ETRAVIRINE

Etravirine is a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). The chemical name for etravirine is 4-[[6-amino-5-bromo-2-[(4-cyanophenyl)amino]-4- pyrimidinyl]oxy]-3,5-dimethylbenzonitrile. Its molecular formula is C20H15BrN6O and its molecular weight is 435.28. Etravirine has the following structural formula: Etravirine is a white to slightly yellowish-brown powder. Etravirine is practically insoluble in water over a wide pH range. It is very slightly soluble in propylene glycol and slightly soluble in ethanol. Etravirine is soluble in polyethylene glycol (PEG)400 and freely soluble in some organic solvents (e.g., N,N-dimethylformamide and tetrahydrofuran). Etravirine 100 mg tablets are available as white to off-white, oval tablets for oral administration. Each 100 mg tablet contains 100 mg of etravirine and the inactive ingredients povidone, microcrystalline cellulose, sodium lauryl sulfate, crospovidone, sodium starch glycolate, silicon dioxide and magnesium stearate. Etravirine 200 mg tablets are available as white to off-white, oval tables for oral administration. Each 200 mg tablet contains 200 mg of etravirine and the inactive ingredients povidone, microcrystalline cellulose, sodium lauryl sulfate, crospovidone, sodium starch glycolate, silicon dioxide and magnesium stearate. chemicalstructure

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)

Adult patients: 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following a meal. ( 2.1 , 2.2 , 2.4 ) Pregnant patients: 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following a meal. ( 2.2 ) Pediatric patients (2 years to less than 18 years of age and weighing at least 10 kg): dosage of etravirine is based on body weight and should not exceed the recommended adult dose. Etravirine tablets should be taken following a meal. ( 2.3 ) 2.1 Recommended Dosage in Adult Patients The recommended oral dosage of etravirine for adult patients is 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following a meal. The type of food does not affect the exposure to etravirine [see Clinical Pharmacology (12.3) ] . 2.2 Recommended Dosage During Pregnancy The recommended oral dosage of etravirine for pregnant individuals is 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following a meal [see Use in Specific Populations (8.1) ] 2.3 Recommended Dosage in Pediatric Patients (2 Years to Less Than 18 Years of Age) The recommended dosage of etravirine for pediatric patients 2 years to less than 18 years of age and weighing at least 10 kg is based on body weight (see Table 1) not exceeding the recommended adult dosage. Etravirine should be taken orally, following a meal. The type of food does not affect the exposure to etravirine [see Clinical Pharmacology (12.3) ] . Table 1: Recommended Dosage of Etravirine Tablets for Pediatric Patients 2 Years to Less Than 18 Years of Age Body Weight kilograms (kg) Dose greater than or equal to 10 kg to less than 20 kg 100 mg twice daily greater than or equal to 20 kg to less than 25 kg 125 mg twice daily greater than or equal to 25 kg to less than 30 kg 150 mg twice daily greater than or equal to 30 kg 200 mg twice daily 2.4 Method of Administration Instruct patients to swallow the etravirine tablet(s) whole with liquid such as water. Patients who are unable to swallow the etravirine tablet(s) whole may disperse the tablet(s) in water. Instruct the patient to do the following: place the tablet(s) in 5 mL (1 teaspoon) of water, or at least enough liquid to cover the medication, stir well until the water looks milky, add approximately 15 mL (1 tablespoon) of liquid. Water may be used but other liquids, such as orange juice or milk, may improve taste. Patients should not place the tablets in orange juice or milk without first adding water. The use of warm (temperature greater than 104°F [greater than 40°C]) or carbonated beverages should be avoided. drink the mixture immediately, rinse the glass several times with orange juice, milk or water and completely swallow the rinse each time to make sure the patient takes the entire dose. 2.1 Recommended Dosage in Adult Patients The recommended oral dosage of etravirine for adult patients is 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following a meal. The type of food does not affect the exposure to etravirine [see Clinical Pharmacology (12.3) ] . 