Atazanavirinteractions

Coadministration of EVOTAZ can alter the concentration of other drugs and other drugs may alter the concentration of EVOTAZ, which may result in known or potentially significant drug interactions. The potential drug-drug interactions must be considered prior to and during therapy.

7.1 Potential for EVOTAZ to

Affect Other Drugs Atazanavir is an inhibitor of CYP3A and UGT1A1 and a weak inhibitor of CYP2C8. Cobicistat is an inhibitor of CYP3A and CYP2D6. The transporters that cobicistat inhibits include P-glycoprotein (P-gp), BCRP, OATP1B1 and OATP1B3. Coadministration of EVOTAZ with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Coadministration of EVOTAZ and drugs primarily metabolized by CYP3A, UGT1A1 and/or CYP2D6 or drugs that are substrates of P-gp, BCRP, OATP1B1 and/or OATP1B3 may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic effects and adverse reactions which may require dose adjustments and/or additional monitoring as shown in Table 5. Use of EVOTAZ is not recommended when coadministered with drugs highly dependent on CYP2C8 for clearance with narrow therapeutic indices (e.g., paclitaxel, repaglinide).

7.2 Potential for

Other Drugs to Affect EVOTAZ Atazanavir and cobicistat are CYP3A4 substrates; therefore, drugs that induce CYP3A4 may decrease atazanavir and cobicistat plasma concentrations and reduce the therapeutic effect of EVOTAZ, leading to development of resistance to atazanavir (see Table 5). Cobicistat is also metabolized by CYP2D6 to a minor extent. Coadministration of EVOTAZ with other drugs that inhibit CYP3A4 may increase the plasma concentrations of cobicistat and atazanavir (see Table 5). Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors, antacids, buffered medications, or H 2 -receptor antagonists are administered with EVOTAZ (see Table 5).

7.3 Established and

Other Potentially Significant Drug Interactions Table 5 provides dosing recommendations as a result of drug interactions with the components of EVOTAZ. These recommendations are based either on observed drug interactions in studies of cobicistat, atazanavir, or atazanavir coadministered with ritonavir or predicted drug interactions based on the expected magnitude of interaction and potential for serious events or loss of therapeutic effect of EVOTAZ.

Table 5: Established and Other Potentially Significant Drug Interactions with EVOTAZ: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies a or Predicted Interactions Concomitant Drug Class: Specific Drugs Effect b on Concentration Clinical Comment a For magnitude of interactions see Clinical Pharmacology (12.3; Table 7). b ↑ = Increase, ↓ = Decrease, ↔ = No change.

HIV Antiretroviral Agents: Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs and NtRTIs) didanosine buffered formulations enteric-coated (EC) capsules ↓ atazanavir ↓ didanosine It is recommended that EVOTAZ be given with food 2 hours before or 1 hour after didanosine buffered formulations. Simultaneous administration of didanosine EC and atazanavir with food results in a decrease in didanosine exposure. Thus, EVOTAZ and didanosine EC should be administered at different times. tenofovir disoproxil fumarate ↓ atazanavir ↑ tenofovir Patients receiving EVOTAZ and tenofovir should be monitored for tenofovir-associated adverse reactions.

HIV Antiretroviral Agents: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) nevirapine ↓ atazanavir ↑ nevirapine Coadministration of EVOTAZ with nevirapine is contraindicated due to potential for loss of atazanavir therapeutic effect and development of resistance, and potential for nevirapine-associated adverse reactions. efavirenz ↓ atazanavir ↓ cobicistat ↔ efavirenz Coadministration of EVOTAZ with efavirenz is not recommended because it may result in a loss of therapeutic effect and development of resistance to atazanavir. etravirine ↓ atazanavir ↓ cobicistat Coadministration of EVOTAZ with etravirine is not recommended because it may result in the loss of therapeutic effect and development of resistance to atazanavir.

HIV Antiretroviral Agents: CCR5 Antagonist maraviroc ↑ maraviroc When coadministering maraviroc and EVOTAZ, patients should receive maraviroc 150 mg twice daily.

