Rilpivirine

1 INDICATIONS AND USAGE Rilpivirine tablets are a human immunodeficiency virus type 1 (HIV-1) specific, non-nucleoside reverse transcriptase inhibitor (NNRTI) indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-naïve patients 12 years of age and older and weighing at least 35 kg with HIV-1 RNA less than or equal to 100,000 copies/mL ( 1.1 ) Limitations of Use: More rilpivirine treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA≥50 copies/mL) compared to rilpivirine treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL. ( 1.1 , 14 ) Rilpivirine tablets are indicated in combination with VOCABRIA (cabotegravir), for short-term treatment of HIV-1 infection in adults and adolescents 12 years and older and weighing at least 35 kg who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine. ( 1.2 ) 1.1 Treatment of HIV-1 in Treatment-Naïve Patients Rilpivirine tablets, in combination with other antiretroviral agents, are indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-naïve patients 12 years of age and older and weighing at least 35 kg with plasma HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy. Limitations of Use More rilpivirine treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure (HIV-1 RNA ≥50 copies/mL) compared to rilpivirine treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL [see Clinical Studies ( 14.1 )] . Additional pediatric use information is approved for Janssen Products LP's Edurant (Rilpivirine) tablets. However, due to Janssen Products LP's marketing exclusivity rights, this drug product is not labeled with that information. 1.2 Treatment of HIV-1 in Combination with Cabotegravir Rilpivirine tablets are indicated in combination with VOCABRIA (cabotegravir) for short-term treatment of HIV-1 infection in adults and adolescents 12 years and older and weighing at least 35 kg who are virologically suppressed (HIV-1 RNA less than 50 copies/mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine, for use as [see Dosage and Administration ( 2.6 )] : oral lead-in to assess the tolerability of rilpivirine prior to administration of rilpivirine extended-release injectable suspension, a component of CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension). oral therapy for patients who will miss planned injection dosing with CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension).

2 DOSAGE AND ADMINISTRATION One 25 mg rilpivirine tablet taken once daily with a meal for patients weighing at least 35 kg. ( 2.2 ) Do not substitute rilpivirine tablets and EDURANT PED tablets for oral suspension on a milligram-per-milligram basis due to differing pharmacokinetic profiles. ( 2.1 , 5.6 ) See full prescribing information for dosing information when used in combination with cabotegravir. ( 2.6 ) For pregnant patients who are already on a stable rilpivirine regimen prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) the recommended dosage in adults and pediatric patients weighing more than 35 kg is one 25 mg tablet once daily taken orally with a meal. ( 2.5 , 12.3 ) Rifabutin coadministration: Take two 25 mg tablets of rilpivirine once daily with a meal for the duration of the rifabutin coadministration. ( 2.7 ) 2.1 Overview of Dosage Form Rilpivirine is available in: Rilpivirine 25 mg film-coated tablets for adults and pediatric patients weighing at least 35 kg Do not substitute rilpivirine tablets and EDURANT PED tablets for oral suspension on a milligram-per-milligram basis due to differing pharmacokinetic profiles. [see Warnings and Precautions (5.6)] . Take rilpivirine tablet once daily with a meal in combination with other antiretrovirals [see Clinical Pharmacology (12.3)] . Additional pediatric use information is approved for Janssen Products LP's Edurant (Rilpivirine) tablets. However, due to Janssen Products LP's marketing exclusivity rights, this drug product is not labeled with that information. 2.2 Recommended Dosage in Treatment-Naïve Adult Patients The recommended dosage of rilpivirine in adult patients is one 25 mg tablet taken orally once daily with a meal [see Use in Specific Populations (8.1) and Clinical Pharmacology ( 12.3 )] . 2.3 Recommended Dosage in Treatment-Naïve Pediatric Patients 12 Years of Age and Older and Weighing at least 35 kg The recommended dosage of rilpivirine tablets in pediatric patients 12 years of age and older and weighing at least 35 kg is based on body weight (see Table 1). Rilpivirine tablets should be taken orally once daily with a meal [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)] . Table 1: Recommended Dosage of Rilpivirine Tablets for Pediatric Patients Body Weight (kg) Rilpivirine 25 mg Tablets Total Daily Dose Greater than or equal to 35 kg 1 tablet once daily 25 mg rilpivirine tablet once daily Additional pediatric use information is approved for Janssen Products LP's Edurant (Rilpivirine) tablets. However, due to Janssen Products LP's marketing exclusivity rights, this drug product is not labeled with that information. 2.5 Recommended Dosage During Pregnancy For pregnant patients who are already on a stable rilpivirine tablets regimen prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) the recommended dosage in adults and pediatric patients weighing at least 35 kg is one 25 mg tablet once daily taken orally with a meal . Refer to Table 1 for dosing recommendations for pediatric patients [see Dosage and Administration ( 2 . 