EVOTAZ

Protease Inhibitors

Oral Administration Oral Solid Formulations

Administer with food.

Severe

AV block / Early / 5.0-6.0
Fanconi syndrome / Delayed / 0-2.0
rhabdomyolysis / Delayed / 0-2.0
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
erythema multiforme / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
renal failure (unspecified) / Delayed / Incidence not known
diabetic ketoacidosis / Delayed / Incidence not known

Moderate

hyperbilirubinemia / Delayed / 73.0-73.0
elevated hepatic enzymes / Delayed / 4.0-6.0
jaundice / Delayed / 6.0-6.0
hematuria / Delayed / 6.0-6.0
hyperamylasemia / Delayed / 4.0-4.0
glycosuria / Early / 3.0-3.0
nephrolithiasis / Delayed / 2.0-2.0
depression / Delayed / 0-2.0
lipodystrophy / Delayed / Incidence not known
hypertriglyceridemia / Delayed / Incidence not known
hypercholesterolemia / Delayed / Incidence not known
cholelithiasis / Delayed / Incidence not known
eosinophilia / Delayed / Incidence not known
PR prolongation / Rapid / Incidence not known
hyperglycemia / Delayed / Incidence not known
diabetes mellitus / Delayed / Incidence not known
bleeding / Early / Incidence not known
hematoma / Early / Incidence not known

Mild

rash / Early / 0-5.0
pruritus / Rapid / 0-5.0
maculopapular rash / Early / 0-5.0
urticaria / Rapid / 0-5.0
folliculitis / Delayed / 0-5.0
nausea / Early / 2.0-2.0
diarrhea / Early / 2.0-2.0
abdominal pain / Early / 0-2.0
vomiting / Early / 0-2.0
fatigue / Early / 0-2.0
headache / Early / 2.0-2.0
insomnia / Early / 0-2.0
abnormal dreams / Early / 0-2.0
Cushingoid features / Delayed / Incidence not known
breast enlargement / Delayed / Incidence not known
gynecomastia / Delayed / Incidence not known

EVOTAZ

Rx

Fixed-dose combination product containing a protease inhibitor (PI) and a pharmacokinetic enhancer
Used with other antiretrovirals to treat HIV-1 infection in treatment-naive and experienced adults and pediatric patients weighing 35 kg or more
Use in treatment-experienced patients should be guided by the number of baseline primary PI resistant substitutions

For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretrovirals. Oral dosage Adults

300 mg/150 mg PO once daily in both treatment-naive and treatment-experienced patients. Use in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions.

Children and Adolescents weighing 35 kg or more

300 mg/150 mg PO once daily in both treatment-naive and treatment-experienced patients. Use in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions.

Hepatic Impairment

Atazanavir; cobicistat is not recommended in patients with any degree of hepatic impairment.

Renal Impairment

No dosage adjustment is recommended for patients with renal insufficiency not managed by hemodialysis; however, atazanavir; cobicistat is not recommended in patients with an estimated CrCl below 70 mL/minute who are also receiving concomitant tenofovir disoproxil fumarate, nor in patients with CrCl less than 30 mL/minute who are receiving concomitant tenofovir alafenamide.
 
Intermittent hemodialysis
Atazanavir; cobicistat is not recommended in treatment-experience patients with end-stage renal disease managed with hemodialysis.

Abacavir; Dolutegravir; Lamivudine: (Moderate) Caution is warranted when atazanavir is administered with dolutegravir as there is a potential for elevated dolutegravir concentrations. Dolutegravir is a substrate of CYP3A4 and uridine glucuronyltransferase (UGT). Atazanavir is an inhibitor of CYP3A4 and UGT1A1. (Moderate) Caution is warranted when cobicistat is administered with dolutegravir as there is a potential for elevated dolutegravir concentrations. Dolutegravir is a substrate of CYP3A4 and P-glycoprotein (P-gp). Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of P-gp.
Abemaciclib: (Major) If coadministration with atazanavir 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 atazanavir is discontinued, increase the dose of abemaciclib to the original dose after 3 to 5 half-lives of atazanavir. Abemaciclib is a CYP3A4 substrate and atazanavir 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. (Major) If coadministration with cobicistat 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 cobicistat is discontinued, increase the dose of abemaciclib to the original dose after 3 to 5 half-lives of cobicistat. Abemaciclib is a CYP3A4 substrate and cobicistat 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.
Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and atazanavir; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; atazanavir 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. (Major) Avoid the concomitant use of acalabrutinib and cobicistat; significantly increased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; cobicistat 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.
Acarbose: (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.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Caution is warranted when cobicistat is administered with diphenhydramine as there is a potential for elevated diphenhydramine and cobicistat concentrations. Diphenhydramine is a substrate/inhibitor of CYP2D6 and a substrate of CYP2C9. Cobicistat is an substrate/inhibitor of CYP2D6.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with atazanavir 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 atazanavir could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If atazanavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Atazanavir is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) Concomitant use of dihydrocodeine with cobicistat 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 cobicistat could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Acetaminophen; Chlorpheniramine: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with atazanavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and 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 reduction of codeine until stable drug effects are achieved. Discontinuation of atazanavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If atazanavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Atazanavir is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with cobicistat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and 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 reduction of codeine until stable drug effects are achieved. Discontinuation of cobicistat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cobicistat is a strong inhibitor of CYP3A4.
Acetaminophen; Dextromethorphan: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Acetaminophen; Diphenhydramine: (Moderate) Caution is warranted when cobicistat is administered with diphenhydramine as there is a potential for elevated diphenhydramine and cobicistat concentrations. Diphenhydramine is a substrate/inhibitor of CYP2D6 and a substrate of CYP2C9. Cobicistat is an substrate/inhibitor of CYP2D6.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of atazanavir 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 atazanavir 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 atazanavir 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. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cobicistat 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 with a combined CYP2D6 and CYP3A4 inhibitor. If cobicistat 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; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of atazanavir is necessary. If atazanavir 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 atazanavir 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 atazanavir 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. (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. If cobicistat 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 cobicistat 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 cobicistat 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.
Adagrasib: (Moderate) Monitor for an increase in adagrasib-related adverse effects during concomitant use of atazanavir. 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 atazanavir 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 adverse effects from both drugs during concomitant use of adagrasib and cobicistat. 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 and cobicistat are both CYP3A substrates and strong CYP3A inhibitors. 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.
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 atazanavir 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 atazanavir has cleared from the circulation (approximately 3 half-lives of atazanavir) 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; atazanavir is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted. (Major) Avoid coadministration of cobicistat 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 cobicistat has cleared from the circulation (approximately 3 half-lives of cobicistat) 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; cobicistat is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
Afatinib: (Moderate) If the concomitant use of cobicistat 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 cobicistat. 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 cobicistat 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.
Albuterol; Budesonide: (Moderate) Avoid coadministration of oral budesonide and cobistat due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Elevated budesonide serum concentrations may result in Cushing's syndrome and adrenal suppression. Budesonide is a CYP3A4 and P-glycoprotein (P-gp) substrate; cobicistat is a strong inhibitor of CYP3A4 and P-gp. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use. (Moderate) Coadministration of budesonide with atazanavir may cause elevated budesonide serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Budesonide is a CYP3A4 substrate; atazanavir 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.
Aldesleukin, IL-2: (Moderate) Caution is warranted when atazanavir is administered with aldesleukin, IL-2 as there is a potential for elevated concentrations of atazanavir. Aldesleukin, IL-2 increases IL-6 concentrations, and IL-6 is an inhibitor of the hepatic isoenzyme CYP3A4; atazanavir is a substrate of CYP3A4. (Moderate) Caution is warranted when cobicistat is administered with aldesleukin, IL-2 as there is a potential for elevated cobicistat concentrations. Aldesleukin, IL-2 is a CYP3A4 inhibitor and cobicistat is a substrate of CYP3A4.
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of protease inhibitors is necessary. If the protease inhibitor is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A substrate, and coadministration with CYP3A inhibitors like protease inhibitors can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If the protease inhibitor is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil. (Moderate) The plasma concentrations of alfentanil may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as hypotension, nausea, itching, and respiratory depression, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor and alfentanil is a CYP3A4 substrate.
Alfuzosin: (Contraindicated) Alfuzosin is contraindicated for use with cobicistat due to the potential for serious/life-threatening reactions, including hypotension. Coadministration is expected to reduce the metabolism and increase systemic exposure to alfuzosin. Alfuzosin is primarily metabolized by CYP3A4; cobicistat is a strong inhibitor of this enzyme. Coadministration of another strong CYP3A4 inhibitor increased the alfuzosin AUC by 2.5-fold to 3.2-fold. (Contraindicated) Concurrent use of alfuzosin and protease inhibitors is contraindicated due to increased alfuzosin exposure. Alfuzosin is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. When coadministered with another strong CYP3A inhibitor, the AUC of alfuzosin was increased by 2.5-fold to 3.2-fold.
Aliskiren: (Moderate) The plasma concentrations of aliskiren may be elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Atazanavir is a CYP3A4 inhibitor. Aliskiren is a substrate of CYP3A4. (Moderate) The plasma concentrations of aliskiren may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and aliskiren is a CYP3A4 and P-gp substrate.
Aliskiren; Hydrochlorothiazide, HCTZ: (Moderate) The plasma concentrations of aliskiren may be elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Atazanavir is a CYP3A4 inhibitor. Aliskiren is a substrate of CYP3A4. (Moderate) The plasma concentrations of aliskiren may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as decreased blood pressure, is recommended during coadministration. Cobicistat is a CYP3A4 and P-glycoprotein (P-gp) inhibitor and aliskiren is a CYP3A4 and P-gp substrate.
Almotriptan: (Moderate) The maximum recommended starting dose of almotriptan is 6.25 mg if coadministration with atazanavir is necessary; do not exceed 12.5 mg within a 24-hour period. Concomitant use of almotriptan and atazanavir should be avoided in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased almotriptan exposure by approximately 60%. (Moderate) The maximum recommended starting dose of almotriptan is 6.25 mg if coadministration with cobicistat is necessary; do not exceed 12.5 mg within a 24-hour period. Concomitant use of almotriptan and cobicistat should be avoided in patients with renal or hepatic impairment. Almotriptan is a CYP3A4; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased almotriptan exposure by approximately 60%.
Alogliptin: (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: (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (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) 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) Due to atazanavir-induced inhibition of CYP3A4 isoenzymes, atazanavir may inhibit the metabolism and thus, increase the serum concentrations of drugs that are largely metabolized via CYP3A4, such as alosetron. Serious drug interactions may occur. If these drugs must be coadministered, monitor patient response and adjust the dose of alosetron if necessary. (Moderate) Concomitant use of alosetron with cobicistat may result in increased serum concentrations of alosetron and increase the risk for adverse reactions. Caution and close monitoring are advised if these drugs are used together. Alosetron is a substrate of hepatic isoenzyme CYP3A4; cobicistat is a strong inhibitor of this enzyme. In a study of healthy female subjects, another strong CYP3A4 inhibitor increased mean alosetron AUC by 29%.
Alpelisib: (Major) Avoid coadministration of alpelisib with cobicistat 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 cobicistat 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: (Contraindicated) Coadministration of atazanavir and alprazolam is contraindicated due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with atazanavir, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased alprazolam exposure by 2.7- to 3.98-fold. (Contraindicated) Coadministration of cobicistat and alprazolam is contraindicated due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with cobicistat, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased alprazolam exposure by 2.7- to 3.98-fold.
Aluminum Hydroxide: (Major) It is recommended that antacids not be given at the some time as atazanavir because of potential interference with absorption of atazanavir. Separate the administration of atazanavir and antacids to avoid the potential for interaction; give atazanavir 2 hours before or 1 hour after the antacid.
Aluminum Hydroxide; Magnesium Carbonate: (Major) It is recommended that antacids not be given at the some time as atazanavir because of potential interference with absorption of atazanavir. Separate the administration of atazanavir and antacids to avoid the potential for interaction; give atazanavir 2 hours before or 1 hour after the antacid.
Aluminum Hydroxide; Magnesium Hydroxide: (Major) It is recommended that antacids not be given at the some time as atazanavir because of potential interference with absorption of atazanavir. Separate the administration of atazanavir and antacids to avoid the potential for interaction; give atazanavir 2 hours before or 1 hour after the antacid.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Major) It is recommended that antacids not be given at the some time as atazanavir because of potential interference with absorption of atazanavir. Separate the administration of atazanavir and antacids to avoid the potential for interaction; give atazanavir 2 hours before or 1 hour after the antacid.
Aluminum Hydroxide; Magnesium Trisilicate: (Major) It is recommended that antacids not be given at the some time as atazanavir because of potential interference with absorption of atazanavir. Separate the administration of atazanavir and antacids to avoid the potential for interaction; give atazanavir 2 hours before or 1 hour after the antacid.
Amiodarone: (Major) Therapeutic monitoring of amiodarone concentrations is recommended when administered concurrently with atazanavir. If atazanavir is boosted with ritonavir, concurrent use of amiodarone is contraindicated. Use of all 3 drugs together may significantly increase amiodarone concentrations and increase the risk for serious or life-threatening cardiac arrhythmias. Atazanavir and ritonavir are CYP3A4 inhibitors; amiodarone is metabolized by this enzyme. (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of amiodarone with cobicistat. Amiodarone is a substrate and inhibitor of CYP3A4 and an inhibitor CYP2D6, cobicistat is a substrate and strong inhibitor of CYP3A and CYP2D6. Concurrent use may result in elevated concentration of both drugs.
Amitriptyline: (Moderate) According to the manufacturer, concurrent use of tricyclic antidepressants (TCAs) and atazanavir may result in elevated TCA plasma concentration, and could increase the potential for serious adverse effects. If these drugs are administered together, carefully titrate the TCA dose based on a clinical assessment of antidepressant response. Patients on a stable dose of TCA who start treatment with atazanavir should be monitored for TCA-associated anticholinergic effects (e.g., sedation, confusion, constipation). In addition to clinical monitoring, the manufacturer suggests obtaining TCA serum concentrations (where available) as an adjunct to assessing the potential for interactions. (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. Concurrent use may result in elevated TCA plasma concentrations.
Amlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Atorvastatin: (Major) Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with atazanavir. When atazanavir is boosted with cobicistat, use of atorvastatin is not recommended. The risk of developing myopathy or rhabdomyolysis increases when these drugs are used together. 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. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined statin and atazanavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. Increased atorvastatin serum concentrations may occur due to atazanavir inhibition of CYP3A4 metabolism. In addition, atorvastatin is a substrate of the drug transporter organic anion transporting polypeptide (OATP1B1); atazanavir is an OATP1B1 inhibitor. (Major) When administering atorvastatin concurrently with cobicistat, use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events (myopathy); DO NOT exceed a maximum daily atorvastatin dose of 20 mg daily. Cobicistat is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration with other strong CYP3A4 inhibitors increased atorvastatin exposure by 3.3- to 4.4-fold. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Benazepril: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Celecoxib: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Olmesartan: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Amlodipine; Valsartan: (Moderate) Concurrent use of atazanavir with valsartan may result in elevated valsartan serum concentrations. Valsartan is a substrate for the drug transporter organic anion transporting polypeptide (OATP1B1/1B3); atazanavir is an OATP1B1 inhibitor. Monitor for increased toxicities if these drugs are given together. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure. (Minor) Caution is warranted when cobicistat is administered with valsartan as there is a potential for increased valsartan concentrations. Valsartan is a substrate of organic anion transporting polypeptide (OATP)1B1. Cobicistat is an inhibitor of OATP.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Concurrent use of atazanavir with valsartan may result in elevated valsartan serum concentrations. Valsartan is a substrate for the drug transporter organic anion transporting polypeptide (OATP1B1/1B3); atazanavir is an OATP1B1 inhibitor. Monitor for increased toxicities if these drugs are given together. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure. (Minor) Caution is warranted when cobicistat is administered with valsartan as there is a potential for increased valsartan concentrations. Valsartan is a substrate of organic anion transporting polypeptide (OATP)1B1. Cobicistat is an inhibitor of OATP.
Amobarbital: (Major) Coadministration of amobarbital and atazanavir may increase the metabolism of atazanavir and lead to decreased atazanavir concentrations resulting in reduction of antiretroviral efficacy and development of viral resistance. If atazanavir and amobarbital are used together, the patient must be closely monitored for antiviral efficacy.
Amoxapine: (Moderate) Atazanavir competitively inhibits the enzymes CYP3A4, CYP1A2 and CYP2C9. Concentrations of drugs that are substrates of these enzymes, such as tricyclic antidepressants, may be increased with concomitant atazanavir use. Amoxapine is related to the tricyclic antidepressants, and until more data is available, similar caution is advised when using amoxapine with atazanavir.
Amoxicillin; Clarithromycin; Omeprazole: (Contraindicated) Coadministration of proton pump inhibitors (PPIs) with atazanavir in treatment-experienced patients is contraindicated. PPIs can be used with atazanavir in treatment-naive patients under specific administration restrictions. In treatment-naive patients >= 40 kg, the PPI dose should not exceed the equivalent of omeprazole 20 mg/day, and the PPI must be administered 12 hours before atazanavir and ritonavir; use the dosage regimen of atazanavir 300 mg boosted with ritonavir 100 mg given once daily with food. While data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant PPIs, the same recommendations regarding timing and maximum doses of concomitant PPIs should be followed. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with a PPI. A randomized, open-label, multiple-dose drug interaction study of atazanavir (300 mg) with ritonavir (100 mg) coadministered with omeprazole 40 mg found a reduction in atazanavir AUC and Cmin of 76% and 78%, respectively. Additionally, after multiple doses of omeprazole (40 mg/day) and atazanavir (400 mg/day, 2 hours after omeprazole) without ritonavir, the AUC of atazanavir was decreased by 94%, Cmax by 96%, and Cmin by 95%. (Major) Avoid concurrent use of clarithromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of clarithromycin, cobicistat, atazanavir and darunavir. Both clarithromycin and cobicistat are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of cobicistat, atazanavir and darunavir. (Major) Coadministration with atazanavir increases clarithromycin serum concentrations. Use caution if these drugs are coadministered, as increased clarithromycin concentrations may cause QT prolongation; a 50% dosage reduction of clarithromycin is recommended. In addition, atazanavir significantly reduces the concentration of 14-OH clarithromycin, the active metabolite of clarithromycin; consider alternative agents for indications other than infections due to Mycobacterium avium complex (MAC). (Minor) The plasma concentrations of omeprazole may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while omeprazole is a CYP3A4 substrate.
Anagrelide: (Moderate) Anagrelide is partially metabolized by CYP1A2. Coadministration of anagrelide with drugs that inhibit CYP1A2, such as atazanavir, could theoretically decrease the elimination of anagrelide and increase the risk of side effects or toxicity. Monitor for increased adverse effects if anagrelide is coadministered with atazanavir.
Antacids: (Major) It is recommended that antacids not be given at the some time as atazanavir because of potential interference with absorption of atazanavir. Separate the administration of atazanavir and antacids to avoid the potential for interaction; give atazanavir 2 hours before or 1 hour after the antacid.
Apalutamide: (Contraindicated) Atazanavir is contraindicated for use with apalutamide due to decreased plasma concentrations of atazanavir, which may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Apalutamide is a strong CYP3A4 inducer and atazanavir is a CYP3A4 substrate. When coadministered with another strong CYP3A4 inducer, the Cmax of atazanavir was reduced by 53%, the AUC by 72%, and the Cmin by 98%. (Major) Coadministration of cobicistat with apalutamide is not recommended as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. In addition, there is a potential for increased apalutamide exposure. If these drugs are used together, monitor for an increase in apalutamide-related adverse reactions. Consider reducing the dose of apalutamide if necessary based on tolerability in patients experiencing grade 3 or higher adverse reactions or intolerable toxicities. Apalutamide is a substrate and strong inducer of CYP3A4. Cobicistat is a substrate and strong inhibitor of CYP3A4. Coadministration with one strong CYP3A4 inhibitor decreased the Cmax of single-dose apalutamide by 22% and the AUC remained similar. Concomitant use with another strong CYP3A4 inhibitor is predicted to increase the single-dose apalutamide AUC by 24% but have no effect on Cmax; the steady-state Cmax and AUC are predicted to increase by 38% and 51%, respectively. The steady-state exposure of the active moieties (unbound apalutamide plus potency-adjusted unbound N-desmethyl apalutamide) is predicted to increase by 28%.
Apixaban: (Major) Apixaban is a substrate of CYP3A4 and CYP2C8; atazanavir is a CYP3A4 substrate/inhibitor and a minor inhibitor of CYP2C8. Coadministration of these drugs may increase apixaban plasma concentrations and risk of adverse events such as bleeding. Avoid concurrent administration if possible; if concurrent administration is required, monitor for signs of bleeding. (Major) Reduce the apixaban dose by 50% when coadministered with drugs that are both strong inhibitors of CYP3A4 and P-gp, such as cobicistat containing medications. If patients are already receiving 2.5 mg twice daily, avoid concomitant administration. Concomitant administration results in increased exposure to apixaban and an increase in the risk of bleeding.
Aprepitant, Fosaprepitant: (Major) Avoid the concomitant use due to substantially increased exposure of aprepitant; increased cobicistat exposure may also occur. If coadministration cannot be avoided, use caution and monitor for an increase in cobicistat- 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. Cobicistat 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. Cobicistat 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 did not result in a clinically significant increase in the AUC of a sensitive substrate. (Major) The manufacturer of aprepitant, fosaprepitant recommends avoiding concomitant use with atazanavir due to substantially increased exposure of aprepitant. Increased atazanavir exposure may also occur with multi-day regimens of oral aprepitant for several days after administration. Atazanavir 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. Atazanavir is also a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of atazanavir. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important.
Aripiprazole: (Major) Recommendations for managing aripiprazole and atazanavir vary by aripiprazole dosage form and CYP2D6 metabolizer status. For aripiprazole oral dosage forms, administer half of the usual dose; administer a quarter of the usual dose to patients known to be poor metabolizers of CYP2D6. For monthly extended-release aripiprazole injections (Abilify Maintena), reduce the dosage from 400 mg to 300 mg/month or from 300 mg to 200 mg/month; administer 200 mg/month to patients known to be poor metabolizers of CYP2D6. 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 CYP2D6 inhibitor; see individual product prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is CYP3A and CYP2D6 substrate; atazanavir is a strong CYP3A inhibitor. (Major) Recommendations for managing aripiprazole and atazanavir vary by aripiprazole dosage form and CYP2D6 metabolizer status. 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 CYP2D6 inhibitor; see individual product prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is CYP3A and CYP2D6 substrate; atazanavir is a strong CYP3A inhibitor. (Major) Recommendations for managing aripiprazole and cobicistat 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; cobicistat is a weak CYP2D6 and strong CYP3A inhibitor. (Major) Recommendations for managing aripiprazole and cobicistat 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; cobicistat is a weak CYP2D6 and strong CYP3A inhibitor.
Armodafinil: (Major) Coadministration of cobicistat with armodafinil is not recommended as there is a potential for elevated armodafinil concentrations and decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Armodafinil is a CYP3A4 substrate/inducer and a P-glycoprotein (P-gp) substrate. Cobicistat is an inhibitor of CYP3A4 and P-gp, and a substrate of CYP3A4.
Artemether; Lumefantrine: (Moderate) Atazanavir is a substrate/inhibitor and artemether is a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased artemether concentrations. Concomitant use warrants caution due to the potential for increased side effects. (Moderate) Atazanavir is a substrate/inhibitor and lumefantrine is a substrate of the CYP3A4 isoenzyme; therefore, coadministration may lead to increased lumefantrine concentrations. Concomitant use warrants caution due to the potential for increased side effects, including increased potentiation of QT prolongation. (Moderate) Caution is warranted when cobicistat with artemether; lumefantrine as there is a potential for elevated artemether, lumefantrine, and cobicistat concentrations. Both artemether and lumefantrine are CYP3A4 substrate and lumefantrine is CYP2D6 inhibitor. Cobicistat is a strong inhibitor of CYP3A4 and a substrate of CYP2D6. Coadministration with another strong CYP3A4 inhibitor increased lumefantrine exposure by 1.6-fold. (Moderate) Caution is warranted when cobicistat with artemether; lumefantrine as there is a potential for elevated artemether, lumefantrine, and cobicistat concentrations. Both artemether and lumefantrine are CYP3A4 substrates and lumefantrine is CYP2D6 inhibitor. Cobicistat is a strong inhibitor of CYP3A4 and a substrate of CYP2D6. In a drug interaction study, administration of a strong CYP3A4 inhibitor, resulted in a moderate increase in exposure to artemether, DHA, and lumefantrine.
Asciminib: (Moderate) Closely monitor for asciminib-related adverse reactions if concurrent use of asciminib 200 mg twice daily with atazanavir is necessary as asciminib exposure may increase. Asciminib is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. (Moderate) Closely monitor for asciminib-related adverse reactions if concurrent use of asciminib 200 mg twice daily with cobicistat is necessary as asciminib exposure may increase. Asciminib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor.
Asenapine: (Moderate) Caution is warranted when atazanavir is administered with asenapine as there is a potential for increased aspenapine concentrations. Asenapine is a substrate of CYP3A4. Atazanavir is an inhibitor of CYP3A4. In addition, asenapine is substrate for uridine glucoronyltransferase (UGT); atazanavir is a UGT1A1 inhibitor. (Moderate) Caution is warranted when cobicistat is administered with asenapine as there is a potential for increased aspenapine concentrations. Asenapine is a substrate of CYP3A4 and CYP2D6. Cobicistat is an inhibitor of CYP3A4 and CYP2D6.
Aspirin, ASA; Butalbital; Caffeine: (Major) Coadministration of butalbital and atazanavir may increase the metabolism of atazanavir and lead to decreased atazanavir concentrations resulting in reduction of antiretroviral efficacy and development of viral resistance. If atazanavir and butalbital are used together, the patient must be closely monitored for antiviral efficacy.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with atazanavir may increase co

