Edurant
(Rilpivirine Hydrochloride)Dosage & Administration
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Edurant Prescribing Information
Indications and Usage (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
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Dosage and Administration (EDURANT is available in two dosage forms:
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)]. 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)] .
Advise patients or caregivers of patients taking EDURANT PED to refer to the Instructions for Use to properly prepare and take the medication. EDURANT PED must be dispersed in drinking water and taken immediately with a meal. If not taken immediately, then the oral suspension should be discarded, and a new dose of medicine should be prepared. The patient should not chew or swallow EDURANT PED whole. The following instructions should be followed:
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 at least 25 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)] . | 03/2024 | ||||||||||||||||
Warnings and Precautions (EDURANT and EDURANT PED have differing pharmacokinetic profiles and are not substitutable on a milligram-per-milligram basis. 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 Clinical Pharmacology (12.3)]. When a pediatric patient weighs 25 kg or greater, they must switch from EDURANT PED tablets for oral suspension to one 25 mg EDURANT tablet daily[see Dosage and Administration (2.3)]. Incorrect dosing of a given formulation may result in underdosing and loss of therapeutic effect and possible development of resistance or possible clinically significant adverse reactions from greater exposure to rilpivirine. | 03/2024 |
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. (
- 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)].
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 Treatment of HIV-1 in Treatment-Naïve PatientsEDURANT 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)].
)14 CLINICAL STUDIES14.1 Treatment-Naïve Adult SubjectsThe evidence of efficacy of EDURANT is based on the analyses of 48- and 96-week data from 2 randomized, double-blinded, active controlled, Phase 3 trials TMC278-C209 (ECHO) and TMC278-C215 (THRIVE) in antiretroviral treatment-naïve adults. Antiretroviral treatment-naïve HIV-1 infected subjects enrolled in the Phase 3 trials had a plasma HIV-1 RNA ≥5000 copies/mL and were screened for susceptibility to N(t)RTIs and for absence of specific NNRTI resistance-associated substitutions (RASs). The Phase 3 trials were identical in design, apart from the background regimen (BR). In TMC278-C209, the BR was fixed to the N(t)RTIs, tenofovir disoproxil fumarate plus emtricitabine. In TMC278-C215, the BR consisted of 2 investigator-selected N(t)RTIs: tenofovir disoproxil fumarate plus emtricitabine or zidovudine plus lamivudine or abacavir plus lamivudine. In both trials, randomization was stratified by screening viral load. In TMC278-C215, randomization was also stratified by N(t)RTI BR.
In the pooled analysis for TMC278-C209 and TMC278-C215, demographics and baseline characteristics were balanced between the EDURANT arm and the efavirenz arm. Table 14 displays selected demographic and baseline disease characteristics of the subjects in the EDURANT and efavirenz arms.
Table 14: Demographic and Baseline Disease Characteristics of Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects in the TMC278-C209 and TMC278-C215 Trials (Pooled Analysis) Pooled Data from the Phase 3 TMC278-C209 and TMC278-C215 Trials EDURANT + BR
N=686Efavirenz + BR
N=682BR=background regimen Demographic CharacteristicsMedian Age, years (range) 36 (18–78) 36 (19–69) Sex Male 76% 76% Female 24% 24% Race White 61% 60% Black/African American 24% 23% Asian 11% 14% Other 2% 2% Not allowed to ask per local regulations 1% 1% Baseline Disease CharacteristicsMedian Baseline Plasma HIV-1 RNA (range), log10copies/mL 5.0 (2–7) 5.0 (3–7) Percentage of Patients with Baseline Plasma Viral Load: ≤100,000 54% 48% >100,000 to ≤500,000 36% 40% >500,000 10% 12% Median Baseline CD4+ Cell Count (range), cells/mm3 249 (1–888) 260 (1–1137) Percentage of Subjects with: Hepatitis B/C Virus Co-infection 7% 10% Percentage of Patients with the Following Background Regimens: tenofovir disoproxil fumarate plus emtricitabine 80% 80% zidovudine plus lamivudine 15% 15% abacavir plus lamivudine 5% 5% Week 96 efficacy outcomes for subjects treated with EDURANT 25 mg once daily from the pooled analysis are shown in Table 15. The incidence of virologic failure was higher in the EDURANT arm than the efavirenz arm at Week 96. Virologic failures and discontinuations due to adverse events mostly occurred in the first 48 weeks of treatment. Regardless of HIV-1 RNA at the start of therapy, more EDURANT treated subjects with CD4+ cell count less than 200 cells/mm3experienced virologic failure compared to EDURANT treated subjects with CD4+ cell count greater than or equal to 200 cells/mm3.
Table 15: Virologic Outcome of Randomized Treatment of Studies TMC278-C209 and TMC278-C215 (Pooled Data) at Week 96 EDURANT + BR
N=686Efavirenz + BR
N=682N=total number of subjects per treatment group; BR=background regimen. Note: Analysis was based on the last observed viral load data within the Week 96 window (Week 90–103), respectively. HIV-1 RNA <50 copies/mLCI=Predicted difference (95% CI) of response rate is -0.2 (-4.7; 4.3) at Week 96.76% 77% HIV-1 RNA ≥50 copies/mLIncludes subjects who had ≥50 copies/mL in the Week 96 window, subjects who discontinued early due to lack or loss of efficacy, subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy and at the time of discontinuation had a viral value of ≥50 copies/mL, and subjects who had a switch in background regimen that was not permitted by the protocol.16% 10% No virologic data at Week 96 windowReasonsDiscontinued study due to adverse event or deathIncludes subjects who discontinued due to an adverse event or death if this resulted in no on-treatment virologic data in the Week 96 window. 4% 8% Discontinued study for other reasons and last available HIV-1 RNA <50 copies/mL (or missing)Includes subjects who discontinued for reasons other than an adverse event, death or lack or loss of efficacy, e.g., withdrew consent, loss to follow-up, etc. 4% 5% Missing data during window but on study <1% <1% HIV-1 RNA <50 copies/mL by Baseline HIV-1 RNA (copies/mL)≤100,000 82% 78% >100,000 70% 75% HIV-1 RNA ≥50 copies/mLby Baseline HIV-1 RNA (copies/mL)≤100,000 9% 8% >100,000 24% 11% HIV-1 RNA <50 copies/mL by CD4+ cell count (cells/mm3)<200 68% 74% ≥200 81% 77% HIV-1 RNA ≥50 copies/mLby CD4+ cell count (cells/mm3)<200 27% 10% ≥200 10% 9% At Week 96, the mean CD4+ cell count increase from baseline was 228 cells/mm3for EDURANT-treated subjects and 219 cells/mm3for efavirenz-treated subjects in the pooled analysis of the TMC278-C209 and TMC278-C215 trials.
Study TMC278-C204 was a randomized, active-controlled, Phase 2b trial in antiretroviral treatment-naïve HIV-1-infected adult subjects consisting of 2 parts: an initial 96 weeks, partially-blinded dose-finding part [EDURANT doses blinded] followed by a long-term, open-label part. After Week 96, subjects randomized to one of the 3 doses of EDURANT were switched to EDURANT 25 mg once daily. Subjects in the control arm received efavirenz 600 mg once daily in addition to a BR in both parts of the study. The BR consisted of 2 investigator-selected N(t)RTIs: zidovudine plus lamivudine or tenofovir disoproxil fumarate plus emtricitabine.
Study TMC278-C204 enrolled 368 HIV-1-infected treatment-naïve adult subjects who had a plasma HIV-1 RNA ≥5000 copies/mL, previously received ≤2 weeks of treatment with an N(t)RTI or protease inhibitor, had no prior use of NNRTIs, and were screened for susceptibility to N(t)RTI and for absence of specific NNRTI RASs.
At 96 weeks, the proportion of subjects with <50 HIV-1 RNA copies/mL receiving EDURANT 25 mg (N=93) compared to subjects receiving efavirenz (N=89) was 76% and 71%, respectively. The mean increase from baseline in CD4+ counts was 146 cells/mm3in subjects receiving EDURANT 25 mg and 160 cells/mm3in subjects receiving efavirenz.
At 240 weeks, 60% (56/93) of subjects who originally received 25 mg once daily achieved HIV RNA <50 copies/mL compared to 57% (51/89) of subjects in the control group.
14.2 Virologically-Suppressed Adults Treated in Combination with CabotegravirThe use of EDURANT in combination with VOCABRIA (cabotegravir) as an oral lead-in and in patients who miss planned injections with CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) was evaluated in two Phase 3 randomized, multicenter, active-controlled, parallel-arm, open-label, non-inferiority trials (Trial 201584: FLAIR [NCT02938520], Trial 201585: ATLAS [NCT2951052]), and one Phase 3b randomized, multicenter, parallel-group, open-label, non-inferiority trial (Trial 207966: ATLAS-2M [NCT03299049]) in subjects who were virologically suppressed (HIV-1 RNA <50 copies/mL). See full prescribing information for VOCABRIA and CABENUVA for additional information.
14.3 Treatment-Naïve Pediatric Subjects (≥12 to less than 18 Years of Age)The pharmacokinetics, safety, tolerability and efficacy of EDURANT 25 mg once daily, in combination with an investigator-selected background regimen (BR) containing two NRTIs, was evaluated in trial TMC278-C213 Cohort 1, a single-arm, open-label Phase 2 trial in antiretroviral treatment-naïve HIV-1 infected pediatric subjects 12 to less than 18 years of age and weighing at least 32 kg. Thirty six (36) subjects were enrolled in the trial to complete at least 48 weeks of treatment. The 36 subjects had a median age of 14.5 years (range: 12 to 17 years), and were 56% female, 89% Black and 11% Asian.
