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Rilpivirine Hydrochloride

Pronunciation: RIL-pi-VIR-een HYE-droe-KLOR-ide
Class: Antiretroviral agent, NNRTI

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Trade Names

Edurant
- Tablets, oral 25 mg

Pharmacology

Inhibits HIV-1 replication by noncompetitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular DNA polymerases alpha, beta, or gamma.

Pharmacokinetics

Absorption

T _max is approximately 4 to 5 h. Bioavailability is unknown. Systemic exposure is decreased by approximately 40% when taken under fasting conditions.

Distribution

Protein binding is approximately 99.7%, primarily to albumin.

Metabolism

Undergoes oxidative metabolism mediated by the CYP3A system.

Elimination

Elimination is 85% (25% as unchanged) in the feces and 6.1% (less than 1% as unchanged) in the urine. Terminal elimination half-life is approximately 50 h.

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.

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.

Children

Pharmacokinetics have not been studied.

Gender

No pharmacokinetic difference has been noted between men and women.

Race

No pharmacokinetic difference has been demonstrated based on race.

Hepatitis B and/or C coinfection

No clinically relevant effect on exposure was found.

Indications and Usage

Treatment of HIV-1 infection in combination with other antiretroviral agents.

Contraindications

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

Dosage and Administration

Adults

PO 25 mg once daily.

General Advice

Tablets should be taken with a meal.

Storage/Stability

Store between 59° and 86°F. Store in original container to protect from light.

Drug Interactions

Antacids (eg, aluminum or magnesium hydroxide, calcium carbonate)

Rilpivirine plasma concentrations may be decreased. Use with caution. Antacids should be administered at least 2 h before or at least 4 h after rilpivirine.

Anticonvulsants (eg, carbamazepine, oxcarbazepine, phenobarbital, phenytoin), proton pump inhibitors (eg, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole), rifamycins (eg, rifabutin, rifampin, rifapentine), St. John's wort, systemic glucocorticoids (eg, dexamethasone)

Rilpivirine plasma concentrations may be decreased because of CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Coadministration is contraindicated.

Azole antifungal agents (eg, fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole)

Rilpivirine plasma concentrations may be increased. No rilpivirine dose adjustment is needed. Ketoconazole plasma concentrations may be decreased. Monitor for breakthrough fungal infection.

Didanosine buffered

Rilpivirine plasma concentrations may be decreased. Use with caution. Didanosine should be administered at least 2 h before or at least 4 h after rilpivirine.

Food

Rilpivirine exposure was approximately 40% lower when taken in a fasted condition compared with a normal caloric meal or high-fat, high-calorie meal. When taken with a protein-rich nutritional drink, rilpivirine exposure was 50% lower than when taken with a meal. Rilpivirine should be taken with a meal.

H ₂ -receptor antagonists (cimetidine, famotidine, nizatidine, ranitidine)

The increase in gastric pH may cause a decrease in rilpivirine plasma concentrations. Use with caution. H ₂ -receptor antagonists should be given at least 12 h before or at least 4 h after rilpivirine.

Macrolide antibiotics (eg, clarithromycin, erythromycin)

Rilpivirine plasma concentrations may be increased. When possible, alternative therapy (eg, azithromycin) should be considered.

Methadone

Both rilpivirine and methadone plasma concentrations may be decreased. No dosage adjustments are required. However, clinical monitoring is recommended because methadone maintenance therapy may need to be adjusted in some patients.

NNRTIs (eg, delavirdine, efavirenz, etravirine, nevirapine)

Rilpivirine plasma concentrations may be decreased by efavirenz, etravirine, and nevirapine, while delavirdine may increase rilpivirine plasma concentrations. Coadministration is not recommended.

