Rilpivirine, an antiretroviral agent, is a human immunodeficiency virus (HIV) nonnucleoside reverse transcriptase inhibitor (NNRTI).1, 4, 8
Rilpivirine is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in treatment-naïve patients 2 years of age and older and weighing ≥14 kg with baseline HIV-1 RNA levels ≤100,000 copies/mL.1, 2, 3, 10, 11, 12, 24, 25, 26, 27, 28, 29, 30, 200, 201, 202 More rilpivirine-treated patients with HIV-1 RNA levels >100,000 copies/mL at therapy initiation experienced virologic failure compared to rilpivirine-treated patients with HIV-1 RNA levels ≤100,000 copies/mL.1
Rilpivirine is also indicated in combination with cabotegravir for short-term treatment of HIV-1 infection in adults and adolescents ≥12 years of age and weighing ≥35 kg who are virologically suppressed (HIV-1 RNA <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, 14, 17, 18, 19, 20, 21, 22, 23
Clinical Experience in Antiretroviral Naïve Adults
Rilpivirine has been evaluated in two phase 3, randomized, double-blind, multicenter, noninferiority studies (studies TMC278-C209 [ECHO], TMC278-C215 [THRIVE]) in antiretroviral-naïve adults with baseline plasma HIV-1 RNA levels of at least 5000 copies/mL.1, 2, 10, 11, 12 Patients enrolled in these studies were screened to ensure they had HIV-1 that did not have specific non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance-associated substitutions and were susceptible to nucleoside reverse transcriptase inhibitors (NRTIs).1, 10, 11 All patients received a background regimen of 2 NRTIs (dual NRTIs); patients enrolled in the ECHO study received a fixed combination of emtricitabine and tenofovir DF (emtricitabine/tenofovir DF) and patients enrolled in the THRIVE study received an investigator-selected dual NRTI option of emtricitabine and tenofovir DF, zidovudine and lamivudine, or abacavir and lamivudine.1, 2, 10, 11, 12 Over 1300 patients (median age, 36 years [range 18-78], 76% male, 60-61% white, 23-24% Black, 11-14% Asian, median baseline plasma HIV-1 RNA level 5.0 log10 copies/mL, median baseline CD4+ T-cell count 249-260 cells/mm3) were randomized to receive rilpivirine 25 mg once daily or efavirenz 600 mg once daily.1, 2 At 48 weeks, rilpivirine was noninferior to efavirenz in both studies.10, 11 Based on pooled results at 48 weeks, 84% of those receiving rilpivirine and 2 NRTIs and 82% of those receiving efavirenz and 2 NRTIs had plasma HIV-1 RNA levels below 50 copies/mL.2 In addition, the mean increase in CD4+ T-cell count from baseline at week 48 was 192 cells/mm3 in patients receiving a rilpivirine regimen and 176 cells/mm3 in those receiving an efavirenz regimen.2 Pooled results at week 96 showed that 76% of those receiving rilpivirine and 2 NRTIs and 77% of those receiving efavirenz and 2 NRTIs had plasma HIV-1 RNA levels below 50 copies/mL.1 The mean increase in CD4+ T-cell count from baseline at week 96 was 228 cells/mm3 in patients receiving a rilpivirine regimen and 219 cells/mm3 in those receiving an efavirenz regimen.1
Pooled data from the ECHO and THRIVE studies indicated that the virologic failure rate at week 96 (plasma HIV-1 RNA levels 50 copies/mL or greater) was 16 or 10% in those randomized to rilpivirine or efavirenz, respectively, and 2 NRTIs; most virologic failures occurred in the first 48 weeks.1 When results were stratified by baseline plasma HIV-1 RNA levels among patients randomized to receive rilpivirine, virologic failure occurred in 9% of patients with baseline plasma HIV-1 RNA levels of 100,000 copies/mL or less and in 24% of those with baseline levels exceeding 100,000 copies/mL.1
Rilpivirine also has been evaluated in a randomized, active-controlled, phase 2b, dose-comparison study (TMC278-C204) in 368 antiretroviral-naïve HIV-infected adults (median age, 35 years, 67% male, 45% white, 24% Black, 18% Asian) with baseline plasma HIV-1 RNA levels of at least 5000 copies/mL.1, 3 Patients enrolled in this study had previously received no more than 2 weeks of treatment with NRTIs or HIV protease inhibitors (PIs), had not previously received any NNRTIs, and were screened to ensure they had HIV-1 that did not have specific NNRTI resistance-associated mutations and were susceptible to NRTIs.1, 3 Patients received an investigator-selected background regimen of 2 NRTIs (lamivudine and zidovudine or emtricitabine and tenofovir DF; administered as fixed-combination preparations whenever possible) and were randomized (1:1:1:1) to receive open-label efavirenz (600 mg once daily) or 1 of 3 blinded rilpivirine dosage regimens (25, 75, or 150 mg once daily) for 96 weeks.1, 3 At 96 weeks, 76% of patients receiving a regimen of rilpivirine 25 mg and 2 NRTIs and 71% of patients receiving a regimen of efavirenz and 2 NRTIs had plasma HIV-1 RNA levels below 50 copies/mL.1, 3 The mean increase in CD4+ T-cell count from baseline was 146 cells/mm3 in those receiving rilpivirine 25 mg and 160 cells/mm3 in those receiving efavirenz.1, 3 At 96 weeks, patients originally randomized to any dose of rilpivirine were switched to an open label rilpivirine regimen of 25 mg once daily and 2 NRTIs for long-term follow-up.1 At 240 weeks, virologic suppression (plasma HIV-1 RNA levels below 50 copies/mL) was achieved in 60% of patients originally randomized to rilpivirine 25 mg and 57% of those randomized to efavirenz.1
Clinical Experience in Antiretroviral-Experienced Adults
Use of rilpivirine in combination with dolutegravir for maintenance of HIV virological suppression in previously-treated adults†was compared to continuation of current antiretroviral therapy in the identical, phase 3, randomized, open-label, multicenter, non-inferiority, SWORD-1 and SWORD-2 trials.24 Patients receiving first- or second-line regimens with sustained virological suppression (HIV viral load <50 copies/mL) for at least 6 months were randomized to switch to rilpivirine with dolutegravir or continue their current regimen.24 Patients randomized to continuation were switched to rilpivirine with dolutegravir after 52 weeks.24 Among 1024 patients who were randomized and included in the primary analysis, no difference in virological suppression was identified between groups at 48 weeks (95% in each group), demonstrating non-inferiority of rilpivirine with dolutegravir.24 In an updated analysis at 148 weeks from randomization, 84% of patients initially randomized to rilpivirine with dolutegravir and 90% of patients who switched to rilpivirine and dolutegravir after 52 weeks maintained virologic suppression.25
Rilpivirine has also been studied in combination with cobicistat-boosted darunavir for maintenance of HIV virological suppression in previously-treated adults†in the phase 3, randomized, open-label, non-inferiority, PROBE 2 trial.26 Patients receiving antiretroviral therapy with stable virological suppression (HIV viral load <50 copies/mL) for at least 6 months were randomized to switch to rilpivirine with cobicistat-boosted darunavir or continue their current regimen.26 Patients randomized to continuation were switched to rilpivirine with cobicistat-boosted darunavir after 24 weeks.26 Among 160 randomized patients, no difference in virological suppression was identified between groups at 24 weeks (90% of patients randomized to rilpivirine with cobicistat-boosted darunavir and 94% of patients randomized to continuation).26 In an updated analysis at 48 weeks from randomization, 88% of patients initially randomized to rilpivirine with cobicistat-boosted darunavir and 95% of patients who switched to rilpivirine with cobicistat-boosted darunavir at 24 weeks maintained virologic suppression.27
