ATAZANAVIR

Atazanavir capsules are indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric patients 6 years and older weighing at least 15 kg.

Limitations of Use:

• Atazanavir is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus. [see Use in Specific Populations ( 8.4)] .
• Use of atazanavir with ritonavir in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions [see Microbiology ( 12.4)] .

• Atazanavir capsules must be taken with food.
• Do not open the capsules.
• The recommended oral dosage of atazanavir capsule depends on the treatment history of the patient and the use of other coadministered drugs. When coadministered with H ₂-receptor antagonists or proton-pump inhibitors, dose separation may be required [see Dosage and Administration ( 2.3, 2.4 and 2.6) and Drug Interactions ( 7)].
• Atazanavir capsules without ritonavir are not recommended for treatment-experienced adult or pediatric patients with prior virologic failure [see Clinical Studies ( 14)].
• Efficacy and safety of atazanavir with ritonavir when ritonavir is administered in doses greater than 100 mg once daily have not been established. The use of higher ritonavir doses may alter the safety profile of atazanavir (cardiac effects, hyperbilirubinemia) and, therefore, is not recommended. Prescribers should consult the complete prescribing information for ritonavir when using ritonavir.

Renal laboratory testing should be performed in all patients prior to initiation of atazanavir capsules and continued during treatment with atazanavir capsules. Renal laboratory testing should include serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination [ see Warnings and Precautions ( 5.5, 5.6)].

Hepatic laboratory testing should be performed in patients with underlying liver disease prior to initiation of atazanavir capsules and continued during treatment with atazanavir capsules [see Warnings and Precautions ( 5.4)].

Table 1 displays the recommended dosage of atazanavir capsules in treatment-naive and treatment-experienced adults. Table 1 also displays recommended dosage of atazanavir capsules and ritonavir when given concomitantly with other antiretroviral drugs and H ₂-receptor antagonists (H2RA). Ritonavir is required with several atazanavir dosage regimens (see the ritonavir complete prescribing information about the safe and effective use of ritonavir). The use of atazanavir in treatment-experienced adult patients without ritonavir is not recommended.

The recommended daily dosage of atazanavir capsules and ritonavir in pediatric patients (6 years of age to less than 18 years of age) is based on body weight (see Table 2).

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

Table 4 includes the recommended dosage of atazanavir capsules and ritonavir in treatment-naive and treatment-experienced pregnant patients. In these patients, atazanavir must be administered with ritonavir. There are no dosage adjustments for postpartum patients (see Table 1 for the recommended atazanavir capsules dosage in adults) [see Use in Specific Populations ( 8.1)] .

For patients with renal impairment, including those with severe renal impairment who are not managed with hemodialysis, no dose adjustment is required for atazanavir capsules. Treatment-naive patients with end-stage renal disease managed with hemodialysis should receive atazanavir capsules 300 mg with ritonavir 100 mg. Atazanavir capsule is not recommended in treatment-experienced patients with HIV-1 infection who have end-stage renal disease managed with hemodialysis   [See Use in Specific Populations ( 8.7)]

Table 5 displays the recommended atazanavir capsule dosage in treatment-naive patients with hepatic impairment. The use of atazanavir capsule in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended. The coadministration of atazanavir with ritonavir in patients with any degree of hepatic impairment is not recommended.

Atazanavir Capsules:

• 100 mg capsule with White to pale yellow coloured granules filled in size 2 hard gelatin capsule, Cap-Blue printed with Cipla 443 with white ink, Body-white.
• 150 mg capsule with White to pale yellow coloured granules filled in size 1 hard gelatin capsule, Cap-Blue printed with Cipla 444 with white ink, Body-light blue.
• 200 mg capsule with White to pale yellow coloured granules filled in size 0 hard gelatin capsule, Cap-Blue printed with Cipla 445 with white ink, Body- Blue.
• 300 mg capsule with White to pale yellow coloured granules filled in size 00 hard gelatin capsule, Cap-Red printed with Cipla 446 with white ink, Body-Blue.

Atazanavir 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 atazanavir capsules [see Warnings and Precautions ( 5.2)] .
• when coadministered with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events (see Table 6).
• when coadministered with drugs that strongly induce CYP3A and may lead to lower exposure and loss of efficacy of atazanavir (see Table 6).

Table 6 displays drugs that are contraindicated with atazanavir capsule.

Atazanavir has been shown to prolong the PR interval of the electrocardiogram in some subjects. In healthy subjects and in subjects with HIV-1 infection treated with atazanavir, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been reports of second-degree AV block and other conduction abnormalities [see Adverse Reactions ( 6.2) and Overdosage ( 10)] . In clinical trials that included electrocardiograms, asymptomatic first-degree AV block was observed in 5.9% of atazanavir-treated subjects (n=920), 5.2% of lopinavir/ritonavir-treated subjects (n=252), 10.4% of nelfinavir-treated subjects (n=48), and 3.0% of efavirenz-treated subjects (n=329). In Study AI424-045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir with ritonavir-treated subjects and 5% (6/116) of lopinavir/ritonavir-treated subjects who had on-study electrocardiogram measurements. Because of limited clinical experience in those with preexisting conduction system disease (eg, marked first-degree AV block or second- or third-degree AV block), ECG monitoring should be considered in these patients [See Clinical Pharmacology ( 12.2) .]

In controlled clinical trials, rash (all grades, regardless of causality) occurred in approximately 20% of subjects with HIV-1 infection treated with atazanavir. The median time to onset of rash in clinical studies was 7.3 weeks and the median duration of rash was 1.4 weeks. Rashes were generally mild-to-moderate maculopapular skin eruptions. Treatment-emergent adverse reactions of moderate or severe rash (occurring at a rate of ≥2%) are presented for the individual clinical studies [see Adverse Reactions ( 6.1) ]. Dosing with atazanavir was often continued without interruption in patients who developed rash. The discontinuation rate for rash in clinical trials was <1%. Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including drug rash, eosinophilia, and systemic symptoms (DRESS) syndrome, have been reported in patients receiving atazanavir. [See Contraindications ( 4) and Adverse Reactions ( 6.1) .] Atazanavir capsule should be discontinued if severe rash develops.

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

Chronic kidney disease in patients with HIV-1 infection treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. Reports included biopsy-proven cases of granulomatous interstitial nephritis associated with the deposition of atazanavir drug crystals in the renal parenchyma. Consider alternatives to atazanavir in patients at high risk for renal disease or with preexisting renal disease. Renal laboratory testing (including serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination) should be conducted in all patients prior to initiating therapy with atazanavir and continued during treatment with atazanavir. Expert consultation is advised for patients who have confirmed renal laboratory abnormalities while taking atazanavir. In patients with progressive kidney disease, discontinuation of atazanavir may be considered [see Dosage and Administration ( 2.3 and 2.8) and Adverse Reactions ( 6.2)] .

Cases of nephrolithiasis and/or cholelithiasis have been reported during postmarketing surveillance in patients with HIV-1 infection receiving atazanavir therapy.. Some patients required hospitalization for additional management and some had complications. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis and/or cholelithiasis occur, temporary interruption or discontinuation of therapy may be considered. [See Adverse Reactions ( 6.2) .]

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

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

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

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

New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in patients with HIV-1 infection receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established. [See Adverse Reactions ( 6.2) .]

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

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

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.

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.

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

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

• cardiac conduction abnormalities [ see Warnings and Precautions ( 5.1)]
• rash [ see Warnings and Precautions ( 5.2)]
• hyperbilirubinemia [see Warnings and Precautions (5.8)]
• chronic kidney disease [see Warnings and Precautions (5.5)]
• nephrolithiasis and cholelithiasis [see Warnings and Precautions ( 5.6)]

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

Adverse Reactions in Treatment-Naive Adult Subjects

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

The most common adverse reactions were nausea, jaundice/scleral icterus, and rash.

Selected clinical adverse reactions of moderate or severe intensity reported in ≥2% of treatment-naive subjects receiving combination therapy including atazanavir 300 mg with ritonavir 100 mg and atazanavir 400 mg (without ritonavir) are presented in Tables 7 and 8, respectively.