In the efficacy analysis, most subjects (75%; 28/36) had baseline HIV RNA <100,000 copies/mL. For these 28 subjects the median baseline plasma HIV-1 RNA was 44,250 (range: 2,060–92,600 copies/mL) and the median baseline CD4+ cell count was 445.5 cells/mm3(range: 123 to 983 cells/mm3).
Among the subjects who had baseline HIV RNA ≤100,000, the proportion with HIV-1 RNA <50 copies/mL at Week 48 was 79% (22/28), versus 50% (4/8) in those with >100,000 copies/mL. The proportion of virologic failures among subjects with a baseline viral load ≤100,000 copies/mL was 21% (6/28), versus 38% (3/8) in those with >100,000 copies/mL. At Week 48, the mean increase in CD4+ cell count from baseline was 201.2 cells/mm3.
14.4 Treatment-Naïve Pediatric Subjects (2 to less than 12 Years of Age)The pharmacokinetics, safety, tolerability and efficacy of EDURANT and EDURANT PED weight-adjusted doses 25, 15 and 12.5 mg once daily in combination with an investigator-selected BR containing two NRTIs, was evaluated in trial TMC278-C213 Cohort 2, a single-arm, open-label Phase 2 trial in antiretroviral treatment-naïve HIV-1 infected pediatric subjects 6 to less than 12 years of age and weighing at least 17 kg. The Week 48 analysis included 18 subjects, 17 (94%) subjects completed the 48-week treatment period, and 1 (6%) subject discontinued the study early due to reaching a virologic endpoint. The 18 subjects had a median age of 9 years (range 6 to 11 years) and the median weight at baseline was 25 kg (range 17 to 51 kg). 89% were Black and 39% were female. The median baseline plasma viral load was 55,400 (range 567–149,000) copies/mL, and the median absolute baseline CD4+ cell count was 432.5 (range 12–2,068) cells/µL.
The number of subjects with HIV-1 RNA <50 copies/mL at Week 48 was 13/18 (72%), while 3/18 (17%) subjects had HIV-1 RNA ≥50 copies/mL at Week 48
[see Microbiology (12.4)]. Two out of 18 (11%) participants in the 15 mg once daily (20 to ≤25 kg) dose-weight group had missing viral load data at Week 48 but remained on study. The viral load for these 2 subjects was <50 copies/mL, post-Week 48. The mean increase (SE) in CD4+ from baseline was 215.9 (62.42) cells/µL at Week 48.The safety and efficacy of EDURANT and EDURANT PED in treatment naïve pediatric subjects 2 to less than 6 years of age is supported by evidence from adequate and well-controlled studies of EDURANT in adults with additional population pharmacokinetic data from adults and pediatric subjects 6 years and older
[see Use in Specific Populations (8.4)and Clinical Pharmacology (12.3)]. - 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
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. (
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
- 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).
- One 25 mg EDURANT tablet taken once daily with a meal for patients weighing at least 25 kg. ()
2.2 Recommended Dosage in Treatment-Naïve Adult PatientsThe 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)]. - 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 Recommended Dosage in Treatment-Naïve Pediatric Patients 2 Years of Age and Older and Weighing at least 14 kgThe 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 Greater than or equal to 25 kg 1 tablet once daily Not recommended 25 mg EDURANT once daily - EDURANT PED must be dispersed in drinking water and taken with a meal. ()
2.4 Preparation and Administration Instructions for EDURANT PED OnlyAdvise patients or caregivers of patients taking EDURANT PED to refer to the Instructions for Use to properly prepare and take the medication.EDURANT PED must be dispersed in drinking water and taken immediately with a meal. If not taken immediately, then the oral suspension should be discarded, and a new dose of medicine should be prepared. The patient should not chew or swallow EDURANT PED whole. The following instructions should be followed:- Place the tablets for oral suspension in a cup, add 5 mL (1 teaspoon) of drinking water at room temperature. Do not crush the tablets.
- Swirl the cup carefully for 1–2 minutes to disperse the tablets. The oral suspension will start to look cloudy.
- Take all the prepared oral suspension immediately or to aid in administration, the oral suspension can be further diluted with 5 mL (1 teaspoon) of drinking water, milk, orange juice or applesauce. Swirl and take all the medicine immediately. A spoon can be used if needed.
- Make sure the entire dose is taken and no medicine is left in the cup. If required, add another 5 mL (1 teaspoon) of drinking water (or alternative beverage or soft food), swirl and drink immediately.
- 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 Overview of Different Dosage FormsEDURANT 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)].)5.6 Different Formulations Are Not SubstitutableEDURANT and EDURANT PED have differing pharmacokinetic profiles and are not substitutable on a milligram-per-milligram basis. 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 Clinical Pharmacology (12.3)].When a pediatric patient weighs 25 kg or greater, they must switch from EDURANT PED tablets for oral suspension to one 25 mg EDURANT tablet daily[see Dosage and Administration (2.3)].Incorrect dosing of a given formulation may result in underdosing and loss of therapeutic effect and possible development of resistance or possible clinically significant adverse reactions from greater exposure to rilpivirine. - See full prescribing information for dosing information when used in combination with cabotegravir. ()
2.6 Recommended Dosage in Combination with Cabotegravir in Adults and Adolescents 12 Years of Age and Older and Weighing at least 35 kgConsult the prescribing information for CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) before initiating EDURANT to ensure therapy with CABENUVA is appropriate.
Oral Lead-In Dosing to Assess Tolerability of RilpivirineOral lead-in should be used for approximately 1 month (at least 28 days) to assess the tolerability of rilpivirine prior to the initiation of CABENUVA. The recommended oral daily dose is one 25 mg tablet of EDURANT (rilpivirine) in combination with one 30 mg tablet of VOCABRIA (cabotegravir). Take EDURANT with VOCABRIA (cabotegravir) orally once daily at approximately the same time each day with a meal
[see Clinical Pharmacology (12.3)].Because EDURANT is indicated in combination with VOCABRIA (cabotegravir), the prescribing information for VOCABRIA (cabotegravir) tablets should also be consulted.
The last oral dose should be taken on the same day injections with CABENUVA are started.
Oral Dosing to Replace Planned Missed Injections of CABENUVAPlanned Missed Injections for Patients on Monthly Dosing ScheduleIf a patient plans to miss a scheduled monthly injection of CABENUVA by more than 7 days, take daily oral therapy for up to 2 months to replace missed injection visits. The recommended oral daily dose is one 25 mg tablet of EDURANT and one 30 mg tablet of VOCABRIA (cabotegravir). Take EDURANT with VOCABRIA (cabotegravir) at approximately the same time each day with a meal. The first dose of oral therapy should be initiated at approximately the same time as the planned missed injection and continued until the day injection dosing is restarted. For oral therapy with EDURANT and VOCABRIA of durations greater than 2 months, an alternative oral regimen is recommended, which may include EDURANT. See full prescribing information for CABENUVA to resume monthly injection dosing.
Planned Missed Injections for Patients on Every-2-Month Dosing ScheduleIf a patient plans to miss a scheduled every-2-month injection of CABENUVA by more than 7 days, take daily oral therapy for a duration of up to 2 months to replace 1 missed scheduled every-2-month injection. The recommended oral daily dose is one 25 mg tablet of EDURANT and one 30 mg tablet of VOCABRIA (cabotegravir). Take EDURANT with VOCABRIA (cabotegravir) at approximately the same time each day with a meal. The first dose of oral therapy should be initiated at approximately the same time as the planned missed injection and continued until the day injection dosing is restarted. For oral therapy with EDURANT and VOCABRIA of durations greater than 2 months, an alternative oral regimen is recommended, which may include EDURANT. See full prescribing information for CABENUVA to resume every-2-month injection dosing.
- 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 Recommended Dosage During PregnancyFor 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 at least 25 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)].)12.3 PharmacokineticsPharmacokinetics in AdultsThe pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in adult antiretroviral treatment-naïve HIV-1-infected subjects. Exposure to rilpivirine was generally lower in HIV-1 infected subjects than in healthy subjects.
Table 7: Pharmacokinetic Estimates of Rilpivirine 25 mg Once Daily in Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects (Pooled Data from Phase 3 Trials through Week 96) Parameter Rilpivirine 25 mg once daily
N=679AUC24h(ng∙h/mL) Mean±Standard Deviation 2235±851 Median (Range) 2096 (198 – 7307) C0h(ng/mL) Mean±Standard Deviation 79±35 Median (Range) 73 (2 – 288) Absorption and BioavailabilityAfter oral administration, the maximum plasma concentration of rilpivirine is generally achieved within 4–5 hours. The absolute bioavailability of EDURANT and EDURANT PED is unknown.
Effects of Food on Oral AbsorptionThe exposure to rilpivirine was approximately 40% lower when EDURANT was taken in a fasted condition as compared to a normal caloric meal (533 kcal) or high-fat high-caloric meal (928 kcal). When EDURANT was taken with only a protein-rich nutritional drink, exposures were 50% lower than when taken with a meal.
Administration of the EDURANT PED 2.5 mg tablets dispersed in drinking water in fasted conditions or after yogurt consumption resulted in a 31% and 28% lower exposure, respectively, compared to administration in fed conditions (a meal containing 533 kcal) in adults.
DistributionRilpivirine is approximately 99.7% bound to plasma proteins
in vitro, primarily to albumin. The distribution of rilpivirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tract secretions) has not been evaluated in humans.MetabolismIn vitroexperiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated by the cytochrome P450 (CYP) 3A system.EliminationThe terminal elimination half-life of rilpivirine is approximately 50 hours. After single dose oral administration of14C-rilpivirine, on average 85% and 6.1% of the radioactivity could be retrieved in feces and urine, respectively. In feces, unchanged rilpivirine accounted for on average 25% of the administered dose. Only trace amounts of unchanged rilpivirine (<1% of dose) were detected in urine.