2 , 2 . 3 )]. Lower exposures of rilpivirine were observed during pregnancy, therefore viral load should be monitored closely [see Use in Specific Populations ( 8.1 ) and Clinical Pharmacology ( 12.3 )] . Additional pediatric use information is approved for Janssen Products LP's Edurant (Rilpivirine) tablets. However, due to Janssen Products LP's marketing exclusivity rights, this drug product is not labeled with that information. 2.6 Recommended Dosage in Combination with Cabotegravir in Adults and Adolescents 12 Years of Age and Older and Weighing at least 35 kg Consult the prescribing information for CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) before initiating rilpivirine tablets to ensure therapy with CABENUVA is appropriate Oral Lead-In Dosing to Assess T…

5 WARNINGS AND PRECAUTIONS Skin and Hypersensitivity Reactions: Severe skin and hypersensitivity reactions have been reported during postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), with rilpivirine-containing regimens. Immediately discontinue treatment if hypersensitivity or rash with systemic symptoms or elevations in hepatic serum biochemistries develop and closely monitor clinical status, including hepatic serum biochemistries. ( 5.1 ) Hepatotoxicity: Hepatic adverse events have been reported in patients with underlying liver disease, including hepatitis B or C virus co-infection, or in patients with elevated baseline transaminases. A few cases of hepatotoxicity have occurred in virus co-infection, or marked elevations in transaminase. Also consider monitoring liver functions tests in patients without pre-existing hepatic dysfunction or other risk factors. ( 5.2 ) Depressive Disorders: Severe depressive disorders have been reported. Immediate medical evaluation is recommended for severe depressive disorders. ( 5.3 ) Patients may develop immune reconstitution syndrome. ( 5.5 ) 5.1 Skin and Hypersensitivity Reactions Severe skin and hypersensitivity reactions have been reported during the postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), with rilpivirine-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. During the Phase 3 clinical trials, treatment-related rashes with at least Grade 2 severity were reported in 3% of subjects receiving rilpivirine. No Grade 4 rash was reported. Overall, most rashes were Grade 1 or 2 and occurred in the first four to six weeks of therapy [see Adverse Reactions ( 6.1 and 6.2 )] . Discontinue rilpivirine tablets immediately if signs or symptoms of severe skin or hypersensitivity reactions develop, including but not limited to, severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis or eosinophilia. Clinical status including laboratory parameters should be monitored and appropriate therapy should be initiated. 5.2 Hepatotoxicity Hepatic adverse events have been reported in patients receiving a rilpivirine-containing regimen. Patients with underlying hepatitis B or C virus infection, or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations with use of rilpivirine. A few cases of hepatic toxicity have been reported in adult patients receiving a rilpivirine-containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Appropriate laboratory testing prior to initiating therapy and monitoring for hepatotoxicity during therapy with rilpivirine tablets are recommended in patients with underlying hepatic disease such as hepatitis B or C virus infection, or in patients with marked elevations in transaminases prior to treatment initiation. Liver enzyme monitoring should also be considered for patients without pre-existing hepatic dysfunction or other risk factors. 5.3 Depressive Disorders The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with rilpivirine tablets. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to rilpivirine tablets, and if so, to determine whether the risks of continued therapy outweigh the benefits During the Phase 3 trials in adults (N=1368) through 96 weeks, the incidence of depressive disorders (regardless of causality, severity) reported among rilpivirine (n=686) or efavirenz (n=682) was 9% and 8%,…

4 CONTRAINDICATIONS Rilpivirine tablets are contraindicated for coadministration with the drugs in Table 2 for which significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to rilpivirine tablets or to the class of NNRTIs [see Drug Interactions ( 7 ) and Clinical Pharmacology ( 12.3 )] . Table 2: Drugs That are Contraindicated with Rilpivirine Tablets Drug Class Contraindicated Drugs in Class Clinical Comment Anticonvulsants Carbamazepine Oxcarbazepine Phenobarbital Phenytoin Potential for significant decreases in rilpivirine plasma concentrations due to CYP3A enzyme induction, which may result in loss of virologic response. Antimycobacterials Rifampin Rifapentine Glucocorticoid (systemic) Dexamethasone (more than a single-dose treatment) Herbal Products St John's wort (Hypericum perforatum) Proton Pump Inhibitors e.g.,Esomeprazole Lansoprazole Omeprazole Pantoprazole Rabeprazole Potential for significant decreases in rilpivirine plasma concentrations due to gastric pH increase, which may result in loss of virologic response. Coadministration of rilpivirine tablets are contraindicated with drugs where significant decreases in rilpivirine plasma concentrations may occur, which may result in loss of virologic response and possible resistance and cross-resistance. ( 4 )

