexidartinib-related adverse effects. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If paritaprevir is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of lonafarnib. Pexidartinib is a UGT substrate and moderate CYP3A inducer; paritaprevir is a CYP3A substrate and UGT inhibitor. Coadministration of another UGT inhibitor increased pexidartinib exposure by 60%. (Major) Avoid concomitant use of pexidartinib and dasabuvir due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If dasabuvir is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of dasabuvir. Pexidartinib is a UGT substrate; dasabuvir is a UGT inhibitor. Coadministration of another UGT inhibitor increased pexidartinib exposure by 60%. (Major) Avoid concomitant use of pexidartinib and ombitasvir due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If ombitasvir is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of ombitasvir. Pexidartinib is a UGT substrate; ombitasvir is a UGT inhibitor. Coadministration of another UGT inhibitor increased pexidartinib exposure by 60%. (Major) Avoid concomitant use of pexidartinib and ritonavir due to the risk of increased pexidartinib exposure which may increase the risk for adverse effects; concomitant use may also decrease ritonavir plasma concentrations and reduce its efficacy. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If ritonavir is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of ritonavir. Pexidartinib is a CYP3A and substrate and moderate CYP3A inducer; ritonavir is a CYP3A substrate and strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased pexidartinib exposure by 70%.
Phenobarbital: (Contraindicated) 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. (Contraindicated) 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. (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Contraindicated) 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. (Contraindicated) 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. (Major) Avoid concomitant use of ritonavir and barbiturates. Concomitant use may decrease the exposure of both drugs, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the barbiturate. A dose increase of the barbiturate may be necessary. Ritonavir is a CYP3A substrate and inducer and barbiturates are CYP3A inducers.
Phentermine; Topiramate: (Moderate) 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. (Moderate) 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. (Moderate) 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.
Phenytoin: (Contraindicated) 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. (Contraindicated) 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. (Major) Avoid concomitant use of ritonavir and hydantoins. Concomitant use may decrease the exposure of ritonavir and hydantoins, resulting in reduced efficacy. If concomitant use is necessary, monitor for decreased virologic response and decreased efficacy of the hydantoin. A dose increase of the hydantoin may be necessary. Ritonavir is a CYP3A substrate and inducer and hydantoins are CYP3A inducers.
Pimavanserin: (Major) Reduce the dose of pimavanserin to 10 mg PO once daily and monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation if coadministration with ritonavir is necessary. Concurrent use may increase pimavanserin exposure. Pimavanserin is a CYP3A4 substrate; ritonavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with a strong CYP3A4 inhibitor increased exposure to pimavanserin by 3-fold.
Pimozide: (Contraindicated) 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 CYP450 inhibitors, such as the protease inhibitors. Increased plasma concentrations of pimozide have been associated with QT prolongation and serious cardiovascular adverse events including death due to TdP.
Pindolol: (Moderate) 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: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Pioglitazone; Glimepiride: (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir.
Pioglitazone; Metformin: (Major) While no dosage adjustment of metformin is recommended in patients with normal hepatic or renal function, careful patient monitoring and dose adjustment of metformin and/or the potentially interfering drug is recommended with concurrent use. Monitor for signs of onset of lactic acidosis such as respiratory distress, somnolence, and non-specific abdominal distress or worsening renal function. Do not use metformin with paritaprevir in patients with renal insufficiency or hepatic impairment. Drugs that interfere with common renal tubular transport systems involved in the renal elimination of metformin could increase systemic exposure to metformin and may increase the risk for lactic acidosis. Paritaprevir is an inhibitor of the organic anion transporters OATP1B1 and OATP1B3. While initial drug-drug interaction studies of paritaprevir-containing hepatitis treatments have not noted an effect on metformin concentrations, more study is needed. (Moderate) Closely monitor blood glucose levels if dasabuvir; ombitasvir; paritaprevir; ritonavir is administered with antidiabetic agents. Dose adjustments of the antidiabetic agents may be needed. Altered blood glucose control, resulting in serious symptomatic hypoglycemia, has been reported in diabetic patients receiving antidiabetic agents in combination with direct acting antivirals, such as dasabuvir; ombitasvir; paritaprevir; ritonavir. (Moderate) 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.
Pirfenidone: (Moderate) 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. (Moderate) 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.
Pirtobrutinib: (Major) Avoid concomitant use of pirtobrutinib and ritonavir due to the risk of increased pirtobrutinib exposure which may increase the risk for adverse effects. If concomitant use is necessary, reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of ritonavir use. Resume the previous dose of pirtobrutinib after ritonavir is discontinued for 5 half-lives. Pirtobrutinib is a CYP3A substrate and ritonavir is a strong CYP3A inhibitor. Concomitant with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%. (Moderate) Monitor for an increase in paritaprevir-related adverse reactions if coadministration with pirtobrutinib is necessary. Concurrent use may increase paritaprevir exposure. Paritaprevir is a P-gp and BCRP substrate and pirtobrutinib is a P-gp and BCRP inhibitor. (Moderate) Monitor for increased dasabuvir-related adverse reactions, including QT prolongation, if coadministered with pirtobrutinib. Concurrent use may increase dasabuvir exposure. Dasabuvir is a CYP2C8 substrate and pirtobrutinib is a moderate CYP2C8 inhibitor.
Pitavastatin: (Major) 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.
Pitolisant: (Moderate) Monitor for decreased efficacy of ritonavir if coadministered with pitolisant. Concurrent use may decrease the plasma concentrations of ritonavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Ritonavir is a CYP3A substrate and pitolisant is a weak CYP3A inducer.
Polatuzumab Vedotin: (Moderate) Monitor for increased polatuzumab vedotin toxicity during coadministration of ritonavir due to the risk of elevated exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; ritonavir is a strong CYP3A4 inhibitor. Strong CYP3A4 inhibitors are predicted to increase the exposure of MMAE by 45%.
Pomalidomide: (Moderate) Use pomalidomide and ritonavir together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and riton