Table 7: Selected Adverse Reactions a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Subjects with HIV-1 Infection, b Study AI424-138

* None reported in this treatment arm.

a Includes events of possible, probable, certain, or unknown relationship to treatment regimen.

b Based on the regimen containing atazanavir.

c Median time on therapy.

d Administered as a fixed-dose

e As a fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily

96 weeks c

Atazanavir 300 mg with ritonavir 100 mg (once daily) and tenofovir DF /emtricitabine d

(n=441)

96 weeks c

Lopinavir/ ritonavir d 400 mg/100 mg (twice daily) and tenofovir DF/emtricitabine e

(n=437) (n=437)

Digestive System

Nausea

4%

8%

Jaundice/scleral icterus

5%

*

Diarrhea

2%

12%

Skin and Appendages

Rash

3%

2%

Table 8: Selected Adverse Reactions a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Subjects with HIV-1 Infection, b Studies AI424-034, AI424-007, and AI424-008

* None reported in this treatment arm.

a Includes events of possible, probable, certain, or unknown relationship to treatment regimen.

b Based on regimens containing atazanavir.

c Median time on therapy.

d Includes long-term follow-up.

e As a fixed-dose product: 150 mg lamivudine/ 300 mg zidovudine twice daily.

Study A

I424-034

Studies AI424-007,

-008

64 weeks c Atazanavir 400 mg (once daily) with lamivudine/ zidovudine e

64 weeks c efavirenz 600 mg (once daily) with lamivudine/ zidovudine e

120 weeks c,d Atazanavir 400 mg (once daily) with stavudine and lamivudine or didanosine

73 weeks c,d nelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or didanosine

(n=404)

(n=401)

(n=279)

(n=191)

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%

Adverse Reactions in Treatment-Experienced Adult Subjects

The safety profile of atazanavir in treatment-experienced adults with HIV-1 infection is based on 119 subjects with HIV-1 infection in clinical trials.

The most common adverse reactions are jaundice/scleral icterus and myalgia.

Selected clinical adverse reactions of moderate or severe intensity reported in ≥2% of treatment-experienced subjects receiving atazanavir with ritonavir are presented in Table 9.

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

* None reported in this treatment arm.

a Includes events of possible, probable, certain, or unknown relationship to treatment regimen.

b Based on the regimen containing atazanavir.

c Median time on therapy.

d As a fixed-dose product.

48 weeks c

Atazanavir with ritonavir 300/100 mg once daily and tenofovir DF and NRTI

48 weeks c

lopinavir/ritonavir 400/100 mg twice daily d and tenofovir DF and NRTI

(n=119)

(n=118)

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 Subjects

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

Table 10: Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Treatment-Naive Subjects with HIV-1 Infection, a Study AI424-138

a Based on the regimen containing atazanavir.

b Median time on therapy.

c Administered as a fixed-dose product

d As a fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily.

e ULN = upper limit of normal.

Variable

Limit d

96 weeks b

Atazanavir 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/ emtricitabine c

96 weeks b

lopinavir 400 mg/ ritonavir 100 mg C (twice daily) and tenofovir DF/ emtricitabine d





(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/mm 3

5%

2%

Table 11: Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Treatment-Naive Subjects with HIV-1 Infection, aStudies A1424-034, A1424-007, and A1424-008

* None reported in this treatment arm.

a Based on regimen(s) containing atazanavir.

b Median time on therapy.

c Includes long-term follow-up.

d ULN = upper limit of normal.

e As a fixed-dose Product: 150 mg lamivudine, 300 mg zidovudine twice daily.

Study A1424

-034

Studies A1424

-007, -008

Variable

Limit d

64 weeks b

Atazanavir

400 mg once daily and lamivudine/ zidovudine e



64 weeks b

efavirenz

600 mg once daily and lamivudine/ zidovudine e



120 weeks b,c

Atazanavir

400 mg

once daily with stavudine and lamivudine or with stavudine and didanosine

73 weeks b,c

nelfinavir

750 mg TID or

1250 mg BID with stavudine and lamivudine or with stavudine and didanosine





(n = 404)

(n = 401)

(n = 279)

(n = 191)

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/mm 3

7%

9%

3%

7%

Change in Lipids from Baseline in Treatment-Naive Subjects with HIV-1 Infection.

For Study AI424-138 and Study AI424-034, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Tables 12 and 13, respectively.

Table 12: Lipid Values, Mean Change from Baseline, Study AI424-138

a Atazanavir 300 mg with ritonavir 100 mg once daily with the fixed-dose Product: 300 mg tenofovir DF, 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 atazanavir with ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 8% in the lopinavir/ritonavir treatment arm and 2% in the atazanavir with ritonavir arm. Through Week 96, serum lipid-reducing agents were used in 10% in the lopinavir/ritonavir treatment arm and 3% in the atazanavir with ritonavir arm.

c Lopinavir/ritonavir (400 mg/100 mg) twice daily with the fixed-dose product 300 mg tenofovir DF/ 200 mg emtricitabine once daily.

d The change from baseline is the mean of within-subject changes from baseline for subjects 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 subjects with LDL-cholesterol measured.

f Fasting.

Atazanavir

with

ritonavir a, b

lopinavir/

ritonavir b,c

Baseline

Week

48

Week

96

Baseline

Week

48

Week

96

mg/dL

mg/dL

Change d

mg/dL

Change d

mg/dL

mg/dL

Change d

mg/dL

Change d

(n=428 e)

(n=372 e)

(n=372 e)

(n=342 e)

(n=342 e)

(n=424 e)

(n=335 e)

(n=335 e)

(n=291 e)

(n=291 e)

LDL-Cholesterol f

92

105

+14%

105

+14%

93

111

+19%

110

+17%

HDL-Cholesterol f

37

46

+29%

44

+21%

36

48

+37%

46

+29%

Total Cholesterol f

149

169

+13%

169

+13%

150

187

+25%

186

+25%

Triglycerides f

126

145

+15%

140

+13%

129

194

+52%

184

+50%

Table 13: Lipid Values, Mean Change from Baseline, Study AI424-034

a Atazanavir 400 mg once daily with the fixed-dose product: 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 atazanavir arm. Through Week 48, serum lipid-reducing agents were used in 3% in the efavirenz treatment arm and 1% in the atazanavir arm.

c Efavirenz 600 mg once daily with the fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily.

d The change from baseline is the mean of within-subject 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 subjects with LDL-cholesterol measured.

f Fasting

Atazanavir a,b

efavirenz b,c

Baseline

Week 48

Week 48

Baseline

Week 48

Week 48

mg/dL

mg/dL

Change d

mg/dL

mg/dL

Change d

(n=383 e)

(n=283 e)

(n=272 e)

(n=378 e)

(n=264 e)

(n=253 e)

LDL-Cholesterol f

98

98

+1%

98

114

+18%

HDL-Cholesterol

39

43

+13%

38

46

+24%

Total Cholesterol

164

168

+2%

162

195

+21%

Triglycerides f

138

124

-9%

129

168

+23%

Laboratory Abnormalities in Treatment-Experienced Subjects with HIV-1 Infection

The percentages of adult treatment-experienced subjects with HIV-1 infection treated with combination therapy including atazanavir with ritonavir having Grade 3–4 laboratory abnormalities are presented in Table 14.

Table 14: Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Treatment-Experienced Subjects with HIV-1 Infection, Study AI424-045 a

a Based on regimen(s) containing atazanavir.

b Median time on therapy.

c ULN = upper limit of normal.

d As a fixed-dose product.

Variable

Limit c

48 weeks b

48 weeks b





Atazanavir with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI

lopinavir/ritonavir





48 weeks b

400/100 mg (twice daily d) and tenofovir DF and NRTI





(n = 119)

(n = 118)

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/mm 3

2%

3%

Neutrophils

< 750 cells/mm 3

7%

8%

Change in Lipids from Baseline in Treatment-Experienced Subjects with HIV-1 Infection

For Study AI424-045, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Table 15. The observed magnitude of dyslipidemia was less with atazanavir /ritonavir than with lopinavir/ritonavir. However, the clinical impact of such findings has not been demonstrated.

Table 15: Lipid Values, Mean Change from Baseline, Study AI424-045

a Atazanavir 300 mg once daily with ritonavir and tenofovir DF, and 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 atazanavir with ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 19% in the lopinavir/ritonavir treatment arm and 8% in the atazanavir with ritonavir arm.

c Lopinavir/ritonavir (400/100 mg), as a fixed dose regimen, BID with tenofovir DF and 1 NRTI.

d The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 48 values and is not a simple difference of the baseline and Week 48 mean values.

e Number of subjects with LDL-cholesterol measured.

f Fasting..

