REYATAZ

Physicians Total Care, Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use REYATAZ safely and effectively. See full prescribing information for REYATAZ.REYATAZ (atazanavir sulfate) Capsules Initial U.S. Approval: 2003RECENT MAJOR CHANGESDosage and Administration (2.2)     10/2011Dosage and Administration (2.3)     02/2011INDICATIONS AND USAGEREYATAZ is a protease inhibitor indicated for use in combination with other antiretroviral agents for the treatment of HIV-1 infection. (1) DOSAGE AND ADMINISTRATION Treatment-naive patients: REYATAZ 300 mg with ritonavir 100 mg once daily with food or REYATAZ 400 mg once daily with food. When coadministered with tenofovir, the recommended dose is REYATAZ 300 mg with ritonavir 100 mg. (2.1) Treatment-experienced patients: REYATAZ 300 mg with ritonavir 100 mg once daily with food. (2.1) Pediatric patients (6 to less than 18 years of age): Dosage is based on body weight not to exceed the adult dose. (2.2) Pregnancy: REYATAZ 300 mg with ritonavir 100 mg once daily with food, with dosing modifications for some concomitant medications. (2.3) Concomitant therapy: Dosing modifications may be required. (2.1, 7) Renal impairment: Dosing modifications may be required. (2.4) Hepatic impairment: Dosing modifications may be required. (2.5) DOSAGE FORMS AND STRENGTHS Capsules: 100 mg, 150 mg, 200 mg, 300 mg. (3, 16) CONTRAINDICATIONS REYATAZ is contraindicated in patients with previously demonstrated hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product. (4) Coadministration with alfuzosin, triazolam, orally administered midazolam, ergot derivatives, rifampin, irinotecan, lovastatin, simvastatin, indinavir, cisapride, pimozide, St. John’s wort, and sildenafil when dosed as REVATIO®. (4) WARNINGS AND PRECAUTIONS Cardiac conduction abnormalities: PR interval prolongation may occur in some patients. Use with caution in patients with preexisting conduction system disease or when administered with other drugs that may prolong the PR interval. (5.2, 6.4, 7.3, 12.2, 17.3) Rash: Discontinue if severe rash develops. (5.3, 6.4, 17.4) Hyperbilirubinemia: Most patients experience asymptomatic increases in indirect bilirubin, which is reversible upon discontinuation. Do not dose reduce. If a concomitant transaminase increase occurs, evaluate for alternative etiologies. (5.4, 6.2) Hepatotoxicity: REYATAZ should be used with caution in patients with hepatic impairment (5.5). Patients with hepatitis B or C infection are at risk of increased transaminases or hepatic decompensation. Monitor hepatic laboratory tests prior to therapy and during treatment. (2.5, 5.5, 6.3, 6.4, 8.8) Nephrolithiasis has been reported. Consider temporary interruption or discontinuation. (5.6, 6.4) Patients receiving REYATAZ may develop new onset or exacerbations of diabetes mellitus/hyperglycemia (5.7, 6.4), immune reconstitution syndrome (5.8), and redistribution/accumulation of body fat. (5.9) Hemophilia: Spontaneous bleeding may occur and additional factor VIII may be required. (5.10) Side EffectsMost common adverse reactions (≥2%) are nausea, jaundice/scleral icterus, rash, headache, abdominal pain, vomiting, insomnia, peripheral neurologic symptoms, dizziness, myalgia, diarrhea, depression, and fever. (6.1, 6.2) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb at 1-800-721-5072 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch DRUG INTERACTIONSCoadministration of REYATAZ can alter the concentration of other drugs and other drugs may alter the concentration of atazanavir. The potential drug-drug interactions must be considered prior to and during therapy. (4, 5.1, 7, 12.3) USE IN SPECIFIC POPULATIONS Pregnancy: Use only if the potential benefit justifies the potential risk. Physicians are encouraged to register patients in the Antiretroviral Pregnancy Registry. (8.1) Nursing mothers should be instructed not to breast-feed due to the potential for postnatal HIV transmission. (8.3) Hepatitis B or C co-infection: Monitor liver enzymes. (5.5, 6.3) Renal impairment: Do not use in treatment-experienced patients with end stage renal disease managed with hemodialysis. (2.4, 8.7) Hepatic impairment: REYATAZ should be used with caution in patients with mild to moderate hepatic impairment. Do not use REYATAZ in patients with severe hepatic impairment. REYATAZ/ritonavir is not recommended. (2.5, 8.8)

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 REYATAZ INDICATIONS AND USAGE
• 2 REYATAZ DOSAGE AND ADMINISTRATION
  • 2.1 Recommended Adult Dosage
  • 2.2 Recommended Pediatric Dosage
  • 2.3 Pregnancy
  • 2.4 Renal Impairment
  • 2.5 Hepatic Impairment
• 3 DOSAGE FORMS AND STRENGTHS
• 4 REYATAZ CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Drug Interactions
  • 5.2 Cardiac Conduction Abnormalities
  • 5.3 Rash
  • 5.4 Hyperbilirubinemia
  • 5.5 Hepatotoxicity
  • 5.6 Nephrolithiasis
  • 5.7 Diabetes Mellitus/Hyperglycemia
  • 5.8 Immune Reconstitution Syndrome
  • 5.9 Fat Redistribution
  • 5.10 Hemophilia
  • 5.11 Resistance/Cross-Resistance
• 6 REYATAZ ADVERSE REACTIONS
  • 6.1 Clinical Trial Experience in Adults
  • 6.2 Clinical Trial Experience in Pediatric Patients
  • 6.3 Patients Co-infected With Hepatitis B and/or Hepatitis C Virus
  • 6.4 Postmarketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Potential for REYATAZ to Affect Other Drugs
  • 7.2 Potential for Other Drugs to Affect Atazanavir
  • 7.3 Established and Other Potentially Significant Drug Interactions
  • 7.4 Drugs with No Observed or Predicted Interactions with REYATAZ
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Age/Gender
  • 8.7 Impaired Renal Function
  • 8.8 Impaired Hepatic Function
• 10 OVERDOSAGE
• 11 REYATAZ DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
  • 12.4 Microbiology
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
  • 14.1 Adult Patients Without Prior Antiretroviral Therapy
  • 14.2 Adult Patients With Prior Antiretroviral Therapy
  • 14.3 Pediatric Patients
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
  • 17.1 Dosing Instructions
  • 17.2 Drug Interactions
  • 17.3 Cardiac Conduction Abnormalities
  • 17.4 Rash
  • 17.5 Hyperbilirubinemia
  • 17.6 Fat Redistribution

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

REYATAZ^® (atazanavir sulfate) is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. This indication is based on analyses of plasma HIV-1 RNA levels and CD4+ cell counts from controlled studies of 96 weeks duration in antiretroviral-naive and 48 weeks duration in antiretroviral-treatment-experienced adult and pediatric patients at least 6 years of age.

