Atazanavir Sulfate

Contraindications ( 4 ) 12/2024

1 INDICATIONS AND USAGE Atazanavir capsules are 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 capsules are 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. ( 1 )

2 DOSAGE AND ADMINISTRATION Pretreatment testing: Renal laboratory testing should be performed in all patients prior to initiation of atazanavir capsules and continued during treatment with atazanavir capsules. Hepatic testing should be performed in patients with underlying liver disease prior to initiation of atazanavir capsules and continued during treatment with atazanavir capsules. ( 2.2 ) Treatment-naive adults: Atazanavir capsules 300 mg with ritonavir 100 mg once daily with food or atazanavir capsules 400 mg once daily with food. ( 2.3 ) Treatment-experienced adults: Atazanavir capsules 300 mg with ritonavir 100 mg once daily with food. ( 2.3 ) Pediatric patients: Atazanavir capsule dosage is based on body weight not to exceed the adult dose and must be taken with food. ( 2.4 ) Pregnancy: Atazanavir capsules 300 mg with ritonavir 100 mg once daily with food, with dosing modifications for some concomitant medications. ( 2.6 ) Dosing modifications: may be required for concomitant therapy ( 2.3 , 2.4 , 2.6 ), renal impairment ( 2.7 ), and hepatic impairment. ( 2.8 ) 2.1 Overview 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 -receptor antagonists or proton-pump inhibitors, dose separation may be required [see Dosage and Administration (2.3 , 2.4 , and 2.6 ) and 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. 2.2 Testing Prior to Initiation and During Treatment with Atazanavir Capsules 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 (5.5 , 5.6) ]. Hepatic laboratory testing should be performed in patients with underlying liver disease prior to initiation of atazanavir capsules and continued during treatment with atazanavir capsules [see Warnings and Precautions (5.4) ]. 2.3 Dosage of Atazanavir Capsules in Adult Patients 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 -receptor antagonists (H2RA). Ritonavir is required with several atazanavir capsules dosage regimens (see the ritonavir complete prescribing information about the safe and effective use of ritonavir). The use of atazanavir capsules in treatment-experienced adult patients without ritonavir is not recommended. Table 1: Recommended Atazanavir Capsules and Ritonavir Dosage in Adults a a See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (e.g., H2RA or proton pump inhibitors [PPIs]), and other antiretroviral drugs (e.g., efavirenz, tenofovir DF, and didanosine). 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 m …

3 DOSAGE FORMS AND STRENGTHS 100 mg Capsules are blue/white size ‘2’ hard gelatin capsule filled with off-white to pale yellow granular powder and imprinted with ‘100 mg’ on blue cap with white edible ink and ‘T23’ on white body with black edible ink. 150 mg Capsules are blue/powder blue size ‘1’ hard gelatin capsule filled with off-white to pale yellow granular powder and imprinted with ‘150 mg’ on blue cap and ‘T24’ on powder blue body with white edible ink. 200 mg Capsules are blue/blue size ‘0’ hard gelatin capsule filled with off-white to pale yellow granular powder and imprinted with ‘200 mg’ on blue cap and ‘T25’ on blue body with white edible ink. 300 mg Capsules are red/blue size ‘00’ hard gelatin capsule filled with off-white to pale yellow granular powder and imprinted with ‘300 mg’ on red cap and ‘T26’ on blue body with white edible ink. Capsules: 100 mg, 150 mg, 200 mg, and 300 mg. (3, 16)

4 CONTRAINDICATIONS Atazanavir capsules are 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 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 See Drug Interactions, Table 16 (7) for parenterally administered midazolam. b See Drug Interactions, Table 16 (7) for sildenafil when dosed as VIAGRA ® for erectile dysfunction. 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 , triazolam 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 when dosed as REVATIO ® for the treatment of pulmonary arterial hypertension Protease Inhibitors Indinavir Non-nucleoside Reverse Transcriptase Inhibitors Nevirapine In patients with previously demonstrated hypersensitivity (e.g., 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. ( 4 )