deine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and 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 reduction of codeine until stable drug effects are achieved. Discontinuation of atazanavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If atazanavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Atazanavir is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with cobicistat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and 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 reduction of codeine until stable drug effects are achieved. Discontinuation of cobicistat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cobicistat is a strong inhibitor of CYP3A4.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Major) It is recommended that antacids not be given at the some time as atazanavir because of potential interference with absorption of atazanavir. Separate the administration of atazanavir and antacids to avoid the potential for interaction; give atazanavir 2 hours before or 1 hour after the antacid.
Aspirin, ASA; Omeprazole: (Contraindicated) Coadministration of proton pump inhibitors (PPIs) with atazanavir in treatment-experienced patients is contraindicated. PPIs can be used with atazanavir in treatment-naive patients under specific administration restrictions. In treatment-naive patients >= 40 kg, the PPI dose should not exceed the equivalent of omeprazole 20 mg/day, and the PPI must be administered 12 hours before atazanavir and ritonavir; use the dosage regimen of atazanavir 300 mg boosted with ritonavir 100 mg given once daily with food. While data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant PPIs, the same recommendations regarding timing and maximum doses of concomitant PPIs should be followed. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with a PPI. A randomized, open-label, multiple-dose drug interaction study of atazanavir (300 mg) with ritonavir (100 mg) coadministered with omeprazole 40 mg found a reduction in atazanavir AUC and Cmin of 76% and 78%, respectively. Additionally, after multiple doses of omeprazole (40 mg/day) and atazanavir (400 mg/day, 2 hours after omeprazole) without ritonavir, the AUC of atazanavir was decreased by 94%, Cmax by 96%, and Cmin by 95%. (Minor) The plasma concentrations of omeprazole may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while omeprazole is a CYP3A4 substrate.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of atazanavir is necessary. If atazanavir 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 atazanavir 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 atazanavir 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. (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. If cobicistat 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 cobicistat 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 cobicistat 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.
Atogepant: (Major) Avoid use of atogepant and atazanavir when atogepant is used for chronic migraine. Limit the dose of atogepant to 10 mg PO once daily for episodic migraine if coadministered with atazanavir. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of CYP3A and OATP1B1/3; atazanavir is a strong CYP3A inhibitor and an OATP1B1 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) Avoid use of atogepant and cobicistat when atogepant is used for chronic migraine. Limit the dose of atogepant to 10 mg PO once daily for episodic migraine if coadministered with cobicistat. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of CYP3A and OATP1B1/3; cobicistat is a strong CYP3A inhibitor and an OATP1B1/3 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. 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.
Atomoxetine: (Moderate) The plasma concentrations of atomoxetine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as dizziness, drowsiness, hypertension, and other cardiac adverse events, is recommended during coadministration and dosage adjustments for atomoxetine may be warranted. Cobicistat is a CYP2D6 inhibitor and atomoxetine is a CYP2D6 substrate.
Atorvastatin: (Major) Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with atazanavir. When atazanavir is boosted with cobicistat, use of atorvastatin is not recommended. The risk of developing myopathy or rhabdomyolysis increases when these drugs are used together. 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. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined statin and atazanavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. Increased atorvastatin serum concentrations may occur due to atazanavir inhibition of CYP3A4 metabolism. In addition, atorvastatin is a substrate of the drug transporter organic anion transporting polypeptide (OATP1B1); atazanavir is an OATP1B1 inhibitor. (Major) When administering atorvastatin concurrently with cobicistat, use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events (myopathy); DO NOT exceed a maximum daily atorvastatin dose of 20 mg daily. Cobicistat is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration with other strong CYP3A4 inhibitors increased atorvastatin exposure by 3.3- to 4.4-fold.
Atorvastatin; Ezetimibe: (Major) Use caution and the lowest atorvastatin dose necessary if atorvastatin must be coadministered with atazanavir. When atazanavir is boosted with cobicistat, use of atorvastatin is not recommended. The risk of developing myopathy or rhabdomyolysis increases when these drugs are used together. 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. The serious risk of myopathy or rhabdomyolysis should be weighed carefully against the benefits of combined statin and atazanavir therapy; there is no assurance that periodic monitoring of CK will prevent the occurrence of severe myopathy and renal damage. Increased atorvastatin serum concentrations may occur due to atazanavir inhibition of CYP3A4 metabolism. In addition, atorvastatin is a substrate of the drug transporter organic anion transporting polypeptide (OATP1B1); atazanavir is an OATP1B1 inhibitor. (Major) When administering atorvastatin concurrently with cobicistat, use the lowest starting dose of atorvastatin and carefully titrate while monitoring for adverse events (myopathy); DO NOT exceed a maximum daily atorvastatin dose of 20 mg daily. Cobicistat is a strong CYP3A4 inhibitor and atorvastatin is a CYP3A4 substrate. Coadministration with other strong CYP3A4 inhibitors increased atorvastatin exposure by 3.3- to 4.4-fold.
Atovaquone: (Major) Concurrent administration of atazanavir plus ritonavir with atovaquone; proguanil has shown to decrease the atovaquone AUC by 46% and the proguanil AUC by 41%. Consider alternative malaria prophylaxis.
Atovaquone; Proguanil: (Major) Concurrent administration of atazanavir plus ritonavir with atovaquone; proguanil has shown to decrease the atovaquone AUC by 46% and the proguanil AUC by 41%. Consider alternative malaria prophylaxis.
Avacopan: (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of atazanavir is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold. (Major) Reduce the dose of avacopan to 30 mg once daily if concomitant use of cobicistat is necessary. Concomitant use may increase avacopan exposure and risk for avacopan-related adverse effects. Avacopan is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased avacopan overall exposure 2.19-fold.
Avanafil: (Major) Concomitant use of avanafil and atazanavir is not recommended due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a substrate of and primarily metabolized by CYP3A4; atazanavir is a strong inhibitor of CYP3A4. Coadministration of avanafil with other strong inhibitors of CYP3A4 has resulted in significantly increased exposure to avanafil; atazanavir would be expected to have similar effects. (Major) Do not use avanafil in patients receiving cobicistat due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a sensitive CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the avanafil AUC by 13-fold.
Avapritinib: (Major) Avoid coadministration of avapritinib with atazanavir due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state. (Major) Avoid coadministration of avapritinib with cobicistat due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Axitinib: (Major) Avoid coadministration of axitinib with atazanavir 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 atazanavir is discontinued. Axitinib is a CYP3A4/5 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers. (Major) Avoid coadministration of axitinib with cobicistat 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 cobicistat is discontinued. Axitinib is a CYP3A4/5 substrate and cobicistat 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 atazanavir is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A 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. (Major) Coadministration of inhaled fluticasone propionate and cobicistat is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A 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.
Bedaquiline: (Major) Concurrent use of bedaquiline and a strong CYP3A4 inhibitor, such as atazanavir, for more than 14 days should be avoided unless the benefits justify the risks. When administered together, atazanavir may inhibit the metabolism of bedaquiline resulting in increased systemic exposure (AUC) and potentially more adverse reactions, such as QT prolongation and hepatotoxicity. (Major) Concurrent use of bedaquiline and cobicistat should be avoided due to the potential risk of adverse reactions to bedaquiline because of increased systemic exposure. Bedaquiline is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased bedaquiline exposure by 22%.
Belinostat: (Contraindicated) Avoid concomitant administration of belinostat with strong UGT1A1 inhibitors such as atazanavir, as belinostat is primarily metabolized by UGT1A1. Coadministration with strong UGT1A1 inhibitors may increase belinostat exposure and result in increased toxicities.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with atazanavir 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 atazanavir 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 atazanavir 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. Atazanavir is a strong inhibitor of CYP3A4. (Moderate) Concurrent use of benzhydrocodone with cobicistat 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 cobicistat 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 cobicistat 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. Cobicistat is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6.
Berotralstat: (Major) Reduce the berotralstat dose to 110 mg PO once daily in patients chronically taking cobicistat. Concurrent use may increase berotralstat exposure and the risk of adverse effects. Additionally, monitor for cobicistat-related adverse effects as concurrent use may also increase cobicistat exposure. Berotralstat is a P-gp and BCRP substrate and moderate CYP3A4 inhibitor; cobicistat is a CYP3A4 substrate and P-gp and BCRP inhibitor. Coadministration with another P-gp and BCRP inhibitor increased berotralstat exposure by 69%.
Beta-adrenergic blockers: (Moderate) Atazanavir can prolong the PR interval. Coadministration with other agents that prolong the PR interval, like beta blockers, may result in elevated risk of conduction disturbances and atrioventricular block.
Betamethasone: (Moderate) Monitor for corticosteroid-related adverse effects if coadministration is necessary. Consider using an alternative treatment to betametasone, such as a corticosteroid less affected by CYP3A4 (i.e., beclomethasone or prednisolone), particularly if long term use is indicated. Atazanavir 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%, leading to increased risk of corticosteroid side effects. (Moderate) Monitor for corticosteroid-related adverse effects if coadministration is necessary. Consider using an alternative treatment to betametasone, such as a corticosteroid less affected by CYP3A4 (i.e., beclomethasone or prednisolone), particularly if long term use is indicated. Cobicistat 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%, leading to increased risk of corticosteroid side effects.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving cobicistat. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving cobicistat. Bleeding risk may be increased; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a substrate of P-gp; cobicistat inhibits P-gp.
Bexarotene: (Major) Coadministration of cobicistat with bexarotene is not recommended as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Bexarotene is a CYP3A4 inducer. Cobicistat is a substrate of CYP3A4.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Concomitant use of bictegravir and atazanavir may result in increased bictegravir plasma concentrations, which may increase the risk of adverse effects. Monitor for increased toxicity if these drugs are used together. Bictegravir is a substrate of CYP3A4 and UGT1A1; atazanavir is a strong inhibitor of CYP3A4 and an inhibitor of UGT1A1. (Moderate) Concurrent use of atazanavir with tenofovir alafenamide may result in elevated tenofovir serum concentrations. Tenofovir alafenamide is a substrate for the drug transporter organic anion transporting polypeptide (OATP1B1/1B3); atazanavir is an OATP1B1 inhibitor. Monitor for increased toxicities if these drugs are given together.
Bortezomib: (Moderate) In vitro studies with human liver microsomes indicate that bortezomib is a significant substrate for CYP3A4. Agents that inhibit CYP3A4, such atazanavir, 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, atazanavir can cause peripheral neuropathy. It may be prudent to monitor patients for signs and symptoms of neuropathy. (Moderate) Monitor for signs of bortezomib toxicity and consider a bortezomib dose reduction if coadministration of cobicistat is necessary. Bortezomib exposure may be increased. Bortezomib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased bortezomib exposure by 35%.
Bosentan: (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. (Major) The plasma concentrations of bosentan may increase when administered with regimens containing cobicistat and atazanavir or darunavir. In addition, coadministration may result in decreased concentrations of cobicistat, atazanavir, and darunavir. In patients receiving the antiretrovirals for at least 10 days, start bosentan at 62.5 mg daily or every other day (depending on tolerability). When the antiretrovirals are initiated in a patients currently receiving bosentan, discontinue bosentan at least 36 hours prior to starting the antiretroviral regimen. After at least 10 days, restart bosentan at 62.5 mg daily or every other day based on tolerability. If switching from a ritonavir boosted antiretroviral regimen to a cobicistat boosted regimen, maintain current bosentan dose.
Bosutinib: (Major) Avoid concomitant use of bosutinib and atazanavir; 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 atazanavir is a moderate CYP3A4 inhibitor. In a cross-over trial in 18 healthy volunteers, the Cmax and AUC values of bosutinib were increased 1.5-fold and 2-fold, respectively, when bosutinib 500 mg PO was administered with a single dose of a moderate CYP3A4 inhibitor. (Major) Avoid concomitant use of bosutinib and cobicistat; 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 cobicistat is a strong CYP3A4 inhibitor. 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: (Moderate) Closely monitor for an increase in brentuximab-related adverse reactions, including peripheral neuropathy or gastrointestinal side effects, if coadministration with cobicistat is necessary. Monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased MMAE exposure by approximately 34%. (Minor) Concomitant administration of brentuximab vedotin and atazanavir 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 atazanavir, may alter MMAE exposure as MMAE is a CYP3A4 substrate. Monitor patients for adverse reactions.
Brexpiprazole: (Major) Because brexpiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the brexpiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as atazanavir. If these agents are used in combination, the patient should be carefully monitored for brexpiprazole-related adverse reactions. Because brexpiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a moderate to strong CYP3A4 inhibitor and moderate to strong CYP2D6 inhibitor should have their brexpiprazole dose reduced to one-quarter (25%) of the usual dose. If the co-administered CYP inhibitor is discontinued, adjust the brexpiprazole dose to its original level. (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 in combination with a moderate to strong inhibitor of CYP2D6. Cobicistat is a moderate to strong inhibitor of both CYP3A4 and CYP2D6. If these agents are used in combination, the patient should be carefully monitored for brexpiprazole-related adverse reactions. If cobicistat is discontinued, adjust the brexpiprazole dosage to its original level.
Brigatinib: (Major) Avoid coadministration of brigatinib with atazanavir 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 atazanavir, resume the brigatinib dose that was tolerated prior to initiation of atazanavir. Brigatinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively. (Major) Avoid coadministration of brigatinib with cobicistat 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 cobicistat, resume the brigatinib dose that was tolerated prior to initiation of cobicistat. Brigatinib is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
Brimonidine; Timolol: (Moderate) Coadministration of cobicistat (a CYP2D6 inhibitor) with beta-blockers metabolized by CYP2D6, such as timolol, may result in elevated beta-blocker serum concentrations. If used concurrently, close clinical monitoring with appropriate beta-blocker dose reductions are advised.
Brincidofovir: (Moderate) Postpone the administration of atazanavir 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 atazanavir is necessary. Brincidofovir is an OATP1B1 substrate and atazanavir is an OATP1B1 inhibitor. In a drug interaction study, the mean AUC and Cmax of brincidofovir increased by 374% and 269%, respectively, when administered with another OATP1B1 inhibitor. (Moderate) Postpone the administration of cobicistat 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 cobicistat is necessary. Brincidofovir is an OATP1B1/3 substrate and cobicistat 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 atazanavir 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; atazanavir is a strong inhibitor of CYP3A4. (Major) When bromocriptine is used for diabetes, avoid coadministration with cobicistat 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; cobicistat is a strong inhibitor of CYP3A4.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Budesonide: (Moderate) Avoid coadministration of oral budesonide and cobistat due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Elevated budesonide serum concentrations may result in Cushing's syndrome and adrenal suppression. Budesonide is a CYP3A4 and P-glycoprotein (P-gp) substrate; cobicistat is a strong inhibitor of CYP3A4 and P-gp. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use. (Moderate) Coadministration of budesonide with atazanavir may cause elevated budesonide serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Budesonide is a CYP3A4 substrate; atazanavir 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.
Budesonide; Formoterol: (Moderate) Avoid coadministration of oral budesonide and cobistat due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Elevated budesonide serum concentrations may result in Cushing's syndrome and adrenal suppression. Budesonide is a CYP3A4 and P-glycoprotein (P-gp) substrate; cobicistat is a strong inhibitor of CYP3A4 and P-gp. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use. (Moderate) Coadministration of budesonide with atazanavir may cause elevated budesonide serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Budesonide is a CYP3A4 substrate; atazanavir 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.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Avoid coadministration of oral budesonide and cobistat due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Elevated budesonide serum concentrations may result in Cushing's syndrome and adrenal suppression. Budesonide is a CYP3A4 and P-glycoprotein (P-gp) substrate; cobicistat is a strong inhibitor of CYP3A4 and P-gp. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use. (Moderate) Coadministration of budesonide with atazanavir may cause elevated budesonide serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Budesonide is a CYP3A4 substrate; atazanavir 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.
Bupivacaine Liposomal: (Moderate) Atazanavir inhibits the CYP3A4 isoenzyme at clinically relevant concentrations, which may lead to increased serum concentrations of local anesthetics and an increased potential for QT prolongation or other adverse effects. (Minor) Plasma concentrations of bupivacaine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as cardiotoxic effects, hypotension, or CNS toxicity, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while bupivacaine is a CYP3A4 substrate.
Bupivacaine: (Moderate) Atazanavir inhibits the CYP3A4 isoenzyme at clinically relevant concentrations, which may lead to increased serum concentrations of local anesthetics and an increased potential for QT prolongation or other adverse effects. (Minor) Plasma concentrations of bupivacaine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as cardiotoxic effects, hypotension, or CNS toxicity, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while bupivacaine is a CYP3A4 substrate.
Bupivacaine; Epinephrine: (Moderate) Atazanavir inhibits the CYP3A4 isoenzyme at clinically relevant concentrations, which may lead to increased serum concentrations of local anesthetics and an increased potential for QT prolongation or other adverse effects. (Minor) Plasma concentrations of bupivacaine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as cardiotoxic effects, hypotension, or CNS toxicity, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while bupivacaine is a CYP3A4 substrate.
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. (Moderate) Atazanavir inhibits the CYP3A4 isoenzyme at clinically relevant concentrations, which may lead to increased serum concentrations of local anesthetics and an increased potential for QT prolongation or other adverse effects. (Moderate) Monitor for lidocaine-related adverse reactions if coadministration with cobicistat is necessary. Lidocaine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. (Minor) Plasma concentrations of bupivacaine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as cardiotoxic effects, hypotension, or CNS toxicity, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while bupivacaine is a CYP3A4 substrate.
Bupivacaine; Meloxicam: (Moderate) Atazanavir inhibits the CYP3A4 isoenzyme at clinically relevant concentrations, which may lead to increased serum concentrations of local anesthetics and an increased potential for QT prolongation or other adverse effects. (Moderate) The plasma concentrations of meloxicam may be elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects is recommended during coadministration. Atazanavir is a CYP3A4 inhibitor, while meloxicam is a CYP3A4 substrate. (Minor) Plasma concentrations of bupivacaine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as cardiotoxic effects, hypotension, or CNS toxicity, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while bupivacaine is a CYP3A4 substrate.
Buprenorphine: (Major) Atazanavir-induced inhibition of CYP3A4 may increase the AUCs of buprenorphine by 93% and norbuprenorphine 76%. When buprenorphine is coadministered with atazanavir/ritonavir the AUCs of buprenophine and norbuprenorphine are increased by 66% and 105%, respectively. Serious drug interactions have been reported following administration of sublingual buprenorphine with atazanavir and atazanavir/ritonavir; although not clinically studied, atazanavir-induced inhibition of UGT1A1 may increase the potential for interaction with orally administered buprenorphine. If atazanavir plus ritonavir must be coadministered with buprenorphine, monitor patient response, including sedation and cognitive effects, and adjust the dose of buprenorphine if necessary. Buprenorphine administered with atazanavir plus ritonavir is not expected to decrease atazanavir concentrations; however, if buprenorphine is administered with atazanavir in the absence of ritonavir, atazanavir concentrations may be decreased. Do not administer atazanavir with buprenorphine with unboosted atazanavir. (Moderate) Concomitant use of buprenorphine and cobicistat can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when cobicistat 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 cobicistat, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If cobicistat is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and cobicistat is a CYP3A inhibitor.
Buprenorphine; Naloxone: (Major) Atazanavir-induced inhibition of CYP3A4 may increase the AUCs of buprenorphine by 93% and norbuprenorphine 76%. When buprenorphine is coadministered with atazanavir/ritonavir the AUCs of buprenophine and norbuprenorphine are increased by 66% and 105%, respectively. Serious drug interactions have been reported following administration of sublingual buprenorphine with atazanavir and atazanavir/ritonavir; although not clinically studied, atazanavir-induced inhibition of UGT1A1 may increase the potential for interaction with orally administered buprenorphine. If atazanavir plus ritonavir must be coadministered with buprenorphine, monitor patient response, including sedation and cognitive effects, and adjust the dose of buprenorphine if necessary. Buprenorphine administered with atazanavir plus ritonavir is not expected to decrease atazanavir concentrations; however, if buprenorphine is administered with atazanavir in the absence of ritonavir, atazanavir concentrations may be decreased. Do not administer atazanavir with buprenorphine with unboosted atazanavir. (Moderate) Concomitant use of buprenorphine and cobicistat can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when cobicistat 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 cobicistat, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If cobicistat is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A and cobicistat is a CYP3A inhibitor. (Moderate) The plasma concentrations of buprenorphine and naloxone may be elevated when administered concurrently with cobicistat. When initiating buprenorphine; naloxone in patients currently on a regimen containing cobicistat and atazanavir or darunavir, use the lowest buprenorphine; naloxone starting dose and slowly titrate to desired effect. When initiating antiretroviral regimens containing cobicistat and atazanavir or darunavir to patients on buprenorphine; naloxone, an adjustment of buprenorphine; naloxone dose may be needed. Monitoring for adverse effects, such as CNS side effects or respiratory depression, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while buprenorphine is a CYP3A4 substrate.
Bupropion: (Moderate) Caution is warranted when cobicistat is administered with bupropion as there is a potential for elevated cobicistat concentrations. Bupropion is a CYP2D6 inhibitor in vitro, while cobicistat is a substrate of CYP2D6.
Bupropion; Naltrexone: (Moderate) Caution is warranted when cobicistat is administered with bupropion as there is a potential for elevated cobicistat concentrations. Bupropion is a CYP2D6 inhibitor in vitro, while cobicistat is a substrate of CYP2D6.
Buspirone: (Moderate) A low dose of buspirone used cautiously is recommended when coadministered with cobicistat. If a patient has been titrated to a stable dosage of buspirone, a dose adjustment of buspirone may be necessary to avoid adverse events attributable to buspirone. Administering cobicistat with buspirone may increase buspirone concentration and risk for adverse events. Buspirone is a sensitive substrate of CYP3A4. Cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the buspirone AUC by 19-fold with an increased incidence of buspirone-related adverse effects. (Moderate) When buspirone is administered with an inhibitor of CYP3A4 like atazanavir, a lower dose of buspirone is recommended. Dose adjustment of either drug should be based on clinical assessment.
Butalbital; Acetaminophen: (Major) Coadministration of butalbital and atazanavir may increase the metabolism of atazanavir and lead to decreased atazanavir concentrations resulting in reduction of antiretroviral efficacy and development of viral resistance. If atazanavir and butalbital are used together, the patient must be closely monitored for antiviral efficacy.
Butalbital; Acetaminophen; Caffeine: (Major) Coadministration of butalbital and atazanavir may increase the metabolism of atazanavir and lead to decreased atazanavir concentrations resulting in reduction of antiretroviral efficacy and development of viral resistance. If atazanavir and butalbital are used together, the patient must be closely monitored for antiviral efficacy.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Coadministration of butalbital and atazanavir may increase the metabolism of atazanavir and lead to decreased atazanavir concentrations resulting in reduction of antiretroviral efficacy and development of viral resistance. If atazanavir and butalbital are used together, the patient must be closely monitored for antiviral efficacy. (Moderate) Concomitant use of codeine with atazanavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and 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 reduction of codeine until stable drug effects are achieved. Discontinuation of atazanavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If atazanavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Atazanavir is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with cobicistat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and 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 reduction of codeine until stable drug effects are achieved. Discontinuation of cobicistat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cobicistat is a strong inhibitor of CYP3A4.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Coadministration of butalbital and atazanavir may increase the metabolism of atazanavir and lead to decreased atazanavir concentrations resulting in reduction of antiretroviral efficacy and development of viral resistance. If atazanavir and butalbital are used together, the patient must be closely monitored for antiviral efficacy. (Moderate) Concomitant use of codeine with atazanavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and 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 reduction of codeine until stable drug effects are achieved. Discontinuation of atazanavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If atazanavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Atazanavir is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with cobicistat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and 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 reduction of codeine until stable drug effects are achieved. Discontinuation of cobicistat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cobicistat is a strong inhibitor of CYP3A4.
Cabazitaxel: (Major) Avoid coadministration of cabazitaxel with atazanavir 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 atazanavir is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%. (Major) Avoid coadministration of cabazitaxel with cobicistat 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 cobicistat is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Cabotegravir; Rilpivirine: (Moderate) Close clinical monitoring is advised when administering atazanavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Atazanavir is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. (Moderate) The plasma concentrations of rilpivirine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Rilpivirine is a CYP3A4 substrate and cobicistat is a strong inhibitor of CYP3A4.
Cabozantinib: (Major) Avoid concomitant use of cabozantinib and atazanavir 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 atazanavir 2 to 3 days after discontinuation of atazanavir. Cabozantinib is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%. (Major) Avoid concomitant use of cabozantinib and cobicistat 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 cobicistat 2 to 3 days after discontinuation of cobicistat. Cabozantinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
Calcifediol: (Moderate) Dose adjustment of calcifediol may be necessary during coadministration with atazanavir. Additionally, serum 25-hydroxyvitamin D, intact PTH, and calcium concentrations should be closely monitored if a patient initiates or discontinues therapy with atazanavir. Atazanavir, 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 Carbonate: (Major) Atazanavir solubility decreases as gastric pH increases. Although drug interactions between atazanavir and antacids have not been specifically studied, based on data with other protease inhibitors, it is recommended that antacids not be given at the same time as atazanavir because of potential interference with absorption of atazanavir. Separate the administration of atazanavir and antacids to avoid the potential for interaction; give atazanavir 2 hours before or 1 hour after the antacid.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Major) Atazanavir solubility decreases as gastric pH increases. Although drug interactions between atazanavir and antacids have not been specifically studied, based on data with other protease inhibitors, it is recommended that antacids not be given at the same time as atazanavir because of potential interference with absorption of atazanavir. Separate the administration of atazanavir and antacids to avoid the potential for interaction; give atazanavir 2 hours before or 1 hour after the antacid. (Major) Coadministration of H2-blockers with atazanavir reduces serum atazanavir concentrations; however, H2-blockers can be used under specific administration restrictions. Although data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant H2-blockers, the same recommendations regarding timing and maximum doses of concomitant H2-blockers should be followed. In treatment-naive patients >= 40 kg, do not exceed an H2- blocker dose equivalent to famotidine 40 mg twice daily, and give atazanavir 300 mg with ritonavir 100 mg once daily with food. Give atazanavir simultaneously with and/or at least 10 hours after the H2- blocker. If a treatment-naive adult or adolescent (>= 40 kg) cannot tolerate ritonavir, do not exceed an H2- blocker dose equivalent to famotidine 20 mg twice daily, and the atazanavir dose should be increased to 400 mg once daily with food given at least 2 hours before or 10 hours after the H2- blocker. Data are insufficent to recommend atazanavir dosing in children or adolescents < 40 kg not receiving ritonavir boosting. In treatment-naive patients on a cobicistat-boosted regimen, cobicistat and atazanavir may be administered without dosage adjustment if given at the same time or a minimum of 10 hours after dosing of the H2-blocker. The H2-blocker dose should not exceed a dose that is comparable to 40 mg/day of famotidine in treatment-naive patients. In treatment-experienced patients >= 40 kg, do not exceed an H2- blocker dose equivalent to famotidine 20 mg twice daily, and give atazanavir 300 mg with ritonavir 100 mg once daily with food. Give atazanavir simultaneously with and/or at least 10 hours after the H2- blocker. In treatment-experienced patients >= 40 kg receiving H2-antagonists and tenofovir, atazanavir should be dosed 400 mg with ritonavir 100 mg once daily with food. In antiretroviral-experienced patients on a cobicistat-boosted regimen, the dosage of cobicistat with atazanavir needs to be increased if administered with H2-blockers; the recommended dose is cobicistat 150 mg/day with atazanavir 400 mg/day and 20 mg/day or less of famotidine or other comparably dosed H2-blocker. Significant reductions in atazanavir serum concentrations may lead to therapeutic failure and the development of HIV resistance. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with an H2- blocker.
Calcium Carbonate; Magnesium Hydroxide: (Major) Atazanavir solubility decreases as gastric pH increases. Although drug interactions between atazanavir and antacids have not been specifically studied, based on data with other protease inhibitors, it is recommended that antacids not be given at the same time as atazanavir because of potential interference with absorption of atazanavir. Separate the administration of atazanavir and antacids to avoid the potential for interaction; give atazanavir 2 hours before or 1 hour after the antacid.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Major) Atazanavir solubility decreases as gastric pH increases. Although drug interactions between atazanavir and antacids have not been specifically studied, based on data with other protease inhibitors, it is recommended that antacids not be given at the same time as atazanavir because of potential interference with absorption of atazanavir. Separate the administration of atazanavir and antacids to avoid the potential for interaction; give atazanavir 2 hours before or 1 hour after the antacid.
Calcium Carbonate; Simethicone: (Major) Atazanavir solubility decreases as gastric pH increases. Although drug interactions between atazanavir and antacids have not been specifically studied, based on data with other protease inhibitors, it is recommended that antacids not be given at the same time as atazanavir because of potential interference with absorption of atazanavir. Separate the administration of atazanavir and antacids to avoid the potential for interaction; give atazanavir 2 hours before or 1 hour after the antacid.
Calcium; Vitamin D: (Major) Atazanavir solubility decreases as gastric pH increases. Although drug interactions between atazanavir and antacids have not been specifically studied, based on data with other protease inhibitors, it is recommended that antacids not be given at the same time as atazanavir because of potential interference with absorption of atazanavir. Separate the administration of atazanavir and antacids to avoid the potential for interaction; give atazanavir 2 hours before or 1 hour after the antacid.
Canagliflozin: (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.
Canagliflozin; Metformin: (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (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 occ urred 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.
Capmatinib: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with atazanavir is necessary. Capmatinib is a CYP3A substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%. (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with cobicistat is necessary. Capmatinib is a CYP3A substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
Carbamazepine: (Contraindicated) Coadministration of carbamazepine with cobicistat-containing regimens is contraindicated. If these drugs are used together, significant decreases in the plasma concentrations of the antiretrovirals may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. In addition, inhibition of CYP3A4 by cobicistat may result in elevated carbamazepine concentrations. Consider use of an alternative anticonvulsant or antiretroviral therapy. (Major) Coadministration of carbamazepine and atazanavir may increase the metabolism of atazanavir and lead to decreased atazanavir concentrations resulting in reduction of antiretroviral efficacy and development of viral resistance. Avoid coadministration of atazanavir with carbamazepine unless atazanavir is boosted with ritonavir. In addition, coadministration of atazanavir and ritonavir with carbamazepine may result in increased carbamazepine concentrations. If atazanavir and carbamazepine are used together, the patient must be closely monitored for antiviral efficacy and carbamazepine toxicity; clinical monitoring of carbamazepine concentrations with dosage titration if necessary is also warranted.
Cariprazine: (Major) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. When a strong CYP3A4 inhibitor, such as atazanavir, 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 adult 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 an adult 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. (Major) The dose of cariprazine should be reduced in patients also receiving cobicistat. When cobicistat 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 initiating cariprazine in a patient who is stable on cobicistat, 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, and then increased to a maximum dose of 3 mg daily. If cobicistat is withdrawn, the cariprazine dosage may need to be increased. Cariprazine is metabolized by CYP3A4 to its major active metabolite. Cobicistat is a strong CYP3A4 inhibitor. Concurrent use with another strong CYP3A4 inhibitor increased the exposure of cariprazine by about 4-fold; increased the AUC of DDCAR metabolite by about 1.5-fold; and decreased DCAR metabolite AUC by about one-third.
Carvedilol: (Moderate) Coadministration of cobicistat (a CYP2D6 inhibitor) with beta-blockers metabolized by CYP2D6, such as carvedilol, may result in elevated beta-blocker serum concentrations. If used concurrently, close clinical monitoring with appropriate beta-blocker dose reductions are advise.
Celecoxib; Tramadol: (Major) As cobicistat is a CYP2D6 and CYP3A4 inhibitor and tramadol is primarily metabolized by CYP2D6 and CYP3A4, concurrent therapy may decrease tramadol metabolism; reduced tramadol dose may be needed during coadministration. This interaction may result in decreased tramadol efficacy and/or increased tramadol-induced risks of serotonin syndrome or seizures. The analgesic activity of tramadol is due to the activity of both the parent drug and the O-desmethyltramadol metabolite (M1), and M1 formation is dependent on CYP2D6. Therefore, use of tramadol with a CYP2D6-inhibitor may alter tramadol efficacy. In addition, inhibition of either or both CYP2D6 and CYP3A4 is expected to result in reduced metabolic clearance of tramadol. This in turn may increase the risk of tramadol-related adverse events including serotonin syndrome and seizures. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Cenobamate: (Moderate) Coadministration of cobicistat with cenobamate may result in significant decreases in the plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Cobicistat is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Ceritinib: (Major) Avoid concomitant use of ceritinib with atazanavir 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 atazanavir is discontinued, resume the dose of ceritinib taken prior to initiating atazanavir. Ceritinib is a CYP3A substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A inhibitor increased ceritinib exposure by 2.9-fold. (Major) Avoid concomitant use of ceritinib with cobicistat due to increased ceritinib exposure which may increase the incidence and severity of adverse reactions; cobicistat exposure may also increase. 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 cobicistat is discontinued, resume the dose of ceritinib taken prior to initiating cobicistat. Both drugs are CYP3A substrates and strong CYP3A4 inhibitors. Coadministration with a strong CYP3A inhibitor increased ceritinib exposure by 2.9-fold.
Chloramphenicol: (Moderate) Caution is warranted when atazanavir is administered with chloramphenicol as there is a potential for elevated concentrations of atazanavir. Chloramphenicol is a CYP3A4 inhibitor; atazanavir is a substrate of CYP3A4. (Moderate) Caution is warranted when cobicistat is administered with chloramphenicol as there is a potential for elevated cobicistat concentrations. Chloramphenicol is a CYP3A4 inhibitor and cobicistat is a substrate of CYP3A4.
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. (Moderate) The plasma concentrations of chlordiazepoxide may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while chlordiazepoxide is a CYP3A4 substrate.
Chlordiazepoxide; Amitriptyline: (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) According to the manufacturer, concurrent use of tricyclic antidepressants (TCAs) and atazanavir may result in elevated TCA plasma concentration, and could increase the potential for serious adverse effects. If these drugs are administered together, carefully titrate the TCA dose based on a clinical assessment of antidepressant response. Patients on a stable dose of TCA who start treatment with atazanavir should be monitored for TCA-associated anticholinergic effects (e.g., sedation, confusion, constipation). In addition to clinical monitoring, the manufacturer suggests obtaining TCA serum concentrations (where available) as an adjunct to assessing the potential for interactions. (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. Concurrent use may result in elevated TCA plasma concentrations. (Moderate) The plasma concentrations of chlordiazepoxide may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while chlordiazepoxide is a CYP3A4 substrate.
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. (Moderate) The plasma concentrations of chlordiazepoxide may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while chlordiazepoxide is a CYP3A4 substrate.
Chlorpheniramine: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6.
Chlorpheniramine; Codeine: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Concomitant use of codeine with atazanavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and 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 reduction of codeine until stable drug effects are achieved. Discontinuation of atazanavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If atazanavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Atazanavir is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with cobicistat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and 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 reduction of codeine until stable drug effects are achieved. Discontinuation of cobicistat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cobicistat is a strong inhibitor of CYP3A4.
Chlorpheniramine; Dextromethorphan: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Concomitant use of dihydrocodeine with atazanavir 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 atazanavir could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If atazanavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Atazanavir is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine. (Moderate) Concomitant use of dihydrocodeine with cobicistat 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 cobicistat could decrease dihydrocodeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to dihydrocodeine. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of dihydrocodeine.
Chlorpheniramine; Hydrocodone: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of atazanavir 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 atazanavir 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 atazanavir 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. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cobicistat 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 with a combined CYP2D6 and CYP3A4 inhibitor. If cobicistat 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) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6.
