REYATAZ (atazanavir sulfate 200 mg) Dailymed

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.

• Capsules: 100 mg, 150 mg, 200 mg, 300 mg. (3, 16)

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 uled in Table 3.

Table 3: 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 13 (7) for parenterally administered midazolam.
b See Drug Interactions, Table 13 (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 midazolama	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	Sildenafilb 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.

• 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)

5 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)

5.1 Drug Interactions

See Table 3 for a uling 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.


Most common adverse reactions (≥2%) are nausea, jaundice/scleral icterus, rash, headache, abdominal pain, vomiting, insomnia, peripheral neurologic symptoms, dizziness, myalgia, diarrhea, depression, and fever. (6.1, 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

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.

Table 4: Selected Treatment-Emergent Adverse Reactions^a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Patients,^b Study AI424-138

	96 weeksc	96 weeksc
	REYATAZ 300 mg with ritonavir100 mg (once daily) and tenofovirwith emtricitabined	lopinavir 400 mg with ritonavir100 mg (twice daily) and tenofovirwith emtricitabined
	(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 5: 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 weeksc REYATAZ 400 mg once daily + lamivudine + zidovudinee	64 weeksc efavirenz 600 mg once daily + lamivudine + zidovudinee	120 weeksc,d REYATAZ 400 mg once daily + stavudine + lamivudine or didanosine	73 weeksc,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 6.

Table 6: Selected Treatment-Emergent Adverse Reactions^a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Experienced Patients,^b Study AI424-045

	48 weeksc REYATAZ/ritonavir 300/100 mgonce daily + tenofovir + NRTI	48 weeksc lopinavir/ritonavir 400/100 mgtwice dailyd + 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 7 and 8, respectively.

Table 7: 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.
Variable	Limitc	96 weeksb	96 weeksb
		REYATAZ 300 mgwith ritonavir 100 mg(once daily) and tenofovirwith emtricitabined	lopinavir 400 mgwith ritonavir 100 mg(twice daily) and tenofovirwith emtricitabined
		(n=441)	(n=437)
Chemistry	High
SGOT/AST	≥5.1 x ULN	3%	1%
SGPT/ALT	≥5.1 x ULN	3%	2%
Total Bilirubin	≥2.6 x ULN	44%	<1%
Lipase	≥2.1 x ULN	2%	2%
Creatine Kinase	≥5.1 x ULN	8%	7%
Total Cholesterol	≥240 mg/dL	11%	25%
Hematology	Low
Neutrophils	<750 cells/mm3	5%	2%

Table 8: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Patients,^a Studies AI424-034, AI424-007, and AI424-008

Variable	Limitd	Study AI424-034		Studies AI424-007, -008
		64 weeksb	64 weeksb	120 weeksb,c	73 weeksb,c
		REYATAZ400 mgonce daily+ lamivudine+ zidovudinee	efavirenz600 mgonce daily+ lamivudine+ zidovudinee	REYATAZ400 mgonce daily+ stavudine+ lamivudine or+ stavudine+ didanosine	nelfinavir750 mg TID or1250 mg BID+ stavudine+ lamivudine or+ stavudine+ didanosine
		(n=404)	(n=401)	(n=279)	(n=191)
* None reported in this treatment arm.
a Based on regimen(s) containing REYATAZ.
b Median time on therapy.
c Includes long-term follow-up.
d ULN = upper limit of normal.
e As a fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily.
Chemistry	High
SGOT/AST	≥5.1 x ULN	2%	2%	7%	5%
SGPT/ALT	≥5.1 x ULN	4%	3%	9%	7%
Total Bilirubin	≥2.6 x ULN	35%	<1%	47%	3%
Amylase	≥2.1 x ULN	*	*	14%	10%
Lipase	≥2.1 x ULN	<1%	1%	4%	5%
Creatine Kinase	≥5.1 x ULN	6%	6%	11%	9%
Total Cholesterol	≥240 mg/dL	6%	24%	19%	48%
Triglycerides	≥751 mg/dL	<1%	3%	4%	2%
Hematology	Low
Hemoglobin	<8.0 g/dL	5%	3%	<1%	4%
Neutrophils	<750 cells/mm3	7%	9%	3%	7%

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.

Table 9: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Experienced Patients, Study AI424-045^a

Variable	Limitc	48 weeksb	48 weeksb
		REYATAZ/ritonavir300/100 mg once daily+ tenofovir + NRTI	lopinavir/ritonavir400/100 mg twice dailyd + tenofovir + NRTI
		(n=119)	(n=118)
a Based on regimen(s) containing REYATAZ.
b Median time on therapy.
c ULN = upper limit of normal.
d As a fixed-dose combination.
Chemistry	High
SGOT/AST	≥5.1 x ULN	3%	3%
SGPT/ALT	≥5.1 x ULN	4%	3%
Total Bilirubin	≥2.6 x ULN	49%	<1%
Lipase	≥2.1 x ULN	5%	6%
Creatine Kinase	≥5.1 x ULN	8%	8%
Total Cholesterol	≥240 mg/dL	25%	26%
Triglycerides	≥751 mg/dL	8%	12%
Glucose	≥251 mg/dL	5%	<1%
Hematology	Low
Platelets	<50,000 cells/mm3	2%	3%
Neutrophils	<750 cells/mm3	7%	8%

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.