Specific PopulationsPregnancy and PostpartumThe exposure (C0hand AUC24h) to total rilpivirine after intake of rilpivirine 25 mg once daily as part of an antiretroviral regimen was 30 to 40% lower during pregnancy (similar for the second and third trimester), compared with postpartum (see Table 8). However, the exposure during pregnancy was not significantly different from exposures obtained in Phase 3 trials. Based on the exposure-response relationship for rilpivirine, this decrease is not considered clinically relevant in patients who are virollogically suppressed. The protein binding of rilpivirine was similar (>99%) during the second trimester, third trimester, and postpartum.
Table 8: Pharmacokinetic Results of Total Rilpivirine After Administration of Rilpivirine 25 mg Once Daily as Part of an Antiretroviral Regimen, During the 2ndTrimester of Pregnancy, the 3rdTrimester of Pregnancy and Postpartum Pharmacokinetics of total rilpivirine
(mean ± SD, tmax: median [range])Postpartum
(6–12 Weeks)
(n=11)2ndTrimester of pregnancy
(n=15)3rdTrimester of pregnancy
(n=13)C0h, ng/mL 111±69.2 65.0±23.9 63.5±26.2 Cmin, ng/mL 84.0±58.8 54.3±25.8 52.9±24.4 Cmax, ng/mL 167±101 121±45.9 123±47.5 tmax, h 4.00 (2.03–25.08) 4.00 (1.00–9.00) 4.00 (2.00–24.93) AUC24h, ng.h/mL 2714±1535 1792±711 1762±662 Pediatric PatientsThe pharmacokinetics of rilpivirine in HIV-1 infected pediatric patients 2 to less than 18 years of age and weighing at least 16 kg receiving the recommended weight-based dosing regimen of EDURANT and EDURANT PED were comparable or slightly higher than those obtained in treatment-naïve HIV-1 infected adult patients (see Table 9and Table 10).
Table 9: Pharmacokinetic Estimates of Rilpivirine After Administration of the Recommended Daily Oral Dosing Regimen in Pediatric Patients ≥6 to <18 Years (Trial TMC278-C213)The 12.5 mg and 15 mg doses were administered as 5 and 6 dispersed 2.5 mg tablets, respectively. The 25 mg dose was administered as one 25 mg tablet. Mean rilpivirine exposure was approximately 40% higher in TMC278HTX2002 compared to TMC278-C213 Pharmacokinetics of rilpivirineIndividual data when N=2
Mean±SD
Median (range)12.5 mg once daily
<20 kg15 mg once daily
≥20 to <25 kg25 mg once daily
≥25 kgNA = not applicable N 2 2 44 AUC24h(ng.h/mL) 1974, 2707
NA (1974 – 2707)1912, 2477
NA (1912 – 2477)2536±979
2413 (973 – 4848)C0h(ng/mL) 68.1, 86.7
NA (68.1 – 86.7)48.3, 80.0
NA (48.3 – 80.0)87.0±34.5
82.7 (27.8 – 171)Table 10: Pharmacokinetic Estimates of Rilpivirine After Administration of the Recommended Daily Oral Dosing Regimen in Pediatric Patients ≥2 to <18 Years (Trial TMC278HTX2002)The 12.5 mg and 15 mg doses were administered as 5 and 6 dispersed 2.5 mg tablets, respectively. The 25 mg dose was administered as one 25 mg tablet. Mean rilpivirine exposure was approximately 40% higher in TMC278HTX2002 compared to TMC278-C213 Pharmacokinetics of rilpivirineIndividual data when N=2
Mean±SD
Median (range)12.5 mg once daily
≥10 to <20 kg15 mg once daily
≥20 to <25 kg25 mg once daily
≥25 kgNA = not applicable N 2 5 18 AUC24h(ng.h/mL) 4375, 5057
NA (4375 – 5057)3541±949
3112 (2689 – 4947)4195±1056
4016 (2732 – 6260)C0h(ng/mL) 151, 163
NA (151 – 163)112±39.8
91.8 (73.7 – 172)134±38.7
121 (78.9 – 220)Renal ImpairmentPharmacokinetic analysis indicated that rilpivirine exposure was similar in HIV-1 infected subjects with mild renal impairment relative to HIV-1 infected subjects with normal renal function. No dose adjustment is required in patients with mild renal impairment. There is limited or no information regarding the pharmacokinetics of rilpivirine in patients with moderate or severe renal impairment or in patients with end-stage renal disease, and rilpivirine concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. The potential impact is not expected to be of clinical relevance for HIV-1-infected subjects with moderate renal impairment, and no dose adjustment is required in these patients. Rilpivirine should be used with caution and with increased monitoring for adverse effects in patients with severe renal impairment or end-stage renal disease. As rilpivirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis
[see Use in Specific Populations (8.6)].Hepatic ImpairmentRilpivirine is primarily metabolized and eliminated by the liver. In a study comparing 8 subjects with mild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 subjects with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure of rilpivirine was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment. EDURANT has not been studied in subjects with severe hepatic impairment (Child-Pugh score C)
[see Use in Specific Populations (8.7)].Sex, Race, Hepatitis B and/or Hepatitis C Virus Co-infectionNo clinically relevant differences in the pharmacokinetics of rilpivirine have been observed between sex, race and patients with hepatitis B and/or C-virus co-infection.
Drug Interactions[see Contraindications (4)and Drug Interactions (7)].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. Coadministration of EDURANT and EDURANT PED and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Coadministration of EDURANT and 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 and to the class of NNRTIs.
EDURANT and EDURANT PED at the recommended doses are not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes.
Drug interaction studies were performed with EDURANT and other drugs likely to be coadministered or commonly used as probes for pharmacokinetic interactions. The effects of coadministration of other drugs on the Cmax, AUC, and Cminvalues of rilpivirine are summarized in Table 11 (effect of other drugs on EDURANT). The effect of coadministration of EDURANT on the Cmax, AUC, and Cminvalues of other drugs are summarized in Table 12 (effect of EDURANT on other drugs). [For information regarding clinical recommendations,
see Drug Interactions (7)].Table 11: Drug Interactions: Pharmacokinetic Parameters for Rilpivirine in the Presence of Coadministered Drugs Coadministered Drug Dose/Schedule N Mean Ratio of Rilpivirine
Pharmacokinetic Parameters With/Without Coadministered Drug
(90% CI); No Effect=1.00Coadministered Drug Rilpivirine Cmax AUC Cmin CI=Confidence Interval; N=maximum number of subjects with data; N.A.=not available; ↑=increase; ↓=decrease; ↔=no change; q.d.=once daily; b.i.d.=twice daily Coadministration With HIV Protease Inhibitors (PIs)Darunavir/ritonavir 800/100 mg q.d. 150 mg q.d.This interaction study has been performed with a dose higher than the recommended dose for EDURANT assessing the maximal effect on the coadministered drug. 14 1.79
(1.56–2.06)2.30
(1.98–2.67)2.78
(2.39–3.24)Lopinavir/ritonavir
(soft gel capsule)400/100 mg b.i.d. 150 mg q.d. 15 1.29
(1.18–1.40)1.52
(1.36–1.70)1.74
(1.46–2.08)Coadministration With HIV Nucleoside or Nucleotide Reverse Transcriptase Inhibitors (NRTIs/N[t]RTIs)Didanosine 400 mg q.d.
delayed release capsules taken 2 hours before rilpivirine150 mg q.d. 21 1.00
(0.90–1.10)1.00
(0.95–1.06)1.00
(0.92–1.09)Tenofovir disoproxil fumarate 300 mg q.d. 150 mg q.d. 16 0.96
(0.81–1.13)1.01
(0.87–1.18)0.99
(0.83–1.16)Coadministration With HIV Integrase Strand Transfer InhibitorsCabotegravir 30 mg q.d. 25 mg q.d. 11 0.96
(0.85–1.09)0.99
(0.89–1.09)0.92
(0.79–1.07)Raltegravir 400 mg b.i.d. 25 mg q.d. 23 1.12
(1.04–1.20)1.12
(1.05–1.19)1.03
(0.96–1.12)Coadministration With other AntiviralsSimeprevir 150 mg q.d. 25 mg q.d. 23 1.04
(0.95–1.13)1.12
(1.05–1.19)1.25
(1.16–1.35)Coadministration With Drugs other than AntiretroviralsAcetaminophen 500 mg single dose 150 mg q.d. 16 1.09
(1.01–1.18)1.16
(1.10–1.22)1.26
(1.16–1.38)Atorvastatin 40 mg q.d. 150 mg q.d. 16 0.91
(0.79–1.06)0.90
(0.81–0.99)0.90
(0.84–0.96)Chlorzoxazone 500 mg single dose taken 2 hours after rilpivirine 150 mg q.d. 16 1.17
(1.08–1.27)1.25
(1.16–1.35)1.18
(1.09–1.28)Ethinylestradiol/Norethindrone 0.035 mg q.d./
1 mg q.d.25 mg q.d. 15 ↔Comparison based on historic controls ↔ ↔ Famotidine 40 mg single dose taken 12 hours before rilpivirine 150 mg single dose 24 0.99
(0.84–1.16)0.91
(0.78–1.07)N.A. Famotidine 40 mg single dose taken 2 hours before rilpivirine 150 mg single dose 23 0.15
(0.12–0.19)0.24
(0.20–0.28)N.A. Famotidine 40 mg single dose taken 4 hours after rilpivirine 150 mg single dose 24 1.21
(1.06–1.39)1.13
(1.01–1.27)N.A. Ketoconazole 400 mg q.d. 150 mg q.d. 15 1.30
(1.13–1.48)1.49
(1.31–1.70)1.76
(1.57–1.97)Methadone 60–100 mg q.d., individualized dose 25 mg q.d. 12 ↔ ↔ ↔ Omeprazole 20 mg q.d. 150 mg q.d. 16 0.60
(0.48–0.73)0.60
(0.51–0.71)0.67
(0.58–0.78)Rifabutin 300 mg q.d. 25 mg q.d. 18 0.69
(0.62–0.76)0.58
(0.52–0.65)0.52
(0.46–0.59)Rifabutin 300 mg q.d. 50 mg q.d. 18 1.43
(1.30–1.56)1.16
(1.06–1.26)0.93
(0.85–1.01)(reference arm for comparison was 25 mg q.d. rilpivirine administered alone) Rifampin 600 mg q.d. 150 mg q.d. 16 0.31
(0.27–0.36)0.20
(0.18–0.23)0.11
(0.10–0.13)Sildenafil 50 mg single dose 75 mg q.d. 16 0.92
(0.85–0.99)0.98
(0.92–1.05)1.04
(0.98–1.09)Table 12: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of EDURANT Coadministered Drug Dose/Schedule N Mean Ratio of Coadministered Drug
Pharmacokinetic Parameters With/Without EDURANT
(90% CI); No Effect=1.00Coadministered Drug Rilpivirine Cmax AUC Cmin CI=Confidence Interval; N=maximum number of subjects with data; N.A.=not available; ↑=increase; ↓=decrease; ↔=no change; q.d.=once daily; b.i.d.=twice daily Coadministration With HIV Protease Inhibitors (PIs)Darunavir/ritonavir 800/100 mg q.d. 150 mg q.d.This interaction study has been performed with a dose higher than the recommended dose for EDURANT (25 mg once daily) assessing the maximal effect on the coadministered drug. 15 0.90
(0.81–1.00)0.89
(0.81–0.99)0.89
(0.68–1.16)Lopinavir/ritonavir
(soft gel capsule)400/100 mg b.i.d. 150 mg q.d. 15 0.96
(0.88–1.05)0.99
(0.89–1.10)0.89
(0.73–1.08)Coadministration With HIV Nucleoside or Nucleotide Reverse Transcriptase Inhibitors (NRTIs/N[t]RTIs)Didanosine 400 mg q.d.
