Rilpivirine (Monograph)

Brand name: Edurant
Drug class: HIV Nonnucleoside Reverse Transcriptase Inhibitors
Chemical name: Benzonitrile, 4-[[4-[[4-[(1E)-2-Cyanoethenyl]-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]-,hydrochloride
Molecular formula: C₂₂H₁₈N₆•HCl
CAS number: 700361-47-3

Medically reviewed by Drugs.com on Sep 26, 2022. Written by ASHP.

Warning

If using emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey) or emtricitabine/rilpivirine/tenofovir DF (Complera), consider that lactic acidosis and severe hepatomegaly with steatosis, including fatalities, have been reported in patients receiving HIV nucleoside reverse transcriptase inhibitors (NRTIs) in conjunction with other antiretrovirals.
If using emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey) or emtricitabine/rilpivirine/tenofovir DF (Complera), consider that severe, acute exacerbations of HBV have been reported following discontinuance of emtricitabine or tenofovir DF in HIV-infected patients coinfected with HBV. These fixed combinations are not labeled by FDA for treatment of chronic HBV infection; safety and efficacy not established in HIV-infected patients coinfected with HBV. Monitor hepatic function closely with both clinical and laboratory follow-up for at least several months after fixed combination is discontinued in coinfected patients. If appropriate, initiation of HBV treatment may be warranted.

Introduction

Antiretroviral; HIV nonnucleoside reverse transcriptase inhibitor (NNRTI).

Uses for Rilpivirine

Treatment of HIV Infection

Treatment of HIV-1 infection in adults and adolescents ≥12 years of age with baseline plasma HIV-1 RNA levels ≤100,000 copies/mL; used in conjunction with other antiretrovirals.

Single-entity rilpivirine used in conjunction with 2 HIV NRTIs in certain antiretroviral-naive adults and adolescents ≥12 years of age. Also commercially available in fixed combinations containing emtricitabine and a tenofovir prodrug (either tenofovir alafenamide or tenofovir disoproxil fumarate [tenofovir DF]); these fixed combinations used in certain patient groups to decrease pill burden and improve compliance.

For initial treatment in antiretroviral-naive adults, experts state that rilpivirine in conjunction with tenofovir alafenamide and emtricitabine or rilpivirine in conjunction with tenofovir DF and emtricitabine (or lamivudine) are alternative NNRTI-based regimens, but use only in patients with baseline plasma HIV-1 RNA levels <100,000 copies/mL and baseline CD4⁺ T-cell count >200 cells/mm³.

For initial treatment in HIV-infected pediatric patients, experts state that rilpivirine and 2 NRTIs is an alternative HIV NNRTI-based regimen in antiretroviral-naive adolescents ≥12 years of age weighing ≥35 kg, but use only in those with baseline plasma HIV-1 RNA levels <100,000 copies/mL.

Emtricitabine/rilpivirine/tenofovir alafenamide fixed combination (Odefsey) can be used alone as a complete treatment regimen in antiretroviral-naive adults and adolescents ≥12 years of age weighing ≥35 kg with baseline plasma HIV-1 RNA levels ≤100,000 copies/mL; also can be used to replace a stable antiretroviral regimen in antiretroviral-experienced patients who are virologically suppressed (i.e., plasma HIV-1 RNA levels <50 copies/mL) on their current regimen for ≥6 months, have no history of treatment failure, and are infected with HIV-1 with no known substitutions associated with resistance to the components of the fixed combination.

Emtricitabine/rilpivirine/tenofovir DF fixed combination (Complera) can be used alone as a complete treatment regimen in antiretroviral-naive adults and adolescents ≥12 years of age weighing ≥35 kg with baseline plasma HIV-1 RNA levels ≤100,000 copies/mL; also can be used to replace a stable antiretroviral regimen in antiretroviral-experienced patients who are virologically suppressed (i.e., plasma HIV-1 RNA levels <50 copies/mL) on their current regimen for ≥6 months, are currently receiving only their first or second antiretroviral regimen, have no history of treatment failure, and have no current evidence or history of resistance to the components of the fixed combination.

Consider that patients with baseline plasma HIV-1 RNA levels >100,000 copies/mL have had higher rates of virologic failure while receiving a rilpivirine regimen than those with lower baseline HIV-1 RNA levels. Also consider that patients with baseline CD4⁺ T-cell counts <200 cells/mm³ (regardless of HIV-1 RNA levels) have had higher rates of virologic failure while receiving a rilpivirine regimen than those with higher baseline CD4⁺ T-cell count.

Patients experiencing virologic failure while receiving a rilpivirine regimen have had higher rates of overall treatment resistance and NNRTI-class cross-resistance than those receiving an efavirenz regimen. In addition, resistance to lamivudine and emtricitabine) developed more frequently in patients receiving rilpivirine and these NRTIs than in patients receiving an efavirenz and these NRTIs.

Postexposure Prophylaxis following Occupational Exposure to HIV (PEP)

Postexposure prophylaxis of HIV infection following occupational exposure^{† [off-label]} (PEP) in health-care personnel and others 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. Used in conjunction with other antiretrovirals.

