EVOTAZ

1 INDICATIONS AND USAGE EVOTAZ is a two-drug combination of atazanavir, a human immunodeficiency virus (HIV-1) protease inhibitor, and cobicistat, a CYP3A inhibitor indicated for use in combination with other antiretroviral agents for the treatment of HIV‑1 infection in adults and pediatric patients weighing at least 35 kg. (1) Limitations of Use Use of EVOTAZ in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions. (1) 1.1 Indications EVOTAZ ® is indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in the following populations [see Dosage and Administration (2.2 , 2.3) ] : • Adult patients • Pediatric patients weighing at least 35 kg. 1.2 Limitations of Use Use of EVOTAZ in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions [see Clinical Pharmacology (12.4) ] .

2 DOSAGE AND ADMINISTRATION • Pretreatment testing: Renal laboratory testing should be performed in all patients prior to initiation of EVOTAZ and continued during treatment with EVOTAZ. Hepatic testing should be performed in patients with underlying liver disease prior to initiation of EVOTAZ and continued during treatment with EVOTAZ. (2.1) • Recommended dosage: One tablet once daily, taken orally with food in adults and pediatric patients weighing at least 35 kg. (2.2) • Renal impairment: EVOTAZ is not recommended for use in treatment-experienced patients with end-stage renal disease managed with hemodialysis. (2.3 , 8.6) • Hepatic impairment: EVOTAZ is not recommended in patients with any degree of hepatic impairment. (2.4 , 8.7) 2.1 Laboratory Testing Prior to Initiation and During Treatment with EVOTAZ Renal Testing Renal laboratory testing should be performed in all patients prior to initiation of EVOTAZ and continued during treatment with EVOTAZ. Renal laboratory testing should include estimated creatinine clearance, serum creatinine, and urinalysis with microscopic examination [see Warnings and Precautions (5.5, 5.6) ] . Cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function [see Warnings and Precautions (5.3) ] . When coadministering EVOTAZ with tenofovir disoproxil fumarate (tenofovir DF), assess estimated creatinine clearance, urine glucose, and urine protein at baseline and routinely monitor during treatment. In patients with chronic kidney disease, also monitor serum phosphorus [see Warnings and Precautions (5.4) ] . Hepatic Testing Hepatic laboratory testing should be performed in patients with underlying liver disease prior to initiation of EVOTAZ and continued during treatment with EVOTAZ [see Warnings and Precautions (5.7) ]. 2.2 Recommended Dosage EVOTAZ is a fixed-dose tablet containing 300 mg of atazanavir and 150 mg of cobicistat. The recommended dosage of EVOTAZ is one tablet taken once daily orally with food [see Clinical Pharmacology (12.3) ] in both treatment-naive and treatment-experienced patients with HIV-1: • Adult patients • Pediatric patients weighing at least 35 kg Administer EVOTAZ in conjunction with other antiretroviral agents [see Drug Interactions (7) ] . Dose separation may be required when taken with H 2 -receptor antagonists or proton-pump inhibitors [see Drug Interactions (7.2 , 7.3) ] . 2.3 Dosage in Patients with Renal Impairment EVOTAZ is not recommended in treatment-experienced patients with HIV-1 who have end-stage renal disease managed with hemodialysis [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ] . EVOTAZ coadministered with tenofovir DF is not recommended in patients with estimated creatinine clearance below 70 mL/min. Coadministration of EVOTAZ and tenofovir DF in combination with concomitant or recent use of a nephrotoxic agent is not recommended [see Warnings and Precautions (5.4) and Adverse Reactions (6.1) ] . 2.4 Not Recommended in Patients with Any Degree of Hepatic Impairment EVOTAZ is not recommended in patients with any degree of hepatic impairment [see Warnings and Precautions (5.7) , Use in Specific Populations (8.7) , and Clinical Pharmacology (12.3) ] . 2.5 Not Recommended During Pregnancy EVOTAZ is not recommended for use during pregnancy and should not be initiated in pregnant individuals due to substantially lower exposures of cobicistat and consequently, lower exposures of atazanavir, during the second and third trimesters. An alternative regimen is recommended for individuals who become pregnant during therapy with EVOTAZ [see Use in Specific Populations (8.1) ] .

5 WARNINGS 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 [see Adverse Reactions (6.1) and Overdosage (10) ] . 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 [see Clinical Pharmacology (12.2) ] . 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 [see Contraindications (4) and Adverse Reactions (6.1) ] . EVOTAZ…

4 CONTRAINDICATIONS 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)

7 DRUG INTERACTIONS 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. (4 , 7 , 12.3) 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 [see Contraindications (4) ] . 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) [see Clinical Pharmacology (12.3; Table 7) ] . 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) [see Dosage and Administration (2.2) ] . 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 [see Contraindications (4) , Warnings and Precautions (5.8) , and Clinical Pharmacology (12.3) ] . 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 [see Warnings and Precautions (5.4) ] . HIV Antiretroviral Agents: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) nevirapine ↓ atazanavir ↑ nevirapine …

