AHFS Class:

• HIV Nonnucleoside Reverse Transcriptase Inhibitors 8:18.08.16

Generic Name(s):

• Rilpivirine Hydrochloride

• Emtricitabine, Rilpivirine Hydrochloride, and Tenofovir Alafenamide

• Emtricitabine, Rilpivirine Hydrochloride, and Tenofovir Disoproxil Fumarate

• Dolutegravir and Rilpivirine Hydrochloride

• Cabotegravir and Rilpivirine Hydrochloride

Rilpivirine, an antiretroviral agent, is a human immunodeficiency virus (HIV) nonnucleoside reverse transcriptase inhibitor (NNRTI).1,4,8

Treatment of HIV Infection

Rilpivirine is used in conjunction with other antiretroviral (ARV) agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in treatment-naïve and previously treated† adults and adolescents ≥12 years of age and weighing ≥35 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 Rilpivirine is included in various ARV regimens recommended in guidelines for treatment of HIV in adults and adolescents, pediatric patients, and pregnant patients ( only in patients aged ≥12 years and weighing ≥35 kg with HIV viral load <100,000 copies/mL).200,201,202 Fixed dose combinations containing rilpivirine and dolutegravir (Juluca^®); rilpivirine and cabotegravir (Cabenuva^®); rilpivirine, emtricitabine, and tenofovir disoproxil fumarate (DF, Complera^®); and rilpivirine, emtricitabine, and tenofovir alafenamide (Odefsey^®) are also used in the treatment of HIV infection.13,14,233,244 See the full prescribing information for use of each of these combination products.

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 ARV 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 ARV 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 ARV 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 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-naive 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

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

Clinical Perspective in Adult and Pediatric Patients

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 ART 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 ARV 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 ARVs 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 ARV 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 ARV regimen generally consists of 2 NRTIs administered in combination with a third active ARV 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 ARV 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 2022 HHS Adult and Adolescent HIV treatment guideline, rilpivirine, an NNRTI, is included in various ARV regimens.200 One of these rilpivirine-containing regimens is listed among alternative initial regimens recommended in certain clinical situations: rilpivirine/tenofovir alafenamide/emtricitabine or rilpivirine/tenofovir DF/emtricitabine (only in patients with <200 cells/mm³, HIV viral load <100,000 copies/mL, and who have drug resistance testing results available).200

In the 2022 HHS Pediatric HIV treatment guideline, rilpivirine is included in various ARV regimens.201 Rilpivirine in combination with 2 NRTIs is recommended as an alternative initial regimen in certain clinical situations (only in patients aged ≥12 years and weighing ≥35 kg with HIV viral load <100,000 copies/mL), based primarily on evidence in adults.201

In the 2022 HHS Perinatal HIV treatment guideline, rilpivirine is included in various ARV 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).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 ARV 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

Clinical Experience

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

Clinical Perspective

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 ARV 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 an ARV regimen not included in the CDC guidelines is being considered, the source virus is known or likely to be resistant to ARVs, or the healthcare provider is inexperienced in prescribing ARVs.198 However, initiation of nPEP should not be delayed while waiting for expert consultation.198

General

Pretreatment Screening

• Assess liver function tests prior to therapy initiation in patients with underlying hepatic disease such as hepatitis B and/or C co-infection or marked elevations in transaminase.1
• Review concomitant medications for potential drug interactions prior to initiation of rilpivirine to avoid potential loss of virologic response.1

Patient Monitoring

• Monitor liver function tests during therapy in patients with underlying hepatic disease such as hepatitis B virus and/or C co-infection, or marked elevations in transaminase.1 Consider monitoring liver function tests if no underlying hepatic dysfunction or risk factors.1
• Review concomitant medications during therapy and consider potential for drug interactions with rilpivirine to avoid potential loss of virologic response.1

Dispensing and Administration Precautions

• Rilpivirine is commercially available as a single entity and in various fixed-combination preparations containing additional ARV agents.13,14,233,244 Refer to the full prescribing information for specific, distinct uses of the combination products.13,14,233,244 Since the ARV agents contained in the fixed combination preparations also may be available in single-entity or other fixed-combination preparations, exercise care to ensure that therapy is not duplicated if a fixed combination is used in conjunction with other ARVs.13,14,233,244

Administration

Rilpivirine hydrochloride is available as oral tablets and is administered orally once daily with a meal.1

Food enhances rilpivirine bioavailability.1 Systemic exposure is 40 or 50% lower if rilpivirine is 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

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 ARVs.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 at 25ºC; (excursions permitted between 15-30ºC).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

