Rilpivirine Hydrochloride

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
Brands: Complera, Edurant

Warning(s)

  • Fixed Combinations
  • If using 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.233

  • If using 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.233 The fixed combination is not labeled by FDA for treatment of chronic HBV infection; safety and efficacy not established in HIV-infected patients coinfected with HBV.233 Monitor hepatic function closely with both clinical and laboratory follow-up for at least several months after fixed combination is discontinued in coinfected patients.233 If appropriate, initiation of HBV treatment may be warranted.233

Introduction

Antiretroviral; HIV nonnucleoside reverse transcriptase inhibitor (NNRTI).1 4 8

Uses for Rilpivirine Hydrochloride

Treatment of HIV Infection

Treatment of HIV-1 infection in antiretroviral-naive adults with baseline plasma HIV-1 RNA levels ≤100,000 copies/mL;1 2 12 200 usually used in conjunction with 2 HIV NRTIs.1

For initial treatment in antiretroviral-naive adults, experts state that rilpivirine in conjunction with tenofovir disoproxil fumarate (tenofovir DF) and emtricitabine (or lamivudine) is a recommended NNRTI-based regimen, 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

Emtricitabine/rilpivirine/tenofovir DF fixed combination (Complera) is used alone as a complete treatment regimen in antiretroviral-naive adults with baseline plasma HIV-1 RNA levels <100,000 copies/mL to decrease pill burden and improve adherence; also may be used to replace a stable antiretroviral regimen in certain antiretroviral-experience adults who are virologically suppressed (i.e., plasma HIV-1 RNA levels <50 copies/mL).233

Slideshow: Flashback: FDA Drug Approvals 2013

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 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

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

Safety and efficacy not established in patients <18 years of age.1 233

Postexposure Prophylaxis following Occupational Exposure to HIV

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

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); 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; 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

Rilpivirine Hydrochloride Dosage and Administration

Administration

Oral Administration

Administer rilpivirine (Edurant) or emtricitabine/rilpivirine/tenofovir DF (Complera) orally once daily with a meal.1 233

Systemic exposure substantially decreased if rilpivirine given on empty stomach or with only a protein-rich nutritional drink.1

Rilpivirine (Edurant): Use in conjunction with other antiretrovirals.1

Emtricitabine/rilpivirine/tenofovir DF (Complera): Use alone as a complete treatment regimen.233 Because antiretrovirals in the fixed combination also are available in single-entity or other fixed-combination preparations, take care to ensure that therapy is not duplicated if used in conjunction with other antiretrovirals.233 (See Use of Fixed Combinations under Cautions.)

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).1 233

Dosage

Commercially available as rilpivirine hydrochloride; dosage expressed in terms of rilpivirine.1

Adults

Treatment of HIV Infection in Antiretroviral-naive Adults
Oral

Rilpivirine (Edurant): 25 mg once daily.1

Emtricitabine/rilpivirine/tenofovir DF (Complera): 1 tablet (emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir DF 300 mg) once daily.233

Treatment of HIV Infection in Antiretroviral-experienced Adults
Oral

Emtricitabine/rilpivirine/tenofovir DF (Complera): 1 tablet (emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir DF 300 mg) once daily.233

Treatment of HIV Infection in Adults Receiving Rifabutin
Oral

Rilpivirine (Edurant): 50 mg once daily.1 (See Specific Drugs under Interactions.)

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.233

Postexposure Prophylaxis following Occupational Exposure to HIV
Oral

Rilpivirine (Edurant): 25 mg once daily.199 Use in conjunction with 2 NRTIs (see Postexposure Prophylaxis following Occupational Exposure to HIV under Uses).199

Emtricitabine/rilpivirine/tenofovir DF (Complera): 1 tablet (emtricitabine 200 mg, rilpivirine 25 mg, and tenofovir DF 300 mg) once daily.199 Use as a complete regimen for PEP.233

Initiate PEP as soon as possible following occupational exposure to HIV (preferably within hours); continue for 4 weeks, if tolerated.199

Special Populations

Hepatic Impairment

Treatment of HIV Infection

Rilpivirine (Edurant): Dosage adjustments not needed in adults with mild or moderate hepatic impairment (Child-Pugh class A or B);1 not studied in those with severe hepatic impairment (Child-Pugh class C).1

Emtricitabine/rilpivirine/tenofovir DF (Complera): Use usual dosage in adults with mild or moderate hepatic impairment (Child-Pugh class A or B);233 not studied in those with severe hepatic impairment (Child-Pugh class C).233

Renal Impairment

Treatment of HIV Infection

Rilpivirine (Edurant): Dosage adjustments not needed in adults with mild or moderate renal impairment.1 Manufacturer makes no specific dosage recommendations for severe renal impairment or end-stage renal disease (ESRD); use with caution.1 (See Renal Impairment under Cautions.)

