FDA Label for Atazanavir

1 Indications And Usage

Atazanavir capsules are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection for patients 6 years 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.
• Use of atazanavir/ritonavir in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions [see Microbiology (12.4)].

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 co-administered drugs. When co-administered with H₂-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 H₂-receptor antagonists (H2RA).  Ritonavir is required with several atazanavir 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

2.4 Dosage Of Atazanavir Capsules In Pediatric Patients

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

When transitioning between formulations, a change in dose may be needed. Consult the dosing table for the specific formulation.

2.6 Dosage Adjustments In Pregnant Patients

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

2.7 Dosage In Patients With Renal Impairment

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 HIV-treatment-experienced patients with end-stage renal disease managed with hemodialysis [see Use in Specific Populations (8.7)].

2.8 Dosage Adjustments In Patients With Hepatic Impairment

Table 5 displays the recommended atazanavir 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 co-administration 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

3 Dosage Forms And Strengths

Atazanavir Capsules:

• Atazanavir capsules, 100 mg are supplied as size ‘2’ hard gelatin capsules having imprinted ‘Amneal 100 mg’ on blue opaque cap with white ink and ‘1135’ on white opaque body with blue ink, filled with off-white to yellow granular powder.
• Atazanavir capsules, 150 mg are supplied as size ‘1’ hard gelatin capsules having imprinted ‘Amneal 150 mg’ on blue opaque cap with white ink and ‘1136’ on powder blue opaque body with blue ink, filled with off-white to yellow granular powder.
• Atazanavir capsules, 200 mg are supplied as size ‘0’ hard gelatin capsules having imprinted ‘Amneal 200 mg’ on blue opaque cap and ‘1137’on blue opaque body with white ink, filled with off-white to yellow granular powder.
• Atazanavir capsules, 300 mg are supplied as size ‘00’ hard gelatin capsules having imprinted ‘Amneal 300 mg’ on red opaque cap and ‘1138’ on blue opaque body with white ink, filled with off-white to yellow granular powder.

4 Contraindications

Atazanavir is contraindicated:

• in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens- Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of atazanavir capsules [see Warnings and Precautions (5.2)].
• when co-administered 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 co-administered with drugs that strongly induce CYP3A and may lead to lower exposure and loss of efficacy of atazanavir (see Table 6).

Table 6 displays drugs that are contraindicated with atazanavir.

Table 6: Drugs that are Contraindicated with Atazanavir (Information in the table applies to  Atazanavir with or without ritonavir, unless otherwise indicated)

Drug Class	Drugs within class that are contraindicated with Atazanavir	Clinical Comment
Alpha 1-Adrenoreceptor Antagonist	Alfuzosin	Potential for increased alfuzosin concentrations, which can result in hypotension.
Antimycobacterials	Rifampin	Rifampin substantially decreases plasma concentrations of atazanavir, which may result in loss of therapeutic effect and development of resistance.
Antineoplastics	Irinotecan	Atazanavir inhibits UGT1A1 and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities.
Antipsychotics	Lurasidone	Potential for serious and/or life-threatening reactions if atazanavir is co-administered with ritonavir.
	Pimozide	Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Benzodiazepines	Triazolam, orally administered midazolama	Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Co-administration of triazolam or orally administered midazolam with atazanavir may cause large increases in the concentration of these benzodiazepines. Potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression.
Ergot Derivatives	Dihydroergotamine, ergotamine, ergonovine, methylergonovine	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.
GI Motility Agent	Cisapride	Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Hepatitis C Direct-Acting Antivirals	Elbasvir/grazoprevir	May increase the risk of ALT elevations due to a significant increase in grazoprevir plasma concentrations.
	Glecaprevir/pibrentasvir	May increase the risk of ALT elevations due to an increase in glecaprevir and pibrentasvir concentrations.
Herbal Products	St. John’s wort (Hypericum perforatum)	Co-administration of St. John’s wort and atazanavir may result in loss of therapeutic effect and development of resistance.
HMG-CoA Reductase Inhibitors	Lovastatin, simvastatin	Potential for serious reactions such as myopathy, including rhabdomyolysis.
PDE5 Inhibitor	Sildenafilb when dosed as REVATIO® for the treatment of pulmonary arterial hypertension	Potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, priapism, and syncope).
Protease Inhibitors	Indinavir	Both atazanavir and indinavir are associated with indirect (unconjugated) hyperbilirubinemia.
Non-nucleoside Reverse Transcriptase Inhibitors	Nevirapine	Nevirapine substantially decreases atazanavir exposure which may result in loss of therapeutic effect and development of resistance. Potential risk for nevirapine-associated adverse reactions due to increased nevirapine exposures.
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.

5.1 Cardiac Conduction Abnormalities

Atazanavir has been shown to prolong the PR interval of the electrocardiogram in some patients. In healthy volunteers and in patients, 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 patients (n=920), 5.2% of lopinavir/ritonavir-treated patients (n=252), 10.4% of nelfinavir-treated patients (n=48), and 3.0% of efavirenz-treated patients (n=329). In Study AI424-045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir/ritonavir-treated patients and 5% (6/116) of lopinavir/ritonavir-treated patients who had on-study electrocardiogram measurements. Because of limited clinical experience in patients with preexisting conduction system disease (e.g., marked first-degree AV block or second- or third-degree AV block). 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 patients 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 drug rash, eosinophilia, and systemic symptoms (DRESS) syndrome, have been reported in patients receiving atazanavir [see Contraindications (4) and Adverse Reactions (6.1)]. Atazanavir should be discontinued if severe rash develops.

5.4 Hepatotoxicity

Patients with underlying hepatitis B or C viral infections or marked elevations in transaminases before treatment may be at increased risk for developing further transaminase elevations or hepatic decompensation. In these patients, hepatic laboratory testing should be conducted prior to initiating therapy with atazanavir and during treatment [see Dosage and Administration (2.2), Adverse Reactions (6.1), and Use in Specific Populations (8.8)].

5.5 Chronic Kidney Disease

Chronic kidney disease in HIV-infected patients treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. Reports included biopsy-proven cases of granulomatous interstitial nephritis associated with the deposition of atazanavir drug crystals in the renal parenchyma. Consider alternatives to atazanavir in patients at high risk for renal disease or with preexisting renal disease. Renal laboratory testing (including serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination) should be conducted in all patients prior to initiating therapy with atazanavir and continued during treatment with atazanavir. Expert consultation is advised for patients who have confirmed renal laboratory abnormalities while taking atazanavir. In patients with progressive kidney disease, discontinuation of atazanavir may be considered [see Dosage and Administration (2.2 and 2.7) and Adverse Reactions (6.2)].

5.6 Nephrolithiasis And Cholelithiasis

Cases of nephrolithiasis and/or cholelithiasis have been reported during postmarketing surveillance in HIV-infected patients receiving atazanavir therapy. Some patients required hospitalization for additional management and some had complications. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis and/or cholelithiasis occur, temporary interruption or discontinuation of therapy may be considered [see Adverse Reactions (6.2)].