Clinical Experience in Virologically-Suppressed Adults in Combination With Cabotegravir
Use of oral rilpivirine in combination with oral cabotegravir has been evaluated in clinical trials as a short-term lead-in to assess tolerability of rilpivirine prior to use of the fixed dose extended-release injectable suspension combination of rilpivirine and cabotegravir (Cabenuva®) and as short-term therapy in patients who miss planned injections of Cabenuva®.1, 18, 19, 20, 21, 22, 23 See full prescribing information for oral cabotegravir (Vocabria®) and Cabenuva® for details of clinical experience with these regimens.14, 17
Clinical Experience in Antiretroviral-Naïve Pediatric Patients
The efficacy and safety of rilpivirine in conjunction with 2 NRTIs were evaluated in the single-arm, open-label, phase 2, PAINT trial (TMC278-C213) in 36 treatment-naïve pediatric patients ≥12 to <18 years of age weighing at least 32 kg (median age, 14.5 years, 56% female, 89% Black, 11% Asian, median baseline plasma HIV-1 RNA level 49,550 copies/mL, median baseline CD4+ T-cell count 438 cells/mm3).1, 28, 233 Of the 36 patients, 24 received rilpivirine in conjunction with emtricitabine and tenofovir DF.233 At week 48, virologic response (plasma HIV-1 RNA levels <50 copies/mL) was achieved in 79% of patients with baseline plasma HIV-1 RNA levels of 100,000 copies/mL or less compared with 50% of those with baseline HIV-1 RNA levels greater than 100,000 copies/mL.1 The mean increase in CD4+ T-cell count from baseline was 201 cells/mm3.1 In a subgroup of patients receiving rilpivirine in conjunction with emtricitabine and tenofovir DF who had baseline plasma HIV-1 RNA levels of 100,000 copies/mL or less, virologic response (plasma HIV-1 RNA levels <50 copies/mL) was achieved by 80% at 48 weeks and the mean increase in CD4+ T-cell count from baseline was 225 cells/mm3 at 48 weeks.233 In 32 patients included in a post-48 week efficacy analysis of PAINT, 24 of whom continued treatment with rilpivirine and 2 NRTIs after week 48 (up to 240 weeks), virologic response was observed in 44% of patients at week 240.29 Among patients with baseline HIV-1 RNA of 100,000 copies/mL or less, virologic response was observed in 48% at week 240, whereas virologic response was observed in 29% at week 240 in patients with baseline HIV-1 RNA levels greater than 100,000 copies/mL.29
The efficacy and safety of rilpivirine tablets and tablets for oral suspension weight-adjusted doses 12.5, 15, and 25 mg once daily in combination with an investigator-selected background regimen containing two NRTIs, was evaluated in Cohort 2 of the single-arm, open-label, phase 2, TMC278-C213 trial.1 This cohort included antiretroviral treatment-naïve HIV-1 infected pediatric subjects 6 to <12 years of age and weighing ≥17 kg.1 Seventeen (94%) of 18 patients completed the 48-week treatment period; patients were a median age of 9 years (range: 6—11 years), median baseline weight of 25 kg (range: 17—51 kg), 89% were Black, and 39% were female.1 The median baseline plasma viral load was 55,400 (range: 567-149,000) copies/mL, and the median absolute baseline CD4+ T-cell count was 432.5 (range: 12-2,068) cells/mm3.1 Results revealed that 13 (72%) of the 18 patients had an HIV-1 RNA level <50 copies/mL at Week 48, while 3 (17%) had HIV-1 RNA level ≥50 copies/mL.1 The mean increase in CD4+ T-cell count from baseline was 215.9 cells/mm3 at Week 48.1
Clinical Experience in Antiretroviral-Experienced Pediatric Patients
Use of fixed- dose combination rilpivirine with emtricitabine and tenofovir DF (Complera®) for treatment of HIV in previously-treated pediatric patients†has been described in a multicenter case series from the Cohort of the Spanish Pediatric HIV Network (CoRISpe) database.30 See full prescribing information for Complera® for details of clinical experience with this regimen.233
Therapeutic options for the treatment and prevention of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving.200, 201, 202 Antiretroviral therapy is recommended for all individuals with HIV regardless of CD4+ counts, and should be initiated as soon as possible after diagnosis of HIV and continued indefinitely.200, 201, 202 The primary goals of antiretroviral therapy are to achieve and maintain durable suppression of HIV viral load (as measured by plasma HIV-1 RNA levels) to a level below which drug-resistance mutations cannot emerge (i.e., below detectable limits), restore and preserve immunologic function, reduce HIV-related morbidity and mortality, improve quality of life, and prevent transmission of HIV.200, 202 While the most appropriate antiretroviral regimen cannot be defined for each clinical scenario, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents, HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, and HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, have developed comprehensive guidelines that provide information on selection and use of antiretrovirals for the treatment or prevention of HIV infection.200, 201, 202 Because of the complexity of managing patients with HIV, it is recommended that clinicians with HIV expertise be consulted when needed.200, 201, 202
The use of combination antiretroviral regimens that generally include 3 drugs from 2 or more drug classes is currently recommended to achieve viral suppression.200, 201 In both treatment-naïve adults and children, an initial regimen generally consists of 2 NRTIs administered in combination with a third active antiretroviral drug from 1 of 3 drug classes: an integrase strand transfer inhibitor (INSTI), a NNRTI, or a PI with a pharmacokinetic enhancer (also known as a booster; the 2 drugs used for this purpose are cobicistat and ritonavir).200, 201, 202 Selection of an initial regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance-test results, comorbid conditions, access, and cost.200, 201, 202 In patients with comorbid infections (e.g., hepatitis B, tuberculosis), regimen selection should also consider the potential for activity against other present infections and timing of initiation relative to other anti-infective regimens.200, 201, 202
In the HHS Adult and Adolescent HIV treatment guideline, rilpivirine is not recommended for initial therapy in the majority of patients with HIV due to the availability of other effective regimens without virologic and immunologic prerequisites to treatment initiation, the presence of substantial drug-drug interactions, and its low genetic barrier to resistance.200 The guideline panel continues to recommend rilpivirine/tenofovir alafenamide/emtricitabine as part of other initial antiretroviral regimens for certain clinical scenarios (e.g., patients with pre-treatment viral loads <100,000 copies/mL and CD4 counts >200 cells/mm3.200
In the HHS Perinatal HIV treatment guideline, rilpivirine is included in various antiretroviral regimens.202 Some of these rilpivirine-containing regimens are listed among alternative initial options for pregnant patients, and include the following: rilpivirine/tenofovir alafenamide/emtricitabine, rilpivirine/tenofovir DF/emtricitabine, and rilpivirine in combination with a preferred dual-NRTI backbone; rilpivirine regimens are recommended only in patients with HIV viral load <100,000 copies/mL and CD4 counts >200 cells/mm3.202
