ATAZANAVIR SULFATE_- atazanavir_capsule

Atazanavir is an HIV-1 antiretroviral drug [see Microbiology (12. 4) Cardiac Electrophysiology Concentration- and dose-dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy participants receiving atazanavir. In placebo-controlled Study AI424-076, the mean (+/-SD) maximum change in PR interval from the predose value was 24 (+/-15) msec following oral dosing with 400 mg of atazanavir (n=65) compared to 13 (+/-11) msec following dosing with placebo (n=67). The PR interval prolongations in this study were asymptomatic. 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) Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of 72 healthy participants. Oral doses of 400 mg (maximum recommended dosage) and 800 mg (twice the maximum recommended dosage) were compared with placebo; there was no concentration-dependent effect of atazanavir on the QTc interval (using Fridericia’s correction). In 1793 participants with HIV-1, receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy participant or participant with HIV-1 in clinical trials had a QTc interval >500 msec [see Warnings and Precautions (5. 1) The pharmacokinetics of atazanavir were evaluated in adult participants who either were healthy, or with HIV-1, after administration of atazanavir 400 mg once daily and after administration of atazanavir 300 mg with ritonavir 100 mg once daily (see Table 17). Table 17: Steady-State Pharmacokinetics of Atazanavir in Healthy Participants or Participants with HIV-1 in the Fed State 400 mg once daily 300 mg with ritonavir 100 mg once daily Parameter Healthy Participants (n=14) Participants with HIV-1 (n=13) Healthy Participants (n=28) Participants with HIV-1 (n=10) C max Geometric mean (CV%) 5199 (26) 2298 (71) 6129 (31) 4422 (58) Mean (SD) 5358 (1371) 3152 (2231) 6450 (2031) 5233 (3033) T max Median 2. 0 AUC (ngh/mL) Geometric mean (CV%) 28132 (28) 14874 (91) 57039 (37) 46073 (66) Mean (SD) 29303 (8263) 22262 (20159) 61435 (22911) 53761 (35294) T-half (h) Mean (SD) 7. 3) C min Geometric mean (CV%) 159 (88) 120 (109) 1227 (53) 636 (97) Mean (SD) 218 (191) 273 (298) b 1441 (757) 862 (838) a b Figure 1 displays the mean plasma concentrations of atazanavir at steady state after atazanavir 400 mg once daily (as two 200 mg capsules) with a light meal and after atazanavir 300 mg (as two 150 mg capsules) with ritonavir 100 mg once daily with a light meal in adult participants with HIV-1. Absorption Atazanavir is rapidly absorbed with a T max max Food Effect Administration of atazanavir with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single 400 mg dose of atazanavir with a light meal (357 kcal, 8. 2 g fat, 10. 6 g protein) resulted in a 70% increase in AUC and 57% increase in C max max max Coadministration of a single 300 mg dose of atazanavir and a 100 mg dose of ritonavir with a light meal (336 kcal, 5. 3 g protein) resulted in a 33% increase in the AUC and a 40% increase in both the C max max max max Distribution Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively). In a multiple-dose study in participants with HIV-1 dosed with atazanavir 400 mg once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and semen. The cerebrospinal fluid/plasma ratio for atazanavir (n=4) ranged between 0. 0226 and seminal fluid/plasma ratio (n=5) ranged between 0. Metabolism Atazanavir is extensively metabolized in humans. The major biotransformation pathways of atazanavir in humans consisted of monooxygenation and dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. Two minor metabolites of atazanavir in plasma have been characterized. Neither metabolite demonstrated in vitro In vitro Elimination Following a single 400 mg dose of 14 Specific Populations Renal Impairment In healthy participants, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. Atazanavir has been studied in adult participants with severe renal impairment (n=20), including those on hemodialysis, at multiple doses of 400 mg once daily. The mean atazanavir C max min max min [see Dosage and Administration (2. 7) Hepatic Impairment Atazanavir has been studied in adult participants with moderate-to-severe hepatic impairment (14 with Child-Pugh B and 2 with Child-Pugh C) after a single 400 mg dose. The mean AUC (0-infinity) [see Dosage and Administration (2. 8) Pediatrics The pharmacokinetic parameters for atazanavir at steady state in pediatric participants taking the capsule formulation were predicted by a population pharmacokinetic model and are summarized in Table 19 by weight ranges that correspond to the recommended doses [see Dosage and Administration (2. 4)] Table 19: Predicted Steady-State Pharmacokinetics of Atazanavir (capsule formulation) with Ritonavir in Pediatric Participants with HIV-1 Body Weight (range in kg) atazanavir with ritonavir Dose (mg) C max (CV%) AUC ngh/mL Geometric Mean (CV%) C min 15 to <35 200/100 3303 (86%) 37235 (84%) 538 (99%) >=35 300/100 2980 (82%) 37643 (83%) 653 (89%) Pregnancy The pharmacokinetic data from pregnant women with HIV-1 receiving atazanavir capsules with ritonavir are presented in Table 20. Table 20: Steady-State Pharmacokinetics of Atazanavir with Ritonavir in Pregnant Women with HIV-1 in the Fed State Pharmacokinetic Parameter Atazanavir 300 mg with ritonavir 100 mg 2nd Trimester (n=5 a 3rd Trimester (n=20) Postpartum b (n=34) C max 3078. 21 Geometric mean (CV%) (50) (48) (31) AUC ngh/mL 27657. 4 Geometric mean (CV%) (43) (43) (32) C min c 538. 59 Geometric mean (CV%) (46) (50) (45) a b c min Drug Interaction Data Atazanavir is a metabolism-dependent CYP3A inhibitor, with a K inact -1 i i i Atazanavir has been shown in vivo Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1. Clinically significant interactions are not expected between atazanavir when administered with ritonavir and substrates of CYP2C8. See the complete prescribing information for ritonavir for information on other potential drug interactions with ritonavir. Based on known metabolic profiles, clinically significant drug interactions are not expected between atazanavir and dapsone, trimethoprim/sulfamethoxazole, azithromycin, or erythromycin. Atazanavir does not interact with substrates of CYP2D6 (e. , nortriptyline, desipramine, metoprolol). Drug interaction studies were performed with atazanavir and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of atazanavir on the AUC, C max min Drug Interactions (7) Table 21: Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugs a Coadministered Drug Coadministered Drug Dose/Schedule Atazanavir Dose/Schedule Ratio (90% Confidence Interval) of Atazanavir Pharmacokinetic Parameters with/without Coadministered Drug; No Effect = 1. 00 C max AUC C min atenolol 50 mg QD, d 7 to 11 400 mg QD, d 1 to 11 1. 74 clarithromycin 500 mg BID, d 7 to 10 400 mg QD, d 1 to 10 1. 91 didanosine (ddI) b ddI: 200 mg x 1 dose, 400 mg x 1 dose 0. 