EVOTAZ SIDE EFFECTS
- Generic Name: atazanavir and cobicistat tablets for oral administration
- Brand Name: Evotaz
SIDE EFFECTS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
- cardiac conduction abnormalities
- rash
- effects on serum creatinine
- new onset or worsening renal impairment when used with tenofovir DF
- chronic kidney disease
- nephrolithiasis and cholelithiasis
- hepatotoxicity
- hyperbilirubinemia
For additional safety information about atazanavir and cobicistat, consult the full prescribing information for these individual products.
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 From Clinical Trial Experience In Adult Subjects
The safety of atazanavir and cobicistat coadministered as single agents is based on Week 144 data from a Phase 3 trial, Study GS-US-216-0114, in which 692 antiretroviral treatment-naive subjects with HIV-1 infection received:
- atazanavir coadministered with cobicistat and emtricitabine/tenofovir DF (N=344) or
- atazanavir coadministered with ritonavir and emtricitabine/tenofovir DF (N=348).
The most common adverse reactions (Grades 2-4) and reported in ≥5% of subjects in the atazanavir coadministered with cobicistat group were jaundice (6%) and rash (5%). The proportion of subjects who discontinued study treatment due to adverse events regardless of severity, was 11% in both the atazanavir coadministered with cobicistat and atazanavir coadministered with ritonavir groups. Table 2 lists the frequency of adverse reactions (Grades 2-4) occurring in at least 2% of subjects in the atazanavir coadministered with cobicistat group in Study GS-US-216-0114.
Table 1: Selected Adverse Reactionsa (Grades 2-4) Reported in ≥2% of Treatment-Naive Adults with HIV-1 Infection in the Atazanavir Coadministered with Cobicistat Group in Study GS-US-216-0114 (Week 144 analysis)
| Atazanavir coadministered with cobicistat and emtricitabine/ tenofovir DF (n=344) |
Atazanavir coadministered with ritonavir and emtricitabine/ tenofovir DF (n=348) |
|
| Jaundice | 6% | 3% |
| Rashb | 5% | 4% |
| Ocular icterus | 4% | 2% |
| Nausea | 2% | 2% |
| Diarrhea | 2% | 1% |
| Headache | 2% | 1% |
| a Frequencies of adverse reactions are based on Grades 2-4 adverse events attributed to study drugs. b Rash events include dermatitis allergic, drug hypersensitivity, pruritus generalized, eosinophilic pustular folliculitis, rash, rash generalized, rash macular, rash maculopapular, rash morbilliform, rash papular, and urticaria. |
||
Less Common Adverse Reactions
Selected adverse reactions of at least moderate severity (≥ Grade 2) occurring in less than 2% of subjects receiving atazanavir coadministered with cobicistat and emtricitabine/tenofovir DF are listed below. These events have been included because of investigator’s assessment of potential causal relationship and were considered serious or have been reported in more than one subject treated with atazanavir coadministered with cobicistat, and reported with greater frequency compared with the atazanavir coadministered with ritonavir group.
Gastrointestinal Disorders: vomiting, upper abdominal pain
General Disorders and Administration Site Conditions: fatigue
Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis
Psychiatric Disorders: depression, abnormal dreams, insomnia
Renal and Urinary Disorders: nephropathy, Fanconi syndrome acquired, nephrolithiasis
Laboratory Abnormalities
The frequency of laboratory abnormalities (Grades 3-4) occurring in at least 2% of subjects in the atazanavir coadministered with cobicistat group in Study GS-US-216-0114 is presented in Table 3.