USPHS recommends 3-drug regimen of raltegravir in conjunction with emtricitabine and tenofovir DF as the preferred regimen for PEP following occupational exposures to HIV. Rilpivirine and 2 NRTIs is one of several alternative regimens. Preferred dual NRTI option for use in PEP regimens is emtricitabine and tenofovir DF (may be given as emtricitabine/tenofovir DF; Truvada); alternative dual NRTIs are tenofovir DF and lamivudine, lamivudine and zidovudine (may be given as lamivudine/zidovudine; Combivir), or zidovudine and emtricitabine.

Management of occupational exposures to HIV is complex and evolving; consult infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) whenever possible. Do not delay initiation of PEP while waiting for expert consultation.

Postexposure Prophylaxis following Nonoccupational Exposure to HIV (nPEP)

Postexposure prophylaxis of HIV infection following nonoccupational exposure^{† [off-label]} (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids that might contain HIV when the exposure represents a substantial risk for HIV transmission. Used in conjunction with other antiretrovirals.

When nPEP indicated in adults and adolescents ≥13 years of age with normal renal function, CDC states preferred regimen is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (given as emtricitabine/tenofovir DF; Truvada); recommended alternative is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF (Truvada). Rilpivirine and 2 NRTIs (may be given as emtricitabine/rilpivirine/tenofovir DF; Complera) is one of several other alternative regimens for nPEP.

Consult infectious disease specialist, clinician with expertise in administration of antiretroviral agents, and/or the National Clinicians’ Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) if nPEP indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment) or if considering a regimen not included in CDC guidelines, source virus is known or likely to be resistant to antiretrovirals, or healthcare provider is inexperienced in prescribing antiretrovirals. Do not delay initiation of nPEP while waiting for expert consultation.

Rilpivirine Dosage and Administration

Administration

Oral Administration

Rilpivirine (Edurant): Administer orally once daily with a meal. Use in conjunction with other antiretrovirals.

Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey): Administer orally once daily with a meal. Use alone as a complete treatment regimen.

Emtricitabine/rilpivirine/tenofovir DF (Complera): Administer orally once daily with a meal. Use alone as a complete treatment regimen.

Systemic exposure substantially decreased if rilpivirine given on empty stomach or with only a protein-rich nutritional drink.

Because antiretrovirals in the fixed combinations also may be available in single-entity or other fixed-combination preparations, take care to ensure that therapy is not duplicated if a fixed combination is used in conjunction with other antiretrovirals. (See Precautions Related to Use of Fixed Combinations under Cautions.)

Do not use single-entity rilpivirine (Edurant) and emtricitabine/rilpivirine/tenofovir alafenamide concomitantly.

Do not use single-entity rilpivirine (Edurant) and emtricitabine/rilpivirine/tenofovir DF (Complera) concomitantly, unless needed for adjustment of rilpivirine dosage (e.g., when fixed combination used concomitantly with rifabutin).

Because of the tenofovir component, determine estimated CL_cr, urine glucose, and urine protein prior to and monitor during treatment with emtricitabine/rilpivirine/tenofovir alafenamide or emtricitabine/rilpivirine/tenofovir DF in all patients. In addition, monitor serum phosphorous in those with chronic kidney disease or at risk for renal impairment. (See Renal Impairment under Cautions.)

Dosage

Available as rilpivirine hydrochloride; dosage expressed in terms of rilpivirine.

Pediatric Patients

Treatment of HIV Infection in Antiretroviral-naive Pediatric Patients

Oral

Rilpivirine (Edurant) in adolescents ≥12 years of age weighing ≥35 kg: 25 mg once daily.

Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey) in adolescents ≥12 years of age weighing ≥35 kg: 1 tablet (emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir alafenamide 25 mg) once daily.

Emtricitabine/rilpivirine/tenofovir DF (Complera) in adolescents ≥12 years of age weighing ≥35 kg: 1 tablet (emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir DF 300 mg) once daily.

Treatment of HIV Infection in Antiretroviral-experienced Pediatric Patients

Oral

Emtricitabine/rilpivirine/tenofovir DF (Complera) in adolescents ≥12 years of age weighing ≥35 kg: 1 tablet (emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir DF 300 mg) once daily.

Treatment of HIV Infection in Pediatric Patients Receiving Rifabutin

Oral

Rilpivirine (Edurant) in adolescents ≥12 years of age weighing ≥35 kg: 50 mg once daily. (See Specific Drugs under Interactions.)

Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey) in adolescents ≥12 years of age weighing ≥35 kg: Concomitant use with rifabutin not recommended.

Emtricitabine/rilpivirine/tenofovir DF (Complera) in adolescents ≥12 years of age weighing ≥35 kg: 1 tablet (emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir DF 300 mg) once daily and 25 mg of single-entity rilpivirine (Edurant) once daily to provide total rilpivirine dosage of 50 mg daily. (See Specific Drugs under Interactions.)

Adults

Treatment of HIV Infection in Antiretroviral-naive Adults

Oral

Rilpivirine (Edurant): 25 mg once daily.

Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey): 1 tablet (emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir alafenamide 25 mg) once daily.

Emtricitabine/rilpivirine/tenofovir DF (Complera): 1 tablet (emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir DF 300 mg) once daily.

Treatment of HIV Infection in Antiretroviral-experienced Adults

Oral

Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey): 1 tablet (emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir alafenamide 25 mg) once daily.

