ETRAVIRINE

1 INDICATIONS AND USAGE Etravirine, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-experienced adult patients and pediatric patients 2 years of age and older [see Microbiology (12.4) and Clinical Studies (14) ] Etravirine is a human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase inhibitor (NNRTI) indicated for treatment of HIV-1 infection in treatment-experienced patients 2 years of age and older. (1)

6 ADVERSE REACTIONS The following adverse reactions are described in greater detail in other sections: Severe skin and hypersensitivity reactions [see Warnings and Precautions (5.1) ] . Immune reconstitution syndrome [see Warnings and Precautions (5.3) ] . The most common adverse drug reactions of moderate to severe intensity (at least 2%) which occurred at a higher rate than placebo in adults are rash and peripheral neuropathy. ( 6.1 ) The most common adverse drug reactions in at least 2% of pediatric patients are rash and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Carnegie Pharmaceuticals, LLC at 1-732-783-7010 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Clinical Trials Experience in Adults The safety assessment is based on all data from 1203 subjects in the Phase 3 placebo-controlled trials, TMC125-C206 and TMC125-C216, conducted in antiretroviral treatment-experienced HIV-1-infected adult subjects, 599 of whom received etravirine tablets (200 mg twice daily). In these pooled trials, the median exposure for subjects in the etravirine tablets arm and placebo arm was 52.3 and 51.0 weeks, respectively. Discontinuations due to adverse drug reactions (ADRs) were 5.2% in the etravirine tablets arm and 2.6% in the placebo arm. The most frequently reported ADR at least Grade 2 in severity was rash (10.0%). Stevens-Johnson syndrome, drug hypersensitivity reaction and erythema multiforme were reported in less than 0.1% of subjects during clinical development with etravirine tablets [see Warnings and Precautions (5.1) ] . A total of 2.2% of HIV-1-infected subjects in Phase 3 trials receiving etravirine tablets discontinued due to rash. In general, in clinical trials, rash was mild to moderate, occurred primarily in the second week of therapy, and was infrequent after Week 4. Rash generally resolved within 1 to 2 weeks on continued therapy. The incidence of rash was higher in women compared to men in the etravirine tablets arm in the Phase 3 trials (rash ≥ Grade 2 was reported in 9/60 [15.0%] women versus 51/539 [9.5%] men; discontinuations due to rash were reported in 3/60 [5.0%] women versus 10/539 [1.9%] men) [see Warnings and Precautions (5.1) ] . Patients with a history of NNRTI-related rash did not appear to be at increased risk for the development of etravirine tablets-related rash compared to patients without a history of NNRTI- related rash. Common Adverse Reactions Clinical ADRs of moderate intensity or greater (greater than or equal to Grade 2) and reported in at least 2% of subjects treated with etravirine tablets and occurring at a higher rate compared to placebo (excess of 1%) are presented in Table 2. Laboratory abnormalities considered ADRs are included in Table 3. Table 2: Adverse Drug Reactions (Grades 2 to 4) in at Least 2% of Adult Subjects (Pooled TMC125-C206 and TMC125-C216 Trials) Preferred Term Etravirine tablets + BR N=599 % Placebo + BR N=604 % Rash 10% 3% Peripheral neuropathy 4% 2% N=total number of subjects per treatment group; BR=background regimen Less Common Adverse Reactions Treatment-emergent ADRs occurring in less than 2% of subjects (599 subjects) receiving etravirine tablets and of at least moderate intensity (greater than or equal to Grade 2) are