Chlorpheniramine; Phenylephrine: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6.
Chlorpheniramine; Pseudoephedrine: (Moderate) Caution is warranted when cobicistat is administered with chlorpheniramine as there is a potential for elevated chlorpheniramine and cobicistat concentrations. Chlorpheniramine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6.
Chlorpromazine: (Major) Caution is warranted when cobicistat is administered with chlorpromazine as there is a potential for elevated chlorpromazine and cobicistat concentrations. Chlorpromazine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6.
Ciclesonide: (Moderate) Coadministration of ciclesonide with atazanavir may cause elevated ciclesonide serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Ciclesonide is a CYP3A4 substrate; atazanavir 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. (Moderate) Coadministration of ciclesonide with cobicistat may cause elevated ciclesonide serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Ciclesonide is a CYP3A4 substrate; cobicistat 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) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with cobicistat. Monitor for an increase in cilostazol-related adverse reactions. Cobicistat is a strong CYP3A4 inhibitor and cilostazol is a CYP3A4 substrate. Coadministration of another strong CYP3A4 inhibitor increased the cilostazol AUC by 117%. (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with protease inhibitors and monitor for an increase in cilostazol-related adverse reactions. Concurrent use may increase cilostazol exposure. Cilostazol is a CYP3A substrate; protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a strong CYP3A inhibitor increased the cilostazol AUC by 117%. Coadministration with a moderate CYP3A inhibitor increased the AUC of cilostazol (single dose) by 73%; the AUC of 4-trans-hydroxycilostazol increased by 141%.
Cimetidine: (Major) Coadministration of H2-blockers with atazanavir reduces serum atazanavir concentrations; however, H2-blockers can be used under specific administration restrictions. Although data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant H2-blockers, the same recommendations regarding timing and maximum doses of concomitant H2-blockers should be followed. In treatment-naive patients >= 40 kg, do not exceed an H2- blocker dose equivalent to famotidine 40 mg twice daily, and give atazanavir 300 mg with ritonavir 100 mg once daily with food. Give atazanavir simultaneously with and/or at least 10 hours after the H2- blocker. If a treatment-naive adult or adolescent (>= 40 kg) cannot tolerate ritonavir, do not exceed an H2- blocker dose equivalent to famotidine 20 mg twice daily, and the atazanavir dose should be increased to 400 mg once daily with food given at least 2 hours before or 10 hours after the H2- blocker. Data are insufficent to recommend atazanavir dosing in children or adolescents < 40 kg not receiving ritonavir boosting. In treatment-naive patients on a cobicistat-boosted regimen, cobicistat and atazanavir may be administered without dosage adjustment if given at the same time or a minimum of 10 hours after dosing of the H2-blocker. The H2-blocker dose should not exceed a dose that is comparable to 40 mg/day of famotidine in treatment-naive patients. In treatment-experienced patients >= 40 kg, do not exceed an H2- blocker dose equivalent to famotidine 20 mg twice daily, and give atazanavir 300 mg with ritonavir 100 mg once daily with food. Give atazanavir simultaneously with and/or at least 10 hours after the H2- blocker. In treatment-experienced patients >= 40 kg receiving H2-antagonists and tenofovir, atazanavir should be dosed 400 mg with ritonavir 100 mg once daily with food. In antiretroviral-experienced patients on a cobicistat-boosted regimen, the dosage of cobicistat with atazanavir needs to be increased if administered with H2-blockers; the recommended dose is cobicistat 150 mg/day with atazanavir 400 mg/day and 20 mg/day or less of famotidine or other comparably dosed H2-blocker. Significant reductions in atazanavir serum concentrations may lead to therapeutic failure and the development of HIV resistance. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with an H2- blocker.
Cinacalcet: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of atazanavir and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%. (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of cobicistat and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Cisapride: (Contraindicated) Coadministration of cisapride with cobicistat is contraindicated. Cobicistat is a strong inhibitor of CYP3A4, and plasma concentrations of drugs extensively metabolized by this enzyme, such as cisapride, are expected to increase with concurrent use. Elevated plasma concentrations of cisapride have been associated with QT prolongation and serious cardiovascular adverse events including death due to torsade de pointes. (Contraindicated) Concomitant use of protease inhibitors and cisapride is contraindicated; use increases cisapride exposure and the risk for cisapride-related adverse effects such as QT/QTc prolongation and torsade de pointes (TdP). Cisapride is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Concomitant use of cisapride with CYP3A inhibitors also is disallowed under the Propulsid Limited Access Program.
Citalopram: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Clarithromycin: (Major) Avoid concurrent use of clarithromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of clarithromycin, cobicistat, atazanavir and darunavir. Both clarithromycin and cobicistat are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of cobicistat, atazanavir and darunavir. (Major) Coadministration with atazanavir increases clarithromycin serum concentrations. Use caution if these drugs are coadministered, as increased clarithromycin concentrations may cause QT prolongation; a 50% dosage reduction of clarithromycin is recommended. In addition, atazanavir significantly reduces the concentration of 14-OH clarithromycin, the active metabolite of clarithromycin; consider alternative agents for indications other than infections due to Mycobacterium avium complex (MAC).
Clindamycin: (Moderate) Monitor for an increase in clindamycin-related adverse reactions with coadministration of atazanavir as concurrent use may increase clindamycin exposure. Clindamycin is a CYP3A4 substrate; atazanavir is a strong inhibitor of CYP3A4. (Moderate) Monitor for an increase in clindamycin-related adverse reactions with coadministration of cobicistat as concurrent use may increase clindamycin exposure. Clindamycin is a CYP3A4 substrate; cobicistat is a strong inhibitor of CYP3A4.
Clobazam: (Major) Coadministration of atazanavir with clobazam is not recommended. There is a potential for elevated clobazam concentrations and altered atazanavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Clobazam is a substrate of CYP3A4. Clobazam is also a weak inducer of CYP3A4. The active metabolite of clobazam, N-desmethylclobazam, is a dose-dependent inducer of CYP3A4. Atazanavir is an inhibitor/substrate of CYP3A4. (Major) Coadministration of cobicistat with clobazam is not recommended. There is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Clobazam is a weak inducer of CYP3A4. Cobicistat is a substrate of CYP3A4.
Clomipramine: (Moderate) According to the manufacturer, concurrent use of tricyclic antidepressants (TCAs) and atazanavir may result in elevated TCA plasma concentration, and could increase the potential for serious adverse effects. If these drugs are administered together, carefully titrate the TCA dose based on a clinical assessment of antidepressant response. Patients on a stable dose of TCA who start treatment with atazanavir should be monitored for TCA-associated anticholinergic effects (e.g., sedation, confusion, constipation). In addition to clinical monitoring, the manufacturer suggests obtaining TCA serum concentrations (where available) as an adjunct to assessing the potential for interactions. (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. Concurrent use may result in elevated TCA plasma concentrations.
Clonazepam: (Moderate) Monitor for increased sedation and respiratory depression if clonazepam is coadministered with cobicistat; adjust the dose of clonazepam if necessary. The systemic exposure of clonazepam may be increased resulting in increase in treatment-related adverse reactions. Cobicistat is a strong CYP3A4 inhibitor and clonazepam is a CYP3A4 substrate. (Moderate) Monitor for increased sedation and respiratory depression if clonazepam is coadministered with protease inhibitors; adjust the dose of clonazepam if necessary. The systemic exposure of clonazepam may be increased resulting in an increase in treatment-related adverse reactions. Clonazepam is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors.
Clopidogrel: (Major) Avoid coadministration of clopidogrel with cobicistat due to the potential for decreased clopidogrel efficacy. Prasugrel may be preferred to clopidogrel if coadministration with cobicistat is necessary. Although clopidogrel is primarily converted to its active metabolite via CYP2C19, it has been suggested that inhibition of CYP3A4 also reduces its conversion to the active metabolite, thereby reducing its antiplatelet effect. Cobicistat is a strong CYP3A4 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. (Moderate) Use caution if coadministration of cobicistat with clorazepate is necessary, as the systemic exposure of the active metabolite of clorazepate may be increased resulting in an increase in treatment-related adverse reactions; adjust the dose of clorazepate if necessary. Cobicistat is a strong CYP3A4 inhibitor. Clorazepate is a pro-drug converted to N-desmethyldiazepam in the GI tract; N-desmethyldiazepam is metabolized by 2C19 and 3A4.
Clozapine: (Moderate) Caution is advisable during concurrent use of atazanavir and clozapine. Atazanavir is an inhibitor of CYP3A4, one of the isoenzymes responsible for the metabolism of clozapine. Treatment with clozapine has been associated with QT prolongation, torsade de pointes (TdP), cardiac arrest, and sudden death. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary. (Moderate) Caution is advisable during concurrent use of cobicistat and clozapine. Cobicistat is an inhibitor of CYP2D6 and CYP3A4, two of the isoenzymes responsible for the metabolism of clozapine. Elevated plasma concentrations of clozapine occurring through CYP inhibition may potentially increase the risk of life-threatening arrhythmias, sedation, anticholinergic effects, seizures, orthostasis, or other adverse effects. According to the manufacturer, patients receiving clozapine in combination with a CYP3A4 or CYP2D6 inhibitor should be monitored for adverse reactions. Consideration should be given to reducing the clozapine dose if necessary. If the inhibitor is discontinued after dose adjustments are made, monitor for lack of clozapine effectiveness and consider increasing the clozapine dose if necessary.
Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with atazanavir due to the risk of cobimetinib toxicity. Cobimetinib is a CYP3A substrate in vitro, and atazanavir is a strong inhibitor of CYP3A. 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). (Major) Avoid the concurrent use of cobimetinib with chronic cobicistat due to the risk of cobimetinib toxicity. If concurrent short-term (14 days or less) use of cobicistat is unavoidable, reduce the dose of cobimetinib to 20 mg once daily for patients normally taking 60 mg daily; after discontinuation of cobicistat, resume cobimetinib at the previous dose. Use an alternative to cobicistat in patients who are already taking a reduced dose of cobimetinib (40 or 20 mg daily). Cobimetinib is a P-glycoprotein (P-gp) substrate as well as a CYP3A substrate in vitro; cobicistat is a moderate inhibitor of both P-gp and CYP3A. In healthy subjects (n = 15), coadministration of a single 10 mg dose of cobimetinib with itraconazole (200 mg once daily for 14 days), a 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) Caution is warranted when atazanavir is administered with cocaine as there is a potential for elevated concentrations of both drugs. Clinical monitoring for adverse effects is recommended during coadministration. Both drugs are substrates and inhibitors of CYP3A4. (Moderate) Caution is warranted when cobicistat is administered with cocaine as there is a potential for elevated concentrations of both drugs. Clinical monitoring for adverse effects is recommended during coadministration. Both drugs are substrates and inhibitors of CYP3A4. Cocaine is also an inhibitor of CYP2D6; cobicistat is a CYP2D6 substrates/inhibitors.
Codeine: (Moderate) Concomitant use of codeine with atazanavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and 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 reduction of codeine until stable drug effects are achieved. Discontinuation of atazanavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If atazanavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Atazanavir is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with cobicistat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and 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 reduction of codeine until stable drug effects are achieved. Discontinuation of cobicistat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cobicistat is a strong inhibitor of CYP3A4.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with atazanavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and 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 reduction of codeine until stable drug effects are achieved. Discontinuation of atazanavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If atazanavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Atazanavir is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with cobicistat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and 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 reduction of codeine until stable drug effects are achieved. Discontinuation of cobicistat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cobicistat is a strong inhibitor of CYP3A4.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with atazanavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and 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 reduction of codeine until stable drug effects are achieved. Discontinuation of atazanavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If atazanavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Atazanavir is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with cobicistat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and 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 reduction of codeine until stable drug effects are achieved. Discontinuation of cobicistat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cobicistat is a strong inhibitor of CYP3A4.
Codeine; Phenylephrine; Promethazine: (Moderate) Caution is warranted when cobicistat is administered with promethazine as there is a potential for elevated promethazine and cobicistat concentrations. Promethazine is a CYP2D6 substrate/inhibitor and cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Concomitant use of codeine with atazanavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and 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 reduction of codeine until stable drug effects are achieved. Discontinuation of atazanavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If atazanavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Atazanavir is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with cobicistat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and 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 reduction of codeine until stable drug effects are achieved. Discontinuation of cobicistat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cobicistat is a strong inhibitor of CYP3A4.
Codeine; Promethazine: (Moderate) Caution is warranted when cobicistat is administered with promethazine as there is a potential for elevated promethazine and cobicistat concentrations. Promethazine is a CYP2D6 substrate/inhibitor and cobicistat is a substrate/inhibitor of CYP2D6. (Moderate) Concomitant use of codeine with atazanavir may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and 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 reduction of codeine until stable drug effects are achieved. Discontinuation of atazanavir could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If atazanavir is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Atazanavir is a strong inhibitor of CYP3A4. (Moderate) Concomitant use of codeine with cobicistat may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased morphine concentrations, and 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 reduction of codeine until stable drug effects are achieved. Discontinuation of cobicistat could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If cobicistat is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. Cobicistat is a strong inhibitor of CYP3A4.
Colchicine: (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and atazanavir 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. Atazanavir can inhibit colchicine's metabolism via 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 atazanavir 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. (Major) Due to the risk for serious colchicine toxicity including multi-organ failure and death, avoid coadministration of colchicine and cobicistat 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. Cobicistat 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 a P-gp/strong CYP3A4 inhibitor like cobicistat 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 atazanavir is contraindicated due to the potential for increased conivaptan exposure. Conivaptan is a sensitive CYP3A substrate; atazanavir 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. (Contraindicated) Coadministration of conivaptan and cobicistat is contraindicated due to the potential for increased conivaptan exposure. Concomitant use may also increase cobicistat exposure and risk for cobicistat-related adverse effects. Conivaptan is a CYP3A substrate and moderate CYP3A inhibitor; cobicistat is a CYP3A substrate and 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) Atazanavir has been shown to decrease the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should be instructed to report any estrogen- related adverse events.
Conjugated Estrogens; Bazedoxifene: (Moderate) Atazanavir has been shown to decrease the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should be instructed to report any estrogen- related adverse events.
Conjugated Estrogens; Medroxyprogesterone: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with atazanavir, 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. (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with medroxyprogesterone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Moderate) Atazanavir has been shown to decrease the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should be instructed to report any estrogen- related adverse events.
Copanlisib: (Major) Avoid the concomitant use of copanlisib and atazanavir 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; atazanavir is a strong CYP3A inhibitor. (Major) Avoid the concomitant use of copanlisib and cobicistat 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; cobicistat is a strong CYP3A inhibitor. The AUC of copanlisib increased by 53% when a single IV dose of copanlisib 60 mg was administered following 10 days of another strong CYP3A4 inhibitor in a drug interaction study in patients with cancer.
Crizotinib: (Major) Avoid concomitant use of atazanavir 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 atazanavir. Crizotinib is a CYP3A substrate and atazanavir 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. (Major) Avoid concomitant use of cobicistat and crizotinib due to increased plasma concentrations of crizotinib, which may increase the incidence and severity of adverse reactions; exposure to cobicistat may also increase. 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 cobicistat. Crizotinib is a CYP3A substrate and moderate inhibitor. Cobicistat is a CYP3A substrate and 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.
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: (Moderate) 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. (Moderate) Cyclosporine therapeutic drug monitoring is recommended when administered concurrently with cobicistat. Use of these medications together may result in elevated cyclosporine serum concentrations, causing an increased risk for cyclosporine-related adverse events. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of cyclosporine.
Dabigatran: (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with cobicistat 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 cobicistat is a P-gp inhibitor.
Dabrafenib: (Major) Avoid coadministration of dabrafenib and cobicistat due to the potential for decreased cobicistat concentrations and increased dabrafenib exposure. If another agent cannot be substituted and coadministration of these agents is unavoidable, monitor patients closely for reduced antiretroviral efficacy and dabrafenib adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity. Both drugs are CYP3A4 substrates. Darafenib is a moderate CYP3A4 inducer, while cobicistat is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the dabrafenib AUC by 71%, hydroxy-dabrafenib AUC by 82%, and desmethyl-dabrafenib AUC by 68%. (Major) Coadministration of atazanavir with dabrafenib is not recommended as there is a potential for elevated dabrafenib concentrations and decreased concentrations of atazanavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Atazanavir is metabolized by CYP3A4; dabrafenib is a moderate CYP3A4 inducer. In addition, darbrafenib is a substrate for CYP2C8; atazanavir is a weak CYP2C8 inhibitor.
Daclatasvir: (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 cobicistat. Taking these drugs together may increase daclatasvir serum concentrations, and potentially increase the risk for adverse effects. (Moderate) Monitor for daclatasvir-related adverse effects during concomitant use of atazanavir. When daclatasvir is used with ritonavir or cobicistat boosted atazanavir, reduce the daclatasvir dose to 30 mg once daily. Concomitant use may increase daclatasvir concentrations and the risk for daclatasvir-related adverse effects. Daclatasvir is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor.
Danazol: (Moderate) Caution is warranted when cobicistat is administered with danazol as there is a potential for elevated cobicistat concentrations. Danazol is a CYP3A4 inhibitor and cobicistat is a substrate of CYP3A4. (Moderate) Danazol is a CYP3A4 inhibitor, and serum concentrations of atazanavir, a CYP3A4 substrate, may increase with co-administration. Co-administer these drugs with caution due to the potential for atazanavir toxicity.
Dapagliflozin: (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: (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (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 a nti-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) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with cobicistat due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively. (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 atazanavir. 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. 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. 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: (Minor) Plasma concentrations of dapsone may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as hemolytic anemia, methemoglobinemia, or peripheral neuropathy, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while dapsone is a CYP3A4 substrate.
Daridorexant: (Major) Avoid concomitant use of daridorexant and atazanavir. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%. (Major) Avoid concomitant use of daridorexant and cobicistat. Concomitant use may increase daridorexant exposure and the risk for daridorexant-related adverse effects. Daridorexant is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Darifenacin: (Major) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with cobicistat due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with atazanavir due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor.
Darolutamide: (Moderate) Monitor patients more frequently for darolutamide-related adverse reactions if coadministration with cobicistat 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. Cobicistat 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: (Contraindicated) Coadministration of atazanavir with darunavir; cobicistat is not recommended, as more than one antiretroviral would require pharmacokinetic enhancement (boosting). Pharmacokinetic data are not available to provide appropriate dosage recommendations, and use of these drugs together may lead to loss of antiretroviral efficacy and development of resistance.
Darunavir; Cobicistat: (Contraindicated) Coadministration of atazanavir with darunavir; cobicistat is not recommended, as more than one antiretroviral would require pharmacokinetic enhancement (boosting). Pharmacokinetic data are not available to provide appropriate dosage recommendations, and use of these drugs together may lead to loss of antiretroviral efficacy and development of resistance.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Contraindicated) Coadministration of atazanavir with darunavir; cobicistat is not recommended, as more than one antiretroviral would require pharmacokinetic enhancement (boosting). Pharmacokinetic data are not available to provide appropriate dosage recommendations, and use of these drugs together may lead to loss of antiretroviral efficacy and development of resistance. (Moderate) Concurrent use of atazanavir with tenofovir alafenamide may result in elevated tenofovir serum concentrations. Tenofovir alafenamide is a substrate for the drug transporter organic anion transporting polypeptide (OATP1B1/1B3); atazanavir is an OATP1B1 inhibitor. Monitor for increased toxicities if these drugs are given together.
Dasatinib: (Major) Avoid coadministration of dasatinib and atazanavir due to the potential for increased dasatinib exposure and subsequent toxicity. An alternative to atazanavir 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 atazanavir 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 atazanavir is stopped, allow a washout of approximately 1 week before increasing the dasatinib dose. Dasatinib is a CYP3A4 substrate; atazanavir 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. (Major) Avoid coadministration of dasatinib and cobicistat due to the potential for increased dasatinib exposure and subsequent toxicity. An alternative to cobicistat 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 cobicistat 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 cobicistat is stopped, allow a washout of approximately 1 week before increasing the dasatinib dose. Dasatinib is a CYP3A4 substrate; cobicistat 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.
Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with atazanavir. 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; atazanavir 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. (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with cobicistat. 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; cobicistat is a strong inhibitor of CYP3A4. Administration of deflazacort with another strong CYP3A4 inhibitor, increased total exposure to 21-desDFZ by about 3-fold.
Delavirdine: (Moderate) Delavirdine and atazanavir are both substrates and inhibitors of CYP3A4. Coadministration may result in increased plasma concentrations of either drug. It is not clear if any dosage adjustments are needed. (Moderate) The plasma concentrations of delavirdine and cobicistat may be elevated when administered concurrently. Clinical monitoring for adverse effects is recommended during coadministration. Delavirdine is a CYP2D6 and CYP3A4 substrate/inhibitor. Cobicistat is a substrate/inhibitor of both CYP2D6 and CYP3A4.
Desipramine: (Moderate) According to the manufacturer, concurrent use of tricyclic antidepressants (TCAs) and atazanavir may result in elevated TCA plasma concentration, and could increase the potential for serious adverse effects. If these drugs are administered together, carefully titrate the TCA dose based on a clinical assessment of antidepressant response. Patients on a stable dose of TCA who start treatment with atazanavir should be monitored for TCA-associated anticholinergic effects (e.g., sedation, confusion, constipation). In addition to clinical monitoring, the manufacturer suggests obtaining TCA serum concentrations (where available) as an adjunct to assessing the potential for interactions. (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. Concurrent use may result in elevated TCA plasma concentrations.
Desogestrel; Ethinyl Estradiol: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with desogestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) If ethinyl estradiol is administered with atazanavir boosted with ritonavir, it is recommended that the dose of ethinyl estradiol be at least 35 mcg. However, the dose of ethinyl estradiol should be no more than 30 mcg when administered with atazanavir that is NOT boosted by ritonavir. The mean exposure and minimum serum concentrations of ethinyl estradiol are increased when administered with atazanavir; but if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased. Data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of atazanavir with desogestrel have not been conducted; therefore, an alternative method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of desogestrel. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Desvenlafaxine: (Moderate) Caution is warranted when cobicistat is administered with desvenlafaxine as there is a potential for elevated cobicistat concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Desvenlafaxine is an inhibitor of CYP2D6; cobicistat is partially metabolized by CYP2D6.
Dexamethasone: (Major) Avoid concurrent use of dexamethasone with cobicistat-containing regimens due to the risk of decreased antiretroviral efficacy and the potential development of viral resistance. In addition, serum concentrations of dexamethasone may be increased, potentially resulting in Cushing's syndrome and adrenal suppression. Consider an alternative corticosteroid (i.e., beclomethasone, prednisone, prednisolone) for long-term use. If concomitant use is necessary, monitor virologic response and for corticosteroid-related adverse effects. Dexamethasone is a CYP3A4 substrate and weak CYP3A inducer; cobicistat is a CYP3A4 substrate and strong CYP3A inhibitor. Another strong CYP3A inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects. (Moderate) Monitor for steroid-related adverse reactions and a decrease in atazanavir efficacy if concomitant use of dexamethasone and atazanavir is necessary. If long term coadministration is required, consider using an alternative corticosteroid, such as prednisone or prednisolone. Concomitant use may increase dexamethasone concentrations and decrease atazanavir exposure. Dexamethasone is a CYP3A substrate and CYP3A inducer; atazanavir is a CYP3A substrate and strong CYP3A inhibitor. Another strong CYP3A inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Dexlansoprazole: (Contraindicated) Coadministration of proton pump inhibitors (PPIs) with atazanavir in treatment-experienced patients is contraindicated. PPIs can be used with atazanavir in treatment-naive patients under specific administration restrictions. In treatment-naive patients >= 40 kg, the PPI dose should not exceed the equivalent of omeprazole 20 mg/day, and the PPI must be administered 12 hours before atazanavir and ritonavir; use the dosage regimen of atazanavir 300 mg boosted with ritonavir 100 mg given once daily with food. While data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant PPIs, the same recommendations regarding timing and maximum doses of concomitant PPIs should be followed. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with a PPI. A randomized, open-label, multiple-dose drug interaction study of atazanavir (300 mg) with ritonavir (100 mg) coadministered with omeprazole 40 mg found a reduction in atazanavir AUC and Cmin of 76% and 78%, respectively. Additionally, after multiple doses of omeprazole (40 mg/day) and atazanavir (400 mg/day, 2 hours after omeprazole) without ritonavir, the AUC of atazanavir was decreased by 94%, Cmax by 96%, and Cmin by 95%. (Minor) The plasma concentrations of dexlansoprazole may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while dexlansoprazole is a CYP3A4 substrate.
Dextromethorphan: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Dextromethorphan; Bupropion: (Moderate) Caution is warranted when cobicistat is administered with bupropion as there is a potential for elevated cobicistat concentrations. Bupropion is a CYP2D6 inhibitor in vitro, while cobicistat is a substrate of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Caution is warranted when cobicistat is administered with diphenhydramine as there is a potential for elevated diphenhydramine and cobicistat concentrations. Diphenhydramine is a substrate/inhibitor of CYP2D6 and a substrate of CYP2C9. Cobicistat is an substrate/inhibitor of CYP2D6. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Dextromethorphan; Guaifenesin: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Dextromethorphan; Quinidine: (Major) Caution is advised when administering quinidine with atazanavir. If atazanavir is boosted with ritonavir, concurrent use of quinidine is contraindicated. Use of all 3 drugs together may significantly increase quinidine concentrations and increase the risk for QT prolongation and serious or life-threatening cardiac arrhythmias. Atazanavir and ritonavir are CYP3A4 inhibitors; quinidine is metabolized by this enzyme. (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of quinidine with cobicistat. Quinidine is a substrate for CYP3A4 and P-glycoprotein (P-gp) and an inhibitor of CYP2D6 and P-gp; cobicistat is a substrate and inhibitor of both these enzymes and an inhibitor of P-gp. Concurrent use may result in elevated plasma concentration of both drugs. (Moderate) Use of dextromethorphan with cobicistat may result in increased dextromethorphan exposure. Cobicistat inhibits CYP2D6 and dextromethorphan is a CYP2D6 substrate. Monitor for dextromethorphan-related side effects, such as drowsiness, nausea or vomiting, sweating, restlessness, or tremor.
Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with protease inhibitors is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and protease inhibitors are moderate to strong CYP3A4 inhibitors. (Moderate) The plasma concentrations of diazepam may be elevated when administered concurrently with cobicistat. Close clinical monitoring is recommended during coadministration; diazepam dose reductions may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of diazepam. These drugs used in combination may result in elevated diazepam plasma concentrations, causing an increased risk for diazepam-related adverse events.
Diclofenac: (Moderate) Caution is warranted when atazanavir is administered with diclofenac as there is a potential for elevated diclofenac concentrations. Diclofenac is a substrate of CYP3A4; atazanavir is an inhibitor of CYP3A4. (Moderate) Caution is warranted when cobicistat is administered with diclofenac as there is a potential for increased diclofenac concentrations. Diclofenac is a substrate of CYP3A4 and CYP2C9. Cobicistat is an inhibitor of CYP3A4.
Diclofenac; Misoprostol: (Moderate) Caution is warranted when atazanavir is administered with diclofenac as there is a potential for elevated diclofenac concentrations. Diclofenac is a substrate of CYP3A4; atazanavir is an inhibitor of CYP3A4. (Moderate) Caution is warranted when cobicistat is administered with diclofenac as there is a potential for increased diclofenac concentrations. Diclofenac is a substrate of CYP3A4 and CYP2C9. Cobicistat is an inhibitor of CYP3A4.
Didanosine, ddI: (Moderate) Separate the administration of atazanavir and didanosine, ddI by giving atazanavir 2 hours before or 1 hour after buffered didanosine. Atazanavir solubility decreases as gastric pH increases. Concomitant administration of atazanavir and buffered didanosine, ddI products resulted in a 4-fold decrease in the AUC of atazanavir. Didanosine chewable/dispersible buffered tablets contain calcium carbonate and magnesium hydroxide, and didanosine buffered powder for oral solution contains dibasic sodium phosphate, sodium citrate, and citric acid. No change in the AUC of enteric-coated didanosine occurred with concurrent use of atazanavir.
Dienogest; Estradiol valerate: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with dienogest. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of atazanavir with dienogest have not been conducted; therefore, an alternative method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of dienogest. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Atazanavir has been shown to decrease the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should be instructed to report any estrogen- related adverse events.
Digoxin: (Moderate) Atazanavir can prolong the PR interval and pharmacodynamic interactions between atazanavir and drugs that also prolong the PR interval, such as digoxin, cannot be ruled out; caution is advised when these drugs are used together; monitor the patient for appropriate clinical responses. (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of digoxin with cobicistat. Digoxin is a substrate for P-gp; cobicistat is an inhibitor of this drug transporter. Concurrent use may result in elevated digoxin plasma concentration.
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. (Contraindicated) Concomitant use of ergotamine with cobicistat is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor.
Diltiazem: (Major) Coadministration of atazanavir with diltiazem may result in increased plasma concentrations of either drug. Concurrent atazanavir use led to a 2-fold increase in the AUC of diltiazem. A 50% dose reduction of diltiazem should be considered and ECG monitoring is recommended when diltiazem is used with atazanavir. Additionally, atazanavir can prolong the PR interval, especially with high serum concentrations. Greater lengthening of the PR interval with the combined use of diltiazem and atazanavir as compared to either alone has been documented. (Moderate) Monitor blood pressure and heart rate if coadministration of diltiazem with cobicistat is necessary. Diltiazem is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
Diphenhydramine: (Moderate) Caution is warranted when cobicistat is administered with diphenhydramine as there is a potential for elevated diphenhydramine and cobicistat concentrations. Diphenhydramine is a substrate/inhibitor of CYP2D6 and a substrate of CYP2C9. Cobicistat is an substrate/inhibitor of CYP2D6.
Diphenhydramine; Ibuprofen: (Moderate) Caution is warranted when cobicistat is administered with diphenhydramine as there is a potential for elevated diphenhydramine and cobicistat concentrations. Diphenhydramine is a substrate/inhibitor of CYP2D6 and a substrate of CYP2C9. Cobicistat is an substrate/inhibitor of CYP2D6.
Diphenhydramine; Naproxen: (Moderate) Caution is warranted when cobicistat is administered with diphenhydramine as there is a potential for elevated diphenhydramine and cobicistat concentrations. Diphenhydramine is a substrate/inhibitor of CYP2D6 and a substrate of CYP2C9. Cobicistat is an substrate/inhibitor of CYP2D6. (Minor) Caution is warranted when atazanavir is administered with naproxen as there is a potential for elevated naproxen concentrations. In vitro data suggest naproxen is a substrate for CYP2C8; atazanavir is a weak inhibitor of this enzyme.
Diphenhydramine; Phenylephrine: (Moderate) Caution is warranted when cobicistat is administered with diphenhydramine as there is a potential for elevated diphenhydramine and cobicistat concentrations. Diphenhydramine is a substrate/inhibitor of CYP2D6 and a substrate of CYP2C9. Cobicistat is an substrate/inhibitor of CYP2D6.
Disopyramide: (Major) Atazanavir inhibits the CYP3A4 isoenzyme at clinically relevant concentrations, which may lead to increased serum concentrations of disopyramide and an increased potential for QT prolongation or other adverse effects. Serious and/or life-threatening drug interactions could potentially occur. (Major) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of disopyramide with cobicistat. Disopyramide is a substrate for CYP3A4; cobicistat is a strong inhibitor of this enzyme. Concurrent use may result in elevated disopyramide plasma concentration. Cases of life-threatening interactions have been reported for disopyramide when given with another strong CYP3A4 inhibitor.
Disulfiram: (Moderate) The plasma concentrations of disulfiram may be elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects is recommended during coadministration. Atazanavir is a CYP3A4 inhibitor, while disulfiram is a CYP3A4 substrate. (Moderate) The plasma concentrations of disulfiram may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while disulfiram is a CYP3A4 substrate.
Docetaxel: (Major) Avoid coadministration of docetaxel with atazanavir 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 atazanavir is a strong CYP3A4 inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased docetaxel exposure by 2.2-fold. (Major) Avoid coadministration of docetaxel with cobicistat 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 cobicistat is a strong CYP3A4 inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased docetaxel exposure by 2.2-fold.
Dofetilide: (Major) Coadministration of CYP3A4 inhibitors, such as atazanavir, with dofetilide may decrease the metabolism of dofetilide, thereby increasing the potential for QT prolongation. Dofetilide is a Class III antiarrhythmic agent that has a well-established risk of QT prolongation and torsade de pointes (TdP). Plasma dofetilide concentrations are correlated with the risk of drug-induced proarrhythmias.
Dolasetron: (Moderate) The plasma concentrations of hydrodolasetron (primary dolasetron metabolite) may be elevated when dolasetron is administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as headache or cardiovascular effects, is recommended during coadministration. Cobicistat is a CYP3A4 and CYP2D6 inhibitor, while hydrodolasetron is a CYP3A4 and CYP2D6 substrate.
Dolutegravir: (Moderate) Caution is warranted when atazanavir is administered with dolutegravir as there is a potential for elevated dolutegravir concentrations. Dolutegravir is a substrate of CYP3A4 and uridine glucuronyltransferase (UGT). Atazanavir is an inhibitor of CYP3A4 and UGT1A1. (Moderate) Caution is warranted when cobicistat is administered with dolutegravir as there is a potential for elevated dolutegravir concentrations. Dolutegravir is a substrate of CYP3A4 and P-glycoprotein (P-gp). Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of P-gp.
Dolutegravir; Lamivudine: (Moderate) Caution is warranted when atazanavir is administered with dolutegravir as there is a potential for elevated dolutegravir concentrations. Dolutegravir is a substrate of CYP3A4 and uridine glucuronyltransferase (UGT). Atazanavir is an inhibitor of CYP3A4 and UGT1A1. (Moderate) Caution is warranted when cobicistat is administered with dolutegravir as there is a potential for elevated dolutegravir concentrations. Dolutegravir is a substrate of CYP3A4 and P-glycoprotein (P-gp). Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of P-gp.
Dolutegravir; Rilpivirine: (Moderate) Caution is warranted when atazanavir is administered with dolutegravir as there is a potential for elevated dolutegravir concentrations. Dolutegravir is a substrate of CYP3A4 and uridine glucuronyltransferase (UGT). Atazanavir is an inhibitor of CYP3A4 and UGT1A1. (Moderate) Caution is warranted when cobicistat is administered with dolutegravir as there is a potential for elevated dolutegravir concentrations. Dolutegravir is a substrate of CYP3A4 and P-glycoprotein (P-gp). Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of P-gp. (Moderate) Close clinical monitoring is advised when administering atazanavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Atazanavir is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. (Moderate) The plasma concentrations of rilpivirine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Rilpivirine is a CYP3A4 substrate and cobicistat is a strong inhibitor of CYP3A4.
Donepezil: (Moderate) Due to atazanavir-induced inhibition of CYP3A4 isoenzymes, atazanavir may inhibit the metabolism and thus, increase the serum concentrations of drugs that are largely metabolized via CYP3A4, such as donepezil. (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Cobicistat is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
Donepezil; Memantine: (Moderate) Due to atazanavir-induced inhibition of CYP3A4 isoenzymes, atazanavir may inhibit the metabolism and thus, increase the serum concentrations of drugs that are largely metabolized via CYP3A4, such as donepezil. (Moderate) The plasma concentrations of donepezil may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or cholinergic effects, is recommended during coadministration. Cobicistat is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor, while donepezil is a CYP3A4 and CYP2D6 substrate.
Doravirine: (Minor) Coadministration of doravirine and atazanavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; atazanavir is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant. (Minor) Coadministration of doravirine and cobicistat may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; cobicistat is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Tenofovir decreases atazanavir AUC and Cmin. If atazanavir and tenofovir, PMPA are to be coadministered, it is recommended that atazanavir 300 mg be given with ritonavir 100 mg and tenofovir 300 mg once per day with food in patients >= 40 kg; atazanavir should not be coadministered with tenofovir without ritonavir. Data are insufficient to recommend atazanavir dosing in children < 40 kg who are also receiving concomitant tenofovir. In three post-marketing clinical trials, atazanavir AUC and Cmin were decreased by approximately 25% and 23 to 40%, respectively, when atazanavir was coadministered with tenofovir, PMPA as compared to atazanavir alone. Coadministration of atazanavir and tenofovir without ritonavir could lead to loss or lack of virologic response and possible resistance to atazanavir. In addition, atazanavir appears to increase tenofovir plasma concentrations, which could lead to adverse effects associated with tenofovir, including renal disorders. Increased tenofovir concentrations have been noted in the following combination regimens: tenofovir with ritonavir 'boosted' atazanavir; tenofovir, atazanavir, and lopinavir; ritonavir. Patients who receive tenofovir with atazanavir and any form/dose of ritonavir should be monitored for tenofovir-associated adverse events, with tenofovir being discontinued in patients who develop such adverse events. Although there are varying results in reports of an interaction between tenofovir and lopinavir; ritonavir, the clinical significance of an interaction is suspected to be insignificant. In treatment-experienced patients >= 40 kg receiving H2-antagonists and tenofovir, atazanavir should be dosed 400 mg with ritonavir 100 mg once daily with food. (Minor) Coadministration of doravirine and atazanavir may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; atazanavir is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant. (Minor) Coadministration of doravirine and cobicistat may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; cobicistat is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Dorzolamide; Timolol: (Moderate) Coadministration of cobicistat (a CYP2D6 inhibitor) with beta-blockers metabolized by CYP2D6, such as timolol, may result in elevated beta-blocker serum concentrations. If used concurrently, close clinical monitoring with appropriate beta-blocker dose reductions are advised.