Atazanavir sulfate

with

ritonavir a,b

Lopinavir

/ritonavir b,c

Baseline

Week 48

Week 48

Baseline

Week 48

Week 48

mg/dL

mg/dL

Change d

mg/dL

mg/dL

Change d

(n=111 e)

(n=75 e)

(n=74 e)

(n=108 e)

(n=76 e)

(n=73 e)

LDL-Cholesterol f

108

98

-10%

104

103

+1%

HDL-Cholesterol

40

39

-7%

39

41

+2%

Total Cholesterol

188

170

-8%

181

187

+6%

Triglycerides f

215

161

-4%

196

224

+30%

Adverse Reactions in Pediatric Subjects with HIV-1 Infection: Atazanavir Capsules

The safety and tolerability of atazanavir capsules with and without ritonavir have been established in pediatric subjects with HIV-1 infection, at least 6 years of age from the open-label, multicenter clinical trial PACTG 1020A.

The safety profile of atazanavir in pediatric subjects with HIV-1 infection (6 to less than 18 years of age) taking the capsule formulation was generally similar to that observed in clinical studies of atazanavir in adults. The most common Grade 2–4 adverse events (≥5%, regardless of causality) reported in pediatric subjects 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 subjects. The most common Grade 3–4 laboratory abnormalities occurring in pediatric subjects taking the capsule formulation 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%.

Adverse Reactions in Subjects with HIV-1 Infection, Co-Infected with Hepatitis B and/or Hepatitis C Virus

In Study AI424-138, 60 subjects administered atazanavir 300 mg with ritonavir 100 mg once daily, and 51 subjects treated with lopinavir/ritonavir 400 mg/100 mg (as fixed-dose product) twice daily, each with fixed-dose tenofovir DF/emtricitabine, were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 10% (6/60) of the subjects administered atazanavir with ritonavir and 8% (4/50) of the subjects treated with lopinavir/ritonavir. AST levels >5 times ULN developed in 10% (6/60) of the subjects administered atazanavir with ritonavir and none (0/50) of the subjects treated with lopinavir/ritonavir.

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

In Studies AI424-008 and AI424-034, 74 subjects treated with atazanavir 400 mg once daily, 58 who received efavirenz, and 12 who received nelfinavir were seropositive for hepatitis B and/or C at study entry. ALT levels >5 times ULN developed in 15% of the subjects treated with atazanavir, 14% of the subjects treated with efavirenz, and 17% of the subjects treated with nelfinavir. AST levels >5 times ULN developed in 9% of the subjects treated with atazanavir, 5% of the subjects treated with efavirenz, and 17% of the subjects treated with nelfinavir. Within atazanavir and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative subjects [see Warnings and Precautions ( 5.8)] .

The following events have been identified during postmarketing use of atazanavir. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: edema

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

Gastrointestinal System: pancreatitis

Hepatic System: hepatic function abnormalities

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

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

Musculoskeletal System: arthralgia

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

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

Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of atazanavir and drugs primarily metabolized by CYP3A or UGT1A1 may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects.

Atazanavir is a weak inhibitor of CYP2C8. Use of atazanavir without ritonavir is not recommended when coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (eg, paclitaxel, repaglinide). When atazanavir with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected. [See Clinical Pharmacology, Table 22 ( 12.3) .]

The magnitude of CYP3A-mediated drug interactions on coadministered drug may change when atazanavir is coadministered with ritonavir. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir.

Atazanavir is a CYP3A4 substrate; therefore, drugs that induce CYP3A4 may decrease atazanavir plasma concentrations and reduce atazanavir therapeutic effect.

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

atazanavir [see Dosage and Administration ( 2.3, 2.4, and 2.6)] .

Table 16 provides dosing recommendations in adults as a result of drug interactions with atazanavir. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.

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

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to atazanavir capsules during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary

Atazanavir has been evaluated in a limited number of women during pregnancy. Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate [see Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. No treatment-related malformations were observed in rats and rabbits, for which the atazanavir exposures were 0.7-1.2 times of those at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). When atazanavir was administered to rats during pregnancy and throughout lactation, reversible neonatal growth retardation was observed [see Data].

Clinical Considerations

Dose Adjustments during Pregnancy and the Postpartum Period

• Atazanavir capsules must be administered with ritonavir in pregnant patients.
• For pregnant patients, no dosage adjustment is required for atazanavir capsule with the following exceptions:
  • For treatment-experienced pregnant women during the second or third trimester, when atazanavir capsule is coadministered with either an H ₂-receptor antagonist or tenofovir DF, atazanavir 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend an atazanavir capsule dose for use with both an H ₂-receptor antagonist and tenofovir DF in treatment-experienced pregnant patients.
• No dosage adjustment is required for postpartum patients. However, patients should be closely monitored for adverse events because atazanavir exposures could be higher during the first 2 months after delivery. [See Dosage and Administration (2.6) and Clinical Pharmacology ( 12.3) .]

Maternal Adverse Reactions

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

Hyperbilirubinemia occurs frequently in patients who take atazanavir [see Warnings and Precautions ( 5.8) ], including those who are pregnant [ see Data].

Advise pregnant women of the potential risks of lactic acidosis syndrome and hyperbilirubinemia.

Fetal/Neonatal Adverse Reactions

All infants, including neonates exposed to atazanavir in utero, should be monitored for the development of severe hyperbilirubinemia during the first few days of life [ see Data].

Data

Human Data

Study AI424-182, atazanavir capsule with ritonavir (300/100 mg or 400/100 mg) coadministered with lamivudine/zidovudine (150 mg/ 300 mg, as fixed-dose product) was administered to 41 pregnant women with HIV-1 infection, during the second or third trimester. Among the 39 women who completed the study, 38 women achieved an HIV-1 RNA less than 50 copies/mL at time of delivery. Six of 20 (30%) women on atazanavir capsule with ritonavir 300/100 mg and 13 of 21 (62%) women on atazanavir capsule with ritonavir 400/100 mg experienced hyperbilirubinemia (total bilirubin greater than or equal to 2.6 times ULN). There were no cases of lactic acidosis observed in clinical trial AI424-182.

Atazanavir drug concentrations in fetal umbilical cord blood were approximately 12% to 19% of maternal concentrations. Among the 40 infants born to 40 pregnant women with HIV-1 infection all had test results that were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. All 40 infants received antiretroviral prophylactic treatment containing zidovudine. No evidence of severe hyperbilirubinemia (total bilirubin levels greater than 20 mg/dL) or acute or chronic bilirubin encephalopathy was observed among neonates in this study. However, 10/36 (28%) infants (6 greater than or equal to 38 weeks gestation and 4 less than 38 weeks gestation) had bilirubin levels of 4 mg/dL or greater within the first day of life.

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

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

Based on prospective reports from the APR of approximately 1600 live births following exposure to atazanavir-containing regimens (including 1037 live births in infants exposed in the first trimester and 569 exposed in second/third trimesters), there was no difference between atazanavir and overall birth defects compared with the background birth defect rate. In the U.S. general population, the estimated background risk of major birth defects in clinically recognized pregnancies is 2-4%.

Animal Data

In animal reproduction studies, there was no evidence of mortality or teratogenicity in offspring born to animals at systemic drug exposure levels (AUC) 0.7 (in rabbits) to 1.2 (in rats) times those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). In pre- and postnatal development studies in the rat, atazanavir caused neonatal growth retardation during lactation that reversed after weaning. Maternal drug exposure at this dose was 1.3 times the human exposure at the recommended clinical exposure. Minimal maternal toxicity occurred at this exposure level.

Risk Summary

The Centers for Disease Control and Prevention recommend that patients with HIV-1 infection, not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Atazanavir has been detected in human milk. No data are available regarding atazanavir effects on milk production. Atazanavir was present in the milk of lactating rats and was associated with neonatal growth retardation that reversed after weaning.

.

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

Atazanavir capsule is indicated in combination with other antiretroviral agents for the treatment of pediatric patients with HIV-1 infection, 6 years of age and older weighing at least 15 kg. Atazanavir is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus [see Indications and Usage (1)]. All atazanavir contraindications, warnings, and precautions apply to pediatric patients [see Contraindications ( 4) and Warnings and Precautions ( 5) ].

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

Clinical studies of atazanavir did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Based on a comparison of mean single-dose pharmacokinetic values for C _max and AUC, a dose adjustment based upon age is not recommended. In general, appropriate caution should be exercised in the administration and monitoring of atazanavir capsule in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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 significant pharmacokinetic differences observed due to age or gender.

Atazanavir capsule is not recommended for use in treatment-experienced patients with HIV-1 infection, who have end-stage renal disease managed with hemodialysis. [See Dosage and Administration ( 2.7) and Clinical Pharmacology ( 12.3) .]

