ATAZANAVIR Drug Interactions: What You Need to Know

INTERACTIONS Coadministration of atazanavir can alter the concentration of other drugs and other drugs may alter the concentration of atazanavir. The potential drug-drug interactions must be considered prior to and during therapy. (4, 7, 12.3)

7.1 Potential for Atazanavir to Affect Other Drugs Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of atazanavir and drugs primarily metabolized by CYP3A or UGT1A1 may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects. Atazanavir is a weak inhibitor of CYP2C8. Use of atazanavir without ritonavir is not recommended when coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (e.g., paclitaxel, repaglinide). When atazanavir with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected <span class="opacity-50 text-xs">[see Clinical Pharmacology, Table 22 (12.3) ]</span> . The magnitude of CYP3A-mediated drug interactions on coadministered drug may change when atazanavir is coadministered with ritonavir. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir.

7.2 Potential for Other Drugs to Affect Atazanavir Atazanavir is a CYP3A4 substrate; therefore, drugs that induce CYP3A4 may decrease atazanavir plasma concentrations and reduce atazanavir&apos;s therapeutic effect (see Table 16) . 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 atazanavir <span class="opacity-50 text-xs">[see Dosage and Administration (2.3 , 2.4 , and 2.6) ]</span> .

7.3 Established and Other Potentially Significant Drug Interactions Table 16 provides dosing recommendations in adults as a result of drug interactions with atazanavir. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.

Table

16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies a or Predicted Interactions (Information in the table applies to atazanavir with or without ritonavir, unless otherwise indicated)

Concomitant Drug

Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment HIV Antiviral Agents Nucleoside Reverse Transcriptase Inhibitors (NRTIs): didanosine buffered formulations enteric coated (EC) capsules ↓ atazanavir ↓ didanosine It is recommended that atazanavir be given (with food) 2 h before or 1 h after didanosine buffered formulations. Simultaneous administration of didanosine EC and atazanavir with food results in a decrease in didanosine exposure. Thus, atazanavir and didanosine EC should be administered at different times.

Nucleotide Reverse Transcriptase

Inhibitors: tenofovir disoproxil fumarate (DF) ↓ atazanavir ↑ tenofovir When coadministered with tenofovir DF in adults, it is recommended that atazanavir 300 mg be given with ritonavir 100 mg and tenofovir DF 300 mg (all as a single daily dose with food). The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir­-associated adverse reactions, including renal disorders. Patients receiving atazanavir and tenofovir DF should be monitored for tenofovir-associated adverse reactions. For pregnant patients taking atazanavir with ritonavir and tenofovir DF, see Dosage and Administration (2.6) . Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): efavirenz ↓ atazanavir In HIV-treatment-naive adult patients: If atazanavir is combined with efavirenz, atazanavir 400 mg (two 200 mg capsules) should be administered with ritonavir 100 mg simultaneously once daily with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime. In HIV-treatment-experienced adult patients: Coadministration of atazanavir with efavirenz is not recommended. nevirapine ↓ atazanavir ↑ nevirapine Coadministration of atazanavir with nevirapine is contraindicated due to the potential loss of virologic response and development of resistance, as well as the potential risk for nevirapine-associated adverse reactions [see Contraindications (4) ].

Protease

Inhibitors: saquinavir (soft gelatin capsules) ↑ saquinavir Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In a clinical study, saquinavir 1200 mg coadministered with atazanavir 400 mg and tenofovir DF 300 mg (all given once daily), and nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see Clinical Studies (14.2) ] . indinavir Coadministration of atazanavir with indinavir is contraindicated. Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia [see Contraindications (4) ]. ritonavir ↑ atazanavir If atazanavir is coadministered with ritonavir, it is recommended that atazanavir 300 mg once daily be given with ritonavir 100 mg once daily with food in adults. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir. Others ↑ other protease inhibitor Coadministration with other protease inhibitors is not recommended. Hepatitis C Antiviral Agents elbasvir/grazoprevir ↑ grazoprevir Coadministration of atazanavir with grazoprevir is contraindicated due to the potential for increased risk of ALT elevations [see Contraindications (4) ]. glecaprevir/pibrentasvir ↑ glecaprevir ↑ pibrentasvir Coadministration of atazanavir with glecaprevir/pibrentasvir is contraindicated due to the potential for increased the risk of ALT elevations [see Contraindications (4) ]. voxilaprevir/sofosbuvir/velpatasvir ↑ voxilaprevir Coadministration with atazanavir is not recommended.