Protease inhibitors (eg, atazanavir, atazanavir/ritonavir, darunavir/ritonavir, fosamprenavir, fosamprenavir/ritonavir, indinavir, lopinavir/ritonavir, nelfinavir, saquinavir/ritonavir, tipranavir/ritonavir)

Rilpivirine plasma concentrations may be increased. Monitor the clinical response. No rilpivirine dose adjustment is required when rilpivirine is coadministered with darunavir/ritonavir or lopinavir/ritonavir.

QT-prolonging drugs (eg, antiarrhythmic agents [eg, amiodarone, bretylium, disopyramide, dofetilide, procainamide, quinidine, sotalol], arsenic trioxide, chlorpromazine, cisapride, dolasetron, droperidol, gatifloxacin, halofantrine, levomethadyl, mefloquine, mesoridazine, moxifloxacin, pentamidine, pimozide, probucol, sparfloxacin, thioridazine, ziprasidone)

Information is limited. An additive effect of rilpivirine with other drugs that prolong the QT interval cannot be excluded. Rilpivirine should be used with caution when administered with a drug with a known risk of torsades de pointes.

Adverse Reactions

CNS

Depressive disorders (4%); headache, insomnia (3%); anxiety, sleep disorders, somnolence (less than 2%); abnormal dream, dizziness, fatigue (1%).

Dermatologic

Rash (3%).

GI

Abdominal discomfort, diarrhea (less than 2%); abdominal pain, nausea, vomiting (1%).

Genitourinary

Glomerulonephritis membranous, glomerulonephritis mesangioproliferative (less than 2%).

Hepatic

Cholecystitis, cholelithiasis (less than 2%).

Lab Tests

Increased ALT (15%); increased total cholesterol (14%); increased AST, increased LDL (12%); increased bilirubin, increased creatinine (5%); increased triglycerides (2%).

Metabolic-Nutritional

Decreased appetite (less than 2%).

Precautions

Monitor

Monitor for depressive disorders (eg, depression, suicide ideation, suicide attempt) throughout treatment.

Pregnancy

Category B .

Lactation

Undetermined. HIV-infected women should not breast-feed to avoid potential transmission of HIV to infant.

Children

Safety and efficacy not established.

Renal Function

No dose adjustment is required in patients with mild or moderate renal impairment. Use with caution in patients with severe renal impairment or ESRD.

Hepatic Function

No dose adjustment of rilpivirine is required in patients with mild or moderate hepatic impairment.

Depressive disorders

Depressive disorders, such as altered mood, depressed mood, depression, dysphoria, major depression, negative thoughts, suicide attempt, and suicidal ideation, have been reported.

Fat redistribution

Redistribution/accumulation of body fat, including breast enlargement, central obesity, cushingoid appearance, dorsocervical fat enlargement (buffalo hump), and peripheral wasting, have been reported.

Immune reconstitution syndrome

Has been reported in patients treated with combination antiretroviral therapy.

Overdosage

Symptoms

None well documented.

Patient Information

Warn patient that this drug is not to be used by itself, but in combination with other antiretroviral agents, and not to change the dose or stop taking any other antiviral agents unless advised by health care provider.
Advise patient to take rilpivirine with a meal once a day.
Inform patients that depressive disorders (eg, depressed mood, depression, dysphoria, mood altered, suicide attempt, suicidal ideation) may occur and to report these symptoms immediately to their health care provider.
Advise patient that changes in body fat distribution may occur and that the cause and long-term health effects of these changes are not known at this time. Advise patient to report changes in body fat distribution to heath care provider.
Advise patient that rilpivirine does not completely eliminate HIV virus and, therefore, does not reduce the risk of transmitting HIV to others. Appropriate precautions (eg, practicing safer sex using a latex or polyurethane condom) must be followed.
Advise patients that if a dose is missed within 12 h of the time they usually take the dose, to take the missed dose with a meal as soon as possible. Then, take the next dose at the regularly scheduled time. If a dose is missed by more than 12 h of the usual administration time, the patient should wait and take the next dose at the regularly scheduled time. The dose should not be doubled to make up for the missed dose.