delayed release capsules taken 2 hours before rilpivirine150 mg q.d. 13 0.96
(0.80–1.14)1.12
(0.99–1.27)N.A. Tenofovir disoproxil fumarate 300 mg q.d. 150 mg q.d. 16 1.19
(1.06–1.34)1.23
(1.16–1.31)1.24
(1.10–1.38)Coadministration With HIV Integrase Strand Transfer InhibitorsCabotegravir 30 mg q.d. 25 mg q.d. 11 1.05
(0.96–1.15)1.12
(1.05–1.19)1.14
(1.04–1.24)Raltegravir 400 mg b.i.d. 25 mg q.d. 23 1.10
(0.77–1.58)1.09
(0.81–1.47)1.27
(1.01–1.60)Coadministration With other AntiviralsSimeprevir 150 mg q.d. 25 mg q.d. 21 1.10
(0.97–1.26)1.06
(0.94–1.19)0.96
(0.83–1.11)Coadministration With Drugs other than AntiretroviralsAcetaminophen 500 mg single dose 150 mg q.d. 16 0.97
(0.86–1.10)0.91
(0.86–0.97)N.A. Atorvastatin 40 mg q.d. 150 mg q.d. 16 1.35
(1.08–1.68)1.04
(0.97–1.12)0.85
(0.69–1.03)2-hydroxy-atorvastatin 16 1.58
(1.33–1.87)1.39
(1.29–1.50)1.32
(1.10–1.58)4-hydroxy-atorvastatin 16 1.28
(1.15–1.43)1.23
(1.13–1.33)N.A. Chlorzoxazone 500 mg single dose taken 2 hours after rilpivirine 150 mg q.d. 16 0.98
(0.85–1.13)1.03
(0.95–1.13)N.A. Digoxin 0.5 mg single dose 25 mg q.d. 22 1.06
(0.97–1.17)0.98
(0.93–1.04)AUC
(0–last)N.A. Ethinylestradiol 0.035 mg q.d. 25 mg q.d. 17 1.17
(1.06–1.30)1.14
(1.10–1.19)1.09
(1.03–1.16)Norethindrone 1 mg q.d. 17 0.94
(0.83–1.06)0.89
(0.84–0.94)0.99
(0.90–1.08)Ketoconazole 400 mg q.d. 150 mg q.d. 14 0.85
(0.80–0.90)0.76
(0.70–0.82)0.34
(0.25–0.46)R(-) methadone 60–100 mg q.d., individualized dose 25 mg q.d. 13 0.86
(0.78–0.95)0.84
(0.74–0.95)0.78
(0.67–0.91)S(+) methadone 13 0.87
(0.78–0.97)0.84
(0.74–0.96)0.79
(0.67–0.92)Metformin 850 mg single dose 25 mg q.d. 20 1.02
(0.95–1.10)0.97
(0.90–1.06)N (maximum number of subjects with data) for AUC
(0–∞)=15N.A. Omeprazole 20 mg q.d. 150 mg q.d. 15 0.86
(0.68–1.09)0.86
(0.76–0.97)N.A. Rifampin 600 mg q.d. 150 mg q.d. 16 1.02
(0.93–1.12)0.99
(0.92–1.07)N.A. 25-desacetylrifampin 16 1.00
(0.87–1.15)0.91
(0.77–1.07)N.A. Sildenafil 50 mg single dose 75 mg q.d. 16 0.93
(0.80–1.08)0.97
(0.87–1.08)N.A. N-desmethyl-sildenafil16 0.90
(0.80–1.02)0.92
(0.85–0.99)N.A. - Rifabutin coadministration: Take two 25 mg tablets of EDURANT once daily with a meal for the duration of the rifabutin coadministration. ()
2.7 Recommended Dosage with Rifabutin CoadministrationIf EDURANT is coadministered with rifabutin, the EDURANT dose should be increased to 50 mg (two 25 mg tablets) once daily, taken with a meal. When rifabutin coadministration is stopped, the EDURANT dose should be decreased to 25 mg once daily, taken with a meal
[see Drug Interactions (7)and Clinical Pharmacology (12.3)].Note that use of CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension) with rifabutin is contraindicated. Refer to CABENUVA labeling for additional detail.
- EDURANT: 25 mg tablets ()
3 DOSAGE FORMS AND STRENGTHS- EDURANT: 25 mg tablets
- EDURANT PED: 2.5 mg tablets for oral suspension
EDURANT 25 mg Film-Coated Tablets25 mg white to off-white, film-coated, round, biconvex, tablet of 6.4 mm, debossed with "TMC" 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.
EDURANT PED 2.5 mg Tablets for Oral Suspension2.5 mg 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.
- EDURANT PED: 2.5 mg tablets for oral suspension ()
3 DOSAGE FORMS AND STRENGTHS- EDURANT: 25 mg tablets
- EDURANT PED: 2.5 mg tablets for oral suspension
EDURANT 25 mg Film-Coated Tablets25 mg white to off-white, film-coated, round, biconvex, tablet of 6.4 mm, debossed with "TMC" 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.
EDURANT PED 2.5 mg Tablets for Oral Suspension2.5 mg 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.
- Pregnancy: Total rilpivirine exposures were generally lower during pregnancy compared to the postpartum period. (,
2.5 Recommended Dosage During PregnancyFor 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 at least 25 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)].,8.1 PregnancyPregnancy Exposure RegistryThere 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 SummaryAvailable 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 ConsiderationsDosing During Pregnancy and the Postpartum PeriodBased 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 Administration (2.5)].Lower exposures of rilpivirine were observed during pregnancy, therefore viral load should be monitored closely[see Clinical Pharmacology (12.3)].DataHuman DataBased 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 (C0hand AUC) of total rilpivirine was approximately 30 to 40% lower during pregnancy compared with postpartum (6 to 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 6–12 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 DataRilpivirine 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.
)12.3 PharmacokineticsPharmacokinetics in AdultsThe pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in adult antiretroviral treatment-naïve HIV-1-infected subjects. Exposure to rilpivirine was generally lower in HIV-1 infected subjects than in healthy subjects.
Table 7: Pharmacokinetic Estimates of Rilpivirine 25 mg Once Daily in Antiretroviral Treatment-Naïve HIV-1-Infected Adult Subjects (Pooled Data from Phase 3 Trials through Week 96) Parameter Rilpivirine 25 mg once daily
N=679AUC24h(ng∙h/mL) Mean±Standard Deviation 2235±851 Median (Range) 2096 (198 – 7307) C0h(ng/mL) Mean±Standard Deviation 79±35 Median (Range) 73 (2 – 288) Absorption and BioavailabilityAfter oral administration, the maximum plasma concentration of rilpivirine is generally achieved within 4–5 hours. The absolute bioavailability of EDURANT and EDURANT PED is unknown.
Effects of Food on Oral AbsorptionThe exposure to rilpivirine was approximately 40% lower when EDURANT was taken in a fasted condition as compared to a normal caloric meal (533 kcal) or high-fat high-caloric meal (928 kcal). When EDURANT was taken with only a protein-rich nutritional drink, exposures were 50% lower than when taken with a meal.
Administration of the EDURANT PED 2.5 mg tablets dispersed in drinking water in fasted conditions or after yogurt consumption resulted in a 31% and 28% lower exposure, respectively, compared to administration in fed conditions (a meal containing 533 kcal) in adults.
DistributionRilpivirine is approximately 99.7% bound to plasma proteins
in vitro, primarily to albumin. The distribution of rilpivirine into compartments other than plasma (e.g., cerebrospinal fluid, genital tract secretions) has not been evaluated in humans.MetabolismIn vitroexperiments indicate that rilpivirine primarily undergoes oxidative metabolism mediated by the cytochrome P450 (CYP) 3A system.EliminationThe terminal elimination half-life of rilpivirine is approximately 50 hours. After single dose oral administration of14C-rilpivirine, on average 85% and 6.1% of the radioactivity could be retrieved in feces and urine, respectively. In feces, unchanged rilpivirine accounted for on average 25% of the administered dose. Only trace amounts of unchanged rilpivirine (<1% of dose) were detected in urine.