Viekira Oral Tab: 250-12.5-75-50mg
Viekira XR Oral Tab ER

Adults

500 mg/day PO for dasabuvir; 25 mg/day PO for ombitasvir; 150 mg/day PO for paritaprevir; 100 mg/day PO for ritonavir.

Geriatric

500 mg/day PO for dasabuvir; 25 mg/day PO for ombitasvir; 150 mg/day PO for paritaprevir; 100 mg/day PO for ritonavir.

Adolescents

Safety and efficacy not established.

Children

Safety and efficacy not established.

Infants

Safety and efficacy not established.

Neonates

Safety and efficacy not established.

Dasabuvir; ombitasvir; paritaprevir; ritonavir combines 3 direct-acting antiviral agents with differing mechanisms of action active against genotype 1 hepatitis C virus (HCV) and non-overlapping resistance profiles. The combination product also contains ritonavir which is not active against HCV but as a potent CYP3A inhibitor acts to increase the peak and trough plasma concentrations of paritaprevir as well as overall drug exposure (i.e., area under the curve).[58664]
 
Dasabuvir: Dasabuvir is a non-nucleoside inhibitor of the HCV RNA-dependent RNA polymerase encoded by the NS5B gene, which is essential for replication. Dasabuvir is considered a non-nucleoside NS5B-palm polymerase inhibitor because it targets the palm domain of the NS5B polymerase. In cell cultures, HCV genotype 1a replicons with NS5B amino acid substitutions were associated with an 8- to 1,472-fold decrease in antiviral activity to dasabuvir. HCV genotype 1b replicons with NS5B amino acid substitutions were associated with a 5- to 1,569-fold decrease in antiviral activity to dasabuvir. In clinical trials, 64 patients were deemed virologic failures after treatment with regimens containing dasabuvir, ombitasvir, and paritaprevir with or without ribavirin. An analysis of these 64 patients found 67% of the genotype 1a failures and 33% of the genotype 1b failures had viruses with emergent NS5B resistance-associated substitutions. Cross-resistance is expected among NS5A inhibitors, NS3/4A protease inhibitors, and non-nucleoside NS5B-palm polymerase inhibitors by class. Dasabuvir retained full activity against HCV replicons containing a single NS5B L159F, S282T, or V321A substitution, which are associated with nucleoside/nucleotide analog NS5B polymerase inhibitor resistance.
Ombitasvir: Ombitasvir is an HCV NS5A inhibitor, which is essential for viral replication and virion assembly. In cell cultures, HCV genotype 1a replicons with single NS5A amino acid substitutions were associated with a 58- to 67,000-fold decrease in antiviral activity to ombitasvir. HCV genotype 1b replicons with single NS5A amino acid substitutions were associated with an 8- to 661-fold decrease in antiviral activity to ombitasvir. Combinations of resistance-associated substitutions led to further deceases in antiviral activity. In clinical trials, 64 patients were deemed virologic failures following treatment with regimens containing dasabuvir, ombitasvir, and paritaprevir with or without ribavirin. An analysis of these 64 patients found 78% of the genotype 1a failures and 33% of the genotype 1b failures had viruses with emergent NS5A resistance-associated substitutions.