The following points should be considered when initiating therapy with REYATAZ:

• In Study AI424-045, REYATAZ/ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV RNA level. This study was not large enough to reach a definitive conclusion that REYATAZ/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measure of proportions below the HIV RNA lower limit of detection [see Clinical Studies (14.2) ].
• The number of baseline primary protease inhibitor mutations affects the virologic response to REYATAZ/ritonavir [see Clinical Pharmacology (12.4) ].

2 DOSAGE AND ADMINISTRATION

General Dosing Recommendations:

• REYATAZ Capsules must be taken with food.
• Do not open the capsules.
• The recommended oral dosage of REYATAZ 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 (2.1) ].
• When coadministered with didanosine buffered or enteric-coated formulations, REYATAZ should be given (with food) 2 hours before or 1 hour after didanosine.
• REYATAZ without ritonavir is not recommended for treatment-experienced adult or pediatric patients with prior virologic failure [see Clinical Studies (14) ].
• Efficacy and safety of REYATAZ with ritonavir in doses greater than 100 mg once daily have not been established. The use of higher ritonavir doses might alter the safety profile of atazanavir (cardiac effects, hyperbilirubinemia) and, therefore, is not recommended. Prescribers should consult the complete prescribing information for NORVIR^® (ritonavir) when using this agent.

2.1 Recommended Adult Dosage

Table 1 summarizes the recommended REYATAZ dosing regimen in adults. All REYATAZ dosing regimens are to be administered as a single dose with food.

[For these drugs and other antiretroviral agents for which dosing modification may be appropriate, see Drug Interactions (7) .]

2.2 Recommended Pediatric Dosage

The recommended daily dosage of REYATAZ for pediatric patients (6 to less than 18 years of age) is based on body weight and should not exceed the recommended adult dosage. REYATAZ Capsules must be taken with food. The data are insufficient to recommend dosing of REYATAZ for any of the following: (1) patients less than 6 years of age, (2) without ritonavir in any pediatric patient less than 13 years of age, and (3) patients less than 40 kg receiving concomitant tenofovir, H₂-receptor antagonists, or proton-pump inhibitors.

The recommended dosage of REYATAZ with ritonavir in pediatric patients at least 6 years of age is shown in Table 2.

For treatment-naive patients at least 13 years of age and at least 40 kg, who are unable to tolerate ritonavir, the recommended dose is REYATAZ 400 mg (without ritonavir) once daily with food. For patients at least 13 years of age and at least 40 kg receiving concomitant tenofovir, H₂-receptor antagonists, or proton-pump inhibitors, REYATAZ should not be administered without ritonavir.

2.3 Pregnancy

Dosing During Pregnancy and the Postpartum Period:

• REYATAZ should not be administered without ritonavir.
• REYATAZ should only be administered to pregnant women with HIV-1 strains susceptible to atazanavir.
• For pregnant patients, no dose adjustment is required for REYATAZ with the following exceptions:
  • For treatment-experienced pregnant women during the second or third trimester, when REYATAZ is
    coadministered with either an H₂-receptor antagonist or tenofovir, REYATAZ 400 mg with ritonavir
    100 mg once daily is recommended. There are insufficient data to recommend a REYATAZ dose
    for use with both an H₂-receptor antagonist and tenofovir in treatment-experienced pregnant
    women.
• No dose 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
  Use in Specific Populations (8.1) and Clinical Pharmacology (12.3) .]

2.4 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 REYATAZ. Treatment-naive patients with end stage renal disease managed with hemodialysis should receive REYATAZ 300 mg with ritonavir 100 mg. REYATAZ should not be administered to HIV-treatment-experienced patients with end stage renal disease managed with hemodialysis. [See Use in Specific Populations (8.7) .]

2.5 Hepatic Impairment

REYATAZ should be used with caution in patients with mild-to-moderate hepatic impairment. For patients with moderate hepatic impairment (Child-Pugh Class B) who have not experienced prior virologic failure, a dose reduction to 300 mg once daily should be considered. REYATAZ should not be used in patients with severe hepatic impairment (Child-Pugh Class C). REYATAZ/ritonavir has not been studied in subjects with hepatic impairment and is not recommended. [See Warnings and Precautions (5.5) and Use in Specific Populations (8.8).]

3 DOSAGE FORMS AND STRENGTHS

• 100 mg capsule with blue cap and white body, printed with white ink “BMS 100 mg” on the cap and with blue ink “3623” on the body.
• 150 mg capsule with blue cap and powder blue body, printed with white ink “BMS 150 mg” on the cap and with blue ink “3624” on the body.
• 200 mg capsule with blue cap and blue body, printed with white ink “BMS 200 mg” on the cap and with white ink “3631” on the body.
• 300 mg capsule with red cap and blue body, printed with white ink “BMS 300 mg” on the cap and with white ink “3622” on the body.

4 CONTRAINDICATIONS

REYATAZ (atazanavir sulfate) is contraindicated:

• in patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of this product.
• when coadministered with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations are associated with serious and/or life-threatening events. These and other contraindicated drugs are listed in Table 3.

5 WARNINGS AND PRECAUTIONS

5.1 Drug Interactions

See Table 3 for a listing of drugs that are contraindicated for use with REYATAZ due to potentially life-threatening adverse events, significant drug interactions, or loss of virologic activity. [See Contraindications (4) .] Please refer to Table 13 for established and other potentially significant drug interactions [see Drug Interactions (7.3) ].

5.2 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 (6.4) 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 (eg, marked first-degree AV block or second- or third-degree AV block), atazanavir should be used with caution in these patients. [See Clinical Pharmacology (12.2) .]

