EVOTAZ

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 Subjects 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 subjects with HIV-1 infection 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 subjects in the atazanavir coadministered with cobicistat group were jaundice (6%) and rash (5%). The proportion of subjects 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 subjects 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 Infection 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 subjects 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 subject 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: depression, abnormal dreams, insomnia Renal and Urinary Disorders: nephropathy, Fanconi syndrome acquired, nephrolithiasis Laboratory Abnormalities The frequency of laboratory abnormalities (Grades 3-4) occurring in at least 2% of subjects in the atazanavir coadministered with cobicistat group in Study GS-US-216-0114 is presented in Table 3. Table 3: Laboratory Abnormalities (Grades 3-4) Reported in ≥2% of HIV-1-Infected Treatment-Naive Adults in the Atazanavir Coadministered with Cobicistat Group in Study GS-US-216-0114 (Week 144 analysis) 144 weeks Atazanavir coadministered with cobicistat and emtricitabine/tenofovir DF 144 weeks Atazanavir coadministered with ritonavir and emtricitabine/tenofovir DF Laboratory Parameter Abnormality (n=344) (n=348) a For subjects with serum amylase >1.5 × upper limit of normal, lipase test was also performed. The frequency of increased lipase (Grades 3-4) occurring in the atazanavir coadministered with cobicistat group (N=46) and atazanavir coadministered with ritonavir group (N=35) was 7% and 3%, respectively. Total Bilirubin (>2.5 × ULN) 73% 66% Creatine Kinase (≥10.0 × ULN) 8% 9% Urine RBC (Hematuria) (>75 RBC/HPF) 6% 3% ALT (>5.0 × ULN) 6% 3% AST (>5.0 × ULN) 4% 3% GGT (>5.0 × ULN) 4% 2% Serum Amylase a (>2.0 × ULN) 4% 2% Urine Glucose (Glycosuria ≥1000 mg/dL) 3% 3% Neutrophils (<750/mm 3 ) 3% 2% Serum Glucose (Hyperglycemia) (≥250 mg/dL) 2% 2% Increase in Serum Creatinine: Cobicistat, a component of EVOTAZ, has been shown to increase serum creatinine and decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.2) ] . In Study GS-US-216-0114, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment in the atazanavir coadministered with cobicistat group, after which they stabilized. The mean (± SD) change in estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method after 144 weeks of treatment was −15.1 ± 16.5 mL/min in the atazanavir coadministered with cobicistat group and −8.0 ± 16.8 mL/min in the atazanavir coadministered with ritonavir group. Serum Lipids Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 4. In both groups, mean values for serum lipids remained within the normal range for each laboratory test. The clinical significance of these changes is unknown. Table 4: Lipid Values, Mean Change from Baseline, Reported in Treatment-Naive Adults with HIV-1 Infection Receiving Atazanavir Coadministered with Cobicistat and Emtricitabine/Tenofovir DF or Atazanavir Coadministered with Ritonavir and Emtricitabine/Tenofovir DF in Study GS-US-216-0114 (Week 144 analysis) Atazanavir coadministered with cobicistat and emtricitabine/tenofovir DF Atazanavir coadministered with ritonavir and emtricitabine/tenofovir DF Baseline mg/dL Week 144 change from baseline a Baseline mg/dL Week 144 change from baseline a Total Cholesterol (fasted) 163 [N=219] +11 [N=219] 165 [N=227] +13 [N=227] HDL-cholesterol (fasted) 43 [N=218] +7 [N=218] 43 [N=228] +6 [N=228] LDL-cholesterol (fasted) 102 [N=218] +11 [N=218] 104 [N=228] +16 [N=228] Triglycerides (fasted) 130 [N=219] +14 [N=219] 131 [N=227] +14 [N=227] a The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 144 values and excludes subjects receiving an HMG-CoA reductase inhibitor drug. Adverse Reactions from Clinical Trial Experience in Pediatric Subjects Although no clinical trial with EVOTAZ as the fixed-dose tablet was conducted in a pediatric population, the safety of atazanavir coadministered with cobicistat plus two nucleoside reverse transcriptase inhibitors was evaluated in treatment-experienced virologically suppressed subjects with HIV-1 infection between the ages of 12 to less than 18 years (N=14) through Week 48 in an open-label clinical trial (Study GS-US-216-0128) [see Clinical Studies (14.2) ] . Results from this study showed that the safety profile of atazanavir and cobicistat coadministered with a background regimen was similar to that in adults. 6.2 Postmarketing Experience See the full prescribing information for atazanavir for postmarketing information on atazanavir.

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 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). • when coadministered with drugs that strongly induce CYP3A and may lead to lower exposure and loss of efficacy of EVOTAZ (see Table 1). • 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) ] . 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 irinotecan Antipsychotics lurasidone, pimozide Ergot Derivatives dihydroergotamine, ergotamine, methylergonovine GI Motility Agent cisapride 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) • Coadministration with certain drugs for which altered plasma concentrations are associated with serious and/or life-threatening events or loss of therapeutic effect. (4)

11 DESCRIPTION EVOTAZ ® is a fixed-dose tablet for oral administration containing the active ingredients atazanavir and cobicistat. Atazanavir is an HIV-1 protease inhibitor. Cobicistat is a mechanism-based inhibitor of cytochrome P450 (CYP) enzymes of the CYP3A family. EVOTAZ tablets contain 342 mg of atazanavir sulfate, equivalent to 300 mg of atazanavir, and 150 mg of cobicistat, as well as the following inactive ingredients in the tablet core: croscarmellose sodium, crospovidone, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, silicon dioxide, sodium starch glycolate, and stearic acid. The tablets are film-coated with a coating material containing the following inactive ingredients: hypromellose, red iron oxide, talc, titanium dioxide, triacetin. Atazanavir: Atazanavir is present as the sulfate salt. The chemical name for atazanavir sulfate is (3 S ,8 S ,9 S ,12 S )-3,12-bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1). Its molecular formula is C 38 H 52 N 6 O 7 •H 2 SO 4 , which corresponds to a molecular weight of 802.9 (sulfuric acid salt). The free base molecular weight is 704.9. Atazanavir sulfate has the following structural formula: Atazanavir sulfate is a white to pale-yellow crystalline powder. It is slightly soluble in water (4-5 mg/mL, free base equivalent) with the pH of a saturated solution in water being about 1.9 at 24 ± 3°C. Cobicistat: The chemical name for cobicistat is 1,3-thiazol-5-ylmethyl [(2 R ,5 R )-5-{[(2 S )-2-[(methyl{[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl)amino]-4-(morpholin-4-yl)butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate. It has a molecular formula of C 40 H 53 N 7 O 5 S 2 and a molecular weight of 776.0. It has the following structural formula: Cobicistat is adsorbed onto silicon dioxide. Cobicistat on silicon dioxide is a white to pale yellow solid with a solubility of 0.1 mg/mL in water at 20°C. atazanavir chemical structure cobicistat chemical structure

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 HIV-1-infected treatment-naïve and treatment-experienced: • 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 infection 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) ] .

10 OVERDOSAGE Treatment for overdosage with EVOTAZ should consist of general supportive measures, including monitoring of vital signs and ECG, and observations of the patient’s clinical status. There is no specific antidote for overdose with EVOTAZ. Since atazanavir is extensively metabolized by the liver and both atazanavir and cobicistat are highly bound plasma proteins, it is unlikely that EVOTAZ will be significantly removed by hemodialysis or peritoneal dialysis. Atazanavir: Human experience of acute overdose with atazanavir is limited. A single self-administered overdose of 29.2 g of atazanavir in a patient with HIV-1 infection (73 times the 400-mg recommended dose of atazanavir administered without a CYP3A inhibitor) was associated with asymptomatic bifascicular block and PR interval prolongation. These events resolved spontaneously. At atazanavir doses resulting in high atazanavir exposures, jaundice due to indirect (unconjugated) hyperbilirubinemia (without associated liver function test changes) or PR interval prolongation may be observed [see Warnings and Precautions (5.1 , 5.10) and Clinical Pharmacology (12.2) ] .

