Dolutegravir + Rilpivirine

Dolutegravir + Rilpivirine is used for: HIV Infection

HIV Infection Indicated as complete regimen to replace current antiretroviral (ART) regimen in virologically suppressed adults Patients with no history of treatment failure and no known substitutions associated with resistance to dolutegravir or rilpivirine HIV-1 RNA <50 copies/mL on a stable ART regimen for ?6 months: 1 tablet (dolutegravir 50 mg/rilpivirine 25 mg) PO qDay Hepatic impairment Mild-to-moderate (Child-Pugh A or B): No dosage adjustment is necessary Severe (Child-Pugh C): Effect on the pharmacokinetics of dolutegravir or rilpivirine is unknown

Renal impairment Mild-to-moderate (CrCl ?30 mL/min): No dosage adjustment is necessary Severe (CrCl <30 mL/min) or end-stage renal disease: Increased monitoring for adverse effects is recommended

Should be taken with meal

Documented hypersensitivity to dolutegravir or rilpivirine

Depressive disorders (including depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, and suicidal ideation) have been associated with rilpivirine Hepatotoxicity Hepatic adverse events were reported in patients receiving a dolutegravir- or rilpivirine-containing regimen; patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations Drug-induced liver injury leading to acute liver failure has been reported with dolutegravir-containing products; monitor for hepatotoxicity Skin and hypersensitivity reactions Hypersensitivity reactions (eg, rash, constitutional findings, and sometimes organ dysfunction, including liver injury) have been reported Severe skin and hypersensitivity reactions have been reported during postmarketing experience, including cases of DRESS, with rilpivirine-containing regimens Discontinue treatment immediately if signs or symptoms of severe skin or hypersensitivity reactions develop

Pregnancy Prospective pregnancy data was insufficient from the APR to adequately assess the birth defects and miscarriage risks In animal reproduction studies, no evidence of adverse developmental outcomes was observed with dolutegravir or rilpivirine During organogenesis in the rat and rabbit, systemic exposures (AUC) to dolutegravir were less than (rabbits) and 38 times (rats) and exposures to rilpivirine were 15 (rats) and 70 (rabbits) times the exposure at the recommended human dose (RHD) In rat prenatal and postnatal development studies, maternal systemic exposures (AUC) to dolutegravir and rilpivirine were ~32 and 63 times, respectively, exposures of each component in humans at the RHD Potential risk of neural tube birth defects Serious cases of neural tube birth defects involving the brain, spine, and spinal cord reported in babies born to women treated with dolutegravir Preliminary results from an ongoing observational study in Botswana found women who had received dolutegravir at the time of becoming pregnant or early in the first trimester appear to be at higher risk for these defects; to date, in this observational study there are no reported cases of babies born with neural tube defects to women starting dolutegravir later in pregnancy Lactation The Centers for Disease Control and Prevention do not recommend HIV-1-infected mothers in the United States breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection Unknown whether dolutegravir/rilpivirine or its components are present in human breast milk, affect human milk production, or have effects on the breastfed infant When administered to lactating rats, dolutegravir and rilpivirine were present in milk Because of potential for HIV-1 transmission (in HIV-negative infants), developing viral resistance (in HIV-positive infants), and adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving therapy

Concomitant use of dolutegravir/rilpivirine and other drugs may result in known or potentially significant drug interactions, loss of therapeutic effect of dolutegravir/rilpivirine, possible development of resistance, or possible increases in toxicities of dolutegravir/rilpivirine Because dolutegravir/rilpivirine is a complete regimen, coadministration with other antiretroviral medications is not recommended Dolutegravir inhibits the renal organic cation transporters (OCT)2 and multidrug and toxin extrusion transporter (MATE)1; thus, it may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 (eg, dofetilide and metformin) Potential for other drugs to affect dolutegravir Dolutegravir is metabolized by uridine diphosphate (UDP)-glucuronosyl transferase (UGT)1A1 with some contribution from CYP3A; dolutegravir is also a substrate of UGT1A3, UGT1A9, breast cancer resistance protein (BCRP), and p-glycoprotein (P-gp) in vitro Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentrations and reduce the therapeutic effect of dolutegravir Coadministration of dolutegravir and other drugs that inhibit these enzymes may increase dolutegravir plasma concentrations

Side effects of Dolutegravir + Rilpivirine : 1-10% Dolutegravir Lipase, Grade 2 (5%) Hyperglycemia, Grade 2 (4%) ALT, Grade 2 (2%) Total bilirubin, Grade 2 (2%) Creatine kinase, Grade 3 or 4 (1%) Lipase, Grade 3 or 4 (2%) Rilpivirine Lipase, Grade 2 (5%) Hyperglycemia, Grade 3 or 4 (5%) Total bilirubin, Grade 2 (4%) Creatine kinase, Grade 3 or 4 (2%) Lipase, Grade 3 or 4 (2%) <1% ALT, Grade 3 or 4 AST, Grade 3 or 4 Creatine kinase, Grade 2 Hyperglycemia, Grade 3 or 4

Dolutegravir Integrase strand transfer inhibitor (INSTI); inhibits catalytic activity of HIV-1 integrase, an HIV-encoded enzyme required for viral replication Rilpivirine Antiviral agent; diarylpyrimidine 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