Emtricitabine/rilpivirine/tenofovir DF (Complera): Do not use in adults with Clcr <50 mL/minute or if dialysis required.233

Geriatric Patients

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

Cautions for Rilpivirine Hydrochloride

Contraindications

  • Rilpivirine and emtricitabine/rilpivirine/tenofovir DF: Concomitant use with drugs that induce CYP3A or elevate gastric pH 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 This includes certain anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin), certain antimycobacterials (rifampin, rifapentine), systemic dexamethasone (given in multiple doses), proton-pump inhibitors (esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole), and certain herbal supplements (St. John’s wort [Hypericum perforatum]).1 233 (See Interactions.)

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

Warnings/Precautions

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 (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

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

Hepatotoxicity

Adverse hepatic effects reported;1 hepatotoxicity reported in some patients without pre-existing hepatic disease or other risk factors.1

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

Perform laboratory tests to evaluate hepatic function prior to and during rilpivirine treatment when used in patients with underlying hepatic disease such as HBV or HCV infection or elevated aminotransferase concentrations.1 Consider liver enzyme monitoring in patients without preexisting hepatic disease or other risk factors.1

Use of Fixed Combinations

Emtricitabine/rilpivirine/tenofovir DF: Consider cautions, precautions, contraindications, and interactions associated with each drug in the fixed combination.233 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

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 the antiretrovirals contained in emtricitabine/rilpivirine/tenofovir DF also are available in single-entity or other fixed-combination preparations, take care to ensure that therapy is not duplicated if the fixed combination is used in conjunction with other antiretrovirals.233

Do not use emtricitabine/rilpivirine/tenofovir DF concomitantly with any preparation containing emtricitabine or tenofovir DF.233 In addition, do not use the fixed combination concomitantly with any preparation containing lamivudine or with adefovir.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 Mechanisms and long-term consequences of fat redistribution unknown; causal relationship not established.1

Immune Reconstitution Syndrome

During initial treatment, 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.1 233

Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) 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.1 233

Specific Populations

Pregnancy

Rilpivirine (Edurant): Category B.1

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

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

Experts state safety and pharmacokinetic data insufficient to recommend routine use of rilpivirine for initial treatment regimens in antiretroviral-naive pregnant women.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.1 233

Pediatric Use

Rilpivirine (Edurant): Safety and efficacy not established in pediatric patients;1 not recommended in children and adolescents <18 years of age.200 201

Emtricitabine/rilpivirine/tenofovir DF (Complera): Safety and efficacy not established in pediatric patients; not recommended in children and adolescents <18 years of age.233

Geriatric Use

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

Hepatic Impairment

Rilpivirine (Edurant) and emtricitabine/rilpivirine/tenofovir DF (Complera) not studied in patients with severe hepatic impairment (Child-Pugh class C).1 233 (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 DF (Complera): Do not use if Clcr <50 mL/minute or 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

Metabolized by CYP3A.1

The following drug interactions are based on studies using rilpivirine.1 Drug interaction studies not performed using emtricitabine/rilpivirine/tenofovir DF.233 When fixed combinations are used, consider interactions associated with each drug in the fixed combination.233

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Concomitant use with drugs that induce CYP3A may decrease rilpivirine concentrations and result in possible loss of virologic response and development of resistance to rilpivirine or the NNRTI class.1

Concomitant use with drugs that inhibit CYP3A may increase rilpivirine concentrations.1

Recommended rilpivirine dosage (25 mg once daily) unlikely to have clinically important pharmacokinetic interactions with drugs metabolized by CYP isoenzymes.1