16 ddI: 200 mg x 1 dose, 400 mg x 1 dose 1. 03 efavirenz 600 mg QD, d 7 to 20 (n=27) 400 mg QD, d 1 to 20 0. 07 600 mg QD, d 7 to 20 400 mg QD, d 1 to 6 (n=23) 1. 48 600 mg QD, 300 mg QD with ritonavir 1. 58 famotidine 40 mg BID, 400 mg QD, d 1 to 6 (n=45), 0. 58 40 mg BID, d 7 to 12 400 mg QD (pm), d 1 to 6 1. 79 40 mg BID, d 11 to 20 c 300 mg QD with ritonavir d 0. 72 20 mg BID, d 11 to 17 300 mg QD with ritonavir d,e 0. 81 40 mg QD (pm), 300 mg QD with ritonavir e 0. 77 40 mg BID, 300 mg QD with ritonavir e 0. 72 40 mg BID, 300 mg QD with ritonavir 1. 86 grazoprevir/elbasvir grazoprevir 200 mg QD d 1 to 35 (n = 11) 300 mg QD with ritonavir 1. 23 elbasvir 50 mg QD 300 mg QD with ritonavir 1. 15 ketoconazole 200 mg QD, 400 mg QD, d 1 to 13 0. 03 nevirapine f,g 200 mg BID, d 1 to 23 300 mg QD with ritonavir h 0. 28 omeprazole 40 mg QD, d 7 to 12 i i 400 mg QD, d 1 to 6 (n=48), j,k l,m pitavastatin 4 mg QD 300 mg QD 1. 06 NA rifabutin 150 mg QD, 400 mg QD, d 1 to 28 1. 13 rifampin 600 mg QD, 300 mg QD with ritonavir 0. 02 ritonavir n 100 mg QD, 300 mg QD, d 1 to 20 1. 89 tenofovir DF o 300 mg QD, d 9 to 16 400 mg QD, d 2 to 16 0. 60 300 mg QD, 300 mg with ritonavir 100 mg 0. 77 p voriconazole 200 mg BID, 300 mg with ritonavir 100 mg 0. 80 voriconazole 50 mg BID, 300 mg with ritonavir 100 mg 0. 69 a b c max min d e f g max min h i j k min max l m min max n max min o p o max min Table 22: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Atazanavir a Coadministered Drug Coadministered Drug Dose/Schedule Atazanavir Dose/Schedule Ratio (90% Confidence Interval) of Coadministered Drug Pharmacokinetic Parameters with/without Atazanavir ; No Effect = 1. 00 C max AUC C min acetaminophen 1 g BID, d 1 to 20 300 mg QD with ritonavir 0. 26 atenolol 50 mg QD, d 7 to 11 400 mg QD, d 1 to 11 1. 02 clarithromycin 500 mg BID, 400 mg QD, 1. 60 ddI b 400 mg QD, d 2 to 8 0. 13 300 mg QD with ritonavir 0. 25 diltiazem 180 mg QD, 400 mg QD, d 1 to 11 1. 42 ethinyl estradiol c Ortho-Novum registered 400 mg QD, ethinyl estradiol: 1. 15 ethinyl estradiol: 1. 48 ethinyl estradiol: 1. 91 ethinyl estradiol & norgestimate d Ortho Tri-Cyclen registered registered e 300 mg QD with ritonavir ethinyl estradiol: 0. 84 f ethinyl estradiol: 0. 81 f ethinyl estradiol: 0. 63 f glecaprevir/ pibrentasvir 300 mg glecaprevir (n=12) 300 mg QD with ritonavir 100 mg QD >=4. 3 g 120 mg pibrentasvir (n=12) 300 mg QD with ritonavir 100 mg QD >=1. 29 g grazoprevir/ elbasvir grazoprevir 200 mg QD d 1 to 35 (n=12) 300 mg QD with ritonavir 100 mg QD 6. 64 elbasvir 50 mg QD 300 mg QD with ritonavir 100 mg QD 4. 45 methadone Stable maintenance 400 mg QD, (R)-methadone h (R)-methadone h (R)-methadone h nevirapine i,j 200 mg BID, 300 mg QD with ritonavir 100 mg 1. 32 omeprazole k 40 mg single dose, 400 mg QD, d 1 to 12 1. 45 NA rifabutin 300 mg QD, 600 mg QD, l 1. 43 150 mg twice 300 mg QD with ritonavir 2. 40 m pitavastatin 4 mg QD 300 mg QD 1. 31 NA rosiglitazone n 4 mg single dose, 400 mg QD, 1. 35 NA rosuvastatin 10 mg single dose 300 mg QD with ritonavir 100 mg up arrow 7-fold o up arrow 3-fold o NA saquinavir p 1200 mg QD, 400 mg QD, d 7 to 13 4. 86 sofosbuvir/ velpatasvir/ voxilaprevir 400 mg sofosbuvir single dose 300 mg with 100 mg ritonavir single dose (n=15) 1. 40 NA 100 mg velpatasvir single dose 300 mg with 100 mg ritonavir single dose (n=15) 1. 93 NA 100 mg voxilaprevir single dose 300 mg with 100 mg ritonavir single dose (n=15) 4. 31 NA tenofovir DF q 300 mg QD, 400 mg QD, d 2 to 16 1. 22 300 mg QD, d 1 to 7 300 mg QD with ritonavir r 1. 29 voriconazole 200 mg BID, 300 mg with ritonavir 0. 61 voriconazole 50 mg BID, 300 mg with ritonavir 4. 65 lamivudine and zidovudine 150 mg lamivudine and 300 mg zidovudine 400 mg QD, d 7 to 12 lamivudine: 1. 04 lamivudine: 1. 03 lamivudine: 1. 12 a b c max min d max min e registered registered registered f g h i j k l m n o p max q r Figure 1 Mechanism of Action Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI). The compound selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions. Antiviral Activity in Cell Culture Atazanavir exhibits anti-HIV-1 activity with a mean 50% effective concentration (EC 50 50 50 Resistance In Cell Culture: Clinical Studies of Treatment-Naive Participants: Comparison of Ritonavir-Boosted Atazanavir vs. Unboosted Atazanavir: Table 23: Summary of Virologic Failures a atazanavir 300 mg with ritonavir 100 mg (n=95) atazanavir 400 mg (n=105) Virologic Failure (>=50 copies/mL) at Week 96 15 (16%) 34 (32%) Virologic Failure with Genotypes and Phenotypes Data 5 17 Virologic Failure Isolates with atazanavir-resistance at Week 96 0/5 (0%) b 4/17 (24%) b Virologic Failure Isolates with I50L Emergence at Week 96 c 0/5 (0%) b 2/17 (12%) b Virologic Failure Isolates with Lamivudine Resistance at Week 96 2/5 (40%) b 11/17 (65%) b a b c Clinical Studies of Treatment-Naive Participants Receiving Atazanavir 300 mg with Ritonavir 100 mg: Clinical Studies of Treatment-Naive Participants Receiving Atazanavir 400 mg without Ritonavir: Clinical Studies of Treatment-Experienced Participants: Cross-Resistance Cross-resistance among PIs has been observed. Baseline phenotypic and genotypic analyses of clinical isolates from atazanavir clinical trials of PI-experienced participants showed that isolates cross-resistant to multiple PIs 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 PIs with >90% of the isolates resistant to indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, and 80% resistant to amprenavir. In treatment-experienced participants, PI-resistant viral isolates that developed the I50L substitution in addition to other PI resistance-associated substitution were also cross-resistant to other PIs. Baseline Genotype/Phenotype and Virologic Outcome Analyses Genotypic and/or phenotypic analysis of baseline virus may aid in determining atazanavir susceptibility before initiation of atazanavir with ritonavir therapy. An association between virologic response at 48 weeks and the number and type of primary PI resistance-associated substitutions detected in baseline HIV-1 isolates from antiretroviral-experienced participants receiving atazanavir with ritonavir once daily or lopinavir / ritonavir (fixed-dose product) twice daily in Study AI424-045 is shown in Table 24. Overall, both the number and type of baseline PI substitutions affected response rates in treatment-experienced participants. In the atazanavir with ritonavir group, participants had lower response rates when 3 or more baseline PI substitutions, including a substitution at position 36, 71, 77, 82, or 90, were present compared to participants with 1 to 2 PI substitutions, including one of these substitutions. Table 24: HIV-1 RNA Response by Number and Type of Baseline PI Substitution, Antiretroviral-Experienced Participants in Study AI424-045, As-Treated Analysis Number and Type of Baseline PI Substitutions a Virologic Response = HIV