5.7 Risk Of Serious Adverse Reactions Due To Drug Interactions

Initiation of atazanavir with ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving atazanavir with ritonavir, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of atazanavir with ritonavir, respectively. These interactions may lead to:

• clinically significant adverse reactions potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.
• clinically significant adverse reactions from greater exposures of atazanavir with ritonavir.
• loss of therapeutic effect of atazanavir with ritonavir and possible development of resistance.

See Table 16 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions (7)]. Consider the potential for drug interactions prior to and during atazanavir/ritonavir therapy; review concomitant medications during atazanavir/ritonavir therapy; and monitor for the adverse reactions associated with the concomitant medications [see Contraindications (4) and Drug Interactions (7)].

5.8 Hyperbilirubinemia

Most patients taking atazanavir experience asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT). This hyperbilirubinemia is reversible upon discontinuation of atazanavir. Hepatic transaminase elevations that occur with hyperbilirubinemia should be evaluated for alternative etiologies. No long-term safety data are available for patients experiencing persistent elevations in total bilirubin >5 times the upper limit of normal (ULN). Alternative antiretroviral therapy to atazanavir may be considered if jaundice or scleral icterus associated with bilirubin elevations presents cosmetic concerns for patients. Dose reduction of atazanavir is not recommended since long-term efficacy of reduced doses has not been established [see Adverse Reactions (6.1)].

5.9 Diabetes Mellitus/Hyperglycemia

New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established [see Adverse Reactions (6.2)].

5.10 Immune Reconstitution Syndrome

Immune  reconstitution  syndrome  has  been  reported  in  patients  treated  with  combination antiretroviral   therapy,   including   atazanavir.  During  the  initial  phase  of  combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response  to  indolent  or  residual  opportunistic  infections  (such  as  Mycobacterium  avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

5.11 Fat Redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

5.12 Hemophilia

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.

5.13 Resistance/Cross-Resistance

Various degrees of cross-resistance among protease inhibitors have been observed. Resistance to atazanavir may not preclude the subsequent use of other protease inhibitors [see Microbiology (12.4)].

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)]

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 Patients

The safety profile of atazanavir in treatment-naive adults is based on 1625 HIV-1 infected patients in clinical trials. 536 patients received atazanavir 300 mg with ritonavir 100 mg and 1089 patients 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  patients  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 Patients,^b Study AI424-138

Table 8: Selected Adverse Reactions^a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Patients,^b Studies AI424-034, AI424-007, and AI424-008

Adverse Reactions in Treatment-Experienced Adult Patients

The safety profile of atazanavir in treatment-experienced adults is based on 119 HIV-1 infected patients 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 patients receiving atazanavir/ritonavir are presented in Table 9.

Table 9: Selected Adverse Reactions^a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Experienced Patients,^b Study AI424-045

Laboratory Abnormalities in Treatment-Naive Patients

The percentages of adult treatment-naive patients treated with combination therapy including atazanavir 300 mg with ritonavir 100 mg and 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 Patients,^a Study AI424-138

Table 11: Grade 3 to 4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Patients,^a Studies AI424-034, AI424-007, and AI424-008

Change in Lipids from Baseline in Treatment-Naive Patients

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

Laboratory Abnormalities in Treatment-Experienced Patients

The percentages of adult treatment-experienced patients treated with combination therapy including atazanavir/ritonavir with 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 Patients, Study AI424-045^a

Change in Lipids from Baseline in Treatment-Experienced Patients

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/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

Adverse Reactions in Pediatric Patients: Atazanavir Capsules

The safety and tolerability of atazanavir capsules with and without ritonavir have been established in pediatric patients at least 6 years of age from the open-label, multicenter clinical trial PACTG 1020A.

The safety profile of atazanavir in pediatric patients (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 patients 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 patients. The most common Grade 3 to 4 laboratory abnormalities occurring in pediatric patients 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 Patients Co-Infected with Hepatitis B and/or Hepatitis C Virus

In Study AI424-138, 60 patients treated with atazanavir/ritonavir 300 mg/100 mg once daily, and 51 patients treated with lopinavir/ritonavir 400 mg/100 mg 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  atazanavir/ritonavir-treated  patients  and 8% (4/50) of the lopinavir/ritonavir-treated patients. AST levels >5 times ULN developed in 10%  (6/60)  of  the  atazanavir/ritonavir-treated  patients  and  none  (0/50)  of  the lopinavir/ritonavir-treated patients.

In Study AI424-045, 20 patients treated with atazanavir/ritonavir 300 mg/100 mg once daily, and 18 patients treated with lopinavir/ritonavir 400 mg/100 mg twice daily, were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 25% (5/20) of the atazanavir/ritonavir-treated patients and 6% (1/18) of the lopinavir/ritonavir-treated patients. AST levels >5 times ULN developed in 10% (2/20) of the atazanavir/ritonavir-treated patients and 6% (1/18) of the lopinavir/ritonavir-treated patients.

In Studies AI424-008 and AI424-034, 74 patients treated with 400 mg of atazanavir 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 atazanavir-treated patients, 14% of the efavirenz-treated patients, and 17% of the nelfinavir-treated patients. AST levels >5 times ULN developed in 9% of the atazanavir-treated patients, 5% of the efavirenz­-treated patients, and 17% of the nelfinavir-treated patients. Within atazanavir and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative patients [see Warnings and Precautions (5.8)].

6.2 Postmarketing Experience

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: edema

Cardiovascular System: second-degree AV block, third-degree AV block, left bundle branch block, QTc prolongation [see Warnings and Precautions (5.1)]

Gastrointestinal System: pancreatitis

Hepatic System: hepatic function abnormalities

Hepatobiliary Disorders:  cholelithiasis [see  Warnings and Precautions (5.6)], cholecystitis, cholestasis

Metabolic System and Nutrition Disorders: diabetes mellitus, hyperglycemia [see Warnings and Precautions (5.9)]

Musculoskeletal System: arthralgia

Renal System: nephrolithiasis [see Warnings and Precautions (5.6)], interstitial nephritis, granulomatous interstitial nephritis, chronic kidney disease [see Warnings and Precautions (5.5)]

Skin and Appendages: alopecia, maculopapular rash [see Contraindications (4) and Warnings and Precautions (5.2)], pruritus, angioedema

7.1 Potential For Atazanavir To Affect Other Drugs

Atazanavir is an inhibitor of CYP3A and UGT1A1. Co-administration 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 co-administered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (e.g., paclitaxel, repaglinide). When atazanavir with ritonavir is co-administered 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 co-administered drug may change when atazanavir is co-administered 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.

Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors, antacids, buffered medications, or H₂-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)

7.4 Drugs With No Observed Interactions With Atazanavir

No clinically significant drug interactions were observed when atazanavir was co-administered with methadone, fluconazole, acetaminophen, atenolol, or the nucleoside reverse transcriptase inhibitors lamivudine or zidovudine [see Clinical Pharmacology, Tables 21 and 22 (12.3)].