Postexposure Prophylaxis following Occupational Exposure to HIV
Rilpivirine has been used in conjunction with 2 NRTIs for postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel and other individuals exposed via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV.199 Rilpivirine in combination with 2 NRTIs is one of several alternative regimens recommended in guidelines for PEP when the preferred regimen cannot be used.199
The US Public Health Service (USPHS) states that the preferred regimen for PEP following an occupational exposure to HIV is a 3-drug regimen of raltegravir used in conjunction with emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada®).199 These experts recommend several alternative regimens that include an INSTI, NNRTI, or PI and 2 NRTIs (dual NRTIs).199 These alternatives include use of rilpivirine and 2 NRTIs when the preferred regimen cannot be used.199 The preferred dual NRTI option for use in PEP regimens is emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada®); alternative dual NRTIs are tenofovir DF and lamivudine, lamivudine and zidovudine (may be administered as the fixed combination lamivudine/zidovudine; Combivir®), or zidovudine and emtricitabine.199
Because management of occupational exposures to HIV is complex and evolving, consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended whenever possible.199 However, initiation of PEP should not be delayed while waiting for expert consultation.199
Postexposure Prophylaxis following Nonoccupational Exposure to HIV
Rilpivirine has been used in conjunction with 2 NRTIs for postexposure prophylaxis of HIV infection following nonoccupational exposure† (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids that might contain HIV, when that exposure represents a substantial risk for HIV transmission.198 Rilpivirine in combination with 2 NRTIs is one of several alternative regimens recommended in guidelines for nPEP.198 A fixed dose combination containing rilpivirine, emtricitabine, and tenofovir DF (Complera®) has been used for nPEP† in this setting.31, 32, 198 See the full prescribing information for use of Complera®.233
Use of fixed dose combination rilpivirine with emtricitabine and tenofovir DF (Complera®) as nPEP† has been described in an open-label, non-randomized trial and a prospective, observational study.31, 32 See full prescribing information for Complera® for details of clinical experience with this regimen.233
When nPEP is indicated following a nonoccupational exposure to HIV, the US Centers for Disease Control and Prevention (CDC) states that the preferred regimen in adults and adolescents 13 years of age or older with normal renal function is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (administered as the fixed combination emtricitabine/tenofovir DF; Truvada®).198 The alternative nPEP regimen recommended in these patients is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF (Truvada®).198 Rilpivirine in combination with 2 NRTIs is one of several other alternative regimens recommended by CDC for nPEP.198
Consultation with an infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended if nPEP is indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if a regimen not included in the CDC guidelines is being considered, the source virus is known or likely to be resistant to antiretrovirals, or the healthcare provider is inexperienced in prescribing antiretrovirals.198 However, initiation of nPEP should not be delayed while waiting for expert consultation.198
Dispensing and Administration Precautions
Rilpivirine hydrochloride is available as oral tablets (Edurant®) and tablets for oral suspension (Edurant PED®); both formulations are administered once daily with a meal.1 Rilpivirine tablets should be administered to adults and pediatric patients weighing ≥25 kg.1 Rilpivirine tablets for oral suspension should be administered only to pediatric patients weighing ≥14 kg to <25 kg.1
Rilpivirine oral tablets and tablets for oral suspension have differing pharmacokinetic profiles; therefore, the tablets and tablets for oral suspension should not be substituted on a milligram-per-milligram basis.1
Rilpivirine tablets for oral suspension must be dispersed in drinking water and immediately consumed with a meal.1 If not consumed immediately, the suspension should be discarded and a new dose prepared.1 Rilpivirine tablets for oral suspension should not be crushed, chewed, or swallowed whole.1
In order to properly prepare the tablets for oral suspension for administration, an appropriate number of tablets should be placed in a cup and 5 mL of room temperature drinking water should be added.1 The cup should be swirled carefully for 1—2 minutes; the oral suspension should begin to have a cloudy appearance.1 After swirling the cup for 1—2 minutes, the oral suspension may be consumed immediately or the suspension can be further diluted with 5 mL of drinking water, orange juice, or applesauce to assist in administration.1 All the medicine within the cup should be consumed immediately; a spoon may be used if needed.1 If medicine is still present in the cup, another 5 mL of drinking water (or alternative beverage or soft food) may be added to the cup, swirled, and consumed immediately.1
Food enhances rilpivirine bioavailability.1 Systemic exposure is approximately 40 or 50% lower if rilpivirine tablets are administered under fasting conditions or with only a protein-rich nutritional drink, respectively, compared with following a standard meal (533 kcal) or high-caloric meal (928 kcal).1, 4 Systemic exposure is 31 or 28% lower if rilpivirine tablets for oral suspension are dispersed in drinking water in fasted conditions or after yogurt consumption, respectively, compared with following a meal in adults containing 533 kcal.1
If a dose of rilpivirine is missed within 12 hours of the time it is usually taken, take the missed dose as soon as possible with a meal.1 If a dose of rilpivirine is missed by more than 12 hours, then skip the missed dose and resume the normal dosing schedule.1
Rilpivirine must be used in conjunction with other antiretrovirals.1 Single-entity rilpivirine should not be used concomitantly with emtricitabine/rilpivirine/tenofovir alafenamide or cabotegravir/rilpivirine injeciton.1, 244, 14 Single-entity rilpivirine should not be used concomitantly with emtricitabine/rilpivirine/tenofovir DF, unless needed for adjustment of rilpivirine dosage (e.g., when the fixed combination is used concomitantly with rifabutin).233
Store rilpivirine tablets and tablets for oral suspension at 20—25ºC; (excursions permitted between 15-30ºC).1 Store tablets in original bottle to protect from light and tablets for oral suspension in original package to protect from moisture.1
Fixed Combinations Containing Rilpivirine
Rilpivirine hydrochloride is commercially available in fixed-combination tablets containing dolutegravir sodium and rilpivirine (Juluca®); emtricitabine, rilpivirine, and tenofovir alafenamide (Odefsey®) and emtricitabine, rilpivirine, and tenofovir DF (Complera®).13, 233, 244 Rilpivirine is also commercially available as an extended-release injectable suspension kit containing copackaged cabotegravir and rilpivirine (Cabenuva®).14 See the full prescribing information for administration of each of these combination products.13, 14, 233, 244