Doxazosin: (Moderate) Monitor blood pressure and for signs of hypotension during coadministration. The plasma concentrations of doxazosin may be elevated when administered concurrently with atazanavir. Atazanavir 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. (Moderate) Monitor blood pressure and for signs of hypotension during coadministration. The plasma concentrations of doxazosin may be elevated when administered concurrently with cobicistat. Cobicistat 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) According to the manufacturer, concurrent use of tricyclic antidepressants (TCAs) and atazanavir may result in elevated TCA plasma concentration, and could increase the potential for serious adverse effects. If these drugs are administered together, carefully titrate the TCA dose based on a clinical assessment of antidepressant response. Patients on a stable dose of TCA who start treatment with atazanavir should be monitored for TCA-associated anticholinergic effects (e.g., sedation, confusion, constipation). In addition to clinical monitoring, the manufacturer suggests obtaining TCA serum concentrations (where available) as an adjunct to assessing the potential for interactions. (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. 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) Atazanavir is a strong CYP3A4 inhibitor; doxorubicin is a major substrate of CYP3A4. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of atazanavir and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity. (Major) Avoid coadministration of cobicistat and doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-glycoprotein (P-gp); doxorubicin is a major CYP2D6, CYP3A4, and P-gp substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, CYP3A4, and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin.
Doxorubicin: (Major) Atazanavir is a strong CYP3A4 inhibitor; doxorubicin is a major substrate of CYP3A4. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of atazanavir and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity. (Major) Avoid coadministration of cobicistat and doxorubicin due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-glycoprotein (P-gp); doxorubicin is a major CYP2D6, CYP3A4, and P-gp substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, CYP3A4, and/or P-gp, resulting in increased concentration and clinical effect of doxorubicin.
Dronabinol: (Major) Use caution if coadministration of dronabinol with atazanavir is necessary, and monitor for an increase in dronabinol-related adverse reactions (e.g., feeling high, dizziness, confusion, somnolence). Dronabinol is a CYP2C9 and 3A4 substrate; atazanavir is a strong inhibitor of CYP3A4. Concomitant use may result in elevated plasma concentrations of dronabinol. (Moderate) Use caution if coadministration of dronabinol with cobicistat 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). Concomitant use may result in elevated plasma concentrations of dronabinol. Cobicistat is a strong inhibitor of CYP3A4; dronabinol is a CYP2C9 and 3A4 substrate.
Dronedarone: (Contraindicated) Coadministration of cobicistat with dronedarone is contraindicated due to the potential for elevated dronedarone concentrations. Dronedarone is a CYP3A4 inhibitor/substrate and a CYP2D6 inhibitor. Cobicistat is an inhibitor/substrate of both CYP3A4 and CYP2D6. (Moderate) Concomitant use of dronedarone with atazanavir may increase dronedarone concentrations. Coadministration with atazanavir; cobicistat is contraindicated. Dronedarone is metabolized by CYP3A. Atazanavir is an inhibitor CYP3A4. No data exist regarding the appropriate dose adjustment needed to allow safe administration of dronedarone with CYP3A4 inhibitors; therefore, use caution when coadministering dronedarone with CYP3A4 inhibitors such as atazanavir.
Droperidol: (Moderate) Droperidol is metabolized by CYP3A4 and with the potential to cause QT prolongation. Caution should be used in patients receiving atazanavir concurrently with drugs metabolized via CYP3A4 and known to cause QT prolongation. Atazanavir inhibits the CYP3A4 isoenzyme at clinically relevant concentrations, which may lead to increased serum concentrations of droperidol and an increased potential for QT prolongation or other adverse effects. Serious and/or life-threatening drug interactions could potentially occur between atazanavir and droperidol.
Drospirenone: (Contraindicated) Coadministration of drospirenone and atazanavir boosted with cobicistat is contraindicated. Taking these drugs concurrently increases drospirenone systemic concentrations, which may result in hyperkalemia. (Major) Drospirenone may be administered concurrently with cobicistat; however, close clinical monitoring for adverse events such as hyperkalemia is recommended. Taking drospirenone with cobicistat may increase drospirenone serum concentrations. Instruct women to report adverse events to their prescribers. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive these drugs together should use an additional barrier method of contraception such as condoms.
Drospirenone; Estetrol: (Contraindicated) Coadministration of drospirenone and atazanavir boosted with cobicistat is contraindicated. Taking these drugs concurrently increases drospirenone systemic concentrations, which may result in hyperkalemia. (Major) Drospirenone may be administered concurrently with cobicistat; however, close clinical monitoring for adverse events such as hyperkalemia is recommended. Taking drospirenone with cobicistat may increase drospirenone serum concentrations. Instruct women to report adverse events to their prescribers. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive these drugs together should use an additional barrier method of contraception such as condoms.
Drospirenone; Estradiol: (Contraindicated) Coadministration of drospirenone and atazanavir boosted with cobicistat is contraindicated. Taking these drugs concurrently increases drospirenone systemic concentrations, which may result in hyperkalemia. (Major) Drospirenone may be administered concurrently with cobicistat; however, close clinical monitoring for adverse events such as hyperkalemia is recommended. Taking drospirenone with cobicistat may increase drospirenone serum concentrations. Instruct women to report adverse events to their prescribers. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive these drugs together should use an additional barrier method of contraception such as condoms. (Moderate) Atazanavir has been shown to decrease the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should be instructed to report any estrogen- related adverse events.
Drospirenone; Ethinyl Estradiol: (Contraindicated) Coadministration of drospirenone and atazanavir boosted with cobicistat is contraindicated. Taking these drugs concurrently increases drospirenone systemic concentrations, which may result in hyperkalemia. (Major) Drospirenone may be administered concurrently with cobicistat; however, close clinical monitoring for adverse events such as hyperkalemia is recommended. Taking drospirenone with cobicistat may increase drospirenone serum concentrations. Instruct women to report adverse events to their prescribers. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive these drugs together should use an additional barrier method of contraception such as condoms. (Major) If ethinyl estradiol is administered with atazanavir boosted with ritonavir, it is recommended that the dose of ethinyl estradiol be at least 35 mcg. However, the dose of ethinyl estradiol should be no more than 30 mcg when administered with atazanavir that is NOT boosted by ritonavir. The mean exposure and minimum serum concentrations of ethinyl estradiol are increased when administered with atazanavir; but if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased. Data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Contraindicated) Coadministration of drospirenone and atazanavir boosted with cobicistat is contraindicated. Taking these drugs concurrently increases drospirenone systemic concentrations, which may result in hyperkalemia. (Major) Drospirenone may be administered concurrently with cobicistat; however, close clinical monitoring for adverse events such as hyperkalemia is recommended. Taking drospirenone with cobicistat may increase drospirenone serum concentrations. Instruct women to report adverse events to their prescribers. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, women who receive these drugs together should use an additional barrier method of contraception such as condoms. (Major) If ethinyl estradiol is administered with atazanavir boosted with ritonavir, it is recommended that the dose of ethinyl estradiol be at least 35 mcg. However, the dose of ethinyl estradiol should be no more than 30 mcg when administered with atazanavir that is NOT boosted by ritonavir. The mean exposure and minimum serum concentrations of ethinyl estradiol are increased when administered with atazanavir; but if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased. Data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Duloxetine: (Moderate) Caution is warranted when cobicistat is administered with duloxetine as there is a potential for elevated duloxetine and cobicistat concentrations. Duloxetine is a CYP2D6 substrate/inhibitor. Cobicistat is a substrate/inhibitor of CYP2D6.
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. (Moderate) The plasma concentrations of dutasteride may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as impotence or libido decrease, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while dutasteride is a CYP3A4 substrate.
Dutasteride; Tamsulosin: (Major) Concurrent use of tamsulosin and cobicistat is not recommended due to the potential for elevated tamsulosin concentrations. Such increases in tamsulosin concentrations may be expected to produce clinically significant and potentially serious side effects, such as hypotension, dizziness, and vertigo. Tamsulosin is metabolized by CYP3A4 and CYP2D6 hepatic enzymes. Cobicistat is a strong inhibitor of CYP3A4 and a CYP2D6 inhibitor. Concomitant treatment with another strong CYP3A4 inhibitor increased the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively. (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. (Moderate) The plasma concentrations of dutasteride may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as impotence or libido decrease, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while dutasteride is a CYP3A4 substrate.
Duvelisib: (Major) Reduce duvelisib dose to 15 mg PO twice daily and monitor for increased toxicity when coadministered with atazanavir. Coadministration may increase the exposure of duvelisib. Duvelisib is a CYP3A substrate; atazanavir 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 atazanavir. (Major) Reduce duvelisib dose to 15 mg PO twice daily and monitor for increased toxicity when coadministered with cobicistat. Coadministration may increase the exposure of duvelisib. Duvelisib is a CYP3A substrate; cobicistat 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 cobicistat.
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 cobicistat may result in increased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and cobicistat is a P-gp inhibitor. Increased concentrations of edoxaban may occur during concomitant use of cobicistat; 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: (Major) Due to induction of the CYP3A4 isoenzyme by efavirenz, coadministration results in significantly decreased atazanavir AUC and Cmin. Do not coadminister these drugs to treatment-experienced patients. Coadministration is acceptable in treatment-naive patients weighing at least40 kg as a regimen of atazanavir 400 mg with ritonavir 100 mg given once daily with food and efavirenz 600 mg given once daily on an empty stomach. (Major) Due to the potential for decreased antiretroviral efficacy, use of efavirenz with cobicistat and darunavir should be avoided. In addition, efavirenz is not recommended for use in combination with cobicistat and atazanavir in antiretroviral-experienced patients; however, this combination may be used in treatment-naive patients if the following dose recommendations are followed: cobicistat 150 mg PO and atazanavir 400 mg PO once daily with food, plus efavirenz 600 mg once daily on an empty stomach. When these drugs are given together, the concentrations of cobicistat, darunavir, and atazanavir are decreased. Efavirenz is a substrate and inducer of CYP3A4, cobicistat is a substrate/inhibitor of CYP3A4, and darunavir and atazanavir are CYP3A4 substrates.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Due to induction of the CYP3A4 isoenzyme by efavirenz, coadministration results in significantly decreased atazanavir AUC and Cmin. Do not coadminister these drugs to treatment-experienced patients. Coadministration is acceptable in treatment-naive patients weighing at least40 kg as a regimen of atazanavir 400 mg with ritonavir 100 mg given once daily with food and efavirenz 600 mg given once daily on an empty stomach. (Major) Due to the potential for decreased antiretroviral efficacy, use of efavirenz with cobicistat and darunavir should be avoided. In addition, efavirenz is not recommended for use in combination with cobicistat and atazanavir in antiretroviral-experienced patients; however, this combination may be used in treatment-naive patients if the following dose recommendations are followed: cobicistat 150 mg PO and atazanavir 400 mg PO once daily with food, plus efavirenz 600 mg once daily on an empty stomach. When these drugs are given together, the concentrations of cobicistat, darunavir, and atazanavir are decreased. Efavirenz is a substrate and inducer of CYP3A4, cobicistat is a substrate/inhibitor of CYP3A4, and darunavir and atazanavir are CYP3A4 substrates. (Moderate) Tenofovir decreases atazanavir AUC and Cmin. If atazanavir and tenofovir, PMPA are to be coadministered, it is recommended that atazanavir 300 mg be given with ritonavir 100 mg and tenofovir 300 mg once per day with food in patients >= 40 kg; atazanavir should not be coadministered with tenofovir without ritonavir. Data are insufficient to recommend atazanavir dosin g in children < 40 kg who are also receiving concomitant tenofovir. In three post-marketing clinical trials, atazanavir AUC and Cmin were decreased by approximately 25% and 23 to 40%, respectively, when atazanavir was coadministered with tenofovir, PMPA as compared to atazanavir alone. Coadministration of atazanavir and tenofovir without ritonavir could lead to loss or lack of virologic response and possible resistance to atazanavir. In addition, atazanavir appears to increase tenofovir plasma concentrations, which could lead to adverse effects associated with tenofovir, including renal disorders. Increased tenofovir concentrations have been noted in the following combination regimens: tenofovir with ritonavir 'boosted' atazanavir; tenofovir, atazanavir, and lopinavir; ritonavir. Patients who receive tenofovir with atazanavir and any form/dose of ritonavir should be monitored for tenofovir-associated adverse events, with tenofovir being discontinued in patients who develop such adverse events. Although there are varying results in reports of an interaction between tenofovir and lopinavir; ritonavir, the clinical significance of an interaction is suspected to be insignificant. In treatment-experienced patients >= 40 kg receiving H2-antagonists and tenofovir, atazanavir should be dosed 400 mg with ritonavir 100 mg once daily with food.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Due to induction of the CYP3A4 isoenzyme by efavirenz, coadministration results in significantly decreased atazanavir AUC and Cmin. Do not coadminister these drugs to treatment-experienced patients. Coadministration is acceptable in treatment-naive patients weighing at least40 kg as a regimen of atazanavir 400 mg with ritonavir 100 mg given once daily with food and efavirenz 600 mg given once daily on an empty stomach. (Major) Due to the potential for decreased antiretroviral efficacy, use of efavirenz with cobicistat and darunavir should be avoided. In addition, efavirenz is not recommended for use in combination with cobicistat and atazanavir in antiretroviral-experienced patients; however, this combination may be used in treatment-naive patients if the following dose recommendations are followed: cobicistat 150 mg PO and atazanavir 400 mg PO once daily with food, plus efavirenz 600 mg once daily on an empty stomach. When these drugs are given together, the concentrations of cobicistat, darunavir, and atazanavir are decreased. Efavirenz is a substrate and inducer of CYP3A4, cobicistat is a substrate/inhibitor of CYP3A4, and darunavir and atazanavir are CYP3A4 substrates. (Moderate) Tenofovir decreases atazanavir AUC and Cmin. If atazanavir and tenofovir, PMPA are to be coadministered, it is recommended that atazanavir 300 mg be given with ritonavir 100 mg and tenofovir 300 mg once per day with food in patients >= 40 kg; atazanavir should not be coadministered with tenofovir without ritonavir. Data are insufficient to recommend atazanavir dosing in children < 40 kg who are also receiving concomitant tenofovir. In three post-marketing clinical trials, atazanavir AUC and Cmin were decreased by approximately 25% and 23 to 40%, respectively, when atazanavir was coadministered with tenofovir, PMPA as compared to atazanavir alone. Coadministration of atazanavir and tenofovir without ritonavir could lead to loss or lack of virologic response and possible resistance to atazanavir. In addition, atazanavir appears to increase tenofovir plasma concentrations, which could lead to adverse effects associated with tenofovir, including renal disorders. Increased tenofovir concentrations have been noted in the following combination regimens: tenofovir with ritonavir 'boosted' atazanavir; tenofovir, atazanavir, and lopinavir; ritonavir. Patients who receive tenofovir with atazanavir and any form/dose of ritonavir should be monitored for tenofovir-associated adverse events, with tenofovir being discontinued in patients who develop such adverse events. Although there are varying results in reports of an interaction between tenofovir and lopinavir; ritonavir, the clinical significance of an interaction is suspected to be insignificant. In treatment-experienced patients >= 40 kg receiving H2-antagonists and tenofovir, atazanavir should be dosed 400 mg with ritonavir 100 mg once daily with food.
Elacestrant: (Major) Avoid concomitant use of elacestrant and atazanavir due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. Elacestrant is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased elacestrant overall exposure by 5.3-fold. (Major) Avoid concomitant use of elacestrant and cobicistat due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. Elacestrant is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased elacestrant overall exposure by 5.3-fold.
Elagolix: (Contraindicated) Concomitant use of elagolix and organic anion transporting polypeptide (OATP) 1B1 inhibitors such as atazanavir is contraindicated. Coadministration may increase elagolix plasma concentrations and decrease atazanavir concentrations. Elagolix is a substrate of CYP3A and OATP1B1, and a weak to moderate CYP3A4 inducer. Atazanavir is a strong inhibitor of CYP3A and a CYP3A4 substrate, and it inhibits OATP1B1. In drug interaction studies, coadministration of elagolix with another strong CYP3A inhibitor increased the Cmax and AUC of elagolix by 77% and 120%, respectively. Increased elagolix concentrations increase the risk for dose-related side effects, including loss of bone mineral density. (Contraindicated) Concomitant use of elagolix and strong organic anion transporting polypeptide (OATP) 1B1 inhibitors such as cobicistat 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. Cobicistat is a combined inhibitor; it is a potent inhibitor of CYP3A and inhibits OATP1B1 and P-gp. 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.
Elagolix; Estradiol; Norethindrone acetate: (Contraindicated) Concomitant use of elagolix and organic anion transporting polypeptide (OATP) 1B1 inhibitors such as atazanavir is contraindicated. Coadministration may increase elagolix plasma concentrations and decrease atazanavir concentrations. Elagolix is a substrate of CYP3A and OATP1B1, and a weak to moderate CYP3A4 inducer. Atazanavir is a strong inhibitor of CYP3A and a CYP3A4 substrate, and it inhibits OATP1B1. In drug interaction studies, coadministration of elagolix with another strong CYP3A inhibitor increased the Cmax and AUC of elagolix by 77% and 120%, respectively. Increased elagolix concentrations increase the risk for dose-related side effects, including loss of bone mineral density. (Contraindicated) Concomitant use of elagolix and strong organic anion transporting polypeptide (OATP) 1B1 inhibitors such as cobicistat 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. Cobicistat is a combined inhibitor; it is a potent inhibitor of CYP3A and inhibits OATP1B1 and P-gp. 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) Atazanavir may decrease the metabolism of oral contraceptives and non-oral combination contraceptives; the mean exposure and minimum serum concentrations of ethinyl estradiol and norethindrone are increased when administered with atazanavir 400 mg daily. However, if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased; data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Moderate) Atazanavir has been shown to decrease the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should be instructed to report any estrogen- related adverse events.
Elbasvir; Grazoprevir: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with atazanavir is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Atazanavir is an inhibitor of the hepatic enzyme CYP3A and the organic anion transporting protein (OATP). Elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a substrate of OATP1B1/3. (Contraindicated) Concurrent administration of elbasvir; grazoprevir with atazanavir is contraindicated. Use of these drugs together is expected to significantly increase the plasma concentrations of elbasvir and grazoprevir, and may result in adverse effects (i.e., elevated ALT concentrations). Atazanavir is an inhibitor of the hepatic enzyme CYP3A and the organic anion transporting protein (OATP1B1). Elbasvir and grazoprevir are metabolized by CYP3A, and grazoprevir is also a substrate of OATP1B1/3. (Major) Concurrent administration of elbasvir with cobicistat is not recommended. 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). Cobicistat is a strong inhibitor of the hepatic enzyme CYP3A, while elbasvir is metabolized by CYP3A. (Major) Concurrent administration of grazoprevir with cobicistat 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). Cobicistat is an inhibitor of the hepatic enzyme CYP3A, while grazoprevir is metabolized by CYP3A.
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. (Contraindicated) Eletriptan is contraindicated with recent use (i.e., within 72 hours) of cobicistat due to the potential for increased eletriptan exposure. Eletriptan is a sensitive substrate of CYP3A4; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the Cmax and AUC of eletriptan by 3-fold and 6-fold, respectively.
Elexacaftor; tezacaftor; ivacaftor: (Major) If atazanavir 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 atazanavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) If cobicistat 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 cobicistat 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 atazanavir; omit the evening dose of ivacaftor. Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; atazanavir 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 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 cobicistat; omit the evening dose of ivacaftor. Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; cobicistat 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 atazanavir; 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); atazanavir is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with cobicistat; 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); cobicistat is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
Eliglustat: (Major) Coadministration of atazanavir and eliglustat is contraindicated in intermediate or poor CYP2D6 metabolizers (IMs or PMs). Use of these agents together is also contraindicated in any patient also receiving a moderate or strong CYP2D6 inhibitor, such as ritonavir. In extensive CYP2D6 metabolizers (EMs), coadministration of eliglustat and atazanavir requires dosage adjustment of eliglustat to 84 mg PO once daily. Atazanavir is a strong CYP3A inhibitor. Eliglustat is a CYP3A and CYP2D6 substrate that is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations. Use of these drugs together may result in increased plasma concentrations of eliglustat, increasing the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); this risk is greatest in CYP2D6 IMs and PMs because a larger portion of the eliglustat dose is metabolized via CYP3A. (Major) Coadministration of eliglustat and cobicistat 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 cobicistat 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 cobicistat, 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. The product labeling for cobicistat states that coadministration of other drugs for which altered plasma concentrations are associated with serious and/or life-threatening effects is contraindicated; however, the interaction between ketoconazole (another potent CYP3A inhibitor) and eliglustat was studied during clinical trials. The resultant data supports eliglustat dosage reduction in EMs instead of contraindication.
Eltrombopag: (Moderate) Eltrombopag is metabolized by CYP2C8. The significance of administering weak inhibitors of CYP2C8, such as atazanavir, on the systemic exposure of eltrombopag has not been established. Monitor patients for signs of eltrombopag toxicity if these drugs are coadministered.
Eluxadoline: (Major) When administered concurrently with atazanavir, 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). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); atazanavir is an OATP1B1 inhibitor. 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 cobicistat, 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). Eluxadoline is a substrate of the organic anion-transporting peptide (OATP1B1); cobicistat is an OATP1B1/1B3 inhibitor. Advise patients against driving or operating machinery until the combine effects of these drugs on the individual patient is known.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of atazanavir boosted with ritonavir and elvitagravir results in significantly elevated plasma concentrations of elvitegravir. The recommended dosing regimen for these drugs used in combination is: elvitegravir 85 mg PO once daily with atazanavir/ritonavir 300/100 mg PO once daily. No data are available for use of other dosage. (Moderate) Concurrent use of atazanavir with tenofovir alafenamide may result in elevated tenofovir serum concentrations. Tenofovir alafenamide is a substrate for the drug transporter organic anion transporting polypeptide (OATP1B1/1B3); atazanavir is an OATP1B1 inhibitor. Monitor for increased toxicities if these drugs are given together.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of atazanavir boosted with ritonavir and elvitagravir results in significantly elevated plasma concentrations of elvitegravir. The recommended dosing regimen for these drugs used in combination is: elvitegravir 85 mg PO once daily with atazanavir/ritonavir 300/100 mg PO once daily. No data are available for use of other dosage. (Moderate) Tenofovir decreases atazanavir AUC and Cmin. If atazanavir and tenofovir, PMPA are to be coadministered, it is recommended that atazanavir 300 mg be given with ritonavir 100 mg and tenofovir 300 mg once per day with food in patients >= 40 kg; atazanavir should not be coadministered with tenofovir without ritonavir. Data are insufficient to recommend atazanavir dosing in children < 40 kg who are also receiving concomitant tenofovir. In three post-marketing clinical trials, atazanavir AUC and Cmin were decreased by approximately 25% and 23 to 40%, respectively, when atazanavir was coadministered with tenofovir, PMPA as compared to atazanavir alone. Coadministration of atazanavir and tenofovir without ritonavir could lead to loss or lack of virologic response and possible resistance to atazanavir. In addition, atazanavir appears to increase tenofovir plasma concentrations, which could lead to adverse effects associated with tenofovir, including renal disorders. Increased tenofovir concentrations have been noted in the following combination regimens: tenofovir with ritonavir 'boosted' atazanavir; tenofovir, atazanavir, and lopinavir; ritonavir. Patients who receive tenofovir with atazanavir and any form/dose of ritonavir should be monitored for tenofovir-associated adverse events, with tenofovir being discontinued in patients who develop such adverse events. Although there are varying results in reports of an interaction between tenofovir and lopinavir; ritonavir, the clinical significance of an interaction is suspected to be insignificant. In treatment-experienced patients >= 40 kg receiving H2-antagonists and tenofovir, atazanavir should be dosed 400 mg with ritonavir 100 mg once daily with food.
Empagliflozin: (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) 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. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Empagliflozin; Linagliptin; Metformin: (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (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. A possible mechanism is impairment of beta-cell function. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment. Patients on antidiabetic therapy, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (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: (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (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 alafenamide: (Moderate) Close clinical monitoring is advised when administering atazanavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Atazanavir is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. (Moderate) Concurrent use of atazanavir with tenofovir alafenamide may result in elevated tenofovir serum concentrations. Tenofovir alafenamide is a substrate for the drug transporter organic anion transporting polypeptide (OATP1B1/1B3); atazanavir is an OATP1B1 inhibitor. Monitor for increased toxicities if these drugs are given together. (Moderate) The plasma concentrations of rilpivirine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Rilpivirine is a CYP3A4 substrate and cobicistat is a strong inhibitor of CYP3A4.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Close clinical monitoring is advised when administering atazanavir with rilpivirine due to an increased potential for rilpivirine-related adverse events. Predictions about the interaction can be made based on metabolic pathways. Atazanavir is an inhibitor of the hepatic isoenzyme CYP3A4; rilpivirine is metabolized by this isoenzyme. Coadministration may result in increased rilpivirine plasma concentrations. (Moderate) Tenofovir decreases atazanavir AUC and Cmin. If atazanavir and tenofovir, PMPA are to be coadministered, it is recommended that atazanavir 300 mg be given with ritonavir 100 mg and tenofovir 300 mg once per day with food in patients >= 40 kg; atazanavir should not be coadministered with tenofovir without ritonavir. Data are insufficient to recommend atazanavir dosing in children < 40 kg who are also receiving concomitant tenofovir. In three post-marketing clinical trials, atazanavir AUC and Cmin were decreased by approximately 25% and 23 to 40%, respectively, when atazanavir was coadministered with tenofovir, PMPA as compared to atazanavir alone. Coadministration of atazanavir and tenofovir without ritonavir could lead to loss or lack of virologic response and possible resistance to atazanavir. In addition, atazanavir appears to increase tenofovir plasma concentrations, which could lead to adverse effects associated with tenofovir, including renal disorders. Increased tenofovir concentrations have been noted in the following combination regimens: tenofovir with ritonavir 'boosted' atazanavir; tenofovir, atazanavir, and lopinavir; ritonavir. Patients who receive tenofovir with atazanavir and any form/dose of ritonavir should be monitored for tenofovir-associated adverse events, with tenofovir being discontinued in patients who develop such adverse events. Although there are varying results in reports of an interaction between tenofovir and lopinavir; ritonavir, the clinical significance of an interaction is suspected to be insignificant. In treatment-experienced patients >= 40 kg receiving H2-antagonists and tenofovir, atazanavir should be dosed 400 mg with ritonavir 100 mg once daily with food. (Moderate) The plasma concentrations of rilpivirine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Rilpivirine is a CYP3A4 substrate and cobicistat is a strong inhibitor of CYP3A4.
Emtricitabine; Tenofovir alafenamide: (Moderate) Concurrent use of atazanavir with tenofovir alafenamide may result in elevated tenofovir serum concentrations. Tenofovir alafenamide is a substrate for the drug transporter organic anion transporting polypeptide (OATP1B1/1B3); atazanavir is an OATP1B1 inhibitor. Monitor for increased toxicities if these drugs are given together.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir decreases atazanavir AUC and Cmin. If atazanavir and tenofovir, PMPA are to be coadministered, it is recommended that atazanavir 300 mg be given with ritonavir 100 mg and tenofovir 300 mg once per day with food in patients >= 40 kg; atazanavir should not be coadministered with tenofovir without ritonavir. Data are insufficient to recommend atazanavir dosing in children < 40 kg who are also receiving concomitant tenofovir. In three post-marketing clinical trials, atazanavir AUC and Cmin were decreased by approximately 25% and 23 to 40%, respectively, when atazanavir was coadministered with tenofovir, PMPA as compared to atazanavir alone. Coadministration of atazanavir and tenofovir without ritonavir could lead to loss or lack of virologic response and possible resistance to atazanavir. In addition, atazanavir appears to increase tenofovir plasma concentrations, which could lead to adverse effects associated with tenofovir, including renal disorders. Increased tenofovir concentrations have been noted in the following combination regimens: tenofovir with ritonavir 'boosted' atazanavir; tenofovir, atazanavir, and lopinavir; ritonavir. Patients who receive tenofovir with atazanavir and any form/dose of ritonavir should be monitored for tenofovir-associated adverse events, with tenofovir being discontinued in patients who develop such adverse events. Although there are varying results in reports of an interaction between tenofovir and lopinavir; ritonavir, the clinical significance of an interaction is suspected to be insignificant. In treatment-experienced patients >= 40 kg receiving H2-antagonists and tenofovir, atazanavir should be dosed 400 mg with ritonavir 100 mg once daily with food.
Encorafenib: (Major) Avoid coadministration of encorafenib and atazanavir 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 atazanavir. If atazanavir is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of atazanavir. Encorafenib is a CYP3A4 substrate; atazanavir 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. (Major) Avoid coadministration of encorafenib and cobicistat 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 cobicistat. If cobicistat is discontinued, the original encorafenib dose may be resumed after 3 to 5 elimination half-lives of cobicistat. Encorafenib is a CYP3A4 substrate; cobicistat 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.
Enfortumab vedotin: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with cobicistat 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; cobicistat 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 atazanavir 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 atazanavir is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of atazanavir. Entrectinib is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the AUC of entrectinib by 6-fold in a drug interaction study. (Major) Avoid coadministration of entrectinib with cobicistat 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 cobicistat is discontinued, resume the original entrectinib dose after 3 to 5 elimination half-lives of cobicistat. Entrectinib is a CYP3A4 substrate; cobicistat 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 atazanavir with strong inducers of CYP3A4, such as enzalutamide, is contraindicated. Taking these drugs together could decrease atazanavir concentrations, and may lead to a reduction in antiretroviral activity. (Major) Coadministration of cobicistat with enzalutamide is not recommended as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Cobicistat is metabolized by CYP3A4; enzalutamide is a strong CYP3A4 inducer.
Eplerenone: (Contraindicated) Coadministration of atazanavir and eplerenone is contraindicated. Atazanavir 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. (Contraindicated) Eplerenone is contraindicated for use with cobicistat due to increased eplerenone exposure which increases the risk of developing hyperkalemia and hypotension. Cobicitat is a strong CYP3A4 inhibitor; eplerenone is a sensitive CYP3A4 substrate. Another strong CYP3A4 inhibitor increased serum eplerenone concentrations by roughly 5-fold.
Erdafitinib: (Major) Avoid coadministration of erdafitinib and atazanavir 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 atazanavir is discontinued, the dose of erdafitinib may be increased in the absence of drug-related toxicity. Erdafitinib is a CYP3A4 substrate and atazanavir 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. (Major) Avoid coadministration of erdafitinib and cobicistat 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 cobicistat is discontinued, the dose of erdafitinib may be increased in the absence of drug-related toxicity. Erdafitinib is a CYP3A4 substrate and cobicistat 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.
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. (Contraindicated) Concomitant use of ergotamine with cobicistat is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor.
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. (Contraindicated) Concomitant use of ergotamine with cobicistat is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor.
Erlotinib: (Major) Avoid coadministration of erlotinib with cobicistat 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 cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%. (Major) Avoid the coadministration of erlotinib with atazanavir due to the risk of increased 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 atazanavir is a strong CYP3A4 inhibitor. Coadministration of erlotinib with another strong CYP3A4 inhibitor increased the erlotinib AUC by 67%.
Ertugliflozin; Metformin: (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (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) 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: (Major) Avoid concurrent use of erythromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of erythromycin, cobicistat, atazanavir and darunavir. Erythromycin is a CYP3A4 inhibitor and a P-glycoprotein (P-gp) substrate. Cobicistat is a substrate of CYP3A4 and a P-gp inhibitor, while both atazanavir and darunavir are CYP3A4 substrates.
Escitalopram: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Eslicarbazepine: (Major) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration may result in significant decreases in the plasma concentrations of the CYP3A4 substrates, cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Consider use of an alternative anticonvulsant. (Major) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as atazanavir, may result in decreased serum concentrations of the substrate. Monitor for decreased efficacy of atazanavir if coadministered with eslicarbazepine.
Esomeprazole: (Contraindicated) Coadministration of proton pump inhibitors (PPIs) with atazanavir in treatment-experienced patients is contraindicated. PPIs can be used with atazanavir in treatment-naive patients under specific administration restrictions. In treatment-naive patients >= 40 kg, the PPI dose should not exceed the equivalent of omeprazole 20 mg/day, and the PPI must be administered 12 hours before atazanavir and ritonavir; use the dosage regimen of atazanavir 300 mg boosted with ritonavir 100 mg given once daily with food. While data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant PPIs, the same recommendations regarding timing and maximum doses of concomitant PPIs should be followed. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with a PPI. A randomized, open-label, multiple-dose drug interaction study of atazanavir (300 mg) with ritonavir (100 mg) coadministered with omeprazole 40 mg found a reduction in atazanavir AUC and Cmin of 76% and 78%, respectively. Additionally, after multiple doses of omeprazole (40 mg/day) and atazanavir (400 mg/day, 2 hours after omeprazole) without ritonavir, the AUC of atazanavir was decreased by 94%, Cmax by 96%, and Cmin by 95%. (Minor) Use caution when administering cobicistat and esomeprazole concurrently. Cobicistat is an inhibitor of CYP3A, and esomeprazole is partially metabolized by CYP3A. Coadministration of cobicistat with CYP3A substrates, such as esomeprazole, can theoretically increase esomeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
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). (Moderate) The plasma concentrations of estazolam may be elevated when administered concurrently with cobicistat. Close clinical monitoring is recommended during coadministration; estazolam dose reductions may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of estazolam. These drugs used in combination may result in elevated estazolam plasma concentrations, causing an increased risk for estazolam-related adverse events.
Esterified Estrogens: (Moderate) Monitor for an increase in estrogen-related adverse effects during concomitant atazanavir use and adjust estrogen dose as appropriate based on response. Atazanavir has been shown to inhibit the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens.
Esterified Estrogens; Methyltestosterone: (Moderate) Monitor for an increase in estrogen-related adverse effects during concomitant atazanavir use and adjust estrogen dose as appropriate based on response. Atazanavir has been shown to inhibit the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens.
Estradiol: (Moderate) Atazanavir has been shown to decrease the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should be instructed to report any estrogen- related adverse events.
Estradiol; Levonorgestrel: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with levonorgestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of atazanavir with levonorgestrel have not been conducted; therefore, an alternative method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of levonorgestrel. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Atazanavir has been shown to decrease the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should be instructed to report any estrogen- related adverse events.
Estradiol; Norethindrone: (Major) Atazanavir may decrease the metabolism of oral contraceptives and non-oral combination contraceptives; the mean exposure and minimum serum concentrations of ethinyl estradiol and norethindrone are increased when administered with atazanavir 400 mg daily. However, if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased; data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Moderate) Atazanavir has been shown to decrease the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should be instructed to report any estrogen- related adverse events.
Estradiol; Norgestimate: (Major) Atazanavir may decrease the metabolism of oral contraceptives and non-oral combination contraceptives; the mean exposure and minimum serum concentrations of ethinyl estradiol and norgestimate are increased when administered with atazanavir 400 mg daily. However, if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased; data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Concurrent administration of cobicistat and norgestimate results in increased norgestimate serum concentrations. Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is also the potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Moderate) Atazanavir has been shown to decrease the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should be instructed to report any estrogen- related adverse events.
Estradiol; Progesterone: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with progesterone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. The metabolism of progesterone may also be inhibited by cobicistat, a strong inhibitor of the CYP3A4 hepatic enzyme. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Moderate) Atazanavir has been shown to decrease the metabolism of ethinyl estradiol; a similar interaction may occur with other estrogens used for hormone replacement therapy. Patients should be instructed to report any estrogen- related adverse events. (Moderate) Use caution if coadministration of atazanavir with progesterone is necessary, as the systemic exposure of progesterone may be increased resulting in an increase in treatment-related adverse reactions. Atazanavir 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).
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. (Major) The total dose of eszopiclone should not exceed 2 mg when administered with cobicistat. Coadministration may increase eszopiclone exposure resulting in increased risk of next-day psychomotor or memory impairment and decreased ability to perform tasks requiring full mental alertness such as driving. CYP3A4 is a primary metabolic pathway for eszopiclone; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased eszopiclone exposure by 2.2-fold.
Ethinyl Estradiol; Norelgestromin: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norelgestromin. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) If ethinyl estradiol is administered with atazanavir boosted with ritonavir, it is recommended that the dose of ethinyl estradiol be at least 35 mcg. However, the dose of ethinyl estradiol should be no more than 30 mcg when administered with atazanavir that is NOT boosted by ritonavir. The mean exposure and minimum serum concentrations of ethinyl estradiol are increased when administered with atazanavir; but if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased. Data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Ethinyl Estradiol; Norethindrone Acetate: (Major) Atazanavir may decrease the metabolism of oral contraceptives and non-oral combination contraceptives; the mean exposure and minimum serum concentrations of ethinyl estradiol and norethindrone are increased when administered with atazanavir 400 mg daily. However, if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased; data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how co bicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) If ethinyl estradiol is administered with atazanavir boosted with ritonavir, it is recommended that the dose of ethinyl estradiol be at least 35 mcg. However, the dose of ethinyl estradiol should be no more than 30 mcg when administered with atazanavir that is NOT boosted by ritonavir. The mean exposure and minimum serum concentrations of ethinyl estradiol are increased when administered with atazanavir; but if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased. Data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Ethinyl Estradiol; Norgestrel: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norgestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) If ethinyl estradiol is administered with atazanavir boosted with ritonavir, it is recommended that the dose of ethinyl estradiol be at least 35 mcg. However, the dose of ethinyl estradiol should be no more than 30 mcg when administered with atazanavir that is NOT boosted by ritonavir. The mean exposure and minimum serum concentrations of ethinyl estradiol are increased when administered with atazanavir; but if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased. Data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of atazanavir with norgestrel have not been conducted; therefore, an alternative method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norgestrel. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Ethosuximide: (Moderate) Atazanavir may inhibit the metabolism of ethosuximide and may necessitate up to a 50% dose reduction of ethosuximide. (Moderate) Close clinical monitoring is advised when administering ethosuximide with cobicistat. Coadministration may result in elevated ethosuximide plasma concentrations. Predictions regarding this interaction may be made based on the metabolic pathway of both drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme responsible for the metabolism of ethosuximide.
Ethotoin: (Major) Ethotoin may increase the metabolism of atazanavir and lead to decreased antiretroviral efficacy. The appropriate drug-dose adjustments necessary to ensure optimum levels of both antiretroviral and anticonvulsant drugs are unknown. Consider using alternative anticonvulsant, or monitoring atazanavir concentrations and boosting with ritonavir if necessary. If atazanavir is added to anticonvulsant therapy, the patient should be observed for changes in the clinical efficacy of the antiretroviral regimen or seizure control. Monitoring of serum concentrations of these drugs is recommended when given concomitantly with atazanavir.
Ethynodiol Diacetate; Ethinyl Estradiol: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with ethynodiol diacetate. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) If ethinyl estradiol is administered with atazanavir boosted with ritonavir, it is recommended that the dose of ethinyl estradiol be at least 35 mcg. However, the dose of ethinyl estradiol should be no more than 30 mcg when administered with atazanavir that is NOT boosted by ritonavir. The mean exposure and minimum serum concentrations of ethinyl estradiol are increased when administered with atazanavir; but if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased. Data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of atazanavir with ethynodiol diacetate have not been conducted; therefore, an alternative method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of ethynodiol diacetate. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Etonogestrel: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with etonogestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy.
Etonogestrel; Ethinyl Estradiol: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with etonogestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) If ethinyl estradiol is administered with atazanavir boosted with ritonavir, it is recommended that the dose of ethinyl estradiol be at least 35 mcg. However, the dose of ethinyl estradiol should be no more than 30 mcg when administered with atazanavir that is NOT boosted by ritonavir. The mean exposure and minimum serum concentrations of ethinyl estradiol are increased when administered with atazanavir; but if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased. Data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Etravirine: (Major) Due to the potential for decreased antiretroviral efficacy and potential for adverse events, use of etravirine with cobicistat is not recommended. When these drugs are given together, the concentrations of cobicistat and etravirine may be decreased and increased, respectively. Both drugs are substrates for CYP3A4. Etravirine is also a CYP3A4 inducer, while cobicistat is a strong CYP3A4 inhibitor. Coadministration of etravirine with another strong CYP3A4 inhibitor increased etravirine exposure by 1.42-fold. (Moderate) Etravirine should not be coadministered with atazanavir, unless atazanavir is boosted with ritonavir. Concomitant use of etravirine and unboosted atazanavir results in significant decreases in atazanavir exposure. Coadministration of etravirine and atazanavir (boosted with ritonavir) causes a decrease in atazanavir Cmin (38%); however, the decrease is not considered clinically relevant, and this drug combination can be administred together without dose adjustments.
Everolimus: (Major) Avoid coadministration of everolimus with atazanavir 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 P-glycoprotein (P-gp) substrate. Atazanavir is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold. (Major) Avoid coadministration of everolimus with cobicistat 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. Cobicistat is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4/P-gp inhibitor increased the AUC of everolimus by 15-fold.
Ezetimibe; Simvastatin: (Contraindicated) Concomitant use of simvastatin with cobicistat is contraindicated due to increased simvastatin exposure and potential for myopathy, including rhabdomyolysis. Simvastatin is a substrate for CYP3A4; cobicistat is a strong CYP3A4 inhibitor. (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.
Famotidine: (Major) Coadministration of H2-blockers with atazanavir reduces serum atazanavir concentrations; however, H2-blockers can be used under specific administration restrictions. Although data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant H2-blockers, the same recommendations regarding timing and maximum doses of concomitant H2-blockers should be followed. In treatment-naive patients >= 40 kg, do not exceed an H2- blocker dose equivalent to famotidine 40 mg twice daily, and give atazanavir 300 mg with ritonavir 100 mg once daily with food. Give atazanavir simultaneously with and/or at least 10 hours after the H2- blocker. If a treatment-naive adult or adolescent (>= 40 kg) cannot tolerate ritonavir, do not exceed an H2- blocker dose equivalent to famotidine 20 mg twice daily, and the atazanavir dose should be increased to 400 mg once daily with food given at least 2 hours before or 10 hours after the H2- blocker. Data are insufficent to recommend atazanavir dosing in children or adolescents < 40 kg not receiving ritonavir boosting. In treatment-naive patients on a cobicistat-boosted regimen, cobicistat and atazanavir may be administered without dosage adjustment if given at the same time or a minimum of 10 hours after dosing of the H2-blocker. The H2-blocker dose should not exceed a dose that is comparable to 40 mg/day of famotidine in treatment-naive patients. In treatment-experienced patients >= 40 kg, do not exceed an H2- blocker dose equivalent to famotidine 20 mg twice daily, and give atazanavir 300 mg with ritonavir 100 mg once daily with food. Give atazanavir simultaneously with and/or at least 10 hours after the H2- blocker. In treatment-experienced patients >= 40 kg receiving H2-antagonists and tenofovir, atazanavir should be dosed 400 mg with ritonavir 100 mg once daily with food. In antiretroviral-experienced patients on a cobicistat-boosted regimen, the dosage of cobicistat with atazanavir needs to be increased if administered with H2-blockers; the recommended dose is cobicistat 150 mg/day with atazanavir 400 mg/day and 20 mg/day or less of famotidine or other comparably dosed H2-blocker. Significant reductions in atazanavir serum concentrations may lead to therapeutic failure and the development of HIV resistance. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with an H2- blocker.
Fedratinib: (Major) Avoid coadministration of fedratinib with atazanavir 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 atazanavir 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; atazanavir is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold. (Major) Avoid coadministration of fedratinib with cobicistat 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 cobicistat 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; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
Felbamate: (Major) Coadministration of felbamate with atazanavir is not recommended. Plasma concentrations of atazanavir may be reduced if these drugs are administered concurrently, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Felbamate is a CYP3A4 inducer; atazanavir is a substrate of CYP3A4. (Major) Coadministration of felbamate with cobicistat is not recommended. Concurrent use may decrease the plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Felbamate is a CYP3A4 inducer, while cobicistat is a substrate of CYP3A4.
Felodipine: (Moderate) Concurrent use of felodipine and cobicistat should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased felodipine AUC and half-life by approximately 8-fold and 2-fold, respectively. (Moderate) Concurrent use of felodipine and protease inhibitors should be approached with caution and conservative dosing of felodipine due to the potential for significant increases in felodipine exposure. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Concurrent use of a strong CYP3A inhibitor increased felodipine AUC and half-life by approximately 8-fold and 2-fold, respectively. Concurrent use of a moderate CYP3A inhibitor increased felodipine AUC and half-life by approximately 2.5-fold and 2-fold, respectively.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of atazanavir is necessary. If atazanavir 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 atazanavir 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 atazanavir 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. (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. If cobicistat 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 cobicistat 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 cobicistat 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.
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. (Major) Limit the dose of fesoterodine to 4 mg once daily in adults and pediatric patients weighing more than 35 kg if coadministered with cobicistat. Avoid use of fesoterodine and cobicistat in pediatric patients weighing 25 to 35 kg. Concurrent use may increase fesoterodine exposure. Fesoterodine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. 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.
Finasteride; Tadalafil: (Major) Avoid coadministration of tadalafil and cobicistat for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of cobicistat for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A. Potent inhibitors of CYP3A, such as cobicistat, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. (Major) For the treatment of erectile dysfunction, do not exceed 10 mg of tadalafil within 72 hours of atazanavir 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 atazanavir therapy. Stop tadalafil at least 24 hours prior to starting atazanavir. After at least 1 week of atazanavir therapy, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on tolerability. Tadalafil is metabolized by CYP3A4, and atazanavir is a potent inhibitor of CYP3A4. Substantially increased tadalafil plasma concentrations may result in increased adverse events including hypotension, syncope, visual changes, and prolonged erection. Although the manufacturer of tadalafil provides recommended dosing for coadministration with ritonavir only, the FDA recommends the same dosage adjustment for the coadministration of tadalafil with all protease inhibitors.
Finerenone: (Contraindicated) Concomitant use of finerenone and atazanavir is contraindicated. Concomitant use may increase finerenone exposure and the risk for finerenone-related adverse reactions. Finerenone is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased overall exposure to finerenone by more than 400%. (Contraindicated) Concomitant use of finerenone and cobicistat is contraindicated. Concomitant use may increase finerenone exposure and the risk for finerenone-related adverse reactions. Finerenone is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased overall exposure to finerenone by more than 400%.
Flecainide: (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of flecainide with cobicistat. Flecainide is a substrate for CYP2D6; cobicistat is an inhibitor of this enzyme. Concurrent use may result in elevated flecainde plasma concentration.
Flibanserin: (Contraindicated) The concomitant use of flibanserin and moderate CYP3A4 inhibitors, such as atazanavir, is contraindicated. Moderate CYP3A4 inhibitors can increase flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following use of a moderate CYP3A4 inhibitor, start flibanserin at least 2 weeks after the last dose of the CYP3A4 inhibitor. If initiating a moderate CYP3A4 inhibitor following flibanserin use, start the moderate CYP3A4 inhibitor at least 2 days after the last dose of flibanserin. (Contraindicated) The concomitant use of flibanserin and strong CYP3A4 inhibitors such as cobicistat is contraindicated due to increased flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following the use of cobicistat, start flibanserin at least 2 weeks after the last dose of cobicistat. If initiating cobicistat following flibanserin use, begin therapy at least 2 days after the last dose of flibanserin. In cases where the benefit of initiating cobicistat therapy within 2 days of stopping flibanserin clearly outweighs the risk of flibanserin-related hypotension and syncope, monitor the patient for signs of hypotension and syncope.
Fluconazole: (Moderate) Caution is warranted when cobicistat is administered with fluconazole as there is a potential for elevated cobicistat concentrations. Fluconazole is a CYP3A4 inhibitor, while cobicistat is a substrate of CYP3A4.
Fluoxetine: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Fluphenazine: (Moderate) Caution is warranted when cobicistat is administered with fluphenazine as there is a potential for elevated concentrations of fluphenazine and cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Fluphenazine and cobicistat are substrates and inhibitors of CYP2D6.
Flurazepam: (Moderate) Monitor for an increase in flurazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with protease inhibitors is necessary. Concurrent use may increase flurazepam exposure. Flurazepam is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. (Moderate) The plasma concentrations of flurazepam may be elevated when administered concurrently with cobicistat. Close clinical monitoring is recommended during coadministration; flurazepam dose reductions may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4; inhibitors of this isoenzyme may reduce the metabolism of flurazepam and increase the potential for benzodiazepine toxicity.
Flurbiprofen: (Moderate) Caution is warranted when atazanavir is administered with flurbiprofen as there is a potential for elevated flubriprofen concentrations. Flurbiprofen is a substrate of uridine glucoronyltransferase (UGT). Atazanavir is an UGT1A1 inhibitor.
Flutamide: (Major) Caution is warranted when atazanavir is administered with flutamide as there is a potential for elevated flutamide concentrations and decreased concentrations of atazanavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Flutamide is a substrate and inducer of CYP3A4. Atazanavir is a CYP3A4 substrate and inhibitor. (Major) Caution is warranted when cobicistat is administered with flutamide as there is a potential for elevated flutamide concentrations and decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Flutamide is a substrate and inducer of CYP3A4. Cobicistat is a CYP3A4 substrate and inhibitor.
Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and atazanavir is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A 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. (Major) Coadministration of inhaled fluticasone propionate and cobicistat is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A 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 atazanavir. 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 atazanavir 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) Avoid concomitant use of salmeterol with cobicistat. 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 cobicistat 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 atazanavir is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A 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. (Major) Coadministration of inhaled fluticasone propionate and cobicistat is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A 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 atazanavir is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A 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. (Major) Coadministration of inhaled fluticasone propionate and cobicistat is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A 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. (Moderate) Caution is warranted when atazanavir is administered with umeclidinium; vilanterol as there is a potential for elevated umeclidinium; vilanterol concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Umeclidinium; vilanterol is a substrate of CYP3A4. Atazanavir is an inhibitor of CYP3A4. (Moderate) Caution is warranted when cobicistat is administered with umeclidinium; vilanterol as there is a potential for elevated umeclidinium; vilanterol concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Umeclidinium; vilanterol is a substrate of CYP3A4, CYP2D6, and P-glycoprotein (P-gp). Cobicistat is an inhibitor of CYP3A4, CYP2D6, and P-gp inhibitor.
Fluticasone; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and atazanavir is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A 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. (Major) Coadministration of inhaled fluticasone propionate and cobicistat is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone exposure resulting in 45% to 86% decreases in serum cortisol AUC. A 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. (Moderate) Caution is warranted when atazanavir is administered with umeclidinium; vilanterol as there is a potential for elevated umeclidinium; vilanterol concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Umeclidinium; vilanterol is a substrate of CYP3A4. Atazanavir is an inhibitor of CYP3A4. (Moderate) Caution is warranted when cobicistat is administered with umeclidinium; vilanterol as there is a potential for elevated umeclidinium; vilanterol concentrations. Clinical monitoring for adverse effects is recommended during coadministration. Umeclidinium; vilanterol is a substrate of CYP3A4, CYP2D6, and P-glycoprotein (P-gp). Cobicistat is an inhibitor of CYP3A4, CYP2D6, and P-gp inhibitor.
Fluvastatin: (Major) The plasma concentrations of fluvastatin may increase when administered with cobicistat. Use the lowest starting dose of fluvastatin and carefully titrate while monitoring for adverse events. (Moderate) Concurrent use of atazanavir with fluvastatin should be done cautiously. Concomitant use may increase the risk of myopathy and rhabdomyolysis. Atazanavir inhibits CYP3A4 metabolism. Because fluvastatin does not rely exclusively on CYP3A4 for its metabolism, atazanavir may not interact to the same extent as expected with other HMG-CoAA reductase inhibitors.
Fluvoxamine: (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4. (Minor) Fluvoxamine is a CYP3A4 inhibitor, and serum concentrations of atazanavir, a CYP3A4 substrate, may increase with co-administration. Co-administer these drugs with caution due to the potential for atazanavir toxicity.
Food: (Major) Advise patients to avoid cannabis use during cobicistat 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 cobicistat is a strong CYP3A inhibitor. 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. (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. (Major) Atazanavir needs to be taken with a light snack or meal, such as dry toast with jelly, apple juice, and coffee with skim milk in order to enhance oral absorption. However, administration with food high in calories and fat can result in a decrease in the AUC of atazanavir.
Formoterol; Mometasone: (Moderate) Coadministration of mometasone with atazanavir may cause elevated mometasone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Mometasone is a CYP3A4 substrate; atazanavir 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. (Moderate) Coadministration of mometasone with cobicistat may cause elevated mometasone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Mometasone is a CYP3A4 substrate; cobicistat 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.
Fosamprenavir: (Major) Avoid concurrent use of fosamprenavir and atazanavir. Concomitant use may decrease the exposure of atazanavir and increase the exposure of fosamprenavir; appropriate doses for this combination with respect to safety and efficacy have not been established. (Major) Coadministration of cobicistat with fosamprenavir is not recommended because pharmacokinetic data are not available to provide appropriate dosing recommendations. Cobicistat is not interchangeable with ritonavir as a boosting agent to fosamprenavir.
Fosphenytoin: (Contraindicated) Coadministration of fosphenytoin with cobicistat-containing regimens is contraindicated. If these drugs are used together, significant decreases in the plasma concentrations of the antiretrovirals may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. Consider use of an alternative anticonvulsant or antiretroviral therapy. (Major) Coadministration of fosphenytoin and atazanavir may increase the metabolism of atazanavir and lead to decreased atazanavir concentrations resulting in reduction of antiretroviral efficacy and development of viral resistance. Avoid coadministration of atazanavir with fosphenytoin unless atazanavir is boosted with ritonavir. Coadministration may also result in decreased phenytoin concentrations. If atazanavir and fosphenytoin are used together, the patient must be closely monitored for antiviral efficacy and decreased fosphenytoin efficacy; clinical monitoring of phenytoin concentrations with dosage titration if necessary is also warranted.
Fostamatinib: (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; atazanavir 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 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; cobicistat is a strong CYP3A4 inhibitor. Coadministration of fostamatinib with another strong CYP3A4 inhibitor increased R406 AUC by 102% and Cmax by 37%.
Futibatinib: (Major) Avoid concurrent use of futibatinib and cobicistat. 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; cobicistat is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with atazanavir is necessary. Gefitinib is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%. (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with cobicistat is necessary. Gefitinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Gilteritinib: (Major) Consider an alternative to atazanavir 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; atazanavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study. (Major) Consider an alternative to cobicistat 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; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
Glasdegib: (Major) Consider an alternative to atazanavir 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; atazanavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study. (Major) Consider an alternative to cobicistat 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; cobicistat 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: (Contraindicated) Coadministration of glecaprevir with atazanavir is contraindicated due to an increased risk of ALT elevations. (Contraindicated) Coadministration of pibrentasvir with atazanavir is contraindicated due to an increased risk of ALT elevations. (Moderate) Caution is advised with the coadministration of glecaprevir and cobicistat as coadministration may increase serum concentrations of glecaprevir and increase the risk of adverse effects. Glecaprevir is a substrate of P-glycoprotein (P-gp), organic anion transporting polypeptide (OATP) 1B1/3, and breast cancer resistance protein (BCRP); cobicistat is an inhibitor of all these transporters. (Moderate) Caution is advised with the coadministration of pibrentasvir and cobicistat as coadministration may increase serum concentrations of pibrentasvir and increase the risk of adverse effects. Pibrentasvir is a substrate of of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); cobicistat is an inhibitor of P-gp and BCRP.
Glipizide; Metformin: (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (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) Caution is warranted when cobicistat is administered with glyburide as there is a potential for elevated glyburide concentrations. Glyburide is a substrate of P-glycoprotein (P-gp) and cobicistat is an inhibitor of P-gp.
Glyburide; Metformin: (Moderate) Caution is warranted when cobicistat is administered with glyburide as there is a potential for elevated glyburide concentrations. Glyburide is a substrate of P-glycoprotein (P-gp) and cobicistat is an inhibitor of P-gp. (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (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.
Granisetron: (Minor) Plasma concentrations of granisetron may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or CNS effects, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while granisetron is a CYP3A4 substrate. (Minor) The plasma concentrations of granisetron may be elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects, such as GI or CNS effects, is recommended during coadministration. Atazanavir is a CYP3A4 inhibitor, while granisetron is a CYP3A4 substrate.
Grapefruit juice: (Moderate) Caution is warranted when cobicistat is administered with grapefruit juice as there is a potential for elevated cobicistat concentrations. Grapefruit juice is a CYP3A4 and CYP2D6 inhibitor, while cobicistat is a substrate of CYP3A4 and CYP2D6. (Moderate) Grapefruit or grapefruit juice ingestion may theoretically increase atazanavir serum concentrations. The possible increase in atazanavir bioavailability would be most likely due to inhibition of the CYP3A4 isoenzyme in the gut. Individuals should not drastically alter their intake of grapefruit or grapefruit juice or should avoid concurrent use unless advised differently by their health care professional.
Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of atazanavir 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 atazanavir 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 atazanavir 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. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cobicistat 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 with a combined CYP2D6 and CYP3A4 inhibitor. If cobicistat 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) Atazanavir may significantly increase guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, the guanfacine dosage should be decreased to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If atazanavir is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is primarily metabolized by CYP3A4, and atazanavir is a strong CYP3A4 inhibitor. (Major) If coadministration of cobicistat with extended-release (ER) guanfacine is necessary, reduce the guanfacine dosage to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for alpha-adrenergic effects including hypotension, drowsiness, lethargy, and bradycardia. If cobicistat is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Cobicistat may significantly increase guanfacine plasma concentrations.
H2-blockers: (Major) Coadministration of H2-blockers with atazanavir reduces serum atazanavir concentrations; however, H2-blockers can be used under specific administration restrictions. Although data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant H2-blockers, the same recommendations regarding timing and maximum doses of concomitant H2-blockers should be followed. In treatment-naive patients >= 40 kg, do not exceed an H2- blocker dose equivalent to famotidine 40 mg twice daily, and give atazanavir 300 mg with ritonavir 100 mg once daily with food. Give atazanavir simultaneously with and/or at least 10 hours after the H2- blocker. If a treatment-naive adult or adolescent (>= 40 kg) cannot tolerate ritonavir, do not exceed an H2- blocker dose equivalent to famotidine 20 mg twice daily, and the atazanavir dose should be increased to 400 mg once daily with food given at least 2 hours before or 10 hours after the H2- blocker. Data are insufficent to recommend atazanavir dosing in children or adolescents < 40 kg not receiving ritonavir boosting. In treatment-naive patients on a cobicistat-boosted regimen, cobicistat and atazanavir may be administered without dosage adjustment if given at the same time or a minimum of 10 hours after dosing of the H2-blocker. The H2-blocker dose should not exceed a dose that is comparable to 40 mg/day of famotidine in treatment-naive patients. In treatment-experienced patients >= 40 kg, do not exceed an H2- blocker dose equivalent to famotidine 20 mg twice daily, and give atazanavir 300 mg with ritonavir 100 mg once daily with food. Give atazanavir simultaneously with and/or at least 10 hours after the H2- blocker. In treatment-experienced patients >= 40 kg receiving H2-antagonists and tenofovir, atazanavir should be dosed 400 mg with ritonavir 100 mg once daily with food. In antiretroviral-experienced patients on a cobicistat-boosted regimen, the dosage of cobicistat with atazanavir needs to be increased if administered with H2-blockers; the recommended dose is cobicistat 150 mg/day with atazanavir 400 mg/day and 20 mg/day or less of famotidine or other comparably dosed H2-blocker. Significant reductions in atazanavir serum concentrations may lead to therapeutic failure and the development of HIV resistance. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with an H2- blocker.
Haloperidol: (Moderate) Caution is warranted when cobicistat is administered with haloperidol as there is a potential for elevated haloperidol concentrations. Haloperidol is a CYP3A4 substrate and CYP2D6 substrate. Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6. (Moderate) Caution should be used in patients receiving atazanavir concurrently with drugs metabolized via CYP3A4 and known to cause QT prolongation. Atazanavir inhibits the CYP3A4 isoenzyme at clinically relevant concentrations, which may lead to increased serum concentrations of the listed drugs and an increased potential for QT prolongation or other adverse effects. Serious and/or life-threatening drug interactions could potentially occur between atazanavir and these drugs. Haloperidol is metabolized by CYP3A4 and with the potential to cause QT prolongation. Avoid use of atazanavir with haloperidol when possible. Downward dosage adjustment of haloperidol may be necessary.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of atazanavir 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 atazanavir 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 atazanavir 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. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cobicistat can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularl y when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced with a combined CYP2D6 and CYP3A4 inhibitor. If cobicistat 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: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of atazanavir 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 atazanavir 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 atazanavir 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. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cobicistat 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 with a combined CYP2D6 and CYP3A4 inhibitor. If cobicistat 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 atazanavir 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 atazanavir 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 atazanavir 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. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cobicistat 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 with a combined CYP2D6 and CYP3A4 inhibitor. If cobicistat 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 atazanavir 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 atazanavir 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 atazanavir 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. (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP2D6 and CYP3A4 substrate, and coadministration with CYP2D6 and CYP3A4 inhibitors like cobicistat 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 with a combined CYP2D6 and CYP3A4 inhibitor. If cobicistat 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.
Hydroxyprogesterone: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with hydroxyprogesterone caproate. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy.
Ibrexafungerp: (Major) Decrease the ibrexafungerp dose to 150 mg PO every 12 hours for 1 day if administered concurrently with atazanavir. Coadministration may result in increased ibrexafungerp exposure and toxicity. Ibrexafungerp is a CYP3A substrate and atazanavir 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. (Major) Decrease the ibrexafungerp dose to 150 mg PO every 12 hours for 1 day if administered concurrently with cobicistat. Coadministration may result in increased ibrexafungerp exposure and toxicity. Ibrexafungerp is a CYP3A substrate and cobicistat 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 atazanavir; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold. (Major) Avoid concomitant use of ibrutinib and cobicistat; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Ibuprofen; Famotidine: (Major) Coadministration of H2-blockers with atazanavir reduces serum atazanavir concentrations; however, H2-blockers can be used under specific administration restrictions. Although data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant H2-blockers, the same recommendations regarding timing and maximum doses of concomitant H2-blockers should be followed. In treatment-naive patients >= 40 kg, do not exceed an H2- blocker dose equivalent to famotidine 40 mg twice daily, and give atazanavir 300 mg with ritonavir 100 mg once daily with food. Give atazanavir simultaneously with and/or at least 10 hours after the H2- blocker. If a treatment-naive adult or adolescent (>= 40 kg) cannot tolerate ritonavir, do not exceed an H2- blocker dose equivalent to famotidine 20 mg twice daily, and the atazanavir dose should be increased to 400 mg once daily with food given at least 2 hours before or 10 hours after the H2- blocker. Data are insufficent to recommend atazanavir dosing in children or adolescents < 40 kg not receiving ritonavir boosting. In treatment-naive patients on a cobicistat-boosted regimen, cobicistat and atazanavir may be administered without dosage adjustment if given at the same time or a minimum of 10 hours after dosing of the H2-blocker. The H2-blocker dose should not exceed a dose that is comparable to 40 mg/day of famotidine in treatment-naive patients. In treatment-experienced patients >= 40 kg, do not exceed an H2- blocker dose equivalent to famotidine 20 mg twice daily, and give atazanavir 300 mg with ritonavir 100 mg once daily with food. Give atazanavir simultaneously with and/or at least 10 hours after the H2- blocker. In treatment-experienced patients >= 40 kg receiving H2-antagonists and tenofovir, atazanavir should be dosed 400 mg with ritonavir 100 mg once daily with food. In antiretroviral-experienced patients on a cobicistat-boosted regimen, the dosage of cobicistat with atazanavir needs to be increased if administered with H2-blockers; the recommended dose is cobicistat 150 mg/day with atazanavir 400 mg/day and 20 mg/day or less of famotidine or other comparably dosed H2-blocker. Significant reductions in atazanavir serum concentrations may lead to therapeutic failure and the development of HIV resistance. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with an H2- blocker.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of atazanavir is necessary. If atazanavir 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 atazanavir 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 atazanavir 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. (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. If cobicistat 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 cobicistat 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 cobicistat 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: (Major) Coadministration of idelalisib with atazanavir may increase idelalisib exposure; use alternative agents if possible. If concomitant use of these drugs is required, monitor patients frequently for signs and symptoms of idelalisib-related adverse reactions (e.g., hepatotoxicity, diarrhea, neutropenia, and infection). Idelalisib and atazanavir are both CYP3A4 substrates and strong CYP3A inhibitors. Coadministration with another strong CYP3A inhibitor increased idelalisib exposure by 1.8-fold. Atazanavir exposure was increased when administered with some strong CYP3A inhibitors but not others. (Major) Coadministration of idelalisib with cobicistat may increase the exposure of both drugs; avoid use and use alternative agents if possible. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. If use of both drugs is required, monitor for idelalisib- and cobicistat-related adverse reactions. Coadministration with a strong CYP3A inhibitor increased idelalisib expoure by 1.8-fold.
Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with atazanavir is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Atazanavir is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment. (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with cobicistat is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Cobicistat 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 cobicistat If chloramphenicol is discontinued, increase the iloperidone dose to the previous level. Increased iloperidone exposure may occur with concurrent use. Iloperidone is a CYP3A4 substrate. Chloramphenicol 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. (Major) The plasma concentrations of iloperidone may be elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects, such as cardiovascular or CNS effects, is recommended during coadministration. A dose reduction of iloperidone may be necessary. Atazanavir is a CYP3A4 inhibitors; iloperidone is a CYP3A4 substrate.
Imatinib: (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) Caution is warranted when cobicistat is administered with imatinib, STI-571 as there is a potential for elevated imatinib and/or cobicistat concentrations. Imatinib is a CYP3A4 substrate and moderate iinhibitor, a weak inhibitor of CYP2D6, and a breast cancer resistance protein (BCRP) substrate. Cobicistat is a strong inhibitor of CYP3A4, a BCRP inhibitor, and a substrate of CYP2D6 and CYP3A4. Coadministration of imatinib with another strong CYP3A4 inhibitor increased imatinib exposure by 40%.
Imipramine: (Moderate) According to the manufacturer, concurrent use of tricyclic antidepressants (TCAs) and atazanavir may result in elevated TCA plasma concentration, and could increase the potential for serious adverse effects. If these drugs are administered together, carefully titrate the TCA dose based on a clinical assessment of antidepressant response. Patients on a stable dose of TCA who start treatment with atazanavir should be monitored for TCA-associated anticholinergic effects (e.g., sedation, confusion, constipation). In addition to clinical monitoring, the manufacturer suggests obtaining TCA serum concentrations (where available) as an adjunct to assessing the potential for interactions. (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. 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) Clinical monitoring for adverse effects, such as headache, nervousness, tremor, or cardiovascular effects, is recommended during coadministration. Plasma concentrations of indacaterol may be elevated when administered concurrently with cobicistat. Cobicistat is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) inhibitor, while indacaterol is a CYP3A4, CYP2D6, and P-gp substrate. Coadministration with other dual inhibitors of CYP3A4 and P-gp has increased exposure of indacaterol from 1.4- to 1.9- fold.
Indacaterol; Glycopyrrolate: (Moderate) Clinical monitoring for adverse effects, such as headache, nervousness, tremor, or cardiovascular effects, is recommended during coadministration. Plasma concentrations of indacaterol may be elevated when administered concurrently with cobicistat. Cobicistat is a CYP3A4, CYP2D6, and P-glycoprotein (P-gp) inhibitor, while indacaterol is a CYP3A4, CYP2D6, and P-gp substrate. Coadministration with other dual inhibitors of CYP3A4 and P-gp has increased exposure of indacaterol from 1.4- to 1.9- fold.
Indinavir: (Contraindicated) Atazanavir is an inhibitor of CYP3A and is associated with indirect (unconjugated) hyperbilirubinemia. Indinavir is a substrate of CYP3A4 and is also associated with increased unconjugated bilirubin. Due to the potential interactions and the increased risk of hyperbilirubinemia, the concomitant use of atazanavir and indinavir is contraindicated; however, the combination has not been studied. (Contraindicated) Concomitant use of indinavir with regimens containing cobicistat and atazanavir is contraindicated. Cobicistat is an inhibitor of CYP3A4, while both atazanavir and indinavir are CYP3A4 substates. In addition, both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia. Taking these drugs together may increase the risk for hepatic adverse events, such as hyperbilirubinemia.
Infigratinib: (Major) Avoid concomitant use of infigratinib and atazanavir. Coadministration may increase infigratinib exposure, increasing the risk for adverse effects. Infigratinib is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC of infigratinib by 622%. (Major) Avoid concomitant use of infigratinib and cobicistat. Coadministration may increase infigratinib exposure, increasing the risk for adverse effects. Infigratinib is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC of infigratinib by 622%.
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 atazanavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Coadministration is contraindicated if atazanavir is boosted with cobicistat. Irinotecan is a CYP3A4 substrate and its active metabolite, SN-38, is a substrate of UGT1A1. Atazanavir is a UGT1A1 inhibitor and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 and UGT1A1 inhibitor increased exposure to both irinotecan and its active metabolite, SN-38. (Major) Avoid administration of cobicistat during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Coadministration is contraindicated if cobicistat is boosted with atazanavir. Irinotecan is a CYP3A4 substrate and its active metabolite, SN-38, is a substrate of UGT1A1. Cobicistat is a UGT1A1 inhibitor and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 and UGT1A1 inhibitor increased exposure to both irinotecan and its active metabolite, SN-38.
Irinotecan: (Major) Avoid administration of atazanavir during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Coadministration is contraindicated if atazanavir is boosted with cobicistat. Irinotecan is a CYP3A4 substrate and its active metabolite, SN-38, is a substrate of UGT1A1. Atazanavir is a UGT1A1 inhibitor and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 and UGT1A1 inhibitor increased exposure to both irinotecan and its active metabolite, SN-38. (Major) Avoid administration of cobicistat during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Coadministration is contraindicated if cobicistat is boosted with atazanavir. Irinotecan is a CYP3A4 substrate and its active metabolite, SN-38, is a substrate of UGT1A1. Cobicistat is a UGT1A1 inhibitor and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 and UGT1A1 inhibitor increased exposure to both irinotecan and its active metabolite, SN-38.
Isavuconazonium: (Contraindicated) Coadministration of isavuconazonium with cobicistat is contraindicated due to the risk of increased isavuconazole exposure. Isavuconazole is a sensitive substrate of CYP3A4 and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased isavuconazole exposure by 422%. (Contraindicated) Concomitant use of isavuconazonium with atazanavir 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; atazanavir 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 atazanavir concentrations would also be expected with coadministration, as atazanavir is a CYP3A4 substrate and isavuconazole is a moderate CYP3A4 inhibitor.
Isoniazid, INH: (Moderate) Caution is warranted when cobicistat is administered with isoniazid, INH as there is a potential for elevated cobicistat concentrations. Isoniazid is a CYP3A4 inhibitor, while cobicistat is a substrate of CYP3A4.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Contraindicated) Atazanavir is contraindicated for use with rifampin. Rifampin induces CYP isoenzymes, thereby decreasing the plasma concentrations and AUC of most protease inhibitors by roughly 90% and leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. (Contraindicated) Coadministration of rifampin with cobicistat is contraindicated. Rifampin induces CYP3A4; cobicistat is a substrate of this enzyme. Concurrent use may result in significant decreases in the plasma concentrations of cobicistat and of the simultaneously administered protease inhibitors (atazanavir or darunavir), leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. (Moderate) Caution is warranted when cobicistat is administered with isoniazid, INH as there is a potential for elevated cobicistat concentrations. Isoniazid is a CYP3A4 inhibitor, while cobicistat is a substrate of CYP3A4.