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 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 [see Contraindications (4) ] . 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 [see Contraindications (4) ] . 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 [see Warnings and Precautions (5.9) ] . 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 [see Contraindications (4) ] . 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 [see Contraindications (4) ] . Antiarrhythmics: dronedarone ↑ dronedarone Coadministration of EVOTAZ with dronedarone is contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) ] . 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 [see Contraindications (4) ] . (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 [see Contraindications (4) ] . 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 [see Contraindications (4) ] . 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 [see Contraindications (4) ] . Antiplatelets: ticagrelor ↑ lurasidone 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 [see Contraindications (4) ] . pimozide ↑ pimozide Coadministration with pimozide is contraindicated due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) ] . 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. 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. 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 [see Contraindications (4) ] . GI Motility Agents : cisapride ↑ cisapride Coadministration of EVOTAZ with cisapride is contraindicated due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) ] . Hepatitis C Direct-Acting Antivirals : elbasvir/grazoprevir ↑ grazoprevir Coadministration of EVOTAZ with elbasvir/grazoprevir is contraindicated due to increased risk of ALT elevations [see Contraindications (4) ] . glecaprevir/pibrentasvir ↑ glecaprevir ↑ pibrentasvir Coadministration of EVOTAZ with glecaprevir/ pibrentasvir is contraindicated due to increased risk of ALT elevations [see Contraindications (4 )] . 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 [see Contraindications (4) ] . 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 [see Contraindications (4) ] . 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 [see Contraindications (4) ] . 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 [see Contraindications (4) ]. (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) [see Contraindications (4) ] . 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 [see Contraindications (4) ] . 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 [see Clinical Pharmacology (12.3; Table 7) ].

