REYATAZ SIDE EFFECTS
- Generic Name: atazanavir sulfate
- Brand Name: Reyataz
- Drug Class: HIV, Protease Inhibitors, Antiretroviral Agents
SIDE EFFECTS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
- cardiac conduction abnormalities
- rash
- hyperbilirubinemia
- chronic kidney disease
- nephrolithiasis and cholelithiasis
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 Subjects
The safety profile of REYATAZ in treatment-naive adults is based on 1625 subjects with HIV-1 infection in clinical trials. 536 subjects received REYATAZ 300 mg with ritonavir 100 mg and 1089 subjects received REYATAZ 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 REYATAZ 300 mg with ritonavir 100 mg and REYATAZ 400 mg (without ritonavir) are presented in Tables 1 and 2, respectively.
Table 1: Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Subjects with HIV-1 Infection,b Study AI424-138
| 96 weeksc REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabined (n=441) |
96 weeksc lopinavir/ritonavird 400 mg/ 100 mg (twice daily) and tenofovir DF/emtricitabinee (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 REYATAZ. 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. |
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Table 2: Selected Adverse Reactionsa 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
| Study AI424-034 | Studies AI424-007, -008 | |||
| 64 weeksc REYATAZ 400 mg (oncedaily) with lamivudine/ zidovudinee (n=404) |
64 weeksc efavirenz 600 mg (once daily) with lamivudine/ zidovudinee (n=401) |
120 weeksc,d REYATAZ 400 mg (once daily) with stavudine and lamivudine or didanosine (n=279) |
73 weeksc,d nelfinavir 750 mg TID or 1250 mg BID with stavudine and 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 REYATAZ. c Median time on therapy. dIncludes long-term follow-up. e As a fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily. |
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Adverse Reactions In Treatment-Experienced Adult Subjects
The safety profile of REYATAZ 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 REYATAZ with ritonavir are presented in Table 3.
Table 3: Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Experienced Subjects with HIV-1 Infection,b Study AI424-045
| 48 weeksc REYATAZ with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI (n=119) |
48 weeksc lopinavir/ritonavir 400/100 mg (twice dailyd) and tenofovir DF and 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 REYATAZ. c Median time on therapy. d As a fixed-dose product. |
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Laboratory Abnormalities In Treatment-Naive Subjects
The percentages of adult treatment-naive subjects with HIV-1 infection treated with combination therapy, including REYATAZ 300 mg with ritonavir 100 mg or REYATAZ 400 mg (without ritonavir) with Grade 3-4 laboratory abnormalities, are presented in Tables 4 and 5, respectively.
Table 4: Grade 3-4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Subjects with HIV-1 Infection,a Study AI424-138
| Variable | Limite | 96 weeksb REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabinec (n=441) |
96 weeksb lopinavir/ritonavir 400 mg/100 mgc (twice daily) and tenofovir DF/emtricitabined (n=437) |
| Chemistry | High | ||
| SGOT/AST | ≥5.1 x ULN | 3% | 1% |
| SGPT/ALT | ≥5.1 x ULN | 3% | 2% |
| Total Bilirubin | ≥2.6 x ULN | 44% | <1% |
| Lipase | ≥2.1 x ULN | 2% | 2% |
| Creatine Kinase | ≥5.1 x ULN | 8% | 7% |
| Total Cholesterol | ≥240 mg/dL | 11% | 25% |
| Hematology | Low | ||
| Neutrophils | <750 cells/mm³ | 5% | 2% |
| a Based on the regimen containing REYATAZ. 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. |
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Table 5: Grade 3-4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Subjects with HIV-1 Infection, Studies AI424-034, AI424-007, and AI424-008
| Variable | Limitd | Study AI424-034 | Studies AI424-007, -008 | ||
| 64 weeksb REYATAZ 400 mg once daily and lamivudine/ zidovudinee (n=404) |
64 weeksb efavirenz 600 mg once daily and lamivudine/ zidovudinee (n=401) |
120 weeksb,c REYATAZ 400 mg once daily with stavudine and lamivudine or with stavudine and didanosine (n=279) |
73 weeksb,c nelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or with stavudine and didanosine (n=191) |
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| Chemistry | High | ||||
| SGOT/AST | ≥5.1 x ULN | 2% | 2% | 7% | 5% |
| SGPT/ALT | ≥5.1 x ULN | 4% | 3% | 9% | 7% |
| Total Bilirubin | ≥2.6 x ULN | 35% | <1% | 47% | 3% |
| Amylase | ≥2.1 x ULN | * | * | 14% | 10% |
| Lipase | ≥2.1 x ULN | <1% | 1% | 4% | 5% |
| Creatine Kinase | ≥5.1 x ULN | 6% | 6% | 11% | 9% |
| Total Cholesterol | ≥240 mg/dL | 6% | 24% | 19% | 48% |
| Triglycerides | ≥751 mg/dL | <1% | 3% | 4% | 2% |
| Hematology | Low | ||||
| Hemoglobin | <8.0 g/dL | 5% | 3% | <1% | 4% |
| Neutrophils | <750 cells/mm³ | 7% | 9% | 3% | 7% |
| * None reported in this treatment arm. a Based on regimen(s) containing REYATAZ. b Median time on therapy. c Includes long-term follow-up. d ULN = upper limit of normal. e As a fixed-dose product: 150 mg lamivudine, 300 mg zidovudine twice daily. |
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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 6 and 7, respectively.