HIV Antiretroviral Agents: Protease Inhibitor indinavir Coadministration with indinavir is contraindicated. Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia. ritonavir or products containing ritonavir ↑ atazanavir Coadministration of EVOTAZ and ritonavir or ritonavir-containing regimens is not recommended due to similar effects of cobicistat and ritonavir on CYP3A. Hepatitis C Antiviral Agents sofosbuvir/velpatasvir/ voxilaprevir ↑ voxilaprevir Coadministration with EVOTAZ is not recommended. Other Agents Alpha 1-adrenoreceptor antagonist: alfuzosin ↑ alfuzosin Coadministration of EVOTAZ with alfuzosin is contraindicated due to the potential for increased alfuzosin concentrations, which can result in hypotension. Antacids and buffered medications (please also see H 2 -receptor antagonists and proton-pump inhibitors below) ↓ atazanavir With concomitant use, administer a minimum of 2 hours apart.

Antianginal: ranolazine ↑ ranolazine Coadministration of EVOTAZ with ranolazine is contraindicated due to the potential for serious and/or life-threatening reactions.

Antiarrhythmics: dronedarone ↑ dronedarone Coadministration of EVOTAZ with dronedarone is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. amiodarone, quinidine lidocaine (systemic), disopyramide, flecainide mexiletine, propafenone digoxin ↑ other antiarrhythmics ↑ digoxin Clinical monitoring is recommended upon coadministration with antiarrhythmics. When coadministering EVOTAZ with digoxin, titrate the digoxin dose and monitor digoxin concentrations. Antibacterials (macrolide or ketolide antibiotics): clarithromycin erythromycin telithromycin ↑ atazanavir ↑ cobicistat ↑ clarithromycin ↑ erythromycin ↑ telithromycin Consider alternative antibiotics.

Anticancer Agents: irinotecan ↑ irinotecan Coadministration of EVOTAZ with irinotecan is contraindicated due to potential for increased irinotecan toxicity. (e.g., dasatinib, nilotinib, vinblastine, vincristine) ↑ other anticancer agents A decrease in the dosage or an adjustment of the dosing interval of dasatinib or nilotinib may be necessary upon coadministration with EVOTAZ. Consult the dasatinib and nilotinib full prescribing information for dosing instructions. For vincristine and vinblastine, monitor for hematologic or gastrointestinal side effects.

Anticoagulants: Direct-acting oral anticoagulants (DOACs) apixaban ↑ apixaban Due to potentially increased bleeding risk, dosing recommendations for coadministration of apixaban with EVOTAZ depends on the apixaban dose. Refer to apixaban dosing instructions for coadministration with strong CYP3A4 and P-gp inhibitors in apixaban prescribing information. rivaroxaban ↑ rivaroxaban Coadministration of EVOTAZ and rivaroxaban is not recommended because it may lead to increased bleeding risk. betrixaban dabigatran etexilate edoxaban ↑ betrixaban ↑ dabigatran ↑ edoxaban Due to potentially increased bleeding risk, dosing recommendations for coadministration of betrixaban, dabigatran, or edoxaban with a P-gp inhibitor such as EVOTAZ depends on DOAC indication and renal function. Refer to DOAC dosing instructions for coadministration with P-gp inhibitors in DOAC prescribing information. warfarin warfarin: effect unknown Monitor the International Normalized Ratio (INR) when EVOTAZ is coadministered with warfarin.

Anticonvulsants: carbamazepine, phenobarbital, phenytoin Anticonvulsants with CYP3A induction effects that are NOT contraindicated (e.g., eslicarbazepine, oxcarbazepine) ↓ atazanavir ↓ cobicistat ↓ atazanavir ↓ cobicistat Coadministration of EVOTAZ with carbamazepine, phenobarbital, or phenytoin is contraindicated due to potential for loss of therapeutic effect and development of resistance. Consider alternative anticonvulsant or antiretroviral therapy to avoid potential changes in exposures. If coadministration is necessary, monitor for lack or loss of virologic response. Anticonvulsants that are metabolized by CYP3A (e.g., clonazepam) ↑ clonazepam Clinical monitoring of anticonvulsants is recommended with EVOTAZ coadministration. Other anticonvulsants (e.g., lamotrigine) lamotrigine: effects unknown Monitoring of lamotrigine concentrations is recommended with EVOTAZ coadministration.