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action EVOTAZ is a fixed-dose tablet consisting of the HIV-1 antiretroviral drug, atazanavir and the CYP3A inhibitor, cobicistat [see Clinical Pharmacology (12.4) ] . 12.2 Pharmacodynamics Cardiac Electrophysiology Atazanavir: In a thorough QT/QTc study in 72 healthy subjects (Study AI424-076), atazanavir 400 mg and 800 mg (C max was 1.2 times and 2.4 times the C max observed with the recommended dosage of EVOTAZ, respectively) without a CYP3A inhibitor did not prolong the QTc interval to any clinically relevant extent. Asymptomatic prolongation of the PR interval was noted in subjects receiving atazanavir. The mean (±SD) maximum change in PR interval from the predose for atazanavir 400 mg (n=65), atazanavir 800 mg (n=66), and placebo (n=67) was 24 (±15) msec, 60 (±25) msec, and 13 (±11) msec, respectively. Steady state atazanavir exposures (C max and AUC tau ) observed in this healthy subject study exceeded those observed in subjects treated with atazanavir coadministered with cobicistat. There is limited information on the potential for a pharmacodynamic interaction in humans between atazanavir and other drugs that prolong the PR interval of the electrocardiogram [see Warnings and Precautions (5.1) ] . In 1793 subjects with HIV-1 infection receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir-containing and comparator regimens. No atazanavir-treated healthy subject or subject with HIV-1 infection in clinical trials had a QTc interval >500 msec [see Warnings and Precautions (5.1) ] . Cobicistat: In a thorough QT/QTc study conducted in 48 healthy subjects (Study GS-US-216-0107), cobicistat 250 mg (1.7 times the recommended dosage in EVOTAZ) and 400 mg (2.7 times the recommended dosage in EVOTAZ) did not prolong the QTc interval to any clinically relevant extent. Asymptomatic prolongation of the PR interval was noted in subjects receiving cobicistat. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline correction was 9.5 (12.1) msec for 250 mg and 20.2 (22.8) msec for 400 mg dose of cobicistat . Effects on Serum Creatinine The effect of cobicistat on serum creatinine was investigated in Study GS-US-216-0121, conducted in subjects with normal renal function (eGFR ≥80 mL/min, N=12) and mild-to-moderate renal impairment (eGFR 50-79 mL/min, N=18). A statistically significant change in estimated glomerular filtration rate, calculated by Cockcroft-Gault method (eGFR CG ) from baseline, was observed after 7 days of treatment with cobicistat 150 mg among subjects with normal renal function (−9.9 ± 13.1 mL/min) and mild-to-moderate renal impairment (−11.9 ± 7.0 mL/min). No statistically significant changes in eGFR CG were observed compared to baseline for subjects with normal renal function or mild-to-moderate renal impairment 7 days after cobicistat was discontinued. The actual glomerular filtration rate, as determined by the clearance of probe drug iohexol, was not altered from baseline following treatment with cobicistat among subjects with normal renal function and mild-to-moderate renal impairment, indicating that cobicistat inhibits tubular secretion of creatinine, reflected as a reduction in eGFR CG , without affecting the actual glomerular filtration rate [see Warnings and Precautions (5.3) ] . 12.3 Pharmacokinetics Absorption, Distribution, Metabolism, and Excretion The pharmacokinetic (PK) properties of the components of EVOTAZ (atazanavir 300 mg and cobicistat 150 mg) were evaluated in healthy adult subjects (Study AI424-511). Results are summarized in Table 6. Table 6: Pharmacokinetic Properties of the Components of EVOTAZ Atazanavir Cobicistat a Following EVOTAZ dosing under fasted conditions. b Values refer to geometric mean ratio (fed / fasted) and (90% confidence interval). c Dosing in mass balance study: cobicistat (single dose administration of [14C] cobicistat after multiple dosing of cobicistat for six days). ND = not determined. Absorption T max (h) 2.0 2.0 Effect of light meal (relative to fasting) AUC ratio b 1.28 (1.17,1.40) 1.24 (1.15,1.34) Effect of high fat meal (relative to fasting) AUC ratio b 0.96 (0.81,1.13) 1.12 (1.01,1.23) Effect of light meal (relative to fasting) C24 ratio b 1.35 (1.22,1.50) ND Effect of high fat meal (relative to fasting) C24 ratio b 1.23 (1.02,1.48) ND Distribution % Bound to human plasma proteins 86 ~98 Source of protein binding data In vitro In vitro Blood-to-plasma ratio ND 0.5 Metabolism Metabolism CYP3A (major) Glucuronidation, N-dealkylation, hydrolysis, oxygenation with dehydrogenation (minor) CYP3A (major) CYP2D6 (minor) Elimination Major route of elimination Metabolism Metabolism t 1/2 (h) 7.2 a 3.5 % Of dose excreted in urine ND 8.2 c % Of dose excreted in feces ND 86.2 c The pharmacokinetics of atazanavir was evaluated in subjects with HIV-1 infection who received atazanavir 300 mg coadministered with cobicistat 150 mg in combination with emtricitabine/tenofovir DF. The steady-state pharmacokinetic parameters of atazanavir coadministered with cobicistat are shown in Table 7 [see Clinical Studies (14) ] . Table 7: Pharmacokinetic Parameters (Mean ± SD) of Atazanavir in the Pharmacokinetic Substudy of Study GS-US-216-0114 Parameter Atazanavir coadministered with cobicistat and emtricitabine/tenofovir DF (n=22) AUC (µg•h/mL) 46.13 ± 26.18 C max (µg/mL) 3.91 ± 1.94 C tau (µg/mL) 0.80 ± 0.72 Specific Populations Pediatric In pediatric subjects aged 12 to less than 18 years who received atazanavir 300 mg coadministered with cobicistat 150 mg (N=12), atazanavir exposures (AUC tau , C max , and C tau ) were 20-60% higher than in adults; the increases were not considered clinically significant (Table 8). Table 8: Multiple Dose Pharmacokinetic Parameters of Atazanavir Following Coadministration of Atazanavir with Cobicistat in Pediatric Subjects with HIV-1 Infection Weighing at Least 35 kg Atazanavir PK Parameter Geometric Mean (CV%) Pediatric subjects (N=12) a Adult subjects (N=30) b CV=Coefficient of Variation a From intensive PK analysis of Study GS-US-216-0128 b From pooled intensive PK analysis of trials with atazanavir + cobicistat. AUC tau (µg/hr/mL) 49.48 (49.1) 39.96 (52.1) C max (µg/mL) 4.32 (49.9) 3.54 (45.8) C tau (µg/mL) 0.91 (96.4) 0.58 (84.7) Renal Impairment Atazanavir: In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. In study AI424-105, atazanavir was studied in adult subjects (n=20) with severe renal impairment (estimated creatinine clearance <30 mL/min, using 24 hour urinary creatinine and serum creatinine levels), including those on hemodialysis, at multiple doses of 400 mg once daily. The mean atazanavir C max was 9% lower, AUC was 19% higher, and C min was 96% higher in subjects with severe renal impairment not undergoing hemodialysis (n=10), than in age-, weight-, and gender-matched subjects with normal renal function. In a 4-hour dialysis session, 2.1% of the administered dose was removed. When atazanavir was administered either prior to, or following hemodialysis (n=10), the geometric means for C max , AUC, and C min were approximately 25% to 43% lower compared to subjects with normal renal function. The mechanism of this decrease is unknown. Cobicistat: No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with severe renal impairment (estimated creatinine clearance <30 mL/min, using the Cockcroft-Gault method) and healthy subjects in Study GS-US-216-0124 [see Use in Specific Populations (8.6) ] . Hepatic Impairment EVOTAZ has not been studied in patients with hepatic impairment. Atazanavir: Increased concentrations of atazanavir are expected in those with moderately or severely impaired hepatic function (Study AI424-015). Cobicistat: No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects (Study GS-US-183-0133). The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of cobicistat has not been studied [see Use in Specific Populations (8.7) ] . Pregnancy and Postpartum 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. Gender, Age, and Race Atazanavir: No clinically important differences in atazanavir pharmacokinetics were observed based on age or gender. Cobicistat: No clinically relevant differences in cobicistat pharmacokinetics were observed based on race or gender. Assessment of Drug Interactions Atazanavir has been shown in vivo not to induce its own metabolism, nor to increase the biotransformation of some drugs metabolized by CYP3A. In a multiple-dose study, atazanavir decreased the urinary ratio of endogenous 6β-OH cortisol to cortisol versus baseline, indicating that CYP3A production was not induced. The effects of cobicistat on the exposure of coadministered drugs are summarized in Table 9. Table 9: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Cobicistat a,b Note: The information listed below is not a comprehensive list of all the available drug interaction data for concomitant medications with cobicistat-containing regimens. Please refer to the U.S. prescribing information for antiretroviral medications administered in combination with cobicistat for additional drug interaction information. Coadministered Drug Coadministered Drug Dose/Schedule Cobicistat Dose/Schedule Ratio (90% Confidence Interval) of Coadministered Drug Pharmacokinetic Parameters with/without cobicistat; No effect = 1.00 C max AUC a All interaction studies conducted in healthy subjects. b Studies of cobicistat conducted in the presence of atazanavir 300 mg. atorvastatin 10 mg single dose (n=16) 150 mg QD (n=16) 18.85 b (13.53, 26.27) 9.22 b (7.58, 11.22) desipramine 50 mg single dose (n=8) 150 mg QD (n=8) 1.24 (1.08, 1.44) 1.65 (1.36, 2.02) digoxin 0.5 mg single dose (n=22) 150 mg QD (n=22) 1.41 (1.29, 1.55) 1.08 (1.00, 1.17) drospirenone/ ethinyl estradiol 3 mg drospirenone single dose (n=14) 150 mg QD (n=14) 1.12 b (1.05, 1.19) 2.30 b (2.00, 2.64) 0.02 ethinyl estradiol single dose (n=14) 150 mg QD (n=14) 0.82 b (0.76, 0.89) 0.78 b (0.73, 0.85) efavirenz 600 mg single dose (n=17) 150 mg QD (n=17) 0.87 (0.80, 0.94) 0.93 (0.89, 0.97) rosuvastatin 10 mg single dose (n=16) 150 mg QD (n=16) 10.58 b (8.72, 12.83) 3.42 b (2.87, 4.07) 12.4 Microbiology Mechanism of Action EVOTAZ is a fixed-dose tablet of atazanavir and the CYP3A inhibitor cobicistat. Atazanavir is an azapeptide HIV-1 protease inhibitor that selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1-infected cells, thus preventing formation of mature virions. Cobicistat is a mechanism-based inhibitor of cytochrome P450 3A (CYP3A). Inhibition of CYP3A-mediated metabolism by cobicistat increases the systemic exposure of the CYP3A substrate atazanavir. Antiviral Activity in Cell Culture Atazanavir exhibits anti−HIV-1 activity with a mean 50% effective concentration (EC 50 value) in the absence of human serum of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT‑2 cells. Atazanavir has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. Atazanavir has variable activity against HIV-2 isolates (1.9-32 nM), with EC 50 values above the EC 50 values of failure isolates. Two-drug combination antiviral activity studies with atazanavir showed no antagonism in cell culture with NNRTIs (delavirdine, efavirenz, and nevirapine), protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine), the HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity. Cobicistat does not inhibit recombinant HIV-1 protease in a biochemical assay and has no detectable antiviral activity in cell culture against HIV-1, hepatitis B or C virus. The antiviral activity in cell culture of selected HIV-1 antiretroviral drugs was not antagonized by cobicistat. Resistance In Cell Culture: HIV-1 isolates with a decreased susceptibility to atazanavir have been selected in cell culture and obtained from patients treated with atazanavir coadministered with ritonavir. HIV-1 isolates with 93- to 183-fold reduced susceptibility to atazanavir from three different viral strains were selected in cell culture by 5 months. The substitutions in these HIV-1 viruses that contributed to atazanavir resistance include I50L, N88S, I84V, A71V, and M46I. Changes were also observed at the protease cleavage sites following drug selection. Recombinant viruses containing the I50L substitution without other major protease inhibitor substitutions were growth impaired and displayed increased susceptibility in cell culture to other protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The I50L and I50V substitutions yielded selective resistance to atazanavir and amprenavir, respectively, and did not appear to be cross-resistant. Clinical Studies: Resistance to EVOTAZ is driven by atazanavir as cobicistat lacks antiviral activity. For the complete atazanavir resistance-associated substitutions, refer to the atazanavir full prescribing information. Clinical Studies of Treatment-Naive Adult Subjects Receiving Atazanavir 300 mg Coadministered with Cobicistat 150 mg: In an analysis of adult subjects who received atazanavir coadministered with cobicistat through Week 144 (Study GS-US-216-0114), evaluable genotypic data from paired baseline and treatment-failure isolates from subjects who had HIV-1 RNA greater than or equal to 400 copies/mL were available for all 21 virologic failures in this group (6%, 21/344). Among the 21 subjects, 3 developed the emtricitabine resistance-associated substitution M184V. No subject developed the tenofovir resistance-associated substitution K65R or K70E, or any primary resistance substitution associated with protease inhibitors. In the ritonavir group, evaluable genotypic data were available for all 19 virologic failures (5%, 19/348). Among the 19 subjects, 1 developed the emtricitabine resistance-associated substitution M184V with no tenofovir or protease inhibitor resistance-associated substitutions. Clinical Study of Pediatric Subjects Receiving Atazanavir Coadministered with Cobicistat: In an as-treated analysis of pediatric subjects between the ages of 12 to less than 18 years who received atazanavir coadministered with cobicistat plus two NRTIs in Study GS-US-216-0128, 3 of 14 subjects qualified for resistance analysis through Week 48; 1 had evaluable data and no significant resistance-associated substitutions in protease or reverse transcriptase [see Clinical Studies (14.2) ] . Cross-Resistance Cross-resistance among protease inhibitors has been observed. Baseline phenotypic and genotypic analyses of clinical isolates from atazanavir clinical trials of protease inhibitor-experienced subjects with HIV-1 infection showed that isolates cross-resistant to multiple protease inhibitors were cross-resistant to atazanavir. Greater than 90% of the isolates with substitutions that included I84V or G48V were resistant to atazanavir. Greater than 60% of isolates containing L90M, G73S/T/C, A71V/T, I54V, M46I/L, or a change at V82 were resistant to atazanavir, and 38% of isolates containing a D30N substitution in addition to other changes were resistant to atazanavir. Isolates resistant to atazanavir were also cross-resistant to other protease inhibitors with >90% of the isolates resistant to indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, and 80% resistant to amprenavir. In treatment-experienced patients, protease inhibitor-resistant viral isolates that developed the I50L substitution in addition to other protease inhibitor resistance-associated substitution were also cross-resistant to other protease inhibitors. International AIDS Society (IAS)-defined protease inhibitor resistance substitutions, depending on the number and type, may confer a reduced virologic response to atazanavir. Please refer to the “Baseline Genotype/Phenotype and Virologic Outcome Analyses” section in the atazanavir full prescribing information.