2.2 Recommended Dosage During Pregnancy The recommended oral dosage of etravirine for pregnant individuals is 200 mg (one 200 mg tablet or two 100 mg tablets) taken twice daily following a meal [see Use in Specific Populations (8.1) ] 2.3 Recommended Dosage in Pediatric Patients (2 Years to Less Than 18 Years of Age) The recommended dosage of etravirine for pediatric patients 2 years to less than 18 years of age and weighing at least 10 kg is based on body weight (see Table 1) not exceeding the recommended adult dosage. Etravirine should be taken orally, following a meal. The type of food does not affect the exposure to etravirine [see Clinical Pharmacology (12.3) ] . Table 1: Recommended Dosage of Etravirine Tablets for Pediatric Patients 2 Years to Less Than 18 Years of Age Body Weight kilograms (kg) Dose greater than or equal to 10 kg to less than 20 kg 100 mg twice daily greater than or equal to 20 kg to less than 25 kg 125 mg twice daily greater than or equal to 25 kg to less than 30 kg 150 mg twice daily greater than or equal to 30 kg 200 mg twice daily 2.4 Method of Administration Instruct patients to swallow the etravirine tablet(s) whole with liquid such as water. Patients who are unable to swallow the etravirine tablet(s) whole may disperse the tablet(s) in water. Instruct the patient to do the following: place the tablet(s) in 5 mL (1 teaspoon) of water, or at least enough liquid to cover the medication, stir well until the water looks milky, add approximately 15 mL (1 tablespoon) of liquid. Water may be used but other liquids, such as orange juice or milk, may improve taste. Patients should not place the tablets in orange juice or milk without first adding water. The use of warm (temperature greater than 104°F [greater than 40°C]) or carbonated beverages should be avoided. drink the mixture immediately, rinse the glass several times with orange juice, milk or water and completely swallow the rinse each time to make sure the patient takes the entire dose.

None. None. ( 4 )

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 Leading Pharma, LLC at 1-844-740-7500 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) ] . 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) ] .

Co-administration of etravirine with other drugs can alter the concentrations of other drugs and other drugs may alter the concentrations of etravirine. The potential drug-drug interactions must be considered prior to and during therapy. ( 7 , 12.3 ) 7.1 Potential for Other Drugs to Affect Etravirine Tablets Etravirine is a substrate of CYP3A, CYP2C9, and CYP2C19. Therefore, co-administration of etravirine tablets with drugs that induce or inhibit CYP3A, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of etravirine tablets (see Table 4) [see Clinical Pharmacology (12.3) ]. 7.2 Potential for Etravirine Tablets to Affect Other Drugs Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P-glycoprotein (P-gp). Therefore, co-administration of drugs that are substrates of CYP3A, CYP2C9 and CYP2C19 or are transported by P-gp with etravirine tablets may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s) (see Table 4) [see Clinical Pharmacology (12.3) ]. 7.3 Significant Drug Interactions Table 4 shows significant drug interactions based on which, alterations in dose or regimen of etravirine tablets and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with etravirine tablets are also included in Table 4 [see Clinical Pharmacology (12.3) ] . Table 4: Significant Drug Interactions Concomitant Drug Class: Drug Name Effect on Concentration of Etravirine or Concomitant Drug Clinical Comment ↑ = increase; ↓ = decrease; ↔ = no change HIV-antiviral agents: integrase strand inhibitors dolutegravir The interaction between INTELENCE and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. ↓ dolutegravir ↔ etravirine Etravirine significantly reduced plasma concentrations of dolutegravir. Using cross - study comparisons to historical pharmacokinetic data for etravirine, dolutegravir did not appear to affect the pharmacokinetics of etravirine. dolutegravir/darunavir/ritonavir ↓ dolutegravir ↔ etravirine The effect of etravirine on dolutegravir plasma concentrations was mitigated by co- administration of darunavir/ritonavir or lopinavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir. dolutegravir/lopinavir/ritonavir ↔ dolutegravir ↔ etravirine Dolutegravir should only be used with etravirine tablets when co- administered with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. HIV-antiviral agents: non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz nevirapine ↓ etravirine Combining two NNRTIs has not been shown to be