Rilpivirine Hydrochloride

Name: Rilpivirine Hydrochloride

Uses for Rilpivirine Hydrochloride

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;1 2 12 200 used in conjunction with other antiretrovirals.1

Single-entity rilpivirine used in conjunction with 2 HIV NRTIs in certain antiretroviral-naive adults and adolescents ≥12 years of age.1 200 201 Also commercially available in fixed combinations containing emtricitabine and a tenofovir prodrug (either tenofovir alafenamide or tenofovir disoproxil fumarate [tenofovir DF]);233 244 these fixed combinations used in certain patient groups to decrease pill burden and improve compliance.200 201

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/mm3.200

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.201

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;244 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.244

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;233 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.233

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.1 233 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.1 233

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.1 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.1

Postexposure Prophylaxis following Occupational Exposure to HIV (PEP)

Postexposure prophylaxis of HIV infection following occupational exposure† (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.199 Used in conjunction with other antiretrovirals.199

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.199 Rilpivirine and 2 NRTIs is one of several alternative regimens.199 Preferred dual NRTI option for use in PEP regimens is emtricitabine and tenofovir DF (may be given as emtricitabine/tenofovir DF; Truvada);199 alternative dual NRTIs are tenofovir DF and lamivudine, lamivudine and zidovudine (may be given as lamivudine/zidovudine; Combivir), or zidovudine and emtricitabine.199

Management of occupational exposures to HIV is complex and evolving;199 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.199 Do not delay initiation of PEP while waiting for expert consultation.199

Postexposure Prophylaxis following Nonoccupational Exposure to HIV (nPEP)

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 the exposure represents a substantial risk for HIV transmission.198 Used in conjunction with other antiretrovirals.198

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);198 recommended alternative is ritonavir-boosted darunavir used in conjunction with emtricitabine/tenofovir DF (Truvada).198 Rilpivirine and 2 NRTIs (may be given as emtricitabine/rilpivirine/tenofovir DF; Complera) is one of several other alternative regimens for nPEP.198

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.198 Do not delay initiation of nPEP while waiting for expert consultation.198

Cautions for Rilpivirine Hydrochloride

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.1 233 244 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]).1 233 244 (See Interactions.)

  • Emtricitabine/rilpivirine/tenofovir alafenamide, emtricitabine/rilpivirine/tenofovir DF: Consider contraindications associated with each drug in the fixed combination.233 244

Warnings/Precautions

Sensitivity Reactions

Severe skin and hypersensitivity reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), reported during postmarketing experience.1 233 244 Some skin reactions were accompanied by constitutional symptoms such as fever;1 233 244 others were associated with organ dysfunction, including elevated hepatic enzyme serum concentrations.1 233 244 Rash generally was grade 1 or 2 and occurred in the first 4–6 weeks of therapy.1 233 244

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).1 233 244 Monitor clinical status, including laboratory parameters, and initiate appropriate therapy.1 233 244

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.1 233 244 (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.1 233 244

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.1 233 244

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.1 233 244

Hepatotoxicity

Adverse hepatic effects reported;1 233 244 hepatotoxicity reported in some patients without preexisting hepatic disease or other risk factors.1 233 244

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.1 233 244

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).1 233 244

Consider liver enzyme monitoring in patients without preexisting hepatic disease or other risk factors.1 233 244

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.233 244 Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug.233 244

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.233 244

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).1 233 (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.200 233 In addition, do not use fixed combinations containing tenofovir DF concomitantly with adefovir.200 233

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.1 233 244

Mechanisms and long-term consequences of adipogenic effects unknown; causal relationship not established.1 233 244

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]);1 233 244 this may necessitate further evaluation and treatment.1 233 244

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) also reported to occur in the setting of immune reconstitution;1 233 244 time to onset is more variable and can occur many months after initiation of antiretroviral therapy.1 233 244

Specific Populations

Pregnancy

Rilpivirine (Edurant): Category B.1

Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey): Insufficient human data to assess risk of birth defects and miscarriage if used in pregnant women.244

Emtricitabine/rilpivirine/tenofovir DF (Complera): Category B.233

Antiretroviral Pregnancy Registry at 800-258-4263 or .1 202 233 244

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/mm3.202

Lactation

Not known whether rilpivirine distributed into human milk;1 distributed into milk in rats.1