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) ] 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 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 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 of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1, b Study AI424-138 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 400 mg/100 mg (twice 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 Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on the regimen containing atazanavir. c Median time on therapy. d Administered as a fixed-dose. e As a fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily. Table 8: Selected Adverse Reactions a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1, b Studies AI424-034, AI424-007, and AI424-008 Study AI424-034 Studies AI424-007, -008 64 weeks c atazanavir 400 mg (once daily) with lamivudine/ zidovudine e (n=404) 64 weeks c efavirenz 600 mg (once daily) with lamivudine/ zidovudine e (n=401) 120 weeks c,d atazanavir 400 mg (once daily) with stavudine and lamivudine or didanosine (n=279) 73 weeks c,d nelfinavir 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% 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/ …

7 DRUG INTERACTIONS Coadministration of atazanavir can alter the concentration of other drugs and other drugs may alter the concentration of atazanavir. The potential drug-drug interactions must be considered prior to and during therapy. (4, 7, 12.3) 7.1 Potential for Atazanavir to Affect Other Drugs Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of atazanavir and drugs primarily metabolized by CYP3A or UGT1A1 may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects. Atazanavir is a weak inhibitor of CYP2C8. Use of atazanavir without ritonavir is not recommended when coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (e.g., paclitaxel, repaglinide). When atazanavir with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected [see Clinical Pharmacology, Table 22 (12.3) ] . The magnitude of CYP3A-mediated drug interactions on coadministered drug may change when atazanavir is coadministered with ritonavir. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir. 7.2 Potential for Other Drugs to Affect Atazanavir Atazanavir is a CYP3A4 substrate; therefore, drugs that induce CYP3A4 may decrease atazanavir plasma concentrations and reduce atazanavir's therapeutic effect (see Table 16) . Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors, antacids, buffered medications, or H 2 -receptor antagonists are administered with atazanavir [see Dosage and Administration (2.3 , 2.4 , and 2.6) ] . 7.3 Established and Other Potentially Significant Drug Interactions Table 16 provides dosing recommendations in adults as a result of drug interactions with atazanavir. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy. Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies a or Predicted Interactions (Information in the table applies to atazanavir with or without ritonavir, unless otherwise indicated) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment HIV Antiviral Agents Nucleoside Reverse Transcriptase Inhibitors (NRTIs): didanosine buffered formulations enteric coated (EC) capsules ↓ atazanavir ↓ didanosine It is recommended that atazanavir be given (with food) 2 h before or 1 h after didanosine buffered formulations. Simultaneous administration of didanosine EC and atazanavir with food results in a decrease in didanosine exposure. Thus, atazanavir and didanosine EC should be administered at different times. Nucleotide Reverse Transcriptase Inhibitors: tenofovir disoproxil fumarate (DF) ↓ atazanavir ↑ tenofovir When coadministered with tenofovir DF in adults, it is recommended that atazanavir 300 mg be given with ritonavir 100 mg and tenofovir DF 300 mg (all as a single daily dose with food). The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir­-associated adverse reactions, including renal disorders. Patients receiving atazanavir and tenofovir DF should be monitored for tenofovir-associated adverse reactions. For pregnant patients taking atazanavir with ritonavir and tenofovir DF, see Dosage and Administration (2.6) . Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): efavirenz ↓ atazanavir In HIV-treatment-naive adult patients: If atazanavir is combined with efavirenz, atazanavir 400 mg (two 200 mg capsules) should be administered with ritonavir 100 mg simultaneously once daily with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedt …

