dolutegravir/rilpivirine (Rx)

Brand and Other Names:Juluca
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

dolutegravir/rilpivirine

tablet

  • 50mg/25mg (equivalent to 52.6mg dolutegravir sodium/27.5mg rilpivirine hydrochloride)

HIV Infection

Indicated as a complete regimen for treatment of HIV-1 infection to replace the current antiretroviral (ART) regimen in adults who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable ART regimen for ≥6 months with no history of treatment failure and no known substitutions associated with resistance to dolutegravir or rilpivirine

1 tablet (dolutegravir 50 mg/rilpivirine 25 mg) PO qDay

Dosage Modifications

See also Contraindications

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

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

Coadministration with dolutegravir/rilpivirine and other drugs

  • Rifabutin: Take an additional 25-mg tablet of rilpivirine for the duration of the rifabutin coadministration
  • Metformin: Limit total daily dose of metformin to 1000 mg/day either when starting metformin or dolutegravir/rilpivirine; when starting or stopping dolutegravir/rilpivirine, metformin dose may require an adjustment; monitor blood glucose when initiating concomitant use and after withdrawal of dolutegravir/rilpivirine
  • Macrolides or ketolides (eg, clarithromycin, erythromycin, telithromycin): Consider alternant antibiotics (eg, azithromycin) if possible
  • Medications containing polyvalent cations (eg, Mg or Al) (cation-containing products or laxatives, sucralfate buffered medications): Administer 4 hr before or 6 hr after taking products containing polyvalent cations
  • Methadone: No dose adjustment for dolutegravir/rilpivirine is necessary; methadone maintenance therapy may need to be adjusted in some patients
  • Oral calcium and iron supplements (eg, multivitamins containing calcium or iron [non-antacid]): Administer dolutegravir/rilpivirine and supplements containing calcium or iron together with a meal or take these supplements 4 hr before or 6 hr after taking dolutegravir/rilpivirine
  • Drugs affecting gastric pH
    • Antacids (eg, aluminum or magnesium hydroxide, calcium carbonate): Administer dolutegravir/rilpivirine 4 hr before or 6 hr after taking antacids
    • H2-receptor antagonists (eg, famotidine, cimetidine, nizatidine, ranitidine): Administer dolutegravir/rilpivirine at least 4 hr before or 12 hr after taking H2-receptor antagonists

Safety and efficacy not established

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Interactions

Interaction Checker

and dolutegravir/rilpivirine

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    Contraindicated

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            Adverse Effects

            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

            Postmarketing Reports

            Musculoskeletal disorders: Arthralgia, myalgia

            Hepatobiliary disorders: Acute liver failure, hepatotoxicity

            Renal and genitourinary disorders: Nephrotic syndrome

            Skin and subcutaneous tissue disorders: Severe skin and hypersensitivity reactions including DRESS (drug rash with eosinophilia and systemic symptoms)

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            Warnings

            Contraindications

            Documented hypersensitivity to dolutegravir or rilpivirine

            Concomitant use with other drugs

            • Also see Cautions and Dosage Modifications
            • Dofetilide, carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifampin, rifapentine, dexamethasone, St. John’s wort, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole

            Cautions

            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 (see Contraindications)

            Drug interactions overview

            • Also see Dosage Modifications
            • 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
            • Potential for other drugs to affect rilpivirine
              • 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 dolutegravir/rilpivirine dose) and 300 mg PO qDay (12 times dolutegravir/rilpivirine dose) have been shown to prolong the QTc interval; consider alternatives to dolutegravir/rilpivirine when coadministered with a drug with a known risk of torsade de pointes
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            Pregnancy & Lactation

            Pregnancy

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

            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

            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

            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.

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            Pharmacology

            Mechanism of Action

            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

            Absorption

            Peak plasma concentration: 3.67 mcg/mL (dolutegravir); 0.13 mcg/mL (rilpivirine)

            Peak plasma time: 3 hr (dolutegravir); 4 hr (rilpivirine)

            AUC ratio, moderate-fat meal: 1.87 (dolutegravir); 1.57 (rilpivirine)

            AUC ratio, high-fat meal: 1.87 (dolutegravir); 1.72 (rilpivirine)

            Distribution

            Protein bound: ~99%

            Blood-to-ratio: 0.5 (dolutegravir); 0.7 (rilpivirine)

            Metabolism

            Dolutegravir: Primarily metabolized by UGT1A1; CYP3A (minor)

            Rilpivirine: Primarily metabolized by CYP3A

            Excretion

            Half-life: 14 hr (dolutegravir); 50 hr (rilpivirine)

            Excretion, urine: 31% (dolutegravir), <1% (unchanged dolutegravir); 6.5% (rilpivirine), <1% (unchanged rilpivirine)

            Excretion, feces: 64% (dolutegravir), 53% (unchanged dolutegravir); 85% (rilpivirine), 25% (unchanged rilpivirine)

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            Administration

            Oral administration

            Take with a meal

            Storage

            Tablets

            • