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 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 H 2-receptor antagonists (H2RA). Ritonavir is required with several atazanavir capsule 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.

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).

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

a Administer atazanavir capsules and ritonavir simultaneously with food. 

b The same recommendations regarding the timing and maximum doses of concomitant PPIs and H2RAs in adults also apply to pediatric patients. See Drug Interactions ( 7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). 

c In treatment-experienced patients, atazanavir capsules must be administered with ritonavir. 

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

aSee Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). 

b Atazanavir capsules are not recommended for treatment-experienced pregnant patients during the second and third trimester taking atazanavir capsules with BOTH tenofovir DF and H2RA.

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 treatment-experienced patients with HIV-1 infection who have 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 capsule dosage in treatment-naive patients with hepatic impairment. The use of atazanavir capsules in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended. The coadministration of atazanavir capsules with ritonavir in patients with any degree of hepatic impairment is not recommended.

Table 5: Recommended Dosage of Atazanavir Capsules in Treatment-Naïve Adults with Hepatic Impairment

5.1 Cardiac Conduction Abnormalities

Atazanavir has been shown to prolong the PR interval of the electrocardiogram in some subjects. In healthy subjects and in subjects with HIV-1 infection 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 subjects (n=920), 5.2% of lopinavir/ritonavir-treated subjects (n=252), 10.4% of nelfinavir-treated subjects (n=48), and 3.0% of efavirenz-treated subjects (n=329). In Study AI424-045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir with ritonavir-treated subjects and 5% (6/116) of lopinavir/ritonavir-treated subjects 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 subjects with HIV-1 infection 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 patients with HIV-1 infection 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 patients with HIV-1 infection 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 therapy containing atazanavir with ritonavir; 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-1 infection 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, and autoimmune hepatitis) 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.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) ].

6.1 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 Subjects



The safety profile of atazanavir in treatment-naive adults is based on 1625 subjects with HIV-1 infection 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 Subjects with HIV-1 Infection, 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.

Table 8: Selected Adverse Reactions a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Subjects with HIV-1 Infection, 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.

Adverse Reactions in Treatment-Experienced Adult Subjects

The safety profile of atazanavir in treatment-experienced adults with HIV-1 infection is based on 119 subjects with HIV-1 infection 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 with ritonavir are presented in Table 9.

Table 9: Selected Adverse Reactions a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Experienced Subjects with HIV-1 Infection, b Study AI424-045

* 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 As a fixed-dose product.

Laboratory Abnormalities in Treatment-Naive Subjects

The percentages of adult treatment-naive subjects with HIV-1 infection treated with combination therapy including atazanavir 300 mg with ritonavir 100 mg or atazanavir 400 mg (without ritonavir) with Grade 3 to 4 laboratory abnormalities are presented in Tables 10 and 11, respectively

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. 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 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)

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 and ritonavir 100 mg once daily.

d  In combination with atazanavir 400 mg once daily.

7.4 Drugs With No Observed Interactions With Atazanavir

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

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 clinical trial 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 infection, 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 infection, all had test results that were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. All 40 infants received antiretroviral prophylactic treatment containing zidovudine. No evidence of severe hyperbilirubinemia (total bilirubin levels greater than 20 mg/dL) or acute or chronic bilirubin encephalopathy was observed among neonates in this study. However, 10/36 (28%) infants (6 greater than or equal to 38 weeks gestation and 4 less than 38 weeks gestation) had bilirubin levels of 4 mg/dL or greater within the first day of life.

Lack of ethnic diversity was a study limitation. In the study population, 33/40 (83%) infants were Black/African American, who have a lower incidence of neonatal hyperbilirubinemia than Caucasians and Asians. In addition, women with Rh incompatibility were excluded, as well as women who had a previous infant who developed hemolytic disease and/or had neonatal pathologic jaundice (requiring phototherapy).

Additionally, of the 38 infants who had glucose samples collected in the first day of life, 3 had adequately collected serum glucose samples with values of less than 40 mg/dL that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis.

Based on prospective reports from the APR of approximately 1600 live births following exposure to atazanavir-containing regimens (including 1037 live births in infants exposed in the first trimester and 569 exposed in second/third trimesters), there was no difference between atazanavir and overall birth defects compared with the background birth defect rate. 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 patients with HIV-1 infection, 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.

8.3 Nursing Mothers

8.4 Pediatric Use

Atazanavir is indicated in combination with other antiretroviral agents for the treatment of pediatric patients with HIV-1 infection, 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 at least 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 treatment-experienced patients with HIV-1 infection, who have 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 with ritonavir is not recommended in patients with any degree of hepatic impairment [see Dosage and Administration ( 2.8) and Clinical Pharmacology ( 12.3)] .

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 subjects receiving atazanavir. In placebo-controlled Study AI424-076, the mean (±SD) maximum change in PR interval from the predose value was 24 (±15) msec following oral dosing with 400 mg of atazanavir (n=65) compared to 13 (±11) msec following dosing with placebo (n=67). The PR interval prolongations in this study were asymptomatic. There is limited information on the potential for a pharmacodynamic interaction in humans between atazanavir and other drugs that prolong the PR interval of the electrocardiogram [see Warnings and Precautions ( 5.1)].

Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of 72 healthy 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 subjects with HIV-1 infection, receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy subject or subject with HIV-1 infection in clinical trials had a QTc interval >500 msec [see Warnings and Precautions ( 5.1)].

12.3 Pharmacokinetics

The pharmacokinetics of atazanavir were evaluated in adult subjects who either were healthy, or with HIV infection, 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 Subjects  with HIV-1 Infection in the Fed State

a  n=26.

b  n=12.

