rilpivirine (Rx)

1-10%

Depressive disorders (4%)

Insomnia (3%)

Headache (3%)

Rash (3%)

Increased AST (2%; grade 3 or higher)

ALT increased (19%)

Abnormal dreams (1%)

Nausea (1%)

Suicidal ideation (4-8%)

Abdominal pain (1%)

Vomiting (1%)

Fatigue (1%)

Dizziness (1%)

Posmarketing reports

Severe skin and hypersensitivity reactions including DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms)

Contraindications

Hypersensitivity

Coadministration with drugs (eg, CYP inducers like phenobarbital, dexamethasone, oxcarbazepine, phenytoin, or carbamazepine) where significant decreases in rilpivirine plasma concentrations may occur, which may result in loss of virologic response and possible resistance and cross-resistance to other NNRTIs

Contraindicated with drugs that increase gastric pH (eg, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole) that may decrease rilpivirine absorption and result in decreased rilpivirine plasma concentrations

Cautions

Coadministration with other NNRTIs may either increase or decrease rilpivirine; avoid use with other NNRTIs

May increase risk for depressive disorders

Hepatic adverse effects reported; patients with underlying hepatitis B or C, or marked increased transaminases prior to treatment may be at increased risk; monitor for hepatotoxicity before initiating and during treatment

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy

Immune reconstitution syndrome: During initial phase of combination ART treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (eg, Mycobacterium avium complex, CMV, Pneumocystis pneumonia, TB)

Severe skin and hypersensitivity reactions reported, including cases of drug reaction with eosinophilia and systemic symptoms (DRESS), with rilpivirine-containing regimens; immediately discontinue treatment if hypersensitivity or rash with systemic symptoms or elevations in hepatic serum biochemistries develop and closely monitor clinical status, including hepatic serum biochemistries

Virologic failure & resistance

• More rilpivirine treated individuals with HIV-1 RNA >100,000 copies/mL at the start of therapy experienced virologic failure compared to those with <100,000 copies/mL
• Observed virologic failure rate in rilpivirine treated individuals conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz
• More individuals treated with rilpivirine developed lamivudine/emtricitabine associated resistance compared to efavirenz

Drug interaction overview

• Drugs that induce or inhibit CYP3A may affect clearance of rilpivirine
• Coadministration with CYP3A4 inducers may decrease plasma concentrations of rilpivirine and result in loss of virologic response and possible resistance to rilpivirine OR to non-nucleoside reverse transcriptase inhibitors (NNRTIs)
• Coadministration with CYP3A4 inhibitors may increase plasma concentrations of rilpivirine
• Coadministration with drugs that increase gastric pH may decrease plasma concentrations of rilpivirine and result in loss of virologic response and possible resistance to rilpivirine or to NNRTIs
• In healthy subjects, rilpivirine 75 mg PO qDay (3 times rilpivirine dose) and 300 mg PO qDay (12 times rilpivirine dose) have been shown to prolong the QTc interval; consider alternatives when coadministered with a drug with a known risk of torsade de pointes

Pregnancy

Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1-800-258-4263

Available data from the APR show no difference in the overall risk of birth defects for rilpivirine compared with the background rate for major birth defects of 2.7% in the Metropolitan Atlanta Congenital Defects Program (MACDP) reference population

Based on experience of HIV-1-infected pregnant women who completed a clinical trial through postpartum period with a rilpivirine-based regimen, no dose adjustments are required for pregnant patients who are already on a stable dose regimen prior to pregnancy and who are virologically suppressed (HIV-1 RNA less than 50 copies per mL); the recommended dosage is one 25 mg tablet once daily taken orally with a meal; lower exposures of drug were observed during pregnancy, therefore viral load should be monitored closely

Animal data

• In animal reproduction studies, no adverse developmental outcomes were observed when drug was administered orally at exposures up to 15 (rats) and 70 (rabbits) times exposure in humans at recommended dose of 25 mg once daily

Lactation

Unknown whether distributed in human breast milk; there are no data on presence of drug in human milk, effects on breastfed infant, or on milk production; drug is present in rat milk

The CDC recommends that women in the United States should not breastfeed their infants because of risk of the following

• Postnatal HIV transmission (in HIV-negative infants)
• Developing viral resistance (in HIV-positive infants)
• Adverse reactions in nursing infants

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Antiviral agent; diarylpyrimidine non-nucleoside reverse transcriptase inhibitor (NNRTI) of HIV-1

Inhibits HIV-1 replication by noncompetitive inhibition of HIV-1 reverse transcriptase

Does not inhibit the human cellular DNA polymerases alpha, beta, and gamma

Absorption

Bioavailability: Absolute bioavailability unknown

Peak Plasma Time: 4-5 hr

Peak Plasma Concentration: 80 ng/mL (mean)

AUC: 2397 ng•h/mL (mean)

Food: Exposure ~40% lower when taken in a fasted condition as compared to a normal caloric meal (533 kcal) or high-fat high-caloric meal (928 kcal); when taken with only a protein-rich nutritional drink, exposures were 50% lower than when taken with a meal

Distribution

Protein Bound: 99.7% (primarily to albumin)

Metabolism

Metabolized primarily by CYP3A

Elimination

Half-life: 50 hr

Excretion: feces (85%), urine (6.1%) bile, other

Oral Administration

Must administer with a meal

Must be able to take with a meal of at least 500 calories on a regular schedule (a protein drink alone does not constitute a meal)

If coadministered with antacids should only be administered either at least 2 hr before or at least 4 hr after rilpivirine