etravirine

RECENT MAJOR CHANGES Indications and Usage (1) 11/2018 Dosage and Administration: Recommended Dosage During Pregnancy (2.2) 11/2018 Warnings and Precautions: Severe Skin and Hypersensitivity Reactions (5.1) 07/2019 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions (5.2) 11/2018 Immune Reconstitution Syndrome (5.3) 07/2019

1 INDICATIONS AND USAGE Etravirine tablets 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 )

2 DOSAGE AND ADMINISTRATION 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 …

3 DOSAGE FORMS AND STRENGTHS 25 mg white to off-white, oval shaped, uncoated tablets debossed with “A56” on one side and score on the other side. 100 mg white to off-white oval shaped, uncoated tablets debossed with “AC75” on one side and plain on the other side. 200 mg white to off-white, oval shaped, uncoated tablets debossed with “AC76” on one side and plain on the other side. Tablets: 25 mg, 100 mg, and 200 mg (3)

4 CONTRAINDICATIONS None. None. ( 4 )

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 Bionpharma Inc. at 1-888-235-BION or 1-888-235-2466 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. Clinical Trials Experience in Adults The safety assessment is based on all data from 1,203 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 (200 mg twice daily). In these pooled trials, the median exposure for subjects in the etravirine arm and placebo arm was 52.3 weeks and 51.0 weeks, respectively. Discontinuations due to adverse drug reactions (ADRs) were 5.2% in the etravirine 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 [see Warnings and Precautions (5.1) ] . A total of 2.2% of HIV-1-infected subjects in Phase 3 trials receiving etravirine 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 week to 2 weeks on continued therapy. The incidence of rash was higher in women compared to men in the etravirine 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-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 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 + 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 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 fai …

7 DRUG INTERACTIONS 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 Etravirine is a substrate of CYP3A, CYP2C9, and CYP2C19. Therefore, co-administration of Etravirine with drugs that induce or inhibit CYP3A, CYP2C9, and CYP2C19 may alter the therapeutic effect or adverse reaction profile of Etravirine (see Table 4 ) [see Clinical Pharmacology (12.3) ]. 7.2 Potential for Etravirine 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 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 and/or co-administered drug may be recommended. Drugs that are not recommended for co-administration with Etravirine 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 Etravirine 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 should only be used with Etravirine when co-administered with atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir. dolutegravir/lopinavir /ritonavir ↔ dolutegravir ↔ etravirine 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 with efavirenz or nevirapine may cause a significant decrease in the plasma concentrations of etravirine and loss of therapeutic effect of Etravirine. Co-administration of Etravirine and other NNRTIs is not recommended. delavirdine ↑ etravirine Combining two NNRTIs has not been shown to be beneficial. Etravirine and delavirdine should not be co-administered. rilpivirine ↓ rilpivirine ↔ etravirine Combining two NNRTIs has not been shown to be beneficial. Co-administration of Etravirine and rilpivirine is not recommended. HIV-antiviral agents: protease inhibitors (PIs) atazanavir (without ritonavir) ↓ atazanavir Co-administration of Etravirine and atazanavir without low-dose ritonavir is not recommended. atazanavir/ritonavir ↓ atazanavir ↔ etravirine Concomitant use of Etravirine with atazanavir/ritonavir decreased atazanavir C min but it is not considered clinically relevant. The mean systemic exposure (AUC) of etravirine after co-administration of Etravirine 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 and darunavir/ritonavir (as part of the background regimen). Etravirine and atazanavir/ritonavir can be co-administered without dose adjustments. atazanavir/cobicistat ↓ atazanavir ↓ cobic …