Atazanavir in combination with diltiazem increased diltiazem plasma concentration by 2-fold with an additive effect on the PR interval. When used in combination with atazanavir, a dose reduction of diltiazem by one-half should be considered and ECG monitoring is recommended. In a pharmacokinetic study between atazanavir 400 mg once daily and atenolol 50 mg once daily, no clinically significant additive effect of atazanavir and atenolol on the PR interval was observed. Dose adjustment of atenolol is not required when used in combination with atazanavir. [See Drug Interactions (7) and Clinical Pharmacology (12.2) .] Pharmacokinetic studies between atazanavir and other drugs that prolong the PR interval including beta blockers [other than atenolol, see Drug Interactions (7) ], verapamil, and digoxin have not been performed. An additive effect of atazanavir and these drugs cannot be excluded; therefore, caution should be exercised when atazanavir is given concurrently with these drugs, especially those that are metabolized by CYP3A (eg, verapamil).

5.3 Rash

In controlled clinical trials, rash (all grades, regardless of causality) occurred in approximately 20% of patients treated with REYATAZ. 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 REYATAZ was often continued without interruption in patients who developed rash. The discontinuation rate for rash in clinical trials was <1%. REYATAZ should be discontinued if severe rash develops. Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions have been reported in patients receiving REYATAZ. [See Contraindications (4) .]

5.4 Hyperbilirubinemia

Most patients taking REYATAZ experience asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT). This hyperbilirubinemia is reversible upon discontinuation of REYATAZ. 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 ULN. Alternative antiretroviral therapy to REYATAZ 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, 6.2) .]

5.5 Hepatotoxicity

Caution should be exercised when administering REYATAZ to patients with hepatic impairment because atazanavir concentrations may be increased. [See Dosage and Administration (2.5) .] 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 REYATAZ and during treatment. [See Adverse Reactions (6.3) and Use in Specific Populations (8.8) .]

5.6 Nephrolithiasis

Cases of nephrolithiasis were reported during postmarketing surveillance in HIV-infected patients receiving REYATAZ therapy. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis occur, temporary interruption or discontinuation of therapy may be considered. [See Adverse Reactions (6.4) .]

5.7 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 (6.4) .]

5.8 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including REYATAZ. 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.

5.9 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.

5.10 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.

5.11 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 Clinical Pharmacology (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 (5.2) ]
• rash [see Warnings and Precautions (5.3) ]
• hyperbilirubinemia [see Warnings and Precautions (5.4) ]
• nephrolithiasis [see Warnings and Precautions (5.6) ]

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.

6.1 Clinical Trial Experience in Adults

Treatment-Emergent Adverse Reactions in Treatment-Naive Patients

The safety profile of REYATAZ in treatment-naive adults is based on 1625 HIV-1 infected patients in clinical trials. 536 patients received REYATAZ 300 mg with ritonavir 100 mg and 1089 patients received REYATAZ 400 mg or higher (without ritonavir).

The most common adverse reactions are 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 REYATAZ 300 mg with ritonavir 100 mg and REYATAZ 400 mg (without ritonavir) are presented in Tables 4 and 5, respectively.

Treatment-Emergent Adverse Reactions in Treatment-Experienced Patients

The safety profile of REYATAZ 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 REYATAZ/ritonavir are presented in Table 6.

Laboratory Abnormalities in Treatment-Naive Patients

The percentages of adult treatment-naive patients treated with combination therapy including REYATAZ (atazanavir sulfate) 300 mg with ritonavir 100 mg and REYATAZ 400 mg (without ritonavir) with Grade 3–4 laboratory abnormalities are presented in Tables 7 and 8, respectively.

Laboratory Abnormalities in Treatment-Experienced Patients

The percentages of adult treatment-experienced patients treated with combination therapy including REYATAZ/ritonavir with Grade 3–4 laboratory abnormalities are presented in Table 9.

Lipids, Change 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 10 and 11, respectively.

Lipids, Change 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 12. The observed magnitude of dyslipidemia was less with REYATAZ/ritonavir than with lopinavir/ritonavir. However, the clinical impact of such findings has not been demonstrated.

6.2 Clinical Trial Experience in Pediatric Patients

The safety and tolerability of REYATAZ 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. Use of REYATAZ in pediatric patients less than 6 years of age is under investigation.

The safety profile of REYATAZ in pediatric patients (6 to less than 18 years of age) was generally similar to that observed in clinical studies of REYATAZ in adults. The most common Grade 2–4 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 3–4 laboratory abnormalities occurring in pediatric patients were elevation of total bilirubin (≥3.2 mg/dL, 58%), neutropenia (9%), and hypoglycemia (4%). All other Grade 3–4 laboratory abnormalities occurred with a frequency of less than 3%.

6.3 Patients Co-infected With Hepatitis B and/or Hepatitis C Virus

Liver function tests should be monitored in patients with a history of hepatitis B or C.

In study AI424-138, 60 patients treated with REYATAZ/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-emtricitabine, were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 10% (6/60) of the REYATAZ/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 REYATAZ/ritonavir-treated patients and none (0/50) of the lopinavir/ritonavir-treated patients.

In study AI424-045, 20 patients treated with REYATAZ/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 REYATAZ/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 REYATAZ/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 REYATAZ (atazanavir sulfate) 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 the upper limit of normal (ULN) developed in 15% of the REYATAZ-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 REYATAZ-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 (5.5) .]

6.4 Postmarketing Experience

The following events have been identified during postmarketing use of REYATAZ. 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 (5.2) ]

Gastrointestinal System: pancreatitis

Hepatic System: hepatic function abnormalities

Hepatobiliary Disorders: cholelithiasis, cholecystitis, cholestasis

Metabolic System and Nutrition Disorders: diabetes mellitus, hyperglycemia [see Warnings and Precautions (5.7) ]

Musculoskeletal System: arthralgia

Renal System: nephrolithiasis [see Warnings and Precautions (5.6) ]

Skin and Appendages: alopecia, maculopapular rash [see Contraindications (4) and Warnings and Precautions (5.3) ], pruritus

7 DRUG INTERACTIONS

See also Contraindications (4) and Clinical Pharmacology (12.3) .

7.1 Potential for REYATAZ to Affect Other Drugs

Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of REYATAZ 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. Caution should be used when REYATAZ without ritonavir is coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (eg, paclitaxel, repaglinide). When REYATAZ with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected. [See Clinical Pharmacology, Table 14 (12.3) .]

The magnitude of CYP3A-mediated drug interactions on coadministered drug may change when REYATAZ is coadministered with ritonavir. See the complete prescribing information for NORVIR^® (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 REYATAZ’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.