7 DRUG INTERACTIONS Rilpivirine is primarily metabolized by cytochrome P450 (CYP)3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Coadministration of rilpivirine tablets and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Coadministration of rilpivirine tablets and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Coadministration of rilpivirine tablets with drugs that increase gastric pH may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Rilpivirine tablets at the recommended doses are not likely to have a clinically relevant effect on the exposure of drugs metabolized by CYP enzymes. Table 6 shows the established and other potentially significant drug interactions based on which alterations in dose or regimen of rilpivirine tablets and/or coadministered drug may be recommended. Drugs that are not recommended for coadministration with rilpivirine tablets are also included in Table 6. [see Dosage and Administration ( 2 ), Contraindications ( 4 ), and Clinical Pharmacology ( 12.3 )]. Table 6: Established and Other Potentially Significant Drug Interactions: Alterations in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction [see Clinical Pharmacology (12.3)] ↑=increase, ↓=decrease, ↔=no change * The interaction between rilpivirine tablets and the drug was evaluated in a clinical study. All other drug-drug interactions shown are predicted. † This interaction study has been performed with a dose higher than the recommended dose for rilpivirine tablets assessing the maximal effect on the coadministered drug. The dosing recommendation is applicable to the recommended doses of rilpivirine once daily. Concomitant Drug Class: Drug Name Effect on Concentration of Rilpivirine or Concomitant Drug Clinical Comment Antacids: antacids (e.g., aluminum or magnesium hydroxide, calcium carbonate) ↔ rilpivirine (antacids taken at least 2 hours before or at least 4 hours after rilpivirine) ↓ rilpivirine (concomitant intake) The combination of rilpivirine tablets and antacids should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). Antacids should only be administered either at least 2 hours before or at least 4 hours after rilpivirine tablets. Anticonvulsants: carbamazepine oxcarbazepine phenobarbital phenytoin ↓ rilpivirine Coadministration is contraindicated with rilpivirine tablets [see Contraindications (4) ] Antimycobacterials: rifampin rifapentine ↓ rilpivirine Coadministration is contraindicated with rilpivirine tablets [see Contraindications (4) ] Antimycobacterials: rifabutin * ↓ rilpivirine Concomitant use of rilpivirine tablets with rifabutin may cause a decrease in the plasma concentrations of rilpivirine (induction of CYP3A enzymes). Throughout coadministration of rilpivirine tablets with rifabutin, the rilpivirine tablets dose should be increased from 25 mg once daily to 50 mg once daily. When rifabutin coadministration is stopped, the rilpivirine tablets dose should be decreased to 25 mg once daily. Azole Antifungal Agents: fluconazole itraconazole ketoconazole *† posaconazole voriconazole ↑ rilpivirine ↓ ketoconazole Concomitant use of rilpivirine tablets with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No rilpivirine dose adjustment is required when rilpivirine tablets are coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with rilpivirine tablets. Glucocorticoid (systemic): dexamethasone (more than a single-dose treatment) ↓ rilp…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to rilpivirine tablets during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1-800-258-4263. Risk Summary Available data from the APR show no difference in the overall risk of birth defects for rilpivirine compared with the background rate for major birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population (see Data) . 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 for major birth defects and miscarriage for the indicated population is unknown. Methodologic limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation. In a clinical trial, total rilpivirine exposures were generally lower during pregnancy compared to the postpartum period (see Data). In animal reproduction studies, no adverse developmental outcomes were observed when rilpivirine was administered orally at exposures up to 15 (rats) and 70 (rabbits) times the exposure in humans (≥12 years of age and weighing at least 32 kg) at the recommended dose of 25 mg once daily (see Data) . Clinical Considerations Dosing During Pregnancy and the Postpartum Period Based on the experience of HIV-1-infected pregnant women who completed a clinical trial through the postpartum period with a rilpivirine-based regimen, no dose adjustments are required for pregnant patients who are already on a stable rilpivirine tablets regimen prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL). [see Dosage and Administration ( 2.5 )]. Lower exposures of rilpivirine were observed during pregnancy, therefore viral load should be monitored closely [see Clinical