These 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: 2003

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:

General Dosing Recommendations:

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) .]

Table 1: REYATAZ Dosing Regimens
Treatment-Naive Patients	REYATAZ 300 mg with ritonavir 100 mg once daily
If unable to tolerate ritonavir	REYATAZ 400 mg once daily
When combined with any of the following: Tenofovir H₂-receptor antagonist Proton-pump inhibitor	REYATAZ 300 mg with ritonavir 100 mg once daily
• The H₂-receptor antagonist dose should not exceed a dose comparable to famotidine 40 mg twice daily. Administer REYATAZ and ritonavir simultaneously with, and/or at least 10 hours after the H₂-receptor antagonist. • If unable to tolerate ritonavir, administer REYATAZ 400 mg once daily at least 2 hours before and at least 10 hours after the H₂-receptor antagonist. No single dose of the H₂-receptor antagonist should exceed a dose comparable to famotidine 20 mg and the total daily dose should not exceed a dose comparable to famotidine 40 mg. • The proton-pump inhibitor dose should not exceed a dose comparable to omeprazole 20 mg daily and must be taken approximately 12 hours prior to REYATAZ and ritonavir.
When combined with efavirenz	REYATAZ 400 mg with ritonavir 100 mg once daily
• Efavirenz should be administered on an empty stomach, preferably at bedtime.
Treatment-Experienced Patients	REYATAZ 300 mg with ritonavir 100 mg once daily
Do not coadminister with proton-pump inhibitors or efavirenz in treatment-experienced patients.
When given with an H₂-receptor antagonist	REYATAZ 300 mg with ritonavir 100 mg once daily
• The H₂-receptor antagonist dose should not exceed a dose comparable to famotidine 20 mg twice daily. Administer REYATAZ and ritonavir simultaneously with, and/or at least 10 hours after the H₂-receptor antagonist.
When given with both tenofovirand an H₂-receptor antagonist	REYATAZ 400 mg with ritonavir 100 mg once daily
• The H₂-receptor antagonist dose should not exceed a dose comparable to famotidine 20 mg twice daily. Administer REYATAZ and ritonavir simultaneously with, and/or at least 10 hours after the H₂-receptor antagonist.

The recommended 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 patients less than 13 years of age, and (3) treatment-experienced pediatric patients with body weight less than 25 kg.

Treatment-Naive Pediatric Patients

The recommended dosage of REYATAZ with ritonavir in treatment-naive 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 39 kg, who are unable to tolerate ritonavir, the recommended dose is REYATAZ 400 mg (without ritonavir) once daily with food.

Table 2: Dosage for Treatment-Naive Pediatric Patients (6 to less than 18 years of age) for REYATAZ Capsules with ritonavir
Body Weight		REYATAZ dose^a,b	ritonavir dose^b
(kg)	(lbs)	(mg)	(mg)
^a The recommended dosage of REYATAZ can be achieved using a combination of commercially available capsule strengths.
^b The dosage of REYATAZ and ritonavir was calculated as follows: 15 kg to less than 20 kg: REYATAZ 8.5 mg/kg with ritonavir 4 mg/kg once daily with food. at least 20 kg: REYATAZ 7 mg/kg with ritonavir 4 mg/kg once daily with food not to exceed REYATAZ 300 mg and ritonavir 100 mg.
^c Ritonavir liquid.
^d Ritonavir capsule or liquid.
15 to less than 25	33 to less than 55	150	80^c
25 to less than 32	55 to less than 70	200	100^d
32 to less than 39	70 to less than 86	250	100^d
at least 39	at least 86	300	100^d

Treatment-Experienced Pediatric Patients

The recommended dosage of REYATAZ with ritonavir in treatment-experienced patients at least 6 years of age is shown in Table 3.

