Rilpivirine Hydrochloride

FDA Drug Information • Also known as: Edurant, Edurant Ped

Brand Names: Edurant, Edurant Ped
Dosage Form: INJECTION, SUSPENSION
Product Type: DRUG FOR FURTHER PROCESSING

Description

11 DESCRIPTION EDURANT ® (rilpivirine) is 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. EDURANT 25 mg tablets are available as a white to off-white, film-coated, round, biconvex, 6.4 mm tablet for oral administration. Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of rilpivirine. Each EDURANT 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, PEG 3000, titanium dioxide and triacetin. EDURANT PED 2.5 mg tablets for oral suspension are available as white to almost white, round 6.5 mm tablet, debossed with "TMC" on one side and "PED" on the other side. Each tablet for oral suspension contains 2.75 mg of rilpivirine hydrochloride equivalent to 2.5 mg rilpivirine. Each tablet for oral suspension also contains the inactive ingredients croscarmellose sodium, lactose monohydrate, mannitol, microcrystalline cellulose, polysorbate 20, povidone K30, sodium lauryl sulfate and sodium stearyl fumarate. Chemical Structure

What Is Rilpivirine Hydrochloride Used For?

1 INDICATIONS AND USAGE EDURANT and EDURANT PED 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 2 years of age and older and weighing at least 14 kg with HIV-1 RNA less than or equal to 100,000 copies/mL. ( 1.1 ). Limitations of Use: More EDURANT 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 EDURANT treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL. ( 1.1 , 14 ) EDURANT is 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 EDURANT and EDURANT PED, in combination with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral treatment-naïve patients 2 years of age and older and weighing at least 14 kg with plasma HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy. Limitations of Use More EDURANT 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 EDURANT treated subjects with HIV-1 RNA less than or equal to 100,000 copies/mL [see Clinical Studies (14.1) ] . 1.2 Treatment of HIV-1 in Combination with Cabotegravir EDURANT is 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).

Dosage and Administration

2 DOSAGE AND ADMINISTRATION One 25 mg EDURANT tablet taken once daily with a meal for patients weighing at least 25 kg. ( 2.2 ) Pediatric patients 2 years of age and older and weighing at least 14 kg to less than 25 kg: Dosage of EDURANT PED is based on body weight. ( 2.3 ) EDURANT PED must be dispersed in drinking water and taken with a meal. ( 2.4 ) Do not substitute EDURANT 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 EDURANT 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 25 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 EDURANT once daily with a meal for the duration of the rifabutin coadministration. ( 2.7 ) 2.1 Overview of Different Dosage Forms EDURANT is available in two dosage forms: EDURANT 25 mg film-coated tablets for adults and pediatric patients weighing at least 25 kg. EDURANT PED 2.5 mg tablets for oral suspension should only be given to pediatric patients weighing at least 14 kg to less than 25 kg [see Dosage and Administration (2.3) ] . Do not substitute EDURANT tablets and EDURANT PED tablets for oral suspension on a milligram-per-milligram basis due to differing pharmacokinetic profiles. A difference in bioavailability between 1 × 25 mg film-coated tablet and 10 × 2.5 mg tablets for oral suspension was observed; therefore, they are NOT substitutable [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3) ]. Take EDURANT and EDURANT PED once daily with a meal in combination with other antiretrovirals [see Clinical Pharmacology (12.3) ]. 2.2 Recommended Dosage in Treatment-Naïve Adult Patients The recommended dosage of EDURANT 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 2 Years of Age and Older and Weighing at least 14 kg The recommended dosage of EDURANT and EDURANT PED in pediatric patients 2 years of age and older and weighing at least 14 kg is based on body weight (see Table 1 ). Both EDURANT and EDURANT PED 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 EDURANT and EDURANT PED for Pediatric Patients Body Weight (kg) EDURANT 25 mg Tablets EDURANT PED 2.5 mg Tablets for Oral Suspension Total Daily Dose 14 kg to less than 20 kg Not recommended 5 tablets once daily 12.5 mg EDURANT PED once daily 20 kg to less than 25 kg Not recommended 6 tablets once daily 15 mg EDURANT PED once daily...