8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission. ( 8.2 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to etravirine during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Prospective pregnancy data from clinical trials and the APR are not sufficient to adequately assess the risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. Etravirine use during pregnancy has been evaluated in a limited number of individuals as reported by the APR, and available data show 1 birth defect in 66 first trimester exposures to etravirine-containing regimens (see Data) . The estimated background rate for major birth defects is 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk of major birth defects and miscarriage for the indicated population is unknown. In animal reproduction studies, no adverse developmental effects were observed with orally administered etravirine at exposures equivalent to those at the maximum recommended human dose (MRHD) of 400 mg daily (see Data) . Data Human Data Based on prospective reports to the APR of 116 live births following exposure to etravirine-containing regimens during pregnancy (including 66 exposed in the first trimester and 38 exposed in the second/third trimester), the number of birth defects in live births for etravirine was 1 out of 66 with first trimester exposure and 0 out of 38 with second/third trimester exposure. Prospective reports from the APR of overall major birth defects in pregnancies exposed to etravirine is compared with a U.S. background major birth defect rate. Methodological limitations of the APR include the use of MACDP as the external comparator group. Limitations of using an external comparator include differences in methodology and populations, as well as confounding due to the underlying disease; these limitations preclude an accurate comparison of outcomes. Etravirine (200 mg twice daily) in combination with other antiretroviral agents was evaluated in a clinical trial enrolling 15 pregnant subjects during the second and third trimesters of pregnancy and postpartum. Thirteen subjects completed the trial through postpartum period (6 weeks to 12 weeks after delivery). The pharmacokinetic data demonstrated that exposure to total etravirine was generally higher during pregnancy compared with postpartum [see Clinical Pharmacology (12.3) ] . Among subjects who were virologically suppressed (HIV-1 RNA less than 50 copies/mL) at baseline (9/13), virologic suppression was maintained through the third trimester and postpartum period. Among subjects with HIV-1 RNA greater than 50 copies/mL and less than 400 copies/mL at baseline (3/13), viral loads remained less than 400 copies/mL. In one subject with HIV-1 RNA greater than 1,000 copies/mL at baseline (1/13), HIV-1 RNA remained greater than 1,000 copies/mL during the study period. Thirteen infants were born to 13 HIV-infected pregnant individuals in this study. HIV-1 test results were not available for 2 infants. Among the eleven infants with HIV-1 test results available, who were born to 11 HIV-infected pregnant individuals who completed the study, all had test results that were negative for HIV-1 at the time of delivery. No unexpected safety findings were observed compared with the known safety profile of etravirine in non-pregnant adults. Animal Data Reproductive and developmental toxicity studies were performed in rats (at 250 mg/kg/day, 500 mg/kg/day and 1,000 mg/kg/day) and rabbits (at 125 mg/kg/day, 2 …

12.1 Mechanism of Action Etravirine is an antiretroviral drug [see Microbiology (12.4) ] .

11 DESCRIPTION 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 C 20 H 15 BrN 6 O 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 colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate and microcrystalline cellulose. Etravirine 200 mg tablets are available as white to off-white, biconvex, oblong tablets for oral administration. Each 200 mg tablet contains 200 mg of etravirine and the inactive ingredients colloidal silicon dioxide, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose and silicified microcrystalline cellulose. Chemical Structure

10 OVERDOSAGE There is no specific antidote for overdose with etravirine tablets. Human experience of overdose with etravirine tablets is limited. The highest dose studied in healthy volunteers was 400 mg once daily. Treatment of overdose with etravirine tablets consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Because etravirine is highly protein bound, dialysis is unlikely to result in significant removal of the active substance.

16 HOW SUPPLIED/STORAGE AND HANDLING Etravirine Tablets USP, 25 mg are supplied as white to off-white, oval shaped, uncoated tablets, debossed with “A56” on one side and score on the other side. They are available as follows: Bottles of 120 with child-resistant closure: NDC 60219-1720-7 Each bottle contains 2 desiccant pouches. Etravirine Tablets USP, 100 mg are supplied as white to off-white, oval shaped, uncoated tablets, debossed with “AC75” on one side and plain on the other side. They are available as follows: Bottles of 120 with child-resistant closure: NDC 60219-1721-7 Each bottle contains 3 desiccant pouches. Etravirine Tablets USP, 200 mg are supplied as white to off-white, oval shaped, uncoated tablets, debossed with “AC76” on one side and plain on the other side. They are available as follows: Bottles of 60 with child-resistant closure: NDC 60219-1722-6 Each bottle contains 3 desiccant pouches. Store etravirine tablets at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP controlled room temperature]. Store in the original bottle. Keep the bottle tightly closed in order to protect from moisture. Do not remove the desiccant pouches.