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women 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 women.
• 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 co-administered with either an H₂-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 H₂-receptor antagonist and tenofovir DF in treatment-experienced pregnant women.
• 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 pregnant women [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 clinical trial AI424-182, atazanavir/ritonavir (300/100 mg or 400/100 mg) in combination with zidovudine/lamivudine was administered to 41 HIV-infected pregnant women during the second or third trimester. Among the 39 women who completed the study, 38 women achieved an HIV RNA less than 50 copies/mL at time of delivery. Six of 20 (30%) women on atazanavir/ritonavir  300/100  mg  and  13  of  21  (62%)  women  on  atazanavir/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 HIV-infected pregnant women, 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  1,600  live  births  following exposure to atazanavir-containing regimens (including 1,037 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. In the U.S. 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.

8.2 Lactation

Risk Summary

The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. 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.

Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed.

8.4 Pediatric Use

Atazanavir capsule is indicated in combination with other antiretroviral agents for the treatment of HIV-1  infection  in  pediatric  patients  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)]. All atazanavir contraindications, warnings, and precautions apply to pediatric patients [see Contraindications (4) and Warnings and Precautions (5)].

The safety, pharmacokinetic profile, and virologic response of atazanavir in pediatric patients 6 years of age and older weighing at least 15 kg were established in an open-label, multicenter clinical trial:   PACTG   1020A [see Clinical Pharmacology (12.3) and Clinical Studies (14.3)]. The safety profile in pediatric patients was generally similar to that observed in adults [see Adverse Reactions (6.1)]. See Dosage and Administration (2.4) for dosing recommendations for the use of atazanavir capsules.

8.5 Geriatric Use

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 and AUC, a dose adjustment based upon age is not recommended. In general, appropriate caution should be exercised in the administration and monitoring of atazanavir in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Age/Gender

A study of the pharmacokinetics of atazanavir was performed in young (n=29; 18 to 40 years) and elderly (n=30; ≥ 65 years) healthy subjects. There were no clinically significant pharmacokinetic differences observed due to age or gender.

8.7 Impaired Renal Function

Atazanavir is not recommended for use in HIV-treatment-experienced patients with end-stage renal disease managed with hemodialysis [see Dosage and Administration (2.7) and Clinical Pharmacology (12.3)].

8.8 Impaired Hepatic Function

Atazanavir is not recommended for use in patients with severe hepatic impairment. Atazanavir/ritonavir is not recommended in patients with any degree of hepatic impairment [see Dosage and Administration (2.8) and Clinical Pharmacology (12.3)].

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 volunteers without symptomatic untoward effects. A single self-administered overdose of 29.2 g of atazanavir in an HIV-infected patient (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.

11 Description

The active ingredient in atazanavir capsules is atazanavir sulfate, which is an HIV-1 protease inhibitor.

The chemical name for atazanavir sulfate is (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1). Its molecular formula is C₃₈H₅₂N₆O₇∙H₂SO₄, which corresponds to a molecular weight of 802.9 (sulfuric acid salt). The free base molecular weight is 704.9. Atazanavir sulfate has the following structural formula:

structure - atazanavir capsules 1

Atazanavir sulfate 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 100 mg, 150 mg, 200 mg, or 300 mg of atazanavir, which are equivalent to 113.9 mg, 170.85 mg, 227.8 mg, or 341.7 mg of atazanavir sulfate, respectively. The capsules also contain the following inactive ingredients:  crospovidone, FD&C blue 1, FD&C red 3 (150 mg only), FD&C red 40 (300 mg only), FD&C yellow 6 (300 mg only), gelatin, lactose monohydrate, magnesium stearate and titanium dioxide.

The white imprinting pharmaceutical ink used for 100 mg, 150 mg, 200 mg and 300 mg containing shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, potassium hydroxide and titanium dioxide.

The blue imprinting pharmaceutical ink used for used for 100 mg and 150 mg containing shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, FD & C Blue # 2 Aluminum Lake (Indigo Carmine).

12.1 Mechanism Of Action

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

12.2 Pharmacodynamics

Cardiac Electrophysiology

Concentration- and dose-dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy volunteers receiving atazanavir. In a 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 subjects. 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 HIV- infected patients receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy subject or HIV-infected patient in clinical trials had a QTc interval >500 msec [see Warnings and Precautions (5.1)].

12.3 Pharmacokinetics

The pharmacokinetics of atazanavir were evaluated in healthy adult volunteers and in HIV- infected patients 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 Subjects or HIV-Infected Patients in the Fed State

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 HIV-infected adult patients.

Figure 1: Mean (SD) Steady-State Plasma Concentrations of Atazanavir 400 mg (n=13) and 300 mg with Ritonavir (n=10) for HIV-Infected Adult Patients

1 - atazanavir capsules 2

Absorption

Atazanavir is rapidly absorbed with a T_max of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and C_max values over the dose range of 200 to 800 mg once daily. Steady-state is achieved between Days 4 and 8, with an accumulation of approximately 2.3 fold.

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 relative to the fasting state. Administration of a single 400-mg dose of atazanavir with a high-fat meal (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% with no change in C_max relative to the fasting state. Administration of atazanavir with either a light meal or high-fat meal decreased the coefficient of variation of AUC and C_max by approximately one-half compared to the fasting state.

Co-administration of a single 300-mg dose of atazanavir and a 100-mg dose of ritonavir with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 33% increase in the AUC and a 40% increase in both the C_max and the 24-hour concentration of atazanavir relative to the fasting state. Co-administration with a high-fat meal (951 kcal, 54.7 g fat, 35.9 g protein) did not affect the AUC of atazanavir relative to fasting conditions and the C_max was within 11% of fasting values. The 24-hour concentration following a high-fat meal was increased by approximately 33% due to delayed absorption; the median T_max increased from 2.0 to 5.0 hours. Co-administration of atazanavir with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and C_max by approximately 25% compared to the fasting state.

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 HIV-infected patients 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 0.0021 and 0.0226 and seminal fluid/plasma ratio (n=5) ranged between 0.11 and 4.42.

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 antiviral activity. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by CYP3A.

Elimination

Following a single 400-mg dose of ¹⁴C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively. The mean elimination half-life of atazanavir in healthy volunteers (n=214) and HIV-infected adult patients (n=13) was approximately 7 hours at steady-state following a dose of 400 mg daily with a light meal.

Specific Populations

Renal Impairment

In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. Atazanavir has been studied in adult subjects with severe renal impairment (n=20), including those on hemodialysis, at multiple doses of 400 mg once daily. The mean atazanavir C_max was 9% lower, AUC was 19% higher, and C_min was 96% higher in subjects with severe  renal  impairment  not  undergoing  hemodialysis  (n=10),  than  in  age-,  weight-,  and gender-matched subjects with normal renal function. In a 4-hour dialysis session, 2.1% of the administered dose was removed. When atazanavir was administered either prior to, or following hemodialysis (n=10), the geometric means for C_max, AUC, and C_min were approximately 25% to 43% lower compared to subjects with normal renal function. The mechanism of this decrease is unknown. Atazanavir is not recommended for use in HIV-treatment-experienced patients with end-stage renal disease managed with hemodialysis [see Dosage and Administration (2.7)].