RNA <400 copies/mL b atazanavir with ritonavir (n=110) lopinavir/ritonavir c (n=113) 3 or more primary PI substitutions including d D30N 75% (6/8) 50% (3/6) M36I/V 19% (3/16) 33% (6/18) M46I/L/T 24% (4/17) 23% (5/22) I54V/L/T/M/A 31% (5/16) 31% (5/16) A71V/T/I/G 34% (10/29) 39% (12/31) G73S/A/C/T 14% (1/7) 38% (3/8) V77I 47% (7/15) 44% (7/16) V82A/F/T/S/I 29% (6/21) 27% (7/26) I84V/A 11% (1/9) 33% (2/6) N88D 63% (5/8) 67% (4/6) L90M 10% (2/21) 44% (11/25) Number of baseline primary PI substitutions a All patients, as-treated 58% (64/110) 59% (67/113) 0 to 2 PI substitutions 75% (50/67) 75% (50/67) 3 to 4 PI substitutions 41% (14/34) 43% (12/28) 5 or more PI substitutions 0% (0/9) 28% (5/18) a b c d The response rates of antiretroviral-experienced participants in Study AI424-045 were analyzed by baseline phenotype (shift in susceptibility in cell culture relative to reference, Table 25). The analyses are based on a select population with 62% of participants receiving an NNRTI-based regimen before study entry compared to 35% receiving a PI-based regimen. Additional data are needed to determine clinically relevant break points for atazanavir. Table 25: Baseline Phenotype by Outcome, Antiretroviral-Experienced Participants in Study AI424-045, As-Treated Analysis Baseline Phenotype a Virologic Response = HIV-1 RNA <400 copies/mL b atazanavir with ritonavir (n=111) lopinavir/ritonavir c (n=111) 0 to 2 71% (55/78) 70% (56/80) >2 to 5 53% (8/15) 44% (4/9) >5 to 10 13% (1/8) 33% (3/9) >10 10% (1/10) 23% (3/13) a b c.

Atazanavir capsule is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric patients 6 years and older weighing at least 15 kg. Limitations of Use: Atazanavir capsules are not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus [see Use in Specific Populations (8. 4) Use of atazanavir capsules with ritonavir in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions [see Microbiology (12. 4) Atazanavir capsule is a protease inhibitor indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric patients 6 years and older weighing at least 15 kg.

Pretreatment testing: 2. 2 Treatment-naive adults: 2. 3 Treatment-experienced adults: 2. 3 Pediatric patients: 2. 4 Pregnancy: 2. 6 Dosing modifications: 2. 8 Atazanavir capsules must be taken with food. Do not open the capsules. The recommended oral dosage of atazanavir capsules depends on the treatment history of the patient and the use of other coadministered drugs. When coadministered with H 2 [see Dosage and Administration (2. 6 Drug Interactions (7) Atazanavir capsules without ritonavir are not recommended for treatment-experienced adult or pediatric patients with prior virologic failure [see Clinical Studies (14) Efficacy and safety of atazanavir capsules with ritonavir when ritonavir is administered in doses greater than 100 mg once daily have not been established. The use of higher ritonavir doses may alter the safety profile of atazanavir (cardiac effects, hyperbilirubinemia) and, therefore, is not recommended. Prescribers should consult the complete prescribing information for ritonavir when using ritonavir. Renal laboratory testing should be performed in all patients prior to initiation of atazanavir capsules and continued during treatment with atazanavir capsules. Renal laboratory testing should include serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination [see Warnings and Precautions (5. 6) [see Warnings and Precautions (5. 4) Table 1 displays the recommended dosage of atazanavir capsules in treatment-naive and treatment-experienced adults. Table 1 also displays recommended dosage of atazanavir capsules and ritonavir when given concomitantly with other antiretroviral drugs and H 2 Table 1: Recommended Atazanavir Capsules and Ritonavir Dosage in Adults a a Drug Interactions (7) Atazanavir Capsules Once Daily Dosage Ritonavir Once Daily Dosage Treatment-Naive Adult Patients recommended regimen 300 mg 100 mg unable to tolerate ritonavir 400 mg N/A in combination with efavirenz 400 mg 100 mg Treatment-Experienced Adult Patients recommended regimen 300 mg 100 mg in combination with both H2RA and tenofovir DF 400 mg 100 mg The recommended daily dosage of atazanavir capsules and ritonavir in pediatric patients (6 years of age to less than 18 years of age) is based on body weight (see Table 2). Table 2: Recommended Dosage of Atazanavir Capsules and Ritonavir in Pediatric Patients (6 to less than 18 years of age) a,b a b Drug Interactions (7) c Body weight Atazanavir Capsules Daily Dosage Ritonavir Daily Dosage Treatment-Naive and Treatment-Experienced c Less than 15 kg Capsules not recommended N/A At least 15 kg to less than 35 kg 200 mg 100 mg At least 35 kg 300 mg 100 mg Treatment-Naive, at least 13 years old and cannot tolerate ritonavir At least 40 kg 400 mg N/A When transitioning between formulations, a change in dose may be needed. Consult the dosing table for the specific formulation. Table 4 includes the recommended dosage of atazanavir capsules and ritonavir in treatment-naive and treatment-experienced pregnant patients. In these patients, atazanavir capsules must be administered with ritonavir. There are no dosage adjustments for postpartum patients (see Table 1 for the recommended atazanavir capsules dosage in adults) [see Use in Specific Populations (8. 1) Table 4: Recommended Dosage of Atazanavir Capsules and Ritonavir in Pregnant Patients a a Drug Interactions (7) b BOTH Atazanavir Capsules Once Daily Dosage Ritonavir Once Daily Dosage Treatment-Naive and Treatment-Experienced Recommended Regimen 300 mg 100 mg Treatment-Experienced During the Second or Third Trimester When Coadministered with either H2RA or Tenofovir DF b In combination with EITHER OR 400 mg 100 mg For patients with renal impairment, including those with severe renal impairment who are not managed with hemodialysis, no dose adjustment is required for atazanavir capsules. Treatment-naive patients with end-stage renal disease managed with hemodialysis should receive atazanavir capsules 300 mg with ritonavir 100 mg. Atazanavir capsules are not recommended in treatment-experienced patients with HIV-1 who have end-stage renal disease managed with hemodialysis [see Use in Specific Populations (8. Table 5 displays the recommended atazanavir capsules dosage in treatment-naive patients with hepatic impairment. The use of atazanavir capsules in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended. The coadministration of atazanavir capsules with ritonavir in patients with any degree of hepatic impairment is not recommended. Table 5: Recommended Dosage of Atazanavir Capsules in Treatment-Naive Adults with Hepatic Impairment Atazanavir Capsules Once Daily Dosage Mild hepatic impairment (Child-Pugh Class A) 400 mg Moderate hepatic impairment (Child-Pugh Class B) 300 mg Severe hepatic impairment (Child-Pugh Class C) Atazanavir capsules with or without.