Other Agents Alpha

1-Adrenoreceptor Antagonist: alfuzosin ↑ alfuzosin Coadministration of atazanavir with alfuzosin is contraindicated due to risk for hypotension [see Contraindications (4) ]. Antacids and buffered medications: ↓ atazanavir Atazanavir should be administered 2 hours before or 1 hour after antacids and buffered medications. Antiarrhythmics: amiodarone, quinidine amiodarone, bepridil, lidocaine (systemic), quinidine ↑ amiodarone, bepridil, lidocaine (systemic), quinidine Concomitant use of atazanavir with ritonavir and either quinidine or amiodarone is contraindicated due to the potential for serious or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) ]. Coadministration with atazanavir without ritonavir has the potential to produce serious and/or life-threatening adverse events but has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with atazanavir without ritonavir. Anticoagulants: warfarin ↑ warfarin Coadministration with atazanavir has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that International Normalized Ratio (INR) be monitored. Direct-Acting Oral Anticoagulants: betrixaban, dabigatran, edoxaban ↑ betrixaban ↑ dabigatran ↑ edoxaban Concomitant use of atazanavir with ritonavir, a strong CYP3A4/P-gp inhibitor, may result in an increased risk of bleeding. Refer to the respective DOAC prescribing information regarding dosing instructions for coadministration with P-gp inhibitors. rivaroxaban apixaban Atazanavir with ritonavir ↑ rivaroxaban Atazanavir ↑ rivaroxaban Atazanavir with ritonavir ↑ apixaban Atazanavir ↑ apixaban Coadministration of atazanavir with ritonavir, a strong CYP3A4/P-gp inhibitor, and rivaroxaban is not recommended, as it may result in an increased risk of bleeding. Coadministration of atazanavir, a CYP3A4 inhibitor, and rivaroxaban may result in an increased risk of bleeding. Close monitoring is recommended when atazanavir is coadministered with rivaroxaban. Concomitant use of atazanavir with ritonavir, a strong CYP3A4/P-gp inhibitor, may result in an increased risk of bleeding. Refer to apixaban dosing instructions for coadministration with strong CYP3A4 and P-gp inhibitors in the apixaban prescribing information. Concomitant use of atazanavir, a CYP3A4 inhibitor, and apixaban may result in an increased risk of bleeding. Close monitoring is recommended when apixaban is coadministered with atazanavir. Antidepressants: tricyclic antidepressants ↑ tricyclic antidepressants Coadministration with atazanavir has the potential to produce serious and/or life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with atazanavir. trazodone ↑ trazodone Nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone with ritonavir. If trazodone is used with a CYP3A4 inhibitor such as atazanavir, the combination should be used with caution and a lower dose of trazodone should be considered. Antiepileptics: carbamazepine ↓ atazanavir ↑ carbamazepine Coadministration of atazanavir (with or without ritonavir) with carbamazepine is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4) ]. phenytoin, phenobarbital ↓ atazanavir ↓ phenytoin ↓ phenobarbital Coadministration of atazanavir (with or without ritonavir) with phenytoin or phenobarbital is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4) ]. lamotrigine ↓ lamotrigine Coadministration of lamotrigine and atazanavir with ritonavir may require dosage adjustment of lamotrigine. No dose adjustment of lamotrigine is required when coadministered with atazanavir without ritonavir. Antifungals: ketoconazole, itraconazole Atazanavir with ritonavir: ↑ ketoconazole ↑ itraconazole Coadministration of ketoconazole has only been studied with atazanavir without ritonavir (negligible increase in atazanavir AUC and C max ). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously when administering atazanavir with ritonavir. voriconazole Atazanavir with ritonavir in participants with a functional CYP2C19 allele: ↓ voriconazole ↓ atazanavir Atazanavir with ritonavir in participants without a functional CYP2C19 allele: ↑ voriconazole ↓ atazanavir The use of voriconazole in patients receiving atazanavir with ritonavir is not recommended unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Patients should be carefully monitored for voriconazole-associated adverse reactions and loss of either voriconazole or atazanavir efficacy during the coadministration of voriconazole and atazanavir with ritonavir. Coadministration of voriconazole with atazanavir (without ritonavir) may affect atazanavir concentrations; however, no data are available. Antigout: colchicine ↑ colchicine The coadministration of atazanavir with colchicine in patients with renal or hepatic impairment is not recommended. Recommended adult dosage of colchicine when administered with atazanavir: Treatment of gout flares: 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 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: rifampin ↓ atazanavir Coadministration of atazanavir with rifampin is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4) ]. rifabutin ↑ 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 is warranted. Antineoplastics: irinotecan apalutamide ivosidenib encorafenib ↑ irinotecan ↓ atazanavir ↓ atazanavir ↑ ivosidenib ↓ atazanavir ↑ encorafenib Coadministration of atazanavir with irinotecan is contraindicated. Atazanavir inhibits UGT1A1 and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities [see Contraindications (4) ]. Coadministration of atazanavir (with or without ritonavir) and apalutamide is contraindicated due to the potential for subsequent loss of virologic response and possible resistance to the class of protease inhibitors [see Contraindications (4) ]. Coadministration of ivosidenib with atazanavir (with or without ritonavir) is contraindicated due to the potential for loss of virologic response and risk of serious adverse events such as QT interval prolongation. Coadministration of encorafenib with atazanavir (with or without ritonavir) is contraindicated due to the potential for the loss of virologic response and risk of serious adverse events such as QT interval prolongation. Antiplatelets ticagrelor clopidogrel ↑ ticagrelor ↓ clopidogrel active metabolite Coadministration with ticagrelor is not recommended due to potential increase in the risk of dyspnea, bleeding and other adverse events associated with ticagrelor. Coadministration of atazanavir (with or without ritonavir) and clopidogrel is not recommended. This is due to the potential reduction of the antiplatelet activity of clopidogrel. Antipsychotics: pimozide ↑ pimozide Coadministration of atazanavir with pimozide is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) ]. lurasidone quetiapine Atazanavir with ritonavir ↑ lurasidone Atazanavir ↑ lurasidone ↑ quetiapine Atazanavir with ritonavir Coadministration of lurasidone with atazanavir with ritonavir is contraindicated. This is due to the potential for serious and/or life-threatening reactions [see Contraindications (4) ]. Atazanavir without ritonavir If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors. Initiation of atazanavir with ritonavir 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 atazanavir with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. Benzodiazepines: midazolam (oral) triazolam ↑ midazolam ↑ triazolam Coadministration of atazanavir with either orally administered midazolam or triazolam is contraindicated. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4, and coadministration with atazanavir can lead to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression [see Contraindications (4) ]. parenterally administered midazolam b ↑ midazolam Coadministration with parenteral midazolam 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. Calcium channel blockers: diltiazem ↑ diltiazem and desacetyl- diltiazem Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of diltiazem and atazanavir with ritonavir has not been studied. felodipine, nifedipine, nicardipine, and verapamil ↑ calcium channel blocker Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended. Corticosteroids: dexamethasone and other corticosteroids (all routes of administration) ↓ atazanavir ↑ corticosteroids Coadministration with dexamethasone or other corticosteroids that induce CYP3A may result in loss of therapeutic effect of atazanavir and development of resistance to atazanavir and/or ritonavir. Alternative corticosteroids should be considered. Coadministration with corticosteroids (all routes of administration) that are metabolized by CYP3A, particularly for long-term use, may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. For coadministration of cutaneously administered corticosteroids sensitive to CYP3A inhibition, refer to the prescribing information of the corticosteroid for additional information. Endothelin receptor antagonists: bosentan Atazanavir ↓ atazanavir Atazanavir with ritonavir ↑ bosentan Coadministration of bosentan and atazanavir without ritonavir is not recommended. For adult patients who have been receiving atazanavir with ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability. For adult patients who have been receiving bosentan, discontinue bosentan at least 36 hours before starting atazanavir with ritonavir. At least 10 days after starting atazanavir with ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability. Ergot derivatives: dihydroergotamine, ergotamine, ergonovine, methylergonovine ↑ ergot derivatives Coadministration of atazanavir with ergot derivatives is contraindicated. This is 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 [see Contraindications (4) ]. GI Motility Agents: cisapride ↑ cisapride Coadministration of atazanavir with cisapride is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) ]. Gonadotropin-releasing hormone Receptor (GnRH) Antagonists: elagolix ↓ atazanavir ↑ elagolix Coadministration of elagolix and atazanavir with or without ritonavir is not recommended due to the potential of loss of virologic response and the potential risk of adverse events such as bone loss and hepatic transaminase elevations associated with elagolix. In the event coadministration is necessary, limit concomitant use of elagolix 200 mg twice daily with atazanavir with or without ritonavir for up to 1 month or limit concomitant use of elagolix 150 mg once daily with atazanavir (with or without ritonavir) for up to 6 months and monitor virologic response.