beneficial. Concomitant use of etravirine tablets with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of Etravirine and loss of therapeutic effect of etravirine tablets. Co-administration of etravirine tablets and other NNRTIs is not recommended. delavirdine rilpivirine ↓ etravirine ↓ rilpivirine ↔ etravirine Combining two NNRTIs has not been shown to be beneficial. Etravirine tablets and delavirdine should not be co-administered. Combining two NNRTIs has not been shown to be beneficial. Co- administration of etravirine tablets and rilpivirine is not recommended. HIV-antiviral agents: protease inhibitors (PIs) atazanavir (without ritonavir) atazanavir/ritonavir atazanavir/cobicistat darunavir/ritonavir darunavir/cobicistat fosamprenavir (without ritonavir) fosamprenavir/ritonavir indinavir (without ritonavir) lopinavir/ritonavir ↓ atazanavir ↓ atazanavir ↔ etravirine ↓ atazanavir ↓ cobicistat ↓ etravirine ↓ cobicistat darunavir: effect unknown ↑ amprenavir ↑ amprenavir ↓ indinavir ↓ etravirine Co-administration of etravirine tablets and atazanavir without low- dose ritonavir is not recommended. Concomitant use of etravirine tablets with atazanavir/ritonavir decreased atazanavir Cmin but it is not considered clinically relevant. The mean systemic exposure (AUC) of etravirine after co-administration of etravirine tablets with atazanavir/ritonavir in HIV-infected subjects was similar to the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of etravirine tablets and darunavir/ritonavir (as part of the background regimen). Etravirine tablets and atazanavir/ritonavir can be co-administered without dose adjustments. Co-administration of etravirine tablets with atazanavir/cobicistat is not recommended because it may result in loss of therapeutic effect and development of resistance to atazanavir. The mean systemic exposure (AUC) of etravirine was reduced when etravirine tablets was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and Etravirine exposures from these trials were determined to be safe and effective, etravirine tablets and darunavir/ritonavir can be co-administered without dose adjustments. Co-administration of etravirine tablets with darunavir/cobicistat is not recommended because it may result in loss of therapeutic effect and development of resistance to darunavir. Concomitant use of etravirine tablets with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. Co-administration of etravirine tablets and fosamprenavir without low-dose ritonavir is not recommended. Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of etravirine tablets and fosamprenavir /ritonavir have not been established. Co- administration of etravirine tablets and fosamprenavir/ritonavir is not recommended. Concomitant use of etravirine tablets with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. Co-administration of etravirine tablets and indinavir without low- dose ritonavir is not recommended. The mean systemic exposure (AUC) of Etravirine was reduced after co-administration of etravirine tablets with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, etravirine tablets and lopinavir/ritonavir can be co-administered without dose adjustments. nelfinavir (without ritonavir) ritonavir saquinavir/ritonavir tipranavir/ritonavir ↑ nelfinavir ↓ etravirine ↓ etravirine ↓ etravirine Concomitant use of etravirine tablets with nelfinavir without low- dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. Co- administration of etravirine tablets and nelfinavir without low- dose ritonavir is not recommended. Concomitant use of etravirine tablets with ritonavir 600 mg twice daily may cause a significant decrease in the plasma concentration of Etravirine and loss of therapeutic effect of etravirine tablets. Co-administration of etravirine tablets and ritonavir 600 mg twice daily is not recommended. The mean systemic exposure (AUC) of etravirine was reduced when etravirine tablets were co-administered with saquinavir/ ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, etravirine tablets and saquinavir/ritonavir can be co-administered without dose adjustments. Concomitant use of etravirine tablets with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of etravirine tablets. Co-administration of etravirine tablets and tipranavir/ritonavir is not recommended. CCR5 antagonists maraviroc maraviroc/darunavir/ritonavir The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir. ↔ etravirine ↓ maraviroc ↑ maraviroc When etravirine tablets are co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg twice daily. No dose adjustment of etravirine tablets is needed. When etravirine tablets are co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., protease inhibitor), the recommended dose of maraviroc is 150 mg twice daily. No dose adjustment of etravirine tablets is needed. Other agents Antiarrhythmics : digoxin amiodarone bepridil disopyramide flecainide lidocaine (systemic) mexiletine propafenone quinidine ↔ etravirine ↑ digoxin ↓ antiarrhythmics For patients who are initiating a combination of etravirine tablets and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating etravirine tablets, no dose adjustment of either etravirine tablets or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect. Concentrations of these antiarrhythmics may be decreased when co- administered with etravirine tablets. Etravirine tablets and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available. Anticoagulant : warfarin ↑ anticoagulants Warfarin concentrations may be increased when co-administered with etravirine tablets. The international normalized ratio (INR) should be monitored when warfarin is combined with etravirine tablets. Anticonvulsants : carbamazepine phenobarbital phenytoin ↓ etravirine Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. Etravirine tablets should not with carbamazepine, phenobarbital, or phenytoin as co- administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of etravirine tablets. Antifungals : fluconazole voriconazole ↑ etravirine ↔ fluconazole voriconazole Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of etravirine tablets or fluconazole is needed. Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of etravirine tablets or voriconazole is needed. Antifungals : itraconazole ketoconazole posaconazole ↑ etravirine ↓ itraconazole ↓ ketoconazole ↔ posaconazole Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and etravirine tablets may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by etravirine tablets. Dose Adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co- administered drugs. Antiinfective : clarithromycin ↑ etravirine ↓ clarithromycin ↑ 14-OH- clarithromycin Clarithromycin exposure was decreased by etravirine tablets; however, concentrations of the active metabolite, 14- hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered for the treatment of MAC. Antimalarial : artemether/lumefantrine ↔ etravirine ↓ artemether ↓ dihydroartemisinin ↓ lumefantrine Caution is warranted when co-administering etravirine tablets and artemether/lumefantrine as it is unknown whether the decrease in exposure of artemether or its active metabolite, dihydroartemisinin, could result in decreased antimalarial efficacy. No dose adjustment is needed for etravirine tablets. Antimycobacterials: rifampin rifapentine ↓ etravirine Rifampin and rifapentine are potent inducers of CYP450 enzymes. Etravirine tablets should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of etravirine tablets. Antimycobacterial: rifabutin ↓ etravirine ↓ rifabutin ↓ 25- O - desacetylrifabutin If etravirine tablets are NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg once daily is recommended. If etravirine tablets are co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure. Benzodiazepine: diazepam ↑ diazepam Concomitant use of etravirine tablets with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed. Corticosteroid : dexamethasone (systemic) ↓ etravirine Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of etravirine tablets. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use. Herbal products : St. John's wort ( Hypericum perforatum ) ↓ etravirine Concomitant use of etravirine tablets with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of etravirine tablets. Etravirine tablets and products containing St. John's wort should not be co-administered. Hepatitis C virus (HCV) direct-acting antivirals : daclatasvir ↓ daclatasvir Co-administration of etravirine tablets with daclatasvir may decrease daclatasvir concentrations. Increase the daclatasvir dose to 90 mg once daily. elbasvir/grazoprevir ↓ elbasvir ↓ grazoprevir Co-administration of etravirine tablets with elbasvir/grazoprevir may decrease elbasvir and grazoprevir concentrations, leading to reduced therapeutic effect of elbasvir/grazoprevir. Co-administration is not recommended. simeprevir ↓ simeprevir Co-administration of etravirine tablets with simeprevir may decrease simeprevir concentrations. Co- administration is not recommended. HMG-CoA reductase