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) hyperbilirubinemia [see Warnings and Precautions (5. 8) chronic kidney disease [see Warnings and Precautions (5. 5) nephrolithiasis and cholelithiasis [ see Warnings and Precautions (5. 6) Most common adverse reactions (>=2%) are nausea, jaundice/scleral icterus, rash, headache, abdominal pain, vomiting, insomnia, peripheral neurologic symptoms, dizziness, myalgia, diarrhea, depression, and fever. gov/medwatch 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 in Treatment-Naive Adult Participants The safety profile of atazanavir in treatment-naive adults is based on 1625 participants with HIV-1 in clinical trials. 536 participants received atazanavir 300 mg with ritonavir 100 mg and 1089 participants received atazanavir 400 mg or higher (without ritonavir). The most common adverse reactions were nausea, jaundice/scleral icterus, and rash. Selected clinical adverse reactions of moderate or severe intensity reported in >= 2% of treatment-naive participants receiving combination therapy including atazanavir 300 mg with ritonavir 100 mg and atazanavir 400 mg (without ritonavir) are presented in Tables 7 and 8, respectively. Table 7: Selected Adverse Reactions a b 96 weeks c atazanavir 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/ emtricitabine d (n=441) 96 weeks c lopinavir/ritonavir d daily) and tenofovir DF/ emtricitabine e (n=437) Digestive System Nausea 4% 8% Jaundice/scleral icterus 5% * Diarrhea 2% 12% Skin and Appendages Rash 3% 2% * None reported in this treatment arm. a b c d e Table 8: Selected Adverse Reactions a b Study AI424-034 Studies AI424-007, -008 64 weeks c 400 mg (once daily) with lamivudine/ zidovudine e (n=404) 64 weeks c zidovudine e (n=401) 120 weeks c,d (n=279) 73 weeks c,d 750 mg TID or 1250 mg BID with stavudine and lamivudine or didanosine (n=191) Body as a Whole Headache 6% 6% 1% 2% Digestive System Nausea 14% 12% 6% 4% Jaundice/scleral icterus 7% * 7% * Vomiting 4% 7% 3% 3% Abdominal pain 4% 4% 4% 2% Diarrhea 1% 2% 3% 16% Nervous System Insomnia 3% 3% <1% * Dizziness 2% 7% <1% * Peripheral neurologic symptoms <1% 1% 4% 3% Skin and Appendages Rash 7% 10% 5% 1% * a b c d e Adverse Reactions in Treatment-Experienced Adult Participants The safety profile of atazanavir in treatment-experienced adults with HIV-1 is based on 119 participants with HIV-1 in clinical trials. The most common adverse reactions are jaundice/scleral icterus and myalgia. Selected clinical adverse reactions of moderate or severe intensity reported in >=2% of treatment-experienced participants receiving atazanavir with ritonavir are presented in Table 9. Table 9: Selected Adverse Reactions a b 48 weeks c Atazanavir with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI (n=119) 48 weeks c lopinavir/ritonavir 400/100 mg (twice daily d (n=118) Body as a Whole Fever 2% * Digestive System Jaundice/scleral icterus 9% * Diarrhea 3% 11% Nausea 3% 2% Nervous System Depression 2% <1% Musculoskeletal System Myalgia 4% * * a b c d Laboratory Abnormalities in Treatment-Naive Participants The percentages of adult treatment-naive participants with HIV-1 treated with combination therapy, including atazanavir 300 mg with ritonavir 100 mg or atazanavir 400 mg (without ritonavir) with Grade 3 to 4 laboratory abnormalities, are presented in Tables 10 and 11, respectively. Table 10: Grade 3 to 4 Laboratory Abnormalities Reported in >=2% of Adult Treatment-Naive Participants with HIV-1, a Variable Limit e 96 weeks b atazanavir 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabine c (n=441) 96 weeks b lopinavir/ritonavir 400 mg/100 mg c tenofovir DF/emtricitabine d (n=437) Chemistry High SGOT/AST >=5. 1 x ULN 3% 1% SGPT/ALT >=5. 1 x ULN 3% 2% Total Bilirubin >=2. 6 x ULN 44% <1% Lipase >=2. 1 x ULN 2% 2% Creatine Kinase >=5. 1 x ULN 8% 7% Total Cholesterol >=240 mg/dL 11% 25% Hematology Low Neutrophils <750 cells/mm 3 5% 2% a b c d e Table 11: Grade 3 to 4 Laboratory Abnormalities Reported in >=2% of Adult Treatment-Naive Participants with HIV-1, a Variable Limit d Study AI424-034 Studies AI424-007, -008 64 weeks b atazanavir 400 mg once daily and lamivudine/ zidovudine e (n=404) 64 weeks b efavirenz 600 mg once daily and lamivudine/ zidovudine e (n=401) 120 weeks b,c atazanavir 400 mg once daily with stavudine and lamivudine or with stavudine and didanosine (n=279) 73 weeks b,c nelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or with stavudine and didanosine (n=191) Chemistry High SGOT/AST >=5. 1 x ULN 2% 2% 7% 5% SGPT/ALT >=5. 1 x ULN 4% 3% 9% 7% Total Bilirubin >=2. 6 x ULN 35% <1% 47% 3% Amylase >=2. 1 x ULN * * 14% 10% Lipase >=2. 1 x ULN <1% 1% 4% 5% Creatine Kinase >=5. 1 x ULN 6% 6% 11% 9% Total Cholesterol >=240 mg/dL 6% 24% 19% 48% Triglycerides >=751 mg/dL <1% 3% 4% 2% Hematology Low Hemoglobin <8. 0 g/dL 5% 3% <1% 4% Neutrophils <750 cells/mm 3 7% 9% 3% 7% * a b c d e Change in Lipids from Baseline in Treatment-Naive Participants with HIV-1 For Study AI424-138 and Study AI424-034, changes from baseline in LDL-cholesterol, HDL- cholesterol, total cholesterol, and triglycerides are shown in Tables 12 and 13, respectively. Table 12: Lipid Values, Mean Change from Baseline, Study AI424-138 atazanavir with ritonavir a,b lopinavir/ritonavir b,c Baseline Week 48 Week 96 Baseline Week 48 Week 96 mg/dL (n=428 e mg/dL (n=372 e Change d (n=372 e mg/dL (n=342 e Change d (n=342 e mg/dL (n=424 e mg/dL (n=335 e Change d (n=335 e mg/dL (n=291 e Change d (n=291 e LDL-Cholesterol f 92 105 +14% 105 +14% 93 111 +19% 110 +17% HDL-Cholesterol f 37 46 +29% 44 +21% 36 48 +37% 46 +29% Total Cholesterol f 149 169 +13% 169 +13% 150 187 +25% 186 +25% Triglycerides f 126 145 +15% 140 +13% 129 194 +52% 184 +50% a b c d e f Table 13: Lipid Values, Mean Change from Baseline, Study AI424-034 atazanavir a,b efavirenz b,c Baseline Week 48 Week 48 Baseline Week 48 Week 48 mg/dL (n=383 e mg/dL (n=283 e Change d (n=272 e mg/dL (n=378 e mg/dL (n=264 e Change d (n=253 e LDL-Cholesterol f 98 98 +1% 98 114 +18% HDL-Cholesterol 39 43 +13% 38 46 +24% Total Cholesterol 164 168 +2% 162 195 +21% Triglycerides f 138 124 -9% 129 168 +23% a b c d e f Laboratory Abnormalities in Treatment-Experienced Participants with HIV-1 The percentages of adult treatment-experienced participants with HIV-1 treated with combination therapy, including atazanavir with ritonavir having Grade 3 to 4 laboratory abnormalities, are presented in Table 14. Table 14: Grade 3 to 4 Laboratory Abnormalities Reported in >=2% of Adult Treatment-Experienced Participants with HIV-1, Study AI424-045 a Variable Limit c 48 weeks b atazanavir with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI (n=119) 48 weeks b 400/100 mg (twice daily d NRTI (n=118) Chemistry High SGOT/AST >=5. 1 x ULN 3% 3% SGPT/ALT >=5. 1 x ULN 4% 3% Total Bilirubin >=2. 