Specific PopulationsPregnancy and PostpartumThe exposure (C0hand AUC24h) to total rilpivirine after intake of rilpivirine 25 mg once daily as part of an antiretroviral regimen was 30 to 40% lower during pregnancy (similar for the second and third trimester), compared with postpartum (see Table 8). However, the exposure during pregnancy was not significantly different from exposures obtained in Phase 3 trials. Based on the exposure-response relationship for rilpivirine, this decrease is not considered clinically relevant in patients who are virollogically suppressed. The protein binding of rilpivirine was similar (>99%) during the second trimester, third trimester, and postpartum.
Table 8: Pharmacokinetic Results of Total Rilpivirine After Administration of Rilpivirine 25 mg Once Daily as Part of an Antiretroviral Regimen, During the 2ndTrimester of Pregnancy, the 3rdTrimester of Pregnancy and Postpartum Pharmacokinetics of total rilpivirine
(mean ± SD, tmax: median [range])Postpartum
(6–12 Weeks)
(n=11)2ndTrimester of pregnancy
(n=15)3rdTrimester of pregnancy
(n=13)C0h, ng/mL 111±69.2 65.0±23.9 63.5±26.2 Cmin, ng/mL 84.0±58.8 54.3±25.8 52.9±24.4 Cmax, ng/mL 167±101 121±45.9 123±47.5 tmax, h 4.00 (2.03–25.08) 4.00 (1.00–9.00) 4.00 (2.00–24.93) AUC24h, ng.h/mL 2714±1535 1792±711 1762±662 Pediatric PatientsThe pharmacokinetics of rilpivirine in HIV-1 infected pediatric patients 2 to less than 18 years of age and weighing at least 16 kg receiving the recommended weight-based dosing regimen of EDURANT and EDURANT PED were comparable or slightly higher than those obtained in treatment-naïve HIV-1 infected adult patients (see Table 9and Table 10).
Table 9: Pharmacokinetic Estimates of Rilpivirine After Administration of the Recommended Daily Oral Dosing Regimen in Pediatric Patients ≥6 to <18 Years (Trial TMC278-C213)The 12.5 mg and 15 mg doses were administered as 5 and 6 dispersed 2.5 mg tablets, respectively. The 25 mg dose was administered as one 25 mg tablet. Mean rilpivirine exposure was approximately 40% higher in TMC278HTX2002 compared to TMC278-C213 Pharmacokinetics of rilpivirineIndividual data when N=2
Mean±SD
Median (range)12.5 mg once daily
<20 kg15 mg once daily
≥20 to <25 kg25 mg once daily
≥25 kgNA = not applicable N 2 2 44 AUC24h(ng.h/mL) 1974, 2707
NA (1974 – 2707)1912, 2477
NA (1912 – 2477)2536±979
2413 (973 – 4848)C0h(ng/mL) 68.1, 86.7
NA (68.1 – 86.7)48.3, 80.0
NA (48.3 – 80.0)87.0±34.5
82.7 (27.8 – 171)Table 10: Pharmacokinetic Estimates of Rilpivirine After Administration of the Recommended Daily Oral Dosing Regimen in Pediatric Patients ≥2 to <18 Years (Trial TMC278HTX2002)The 12.5 mg and 15 mg doses were administered as 5 and 6 dispersed 2.5 mg tablets, respectively. The 25 mg dose was administered as one 25 mg tablet. Mean rilpivirine exposure was approximately 40% higher in TMC278HTX2002 compared to TMC278-C213 Pharmacokinetics of rilpivirineIndividual data when N=2
Mean±SD
Median (range)12.5 mg once daily
≥10 to <20 kg15 mg once daily
≥20 to <25 kg25 mg once daily
≥25 kgNA = not applicable N 2 5 18 AUC24h(ng.h/mL) 4375, 5057
NA (4375 – 5057)3541±949
3112 (2689 – 4947)4195±1056
4016 (2732 – 6260)C0h(ng/mL) 151, 163
NA (151 – 163)112±39.8
91.8 (73.7 – 172)134±38.7
121 (78.9 – 220)Renal ImpairmentPharmacokinetic analysis indicated that rilpivirine exposure was similar in HIV-1 infected subjects with mild renal impairment relative to HIV-1 infected subjects with normal renal function. No dose adjustment is required in patients with mild renal impairment. There is limited or no information regarding the pharmacokinetics of rilpivirine in patients with moderate or severe renal impairment or in patients with end-stage renal disease, and rilpivirine concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. The potential impact is not expected to be of clinical relevance for HIV-1-infected subjects with moderate renal impairment, and no dose adjustment is required in these patients. Rilpivirine should be used with caution and with increased monitoring for adverse effects in patients with severe renal impairment or end-stage renal disease. As rilpivirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis
[see Use in Specific Populations (8.6)].Hepatic ImpairmentRilpivirine is primarily metabolized and eliminated by the liver. In a study comparing 8 subjects with mild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 subjects with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure of rilpivirine was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment. EDURANT has not been studied in subjects with severe hepatic impairment (Child-Pugh score C)
[see Use in Specific Populations (8.7)].Sex, Race, Hepatitis B and/or Hepatitis C Virus Co-infectionNo clinically relevant differences in the pharmacokinetics of rilpivirine have been observed between sex, race and patients with hepatitis B and/or C-virus co-infection.
Drug Interactions[see Contraindications (4)and Drug Interactions (7)].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. Coadministration of EDURANT and EDURANT PED and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Coadministration of EDURANT and 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 and to the class of NNRTIs.
EDURANT and EDURANT PED at the recommended doses are not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes.
Drug interaction studies were performed with EDURANT and other drugs likely to be coadministered or commonly used as probes for pharmacokinetic interactions. The effects of coadministration of other drugs on the Cmax, AUC, and Cminvalues of rilpivirine are summarized in Table 11 (effect of other drugs on EDURANT). The effect of coadministration of EDURANT on the Cmax, AUC, and Cminvalues of other drugs are summarized in Table 12 (effect of EDURANT on other drugs). [For information regarding clinical recommendations,
see Drug Interactions (7)].Table 11: Drug Interactions: Pharmacokinetic Parameters for Rilpivirine in the Presence of Coadministered Drugs Coadministered Drug Dose/Schedule N Mean Ratio of Rilpivirine
Pharmacokinetic Parameters With/Without Coadministered Drug
(90% CI); No Effect=1.00Coadministered Drug Rilpivirine Cmax AUC Cmin CI=Confidence Interval; N=maximum number of subjects with data; N.A.=not available; ↑=increase; ↓=decrease; ↔=no change; q.d.=once daily; b.i.d.=twice daily Coadministration With HIV Protease Inhibitors (PIs)Darunavir/ritonavir 800/100 mg q.d. 150 mg q.d.This interaction study has been performed with a dose higher than the recommended dose for EDURANT assessing the maximal effect on the coadministered drug. 14 1.79
(1.56–2.06)2.30
(1.98–2.67)2.78
(2.39–3.24)Lopinavir/ritonavir
(soft gel capsule)400/100 mg b.i.d. 150 mg q.d. 15 1.29
(1.18–1.40)1.52
(1.36–1.70)1.74
(1.46–2.08)Coadministration With HIV Nucleoside or Nucleotide Reverse Transcriptase Inhibitors (NRTIs/N[t]RTIs)Didanosine 400 mg q.d.