12.1 Mechanism of Action EVOTAZ is a fixed-dose tablet consisting of the HIV-1 antiretroviral drug, atazanavir and the CYP3A inhibitor, cobicistat [see Clinical Pharmacology (12.4) ] .

12.2 Pharmacodynamics Cardiac Electrophysiology Atazanavir: In a thorough QT/QTc study in 72 healthy subjects (Study AI424-076), atazanavir 400 mg and 800 mg (C max was 1.2 times and 2.4 times the C max observed with the recommended dosage of EVOTAZ, respectively) without a CYP3A inhibitor did not prolong the QTc interval to any clinically relevant extent. Asymptomatic prolongation of the PR interval was noted in subjects receiving atazanavir. The mean (±SD) maximum change in PR interval from the predose for atazanavir 400 mg (n=65), atazanavir 800 mg (n=66), and placebo (n=67) was 24 (±15) msec, 60 (±25) msec, and 13 (±11) msec, respectively. Steady state atazanavir exposures (C max and AUC tau ) observed in this healthy subject study exceeded those observed in subjects treated with atazanavir coadministered with cobicistat. There is limited information on the potential for a pharmacodynamic interaction in humans between atazanavir and other drugs that prolong the PR interval of the electrocardiogram [see Warnings and Precautions (5.1) ] . In 1793 subjects with HIV-1 infection receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir-containing and comparator regimens. No atazanavir-treated healthy subject or subject with HIV-1 infection in clinical trials had a QTc interval >500 msec [see Warnings and Precautions (5.1) ] . Cobicistat: In a thorough QT/QTc study conducted in 48 healthy subjects (Study GS-US-216-0107), cobicistat 250 mg (1.7 times the recommended dosage in EVOTAZ) and 400 mg (2.7 times the recommended dosage in EVOTAZ) did not prolong the QTc interval to any clinically relevant extent. Asymptomatic prolongation of the PR interval was noted in subjects receiving cobicistat. The maximum mean (95% upper confidence bound) difference in PR from placebo after baseline correction was 9.5 (12.1) msec for 250 mg and 20.2 (22.8) msec for 400 mg dose of cobicistat . Effects on Serum Creatinine The effect of cobicistat on serum creatinine was investigated in Study GS-US-216-0121, conducted in subjects with normal renal function (eGFR ≥80 mL/min, N=12) and mild-to-moderate renal impairment (eGFR 50-79 mL/min, N=18). A statistically significant change in estimated glomerular filtration rate, calculated by Cockcroft-Gault method (eGFR CG ) from baseline, was observed after 7 days of treatment with cobicistat 150 mg among subjects with normal renal function (−9.9 ± 13.1 mL/min) and mild-to-moderate renal impairment (−11.9 ± 7.0 mL/min). No statistically significant changes in eGFR CG were observed compared to baseline for subjects with normal renal function or mild-to-moderate renal impairment 7 days after cobicistat was discontinued. The actual glomerular filtration rate, as determined by the clearance of probe drug iohexol, was not altered from baseline following treatment with cobicistat among subjects with normal renal function and mild-to-moderate renal impairment, indicating that cobicistat inhibits tubular secretion of creatinine, reflected as a reduction in eGFR CG , without affecting the actual glomerular filtration rate [see Warnings and Precautions (5.3) ] .

12.3 Pharmacokinetics Absorption, Distribution, Metabolism, and Excretion The pharmacokinetic (PK) properties of the components of EVOTAZ (atazanavir 300 mg and cobicistat 150 mg) were evaluated in healthy adult subjects (Study AI424-511). Results are summarized in Table 6. Table 6: Pharmacokinetic Properties of the Components of EVOTAZ Atazanavir Cobicistat a Following EVOTAZ dosing under fasted conditions. b Values refer to geometric mean ratio (fed / fasted) and (90% confidence interval). c Dosing in mass balance study: cobicistat (single dose administration of [14C] cobicistat after multiple dosing of cobicistat for six days). ND = not determined. Absorption T max (h) 2.0 2.0 Effect of light meal (relative to fasting) AUC ratio b 1.28 (1.17,1.40) 1.24 (1.15,1.34) Effect of high fat meal (relative to fasting) AUC ratio b 0.96 (0.81,1.13) 1.12 (1.01,1.23) Effect of light meal (relative to fasting) C24 ratio b 1.35 (1.22,1.50) ND Effect of high fat meal (relative to fasting) C24 ratio b 1.23 (1.02,1.48) ND Distribution % Bound to human plasma proteins 86 ~98 Source of protein binding data In vitro In vitro Blood-to-plasma ratio ND 0.5 Metabolism Metabolism CYP3A (major) Glucuronidation, N-dealkylation, hydrolysis, oxygenation with dehydrogenation (minor) CYP3A (major) CYP2D6 (minor) Elimination Major route of elimination Metabolism Metabolism t 1/2 (h) 7.2 a 3.5 % Of dose excreted in urine ND 8.2 c % Of dose excreted in feces ND 86.2 c The pharmacokinetics of atazanavir was evaluated in subjects with HIV-1 infection who received atazanavir 300 mg coadministered with cobicistat 150 mg in combination with emtricitabine/tenofovir DF. The steady-state pharmacokinetic parameters of atazanavir coadministered with cobicistat are shown in Table 7 [see Clinical Studies (14) ] . Table 7: Pharmacokinetic Parameters (Mean ± SD) of Atazanavir in the Pharmacokinetic Substudy of Study GS-US-216-0114 Parameter Atazanavir coadministered with cobicistat and emtricitabine/tenofovir DF (n=22) AUC (µg•h/mL) 46.13 ± 26.18 C max (µg/mL) 3.91 ± 1.94 C tau (µg/mL) 0.80 ± 0.72 Specific Populations Pediatric In pediatric subjects aged 12 to less than 18 years who received atazanavir 300 mg coadministered with cobicistat 150 mg (N=12), atazanavir exposures (AUC tau , C max , and C tau ) were 20-60% higher than in adults; the increases were not considered clinically significant (Table 8). Table 8: Multiple Dose Pharmacokinetic Parameters of Atazanavir Following Coadministration of Atazanavir with Cobicistat in Pediatric Subjects with HIV-1 Infection Weighing at Least 35 kg Atazanavir PK Parameter Geometric Mean (CV%) Pediatric subjects (N=12) a Adult subjects (N=30) b CV=Coefficient of Variation a From intensive PK analysis of Study GS-US-216-0128 b From pooled intensive PK analysis of trials with atazanavir + cobicistat. AUC tau (µg/hr/mL) 49.48 (49.1) 39.96 (52.1) C max (µg/mL) 4.32 (49.9) 3.54 (45.8) C tau (µg/mL) 0.91 (96.4) 0.58 (84.7) Renal Impairment Atazanavir: In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. In study AI424-105, atazanavir was studied in adult subjects (n=20) with severe renal impairment (estimated creatinine clearance <30 mL/min, using 24 hour urinary creatinine and serum creatinine levels), including those on hemodialysis, at multiple doses of 400 mg once daily. The mean atazanavir C max was 9% lower, AUC was 19% higher, and C min was 96% higher in subjects with severe renal impairment not undergoing hemodialysis (n=10), than in age-, weight-, and gender-matched subjects with normal renal function. In a 4-hour dialysis session, 2.1% of the administered dose was removed. When atazanavir was administered either prior to, or following hemodialysis (n=10), the geometric means for C max , AUC, and C min were approximately 25% to 43% lower compared to subjects with normal renal function. The mechanism of this decrease is unknown. Cobicistat: No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with severe renal impairment (estimated creatinine clearance <30 mL/min, using the Cockcroft-Gault method) and healthy subjects in Study GS-US-216-0124 [see Use in Specific Populations (8.6) ] . Hepatic Impairment EVOTAZ has not been studied in patients with hepatic impairment. Atazanavir: Increased concentrations of atazanavir are expected in those with moderately or severely impaired hepatic function (Study AI424-015). Cobicistat: No clinically relevant differences in cobicistat pharmacokinetics were observed between subjects with moderate hepatic impairment (Child-Pugh Class B) and healthy subjects (Study GS-US-183-0133). The effect of severe hepatic impairment (Child-Pugh Class C) on the pharmacokinetics of cobicistat has not been studied [see Use in Specific Populations (8.7) ] . Pregnancy and Postpartum 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. Gender, Age, and Race Atazanavir: No clinically important differences in atazanavir pharmacokinetics were observed based on age or gender. Cobicistat: No clinically relevant differences in cobicistat pharmacokinetics were observed based on race or gender. Assessment of Drug Interactions Atazanavir has been shown in vivo not to induce its own metabolism, nor to increase the biotransformation of some drugs metabolized by CYP3A. In a multiple-dose study, atazanavir decreased the urinary ratio of endogenous 6β-OH cortisol to cortisol versus baseline, indicating that CYP3A production was not induced. The effects of cobicistat on the exposure of coadministered drugs are summarized in Table 9. Table 9: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Cobicistat a,b Note: The information listed below is not a comprehensive list of all the available drug interaction data for concomitant medications with cobicistat-containing regimens. Please refer to the U.S. prescribing information for antiretroviral medications administered in combination with cobicistat for additional drug interaction information. Coadministered Drug Coadministered Drug Dose/Schedule Cobicistat Dose/Schedule Ratio (90% Confidence Interval) of Coadministered Drug Pharmacokinetic Parameters with/without cobicistat; No effect = 1.00 C max AUC a All interaction studies conducted in healthy subjects. b Studies of cobicistat conducted in the presence of atazanavir 300 mg. atorvastatin 10 mg single dose (n=16) 150 mg QD (n=16) 18.85 b (13.53, 26.27) 9.22 b (7.58, 11.22) desipramine 50 mg single dose (n=8) 150 mg QD (n=8) 1.24 (1.08, 1.44) 1.65 (1.36, 2.02) digoxin 0.5 mg single dose (n=22) 150 mg QD (n=22) 1.41 (1.29, 1.55) 1.08 (1.00, 1.17) drospirenone/ ethinyl estradiol 3 mg drospirenone single dose (n=14) 150 mg QD (n=14) 1.12 b (1.05, 1.19) 2.30 b (2.00, 2.64) 0.02 ethinyl estradiol single dose (n=14) 150 mg QD (n=14) 0.82 b (0.76, 0.89) 0.78 b (0.73, 0.85) efavirenz 600 mg single dose (n=17) 150 mg QD (n=17) 0.87 (0.80, 0.94) 0.93 (0.89, 0.97) rosuvastatin 10 mg single dose (n=16) 150 mg QD (n=16) 10.58 b (8.72, 12.83) 3.42 b (2.87, 4.07)