Dosage

Rilpivirine is commercially available as rilpivirine hydrochloride;1 dosage is expressed in terms of rilpivirine.1

Pediatric Dosage

Treatment of HIV Infection in Antiretroviral-naïve Pediatric Patients

For the treatment of HIV-1 infection in antiretroviral-naïve adolescents 12 years of age or older weighing at least 35 kg with plasma RNA levels ≤100,000 copies/mL at therapy initiation, the usual dosage of rilpivirine (Edurant^®) is 25 mg once daily.1

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 Pediatric Patients Receiving Rifabutin

If single-entity rilpivirine is used in conjunction with other ARVs for the treatment of HIV-1 infection in pediatric patients weighing at least 35 kg receiving rifabutin, an increased rilpivirine dosage of 50 mg daily should be used.1 When rifabutin coadministration is stopped, the rilpivirine dose should be decreased to 25 mg once daily.1

Adult Dosage

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

Treatment of HIV Infection in Adults Receiving Rifabutin

If single-entity rilpivirine is used in conjunction with other ARVs for the treatment of HIV-1 infection in adults receiving rifabutin, an increased rilpivirine dosage of 50 mg daily should be used.1 When rifabutin coadministration is stopped, the rilpivirine dose should be decreased to 25 mg once daily.1

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

Special Populations

Hepatic Impairment

Dosage adjustment of rilpivirine (Edurant^®) 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

Renal Impairment

Dosage adjustment of rilpivirine (Edurant^®) 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

Geriatric Use

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

Contraindications

Concomitant use of rilpivirine with drugs that induce cytochrome P-450 isoenzyme 3A (CYP3A) or drugs that elevate gastric pH is contraindicated since substantially decreased plasma rilpivirine concentrations may occur and may result in loss of virologic response and development of resistance to rilpivirine and/or class resistance to HIV NNRTIs.1

Warnings/Precautions

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 (ARV) 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 ARV 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

Hepatotoxicity

Adverse hepatic effects have been reported in patients receiving rilpivirine in conjunction with other ARVs.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 transaminase 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

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 ARV therapy.1

Specific Populations

Pregnancy

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 rilpirivine exposures 15-70 -times the equivalent human exposure.1

No dosage adjustments are necessary in pregnancy for females who are stable on a rilpivirine-containing regimen prior to pregnancy and who are virologically suppressed (<50 copies/mL).1 The recommended dosage in pregnancy is 25 mg once daily.1 Monitor viral load closely in pregnant women; lower rilpivirine exposures have been observed in pregnant individuals.1

Lactation

It is not known whether rilpivirine is distributed into human milk or the effects on a breastfed infant or milk production; however, the drug is distributed into milk in rats.1

Because of the risk of adverse effects in the infant and the risk of HIV transmission, HIV-infected females should not breast-feed infants.1

Pediatric Use

Safety and efficacy of single-entity rilpivirine (Edurant^®) have not been established in pediatric patients younger than 12 years of age or weighing <35 kg.1,201

Depressive disorders have been reported in pediatric patients 12 to <18 years of age receiving rilpivirine-containing regimens.1

Geriatric Use

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

Hepatic Impairment

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

Renal Impairment

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

Common Adverse Effects

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

Antacids

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

Proton-pump Inhibitors

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 (QT_c) interval that are not considered clinically important; however, higher rilpivirine dosage (75 or 300 mg once daily) results in clinically important prolongation of the QT_c interval.1

Anticonvulsants

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

Antifungal Agents

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

Antimycobacterial Agents

Rifampin and Rifapentine

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

Rifabutin

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

Antiretroviral Agents

HIV Entry and Fusion Inhibitors

Enfuvirtide

No in vitro evidence of antagonistic antiretroviral effects between rilpivirine and enfuvirtide.1,6

Maraviroc

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)

Cabotegravir

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

Raltegravir

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 delavirdine and rilpivirine may result in increased rilpivirine plasma concentrations; concomitant use of efavirenz, etravirine, or nevirapine may result in decreased rilpivirine plasma concentrations.1

Concomitant use of rilpivirine and other NNRTIs (delavirdine, 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, didanosine, 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

Didanosine

Pharmacokinetic interactions were not observed when didanosine delayed-release capsules were administered 2 hours before rilpivirine.1 Although dosage adjustments are not needed if rilpivirine and didanosine are used concomitantly, didanosine should be administered (without food) at least 2 hours before or 4 hours after rilpivirine (with food).1

Tenofovir

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

HIV Protease Inhibitors (PIs)