6 x ULN 49% <1% Lipase >=2. 1 x ULN 5% 6% Creatine Kinase >=5. 1 x ULN 8% 8% Total Cholesterol >=240 mg/dL 25% 26% Triglycerides >=751 mg/dL 8% 12% Glucose >=251 mg/dL 5% <1% Hematology Low Platelets <50,000 cells/mm 3 2% 3% Neutrophils <750 cells/mm 3 7% 8% a b c d Change in Lipids from Baseline in Treatment-Experienced Participants with HIV-1 For Study AI424-045, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Table 15. The observed magnitude of dyslipidemia was less with atazanavir with ritonavir than with lopinavir/ritonavir. However, the clinical impact of such findings has not been demonstrated. Table 15: Lipid Values, Mean Change from Baseline, Study AI424-045 Atazanavir with ritonavir a,b Lopinavir/ritonavir b,c Baseline Week 48 Week 48 Baseline Week 48 Week 48 mg/dL (n=111 e mg/dL (n=75 e Change d (n=74 e mg/dL (n=108 e mg/dL (n=76 e Change d (n=73 e LDL-Cholesterol f 108 98 -10% 104 103 +1% HDL-Cholesterol 40 39 -7% 39 41 +2% Total Cholesterol 188 170 -8% 181 187 +6% Triglycerides f 215 161 -4% 196 224 +30% a b c d e f Adverse Reactions in Pediatric Participants with HIV-1: Atazanavir Capsules The safety and tolerability of atazanavir capsules with and without ritonavir have been established in pediatric participants with HIV-1, at least 6 years of age from the open-label, multicenter clinical trial PACTG 1020A. The safety profile of atazanavir in pediatric participants with HIV-1 (6 to less than 18 years of age) taking the capsule formulation was generally similar to that observed in clinical studies of atazanavir in adults. The most common Grade 2 to 4 adverse events (>=5%, regardless of causality) reported in pediatric participants were cough (21%), fever (18%), jaundice/scleral icterus (15%), rash (14%), vomiting (12%), diarrhea (9%), headache (8%), peripheral edema (7%), extremity pain (6%), nasal congestion (6%), oropharyngeal pain (6%), wheezing (6%), and rhinorrhea (6%). Asymptomatic second-degree atrioventricular block was reported in <2% of participants. The most common Grade 3 to 4 laboratory abnormalities occurring in pediatric participants taking the capsule formulation were elevation of total bilirubin (>=3. 2 mg/dL, 58%), neutropenia (9%), and hypoglycemia (4%). All other Grade 3 to 4 laboratory abnormalities occurred with a frequency of less than 3%. Adverse Reactions in Participants with HIV-1 and Hepatitis B and/or Hepatitis C Virus In Study AI424-138, 60 participants administered atazanavir 300 mg with ritonavir 100 mg once daily, and 51 participants treated with lopinavir/ritonavir 400 mg/100 mg (as fixed-dose product) twice daily, each with fixed-dose tenofovir DF/emtricitabine, were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 10% (6/60) of the participants administered atazanavir with ritonavir and 8% (4/50) of the participants treated with lopinavir/ritonavir. AST levels >5 times ULN developed in 10% (6/60) of the participants administered atazanavir with ritonavir and none (0/50) of the participants treated with lopinavir/ritonavir. In Study AI424-045, 20 participants administered atazanavir 300 mg with ritonavir 100 mg once daily, and 18 participants treated with lopinavir/ritonavir 400 mg/100 mg twice daily (as fixed-dose product), were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 25% (5/20) of the participants administered atazanavir with ritonavir and 6% (1/18) of the participants treated with lopinavir/ritonavir treated. AST levels >5 times ULN developed in 10% (2/20) of the participants administered atazanavir with ritonavir and 6% (1/18) of the participants treated with lopinavir/ritonavir. In Studies AI424-008 and AI424-034, 74 participants treated with atazanavir 400 mg once daily, 58 who received efavirenz, and 12 who received nelfinavir were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 15% of the participants treated with atazanavir, 14% of the participants treated with efavirenz, and 17% of the participants treated with nelfinavir. AST levels >5 times ULN developed in 9% of the participants treated with atazanavir, 5% of the participants treated with efavirenz, and 17% of the participants treated with nelfinavir. Within atazanavir and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative participants [see Warnings and Precautions (5. 8) The following events have been identified during postmarketing use of atazanavir. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Cardiovascular System: [see Warnings and Precautions (5. 1) Gastrointestinal System: Hepatic System: Hepatobiliary Disorders: [see Warnings and Precautions (5. 6) Metabolic System and Nutrition Disorders: [see Warnings and Precautions (5. 9) Musculoskeletal System: Renal System: [see Warnings and Precautions (5. 6) [see Warnings and Precautions (5. 5) [see Contraindications (4) Warnings and Precautions (5.

Atazanavir capsules are contraindicated: in patients with previously demonstrated clinically significant hypersensitivity (e. , Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of atazanavir capsules [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 6). when coadministered with drugs that are strong inducers of CYP3A due to the potential for loss of therapeutic effect and development of resistance. Coadministration is contraindicated with, but not limited to, the following drugs listed in Table 6: Table 6: Drugs Contraindicated with Atazanavir Capsules (Information in the table applies to atazanavir capsules with or without ritonavir, unless otherwise indicated) a Drug Interactions, Table 16 (7) b Drug Interactions, Table 16 (7) registered Drug Class Drugs within class that are contraindicated with atazanavir capsules Alpha 1­-adrenoreceptor antagonist Alfuzosin Antiarrhythmics Amiodarone (with ritonavir), quinidine (with ritonavir) Anticonvulsants Carbamazepine, phenobarbital, phenytoin Antimycobacterials Rifampin Antineoplastics Apalutamide, encorafenib, irinotecan, ivosidenib Antipsychotics Lurasidone (with ritonavir), pimozide Benzodiazepines Orally administered midazolam a Ergot Derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine GI Motility Agent Cisapride Hepatitis C Direct-Acting Antivirals Elbasvir/grazoprevir; glecaprevir/pibrentasvir Herbal Products St. John’s wort ( Hypericum perforatum Lipid-Modifying Agents: Lomitapide, lovastatin, simvastatin Phosphodiesterase-5 (PDE-5) Inhibitor Sildenafil b registered Protease Inhibitors Indinavir Non-nucleoside Reverse Transcriptase Inhibitors Nevirapine In patients with previously demonstrated hypersensitivity (e. , Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of atazanavir capsule. ( 4 Coadministration with drugs that are strong inducers of CYP3A, due to the potential for loss of therapeutic effect and development of resistance. ( 4 Coadministration 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.