7.3 Established and Other Potentially Significant Drug Interactions

Table 13 provides dosing recommendations as a result of drug interactions with REYATAZ. 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.

7.4 Drugs with No Observed or Predicted Interactions with REYATAZ

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 NORVIR^® for information on other potential drug interactions with ritonavir.

Based on known metabolic profiles, clinically significant drug interactions are not expected between REYATAZ (atazanavir sulfate) and fluvastatin, pravastatin, dapsone, trimethoprim/sulfamethoxazole, azithromycin, or erythromycin. REYATAZ does not interact with substrates of CYP2D6 (eg, nortriptyline, desipramine, metoprolol). Additionally, no clinically significant drug interactions were observed when REYATAZ was coadministered with methadone, fluconazole, acetaminophen, or atenolol. [See Clinical Pharmacology, Tables 17 and 18 (12.3) .]

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B

Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to REYATAZ, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.

Risk Summary

Atazanavir has been evaluated in a limited number of women during pregnancy and postpartum. Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate. However, because the studies in humans cannot rule out the possibility of harm, REYATAZ should be used during pregnancy only if clearly needed.

Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using REYATAZ in combination with nucleoside analogues. Nucleoside analogues are associated with an increased risk of lactic acidosis syndrome.

Hyperbilirubinemia occurs frequently in patients who take REYATAZ, including pregnant women. All infants, including neonates exposed to REYATAZ in-utero, should be monitored for the development of severe hyperbilirubinemia during the first few days of life.

Clinical Considerations

Dosing During Pregnancy and the Postpartum Period:

• REYATAZ should not be administered without ritonavir.
• REYATAZ should only be administered to pregnant women with HIV-1 strains susceptible to atazanavir.
• For pregnant patients, no dose adjustment is required for REYATAZ with the following exceptions:
  • For treatment-experienced pregnant women during the second or third trimester, when REYATAZ is coadministered with either an H₂-receptor antagonist or tenofovir, REYATAZ 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend a REYATAZ dose for use with both an H₂-receptor antagonist and tenofovir in treatment-experienced pregnant women.
• No dose 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, 2.3) and Clinical Pharmacology (12.3) .]

Human Data

Clinical Trials: In clinical trial AI424-182, REYATAZ/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 <50 copies/mL at time of delivery. Six of 20 (30%) women on REYATAZ/ritonavir 300/100 mg and 13 of 21 (62%) women on REYATAZ/ritonavir 400/100 mg experienced hyperbilirubinemia (total bilirubin greater than or equal to 2.6 times the upper limit of normal). There were no cases of lactic acidosis observed in clinical trial AI424-182.

Atazanavir drug concentrations in fetal umbilical cord blood were approximately 12–19% 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 <40 mg/dL that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis.

Antiretroviral Pregnancy Registry Data : As of January 2010, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 635 exposures to atazanavir-containing regimens (425 exposed in the first trimester and 160 and 50 exposed in second and third trimester, respectively). Birth defects occurred in 9 of 393 (2.3%) live births (first trimester exposure) and 5 of 212 (2.4%) live births (second/third trimester exposure). Among pregnant women in the U.S. reference population, the background rate of birth defects is 2.7%. There was no association between atazanavir and overall birth defects observed in the APR.

Pharmacokinetics of Atazanavir in Pregnancy

[See Clinical Pharmacology (12.3) .]

Animal Data

In animal reproduction studies, there was no evidence of 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 post-natal development studies in the rat, atazanavir caused body weight loss or weight gain suppression in the animal offspring with maternal drug exposure (AUC) 1.3 times the human exposure at this clinical dose. However, maternal toxicity also occurred at this exposure level.

8.3 Nursing Mothers

The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. It is not known whether atazanavir is present in human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are taking REYATAZ.

8.4 Pediatric Use

REYATAZ should not be administered to pediatric patients below the age of 3 months due to the risk of kernicterus.

The safety, activity, and pharmacokinetic profiles of REYATAZ in pediatric patients ages 3 months to less than 6 years have not been established.

The safety, pharmacokinetic profile, and virologic response of REYATAZ were evaluated in pediatric patients 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 (6.2) ]. Please see Dosage and Administration (2.2) for dosing recommendations for pediatric patients 6 years of age and older.

8.5 Geriatric Use

Clinical studies of REYATAZ 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 REYATAZ 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; 18–40 years) and elderly (n=30; ≥65 years) healthy subjects. There were no clinically important pharmacokinetic differences observed due to age or gender.

8.7 Impaired Renal Function

In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. REYATAZ 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. Atazanavir was not appreciably cleared during hemodialysis. 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. REYATAZ should not be administered to HIV-treatment-experienced patients with end stage renal disease managed with hemodialysis. [See Dosage and Administration (2.4) .]

8.8 Impaired Hepatic Function

Atazanavir is metabolized and eliminated primarily by the liver. REYATAZ (atazanavir sulfate) 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. Increased concentrations of atazanavir are expected in patients with moderately or severely impaired hepatic function. The pharmacokinetics of REYATAZ in combination with ritonavir have not been studied in subjects with hepatic impairment. REYATAZ should not be administered to patients with severe hepatic impairment. REYATAZ/ritonavir is not recommended for use in patients with hepatic impairment. [See Dosage and Administration (2.5) and Warnings and Precautions (5.5) .]

10 OVERDOSAGE

Human experience of acute overdose with REYATAZ is limited. Single doses up to 1200 mg have been taken by healthy volunteers without symptomatic untoward effects. A single self-administered overdose of 29.2 g of REYATAZ 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 high doses that lead to high drug exposures, jaundice due to indirect (unconjugated) hyperbilirubinemia (without associated liver function test changes) or PR interval prolongation may be observed. [See Warnings and Precautions (5.2, 5.4) and Clinical Pharmacology (12.2) .]

Treatment of overdosage with REYATAZ 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 REYATAZ. 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

REYATAZ^® (atazanavir sulfate) is an azapeptide inhibitor of HIV-1 protease.

The chemical name for atazanavir sulfate is (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1). Its molecular formula is 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:

Atazanavir sulfate is a white to pale yellow crystalline powder. It is slightly soluble in water (4–5 mg/mL, free base equivalent) with the pH of a saturated solution in water being about 1.9 at 24 ± 3° C.