20230512

15

3 DOSAGE FORMS AND STRENGTHS EVOTAZ tablets contain 342 mg atazanavir sulfate, equivalent to 300 mg of atazanavir, and 150 mg of cobicistat and are oval, biconvex, pink, film-coated, and debossed with “3641” on one side and plain on the other side. • Tablets: 300 mg of atazanavir and 150 mg of cobicistat. (3)

EVOTAZ atazanavir and cobicistat ATAZANAVIR SULFATE ATAZANAVIR COBICISTAT COBICISTAT MICROCRYSTALLINE CELLULOSE CROSCARMELLOSE SODIUM SODIUM STARCH GLYCOLATE TYPE A POTATO STEARIC ACID MAGNESIUM STEARATE HYDROXYPROPYL CELLULOSE (1600000 WAMW) SILICON DIOXIDE CROSPOVIDONE (120 .MU.M) biconvex 3641

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Atazanavir: Long-term carcinogenicity studies in mice and rats were carried out with atazanavir for two years. In the mouse study, drug-related increases in hepatocellular adenomas were found in females at 360 mg/kg/day. The systemic drug exposure (AUC) at the NOAEL in females, (120 mg/kg/day) was 2.8 times and in males (80 mg/kg/day) was 2.9 times higher than those in humans at the clinical dose (300 mg/day atazanavir coadministered with 100 mg/day ritonavir, nonpregnant patients). In the rat study, no drug-related increases in tumor incidence were observed at doses up to 1200 mg/kg/day, for which AUCs were 1.1 (males) or 3.9 (females) times those measured in humans at the clinical dose. Cobicistat: In a long-term carcinogenicity study in mice, no drug-related increases in tumor incidence were observed at doses up to 50 and 100 mg/kg/day (males and females, respectively). Cobicistat exposures at these doses were approximately 7 (male) and 16 (females) times, respectively, the human systemic exposure at the therapeutic daily dose. In a long-term carcinogenicity study of cobicistat in rats, an increased incidence of follicular cell adenomas and/or carcinomas in the thyroid gland was observed at doses of 25 and 50 mg/kg/day in males, and at 30 mg/kg/day in females. The follicular cell findings are considered to be rat-specific, secondary to hepatic microsomal enzyme induction and thyroid hormone imbalance, and are not relevant for humans. At the highest doses tested in the rat carcinogenicity study, systemic exposures were approximately 2 times the human systemic exposure at the therapeutic daily dose. Mutagenesis Atazanavir: Atazanavir tested positive in an in vitro clastogenicity test using primary human lymphocytes, in the absence and presence of metabolic activation. Atazanavir tested negative in the in vitro Ames reverse-mutation assay, in vivo micronucleus and DNA repair tests in rats, and in vivo DNA damage test in rat duodenum (comet assay). Cobicistat: Cobicistat was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays. Impairment of Fertility Atazanavir: At the systemic drug exposure levels (AUC) 0.9 (in male rats) or 2.3 (in female rats) times that of the human clinical dose, (300 mg/day atazanavir coadministered with 100 mg/day ritonavir) significant effects on mating, fertility, or early embryonic development were not observed. Cobicistat: Cobicistat did not affect fertility in male or female rats at daily exposures (AUC) approximately 3-fold higher than human exposures at the recommended 150 mg daily dose. Fertility was normal in the offspring of rats exposed daily from before birth ( in utero ) through sexual maturity at daily exposures (AUC) of approximately similar human exposures at the recommended 150 mg daily dose.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Atazanavir: Long-term carcinogenicity studies in mice and rats were carried out with atazanavir for two years. In the mouse study, drug-related increases in hepatocellular adenomas were found in females at 360 mg/kg/day. The systemic drug exposure (AUC) at the NOAEL in females, (120 mg/kg/day) was 2.8 times and in males (80 mg/kg/day) was 2.9 times higher than those in humans at the clinical dose (300 mg/day atazanavir coadministered with 100 mg/day ritonavir, nonpregnant patients). In the rat study, no drug-related increases in tumor incidence were observed at doses up to 1200 mg/kg/day, for which AUCs were 1.1 (males) or 3.9 (females) times those measured in humans at the clinical dose. Cobicistat: In a long-term carcinogenicity study in mice, no drug-related increases in tumor incidence were observed at doses up to 50 and 100 mg/kg/day (males and females, respectively). Cobicistat exposures at these doses were approximately 7 (male) and 16 (females) times, respectively, the human systemic exposure at the therapeutic daily dose. In a long-term carcinogenicity study of cobicistat in rats, an increased incidence of follicular cell adenomas and/or carcinomas in the thyroid gland was observed at doses of 25 and 50 mg/kg/day in males, and at 30 mg/kg/day in females. The follicular cell findings are considered to be rat-specific, secondary to hepatic microsomal enzyme induction and thyroid hormone imbalance, and are not relevant for humans. At the highest doses tested in the rat carcinogenicity study, systemic exposures were approximately 2 times the human systemic exposure at the therapeutic daily dose. Mutagenesis Atazanavir: Atazanavir tested positive in an in vitro clastogenicity test using primary human lymphocytes, in the absence and presence of metabolic activation. Atazanavir tested negative in the in vitro Ames reverse-mutation assay, in vivo micronucleus and DNA repair tests in rats, and in vivo DNA damage test in rat duodenum (comet assay). Cobicistat: Cobicistat was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or rat micronucleus assays. Impairment of Fertility Atazanavir: At the systemic drug exposure levels (AUC) 0.9 (in male rats) or 2.3 (in female rats) times that of the human clinical dose, (300 mg/day atazanavir coadministered with 100 mg/day ritonavir) significant effects on mating, fertility, or early embryonic development were not observed. Cobicistat: Cobicistat did not affect fertility in male or female rats at daily exposures (AUC) approximately 3-fold higher than human exposures at the recommended 150 mg daily dose. Fertility was normal in the offspring of rats exposed daily from before birth ( in utero ) through sexual maturity at daily exposures (AUC) of approximately similar human exposures at the recommended 150 mg daily dose.