Paritaprevir: Paritaprevir is an HCV NS3/4A protease inhibitor, which is necessary for the proteolytic cleavage of the HCV encoded polyprotein into mature forms and is essential for viral replication. In cell cultures, HCV genotype 1a replicons with single NS3 amino acid substitutions were associated with a 7- to 219-fold decrease in antiviral activity to paritaprevir. HCV genotype 1b replicons with single NS3 amino acid substitutions were associated with a 7- to 159-fold decrease in antiviral activity to paritaprevir. Combinations of resistance-associated substitutions led to further deceases in antiviral activity. In clinical trials, 64 patients were deemed virologic failures following treatment with regimens containing dasabuvir, ombitasvir, and paritaprevir with or without ribavirin. An analysis of these 64 patients found 88% of the genotype 1a failures and 67% of the genotype 1b failures had viruses with emergent NS3 resistance-associated substitutions.[58664]

Dasabuvir; ombitasvir; paritaprevir; ritonavir is administered orally.
Dasabuvir: Once in the systemic circulation, dasabuvir is more than 99.5% bound to human plasma proteins. It has a volume of distribution at steady state of 149 L, and a mean blood-to-plasma ratio of 0.7. The drug is metabolized by the hepatic isoenzymes CYP2C8 (major) and CYP3A (minor). Elimination occurs primarily via the feces (94.4% of a radiolabeled dose), with small amounts excreted in the urine (2% of a radiolabeled dose). The mean elimination half-life is approximately 5.5 to 6 hours.[58664]
Ombitasvir: Systemically absorbed ombitasvir is extensively protein bound at more than 99.9%, has a volume of distribution at steady state of 173 L, and a mean blood-to-plasma ratio of 0.49. The drug undergoes metabolism primarily via amide hydrolysis, followed by oxidative metabolism; CYP isoenzymes contribute little to the metabolism of ombitasvir. The feces are the main route of elimination, accounting for 90.2% of a radiolabeled dose, with urine accounting for only 1.91% of the dose. Ombitasvir has a mean elimination half-life of approximately 21 to 25 hours.[58664]
Paritaprevir: Paritaprevir is 97% to 98.6% protein-bound, with a mean blood-to-plasma ratio of 0.7 and a steady-state volume of distribution of 103 L. Metabolism occurs via the hepatic isoenzymes CYP3A4 (major) and CYP3A5 (minor). The drug is eliminated primarily via the feces (88% of a radiolabeled dose), with limited amounts excreted in the urine (8.8% of a radiolabeled dose). The mean elimination half-life is 5.5 hours.[58664]
Ritonavir: Once in the systemic circulation, ritonavir has an apparent volume of distribution at steady state of 21.5 L and a mean blood-to-plasma ratio of 0.6. Most of the circulating drug (more than 99%) is bound to human plasma proteins. Metabolism occurs via the hepatic isoenzymes CYP3A (primarily) and CYP2D6 (secondary). Follow administration of a single radiolabeled dose, 86.4% of the radioactivity was observed in the feces, with 11.3% excreted in the urine. The mean elimination half-life is 4 hours.[58664]
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, CYP3A5, CYP2C8, CYP2D6, P-glycoprotein (P-gp), uridine glucuronyltransferase (UGT1A1), organic anion transporting polypeptides (OATP1B1 and OATP1B3), breast cancer resistance protein (BCRP)
Ritonavir is a potent inhibitor of CYP3A4 and an inhibitor of the drug transporter BCRP. The other 3 drugs each inhibit at least 1 drug transporter, but have limited effect on the CYP450 isoenzyme system: paritaprevir inhibits UGT1A1, OATP1B1, OATP1B3, and BCRP; dasabuvir inhibits UGT1A1 and BCRP; ombitasvir inhibits UGT1A1. All 4 drugs are substrates for the drug transporter P-gp. Also, paritaprevir is also a substrate for CYP3A4/5, BCRP, OATP1B1, and OATP1B3; dasabuvir is also a substrate for CYP2C8, CYP3A, and BCRP; ombitasvir is also a substrate for BCRP; and ritonavir is also a substrate for CYP3A and CYP2D6 [58664]