Drugs that Increase Gastric pH

Possible pharmacokinetic interaction (decreased rilpivirine concentrations, possible loss of virologic response, and development of drug resistance or NNRTI-class resistance) with drugs that cause gastric pH elevation.1

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 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

Use caution if rilpivirine is used concomitantly with drugs known to increase risk of torsades de pointes.1

Specific Drugs

Drug

Interaction

Comments

Abacavir

Pharmacokinetic interactions unlikely1

No in vitro evidence of antagonistic antiretroviral effects 1 6

Acetaminophen

No clinically important pharmacokinetic interaction1

Dosage adjustments not needed1

Antacids (aluminum hydroxide, calcium carbonate, magnesium hydroxide)

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

Use with caution; take antacid at least 2 hours before or 4 hours after rilpivirine1

Anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin)

Possible decreased rilpivirine concentrations1

Concomitant use contraindicated1

Antifungals, azoles

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

Fluconazole, itraconazole, posaconazole, voriconazole: Possible increased rilpivirine concentrations and decreased azole antifungal concentrations1

Dosage adjustments of rilpivirine not needed;1 monitor for breakthrough fungal infections1

Antimycobacterials, rifamycins

Rifabutin or rifampin: Decreased rilpivirine concentrations and AUC1

Rifabutin: Increase rilpivirine dosage to 50 mg once daily; 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 daily233

Rifampin, rifapentine: Concomitant use contraindicated1

Atazanavir

Atazanavir or ritonavir-boosted atazanavir: Possible increased rilpivirine concentrations; not expected to affect atazanavir concentrations1

No in vitro evidence of antagonistic antiretroviral effects 1 6

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

Avanafil

Data not available200

Concomitant use not recommended200

Benzodiazepines

Alprazolam: Data not available200

Alprazolam: Monitor for alprazolam therapeutic effects200

Chlorzoxazone

No clinically important pharmacokinetic interaction1

Dosage adjustments not needed1

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 contraindicated1

Darunavir

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

No in vitro evidence of antagonistic antiretroviral effects1 6

Ritonavir-boosted darunavir: Dosage adjustments not needed1

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); dosage adjustments not needed1

Digoxin

No clinically important effect on digoxin pharmacokinetics1

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

Elvitegravir and cobicistat

Fixed combination of elvitegravir, cobicistat, emtricitabine, and tenofovir DF (EVG/COBI/TDF/FTC): Possible altered concentrations of elvitegravir, cobicistat, and/or rilpivirine200

EVG/COBI/TDF/FTC: Do not use concomitantly200

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

No clinically important pharmacokinetic interaction with hormonal contraceptives containing ethinyl estradiol and norethindrone1

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; 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

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; take histamine H2-receptor antagonist at least 12 hours before or at least 4 hours after rilpivirine1

HMG-CoA reductase inhibitors (statins)

Atorvastatin: No clinically important pharmacokinetic interaction1

Pitavastatin: Data not available; 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

Lopinavir/ritonavir

Increased rilpivirine concentrations and AUC; 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

Clarithromycin. erythromycin, or telithromycin: Consider alternative (e.g., azithromycin) whenever possible1

Maraviroc

Clinically important pharmacokinetic interactions unlikely1

No in vitro evidence of antagonistic antiretroviral effects 1 6

Metformin

No clinically important effect on metformin pharmacokinetics1

Methadone

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

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

Nelfinavir

Possible increased rilpivirine concentrations; 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

Proton-pump inhibitors

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

Esomeprazole, lansoprazole, pantoprazole, rabeprazole: Possible decreased rilpivirine concentrations with possible loss of virologic response and development of resistance1

Concomitant use contraindicated1

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 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

Concomitant use contraindicated1

Saquinavir

Ritonavir-boosted saquinavir: Possible increased rilpivirine concentrations; 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 interaction1

Dosage adjustments not needed1

Simeprevir

No clinically important effect on rilpivirine or simeprevir pharmacokinetics200

Dosage adjustments not needed for either drug1

Sofosbuvir

No clinically important effect on rilpivirine or sofosbuvir pharmacokinetics188

Dosage adjustments not needed for either drug188

Stavudine

Pharmacokinetic interactions unlikely1

No in vitro evidence of antagonistic antiretroviral effects 1 6

Telaprevir

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

Dosage adjustments not needed for either drug1

Tenofovir

Increased tenofovir concentrations and AUC; 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; 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.)