Isoniazid, INH; Rifampin: (Contraindicated) Atazanavir is contraindicated for use with rifampin. Rifampin induces CYP isoenzymes, thereby decreasing the plasma concentrations and AUC of most protease inhibitors by roughly 90% and leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. (Contraindicated) Coadministration of rifampin with cobicistat is contraindicated. Rifampin induces CYP3A4; cobicistat is a substrate of this enzyme. Concurrent use may result in significant decreases in the plasma concentrations of cobicistat and of the simultaneously administered protease inhibitors (atazanavir or darunavir), leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. (Moderate) Caution is warranted when cobicistat is administered with isoniazid, INH as there is a potential for elevated cobicistat concentrations. Isoniazid is a CYP3A4 inhibitor, while cobicistat is a substrate of CYP3A4.
Isradipine: (Moderate) Coadministration of cobicistat (a strong CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as isradipine, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate reductions are advised. (Moderate) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with protease inhibitors is necessary. Concomitant use may increase isradipine exposure. Isradipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors.
Istradefylline: (Major) Do not exceed 20 mg once daily of istradefylline if administered with atazanavir as istradefylline exposure and adverse effects may increase. Atazanavir is a strong CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study. (Major) Do not exceed 20 mg once daily of istradefylline if administered with cobicistat as istradefylline exposure and adverse effects may increase. Cobicistat 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) Avoid concurrent use of itraconazole with regimens containing cobicistat and atazanavir or darunavir. Use of these drugs together may result in increased plasma concentrations of itraconazole, cobicistat, atazanavir, and darunavir. Specific dosage recommendations have not been determined. (Major) Coadministration of atazanavir and itraconazole may result in increased serum concentrations of itraconazole. While clinically significant interactions are not expected with atazanavir monotherapy, the addition of cobicistat to atazanavir may cause a significant interaction and therefore, atazanavir; cobicistat should be avoided in combination with itraconazole. Atazanavir is a CYP3A4 inhibitor and itraconazole is a CYP3A4 substrate. Caution and close monitoring of the anticipated responses are recommended when coadministered.
Ivabradine: (Contraindicated) Coadministration of cobicistat with ivabradine is contraindicated due to an increase in plasma concentrations of ivabradine, which may exacerbate bradycardia and conduction disturbances. Ivabradine is primarily metabolized by CYP3A4; cobicistat is a strong inhibitor of CYP3A4. Coadministration with another strong CYP3A4 inhibitor increased ivabradine exposure by 7.7-fold. (Contraindicated) Coadministration of ivabradine and atazanvir is contraindicated. Ivabradine is primarily metabolized by CYP3A4; atazanavir 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 atazanavir 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 atazanavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) If cobicistat 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 cobicistat 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 atazanavir 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 atazanavir is discontinued, wait at least 5 half-lives of atazanavir before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and atazanavir 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. (Major) Avoid coadministration of ivosidenib with cobicistat 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 cobicistat is discontinued, wait at least 5 half-lives of cobicistat before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and cobicistat 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 atazanavir 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 atazanavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ixabepilone exposure by 79%. (Major) Avoid concurrent use of ixabepilone and cobicistat 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 cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ixabepilone exposure by 79%.
Ketoconazole: (Major) Avoid atazanavir 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 atazanavir is a strong CYP3A inhibitor. (Major) Avoid cobicistat for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of both drugs and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for adverse reactions; a ketoconazole dose reduction may be necessary. Both ketoconazole and cobicistat are CYP3A substrates and strong CYP3A inhibitors.
Lacosamide: (Moderate) Lacosamide causes PR interval prolongation in some patients. Caution is advised during coadministration of lacosamide with other drugs that cause PR prolongation, such as atazanavir, since further PR prolongation is possible. If concurrent use is necessary, an ECG is recommended prior to initiation of lacosamide and after the drug is titrated to the maintenence dose. Patients receiving intravenous lacosamide should be closely monitored due to the potential for profound bradycardia and AV block during coadministration.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Tenofovir decreases atazanavir AUC and Cmin. If atazanavir and tenofovir, PMPA are to be coadministered, it is recommended that atazanavir 300 mg be given with ritonavir 100 mg and tenofovir 300 mg once per day with food in patients >= 40 kg; atazanavir should not be coadministered with tenofovir without ritonavir. Data are insufficient to recommend atazanavir dosing in children < 40 kg who are also receiving concomitant tenofovir. In three post-marketing clinical trials, atazanavir AUC and Cmin were decreased by approximately 25% and 23 to 40%, respectively, when atazanavir was coadministered with tenofovir, PMPA as compared to atazanavir alone. Coadministration of atazanavir and tenofovir without ritonavir could lead to loss or lack of virologic response and possible resistance to atazanavir. In addition, atazanavir appears to increase tenofovir plasma concentrations, which could lead to adverse effects associated with tenofovir, including renal disorders. Increased tenofovir concentrations have been noted in the following combination regimens: tenofovir with ritonavir 'boosted' atazanavir; tenofovir, atazanavir, and lopinavir; ritonavir. Patients who receive tenofovir with atazanavir and any form/dose of ritonavir should be monitored for tenofovir-associated adverse events, with tenofovir being discontinued in patients who develop such adverse events. Although there are varying results in reports of an interaction between tenofovir and lopinavir; ritonavir, the clinical significance of an interaction is suspected to be insignificant. In treatment-experienced patients >= 40 kg receiving H2-antagonists and tenofovir, atazanavir should be dosed 400 mg with ritonavir 100 mg once daily with food.
Lamotrigine: (Major) Adjustments in lamotrigine maintenance dose regimens may be necessary with concomitant use of atazanavir boosted with ritonavir. No dose adjustments during dose escalation are necessary. Monitoring lamotrigine plasma concentrations may be indicated, particularly during dosage adjustments. Lamotrigine is metabolized predominantly by glucuronic acid conjugation, and atazanavir with ritonavir induces glucuronidation. Daily doses of atazanavir/ritonavir (300 mg/100 mg) in healthy volunteers reduced the AUC and Cmax of a single lamotrigine dose (100 mg) by approximately 32% and 6%, respectively. The lamotrigine half-life decreased by 27%. Concurrent use of lamotrigine and unboosted atazanavir is not expected to alter the plasma concentration of lamotrigine, and no dose adjustment of lamotrigine is necessary when administered without ritonavir.
Lansoprazole: (Contraindicated) Coadministration of proton pump inhibitors (PPIs) with atazanavir in treatment-experienced patients is contraindicated. PPIs can be used with atazanavir in treatment-naive patients under specific administration restrictions. In treatment-naive patients >= 40 kg, the PPI dose should not exceed the equivalent of omeprazole 20 mg/day, and the PPI must be administered 12 hours before atazanavir and ritonavir; use the dosage regimen of atazanavir 300 mg boosted with ritonavir 100 mg given once daily with food. While data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant PPIs, the same recommendations regarding timing and maximum doses of concomitant PPIs should be followed. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with a PPI. A randomized, open-label, multiple-dose drug interaction study of atazanavir (300 mg) with ritonavir (100 mg) coadministered with omeprazole 40 mg found a reduction in atazanavir AUC and Cmin of 76% and 78%, respectively. Additionally, after multiple doses of omeprazole (40 mg/day) and atazanavir (400 mg/day, 2 hours after omeprazole) without ritonavir, the AUC of atazanavir was decreased by 94%, Cmax by 96%, and Cmin by 95%. (Minor) Use caution when administering cobicistat and lansoprazole concurrently. Cobicistat is an inhibitor of CYP3A. Coadministration of cobicistat with CYP3A substrates, such as lansoprazole, can increase lansoprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Lansoprazole; Amoxicillin; Clarithromycin: (Contraindicated) Coadministration of proton pump inhibitors (PPIs) with atazanavir in treatment-experienced patients is contraindicated. PPIs can be used with atazanavir in treatment-naive patients under specific administration restrictions. In treatment-naive patients >= 40 kg, the PPI dose should not exceed the equivalent of omeprazole 20 mg/day, and the PPI must be administered 12 hours before atazanavir and ritonavir; use the dosage regimen of atazanavir 300 mg boosted with ritonavir 100 mg given once daily with food. While data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant PPIs, the same recommendations regarding timing and maximum doses of concomitant PPIs should be followed. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with a PPI. A randomized, open-label, multiple-dose drug interaction study of atazanavir (300 mg) with ritonavir (100 mg) coadministered with omeprazole 40 mg found a reduction in atazanavir AUC and Cmin of 76% and 78%, respectively. Additionally, after multiple doses of omeprazole (40 mg/day) and atazanavir (400 mg/day, 2 hours after omeprazole) without ritonavir, the AUC of atazanavir was decreased by 94%, Cmax by 96%, and Cmin by 95%. (Major) Avoid concurrent use of clarithromycin with regimens containing cobicistat and atazanavir or darunavir; use of an alternative antibiotic is recommended. Taking these drugs together may result in elevated concentrations of clarithromycin, cobicistat, atazanavir and darunavir. Both clarithromycin and cobicistat are inhibitors of CYP3A4, an isoenzyme responsible for the metabolism of cobicistat, atazanavir and darunavir. (Major) Coadministration with atazanavir increases clarithromycin serum concentrations. Use caution if these drugs are coadministered, as increased clarithromycin concentrations may cause QT prolongation; a 50% dosage reduction of clarithromycin is recommended. In addition, atazanavir significantly reduces the concentration of 14-OH clarithromycin, the active metabolite of clarithromycin; consider alternative agents for indications other than infections due to Mycobacterium avium complex (MAC). (Minor) Use caution when administering cobicistat and lansoprazole concurrently. Cobicistat is an inhibitor of CYP3A. Coadministration of cobicistat with CYP3A substrates, such as lansoprazole, can increase lansoprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Lapatinib: (Major) Avoid coadministration of lapatinib with atazanavir due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If atazanavir is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and atazanavir 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) Avoid coadministration of lapatinib with cobicistat due to increased plasma concentrations of lapatinib. If concomitant use is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily. If cobicistat is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Lapatinib is a CYP3A4 substrate and cobicistat 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.
Larotrectinib: (Major) Avoid coadministration of larotrectinib with atazanavir due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If atazanavir is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of atazanavir. Larotrectinib is a CYP3A4 substrate; atazanavir 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. (Major) Avoid coadministration of larotrectinib with cobicistat due to increased larotrectinib exposure resulting in increased treatment-related adverse effects. If coadministration cannot be avoided, reduce the larotrectinib dose by 50%. If cobicistat is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of cobicistat. Larotrectinib is a CYP3A4 substrate; cobicistat 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.
Ledipasvir; Sofosbuvir: (Moderate) Caution is warranted when cobicistat is administered with ledipasvir; sofosbuvir as there is a potential for elevated concentrations of ledipasvir and sofosbuvir. Cobicistat is an inhibitor of the transporters P-glycoprotein and breast cancer resistance protein (BCRP). Both ledipasvir and sofosbuvir are substrates of P-gp and BCRP. According to the manufacturer, no dosage adjustments are required when ledipasvir; sofosbuvir is administered concurrently with P-gp or BCRP inhibitors; however, if these drugs are given together, consider increased monitoring for potential adverse effect. (Moderate) In an interaction study, use of cobicistat with sofosbuvir resulted in a 37% increase in sofosbuvir exposure; however, no dose adjustments are required. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is an inhibitor of the transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). Sofosbuvir is a substrate of P-gp and BCRP.
Lefamulin: (Major) Avoid coadministration of atazanavir with oral lefamulin due to increased lefamulin exposure; atazanavir may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the exposure of oral and intravenous lefamulin by 165% and 31%, respectively. (Major) Avoid coadministration of cobicistat with oral lefamulin due to increased lefamulin exposure; cobicistat may be administered with intravenous lefamulin. Lefamulin is a CYP3A4 and P-gp substrate; cobicistat 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 atazanavir as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration of lemborexant with another strong/moderate CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold. (Major) Avoid coadministration of lemborexant and cobicistat as concurrent use is expected to significantly increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of lemborexant with another strong CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold.
Lenacapavir: (Major) Avoid concomitant use of lenacapavir and atazanavir boosted with ritonavir or cobicistat and consider alternative therapy. Concomitant use may increase lenacapavir exposure and the risk for lenacapavir-related adverse reactions. Lenacapavir is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant use of lenacapavir with atazanavir boosted cobicistat was observed to increase lenacapavir overall exposure by 4.21-fold.
Leniolisib: (Major) Avoid concomitant use of leniolisib and atazanavir due to the risk for increased leniolisib exposure which may increase the risk for adverse effects. Leniolisib is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased leniolisib overall exposure by 2-fold. (Major) Avoid concomitant use of leniolisib and cobicistat due to the risk for increased leniolisib exposure which may increase the risk for adverse effects. Leniolisib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased leniolisib overall exposure by 2-fold.
Lesinurad: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of atazanavir; monitor for potential reduction in efficacy. Atazanavir is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Lesinurad; Allopurinol: (Moderate) Lesinurad may decrease the systemic exposure and therapeutic efficacy of atazanavir; monitor for potential reduction in efficacy. Atazanavir is a CYP3A substrate, and lesinurad is a weak CYP3A inducer.
Letermovir: (Moderate) Administering atazanavir 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, kidney stones, and gastrointestinal events. Atazanavir is an inhibitor of the organic anion-transporting polypeptides (OATP1B1), and a substrate of CYP3A4. Letermovir is an OATP1B1 substrate and a moderate CYP3A4 inhibitor. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor. (Moderate) Administering cobicistat concurrently with letermovir may result in increased concentrations of both drugs. The impact on the concentration of cobicistat may be increased in patients who are receiving letermovir with cyclosporine. Closely monitor for adverse events, including tachycardia, atrial fibrillation, and gastrointestinal events. Cobicistat is an inhibitor of the organic anion-transporting polypeptides (OATP1B1/3), and a substrate of CYP3A4. Letermovir is an OATP1B1/3 substrate and a moderate CYP3A4 inhibitor. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Leuprolide; Norethindrone: (Major) Atazanavir may decrease the metabolism of oral contraceptives and non-oral combination contraceptives; the mean exposure and minimum serum concentrations of ethinyl estradiol and norethindrone are increased when administered with atazanavir 400 mg daily. However, if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased; data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy.
Levamlodipine: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Levoketoconazole: (Major) Avoid atazanavir 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 atazanavir is a strong CYP3A inhibitor. (Major) Avoid cobicistat for 2 weeks prior to and during treatment with ketoconazole. Concomitant use may increase exposure of both drugs and increase the risk of adverse effects. If concomitant use is necessary, monitor closely for adverse reactions; a ketoconazole dose reduction may be necessary. Both ketoconazole and cobicistat are CYP3A substrates and strong CYP3A inhibitors.
Levomilnacipran: (Major) Do not exceed a levomilnacipran dose of 80 mg once daily if coadministration with cobicistat is necessary. Levomilnacipran is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased levomilnacipran exposure by about 50%.
Levonorgestrel: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with levonorgestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of atazanavir with levonorgestrel have not been conducted; therefore, an alternative method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of levonorgestrel. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
Levonorgestrel; Ethinyl Estradiol: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with levonorgestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) If ethinyl estradiol is administered with atazanavir boosted with ritonavir, it is recommended that the dose of ethinyl estradiol be at least 35 mcg. However, the dose of ethinyl estradiol should be no more than 30 mcg when administered with atazanavir that is NOT boosted by ritonavir. The mean exposure and minimum serum concentrations of ethinyl estradiol are increased when administered with atazanavir; but if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased. Data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of atazanavir with levonorgestrel have not been conducted; therefore, an alternative method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of levonorgestrel. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with levonorgestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) If ethinyl estradiol is administered with atazanavir boosted with ritonavir, it is recommended that the dose of ethinyl estradiol be at least 35 mcg. However, the dose of ethinyl estradiol should be no more than 30 mcg when administered with atazanavir that is NOT boosted by ritonavir. The mean exposure and minimum serum concentrations of ethinyl estradiol are increased when administered with atazanavir; but if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased. Data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of atazanavir with levonorgestrel have not been conducted; therefore, an alternative method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of levonorgestrel. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with levonorgestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) If ethinyl estradiol is administered with atazanavir boosted with ritonavir, it is recommended that the dose of ethinyl estradiol be at least 35 mcg. However, the dose of ethinyl estradiol should be no more than 30 mcg when administered with atazanavir that is NOT boosted by ritonavir. The mean exposure and minimum serum concentrations of ethinyl estradiol are increased when administered with atazanavir; but if atazanavir is boosted with ritona vir, mean exposure of ethinyl estradiol will be decreased. Data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Studies evaluating use of atazanavir with levonorgestrel have not been conducted; therefore, an alternative method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of levonorgestrel. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
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. (Moderate) Monitor for lidocaine-related adverse reactions if coadministration with cobicistat is necessary. Lidocaine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
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. (Moderate) Monitor for lidocaine-related adverse reactions if coadministration with cobicistat is necessary. Lidocaine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
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. (Moderate) Atazanavir inhibits the CYP3A4 isoenzyme at clinically relevant concentrations, which may lead to increased serum concentrations of local anesthetics and an increased potential for QT prolongation or other adverse effects. (Moderate) Monitor for lidocaine-related adverse reactions if coadministration with cobicistat is necessary. Lidocaine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
Linagliptin: (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, such as linagliptin, should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated.
Linagliptin; Metformin: (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (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, such as linagliptin, 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.
Lomitapide: (Contraindicated) Concomitant use of atazanavir and lomitapide is contraindicated. If treatment with atazanavir is unavoidable, lomitapide should be stopped during the course of treatment. Atazanavir is a moderate CYP3A4 inhibitor. The exposure to lomitapide was increased 27-fold in the presence of ketoconazole, a strong CYP3A4 inhibitor. Although concomitant use of moderate CYP3A4 inhibitors with lomitapide has not been studied, a significant increase in lomitapide exposure is likely during concurrent use. (Contraindicated) Concomitant use of cobicistat and lomitapide is contraindicated due to the potential of markedly increased lomitapide concentrations and the associated elevation of serum transaminases. Cobicistat is a strong CYP3A4 inhibitor. The exposure to lomitapide was increased 27-fold in the presence another strong CYP3A4 inhibitor.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and atazanavir is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%. (Contraindicated) Coadministration of lonafarnib and cobicistat 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; cobicistat is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
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 atazanavir. Concurrent use may increase loperamide exposure. Loperamide is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 and P-gp inhibitor increased loperamide exposure by 3.8-fold. (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 cobicistat. Concurrent use may increase loperamide exposure. Loperamide is a CYP3A4 and P-gp substrate and cobicistat is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4 and P-gp inhibitor increased loperamide exposure by 3.8-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 atazanavir. Concurrent use may increase loperamide exposure. Loperamide is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 and P-gp inhibitor increased loperamide exposure by 3.8-fold. (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 cobicistat. Concurrent use may increase loperamide exposure. Loperamide is a CYP3A4 and P-gp substrate and cobicistat is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4 and P-gp inhibitor increased loperamide exposure by 3.8-fold.
Lopinavir; Ritonavir: (Contraindicated) Use of ritonavir with cobicistat is not recommended, because of similar effects on CYP3A. Both ritonavir and cobicistat are potent inhibitors of CYP3A4. (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.
Lorazepam: (Moderate) Monitor for an increase in lorazepam-related adverse reactions and consider reducing the dose of lorazepam if concomitant use of lorazepam and atazanavir 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 atazanavir is an UGT inhibitor.
Lorcaserin: (Moderate) Caution is warranted when cobicistat is administered with lorcaserin as there is a potential for elevated cobicistat concentrations. Lorcaserin is a CYP2D6 inhibitor. Cobicistat is a substrate of CYP2D6.
Lorlatinib: (Major) Avoid coadministration of lorlatinib with atazanavir due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions of lorlatinib; exposure to atazanavir may also decrease. 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 atazanavir is discontinued, resume the original dose of lorlatinib after 3 plasma half-lives of atazanavir. Lorlatinib is a CYP3A4 substrate and a moderate CYP3A4 inducer. Atazanavir is a CYP3A4 substrate and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%. Concomitant administration of atazanavir with CYP3A4 inducers may decrease plasma concentrations, reducing efficacy and increasing the potential for viral resistance. (Major) Avoid coadministration of lorlatinib with cobicistat due to increased plasma concentrations of lorlatinib, which may increase the incidence and severity of adverse reactions of lorlatinib; plasma concentrations of cobicistat may also decrease. 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 cobicistat is discontinued, resume the original dose of lorlatinib after 3 half-lives of cobicistat. Lorlatinib is a CYP3A4 substrate and a moderate CYP3A4 inducer. Cobicistat is a CYP3A4 substrate and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%. Coadministration of cobicistat with moderate CYP3A4 inducers may reduce antiretroviral efficacy and increase the potential development of viral resistance.
Losartan: (Minor) Caution is warranted when atazanavir is administered with losartan as there is a potential for elevated losartan concentrations. Losartan is a substrate of CYP3A4; atazanavir is an inhibitor of CYP3A4. (Minor) Caution is warranted when cobicistat is administered with losartan as there is a potential for increased losartan concentrations. Losartan is a substrate of CYP3A4; cobicistat is an inhibitor of CYP3A4.
Losartan; Hydrochlorothiazide, HCTZ: (Minor) Caution is warranted when atazanavir is administered with losartan as there is a potential for elevated losartan concentrations. Losartan is a substrate of CYP3A4; atazanavir is an inhibitor of CYP3A4. (Minor) Caution is warranted when cobicistat is administered with losartan as there is a potential for increased losartan concentrations. Losartan is a substrate of CYP3A4; cobicistat is an inhibitor of CYP3A4.
Lovastatin: (Contraindicated) Concomitant use of lovastatin with cobicistat is contraindicated due to the potential for myopathy, including rhabdomyolysis. Coadministration is expected to significantly increase lovastatin plasma concentrations. Lovastatin is a substrate for CYP3A4; cobicistat is a strong inhibitor of CYP3A. Coadministration with another strong CYP3A4 inhibitor increased lovastatin exposure by 11 to 36-fold. (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: (Major) If atazanavir 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 atazanavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) If cobicistat 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 cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Lumacaftor; ivacaftor is expected to decrease the therapeutic efficacy of atazanavir; avoid concurrent use. If concomitant use cannot be avoided, consider limiting concurrent use to regimens in which atazanavir is boosted with ritonavir and monitor antiretroviral efficacy carefully. Lumacaftor; ivacaftor dosage adjustment is not required when atazanavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking atazanavir, 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 atazanavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Atazanavir 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 atazanavir and decrease its therapeutic efficacy. Although atazanavir 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.
Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor is expected to decrease the therapeutic efficacy of atazanavir; avoid concurrent use. If concomitant use cannot be avoided, consider limiting concurrent use to regimens in which atazanavir is boosted with ritonavir and monitor antiretroviral efficacy carefully. Lumacaftor; ivacaftor dosage adjustment is not required when atazanavir is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking atazanavir, 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 atazanavir. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Atazanavir 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 atazanavir and decrease its therapeutic efficacy. Although atazanavir 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. (Major) Lumacaftor; ivacaftor may decrease the therapeutic efficacy of cobicistat; avoid concurrent use if possible. If concomitant use of cobicistat is necessary, monitor antiretroviral efficacy, consider the use of therapeutic drug monitoring, and adjust drug dosages as necessary. Lumacaftor; ivacaftor dosage adjustment is not required when cobicistat is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking cobicistat, 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 cobicistat. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A to reach steady state. Cobicistat 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 cobicistat and decrease its therapeutic efficacy. Although cobicistat 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.
Lumateperone: (Major) Reduce the dose of lumateperone to 10.5 mg once daily if concomitant use of cobicistat is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor increased lumateperone exposure by approximately 4-fold. (Major) Reduce the dose of lumateperone to 10.5 mg once daily if concomitant use with atazanavir is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; atazanavir is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor increased lumateperone exposure by approximately 4-fold.
Lurasidone: (Contraindicated) Coadministration of cobicistat (or cobicistat containing medications) with lurasidone is contraindicated due to the potential for serious or life-threatening reactions, such as CNS effects and extrapyramidal symptoms. The plasma concentrations of lurasidone may be elevated when administered concurrently with cobicistat. Cobicistat is a strong CYP3A4 inhibitor, while lurasidone is a sensitive CYP3A4 substrate. Coadministration with another strong CYP3A4 inhibitor increased lurasidone exposure by 9-fold. (Major) Atazanavir is a moderate inhibitor of CYP3A4 and has the potential for interactions with substrates of CYP3A4 such as lurasidone. Concurrent use of these medications may lead to an increased risk of lurasidone-related adverse reactions. If a moderate inhibitor of CYP3A4 is being prescribed and lurasidone is added in an adult patient, the recommended starting dose of lurasidone is 20 mg/day and the maximum recommended daily dose of lurasidone is 80 mg/day. If a moderate CYP3A4 inhibitor is added to an existing lurasidone regimen, reduce the lurasidone dose to one-half of the original dose. Patients should be monitored for efficacy and toxicity. Concurrent use of lurasidone and atazanavir boosted with ritonavir or atazanavir; cobicistat is contraindicated.
Lurbinectedin: (Major) Avoid concomitant use of lurbinectedin and atazanavir due to the risk of increased lurbinectedin exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of lurbinectedin by 50%. Lurbinectedin is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of lurbinectedin by 2.7-fold. (Major) Avoid concomitant use of lurbinectedin and cobicistat due to the risk of increased lurbinectedin exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of lurbinectedin by 50%. Lurbinectedin is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of lurbinectedin by 2.7-fold.
Macitentan: (Major) Avoid coadministration of macitentan with cobicistat due to increased plasma concentrations of macitentan. Macitentan is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased macitentan exposure by approximately 2.3-fold.
Magnesium Hydroxide: (Major) It is recommended that antacids not be given at the some time as atazanavir because of potential interference with absorption of atazanavir. Separate the administration of atazanavir and antacids to avoid the potential for interaction; give atazanavir 2 hours before or 1 hour after the antacid.
Maprotiline: (Major) The plasma concentrations of maprotiline may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Maprotiline serum concentration monitoring may be useful to guide dosage adjustments and prevent toxicity. Cobicistat is a CYP2D6 inhibitor, while maprotiline is a CYP2D6 substrate. (Moderate) Atazanavir competitively inhibits the enzymes CYP3A4, CYP1A2 and CYP2C9. Concentrations of drugs that are substrates of these enzymes (e.g., tricyclic antidepressants) may be increased with concomitant atazanavir use. According to the manufacturer of atazanavir, coadministration of atazanavir in a patient on a tricyclic antidepressant (TCA) may result in increased serum concentrations of the TCA, and the two drugs should be coadministered with caution due to a potential for serious adverse events. Monitor the patient for anticholinergic effects (e.g., sedation, confusion, constipation) associated with TCA use. The manufacturer recommends TCA concentration monitoring if atazanavir is used concomitantly with a TCA. Maprotiline is related to the tricyclic antidepressants, and until more data is available, similar caution is advised when using maprotiline with atazanavir.
Maraviroc: (Major) Coadministration of maraviroc (a substrate of CYP3A, P-gp, and OATP1B1) with cobicistat (a CYP3A4, P-gp, OATP1B1 inhibitor) may result in increased maraviroc concentrations. Reduce the dose of maraviroc when coadministered with cobicistat; coadministration is contraindicated in patients with CrCl less than 30 mL/min. Adjust the maraviroc dosage as follows when administered with cobicistat (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. (Major) Coadministration of maraviroc, a CYP3A and OATP1B1 substrate, with atazanavir, a strong CYP3A4 inhibitor and in vitro inhibitor of OATP1B1, may result in increased 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 atazanavir (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.
Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with atazanavir due to risk of heart failure due to systolic dysfunction. Concomitant use increases mavacamten exposure and may decrease the plasma concentrations of atazanavir leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mavacamten is a substrate and moderate inducer of CYP3A and atazanavir 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%. (Contraindicated) Mavacamten is contraindicated for use with cobicistat due to risk of heart failure due to systolic dysfunction. Concomitant use increases mavacamten exposure and may decrease the plasma concentrations of cobicistat leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Mavacamten is a substrate and moderate inducer of CYP3A and cobicistat 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) The plasma concentrations of meclizine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a CYP2D6 inhibitor, while meclizine is a CYP2D6 substrate.
Medroxyprogesterone: (Major) Coadministration of medroxyprogesterone, a CYP3A substrate with atazanavir, 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. (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with medroxyprogesterone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy.
Mefloquine: (Moderate) Mefloquine is metabolized by CYP3A4. Atazanavir is an inhibitor of this enzyme and may decrease the clearance of mefloquine and increase mefloquine systemic exposure. (Moderate) The plasma concentrations of mefloquine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or neurophsychiatric effects, is recommended during coadministration. Cobicistat is a strong inhibitor of CYP3A4 and P-glycoprotein (P-gp) inhibitor, while mefloquine is a CYP3A4 and P-gp substrate.
Meloxicam: (Moderate) The plasma concentrations of meloxicam may be elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects is recommended during coadministration. Atazanavir is a CYP3A4 inhibitor, while meloxicam is a CYP3A4 substrate.
Mepivacaine: (Moderate) Atazanavir inhibits the CYP3A4 isoenzyme at clinically relevant concentrations, which may lead to increased serum concentrations of local anesthetics and an increased potential for QT prolongation or other adverse effects.
Metformin: (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (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: (Moderate) Coadministration of repaglinide and cobicistat may increase plasma concentrations of repaglinide; if coadministration is necessary, repaglinide dosage adjustment may be required and an increased frequency of glucose monitoring is recommended. Cobicistat is a strong CYP3A4 inhibitor and an inhibitor of organic anion transporting polypeptide (OATP). Repaglinide is a CYP3A4 and OATP1B1 substrate. Coadministration with other strong CYP3A4 inhibitors increased repaglinide exposure by up to 1.5-fold. (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 metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (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: (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (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) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with cobicistat due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor with a single 100 mg dose of saxagliptin and a single 20 mg dose of saxagliptin increased the saxagliptin AUC by 2.45-fold and 3.67-fold, respectively. (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 atazanavir. 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. Patients on antidiabetic therapy should be closely monitored for changes in glycemic control, specifically hyperglycemia, if protease inhibitor therapy is initiated. (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (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: (Moderate) Concurrent administration of metformin and cobicistat may increase the risk of lactic acidosis. Cobicistat is a potent inhibitor of the human multidrug and toxic extrusion 1 (MATE1) on proximal renal tubular cells; metformin is a MATE1 substrate. Inhibition of MATE1 by cobicistat may decrease metformin eliminiation by blocking renal tubular secretion. If these drugs are given together, closely monitor for signs of metformin toxicity; metformin dose adjustments may be needed. (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) Caution is advised with the coadministration of atazanavir and methadone as concurrent use may result in increased concentrations of methadone. Methadone is primarily metabolized by CYP3A4; atazanavir is a CYP3A4 inhibitor. No clinically significant drug interaction was observed when atazanavir was coadministered with a stable maintenance dose of methadone. However, if coadministered, patients should be regularly monitored for excessive methadone-related side effects, as the theoretical possibility for atazanavir to inhibit methadone metabolism does exist. (Moderate) The plasma concentrations of methadone may be elevated when administered concurrently with cobicistat. When initiating methadone in patients currently on a regimen containing cobicistat and atazanavir or darunavir, use the lowest methadone starting dose and slowly titrate to desired effect. When initiating antiretroviral regimens containing cobicistat and atazanavir or darunavir to patients on methadone, an adjustment of methadone dose may be needed. Monitoring for adverse effects, such as CNS side effects or respiratory depression, is recommended during coadministration. Methadone is metabolized primarily by the cytochrome P450 isoenzymes CYP2C19, CYP3A4, and CYP2B6, and to a lesser extent, by CYP2C9 and CYP2D6. Methadone also is a substrate of P-glycoprotein (P-gp). Cobicistat is an inhibitor of CYP3A4, CYP2D6, and P-gp.
Methamphetamine: (Moderate) The plasma concentrations of methamphetamine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a CYP2D6 inhibitor, while methamphetamine is a CYP2D6 substrate.
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. (Contraindicated) Coadministration of methylergonovine with cobicistat is contraindicated. Cobicistat is an inhibitor of CYP3A, and plasma concentrations of drugs extensively metabolized by this enzyme, such as ergot alkaloids, are expected to increase with concurrent use. Elevated plasma concentrations of ergot alkaloids are associated with risk of acute ergot toxicity which is characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
Methylprednisolone: (Moderate) Coadministration of methylprednisolone with atazanavir may cause elevated methylprednisolone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Methylprednisolone is a CYP3A4 substrate; atazanavir 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. (Moderate) Coadministration of methylprednisolone with cobicistat may cause elevated methylprednisolone serum concentrations, potentially resulting in Cushing's syndrome or adrenal suppression. Cobicistat is a CYP3A4 inhibitor, while methylprednisolone is a CYP3A4 substrate. Corticosteroids, such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A4 inhibitors, should be considered, especially for long-term use.
Metoclopramide: (Moderate) Caution is warranted when cobicistat is administered with metoclopramide as there is a potential for elevated metoclopramide and cobicistat concentrations. Metoclopramide is a CYP2D6 substrate/inhibitor and cobicistat is a substrate/inhibitor of CYP2D6.
Metoprolol: (Moderate) Monitor for increased metoprolol adverse reactions including bradycardia and hypotension during coadministration. A dosage reduction for metoprolol may be needed based on response. Concurrent use may increase metoprolol exposure. Metoprolol is a CYP2D6 substrate; cobicistat is a weak CYP2D6 inhibitor.
Metoprolol; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for increased metoprolol adverse reactions including bradycardia and hypotension during coadministration. A dosage reduction for metoprolol may be needed based on response. Concurrent use may increase metoprolol exposure. Metoprolol is a CYP2D6 substrate; cobicistat is a weak CYP2D6 inhibitor.
Mexiletine: (Moderate) Caution and therapeutic drug concentrations monitoring, if available, is recommended during coadministration of mexiletine with cobicistat. Mexiletine is a substrate for CYP2D6; cobicistat is an inhibitor of this enzyme. Concurrent use may result in elevated mexiletine plasma concentration.
Midazolam: (Major) Protease inhibitors may increase midazolam concentrations; the risk for midazolam-related adverse effects varies by midazolam dosage form and route of administration. Oral midazolam use is contraindicated. Intranasal midazolam should be avoided when possible. Additional monitoring and a dosage reduction may be necessary with parenteral midazolam. Midazolam is a CYP3A substrate and protease inhibitors are CYP3A inhibitors. Protease inhibitors have been shown to increase oral midazolam AUCs by up to 3-fold, resulting in clinically significant potentiation of sedation. (Major) Use of orally administered midazolam with cobicistat is contraindicated due to the risk for prolonged/increased sedation and respiratory depression. Midazolam is extensively metabolized by CYP3A4; cobicistat is a strong inhibitor of this enzyme. Concurrent use is expected to produce large increases in the plasma concentrations of midazolam. Elevations in midazolam concentrations may also be observed with the parenteral formulation of midazolam; however, this formulation may be administered with cobicistat if given in as setting with close clinical monitoring and appropriate medical management. Consider reducing the dose of parenteral midazolam.
Midostaurin: (Major) Avoid the concomitant use of midostaurin and atazanavir 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 atazanavir 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. (Major) Avoid the concomitant use of midostaurin and cobicistat 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 cobicistat 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.
Mifepristone: (Major) Caution is advised when administering atazanavir with mifepristone because increased serum concentrations of either drug may occur. When mifepristone is used in the treatment of Cushing's syndrome, coadministration with atazanavir 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 atazanavir, initiate mifepristone at a dose of 300 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with atazanavir is initiated in a patient already receiving mifepristone 300 mg, dosage adjustments are not required. If therapy with atazanavir 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 atazanavir 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 atazanavir is initiated in a patient already receiving 1,200 mg, reduce the mifepristone dose to 900 mg. Both mifepristone and atazanavir are substrates and strong inhibitors of CYP3A4. (Major) Caution is advised when administering cobicistat with mifepristone because increased serum concentrations of either drug may occur. When mifepristone is used in the treatment of Cushing's syndrome, coadministration with cobicistat 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 cobicistat, initiate mifepristone at a dose of 300 mg and titrate to a maximum of 900 mg if clinically indicated. If therapy with cobicistat is initiated in a patient already receiving mifepristone 300 mg, dosage adjustments are not required. If therapy with cobicistat 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 cobicistat 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 cobicistat is initiated in a patient already receiving 1,200 mg, reduce the mifepristone dose to 900 mg. Both mifepristone and cobicistat are substrates and strong inhibitors of CYP3A4.