NDA206353

EVOTAZ

atazanavir and cobicistat

0003-3641

HUMAN PRESCRIPTION DRUG

ORAL

12.4 Microbiology Mechanism of Action EVOTAZ is a fixed-dose tablet of atazanavir and the CYP3A inhibitor cobicistat. Atazanavir is an azapeptide HIV-1 protease inhibitor that selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1-infected cells, thus preventing formation of mature virions. Cobicistat is a mechanism-based inhibitor of cytochrome P450 3A (CYP3A). Inhibition of CYP3A-mediated metabolism by cobicistat increases the systemic exposure of the CYP3A substrate atazanavir. Antiviral Activity in Cell Culture Atazanavir exhibits anti−HIV-1 activity with a mean 50% effective concentration (EC 50 value) in the absence of human serum of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT‑2 cells. Atazanavir has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. Atazanavir has variable activity against HIV-2 isolates (1.9-32 nM), with EC 50 values above the EC 50 values of failure isolates. Two-drug combination antiviral activity studies with atazanavir showed no antagonism in cell culture with NNRTIs (delavirdine, efavirenz, and nevirapine), protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, and zidovudine), the HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity. Cobicistat does not inhibit recombinant HIV-1 protease in a biochemical assay and has no detectable antiviral activity in cell culture against HIV-1, hepatitis B or C virus. The antiviral activity in cell culture of selected HIV-1 antiretroviral drugs was not antagonized by cobicistat. Resistance In Cell Culture: HIV-1 isolates with a decreased susceptibility to atazanavir have been selected in cell culture and obtained from patients treated with atazanavir coadministered with ritonavir. HIV-1 isolates with 93- to 183-fold reduced susceptibility to atazanavir from three different viral strains were selected in cell culture by 5 months. The substitutions in these HIV-1 viruses that contributed to atazanavir resistance include I50L, N88S, I84V, A71V, and M46I. Changes were also observed at the protease cleavage sites following drug selection. Recombinant viruses containing the I50L substitution without other major protease inhibitor substitutions were growth impaired and displayed increased susceptibility in cell culture to other protease inhibitors (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The I50L and I50V substitutions yielded selective resistance to atazanavir and amprenavir, respectively, and did not appear to be cross-resistant. Clinical Studies: Resistance to EVOTAZ is driven by atazanavir as cobicistat lacks antiviral activity. For the complete atazanavir resistance-associated substitutions, refer to the atazanavir full prescribing information. Clinical Studies of Treatment-Naive Adult Subjects Receiving Atazanavir 300 mg Coadministered with Cobicistat 150 mg: In an analysis of adult subjects who received atazanavir coadministered with cobicistat through Week 144 (Study GS-US-216-0114), evaluable genotypic data from paired baseline and treatment-failure isolates from subjects who had HIV-1 RNA greater than or equal to 400 copies/mL were available for all 21 virologic failures in this group (6%, 21/344). Among the 21 subjects, 3 developed the emtricitabine resistance-associated substitution M184V. No subject developed the tenofovir resistance-associated substitution K65R or K70E, or any primary resistance substitution associated with protease inhibitors. In the ritonavir group, evaluable genotypic data were available for all 19 virologic failures (5%, 19/348). Among the 19 subjects, 1 developed the emtricitabine resistance-associated substitution M184V with no tenofovir or protease inhibitor resistance-associated substitutions. Clinical Study of Pediatric Subjects Receiving Atazanavir Coadministered with Cobicistat: In an as-treated analysis of pediatric subjects between the ages of 12 to less than 18 years who received atazanavir coadministered with cobicistat plus two NRTIs in Study GS-US-216-0128, 3 of 14 subjects qualified for resistance analysis through Week 48; 1 had evaluable data and no significant resistance-associated substitutions in protease or reverse transcriptase [see Clinical Studies (14.2) ] . Cross-Resistance Cross-resistance among protease inhibitors has been observed. Baseline phenotypic and genotypic analyses of clinical isolates from atazanavir clinical trials of protease inhibitor-experienced subjects with HIV-1 infection showed that isolates cross-resistant to multiple protease inhibitors were cross-resistant to atazanavir. Greater than 90% of the isolates with substitutions that included I84V or G48V were resistant to atazanavir. Greater than 60% of isolates containing L90M, G73S/T/C, A71V/T, I54V, M46I/L, or a change at V82 were resistant to atazanavir, and 38% of isolates containing a D30N substitution in addition to other changes were resistant to atazanavir. Isolates resistant to atazanavir were also cross-resistant to other protease inhibitors with >90% of the isolates resistant to indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, and 80% resistant to amprenavir. In treatment-experienced patients, protease inhibitor-resistant viral isolates that developed the I50L substitution in addition to other protease inhibitor resistance-associated substitution were also cross-resistant to other protease inhibitors. International AIDS Society (IAS)-defined protease inhibitor resistance substitutions, depending on the number and type, may confer a reduced virologic response to atazanavir. Please refer to the “Baseline Genotype/Phenotype and Virologic Outcome Analyses” section in the atazanavir full prescribing information.

EVOTAZ (atazanavir and cobicistat) tablet Representative Packaging See HOW SUPPLIED section for a complete list of available packages of EVOTAZ. NDC 0003-3641-11 30 Tablets EVOTAZ ® (atazanavir and cobicistat) tablets 300 mg/150 mg Rx only Take with food. Note to pharmacist: Do not cover ALERT box with pharmacy label. ALERT: Find out about medicines that should NOT be taken with EVOTAZ ® EVOTAZ 300 mg/150 mg 30 count bottle label