Herbal

Products: St. John’s wort (Hypericum perforatum) ↓ atazanavir Coadministration of products containing St. John’s wort with atazanavir is contraindicated. This may result in loss of therapeutic effect of atazanavir and the development of resistance [see Contraindications (4) ]. Kinase inhibitors: fostamatinib ↑ R406 (active metabolite of fostamatinib) When coadministering fostamatinib with atazanavir (with or without ritonavir), monitor for toxicities of R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required. Lipid-modifying agents HMG-CoA reductase inhibitors: lovastatin, simvastatin ↑ lovastatin ↑ simvastatin Coadministration of atazanavir with lovastatin or simvastatin is contraindicated. This is due to the potential for serious reactions such as myopathy, including rhabdomyolysis [see Contraindications (4) ]. atorvastatin, rosuvastatin ↑ atorvastatin ↑ rosuvastatin Titrate atorvastatin dose carefully and use the lowest necessary dose. Rosuvastatin dose should not exceed 10 mg/day. The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including atazanavir, are used in combination with these drugs.

Other Lipid Modifying

Agents: lomitapide ↑ lomitapide Coadministration of atazanavir with lomitapide is contraindicated. This is due to the potential for risk of markedly increased transaminase levels and hepatotoxicity associated with increased plasma concentrations of lomitapide. The mechanism of interaction is CYP3A4 inhibition by atazanavir and/or ritonavir [see Contraindications (4) ]. H 2 -Receptor antagonists ↓ atazanavir Coadministration may result in loss of virologic response and development of resistance. In HIV-treatment-naive adult patients: Atazanavir 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H 2 -receptor antagonist (H2RA). An H2RA dose comparable to famotidine 20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with atazanavir 300 mg with ritonavir 100 mg in treatment-naive patients. OR For patients unable to tolerate ritonavir, atazanavir 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H2RA. No single dose of the H2RA should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg. The use of atazanavir without ritonavir in pregnant patients is not recommended. In treatment-experienced adult patients: Whenever an H2RA is given to a patient receiving atazanavir with ritonavir, the H2RA dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the atazanavir with ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2RA.