Miglitol: (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) Caution is warranted when cobicistat is administered with mirabegron as there is a potential for elevated cobicistat concentrations. Mirabegron is a moderate CYP2D6 inhibitor. Cobicistat is a substrate of CYP2D6 and CYP3A4.
Mirtazapine: (Moderate) Concurrent administration of mirtazapine and atazanavir may result in elevated mirtazapine plasma concentrations. If these drugs are coadministered, monitor patients for adverse effects associated with mirtazapine, such as constipation, drowsiness, dizziness, and QT prolongation, and decrease the dose if necessary. Mirtazapine is a substrate of CYP3A4 and protease inhibitors are potent inhibitors of CYP3A4. (Moderate) Monitor for an increase in mirtazapine-related adverse reactions if coadministration with cobicistat is necessary. Mirtazapine is a CYP3A substrate; cobicistat is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the Cmax and AUC of a single dose of mirtazapine by approximately 40% and 50%, respectively.
Mirvetuximab Soravtansine: (Moderate) Closely monitor for mirvetuximab soravtansine-related adverse reactions if concomitant use of atazanavir is necessary. DM4, the cytotoxic component of mirvetuximab soravtansine, is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant use may increase unconjugated DM4 exposure. (Moderate) Closely monitor for mirvetuximab soravtansine-related adverse reactions if concomitant use of cobicistat is necessary. DM4, the cytotoxic component of mirvetuximab soravtansine, is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use may increase unconjugated DM4 exposure.
Mitapivat: (Major) Avoid coadministration of mitapivat with atazanavir due to increased risk of adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors increased mitapivat overall exposure by 3.6 to 4.9-fold. (Major) Avoid coadministration of mitapivat with cobicistat due to increased risk of adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors increased mitapivat overall exposure by 3.6 to 4.9-fold.
Mitotane: (Contraindicated) Atazanavir is contraindicated for use with mitotane. Mitotane is a strong CYP3A4 inducer and atazanavir is a CYP3A4 substrate; coadministration significantly reduces plasma concentrations of atazanavir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. When coadministered with another strong CYP3A4 inducer (rifampin 600 mg daily; n = 16), the ratio of atazanavir pharmacokinetic parameters was significantly affected as follows (where 1 = no change): Cmax, 0.47 (90% CI, 0.41 to 0.53), AUC, 0.28 (90% CI, 0.25 to 0.32), and Cmin, 0.02 (90% CI, 0.02 to 0.03). (Contraindicated) Coadministration of mitotane with cobicistat is contraindicated. Mitotane is a strong inducer of CYP3A4; cobicistat is a substrate of this enzyme. Concurrent use may result in significant decreases in the plasma concentrations of cobicistat, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and atazanavir. Concomitant use may increase mobocertinib exposure and the risk for adverse reactions such as QT prolongation. Mobocertinib is a CYP3A substrate and atazanavir 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%. (Major) Avoid concomitant use of mobocertinib and cobicistat. Concomitant use may increase mobocertinib exposure and the risk for adverse reactions such as QT prolongation. Mobocertinib is a CYP3A substrate and cobicistat 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: (Major) Coadministration of atazanavir with modafinil is not recommended as there is a potential for elevated modafinil concentrations and decreased atazanavir concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Modafinil is a CYP3A4 substrate/inducer. Atazanavir is an inhibitor/substrate of CYP3A4. (Major) Coadministration of cobicistat with modafinil is not recommended as there is a potential for elevated modafinil concentrations and decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Modafinil is a CYP3A4 substrate/inducer. Cobicistat is an inhibitor/substrate of CYP3A4.
Mometasone: (Moderate) Coadministration of mometasone with atazanavir may cause elevated mometasone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Mometasone is a CYP3A4 substrate; atazanavir 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. (Moderate) Coadministration of mometasone with cobicistat may cause elevated mometasone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Mometasone is a CYP3A4 substrate; cobicistat 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.
Morphine: (Moderate) The plasma concentrations of morphine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as oversedation, respiratory depression, and hypotension, is recommended during coadministration. Cobicistat is a P-glycoprotein (P-gp) inhibitor, while morphine is a P-gp substrate.
Morphine; Naltrexone: (Moderate) The plasma concentrations of morphine may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as oversedation, respiratory depression, and hypotension, is recommended during coadministration. Cobicistat is a P-glycoprotein (P-gp) inhibitor, while morphine is a P-gp substrate.
Nafcillin: (Major) Caution is warranted when atazanavir is administered with nafcillin as there is a potential for decreased concentrations of atazanavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nafcillin is an inducer of CYP3A4. Atazanavir is a CYP3A4 substrate. (Major) Caution is warranted when cobicistat is administered with nafcillin as there is a potential for decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nafcillin is an inducer of CYP3A4. Cobicistat is a CYP3A4 substrate.
Naldemedine: (Major) Monitor for potential naldemedine-related adverse reactions if coadministered with atazanavir. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 substrate; atazanavir is a CYP3A4 inhibitor. (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with cobicistat. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 and P-glycoprotein (P-gp) substrate; cobicistat is a moderate P-gp inhibitor and strong CYP3A4 inhibitor.
Naloxegol: (Contraindicated) Concomitant use of naloxegol with atazanavir is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as atazanavir, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning. (Contraindicated) Concomitant use of naloxegol with cobicistat is contraindicated. Naloxegol is metabolized primarily by CYP3A. Strong CYP3A4 inhibitors, such as cobicistat, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Naloxone: (Moderate) The plasma concentrations of buprenorphine and naloxone may be elevated when administered concurrently with cobicistat. When initiating buprenorphine; naloxone in patients currently on a regimen containing cobicistat and atazanavir or darunavir, use the lowest buprenorphine; naloxone starting dose and slowly titrate to desired effect. When initiating antiretroviral regimens containing cobicistat and atazanavir or darunavir to patients on buprenorphine; naloxone, an adjustment of buprenorphine; naloxone dose may be needed. Monitoring for adverse effects, such as CNS side effects or respiratory depression, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while buprenorphine is a CYP3A4 substrate.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with atazanavir is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and atazanavir 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. (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with cobicistat is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and cobicistat 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: (Major) Avoid concomitant use of sirolimus and cobicistat. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and cobicistat is a strong CYP3A and P-gp inhibitor. (Major) Avoid concomitant use of sirolimus and protease inhibitors; a sirolimus dosage reduction may be considered if concomitant use is necessary. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects.
Naproxen: (Minor) Caution is warranted when atazanavir is administered with naproxen as there is a potential for elevated naproxen concentrations. In vitro data suggest naproxen is a substrate for CYP2C8; atazanavir is a weak inhibitor of this enzyme.
Naproxen; Esomeprazole: (Contraindicated) Coadministration of proton pump inhibitors (PPIs) with atazanavir in treatment-experienced patients is contraindicated. PPIs can be used with atazanavir in treatment-naive patients under specific administration restrictions. In treatment-naive patients >= 40 kg, the PPI dose should not exceed the equivalent of omeprazole 20 mg/day, and the PPI must be administered 12 hours before atazanavir and ritonavir; use the dosage regimen of atazanavir 300 mg boosted with ritonavir 100 mg given once daily with food. While data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant PPIs, the same recommendations regarding timing and maximum doses of concomitant P PIs should be followed. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with a PPI. A randomized, open-label, multiple-dose drug interaction study of atazanavir (300 mg) with ritonavir (100 mg) coadministered with omeprazole 40 mg found a reduction in atazanavir AUC and Cmin of 76% and 78%, respectively. Additionally, after multiple doses of omeprazole (40 mg/day) and atazanavir (400 mg/day, 2 hours after omeprazole) without ritonavir, the AUC of atazanavir was decreased by 94%, Cmax by 96%, and Cmin by 95%. (Minor) Caution is warranted when atazanavir is administered with naproxen as there is a potential for elevated naproxen concentrations. In vitro data suggest naproxen is a substrate for CYP2C8; atazanavir is a weak inhibitor of this enzyme. (Minor) Use caution when administering cobicistat and esomeprazole concurrently. Cobicistat is an inhibitor of CYP3A, and esomeprazole is partially metabolized by CYP3A. Coadministration of cobicistat with CYP3A substrates, such as esomeprazole, can theoretically increase esomeprazole exposure leading to increased or prolonged therapeutic effects and adverse events; however, the clinical impact of this has not yet been determined.
Naproxen; Pseudoephedrine: (Minor) Caution is warranted when atazanavir is administered with naproxen as there is a potential for elevated naproxen concentrations. In vitro data suggest naproxen is a substrate for CYP2C8; atazanavir is a weak inhibitor of this enzyme.
Nateglinide: (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) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with cobicistat. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as cobicistat, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
Nebivolol; Valsartan: (Moderate) Concurrent use of atazanavir with valsartan may result in elevated valsartan serum concentrations. Valsartan is a substrate for the drug transporter organic anion transporting polypeptide (OATP1B1/1B3); atazanavir is an OATP1B1 inhibitor. Monitor for increased toxicities if these drugs are given together. (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with cobicistat. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as cobicistat, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible. (Minor) Caution is warranted when cobicistat is administered with valsartan as there is a potential for increased valsartan concentrations. Valsartan is a substrate of organic anion transporting polypeptide (OATP)1B1. Cobicistat is an inhibitor of OATP.
Nefazodone: (Major) Nefazodone and atazanavir are both substrates and inhibitors of CYP3A4. Coadministration could result in increased plasma concentrations of either drug; caution and close monitoring are recommended. (Moderate) Caution is warranted when cobicistat is administered with nefazodone as there is a potential for elevated nefazodone and cobicistat concentrations. Both nefazodone and cobicistat are substrates and strong inhibitors of CYP3A4.
Neratinib: (Major) Avoid concomitant use of atazanavir with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and atazanavir 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. (Major) Avoid concomitant use of cobicistat with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and cobicistat 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.
Netupitant, Fosnetupitant; Palonosetron: (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4 since the plasma concentrations of the primary substrate can increase; the inhibitory effect on CYP3A4 can last for multiple days. Atazanavir is partially metabolized by CYP3A4. In addition, netupitant is mainly metabolized by CYP3A4. Coadministration of netupitant; palonosetron with a strong CYP3A4 inhibitor can significantly increase the systemic exposure to netupitant. Atazanavir is a strong CYP3A4 inhibitor. No dosage adjustment is necessary for single dose administration of netupitant; palonosetron. (Moderate) Netupitant is a moderate inhibitor of CYP3A4 and should be used with caution in patients receiving concomitant medications that are primarily metabolized through CYP3A4, such as cobicistat. The plasma concentrations of cobicistat can increase when co-administered with netupitant; the inhibitory effect on CYP3A4 can last for multiple days. In addition, netupitant is mainly metabolized by CYP3A4. Cobicistat has been shown to be a strong CYP3A4 inhibitor, and may increase netupitant exposure. Coadministration with another strong CYP3A4 inhibitor increased netupitant exposure by 140%. No dosage adjustment is necessary. (Moderate) The plasma concentrations of palonosetron may be elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Atazanavir is a CYP3A4 inhibitor; palonosetron is a substrate of CYP3A4. (Moderate) The plasma concentrations of palonosetron may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Cobicistat is an inhibitor of CYP3A4 and CYP2D6; palonosetron is a substrate of both CYP3A4 and CYP2D6.
Nevirapine: (Contraindicated) Coadministration of nevirapine with regimens containing cobicistat and atazanavir are contraindicated; use of nevirapine with regimens containing cobicistat and darunavir are also not recommended. Nevirapine is a substrate and inducer of CYP3A4, cobicistat is a substrate/inhibitor of CYP3A4, while atazanavir are darunavir are CYP3A4 substrates. If these drugs are used together, the concentrations of nevirapine may increase and the concentrations of atazanavir, darunavir, and cobicistat may decrease; thereby, increasing the risk for nevirapine-associated adverse reactions and potentally decreasing the antiretroviral efficacy of atazanavir and darunavir. (Major) Do not coadminister atazanavir and nevirapine. Coadministration leads to substantially decreased atazanavir concentrations and increased nevirapine concentrations, which could lead to toxicity.
Niacin; Simvastatin: (Contraindicated) Concomitant use of simvastatin with cobicistat is contraindicated due to increased simvastatin exposure and potential for myopathy, including rhabdomyolysis. Simvastatin is a substrate for CYP3A4; cobicistat is a strong CYP3A4 inhibitor. (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. (Moderate) Coadministration of cobicistat with nicardipine may result in elevated cobicistat serum concentrations. Cobicistat is a substrate of CYP3A4 and CYP2D6. Nicardipine is an inhibitor of CYP2D6 and CYP3A4.
Nicotine: (Minor) Caution is warranted when cobicistat is administered with nicotine as there is a potential for decreased cobicistat concentrations. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nicotine is an inducer of CYP2D6; cobicistat is a CYP2D6 substrate.
Nifedipine: (Moderate) Atazanavir may interact with certain calcium-channel blockers that undergo significant metabolism via CYP3A4, including nifedipine. Cautious dose titration of amlodipine should be considered; the patient should be monitored for the proper clinical responses to calcium-channel blocker therapy. (Moderate) Coadministration of cobicistat (a strong CYP3A4 inhibitor) with calcium-channel blockers metabolized by CYP3A4, such as nifedipine, may result in elevated calcium-channel blockers serum concentrations. If used concurrently, close clinical monitoring with appropriate reductions are advised.
Nilotinib: (Major) Avoid the concomitant use of nilotinib and atazanavir. 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 atazanavir is discontinued, a washout period should be allowed before adjusting the nilotinib dosage upward to the indicated dose. Nilotinib is a substrate of CYP3A4 and atazanavir is a strong inhibitor of CYP3A4. (Major) Avoid the concomitant use of nilotinib and cobicistat. 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 cobicistat 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 cobicistat is a substrate and a strong inhibitor of CYP3A4.
Nimodipine: (Major) Avoid coadministration of nimodipine with cobicistat due to the risk of significant hypotension. If concomitant use is unavoidable, monitor blood pressure and reduce the dose of nimodipine as clinically appropriate. Nimodipine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. (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 cobicistat, may 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. Cobicistat is a mild inhibitor of both P-gp and CYP3A4; 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%.
Nirmatrelvir; Ritonavir: (Contraindicated) Use of ritonavir with cobicistat is not recommended, because of similar effects on CYP3A. Both ritonavir and cobicistat are potent inhibitors of CYP3A4. (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.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with cobicistat due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. (Major) Avoid coadministration of nisoldipine with protease inhibitors due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with another CYP3A inhibitor increased the AUC of nisoldipine by 30% to 45%.
Nizatidine: (Major) Coadministration of H2-blockers with atazanavir reduces serum atazanavir concentrations; however, H2-blockers can be used under specific administration restrictions. Although data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant H2-blockers, the same recommendations regarding timing and maximum doses of concomitant H2-blockers should be followed. In treatment-naive patients >= 40 kg, do not exceed an H2- blocker dose equivalent to famotidine 40 mg twice daily, and give atazanavir 300 mg with ritonavir 100 mg once daily with food. Give atazanavir simultaneously with and/or at least 10 hours after the H2- blocker. If a treatment-naive adult or adolescent (>= 40 kg) cannot tolerate ritonavir, do not exceed an H2- blocker dose equivalent to famotidine 20 mg twice daily, and the atazanavir dose should be increased to 400 mg once daily with food given at least 2 hours before or 10 hours after the H2- blocker. Data are insufficent to recommend atazanavir dosing in children or adolescents < 40 kg not receiving ritonavir boosting. In treatment-naive patients on a cobicistat-boosted regimen, cobicistat and atazanavir may be administered without dosage adjustment if given at the same time or a minimum of 10 hours after dosing of the H2-blocker. The H2-blocker dose should not exceed a dose that is comparable to 40 mg/day of famotidine in treatment-naive patients. In treatment-experienced patients >= 40 kg, do not exceed an H2- blocker dose equivalent to famotidine 20 mg twice daily, and give atazanavir 300 mg with ritonavir 100 mg once daily with food. Give atazanavir simultaneously with and/or at least 10 hours after the H2- blocker. In treatment-experienced patients >= 40 kg receiving H2-antagonists and tenofovir, atazanavir should be dosed 400 mg with ritonavir 100 mg once daily with food. In antiretroviral-experienced patients on a cobicistat-boosted regimen, the dosage of cobicistat with atazanavir needs to be increased if administered with H2-blockers; the recommended dose is cobicistat 150 mg/day with atazanavir 400 mg/day and 20 mg/day or less of famotidine or other comparably dosed H2-blocker. Significant reductions in atazanavir serum concentrations may lead to therapeutic failure and the development of HIV resistance. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with an H2- blocker.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) Atazanavir may decrease the metabolism of oral contraceptives and non-oral combination contraceptives; the mean exposure and minimum serum concentrations of ethinyl estradiol and norethindrone are increased when administered with atazanavir 400 mg daily. However, if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased; data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) If ethinyl estradiol is administered with atazanavir boosted with ritonavir, it is recommended that the dose of ethinyl estradiol be at least 35 mcg. However, the dose of ethinyl estradiol should be no more than 30 mcg when administered with atazanavir that is NOT boosted by ritonavir. The mean exposure and minimum serum concentrations of ethinyl estradiol are increased when administered with atazanavir; but if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased. Data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Norethindrone: (Major) Atazanavir may decrease the metabolism of oral contraceptives and non-oral combination contraceptives; the mean exposure and minimum serum concentrations of ethinyl estradiol and norethindrone are increased when administered with atazanavir 400 mg daily. However, if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased; data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy.
Norethindrone; Ethinyl Estradiol: (Major) Atazanavir may decrease the metabolism of oral contraceptives and non-oral combination contraceptives; the mean exposure and minimum serum concentrations of ethinyl estradiol and norethindrone are increased when administered with atazanavir 400 mg daily. However, if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased; data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) If ethinyl estradiol is administered with atazanavir boosted with ritonavir, it is recommended that the dose of ethinyl estradiol be at least 35 mcg. However, the dose of ethinyl estradiol should be no more than 30 mcg when administered with atazanavir that is NOT boosted by ritonavir. The mean exposure and minimum serum concentrations of ethinyl estradiol are increased when administered with atazanavir; but if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased. Data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) Atazanavir may decrease the metabolism of oral contraceptives and non-oral combination contraceptives; the mean exposure and minimum serum concentrations of ethinyl estradiol and norethindrone are increased when administered with atazanavir 400 mg daily. However, if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased; data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norethindrone. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) If ethinyl estradiol is administered with atazanavir boosted with ritonavir, it is recommended that the dose of ethinyl estradiol be at least 35 mcg. However, the dose of ethinyl estradiol should be no more than 30 mcg when administered with atazanavir that is NOT boosted by ritonavir. The mean exposure and minimum serum concentrations of ethinyl estradiol are increased when administered with atazanavir; but if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased. Data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Norgestimate; Ethinyl Estradiol: (Major) Atazanavir may decrease the metabolism of oral contraceptives and non-oral combination contraceptives; the mean exposure and minimum serum concentrations of ethinyl estradiol and norgestimate are increased when administered with atazanavir 400 mg daily. However, if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased; data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Major) Concurrent administration of cobicistat and norgestimate results in increased norgestimate serum concentrations. Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is also the potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) If ethinyl estradiol is administered with atazanavir boosted with ritonavir, it is recommended that the dose of ethinyl estradiol be at least 35 mcg. However, the dose of ethinyl estradiol should be no more than 30 mcg when administered with atazanavir that is NOT boosted by ritonavir. The mean exposure and minimum serum concentrations of ethinyl estradiol are increased when administered with atazanavir; but if atazanavir is boosted with ritonavir, mean exposure of ethinyl estradiol will be decreased. Data are limited regarding use of atazanavir with cobicistat. Instruct women to report any breakthrough bleeding or other adverse effects to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms. (Moderate) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with estrogens, such as ethinyl estradiol, or mestranol, which is converted to ethinyl estradiol. There is a potential for altered efficacy for combined hormonal contraceptives. Insufficient data are available to make dosage recommendations, particularly when cobicistat is used in combination regimens with other antiviral therapies. Consider alternative or additional methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When patients are taking estrogen for hormone replacement therapy (HRT), it may be prudent to monitor for reduced clinical efficacy or unusual vaginal bleeding patterns.
Norgestrel: (Major) Consider the benefits and risk of administering antiretroviral regimens containing cobicistat with norgestrel. Insufficient data are available to make dosage recommendations, particularly when cobicistat is combined in other antiviral regimens. It is not clear how cobicistat alters various progestin-only agents used for contraception, fertility or luteal support, or for hormone replacement therapy (HRT). Instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. There is a potential for altered efficacy for combined hormonal contraceptives. Consider alternative methods of contraception, such as condoms, to prevent unwanted pregnancy and transmission of HIV/AIDS. When progestins are used for other purposes, monitor for altered clinical response to hormonal therapy. (Major) Studies evaluating use of atazanavir with norgestrel have not been conducted; therefore, an alternative method of contraception is recommended. Taking these drugs together may alter the exposure and serum concentrations of norgestrel. If the drugs must be used together, instruct women to report any breakthrough bleeding or other adverse effects (e.g., insulin resistance, dyslipidemia, and acne) to their prescribers. It may be prudent for women who receive hormonal contraceptives with atazanavir boosted with ritonavir or cobicistat to use an additional method of contraception to protect against unwanted pregnancy. Further, because hormonal contraceptives do not protect against the transmission of HIV/AIDS and other sexually transmitted diseases, HIV-infected women should use an additional barrier method of contraception such as condoms.
Nortriptyline: (Moderate) According to the manufacturer, concurrent use of tricyclic antidepressants (TCAs) and atazanavir may result in elevated TCA plasma concentration, and could increase the potential for serious adverse effects. If these drugs are administered together, carefully titrate the TCA dose based on a clinical assessment of antidepressant response. Patients on a stable dose of TCA who start treatment with atazanavir should be monitored for TCA-associated anticholinergic effects (e.g., sedation, confusion, constipation). In addition to clinical monitoring, the manufacturer suggests obtaining TCA serum concentrations (where available) as an adjunct to assessing the potential for interactions. (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of tricyclic antidepressants (TCAs) and cobicistat. Concurrent use may result in elevated TCA plasma concentrations.
Olanzapine: (Moderate) Caution is warranted when atazanavir is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of uridine glucoronyltransferase (UGT). Atazanavir is an inhibitor of UGT1A1. (Moderate) Caution is warranted when cobicistat is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of CYP2D6. Cobicistat is an inhibitor of CYP2D6.
Olanzapine; Fluoxetine: (Moderate) Caution is warranted when atazanavir is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of uridine glucoronyltransferase (UGT). Atazanavir is an inhibitor of UGT1A1. (Moderate) Caution is warranted when cobicistat is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of CYP2D6. Cobicistat is an inhibitor of CYP2D6. (Moderate) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicistat. Concurrent use may result in elevated SSRI plasma concentrations. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. All SSRIs are substrates for the hepatic isoenzyme CYP2D6, while citalopram, escitalopram, and sertraline are also substrates for CYP3A4; cobicistat is an inhibitor of both CYP2D6 and CYP3A4.
Olanzapine; Samidorphan: (Moderate) Caution is warranted when atazanavir is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of uridine glucoronyltransferase (UGT). Atazanavir is an inhibitor of UGT1A1. (Moderate) Caution is warranted when cobicistat is administered with olanzapine as there is a potential for elevated olanzapine concentrations. Olanzapine is a substrate of CYP2D6. Cobicistat is an inhibitor of CYP2D6.
Olaparib: (Major) Avoid coadministration of olaparib with atazanavir 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 atazanavir is discontinued. Olaparib is a CYP3A substrate and atazanavir 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%. (Major) Avoid coadministration of olaparib with cobicistat 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 cobicistat is discontinued. Olaparib is a CYP3A substrate and cobicistat 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 atazanavir is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and atazanavir may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If atazanavir 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 atazanavir is a strong CYP3A4 inhibitor. (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 cobicistat is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and cobicistat may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If cobicistat 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 cobicistat is a strong CYP3A4 inhibitor.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with cobicistat is necessary; adjust the dose of amlodipine as clinically appropriate. Cobicistat is a strong CYP3A inhibitor and amlodipine is a CYP3A substrate. Coadministration with a moderate CYP3A4 inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. Strong CYP3A4 inhibitors may increase the plasma concentrations of amlodipine to a greater extent. (Moderate) Monitor for symptoms of hypotension and edema if coadministration of amlodipine with protease inhibitors is necessary; adjust the dose of amlodipine as clinically appropriate. Amlodipine is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with a moderate CYP3A inhibitor in elderly hypertensive patients increased systemic exposure to amlodipine by 60%. However, coadministration with another moderate CYP3A inhibitor in healthy volunteers did not significantly change amlodipine exposure.
Olopatadine; Mometasone: (Moderate) Coadministration of mometasone with atazanavir may cause elevated mometasone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Mometasone is a CYP3A4 substrate; atazanavir 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. (Moderate) Coadministration of mometasone with cobicistat may cause elevated mometasone serum concentrations, potentially resulting in Cushing's syndrome and adrenal suppression. Mometasone is a CYP3A4 substrate; cobicistat 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.
Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and atazanavir. 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. Omaveloxolone is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased omaveloxolone overall exposure by 4-fold. (Major) Avoid concomitant use of omaveloxolone and cobicistat. 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. Omaveloxolone is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased omaveloxolone overall exposure by 4-fold.
Omeprazole: (Contraindicated) Coadministration of proton pump inhibitors (PPIs) with atazanavir in treatment-experienced patients is contraindicated. PPIs can be used with atazanavir in treatment-naive patients under specific administration restrictions. In treatment-naive patients >= 40 kg, the PPI dose should not exceed the equivalent of omeprazole 20 mg/day, and the PPI must be administered 12 hours before atazanavir and ritonavir; use the dosage regimen of atazanavir 300 mg boosted with ritonavir 100 mg given once daily with food. While data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant PPIs, the same recommendations regarding timing and maximum doses of concomitant PPIs should be followed. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with a PPI. A randomized, open-label, multiple-dose drug interaction study of atazanavir (300 mg) with ritonavir (100 mg) coadministered with omeprazole 40 mg found a reduction in atazanavir AUC and Cmin of 76% and 78%, respectively. Additionally, after multiple doses of omeprazole (40 mg/day) and atazanavir (400 mg/day, 2 hours after omeprazole) without ritonavir, the AUC of atazanavir was decreased by 94%, Cmax by 96%, and Cmin by 95%. (Minor) The plasma concentrations of omeprazole may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while omeprazole is a CYP3A4 substrate.
Omeprazole; Amoxicillin; Rifabutin: (Contraindicated) Coadministration of proton pump inhibitors (PPIs) with atazanavir in treatment-experienced patients is contraindicated. PPIs can be used with atazanavir in treatment-naive patients under specific administration restrictions. In treatment-naive patients >= 40 kg, the PPI dose should not exceed the equivalent of omeprazole 20 mg/day, and the PPI must be administered 12 hours before atazanavir and ritonavir; use the dosage regimen of atazanavir 300 mg boosted with ritonavir 100 mg given once daily with food. While data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant PPIs, the same recommendations regarding timing and maximum doses of concomitant PPIs should be followed. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with a PPI. A randomized, open-label, multiple-dose drug interaction study of atazanavir (300 mg) with ritonavir (100 mg) coadministered with omeprazole 40 mg found a reduction in atazanavir AUC and Cmin of 76% and 78%, respectively. Additionally, after multiple doses of omeprazole (40 mg/day) and atazanavir (400 mg/day, 2 hours after omeprazole) without ritonavir, the AUC of atazanavir was decreased by 94%, Cmax by 96%, and Cmin by 95%. (Major) Avoid concurrent use of rifabutin and cobicistat-containing antiretroviral regimens. Concomitant use may decrease cobicistat exposure which may reduce its efficacy and increase rifabutin exposure and risk of adverse effects. Rifabutin is a CYP3A substrate and moderate CYP3A inducer; cobicistat is a CYP3A substrate and strong CYP3A inhibitor. (Major) Reduce the rifabutin dose to 150 mg PO once daily and monitor for adverse effects, such as uveitis and neutropenia, if concomitant use with atazanavir is necessary. Avoid concurrent use of rifabutin and atazanavir boosted with cobicistat. Although the FDA-approved labeling recommends reducing the rifabutin dose by at least 75% (to a maximum 150 mg every other day or 3 times per week), lower rifabutin exposure has been reported in persons living with HIV than in healthy subjects and acquired rifamycin resistance has been reported in these persons receiving 3 times weekly regimens. Monitor response and consider therapeutic drug monitoring (TDM) when rifabutin is used with atazanavir boosted with ritonavir and adjust dose accordingly. Rifabutin is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Coadministration with atazanavir/ritonavir increased the AUC of rifabutin by approximately 110%. (Minor) The plasma concentrations of omeprazole may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while omeprazole is a CYP3A4 substrate.
Omeprazole; Sodium Bicarbonate: (Contraindicated) Coadministration of proton pump inhibitors (PPIs) with atazanavir in treatment-experienced patients is contraindicated. PPIs can be used with atazanavir in treatment-naive patients under specific administration restrictions. In treatment-naive patients >= 40 kg, the PPI dose should not exceed the equivalent of omeprazole 20 mg/day, and the PPI must be administered 12 hours before atazanavir and ritonavir; use the dosage regimen of atazanavir 300 mg boosted with ritonavir 100 mg given once daily with food. While data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant PPIs, the same recommendations regarding timing and maximum doses of concomitant PPIs should be followed. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with a PPI. A randomized, open-label, multiple-dose drug interaction study of atazanavir (300 mg) with ritonavir (100 mg) coadministered with omeprazole 40 mg found a reduction in atazanavir AUC and Cmin of 76% and 78%, respectively. Additionally, after multiple doses of omeprazole (40 mg/day) and atazanavir (400 mg/day, 2 hours after omeprazole) without ritonavir, the AUC of atazanavir was decreased by 94%, Cmax by 96%, and Cmin by 95%. (Major) It is recommended that antacids not be given at the some time as atazanavir because of potential interference with absorption of atazanavir. Separate the administration of atazanavir and antacids to avoid the potential for interaction; give atazanavir 2 hours before or 1 hour after the antacid. (Minor) The plasma concentrations of omeprazole may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while omeprazole is a CYP3A4 substrate.
Ondansetron: (Moderate) The plasma concentrations of ondansetron may be elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects, such as GI or CNS effects, is recommended during coadministration. Atazanavir is an inhibitor of CYP3A4. Ondansetron is a CYP3A4 substrate. (Moderate) The plasma concentrations of ondansetron may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as GI or CNS effects, is recommended during coadministration. Cobicistat is a strong inhibitor of CYP3A4 and an inhibitor of CYP2D6 and P-glycoprotein (P-gp) inhibitor. Ondansetron is a CYP3A4, CYP2D6, and P-gp substrate.
Oritavancin: (Major) Atazanavir is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of atazanavir may be reduced if these drugs are administered concurrently. (Major) Plasma concentrations and efficacy of cobicistat and/or the drugs that are boosted by cobicistat may be reduced if these drugs are administered concurrently with oritavancin. Cobicistat is metabolized by CYP3A4 and CYP2D6; oritavancin is a weak CYP3A4 and CYP2D6 inducer. Cobicistat is a CYP3A4 inhibitor indicated to increase systemic exposure of other antiretrovirals.
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 atazanavir; concurrent use may increase osilodrostat exposure and the risk of osilodrostat-related adverse reactions. Osilodrostat is a CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. (Major) Reduce the dose of osilodrostat by one-half during coadministration of cobicistat; concurrent use may increase osilodrostat exposure and the risk of osilodrostat-related adverse reactions. Osilodrostat is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
Ospemifene: (Moderate) Caution is warranted when atazanavir is administered with ospemifene as there is a potential for elevated concentrations of ospemifene. Clinical monitoring for ospemifene-related adverse effects is recommended during coadministration. Atazanavir is an inhibitor of CYP3A4 and ospemifene is a substrate for CYP3A4. (Moderate) Monitor for an increase in ospemifene-related adverse reactions if coadministration with cobicistat is necessary. Ospemifene is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor.
Oxcarbazepine: (Major) Coadministration of oxcarbazepine with regimens containing cobicistat and atazanavir or darunavir should be avoided. If these drugs are used together, significant decreases in the plasma concentrations of cobicistat, atazanavir and potentally darunavir may occur, resulting in reduction of antiretroviral efficacy and development of viral resistance. Consider use of an alternative anticonvulsant or antiretroviral therapy. (Major) Oxcarbazepine may increase the metabolism of atazanavir and lead to decreased antiretroviral efficacy. Treatment failures have been reported with other protease inhibitors when carbamazepine was used concomitantly. If atazanavir is added to anticonvulsant therapy, the patient should be observed for changes in the clinical efficacy of the antiretroviral regimen or seizure control. Monitor serum concentrations.
Oxybutynin: (Moderate) Monitor for an increase in oxybutynin-related adverse reactions if coadministration with protease inhibitors is necessary. Oxybutynin is a CYP3A substrate and protease inhibitors are moderate to strong CYP3A inhibitors. Coadministration with another strong CYP3A inhibitor increased mean oxybutynin plasma concentrations by approximately 2-fold. Concomitant use with moderate CYP3A inhibitors may alter the mean pharmacokinetic parameters of oxybutynin, although the clinical relevance of these potential interactions is unknown. (Moderate) The plasma concentrations of oxybutynin may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as increased anticholinergic activity, is recommended during coadministration. Cobicistat is a CYP3A4 inhibitor, while oxybutynin is a CYP3A4 substrate.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of atazanavir is necessary. If atazanavir 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 atazanavir 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 atazanavir 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. (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of cobicistat is necessary. If cobicistat 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 cobicistat 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 cobicistat 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.
Paclitaxel: (Moderate) Due to atazanavir-induced inhibition of CYP3A4 isoenzymes, atazanavir may inhibit the metabolism and thus, increase the serum concentrations of drugs that are largely metabolized via CYP3A4 including paclitaxel. If atazanavir and paclitaxel must be coadministered, the dosage of paclitaxel may need to be downwardly adjusted and conversely, upward dosage adjustment of paclitaxel may be required when atazanavir is discontinued. (Moderate) Plasma concentrations of paclitaxel may be elevated when administered concurrently with cobicistat. Cobicistat is a strong inhibitor of CYP3A4 and P-glycoprotein (P-gp) inhibitor, while paclitaxel is a CYP3A4 and P-gp substrate. Some experts state that pharmacokinetic interactions between paclitaxel and some CYP3A4 inhibitors do not appear to be clinically significant. However, combining the drugs in clinical practice may require close monitoring to ensure proper therapeutic responses.
Pacritinib: (Contraindicated) Concurrent use of pacritinib with atazanavir is contraindicated due to increased pacritinib exposure which increases the risk of adverse reactions. Pacritinib is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. (Contraindicated) Concurrent use of pacritinib with cobicistat is contraindicated due to increased pacritinib exposure which increases the risk of adverse reactions. Pacritinib is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor.
Palbociclib: (Major) Avoid coadministration of atazanavir with palbociclib; significantly increased palbociclib exposure 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 atazanavir is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of atazanavir) to the dose used before initiation of atazanavir. Palbociclib is primarily metabolized by CYP3A4 and atazanavir 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. (Major) Avoid coadministration of cobicistat 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 cobicistat is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of cobicistat) to the dose used before initiation of cobicistat. Palbociclib is primarily metabolized by CYP3A4 and cobicistat 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.
Palonosetron: (Moderate) The plasma concentrations of palonosetron may be elevated when administered concurrently with atazanavir. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Atazanavir is a CYP3A4 inhibitor; palonosetron is a substrate of CYP3A4. (Moderate) The plasma concentrations of palonosetron may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects, such as CNS effects, is recommended during coadministration. Cobicistat is an inhibitor of CYP3A4 and CYP2D6; palonosetron is a substrate of both CYP3A4 and CYP2D6.
Palovarotene: (Major) Avoid concomitant use of palovarotene and atazanavir due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. Palovarotene is a CYP3A substrate and atazanavir is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased palovarotene overall exposure by 3-fold. (Major) Avoid concomitant use of palovarotene and cobicistat due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. Palovarotene is a CYP3A substrate and cobicistat is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased palovarotene overall exposure by 3-fold.
Panobinostat: (Major) Reduce the starting dose of panobinostat to 10 mg when coadministered with cobicistat. Concurrent use may increase systemic exposure of panobinostat. Panobinostat is a CYP3A4 substrate; cobicistat is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of panobinostat by 73%.
Pantoprazole: (Contraindicated) Coadministration of proton pump inhibitors (PPIs) with atazanavir in treatment-experienced patients is contraindicated. PPIs can be used with atazanavir in treatment-naive patients under specific administration restrictions. In treatment-naive patients >= 40 kg, the PPI dose should not exceed the equivalent of omeprazole 20 mg/day, and the PPI must be administered 12 hours before atazanavir and ritonavir; use the dosage regimen of atazanavir 300 mg boosted with ritonavir 100 mg given once daily with food. While data are insufficient to recommend atazanavir dosing in children < 40 kg receiving concomitant PPIs, the same recommendations regarding timing and maximum doses of concomitant PPIs should be followed. Closely monitor patients for antiretroviral therapeutic failure and resistance development during treatment with a PPI. A randomized, open-label, multiple-dose drug interaction study of atazanavir (300 mg) with ritonavir (100 mg) coadministered with omeprazole 40 mg found a reduction in atazanavir AUC and Cmin of 76% and 78%, respectively. Additionally, after multiple doses of omeprazole (40 mg/day) and atazanavir (400 mg/day, 2 hours after omeprazole) without ritonavir, the AUC of atazanavir was decreased by 94%, Cmax by 96%, and Cmin by 95%.
Paricalcitol: (Moderate) Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with both paricalcitol and cobicistat, or during periods of dose titration. If hypercalcemia occurs, the dose of paricalcitol should be reduced or withheld until these parameters are normalized. Paricalcitol is a CYP3A4 substrate and cobicistat is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor approximately doubled the exposure of 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) Close monitoring for antidepressant response and careful dose titrations of the antidepressant therapy is recommended during coadministration of selective serotonin reuptake inhibitors (SSRIs) and cobicist