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Instructions for Use Advise patients to take EVOTAZ with food every day and that EVOTAZ must always be used in combination with other antiretroviral drugs. Inform patients to avoid missing doses as it can result in development of resistance, and not to discontinue therapy without consulting with their healthcare provider. Advise patients if a dose of EVOTAZ is missed, they should take the dose as soon as possible and then return to their normal schedule; however, if a dose is skipped, the patient should not double the next dose [see Dosage and Administration (2.2, 2.3) ] . Drug Interactions EVOTAZ may interact with many drugs; therefore, inform patients of the potential for serious drug interactions with EVOTAZ, and that some drugs are contraindicated with EVOTAZ and other drugs require dosage adjustment. Advise patients to report to their healthcare provider the use of any other prescription, nonprescription medication, or herbal products, particularly St. John’s wort. Instruct patients receiving hormonal contraceptives to use additional or alternative non-hormonal contraceptive measures during therapy with EVOTAZ because no data are available to make recommendations regarding use of hormonal contraceptives and atazanavir coadministered with cobicistat [see Contraindications (4) , Warnings and Precautions (5.8, 5.9) , and Drug Interactions (7) ] . Cardiac Conduction Abnormalities Inform patients that EVOTAZ may produce changes in the electrocardiogram (e.g., PR prolongation). Advise patients to consult their healthcare provider if they are experiencing symptoms such as dizziness or lightheadedness [see Warnings and Precautions (5.1) ] . Severe Skin Reactions Inform patients that mild rashes without other symptoms have been reported with atazanavir use. These rashes go away within two weeks with no change in treatment. However, inform patients there have been reports of severe skin reactions (e.g., Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions) with atazanavir use. Advise patients to seek medical evaluation immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, muscle or joint aches, blisters, oral lesions, conjunctivitis, or facial edema) [see Warnings and Precautions (5.2) ] . Chronic Kidney Disease Inform patients that treatment with EVOTAZ may lead to the development of chronic kidney disease, and to maintain adequate hydration while taking EVOTAZ [see Warnings and Precautions (5.5) ]. Nephrolithiasis and Cholelithiasis Inform patients that kidney stones and/or gallstones have been reported with atazanavir use. Some patients with kidney stones and/or gallstones required hospitalization for additional management and some had complications [see Warnings and Precautions (5.6) ] . Hyperbilirubinemia Inform patients that asymptomatic elevations in indirect bilirubin have occurred in patients receiving atazanavir, a component of EVOTAZ. Tell patients this may be accompanied by yellowing of the skin or whites of the eyes and alternative antiretroviral therapy may be considered if they have cosmetic concerns [see Warnings and Precautions (5.10) ] . Immune Reconstitution Syndrome Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV-1 infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV-1 treatment is started [see Warnings and Precautions (5.11) ] . Fat Redistribution Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy including protease inhibitors and that the cause and long-term health effects of these conditions are not known at this time [see Warnings and Precautions (5.13) ] . Not Recommended During Pregnancy Advise patients that EVOTAZ is not recommended during pregnancy and to alert their healthcare provider if they get pregnant while taking EVOTAZ [see Use in Specific Populations (8.1) ] . Pregnancy Registry Inform patients that there is a pregnancy exposure registry to monitor fetal outcomes of pregnant individuals exposed to EVOTAZ during pregnancy [see Use in Specific Populations (8.1) ] . Lactation Advise individuals with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk. Atazanavir, a component of EVOTAZ, can also be passed to the baby in breast milk, and it is not known whether it could harm the baby [see Use in Specific Populations (8.2) ] .

14 CLINICAL STUDIES 14.1 Clinical Trial Results in Treatment-Naive Adult Subjects with HIV-1 Infection – Study GS-US-216-0114 The safety and efficacy of atazanavir coadministered with cobicistat were evaluated in a randomized, double-blind, active-controlled trial (Study GS-US-216-0114 [NCT01108510]) in treatment-naive subjects with HIV-1 infection with baseline estimated creatinine clearance above 70 mL/min (N=692). Subjects were randomized in a 1:1 ratio to receive either atazanavir 300 mg coadministered with cobicistat 150 mg once daily or atazanavir 300 mg coadministered with ritonavir 100 mg once daily. All subjects received concomitant treatment with 300 mg of tenofovir DF and 200 mg of emtricitabine once a day administered as a single tablet. Randomization was stratified by screening HIV-1 RNA level (≤100,000 copies/mL or >100,000 copies/mL). The mean age of subjects was 37 years (range: 19-70); 83% were male, 60% were White, 18% were Black, and 12% were Asian. The mean baseline plasma HIV-1 RNA was 4.8 log 10 copies/mL (range: 3.2-6.4). The mean baseline CD4+ cell count was 352 cells/mm 3 (range: 1-1455) and 17% had CD4+ cell counts ≤200 cells/mm 3 . Forty percent (40%) of patients had baseline viral loads >100,000 copies/mL. Virologic outcomes in Study GS-US-216-0114 through Week 144 are presented in Table 10. In Study GS-US-216-0114, the mean increase from baseline in CD4+ cell count at Week 144 was 281 cells/mm 3 in patients receiving atazanavir coadministered with cobicistat and 297 cells/mm 3 in patients receiving atazanavir coadministered with ritonavir. Table 10: Virologic Outcomes of Randomized Treatment of Study GS-US-216-0114 in Treatment-Naive Adults with HIV-1 Infection at Week 144 a Atazanavir 300 mg coadministered with cobicistat 150 mg (once daily) + emtricitabine/tenofovir disoproxil fumarate (n=344) Atazanavir 300 mg coadministered with ritonavir 100 mg + emtricitabine/tenofovir disoproxil fumarate (n=348) a Week 144 window is between Day 967 and 1050 (inclusive). b Includes subjects who had ≥50 copies/mL in the Week 48 window; subjects who discontinued early due to lack or loss of efficacy; subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL. c Includes subjects who discontinued due to adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window. There were no deaths reported in Study GS-US-216-0114. d Includes subjects who discontinued for reasons other than an adverse event, death, or lack or loss of efficacy (e.g., withdrew consent, lost to follow-up, etc). HIV-1 RNA <50 copies/mL 72% 74% Treatment Difference −2.1% (95% CI = −8.7%, 4.5%) HIV-1 RNA ≥50 copies/mL b 8% 5% No Virologic Data at Week 48 Window 20% 21% Discontinued Study Drug Due to AE or Death c 11% 11% Discontinued Study Drug Due to Other Reasons and Last Available HIV-1 RNA <50 copies/mL d 8% 10% Missing Data During Window, but on Study Drug <1% <1% 14.2 Clinical Trial Results in Virologically Suppressed Pediatric Subjects with HIV-1 Infection – Study GS-US-216-0128 Study GS-US-216-0128 (NCT02016924) was a Phase 2/3 multicenter, open-label trial to evaluate the pharmacokinetics, safety, and efficacy of atazanavir coadministered with cobicistat in pediatric subjects ages 12 years and older with HIV-1 infection who were virologically suppressed and had a baseline estimated creatinine clearance ≥90 mL/min/1.73 m 2 . Subjects were on a stable antiretroviral regimen (for at least 3 months), consisting of atazanavir administered with ritonavir, combined with 2 nucleotide reverse transcriptase inhibitors (NRTIs). They were switched from ritonavir to cobicistat 150 mg once daily and continued atazanavir (N=14) and 2 NRTIs. The mean age of subjects was 14 years (range 12–17 years); median weight was 53 kg; 71% were male, 57% were Asian, 29% were White, 14% were Black, and 71% were not Hispanic or Latino. At baseline, 13/14 subjects had plasma HIV-1 RNA <50 copies/mL and 1 subject had plasma HIV‑1 RNA of 50 copies/mL. In subjects who switched to atazanavir coadministered with cobicistat, 93% (13/14) of subjects remained suppressed (HIV-1 RNA <50 copies/mL), and 1 subject experienced virologic failure at Week 48. From a median baseline CD4+ cell count and CD4+% of 770 cells/mm 3 (range 486 to 1765 cells/mm 3 ) and 33% (range 23% to 45%), respectively, the median change from baseline in CD4+ cell count and CD4+% at Week 48 was ‑60 cells/mm 3 (range ‑500 to 705 cells/mm 3 ) and ‑0.3% (range ‑6% to 8%), respectively.

8.5 Geriatric Use Clinical studies with the components of EVOTAZ did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of EVOTAZ in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3) ] .

8.4 Pediatric Use The safety and effectiveness of EVOTAZ for the treatment of HIV-1 infection in pediatric subjects weighing at least 35 kg was established through a study with components of EVOTAZ. Use of EVOTAZ for this indication is supported by evidence from adequate and well-controlled studies in adults, and by pharmacokinetic, safety, and virologic data from an open-label trial of components of EVOTAZ (Study GS-US-216-0128) in pediatric subjects with HIV-1 infection aged 12 years and older. The safety in these subjects through 48 weeks was similar to that in antiretroviral treatment-naive adults [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.2) ] . Safety and effectiveness of EVOTAZ in the pediatric population weighing less than 35 kg have not been established. Atazanavir, a component of EVOTAZ, is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus.