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

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

Cardiac Electrophysiology

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

Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of 72 healthy subjects. Oral doses of 400 mg (maximum recommended dosage) and 800 mg (twice the maximum recommended dosage) were compared with placebo; there was no concentration-dependent effect of atazanavir on the QTc interval (using Fridericia's correction). In 1793 subjects with HIV-1 infection, receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy subject or subject with HIV-1 infection in clinical trials had a QTc interval >500 msec. [See Warnings and Precautions ( 5.1) .]

The pharmacokinetics of atazanavir were evaluated in adult subjects who either were healthy, or with HIV infection, after administration of atazanavir 400 mg once daily and after administration of atazanavir 300 mg with ritonavir 100 mg once daily.

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

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

Absorption

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

Food Effect

Administration of atazanavir with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single 400-mg dose of atazanavir with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and 57% increase in C max relative to the fasting state. Administration of a single 400-mg dose of atazanavir with a high-fat meal (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% with no change in C max relative to the fasting state. Administration of atazanavir with either a light meal or high-fat meal decreased the coefficient of variation of AUC and C max by approximately one-half compared to the fasting state.

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

Distribution

Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively). In a multiple-dose study in subjects with HIV-1 infection dosed with atazanavir 400 mg once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and semen. The cerebrospinal fluid/plasma ratio for atazanavir (n=4) ranged between 0.0021 and 0.0226 and seminal fluid/plasma ratio (n=5) ranged between 0.11 and 4.42.

Metabolism

Atazanavir is extensively metabolized in humans. The major biotransformation pathways of atazanavir in humans consisted of monooxygenation and dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. Two minor metabolites of atazanavir in plasma have been characterized. Neither metabolite demonstrated in vitro antiviral activity. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by CYP3A.

Elimination

Following a single 400-mg dose of 14C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively. The mean elimination half-life of atazanavir in healthy subjects (n=214) and adult subjects with HIV-1 infection (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal.

Specific Populations

Renal Impairment

In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. Atazanavir has been studied in adult subjects with severe renal impairment (n=20), including those on hemodialysis, at multiple doses of 400 mg once daily. The mean atazanavir C max was 9% lower, AUC was 19% higher, and C min was 96% higher in subjects with severe renal impairment not undergoing hemodialysis (n=10), than in age-, weight-, and gender-matched subjects with normal renal function. In a 4-hour dialysis session, 2.1% of the administered dose was removed. When atazanavir was administered either prior to, or following hemodialysis (n=10), the geometric means for C max, AUC, and C min were approximately 25% to 43% lower compared to subjects with normal renal function. The mechanism of this decrease is unknown. Atazanavir is not recommended for use in HIV-treatment-experienced patients HIV-1 who have end-stage renal disease managed with hemodialysis. [See Dosage and Administration (2.7).]

Hepatic Impairment

Atazanavir has been studied in adult subjects with moderate-to-severe hepatic impairment (14 Child-Pugh B and 2 Child-Pugh C subjects) after a single 400-mg dose. The mean AUC (0-∞) was 42% greater in subjects with impaired hepatic function than in healthy subjects. The mean half-life of atazanavir in hepatically impaired subjects was 12.1 hours compared to 6.4 hours in healthy subjects.

A dose reduction to 300 mg is recommended for patients with moderate hepatic impairment (Child-Pugh Class B) who have not experienced prior virologic failure as increased concentrations of atazanavir are expected. Atazanavir is not recommended for use in patients with severe hepatic impairment. The pharmacokinetics of atazanavir in combination with ritonavir has not been studied in subjects with hepatic impairment; thus, coadministration of atazanavir with ritonavir is not recommended for use in patients with any degree of hepatic impairment. [See Dosage and Administration (2.8).]

Pediatrics

The pharmacokinetic parameters for atazanavir at steady state in pediatric subjects taking the capsule formulation were predicted by a population pharmacokinetic model and are summarized in 19 by weight ranges that correspond to the recommended doses. [See Dosage and Administration (2.4).]

Pregnancy

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

Drug Interaction Data

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

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

Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1. Clinically significant interactions are not expected between atazanavir when administered with ritonavir and substrates of CYP2C8. See the complete prescribing information for ritonavir for information on other potential drug interactions with ritonavir.

Based on known metabolic profiles, clinically significant drug interactions are not expected between atazanavir and dapsone, trimethoprim/sulfamethoxazole, azithromycin, or erythromycin. Atazanavir does not interact with substrates of CYP2D6 (eg, nortriptyline, desipramine, metoprolol).

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

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

a Data provided are under fed conditions unless otherwise noted.

b All drugs were given under fasted conditions.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

NA = not available.

Coadministered Drug Coadministered Drug Dose/Schedule Atazanavir Dose/Schedule Ratio (90% Confidence Interval) of Atazanavir Pharmacokinetic Parameters with/without Coadministered Drug;

No Effect = 1.00 C max AUC C min atenolol 50 mg QD,

d 7–11 (n=19) and d 19–23 400 mg QD,

d 1–11

(n=19) 1.00

(0.89, 1.12) 0.93

(0.85, 1.01) 0.74

(0.65, 0.86) clarithromycin 500 mg BID,

d 7–10 (n=29) and d 18–21 400 mg QD,

d 1–10

(n=29) 1.06

(0.93, 1.20) 1.28

(1.16, 1.43) 1.91

(1.66, 2.21) didanosine (ddI) (buffered tablets) and stavudine (d4T) b ddI: 200 mg x 1 dose, d4T: 40 mg x 1 dose (n=31)

ddI: 200 mg x 1 dose, d4T: 40 mg x 1 dose (n=32) 400 mg x 1 dose simultaneously with ddI and d4T (n=31)

400 mg x 1 dose 1 h after ddI + d4T (n=32) 0.11

(0.06, 0.18)

1.12

(0.67, 1.18) 0.13

(0.08, 0.21)

1.03

(0.64, 1.67) 0.16

(0.10, 0.27)

1.03

(0.61, 1.73) efavirenz 600 mg QD,

d 7–20 (n=27)

600 mg QD,

d 7–20 (n=13)

600 mg QD,

d 11–24 (pm) (n=14) 400 mg QD,

d 1–20 (n=27)

400 mg QD,

d 1–6 (n=23) then 300 mg with ritonavir 100 mg QD,

2 h before efavirenz,

d 7–20 (n=13)

300 mg QD with ritonavir 100 mg QD,

d 1–10 (pm) (n=22), then 400 mg QD with ritonavir 100 mg QD,

d 11–24 (pm), (simultaneous with efavirenz) (n=14) 0.41

(0.33, 0.51)

1.14

(0.83, 1.58)

1.17

(1.08, 1.27) 0.26

(0.22, 0.32)

1.39

(1.02, 1.88)

1.00

(0.91, 1.10) 0.07

(0.05, 0.10)

1.48

(1.24, 1.76)

0.58

(0.49, 0.69) famotidine 40 mg BID,

d 7–12 (n=15)

40 mg BID, d 7–12 (n=14)

40 mg BID,

d 11–20 (n=14) c
20 mg BID, d 11–17 (n=18)

40 mg QD (pm),

d 18–24 (n=20)

40 mg BID,

d 18–24 (n=18)

40 mg BID,

d 11–20 (n=15) 400 mg QD,

d 1–6 (n=45), d 7–12 (simultaneous administration) (n=15)

400 mg QD (pm), d 1–6 (n=14), d 7–12 (10 h after, 2 h before famotidine) (n=14)

300 mg QD with ritonavir 100 mg QD,

d 1–10 (n=46), d 11–20 d (simultaneous administration) (n=14)

300 mg QD with ritonavir 100 mg QD and tenofovir DF 300 mg QD, d 1–10 (am) (n=39), d 11–17 (am) (simultaneous administration with am famotidine) (n=18) d,e

300 mg QD with ritonavir 100 mg QD and tenofovir DF 300 mg QD,

d 1–10 (am) (n=39), d 18–24 (am) (12 h after pm famotidine) (n=20) e

300 mg QD with ritonavir 100 mg QD and tenofovir DF 300 mg QD, d 1–10 (am) (n=39), d 18–24 (am) (10 h after pm famotidine and 2 h before am famotidine) (n=18) e

300 mg QD with ritonavir 100 mg QD,

d 1–10 (am) (n=46), then 400 mg QD with ritonavir 100 mg QD,

d 11–20 (am) (n=15) 0.53

(0.34, 0.82)

