Emtricitabine/rilpivirine/tenofovir AF

Black Box Warnings

Not approved for chronic hepatitis B virus (HBV) infection and the safety and efficacy have not been established in patients coinfected with HBV and HIV-1; severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 (including thos who have discontinued emtricitabine or tenofovir)

Hepatic function should be monitored closely in these patients; if appropriate, initiation of antihepatitis B therapy may be warranted

Contraindications

Coadministration with drugs that significantly decrease rilpivirine plasma concentrations due to CYP3A enzyme induction (eg, carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, dexamethasone [>1 dose], St John’s wort)

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

Cautions

Patients with HIV-1 infection should be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy (ART); not approved for the treatment of chronic HBV infection (see Black Box Warnings)

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

Rilpivirine may increase risk for depressive disorders; evaluate patients with severe depressive symptoms to assess whether symptoms are treatment-related, and determine whether the risks of continuing therapy outweigh the benefits

Hepatic adverse effects reported with rilpivirine; 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 (see Dosage Modifications)

Fat redistribution and accumulation observed with ART therapy

Immune reconstitution syndrome reported, including the occurrence of autoimmune disorders (eg, Grave disease, polymyositis, Guillain-Barre syndrome) with variable time to onset

Decreases in bone mineral density (BMD) and cases of osteomalacia associated with proximal renal tubulopathy reported with tenofovir; consider monitoring BMD with a history of pathologic fracture or if risk factors for bone loss exist

Lactic acidosis/ severe hepatomegaly with steatosis

• Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including emtricitabine and tenofovir DF, alone or in combination with other antiretrovirals
• Treatment should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations)

New-onset or worsening renal impairment

• Estimated CrCl, urine glucose, and urine protein should be assessed in all patients before initiating
• Avoid concurrent or recent use of nephrotoxic drugs
• Cases of acute renal failure and Fanconi syndrome reported with the use of tenofovir prodrugs; monitor estimated CrCl, urine glucose, and urine protein in all patients prior to initiating and during therapy; additionally, monitor serum phosphorus in patients with or at risk for renal impairment
• Discontinue drug if clinically significant decreases in renal function or evidence of Fanconi syndrome develop
• Do not initiate with CrCl <30 mL/min

Drug interactions overview

• Rilpivirine is primarily metabolized by CYP3A, and drugs that induce or inhibit CYP3A may affect the clearance of rilpivirine (see Contraindications)
• Concomitant use with other drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effects and possible development of resistance
• Supratherapeutic rilpivirine doses (ie, 75 mg and 300 mg qDay) have been shown to prolong the QTc interval; caution when coadministered with a drug known to increase risk of torsade de pointes
• Rilpivirine use with proton pump inhibitors is contraindicated and use of RPV with H2-receptor antagonists requires staggered administration (see Contraindications)
• Coadministration of Odefsey with other drugs that inhibit P-gp/BCRP may increase the absorption and plasma concentration of tenofovir AF; drugs that induce P-gp activity are expected to decrease the absorption of TAF, resulting in decreased plasma concentration of TAF, which may lead to loss of therapeutic effect of Odefsey and development of resistance
• Coadministration of Odefsey with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of FTC, tenofovir, and other renally eliminated drugs and this may increase the risk of adverse reactions
• See Drug Interactions

Pregnancy

There are insufficient human data on the use of Odefsey during pregnancy to inform a drug-associated risk of birth defects and miscarriage

Tenofovir alafenamide (TAF) use in women during pregnancy has not been evaluated; however, emtricitabine (FTC) and rilpivirine (RPV) use during pregnancy has been evaluated in a limited number of women reported to the Antiretroviral Pregnancy Registry (APR)

Available data from the APR show no difference in the risk of overall major birth defects for FTC (2.4%) compared with the background rate for major birth defects of 2.7%

An ART pregnancy registry has been established; healthcare providers should encourage patients to register (1-800-258-426)

Lactation

In the United States, the Centers for Disease Control and Prevention recommend that HIV-infected mothers not breastfeed their infants, to avoid risking postnatal transmission of HIV

Based on published data, FTC has been shown to be present in human breast milk; it is unknown if RPV and TAF are present in human breast milk; RPV is present in rat milk and tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of; presence of TAF in animal milk is unknown

Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

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.