No in vitro evidence of antagonistic antiretroviral effects between rilpivirine and PIs (amprenavir [commercially available as fosamprenavir], atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir).1

Atazanavir

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

Darunavir

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

Fosamprenavir

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

Indinavir

Concomitant use of rilpivirine and indinavir may result in increased rilpivirine plasma concentrations, but is not expected to affect indinavir concentrations.1 Dosage adjustments are not necessary if rilpivirine and indinavir are used concomitantly.1

Lopinavir

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

Nelfinavir

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

Saquinavir

Concomitant use of rilpivirine and ritonavir-boosted saquinavir may result in increased rilpivirine plasma concentrations, but is not expected to affect saquinavir concentrations.1

Dosage adjustments are not needed if ritonavir-boosted saquinavir and rilpivirine are used concomitantly.1

Tipranavir

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

Atorvastatin

Clinically important pharmacokinetic interactions have not been observed when atorvastatin and rilpivirine were used concomitantly; dosage adjustments are not needed.1

Chlorzoxazone

Clinically important pharmacokinetic interactions between rilpivirine and chlorzoxazone have not been observed; dosage adjustments are not needed.1

Dexamethasone

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

Digoxin

Rilpivirine does not have a clinically important effect on digoxin pharmacokinetics.1

Estrogens and Progestins

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

Metformin

Rilpivirine does not have a clinically important effect on metformin pharmacokinetics.1

Methadone

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

Sildenafil

Clinically important pharmacokinetic interactions have not been observed when sildenafil and rilpivirine were used concomitantly; dosage adjustments are not needed.1

Simeprevir

Concomitant use of simeprevir and rilpivirine does not have a clinically important effect on simeprevir or rilpivirine pharmacokinetics; dosage adjustments are not needed.1

Ribavirin

Clinically important pharmacokinetic interactions between rilpivirine and ribavirin are not expected.1

St. John's Wort

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

Description

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 (delavirdine, 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 (<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 gender, race, or hepatitis B and/or C coinfection have not been observed.1 Pharmacokinetics in treatment-naïve HIV-1-infected pediatric patients 12 to less than 18 years of age receiving rilpivirine 25 mg once daily are similar to 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

Advice to Patients

• Advise patients of the critical nature of compliance with human immunodeficiency virus (HIV) therapy and importance of remaining under the care of a clinician.1 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1
• Counsel patients on the importance of using single-entity rilpivirine in conjunction with other antiretrovirals—not for monotherapy.1
• Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1
• Advise patients that sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to acquired immunodeficiency syndrome (AIDS) and death.1
• Advise patients that effective antiretroviral regimens can decrease HIV concentrations in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others.200 Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids), never sharing personal items that can have blood or body fluids on them (e.g., toothbrushes, razor blades), and never reusing or sharing needles.1,200
• Advise patients of the importance of taking once daily with a meal;1 a protein drink alone does not constitute a meal.1 Food enhances absorption of rilpivirine.1
• Counsel patients that if a missed dose of rilpivirine is remembered within 12 hours, it should be taken with a meal as soon as possible and the next dose taken at the regularly scheduled time.1 If the missed dose is remembered more than 12 hours after the scheduled time, the dose should be omitted and the next dose taken at the regularly scheduled time.1 Advise patients that doses that are larger or smaller than the prescribed dosage should not be taken at any time.1
• Advise patients that skin reactions ranging from mild to severe, including drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported with rilpivirine-containing antiretroviral regimens.1 Instruct patients to immediately stop taking rilpivirine (single-entity or fixed-combination preparations) and contact a clinician if rash develops and is also associated with fever, blisters, mucosal involvement, eye inflammation (conjunctivitis), swelling of the face, eyes, lips, mouth, tongue, or throat which may lead to difficulty swallowing or breathing, or any signs and symptoms of liver problems.1
• Advise patients that depressive disorders (e.g., depressed mood, depression, dysphoria, major depression, altered mood, negative thoughts, suicide attempt, suicidal ideation) have been reported.1 Importance of immediately contacting clinician if depressive symptoms (e.g., feeling sad, hopeless, anxious, or restless; hurting oneself; having thoughts of hurting oneself) occur.1
• Advise patients that hepatotoxicity has been reported in patients receiving rilpivirine.1
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements (e.g., St. John's wort), and any concomitant illnesses.1
• Importance of females informing clinicians if they are or plan to become pregnant or plan to breast-feed.1
• Importance of advising patients of other important precautionary information.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.

1. Janssen Therapeutics. Edurant^® (rilpivirine) tablets prescribing information. Titusville, NJ; 2022 Oct.

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.

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