Side Effects (Adverse Reactions)

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 EDURANT or EDURANT PED (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 Janssen Products, LP at 1-800-526-7736 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 EDURANT (25 mg once daily) [see Clinical Studies (14.1) ] . The median duration of exposure for patients in the EDURANT 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 EDURANT 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 EDURANT arm and 11 (2%) subjects in the efavirenz arm. Rash led to discontinuation in 1 (<1%) subject in the EDURANT 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 Intensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity). (Grades 2–4) Occurring in at Least 2% of Antiretroviral Treatment-Naïve HIV-1 Infected Adult Subjects (Week 96 Analysis) System Organ Class, Preferred Term, % Pooled Data from the Phase 3 TMC278-C209 and TMC278-C215 Trials EDURANT + BR N=686 Efavirenz + BR N=682 N=total number of subjects per treatment group; BR=background regimen 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 Includes adverse reactions reported as depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicide ideation. 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 EDURANT 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 EDURANT. Gastrointestinal Disorders : diarrhea, abdominal discomfort Hepatobiliary...

Drug Interactions

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 EDURANT or EDURANT PED 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 EDURANT or EDURANT PED and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Coadministration of EDURANT or EDURANT PED 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. EDURANT or EDURANT PED 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 EDURANT or EDURANT PED and/or coadministered drug may be recommended. Drugs that are not recommended for coadministration with EDURANT or EDURANT PED 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) ] Concomitant Drug Class: Drug Name Effect on Concentration of Rilpivirine or Concomitant Drug Clinical Comment ↑=increase, ↓=decrease, ↔=no change 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) The combination of EDURANT or EDURANT PED 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 EDURANT or EDURANT PED. ↓ rilpivirine (concomitant intake) Anticonvulsants: carbamazepine oxcarbazepine phenobarbital phenytoin ↓ rilpivirine Coadministration is contraindicated with EDURANT or EDURANT PED [see Contraindications (4) ] . Antimycobacterials: rifampin rifapentine ↓ rilpivirine Coadministration is contraindicated with EDURANT or EDURANT PED [see Contraindications (4) ] . Antimycobacterials: rifabutin The interaction between EDURANT and the drug was evaluated in a clinical study. All other drug-drug interactions shown are predicted. ↓ rilpivirine Concomitant use of EDURANT with rifabutin may cause a decrease in the plasma concentrations of rilpivirine (induction of CYP3A enzymes). Throughout coadministration of EDURANT with rifabutin, the EDURANT dose should be increased from 25 mg once daily to 50 mg once daily. When...

Contraindications

4 CONTRAINDICATIONS EDURANT and EDURANT PED 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 EDURANT or EDURANT PED or to the class of NNRTIs [see Drug Interactions (7) and Clinical Pharmacology (12.3) ] . Table 2: Drugs That are Contraindicated with EDURANT and EDURANT PED 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 EDURANT or EDURANT PED is 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 )

Pregnancy and Breastfeeding

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to EDURANT 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 EDURANT regimen prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) [see Dosage and...

Overdosage

10 OVERDOSAGE There is no specific antidote for overdose with EDURANT or EDURANT PED. Human experience of overdose with EDURANT or EDURANT PED is limited. Treatment of overdose with EDURANT or EDURANT PED 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.

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING EDURANT Tablets EDURANT ® (rilpivirine) 25 mg tablets are supplied as white to off-white, film-coated, round, biconvex, 6.4 mm tablets. Each tablet contains 27.5 mg of rilpivirine hydrochloride, which is equivalent to 25 mg of rilpivirine. Each tablet is debossed with "TMC" on one side and "25" on the other side. EDURANT 25 mg tablets are packaged in bottles in the following configuration: 25 mg tablets-bottles of 30 (NDC 59676-278-01). Store EDURANT tablets in the original bottle in order to protect from light. Store EDURANT 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]. EDURANT PED Tablets for Oral Suspension EDURANT ® PED (rilpivirine) 2.5 mg tablets for oral suspension are supplied as white to almost white, round 6.5 mm tablets, debossed with "TMC" on one side and "PED" on the other side. Each tablet for oral suspension contains 2.75 mg rilpivirine hydrochloride equivalent to 2.5 mg rilpivirine. EDURANT PED 2.5 mg tablets for oral suspension are packaged in aluminum cold form film blister with integrated desiccant and an aluminum peelable lidding foil. Each blister contains 10 tablets with 9 blisters per carton (NDC 59676-280-90). Store EDURANT PED tablets for oral suspension in the original package in order to protect from light and moisture. Store 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].

About This Information

This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

What are side effects?

Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

What are drug interactions?

Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.