1.08

(0.82, 1.41)

0.86

(0.79, 0.94)

0.91

(0.84, 0.99)

0.89

(0.81, 0.97)

0.74

(0.66, 0.84)

1.02

(0.87, 1.18) 0.59

(0.40, 0.87)

0.95

(0.74, 1.21)

0.82

(0.75, 0.89)

0.90

(0.82, 0.98)

0.88

(0.80, 0.96)

0.79

(0.70, 0.88)

1.03

(0.86, 1.22) 0.58

(0.37, 0.89)

0.79

(0.60, 1.04)

0.72

(0.64, 0.81)

0.81

(0.69, 0.94)

0.77

(0.63, 0.93)

0.72

(0.63, 0.83)

0.86

(0.68, 1.08) grazoprevir/

elbasvir grazoprevir 200 mg QD

d 1 - 35

(n = 11) 300 mg QD with ritonavir 100

mg QD, d 1 - 35

(n = 11) 1.12

(1.01, 1.24) 1.43

(1.30, 1.57) 1.23

(1.13, 1.34) elbasvir 50 mg QD

d 1 - 35

(n = 8) 300 mg QD with ritonavir 100

mg QD, d 1 - 35

(n = 8) 1.02

(0.96, 1.08) 1.07

(0.98,1.17) 1.15

(1.02, 1.29) ketoconazole 200 mg QD,

d 7–13 (n=14) 400 mg QD,

d 1–13 (n=14) 0.99

(0.77, 1.28) 1.10

(0.89, 1.37) 1.03

(0.53, 2.01) nevirapine f,g 200 mg BID,

d 1–23 (n=23) 300 mg QD with ritonavir 100 mg QD, d 4–13, then 400 mg QD with ritonavir 100 mg QD, d 14–23 (n=23) h 0.72

(0.60, 0.86)

1.02

(0.85, 1.24) 0.58

(0.48, 0.71)

0.81

(0.65, 1.02) 0.28

(0.20, 0.40)

0.41

(0.27, 0.60) omeprazole 40 mg QD,

d 7–12 (n=16) i

40 mg QD,

d 11–20 (n=15) i

20 mg QD,

d 17–23 (am) (n=13)

20 mg QD,

d 17–23 (am) (n=14) 400 mg QD,

d 1–6 (n=48), d 7–12 (n=16)

300 mg QD with ritonavir 100 mg QD,

d 1–20 (n=15)

300 mg QD with ritonavir 100 mg QD,

d 7–16 (pm) (n=27), d 17–23 (pm) (n=13) j,k

300 mg QD with ritonavir 100 mg QD,

d 7–16 (am) (n=27), then 400 mg QD with ritonavir 100 mg QD,

d 17–23 (am) (n=14) l,m 0.04

(0.04, 0.05)

0.28

(0.24, 0.32)

0.61

(0.46, 0.81)

0.69

(0.58, 0.83) 0.06

(0.05, 0.07)

0.24

(0.21, 0.27)

0.58

(0.44, 0.75)

0.70

(0.57, 0.86) 0.05

(0.03, 0.07)

0.22

(0.19, 0.26)

0.54

(0.41, 0.71)

0.69

(0.54, 0.88) pitavastatin 4 mg QD for 5 days 300 mg QD for 5 days 1.13

(0.96, 1.32) 1.06

(0.90, 1.26) NA rifabutin 150 mg QD,

d 15–28 (n=7) 400 mg QD,

d 1–28 (n=7) 1.34

(1.14, 1.59) 1.15

(0.98, 1.34) 1.13

(0.68, 1.87) rifampin 600 mg QD,

d 17–26 (n=16) 300 mg QD with ritonavir 100 mg QD,

d 7–16 (n=48),

d 17–26 (n=16) 0.47

(0.41, 0.53) 0.28

(0.25, 0.32) 0.02

(0.02, 0.03) ritonavir n 100 mg QD, d 11–20 (n=28) 300 mg QD,

d 1–20 (n=28) 1.86

(1.69, 2.05) 3.38

(3.13, 3.63) 11.89

(10.23, 13.82) tenofovir DF o 300 mg QD,

d 9–16 (n=34) 400 mg QD,

d 2–16 (n=34) 0.79

(0.73, 0.86) 0.75

(0.70, 0.81) 0.60

(0.52, 0.68) 300 mg QD,

d 15–42 (n=10) 300mg with ritonavir 100 mg QD,

d 1–42 (n=10) 0.72 p

(0.50, 1.05) 0.75 p (0.58, 0.97) 0.77 p

(0.54, 1.10) voriconazole

(Subjects with at least one functional CYP2C19 allele) 200 mg BID, d 2–3, 22–30; 400 mg BID, d 1, 21 (n=20) 300 mg with ritonavir 100 mg QD,

d 11–30 (n=20) 0.87

(0.80, 0.96) 0.88

(0.82, 0.95) 0.80

(0.72, 0.90) voriconazole (Subjects without a functional CYP2C19 allele) 50 mg BID, d 2–3, 22–30; 100 mg BID, d 1, 21 (n=8) 300 mg with ritonavir 100 mg QD,

d 11–30 (n=8) 0.81

(0.66, 1.00) 0.80

(0.65, 0.97) 0.69

(0.54, 0.87)

< class="Noautorules" id="ID458" width="638"> 19: Predicted Steady-State Pharmacokinetics of Atazanavir (capsule formulation) with Ritonavir in Pediatric Subjects with HIV-1 Infection. Body Weight Atazanavir with ritonavir C max ng/mL AUC ng•h/mL C min ng/mL (range in kg) Dose (mg) Geometric Geometric Geometric Mean Mean Mean (CV%) (CV%) (CV%) 15 to < 35 200/100 3303 (86 %) 37235 (84 %) 538 (99 %) ≥ 35 300/100 2980 (82 %) 37643 (83 %) 653 (89 %)

Table 17: Steady-State Pharmacokinetics of Atazanavir in Healthy Subjects or Subjects with HIV-1 Infection in the Fed State

a n=26.

b n=12.

400 mg once daily 300 mg with ritonavir 100 mg once daily
Healthy Subjects with HIV-1 Infection Healthy Subjects with HIV-1 Infection
Subjects (n=13) Subjects (n=10
(n=14) (n=28)
C max (ng/mL)
Geometric mean
(CV%) 5199 (26) 2298 (71) 6129 (31) 4422 (58)
Mean (SD) 5358 (1371) 3152 (2231) 6450 (2031) 5233 (3033)
T max (h)
Median 2.5 2.0 2.7 3.0
AUC (ng•h/mL)
Geometric mean
(CV%) 28132 (28) 14874 (91) 57039 (37) 46073 (66)
Mean (SD) 29303 (8263) 22262 (20159) 61435 (22911) 53761 (35294)
T-half (h)
Mean (SD) 7.9 (2.9) 6.5 (2.6) 18.1 (6.2) a 8.6 (2.3)
C min (ng/mL)
Geometric mean
(CV%) 159 (88) 120 (109) 1227 (53) 636 (97)
Mean (SD) 218 (191) 273 (298) b 1441 (757) 862 (838)

Table 20: Steady-State Pharmacokinetics of Atazanavir with Ritonavir in Pregnant Women with HIV-1 Infection in the Fed State

a Available data during the 2 nd trimester are limited.

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

c C min is concentration 24 hours post-dose

Pharmacokinetic Parameter Atazanavir 300 mg with ritonavir 100 mg
2 nd Trimester 3 rd Trimester Postpartum b
(n=5 a) (n=20) (n=34)
C max ng/mL 3078.85 3291.46 5721.21
Geometric mean (CV%) (50) (48) (31)
AUC ng•h/mL 27657.1 34251.5 61990.4
Geometric mean (CV%) (43) (43) (32)
C min ng/mL c 538.70 668.48 1462.59
Geometric mean (CV%) (46) (50) (45)

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

a Data provided are under fed conditions unless otherwise noted.

b 400 mg ddI EC and atazanavir were administered together with food on Days 8 and 19.

c Upon further dose normalization of ethinyl estradiol 25 mcg with atazanavir relative to ethinyl estradiol 35 mcg without atazanavir, the ratio of geometric means (90% confidence intervals) for C max, AUC, and C min were 0.82 (0.73, 0.92), 1.06 (0.95, 1.17), and 1.35 (1.11, 1.63), respectively.

d Upon further dose normalization of ethinyl estradiol 35 mcg with atazanavir with ritonavir relative to ethinyl estradiol 25 mcg without atazanavir with ritonavir, the ratio of geometric means (90% confidence intervals) for C max, AUC, and C min were 1.17 (1.03, 1.34), 1.13 (1.05, 1.22), and 0.88 (0.77, 1.00), respectively.

e All subjects were on a 28-day lead-in period; one full cycle of Ortho Tri-Cyclen ®. Ortho Tri-Cyclen ® contains 35 mcg of ethinyl estradiol. Ortho Tri-Cyclen ® LO contains 25 mcg of ethinyl estradiol. Results were dose normalized to an ethinyl estradiol dose of 35 mcg.

f 17-deacetyl norgestimate is the active component of norgestimate.

g Effect of atazanavir with ritonavir on the first dose of glecaprevir and pibrentasvir is reported.

h (R)-methadone is the active isomer of methadone.