Emtricitabine/rilpivirine/tenofovir DF (Complera): 1 tablet (emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir DF 300 mg) once daily.

Treatment of HIV Infection in Adults Receiving Rifabutin

Oral

Rilpivirine (Edurant): 50 mg once daily. (See Specific Drugs under Interactions.)

Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey): Concomitant use with rifabutin not recommended.

Emtricitabine/rilpivirine/tenofovir DF (Complera): 1 tablet (emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir DF 300 mg) once daily and 25 mg of single-entity rilpivirine (Edurant) once daily to provide total rilpivirine dosage of 50 mg daily. (See Specific Drugs under Interactions.)

Postexposure Prophylaxis following Occupational Exposure to HIV (PEP)† [off-label]

Oral

Rilpivirine (Edurant): 25 mg once daily. Use in conjunction with 2 NRTIs (see Postexposure Prophylaxis following Occupational Exposure to HIV [PEP] under Uses).

Emtricitabine/rilpivirine/tenofovir DF (Complera): 1 tablet (emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir DF 300 mg) once daily. Use as a complete regimen for PEP.

Initiate PEP as soon as possible following occupational exposure to HIV (preferably within hours); continue for 4 weeks, if tolerated.

Postexposure Prophylaxis following Nonoccupational Exposure to HIV (nPEP)† [off-label]

Oral

Emtricitabine/rilpivirine/tenofovir DF (Complera): 1 tablet (200 mg of emtricitabine, 25 mg of rilpivirine, and 300 mg of tenofovir DF) once daily. Use as a complete regimen for nPEP.

Initiate nPEP as soon as possible (within 72 hours) following nonoccupational exposure that represents a substantial risk for HIV transmission and continue for 28 days.

nPep not recommended if exposed individual seeks care >72 hours after exposure.

Special Populations

Hepatic Impairment

Treatment of HIV Infection

Rilpivirine (Edurant): Use usual dosage in patients with mild or moderate hepatic impairment (Child-Pugh class A or B); not studied in those with severe hepatic impairment (Child-Pugh class C).

Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey): Use usual dosage in patients with mild or moderate hepatic impairment (Child-Pugh class A or B); not studied in those with severe hepatic impairment (Child-Pugh class C).

Emtricitabine/rilpivirine/tenofovir DF (Complera): Use usual dosage in patients with mild or moderate hepatic impairment (Child-Pugh class A or B); not studied in those with severe hepatic impairment (Child-Pugh class C).

Renal Impairment

Treatment of HIV Infection

Rilpivirine (Edurant): Use usual dosage in patients with mild or moderate renal impairment. Manufacturer makes no specific dosage recommendations for those with severe renal impairment or end-stage renal disease (ESRD); use with caution. (See Renal Impairment under Cautions.)

Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey): Use usual dosage in patients with estimated Cl_cr ≥30 mL/minute; not recommended in those with severe renal impairment (estimated Cl_cr <30 mL/minute).

Emtricitabine/rilpivirine/tenofovir DF (Complera): Do not use in those with moderate, severe, or end-stage renal impairment (estimated Cl_cr <50 mL/minute) or if dialysis required.

Geriatric Patients

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Cautions for Rilpivirine

Contraindications

Rilpivirine, emtricitabine/rilpivirine/tenofovir alafenamide, emtricitabine/rilpivirine/tenofovir DF: Concomitant use with drugs that induce CYP3A or elevate gastric pH 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 other NNRTIs. This includes certain anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin), certain antimycobacterials (rifampin, rifapentine), systemic dexamethasone (given in multiple doses), proton-pump inhibitors (dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole), and certain herbal supplements (St. John’s wort [Hypericum perforatum]). (See Interactions.)
Emtricitabine/rilpivirine/tenofovir alafenamide, emtricitabine/rilpivirine/tenofovir DF: Consider contraindications associated with each drug in the fixed combination.

Warnings/Precautions

Sensitivity Reactions

Severe skin and hypersensitivity reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), reported during postmarketing experience. Some skin reactions were accompanied by constitutional symptoms such as fever; others were associated with organ dysfunction, including elevated hepatic enzyme serum concentrations. Rash generally was grade 1 or 2 and occurred in the first 4–6 weeks of therapy.

Immediately discontinue rilpivirine, emtricitabine/rilpivirine/tenofovir alafenamide, or emtricitabine/rilpivirine/tenofovir DF 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). Monitor clinical status, including laboratory parameters, and initiate appropriate therapy.

Interactions

Concomitant use with certain drugs (e.g., drugs that may reduce rilpivirine concentrations, drugs known to increase risk of torsades de pointes) is contraindicated or requires particular caution. (See Contraindications and see Interactions.)

Depressive Disorders

Depressive disorders (e.g., depressed mood, depression, dysphoria, major depression, altered mood, negative thoughts, suicide attempt, suicidal ideation) reported.

Depressive disorders reported in 9% of adults receiving rilpivirine in phase 3 clinical trials and in 19% of pediatric patients 12 to <18 years of age receiving rilpivirine in phase 2 clinical trials.

Advise patients experiencing severe depressive symptoms to seek immediate medical evaluation to determine the likelihood that symptoms are related to rilpivirine and to determine if benefits of continued rilpivirine outweigh risks.