Antidepressants: Selective Serotonin Reuptake Inhibitors (SSRIs) (e.g., paroxetine) SSRIs: effects unknown When coadministering with SSRIs, TCAs, or trazodone, careful dose titration of the antidepressant to the desired effect, using the lowest feasible initial or maintenance dose, and monitoring for antidepressant response are recommended. Tricyclic Antidepressants (TCAs) (e.g., amitriptyline, desipramine, imipramine, nortriptyline) ↑ TCAs Other Antidepressants (e.g., trazodone) ↑ trazodone Antifungals: ketoconazole, itraconazole ↑ atazanavir ↑ cobicistat ↑ ketoconazole ↑ itraconazole Specific dosing recommendations are not available for coadministration of EVOTAZ with either itraconazole or ketoconazole. voriconazole effects unknown Coadministration with voriconazole is not recommended unless the benefit/risk assessment justifies the use of voriconazole.

Antigout: colchicine ↑ colchicine Coadministration of EVOTAZ with colchicine in patients with renal or hepatic impairment is contraindicated due to the potential for serious and/or life-threatening reactions. Recommended dosage of colchicine when administered with EVOTAZ: Treatment of gout flares: 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Treatment course should be repeated no earlier than 3 days.

Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).

Antimycobacterials: Rifabutin atazanavir: effect unknown cobicistat: effect unknown ↑ rifabutin A rifabutin dose reduction of up to 75% (e.g., 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions, including neutropenia and uveitis, is warranted. rifampin ↓ atazanavir ↓ cobicistat Coadministration with rifampin is contraindicated due to potential for loss of therapeutic effect and development of resistance.

Antineoplastics: apalutamide ↓ atazanavir ↓cobicistat Coadministration with apalutamide is contraindicated due to the potential for substantial decrease in plasma concentrations of atazanavir and cobicistat, which may result in loss of virologic response of EVOTAZ and possible resistance to atazanavir or to other protease inhibitors..

Mechanism: The mechanism of interaction is CYP3A4 induction by apalutamide. ivosidenib ↓ atazanavir ↓ cobicistat ↑ ivosidenib Coadministration with ivosidenib is contraindicated due to the potential for loss of virologic response of EVOTAZ, development of resistance, and risk of serious adverse events such as QT interval prolongation..

Mechanism: The mechanism of interaction is CYP3A4 induction by ivosidenib. encorafenib ↓ atazanavir ↓ cobicistat ↑ encorafenib Coadministration with encorafenib is contraindicated due to the potential for loss of virologic response of EVOTAZ, development of resistance, and risk of serious adverse events such as QT interval prolongation..

Mechanism: The mechanism of interaction is CYP3A4 induction by encorafenib.

Antiplatelets: ticagrelor ↑ ticagrelor Coadministration with ticagrelor is not recommended due to the potential increase of the antiplatelet activity of ticagrelor. clopidogrel ↓ clopidogrel active metabolite Coadministration with clopidogrel is not recommended due to the potential reduction of the antiplatelet activity of clopidogrel. prasugrel ↔ prasugrel active metabolite No dose adjustment is needed when prasugrel is coadministered with atazanavir and/or cobicistat.

Antipsychotics: lurasidone ↑ lurasidone Coadministration with lurasidone is contraindicated due to the potential for serious and/or life-threatening reactions. pimozide ↑ pimozide Coadministration with pimozide is contraindicated due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias. quetiapine ↑ quetiapine Initiation of EVOTAZ in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking EVOTAZ: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. (e.g., perphenazine, risperidone, thioridazine) ↑ antipsychotic A decrease in the dose of antipsychotics that are metabolized by CYP3A or CYP2D6 may be needed when coadministered with EVOTAZ. Beta-agonist (inhaled): salmeterol ↑ salmeterol Coadministration with salmeterol is not recommended due to an increased risk of cardiovascular adverse reactions associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia.

Beta-Blockers: (e.g., metoprolol, carvedilol, timolol) ↔ atazanavir ↑ beta-blockers Clinical monitoring is recommended when beta-blockers that are metabolized by CYP2D6 are coadministered with EVOTAZ.