delayed release capsules taken 2 hours before rilpivirine150 mg q.d. 21 1.00
(0.90–1.10)1.00
(0.95–1.06)1.00
(0.92–1.09)Tenofovir disoproxil fumarate 300 mg q.d. 150 mg q.d. 16 0.96
(0.81–1.13)1.01
(0.87–1.18)0.99
(0.83–1.16)Coadministration With HIV Integrase Strand Transfer InhibitorsCabotegravir 30 mg q.d. 25 mg q.d. 11 0.96
(0.85–1.09)0.99
(0.89–1.09)0.92
(0.79–1.07)Raltegravir 400 mg b.i.d. 25 mg q.d. 23 1.12
(1.04–1.20)1.12
(1.05–1.19)1.03
(0.96–1.12)Coadministration With other AntiviralsSimeprevir 150 mg q.d. 25 mg q.d. 23 1.04
(0.95–1.13)1.12
(1.05–1.19)1.25
(1.16–1.35)Coadministration With Drugs other than AntiretroviralsAcetaminophen 500 mg single dose 150 mg q.d. 16 1.09
(1.01–1.18)1.16
(1.10–1.22)1.26
(1.16–1.38)Atorvastatin 40 mg q.d. 150 mg q.d. 16 0.91
(0.79–1.06)0.90
(0.81–0.99)0.90
(0.84–0.96)Chlorzoxazone 500 mg single dose taken 2 hours after rilpivirine 150 mg q.d. 16 1.17
(1.08–1.27)1.25
(1.16–1.35)1.18
(1.09–1.28)Ethinylestradiol/Norethindrone 0.035 mg q.d./
1 mg q.d.25 mg q.d. 15 ↔Comparison based on historic controls ↔ ↔ Famotidine 40 mg single dose taken 12 hours before rilpivirine 150 mg single dose 24 0.99
(0.84–1.16)0.91
(0.78–1.07)N.A. Famotidine 40 mg single dose taken 2 hours before rilpivirine 150 mg single dose 23 0.15
(0.12–0.19)0.24
(0.20–0.28)N.A. Famotidine 40 mg single dose taken 4 hours after rilpivirine 150 mg single dose 24 1.21
(1.06–1.39)1.13
(1.01–1.27)N.A. Ketoconazole 400 mg q.d. 150 mg q.d. 15 1.30
(1.13–1.48)1.49
(1.31–1.70)1.76
(1.57–1.97)Methadone 60–100 mg q.d., individualized dose 25 mg q.d. 12 ↔ ↔ ↔ Omeprazole 20 mg q.d. 150 mg q.d. 16 0.60
(0.48–0.73)0.60
(0.51–0.71)0.67
(0.58–0.78)Rifabutin 300 mg q.d. 25 mg q.d. 18 0.69
(0.62–0.76)0.58
(0.52–0.65)0.52
(0.46–0.59)Rifabutin 300 mg q.d. 50 mg q.d. 18 1.43
(1.30–1.56)1.16
(1.06–1.26)0.93
(0.85–1.01)(reference arm for comparison was 25 mg q.d. rilpivirine administered alone) Rifampin 600 mg q.d. 150 mg q.d. 16 0.31
(0.27–0.36)0.20
(0.18–0.23)0.11
(0.10–0.13)Sildenafil 50 mg single dose 75 mg q.d. 16 0.92
(0.85–0.99)0.98
(0.92–1.05)1.04
(0.98–1.09)Table 12: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of EDURANT Coadministered Drug Dose/Schedule N Mean Ratio of Coadministered Drug
Pharmacokinetic Parameters With/Without EDURANT
(90% CI); No Effect=1.00Coadministered Drug Rilpivirine Cmax AUC Cmin CI=Confidence Interval; N=maximum number of subjects with data; N.A.=not available; ↑=increase; ↓=decrease; ↔=no change; q.d.=once daily; b.i.d.=twice daily Coadministration With HIV Protease Inhibitors (PIs)Darunavir/ritonavir 800/100 mg q.d. 150 mg q.d.This interaction study has been performed with a dose higher than the recommended dose for EDURANT (25 mg once daily) assessing the maximal effect on the coadministered drug. 15 0.90
(0.81–1.00)0.89
(0.81–0.99)0.89
(0.68–1.16)Lopinavir/ritonavir
(soft gel capsule)400/100 mg b.i.d. 150 mg q.d. 15 0.96
(0.88–1.05)0.99
(0.89–1.10)0.89
(0.73–1.08)Coadministration With HIV Nucleoside or Nucleotide Reverse Transcriptase Inhibitors (NRTIs/N[t]RTIs)Didanosine 400 mg q.d.
delayed release capsules taken 2 hours before rilpivirine150 mg q.d. 13 0.96
(0.80–1.14)1.12
(0.99–1.27)N.A. Tenofovir disoproxil fumarate 300 mg q.d. 150 mg q.d. 16 1.19
(1.06–1.34)1.23
(1.16–1.31)1.24
(1.10–1.38)Coadministration With HIV Integrase Strand Transfer InhibitorsCabotegravir 30 mg q.d. 25 mg q.d. 11 1.05
(0.96–1.15)1.12
(1.05–1.19)1.14
(1.04–1.24)Raltegravir 400 mg b.i.d. 25 mg q.d. 23 1.10
(0.77–1.58)1.09
(0.81–1.47)1.27
(1.01–1.60)Coadministration With other AntiviralsSimeprevir 150 mg q.d. 25 mg q.d. 21 1.10
(0.97–1.26)1.06
(0.94–1.19)0.96
(0.83–1.11)Coadministration With Drugs other than AntiretroviralsAcetaminophen 500 mg single dose 150 mg q.d. 16 0.97
(0.86–1.10)0.91
(0.86–0.97)N.A. Atorvastatin 40 mg q.d. 150 mg q.d. 16 1.35
(1.08–1.68)1.04
(0.97–1.12)0.85
(0.69–1.03)2-hydroxy-atorvastatin 16 1.58
(1.33–1.87)1.39
(1.29–1.50)1.32
(1.10–1.58)4-hydroxy-atorvastatin 16 1.28
(1.15–1.43)1.23
(1.13–1.33)N.A. Chlorzoxazone 500 mg single dose taken 2 hours after rilpivirine 150 mg q.d. 16 0.98
(0.85–1.13)1.03
(0.95–1.13)N.A. Digoxin 0.5 mg single dose 25 mg q.d. 22 1.06
(0.97–1.17)0.98
(0.93–1.04)AUC
(0–last)N.A. Ethinylestradiol 0.035 mg q.d. 25 mg q.d. 17 1.17
(1.06–1.30)1.14
(1.10–1.19)1.09
(1.03–1.16)Norethindrone 1 mg q.d. 17 0.94
(0.83–1.06)0.89
(0.84–0.94)0.99
(0.90–1.08)Ketoconazole 400 mg q.d. 150 mg q.d. 14 0.85
(0.80–0.90)0.76
(0.70–0.82)0.34
(0.25–0.46)R(-) methadone 60–100 mg q.d., individualized dose 25 mg q.d. 13 0.86
(0.78–0.95)0.84
(0.74–0.95)0.78
(0.67–0.91)S(+) methadone 13 0.87
(0.78–0.97)0.84
(0.74–0.96)0.79
(0.67–0.92)Metformin 850 mg single dose 25 mg q.d. 20 1.02
(0.95–1.10)0.97
(0.90–1.06)N (maximum number of subjects with data) for AUC
(0–∞)=15N.A. Omeprazole 20 mg q.d. 150 mg q.d. 15 0.86
(0.68–1.09)0.86
(0.76–0.97)N.A. Rifampin 600 mg q.d. 150 mg q.d. 16 1.02
(0.93–1.12)0.99
(0.92–1.07)N.A. 25-desacetylrifampin 16 1.00
(0.87–1.15)0.91
(0.77–1.07)N.A. Sildenafil 50 mg single dose 75 mg q.d. 16 0.93
(0.80–1.08)0.97
(0.87–1.08)N.A. N-desmethyl-sildenafil16 0.90
(0.80–1.02)0.92
(0.85–0.99)N.A.
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
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
| 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: rifabutinThe 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 rifabutin coadministration is stopped, the EDURANT dose should be decreased to 25 mg once daily. |
Azole Antifungal Agents: fluconazole itraconazole ketoconazoleThis interaction study has been performed with a dose higher than the recommended dose for EDURANT assessing the maximal effect on the coadministered drug. The dosing recommendation is applicable to the recommended doses of EDURANT once daily. posaconazole voriconazole | ↑ rilpivirine ↓ ketoconazole | Concomitant use of EDURANT or EDURANT PED 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 EDURANT or EDURANT PED is coadministered with azole antifungal agents. Clinically monitor for breakthrough fungal infections when azole antifungals are coadministered with EDURANT or EDURANT PED. |
Glucocorticoid (systemic): dexamethasone (more than a single-dose treatment) | ↓ rilpivirine | Coadministration is contraindicated with EDURANT or EDURANT PED [see Contraindications (4)] . |
H2-Receptor Antagonists: cimetidine famotidine nizatidine ranitidine | ↔ rilpivirine (famotidine taken 12 hours before rilpivirine or 4 hours after rilpivirine) | The combination of EDURANT or EDURANT PED and H2-receptor antagonists should be used with caution as coadministration may cause significant decreases in rilpivirine plasma concentrations (increase in gastric pH). H2-receptor antagonists should only be administered at least 12 hours before or at least 4 hours after EDURANT or EDURANT PED. |
| ↓ rilpivirine (famotidine taken 2 hours before rilpivirine) | ||
Herbal Products: St. John's wort ( Hypericum perforatum ) | ↓ rilpivirine | Coadministration is contraindicated with EDURANT or EDURANT PED [see Contraindications (4)] . |
HIV-Antiviral Agents: Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) | ||
| NNRTI (delavirdine) | ↑ rilpivirine ↔ delavirdine | It is not recommended to coadminister EDURANT or EDURANT PED with delavirdine and other NNRTIs. |
| Other NNRTIs (efavirenz, etravirine, nevirapine) | ↓ rilpivirine ↔ other NNRTIs | |
HIV-Antiviral Agents: Nucleoside Reverse Transcriptase Inhibitors (NRTIs) | ||
| didanosine | ↔ rilpivirine ↔ didanosine | No dose adjustment is required when EDURANT or EDURANT PED is coadministered with didanosine. Didanosine is to be administered on an empty stomach and at least two hours before or at least four hours after EDURANT or EDURANT PED (which should be administered with a meal). |
HIV-Antiviral Agents: Protease Inhibitors (PIs)-Boosted (i.e., with coadministration of low-dose ritonavir) or Unboosted (i.e., without coadministration of low-dose ritonavir) | ||
| darunavir/ritonavir | ↑ rilpivirine ↔ boosted darunavir | Concomitant use of EDURANT or EDURANT PED with darunavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when EDURANT or EDURANT PED is coadministered with darunavir/ritonavir. |
| Lopinavir/ritonavir | ↑ rilpivirine ↔ boosted lopinavir | Concomitant use of EDURANT or EDURANT PED with lopinavir/ritonavir may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). No dose adjustment is required when EDURANT or EDURANT PED is coadministered with lopinavir/ritonavir. |
| Other boosted PIs (atazanavir/ritonavir, fosamprenavir/ritonavir, saquinavir/ritonavir, tipranavir/ritonavir) | ↑ rilpivirine ↔ boosted PI | Concomitant use of EDURANT or EDURANT PED with boosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). EDURANT or EDURANT PED is not expected to affect the plasma concentrations of coadministered PIs. |
| Unboosted PIs (atazanavir, fosamprenavir, indinavir, nelfinavir) | ↑ rilpivirine ↔ unboosted PI | Concomitant use of EDURANT or EDURANT PED with unboosted PIs may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes). EDURANT or EDURANT PED is not expected to affect the plasma concentrations of coadministered PIs. |
Macrolide or ketolide antibiotics: azithromycin clarithromycin erythromycin | ↑ rilpivirine ↔ azithromycin ↔ clarithromycin ↔ erythromycin | Macrolides are expected to increase concentrations of rilpivirine and are associated with a risk of Torsade de Pointes [Warnings and Precautions (5.4)]. Where possible, consider alternatives, such as azithromycin, which increases rilpivirine concentrations less than other macrolides. |
Narcotic Analgesics: methadone | ↓ R(-) methadone ↓ S(+) methadone | No dose adjustments are required when initiating coadministration of methadone with EDURANT or EDURANT PED. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients. |
Proton Pump Inhibitors: e.g., esomeprazole lansoprazole omeprazole pantoprazole rabeprazole | ↓ rilpivirine | Coadministration is contraindicated with EDURANT or EDURANT PED [see Contraindications (4)] . |
In addition to the drugs included in Table 6, the interaction between EDURANT and the following drugs was evaluated in clinical studies and no dose adjustment is needed for either drug
- Consider alternatives to EDURANT or EDURANT PED when coadministered with drugs with a known risk of torsade de pointes.