inhibitors : atorvastatin ↔ etravirine ↓ atorvastatin ↑ 2-OH-atorvastatin The combination of etravirine tablets and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response. pravastatin rosuvastatin ↔ etravirine ↔ pravastatin ↔ rosuvastatin No interaction between pravastatin, rosuvastatin and etravirine tablets are expected. Lovastatin simvastatin fluvastatin pitavastatin ↓ lovastatin ↓ simvastatin ↑ fluvastatin ↑ pitavastatin Lovastatin and simvastatin are CYP3A substrates and co-administration with etravirine tablets may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin and pitavastatin are metabolized by CYP2C9 and co-administration with etravirine tablets may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary. Immunosuppressants : cyclosporine Sirolimus tacrolimus ↓ immunosuppressant Etravirine tablets and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected. Narcotic analgesics/treatment of opioid dependence: buprenorphine buprenorphine/naloxone methadone ↔ etravirine ↓ buprenorphine ↔ Norbuprenorphine ↔ methadone Etravirine tablets and buprenorphine (or buprenorphine/naloxone) can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as buprenorphine (or buprenorphine/naloxone) maintenance therapy may need to be adjusted in some patients. Etravirine tablets and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients. Phosphodiesterase type 5 (PDE-5) inhibitors : sildenafil tadalafil vardenafil ↓ sildenafil ↓ N-desmethyl- sildenafil Etravirine tablets and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect. Platelet aggregation inhibitors: clopidogrel ↓ clopidogrel (active) metabolite Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co- administered with etravirine tablets. Alternatives to clopidogrel should be considered. 7.4 Drugs Without Clinically Significant Interactions with Etravirine Tablets In addition to the drugs included in Table 4, the interaction between etravirine tablets and the following drugs were evaluated in clinical studies and no dose adjustment is needed for either drug [see Clinical Pharmacology (12.3) ] : didanosine, enfuvirtide (ENF), ethinylestradiol/norethindrone, omeprazole, paroxetine, raltegravir, ranitidine, and tenofovir disoproxil fumarate. 7.1 Potential for Other Drugs to Affect Etravirine Tablets Etravirine is a substrate of CYP3A, CYP2C9, and CYP2C19. Therefore, co-administration of etravirine tablets with drugs that induce or inhibit CYP3A, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of etravirine tablets (see Table 4) [see Clinical Pharmacology (12.3) ]. 7.2 Potential for Etravirine Tablets to Affect Other Drugs Etravirine is an inducer of CYP3A and inhibitor of CYP2C9, CYP2C19 and P-glycoprotein (P-gp). Therefore, co-administration of drugs that are substrates of CYP3A, CYP2C9 and CYP2C19 or are transported by P-gp with etravirine tablets may alter the therapeutic effect or adverse reaction profile of the co-administered drug(s) (see Table 4) [see Clinical Pharmacology (12.3) ]. 7.3 Significant Drug Interactions Table 4 shows significant drug interactions based on which, alterations in dose or regimen of etravirine tablets and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with etravirine tablets are also included in Table 4 [see Clinical Pharmacology (12.3) ] . Table 4: Significant Drug Interactions Concomitant Drug Class: Drug Name Effect on Concentration of Etravirine or Concomitant Drug Clinical Comment ↑ = increase; ↓ = decrease; ↔ = no change HIV-antiviral agents: integrase strand inhibitors dolutegravir The interaction between INTELENCE and the drug was evaluated in a clinical study. All other drug interactions shown are predicted. ↓ dolutegravir ↔ etravirine Etravirine significantly reduced plasma concentrations of dolutegravir. Using cross - study comparisons to historical pharmacokinetic data for etravirine, dolutegravir did not appear to affect the pharmacokinetics of etravirine. dolutegravir/darunavir/ritonavir ↓ dolutegravir ↔ etravirine The effect of etravirine on dolutegravir plasma concentrations was mitigated by co- administration of darunavir/ritonavir or lopinavir/ritonavir, and is expected to be mitigated by atazanavir/ritonavir. dolutegravir/lopinavir/ritonavir ↔ dolutegravir ↔ etravirine Dolutegravir should only be used with etravirine tablets when co- administered with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. HIV-antiviral agents: non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz nevirapine ↓ etravirine Combining two NNRTIs has not been