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, including 347 exposures in the first trimester and 79 exposures in the second/third trimester. Birth defects occurred in 13 of 347 (3.7%, 95% CI: 2.0% to 6.3%) live births with first trimester exposure and 1 of 79 (1.3%, 95% CI: 0.0% to 6.9%) with second/third trimester exposure to cobicistat-containing regimens. Among pregnant individuals in the U.S. reference population, the background rate of birth defects is 2.7%. There was no increase in the overall rate of birth defects for cobicistat compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease. Animal Data Atazanavir Atazanavir was administered orally to pregnant rats (at 0, 200, 600, and 1920 mg/kg/day) and rabbits (at 0, 4, 15, and 60 mg/kg/day) during organogenesis (on gestation Days 6 through 15 and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with atazanavir at exposures (AUC) approximately 1.2 times higher (rats) and 0.7 times (rabbits) human exposures at the MRHD. In a rat pre- and postnatal developmental study, atazanavir was administered orally at doses of 0, 50, 220, and 1000 mg/kg/day from gestation Day 6 to postnatal Day 20. At a maternal toxic dose (1000 mg/kg/day), atazanavir caused body weight loss or weight gain suppression in the animal offspring at atazanavir exposures (AUC) of approximately 1.3 times higher than human exposures at the MRHD. Cobicistat Cobicistat was administered orally to pregnant rats at doses of 0, 25, 50, 125 mg/kg/day on gestation Day 6 to 17. Maternal toxicity was noted at 125 mg/kg/day and was associated with increases in post-implantation loss and decreased fetal weights. No malformations were noted at doses up to 125 mg/kg/day. Systemic exposures (AUC) at 50 mg/kg/day in pregnant females were 1.4 times higher than the human exposures at the MRHD. In pregnant rabbits, cobicistat was administered orally at doses of 0, 20, 50, and 100 mg/kg/day during the gestation Days 7 to 20. No maternal or embryo/fetal effects were noted at the highest dose of 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg/day were 3.3 times higher than exposures at the MRHD. In a pre- and postnatal developmental study in rats, cobicistat was administered orally at doses of 0, 10, 30, and 75 mg/kg from gestation Day 6 to postnatal Day 20, 21, or 22. At doses of 75 mg/kg/day of cobicistat, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were 0.9 times lower than exposures at the MRHD.

8 USE IN SPECIFIC POPULATIONS • Pregnancy: EVOTAZ is not recommended during pregnancy and should not be initiated in pregnant individuals; use of an alternative regimen is recommended. (2.5 , 8.1) • Lactation: Breastfeeding is not recommended due to the potential for postnatal HIV transmission. (8.2) • Pediatrics: EVOTAZ is not recommended for patients weighing less than 35 kg. (8.4) 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, including 347 exposures in the first trimester and 79 exposures in the second/third trimester. Birth defects occurred in 13 of 347 (3.7%, 95% CI: 2.0% to 6.3%) live births with first trimester exposure and 1 of 79 (1.3%, 95% CI: 0.0% to 6.9%) with second/third trimester exposure to cobicistat-containing regimens. Among pregnant individuals in the U.S. reference population, the background rate of birth defects is 2.7%. There was no increase in the overall rate of birth defects for cobicistat compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease. Animal Data Atazanavir Atazanavir was administered orally to pregnant rats (at 0, 200, 600, and 1920 mg/kg/day) and rabbits (at 0, 4, 15, and 60 mg/kg/day) during organogenesis (on gestation Days 6 through 15 and 7 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with atazanavir at exposures (AUC) approximately 1.2 times higher (rats) and 0.7 times (rabbits) human exposures at the MRHD. In a rat pre- and postnatal developmental study, atazanavir was administered orally at doses of 0, 50, 220, and 1000 mg/kg/day from gestation Day 6 to postnatal Day 20. At a maternal toxic dose (1000 mg/kg/day), atazanavir caused body weight loss or weight gain suppression in the animal offspring at atazanavir exposures (AUC) of approximately 1.3 times higher than human exposures at the MRHD. Cobicistat Cobicistat was administered orally to pregnant rats at doses of 0, 25, 50, 125 mg/kg/day on gestation Day 6 to 17. Maternal toxicity was noted at 125 mg/kg/day and was associated with increases in post-implantation loss and decreased fetal weights. No malformations were noted at doses up to 125 mg/kg/day. Systemic exposures (AUC) at 50 mg/kg/day in pregnant females were 1.4 times higher than the human exposures at the MRHD. In pregnant rabbits, cobicistat was administered orally at doses of 0, 20, 50, and 100 mg/kg/day during the gestation Days 7 to 20. No maternal or embryo/fetal effects were noted at the highest dose of 100 mg/kg/day. Systemic exposures (AUC) at 100 mg/kg/day were 3.3 times higher than exposures at the MRHD. In a pre- and postnatal developmental study in rats, cobicistat was administered orally at doses of 0, 10, 30, and 75 mg/kg from gestation Day 6 to postnatal Day 20, 21, or 22. At doses of 75 mg/kg/day of cobicistat, neither maternal nor developmental toxicity was noted. Systemic exposures (AUC) at this dose were 0.9 times lower than exposures at the MRHD. 8.2 Lactation Risk Summary The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. There is no information regarding the effects of EVOTAZ on the breastfed infant or on milk production. Atazanavir has been detected in human milk. No data are available regarding atazanavir effects on milk production. Cobicistat is present in rat milk (see Data) . There is no information regarding the presence of cobicistat in human milk, the effects on the breastfed infant, or the effects on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-1 negative infants), (2) developing viral resistance (in HIV-1 positive infants), and (3) adverse reactions in a breastfed infant, instruct individuals with HIV-1 infection not to breastfeed. Data Animal Data Cobicistat: During the prenatal and postnatal development toxicology study at doses up to 75 mg/kg/day, mean cobicistat milk to plasma ratio of up to 1.9 was measured 2 hours after administration to rats on lactation Day 10. 8.3 Females and Males of Reproductive Potential Contraception Atazanavir and cobicistat, components of EVOTAZ, interact with certain oral contraceptives [see Contraindications (4) and Drug Interactions (7.3) ] . Nonhormonal forms of contraceptive should be considered. 8.4 Pediatric Use The safety and effectiveness of EVOTAZ for the treatment of HIV-1 infection in pediatric subjects weighing at least 35 kg was established through a study with components of EVOTAZ. Use of EVOTAZ for this indication is supported by evidence from adequate and well-controlled studies in adults, and by pharmacokinetic, safety, and virologic data from an open-label trial of components of EVOTAZ (Study GS-US-216-0128) in pediatric subjects with HIV-1 infection aged 12 years and older. The safety in these subjects through 48 weeks was similar to that in antiretroviral treatment-naive adults [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.2) ] . Safety and effectiveness of EVOTAZ in the pediatric population weighing less than 35 kg have not been established. Atazanavir, a component of EVOTAZ, is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus. 8.5 Geriatric Use Clinical studies with the components of EVOTAZ did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of EVOTAZ in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy [see Clinical Pharmacology (12.3) ] . 8.6 Renal Impairment EVOTAZ is not recommended for use in treatment-experienced patients with HIV-1 infection who have end-stage renal disease managed with hemodialysis [see Dosage and Administration (2.3) , Warnings and Precautions (5.3) , and Clinical Pharmacology (12.3) ] . 8.7 Hepatic Impairment EVOTAZ is not recommended for use in patients with any degree of hepatic impairment [see Dosage and Administration (2.4) , Warnings and Precautions (5.7) , and Clinical Pharmacology (12.3) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING EVOTAZ ® tablets, 300 mg atazanavir and 150 mg cobicistat, are oval, biconvex, pink, film-coated, debossed with “3641” on one side and plain on the other side. Each bottle contains 30 tablets (NDC-0003-3641-11), a silica gel desiccant and is closed with a child-resistant closure. Store EVOTAZ tablets at 25°C (77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Keep container tightly closed.