Atazanavir (Page 4 of 12)

5.11 Fat Redistribution

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

5.12 Hemophilia

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.

5.13 Resistance/Cross-Resistance

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

6 ADVERSE REACTIONS

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

6.1 Clinical Trial Experience

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

Adverse Reactions in Treatment-Naive Adult Patients

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

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

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

Table 7: Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Patients,b Study AI424-138

96 weeks c

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

(n=441)

96 weeks c

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

(n=437)

Digestive System

Nausea

4%

8%

Jaundice/scleral icterus

5%

*

Diarrhea

2%

12%

Skin and Appendages

Rash

3%

2%

* 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 combination: 300 mg tenofovir DF, 200 mg emtricitabine once daily.

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

Study AI424-034

Studies AI424-007, -008

64 weeksc Atazanavir 400 mg once daily + lamivudine + zidovudinee

(n=404)

64 weeksc Efavirenz 600 mg once daily + lamivudine + zidovudinee

(n=401)

120 weeksc,d Atazanavir 400 mg once daily + stavudine + lamivudine or didanosine

(n=279)

73 weeksc,d Nelfinavir 750 mg TID or 1250 mg BID + stavudine + lamivudine or didanosine

(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%

* 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 combination: 150 mg lamivudine, 300 mg zidovudine twice daily.

Adverse Reactions in Treatment-Experienced Adult Patients

The safety profile of atazanavir in treatment-experienced adults is based on 119 HIV-1 infected patients in clinical trials.

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

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

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

48 weeksc Atazanavir/ritonavir 300/100 mg once daily + tenofovir DF + NRTI

(n=119)

48 weeksc Lopinavir/ritonavir 400/100 mg twice dailyd + tenofovir DF + NRTI

(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%

*

* 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 combination.

Laboratory Abnormalities in Treatment-Naive Patients

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

Table 10: Grade 3 to 4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Patients,a Study AI424-138

Variable

Limitd

96 weeksb

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

(n=441)

96 weeksb

Lopinavir 400 mg with ritonavir 100 mg (twice daily) and tenofovir DF with emtricitabinec

(n=437)

Chemistry

High

SGOT/AST

≥5.1 × ULN

3%

1%

SGPT/ALT

≥5.1 × ULN

3%

2%

Total Bilirubin

≥2.6 × ULN

44%

<1%

Lipase

≥2.1 × ULN

2%

2%

Creatine Kinase

≥5.1 × ULN

8%

7%

Total Cholesterol

≥240 mg/dL

11%

25%

Hematology

Low

Neutrophils

<750 cells/mm3

5%

2%

a Based on the regimen containing atazanavir.

b Median time on therapy.

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

d ULN = upper limit of normal.

Table 11: Grade 3 to 4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Patients,a Studies AI424-034, AI424-007, and AI424-008

Variable

Limitd

Study AI424-034

Studies AI424-007, -008

64 weeksb

64 weeksb

120 weeksb,c

73 weeksb,c

Atazanavir 400 mg once daily + lamivudine + zidovudinee

Efavirenz 600 mg once daily + lamivudine + zidovudinee

Atazanavir 400 mg once daily + stavudine + lamivudine or + stavudine + didanosine

Nelfinavir 750 mg TID or 1250 mg BID + stavudine + lamivudine or + stavudine + didanosine

(n=404)

(n=401)

(n=279)

(n=191)

Chemistry

High

SGOT/AST

≥5.1 × ULN

2%

2%

7%

5%

SGPT/ALT

≥5.1 × ULN

4%

3%

9%

7%

Total Bilirubin

≥2.6 × ULN

35%

<1%

47%

3%

Amylase

≥2.1 × ULN

*

*

14%

10%

Lipase

≥2.1 × ULN

<1%

1%

4%

5%

Creatine Kinase

≥5.1 × ULN

6%

6%

11%

9%

Total Cholesterol

≥240 mg/dL

6%

24%

19%

48%

Triglycerides

≥751 mg/dL

<1%

3%

4%

2%

Hematology

Low

Hemoglobin

<8.0 g/dL

5%

3%

<1%

4%

Neutrophils

<750 cells/mm3

7%

9%

3%

7%

* 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 combination: 150 mg lamivudine, 300 mg zidovudine twice daily.

Change in Lipids from Baseline in Treatment-Naive Patients

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

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

Atazanavir/ritonavira,b

Lopinavir/ritonavirb,c

Baseline

Week 48

Week 96

Baseline

Week 48

Week 96

mg/dL

mg/dL

Changed

mg/dL

Changed

mg/dL

mg/dL

Changed

mg/dL

Changed

(n=428e)

(n=372e)

(n=372e)

(n=342e)

(n=342e)

(n=424e)

(n=335e)

(n=335e)

(n=291e)

(n=291e)

LDL-Cholesterolf

92

105

+14%

105

+14%

93

111

+19%

110

+17%

HDL-Cholesterolf

37

46

+29%

44

+21%

36

48

+37%

46

+29%

Total Cholesterolf

149

169

+13%

169

+13%

150

187

+25%

186

+25%

Triglyceridesf

126

145

+15%

140

+13%

129

194

+52%

184

+50%

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

c Lopinavir 400 mg with ritonavir 100 mg twice daily with the fixed-dose combination 300 mg tenofovir DF, 200 mg emtricitabine once daily.

d The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 48 or Week 96 values and is not a simple difference of the baseline and Week 48 or Week 96 mean values, respectively.

e Number of patients with LDL-cholesterol measured.

f Fasting.