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

j Subjects were treated with nevirapine prior to study entry.

k Omeprazole was used as a metabolic probe for CYP2C19. Omeprazole was given 2 hours after atazanavir on Day 7; and was given alone 2 hours after a light meal on Day 20.

l Not the recommended therapeutic dose of atazanavir.

m When compared to rifabutin 150 mg QD alone d1-10 (n=14). Total of rifabutin and 25-O-desacetyl-rifabutin: AUC 2.19 (1.78, 2.69).

n Rosiglitazone used as a probe substrate for CYP2C8.

o Mean ratio (with/without coadministered drug). ↑ indicates an increase in rosuvastatin exposure.

p The combination of atazanavir and saquinavir 1200 mg QD produced daily saquinavir exposures similar to the values produced by the standard therapeutic dosing of saquinavir at 1200 mg TID. However, the C max is about 79% higher than that for the standard dosing of saquinavir (soft gelatin capsules) alone at 1200 mg TID.

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

r Administration of tenofovir DF and atazanavir was temporally separated by 12 hours.

NA = not available.

Coadministered Drug Coadministered Drug Dose/Schedule Atazanavir Dose/Schedule Ratio (90% Confidence Interval) of Coadministered Drug Pharmacokinetic Parameters with/without Atazanavir;

No Effect = 1.00
C max AUC C min
acetaminophen 1 gm BID,

d 1–20 (n=10) 300 mg QD with ritonavir 100 mg QD, d 11–20 (n=10) 0.87

(0.77, 0.99) 0.97

(0.91, 1.03) 1.26

(1.08, 1.46)
atenolol 50 mg QD,

d 7–11 (n=19) and d 19–23 400 mg QD,

d 1–11 (n=19) 1.34

(1.26, 1.42) 1.25

(1.16, 1.34) 1.02

(0.88, 1.19)
clarithromycin 500 mg BID,

d 7–10 (n=21) and d 18–21 400 mg QD,

d 1–10 (n=21) 1.50

(1.32, 1.71) OH-clarithromycin: 0.28 (0.24, 0.33) 1.94 (1.75, 2.16)

OH-clarithromycin: 0.30

(0.26, 0.34) 2.60 (2.35, 2.88)

OH-clarithromycin: 0.38 (0.34, 0.42)
ddI (enteric-coated [EC] capsules) b 400 mg d 1 (fasted), d 8 (fed) (n=34) 400 mg QD,

d 2–8 (n=34) 0.64

(0.55, 0.74) 0.66

(0.60, 0.74) 1.13

(0.91, 1.41)
400 mg d 1 (fasted), d 19 (fed) (n=31) 300 mg QD with ritonavir 100 mg QD, d 9–19 (n=31) 0.62

(0.52, 0.74) 0.66

(0.59, 0.73) 1.25

(0.92, 1.69)
diltiazem 180 mg QD,

d 7–11 (n=28) and d 19–23 400 mg QD,

d 1–11 (n=28) 1.98

(1.78, 2.19) desacetyl-diltiazem: 2.72 (2.44, 3.03) 2.25

(2.09, 2.16) desacetyl-diltiazem: 2.65

(2.45, 2.87) 2.42

(2.14, 2.73) desacetyl-diltiazem: 2.21 (2.02, 2.42)
ethinyl estradiol & norethindrone c Ortho-Novum ® 7/7/7 QD, d 1–29 (n=19) 400 mg QD,

d 16–29 (n=19) ethinyl estradiol: 1.15

(0.99, 1.32) norethindrone: 1.67

(1.42, 1.96) ethinyl estradiol: 1.48

(1.31, 1.68) norethindrone: 2.10

(1.68, 2.62) ethinyl estradiol: 1.91

(1.57, 2.33) norethindrone: 3.62

(2.57, 5.09) ethinyl estradiol & norgestimate d Ortho Tri-Cyclen ® QD,

d 1–28 (n=18), then Ortho Tri-Cyclen ® LO QD, d 29–42 e (n=14) 300 mg QD with ritonavir 100 mg QD, d 29–42 (n=14) ethinyl estradiol: 0.84

(0.74, 0.95)

17-deacetyl norgestimate: f 1.68

(1.51, 1.88) ethinyl estradiol: 0.81

(0.75, 0.87)

17-deacetyl norgestimate: f 1.85

(1.67, 2.05) ethinyl estradiol: 0.63

(0.55, 0.71)

17-deacetyl norgestimate: f 2.02

(1.77, 2.31)
glecaprevir/ pibrentasvir 300 mg glecaprevir (n=12) 300 mg QD with ritonavir 100 mg QD

(n=12) ≥4.06 g (3.15, 5.23) ≥6.53 g (5.24, 8.14) ≥14.3 g (9.85, 20.7)
120 mg pibrentasvir

(n=12) 300 mg QD with ritonavir 100 mg QD

(n=12) ≥1.29 g (1.15, 1.45) ≥1.64 g (1.48, 1.82) ≥2.29 g (1.95, 2.68)
grazoprevir/ elbasvir grazoprevir 200 mg

QD

d 1 - 35

(n = 12) 300 mg QD with ritonavir 100 mg QD

d 1 -35

(n=12) 6.24

(4.42, 8.81) 10.58

(7.78, 14.39) 11.64

(7.96, 17.02)
elbasvir 50 mg QD d 1 - 35

(n = 10) 300 mg QD with ritonavir 100 mg QD

d 1 -35

(n=10) 4.15

(3.46, 4.97) 4.76

(4.07, 5.56) 6.45

(5.51 7.54)
methadone Stable maintenance dose, d 1–15 (n=16) 400 mg QD,

d 2–15 (n=16) (R)-methadone h 0.91

(0.84, 1.0) total: 0.85

(0.78, 0.93) (R)-methadone h 1.03

(0.95, 1.10)

total: 0.94

(0.87, 1.02) (R)-methadone h 1.11

(1.02, 1.20)

total: 1.02

(0.93, 1.12)
nevirapine i,j 200 mg BID,

d 1–23 (n=23) 300 mg QD with ritonavir 100 mg QD, d 4–13, then

400 mg QD with ritonavir 100 mg QD, d 14–23 (n=23) 1.17

(1.09, 1.25)

1.21

(1.11, 1.32) 1.25

(1.17, 1.34)
1.26

(1.17, 1.36) 1.32

(1.22, 1.43)
1.35

(1.25, 1.47)
omeprazole k 40 mg single dose, d 7 and

d 20 (n=16) 400 mg QD,

d 1–12 (n=16) 1.24

(1.04, 1.47) 1.45

(1.20, 1.76) NA
rifabutin 300 mg QD,

d 1–10 then 150 mg QD, d 11–20 (n=3) 600 mg QD, l

d 11–20 (n=3) 1.18 (0.94, 1.48) 25-O-desacetyl-rifabutin: 8.20 (5.90, 11.40) 2.10

(1.57, 2.79) 25-O-desacetyl-rifabutin: 22.01 (15.97, 30.34) 3.43

(1.98, 5.96) 25-O-desacetyl-rifabutin: 75.6 (30.1, 190.0)
150 mg twice weekly, d 1-15 (n=7) 300 mg QD with ritonavir 100mg QD, d 1-17 (n=7) 2.49 m (2.03, 3.06)

25-O-desacetyl-rifabutin: 7.77 (6.13, 9.83) 1.48 m (1.19, 1.84) 25-O-desacetyl-rifabutin: 10.90 (8.14, 14.61) 1.40 m

(1.05, 1.87)

25-O-desacetyl-rifabutin: 11.45 (8.15, 16.10)
pitavastatin 4 mg QD for 5 days 300 mg QD for 5 days 1.60