• Atazanavir 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H2RA.
• Atazanavir 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir DF and an H2RA.
• Atazanavir 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with either tenofovir DF or an H2RA for pregnant patients during the second and third trimester. Atazanavir is not recommended for pregnant patients during the second and third trimester taking atazanavir with both tenofovir DF and an H2RA. Hormonal contraceptives: ethinyl estradiol and norgestimate or norethindrone ↓ ethinyl estradiol ↑ norgestimate c ↑ ethinyl estradiol ↑ norethindrone d Use caution if considering coadministration of oral contraceptives with atazanavir or atazanavir with ritonavir. If atazanavir with ritonavir is coadministered with an oral contraceptive, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol. If atazanavir is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol. Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne. Coadministration of atazanavir or atazanavir with ritonavir and other hormonal contraceptives (e.g., contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended. Immunosuppressants: cyclosporine, sirolimus, tacrolimus ↑ immunosuppressants Therapeutic concentration monitoring is recommended for these immunosuppressants when coadministered with atazanavir. Inhaled beta agonist: salmeterol ↑ salmeterol Coadministration of salmeterol with atazanavir is not recommended. Concomitant use of salmeterol and atazanavir may result in increased risk of cardiovascular adverse reactions associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. Inhaled/nasal steroid: fluticasone Atazanavir ↑ fluticasone Concomitant use of fluticasone propionate and atazanavir without ritonavir should be used with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. Atazanavir with ritonavir ↑ fluticasone With concomitant use of fluticasone propionate and atazanavir with ritonavir systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Coadministration of fluticasone propionate and atazanavir with ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see Warnings and Precautions (5.1) ] . Macrolide antibiotics: clarithromycin ↑ clarithromycin ↓ 14-OH clarithromycin ↑ atazanavir Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with atazanavir. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium avium complex. Coadministration of atazanavir with ritonavir and clarithromycin has not been studied. Opioids: buprenorphine Atazanavir or atazanavir with ritonavir ↑ buprenorphine ↑ norbuprenorphine Atazanavir ↓ atazanavir Coadministration of atazanavir with ritonavir and buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. The coadministration of atazanavir and buprenorphine without ritonavir is not recommended. PDE5 inhibitors: sildenafil, tadalafil, vardenafil ↑ sildenafil ↑ tadalafil ↑ vardenafil Coadministration with atazanavir has not been studied but may result in an increase in PDE5 inhibitor-associated adverse reactions, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Coadministration of atazanavir with REVATIO ® (sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated [see Contraindications (4) ] . The following dose adjustments are recommended for the use of ADCIRCA ® (tadalafil) with atazanavir: Coadministration of ADCIRCA ® in patients on atazanavir (with or without ritonavir): For patients receiving atazanavir (with or without ritonavir) for at least one week, start ADCIRCA ® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability. Coadministration of atazanavir (with or without ritonavir) in patients on ADCIRCA ® : Avoid the use of ADCIRCA ® when starting atazanavir (with or without ritonavir). Stop ADCIRCA ® at least 24 hours before starting atazanavir (with or without ritonavir). At least one week after starting atazanavir (with or without ritonavir), resume ADCIRCA ® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: Use VIAGRA ® (sildenafil) with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events. Use CIALIS ® (tadalafil) with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events. Atazanavir with ritonavir: Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions. Atazanavir: Use vardenafil with caution at reduced doses of no more than 2.5 mg every 24 hours with increased monitoring for adverse reactions. Proton-pump inhibitors: omeprazole ↓ atazanavir Coadministration of atazanavir with or without ritonavir and omeprazole may result in loss of virologic response and development of resistance. In HIV-treatment-naive adult patients: The proton-pump inhibitor (PPI) dose should not exceed a dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to the atazanavir 300 mg with ritonavir 100 mg dose. In HIV-treatment-experienced adult patients: Coadministration of atazanavir with PPIs is not recommended. a For magnitude of interactions see Clinical Pharmacology, Tables 21 and 22 (12.3) . b See Contraindications (4) , Table 6 for orally administered midazolam. c In combination with atazanavir 300 mg with ritonavir 100 mg once daily. d In combination with atazanavir 400 mg once daily.

7.4 Drugs with No Observed Interactions with Atazanavir No clinically significant drug interactions were observed when atazanavir was coadministered with methadone, fluconazole, acetaminophen, atenolol, or the nucleoside reverse transcriptase inhibitors lamivudine or zidovudine <span class="opacity-50 text-xs">[see Clinical Pharmacology, Tables 21 and 22 (12.3) ]</span>.

The concomitant use of EVOTAZ and the following drugs in Table 1, are contraindicated due to the potential for serious and/or life-threatening events or loss of therapeutic effect [see Warnings and Precautions (5.8 , 5.9) , Drug Interactions (7) , and Clinical Pharmacology (12.3) ]. EVOTAZ is contraindicated:

• in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product [see Warnings and Precautions (5.2) ] .
• when coadministered with drugs that strongly induce CYP3A4, which may lead to lower exposure of EVOTAZ resulting in potential loss of efficacy and development of possible resistance (Table 5).
• when coadministered with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events (see Table 5). For additional information, including clinical comments and potential impact on exposure levels associated with drugs that are contraindicated with EVOTAZ, refer to Table 5 [see Drug Interactions (7.3) ] . Coadministration is contraindicated with, but not limited to, the following drugs: Table 1: Drugs Contraindicated with EVOTAZ Drug Class Drugs within class that are contraindicated with EVOTAZ a Refer to Table 5 for sildenafil when administered for erectile dysfunction [see Drug Interactions (7.3) ]. b Refer to Table 5 for parenterally administered midazolam [see Drug Interactions (7.3) ].