Table 3: Dosage for Treatment-Experienced Pediatric Patients (6 to less than 18 years of age) for REYATAZ Capsules with ritonavir
Body Weight		REYATAZ dose^a,b	ritonavir dose^b
(kg)	(lbs)	(mg)	(mg)
^a The recommended dosage of REYATAZ can be achieved using a combination of commercially available capsule strengths.
^b The dosage was calculated as REYATAZ 7 mg/kg with ritonavir 4 mg/kg once daily with food not to exceed REYATAZ 300 mg and ritonavir 100 mg.
^c Ritonavir capsule or liquid.
25 to less than 32	55 to less than 70	200	100^c
32 to less than 39	70 to less than 86	250	100^c
at least 39	at least 86	300	100^c

Dosing During Pregnancy and the Postpartum Period:

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) .]

REYATAZ should be used with caution in patients with mild-to-moderate hepatic impairment. For patients with moderatehepatic 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 hepaticimpairment and is not recommended. [See Warnings and Precautions (5.5) and Use in Specific Populations (8.8).]

REYATAZ (atazanavir sulfate) is contraindicated:

Table 4: Drugs That Are Contraindicated with REYATAZ (atazanavir) (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)
Drug Class	Drugs within class that are contraindicated with REYATAZ	Clinical Comment
^a See Drug Interactions, Table 14 (7) for parenterally administered midazolam.
^b See Drug Interactions, Table 14 (7) for sildenafil when dosed as VIAGRA^® for erectile dysfunction.
Alpha 1-Adrenoreceptor Antagonist	Alfuzosin	Potential for increased alfuzosin concentrations, which can result in hypotension.
Antimycobacterials	Rifampin	Rifampin substantially decreases plasma concentrations of atazanavir, which may result in loss of therapeutic effect and development of resistance.
Antineoplastics	Irinotecan	Atazanavir inhibits UGT1A1 and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities.
Benzodiazepines	Triazolam, orally administered midazolam^a	Triazolam and orally administered midazolam are extensively metabolized by CYP3A4. Coadministration of triazolam or orally administered midazolam with REYATAZ may cause large increases in the concentration of these benzodiazepines. Potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression.
Ergot Derivatives	Dihydroergotamine, ergotamine, ergonovine, methylergonovine	Potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI Motility Agent	Cisapride	Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal Products	St. John’s wort (Hypericum perforatum)	Patients taking REYATAZ should not use products containing St. John’s wort because coadministration may be expected to reduce plasma concentrations of atazanavir. This may result in loss of therapeutic effect and development of resistance.
HMG-CoA Reductase Inhibitors	Lovastatin, simvastatin	Potential for serious reactions such as myopathy including rhabdomyolysis.
Neuroleptic	Pimozide	Potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
PDE5 Inhibitor	Sildenafil^b when dosed as REVATIO^® for the treatment of pulmonary arterial hypertension	A safe and effective dose in combination with REYATAZ has not been established for sildenafil (REVATIO^®) when used for the treatment of pulmonary hypertension. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, priapism, and syncope).
Protease Inhibitors	Indinavir	Both REYATAZ and indinavir are associated with indirect (unconjugated) hyperbilirubinemia.

See Table 4 for a listing of drugs that are contraindicated for use with REYATAZ due to potentially life-threateningadverse events, significant drug interactions, or loss of virologic activity. [See Contraindications (4) .] Please refer to Table 14 for established and other potentially significant drug interactions [see Drug Interactions (7.3) ].

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 rare 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).

In controlled clinical trials, rash (all grades, regardless of causality) occurred in approximately 20% of patientstreated 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) .]

Most patients taking REYATAZ experience asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibitionof UDP-glucuronosyl transferase (UGT). This hyperbilirubinemia is reversible upon discontinuation of REYATAZ. Hepatic transaminase elevations that occurwith hyperbilirubinemia should be eva luated for alternative etiologies. No long-term safety data are available for patients experiencing persistent elevationsin total bilirubin >5 times ULN. Alternative antiretroviral therapy to REYATAZ may be considered if jaundice or scleral icterus associated with bilirubinelevations presents cosmetic concerns for patients. Dose reduction of atazanavir is not recommended since long-term efficacy of reduced doses has not beenestablished. [See Adverse Reactions (6.1, 6.2) .]