- EDURANT and EDURANT PED should not be used in combination with NNRTIs.
- Coadministration of EDURANT or EDURANT PED with drugs that induce or inhibit CYP3A may affect the plasma concentrations of rilpivirine.
- Coadministration of EDURANT or EDURANT PED with drugs that increase gastric pH may decrease plasma concentrations of rilpivirine.
- Refer to the Full Prescribing Information for other drugs that should not be coadministered with EDURANT or EDURANT PED and for other drugs that may require a change in dose or regimen.
There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and drugs that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, 75 mg once daily and 300 mg once daily (3 times and 12 times the dose in EDURANT) have been shown to prolong the QTc interval of the electrocardiogram
The pharmacokinetic properties of rilpivirine have been evaluated in adult healthy subjects and in adult antiretroviral treatment-naïve HIV-1-infected subjects. Exposure to rilpivirine was generally lower in HIV-1 infected subjects than in healthy subjects.
| Parameter | Rilpivirine 25 mg once daily N=679 |
|---|---|
| AUC24h(ng∙h/mL) | |
| Mean±Standard Deviation | 2235±851 |
| Median (Range) | 2096 (198 – 7307) |
| C0h(ng/mL) | |
| Mean±Standard Deviation | 79±35 |
| Median (Range) | 73 (2 – 288) |
After oral administration, the maximum plasma concentration of rilpivirine is generally achieved within 4–5 hours. The absolute bioavailability of EDURANT and EDURANT PED is unknown.
The exposure to rilpivirine was approximately 40% lower when EDURANT was taken in a fasted condition as compared to a normal caloric meal (533 kcal) or high-fat high-caloric meal (928 kcal). When EDURANT was taken with only a protein-rich nutritional drink, exposures were 50% lower than when taken with a meal.
Administration of the EDURANT PED 2.5 mg tablets dispersed in drinking water in fasted conditions or after yogurt consumption resulted in a 31% and 28% lower exposure, respectively, compared to administration in fed conditions (a meal containing 533 kcal) in adults.
Rilpivirine is approximately 99.7% bound to plasma proteins
The terminal elimination half-life of rilpivirine is approximately 50 hours. After single dose oral administration of14C-rilpivirine, on average 85% and 6.1% of the radioactivity could be retrieved in feces and urine, respectively. In feces, unchanged rilpivirine accounted for on average 25% of the administered dose. Only trace amounts of unchanged rilpivirine (<1% of dose) were detected in urine.
The exposure (C0hand AUC24h) to total rilpivirine after intake of rilpivirine 25 mg once daily as part of an antiretroviral regimen was 30 to 40% lower during pregnancy (similar for the second and third trimester), compared with postpartum (see Table 8). However, the exposure during pregnancy was not significantly different from exposures obtained in Phase 3 trials. Based on the exposure-response relationship for rilpivirine, this decrease is not considered clinically relevant in patients who are virollogically suppressed. The protein binding of rilpivirine was similar (>99%) during the second trimester, third trimester, and postpartum.
| Pharmacokinetics of total rilpivirine (mean ± SD, tmax: median [range]) | Postpartum (6–12 Weeks) (n=11) | 2ndTrimester of pregnancy (n=15) | 3rdTrimester of pregnancy (n=13) |
|---|---|---|---|
| C0h, ng/mL | 111±69.2 | 65.0±23.9 | 63.5±26.2 |
| Cmin, ng/mL | 84.0±58.8 | 54.3±25.8 | 52.9±24.4 |
| Cmax, ng/mL | 167±101 | 121±45.9 | 123±47.5 |
| tmax, h | 4.00 (2.03–25.08) | 4.00 (1.00–9.00) | 4.00 (2.00–24.93) |
| AUC24h, ng.h/mL | 2714±1535 | 1792±711 | 1762±662 |
The pharmacokinetics of rilpivirine in HIV-1 infected pediatric patients 2 to less than 18 years of age and weighing at least 16 kg receiving the recommended weight-based dosing regimen of EDURANT and EDURANT PED were comparable or slightly higher than those obtained in treatment-naïve HIV-1 infected adult patients (see Table 9and Table 10).
| Pharmacokinetics of rilpivirineIndividual data when N=2 Mean±SD Median (range) | 12.5 mg once daily <20 kg | 15 mg once daily ≥20 to <25 kg | 25 mg once daily ≥25 kg |
|---|---|---|---|
| NA = not applicable | |||
| N | 2 | 2 | 44 |
| AUC24h(ng.h/mL) | 1974, 2707 NA (1974 – 2707) | 1912, 2477 NA (1912 – 2477) | 2536±979 2413 (973 – 4848) |
| C0h(ng/mL) | 68.1, 86.7 NA (68.1 – 86.7) | 48.3, 80.0 NA (48.3 – 80.0) | 87.0±34.5 82.7 (27.8 – 171) |
| Pharmacokinetics of rilpivirineIndividual data when N=2 Mean±SD Median (range) | 12.5 mg once daily ≥10 to <20 kg | 15 mg once daily ≥20 to <25 kg | 25 mg once daily ≥25 kg |
|---|---|---|---|
| NA = not applicable | |||
| N | 2 | 5 | 18 |
| AUC24h(ng.h/mL) | 4375, 5057 NA (4375 – 5057) | 3541±949 3112 (2689 – 4947) | 4195±1056 4016 (2732 – 6260) |
| C0h(ng/mL) | 151, 163 NA (151 – 163) | 112±39.8 91.8 (73.7 – 172) | 134±38.7 121 (78.9 – 220) |
Pharmacokinetic analysis indicated that rilpivirine exposure was similar in HIV-1 infected subjects with mild renal impairment relative to HIV-1 infected subjects with normal renal function. No dose adjustment is required in patients with mild renal impairment. There is limited or no information regarding the pharmacokinetics of rilpivirine in patients with moderate or severe renal impairment or in patients with end-stage renal disease, and rilpivirine concentrations may be increased due to alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. The potential impact is not expected to be of clinical relevance for HIV-1-infected subjects with moderate renal impairment, and no dose adjustment is required in these patients. Rilpivirine should be used with caution and with increased monitoring for adverse effects in patients with severe renal impairment or end-stage renal disease. As rilpivirine is highly bound to plasma proteins, it is unlikely that it will be significantly removed by hemodialysis or peritoneal dialysis
Rilpivirine is primarily metabolized and eliminated by the liver. In a study comparing 8 subjects with mild hepatic impairment (Child-Pugh score A) to 8 matched controls, and 8 subjects with moderate hepatic impairment (Child-Pugh score B) to 8 matched controls, the multiple dose exposure of rilpivirine was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment. EDURANT has not been studied in subjects with severe hepatic impairment (Child-Pugh score C)
No clinically relevant differences in the pharmacokinetics of rilpivirine have been observed between sex, race and patients with hepatitis B and/or C-virus co-infection.
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. Coadministration of EDURANT and EDURANT PED and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. Coadministration of EDURANT and 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 and to the class of NNRTIs.
EDURANT and EDURANT PED at the recommended doses are not likely to have a clinically relevant effect on the exposure of medicinal products metabolized by CYP enzymes.