Calcium channel blockers: (e.g., amlodipine, diltiazem, felodipine, nifedipine, and verapamil) ↑ calcium channel blocker Clinical monitoring is recommended for coadministration with calcium channel blockers metabolized by CYP3A. ECG monitoring is recommended.

Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone triamcinolone ↓ atazanavir ↓ cobicistat ↑ corticosteroids Coadministration with oral dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to atazanavir. Consider alternative corticosteroids. Coadministration with corticosteroids (all routes of administration) whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushing’s syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone, prednisone, and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use.

Kinase inhibitors: fostamatinib ↑ R406 active metabolite of fostamatinib Coadministration with fostamatinib may increase the plasma concentration of R406, the active metabolite of fostamatinib. Monitor for toxicities of R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required.

Endothelin receptor antagonists: bosentan ↓ atazanavir ↓ cobicistat ↑ bosentan Initiation of bosentan in patients taking EVOTAZ: For patients who have been receiving EVOTAZ for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability. Initiation of EVOTAZ in patients taking bosentan: Discontinue bosentan at least 36 hours before starting EVOTAZ. After at least 10 days following initiation of EVOTAZ, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability. Switching from atazanavir coadministered with ritonavir to EVOTAZ: Maintain bosentan dose. Gonadotropin releasing hormone antagonist Receptor (GnRH): elagolix ↓ atazanavir ↓ cobicistat ↑ elagolix Coadministration of EVOTAZ with elagolix may result in decreased plasma concentrations of atazanavir and/or cobicistat. Concomitant use of elagolix 200 mg twice daily with EVOTAZ for more than 1 month is not recommended due to the potential risk of adverse events such as bone loss and hepatic transaminase elevations. Limit concomitant use of elagolix 150 mg once daily with EVOTAZ to 6 months. In addition, monitor virologic responses due to the potential reduction in atazanavir/cobicistat exposure.

Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine ↑ ergot derivatives Coadministration of EVOTAZ with ergot derivatives is contraindicated due to the potential for serious and/or life-threatening events such as acute ergot toxicity, characterized by peripheral vasospasm and ischemia of the extremities and other tissues.

Hepatitis C Direct-Acting Antivirals: elbasvir/grazoprevir ↑ grazoprevir Coadministration of EVOTAZ with elbasvir/grazoprevir is contraindicated due to increased risk of ALT elevations. glecaprevir/pibrentasvir ↑ glecaprevir ↑ pibrentasvir Coadministration of EVOTAZ with glecaprevir/ pibrentasvir is contraindicated due to increased risk of ALT elevations.

Herbal Products: St. John’s wort ( Hypericum perforatum) ↓ atazanavir ↓ cobicistat Coadministration of products containing St. John’s wort and EVOTAZ is contraindicated due to potential for loss of therapeutic effect and development of resistance. H 2 ‑Receptor antagonists (H 2 RA ): (e.g., famotidine) ↓ atazanavir Coadministration of EVOTAZ with tenofovir DF and an H 2 RA in treatment-experienced patients is not recommended. Administer EVOTAZ either at the same time or at a minimum of 10 hours after a dose of the H 2 RA. The dose of the H 2 RA should not exceed a dose comparable to famotidine 40 mg twice daily in treatment-naive patients or 20 mg twice daily in treatment-experienced patients.

Lipid-modifying agents: Other lipid-modifying agents: lomitapide ↑ lomitapide Coadministration with lomitapide is contraindicated due to the potential for risk of markedly increased transaminase levels and hepatoxicity.

HMG-CoA reductase inhibitors: lovastatin simvastatin ↑lovastatin ↑simvastatin Coadministration with lovastatin or simvastatin is contraindicated due to the potential for serious reactions such as myopathy, including rhabdomyolysis.

Other HMG-CoA reductase inhibitors: atorvastatin, fluvastatin, pravastatin, rosuvastatin ↑ HMG-CoA reductase inhibitors Coadministration of EVOTAZ with atorvastatin is not recommended. For HMG-CoA reductase inhibitors that are not contraindicated with EVOTAZ, start with the lowest recommended dose and titrate while monitoring for safety (e.g., myopathy). Dosage recommendations with rosuvastatin are as follows. Rosuvastatin dose should not exceed 10 mg/day.