Hepatic Impairment

Atazanavir has been studied in adult subjects with moderate-to-severe hepatic impairment (14 Child-Pugh B and 2 Child-Pugh C subjects) after a single 400 mg dose. The mean AUC_(0-∞) was 42% greater in subjects with impaired hepatic function than in healthy volunteers. The mean half-life of atazanavir in hepatically impaired subjects was 12.1 hours compared to 6.4 hours in healthy volunteers. A dose reduction to 300 mg is recommended for patients with moderate hepatic impairment (Child-Pugh Class B) who have not experienced prior virologic failure as increased concentrations of atazanavir are expected. Atazanavir is not recommended for use in patients with severe hepatic impairment. The pharmacokinetics of atazanavir in combination with ritonavir has not been studied in subjects with hepatic impairment; thus, co-administration of atazanavir with ritonavir is not recommended for use in patients with any degree of hepatic impairment [see Dosage and Administration (2.8)].

Pediatrics

The pharmacokinetic parameters for atazanavir at steady-state in pediatric patients 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 HIV-Infected Pediatric Patients

Pregnancy

The pharmacokinetic data from HIV-infected pregnant women receiving atazanavir capsules with ritonavir are presented in Table 20.

Table 20: Steady-State Pharmacokinetics of Atazanavir with Ritonavir in HIV-Infected Pregnant Women in the Fed State

Drug Interaction Data

Atazanavir is a metabolism-dependent CYP3A inhibitor, with a K_inact value of 0.05 to 0.06 min⁻¹ and K_i value of 0.84 to 1.0 μM. Atazanavir is also a direct inhibitor for UGT1A1 (K_i=1.9 μM) and CYP2C8 (K_i=2.1 μM).

Atazanavir has been shown in vivo not to induce its own metabolism nor to increase the biotransformation of some drugs metabolized by CYP3A. In a multiple-dose study, atazanavir decreased the urinary ratio of endogenous 6β-OH cortisol to cortisol versus baseline, indicating that CYP3A production was not induced.

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.g., nortriptyline, desipramine, metoprolol).

Drug interaction studies were performed with atazanavir and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of atazanavir on the AUC, C_max, and C_min are summarized in Tables 21 and 22. Neither didanosine EC nor diltiazem had a significant effect on atazanavir exposures (see Table 22 for effect of atazanavir on didanosine EC or diltiazem exposures). Atazanavir did not have a significant effect on the exposures of didanosine (when administered as the buffered tablet), stavudine, or fluconazole. For information regarding clinical recommendations, see Drug Interactions (7).

Table 21: Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Co-administered Drugs^a

Table 22: Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Atazanavir^a

12.4 Microbiology

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 (EC₅₀) in the absence of human serum of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT-2 cells. ATV has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. ATV has variable activity against HIV-2 isolates (1.9-32 nM), with EC₅₀ values above the EC₅₀ values of failure isolates. Two-drug combination antiviral activity studies with ATV showed no antagonism in cell culture with PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NNRTIs (delavirdine, efavirenz, and nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir DF, and zidovudine), the HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity.

Resistance

In Cell Culture: HIV-1 isolates with a decreased susceptibility to ATV have been selected in cell culture and obtained from patients treated with ATV or atazanavir/ritonavir (ATV/RTV). HIV-1 isolates with 93- to 183-fold reduced susceptibility to ATV from three different viral strains were selected in cell culture by 5 months. The substitutions in these HIV-1 viruses that contributed to ATV resistance include I50L, N88S, I84V, A71V, and M46I. Changes were also observed at the protease cleavage sites following drug selection. Recombinant viruses containing the I50L substitution without other major PI substitutions were growth impaired and displayed increased susceptibility in cell culture to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The I50L and I50V substitutions yielded selective resistance to ATV and amprenavir, respectively, and did not appear to be cross-resistant.

Clinical Studies of Treatment-Naive Patients: Comparison of Ritonavir-Boosted Atazanavir vs. Unboosted Atazanavir: Study AI424-089 compared atazanavir 300 mg once daily with ritonavir 100 mg vs. atazanavir 400 mg once daily when administered with lamivudine and extended-release stavudine in HIV-infected treatment-naive patients. A summary of the number of virologic failures and virologic failure isolates with ATV resistance in each arm is shown in Table 23.

Table 23: Summary of Virologic Failures^a at Week 96 in Study AI424-089: Comparison of Ritonavir Boosted Atazanavir vs. Unboosted Atazanavir: Randomized Patients

Clinical Studies of Treatment-Naive Patients Receiving Atazanavir 300 mg with Ritonavir 100 mg: In Phase III Study AI424-138, an as-treated genotypic and phenotypic analysis was conducted on samples from patients who experienced virologic failure (HIV-1 RNA ≥400 copies/mL) or discontinued before achieving suppression on ATV/RTV (n=39; 9%) and LPV/RTV (n=39; 9%) through 96 weeks of treatment. In the ATV/RTV arm, one of the virologic failure isolates had a 56-fold decrease in ATV susceptibility emerge on therapy with the development of PI resistance-associated substitutions L10F, V32I, K43T, M46I, A71I, G73S, I85I/V, and L90M. The NRTI resistance-associated substitution M184V also emerged on treatment in this isolate conferring emtricitabine resistance. Two ATV/RTV-virologic failure isolates had baseline phenotypic ATV resistance and IAS-defined major PI resistance-associated substitutions at baseline. The I50L substitution emerged on study in one of these failure isolates and was associated with a 17-fold decrease in ATV susceptibility from baseline and the other failure isolate with baseline ATV resistance and PI substitutions (M46M/I and I84I/V) had additional IAS-defined major PI substitutions (V32I, M46I, and I84V) emerge on ATV treatment associated with a 3-fold decrease in ATV susceptibility from baseline. Five of the treatment failure isolates in the ATV/RTV arm developed phenotypic emtricitabine resistance with the emergence of either the M184I (n=1) or the M184V (n=4) substitution on therapy and none developed phenotypic tenofovir disoproxil resistance. In the LPV/RTV arm, one of the virologic failure patient isolates had a 69-fold decrease in LPV susceptibility emerge on therapy with the development of PI substitutions L10V, V11I, I54V, G73S, and V82A in addition to baseline PI substitutions L10L/I, V32I, I54I/V, A71I, G73G/S, V82V/A, L89V, and L90M. Six LPV/RTV virologic failure isolates developed the M184V substitution and phenotypic emtricitabine resistance and two developed phenotypic tenofovir disoproxil resistance.