Rilpivirine is commercially available as rilpivirine hydrochloride; dosage is expressed in terms of rilpivirine.1
Treatment of HIV Infection in Antiretroviral-naïve Pediatric Patients
For the treatment of HIV-1 infection in antiretroviral-naïve pediatric patients 2 years of age or older weighing at least 14 kg, rilpivirine dosage is based on body weight.1 Table 1 provides recommended dosage regimens.1
Body Weight (kg) | Edurant® 25 mg Tablets | Edurant PED® Tablets for Oral Suspension | Total Daily Dose |
|---|---|---|---|
14 to <20 | Not recommended | 5 tablets once daily | 12.5 mg Edurant PED® once daily |
20 to <25 | Not recommended | 6 tablets once daily | 15 mg Edurant PED® once daily |
≥25 | 1 tablet once daily | Not recommended | 25 mg Edurant® once daily |
Treatment of HIV Infection in Antiretroviral-experienced Pediatric Patients in Combination with Cabotegravir
For the treatment of HIV-1 infection in previously treated adolescents 12 years of age and older weighing at least 35 kg who are virologically suppressed (HIV-1 RNA levels <50 copies/mL) in combination with cabotegravir oral tablets (Vocabria®), the usual dosage of rilpivirine (Edurant®) is 25 mg once daily.1 Single-entity rilpivirine is indicated in combination with cabotegravir (Vocabria®) for short-term treatment to assess the tolerability of rilpivirine prior to cabotegravir/rilpivirine (Cabenuva®) initiation, and as a dosing bridge when missed injections of cabotegravir/rilpivirine (Cabenuva®) are planned; consult the prescribing information of these products before initiating rilpivirine oral tablets.1, 14, 17
Oral lead-in therapy should be used for approximately 1 month (at least 28 days) to assess rilpivirine tolerability prior to initiation of cabotegravir/rilpivirine (Cabenuva®) .1, 14 The last oral dose of rilpivirine (Edurant®) and cabotegravir (Vocabria®) should be administered on the same day that cabotegravir/rilpivirine (Cabenuva®) is initiated.1, 14, 17
If a scheduled monthly injection of cabotegravir/rilpivirine (Cabenuva®) is planned to be missed by more than 7 days, daily oral rilpivirine (Edurant®) and cabotegravir (Vocabria®) can be taken together for up to 2 months to replace missed injection visits.1, 14, 17 The recommended oral daily dose is one 25-mg tablet of rilpivirine and one 30-mg tablet of cabotegravir.1 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.1, 14, 17 For durations longer than 2 months, use an alternative oral regimen.1, 14, 17
If a scheduled every-2-month injection of cabotegravir/rilpivirine (Cabenuva®) is planned to be missed by more than 7 days, daily oral rilpivirine (Edurant®) and cabotegravir (Vocabria®) can be taken together for up to 2 months to replace 1 missed scheduled every-2-month injection.1, 14 The recommended oral daily dose is one 25-mg tablet of rilpivirine and one 30-mg tablet of cabotegravir.1 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.1, 14, 17 For durations longer than 2 months, use an alternative oral regimen.1, 14, 17
Treatment of HIV Infection in Antiretroviral-naïve Adults
For the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral-naïve adults, the usual dosage of rilpivirine (Edurant®) is 25 mg once daily.1
Treatment of HIV Infection in Antiretroviral-experienced Adults in Combination with Cabotegravir
For the treatment of HIV-1 infection in previously treated adults who are virologically suppressed (HIV-1 RNA <50 copies/mL), the usual dosage of rilpivirine (Edurant®) is 25 mg once daily.1 Single-entity rilpivirine is indicated in combination with cabotegravir (Vocabria®) for short-term treatment to assess the tolerability of rilpivirine prior to cabotegravir/rilpivirine (Cabenuva®) initiation, and as a dosing bridge when missed injections of Cabenuva® are planned; consult the prescribing information of these products before initiating rilpivirine oral tablets.1, 14, 17
Oral lead-in therapy should be used for approximately 1 month (at least 28 days) to assess rilpivirine tolerability prior to initiation of cabotegravir/rilpivirine (Cabenuva®) .1, 14 The last oral dose of rilpivirine (Edurant®) and cabotegravir (Vocabria®) should be administered on the same day that cabotegravir/rilpivirine (Cabenuva®) is initiated.1, 14, 17
If a scheduled monthly injection of cabotegravir/rilpivirine (Cabenuva®) is planned to be missed by more than 7 days, daily oral rilpivirine (Edurant®) and cabotegravir (Vocabria®) can be taken together for up to 2 months to replace missed injection visits.1, 14, 17 The recommended oral daily dose is one 25-mg tablet of rilpivirine and one 30-mg tablet of cabotegravir.1 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.1, 14, 17 For durations longer than 2 months, use an alternative oral regimen.1, 14, 17
If a scheduled every-2-month injection of cabotegravir/rilpivirine (Cabenuva®) is planned to be missed by more than 7 days, daily oral rilpivirine (Edurant®) and cabotegravir (Vocabria®) can be taken together for up to 2 months to replace 1 missed scheduled every-2-month injection.1, 14 The recommended oral daily dose is one 25-mg tablet of rilpivirine and one 30-mg tablet of cabotegravir.1 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.1, 14, 17 For durations longer than 2 months, use an alternative oral regimen.1, 14, 17
Postexposure Prophylaxis following Occupational Exposure to HIV
For postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel or other individuals, rilpivirine is administered in a dosage of 25 mg once daily in conjunction with 2 HIV NRTIs.199
The PEP regimen should be initiated as soon as possible following occupational exposure to HIV (preferably within hours) and continued for 4 weeks, if tolerated.199
Postexposure Prophylaxis following Nonoccupational Exposure to HIV
When emtricitabine/rilpivirine/tenofovir DF (Complera®) is used as a complete regimen for postexposure prophylaxis of HIV infection following nonoccupational exposure† (nPEP), adults should receive 1 tablet (200 mg of emtricitabine, 25 mg of rilpivirine, and 300 mg of tenofovir DF) once daily.198
The nPEP regimen should be initiated as soon as possible (within 72 hours) following nonoccupational exposure to HIV and continued for 28 days.198 If the exposed individual seeks care more than 72 hours after the exposure, nPEP is not recommended.198
Dosage Modification with Rifabutin Coadministration
If rilpivirine (Edurant®) is coadministered with rifabutin, the rilpivirine dosage should be increased to 50 mg once daily.1 If rifabutin coadministration is halted, the rilpivirine dosage should be decreased to 25 mg once daily.1
Dosage adjustment of rilpivirine is not necessary for the treatment of HIV-1 infection in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1 Rilpivirine has not been studied in those with severe hepatic impairment (Child-Pugh class C).1
Consult the product labeling of commercially available fixed-combination products containing rilpivirine for specific dosage adjustments of each component in hepatic impairment.13, 14, 233, 244
Dosage adjustment of rilpivirine is not necessary for the treatment of HIV-1 infection in patients with mild or moderate renal impairment.1 The manufacturer makes no specific dosage recommendations for those with severe renal impairment or end-stage renal disease; rilpivirine should be used with caution in such individuals.1