Pregnancy: 8. 1 Hepatitis B or C co-infection: 5. 1 Renal impairment: 2. 7 Hepatic impairment: 2. 8 Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to atazanavir during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Atazanavir has been evaluated in a limited number of women during pregnancy. Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate [see Data]. [see Data] Clinical Considerations Dose Adjustments during Pregnancy and the Postpartum Period Atazanavir must be administered with ritonavir in pregnant patients. For pregnant patients, no dosage adjustment is required for atazanavir with the following exceptions: For treatment-experienced pregnant women during the second or third trimester, when atazanavir is coadministered with either an H 2 or 2 and No dosage adjustment is required for postpartum patients. However, patients should be closely monitored for adverse events because atazanavir exposures could be higher during the first 2 months after delivery [see Dosage and Administration (2. 6) Clinical Pharmacology (12. 3) Maternal Adverse Reactions Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women 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 [see Warnings and Precautions (5. 8) [see Data] Advise pregnant women of the potential risks of lactic acidosis syndrome and hyperbilirubinemia. Fetal/Neonatal Adverse Reactions All infants, including neonates exposed to atazanavir in utero [see Data]. Data Human Data In Study AI424-182, atazanavir with ritonavir (300/100 mg or 400/100 mg) coadministered with lamivudine/zidovudine (150 mg/ 300 mg, as fixed-dose product) was administered to 41 pregnant women with HIV-1, during the second or third trimester. Among the 39 women who completed the study, 38 women achieved an HIV-1 RNA less than 50 copies/mL at time of delivery. Six of 20 (30%) women on atazanavir with ritonavir 300/100 mg and 13 of 21 (62%) women on atazanavir with ritonavir 400/100 mg experienced hyperbilirubinemia (total bilirubin greater than or equal to 2. 6 times ULN). There were no cases of lactic acidosis observed in clinical trial AI424-182. Atazanavir drug concentrations in fetal umbilical cord blood were approximately 12% to 19% of maternal concentrations. Among the 40 infants born to 40 pregnant women with HIV-1, all had test results that were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. All 40 infants received antiretroviral prophylactic treatment containing zidovudine. No evidence of severe hyperbilirubinemia (total bilirubin levels greater than 20 mg/dL) or acute or chronic bilirubin encephalopathy was observed among neonates in this study. However, 10/36 (28%) infants (6 greater than or equal to 38 weeks gestation and 4 less than 38 weeks gestation) had bilirubin levels of 4 mg/dL or greater within the first day of life. Lack of ethnic diversity was a study limitation. In the study population, 33/40 (83%) infants were Black/African American, who have a lower incidence of neonatal hyperbilirubinemia than Caucasians and Asians. In addition, women with Rh incompatibility were excluded, as well as women who had a previous infant who developed hemolytic disease and/or had neonatal pathologic jaundice (requiring phototherapy). Additionally, of the 38 infants who had glucose samples collected in the first day of life, 3 had adequately collected serum glucose samples with values of less than 40 mg/dL that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis. Based on prospective reports from the APR of approximately 1600 live births following exposure to atazanavir-containing regimens (including 1037 live births in infants exposed in the first trimester and 569 exposed in second/third trimesters), there was no difference between atazanavir, and overall birth defects compared with the background birth defect rate. general population, the estimated background risk of major birth defects in clinically recognized pregnancies is 2 to 4%. Animal Data In animal reproduction studies, there was no evidence of mortality or teratogenicity in offspring born to animals at systemic drug exposure levels (AUC) 0. 7 (in rabbits) to 1. 2 (in rats) times those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). In pre- and postnatal development studies in the rat, atazanavir caused neonatal growth retardation during lactation that reversed after weaning. Maternal drug exposure at this dose was 1. 3 times the human exposure at the recommended clinical exposure. Minimal maternal toxicity occurred at this exposure level. Risk Summary Atazanavir has been detected in human milk. No data are available regarding atazanavir effects on milk production. Atazanavir was present in the milk of lactating rats and was associated with neonatal growth retardation that reversed after weaning. Potential risks of breastfeeding include: (1) HIV-1 transmission (in infants without HIV-1), (2) developing viral resistance (in infants with HIV-1), and (3) adverse reactions in a breastfed infant similar to those seen in adults. Atazanavir capsule is indicated in combination with other antiretroviral agents for the treatment of pediatric patients with HIV-1, 6 years of age and older weighing at least 15 kg. Atazanavir is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus [see Indications and Usage (1) [see Contraindications (4) Warnings and Precautions (5) [see Clinical Pharmacology (12. 3) Clinical Studies (14. 3) [see Adverse Reactions (6. 1) Dosage and Administration (2. 4) Clinical studies of atazanavir did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Based on a comparison of mean single-dose pharmacokinetic values for C max A study of the pharmacokinetics of atazanavir was performed in young (n=29; 18 to 40 years) and elderly (n=30; >=65 years) healthy participants. There were no clinically significant pharmacokinetic differences observed due to age or gender. Atazanavir is not recommended for use in treatment-experienced patients with HIV-1, who have end-stage renal disease managed with hemodialysis [see Dosage and Administration (2. 7) Clinical Pharmacology (12. 3) Atazanavir is not recommended for use in patients with severe hepatic impairment. Atazanavir with ritonavir is not recommended in patients with any degree of hepatic impairment [see Dosage and Administration (2. 8) Clinical Pharmacology (12.

Coadministration of atazanavir can alter the concentration of other drugs and other drugs may alter the concentration of atazanavir. The potential drug-drug interactions must be considered prior to and during therapy. 3) Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of atazanavir and drugs primarily metabolized by CYP3A or UGT1A1 may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects. [see Clinical Pharmacology, Table 22 (12. 3) Atazanavir is a CYP3A4 substrate; therefore, drugs that induce CYP3A4 may decrease atazanavir plasma concentrations and reduce atazanavir's therapeutic effect (see Table 16) 2 [see Dosage and Administration (2. 6) Table 16 provides dosing recommendations in adults as a result of drug interactions with atazanavir. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy. Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies a Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment HIV Antiviral Agents Nucleoside Reverse Transcriptase Inhibitors (NRTIs): down arrow atazanavir It is recommended that atazanavir be given (with food) 2 h before or 1 h after didanosine buffered formulations. Simultaneous administration of didanosine EC and atazanavir with food results in a decrease in didanosine exposure. Thus, atazanavir and didanosine EC should be administered at different times. Nucleotide Reverse Transcriptase Inhibitors: down arrow atazanavir When coadministered with tenofovir DF in adults, it is recommended that atazanavir 300 mg be given with ritonavir 100 mg and tenofovir DF 300 mg (all as a single daily dose with food). The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir­-associated adverse reactions, including renal disorders. Patients receiving atazanavir and tenofovir DF should be monitored for tenofovir-associated adverse reactions. For pregnant patients taking atazanavir with ritonavir and see Dosage and Administration (2. 6) Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): down arrow atazanavir In HIV-treatment-naive adult patients: In HIV-treatment-experienced adult patients: nevirapine down arrow atazanavir Coadministration of atazanavir with nevirapine is contraindicated due to the potential loss of virologic response and development of resistance, as well as the potential risk for nevirapine-associated adverse reactions [see Contraindications (4) Protease Inhibitors: up arrow saquinavir Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In a clinical study, saquinavir 1200 mg coadministered with atazanavir 400 mg and tenofovir DF 300 mg (all given once daily), and nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see Clinical Studies (14. 2) indinavir Coadministration of atazanavir with indinavir is contraindicated. Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia [see Contraindications (4) ritonavir up arrow atazanavir If atazanavir is coadministered with ritonavir, it is recommended that atazanavir 300 mg once daily be given with ritonavir 100 mg once daily with food in adults. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir. Others up arrow other protease inhibitor Coadministration with other protease inhibitors is not recommended. Hepatitis C Antiviral Agents elbasvir/grazoprevir up arrow grazoprevir Coadministration of atazanavir with grazoprevir is contraindicated due to the potential for increased risk of ALT elevations [see Contraindications (4) up arrow glecaprevir Coadministration of atazanavir with glecaprevir/pibrentasvir is contraindicated due to the potential for increased the risk of ALT elevations [see Contraindications (4) voxilaprevir/sofosbuvir/velpatasvir up arrow voxilaprevir Coadministration with atazanavir is not recommended. Other Agents Alpha 1-Adrenoreceptor Antagonist: up arrow alfuzosin Coadministration of atazanavir with alfuzosin is contraindicated due to risk for hypotension [see Contraindications (4) Antacids and buffered medications: down arrow atazanavir Atazanavir should be administered 2 hours before or 1 hour after antacids and buffered medications. Antiarrhythmics: Concomitant use of atazanavir with ritonavir and either quinidine or amiodarone is contraindicated due to the potential for serious or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) Anticoagulants: up arrow warfarin Coadministration with atazanavir has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that International Normalized Ratio (INR) be monitored. Direct-Acting Oral Anticoagulants: up arrow betrixaban Concomitant use of atazanavir with ritonavir, a strong CYP3A4/P-gp inhibitor, may result in an increased risk of bleeding. Refer to the respective DOAC prescribing information regarding dosing instructions for coadministration with P-gp inhibitors. rivaroxaban Atazanavir with ritonavir Atazanavir Atazanavir with ritonavir Atazanavir Coadministration of atazanavir with ritonavir, a strong CYP3A4/P-gp inhibitor, and rivaroxaban is not recommended, as it may result in an increased risk of bleeding. Antidepressants: up arrow tricyclic Coadministration with atazanavir has the potential to produce serious and/or life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with atazanavir. trazodone up arrow trazodone Nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone with ritonavir. If trazodone is used with a CYP3A4 inhibitor such as atazanavir, the combination should be used with caution and a lower dose of trazodone should be considered. Antiepileptics: down arrow atazanavir Coadministration of atazanavir (with or without ritonavir) with carbamazepine is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4) phenytoin, phenobarbital down arrow atazanavir Coadministration of atazanavir (with or without ritonavir) with phenytoin or phenobarbital is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4) lamotrigine down arrow lamotrigine Coadministration of lamotrigine and atazanavir with Antifungals: Atazanavir with ritonavir: Coadministration of ketoconazole has only been studied with atazanavir without ritonavir (negligible increase in atazanavir AUC and C max voriconazole Atazanavir with ritonavir in participants with a functional CYP2C19 allele: Atazanavir with ritonavir in participants without a functional CYP2C19 allele: The use of voriconazole in patients receiving atazanavir with ritonavir is not recommended unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Patients should be carefully monitored for voriconazole-associated adverse reactions and loss of either voriconazole or atazanavir efficacy during the coadministration of voriconazole and atazanavir with ritonavir. Coadministration of voriconazole with atazanavir (without ritonavir) may affect atazanavir concentrations; however, no data are available. Antigout: up arrow colchicine The coadministration of atazanavir with colchicine in patients with renal or hepatic impairment is not recommended. Recommended adult dosage of colchicine when administered with atazanavir: Treatment of gout flares: Prophylaxis of gout flares: twice once a day once once every other day. Treatment of familial Mediterranean fever (FMF): Antimycobacterials: down arrow atazanavir Coadministration of atazanavir with rifampin is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4) rifabutin up arrow rifabutin A rifabutin dose reduction of up to 75% (e. , 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted. Antineoplastics: irinotecan up arrow irinotecan Coadministration of atazanavir with irinotecan is contraindicated. Atazanavir inhibits UGT1A1 and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities [see Contraindications (4) [see Contraindications (4) Antiplatelets Antipsychotics: up arrow pimozide Coadministration of atazanavir with pimozide is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) lurasidone Atazanavir with ritonavir Atazanavir Atazanavir with ritonavir [see Contraindications (4) Atazanavir without ritonavir Initiation of atazanavir with ritonavir in patients taking quetiapine: Initiation of quetiapine in patients taking atazanavir with ritonavir: Benzodiazepines: up arrow midazolam Coadministration of atazanavir with either orally administered midazolam or triazolam is contraindicated. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4, and coadministration with atazanavir can lead to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression [see Contraindications (4) parenterally administered b up arrow midazolam Coadministration with parenteral midazolam should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Calcium channel blockers: up arrow diltiazem and Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of diltiazem and atazanavir with ritonavir has not been studied. Caution is warranted. Dose titration of the calcium channel blocker should be considered. Corticosteroids: (all routes of administration) Endothelin receptor antagonists: Atazanavir Atazanavir with ritonavir Coadministration of bosentan and atazanavir without ritonavir is not recommended. Ergot derivatives: up arrow ergot derivatives Coadministration of atazanavir with ergot derivatives is contraindicated. This is due to the potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues [see Contraindications (4) GI Motility Agents: up arrow cisapride Coadministration of atazanavir with cisapride is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) Gonadotropin-releasing hormone Receptor (GnRH) Antagonists: down arrow atazanavir Coadministration of elagolix and atazanavir with or without ritonavir is not recommended due to the potential of loss of virologic response and the potential risk of adverse events such as bone loss and hepatic transaminase elevations associated with elagolix. Herbal Products: (Hypericum perforatum) down arrow atazanavir Coadministration of products containing St. John’s wort with atazanavir is contraindicated. This may result in loss of therapeutic effect of atazanavir and the development of resistance [see Contraindications (4) Kinase inhibitors: up arrow R406 (active metabolite When coadministering fostamatinib with atazanavir (with or without ritonavir), monitor for toxicities of R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required. Lipid-modifying agents HMG-CoA reductase inhibitors: up arrow lovastatin Coadministration of atazanavir with lovastatin or simvastatin is contraindicated. This is due to the potential for serious reactions such as myopathy, including rhabdomyolysis [see Contraindications (4) atorvastatin, rosuvastatin up arrow atorvastatin Titrate atorvastatin dose carefully and use the lowest necessary dose. Rosuvastatin dose should not exceed 10 mg/day. The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including atazanavir, are used in combination with these drugs. Other Lipid Modifying Agents: lomitapide up arrow lomitapide Coadministration of atazanavir with lomitapide is contraindicated. This is due to the potential for risk of markedly increased transaminase levels and hepatotoxicity associated with increased plasma concentrations of lomitapide. The mechanism of interaction is CYP3A4 inhibition by atazanavir and/or ritonavir [see Contraindications (4) H 2 -Receptor antagonists down arrow atazanavir Coadministration may result in loss of virologic response and development of resistance. In HIV-treatment-naive adult patients: 2 In treatment-experienced adult patients: Hormonal contraceptives: down arrow ethinyl estradiol c d Use caution if considering coadministration of oral contraceptives with atazanavir or atazanavir with ritonavir. Immunosuppressants: up arrow immunosuppressants Therapeutic concentration monitoring is recommended for these immunosuppressants when coadministered with atazanavir. Inhaled beta agonist: up arrow salmeterol Coadministration of salmeterol with atazanavir is not recommended. Concomitant use of salmeterol and atazanavir may result in increased risk of cardiovascular adverse reactions associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. Inhaled/nasal steroid: Atazanavir Concomitant use of fluticasone propionate and atazanavir without ritonavir should be used with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. Atazanavir with ritonavir With concomitant use of fluticasone propionate and atazanavir with ritonavir systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Coadministration of fluticasone propionate and atazanavir with ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see Warnings and Precautions (5. 1) Macrolide antibiotics: up arrow clarithromycin Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with atazanavir. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium avium Opioids: Atazanavir or atazanavir with ritonavir Atazanavir Coadministration of atazanavir with ritonavir and buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. PDE5 inhibitors: up arrow sildenafil Coadministration with atazanavir has not been studied but may result in an increase in PDE5 inhibitor-associated adverse reactions, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): registered [see Contraindications (4) registered registered For patients receiving atazanavir (with or without ritonavir) for at least one week, start ADCIRCA registered registered Avoid the use of ADCIRCA registered registered registered Use of PDE5 inhibitors for erectile dysfunction: registered registered Atazanavir with ritonavir: Atazanavir: Proton-pump inhibitors: down arrow atazanavir Coadministration of atazanavir with or without ritonavir and omeprazole may result in loss of virologic response and development of resistance. In HIV-treatment-naive adult patients: In HIV-treatment-experienced adult patients: a Clinical Pharmacology, Tables 21 and 22 (12. 3) b Contraindications (4) , Table 6 c d No clinically significant drug interactions were observed when atazanavir was coadministered with methadone, fluconazole, acetaminophen, atenolol, or the nucleoside reverse transcriptase inhibitors lamivudine or zidovudine [see Clinical Pharmacology, Tables 21 and 22 (12.