Clinical Studies of Treatment-Naive Patients Receiving Atazanavir 400 mg without Ritonavir: ATV-resistant clinical isolates from treatment-naive patients who experienced virologic failure on atazanavir 400 mg treatment without ritonavir often developed an I50L substitution (after an average of 50 weeks of ATV therapy), often in combination with an A71V substitution, but also developed one or more other PI substitutions (e.g., V32I, L33F, G73S, V82A, I85V, or N88S) with or without the I50L substitution. In treatment-naive patients, viral isolates that developed the I50L substitution, without other major PI substitutions, showed phenotypic resistance to ATV but retained in cell culture susceptibility to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir); however, there are no clinical data available to demonstrate the effect of the I50L substitution on the efficacy of subsequently administered PIs.

Clinical Studies of Treatment-Experienced Patients: In studies of treatment-experienced patients treated with ATV or ATV/RTV, most ATV-resistant isolates from patients who experienced virologic failure developed substitutions that were associated with resistance to multiple PIs and displayed decreased susceptibility to multiple PIs. The most common protease substitutions to develop in the viral isolates of patients who failed treatment with ATV 300 mg once daily and RTV 100 mg once daily (together with tenofovir DF and an NRTI) included V32I, L33F/V/I,E35D/G,   M46I/L,   I50L,   F53L/V,   I54V,   A71V/T/I,   G73S/T/C,   V82A/T/L,   I85V,   and L89V/Q/M/T. Other substitutions that developed on ATV/RTV treatment including E34K/A/Q, G48V, I84V, N88S/D/T, and L90M occurred in less than 10% of patient isolates. Generally, if multiple PI resistance substitutions were present in the HIV-1 virus of the patient at baseline, ATV resistance developed through substitutions associated with resistance to other PIs and could include the development of the I50L substitution. The I50L substitution has been detected in treatment-experienced patients experiencing virologic failure after long-term treatment. Protease cleavage site changes also emerged on ATV treatment but their presence did not correlate with the level of ATV resistance.

Cross-Resistance

Cross-resistance among PIs has been observed. Baseline phenotypic and genotypic analyses of clinical isolates from ATV clinical trials of PI-experienced patients showed that isolates cross-resistant to multiple PIs were cross-resistant to ATV. Greater than 90% of the isolates with substitutions that included I84V or G48V were resistant to ATV. Greater than 60% of isolates containing L90M, G73S/T/C, A71V/T, I54V, M46I/L, or a change at V82 were resistant to ATV, and 38% of isolates containing a D30N substitution in addition to other changes were resistant to ATV. Isolates resistant to ATV 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 patients, 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 ATV susceptibility before initiation of ATV/RTV 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 patients receiving ATV/RTV once daily or lopinavir (LPV)/RTV 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 patients. In the ATV/RTV group, patients 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 patients with 1 to 2 PI substitutions, including one of these substitutions.

Table 24: HIV RNA Response by Number and Type of Baseline PI Substitution, Antiretroviral-Experienced Patients in Study AI424-045, As-Treated Analysis

The response rates of antiretroviral-experienced patients 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 patient population with 62% of patients 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 Patients in Study AI424-045, As-Treated Analysis

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

Long-term carcinogenicity studies in mice and rats were carried out with atazanavir for two years. In the mouse study, drug-related increases in hepatocellular adenomas were found in females at 360 mg/kg/day. The systemic drug exposure (AUC) at the NOAEL (no observable adverse effect level) in females, (120 mg/kg/day) was 2.8 times and in males (80 mg/kg/day) was 2.9 times higher than those in humans at the clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir, non-pregnant patients). In the rat study, no drug-related increases in tumor incidence were observed at doses up to 1200 mg/kg/day, for which AUCs were 1.1 (males) or 3.9 (females) times those measured in humans at the clinical dose.

Mutagenesis

Atazanavir tested positive in an in vitro clastogenicity test using primary human lymphocytes, in the absence and presence of metabolic activation. Atazanavir tested negative in the in vitro Ames reverse-mutation assay, in vivo micronucleus and DNA repair tests in rats, and in vivo DNA damage test in rat duodenum (comet assay).

Impairment of Fertility

At the systemic drug exposure levels (AUC) 0.9 (in male rats) or 2.3 (in female rats) times that of  the  human  clinical  dose,  (300  mg/day  atazanavir  boosted  with  100  mg/day  ritonavir) significant effects on mating, fertility, or early embryonic development were not observed.

14.1 Adult Patients Without Prior Antiretroviral Therapy

Study AI424-138: a 96-week study comparing the antiviral efficacy and safety of atazanavir/ritonavir with lopinavir/ritonavir, each in combination with fixed-dose tenofovir DF - emtricitabine in HIV-1 infected treatment-naive subjects. Study AI424-138  was  a 96-week, open-label, randomized, multicenter study, comparing atazanavir (300 mg once daily) with ritonavir (100 mg once daily) to lopinavir with ritonavir (400/100 mg twice daily), each in combination  with  fixed-dose  tenofovir DF with  emtricitabine  (300/200  mg  once  daily),  in 878 antiretroviral treatment-naive treated patients. Patients had a mean age of 36 years (range: 19 to 72), 49% were Caucasian, 18% Black, 9% Asian, 23% Hispanic/Mestizo/mixed race, and 68% were male. The median baseline plasma CD4+ cell count was 204 cells/mm³ (range: 2 to 810 cells/mm³) and the mean baseline plasma HIV-1 RNA level was 4.94 log₁₀ copies/mL (range: 2.60 to 5.88 log₁₀ copies/mL). Treatment response and outcomes through Week 96 are presented in Table 26.

Table 26: Outcomes of Treatment Through Week 96 in Treatment-Naive Adults (Study AI424-138)

Through 96 weeks of therapy, the proportion of responders among patients with high viral loads (ie, baseline HIV RNA ≥100,000 copies/mL) was comparable for the atazanavir/ritonavir (165 of 223 patients, 74%) and lopinavir/ritonavir (148 of 222 patients, 67%) arms. At 96 weeks, the median increase from baseline in CD4+ cell count was 261 cells/mm³ for the atazanavir/ritonavir arm and 273 cells/mm³ for the lopinavir/ritonavir arm.

Study AI424-034: atazanavir once daily compared to efavirenz once daily, each in combination with fixed-dose lamivudine + zidovudine twice daily. Study AI424-034 was a randomized, double-blind, multicenter trial comparing atazanavir (400 mg once daily) to efavirenz (600 mg once daily), each in combination with a fixed-dose combination of lamivudine (3TC) (150 mg) and zidovudine (ZDV) (300 mg) given twice daily, in 810 antiretroviral treatment-naive patients. Patients had a mean age of 34 years (range: 18 to 73), 36% were Hispanic, 33% were Caucasian, and 65% were male. The mean baseline CD4+ cell count was 321 cells/mm³ (range: 64 to 1424 cells/mm³) and the mean baseline plasma HIV-1 RNA level was 4.8 log₁₀ copies/mL (range: 2.2 to 5.9 log₁₀ copies/mL). Treatment response and outcomes through Week 48 are presented in Table 27.