Consult the product labeling of commercially available fixed-combination products containing rilpivirine for specific dosage adjustments of each component in renal impairment.13, 14, 233, 244
The manufacturer makes no specific dosage recommendations for geriatric patients.1
Consult the product labeling of commercially available fixed-combination products containing rilpivirine for specific dosage adjustments of each component in geriatric patients.13, 14, 233, 244
Skin and Hypersensitivity Reactions
Severe skin and hypersensitivity reactions, including cases of drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported during postmarketing experience in patients receiving rilpivirine-containing antiretroviral regimens.1 While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunction, including elevated serum concentrations of hepatic enzymes.1 During phase 3 studies of rilpivirine-containing regimens, treatment-associated rash with at least grade 2 severity was reported in 1—3% of patients.1 Most rashes were grade 1 or 2 and occurred in the first 4—6 weeks of therapy.1
Rilpivirine should be discontinued immediately if signs or symptoms of severe skin or hypersensitivity reactions develop (e.g., severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis, or eosinophilia).1 Clinical status, including laboratory parameters, should be monitored and appropriate therapy initiated.1
Adverse hepatic effects have been reported in patients receiving rilpivirine in conjunction with other antiretrovirals.1 Hepatotoxicity has been reported in patients receiving rilpivirine who had no preexisting hepatic disease or other risk factors.1
HIV-infected patients with hepatitis B virus (HBV) or hepatitis C virus (HCV) coinfection or markedly elevated serum aminotransferase concentrations prior to initiation of rilpivirine may be at increased risk for development or worsening of aminotransferase elevations.1 If rilpivirine is used in patients with underlying hepatic disease (e.g., HBV or HCV infection, markedly elevated aminotransferase concentrations), laboratory tests should be performed to evaluate hepatic function prior to and during rilpivirine treatment.1 Liver enzyme monitoring also should be considered in patients without preexisting hepatic disease or other risk factors.1
Depressive disorders (e.g., depressed mood, depression, dysphoria, major depression, altered mood, negative thoughts, suicide attempt, suicidal ideation) have been reported in patients receiving rilpivirine.1 During phase 3 studies, 9% of adults receiving rilpivirine reported depressive disorders compared with 8% of patients receiving efavirenz.1 While most depressive events were reported to be mild or moderate in severity, 1% of adults in each treatment group reported a grade 3 or 4 depressive disorder and 1% in each treatment group discontinued therapy as a result of a depressive disorder.1 Suicidal ideation was reported in 4 adults in each treatment group and suicide attempt was reported in 2 adults receiving rilpivirine.1
During a phase 2 study evaluating rilpivirine in pediatric patients 12 to <18 years of age, the incidence of depressive disorders was 19.4%.1 While most depressive events were reported to be mild or moderate in severity, 5.6% of pediatric patients reported a grade 3 or 4 depressive disorder.1 Suicidal ideation and suicide attempt were reported in a single pediatric patient.1
Patients experiencing severe depressive symptoms should seek immediate medical evaluation to determine the likelihood that symptoms are related to rilpivirine and to determine if the benefits of continued rilpivirine therapy outweigh the risks.1
Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions
Concomitant use of rilpivirine with certain drugs (e.g., drugs that may reduce rilpivirine concentrations, drugs known to increase the risk of torsade de pointes) is contraindicated or requires particular caution.1 Some drug interactions may lead to loss of virologic effect of rilpivirine and the possible development of resistance.1 Consider the potential for drug interactions with concomitant medications prior to and during treatment with rilpivirine.1
Immune Reconstitution Syndrome
During the initial phase of treatment, HIV-infected patients whose immune systems respond to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium , M. tuberculosis , cytomegalovirus [CMV], Pneumocystis jirovecii [formerly P. carinii ]); such responses may necessitate further evaluation and treatment.1
Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome, autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of therapy.1
Formulations Are Not Substitutable
Rilpivirine tablets (Edurant®) and tablets for oral suspension (Edurant PED®) have differing pharmacokinetic profiles and are not substitutable on a milligram-per-milligram basis.1 When a pediatric patient weighs ≥25 kg, they must switch from rilpivirine tablets for oral suspension (Edurant PED®) to one 25 mg tablet rilpivirine tablet (Edurant®) daily.1 Incorrect dosing of a given formulation may lead to a loss of therapeutic effect and possible resistance development or the occurrence of clinically significant adverse reactions due to increased rilpivirine exposure.1
The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to rilpivirine during pregnancy.1 Clinicians are encouraged to register patients in the APR by calling 800-258-4263 or visiting [Web].1
The overall risk of birth defects with first-trimester exposure for rilpivirine was not markedly different compared to the background rate for major birth defects of 2.7% in the United States reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP).1 Limitations of using an external comparator (the MACDP) includes differences in populations and methodology, and confounding due to the underlying disease.1 The rate of miscarriage is not reported in the APR.1
In a small study of 19 HIV-1 infected women on a rilpivirine-based regimen, protein binding was similar during the second and third trimesters and the postpartum period; however, total exposure of rilpivirine was approximately 30-40% lower during pregnancy when compared to the postpartum period.1 Of the 12 virologically suppressed patients at baseline (<50 copies/mL), virologic suppression with a rilpivirine-based regimen was maintained through the third trimester in 10 patients, and was well-tolerated.1 Among 10 infants born to HIV-1 infected women, all were HIV-1 negative at delivery and for 16 weeks post-partum.1 All infants received prophylactic zidovudine treatment at delivery.1
Animal data have shown no increases in embryo-fetal toxicity at rilpivirine exposures 15-70 times the equivalent human exposure.1
Monitor viral load closely in pregnant women; lower rilpivirine exposures have been observed in pregnant individuals.1
Based on limited data, rilpivirine is present in human milk; however, there are no data on the effects of rilpivirine on the breast-fed infant or on milk production.1
The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding.202 The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding.202 During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant.202 Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk.202 Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.202
Safety and efficacy of rilpivirine tablets (Edurant®) and tablets for oral suspension (Edurant PED®) have been established for the treatment of HIV-1 infection in treatment-naïve pediatric patients ≥2 years of age and weighing ≥14 kg.1