shown to be beneficial. Concomitant use of etravirine tablets with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of Etravirine and loss of therapeutic effect of etravirine tablets. Co-administration of etravirine tablets and other NNRTIs is not recommended. delavirdine rilpivirine ↓ etravirine ↓ rilpivirine ↔ etravirine Combining two NNRTIs has not been shown to be beneficial. Etravirine tablets and delavirdine should not be co-administered. Combining two NNRTIs has not been shown to be beneficial. Co- administration of etravirine tablets and rilpivirine is not recommended. HIV-antiviral agents: protease inhibitors (PIs) atazanavir (without ritonavir) atazanavir/ritonavir atazanavir/cobicistat darunavir/ritonavir darunavir/cobicistat fosamprenavir (without ritonavir) fosamprenavir/ritonavir indinavir (without ritonavir) lopinavir/ritonavir ↓ atazanavir ↓ atazanavir ↔ etravirine ↓ atazanavir ↓ cobicistat ↓ etravirine ↓ cobicistat darunavir: effect unknown ↑ amprenavir ↑ amprenavir ↓ indinavir ↓ etravirine Co-administration of etravirine tablets and atazanavir without low- dose ritonavir is not recommended. Concomitant use of etravirine tablets with atazanavir/ritonavir decreased atazanavir Cmin but it is not considered clinically relevant. The mean systemic exposure (AUC) of etravirine after co-administration of etravirine tablets with atazanavir/ritonavir in HIV-infected subjects was similar to the mean systemic exposure of etravirine observed in the Phase 3 trials after co-administration of etravirine tablets and darunavir/ritonavir (as part of the background regimen). Etravirine tablets and atazanavir/ritonavir can be co-administered without dose adjustments. Co-administration of etravirine tablets with atazanavir/cobicistat is not recommended because it may result in loss of therapeutic effect and development of resistance to atazanavir. The mean systemic exposure (AUC) of etravirine was reduced when etravirine tablets was co-administered with darunavir/ritonavir. Because all subjects in the Phase 3 trials received darunavir/ritonavir as part of the background regimen and Etravirine exposures from these trials were determined to be safe and effective, etravirine tablets and darunavir/ritonavir can be co-administered without dose adjustments. Co-administration of etravirine tablets with darunavir/cobicistat is not recommended because it may result in loss of therapeutic effect and development of resistance to darunavir. Concomitant use of etravirine tablets with fosamprenavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of amprenavir. Co-administration of etravirine tablets and fosamprenavir without low-dose ritonavir is not recommended. Due to a significant increase in the systemic exposure of amprenavir, the appropriate doses of the combination of etravirine tablets and fosamprenavir /ritonavir have not been established. Co- administration of etravirine tablets and fosamprenavir/ritonavir is not recommended. Concomitant use of etravirine tablets with indinavir without low-dose ritonavir may cause a significant alteration in the plasma concentration of indinavir. Co-administration of etravirine tablets and indinavir without low- dose ritonavir is not recommended. The mean systemic exposure (AUC) of Etravirine was reduced after co-administration of etravirine tablets with lopinavir/ritonavir (tablet). Because the reduction in the mean systemic exposures of etravirine in the presence of lopinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, etravirine tablets and lopinavir/ritonavir can be co-administered without dose adjustments. nelfinavir (without ritonavir) ritonavir saquinavir/ritonavir tipranavir/ritonavir ↑ nelfinavir ↓ etravirine ↓ etravirine ↓ etravirine Concomitant use of etravirine tablets with nelfinavir without low- dose ritonavir may cause a significant alteration in the plasma concentration of nelfinavir. Co- administration of etravirine tablets and nelfinavir without low- dose ritonavir is not recommended. Concomitant use of etravirine tablets with ritonavir 600 mg twice daily may cause a significant decrease in the plasma concentration of Etravirine and loss of therapeutic effect of etravirine tablets. Co-administration of etravirine tablets and ritonavir 600 mg twice daily is not recommended. The mean systemic exposure (AUC) of etravirine was reduced when etravirine tablets were co-administered with saquinavir/ ritonavir. Because the reduction in the mean systemic exposures of etravirine in the presence of saquinavir/ritonavir