Alpha

1-adrenoreceptor antagonist alfuzosin Antianginal ranolazine Antiarrhythmics dronedarone Anticonvulsants carbamazepine, phenobarbital, phenytoin Antigout colchicine (when used in patients with hepatic and/or renal impairment) Antimycobacterials rifampin Antineoplastics apalutamide, encorafenib, irinotecan, ivosidenib Antipsychotics lurasidone, pimozide Ergot Derivatives dihydroergotamine, ergotamine, methylergonovine Hepatitis C Direct-Acting Antivirals elbasvir/grazoprevir; glecaprevir/pibrentasvir Herbal Products St. John’s wort ( Hypericum perforatum )

Hormonal

Contraceptives drospirenone/ethinyl estradiol Lipid-modifying Agents lomitapide, lovastatin, simvastatin Non-nucleoside Reverse Transcriptase Inhibitor nevirapine Phosphodiesterase-5 (PDE-5) Inhibitor sildenafil a when administered for the treatment of pulmonary arterial hypertension Protease Inhibitors indinavir Sedative/hypnotics triazolam, orally administered midazolam b

• EVOTAZ is contraindicated in patients with previously demonstrated hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product. (4)
• EVOTAZ is contraindicated with drugs that are strong inducers of CYP3A4 due to the potential for loss of therapeutic effect and development of possible resistance. (4)
• EVOTAZ is contraindicated with certain drugs for which altered plasma concentrations are associated with serious and/or life-threatening events or loss of therapeutic effect. (4)

AND PRECAUTIONS

• Cardiac conduction abnormalities: PR interval prolongation may occur in some patients. Consider ECG monitoring in patients with preexisting conduction system disease or when administered with other drugs that may prolong the PR interval. ( 5.1 , 6 , 7.3 , 12.2 , 17 )
• Severe skin reactions: Discontinue if severe rash develops. ( 5.2 , 6.1 , 17 )
• Assess creatinine clearance (CLcr) before initiating treatment. Consider alternative medications that do not require dosage adjustments in patients with renal impairment. ( 5.3 )
• When cobicistat, a component of EVOTAZ, is used in combination with a tenofovir disoproxil fumarate (tenofovir DF)-containing regimen, cases of acute renal failure and Fanconi syndrome have been reported. ( 5.4 )
• When used with tenofovir DF, assess urine glucose and urine protein at baseline and monitor CLcr, urine glucose, and urine protein. Monitor serum phosphorus in patients with or at risk for renal impairment. Coadministration with tenofovir DF is not recommended in patients with CLcr below 70 mL/min or in patients also receiving a nephrotoxic agent. ( 5.4 )
• Chronic kidney disease has been reported during postmarketing surveillance in patients with HIV-1 treated with atazanavir, with or without ritonavir. Consider alternatives in patients at high risk for renal disease or with preexisting renal disease. Monitor renal laboratory tests prior to therapy and during treatment with EVOTAZ. Consider discontinuation of EVOTAZ in patients with progressive renal disease. ( 5.5 )
• Nephrolithiasis and cholelithiasis have been reported. Consider temporary interruption or discontinuation. ( 5.6 , 6 )
• Hepatotoxicity: Patients with hepatitis B or C are at risk of increased transaminases or hepatic decompensation. Monitor hepatic laboratory tests prior to therapy and during treatment. ( 2.5 , 5.7 , 8.7 )
• Antiretrovirals that are not recommended: EVOTAZ is not recommended for use with ritonavir or products containing ritonavir, or in combination with other antiretroviral drugs that require CYP3A inhibition to achieve adequate exposures (e.g., other protease inhibitors and elvitegravir). ( 5.9 )
• Hyperbilirubinemia: Most patients experience asymptomatic increases in indirect bilirubin, which is reversible upon discontinuation. If a concomitant transaminase increase occurs, evaluate for alternative etiologies. ( 5.10 , 6 )
• Patients receiving EVOTAZ may develop immune reconstitution syndrome ( 5.11 ), new onset or exacerbations of diabetes mellitus/hyperglycemia ( 5.12 , 6 ), and redistribution/accumulation of body fat ( 5.13 ).
• Hemophilia: Spontaneous bleeding may occur and additional factor VIII may be required. ( 5.14 )