REYATAZ Capsules are available for oral administration in strengths containing the equivalent of 100 mg, 150 mg, 200 mg, or 300 mg of atazanavir as atazanavir sulfate and the following inactive ingredients: crospovidone, lactose monohydrate, and magnesium stearate. The capsule shells contain the following inactive ingredients: gelatin, FD&C Blue #2, titanium dioxide, black iron oxide, red iron oxide, and yellow iron oxide. The capsules are printed with ink containing shellac, titanium dioxide, FD&C Blue #2, isopropyl alcohol, ammonium hydroxide, propylene glycol, n-butyl alcohol, simethicone, and dehydrated alcohol.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Atazanavir is an antiviral drug [see Clinical Pharmacology (12.4) ].

12.2 Pharmacodynamics

Effects on Electrocardiogram

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 (5.2) .]

Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of 72 healthy subjects. Oral doses of 400 mg and 800 mg 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 (5.2) .]

In a pharmacokinetic study between atazanavir 400 mg once daily and diltiazem 180 mg once daily, a CYP3A substrate, there was a 2-fold increase in the diltiazem plasma concentration and an additive effect on the PR interval. In a pharmacokinetic study between atazanavir 400 mg once daily and atenolol 50 mg once daily, there was no substantial additive effect of atazanavir and atenolol on the PR interval. [See Warnings and Precautions (5.2) .]

12.3 Pharmacokinetics

The pharmacokinetics of atazanavir were evaluated in healthy adult volunteers and in HIV-infected patients after administration of REYATAZ 400 mg once daily and after administration of REYATAZ 300 mg with ritonavir 100 mg once daily (see Table 14).

Figure 1 displays the mean plasma concentrations of atazanavir at steady state after REYATAZ 400 mg once daily (as two 200-mg capsules) with a light meal and after REYATAZ 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

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 200–800 mg once daily. Steady state is achieved between Days 4 and 8, with an accumulation of approximately 2.3-fold.

Food Effect

Administration of REYATAZ with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single 400-mg dose of REYATAZ 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 REYATAZ 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 REYATAZ (atazanavir sulfate) 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 REYATAZ 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 REYATAZ 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 REYATAZ 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.

Special Populations

Pediatrics

The pharmacokinetic parameters for atazanavir at steady state in pediatric patients were predicted by a population pharmacokinetic model and are summarized in Table 15 by weight ranges that correspond to the recommended doses. [See Dosage and Administration (2.2) .]

Pregnancy

The pharmacokinetic data from HIV-infected pregnant women receiving REYATAZ Capsules with ritonavir are presented in Table 16.

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, REYATAZ decreased the urinary ratio of endogenous 6β-OH cortisol to cortisol versus baseline, indicating that CYP3A production was not induced.

Drug interaction studies were performed with REYATAZ and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of REYATAZ on the AUC, C_max, and C_min are summarized in Tables 17 and 18. For information regarding clinical recommendations, see Drug Interactions (7) .

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 to 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 NNRTIs (delavirdine, efavirenz, and nevirapine), PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, 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 REYATAZ vs. Unboosted REYATAZ: Study AI424-089 compared REYATAZ 300 mg once daily with ritonavir 100 mg vs. REYATAZ 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 19.

Clinical Studies of Treatment-Naive Patients Receiving REYATAZ 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 150L 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 susceptibiity 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 REYATAZ 400 mg Without Ritonavir: ATV-resistant clinical isolates from treatment-naive patients who experienced virologic failure on REYATAZ 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 (eg, 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 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 20.

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 1–2 PI substitutions, including one of these substitutions.

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 21). 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 REYATAZ.

13 NONCLINICAL TOXICOLOGY

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 CLINICAL STUDIES

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-emtricitabine in HIV-1 infected treatment-naive subjects. Study AI424-138 is a 96-week open-label, randomized, multicenter study, comparing REYATAZ (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 with emtricitabine (300/200 mg once daily), in 878 antiretroviral treatment-naive treated patients. Patients had a mean age of 36 years (range: 19–72), 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 22.

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 REYATAZ/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 REYATAZ/ritonavir arm and 273 cells/mm³ for the lopinavir/ritonavir arm.

Study AI424-034: REYATAZ 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 REYATAZ (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 23.

Through 48 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 REYATAZ and efavirenz arms. The mean increase from baseline in CD4+ cell count was 176 cells/mm³ for the REYATAZ arm and 160 cells/mm³ for the efavirenz arm.

Study AI424-008: REYATAZ 400 mg once daily compared to REYATAZ 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 REYATAZ, comparing REYATAZ 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 24.

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

14.2 Adult Patients With Prior Antiretroviral Therapy

Study AI424-045: REYATAZ once daily + ritonavir once daily compared to REYATAZ once daily + saquinavir (soft gelatin capsules) once daily, and compared to lopinavir + ritonavir twice daily, each in combination with tenofovir + one NRTI. Study AI424-045 is an ongoing, randomized, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (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 and one NRTI, in 347 (of 358 randomized) patients who experienced virologic failure on HAART regimens containing PIs, NRTIs, and NNRTIs. The mean time of prior exposure to antiretrovirals was 139 weeks for PIs, 283 weeks for NRTIs, and 85 weeks for NNRTIs. 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 REYATAZ/ritonavir and lopinavir/ritonavir treatment arms are presented in Table 25. REYATAZ/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 REYATAZ/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measure of proportions below the HIV RNA lower limit of detection. [See Clinical Pharmacology, Tables 20 and 21 (12.4) .]

No patients in the REYATAZ/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 REYATAZ 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, coadministration of REYATAZ 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 REYATAZ (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 REYATAZ (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 REYATAZ treatment arm and −2.02 log₁₀ copies/mL in the lopinavir/ritonavir arm. Based on the results of this study, REYATAZ without ritonavir is inferior to lopinavir/ritonavir in PI-experienced patients with prior virologic failure and is not recommended for such patients.

14.3 Pediatric Patients

Assessment of the pharmacokinetics, safety, tolerability, and efficacy of REYATAZ is based on data from the open-label, multicenter clinical trial PACTG 1020A conducted in patients from 3 months to 21 years of age. In this study, 193 patients (86 antiretroviral-naive and 107 antiretroviral-experienced) received once daily REYATAZ, with or without ritonavir, in combination with two NRTIs.

One-hundred and five patients (6 to less than 18 years of age) treated with the REYATAZ 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

REYATAZ^® (atazanavir sulfate) Capsules are available in the following strengths and configurations of plastic bottles with child-resistant closures.

