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Rilpivirine

Pronunciation

(ril pi VIR een)

Index Terms

  • Rilpivirine HCl
  • TMC278

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Edurant: 25 mg

Brand Names: U.S.

  • Edurant

Pharmacologic Category

  • Antiretroviral, Reverse Transcriptase Inhibitor, Non-nucleoside (Anti-HIV)

Pharmacology

As a non-nucleoside reverse transcriptase inhibitor, rilpivirine has activity against HIV-1 by binding to reverse transcriptase. It consequently blocks the RNA-dependent and DNA-dependent DNA polymerase activities, including HIV-1 replication. It does not require intracellular phosphorylation for antiviral activity.

Absorption

Increased 40% with a meal (normal-to-high calorie)

Metabolism

Hepatic, primarily by CYP3A4

Excretion

Feces (85%, ~25% as unchanged drug); urine (~6%; <1% as unchanged drug)

Time to Peak

Plasma: 4 to 5 hours

Half-Life Elimination

~50 hours

Protein Binding

99.7% (primarily albumin)

Special Populations: Renal Function Impairment

Exposure was similar in HIV-1-infected subjects with mild renal impairment relative to HIV-1–infected subjects with healthy renal function; no dose adjustment is required. There is limited information regarding the pharmacokinetics in patients with moderate or severe renal impairment or in patients with ESRD. Concentrations may be increased because of alteration of drug absorption, distribution, and metabolism secondary to renal dysfunction. The potential impact is not expected to be of clinical relevance for subjects with moderate renal impairment; no dose adjustment is required.

Special Populations: Hepatic Function Impairment

The multiple-dose exposure was 47% higher in subjects with mild hepatic impairment and 5% higher in subjects with moderate hepatic impairment; no dose adjustment is required. Rilpivirine has not been studied in subjects with severe hepatic impairment.

Use: Labeled Indications

HIV-1 infection: Treatment of HIV-1 infections in antiretroviral treatment-naive patients with HIV-1 RNA ≤100,000 copies/mL at the start of therapy in combination with at least 2 other antiretroviral agents

Contraindications

Coadministration with anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin), antimycobacterials (rifampin, rifapentine), proton pump inhibitors (esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole), systemic dexamethasone (more than a single dose), or St John's wort.

Canadian labeling: Additional contraindications (not in US labeling): Hypersensitivity to rilpivirine or any component of the formulation

Dosing: Adult

HIV-1 infection: Patients ≥35 kg: Oral: 25 mg once daily.

Dosage adjustment for concomitant therapy with rifabutin: Increase to 50 mg once daily in patients on concomitant rifabutin. Decrease to 25 mg once daily when rifabutin is stopped.

Dosing: Pediatric

HIV-1 infection: Children ≥12 years and Adolescents ≥35 kg: Refer to adult dosing.

Dosage adjustment for concomitant therapy with rifabutin: Refer to adult dosing.

Dosing: Renal Impairment

Mild or moderate renal impairment: No dosage adjustment necessary.

Severe or end-stage renal impairment (ESRD): Use with caution; no dosage adjustment necessary (HHS [adult] 2015).

Hemodialysis/peritoneal dialysis: Due to extensive protein binding, significant removal by hemodialysis or peritoneal dialysis is unlikely.

Dosing: Hepatic Impairment

Mild to moderate impairment (Child-Pugh class A or B): No dosage adjustment necessary.

Severe impairment (Child-Pugh class C): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). Department of Health and Human Services (HHS) HIV treatment guidelines also have no dosage recommendation (HHS [adult] 2015). The Canadian labeling recommends avoiding use due to lack of data.

Administration

Swallow tablet whole with water. Administer with a normal- to high-calorie meal. Taking with a protein supplement drink alone does not increase absorption.

Dietary Considerations

Take with a normal- to high-calorie meal. Taking with a protein supplement drink alone does not increase absorption.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Keep in original container; protect from light.

Drug Interactions

Antacids: May decrease the serum concentration of Rilpivirine. Management: Administer antacids at least 2 hours before or 4 hours after rilpivirine. Consider therapy modification

Antihepaciviral Combination Products: May increase the serum concentration of Rilpivirine. Avoid combination

Boceprevir: May increase the serum concentration of Rilpivirine. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CarBAMazepine: May decrease the serum concentration of Rilpivirine. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Rilpivirine. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Darunavir: May increase the serum concentration of Rilpivirine. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Dexamethasone (Systemic): May decrease the serum concentration of Rilpivirine. Avoid combination

Didanosine: Rilpivirine may decrease the absorption of Didanosine. More specifically, simultaneous coadministration of these drugs creates a conflict between recommendations to administer with (rilpivirine) and without (didanosine) food. Didanosine may decrease the absorption of Rilpivirine. More specifically, simultaneous coadministration of these drugs creates a conflict between recommendations to administer with (rilpivirine) and without (didanosine) food. Management: Administer didanosine on an empty stomach at least 2 hours before or 4 hours after rilpivirine, due to the requirement that rilpivirine be administered with food. Consider therapy modification