(1.39, 1.85) 1.31

(1.23, 1.39) NA
rosiglitazone n 4 mg single dose, d 1, 7, 17 (n=14) 400 mg QD,

d 2–7, then 300 mg QD with ritonavir 100 mg QD, d 8–17 (n=14) 1.08

(1.03, 1.13)

0.97

(0.91, 1.04) 1.35

(1.26, 1.44)

0.83

(0.77, 0.89) NA

NA
rosuvastatin 10 mg single dose 300 mg QD with ritonavir 100 mg QD for 7 days ↑7-fold o ↑3-fold o NA
saquinavir p (soft gelatin capsules) 1200 mg QD,

d 1–13 (n=7) 400 mg QD,

d 7–13 (n=7) 4.39

(3.24, 5.95) 5.49

(4.04, 7.47) 6.86

(5.29, 8.91)
sofosbuvir/ velpatasvir/ voxilaprevir 400 mg sofosbuvir single dose (n=15) 300 mg/100 mg ritonavir single dose (n=15) 1.29 (1.09, 1.52) sofosbuvir metabolite GS-331007 1.05 (0.99, 1.12) 1.40 (1.25, 1.57) sofosbuvir metabolite GS-331007 1.25 (1.16, 1.36) NA
100 mg velpatasvir single dose (n=15) 300 mg with 100 mg ritonavir single dose (n=15) 1.29 (1.07, 1.56) 1.93 (1.58, 2.36) NA
100 mg voxilaprevir single dose (n=15) 300 mg with 100 mg ritonavir single dose (n=15) 4.42 (3.65, 5.35) 4.31 (3.76, 4.93) NA
tenofovir DF q 300 mg QD,

d 9–16 (n=33) and d 24–30 (n=33) 400 mg QD,

d 2–16 (n=33) 1.14

(1.08, 1.20) 1.24

(1.21, 1.28) 1.22

(1.15, 1.30)
300 mg QD,

d 1–7 (pm) (n=14) d 25–34 (pm) (n=12) 300 mg QD with ritonavir

100 mg QD,

d 25–34 (am) (n=12) r 1.34

(1.20, 1.51) 1.37

(1.30, 1.45) 1.29

(1.21, 1.36)
voriconazole (Subjects with at least one functional CYP2C19 allele) 200 mg BID,

d 2–3, 22–30; 400 mg BID,

d 1, 21 (n=20) 300 mg with ritonavir 100 mg QD,

d 11–30 (n=20) 0.90

(0.78, 1.04) 0.67

(0.58, 0.78) 0.61

(0.51, 0.72)
voriconazole (Subjects without

a functional

CYP2C19 allele) 50 mg BID,

d 2–3, 22–30; 100 mg BID,

d 1, 21 (n=8) 300 mg with ritonavir 100 mg QD,

d 11–30 (n=8) 4.38

(3.55, 5.39) 5.61

(4.51, 6.99) 7.65

(5.71, 10.2)
lamivudine and zidovudine 150 mg lamivudine and 300 mg zidovudine BID, d 1–12 (n=19) 400 mg QD,

d 7–12 (n=19) lamivudine: 1.04

(0.92, 1.16) zidovudine: 1.05

(0.88, 1.24) zidovudine glucuronide: 0.95

(0.88, 1.02) lamivudine: 1.03

(0.98, 1.08) zidovudine:

1.05

(0.96, 1.14) zidovudine glucuronide: 1.00

(0.97, 1.03) lamivudine:

1.12

(1.04, 1.21) zidovudine:

0.69

(0.57, 0.84) zidovudine glucuronide: 0.82

(0.62, 1.08)

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 (EC ₅₀) 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. Atazanavir has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. Atazanavir has variable activity against HIV-2 isolates (1.9-32 nM), with EC ₅₀ values above the EC ₅₀ values of failure isolates. Two-drug combination antiviral activity studies with atazanavir showed no antagonism in cell culture with PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NNRTIs (delavirdine, efavirenz, and nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir DF, and zidovudine), the HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity.

Resistance

In Cell Culture: HIV-1 isolates with a decreased susceptibility to atazanavir have been selected in cell culture and obtained from patients treated with atazanavir or atazanavir with ritonavir. HIV-1 isolates with 93- to 183-fold reduced susceptibility to atazanavir from three different viral strains were selected in cell culture by 5 months. The substitutions in these HIV-1 viruses that contributed to atazanavir 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 atazanavir and amprenavir, respectively, and did not appear to be cross-resistant.

Clinical Studies of Treatment-Naive Subjects:  Comparison of Ritonavir-Boosted Atazanavir vs. Unboosted Atazanavir: Study AI424-089 compared atazanavir 300 mg once daily with ritonavir 100 mg vs. atazanavir 400 mg once daily when administered with lamivudine and extended-release stavudine in treatment-naive subjects with HIV-1 infection . A summary of the number of virologic failures and virologic failure isolates with atazanavir resistance in each arm is shown in Table 23.

Clinical Studies of Treatment-Naive Subjects Receiving Atazanavir 300 mg with Ritonavir 100 mg: In Phase 3 Study AI424-138, an as-treated genotypic and phenotypic analysis was conducted on samples from subjects who experienced virologic failure (HIV-1 RNA ≥400 copies/mL) or discontinued before achieving suppression on atazanavir with ritonavir (n=39; 9%) and lopinavir/ritonavir (n=39; 9%) through 96 weeks of treatment. In the atazanavir with ritonavir arm, one of the virologic failure isolates had a 56-fold decrease in atazanavir 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 atazanavir with ritonavir -virologic failure isolates had baseline phenotypic atazanavir resistance and IAS-defined major PI resistance-associated substitutions at baseline. The I50L substitution emerged on study in one of these failure isolates and was associated with a 17-fold decrease in atazanavir susceptibility from baseline and the other failure isolate with baseline atazanavir resistance and PI substitutions (M46M/I and I84I/V) had additional IAS-defined major PI substitutions (V32I, M46I, and I84V) emerge on atazanavir treatment associated with a 3-fold decrease in atazanavir susceptibility from baseline. Five of the treatment failure isolates in the atazanavir with ritonavir 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 lopinavir/ritonavir arm, one of the virologic failure subject isolates had a 69-fold decrease in lopinavir 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 lopinavir/ritonavir virologic failure isolates developed the M184V substitution and phenotypic emtricitabine resistance and two developed phenotypic tenofovir disoproxil resistance.

Clinical Studies of Treatment-Naive Subjects Receiving Atazanavir 400 mg without Ritonavir: atazanavir-resistant clinical isolates from treatment-naive subjects who experienced virologic failure on atazanavir 400 mg treatment without ritonavir often developed an I50L substitution (after an average of 50 weeks of atazanavir 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 subjects, viral isolates that developed the I50L substitution, without other major PI substitutions, showed phenotypic resistance to atazanavir 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 Subjects: In studies of treatment-experienced subjects treated with atazanavir or atazanavir with ritonavir, most atazanavir-resistant isolates from subjects 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 subjects who failed treatment with atazanavir 300 mg once daily and ritonavir 100 mg once daily (together with tenofovir DF and an NRTI) included V32I, L33F/V/I, E35D/G, M46I/L, I50L, F53L/V, I54V, A71V/T/I, G73S/T/C, V82A/T/L, I85V, and L89V/Q/M/T. Other substitutions that developed on atazanavir with ritonavir treatment including E34K/A/Q, G48V, I84V, N88S/D/T, and L90M occurred in less than 10% of subject isolates. Generally, if multiple PI resistance substitutions were present in the HIV-1 virus of the subject at baseline, atazanavir 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 subjects experiencing virologic failure after long-term treatment. Protease cleavage site changes also emerged on atazanavir treatment but their presence did not correlate with the level of atazanavir resistance.

Cross-Resistance

Cross-resistance among PIs has been observed. Baseline phenotypic and genotypic analyses of clinical isolates from atazanavir clinical trials of PI-experienced subjects showed that isolates cross-resistant to multiple PIs were cross-resistant to atazanavir. Greater than 90% of the isolates with substitutions that included I84V or G48V were resistant to atazanavir. Greater than 60% of isolates containing L90M, G73S/T/C, A71V/T, I54V, M46I/L, or a change at V82 were resistant to atazanavir, and 38% of isolates containing a D30N substitution in addition to other changes were resistant to atazanavir. Isolates resistant to atazanavir 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 subjects, 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 atazanavir susceptibility before initiation of atazanavir with ritonavir 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 subjects receiving atazanavir with ritonavir once daily or lopinavir ritonavir (fixed-dose product) twice daily in Study AI424-045 is shown in Table 24.