* atazanavir equivalent as atazanavir sulfate.

REYATAZ (atazanavir sulfate) Capsules should be stored at 25° C (77° F); excursions permitted to 15–30° C (59–86° F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Patient Information).

A statement to patients and healthcare providers is included on the product’s bottle label: ALERT: Find out about medicines that should NOT be taken with REYATAZ.

Patients should be informed that REYATAZ is not a cure for HIV infection and that they may continue to develop opportunistic infections and other complications associated with HIV disease. Patients should be told that there are currently no data demonstrating that therapy with REYATAZ can reduce the risk of transmitting HIV to others through sexual contact.

17.1 Dosing Instructions

Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a physician while using REYATAZ. Patients should be advised to take REYATAZ with food every day and take other concomitant antiretroviral therapy as prescribed. REYATAZ must always be used in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting with their doctor. If a dose of REYATAZ is missed, patients 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.

17.2 Drug Interactions

REYATAZ may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, nonprescription medication, or herbal products, particularly St. John’s wort.

Patients receiving a PDE5 inhibitor and atazanavir should be advised that they may be at an increased risk of PDE5 inhibitor-associated adverse events including hypotension, syncope, visual disturbances, and priapism, and should promptly report any symptoms to their doctor.

Patients should be informed that REVATIO^® (used to treat pulmonary arterial hypertension) is contraindicated with REYATAZ and that dose adjustments are necessary when REYATAZ is used with CIALIS^®, LEVITRA^® or VIAGRA^® (used to treat erectile dysfunction), or ADCIRCA^® (used to treat pulmonary arterial hypertension).

17.3 Cardiac Conduction Abnormalities

Patients should be informed that atazanavir may produce changes in the electrocardiogram (eg, PR prolongation). Patients should consult their physician if they are experiencing symptoms such as dizziness or lightheadedness.

17.4 Rash

Patients should be informed that mild rashes without other symptoms have been reported with REYATAZ use. These rashes go away within two weeks with no change in treatment. However, there have been a few reports of severe skin reactions (eg, Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions) with REYATAZ use. Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions (including, but not limited to, severe rash or rash accompanied by one or more of the following: fever, general malaise, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction) must discontinue REYATAZ and seek medical evaluation immediately.

17.5 Hyperbilirubinemia

Patients should be informed that asymptomatic elevations in indirect bilirubin have occurred in patients receiving REYATAZ. 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.

17.6 Fat Redistribution

Patients should be informed 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. It is unknown whether long-term use of REYATAZ will result in a lower incidence of lipodystrophy than with other protease inhibitors.

Patient Information

REYATAZ ^® (RAY-ah-taz)

(generic name = atazanavir sulfate)

Capsules

ALERT: Find out about medicines that should NOT be taken with REYATAZ. Read the section “What important information should I know about taking REYATAZ with other medicines?”

Read the Patient Information that comes with REYATAZ before you start using it and each time you get a refill. There may be new information. This leaflet provides a summary about REYATAZ and does not include everything there is to know about your medicine. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.

What is REYATAZ?

REYATAZ is a prescription medicine used with other anti-HIV medicines to treat people 6 years of age and older who are infected with the human immunodeficiency virus (HIV). HIV is the virus that causes acquired immune deficiency syndrome (AIDS). REYATAZ is a type of anti-HIV medicine called a protease inhibitor. HIV infection destroys CD4+ (T) cells, which are important to the immune system. The immune system helps fight infection. After a large number of (T) cells are destroyed, AIDS develops. REYATAZ helps to block HIV protease, an enzyme that is needed for the HIV virus to multiply. REYATAZ may lower the amount of HIV in your blood, help your body keep its supply of CD4+ (T) cells, and reduce the risk of death and illness associated with HIV.

Does REYATAZ cure HIV or AIDS?

REYATAZ does not cure HIV infection or AIDS. At present there is no cure for HIV infection. People taking REYATAZ may still get opportunistic infections or other conditions that happen with HIV infection. Opportunistic infections are infections that develop because the immune system is weak. Some of these conditions are pneumonia, herpes virus infections, and Mycobacterium avium complex (MAC) infections. It is very important that you see your healthcare provider regularly while taking REYATAZ.

REYATAZ does not lower your chance of passing HIV to other people through sexual contact, sharing needles, or being exposed to your blood. For your health and the health of others, it is important to always practice safer sex by using a latex or polyurethane condom or other barrier to lower the chance of sexual contact with semen, vaginal secretions, or blood. Never use or share dirty needles.

Who should not take REYATAZ?

Do not take REYATAZ if you:

• are taking certain medicines. (See “What important information should I know about taking REYATAZ with other medicines?”) Serious life-threatening side effects or death may happen. Before you take REYATAZ, tell your healthcare provider about all medicines you are taking or planning to take. These include other prescription and nonprescription medicines, vitamins, and herbal supplements.
• are allergic to REYATAZ or to any of its ingredients. The active ingredient is atazanavir sulfate. See the end of this leaflet for a complete list of ingredients in REYATAZ. Tell your healthcare provider if you think you have had an allergic reaction to any of these ingredients.

What should I tell my healthcare provider before I take REYATAZ?

Tell your healthcare provider:

• If you are pregnant or plan to become pregnant. REYATAZ use during pregnancy has not been associated with an increase in birth defects. Pregnant women have experienced serious side effects when taking REYATAZ with other HIV medicines called nucleoside analogues. You and your healthcare provider will need to decide if REYATAZ is right for you. If you use REYATAZ while you are pregnant, talk to your healthcare provider about the Antiretroviral Pregnancy Registry.
  • After your baby is born, tell your healthcare provider if your baby’s skin or the white part of his/her eyes turns yellow.
• If you are breast-feeding. You should not breast-feed if you are HIV-positive because of the chance of passing HIV to your baby. Also, it is not known if REYATAZ can pass into your breast milk and if it can harm your baby. If you are a woman who has or will have a baby, talk with your healthcare provider about the best way to feed your baby.
• If you have liver problems or are infected with the hepatitis B or C virus. See “What are the possible side effects of REYATAZ?”
• If you have end stage kidney disease managed with hemodialysis.
• If you have diabetes. See “What are the possible side effects of REYATAZ?”
• If you have hemophilia. See “What are the possible side effects of REYATAZ?”
• About all the medicines you take including prescription and nonprescription medicines, vitamins, and herbal supplements. Keep a list of your medicines with you to show your healthcare provider. For more information, see “What important information should I know about taking REYATAZ with other medicines?” and “Who should not take REYATAZ?” Some medicines can cause serious side effects if taken with REYATAZ.