Hepatotoxicity

Adverse hepatic effects reported; hepatotoxicity reported in some patients without preexisting hepatic disease or other risk factors.

HIV-infected patients with HBV or HCV coinfection or marked elevations in aminotransferase concentrations prior to rilpivirine treatment may be at increased risk for development or worsening of aminotransferase concentration elevations.

In patients with underlying hepatic disease (e.g., HBV or HCV infection, elevated aminotransferase concentrations), perform laboratory tests to evaluate hepatic function prior to and during rilpivirine treatment (single entity or fixed combinations).

Consider liver enzyme monitoring in patients without preexisting hepatic disease or other risk factors.

Precautions Related to Use of Fixed Combinations

Emtricitabine/rilpivirine/tenofovir alafenamide, emtricitabine/rilpivirine/tenofovir DF: Consider cautions, precautions, contraindications, and interactions associated with each drug in the fixed combination. Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug.

Because the antiretrovirals contained in the fixed combinations also may be available in single-entity or other fixed-combination preparations, take care to ensure that therapy is not duplicated if a fixed combination is used in conjunction with other antiretrovirals.

Do not use emtricitabine/rilpivirine/tenofovir DF concomitantly with single-entity rilpivirine, unless needed for adjustment of rilpivirine dosage (e.g., when fixed combination used concomitantly with rifabutin). (See Specific Drugs under Interactions.)

Because of similarities between emtricitabine and lamivudine, do not use fixed combinations containing emtricitabine concomitantly with any preparation containing lamivudine. In addition, do not use fixed combinations containing tenofovir DF concomitantly with adefovir.

Adipogenic Effects

Possible redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (“buffalo hump”), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance.

Mechanisms and long-term consequences of adipogenic effects unknown; causal relationship not established.

Immune Reconstitution Syndrome

During initial treatment, HIV-infected patients who 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]); this may necessitate further evaluation and treatment.

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) also reported to occur in the setting of immune reconstitution; time to onset is more variable and can occur many months after initiation of antiretroviral therapy.

Specific Populations

Pregnancy

Rilpivirine (Edurant): Category B.

Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey): Insufficient human data to assess risk of birth defects and miscarriage if used in pregnant women.

Emtricitabine/rilpivirine/tenofovir DF (Complera): Category B.

Antiretroviral Pregnancy Registry at 800-258-4263 or [Web].

Experts state rilpivirine in conjunction with tenofovir DF and emtricitabine (or rilpivirine in conjunction with a preferred 2-NRTI backbone) is an alternative NNRTI-based regimen for initial treatment of HIV-1 infection in pregnant women, but use only in patients with baseline plasma HIV-1 RNA levels <100,000 copies/mL and baseline CD4⁺ T-cell count >200 cells/mm³.

Lactation

Not known whether rilpivirine distributed into human milk; distributed into milk in rats.

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.

Pediatric Use

Rilpivirine (Edurant): Safety, efficacy, and pharmacokinetics not established in pediatric patients <12 years of age.

Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey): Safety and efficacy not established in pediatric patients <12 years of age or weighing <35 kg.

Emtricitabine/rilpivirine/tenofovir DF (Complera): Safety and efficacy not established in pediatric patients <12 years of age or weighing <35 kg.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Hepatic Impairment

Rilpivirine (Edurant), emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey), emtricitabine/rilpivirine/tenofovir DF (Complera): Not studied in patients with severe hepatic impairment (Child-Pugh class C). (See Hepatic Impairment under Dosage and Administration.)

Higher incidence of increased serum aminotransferase concentrations reported in HIV-infected patients coinfected with HBV and/or HCV compared with those without coinfection.

Renal Impairment

Rilpivirine (Edurant): Use with caution and increased monitoring for adverse effects in patients with severe renal impairment or ESRD; increased rilpivirine concentrations possible due to alterations in absorption, distribution, or metabolism. (See Renal Impairment under Dosage and Administration.)

Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey): Not recommended in those with severe renal impairment (estimated Cl_cr <30 mL/minute).

Emtricitabine/rilpivirine/tenofovir DF (Complera): Do not use in those with moderate, severe, or end-stage renal impairment (estimated Cl_cr <50 mL/minute) or if dialysis required.

Common Adverse Effects

Depressive disorders (see Depressive Disorders under Cautions), insomnia, headache, rash, increased serum AST and/or ALT concentrations (>2.5 times ULN).

Interactions for Rilpivirine

Rilpivirine is metabolized by CYP3A.

Tenofovir alafenamide, a component of emtricitabine/rilpivirine/tenofovir alafenamide, is a substrate of P-glycoprotein (P-gp) transport.

The following drug interactions are based on studies using rilpivirine, emtricitabine/rilpivirine/tenofovir alafenamide, emtricitabine/rilpivirine/tenofovir DF, or the individual components of fixed combinations, or are predicted to occur. When a fixed combination used, consider interactions associated with each drug in the fixed combination.

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP3A inducers: Possible decreased rilpivirine concentrations and possible loss of virologic response and development of resistance to rilpivirine or the NNRTI class.

CYP3A inhibitors: Possible increased rilpivirine concentrations.

CYP substrates: Recommended rilpivirine dosage (25 mg once daily) unlikely to have clinically important pharmacokinetic interactions.