is similar to the reduction in mean systemic exposures of etravirine in the presence of darunavir/ritonavir, etravirine tablets and saquinavir/ritonavir can be co-administered without dose adjustments. Concomitant use of etravirine tablets with tipranavir/ritonavir may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of etravirine tablets. Co-administration of etravirine tablets and tipranavir/ritonavir is not recommended. CCR5 antagonists maraviroc maraviroc/darunavir/ritonavir The reference for etravirine exposure is the pharmacokinetic parameters of etravirine in the presence of darunavir/ritonavir. ↔ etravirine ↓ maraviroc ↑ maraviroc When etravirine tablets are co-administered with maraviroc in the absence of a potent CYP3A inhibitor (e.g., ritonavir boosted protease inhibitor), the recommended dose of maraviroc is 600 mg twice daily. No dose adjustment of etravirine tablets is needed. When etravirine tablets are co-administered with maraviroc in the presence of a potent CYP3A inhibitor (e.g., protease inhibitor), the recommended dose of maraviroc is 150 mg twice daily. No dose adjustment of etravirine tablets is needed. Other agents Antiarrhythmics : digoxin amiodarone bepridil disopyramide flecainide lidocaine (systemic) mexiletine propafenone quinidine ↔ etravirine ↑ digoxin ↓ antiarrhythmics For patients who are initiating a combination of etravirine tablets and digoxin, the lowest dose of digoxin should initially be prescribed. For patients on a stable digoxin regimen and initiating etravirine tablets, no dose adjustment of either etravirine tablets or digoxin is needed. The serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect. Concentrations of these antiarrhythmics may be decreased when co- administered with etravirine tablets. Etravirine tablets and antiarrhythmics should be co-administered with caution. Drug concentration monitoring is recommended, if available. Anticoagulant : warfarin ↑ anticoagulants Warfarin concentrations may be increased when co-administered with etravirine tablets. The international normalized ratio (INR) should be monitored when warfarin is combined with etravirine tablets. Anticonvulsants : carbamazepine phenobarbital phenytoin ↓ etravirine Carbamazepine, phenobarbital and phenytoin are inducers of CYP450 enzymes. Etravirine tablets should not with carbamazepine, phenobarbital, or phenytoin as co- administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of etravirine tablets. Antifungals : fluconazole voriconazole ↑ etravirine ↔ fluconazole voriconazole Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of etravirine tablets or fluconazole is needed. Co-administration of etravirine and voriconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and voriconazole should be co-administered with caution. No dose adjustment of etravirine tablets or voriconazole is needed. Antifungals : itraconazole ketoconazole posaconazole ↑ etravirine ↓ itraconazole ↓ ketoconazole ↔ posaconazole Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and etravirine tablets may increase plasma concentrations of etravirine. Simultaneously, plasma concentrations of itraconazole or ketoconazole may be decreased by etravirine tablets. Dose Adjustments for itraconazole, ketoconazole or posaconazole may be necessary depending on the other co- administered drugs. Antiinfective : clarithromycin ↑ etravirine ↓ clarithromycin ↑ 14-OH- clarithromycin Clarithromycin exposure was decreased by etravirine tablets; however, concentrations of the active metabolite, 14- hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered for the treatment of MAC. Antimalarial : artemether/lumefantrine ↔ etravirine ↓ artemether ↓ dihydroartemisinin ↓ lumefantrine Caution is warranted when co-administering etravirine tablets and artemether/lumefantrine as it is unknown whether the decrease in exposure of artemether or its active metabolite, dihydroartemisinin, could result in decreased antimalarial efficacy. No dose adjustment is needed for etravirine tablets. Antimycobacterials: rifampin rifapentine ↓ etravirine Rifampin and rifapentine are potent inducers of CYP450 enzymes. Etravirine tablets should not be used with rifampin or rifapentine as co-administration may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of etravirine tablets. Antimycobacterial: rifabutin ↓ etravirine ↓ rifabutin ↓ 25- O - desacetylrifabutin If etravirine tablets are NOT co-administered with a protease inhibitor/ritonavir, then rifabutin at a dose of 300 mg once daily is