How should I take REYATAZ?

• Take REYATAZ once every day exactly as instructed by your healthcare provider.
  Your healthcare provider will prescribe the amount of REYATAZ that is right for you.
• Always take REYATAZ with food (a meal or snack) to help it work better. Swallow the capsules whole. Do not open the capsules. Take REYATAZ at the same time each day.
• If you are taking antacids or didanosine (VIDEX ^® or VIDEX ^® EC), take REYATAZ 2 hours before or 1 hour after these medicines.
• If you are taking medicines for indigestion, heartburn, or ulcers such as AXID ^® (nizatidine), PEPCID AC ^® (famotidine), TAGAMET ^® (cimetidine), ZANTAC ^® (ranitidine), AcipHex ^® (rabeprazole), NEXIUM ^® (esomeprazole), PREVACID ^® (lansoprazole), PRILOSEC ^® (omeprazole), or PROTONIX ^® (pantoprazole), talk to your healthcare provider.
• Do not change your dose or stop taking REYATAZ without first talking with your healthcare provider. It is important to stay under a healthcare provider’s care while taking REYATAZ.
• When your supply of REYATAZ starts to run low, get more from your healthcare provider or pharmacy. It is important not to run out of REYATAZ. The amount of HIV in your blood may increase if the medicine is stopped for even a short time.
• If you miss a dose of REYATAZ, take it as soon as possible and then take your next scheduled dose at its regular time. If, however, it is within 6 hours of your next dose, do not take the missed dose. Wait and take the next dose at the regular time. Do not double the next dose. It is important that you do not miss any doses of REYATAZ or your other anti-HIV medicines.
• If you take more than the prescribed dose of REYATAZ, call your healthcare provider or poison control center right away.

What are the possible side effects of REYATAZ?

The following list of side effects is not complete. Report any new or continuing symptoms to your healthcare provider. If you have questions about side effects, ask your healthcare provider. Your healthcare provider may be able to help you manage these side effects.

The following side effects have been reported with REYATAZ:

• mild rash (redness and itching) without other symptoms sometimes occurs in patients taking REYATAZ, most often in the first few weeks after the medicine is started. Rashes usually go away within 2 weeks with no change in treatment. Tell your healthcare provider if rash occurs.
• severe rash: Rash may develop in association with other symptoms which could be serious and potentially cause death.

  If you develop a rash with any of the following symptoms stop using REYATAZ and call your healthcare provider right away:

  • shortness of breath
  • general ill feeling or “flu-like” symptoms
  • fever
  • muscle or joint aches
  • conjunctivitis (red or inflamed eyes, like “pink eye”)
  • blisters
  • mouth sores
  • swelling of your face
• yellowing of the skin or eyes. These effects may be due to increases in bilirubin levels in the blood (bilirubin is made by the liver). Although these effects may not be damaging to your liver, skin, or eyes, call your healthcare provider promptly if your skin or the white part of your eyes turn yellow.
• a change in the way your heart beats (heart rhythm change). Call your healthcare provider right away if you get dizzy or lightheaded. These could be symptoms of a heart problem.
• diabetes and high blood sugar (hyperglycemia) sometimes happen in patients taking protease inhibitor medicines like REYATAZ. Some patients had diabetes before taking protease inhibitors while others did not. Some patients may need changes in their diabetes medicine.
• if you have liver disease including hepatitis B or C, your liver disease may get worse when you take anti-HIV medicines like REYATAZ.
• kidney stones have been reported in patients taking REYATAZ. If you develop signs or symptoms of kidney stones (pain in your side, blood in your urine, pain when you urinate) tell your healthcare provider promptly.
• some patients with hemophilia have increased bleeding problems with protease inhibitors like REYATAZ.
• changes in body fat. These changes may include an increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the trunk. Loss of fat from the legs, arms, and face may also happen. The cause and long-term health effects of these conditions are not known at this time.
• immune reconstitution syndrome. In some patients with advanced HIV infection (AIDS) and a history of opportunistic infection, signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment, including REYATAZ, is started.

Other common side effects of REYATAZ taken with other anti-HIV medicines include nausea; headache; stomach pain; vomiting; diarrhea; depression; fever; dizziness; trouble sleeping; numbness, tingling, or burning of hands or feet; and muscle pain.

Gallbladder disorders (which may include gallstones and gallbladder inflammation) have been reported in patients taking REYATAZ.

What important information should I know about taking REYATAZ with other medicines?

Do not take REYATAZ if you take the following medicines (not all brands may be listed; tell your healthcare provider about all the medicines you take). REYATAZ may cause serious, life-threatening side effects or death when used with these medicines.

• Ergot medicines: dihydroergotamine, ergonovine, ergotamine, and methylergonovine such as CAFERGOT^®, MIGRANAL^®, D.H.E. 45^®, ergotrate maleate, METHERGINE^®, and others (used for migraine headaches).
• ORAP^® (pimozide, used for Tourette’s disorder).
• PROPULSID^® (cisapride, used for certain stomach problems).
• Triazolam, also known as HALCION^® (used for insomnia).
• Midazolam, also known as VERSED^® (used for sedation), when taken by mouth.

Do not take the following medicines with REYATAZ because of possible serious side effects:

• CAMPTOSAR^® (irinotecan, used for cancer).
• CRIXIVAN^® (indinavir, used for HIV infection). Both REYATAZ and CRIXIVAN sometimes cause increased levels of bilirubin in the blood.
• Cholesterol-lowering medicines MEVACOR^® (lovastatin) or ZOCOR^® (simvastatin).
• UROXATRAL^® (alfuzosin, used to treat benign enlargement of the prostate).
• REVATIO^® (sildenafil, used to treat pulmonary arterial hypertension).

Do not take the following medicines with REYATAZ because they may lower the amount of REYATAZ in your blood. This may lead to an increased HIV viral load. Resistance to REYATAZ or cross-resistance to other HIV medicines may develop:

• Rifampin (also known as RIMACTANE^®, RIFADIN^®, RIFATER^®, or RIFAMATE^®, used for tuberculosis).
• St. John’s wort (Hypericum perforatum), an herbal product sold as a dietary supplement, or products containing St. John’s wort.
• VIRAMUNE^® (nevirapine, used for HIV infection).