Gender differences in pharmacokinetics not observed.1

Race not expected to affect rilpivirine exposure.1

Pharmacokinetics not studied in pediatric patients.1

Pharmacokinetics not studied in pregnant women.1

Stability

Storage

Oral

Tablets

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

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

Actions and Spectrum

  • Inhibits replication of HIV-1 by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase.1 7 8

  • 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.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 emergence of some resistance mutations in HIV-1 reverse transcriptase.4 5 7 9

  • Active in vitro against wild-type HIV-1, but has limited activity against HIV type 2 (HIV-2).1 6 Active in vitro against some clinical HIV-1 isolates resistant to other commercially available NNRTIs (delavirdine, efavirenz, nevirapine).1 6 8

  • 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 Up to 90% of rilpivirine-resistant isolates that developed in patients receiving rilpivirine in clinical studies were resistant to etravirine.8

  • 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.1 8

Advice to Patients

  • Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 233 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1 233

  • Importance of using rilpivirine in conjunction with other antiretrovirals—not for monotherapy.1 Emtricitabine/rilpivirine/tenofovir DF (Complera) is used alone as a complete treatment regimen.233

  • Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.1 233

  • Advise patients that sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to acquired immunodeficiency disease (AIDS) and death.1 233

  • 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.1 200 233

  • Importance of reading patient information provided by the manufacturer.1 233

  • Importance of taking once daily with a meal;1 233 a protein drink alone does not constitute a meal.1 233 Food enhances absorption of rilpivirine.1

  • If a missed dose 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.1 233 If the missed dose is remembered more than 12 hours after the scheduled time, the missed dose should be omitted and the next dose taken at the regularly scheduled time.1 233 Advise patients that doses that are larger or smaller than the prescribed dosage should not be taken at any time.1 233

  • Advise patients that depressive disorders (depressed mood, depression, dysphoria, major depression, altered mood, negative thoughts, suicide attempt, suicidal ideation) have been reported.1 233 Importance of immediately contacting clinician if depressive symptoms (e.g., feeling sad, hopeless, anxious, or restless; hurting oneself; having thoughts of hurting oneself) occur.1 233

  • Advise patients that hepatotoxicity has been reported in patients receiving rilpivirine.1

  • Redistribution/accumulation of body fat may occur with antiretroviral therapy, with as yet unknown long-term health effects.1 233

  • 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.1 233 (See Contraindications.)

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 233 Advise HIV-infected women not to breast-feed.1 233

  • Importance of advising patients of other important precautionary information.1 233 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Rilpivirine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

25 mg (of rilpivirine)

Edurant

Janssen

Rilpivirine Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

25 mg (of rilpivirine) with Emtricitabine 200 mg and Tenofovir Disoproxil Fumarate 300 mg

Complera

Gilead

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 10/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Edurant 25MG Tablets (JANSSEN PRODUCTS): 30/$739.97 or 90/$2,129.88

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions October 30, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Janssen Therapeutics. Edurant (rilpivirine) tablets prescribing information. Titusville, NJ; 2014 May.

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. [PubMed 23835510]

188. Gilean Sciences Inc. Sovaldi (sofosbuvir) tablet prescribing information. Foster City, CA; 2013 Dec.

199. Kuhar DT, Henderson DK, Struble KA et al. Updated US Public Health Service guidelines for the management of occupational exposures to human immunodeficiency virus and recommendations for postexposure prophylaxis. Infect Control Hosp Epidemiol. 2013; 34:875-92. [PubMed 23917901]

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents (May 1, 2014). Updates may be available at HHS AIDS Information (AIDSinfo) website.

201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (February 12, 2014). Updates may be available at HHS AIDS Information (AIDSinfo) website.

202. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States (March 28, 2014). Updates may be available at HHS AIDS Information (AIDSinfo) website.

233. Gilead Sciences. Complera (emtricitabine/rilpivirine/tenofovir disoproxil fumarate) tablets prescribing information. Foster City, CA; 2014 Jun.

236. ViiV Healthcare. Tivicay (dolutegravir) tablets prescribing information. Research Triangle Park, NC; 2014 May.

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