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to EVOTAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary EVOTAZ is not recommended for use during pregnancy and should not be initiated in pregnant individuals [see Dosage and Administration (2.5) ] ; use of an alternative regimen is recommended for individuals who become pregnant during therapy with EVOTAZ. Pharmacokinetic data from studies conducted in pregnant individuals receiving cobicistat showed substantially lower exposures during the second and third trimesters, and consequently also for the coadministered antiretroviral agent. Consult the full prescribing information for cobicistat for additional information. Pharmacokinetic data from the evaluation of atazanavir and cobicistat in a limited number of pregnant individuals showed a similar trend in lower exposures of the antiretroviral component, atazanavir. Prospective pregnancy data from the APR are not sufficient to adequately assess the risk of birth defects or miscarriage. Atazanavir use during pregnancy has been evaluated in a limited number of individuals. Available data from the APR show no increase in the risk of overall major birth defects for atazanavir compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data) . The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15−20%. In animal reproduction studies, no evidence of adverse developmental outcomes was observed following oral administration of the components of EVOTAZ (atazanavir or cobicistat) to pregnant rats and rabbits (see Data) . During organogenesis in the rat and rabbit, atazanavir exposures (AUC) were similar to those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir), while exposures were up to 1.4 (rats) and 3.3 (rabbits) times human exposures at the maximal recommended human dose (MRHD) of 150 mg (see Data) . Clinical Considerations EVOTAZ is not recommended for use during pregnancy and should not be initiated in pregnant individuals. An alternative regimen is recommended for individuals who become pregnant during therapy with EVOTAZ (see Risk Summary) . Maternal Adverse Reactions Atazanavir Reports of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant individuals using atazanavir in combination with nucleoside analogues, which are associated with an increased risk of lactic acidosis syndrome. Hyperbilirubinemia occurs frequently in patients who take atazanavir, including pregnant individuals. Refer to the atazanavir prescribing information for use of atazanavir in pregnancy. Fetal/Neonatal Adverse Reactions Atazanavir Infants exposed to atazanavir in utero may develop severe hyperbilirubinemia during the first few days of life. Data Human Data Atazanavir The APR has received prospective reports of live births following exposure to atazanavir-containing regimens during pregnancy, including 1361 exposures in the first trimester and 737 exposures in second/third trimester. Birth defects occurred in live births in 30 of 1361 (2.2%, 95% CI: 1.5% to 3.1%) with first trimester exposure to atazanavir-containing regimens and 17 of 737 (2.3%, 95% CI: 1.3% to 3.7%) with second/third trimester exposure to atazanavir-containing regimens. There was no increase in the overall rate of birth defects for atazanavir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. Cobicistat The APR has received prospective reports of live births following exposure to cobicistat-containing regimens during pregnancy, …

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • cardiac conduction abnormalities [see Warnings and Precautions (5.1) ] • rash [see Warnings and Precautions (5.2) ] • effects on serum creatinine [see Warnings and Precautions (5.3) ] • new onset or worsening renal impairment when used with tenofovir DF [see Warnings and Precautions (5.4) ] • chronic kidney disease [see Warnings and Precautions (5.5) ] • nephrolithiasis and cholelithiasis [see Warnings and Precautions (5.6) ] • hepatotoxicity [see Warnings and Precautions (5.7) ] • hyperbilirubinemia [see Warnings and Precautions (5.10) ] For additional safety information about atazanavir and cobicistat, consult the full prescribing information for these individual products. Most common adverse reactions seen with atazanavir coadministered with cobicistat (greater than 5%, Grades 2-4) are jaundice and rash. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions from Clinical Trial Experience in Adult Participants The safety of atazanavir and cobicistat coadministered as single agents is based on Week 144 data from a Phase 3 trial, Study GS-US-216-0114, in which 692 antiretroviral treatment-naive participants with HIV-1 received: • atazanavir coadministered with cobicistat and emtricitabine/tenofovir DF (N=344) or • atazanavir coadministered with ritonavir and emtricitabine/tenofovir DF (N=348). The most common adverse reactions (Grades 2-4) and reported in ≥5% of participants in the atazanavir coadministered with cobicistat group were jaundice (6%) and rash (5%). The proportion of participants who discontinued study treatment due to adverse events regardless of severity, was 11% in both the atazanavir coadministered with cobicistat and atazanavir coadministered with ritonavir groups. Table 2 lists the frequency of adverse reactions (Grades 2-4) occurring in at least 2% of participants in the atazanavir coadministered with cobicistat group in Study GS-US-216-0114. Table 2: Selected Adverse Reactions a (Grades 2-4) Reported in ≥2% of Treatment-Naive Adults with HIV-1 in the Atazanavir Coadministered with Cobicistat Group in Study GS-US-216-0114 (Week 144 analysis) Atazanavir coadministered with cobicistat and emtricitabine/tenofovir DF (n=344) Atazanavir coadministered with ritonavir and emtricitabine/tenofovir DF (n=348) Jaundice 6% 3% Rash b 5% 4% Ocular icterus 4% 2% Nausea 2% 2% Diarrhea 2% 1% Headache 2% 1% a Frequencies of adverse reactions are based on Grades 2-4 adverse events attributed to study drugs. b Rash events include dermatitis allergic, drug hypersensitivity, pruritus generalized, eosinophilic pustular folliculitis, rash, rash generalized, rash macular, rash maculopapular, rash morbilliform, rash papular, and urticaria. Less Common Adverse Reactions Selected adverse reactions of at least moderate severity (≥ Grade 2) occurring in less than 2% of participants receiving atazanavir coadministered with cobicistat and emtricitabine/tenofovir DF are listed below. These events have been included because of investigator’s assessment of potential causal relationship and were considered serious or have been reported in more than one participant treated with atazanavir coadministered with cobicistat and reported with greater frequency compared with the atazanavir coadministered with ritonavir group. Gastrointestinal Disorders: vomiting, upper abdominal pain General Disorders and Administration Site Conditions: fatigue Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis Psychiatric Disorders: depressio…