The following medicines are not recommended with REYATAZ:

• SEREVENT DISKUS^® (salmeterol) and ADVAIR^® (salmeterol with fluticasone), used to treat asthma, emphysema/chronic obstructive pulmonary disease also known as COPD.

Do not take the following medicine if you are taking REYATAZ and NORVIR^® together:

• VFEND^® (voriconazole).

The following medicines may require your healthcare provider to monitor your therapy more closely (for some medicines a change in the dose or dose schedule may be needed):

• CIALIS^® (tadalafil), LEVITRA^® (vardenafil), or VIAGRA^® (sildenafil), used to treat erectile dysfunction. REYATAZ may increase the chances of serious side effects that can happen with CIALIS, LEVITRA, or VIAGRA. Do not use CIALIS, LEVITRA, or VIAGRA while you are taking REYATAZ unless your healthcare provider tells you it is okay.
• ADCIRCA^® (tadalafil) or TRACLEER^® (bosentan), used to treat pulmonary arterial hypertension.
• LIPITOR^® (atorvastatin) or CRESTOR^® (rosuvastatin). There is an increased chance of serious side effects if you take REYATAZ with this cholesterol-lowering medicine.
• Medicines for abnormal heart rhythm: CORDARONE^® (amiodarone), lidocaine, quinidine (also known as CARDIOQUIN^®, QUINIDEX^®, and others).
• MYCOBUTIN^® (rifabutin, an antibiotic used to treat tuberculosis).
• BUPRENEX^®, SUBUTEX^®, SUBOXONE^® (buprenorphine or buprenorphine/naloxone, used to treat pain and addiction to narcotic painkillers).
• VASCOR^® (bepridil, used for chest pain).
• COUMADIN^® (warfarin).
• Tricyclic antidepressants such as ELAVIL^® (amitriptyline), NORPRAMIN^® (desipramine), SINEQUAN^® (doxepin), SURMONTIL^® (trimipramine), TOFRANIL^® (imipramine), or VIVACTIL^® (protriptyline).
• Medicines to prevent organ transplant rejection: SANDIMMUNE^® or NEORAL^® (cyclosporin), RAPAMUNE^® (sirolimus), or PROGRAF^® (tacrolimus).
• The antidepressant trazodone (DESYREL^® and others).
• Fluticasone propionate (FLONASE^®, FLOVENT^®), given by nose or inhaled to treat allergic symptoms or asthma. Your doctor may choose not to keep you on fluticasone, especially if you are also taking NORVIR^®.
• Colchicine (COLCRYS^®), used to prevent or treat gout or treat familial Mediterranean fever.

The following medicines may require a change in the dose or dose schedule of either REYATAZ or the other medicine:

• INVIRASE^® (saquinavir).
• NORVIR^® (ritonavir).
• SUSTIVA^® (efavirenz).
• Antacids or buffered medicines.
• VIDEX^® (didanosine).
• VIREAD^® (tenofovir disoproxil fumarate).
• MYCOBUTIN^® (rifabutin).
• Calcium channel blockers such as CARDIZEM^® or TIAZAC^® (diltiazem), COVERA-HS^® or ISOPTIN SR^® (verapamil) and others.
• BIAXIN^® (clarithromycin).
• Medicines for indigestion, heartburn, or ulcers such as AXID^® (nizatidine), PEPCID AC^® (famotidine), TAGAMET^® (cimetidine), or ZANTAC^® (ranitidine).

Talk to your healthcare provider about choosing an effective method of contraception. REYATAZ may affect the safety and effectiveness of hormonal contraceptives such as birth control pills or the contraceptive patch. Hormonal contraceptives do not prevent the spread of HIV to others.

Remember:

• Know all the medicines you take.
• Tell your healthcare provider about all the medicines you take.
• Do not start a new medicine without talking to your healthcare provider.

How should I store REYATAZ?

• Store REYATAZ Capsules at room temperature, 59° to 86° F (15° to 30° C). Do not store this medicine in a damp place such as a bathroom medicine cabinet or near the kitchen sink.
• Keep your medicine in a tightly closed container.
• Keep all medicines out of the reach of children and pets at all times. Do not keep medicine that is out of date or that you no longer need. Dispose of unused medicines through community take-back disposal programs when available or place REYATAZ in an unrecognizable, closed container in the household trash.

General information about REYATAZ

This medicine was prescribed for your particular condition. Do not use REYATAZ for another condition. Do not give REYATAZ to other people, even if they have the same symptoms you have. It may harm them. Keep REYATAZ and all medicines out of the reach of children and pets.

This summary does not include everything there is to know about REYATAZ. Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Remember no written summary can replace careful discussion with your healthcare provider. If you would like more information, talk with your healthcare provider or you can call 1-800-321-1335.

What are the ingredients in REYATAZ?

Active Ingredient: atazanavir sulfate

Inactive Ingredients: Crospovidone, lactose monohydrate (milk sugar), magnesium stearate, gelatin, FD&C Blue #2, and titanium dioxide.

VIDEX^® and REYATAZ^® are registered trademarks of Bristol-Myers Squibb Company. COUMADIN^® and SUSTIVA^® are registered trademarks of Bristol-Myers Squibb Pharma Company. DESYREL^® is a registered trademark of Mead Johnson and Company. Other brands listed are the trademarks of their respective owners and are not trademarks of Bristol-Myers Squibb Company.

Bristol-Myers Squibb Company
Princeton, NJ 08543 USA

1246226B0
Rev October 2011

Additional barcode labeling by:

Physicians Total Care, Inc.

Tulsa, Oklahoima 74146

REPRESENTATIVE PACKAGING

NDC 54868-4857-0
60 Capsules

REYATAZ^®
(atazanavir sulfate)
150 mg

Rx only

Note to pharmacist: Do not cover ALERT box with pharmacy label.
ALERT: Find out about medicines that
should NOT be taken with REYATAZ^®

REPRESENTATIVE PACKAGING

NDC 54868-5838-0
30 Capsules

REYATAZ^®
(atazanavir sulfate)
300 mg

Rx only

Note to pharmacist: Do not cover ALERT box with pharmacy label.
ALERT: Find out about medicines that
should NOT be taken with REYATAZ^®