Drugs Affected by P-glycoprotein Transport

P-gp inhibitors: If used with emtricitabine/rilpivirine/tenofovir alafenamide, possible increased absorption of tenofovir alafenamide; may result in increased plasma concentrations of tenofovir alafenamide and increased adverse effects.

P-gp inducers: If used with emtricitabine/rilpivirine/tenofovir alafenamide, possible decreased absorption of tenofovir alafenamide; may result in decreased plasma concentrations of tenofovir alafenamide leading to loss of therapeutic effect and development of resistance.

Drugs that Increase Gastric pH

Possible decreased rilpivirine concentrations, loss of virologic response, and development of drug resistance or NNRTI-class resistance.

Drugs that Prolong the QT Interval

Only limited data available to date regarding potential for pharmacodynamic interaction if used concomitantly with drugs known to prolong QT interval and increase the risk of torsades de pointes. In healthy individuals, rilpivirine dosages of 75 or 300 mg daily (substantially higher than recommended dosage) resulted in clinically important prolongation of QT_c interval.

Use caution if rilpivirine or emtricitabine/rilpivirine/tenofovir DF used concomitantly with drugs known to increase risk of torsades de pointes. Consider alternative to emtricitabine/rilpivirine/tenofovir alafenamide in patients receiving drugs known to increase risk of torsades de pointes.

Nephrotoxic Drugs or Drugs Eliminated by Renal Excretion

If used with emtricitabine/rilpivirine/tenofovir alafenamide or emtricitabine/rilpivirine/tenofovir DF: Potential increased concentrations of emtricitabine, tenofovir, and/or concomitant drug.