Overall, both the number and type of baseline PI substitutions affected response rates in treatment-experienced subjects. In the atazanavir with ritonavir group, subjects 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 subjects with 1–2 PI substitutions, including one of these substitutions.

The response rates of antiretroviral-experienced subjects in Study AI424-045 were analyzed by baseline phenotype (shift in susceptibility in cell culture relative to reference, Table 25). The analyses are based on a select population with 62% of subjects receiving an NNRTI-based regimen before study entry compared to 35% receiving a PI-based regimen. Additional data are needed to determine clinically relevant break points for atazanavir.

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.

Study AI424-138:  a 96-week study comparing the antiviral efficacy and safety of either atazanavir or lopinavir/ritonavir, each in combination with fixed-dose tenofovir DF-emtricitabine in treatment-naive subjects with HIV-1 infection. Study AI424-138 (NCT00272779) was a 96-week, open-label, randomized, multicenter study, comparing atazanavir (300 mg once daily) with ritonavir (100 mg once daily) to lopinavir/ritonavir (400/100 mg twice daily as fixed-dose product), each in combination with the fixed-dose product, tenofovir DF/emtricitabine (300/200 mg once daily), in 878 antiretroviral treatment-naive subjects. Subjects 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/mm ³ (range: 2 to 810 cells/mm ³) and the mean baseline plasma HIV-1 RNA level was 4.94 log ₁₀ copies/mL (range: 2.60 to 5.88 log ₁₀ copies/mL). Treatment response and outcomes through Week 96 are presented in Table 26.

.

Through 96 weeks of therapy, the proportion of responders among subjects with high viral loads (ie, baseline HIV-1 RNA ≥100,000 copies/mL) was comparable for the atazanavir with ritonavir (165 of 223 subjects, 74%) and lopinavir/ritonavir (148 of 222 subjects, 67%) arms. At 96 weeks, the median increase from baseline in CD4+ cell count was 261 cells/mm ³ for the atazanavir with ritonavir arm and 273 cells/mm ³ for the lopinavir/ritonavir arm.

Study AI424-034:  Atazanavir once daily compared to efavirenz once daily, each in combination with fixed-dose lamivudine/zidovudine twice daily. Study AI424-034 (NCT00013897) was a randomized, double-blind, multicenter trial comparing atazanavir (400 mg once daily) to efavirenz (600 mg once daily), each in combination with the fixed-dose product of lamivudine/zidovudine (150 mg/300 mg) given twice daily, in 810 antiretroviral treatment-naive subjects. Subjects 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/mm ³ (range: 64 to 1424 cells/mm ³) and the mean baseline plasma HIV-1 RNA level was 4.8 log ₁₀ copies/mL (range: 2.2 to 5.9 log ₁₀ copies/mL). Treatment response and outcomes through Week 48 are presented in Table 27.

Through 48 weeks of therapy, the proportion of responders among subjects with high viral loads (ie, baseline HIV RNA ≥100,000 copies/mL) was comparable for the atazanavir and efavirenz arms. The mean increase from baseline in CD4+ cell count was 176 cells/mm ³ for the atazanavir arm and 160 cells/mm ³ for the efavirenz arm.

Study AI424-008:  Atazanavir 400 mg once daily compared to Atazanavir 600 mg once daily, and compared to nelfinavir 1250 mg twice daily, each in combination with stavudine and lamivudine twice daily. Study AI424-008 (NCT identifier not available) was a 48-week, randomized, multicenter trial, blinded to dose of atazanavir, comparing atazanavir at two dose levels (400 mg and 600 mg once daily) to nelfinavir (1250 mg twice daily), each in combination with stavudine (40 mg) and lamivudine (150 mg) given twice daily, in 467 antiretroviral treatment-naive subjects. Subjects 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/mm ³ (range: 4 to 1003 cells/mm ³) and the mean baseline plasma HIV-1 RNA level was 4.7 log ₁₀ copies/mL (range: 1.8 to 5.9 log ₁₀ copies/mL). Treatment response and outcomes through Week 48 are presented in Table 28.

Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 234 cells/mm ³ for the atazanavir 400-mg arm and 211 cells/mm ³ for the nelfinavir arm.

Study AI424-045:  Atazanavir once daily with ritonavir once daily compared to atazanavir once daily and saquinavir (soft gelatin capsules) once daily, and compared to lopinavir/ritonavir twice daily, each in combination with tenofovir DF and one NRTI. Study AI424-045 (NCT00035932) was a randomized, multicenter trial comparing atazanavir (300 mg once daily) with ritonavir (100 mg once daily) to atazanavir (400 mg once daily) with saquinavir soft gelatin capsules (1200 mg once daily), and to lopinavir/ritonavir (400/100 mg twice daily as fixed-dose product), each in combination with tenofovir DF and one NRTI, in 347 (of 358 randomized) subjects who experienced virologic failure on highly active antiretroviral therapy regimens containing PIs, NNRTIs, and NRTIs. The mean time of prior exposure to antiretrovirals was 139 weeks for PIs, 85 weeks for NNRTIs, and 283 weeks for NRTIs. The mean age was 41 years (range: 24 to 74); 60% were Caucasian, and 78% were male. The mean baseline CD4+ cell count was 338 cells/mm ³ (range: 14 to 1543 cells/mm ³) and the mean baseline plasma HIV-1 RNA level was 4.4 log ₁₀ copies/mL (range: 2.6 to 5.88 log ₁₀ copies/mL).

Treatment outcomes through Week 48 for the atazanavir with ritonavir and lopinavir/ritonavir treatment arms are presented in Table 29. Atazanavir with ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV-1 RNA level. Study AI424-045 was not large enough to reach a definitive conclusion that atazanavir with ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measure of proportions below the HIV-1 RNA lower limit of quantification. [See Microbiology, Tables 24 and 25 ( 12.4) .]

No subjects in the atazanavir with ritonavir treatment arm and three subjects in the lopinavir/ritonavir treatment arm experienced a new-onset CDC Category C event during the study.

In Study AI424-045, the mean change from baseline in plasma HIV-1 RNA for atazanavir 400 mg with saquinavir (n=115) was −1.55 log ₁₀ 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/mm ³Through 48 weeks of treatment, the proportion of subjects in this treatment arm with plasma HIV-1 RNA <400 (<50) copies/mL was 38% (26%). In this study, coadministration of atazanavir and saquinavir did not provide adequate efficacy [see Drug Interactions ( 7) ].

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

Study AI424-043 (NCT00028301): Study AI424-043 was a randomized, open-label, multicenter trial comparing atazanavir (400 mg once daily) to lopinavir/ritonavir (400/100 mg twice daily as fixed-dose product), each in combination with two NRTIs, in 300 subjects who experienced virologic failure to only one prior PI-containing regimen. Through 48 weeks, the proportion of subjects with plasma HIV-1 RNA <400 (<50) copies/mL was 49% (35%) for subjects randomized to atazanavir (n=144) and 69% (53%) for subjects randomized to lopinavir/ritonavir (n=146). The mean change from baseline was −1.59 log ₁₀ copies/mL in the atazanavir treatment arm and −2.02 log ₁₀ copies/mL in the lopinavir/ritonavir arm. Based on the results of this study, atazanavir without ritonavir was inferior to lopinavir/ritonavir in PI-experienced subjects with prior virologic failure and is not recommended for such patients.

Pediatric Trials with Atazanavir Capsules

Study AI424-040; PACTG 1020A (NCT00006604): Assessment of the pharmacokinetics, safety, tolerability, and virologic response of atazanavir capsule was based on data from this open-label, multicenter clinical trial which included subjects from 6 years to 21 years of age. In this study, 105 subjects (43 antiretroviral-naive and 62 antiretroviral-experienced) received once daily atazanavir capsule formulation, with or without ritonavir, in combination with two NRTIs.

One-hundred five (105) subjects (6 to less than 18 years of age) treated with the atazanavir capsule formulation, with or without ritonavir, were evaluated. Using an intent-to-treat (ITT) analysis, the overall proportions of antiretroviral-naive and -experienced subjects with HIV-1 RNA <400 copies/mL at Week 96 were 51% (22/43) and 34% (21/62), respectively. The overall proportions of antiretroviral-naive and -experienced subjects with HIV-1 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/mm ³ in antiretroviral-naive subjects and 220 cells/mm ³ in antiretroviral-experienced subjects.