Pharmacology ( 12.3 )] . Data Human Data Based on prospective reports to the APR of over 550 exposures to rilpivirine during the first trimester of pregnancy resulting in live births, there was no significant difference between the overall risk of birth defects with rilpivirine compared to the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of birth defects in live births was 1.4% (95% CI: 0.6% to 2.8%) and 1.5% (95% CI: 0.3% to 4.3%) following first and second/third trimester exposure, respectively, to rilpivirine-containing regimens. Rilpivirine in combination with a background regimen was evaluated in a clinical trial of 19 HIV-1 infected pregnant women during the second and third trimesters and postpartum. Each of the women were on a rilpivirine-based regimen at the time of enrollment. Twelve subjects completed the trial through the postpartum period (6 -12 weeks after delivery) and pregnancy outcomes are missing for six subjects. The exposure (C 0h and AUC) of total rilpivirine was approximately 30 to 40% lower during pregnancy compared with postpartum (6 -12 weeks). The protein binding of rilpivirine was similar (>99%) during second trimester, third trimester, and postpartum period. One subject discontinued the trial following spontaneous termination of the pregnancy at 25 weeks gestation due to suspected premature rupture of membranes. Among the 12 subjects who were virologically suppressed at baseline (less than 50 copies/mL), virologic response was preserved in 10 subjects (83.3%) through the third trimester visit and in 9 subjects (75%) through the 6 to12 week postpartum visit. Virologic outcomes during the third trimester visit were missing for two subjects who were withdrawn (one subject was nonadherent to the study drug and one subject …

6 ADVERSE REACTIONS The following adverse reactions are discussed below and in other sections of the labeling: Skin and Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )] Hepatotoxicity [see Warnings and Precautions ( 5.2 )] Depressive Disorders [see Warnings and Precautions ( 5.3 )] The most common adverse reactions to rilpivirine tablets (incidence >2%) of at least moderate to severe intensity (≥ Grade 2) were depressive disorders, headache, insomnia and rash. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Somerset Therapeutics, LLC at 1-800-417-9175 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 clinical practice. Clinical Trials Experience in Adults The safety assessment is based on the Week 96 pooled data from 1368 patients in the Phase 3 controlled trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naïve HIV-1 infected adult patients, 686 of whom received rilpivirine (25 mg once daily) [see Clinical Studies ( 14.1 )] . The median duration of exposure for patients in the rilpivirine arm and efavirenz arm was 104.3 and 104.1 weeks, respectively. Most adverse reactions occurred in the first 48 weeks of treatment. The proportion of subjects who discontinued treatment with rilpivirine tablets or efavirenz due to adverse reaction, regardless of severity, was 2% and 4%, respectively. The most common adverse reactions leading to discontinuation were psychiatric disorders: 10 (1%) subjects in the rilpivirine arm and 11 (2%) subjects in the efavirenz arm. Rash led to discontinuation in 1 (<1%) subject in the rilpivirine arm and 10 (2%) subjects in the efavirenz arm Common Adverse Reactions Adverse reactions of at least moderate intensity (≥Grade 2) reported in at least 2% of adult subjects are presented in Table 3. Selected laboratory abnormalities are included in Table 4. Table 3: Selected Adverse Reactions of at Least Moderate Intensity * (Grades 2–4) Occurring in at Least 2% of Antiretroviral Treatment-Naïve HIV-1 Infected Adult Subjects (Week 96 Analysis) N=total number of subjects per treatment group; BR=background regimen * Intensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity). † Includes adverse reactions reported as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicide ideation. System Organ Class, Preferred Term, % Pooled Data from the Phase 3 TMC278-C209 and TMC278-C215 Trials Rilpivirine + BR N=686 Efavirenz + BR N=682 Gastrointestinal Disorders Abdominal pain 2% 2% Nausea 1% 3% Vomiting 1% 2% General Disorders and Administration Site Conditions Fatigue 2% 2% Nervous System Disorders Headache 3% 4% Dizziness 1% 7% Psychiatric Disorders Depressive disorders † 5% 4% Insomnia 3% 4% Abnormal dreams 2% 4% Skin and Subcutaneous Tissue Disorders Rash 3% 11% No new adverse reaction terms were identified in adult subjects in the Phase 3 TMC278-C209 and TMC278-C215 trials between 48 weeks and 96 weeks nor in the Phase 2b TMC278-C204 trial through 240 weeks. The incidence of adverse events in the Phase 2b TMC278-C204 trial was similar to the Phase 3 trials through 96 weeks. Less Common Adverse Reactions Adverse reactions of at least moderate intensity (≥Grade 2) occurring in less than 2% of antiretroviral treatment-naïve subjects receiving rilpivirine are listed below by System Organ Class. Some adverse events have been included because of investigator's assessment of potential causal relationship and were considered serious or have been reported in more than 1 subject treated with rilpivirine Gastrointestinal Disorders…