8 USE IN SPECIFIC POPULATIONS Pregnancy: Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate. ( 8.1 ) Hepatitis B or C co-infection: Monitor liver enzymes. ( 5.4 , 6.1 ) Renal impairment: Atazanavir is not recommended for use in treatment-experienced patients with end-stage renal disease managed with hemodialysis. ( 2.7 , 8.7 ) Hepatic impairment: Atazanavir is not recommended in patients with severe hepatic impairment. Atazanavir with ritonavir is not recommended in patients with any degree of hepatic impairment. ( 2.8 , 8.8 ) 8.1 Pregnancy 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]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. No treatment-related malformations were observed in rats and rabbits, for which the atazanavir exposures were 0.7 to 1.2 times of those at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). When atazanavir was administered to rats during pregnancy and throughout lactation, reversible neonatal growth retardation was observed [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 -receptor antagonist or tenofovir DF, atazanavir 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend a atazanavir dose for use with both an H 2 -receptor antagonist and tenofovir DF in treatment-experienced pregnant patients. 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) and 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) ] , including those who are pregnant [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 , should be monitored for the development of severe hyperbilirubinemia during the first few days of life [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). Ther …

12.1 Mechanism of Action Atazanavir is an HIV-1 antiretroviral drug [see Microbiology ( 12.4 )].

11 DESCRIPTION The active ingredient in atazanavir capsules is atazanavir sulfate, USP, which is an HIV-1 protease inhibitor. The chemical name for atazanavir sulfate, USP 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, USP has the following structural formula: Atazanavir sulfate, USP is a white to pale-yellow crystalline powder. It is slightly soluble in water (4 to 5 mg/mL, free base equivalent) with the pH of a saturated solution in water being about 1.9 at 24 ± 3 ○ C. Atazanavir capsules are available for oral administration in strengths of 150 mg, 200 mg, or 300 mg of atazanavir, which are equivalent to 170.8 mg, 227.8 mg, or 341.69 mg of atazanavir sulfate, USP, respectively. The capsules contain the following inactive ingredients: crospovidone, lactose monohydrate, and magnesium stearate. The capsule shells contain the following inactive ingredients: FD&C Blue No. 1, gelatin, and titanium dioxide. The 300 mg capsule shells also contain FD&C Red No. 40. The capsules are printed with black ink containing D&C Yellow No. 10 aluminum lake, FD&C Blue No. 1 aluminum lake, FD&C Blue No. 2 aluminum lake, FD&C Red No. 40 aluminum lake, iron oxide black, shellac, and may contain propylene glycol. structural formula

10 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Atazanavir Capsules, 100 mg are blue/white size ‘2’ hard gelatin capsule filled with off-white to pale yellow granular powder and imprinted with ‘100 mg’ on blue cap with white edible ink and ‘T23’ on white body with black edible ink. Bottles of 60 NDC 65862-710-60 Bottles of 500 NDC 65862-710-05 3 x 10 Unit-dose Capsules NDC 65862-710-03 Atazanavir Capsules, 150 mg are blue/powder blue size ‘1’ hard gelatin capsule filled with off-white to pale yellow granular powder and imprinted with ‘150 mg’ on blue cap and ‘T24’ on powder blue body with white edible ink. Bottles of 60 NDC 65862-711-60 Bottles of 180 NDC 65862-711-18 Bottles of 500 NDC 65862-711-05 3 x 10 Unit-dose Capsules NDC 65862-711-03 Atazanavir Capsules, 200 mg are blue/blue size ‘0’ hard gelatin capsule filled with off-white to pale yellow granular powder and imprinted with ‘200 mg’ on blue cap and ‘T25’ on blue body with white edible ink. Bottles of 60 NDC 65862-712-60 Bottles of 180 NDC 65862-712-18 Bottles of 500 NDC 65862-712-05 3 x 10 Unit-dose Capsules NDC 65862-712-03 Atazanavir Capsules, 300 mg are red/blue size ‘00’ hard gelatin capsule filled with off-white to pale yellow granular powder and imprinted with ‘300 mg’ on red cap and ‘T26’ on blue body with white edible ink. Bottles of 30 NDC 65862-713-30 Bottles of 90 NDC 65862-713-90 Bottles of 500 NDC 65862-713-05 3 x 10 Unit-dose Capsules NDC 65862-713-03 Keep capsules in a tightly closed container. Store at 20 o to 25 o C (68 o to 77 o F) [see USP Controlled Room Temperature].