Table 27: Outcomes of Randomized Treatment Through Week 48 in Treatment-Naive Adults (Study AI424-034)

Through 48 weeks of therapy, the proportion of responders among patients with high viral loads (i.e. baseline HIV 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/mm³ for the atazanavir arm and 160 cells/mm³ for the efavirenz arm.

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. Study AI424-008 was a 48-week, randomized, multicenter trial, blinded to dose of atazanavir, comparing atazanavir at two dose levels (400 mg and 600 mg once daily) to nelfinavir (1250 mg twice daily), each in combination with stavudine (40 mg) and lamivudine (150 mg) given twice daily, in 467 antiretroviral treatment-naive patients. Patients had a mean age of 35 years (range: 18 to 69), 55% were Caucasian, and 63% were male. The mean baseline CD4+ cell count was 295 cells/mm³ (range: 4 to 1003 cells/mm³) and the mean baseline plasma HIV-1 RNA level was 4.7 log₁₀ copies/mL (range: 1.8 to 5.9 log₁₀ copies/mL). Treatment response and outcomes through Week 48 are presented in Table 28.

Table 28: Outcomes of Randomized Treatment Through Week 48 in Treatment-Naive Adults (Study AI424-008)

Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 234 cells/mm³ for the atazanavir 400 mg arm and 211 cells/mm³ for the nelfinavir arm.

14.2 Adult Patients With Prior Antiretroviral Therapy

Study AI424-045: atazanavir once daily + ritonavir once daily compared to atazanavir once daily + saquinavir (soft gelatin capsules) once daily, and compared to lopinavir + ritonavir twice daily, each in combination with tenofovir DF + one NRTI. Study AI424-045 was a randomized, multicenter trial comparing atazanavir (300 mg once daily) with ritonavir (100 mg once daily) to atazanavir (400 mg once daily) with saquinavir soft gelatin capsules (1200 mg once daily), and to lopinavir + ritonavir (400/100 mg twice daily), each in combination with tenofovir DF and one NRTI, in 347 (of 358 randomized) patients who experienced virologic failure on HAART regimens containing PIs, NNRTIs, and NRTIs. The mean time of prior exposure to antiretrovirals was 139 weeks for PIs, 85 weeks for NNRTIs, and 283 weeks for NRTIs. The mean age was 41 years (range: 24 to 74); 60% were Caucasian, and 78% were male. The mean baseline CD4+ cell count was 338 cells/mm³ (range: 14 to 1543 cells/mm³) and the mean baseline plasma HIV-1 RNA level was 4.4 log₁₀ copies/mL (range: 2.6 to 5.88 log₁₀ copies/mL).

Treatment outcomes through Week 48 for the atazanavir/ritonavir and lopinavir/ritonavir treatment arms are presented in Table 29. Atazanavir/ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV RNA level. Study AI424-045 was not large enough to reach a definitive conclusion that atazanavir/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measure of proportions below the HIV 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 (Patients with Prior Antiretroviral Experience)

No patients in the atazanavir/ritonavir treatment arm and three patients 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 log₁₀ copies/mL, and the time-averaged difference in change in HIV-1 RNA levels versus lopinavir/ritonavir was 0.33. The corresponding mean increase in CD4+ cell count was 72 cells/mm³. Through 48 weeks of treatment, the proportion of patients in this treatment arm with plasma HIV-1 RNA <400 (<50) copies/mL was 38% (26%). In this study, co-administration of atazanavir and saquinavir did not provide adequate efficacy [see Drug Interactions (7)].

Study AI424-045 also compared changes from baseline in lipid values [see Adverse Reactions (6.1)].

Study AI424-043: Study AI424-043 was a randomized, open-label, multicenter trial comparing atazanavir (400 mg once daily) to lopinavir/ritonavir (400/100 mg twice daily), each in combination with two NRTIs, in 300 patients who experienced virologic failure to only one prior PI-containing regimen. Through 48 weeks, the proportion of patients with plasma HIV-1 RNA <400 (<50) copies/mL was 49% (35%) for patients randomized to atazanavir (n=144) and 69% (53%) for patients randomized to lopinavir/ritonavir (n=146). The mean change from baseline was −1.59 log₁₀ copies/mL in the atazanavir treatment arm and −2.02 log₁₀ copies/mL in the lopinavir/ritonavir arm. Based on the results of this study, atazanavir without ritonavir was inferior to lopinavir/ritonavir in PI-experienced patients with prior virologic failure and is not recommended for such patients.

14.3 Pediatric Patients

Pediatric Trials with Atazanavir Capsules

Assessment of the pharmacokinetics, safety, tolerability, and virologic response of atazanavir capsules was based on data from the open-label, multicenter clinical trial PACTG 1020A which included patients from 6 years to 21 years of age. In this study, 105 patients (43 antiretroviral­-naive and 62 antiretroviral-experienced) received once daily atazanavir capsule formulation, with or without ritonavir, in combination with two NRTIs.

One-hundred five (105) patients (6 to less than 18 years of age) treated with the atazanavir capsule formulation, with or without ritonavir, were evaluated. Using an ITT analysis, the overall proportions of antiretroviral-naive and -experienced patients with HIV RNA <400 copies/mL at Week 96 were 51% (22/43) and 34% (21/62), respectively. The overall proportions of antiretroviral-naive and -experienced patients with HIV 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/mm³ in antiretroviral-naive patients and 220 cells/mm³ in antiretroviral-experienced patients.

16 How Supplied/Storage And Handling

Atazanavir Capsules, 100 mg are supplied as size ‘2’ hard gelatin capsules having imprinted ‘Amneal 100 mg’ on blue opaque cap with white ink and ‘1135’ on white opaque body with blue ink, filled with off-white to yellow granular powder. They are available as follows:

Bottles of 60:                                                            NDC 69238-1135-6

Atazanavir Capsules, 150 mg are supplied as size ‘1’ hard gelatin capsules having imprinted ‘Amneal 150 mg’ on blue opaque cap with white ink and ‘1136’ on powder blue opaque body with blue ink, filled with off-white to yellow granular powder. They are available as follows:

Bottles of 60:                                                            NDC 69238-1136-6

Atazanavir Capsules, 200 mg are supplied as size ‘0’ hard gelatin capsules having imprinted ‘Amneal 200 mg’ on blue opaque cap and ‘1137’on blue opaque body with white ink, filled with off-white to yellow granular powder. They are available as follows:

Bottles of 60:                                                            NDC 69238-1137-6

Atazanavir Capsules, 300 mg are supplied as size ‘00’ hard gelatin capsules having imprinted ‘Amneal 300 mg’ on red opaque cap and ‘1138’ on blue opaque body with white ink, filled with off-white to yellow granular powder. They are available as follows:

Bottles of 30:                                                            NDC 69238-1138-3

Store atazanavir capsules at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

17 Patient Counseling Information

Advise  the  patient  to  read  the  FDA-approved  patient  labeling  (Patient  Information).

