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The following adverse reaction is described in greater detail in another section of the labeling:

  • New Onset or Worsening Renal Impairment When Used with Tenofovir Disoproxil Fumarate [see WARNINGS AND PRECAUTIONS]

Clinical Trials 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.

The safety of TYBOST has been established from a Phase 2 trial, Study 105, and a Phase 3 trial, Study 114. In the pooled analysis, 771 HIV-1 infected, antiretroviral treatment-naïve adults received for at least 48 weeks:

  • TYBOST coadministered with atazanavir and tenofovir DF/emtricitabine (administered as TRUVADA) (N=394) or;
  • ritonavir coadministered with atazanavir and tenofovir DF/emtricitabine (administered as TRUVADA ) (N=377).

The most common adverse reactions (all Grades) and reported in > 10% of subjects in the TYBOST group were jaundice (13%), ocular icterus (15%), and nausea (12%); the most common adverse reactions in the ritonavir group were jaundice (11%), ocular icterus (17%), nausea (11%), and diarrhea (11%). The proportion of subjects who discontinued study treatment due to adverse events, regardless of severity, was 7% in both the TYBOST and ritonavir group. Table 3 displays the frequency of adverse reactions (Grades 2-4) occurring in at least 2% of subjects in the TYBOST group in pooled Studies 105 and 114.

Table 3 : Selected Adverse Reactionsa (Grades 2-4) Reported in ≥ 2% of HIV-1 Infected Treatment-Naïve Adults in the TYBOST Coadministered with Atazanavir Group in Studies 105 and 114 (Week 48 pooled Analysis)

  TYBOST Coadministered with Atazanavir + TRUVADA
N=394
Ritonavir Coadministered with Atazanavir + TRUVADA
N=377
Jaundice 5% 3%
Rashb 5% 4%
Ocular icterus 3% 1%
Nausea 2% 2%
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 maculo-papular, rash morbilliform, rash papular, and urticaria.

Nephrolithiasis

Nephrolithiasis has previously been identified in patients receiving atazanavir. In the pooled analysis of Studies 105 and 114 through 48 weeks, 8 subjects (2%) receiving TYBOST coadministered with atazanavir and TRUVADA developed nephrolithiasis compared with no subjects receiving ritonavir coadministered with atazanavir and TRUVADA. Median time to onset of nephrolithiasis in the TYBOST group was 24 weeks. Causality in these cases could not be determined with certainty, but the majority of renal stone events were not serious and no subject discontinued study drug.

Less Common Adverse Reactions

Selected adverse reactions of at least moderate severity ( ≥ Grade 2) occurring in less than 2% of subjects receiving TYBOST coadministered with atazanavir and TRUVADA are listed below. These events have been included because of the investigator's assessment of potential causal relationship and were considered serious or have been reported in more than one subject treated with TYBOST and with greater frequency compared with ritonavir.

Gastrointestinal Disorders: diarrhea, vomiting, upper abdominal pain

General Disorders and Administration Site Conditions: fatigue

Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis

Nervous System Disorders: headache

Psychiatric Disorders: depression, abnormal dreams, insomnia

Renal and Urinary Disorders: nephropathy, Fanconi syndrome acquired

Refer to the prescribing information for atazanavir or darunavir for information regarding adverse reactions with these drugs.

Laboratory Abnormalities

The frequency of laboratory abnormalities (Grades 3-4) occurring in at least 2% of subjects in the TYBOST group in Studies 105 and 114 is presented in Table 4.

Table 4 : Laboratory Abnormalities (Grades 3-4) in ≥ 2% of HIV-1 Infected Treatment-Naïve Adults in the TYBOST Coadministered with Atazanavir Group in Studies 105 and 114 (Week 48 pooled Analysis)

  TYBOST + Atazanavir + TRUVADA Ritonavir + Atazanavir + TRUVADA
Laboratory Parameter Abnormality N=394 N=377
Total Bilirubin ( > 2.5 x ULN) 65% 56%
Creatine Kinase ( ≥ 10.0 x ULN) 5% 6%
Serum Amylasea ( > 2.0 x ULN) 4% 2%
ALT ( > 5.0 x ULN) 3% 2%
AST ( > 5.0 x ULN) 3% 2%
GGT ( > 5.0 x ULN) 2% 1%
Urine Glucose (Glycosuria) ( ≥ 1000 mg/dL) 3% 1%
Urine RBC (Hematuria) ( > 75 RBC/HPF) 3% 2%
a For subjects with serum amylase > 1.5 x upper limit of normal, lipase test was also performed. The frequency of increased lipase (Grades 3-4) occurring in the TYBOST (N=44) and ritonavir (N=34) groups was 9% and 6%, respectively.

Increase in Serum Creatinine: TYBOST causes increases in serum creatinine and decreases in estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. In Studies 105 and 114, increases in serum creatinine and decreases in estimated creatinine clearance occurred early in treatment with TYBOST, after which they stabilized. The mean (± SD) change in estimated glomerular filtration rate (eGFR) by Cockcroft-Gault method after 48 weeks of treatment was -13.4 ± 15.2 mL/min in the TYBOST group and -9.1 ± 14.7 mL/min in the ritonavir group.

Serum Lipids: Changes from baseline in total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides are presented in Table 5. In both groups, mean values for serum lipids remained within the study reference range for each laboratory test. The clinical significance of these changes is unknown.

Table 5 : Lipid Values, Mean Change from Baseline, Reported in HIV-1 Infected Treatment-Naïve Adults Receiving TYBOST Coadministered with Atazanavir + TRUVADA or Ritonavir Coadministered with Atazanavir + TRUVADA in Studies 105 and 114 (Week 48 pooled Analysis)

  TYBOST + Atazanavir + TRUVADA Ritonavir + Atazanavir + TRUVADA
Baseline Week 48 Baseline Week 48
mg/dL Change from baselinea mg/dL Change from baselinea
Total Cholesterol (fasted) 164
[N=307]
+4
[N=307]
165
[N=299]
+8
[N=299]
HDL-cholesterol (fasted) 44
[N=306]
+3
[N=306]
43
[N=299]
+3
[N=299]
LDL-cholesterol (fasted) 102
[N=307]
+5
[N=307]
103
[N=300]
+7
[N=300]
Triglycerides (fasted) 128
[N=307]
+15
[N=307]
131
[N=299]
+29
[N=299]
a The change from baseline is the mean of within-patient changes from baseline for patients with both baseline and Week 48 values. Analysis excludes subjects receiving an HMG-CoA reductase inhibitor drug.