EVOTAZ Oral Tab: 300-150mg

Adults

300 mg/150 mg PO daily.

Geriatric

300 mg/150 mg PO daily.

Adolescents

weighing 35 kg or more: 300 mg/150 mg PO daily.
weighing less than 35 kg: Safety and efficacy have not been established.

Children

weighing 35 kg or more: 300 mg/150 mg PO daily.
weighing less than 35 kg: Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

Cobicistat: Cobicistat is an inhibitor of CYP3A enzymes. It is used as a pharmacokinetic enhancer to increase the serum concentration of CYP3A substrates, such as atazanavir. Cobicistat has no antiviral activity.
 
Atazanavir: Atazanavir inhibits the human immunodeficiency virus (HIV) type 1 aspartic protease, which is an enzyme involved in the replication of HIV. The protease enzyme plays an essential role in processing key structural proteins in HIV-1. During the later stages of the HIV growth cycle, the gag and gag-pol gene products are first translated into polyproteins and become immature budding particles. Protease is responsible for cleaving these precursor molecules to produce the final structural proteins of a mature virion core and to activate reverse transcriptase for a new round of infection. Thus, protease is necessary for the production of mature virions. Protease inhibition renders the virus noninfectious. Because HIV protease inhibitors inhibit the HIV replication cycle after translation and before assembly, they are active in acutely and chronically infected cells, and in cells not normally affected by dideoxynucleoside reverse transcriptase inhibitors (i.e., monocytes and macrophages). In cell culture, the EC50 (50% effective concentration) of atazanavir is 2 to 5 nM against HIV-1 isolates; however, the anti-HIV-2 activity is variable (1.9 to 32 nM).
 
HIV-1 isolates with a 93- to 183-fold reduction in susceptibility to atazanavir were observed in cell cultures obtained from atazanavir plus ritonavir treated patients. These viruses were found to have undergone amino acid changes, which included I50L, N88S, 184V, A71V, and M46I. Notably, the viruses that developed only the I50L mutation did not confer resistance to other protease inhibitors; in fact, these viral strains displayed increased susceptibility to the other protease inhibitors. However, cross-resistance was observed when I50L developed in combination with other resistant-associated substitutions. An analysis of phenotypic and genotypic data from atazanavir-resistant isolates with I50L and other protease inhibitor-resistant substitutions found more than 90% were resistant to indinavir, lopinavir, nelfinavir, ritonavir and saquinavir, and more than 80% were resistant to amprenavir.
 
In clinical trials, treatment failure occurred in 21 of 344 antiretroviral-naive patients receiving atazanavir; cobicistat with emtricitabine and tenofovir. An evaluation of these virologic failures identified 3 emtricitabine-associated resistant substitutions (M184V), but no resistant substitutions associated with either protease inhibitors or tenofovir (i.e., K65R or K70E).

Atazanavir; cobicistat is administered orally.[58761]
Atazanavir: Atazanavir is 86% protein-bound with binding independent of concentration. Atazanavir is extensively metabolized by CYP3A4 with other minor biotransformation pathways for atazanavir or its metabolites consisting of glucuronidation, N-dealkylation, hydrolysis, and oxygenations with dehydrogenation. The mean half-life of atazanavir in healthy volunteers (n = 62) and adults with HIV (n = 13) is approximately 7.5 hours at steady state after a single atazanavir; cobicistat dose administered with a light meal.[58761]
Cobicistat: Cobicistat is approximately 98% protein bound with a mean blood-to-plasma ration of approximately 0.5. Cobicistat is metabolized by CYP3A4 and to a minor extent by CYP2D6 and does not undergo glucuronidation. The median terminal half-life of cobicistat is approximately 3.5 hours. With single-dose administration after multiple dosing for 6 days, 86.2% was excreted in the feces and 8.2% was excreted in the urine.[58761]
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP2D6, CYP3A4, CYP2C8, uridine glucuronosyltransferase (UGT1A1), P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), human multidrug and toxic extrusion 1 (MATE1), organic anion transporting polypeptide (OATP1B1/1B3)
Atazanavir is an inhibitor of the hepatic enzymes CYP3A and CYP2C8 (weak), and the drug transporters UGT1A1 and OATP1B1.[61511] [61512] Atazanavir is a substrate of CYP3A4. Cobicistat is a significant substrate of CYP3A, with minor amounts being metabolized by CYP2D6. Cobicistat also inhibits both CYP3A and CYP2D6, and is an inhibitor of the transporters P-gp, BCRP, MATE1, OATP1B1, and OATP1B3. Concomitant administration with CYP3A4 inducers may lead to a loss of virologic efficacy and possible resistance. Coadministration with a potent CYP3A4 inhibitor (ketoconazole) does not require dosage adjustments.[58000] [58761] [62018]

Oral Route

One atazanavir; cobicistat tablet provided comparable atazanavir exposures to 1 atazanavir capsule (300 mg) plus 1 cobicistat tablet (150 mg) after single-dose administration with a light meal in healthy patients (n = 62).[58761]
Atazanavir: Atazanavir is rapidly absorbed with a median Tmax of approximately 2 hours after multiple daily doses of atazanavir; cobicistat in HIV-infected patients. Administration of a single dose of atazanavir; cobicistat with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 42% increase in atazanavir Cmax and a 28% increase in atazanavir AUC relative to a fasting state. Administration of a single dose with a high-fat meal (1,038 kcal, 59 g fat, 37 g protein) resulted in a 14% reduction in the atazanavir Cmax with no change in the AUC relative to a fasting state. The 24-hour atazanavir concentration after a high-fat meal was increased by approximately 23% due to delayed absorption with the median Tmax increasing from 2 hours to 3.5 hours.[58761]
Cobicistat: The median cobicistat Tmax is approximately 2 hours after the atazanavir; cobicistat dose. Steady-state cobicistat parameters (n = 22; mean +/- SD) include a Cmax of 1.5 (+/- 0.5) mcg/mL, an AUC of 11.1 (+/- 4.5) mcg x hour/mL, and a Cmax of 0.05 (+/- 0.07) mcg/mL. Administration of a single dose of atazanavir; cobicistat with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 31% increase in cobicistat Cmax and a 24% increase in cobicistat AUC relative to a fasting state. Administration of a single dose with a high-fat meal (1,038 kcal, 59 g fat, 37 g protein) resulted in no change in cobicistat exposure (Cmax or AUC) relative to a fasting state.[58761]
 
The steady-state pharmacokinetic parameters of atazanavir coadministered with cobicistat (n = 22) are comparable to those observed with ritonavir (n = 26). The AUC of atazanavir or atazanavir paired with cobicistat is 46.13 mcg x hour/mL compared to 47.59 mcg x hour/mL when paired with ritonavir. The atazanavir Cmax is 3.91 mcg/mL when paired with cobicistat compared to 4.76 mcg/mL when paired with ritonavir.[58761]

Pregnancy

Antiretroviral therapy should be provided to all patients during pregnancy, regardless of HIV RNA concentrations or CD4 cell count. Using highly active antiretroviral combination therapy (HAART) to maximally suppress viral replication is the most effective strategy to prevent the development of resistance and to minimize the risk of perinatal transmission. Begin HAART as soon as pregnancy is recognized, or HIV is diagnosed. Atazanavir; cobicistat is not recommended for use as an initial therapy in pregnant patients and patients who are trying to conceive, as substantially reduced cobicistat concentrations during the second and third trimesters may result in inadequate atazanavir concentrations and subsequent viral breakthroughs. Consider the use of more effective antiretroviral regimens, such as replacing cobicistat with low-dose ritonavir as an atazanavir pharmacokinetic enhancer during pregnancy. For people who conceive while suppressed on atazanavir; cobicistat, guidelines recommend the provider and patient engage in shared decision-making regarding continued use. If the decision is made with the patient to continue use during pregnancy, viral loads should be monitored more frequently (i.e., every 1 to 2 months). Available data from the Antiretroviral Pregnancy Registry, which includes more than 1,460 first trimester exposures to atazanavir and more than 505 first trimester exposures to cobicistat, have shown no difference in the risk of overall major birth defects when compared to the 2.7% background rate among pregnant women in the US. When exposure occurred in the first trimester, the prevalence of defects was 2.5% (95% CI: 1.7 to 3.4) for atazanavir and 3.6% (95% CI: 2.11 to 5.5) for cobicistat. It should be taken into consideration that atazanavir is frequently associated with hyperbilirubinemia; consider additional monitoring during the antepartum period. It is not known whether atazanavir use during pregnancy will exacerbate hyperbilirubinemia and lead to kernicterus in an infant. Monitoring for the development of hyperbilirubinemia in all infants exposed to atazanavir in-utero is recommended. In addition, healthcare professionals are advised to monitor for signs of lactic acidosis as severe, sometimes fatal, cases have occurred in pregnant patients who received atazanavir in combination with nucleoside analogs; nucleoside analogs are known to be associated with the development of lactic acidosis. Regular laboratory monitoring is recommended to determine antiretroviral efficacy. Monitor CD4 counts at the initial visit. Patients who have been on HAART for at least 2 years and have consistent viral suppression and CD4 counts consistently greater than 300 cells/mm3 do not need CD4 counts monitored after the initial visit during the pregnancy. However, CD4 counts should be monitored every 3 months during pregnancy for patients on HAART less than 2 years, patients with CD4 count less than 300 cells/mm3, or patients with inconsistent adherence or detectable viral loads. Monitor plasma HIV RNA at the initial visit (with review of prior levels), 2 to 4 weeks after initiating or changing therapy, monthly until undetectable, and then at least every 3 months during pregnancy. Viral load should also be assessed at approximately 36 weeks gestation, or within 4 weeks of delivery, to inform decisions regarding mode of delivery and optimal treatment for newborns. Patients whose HIV RNA levels are above the threshold for resistance testing (usually greater than 500 copies/mL but may be possible for levels greater than 200 copies/mL in some laboratories) should undergo antiretroviral resistance testing (genotypic testing, and if indicated, phenotypic testing). Resistance testing should be conducted before starting therapy in treatment-naive patients who have not been previously tested, starting therapy in treatment-experienced patients (including those who have received pre-exposure prophylaxis), modifying therapy in patients who become pregnant while receiving treatment, or modifying therapy in patients who have suboptimal virologic response to treatment that was started during pregnancy. DO NOT delay initiation of antiretroviral therapy while waiting on the results of resistance testing; treatment regimens can be modified, if necessary, once the testing results are known. First trimester ultrasound is recommended to confirm gestational age and provide an accurate estimation of gestational age at deliver. A second trimester ultrasound can be used for both anatomical survey and determination of gestational age in those patients not seen until later in gestation. Perform standard glucose screening in patients receiving antiretroviral therapy at 24 to 28 weeks gestation, although it should be noted that some experts would perform earlier screening with ongoing chronic protease inhibitor-based therapy initiated prior to pregnancy, similar to recommendations for patients with high-risk factors for glucose intolerance. Liver function testing is recommended within 2 to 4 weeks after initiating or changing antiretroviral therapy, and approximately every 3 months thereafter during pregnancy (or as needed). All pregnant patients should be counseled about the importance of adherence to their antiretroviral regimen to reduce the potential for developing resistance and perinatal transmission. It is strongly recommended that antiretroviral therapy, once initiated, not be discontinued. If a patient decides to discontinue therapy, a consultation with an HIV specialist is recommended. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to atazanavir; cobicistat; information about the registry can be obtained at www.apregistry.com or by calling 1-800-258-4263.

HIV treatment guidelines recommend clinicians provide mothers with evidence-based, patient-centered counseling to support shared decision-making regarding infant feeding. Inform patients that use of replacement feeding (i.e., formula or banked pasteurized donor human milk) eliminates the risk of HIV transmission; thus, replacement feeding is recommended for use when mothers with HIV are not on antiretroviral therapy (ART) or do not have suppressed viral load during pregnancy, as well as at delivery. For patients on ART who have achieved and maintained viral suppression during pregnancy (at minimum throughout the third trimester) and postpartum, the transmission risk from breast-feeding is less than 1%, but not zero. Virologically suppressed mothers who choose to breast-feed should be supported in this decision. If breast-feeding is chosen, counsel the patient about the importance of adherence to therapy and recommend that the infant be exclusively breast-fed for up to 6 months of age, as exclusive breast-feeding has been associated with a lower rate of HIV transmission as compared to mixed feeding (i.e., breast milk and formula). Promptly identify and treat mastitis, thrush, and cracked or bleeding nipples, as these conditions may increase the risk of HIV transmission through breast-feeding. Breast-fed infants should undergo immediate diagnostic and virologic HIV testing. Testing should continue throughout breast-feeding and up to 6 months after cessation of breast-feeding. For expert consultation, healthcare workers may contact the Perinatal HIV Hotline (888-448-8765). There are limited data regarding the use of atazanavir during breast-feeding and excretion of cobicistat into human breast milk is unknown. In 1 small study involving 3 lactating women, the median ratio of atazanavir human breast milk to plasma concentration was 13%. Antiretroviral medications whose passage into human breast milk have been evaluated include nevirapine, zidovudine, lamivudine, and nelfinavir.