Table 6: Lipid Values, Mean Change from Baseline, Study AI424-138
| REYATAZ with ritonavira,b | lopinavir/ritonavirb,c | |||||||||
| Baselinemg/dL (n=428e) |
Week 48 | Week 96 | Baseline | Week 48 | Week 96 | |||||
| mg/dL (n=372e) |
Changed (n=372e) |
mg/dL (n=342e) |
Changed (n=342e) |
mg/dL (n=424e) |
mg/dL (n=335e) |
Changed (n=335e) |
mg/dL (n=291e) |
Changed (n=291e) |
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| 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 REYATAZ 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 REYATAZ with ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 8% in the lopinavir/ritonavir treatment arm and 2% in the REYATAZ with ritonavir arm. Through Week 96, serum lipid-reducing agents were used in 10% in the lopinavir/ritonavir treatment arm and 3% in the REYATAZ 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. |
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Table 7: Lipid Values, Mean Change from Baseline, Study AI424-034
| Baseline mg/dL (n=383e) |
REYATAZa,b Week 48 mg/dL (n=283e) |
Week 48 Changed (n=272e) |
Baseline mg/dL (n=378e) |
efavirenzb,c 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 REYATAZ 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 REYATAZ arm. Through Week 48, serum lipid-reducing agents were used in 3% in the efavirenz treatment arm and 1% in the REYATAZ arm. c Efavirenz 600 mg once daily with the fixed-dose 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. |
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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 REYATAZ with ritonavir having Grade 3-4 laboratory abnormalities, are presented in Table 8.
Table 8: Grade 3-4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Experienced Subjects with HIV-1 Infection, Study AI424-045a
| Variable | Limitc | 48 weeksb REYATAZ with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI (n=119) |
48 weeksb lopinavir/ritonavir 400/100 mg (twice dailyd) and tenofovir DF and 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 | T. <50,000 cells/mm³ | 2% | 3% |
| Neutrophils | <750 cells/mm³ | 7% | 8% |
| a Based on regimen(s) containing REYATAZ. b Median time on therapy. c ULN = upper limit of normal. d As a fixed-dose product. |
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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 9. The observed magnitude of dyslipidemia was less with REYATAZ with ritonavir than with lopinavir/ritonavir. However, the clinical impact of such findings has not been demonstrated.
Table 9: Lipid Values, Mean Change from Baseline, Study AI424-045
| REYATAZ with 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 REYATAZ 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 REYATAZ with ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 19% in the lopinavir/ritonavir treatment arm and 8% in the REYATAZ 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. |
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Adverse Reactions In Pediatric Subjects With HIV-1 Infection
REYATAZ Capsules – The safety and tolerability of REYATAZ 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 REYATAZ 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 REYATAZ 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 Pediatric Subjects With HIV-1 Infection: REYATAZ Oral Powder
The data described below reflect exposure to REYATAZ oral powder in 155 subjects weighing at least 5 kg to less than 35 kg, including 134 subjects exposed for 48 weeks. These data are from two pooled, open-label, multi-center clinical trials in treatment-naive and treatment-experienced pediatric subjects with HIV-1 infection (AI424-397 [PRINCE I] and AI424-451 [PRINCE II]). Age ranged from 3 months to 10 years of age. In these studies, 51% were female and 49% were male. All subjects received ritonavir and 2 nucleoside reverse transcriptase inhibitors (NRTIs).
The safety profile of REYATAZ in pediatric subjects taking REYATAZ oral powder was generally similar to that observed in clinical studies of REYATAZ in pediatric subjects taking REYATAZ capsules. The most common Grade 3-4 laboratory abnormalities occurring in pediatric subjects weighing 5 kg to less than 35 kg taking REYATAZ oral powder were increased amylase (33%), neutropenia (9%), increased SGPT/ALT (9%), elevation of total bilirubin (≥2.6 times ULN, 16%), and increased lipase (8%). 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 REYATAZ 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 REYATAZ 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 REYATAZ with ritonavir and none (0/50) of the subjects treated with lopinavir/ritonavir.
In Study AI424-045, 20 subjects administered REYATAZ 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 REYATAZ 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 REYATAZ with ritonavir and 6% (1/18) of the subjects treated with lopinavir/ritonavir.
In Studies AI424-008 and AI424-034, 74 subjects treated with REYATAZ 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 REYATAZ, 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 REYATAZ, 5% of the subjects treated with efavirenz, and 17% of the subjects treated with nelfinavir. Within REYATAZ and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative subjects.
Postmarketing Experience
The following events have been identified during postmarketing use of REYATAZ. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Body as a Whole: edema
Cardiovascular System: second-degree AV block, third-degree AV block, left bundle branch block, QTc prolongation
Gastrointestinal System: pancreatitis
Hepatic System: hepatic function abnormalities
Hepatobiliary Disorders: cholelithiasis, cholecystitis, cholestasis
Metabolic System and Nutrition Disorders: diabetes mellitus, hyperglycemia
Musculoskeletal System: arthralgia
Renal System: nephrolithiasis, interstitial nephritis, granulomatous interstitial nephritis, chronic kidney disease
Skin and Appendages: alopecia, maculopapular rash, pruritus, angioedema.
SRC: NLM .