Drug interaction studies were performed with EDURANT and other drugs likely to be coadministered or commonly used as probes for pharmacokinetic interactions. The effects of coadministration of other drugs on the Cmax, AUC, and Cminvalues of rilpivirine are summarized in Table 11 (effect of other drugs on EDURANT). The effect of coadministration of EDURANT on the Cmax, AUC, and Cminvalues of other drugs are summarized in Table 12 (effect of EDURANT on other drugs). [For information regarding clinical recommendations,
| Coadministered Drug | Dose/Schedule | N | Mean Ratio of Rilpivirine Pharmacokinetic Parameters With/Without Coadministered Drug (90% CI); No Effect=1.00 | |||
|---|---|---|---|---|---|---|
| Coadministered Drug | Rilpivirine | Cmax | AUC | Cmin | ||
| CI=Confidence Interval; N=maximum number of subjects with data; N.A.=not available; ↑=increase; ↓=decrease; ↔=no change; q.d.=once daily; b.i.d.=twice daily | ||||||
Coadministration With HIV Protease Inhibitors (PIs) | ||||||
| Darunavir/ritonavir | 800/100 mg q.d. | 150 mg q.d.This interaction study has been performed with a dose higher than the recommended dose for EDURANT assessing the maximal effect on the coadministered drug. | 14 | 1.79 (1.56–2.06) | 2.30 (1.98–2.67) | 2.78 (2.39–3.24) |
| Lopinavir/ritonavir (soft gel capsule) | 400/100 mg b.i.d. | 150 mg q.d. | 15 | 1.29 (1.18–1.40) | 1.52 (1.36–1.70) | 1.74 (1.46–2.08) |
Coadministration With HIV Nucleoside or Nucleotide Reverse Transcriptase Inhibitors (NRTIs/N[t]RTIs) | ||||||
| Didanosine | 400 mg q.d. delayed release capsules taken 2 hours before rilpivirine | 150 mg q.d. | 21 | 1.00 (0.90–1.10) | 1.00 (0.95–1.06) | 1.00 (0.92–1.09) |
| Tenofovir disoproxil fumarate | 300 mg q.d. | 150 mg q.d. | 16 | 0.96 (0.81–1.13) | 1.01 (0.87–1.18) | 0.99 (0.83–1.16) |
Coadministration With HIV Integrase Strand Transfer Inhibitors | ||||||
| Cabotegravir | 30 mg q.d. | 25 mg q.d. | 11 | 0.96 (0.85–1.09) | 0.99 (0.89–1.09) | 0.92 (0.79–1.07) |
| Raltegravir | 400 mg b.i.d. | 25 mg q.d. | 23 | 1.12 (1.04–1.20) | 1.12 (1.05–1.19) | 1.03 (0.96–1.12) |
Coadministration With other Antivirals | ||||||
| Simeprevir | 150 mg q.d. | 25 mg q.d. | 23 | 1.04 (0.95–1.13) | 1.12 (1.05–1.19) | 1.25 (1.16–1.35) |
Coadministration With Drugs other than Antiretrovirals | ||||||
| Acetaminophen | 500 mg single dose | 150 mg q.d. | 16 | 1.09 (1.01–1.18) | 1.16 (1.10–1.22) | 1.26 (1.16–1.38) |
| Atorvastatin | 40 mg q.d. | 150 mg q.d. | 16 | 0.91 (0.79–1.06) | 0.90 (0.81–0.99) | 0.90 (0.84–0.96) |
| Chlorzoxazone | 500 mg single dose taken 2 hours after rilpivirine | 150 mg q.d. | 16 | 1.17 (1.08–1.27) | 1.25 (1.16–1.35) | 1.18 (1.09–1.28) |
| Ethinylestradiol/Norethindrone | 0.035 mg q.d./ 1 mg q.d. | 25 mg q.d. | 15 | ↔Comparison based on historic controls | ↔ | ↔ |
| Famotidine | 40 mg single dose taken 12 hours before rilpivirine | 150 mg single dose | 24 | 0.99 (0.84–1.16) | 0.91 (0.78–1.07) | N.A. |
| Famotidine | 40 mg single dose taken 2 hours before rilpivirine | 150 mg single dose | 23 | 0.15 (0.12–0.19) | 0.24 (0.20–0.28) | N.A. |
| Famotidine | 40 mg single dose taken 4 hours after rilpivirine | 150 mg single dose | 24 | 1.21 (1.06–1.39) | 1.13 (1.01–1.27) | N.A. |
| Ketoconazole | 400 mg q.d. | 150 mg q.d. | 15 | 1.30 (1.13–1.48) | 1.49 (1.31–1.70) | 1.76 (1.57–1.97) |
| Methadone | 60–100 mg q.d., individualized dose | 25 mg q.d. | 12 | ↔ | ↔ | ↔ |
| Omeprazole | 20 mg q.d. | 150 mg q.d. | 16 | 0.60 (0.48–0.73) | 0.60 (0.51–0.71) | 0.67 (0.58–0.78) |
| Rifabutin | 300 mg q.d. | 25 mg q.d. | 18 | 0.69 (0.62–0.76) | 0.58 (0.52–0.65) | 0.52 (0.46–0.59) |
| Rifabutin | 300 mg q.d. | 50 mg q.d. | 18 | 1.43 (1.30–1.56) | 1.16 (1.06–1.26) | 0.93 (0.85–1.01) |
| (reference arm for comparison was 25 mg q.d. rilpivirine administered alone) | ||||||
| Rifampin | 600 mg q.d. | 150 mg q.d. | 16 | 0.31 (0.27–0.36) | 0.20 (0.18–0.23) | 0.11 (0.10–0.13) |
| Sildenafil | 50 mg single dose | 75 mg q.d. | 16 | 0.92 (0.85–0.99) | 0.98 (0.92–1.05) | 1.04 (0.98–1.09) |
| Coadministered Drug | Dose/Schedule | N | Mean Ratio of Coadministered Drug Pharmacokinetic Parameters With/Without EDURANT (90% CI); No Effect=1.00 | |||
|---|---|---|---|---|---|---|
| Coadministered Drug | Rilpivirine | Cmax | AUC | Cmin | ||
| CI=Confidence Interval; N=maximum number of subjects with data; N.A.=not available; ↑=increase; ↓=decrease; ↔=no change; q.d.=once daily; b.i.d.=twice daily | ||||||
Coadministration With HIV Protease Inhibitors (PIs) | ||||||
| Darunavir/ritonavir | 800/100 mg q.d. | 150 mg q.d.This interaction study has been performed with a dose higher than the recommended dose for EDURANT (25 mg once daily) assessing the maximal effect on the coadministered drug. | 15 | 0.90 (0.81–1.00) | 0.89 (0.81–0.99) | 0.89 (0.68–1.16) |
| Lopinavir/ritonavir (soft gel capsule) | 400/100 mg b.i.d. | 150 mg q.d. | 15 | 0.96 (0.88–1.05) | 0.99 (0.89–1.10) | 0.89 (0.73–1.08) |
Coadministration With HIV Nucleoside or Nucleotide Reverse Transcriptase Inhibitors (NRTIs/N[t]RTIs) | ||||||
| Didanosine | 400 mg q.d. delayed release capsules taken 2 hours before rilpivirine | 150 mg q.d. | 13 | 0.96 (0.80–1.14) | 1.12 (0.99–1.27) | N.A. |
| Tenofovir disoproxil fumarate | 300 mg q.d. | 150 mg q.d. | 16 | 1.19 (1.06–1.34) | 1.23 (1.16–1.31) | 1.24 (1.10–1.38) |
Coadministration With HIV Integrase Strand Transfer Inhibitors | ||||||
| Cabotegravir | 30 mg q.d. | 25 mg q.d. | 11 | 1.05 (0.96–1.15) | 1.12 (1.05–1.19) | 1.14 (1.04–1.24) |
| Raltegravir | 400 mg b.i.d. | 25 mg q.d. | 23 | 1.10 (0.77–1.58) | 1.09 (0.81–1.47) | 1.27 (1.01–1.60) |
Coadministration With other Antivirals | ||||||
| Simeprevir | 150 mg q.d. | 25 mg q.d. | 21 | 1.10 (0.97–1.26) | 1.06 (0.94–1.19) | 0.96 (0.83–1.11) |
Coadministration With Drugs other than Antiretrovirals | ||||||
| Acetaminophen | 500 mg single dose | 150 mg q.d. | 16 | 0.97 (0.86–1.10) | 0.91 (0.86–0.97) | N.A. |
| Atorvastatin | 40 mg q.d. | 150 mg q.d. | 16 | 1.35 (1.08–1.68) | 1.04 (0.97–1.12) | 0.85 (0.69–1.03) |
| 2-hydroxy-atorvastatin | 16 | 1.58 (1.33–1.87) | 1.39 (1.29–1.50) | 1.32 (1.10–1.58) | ||
| 4-hydroxy-atorvastatin | 16 | 1.28 (1.15–1.43) | 1.23 (1.13–1.33) | N.A. | ||
| Chlorzoxazone | 500 mg single dose taken 2 hours after rilpivirine | 150 mg q.d. | 16 | 0.98 (0.85–1.13) | 1.03 (0.95–1.13) | N.A. |
| Digoxin | 0.5 mg single dose | 25 mg q.d. | 22 | 1.06 (0.97–1.17) | 0.98 (0.93–1.04)AUC (0–last) | N.A. |
| Ethinylestradiol | 0.035 mg q.d. | 25 mg q.d. | 17 | 1.17 (1.06–1.30) | 1.14 (1.10–1.19) | 1.09 (1.03–1.16) |
| Norethindrone | 1 mg q.d. | 17 | 0.94 (0.83–1.06) | 0.89 (0.84–0.94) | 0.99 (0.90–1.08) | |
| Ketoconazole | 400 mg q.d. | 150 mg q.d. | 14 | 0.85 (0.80–0.90) | 0.76 (0.70–0.82) | 0.34 (0.25–0.46) |
| R(-) methadone | 60–100 mg q.d., individualized dose | 25 mg q.d. | 13 | 0.86 (0.78–0.95) | 0.84 (0.74–0.95) | 0.78 (0.67–0.91) |
| S(+) methadone | 13 | 0.87 (0.78–0.97) | 0.84 (0.74–0.96) | 0.79 (0.67–0.92) | ||
| Metformin | 850 mg single dose | 25 mg q.d. | 20 | 1.02 (0.95–1.10) | 0.97 (0.90–1.06)N (maximum number of subjects with data) for AUC (0–∞)=15 | N.A. |
| Omeprazole | 20 mg q.d. | 150 mg q.d. | 15 | 0.86 (0.68–1.09) | 0.86 (0.76–0.97) | N.A. |
| Rifampin | 600 mg q.d. | 150 mg q.d. | 16 | 1.02 (0.93–1.12) | 0.99 (0.92–1.07) | N.A. |
| 25-desacetylrifampin | 16 | 1.00 (0.87–1.15) | 0.91 (0.77–1.07) | N.A. | ||
| Sildenafil | 50 mg single dose | 75 mg q.d. | 16 | 0.93 (0.80–1.08) | 0.97 (0.87–1.08) | N.A. |
N -desmethyl-sildenafil | 16 | 0.90 (0.80–1.02) | 0.92 (0.85–0.99) | N.A. | ||
| 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. |