Atazanavir is not a cure for HIV infection. Advise patients to remain under the care of a healthcare provider while using atazanavir.

Cardiac Conduction Abnormalities

Inform patients that atazanavir may produce changes in the electrocardiogram (e.g., PR prolongation).  Tell  patients  to  consult  their  healthcare  provider  if  they  are  experiencing symptoms such as dizziness or lightheadedness [see Warnings and Precautions (5.1)].

Severe Skin Reaction

Inform patients that there have been reports of severe skin reactions (e.g., Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions) with atazanavir use. Advise patients that if signs or symptoms of severe skin reactions or hypersensitivity reactions develop, they must discontinue atazanavir and seek medical evaluation immediately [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

Hyperbilirubinemia

Inform patients that asymptomatic elevations in indirect bilirubin have occurred in patients receiving atazanavir. This may be accompanied by yellowing of the skin or whites of the eyes and alternative antiretroviral therapy may be considered if the patient has cosmetic concerns [see Warnings and Precautions (5.8)].

Chronic Kidney Disease

Inform patients that treatment with atazanavir may lead to the development of chronic kidney disease, and to maintain adequate hydration while taking atazanavir [see Warnings and Precautions (5.5)].

Nephrolithiasis and Cholelithiasis

Inform patients that kidney stones and/or gallstones have been reported with atazanavir use. Some patients with kidney stones and/or gallstones required hospitalization for additional management and some had complications. Discontinuation of atazanavir may be necessary as part of the medical management of these adverse events [see Warnings and Precautions (5.6)].

Drug Interactions

Atazanavir may lead to significant interaction with some drugs; therefore, advise patients to report the use of any other prescription, nonprescription medication, or herbal products, particularly St. John’s wort, to their healthcare provider prior to use [see Contraindications (4), Warnings and Precautions (5.7)].

Immune Reconstitution Syndrome

Advise patients to inform their healthcare provider immediately of any symptoms of infection, as in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started [see Warnings and Precautions (5.10)].

Fat Redistribution

Inform patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy including protease inhibitors and that the cause and long-term health effects of these conditions are not known at this time [see Warnings and Precautions (5.11)].

Dosing Instructions

Advise patients to take atazanavir capsules with food every day and take other concomitant antiretroviral therapy as prescribed. Atazanavir capsules must always be used in combination with other antiretroviral drugs. Advise patients that they should not alter the dose or discontinue therapy without consulting with their healthcare provider. Tell patients if a dose of atazanavir capsules is missed, they should take the dose as soon as possible and then return to their normal schedule; however, if a dose is skipped the patient should not double the next dose.

Pregnancy

Inform pregnant patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atazanavir during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry [see Use in Specific Populations (8.1)].

Lactation

Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk. Atazanavir can also be passed to the baby in breast milk and it is not known whether it could harm the baby [see Use in Specific Populations (8.2)].

All brand names listed are the trademarks of their respective owners.

Manufactured by:
Amneal Pharmaceuticals Pvt. Ltd.
Oral Solid Dosage Unit
Ahmedabad 382213, INDIA

Distributed by:
Amneal Pharmaceuticals LLC
Bridgewater, NJ 08807

Rev. 05-2020-01

Patient Information

Atazanavir (a" ta zan' a vir) Capsules

Important: Ask your healthcare provider or pharmacist about medicines that should not be taken with atazanavir capsules. For more information, see “Who should not take atazanavir capsules?” and “What should I tell my healthcare provider before taking atazanavir capsules?”

What are atazanavir capsules?

Atazanavir capsules are a prescription HIV-1 (Human Immunodeficiency Virus-type 1) medicine that is used with other antiretroviral medicines to treat HIV-1 infection in adults and children 6 years of age and older and who weigh at least 15 kg. HIV-1 is the virus that causes AIDS (Acquired Immunodeficiency Syndrome).

Atazanavir should not be used in children younger than 3 months of age.

When used with other antiretroviral medicines to treat HIV-1 infection, atazanavir capsules may help:

• reduce the amount of HIV-1 in your blood. This is called “viral load”.
• increase the number of CD4+ (T) cells in your blood that help fight off other infections.

Reducing the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may help improve your immune system. This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic infections).

Atazanavir capsules do not cure HIV-1 infection or AIDS. You must keep taking HIV-1 medicines to control HIV-1 infection and decrease HIV-related illnesses.

Who should not take atazanavir capsules?

Do not take atazanavir capsule if you:

• are allergic to atazanavir or any of the ingredients in atazanavir capsules. See the end of this leaflet for a complete list of ingredients in atazanavir capsules.
• are taking any of the following medicines. Taking atazanavir capsules with these medicines may affect how atazanavir capsules works. Atazanavir capsules may cause serious life-threatening side effects or death when used with these medicines:
• alfuzosin (UROXATRAL^®)
• cisapride (PROPULSID^®)
• elbasvir/grazoprevir (ZEPATIER^®)
• ergot medicines including:
• ergotamine tartrate (CAFERGOT^®, MIGERGOT^®, ERGOMAR^®, ERGOSTAT^®, MEDIHALER^®, Ergotamine, WIGRAINE^®, WIGRETTES^®)
• dihydroergotamine mesylate (D.H.E. 45^®, MIGRANAL^®)
• methylergonovine (METHERGINE^®)
• glecaprevir/pibrentasvir (MAVYRET^®)
• indinavir (CRIXIVAN^®)
• irinotecan (CAMPTOSAR^®)
• lurasidone (LATUDA^®) if atazanavir is used with ritonavir (NORVIR^®)
• lovastatin (ADVICOR^®, ALTOPREV^®, MEVACOR^®)
• midazolam (VERSED^®), when taken by mouth for sedation
• nevirapine (VIRAMUNE^®, VIRAMUNE XR^®)
• pimozide (ORAP^®)
• rifampin (RIFADIN^®, RIFAMATE^®, RIFATER^®, RIMACTANE^®)
• sildenafil (REVATIO^®), when used for the treatment of pulmonary arterial hypertension
• simvastatin (SIMCOR^®, VYTORIN^®, ZOCOR^®)
• St. John’s wort (Hypericum perforatum)
• triazolam (HALCION^®)

Serious problems can happen if you or your child takes any of the medicines listed above with atazanavir capsules.

What should I tell my healthcare provider before taking atazanavir capsules?