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

Atazanavira,b

Efavirenzb,c

Baseline

mg/dL

(n=383e)

Week 48

mg/dL

(n=283e)

Week 48

Changed

(n=272e)

Baseline

mg/dL

(n=378e)

Week 48

mg/dL

(n=264e)

Week 48

Changed

(n=253e)

LDL-Cholesterolf

98

98

+1%

98

114

+18%

HDL-Cholesterol

39

43

+13%

38

46

+24%

Total Cholesterol

164

168

+2%

162

195

+21%

Triglyceridesf

138

124

−9%

129

168

+23%

a Atazanavir 400 mg once daily with the fixed-dose combination: 150 mg lamivudine, 300 mg zidovudine twice daily.

b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 0% in the efavirenz treatment arm and <1% in the 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 combination: 150 mg lamivudine, 300 mg zidovudine twice daily.

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

e Number of patients with LDL-cholesterol measured.

f Fasting.

Laboratory Abnormalities in Treatment-Experienced Patients

The percentages of adult treatment-experienced patients treated with combination therapy including atazanavir/ritonavir with Grade 3 to 4 laboratory abnormalities are presented in Table 14.

Table 14: Grade 3 to 4 Laboratory Abnormalities Reported in2% of Adult Treatment-Experienced Patients, Study AI424-045a

48 weeksb

48 weeksb

Atazanavir/ritonavir 300/100 mg once daily + tenofovir DF + NRTI

Lopinavir/ritonavir 400/100 mg twice dailyd + tenofovir DF + NRTI

Variable

Limitc

(n=119)

(n=118)

Chemistry

High

SGOT/AST

≥5.1 × ULN

3%

3%

SGPT/ALT

≥5.1 × ULN

4%

3%

Total Bilirubin

≥2.6 × ULN

49%

<1%

Lipase

≥2.1 × ULN

5%

6%

Creatine Kinase

≥5.1 × ULN

8%

8%

Total Cholesterol

≥240 mg/dL

25%

26%

Triglycerides

≥751 mg/dL

8%

12%

Glucose

≥251 mg/dL

5%

<1%

Hematology

Low

Platelets

<50,000 cells/mm3

2%

3%

Neutrophils

<750 cells/mm3

7%

8%

a Based on regimen(s) containing atazanavir.

b Median time on therapy.

c ULN = upper limit of normal.

d As a fixed-dose combination.

Change in Lipids from Baseline in Treatment-Experienced Patients

For Study AI424-045, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Table 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

Atazanavir/ritonavira,b

Lopinavir/ritonavirb,c

Baseline

mg/dL (n=111e)

Week 48

mg/dL

(n=75e)

Week 48

Changed

(n=74e)

Baseline

mg/dL

(n=108e)

Week 48

mg/dL

(n=76e)

Week 48

Changed

(n=73e)

LDL-Cholesterolf

108

98

−10%

104

103

+1%

HDL-Cholesterol

40

39

−7%

39

41

+2%

Total Cholesterol

188

170

−8%

181

187

+6%

Triglyceridesf

215

161

−4%

196

224

+30%

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

c Lopinavir/ritonavir (400/100 mg) BID + tenofovir DF + 1 NRTI.

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

e Number of patients with LDL-cholesterol measured.

f Fasting.

Adverse Reactions in Pediatric Patients: Atazanavir Capsules

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

The safety profile of atazanavir in pediatric patients (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 to 4 adverse events (≥5%, regardless of causality) reported in pediatric patients were cough (21%), fever (18%), jaundice/scleral icterus (15%), rash (14%), vomiting (12%), diarrhea (9%), headache (8%), peripheral edema (7%), extremity pain (6%), nasal congestion (6%), oropharyngeal pain (6%), wheezing (6%), and rhinorrhea (6%). Asymptomatic second-degree atrioventricular block was reported in <2% of patients. The most common Grade 3 to 4 laboratory abnormalities occurring in pediatric patients taking the capsule formulation were elevation of total bilirubin (≥3.2 mg/dL, 58%), neutropenia (9%), and hypoglycemia (4%). All other Grade 3 to 4 laboratory abnormalities occurred with a frequency of less than 3%.

Adverse Reactions in Patients Co-Infected with Hepatitis B and/or Hepatitis C Virus

In Study AI424-138, 60 patients treated with atazanavir/ritonavir 300 mg/100 mg once daily, and 51 patients treated with lopinavir/ritonavir 400 mg/100 mg twice daily, each with fixed dose tenofovir 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 atazanavir/ritonavir-treated patients and 8% (4/50) of the lopinavir/ritonavir-treated patients. AST levels >5 times ULN developed in 10% (6/60) of the atazanavir/ritonavir-treated patients and none (0/50) of the lopinavir/ritonavir-treated patients.

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

In Studies AI424-008 and AI424-034, 74 patients treated with 400 mg of atazanavir 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 atazanavir-treated patients, 14% of the efavirenz-treated patients, and 17% of the nelfinavir-treated patients. AST levels >5 times ULN developed in 9% of the atazanavir-treated patients, 5% of the efavirenz­-treated patients, and 17% of the nelfinavir-treated patients. Within atazanavir and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative patients [see Warnings and Precautions (5.8)].

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