Figure 1 displays the mean plasma concentrations of atazanavir at steady state after atazanavir 400 mg once daily (as two 200-mg capsules) with a light meal and after atazanavir 300 mg (as two 150-mg capsules) with ritonavir 100 mg once daily with a light meal in adult subjects with HIV-1 infection. 

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 Subjects with HIV-1 Infection

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.

Coadministration 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. Coadministration 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. Coadministration 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 subjects with HIV-1 infection 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 subjects (n=214) and adult subjects with HIV-1 infection (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 Cmin 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 treatment-experienced patients with HIV-1 who have 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 to ∞ ) was 42% greater in subjects with impaired hepatic function than in healthy subjects. The mean half-life of atazanavir in hepatically impaired subjects was 12.1 hours compared to 6.4 hours in healthy subjects. 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, coadministration 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 subjects taking the capsule formulation were predicted by a population pharmacokinetic model and are summarized in Table 19 by weight ranges that correspond to the recommended doses [see Dosage and Administration (2.4)]. 

Table 19: Predicted Steady-State Pharmacokinetics of Atazanavir (capsule formulation) with Ritonavir in Pediatric Subjects with HIV-1 Infection 

Pregnancy

The pharmacokinetic data from pregnant women with HIV-1 infection receiving atazanavir capsules with ritonavir are presented in Table 20.

 a  Available data during the 2nd trimester are limited.

b  Atazanavir peak concentrations and AUCs were found to be approximately 28% to 43% higher during the postpartum period (4 to 12 weeks) than       those observed historically in, non-pregnant patients with HIV-1 Infection. Atazanavir plasma trough concentrations were approximately 2.2-fold         higher during the postpartum period when compared to those observed historically in non-pregnant patients with HIV-1 infection.

c  C min is concentration 24 hours post-dose.

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 (eg, nortriptyline, desipramine, metoprolol).

Drug interaction studies were performed with atazanavir and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of atazanavir on the AUC, C max, 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,

Table 21: Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugs a

 a Data provided are under fed conditions unless otherwise noted.

b  All drugs were given under fasted conditions.

c  Atazanavir 300 mg plus ritonavir 100 mg once daily coadministered with famotidine 40 mg twice daily resulted in atazanavir geometric mean               C max that was similar and AUC and C min values that were 1.79 ­and 4.46-fold higher relative to atazanavir 400 mg once daily alone.

d  Similar results were noted when famotidine 20 mg BID was administered 2 hours after and 10 hours before atazanavir 300 mg and ritonavir               100 mg and tenofovir DF 300 mg.

e  Coadministration of atazanavir with ritonavir and tenofovir DF was administered after a light meal.

f  Study was conducted in subjects with HIV-1 infection.

g  Compared with atazanavir 400 mg historical data without nevirapine (n=13), the ratio of geometric means (90% confidence intervals)  for                     C max, AUC, and C min were 1.42  (0.98, 2.05), 1.64 (1.11, 2.42), and  1.25 (0.66, 2.36), respectively, for atazanavir with ritonavir 300/100 mg;               and 2.02 (1.42, 2.87), 2.28 (1.54, 3.38), and 1.80 (0.94, 3.45), respectively, for atazanavir with ritonavir 400/100 mg.

h  Parallel group design; n=23 for atazanavir with ritonavir and nevirapine, n=22 for atazanavir 300 mg/ritonavir 100 mg without nevirapine.                     Subjects were treated with nevirapine prior to study entry.

i  Omeprazole 40 mg was administered on an empty stomach 2 hours before atazanavir.

j  Omeprazole 20 mg was administered 30 minutes prior to a light meal in the morning and atazanavir 300 mg with ritonavir 100 mg in the                       evening after a light meal, separated by 12 hours from omeprazole.

k  Atazanavir 300 mg with ritonavir 100 mg once daily separated by 12 hours from omeprazole 20 mg daily resulted in increases in atazanavir                 geometric mean AUC (10%) and C min (2.4-fold), with a decrease in C max (29%) relative to atazanavir 400 mg once daily in the absence of                   omeprazole (study days 1-6).

l  Omeprazole 20 mg was given 30 minutes prior to a light meal in the morning and atazanavir 400 mg with ritonavir 100 mg once daily after a                 light meal, 1 hour after omeprazole. Effects on atazanavir concentrations were similar when atazanavir 400 mg with ritonavir 100 mg was                   separated from omeprazole 20 mg by 12 hours.

m  Atazanavir 400 mg with ritonavir 100 mg once daily administered with omeprazole 20 mg once daily resulted in increases in atazanavir geometric     mean AUC (32%) and C min (3.3-fold), with a decrease in Cmax (26%) relative to atazanavir 400 mg once daily in the absence of omeprazole                (study days 1–6).

n  Compared with atazanavir 400 mg QD historical data, administration of atazanavir with ritonavir 300/100 mg QD increased the atazanavir                    geometric mean values of C max, AUC, and C min by 18%, 103%, and 671%, respectively.

o  Note that similar results were observed in studies where administration of tenofovir DF and atazanavir was   separated by 12 hours.

p  Ratio of atazanavir with ritonavir with tenofovir DF to atazanavir with ritonavir. Atazanavir 300 mg with ritonavir 100 mg results in higher atazanavir     exposure than atazanavir 400 mg (see footnoteo). The geometric mean values of atazanavir pharmacokinetic parameters when coadministered         with ritonavir and tenofovir DF were: C max = 3190 ng/mL, AUC = 34459 ng•h/mL, and Cmin = 491 ng/mL. Study was conducted in subjects with       HIV-1 infection.

 NA = not available.



Table 22: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Atazanavir a