Rilpivirine

RECENT MAJOR CHANGES Warnings and Precautions 03/2024 Different Formulations Are Not Substitutable ( 5.6 )

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 …

3 DOSAGE FORMS AND STRENGTHS Rilpivirine 25 mg Film-Coated Tablets 25 mg white to off-white, film-coated, round, biconvex, tablet of 6.5 mm, debossed with "RP" on one side and "25" on the other side. Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of rilpivirine. Rilpivirine: 25 mg tablets ( 3 )

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 )

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 (1.3-≤1.8 x ULN 1% 1% Grade 3 >1.8-≤3.4 x ULN 3.4 x ULN 0 2.5-≤5.0 x ULN 4% 7% Grade 3 >5.0-≤10.0 x ULN 2% 2% Grade 4 >10.0 x ULN 1% 1% Increased ALT Grade 1 ≥1.25-≤2.5 x ULN 18% 20% Grade 2 >2.5-≤5.0 x ULN 5% 7% Grade 3 >5.0-≤10.0 x ULN 1% 2% Grade 4 >10.0 x ULN 1% 1% Increased Total Bilirubin Grade 1 ≥1.1-≤1.5 x ULN 5% 1.5-≤2.5 x ULN 3% 1% Grade 3 >2.5-≤5.0 x ULN 1% 5.0 x ULN 0 0 Increased Total Cholesterol (fasted) Grade 1 5.18-6.19 mmol/L 200-239 mg/dL 17% 31% Grade 2 6.20-7.77 mmol/L 240-300 mg/dL 7% 19% Grade 3 >7.77 mmol/L >300 mg/dL 13.56 mmol/L >1,200 mg/dL 0 1% Adrenal Function In the pooled Phase 3 trials, at Week 96, there was an overall mean change from baseline in basal cortisol of -0.69 (-1.12, 0.27) micrograms/dL in the rilpivirine group and of -0.02 (-0.48, 0.44) micrograms/dL in the efavirenz group In the rilpivirine group, 43/588 (7%) of subjects with a normal 250 micrograms ACTH stimulation test at baseline developed an abnormal 250 micrograms ACTH stimulation test (peak cortisol level <18.1 micrograms/dL) during the trial compared to 18/561 (3%) in the efavirenz group. Of the subjects who developed an abnormal 250 micrograms ACTH stimulation test during the trial, fourteen subjects in the rilpivirine group and nine subjects in the efavirenz group had an abnormal 250 micrograms ACTH stimulation test at Week 96. Overall, there were no serious adverse events, deaths, or treatment discontinuations that could clearly be attributed to adrenal insufficiency. The clinical significance of the higher abnormal rate of 250 micrograms ACTH stimulation tests in the rilpivirine group is not known. Serum Creatinine In the pooled Phase 3 trials, an increase in serum creatinine was observed over the 96 weeks of treatment with rilpivirine. Most of this increase occurred within the first four weeks of treatment, with a mean change of 0.1 mg/dL (range: -0.3 mg/dL to 0.6 mg/dL) observed after 96 weeks of treatment. In subjects who entered the trial with mild or moderate renal impairment, the serum creatinine increase observed was similar to that seen in subjects with normal renal function. These changes are not consi …

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 USE IN SPECIFIC POPULATIONS Pregnancy: Total rilpivirine exposures were generally lower during pregnancy compared to the postpartum period. ( 2.5 , 8.1 , 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. 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 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 withdrew consent). Among the 10 infants with HIV test results available, born to 10 HIV-infected pregnant women, all had test results that were negative for HIV-1 at the time of delivery and up to 16 weeks postpartum. All 10 infants received antiretroviral prophylactic treatment with zidovudine. Rilpivirine was well tolerated during pregnancy and postpartum. There were no new safety findings compared with the known safety profile of rilpivirine in HIV-1-infected adults. Animal Data Rilpivirine was administered orally to pregnant rats (40, 120, or 400 mg per kg per day) and rabbits (5, 10, or 20 mg per kg per day) through organogenesis (on gestation Days 6 through 17, and 6 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with rilpivirine in rats and rabbits at exposures 15 (rats) and 70 (rabbits) times higher than the exposure in humans (≥12 years of age and weighing >32 kg) at the recommended dose of 25 mg once daily. In a pre- and postnatal development study, rilpivirine was administered orally up to 400 mg/kg/day through lactation. No adverse effects were noted in the offspring at maternal exposures up to 63 times the exposure in humans (≥12 years of age and weighing >32 kg) at the recommended dose of 25 mg daily. 8.2 Lactation Risk Summary Based on limited data after oral administration, rilpivirine is present in human breast milk. The data do not allow determination of the amount of rilpivirine that is transferred to milk. There are no data on the effects on a breastfed infant, or the effects on milk production. Rilpivirine is present in rat milk ( see Data ). Potential risks of breastfeeding include: (( 1 ) HIV transmission (in HIV-negative infants), ( 2 ) developing viral resistance (in HIV-positive infants), and ( 3 ) adverse reactions in a …

12.1 Mechanism of Action Rilpivirine is an antiviral drug [see Microbiology ( 12.4 )] .

11 DESCRIPTION Rilpivirine tablets are a non-nucleoside reverse transcriptase inhibitor (NNRTI) of human immunodeficiency virus type 1 (HIV-1). The chemical name for rilpivirine hydrochloride is 4-[[4-[[4-[(E)-2-cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile monohydrochloride. Its molecular formula is C 22 H 18 N 6 • HCl and its molecular weight is 402.88. Rilpivirine hydrochloride has the following structural formula: Rilpivirine hydrochloride is a white to almost white powder. Rilpivirine hydrochloride is practically insoluble in water over a wide pH range. Rilpivirine 25 mg tablets are available as a white to off-white, film-coated, round, biconvex, 6.5 mm tablet for oral administration. Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of rilpivirine. Each rilpivirine 25 mg tablet also contains the inactive ingredients croscarmellose sodium, lactose monohydrate, magnesium stearate, polysorbate 20, povidone K30 and silicified microcrystalline cellulose. The tablet coating contains hypromellose 2910 6 mPa.s, lactose monohydrate, polyethylene glycol 3000, titanium dioxide and triacetin. rilpivirine-structure

10 OVERDOSAGE There is no specific antidote for overdose with rilpivirine tablets. Human experience of overdose with rilpivirine tablets are limited. Treatment of overdose with rilpivirine tablets consists of general supportive measures including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient. It is advisable to contact a poison control center to obtain the latest recommendations for the management of an overdose. Since rilpivirine is highly bound to plasma protein, dialysis is unlikely to result in significant removal of the active substance.

16 HOW SUPPLIED/STORAGE AND HANDLING Rilpivirine Tablets Rilpivirine 25 mg tablets are supplied as white to off-white, film-coated, round, biconvex, 6.5 mm tablets. Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of rilpivirine. Each tablet is debossed with "RP" on one side and "25" on the other side. Rilpivirine 25 mg tablets are packaged in bottles in the following configuration: 25 mg tablets-bottles of 30 (NDC 70069-848-30) Store rilpivirine tablets in the original bottle in order to protect from light. Store rilpivirine tablets at 20° to 25°C (68° to 77°F); with excursions permitted to 15° to 30°C (59° to 86°F) [see USP controlled room temperature].