5.1 Cardiac Conduction Abnormalities Atazanavir prolongs the PR interval of the electrocardiogram in some patients. In healthy participants and in participants with HIV-1 treated with atazanavir, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been reports of second-degree AV block and other conduction abnormalities <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) and Overdosage (10) ]</span> . In clinical trials of atazanavir in participants with HIV-1 that included electrocardiograms, asymptomatic first-degree AV block was observed in 6% of participants treated with atazanavir (n=920) and 5% of participants (n=118) treated with atazanavir coadministered with ritonavir. Because of limited clinical experience in patients with preexisting conduction system disease (e.g., marked first-degree AV block or second- or third-degree AV block), consider ECG monitoring in these patients <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.2) ]</span> .

5.2 Severe Skin Reactions Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including drug rash, eosinophilia and systemic symptoms (DRESS) syndrome, have been reported in patients receiving atazanavir <span class="opacity-50 text-xs">[see Contraindications (4) and Adverse Reactions (6.1) ]</span> . EVOTAZ should be discontinued if severe rash develops. Mild-to-moderate maculopapular skin eruptions have also been reported in atazanavir clinical trials. These reactions had a median time to onset of 7.3 weeks and median duration of 1.4 week and generally did not result in treatment discontinuation.

5.3 Effects on Serum Creatinine Cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function. This effect should be considered when interpreting changes in estimated creatinine clearance in patients initiating EVOTAZ, particularly in patients with medical conditions or receiving drugs needing monitoring with estimated creatinine clearance. Prior to initiating therapy with EVOTAZ, assess estimated creatinine clearance <span class="opacity-50 text-xs">[see Dosage and Administration (2.1) ]</span> . Dosage recommendations are not available for drugs that require dosage adjustments in cobicistat-treated patients with renal impairment <span class="opacity-50 text-xs">[see Adverse Reactions (6.1) , Drug Interactions (7.3) , and Clinical Pharmacology (12.2) ]</span> . Consider alternative medications that do not require dosage adjustments in patients with renal impairment. Although cobicistat may cause modest increases in serum creatinine and modest declines in estimated creatinine clearance without affecting renal glomerular function, patients who experience a confirmed increase in serum creatinine of greater than 0.4 mg/dL from baseline should be closely monitored for renal safety.

5.4 New Onset or Worsening Renal Impairment When Used with Tenofovir DF Renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported when cobicistat was used in an antiretroviral regimen that contained tenofovir DF. Therefore, coadministration of EVOTAZ and tenofovir DF is not recommended in patients who have an estimated creatinine clearance below 70 mL/min <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> .

• When EVOTAZ is used with tenofovir DF, document urine glucose and urine protein at baseline and perform routine monitoring of estimated creatinine clearance, urine glucose, and urine protein during treatment.
• Measure serum phosphorus in patients with or at risk for renal impairment.
• Coadministration of EVOTAZ and tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent is not recommended. In a clinical trial over 144 weeks (N=692), 10 (2.9%) participants treated with atazanavir coadministered with cobicistat and tenofovir DF and 11 (3.2%) participants treated with atazanavir coadministered with ritonavir and tenofovir DF discontinued study drug due to a renal adverse event. Seven of the 10 participants (2.0% overall) in the cobicistat group had laboratory findings consistent with proximal renal tubulopathy leading to study drug discontinuation, compared to 7 of 11 participants (2.0% overall) in the ritonavir group. One participant in the cobicistat group had renal impairment at baseline (e.g., estimated creatinine clearance less than 70 mL/min). The laboratory findings in these 7 participants treated with cobicistat, with evidence of proximal tubulopathy improved but did not completely resolve in all participants upon discontinuation of cobicistat coadministered with atazanavir and tenofovir DF. Renal replacement therapy was not required in any participant.