Hormonal contraceptives: drospirenone/ethinyl estradiol ↑ drospirenone Coadministration with drospirenone-containing products is contraindicated due to the potential for drospirenone-associated hyperkalemia. (e.g., progestin/estrogen) progestin and estrogen: effects unknown No data are available to make recommendations on the coadministration of EVOTAZ and oral or other hormonal contraceptives. Alternative nonhormonal forms of contraception should be considered.

Immunosuppressants: (e.g., cyclosporine, everolimus, sirolimus, tacrolimus) ↑ immunosuppressants Therapeutic concentration monitoring is recommended for these immunosuppressants when coadministered with EVOTAZ.

Narcotic analgesics: For treatment of opioid dependence: buprenorphine, naloxone, methadone buprenorphine or buprenorphine/naloxone: effects unknown methadone: effects unknown Initiation of buprenorphine, buprenorphine/naloxone or methadone in patients taking EVOTAZ: Carefully titrate the dose of buprenorphine, buprenorphine/naloxone or methadone to the desired effect; use the lowest feasible initial or maintenance dose. Initiation of EVOTAZ in patients taking buprenorphine, buprenorphine/naloxone or methadone: A dose adjustment for buprenorphine, buprenorphine/naloxone or methadone may be needed. Monitor clinical signs and symptoms. fentanyl ↑ fentanyl When EVOTAZ is coadministered with fentanyl, careful monitoring of therapeutic and adverse effects of fentanyl (including potentially fatal respiratory depression) is recommended. tramadol ↑ tramadol When EVOTAZ is coadministered with tramadol, a decreased dose of tramadol may be needed. Phosphodiesterase-5 (PDE-5) inhibitors: avanafil, sildenafil, tadalafil, vardenafil ↑ PDE-5 inhibitors Use of PDE-5 inhibitors for pulmonary arterial hypertension (PAH): Coadministration of EVOTAZ with sildenafil is contraindicated due to the potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, priapism, and syncope).

Tadalafil: The following dose adjustments are recommended for the use of tadalafil with EVOTAZ: Initiation of tadalafil in patients taking EVOTAZ: o For patients receiving EVOTAZ for at least one week, start tadalafil at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability. Initiation of EVOTAZ in patients taking tadalafil: o Avoid the use of tadalafil when starting EVOTAZ. Stop tadalafil at least 24 hours before starting EVOTAZ. At least one week after starting EVOTAZ, resume tadalafil at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability. Patients switching from atazanavir coadministered with ritonavir to EVOTAZ: o Maintain tadalafil dose. Use of PDE-5 inhibitors for erectile dysfunction: Avanafil: Not recommended because a safe and effective dose of avanafil has not been established.

Sildenafil: Reduced dosage to 25 mg every 48 hours with increased monitoring for adverse reactions.

Tadalafil: Reduced dosage to 10 mg every 72 hours with increased monitoring for adverse reactions.

Vardenafil: Reduced dosage to no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions. Proton-pump inhibitors (PPI): (e.g., omeprazole) ↓ atazanavir In treatment-naive patients, administer EVOTAZ a minimum of 12 hours after administration of the PPI. The dose of the PPI should not exceed a dose comparable to omeprazole 20 mg daily. In treatment-experienced patients, coadministration of EVOTAZ with PPI is not recommended.

Sedatives/Hypnotics: Benzodiazepines midazolam (oral) triazolam ↑ midazolam ↑ triazolam Coadministration of triazolam or orally administered midazolam is contraindicated due to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4.

Other Benzodiazepines: clorazepate diazepam estazolam flurazepam parenterally administered midazolam ↑ sedatives/hypnotics Parenterally administered midazolam: Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.

Other Sedatives/Hypnotics: buspirone, zolpidem With other sedatives/hypnotics that are CYP3A metabolized, a dose reduction may be necessary and clinical monitoring is recommended.

7.4 Drugs with

No Observed or Predicted Interactions with the Components of EVOTAZ Based on known metabolic profiles, clinically significant drug interactions are not expected between EVOTAZ and acetaminophen, atenolol, dapsone, fluconazole, trimethoprim/sulfamethoxazole, or azithromycin.