The use of rilpivirine in this patient population is supported by the results of 3 trials (i.e., Trial TMC278-C213, Trial TMC278HTX2002, MOCHA trial).1 The single arm, open-label, phase 2, TMC278-C213 trial involved 2 cohorts of treatment-naïve HIV-1 infected pediatric patients.1 Cohort 1 assessed the efficacy, safety, and pharmacokinetics of rilpivirine tablets in 36 pediatric patients (12 to <18 years of age and weighing ≥32 kg).1 Cohort 2 assessed the safety, tolerability, antiviral activity, and pharmacokinetics of rilpivirine tablets and tablets for oral suspension weight-adjusted doses in 18 pediatric patients (6 to <12 years of age and weighing ≥17 kg).1 The single-arm, open-label, phase 2, TMC278HTX2002 trial assessed the safety, tolerability, antiviral activity, and pharmacokinetics of rilpivirine tablets and tablets for oral suspension weight-adjusted doses in 26 pediatric patients (2 to <12 years of age and weighing ≥16 kg).1 In the ongoing MOCHA trial, the safety, tolerability, and pharmacokinetics of oral/injectable cabotegravir and oral/injectable rilpivirine are being evaluated.1
Rilpivirine tablets for oral suspension (Edurant PED®) are not recommended for use in pediatric patients <2 years of age or weighing <14 kg.1
Experience in those 65 years of age and older is insufficient to determine whether they respond differently to rilpivirine than younger adults.1 Dosage should be selected with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.1
Rilpivirine (Edurant®) has not been studied in patients with severe hepatic impairment (Child-Pugh class C).1
During phase 3 clinical trials evaluating rilpivirine, HIV-infected patients coinfected with HBV and/or HCV had a higher incidence of increased serum aminotransferase concentrations compared with those without coinfection.1
Rilpivirine (Edurant®) should be used with caution, and with increased monitoring for adverse effects, in patients with severe renal impairment or end-stage renal disease since concentrations of the drug may be increased due to alterations in absorption, distribution, or metabolism.1
Adverse effects of at least moderate to severe intensity reported in 2% or more of patients in clinical trials include depressive disorders, insomnia, headache, and rash.1
Most rilpivirine drug interaction studies reported to date used rilpivirine dosages of 75 or 150 mg once daily;1 these dosages are considerably higher than the usually recommended rilpivirine dosage (25 mg once daily).1 Rilpivirine is primarily metabolized by cytochrome P-450 isoenzyme 3A (CYP3A).1
The following drug interactions are based on studies using single-entity rilpivirine.1 When rilpivirine fixed combinations are used, interactions associated with each drug in the fixed combination should be considered.13, 14, 233, 244
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Rilpivirine is metabolized by CYP3A.1 Concomitant use with drugs that induce CYP3A may result in decreased plasma rilpivirine concentrations and may result in possible loss of virologic response and development of resistance to rilpivirine or the HIV NNRTI class.1 Concomitant use with drugs that inhibit CYP3A may result in increased plasma rilpivirine concentrations.1
When the recommended rilpivirine dosage (25 mg once daily) is used, it is unlikely to have clinically important effects on the pharmacokinetics of drugs that are metabolized by CYP isoenzymes.1
Drugs that Increase Gastric pH
Concomitant use of rilpivirine and drugs that increase gastric pH may result in decreased plasma rilpivirine concentrations and may result in loss of virologic response and development of resistance to rilpivirine or the NNRTI class.1
Potential pharmacokinetic interaction if antacids such as aluminum hydroxide, calcium carbonate, or magnesium hydroxide are used concomitantly with rilpivirine (decreased plasma rilpivirine concentrations).1
Antacids and rilpivirine should be used concomitantly with caution; antacids should be administered at least 2 hours before or at least 4 hours after rilpivirine.1
Histamine H2-receptor Antagonists
Concomitant use of famotidine and rilpivirine has resulted in decreased rilpivirine plasma concentrations and area under the concentration-time curve (AUC).1 Concomitant use of other histamine H2-receptor antagonists may result in decreased rilpivirine plasma concentrations.1
Histamine H2-receptor antagonists and rilpivirine should be used concomitantly with caution; histamine H2-receptor antagonists should be administered at least 12 hours before or at least 4 hours after rilpivirine.1
Concomitant use of omeprazole and rilpivirine has resulted in decreased rilpivirine plasma concentrations and AUC.1 Concomitant use of other proton-pump inhibitors (e.g., esomeprazole, lansoprazole, pantoprazole, rabeprazole) also may result in decreased rilpivirine plasma concentrations.1
Concomitant use of proton-pump inhibitors and rilpivirine is contraindicated.1
Drugs that Prolong the QT Interval
Only limited data are available to date regarding the potential for pharmacodynamic interactions if rilpivirine is used concomitantly with drugs known to prolong the QT interval and increase the risk of torsade de pointes.1 Data from healthy individuals indicate that the recommended rilpivirine dosage (25 mg once daily) can result in increases in the corrected QT (QTc) interval that are not considered clinically important; however, higher rilpivirine dosage (75 or 300 mg once daily) results in clinically important prolongation of the QTc interval.1
Potential pharmacokinetic interactions when rilpivirine is used concomitantly with carbamazepine, oxcarbazepine, phenobarbital, or phenytoin may result in decreased virologic response.1
Concomitant use of anticonvulsants (e.g., carbamazepine, oxcarbazepine, phenobarbital, phenytoin) and rilpivirine is contraindicated.1
Concomitant use of ketoconazole and rilpivirine has resulted in increased rilpivirine plasma concentrations and AUC and decreased ketoconazole plasma concentrations and AUC.1 Concomitant use of other azole antifungals (e.g., fluconazole, itraconazole, posaconazole, voriconazole) and rilpivirine also may result in increased rilpivirine plasma concentrations and decreased antifungal plasma concentrations.1
When rilpivirine is used concomitantly with an azole antifungal (e.g., fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole), dosage adjustments are not needed; however, patients should be monitored for breakthrough fungal infections.1
Concomitant use of rilpivirine and rifampin or rifapentine results in decreased rilpivirine plasma concentrations and AUC and potential loss of virologic response.1
Concomitant use of rifampin or rifapentine with rilpivirine is contraindicated.1
Concomitant use of rifabutin and rilpivirine results in decreased rilpivirine plasma concentrations and AUC.1
If single-entity rilpivirine is used concomitantly with rifabutin, rilpivirine dosage should be increased to 50 mg once daily;1 if rifabutin is discontinued, the usual dosage of single-entity rilpivirine (25 mg once daily) should be resumed.1
HIV Entry and Fusion Inhibitors
No in vitro evidence of antagonistic antiretroviral effects between rilpivirine and enfuvirtide.1, 6
No in vitro evidence of antagonistic antiretroviral effects between rilpivirine and maraviroc.1, 6
Clinically important pharmacokinetic interactions are not expected.1
HIV Integrase Inhibitors (INSTIs)