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 developingfurther transaminase elevations or hepatic decompensation. In these patients, appropriate laboratory testing should be conducted prior to initiating therapywith REYATAZ and these patients should be monitored during treatment. [See Adverse Reactions (6.3) and Use in Specific Populations (8.8) .]

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

New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported duringpostmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments ofinsulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinuedprotease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimatesof frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established. [See Adverse Reactions (6.4) .]

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

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

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, treatmentwith protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.

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) .]

The following adverse reactions are discussed in greater detail in other sections of the labeling:

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drugcannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

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 5 and 6, respectively.

Table 5: Selected Treatment-Emergent Adverse Reactions^a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Patients,^b Study AI424-138
	96 weeks^c	96 weeks^c
	REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir with emtricitabine^d	lopinavir 400 mg with ritonavir 100 mg (twice daily)and tenofovir with emtricitabine^d
	(n=441)	(n=437)
* 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 REYATAZ.
^c Median time on therapy.
^d As a fixed-dose combination: 300 mg tenofovir, 200 mg emtricitabine once daily.
Digestive System
Nausea	4%	8%
Jaundice/scleral icterus	5%	*
Diarrhea	2%	12%
Skin and Appendages
Rash	3%	2%

Table 6: Selected Treatment-Emergent Adverse Reactions^a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Patients,^b Studies AI424-034, AI424-007, and AI424-008
	Study AI424-034		Studies AI424-007, -008
	64 weeks^c REYATAZ 400 mg once daily + lamivudine + zidovudine^e	64 weeks^c efavirenz 600 mg once daily + lamivudine + zidovudine^e	120 weeks^c,d REYATAZ 400 mg once daily + stavudine + lamivudine or didanosine	73 weeks^c,d nelfinavir 750 mg TID or 1250 mg BID + stavudine + lamivudine or didanosine
	(n=404)	(n=401)	(n=279)	(n=191)
* None reported in this treatment arm.
^a Includes events of possible, probable, certain, or unknown relationship to treatment regimen.
^b Based on regimens containing REYATAZ.
^c Median time on therapy.
^d Includes long-term follow-up.
^e As a fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily.
Body as a Whole
Headache	6%	6%	1%	2%
Digestive System
Nausea	14%	12%	6%	4%
Jaundice/scleral icterus	7%	*	7%	*
Vomiting	4%	7%	3%	3%
Abdominal pain	4%	4%	4%	2%
Diarrhea	1%	2%	3%	16%
Nervous System
Insomnia	3%	3%	<1%	*
Dizziness	2%	7%	<1%	*
Peripheral neurologic symptoms	<1%	1%	4%	3%
Skin and Appendages
Rash	7%	10%	5%	1%

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 7.

Table 7: Selected Treatment-Emergent Adverse Reactions^a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Experienced Patients,^b Study AI424-045
	48 weeks^c REYATAZ/ritonavir 300/100 mg once daily + tenofovir + NRTI	48 weeks^c lopinavir/ritonavir 400/100 mg twice daily^d + tenofovir + NRTI
	(n*119)	(n*118)
* 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 REYATAZ.
^c Median time on therapy.
^d As a fixed-dose combination.
Body as a Whole
Fever	2%	*
Digestive System
Jaundice/scleral icterus	9%	*
Diarrhea	3%	11%
Nausea	3%	2%
Nervous System
Depression	2%	<1%
Musculoskeletal System
Myalgia	4%	*

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 8 and 9, respectively.

Table 8: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Patients,^a Study AI424-138
^a Based on the regimen containing REYATAZ.
^b Median time on therapy.
^c ULN = upper limit of normal.
^d As a fixed-dose combination: 300 mg tenofovir, 200 mg emtricitabine once daily.