Efavirenz: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Efavirenz. Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Efavirenz. Avoid combination

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Ergonovine: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Ergonovine. Specifically, this would be most likely with delavrdine, while other Non-Nucleoside Reverse Transcriptase Inhibitors may be more likely to decrease the concentration of Ergonovine. Avoid combination

Etravirine: Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Etravirine. This has been observed with the NNRTIs efavirenz and nevirapine. Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Etravirine. This has been observed with delavirdine. Avoid combination

Fosphenytoin: May decrease the serum concentration of Rilpivirine. Avoid combination

H2-Antagonists: May decrease the serum concentration of Rilpivirine. Management: Administer histamine H2 receptor antagonists at least 12 hours before or 4 hours after rilpivirine. Consider therapy modification

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Ketoconazole (Systemic): May increase the serum concentration of Rilpivirine. Rilpivirine may decrease the serum concentration of Ketoconazole (Systemic). Monitor therapy

Lopinavir: May increase the serum concentration of Rilpivirine. Monitor therapy

Macrolide Antibiotics: May increase the serum concentration of Rilpivirine. Management: Consider the use of azithromycin or another non-macrolide alternative when appropriate to avoid this potential interaction. Exceptions: Roxithromycin. Consider therapy modification

Methadone: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the metabolism of Methadone. Management: Methadone dosage adjustments will likely be required with efavirenz and nevirapine, and may be necessary with rilpivirine as well. Consider therapy modification

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Orlistat: May decrease the serum concentration of Antiretroviral Agents. Monitor therapy

OXcarbazepine: May decrease the serum concentration of Rilpivirine. Avoid combination

PHENobarbital: May decrease the serum concentration of Rilpivirine. Avoid combination

Phenytoin: May decrease the serum concentration of Rilpivirine. Avoid combination

Primidone: May decrease the serum concentration of Rilpivirine. Avoid combination

Proton Pump Inhibitors: May decrease the serum concentration of Rilpivirine. Avoid combination

Reverse Transcriptase Inhibitors (Non-Nucleoside): May increase the serum concentration of Rilpivirine. This mechanism applies to coadministration of delavirdine. Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Rilpivirine. This mechanism applies to coadministration of efavirenz, etravirine, and nevirapine. Avoid combination

Rifabutin: May decrease the serum concentration of Rilpivirine. Management: Increase the rilpivirine adult dose to 50 mg/day during rifabutin treatment. Decrease back to 25 mg/day following rifabutin discontinuation. Use of rifabutin with the emtricitabine/rilpivirine/tenofovir alafenamide combination product is not recommended. Consider therapy modification

Rifamycin Derivatives: May decrease the serum concentration of Rilpivirine. Exceptions: Rifabutin. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of Reverse Transcriptase Inhibitors (Non-Nucleoside). Specifically, St. Johns Wort may increase the metabolism of Reverse Transcriptase Inhibitors (Non-Nucleoside). Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Adverse Reactions

>10%:

Central nervous system: Depression (5% to 9%; children and adolescents: 19%), headache (3%; children and adolescents: 19%), drowsiness (children and adolescents: 14%)

Endocrine & metabolic: Decreased plasma cortisol (7%; children and adolescents: 20%; decrease from baseline via ACTH stimulation test; clinical significance is unknown), increased serum cholesterol (7% to 17%), increased LDL cholesterol (5% to 14%)

Gastrointestinal: Nausea (1%; children and adolescents: 11%)

Hepatic: Increased serum ALT (5% to 18%), increased serum AST (4% to 16%)

1% to 10%:

Central nervous system: Dizziness (1%; children and adolescents: 8%), insomnia (3%), abnormal dreams (2%), fatigue (2%)

Dermatologic: Skin rash (3% to 6%)

Endocrine & metabolic: Increased serum triglycerides (2%)

Gastrointestinal: Abdominal pain (2%; children and adolescents: 8%), vomiting (1%; children and adolescents: 6%)

Hepatic: Increased serum bilirubin (3% to 5%)

Renal: Increased serum creatinine (1% to 6%)

<1% (Limited to important or life-threatening): Conjunctivitis, DRESS syndrome, hepatitis, hypersensitivity reaction, localized vesiculation, nephrotic syndrome, suicidal ideation

Warnings/Precautions

Concerns related to adverse effects:

• Depressive disorders: May cause depression, depressed mood, dysphoria, mood changes, negative thoughts, suicide attempts, or suicidal ideation; if changes are noted, seek professional intervention immediately; reevaluate risk versus benefit of continued rilpivirine therapy.