OVERDOSAGE
Human experience of acute overdose with atazanavir is limited. Single doses up to 1200 mg (three times the 400 mg maximum recommended dose) have been taken by healthy participants without symptomatic untoward effects. A single self-administered overdose of 29.2 g of atazanavir in a patient with HIV-1 (73 times the 400 mg recommended dose) 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 5.8) and Clinical Pharmacology (12.2) Treatment of overdosage with atazanavir should consist of general supportive measures, including monitoring of vital signs and ECG, and observations of the patient’s clinical status. If indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with atazanavir. Since atazanavir is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicine.
NONCLINICAL TOXICOLOGY
Carcinogenesis in vitro in vitro in vivo in vivo
CLINICAL STUDIES
Study AI424-138: a 96-week study comparing the antiviral efficacy and safety of either atazanavir or lopinavir/ritonavir, each in combination with fixed-dose tenofovir DF-emtricitabine in treatment-naive participants with HIV-1 infection. (NCT00272779) 3 3 10 10 Table 26: Outcomes of Treatment Through Week 96 in Treatment-Naive Adults (Study AI424-138) atazanavir 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabine (once daily) a (n=441) lopinavir/ritonavir b tenofovir DF/emtricitabine (once daily) a (n=437) Outcome 96 Weeks 96 Weeks Responder c,d,e 75% 68% Virologic failure f 17% 19% Rebound 8% 10% Never suppressed through Week 96 9% 9% Death 1% 1% Discontinued due to adverse event 3% 5% Discontinued for other reasons g 4% 7% a b c registered d e f g Through 96 weeks of therapy, the proportion of responders among participants with high viral loads (i. , baseline HIV-1 RNA >=100,000 copies/mL) was comparable for the atazanavir with ritonavir (165 of 223 participants, 74%) and lopinavir/ritonavir (148 of 222 participants, 67%) arms. At 96 weeks, the median increase from baseline in CD4+ cell count was 261 cells/mm 3 3 Study AI424-034: Atazanavir once daily compared to efavirenz once daily, each in combination with fixed-dose lamivudine/zidovudine twice daily. (NCT00013897) 3 3 10 10 Table 27: Outcomes of Randomized Treatment Through Week 48 in Treatment-Naive Adults (Study AI424-034) atazanavir 400 mg once daily and lamivudine/zidovudine d efavirenz 600 mg once daily and lamivudine/zidovudine d Outcome (n=405) (n=405) Responder a 67% (32%) 62% (37%) Virologic failure b 20% 21% Rebound 17% 16% Never suppressed through Week 48 3% 5% Death en dash <1% Discontinued due to adverse event 5% 7% Discontinued for other reasons c 8% 10% a registered TM b c d Through 48 weeks of therapy, the proportion of responders among participants with high viral loads (i. , baseline HIV-1 RNA >=100,000 copies/mL) was comparable for the atazanavir and efavirenz arms. The mean increase from baseline in CD4+ cell count was 176 cells/mm 3 3 Study AI424-008: Atazanavir 400 mg once daily compared to atazanavir 600 mg once daily, and compared to nelfinavir 1250 mg twice daily, each in combination with stavudine and lamivudine twice daily. 3 3 10 10 Table 28: Outcomes of Randomized Treatment Through Week 48 in Treatment-Naive Adults (Study AI424-008) atazanavir 400 mg once daily with lamivudine and stavudine nelfinavir 1250 mg twice daily with lamivudine and stavudine Outcome (n=181) (n=91) Responder a 67% (33%) 59% (38%) Virologic failure b 24% 27% Rebound 14% 14% Never suppressed through Week 48 10% 13% Death <1% en dash Discontinued due to adverse event 1% 3% Discontinued for other reasons c 7% 10% a registered TM b c Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 234 cells/mm 3 3 Study AI424-045: Atazanavir once daily with ritonavir once daily compared to atazanavir once daily and saquinavir (soft gelatin capsules) once daily, and compared to lopinavir/ritonavir twice daily, each in combination with tenofovir DF and one NRTI. (NCT00035932): 3 3 10 10 Treatment outcomes through Week 48 for the atazanavir with ritonavir and lopinavir/ritonavir treatment arms are presented in Table 29. Atazanavir with ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV-1 RNA level. Study AI424-045 was not large enough to reach a definitive conclusion that atazanavir with ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measure of proportions below the HIV-1 RNA lower limit of quantification [see Microbiology, Tables 24 and 25 (12. 4) Table 29: Outcomes of Treatment Through Week 48 in Study AI424-045 (Participants with Prior Antiretroviral Experience) atazanavir 300 mg with ritonavir 100 mg once daily and tenofovir DF and 1 NRTI lopinavir/ritonavir (400/100 mg) twice daily and tenofovir DF and 1 NRTI Difference a (atazanavir- lopinavir/ritonavir) b Outcome (n=119) (n=118) (CI) HIV-1 RNA Change from 10 c −1. 12 c CD4+ Change from Baseline (cells/mm 3 e 116 123 −7 (−67, 52) Percent of Participants Responding e HIV-1 RNA <400 copies/mL c 55% 57% -2. 2% HIV-1 RNA <50 copies/mL c 38% 45% −7. 1% a b c registered TM d e f No participants in the atazanavir with ritonavir treatment arm and three participants in the lopinavir/ritonavir treatment arm experienced a new-onset CDC Category C event during the study. In Study AI424-045, the mean change from baseline in plasma HIV-1 RNA for atazanavir 400 mg with saquinavir (n=115) was −1. 55 log 10 3 [see Drug Interactions (7) Study AI424-045 also compared changes from baseline in lipid values. [See Adverse Reactions (6. 1) Study AI424-043 (NCT00028301): 10 10 Pediatric Trials with Atazanavir Capsules Study AI424-040; PACTG 1020A (NCT00006604): One-hundred five (105) participants (6 to less than 18 years of age) treated with the atazanavir capsule formulation, with or without ritonavir, were evaluated. Using an intent-to-treat (ITT) analysis, the overall proportions of antiretroviral-naive and -experienced participants with HIV-1 RNA <400 copies/mL at Week 96 were 51% (22/43) and 34% (21/62), respectively. The overall proportions of antiretroviral-naive and -experienced participants with HIV-1 RNA <50 copies/mL at Week 96 were 47% (20/43) and 24% (15/62), respectively. The median increase from baseline in absolute CD4 count at 96 weeks of therapy was 335 cells/mm 3 3.

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