Atazanavir

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 of age and older weighing at least 15 kg. Limitations of Use: Atazanavir is 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 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 of age 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 (eg, H2RA or proton pump inhibitors [PPIs]), and other antiretroviral drugs (eg, 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 300mg 100 mg in combination with both H2RA and tenofovir DF 400mg 100 mg 2.4 …

5 WARNINGS AND PRECAUTIONS Cardiac conduction abnormalities: PR interval prolongation may occur in some patients. ECG monitoring should be considered in patients with preexisting conduction system disease or when administered with other drugs that may prolong the PR interval. ( 5.1 , 7.3 , 12.2 , 17 ) Severe Skin Reactions: Discontinue if severe rash develops. ( 5.2 , 17 ) Hyperbilirubinemia: Most patients experience asymptomatic increases in indirect bilirubin, which is reversible upon discontinuation. Do not dose reduce. If a concomitant transaminase increase occurs, evaluate for alternative etiologies. ( 5.8 ) Hepatotoxicity: Patients with hepatitis B or C virus are at risk of increased transaminases or hepatic decompensation. Monitor hepatic laboratory tests prior to therapy and during treatment. ( 2.8 , 5.4 , 8.8 ) Chronic kidney disease has been reported during postmarketing surveillance in patients with HIV-1 treated with atazanavir, with or without ritonavir. Consider alternatives in patients at high risk for renal disease or with preexisting renal disease. Monitor renal laboratory tests prior to therapy and during treatment. Consider discontinuation of atazanavir in patients with progressive renal disease. ( 5.5 ) Nephrolithiasis and cholelithiasis have been reported. Consider temporary interruption or discontinuation. ( 5.6 ) The concomitant use of atazanavir with ritonavir and certain other medications may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatment for potential drug interactions. ( 5.7 , 7.3 ) Patients receiving atazanavir may develop new onset or exacerbations of diabetes mellitus/hyperglycemia ( 5.9 ), immune reconstitution syndrome ( 5.10 ), and redistribution/accumulation of body fat. ( 5.11 ) Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required. ( 5.12 ) 5.1 Cardiac Conduction Abnormalities Atazanavir has been shown to prolong the PR interval of the electrocardiogram in some study participants. In healthy participants and in participants with HIV-1 treated with atazanavir, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been reports of second-degree AV block and other conduction abnormalities [see Adverse Reactions (6.2) and Overdosage (10) ] . In clinical trials that included electrocardiograms, asymptomatic first-degree AV block was observed in 5.9% of atazanavir-treated participants (n=920), 5.2% of lopinavir/ritonavir-treated participants (n=252), 10.4% of nelfinavir-treated participants (n=48), and 3.0% of efavirenz-treated participants (n=329). In Study AI424-045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir with ritonavir-treated participants and 5% (6/116) of lopinavir/ritonavir-treated participants who had on-study electrocardiogram measurements. Because of limited clinical experience in those with preexisting conduction system disease (eg, marked first-degree AV block or second- or third-degree AV block), ECG monitoring should be considered in these patients [see Clinical Pharmacology (12.2) ] . 5.2 Severe Skin Reactions In controlled clinical trials, rash (all grades, regardless of causality) occurred in approximately 20% of participants with HIV-1 treated with atazanavir. The median time to onset of rash in clinical studies was 7.3 weeks and the median duration of rash was 1.4 weeks. Rashes were generally mild-to-moderate maculopapular skin eruptions. Treatment-emergent adverse reactions of moderate or severe rash (occurring at a rate of ≥2%) are presented for the individual clinical studies [see Adverse Reactions (6.1) ] . Dosing with atazanavir was often continued without interruption in patients who developed rash. The discontinuation rate for rash in clinical trials was <1%. Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including…

4 CONTRAINDICATIONS Atazanavir capsules are contraindicated: in patients with previously demonstrated clinically significant hypersensitivity (eg, 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) In patients with previously demonstrated hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of atazanavir capsules. ( 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 ) atazanavir-figue11.jpg

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 (eg, 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 a For magnitude of interactions see Clinical Pharmacology, Tables 21 and 22 (12.3) . b See Contraindications (4) , Table 6 for orally administered midazolam. c In combination with atazanavir 300 mg with ritonavir 100 mg once daily. d In combination with atazanavir 400 mg once daily. 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…

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). 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…

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 Laurus Generics Inc. at 1-833-3-LAURUS (1-833-352-8787) 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 1,625 participants with HIV-1 in clinical trials. 536 participants received atazanavir 300 mg with ritonavir 100 mg and 1,089 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 * 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. 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% 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 * None reported in this treatment arm. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on regimens containing atazanavir. c Median time on therapy. d Includes long-term follow-up. e As a fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily. 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% <1% * Dizziness 2% 7% <1% * Peripheral neurologic symptoms <1% 1% 4% 3% Skin and Appendages Rash 7% 10% 5% 1% 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 adv…