listed below by body system: Cardiac Disorders : myocardial infarction, angina pectoris, atrial fibrillation Ear and Labyrinth Disorders : vertigo Eye Disorders : blurred vision Gastrointestinal Disorders : gastroesophageal reflux disease, flatulence, gastritis, abdominal distension, pancreatitis, constipation, dry mouth, hematemesis, retching, stomatitis General Disorders and Administration Site Conditions : sluggishness Hematologic Disorders : hemolytic anemia Hepatobiliary Disorders : hepatic failure, hepatomegaly, cytolytic hepatitis, hepatic steatosis, hepatitis Immune System Disorders : drug hypersensitivity, immune reconstitution syndrome Metabolism and Nutrition Disorders : diabetes mellitus, anorexia, dyslipidemia Nervous System Disorders : paresthesia, somnolence, convulsion, hypoesthesia, amnesia, syncope, disturbance in attention, hypersomnia, tremor Psychiatric Disorders : anxiety, sleep disorders, abnormal dreams, confusional state, disorientation, nervousness,, nightmares Renal and Urinary Disorders: acute renal failure Reproductive System and Breast Disorders : gynecomastia Respiratory, Thoracic and Mediastinal Disorders : exertional dyspnea, bronchospasm Skin and Subcutaneous Tissue Disorders : night sweats, lipohypertrophy, prurigo, hyperhidrosis, dry skin, swelling face Additional ADRs of at least moderate intensity observed in other trials were acquired lipodystrophy, angioneurotic edema, erythema multiforme and hemorrhagic stroke, each reported in no more than 0.5% of subjects. Laboratory Abnormalities in Treatment-Experienced Patients Selected Grade 2 to Grade 4 laboratory abnormalities that represent a worsening from baseline observed in adult subjects treated with etravirine tablets are presented in Table 3. Table 3: Selected Grade 2 to 4 Laboratory Abnormalities Observed in Treatment-Experienced Subjects (Pooled TMC125-C206 and TMC125- C216 Trials) Laboratory Parameter DAIDS Toxicity Range Etravirine tablets + BR N=599 % Placebo + BR N=604 % GENERAL BIOCHEMISTRY Pancreatic amylase Grade 2 > 1.5–2 × ULN 7% 8% Grade 3 > 2–5 × ULN 7% 8% Grade 4 5 × ULN 2% 1% Lipase Grade 2 > 1.5–3 × ULN 4% 6% Grade 3 > 3–5 × ULN 2% 2% Grade 4 5 × ULN 1% < 1% Creatinine Grade 2 > 1.4–1.8 × ULN 6% 5% Grade 3 > 1.9–3.4 × ULN 2% 1% Grade 4 > 3.4 × ULN 0% < 1% HEMATOLOGY Decreased hemoglobin Grade 2 90–99 g/L 2% 4% Grade 3 70–89 g/L < 1% < 1% Grade 4 < 70 g/L < 1% < 1% White blood cell count Grade 2 1,500–1,999/mm 3 2% 3% Grade 3 1,000–1,499/mm 3 1% 4% Grade 4 < 1,000/mm 3 1% < 1% Neutrophils Grade 2 750–999/mm 3 5% 6% Grade 3 500–749/mm 3 4% 4% Grade 4 < 500/mm 3 2% 3% Platelet count Grade 2 50,000– 99,999/mm 3 3% 5% Grade 3 25,000– 49,999/mm 3 1% 1% Grade 4 < 25,000/mm 3 < 1% < 1% LIPIDS AND GLUCOSE Total cholesterol Grade 2 > 6.20–7.77 mmol/L 240–300 mg/dL 20% 17% Grade 3 > 7.77 mmol/L 300 mg/dL 8% 5% Low density lipoprotein Grade 2 4.13–4.9 mmol/L 160–190 mg/dL 13% 12% Grade 3 > 4.9 mmol/L > 190 mg/dL 7% 7% Triglycerides Grade 2 5.65–8.48 mmol/L 500–750 mg/dL 9% 7% Grade 3 8.49–13.56 mmol/L 751–1200 mg/dL 6% 4% Grade 4 > 13.56 mmol/L > 1200 mg/dL 4% 2% Elevated glucose levels Grade 2 6.95–13.88 mmol/L 161–250 mg/dL 15% 13% Grade 3 13.89–27.75 mmol/L 251–500 mg/dL 4% 2% Grade 4 > 27.75 mmol/L > 500 mg/dL 0% < 1% HEPATIC PARAMETERS Alanine amino transferase Grade 2 2.6–5 × ULN 6% 5% Grade 3 5.1–10 × ULN 3% 2% Grade 4 > 10 × ULN 1% < 1% Aspartate amino transferase Grade 2 2.6–5 × ULN 6% 8% Grade 3 5.1–10 × ULN 3% 2% Grade 4 > 10 × ULN < 1% < 1% ULN=Upper Limit of Normal; BR=background regimen Patients Co-Infected With Hepatitis B and/or Hepatitis C Virus In Phase 3 trials TMC125-C206 and TMC125-C216, 139 subjects (12.3%) with