Specific Drugs

Drug	Interaction	Comments
Abacavir	Pharmacokinetic interactions unlikely No in vitro evidence of antagonistic antiretroviral effects
Acetaminophen	No clinically important pharmacokinetic interactions	Dosage adjustments not needed
Acyclovir, valacyclovir	If used with emtricitabine/rilpivirine/tenofovir alafenamide or emtricitabine/rilpivirine/tenofovir DF, possible increased concentrations of emtricitabine, tenofovir, and/or acyclovir and increased risk of adverse effects
Aminoglycosides (e.g., gentamicin)	Gentamicin: If used with emtricitabine/rilpivirine/tenofovir alafenamide or emtricitabine/rilpivirine/tenofovir DF, possible increased concentrations of emtricitabine, tenofovir, and/or the aminoglycoside and increased risk of adverse effects
Antacids (aluminum hydroxide, calcium carbonate, magnesium hydroxide)	Possible decreased rilpivirine concentrations with possible loss of virologic response and development of resistance	Use with caution; take antacid at least 2 hours before or 4 hours after rilpivirine (single entity or fixed combinations)
Anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin)	Possible decreased rilpivirine concentrations	Concomitant use with rilpivirine (single entity or fixed combinations) contraindicated
Antifungals, azoles	Ketoconazole: Increased rilpivirine concentrations and AUC; decreased ketoconazole concentrations and AUC Fluconazole, isavuconazonium, itraconazole, posaconazole, voriconazole: Possible increased rilpivirine concentrations and decreased azole antifungal concentrations; if used with emtricitabine/rilpivirine/tenofovir alafenamide, increased tenofovir alafenamide concentrations also possible	Dosage adjustments not needed if used with rilpivirine (single entity or fixed combinations); monitor for breakthrough fungal infections
Antimycobacterials, rifamycins	Rifabutin, rifampin, rifapentine: Decreased rilpivirine concentrations and AUC	Rifabutin: Increase single-entity rilpivirine dosage to 50 mg once daily; if rifabutin is stopped, resume usual rilpivirine dosage (25 mg once daily); if using emtricitabine/rilpivirine/tenofovir DF, use 1 tablet of fixed combination and a 25-mg tablet of single-entity rilpivirine once daily to provide total rilpivirine dosage of 50 mg daily; concomitant use with emtricitabine/rilpivirine/tenofovir alafenamide not recommended Rifampin, rifapentine: Concomitant use with rilpivirine (single entity or fixed combinations) contraindicated
Atazanavir	Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Possible increased rilpivirine concentrations; not expected to affect atazanavir concentrations No in vitro evidence of antagonistic antiretroviral effects	Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Dosage adjustments not needed
Avanafil	Data not available	Concomitant use not recommended
Benzodiazepines	Alprazolam: Data not available Lorazepam, midazolam: If used with emtricitabine/rilpivirine/tenofovir alafenamide, clinically important interactions not expected	Alprazolam: Monitor for alprazolam therapeutic effects
Buprenorphine	Emtricitabine/rilpivirine/tenofovir alafenamide: Clinically important pharmacokinetic interactions not expected
Chlorzoxazone	No clinically important pharmacokinetic interactions	Dosage adjustments not needed
Cidofovir	If used with emtricitabine/rilpivirine/tenofovir alafenamide or emtricitabine/rilpivirine/tenofovir DF, possible increased concentrations of emtricitabine, tenofovir, and/or cidofovir and increased risk of adverse effects
Corticosteroids	Systemic dexamethasone: Possible decreased rilpivirine concentrations if more than a single dose of dexamethasone used	Systemic dexamethasone: Concomitant use of more than a single dose of dexamethasone with rilpivirine (single-entity or fixed combinations) contraindicated
Daclatasvir	Clinically important pharmacokinetic interactions not expected	Dosage adjustments not needed
Darunavir	Ritonavir-boosted darunavir: Increased rilpivirine concentrations and AUC; no clinically important effects on darunavir concentrations Cobicistat-boosted darunavir: Possible increased rilpivirine concentrations No in vitro evidence of antagonistic antiretroviral effects	Ritonavir-boosted or cobicistat-boosted darunavir: Dosage adjustments not needed
Delavirdine	Possible increased rilpivirine concentrations	Concomitant use not recommended
Didanosine	No effect on rilpivirine or didanosine concentrations when administered 2 hours apart No in vitro evidence of antagonistic antiretroviral effects	Administer didanosine (without food) at least 2 hours before or 4 hours after rilpivirine (with food); dosage adjustments not needed
Digoxin	No clinically important effect on digoxin pharmacokinetics
Dolutegravir	No clinically important effect on rilpivirine or dolutegravir pharmacokinetics	Dosage adjustments not needed
Efavirenz	Possible decreased rilpivirine concentrations No in vitro evidence of antagonistic antiretroviral effects	Concomitant use not recommended
Elbasvir and grazoprevir	Fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir): No clinically important effect on elbasvir, grazoprevir, or rilpivirine pharmacokinetics	Elbasvir/grazoprevir: Dosage adjustments not needed
Elvitegravir	Cobicistat-boosted elvitegravir: Possible altered elvitegravir, cobicistat, and/or rilpivirine concentrations Elvitegravir in conjunction with ritonavir-boosted PI: Increased rilpivirine concentrations expected	Cobicistat-boosted elvitegravir: Do not use concomitantly Elvitegravir in conjunction with ritonavir-boosted PI: Dosage adjustments not needed, but elvitegravir dosage depends on which ritonavir-boosted PI is used
Emtricitabine	Pharmacokinetic interactions unlikely No in vitro evidence of antagonistic antiretroviral effects
Enfuvirtide	No in vitro evidence of antagonistic antiretroviral effects
Estrogens/progestins	Contraceptives containing ethinyl estradiol and norethindrone: No clinically important pharmacokinetic interactions Fixed combination of ethinyl estradiol and norgestimate: Clinically important pharmacokinetic interactions not expected with emtricitabine/rilpivirine/tenofovir alafenamide	Contraceptives containing ethinyl estradiol and norethindrone: Dosage adjustments not needed
Etravirine	Possible decreased rilpivirine concentrations No in vitro evidence of antagonistic antiretroviral effects	Concomitant use not recommended
Fosamprenavir	Fosamprenavir or ritonavir-boosted fosamprenavir: Possible increased rilpivirine concentrations; not expected to affect amprenavir concentrations (active metabolite of fosamprenavir) No in vitro evidence of antagonistic antiretroviral effects with amprenavir (active metabolite of fosamprenavir)	Fosamprenavir (with or without low-dose ritonavir): Dosage adjustments not needed