5.5 Chronic Kidney Disease Chronic kidney disease in patients with HIV-1 treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. Reports included biopsy-proven cases of granulomatous interstitial nephritis associated with the deposition of atazanavir drug crystals in the renal parenchyma. Consider alternatives to EVOTAZ in patients at high risk for renal disease or with preexisting renal disease. Renal laboratory testing (including serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination) should be conducted in all patients prior to initiating therapy with EVOTAZ and continued during treatment with EVOTAZ. Expert consultation is advised for patients who have confirmed renal laboratory abnormalities while taking EVOTAZ. In patients with progressive kidney disease, discontinuation of EVOTAZ may be considered <span class="opacity-50 text-xs">[see Dosage and Administration (2.1 , 2.3 ) and Adverse Reactions (6.1) ]</span>.

5.6 Nephrolithiasis and Cholelithiasis Cases of nephrolithiasis and/or cholelithiasis have been reported during postmarketing surveillance in patients with HIV-1 receiving atazanavir therapy. Some patients required hospitalization for additional management and some had complications. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis and/or cholelithiasis occur, temporary interruption or discontinuation of therapy may be considered <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 , 6.1 )]</span> .

5.7 Hepatotoxicity Patients with underlying hepatitis B or C virus or marked elevations in transaminases may be at increased risk for developing further transaminase elevations or hepatic decompensation. In these patients, hepatic laboratory testing should be conducted prior to initiating therapy with EVOTAZ and during treatment <span class="opacity-50 text-xs">[see Dosage and Administration (2.4) and Use in Specific Populations (8.7) ]</span> .

5.8 Risk of Serious Adverse Reactions or Loss of Virologic Response Due to Drug Interactions Initiation of EVOTAZ, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving EVOTAZ, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of EVOTAZ, respectively. Increased concentrations of EVOTAZ may lead to:

• clinically significant adverse reactions, potentially leading to severe, life threatening, or fatal events from higher exposures of concomitant medications.
• clinically significant adverse reactions from higher exposures of EVOTAZ. Decreased concentrations of EVOTAZ may lead to:
• loss of therapeutic effect of EVOTAZ and possible development of resistance.

See Table

5 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7.3) ] . Consider the potential for drug interactions prior to and during EVOTAZ therapy; review concomitant medications during EVOTAZ therapy; and monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4) and Drug Interactions (7) ] . When used with concomitant medications, EVOTAZ may result in different drug interactions than those observed or expected with atazanavir coadministered with ritonavir. Complex or unknown mechanisms of drug interactions preclude extrapolation of drug interactions with atazanavir coadministered with ritonavir to certain EVOTAZ interactions [see Drug Interactions (7) and Clinical Pharmacology (12.3) ] .

5.9 Antiretrovirals that are Not Recommended EVOTAZ is not recommended in combination with other antiretroviral drugs that require CYP3A inhibition to achieve adequate exposures (e.g., other HIV protease inhibitors or elvitegravir) because dosing recommendations for such combinations have not been established and coadministration may result in decreased plasma concentrations of the antiretroviral agents, leading to loss of therapeutic effect and development of resistance. EVOTAZ is not recommended in combination with ritonavir or products containing ritonavir due to similar effects of cobicistat and ritonavir on CYP3A.

See Drug

Interactions (7) for additional recommendations on use with other antiretroviral agents.

5.10 Hyperbilirubinemia Most patients taking atazanavir experience asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyltransferase (UGT). This hyperbilirubinemia is reversible upon discontinuation of atazanavir. Hepatic transaminase elevations that occur with hyperbilirubinemia should be evaluated for alternative etiologies. No long-term safety data are available for patients experiencing persistent elevations in total bilirubin greater than 5 times the upper limit of normal (ULN). Alternative antiretroviral therapy to EVOTAZ may be considered if jaundice or scleral icterus associated with bilirubin elevations presents cosmetic concerns for patients <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span> .

5.11 Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including atazanavir, a component of EVOTAZ. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium , cytomegalovirus, Pneumocystis jirovecii pneumonia, or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.12 Diabetes Mellitus/Hyperglycemia New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in patients with HIV-1 receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.

5.13 Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

5.14 Hemophilia There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients, additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.