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1 202 233 244

Pediatric Use

Rilpivirine (Edurant): Safety, efficacy, and pharmacokinetics not established in pediatric patients <12 years of age.1 201

Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey): Safety and efficacy not established in pediatric patients <12 years of age or weighing <35 kg.244

Emtricitabine/rilpivirine/tenofovir DF (Complera): Safety and efficacy not established in pediatric patients <12 years of age or weighing <35 kg.233

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1 233 244

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1 233

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).1 233 244 (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.1

Renal Impairment

Rilpivirine (Edurant): Use with caution and increased monitoring for adverse effects in patients with severe renal impairment or ESRD;1 increased rilpivirine concentrations possible due to alterations in absorption, distribution, or metabolism.1 (See Renal Impairment under Dosage and Administration.)

Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey): Not recommended in those with severe renal impairment (estimated Clcr <30 mL/minute).244

Emtricitabine/rilpivirine/tenofovir DF (Complera): Do not use in those with moderate, severe, or end-stage renal impairment (estimated Clcr <50 mL/minute) or if dialysis required.233

Common Adverse Effects

Depressive disorders (see Depressive Disorders under Cautions), insomnia, headache, rash, increased serum AST and/or ALT concentrations (>2.5 times ULN).1

Interactions for Rilpivirine Hydrochloride

Rilpivirine is metabolized by CYP3A.1

Tenofovir alafenamide, a component of emtricitabine/rilpivirine/tenofovir alafenamide, is a substrate of P-glycoprotein (P-gp) transport.244

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.1 233 244 When a fixed combination used, consider interactions associated with each drug in the fixed combination.233 244

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.1

CYP3A inhibitors: Possible increased rilpivirine concentrations.1

CYP substrates: Recommended rilpivirine dosage (25 mg once daily) unlikely to have clinically important pharmacokinetic interactions.1

Drugs Affected by P-glycoprotein Transport

P-gp inhibitors: If used with emtricitabine/rilpivirine/tenofovir alafenamide, possible increased absorption of tenofovir alafenamide;244 may result in increased plasma concentrations of tenofovir alafenamide and increased adverse effects.244

P-gp inducers: If used with emtricitabine/rilpivirine/tenofovir alafenamide, possible decreased absorption of tenofovir alafenamide;244 may result in decreased plasma concentrations of tenofovir alafenamide leading to loss of therapeutic effect and development of resistance.244

Drugs that Increase Gastric pH

Possible decreased rilpivirine concentrations, loss of virologic response, and development of drug resistance or NNRTI-class resistance.1 233 244

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.1 233 244 In healthy individuals, rilpivirine dosages of 75 or 300 mg daily (substantially higher than recommended dosage) resulted in clinically important prolongation of QTc interval.1 233 244

Use caution if rilpivirine or emtricitabine/rilpivirine/tenofovir DF used concomitantly with drugs known to increase risk of torsades de pointes.1 233 Consider alternative to emtricitabine/rilpivirine/tenofovir alafenamide in patients receiving drugs known to increase risk of torsades de pointes.244

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.233 244

Specific Drugs

Drug

Interaction

Comments

Abacavir

Pharmacokinetic interactions unlikely1

No in vitro evidence of antagonistic antiretroviral effects 1 6

Acetaminophen

No clinically important pharmacokinetic interactions1 233 244

Dosage adjustments not needed1

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 effects233 244

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 effects233 244

Antacids (aluminum hydroxide, calcium carbonate, magnesium hydroxide)

Possible decreased rilpivirine concentrations with possible loss of virologic response and development of resistance1

Use with caution;1 233 244 take antacid at least 2 hours before or 4 hours after rilpivirine (single entity or fixed combinations)1 233 244

Anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin)

Possible decreased rilpivirine concentrations1

Concomitant use with rilpivirine (single entity or fixed combinations) contraindicated1 233 244

Antifungals, azoles

Ketoconazole: Increased rilpivirine concentrations and AUC;1 decreased ketoconazole concentrations and AUC1

Fluconazole, isavuconazonium, itraconazole, posaconazole, voriconazole: Possible increased rilpivirine concentrations and decreased azole antifungal concentrations;1 200 if used with emtricitabine/rilpivirine/tenofovir alafenamide, increased tenofovir alafenamide concentrations also possible244