• Fat redistribution: May cause redistribution of fat (eg, buffalo hump, peripheral wasting with increased abdominal girth, cushingoid appearance).

• Hepatotoxicity: Has been reported during use. Patients with significant transaminase elevations or hepatitis B or C prior to treatment may be at greater risk for hepatic adverse events. Hepatotoxicity has occurred in a few adult patients with no prior hepatic disease or risk factors. Baseline and periodic laboratory LFT evaluation during therapy is recommended for patients with pre-existing risk factors; also consider LFT monitoring in patients without identifiable hepatic disease risk.

• Hypersensitivity: Hypersensitivity and severe skin reactions have been reported, including severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis or eosinophilia, or drug reaction with eosinophilia and systemic symptoms (DRESS) with rilpivirine-containing regimens. Some skin reactions were accompanied by constitutional symptoms (eg, fever); other skin reactions were associated with organ dysfunction (eg, hepatic serum biochemistry elevations). In clinical trials, treatment-related rashes ≥ Grade 2 were reported in 3% of patients. Most rashes were Grade 1 or 2 and occurred within the first 4 to 6 weeks of therapy. No Grade 4 rashes were reported. Monitor laboratory parameters and clinical status; discontinue if any hypersensitivity or skin rash develop.

• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves’ disease, polymyositis, Guillain-Barré syndrome) later in therapy; further evaluation and treatment may be required.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• QTc prolongation: Doses >25 mg daily (ie, 75 mg daily, 300 mg daily) have been associated with QTc prolongation; use caution when coadministering with a drug with a known risk of torsades de pointes (HHS [adult] 2015).

Other warnings/precautions:

• Appropriate use: Do not use in adolescent and adult HIV-1 patients with a pre-ART of CD4 count <200 cells/mm3 and/or HIV RNA >100,000 copies/mL (HHS [adult] 2015).

Monitoring Parameters

Cholesterol, triglycerides, hepatic transaminases; signs of skin rash, fever, and/or hypersensitivity reactions, signs and symptoms of infection

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies. Rilpivirine has moderate to high placental transfer. Available data in pregnant women are insufficient to evaluate the overall risk of birth defects. Hypersensitivity reactions (including hepatic toxicity and rash) are more common in women on NNRTI therapy; it is not known if pregnancy increases this risk. The HHS Perinatal HIV Guidelines recommend rilpivirine in combination with emtricitabine and tenofovir (or rilpivirine plus a preferred two NRTI backbone) as an alternative NNRTI regimen for use in antiretroviral-naive pregnant women with a pre-treatment HIV RNA ≤100,000 copies/mL and CD4 cell count ≥200 cells/mm3. The pharmacokinetics are not significantly altered in pregnancy and dosing adjustment is not needed.

Combination antiretroviral therapy (cART) therapy is recommended for all HIV-infected pregnant women. The goal of therapy is to keep the viral load below the limit of detection and prevent perinatal transmission. Therapy must be individualized. In general, women who become pregnant on a stable cART regimen may continue that regimen if viral suppression is effective, contraindications for use in pregnancy are not present, and the regimen is well tolerated. For HIV infected couples planning a pregnancy, maximum viral suppression with cART is recommended prior to conception for the HIV-infected partner(s). When HIV is diagnosed during pregnancy in a woman who has never received antiretroviral therapy, cART should be considered as soon as possible after diagnosis to reduce the risk of perinatal transmission. If antiretroviral drug-resistance testing is done, treatment may be started prior to obtaining results, then adjusted accordingly. Monitoring during pregnancy is more frequent than in non-pregnant adults. If cART must be interrupted for <24 hours, stop then restart all medications simultaneously in order to decrease the chance of developing resistance. Long-term follow-up is recommended for all infants exposed to antiretroviral medications; children who develop significant organ system abnormalities (particularly of the CNS or heart) should be evaluated for potential mitochondrial dysfunction.

HIV infected women not planning a pregnancy may use any available type of contraception, considering possible drug interactions and contraindications of the specific method. In addition, consistent use of condoms is also recommended (even during pregnancy) to prevent transmission of HIV or other sexually transmitted diseases.

Health care providers are encouraged to enroll pregnant women exposed to antiretroviral medications as early in pregnancy as possible in the Antiretroviral Pregnancy Registry (1-800-258-4263 or www.APRegistry.com). Health care providers caring for HIV-infected women and their infants may contact the National Perinatal HIV Hotline (888-448-8765) for clinical consultation (HHS [perinatal] 2016).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, dizziness, fatigue, headache or insomnia. Have patient report immediately to prescriber signs of infection, signs of depression (suicidal ideation, anxiety, emotional instability, or illogical thinking), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), arrhythmia, change in body fat, severe abdominal pain, shortness of breath, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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