Table 2: Laboratory Abnormalities (Grades 3-4) Reported in ≥2% of HIV-1-Infected Treatment-Naive Adults in the Atazanavir Coadministered with Cobicistat Group in Study GS-US-216-0114 (Week 144 analysis)
| Laboratory Parameter Abnormality | 144 weeks Atazanavir coadministered with cobicistat and emtricitabine/ tenofovir DF (n=344) |
144 weeks Atazanavir coadministered with ritonavir and emtricitabine/ tenofovir DF (n=348) |
| Total Bilirubin (>2.5 × ULN) | 73% | 66% |
| Creatine Kinase (≥10.0 × ULN) | 8% | 9% |
| Urine RBC (Hematuria) (>75 RBC/HPF) | 6% | 3% |
| ALT (>5.0 × ULN) | 6% | 3% |
| AST (>5.0 × ULN) | 4% | 3% |
| GGT (>5.0 × ULN) | 4% | 2% |
| Serum Amylasea (>2.0 × ULN) | 4% | 2% |
| Urine Glucose (Glycosuria ≥1000 mg/dL) | 3% | 3% |
| Neutrophils (<750/mm3) | 3% | 2% |
| Serum Glucose (Hyperglycemia) (≥250 mg/dL) | 2% | 2% |
| a For subjects with serum amylase >1.5 × upper limit of normal, lipase test was also performed. The frequency of increased lipase (Grades 3-4) occurring in the atazanavir coadministered with cobicistat group (N=46) and atazanavir coadministered with ritonavir group (N=35) was 7% and 3%, respectively. | ||
Increase in Serum Creatinine
Cobicistat, a component of EVOTAZ, has been shown to increase serum creatinine and decrease estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function . In Study GS-US-216-0114, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment in the atazanavir coadministered with cobicistat group, after which they stabilized. The mean (± SD) change in estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method after 144 weeks of treatment was −15.1 ± 16.5 mL/min in the atazanavir coadministered with cobicistat group and −8.0 ± 16.8 mL/min in the atazanavir coadministered with ritonavir group.
Serum Lipids
Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 4. In both groups, mean values for serum lipids remained within the normal range for each laboratory test. The clinical significance of these changes is unknown.
Table 3: Lipid Values, Mean Change from Baseline, Reported in Treatment-Naive Adults with HIV-1 Infection Receiving Atazanavir Coadministered with Cobicistat and Emtricitabine/Tenofovir DF or Atazanavir Coadministered with Ritonavir and Emtricitabine/Tenofovir DF in Study GS-US-216-0114 (Week 144 analysis)
| Atazanavir coadministered with cobicistat and emtricitabine/ tenofovir DF | Atazanavir coadministered with ritonavir and emtricitabine/ tenofovir DF | |||
| Baseline mg/dL | Week 144 change from baselinea | Baseline mg/dL | Week 144 change from baselinea | |
| Total Cholesterol (fasted) | 163 [N=219] | +11 [N=219] | 165 [N=227] | +13 [N=227] |
| HDL-cholesterol (fasted) | 43 [N=218] | +7 [N=218] | 43 [N=228] | +6 [N=228] |
| LDL-cholesterol (fasted) | 102 [N=218] | +11 [N=218] | 104 [N=228] | +16 [N=228] |
| Triglycerides (fasted) | 130 [N=219] | +14 [N=219] | 131 [N=227] | +14 [N=227] |
| a The change from baseline is the mean of within-subject changes from baseline for subjects with both baseline and Week 144 values and excludes subjects receiving an HMG-CoA reductase inhibitor drug. | ||||
Adverse Reactions From Clinical Trial Experience In Pediatric Subjects
Although no clinical trial with EVOTAZ as the fixed-dose tablet was conducted in a pediatric population, the safety of atazanavir coadministered with cobicistat plus two nucleoside reverse transcriptase inhibitors was evaluated in treatment-experienced virologically suppressed subjects with HIV-1 infection between the ages of 12 to less than 18 years (N=14) through Week 48 in an open-label clinical trial (Study GS-US-216-0128) . Results from this study showed that the safety profile of atazanavir and cobicistat coadministered with a background regimen was similar to that in adults.
Postmarketing Experience
See the full prescribing information for atazanavir for postmarketing information on atazanavir.
SRC: NLM .