Concomitant use of cabotegravir and rilpivirine does not have a clinically important effect on rilpivirine plasma concentrations or AUC.1 No dosage adjustments necessary.1
No in vitro evidence of antagonistic antiretroviral effects between rilpivirine and raltegravir.1
Concomitant use of raltegravir and rilpivirine does not have a clinically important effect on plasma concentrations or AUC of raltegravir or rilpivirine.1 Dosage adjustments are not needed for either drug.1
HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)
No in vitro evidence of antagonistic antiretroviral effects between rilpivirine and NNRTIs (efavirenz, etravirine, nevirapine).1
Concomitant use of efavirenz, etravirine, or nevirapine may result in decreased rilpivirine plasma concentrations.1
Concomitant use of rilpivirine and other NNRTIs (efavirenz, etravirine, nevirapine) is not recommended.1
HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
No in vitro evidence of antagonistic antiretroviral effects between rilpivirine and NRTIs (abacavir, emtricitabine, lamivudine, tenofovir, zidovudine).1
Although not specifically studied, clinically important pharmacokinetic interactions are not expected if rilpivirine is used concomitantly with abacavir, emtricitabine, lamivudine, or zidovudine.1
Concomitant use of tenofovir DF and rilpivirine has resulted in increased tenofovir plasma concentrations and AUC, but did not have a clinically important effect on rilpivirine plasma concentrations or AUC.1
Dosage adjustments are not needed if tenofovir DF and rilpivirine are used concomitantly.1
No in vitro evidence of antagonistic antiretroviral effects between rilpivirine and PIs (amprenavir [commercially available as fosamprenavir], atazanavir, darunavir, lopinavir, nelfinavir, ritonavir, tipranavir).1
Concomitant use of rilpivirine and ritonavir-boosted atazanavir or unboosted atazanavir may result in increased rilpivirine plasma concentrations, but is not expected to affect atazanavir concentrations.1
Dosage adjustments are not needed if rilpivirine is used concomitantly with ritonavir-boosted or unboosted atazanavir.1
Concomitant use of rilpivirine and ritonavir-boosted darunavir resulted in increased rilpivirine plasma concentrations and AUC, but did not have a clinically important effect on darunavir concentrations or AUC.1
Dosage adjustments are not needed if rilpivirine is used concomitantly with ritonavir-boosted darunavir.1
Concomitant use of rilpivirine and fosamprenavir or ritonavir-boosted fosamprenavir may result in increased rilpivirine plasma concentrations, but is not expected to affect amprenavir concentrations (active metabolite of fosamprenavir).1
Dosage adjustments are not needed if fosamprenavir (with or without low-dose ritonavir) and rilpivirine are used concomitantly.1
Concomitant use of rilpivirine and the fixed combination of lopinavir and ritonavir (lopinavir/ritonavir) increased rilpivirine plasma concentrations and AUC, but did not have a clinically important effect on lopinavir plasma concentrations or AUC.1
Dosage adjustments are not needed if lopinavir/ritonavir and rilpivirine are used concomitantly.1
Concomitant use of nelfinavir may result in increased rilpivirine plasma concentrations, but is not expected to affect nelfinavir concentrations.1 Dosage adjustments are not necessary if nelfinavir and rilpivirine are used concomitantly.1
Concomitant use of rilpivirine and ritonavir-boosted tipranavir may result in increased rilpivirine plasma concentrations, but is not expected to affect tipranavir concentrations.1
Dosage adjustments are not needed if ritonavir-boosted tipranavir and rilpivirine are used concomitantly.200
Clinically important pharmacokinetic interactions have not been observed when atorvastatin and rilpivirine were used concomitantly; dosage adjustments are not needed.1
Clinically important pharmacokinetic interactions between rilpivirine and chlorzoxazone have not been observed; dosage adjustments are not needed.1
Potential pharmacokinetic interaction if multiple doses of systemic dexamethasone are used concomitantly with rilpivirine (decreased plasma rilpivirine concentrations).1 Concomitant use of more than a single dose of dexamethasone with rilpivirine is contraindicated.1
Rilpivirine does not have a clinically important effect on digoxin pharmacokinetics.1
Clinically important pharmacokinetic interactions have not been observed when usual rilpivirine dosage was used concomitantly with hormonal contraceptives containing ethinyl estradiol and norethindrone; dosage adjustments are not needed.1
Macrolides or Ketolide Antibiotics
Concomitant use of rilpivirine and clarithromycin or erythromycin may result in increased rilpivirine plasma concentrations and is associated with an increased risk of torsade de points, but is not expected to affect plasma concentrations of the macrolide.1 When possible, an alternative agent, or a macrolide such as azithromycin should be considered since azithromycin has less effect on rilpivirine concentrations in comparison to other macrolides.1
Rilpivirine does not have a clinically important effect on metformin pharmacokinetics.1
Concomitant use of methadone and usual rilpivirine dosage resulted in decreased concentrations of the R-enantiomer of methadone and increased concentrations of the S-enantiomer of methadone in a clinical study, but did not have a clinically important effect on rilpivirine concentrations or AUC.1
Although adjustment of initial methadone dosage is not needed when methadone and rilpivirine are used concomitantly, close monitoring is recommended and methadone maintenance dosage may need to be adjusted in some patients.1
Clinically important pharmacokinetic interactions between rilpivirine and ribavirin are not expected.1
Clinically important pharmacokinetic interactions have not been observed when sildenafil and rilpivirine were used concomitantly; dosage adjustments are not needed.1
Potential pharmacokinetic interaction if St. John's wort ( Hypericum perforatum ) is used concomitantly with rilpivirine (decreased plasma rilpivirine concentrations); may result in loss of therapeutic effect and development of resistance.1 Concomitant use of St. John's wort and rilpivirine is contraindicated.1
Rilpivirine, a diarylpyrimidine human immunodeficiency virus (HIV) nonnucleoside reverse transcriptase inhibitor (NNRTI), inhibits replication of HIV type 1 (HIV-1) by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase.1, 4, 7, 8 Diarylpyrimidine NNRTIs (e.g., rilpivirine, etravirine) are capable of adapting to mutations in HIV-1 reverse transcriptase because of structural flexibility that allows for binding to the allosteric NNRTI binding pocket in a variety of conformations.5, 6, 7 Unlike other currently available NNRTIs, rilpivirine contains a cyanovinyl group that contributes to potency and maintains the drug's binding ability, despite the emergence of some resistance mutations.4, 5, 7, 9 In vitro, rilpivirine is highly active against wild-type HIV-1, but has limited activity against HIV type 2 (HIV-2).1, 6 Rilpivirine has been active against some clinical HIV-1 isolates resistant to other commercially available NNRTIs (efavirenz, nevirapine).1, 6, 8 However rilpivirine-resistant strains have been selected in cell culture and have emerged during clinical use.1, 3, 6, 10
