Atazanavir Sulfate (Page 4 of 11)

5.10 Immune Reconstitution Syndrome

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-Barré 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.

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 Reactions a 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 weeks c atazanavir 400 mg once daily + lamivudine + zidovudine e (n=404) 64 weeks c efavirenz 600 mg once daily + lamivudine + zidovudine e (n=401) 120 weeks c,d atazanavir 400 mg once daily + stavudine + lamivudine or didanosine (n=279) 73 weeks c,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 weeks c atazanavir/ritonavir 300/100 mg once daily + tenofovir DF + NRTI (n=119) 48 weeks c lopinavir/ritonavir 400/100 mg twice daily d + 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 Limit d 96 weeks b atazanavir 300 mg with ritonavir 100 mg (once daily) and tenofovir DF with emtricitabine c (n=441) 96 weeks b lopinavir 400 mg with ritonavir 100 mg (twice daily) and tenofovir DF with emtricitabine c (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%
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 Limit d Study AI424-034 Studies AI424-007, -008
64 weeks b atazanavir 400 mg once daily + lamivudine + zidovudine e (n=404) 64 weeks b efavirenz 600 mg once daily + lamivudine + zidovudine e (n=401) 120 weeks b,c atazanavir 400 mg once daily + stavudine + lamivudine or + stavudine + didanosine (n=279) 73 weeks b,c nelfinavir 750 mg TID or 1250 mg BID + stavudine + lamivudine or + stavudine + didanosine (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%
* 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/ritonavir a,b lopinavir/ritonavir b,c
Baseline Week 48 Week 96 Baseline Week 48 Week 96
mg/dL (n=428 e) mg/dL (n=372 e) Change d (n=372 e) mg/dL (n=342 e) Change d (n=342 e) mg/dL (n=424 e) mg/dL (n=335 e) Change d (n=335 e) mg/dL (n=291 e) Change d (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%
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
atazanavir a,b efavirenz b,c
Baseline Week 48 Week 48 Baseline Week 48 Week 48
mg/dL (n=383 e) mg/dL (n=283 e) Change d (n=272 e) mg/dL (n=378 e) mg/dL (n=264 e) Change d (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%
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 in ≥2% of Adult Treatment-Experienced Patients, Study AI424-045 a
Variable Limit c 48 weeks b atazanavir /ritonavir 300/100 mg once daily + tenofovir DF + NRTI (n=119) 48 weeks b lopinavir/ritonavir 400/100 mg twice daily d + tenofovir DF + NRTI (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%
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/ritonavir a,b lopinavir/ritonavir b,c
Baseline mg/dL (n=111 e) Week 48 mg/dL (n=75 e) Week 48 Change d (n=74 e) Baseline mg/dL (n=108 e) Week 48 mg/dL (n=76 e) Week 48 Change d (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%
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) ].

All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.

This site is provided for educational and informational purposes only, in accordance with our Terms of Use, and is not intended as a substitute for the advice of a medical doctor, nurse, nurse practitioner or other qualified health professional.

Privacy Policy | Copyright © 2020. All Rights Reserved.