recommended. If etravirine tablets are co-administered with darunavir/ritonavir, lopinavir/ritonavir or saquinavir/ritonavir, then rifabutin should not be co-administered due to the potential for significant reductions in etravirine exposure. Benzodiazepine: diazepam ↑ diazepam Concomitant use of etravirine tablets with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed. Corticosteroid : dexamethasone (systemic) ↓ etravirine Systemic dexamethasone induces CYP3A and can decrease etravirine plasma concentrations. This may result in loss of therapeutic effect of etravirine tablets. Systemic dexamethasone should be used with caution or alternatives should be considered, particularly for long-term use. Herbal products : St. John's wort ( Hypericum perforatum ) ↓ etravirine Concomitant use of etravirine tablets with products containing St. John's wort may cause significant decreases in etravirine plasma concentrations and loss of therapeutic effect of etravirine tablets. Etravirine tablets and products containing St. John's wort should not be co-administered. Hepatitis C virus (HCV) direct-acting antivirals : daclatasvir ↓ daclatasvir Co-administration of etravirine tablets with daclatasvir may decrease daclatasvir concentrations. Increase the daclatasvir dose to 90 mg once daily. elbasvir/grazoprevir ↓ elbasvir ↓ grazoprevir Co-administration of etravirine tablets with elbasvir/grazoprevir may decrease elbasvir and grazoprevir concentrations, leading to reduced therapeutic effect of elbasvir/grazoprevir. Co-administration is not recommended. simeprevir ↓ simeprevir Co-administration of etravirine tablets with simeprevir may decrease simeprevir concentrations. Co- administration is not recommended. HMG-CoA reductase inhibitors : atorvastatin ↔ etravirine ↓ atorvastatin ↑ 2-OH-atorvastatin The combination of etravirine tablets and atorvastatin can be given without dose adjustments, however, the dose of atorvastatin may need to be altered based on clinical response. pravastatin rosuvastatin ↔ etravirine ↔ pravastatin ↔ rosuvastatin No interaction between pravastatin, rosuvastatin and etravirine tablets are expected. Lovastatin simvastatin fluvastatin pitavastatin ↓ lovastatin ↓ simvastatin ↑ fluvastatin ↑ pitavastatin Lovastatin and simvastatin are CYP3A substrates and co-administration with etravirine tablets may result in lower plasma concentrations of the HMG-CoA reductase inhibitor. Fluvastatin and pitavastatin are metabolized by CYP2C9 and co-administration with etravirine tablets may result in higher plasma concentrations of the HMG-CoA reductase inhibitor. Dose adjustments for these HMG-CoA reductase inhibitors may be necessary. Immunosuppressants : cyclosporine Sirolimus tacrolimus ↓ immunosuppressant Etravirine tablets and systemic immunosuppressants should be co-administered with caution because plasma concentrations of cyclosporine, sirolimus, or tacrolimus may be affected. Narcotic analgesics/treatment of opioid dependence: buprenorphine buprenorphine/naloxone methadone ↔ etravirine ↓ buprenorphine ↔ Norbuprenorphine ↔ methadone Etravirine tablets and buprenorphine (or buprenorphine/naloxone) can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as buprenorphine (or buprenorphine/naloxone) maintenance therapy may need to be adjusted in some patients. Etravirine tablets and methadone can be co-administered without dose adjustments, however, clinical monitoring for withdrawal symptoms is recommended as methadone maintenance therapy may need to be adjusted in some patients. Phosphodiesterase type 5 (PDE-5) inhibitors : sildenafil tadalafil vardenafil ↓ sildenafil ↓ N-desmethyl- sildenafil Etravirine tablets and sildenafil can be co-administered without dose adjustments, however, the dose of sildenafil may need to be altered based on clinical effect. Platelet aggregation inhibitors: clopidogrel ↓ clopidogrel (active) metabolite Activation of clopidogrel to its active metabolite may be decreased when clopidogrel is co- administered with etravirine tablets. Alternatives to clopidogrel should be considered. 7.4 Drugs Without Clinically Significant Interactions with Etravirine Tablets In addition to the drugs included in Table 4, the interaction between etravirine tablets and the following drugs were evaluated in clinical studies and no dose adjustment is needed for either drug [see Clinical Pharmacology (12.3) ] : didanosine, enfuvirtide (ENF), ethinylestradiol/norethindrone, omeprazole, paroxetine, raltegravir, ranitidine, and tenofovir disoproxil fumarate.