Ganciclovir, valganciclovir	If used with emtricitabine/rilpivirine/tenofovir alafenamide or emtricitabine/rilpivirine/tenofovir DF, possible increased concentrations of emtricitabine, tenofovir, and/or ganciclovir and increased risk of adverse effects
Histamine H₂-receptor antagonists	Famotidine: Decreased rilpivirine concentrations with possible loss of virologic response and development of resistance Cimetidine, nizatidine, ranitidine: Possible decreased rilpivirine concentrations	Use with caution; take histamine H₂-receptor antagonist at least 12 hours before or at least 4 hours after rilpivirine (single entity or fixed combinations)
HMG-CoA reductase inhibitors (statins)	Atorvastatin: No clinically important pharmacokinetic interactions with rilpivirine Pitavastatin: Data not available; clinically important interactions not expected	Atorvastatin: Dosage adjustments not needed Pitavastatin: Dosage adjustments not needed
Indinavir	Possible increased rilpivirine concentrations; not expected to affect indinavir concentrations No in vitro evidence of antagonistic antiretroviral effects
Lamivudine	Pharmacokinetic interactions unlikely No in vitro evidence of antagonistic antiretroviral effects
Ledipasvir and sofosbuvir	Rilpivirine: No clinically important pharmacokinetic interactions with fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir) Emtricitabine/rilpivirine/tenofovir alafenamide: Clinically important pharmacokinetic interactions not expected Emtricitabine/rilpivirine/tenofovir DF: No clinically important effects on rilpivirine, ledipasvir, or sofosbuvir pharmacokinetics; increased tenofovir concentrations	Rilpivirine: Dosage adjustments not needed Emtricitabine/rilpivirine/tenofovir DF: If used with ledipasvir/sofosbuvir, monitor for tenofovir-associated adverse effects
Lopinavir/ritonavir	Increased rilpivirine concentrations and AUC; no clinically important effect on lopinavir concentrations or AUC No in vitro evidence of antagonistic antiretroviral effects	Dosage adjustments not needed
Macrolides	Clarithromycin, erythromycin, or telithromycin: Possible increased rilpivirine concentrations	Clarithromycin. erythromycin, or telithromycin: Consider alternative (e.g., azithromycin) whenever possible in patients receiving rilpivirine (single entity or fixed combinations)
Maraviroc	Clinically important pharmacokinetic interactions unlikely No in vitro evidence of antagonistic antiretroviral effects
Metformin	Rilpivirine has no clinically important effects on metformin pharmacokinetics
Methadone	Decreased methadone concentrations and AUC; no clinically important effects on rilpivirine concentrations or AUC	Adjustment of initial methadone dosage not needed; closely monitor for methadone efficacy; adjustment of maintenance methadone dosage may be needed
Naloxone	Emtricitabine/rilpivirine/tenofovir alafenamide: Clinically important pharmacokinetic interactions not expected
Nelfinavir	Possible increased rilpivirine concentrations; not expected to affect nelfinavir concentrations No in vitro evidence of antagonistic antiretroviral effects
Nevirapine	Possible decreased rilpivirine concentrations No in vitro evidence of antagonistic antiretroviral effects	Concomitant use not recommended
NSAIAs	High-dose or multiple NSAIAs: If used with emtricitabine/rilpivirine/tenofovir alafenamide or emtricitabine/rilpivirine/tenofovir DF, possible increased concentrations of emtricitabine, tenofovir, and/or the NSAIA and increased risk of adverse effects	Avoid emtricitabine/rilpivirine/tenofovir alafenamide or emtricitabine/rilpivirine/tenofovir DF in patients who are receiving or have recently received a nephrotoxic drug (e.g., high-dose or multiple NSAIAs)
Ombitasvir, paritaprevir, and ritonavir	Fixed combination of ombitasvir, paritaprevir, and ritonavir with or without dasabuvir: Substantially increased rilpivirine concentrations and AUC and possible increased potential for QT interval prolongation	Ombitasvir/paritaprevir/ritonavir with or without dasabuvir: Concomitant use with rilpivirine not recommended
Proton-pump inhibitors	Omeprazole: Decreased rilpivirine concentrations and AUC with possible loss of virologic response and development of resistance Dexlansoprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole: Possible decreased rilpivirine concentrations with possible loss of virologic response and development of resistance	Concomitant use with rilpivirine (single entity or fixed combinations) contraindicated
Raltegravir	No clinically important effect on raltegravir or rilpivirine concentrations or AUC No in vitro evidence of antagonistic antiretroviral effects	Dosage adjustments not needed for either drug
Ribavirin	Pharmacokinetic interactions with rilpivirine unlikely
Ritonavir	No in vitro evidence of antagonistic antiretroviral effects
St. John’s wort (Hypericum perforatum)	Possible decreased rilpivirine concentrations with possible loss of virologic response and development of resistance	Concomitant use with rilpivirine (single entity or fixed combinations) contraindicated
Saquinavir	Ritonavir-boosted saquinavir: Possible increased rilpivirine concentrations; not expected to affect saquinavir concentrations No in vitro evidence of antagonistic antiretroviral effects	Ritonavir-boosted saquinavir: Dosage adjustments not needed
Sildenafil	No clinically important pharmacokinetic interaction with rilpivirine	Dosage adjustments not needed
Simeprevir	Rilpivirine: No clinically important effect on rilpivirine or simeprevir pharmacokinetics Emtricitabine/rilpivirine/tenofovir alafenamide: Clinically important pharmacokinetic interactions not expected	Dosage adjustments not needed for either drug
Sofosbuvir	No clinically important effects on rilpivirine or sofosbuvir pharmacokinetics	Dosage adjustments not needed for either drug
Sofosbuvir and velpatasvir	Fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir): No clinically important interactions with rilpivirine
Stavudine	Pharmacokinetic interactions unlikely No in vitro evidence of antagonistic antiretroviral effects
Tenofovir	Increased tenofovir concentrations and AUC; no clinically important effects on rilpivirine concentrations or AUC No in vitro evidence of antagonistic antiretroviral effects	Dosage adjustments not needed
Tipranavir	Ritonavir-boosted tipranavir: Possible increased rilpivirine concentrations; not expected to affect tipranavir concentrations No in vitro evidence of antagonistic antiretroviral effects	Ritonavir-boosted tipranavir: Dosage adjustments not needed
Zidovudine	Pharmacokinetic interactions unlikely No in vitro evidence of antagonistic antiretroviral effects