Cross-resistance can occur between rilpivirine and other commercially available NNRTIs,1, 6, 10, 11 and is expected in patients who have virologic failure while receiving a regimen that contains rilpivirine.1 Considerable cross-resistance occurs between rilpivirine and etravirine; up to 90% of rilpivirine-resistant isolates that developed in patients receiving rilpivirine in phase 3 clinical studies also were resistant to etravirine.1, 8 In addition, patients experiencing virologic failure while receiving a rilpivirine regimen in phase 3 clinical studies were more likely to have developed NNRTI-class resistance and treatment-emergent resistance to nucleoside and HIV nucleotide reverse transcriptase inhibitors (NRTIs) than patients experiencing virologic failure while receiving an efavirenz regimen.1, 8, 10, 11
After oral administration, peak rilpivirine plasma concentrations are generally attained within 4-5 hours.1 Rilpivirine is primarily metabolized in the liver by cytochrome (CYP) P-450 isoenzyme 3A.1 After a single oral dose, an average of 85% of the dose is eliminated in feces (75% as metabolites) and 6% is eliminated in urine (only trace amounts as unchanged rilpivirine).1 The terminal elimination half-life of rilpivirine is approximately 50 hours.1 In individuals with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment receiving multiple doses of rilpivirine, exposure to the drug was 47 or 5% higher, respectively, compared to healthy individuals.1 Coinfection with HIV and hepatitis B virus (HBV) and/or hepatitis C virus (HCV) does not appear to have a clinically important effect on exposure to the drug.1 Mild renal impairment does not have a clinically important effect on rilpivirine pharmacokinetics.1 Only limited data are available regarding pharmacokinetics of the drug in patients with moderate or severe renal impairment or end-stage renal disease, but rilpivirine concentrations may be increased as a result of altered absorption, distribution, or elimination.1 In vitro studies indicate that rilpivirine is approximately 99.7% bound to plasma proteins, primarily albumin.1 Because rilpivirine is highly bound to plasma proteins, peritoneal dialysis and hemodialysis are unlikely to result in clinically important removal of the drug.1 Total exposure to rilpivirine dosage of 25 mg once daily is 30-40% lower during pregnancy when compared to the postpartum period; however, based on the exposure-response relationship of rilpivirine, this is not considered clinically relevant in patients who are virologically suppressed (viral load <50 copies/mL).1 Protein binding of rilpivirine is approximately 99% during the second and third trimesters, and the postpartum period.1 Clinically relevant differences in pharmacokinetics based on sex, race, or hepatitis B and/or C coinfection have not been observed.1 Pharmacokinetics in treatment-naïve HIV-1-infected pediatric patients 2 to less than 18 years of age and weighing ≥16 kg receiving the recommended weight-based dosing regimen of rilpivirine tablets and tablets for oral suspension are similar or slightly higher than those observed in treatment-naïve adult patients.1 In clinical trials, body weight in pediatric patients (ranging from 33-93 kg) did not have a clinically important effect on rilpivirine pharmacokinetics.1
Additional Information
The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
1. Janssen Therapeutics. Edurant® (rilpivirine) tablets and Edurant® tablets for oral suspension prescribing information. Horsham, PA; 2024 Mar.
2. Cohen CJ, Molina JM, Cahn P et al. Efficacy and safety of rilpivirine (TMC278) versus efavirenz at 48 weeks in treatment-naive HIV-1-infected patients: pooled results from the phase 3 double-blind randomized ECHO and THRIVE Trials. J Acquir Immune Defic Syndr . 2012; 60:33-42. [PubMed 22343174]
3. Pozniak AL, Morales-Ramirez J, Katabira E et al. Efficacy and safety of TMC278 in antiretroviral-naive HIV-1 patients: week 96 results of a phase IIb randomized trial. AIDS . 2010; 24:55-65. [PubMed 19926964]
4. Ripamonti D, Maggiolo F. Rilpivirine, a non-nucleoside reverse transcriptase inhibitor for the treatment of HIV infection. Curr Opin Investig Drugs . 2008; 9:899-912. [PubMed 18666038]
5. Chen X, Zhan P, Li D et al. Recent advances in DAPYs and related analogues as HIV-1 NNRTIs. Curr Med Chem . 2011; 18:359-76. [PubMed 21143120]
6. Azijn H, Tirry I, Vingerhoets J et al. TMC278, a next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI), active against wild-type and NNRTI-resistant HIV-1. Antimicrob Agents Chemother . 2010; 54:718-27. [PubMed 19933797]
7. Fulco PP, McNicholl IR. Etravirine and rilpivirine: nonnucleoside reverse transcriptase inhibitors with activity against human immunodeficiency virus type 1 strains resistant to previous nonnucleoside agents. Pharmacotherapy . 2009; 29:281-94. [PubMed 19249947]
8. Miller CD, Crain J, Tran B et al. Rilpivirine: a new addition to the anti-HIV-1 armamentarium. Drugs Today (Barc) . 2011; 47:5-15. [PubMed 21373646]
9. Das K, Bauman JD, Clark AD et al. High-resolution structures of HIV-1 reverse transcriptase/TMC278 complexes: strategic flexibility explains potency against resistance mutations. Proc Natl Acad Sci U S A . 2008; 105:1466-71. [PubMed 18230722]
10. Molina JM, Cahn P, Grinsztejn B et al. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial. Lancet . 2011; 378:238-46. [PubMed 21763936]
11. Cohen CJ, Andrade-Villanueva J, Clotet B et al. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial. Lancet . 2011; 378:229-37. [PubMed 21763935]
12. Nelson MR, Elion RA, Cohen CJ et al. Rilpivirine versus efavirenz in HIV-1-infected subjects receiving emtricitabine/tenofovir DF: pooled 96-week data from ECHO and THRIVE Studies. HIV Clin Trials . 2013 May-Jun; 14:81-91.
13. ViiV Healthcare Company. Juluca® (dolutegravir sodium and rilpivirine hydrochloride) tablets prescribing information. Durham, NC; 2022 Oct.
14. ViiV Healthcare Company. Cabenuva® (cabotegravir and rilpivirine) prescribing information. Research Triangle Park, NC; 2022 Apr.
17. ViiV Healthcare Company. Vocabria® (cabotegravir sodium) tablets prescribing information. Research Triangle Park, NC; 2022 Mar.
18. Orkin C, Arasteh K, Górgolas Hernández-Mora M et al. Long-Acting Cabotegravir and Rilpivirine after Oral Induction for HIV-1 Infection. N Engl J Med. 2020; 382:1124-1135.
19. Orkin C, Bernal Morell E, Tan DHS et al. Initiation of long-acting cabotegravir plus rilpivirine as direct-to-injection or with an oral lead-in in adults with HIV-1 infection: week 124 results of the open-label phase 3 FLAIR study. Lancet HIV. 2021; 8:e668-e678.
20. Swindells S, Andrade-Villanueva J-F, Richmond GJ et al. Long-Acting Cabotegravir and Rilpivirine for Maintenance of HIV-1 Suppression. N Engl J Med. 2020; 382:1112-23.
21. Swindells S, Luts T, Van Zyl L et al. Week 96 extension results of a Phase 3 study evaluating long-acting cabotegravir with rilpivirine for HIV-1 treatment. AIDS. 2022; 36:185-94.
22. Overton ET, Richmond G, Rizzardini G et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study. Lancet. 2020; 396:1994-2005.
23. Jaeger H, Overton ET, Richmond G et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 96-week results: a randomised, multicentre, open-label, phase 3b, non-inferiority study. Lancet HIV. 2021; 8:e679-e689.
24. Llibre JM, Hung CC, Brinson C et al. Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies. Lancet. 2018; 391:839-49.
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