Dosage adjustments not needed if used with rilpivirine (single entity or fixed combinations);1 200 233 244 monitor for breakthrough fungal infections1 200 233 244

Antimycobacterials, rifamycins

Rifabutin, rifampin, rifapentine: Decreased rilpivirine concentrations and AUC1 200

Rifabutin: Increase single-entity rilpivirine dosage to 50 mg once daily;1 if rifabutin is stopped, resume usual rilpivirine dosage (25 mg once daily);1 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;233 concomitant use with emtricitabine/rilpivirine/tenofovir alafenamide not recommended244

Rifampin, rifapentine: Concomitant use with rilpivirine (single entity or fixed combinations) contraindicated1 233 244

Atazanavir

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Possible increased rilpivirine concentrations;1 200 not expected to affect atazanavir concentrations1 200

No in vitro evidence of antagonistic antiretroviral effects 1 6

Ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir: Dosage adjustments not needed200

Avanafil

Data not available200

Concomitant use not recommended200

Benzodiazepines

Alprazolam: Data not available200

Lorazepam, midazolam: If used with emtricitabine/rilpivirine/tenofovir alafenamide, clinically important interactions not expected244

Alprazolam: Monitor for alprazolam therapeutic effects200

Buprenorphine

Emtricitabine/rilpivirine/tenofovir alafenamide: Clinically important pharmacokinetic interactions not expected244

Chlorzoxazone

No clinically important pharmacokinetic interactions1 233 244

Dosage adjustments not needed1

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 effects233 244

Corticosteroids

Systemic dexamethasone: Possible decreased rilpivirine concentrations if more than a single dose of dexamethasone used1

Systemic dexamethasone: Concomitant use of more than a single dose of dexamethasone with rilpivirine (single-entity or fixed combinations) contraindicated1 233 244

Daclatasvir

Clinically important pharmacokinetic interactions not expected178

Dosage adjustments not needed200

Darunavir

Ritonavir-boosted darunavir: Increased rilpivirine concentrations and AUC;1 200 no clinically important effects on darunavir concentrations1 200

Cobicistat-boosted darunavir: Possible increased rilpivirine concentrations200

No in vitro evidence of antagonistic antiretroviral effects1 6

Ritonavir-boosted or cobicistat-boosted darunavir: Dosage adjustments not needed1 200

Delavirdine

Possible increased rilpivirine concentrations1

Concomitant use not recommended1 200

Didanosine

No effect on rilpivirine or didanosine concentrations when administered 2 hours apart1

No in vitro evidence of antagonistic antiretroviral effects 1 6

Administer didanosine (without food) at least 2 hours before or 4 hours after rilpivirine (with food);1 dosage adjustments not needed1

Digoxin

No clinically important effect on digoxin pharmacokinetics1 233 244

Dolutegravir

No clinically important effect on rilpivirine or dolutegravir pharmacokinetics200 236

Dosage adjustments not needed200

Efavirenz

Possible decreased rilpivirine concentrations1

No in vitro evidence of antagonistic antiretroviral effects 1 6

Concomitant use not recommended1 200

Elbasvir and grazoprevir

Fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir): No clinically important effect on elbasvir, grazoprevir, or rilpivirine pharmacokinetics177

Elbasvir/grazoprevir: Dosage adjustments not needed177

Elvitegravir

Cobicistat-boosted elvitegravir: Possible altered elvitegravir, cobicistat, and/or rilpivirine concentrations200

Elvitegravir in conjunction with ritonavir-boosted PI: Increased rilpivirine concentrations expected200

Cobicistat-boosted elvitegravir: Do not use concomitantly200

Elvitegravir in conjunction with ritonavir-boosted PI: Dosage adjustments not needed, but elvitegravir dosage depends on which ritonavir-boosted PI is used200

Emtricitabine

Pharmacokinetic interactions unlikely1

No in vitro evidence of antagonistic antiretroviral effects 1 6

Enfuvirtide

No in vitro evidence of antagonistic antiretroviral effects 1 6

Estrogens/progestins

Contraceptives containing ethinyl estradiol and norethindrone: No clinically important pharmacokinetic interactions1 233 244