Rilpivirine Pharmacokinetics

Absorption

Bioavailability

Absolute oral bioavailability unknown.

Peak plasma rilpivirine concentrations attained within approximately 4–5 hours.

Fixed-combination tablet containing emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir DF 300 mg (emtricitabine/rilpivirine/tenofovir DF; Complera) taken with a meal is bioequivalent to a 200-mg emtricitabine capsule, 25-mg rilpivirine tablet, and 300-mg tenofovir DF tablet taken simultaneously with a meal.

Food

Systemic exposure decreased by about 40–50% if rilpivirine administered under fasting conditions or with only a protein-rich nutritional drink (300 kcal, 8 grams of fat) compared with administration with a meal.

Administration with a standard meal (533 kcal, 21 grams of fat) or high-fat, high-calorie meal (982 kcal, 56 grams of fat) results in similar rilpivirine exposures.

Distribution

Extent

Distribution into compartments other than plasma (e.g., CSF, genital tract secretions) not evaluated.

Plasma Protein Binding

Approximately 99.7% (in vitro), principally albumin.

Elimination

Metabolism

Metabolized principally in the liver by CYP3A.

Elimination Route

Following oral administration of a single dose, 85% of rilpivirine dose eliminated in feces (75% as metabolites) and 6% eliminated in urine (<1% as unchanged rilpivirine).

Because rilpivirine is highly bound to plasma proteins, clinically important removal by peritoneal dialysis or hemodialysis is unlikely.

Half-life

Terminal elimination half-life is about 50 hours.

Special Populations

Mild or moderate hepatic impairment (Child-Pugh class A or B) increases rilpivirine exposure by 47 or 5%, respectively. (See Hepatic Impairment under Warnings/Precautions.)

Coinfection with HIV and HBV or HCV does not alter rilpivirine exposure.

Mild renal impairment does not alter rilpivirine exposure. Only limited data available for patients with moderate or severe renal impairment; rilpivirine concentrations may be increased as a result of altered absorption, distribution, or elimination. (See Renal Impairment under Cautions.)

Pharmacokinetics in treatment-naive HIV-1-infected pediatric patients 12 to <18 years of age receiving rilpivirine 25 mg once daily is similar to those observed in treatment-naive adult patients.

Gender differences in pharmacokinetics not observed.

Race not expected to affect rilpivirine exposure.

Pharmacokinetics not studied in pregnant women.

Stability

Storage

Oral

Tablets

Rilpivirine (Edurant): 25°C (may be exposed to 15–30°C); store in original container.

Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey): <30°C. Dispense in original container; keep tightly closed.

Emtricitabine/rilpivirine/tenofovir DF (Complera): 25°C (may be exposed to 15–30°C). Dispense in original container; keep tightly closed.

Actions and Spectrum

Inhibits replication of HIV-1 by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase.
Like etravirine, rilpivirine is a diarylpyrimidine NNRTI; structural flexibility of these drugs allows for binding to the allosteric NNRTI binding pocket in a variety of conformations.
Unlike other currently available NNRTIs, rilpivirine contains a cyanovinyl group that contributes to potency and maintains the drug’s binding ability despite emergence of some resistance mutations in HIV-1 reverse transcriptase.
Active in vitro against wild-type HIV-1, but has limited activity against HIV type 2 (HIV-2). Active in vitro against some clinical HIV-1 isolates resistant to other commercially available NNRTIs (delavirdine, efavirenz, nevirapine).
Rilpivirine-resistant strains have been selected in cell culture and have emerged during clinical use.
Cross-resistance can occur between rilpivirine and other commercially available NNRTIs. Up to 90% of rilpivirine-resistant isolates that developed in patients receiving rilpivirine in clinical studies were resistant to etravirine.
Patients in clinical studies experiencing virologic failure while receiving a rilpivirine regimen were more likely to develop NNRTI-class resistance and treatment-emergent resistance to NRTIs than patients receiving an efavirenz regimen.

Advice to Patients

Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician. Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.
Importance of using single-entity rilpivirine in conjunction with other antiretrovirals—not for monotherapy.
Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey) and emtricitabine/rilpivirine/tenofovir DF (Complera) are used alone as a complete treatment regimen.
Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.
Advise patients that sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to acquired immunodeficiency disease (AIDS) and death.
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. 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.
Importance of reading patient information provided by the manufacturer.
Importance of taking once daily with a meal; a protein drink alone does not constitute a meal. Food enhances absorption of rilpivirine.
If a missed dose of single-entity rilpivirine or emtricitabine/rilpivirine/tenofovir DF is remembered within 12 hours, take the dose with a meal as soon as possible and take next dose at regularly scheduled time. If the missed dose is remembered more than 12 hours after the scheduled time, omit the missed dose and take next dose at regularly scheduled time. Advise patients that doses that are larger or smaller than the prescribed dosage should not be taken at any time.
Advise patients that skin reactions ranging from mild to severe, including DRESS, reported with rilpivirine-containing antiretroviral regimens. Instruct patients to immediately stop taking rilpivirine (single entity or fixed combinations) and contact a clinician if a 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.
Advise patients that depressive disorders (depressed mood, depression, dysphoria, major depression, altered mood, negative thoughts, suicide attempt, suicidal ideation) have been reported. Importance of immediately contacting clinician if depressive symptoms (e.g., feeling sad, hopeless, anxious, or restless; hurting oneself; having thoughts of hurting oneself) occur.
Advise patients that hepatotoxicity has been reported in patients receiving rilpivirine.
Redistribution/accumulation of body fat may occur; cause and long-term health effects unknown.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal products (e.g., St. John’s wort), and any concomitant illnesses. (See Contraindications.)
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed. Advise HIV-infected women not to breast-feed.
Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

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.

Rilpivirine Hydrochloride
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	25 mg (of rilpivirine)	Edurant	Janssen

Rilpivirine Hydrochloride Combinations
Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets, film-coated	25 mg (of rilpivirine) with Emtricitabine 200 mg and Tenofovir Alafenamide Fumarate 25 mg (of tenofovir alafenamide)	Odefsey	Gilead
		25 mg (of rilpivirine) with Emtricitabine 200 mg and Tenofovir Disoproxil Fumarate 300 mg	Complera	Gilead