Table 10: Lipid Values, Mean Change from Baseline, Study AI424-138

	REYATAZ/ritonavira,b					lopinavir/ritonavirb,c
	Baseline	Week 48		Week 96		Baseline	Week 48		Week 96
	mg/dL	mg/dL	Changed	mg/dL	Changed	mg/dL	mg/dL	Changed	mg/dL	Changed
	(n=428e)	(n=372e)	(n=372e)	(n=342e)	(n=342e)	(n=424e)	(n=335e)	(n=335e)	(n=291e)	(n=291e)
	a REYATAZ 300 mg with ritonavir 100 mg once daily with the fixed-dose combination: 300 mg tenofovir, 200 mg emtricitabine once daily.
b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 1% in the lopinavir/ritonavir treatment arm and 1% in the REYATAZ/ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 8% in the lopinavir/ritonavir treatment arm and 2% in the REYATAZ/ritonavir arm. Through Week 96, serum lipid-reducing agents were used in 10% in the lopinavir/ritonavir treatment arm and 3% in the REYATAZ/ritonavir arm.
c Lopinavir 400 mg with ritonavir 100 mg twice daily with the fixed-dose combination 300 mg tenofovir, 200 mg emtricitabine once daily.
d The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 48 or Week 96 values and is not a simple difference of the baseline and Week 48 or Week 96 mean values, respectively.
e Number of patients with LDL-cholesterol measured.
f Fasting.
LDL-Cholesterolf	92	105	+14%	105	+14%	93	111	+19%	110	+17%
HDL-Cholesterolf	37	46	+29%	44	+21%	36	48	+37%	46	+29%
Total Cholesterolf	149	169	+13%	169	+13%	150	187	+25%	186	+25%
Triglyceridesf	126	145	+15%	140	+13%	129	194	+52%	184	+50%

Table 11: Lipid Values, Mean Change from Baseline, Study AI424-034

	REYATAZa,b			efavirenzb,c
	Baseline	Week 48	Week 48	Baseline	Week 48	Week 48
	mg/dL	mg/dL	Changed	mg/dL	mg/dL	Changed
	(n=383e)	(n=283e)	(n=272e)	(n=378e)	(n=264e)	(n=253e)
a REYATAZ 400 mg once daily with the fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily.
b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 0% in the efavirenz treatment arm and <1% in the REYATAZ arm. Through Week 48, serum lipid-reducing agents were used in 3% in the efavirenz treatment arm and 1% in the REYATAZ arm.
c Efavirenz 600 mg once daily with the fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily.
d The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 48 values and is not a simple difference of the baseline and Week 48 mean values.
e Number of patients with LDL-cholesterol measured.
f Fasting.
LDL-Cholesterolf	98	98	+1%	98	114	+18%
HDL-Cholesterol	39	43	+13%	38	46	+24%
Total Cholesterol	164	168	+2%	162	195	+21%
Triglyceridesf	138	124	-9%	129	168	+23%

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.

Table 12: Lipid Values, Mean Change from Baseline, Study AI424-045

	REYATAZ/ritonavira,b			lopinavir/ritonavirb,c
	Baseline	Week 48	Week 48	Baseline	Week 48	Week 48
	mg/dL	mg/dL	Changed	mg/dL	mg/dL	Changed
	(n=111e)	(n=75e)	(n=74e)	(n=108e)	(n=76e)	(n=73e)
a REYATAZ 300 mg once daily + ritonavir + tenofovir + 1 NRTI.
b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 4% in the lopinavir/ritonavir treatment arm and 4% in the REYATAZ/ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 19% in the lopinavir/ritonavir treatment arm and 8% in the REYATAZ/ritonavir arm.
c Lopinavir/ritonavir (400/100 mg) BID + tenofovir + 1 NRTI.
d The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 48 values and is not a simple difference of the baseline and Week 48 mean values.
e Number of patients with LDL-cholesterol measured.
f Fasting.
LDL-Cholesterolf	108	98	-10%	104	103	+1%
HDL-Cholesterol	40	39	-7%	39	41	+2%
Total Cholesterol	188	170	-8%	181	187	+6%
Triglyceridesf	215	161	-4%	196	224	+30%

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

• 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)

8.1 Pregnancy

TERATOGENIC EFFECTS SECTION

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.

TERATOGENIC EFFECTS SECTION

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.

TERATOGENIC EFFECTS SECTION

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) .]

TERATOGENIC EFFECTS SECTION

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.

TERATOGENIC EFFECTS SECTION

Pharmacokinetics of Atazanavir in Pregnancy

[See Clinical Pharmacology (12.3) .]

TERATOGENIC EFFECTS SECTION

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) .]