Fixed combination of ethinyl estradiol and norgestimate: Clinically important pharmacokinetic interactions not expected with emtricitabine/rilpivirine/tenofovir alafenamide244

Contraceptives containing ethinyl estradiol and norethindrone: Dosage adjustments not needed1

Etravirine

Possible decreased rilpivirine concentrations1

No in vitro evidence of antagonistic antiretroviral effects 1 6

Concomitant use not recommended1 200

Fosamprenavir

Fosamprenavir or ritonavir-boosted fosamprenavir: Possible increased rilpivirine concentrations;1 not expected to affect amprenavir concentrations (active metabolite of fosamprenavir)1

No in vitro evidence of antagonistic antiretroviral effects with amprenavir (active metabolite of fosamprenavir)1 6

Fosamprenavir (with or without low-dose ritonavir): Dosage adjustments not needed200

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 effects233 244

Histamine H2-receptor antagonists

Famotidine: Decreased rilpivirine concentrations with possible loss of virologic response and development of resistance1

Cimetidine, nizatidine, ranitidine: Possible decreased rilpivirine concentrations1

Use with caution;1 233 take histamine H2-receptor antagonist at least 12 hours before or at least 4 hours after rilpivirine (single entity or fixed combinations)1 233 244

HMG-CoA reductase inhibitors (statins)

Atorvastatin: No clinically important pharmacokinetic interactions with rilpivirine1 233 244

Pitavastatin: Data not available;200 clinically important interactions not expected200

Atorvastatin: Dosage adjustments not needed1

Pitavastatin: Dosage adjustments not needed200

Indinavir

Possible increased rilpivirine concentrations; not expected to affect indinavir concentrations1

No in vitro evidence of antagonistic antiretroviral effects 1 6

Lamivudine

Pharmacokinetic interactions unlikely1

No in vitro evidence of antagonistic antiretroviral effects 1 6

Ledipasvir and sofosbuvir

Rilpivirine: No clinically important pharmacokinetic interactions with fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir)200 233

Emtricitabine/rilpivirine/tenofovir alafenamide: Clinically important pharmacokinetic interactions not expected244

Emtricitabine/rilpivirine/tenofovir DF: No clinically important effects on rilpivirine, ledipasvir, or sofosbuvir pharmacokinetics;233 increased tenofovir concentrations233

Rilpivirine: Dosage adjustments not needed200

Emtricitabine/rilpivirine/tenofovir DF: If used with ledipasvir/sofosbuvir, monitor for tenofovir-associated adverse effects233

Lopinavir/ritonavir

Increased rilpivirine concentrations and AUC;1 no clinically important effect on lopinavir concentrations or AUC1

No in vitro evidence of antagonistic antiretroviral effects1 6

Dosage adjustments not needed1

Macrolides

Clarithromycin, erythromycin, or telithromycin: Possible increased rilpivirine concentrations1 233 244

Clarithromycin. erythromycin, or telithromycin: Consider alternative (e.g., azithromycin) whenever possible in patients receiving rilpivirine (single entity or fixed combinations)1 233 244

Maraviroc

Clinically important pharmacokinetic interactions unlikely1

No in vitro evidence of antagonistic antiretroviral effects 1 6

Metformin

Rilpivirine has no clinically important effects on metformin pharmacokinetics1 233 244

Methadone

Decreased methadone concentrations and AUC; no clinically important effects on rilpivirine concentrations or AUC1 233 244

Adjustment of initial methadone dosage not needed;1 233 244 closely monitor for methadone efficacy; adjustment of maintenance methadone dosage may be needed1 233 244

Naloxone

Emtricitabine/rilpivirine/tenofovir alafenamide: Clinically important pharmacokinetic interactions not expected244

Nelfinavir

Possible increased rilpivirine concentrations;1 not expected to affect nelfinavir concentrations1

No in vitro evidence of antagonistic antiretroviral effects 1 6

Nevirapine

Possible decreased rilpivirine concentrations1

No in vitro evidence of antagonistic antiretroviral effects 1 6

Concomitant use not recommended1 200

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 effects233 244

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)233 244

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 prolongation179 180 200

Ombitasvir/paritaprevir/ritonavir with or without dasabuvir: Concomitant use with rilpivirine not recommended179 180 200

Proton-pump inhibitors

Omeprazole: Decreased rilpivirine concentrations and AUC with possible loss of virologic response and development of resistance1

Dexlansoprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole: Possible decreased rilpivirine concentrations with possible loss of virologic response and development of resistance1 233 244

Concomitant use with rilpivirine (single entity or fixed combinations) contraindicated1 233 244

Raltegravir

No clinically important effect on raltegravir or rilpivirine concentrations or AUC1

No in vitro evidence of antagonistic antiretroviral effects 1 6

Dosage adjustments not needed for either drug1

Ribavirin

Pharmacokinetic interactions with rilpivirine unlikely1

Ritonavir

No in vitro evidence of antagonistic antiretroviral effects 1 6

St. John’s wort (Hypericum perforatum)

Possible decreased rilpivirine concentrations with possible loss of virologic response and development of resistance1 233 244

Concomitant use with rilpivirine (single entity or fixed combinations) contraindicated1 233 244

Saquinavir

Ritonavir-boosted saquinavir: Possible increased rilpivirine concentrations;1 not expected to affect saquinavir concentrations1

No in vitro evidence of antagonistic antiretroviral effects 1 6

Ritonavir-boosted saquinavir: Dosage adjustments not needed200

Sildenafil

No clinically important pharmacokinetic interaction with rilpivirine1 233 244

Dosage adjustments not needed1

Simeprevir

Rilpivirine: No clinically important effect on rilpivirine or simeprevir pharmacokinetics200 233

Emtricitabine/rilpivirine/tenofovir alafenamide: Clinically important pharmacokinetic interactions not expected244

Dosage adjustments not needed for either drug200

Sofosbuvir

No clinically important effects on rilpivirine or sofosbuvir pharmacokinetics188 233 244

Dosage adjustments not needed for either drug188

Sofosbuvir and velpatasvir

Fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir): No clinically important interactions with rilpivirine176

Stavudine

Pharmacokinetic interactions unlikely1

No in vitro evidence of antagonistic antiretroviral effects 1 6

Tenofovir

Increased tenofovir concentrations and AUC;1 no clinically important effects on rilpivirine concentrations or AUC1

No in vitro evidence of antagonistic antiretroviral effects 1 6

Dosage adjustments not needed1

Tipranavir

Ritonavir-boosted tipranavir: Possible increased rilpivirine concentrations;1 not expected to affect tipranavir concentrations1

No in vitro evidence of antagonistic antiretroviral effects1 6

Ritonavir-boosted tipranavir: Dosage adjustments not needed200

Zidovudine

Pharmacokinetic interactions unlikely1

No in vitro evidence of antagonistic antiretroviral effects 1 6

Rilpivirine Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Absolute oral bioavailability unknown.1

Peak plasma rilpivirine concentrations attained within approximately 4–5 hours.1

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.233

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.1 4

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.1 4

Distribution

Extent

Distribution into compartments other than plasma (e.g., CSF, genital tract secretions) not evaluated.1

Plasma Protein Binding

Approximately 99.7% (in vitro), principally albumin.1

Elimination

Metabolism

Metabolized principally in the liver by CYP3A.1

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).1

Because rilpivirine is highly bound to plasma proteins, clinically important removal by peritoneal dialysis or hemodialysis is unlikely.1

Half-life

Terminal elimination half-life is about 50 hours.1

Special Populations

Mild or moderate hepatic impairment (Child-Pugh class A or B) increases rilpivirine exposure by 47 or 5%, respectively.1 (See Hepatic Impairment under Warnings/Precautions.)

Coinfection with HIV and HBV or HCV does not alter rilpivirine exposure.1

Mild renal impairment does not alter rilpivirine exposure.1 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.1 (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.1

Gender differences in pharmacokinetics not observed.1

Race not expected to affect rilpivirine exposure.1

Pharmacokinetics not studied in pregnant women.1

Stability

Storage

Oral

Tablets

Rilpivirine (Edurant): 25°C (may be exposed to 15–30°C);1 store in original container.1

Emtricitabine/rilpivirine/tenofovir alafenamide (Odefsey): <30°C.244 Dispense in original container;244 keep tightly closed.244

Emtricitabine/rilpivirine/tenofovir DF (Complera): 25°C (may be exposed to 15–30°C).233 Dispense in original container;233 keep tightly closed.233

(web3)