Oral Route

Following oral administration, maximum plasma drug concentrations are observed in approximately 4 to 5 hours for all components. With continual dosing, steady-state exposures are achieved in approximately 12 days. To increase drug exposure, dasabuvir; ombitasvir; paritaprevir; ritonavir must always be administered with food.
 
Dasabuvir: The absolute oral bioavailability of dasabuvir is 70%. The drug displays linear pharmacokinetics with increasing doses resulting in proportional increases in drug exposure (AUC); accumulation has been found to be minimal (0.96-fold). Drug exposures are also increased when administered with food. Administering dasabuvir with a meal increases exposures by 22% to 30% as compared to fasting conditions; these increases are observed regardless of the meals fat or caloric content.[58664]
Ombitasvir: The absolute oral bioavailability of ombitasvir is 48%. The drug displays linear pharmacokinetics with increasing doses resulting in proportional increases in drug exposure (AUC); accumulation has been found to be minimal (0.9- to 1.03-fold). Drug exposures are also increased when administered with food. Administering ombitasvir with a meal increases exposures by 76% to 82% as compared to fasting conditions; these increases are observed regardless of the meals fat or caloric content.[58664]
Paritaprevir: The absolute oral bioavailability of paritaprevir is 53%. The drug displays non-linear pharmacokinetics with increasing doses resulting in more than proportional increases in drug exposure (AUC); accumulation has been found to be 1.5- to 2-fold. Drug exposures are also increased when administered with food. Administering paritaprevir with a meal increases exposures by 180% to 211% as compared to fasting conditions; these increases are observed regardless of the meals fat or caloric content.[58664]
Ritonavir: The absolute oral bioavailability of ritonavir has not been evaluated. The drug displays non-linear pharmacokinetics with increasing doses resulting in more than proportional increases in drug exposure (AUC); accumulation has been found to be up to 1.5- to 2-fold. Drug exposures are also increased when administered with food. Administering ritonavir with a meal increases exposures by 44% to 49% as compared to fasting conditions; these increases are observed regardless of the meals fat or caloric content.[58664]

Pregnancy

According to the manufacturer, it is not known if dasabuvir; ombitasvir; paritaprevir; ritonavir or their metabolites are excreted in human milk. Consider the benefits of breast-feeding, the risk of infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, health care providers are encouraged to report the adverse effect to the FDA.