Before taking atazanavir capsules, tell your healthcare provider if you:

• have heart problems
• have liver problems, including hepatitis B or C virus infection
• are receiving dialysis treatment
• have diabetes
• have hemophilia
• have any other medical conditions
• are pregnant or plan to become pregnant. Talk to your healthcare provider about taking atazanavir capsules during your pregnancy or if you are planning to become pregnant while you are taking atazanavir capsules.
• Hormonal forms of birth control, such as injections, vaginal rings or implants, contraceptive patch, and some birth control pills may not work during treatment with atazanavir capsules. Talk to your healthcare provider about forms of birth control that may be used during treatment with atazanavir capsules.
• Pregnancy Registry. There is a pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.
• After your baby is born, tell your healthcare provider if your baby’s skin or the white part of the eyes turns yellow.
• are breastfeeding or plan to breastfeed. Do not breastfeed if you are taking atazanavir capsules. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. Atazanavir can pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Some medicines interact with atazanavir capsules. Keep a list of your medicines to show your healthcare provider and pharmacist. You can ask your healthcare provider or pharmacist for a list of medicines that interact with atazanavir capsules. Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take atazanavir capsules with other medicines.

How should I take atazanavir capsules?

• Take atazanavir capsules exactly as your healthcare provider tells you to.
• Do not change your dose or stop taking atazanavir capsules unless your healthcare provider tells you to.
• Stay under the care of your healthcare provider during treatment with atazanavir capsules.
• Atazanavir capsules must be used with other antiretroviral medicines.
• Take atazanavir capsules 1 time each day.
• Atazanavir comes as capsules.
• Take atazanavir capsules with food.
• Swallow the capsules whole. Do not open the capsules.
• Your child’s healthcare provider will prescribe the right dose of atazanavir based on your child’s weight.
• If you miss a dose of atazanavir capsules, take it as soon as you remember. Then take the next dose at your regular time. Do not take 2 doses at the same time.
• If you take too much atazanavir capsules, call your healthcare provider or go to the nearest hospital emergency room right away.

When your supply of atazanavir capsules starts to run low, get more from your healthcare provider or pharmacy. It is important not to run out of atazanavir capsules. The amount of HIV-1 in your blood may increase if the medicine is stopped for even a short time. The virus may become resistant to atazanavir capsules and harder to treat.

What are the possible side effects of atazanavir capsules?

Atazanavir capsules can cause serious side effects, including:

• A change in the way your heart beats (heart rhythm change). Tell your healthcare provider right away if you get dizzy or lightheaded. These could be symptoms of a heart problem.
• Skin rash. Skin rash is common with atazanavir capsules but can sometimes be severe. Skin rash usually goes away within 2 weeks without any change in treatment. Severe rash may develop in association with other symptoms which could be serious. If you develop a severe rash or a rash with any of the following symptoms, stop taking atazanavir capsules and call your healthcare provider right away:

general feeling of discomfort or “flu-like” symptoms fever muscle or joint aches red or inflamed eyes, like “pink eye” (conjunctivitis)

blisters mouth sores swelling of your face painful, warm, or red lump under your skin

• Yellowing of your skin or the white part of your eyes is common with atazanavir capsules, and is usually not harmful in adults and infants older than 3 months of age; but it could also be a symptom of a serious problem. These effects may be due to increases in bilirubin levels in your blood (bilirubin is made by the liver). Although these effects may not be damaging to your liver, skin, or eyes, tell your healthcare provider right away if your skin or the white part of your eyes turns yellow.
• Liver problems. If you have liver problems, including hepatitis B or C infection, your liver problems may get worse when you take atazanavir capsules. Your healthcare provider will do blood tests to check your liver before you start atazanavir capsules and during treatment. Tell your healthcare provider right away if you get any of the following symptoms:

dark “tea-colored” urine your skin or the white part of your eyes turns yellow light colored stools nausea

itching stomach-area pain

• Chronic kidney disease. Atazanavir capsules may affect how well your kidneys work. Your healthcare provider will do blood and urine tests to check your kidneys before you start Atazanavir capsules and during treatment.
• Kidney stones have happened in some people who take atazanavir capsules. Tell your healthcare provider right away if you get symptoms of kidney stones which may include, pain in your low back or low stomach-area, blood in your urine, or pain when you urinate.
• Gallbladder problems have happened in some people who take atazanavir capsules. Tell your healthcare provider right away if you get symptoms of gallbladder problems which may include:
• pain in the right or middle upper stomach area
• nausea and vomiting
• fever
• your skin or the white part of your eyes turns yellow
• Diabetes and high blood sugar (hyperglycemia) have happened or have worsened in some people who take protease inhibitor medicines like atazanavir capsules. Some people have had to start taking medicine to treat diabetes or have had to change their diabetes medicine.
• Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider if you start having new symptoms after starting atazanavir capsules.
• Changes in body fat can happen in people taking HIV-1 medicines. These changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the main part of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.
• Increased bleeding problems in people with hemophilia have happened when taking protease inhibitors like atazanavir capsules.

The most common side effects of atazanavir capsules include:

nausea	dizziness
headache	muscle pain
stomach-area pain	diarrhea
vomiting	depression
trouble sleeping	fever
numbness, tingling, or burning of hands or feet

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of atazanavir capsules. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store atazanavir capsules?

Atazanavir capsules:

• Store atazanavir capsules at room temperature, between 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F).
• Keep capsules in a tightly closed container.

Keep atazanavir capsules and all medicines out of the reach of children.

General information about the safe and effective use of atazanavir capsules

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use atazanavir capsules for a condition for which it was not prescribed. Do not give atazanavir capsules to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about atazanavir capsules that is written for health professionals.

For more information, go to www.amneal.com or call 1­-877-835-5472.

What are the ingredients in atazanavir capsules?

Active ingredient: atazanavir sulfate

Inactive ingredients:

Atazanavir capsules: crospovidone, FD&C blue 1, FD&C red 3 (150 mg only), FD&C red 40 (300 mg only), FD&C yellow 6 (300 mg only), gelatin, lactose monohydrate, magnesium stearate and titanium dioxide.

The white imprinting pharmaceutical ink used for 100 mg, 150 mg, 200 mg and 300 mg containing shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, potassium hydroxide and titanium dioxide.

The blue imprinting pharmaceutical ink used for used for 100 mg and 150 mg containing shellac, dehydrated alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, strong ammonia solution, FD & C Blue # 2 Aluminum Lake (Indigo Carmine).

^®The brands listed are the trademarks of their respective owners.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Manufactured by:
Amneal Pharmaceuticals Pvt. Ltd.
Oral Solid Dosage Unit
Ahmedabad 382213, INDIA

Distributed by:
Amneal Pharmaceuticals LLC
Bridgewater, NJ 08807

Rev. 05-2020-01

Principal Display Panel

NDC 69238-1135-6

Atazanavir Capsules, 100 mg

Rx only

60 Capsules

Amneal Pharmaceuticals LLC

1 - atazanavir capsules 3

NDC 69238-1136-6

Atazanavir Capsules, 150 mg

Rx only

60 Capsules

Amneal Pharmaceuticals LLC

NDC 69238-1137-6

Atazanavir Capsules, 200 mg

Rx only

60 Capsules

Amneal Pharmaceuticals LLC

NDC 69238-1138-3

Atazanavir Capsules, 300 mg

Rx only

30 Capsules

Amneal Pharmaceuticals LLC