chronic hepatitis B and/or hepatitis C virus co-infection out of 1129 subjects were permitted to enroll. AST and ALT abnormalities occurred more frequently in hepatitis B and/or hepatitis C virus co-infected subjects for both treatment groups. Grade 2 or higher laboratory abnormalities that represent a worsening from baseline of AST, ALT or total bilirubin occurred in 27.8%, 25.0% and 7.1% respectively, of etravirine tablets-treated co-infected subjects as compared to 6.7%, 7.5% and 1.8% of non-co-infected etravirine tablets-treated subjects. In general, adverse events reported by etravirine tablets-treated subjects with hepatitis B and/or hepatitis C virus co-infection were similar to etravirine tablets-treated subjects without hepatitis B and/or hepatitis C virus co-infection. Clinical Trials Experience in Pediatric Subjects (2 Years to Less Than 18 years of age) The safety assessment in pediatric subjects is based on two single-arm trials. TMC125-C213 is a Phase 2 trial in which 101 antiretroviral treatment-experienced HIV-1 infected pediatric subjects 6 years to less than 18 years of age received etravirine tablets in combination with other antiretroviral agents (Week 24 analysis). TMC125-C234/IMPAACT P1090 is a Phase 1/2 trial in which 20 antiretroviral treatment- experienced HIV-1 infected pediatric subjects 2 years to less than 6 years of age received etravirine tablets in combination with other antiretroviral agents (Week 24 analysis) [see Clinical Studies (14.2) ] . In TMC125-C213, the frequency, type and severity of adverse drug reactions in pediatric subjects 6 years to less than 18 years of age were comparable to those observed in adult subjects, except for rash which was observed more frequently in pediatric subjects. The most common adverse drug reactions in at least 2% of pediatric subjects were rash and diarrhea. Rash was reported more frequently in female subjects than in male subjects (rash ≥ Grade 2 was reported in 13/64 [20.3%] females versus 2/37 [5.4%] males; discontinuations due to rash were reported in 4/64 [6.3%] females versus 0/37 [0%] males). Rash (greater than or equal to Grade 2) occurred in 15% of pediatric subjects from 6 years to less than 18 years of age. In the majority of cases, rash was mild to moderate, of macular/papular type, and occurred in the second week of therapy. Rash was self-limiting and generally resolved within 1 week on continued therapy. The safety profile for subjects who completed 48 weeks of treatment was similar to the safety profile for subjects who completed 24 weeks of treatment. In TMC125-C234/IMPAACT P1090, the frequency, type and severity of adverse drug reactions in pediatric subjects 2 years to less than 6 years of age through Week 24 were comparable to those observed in adults. The most common adverse drug reactions (any grade) of pediatric subjects were rash (50% [10/20]) and diarrhea (25% [5/20]). In this age group, no subjects had Grade 3 or Grade 4 rash and no subjects discontinued prematurely due to rash. One subject discontinued etravirine due to asymptomatic lipase elevation. 6.2 Postmarketing Experience The following events have been identified during postmarketing use of etravirine tablets. Because these events 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. Immune System Disorders : Severe hypersensitivity reactions including DRESS and cases of hepatic failure have been reported [see Warnings and Precautions (5.1) ] . Musculoskeletal and Connective Tissue Disorders : rhabdomyolysis Skin and Subcutaneous Tissue Disorders : Fatal cases of toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported [see Warnings and Precautions (5.1) ] .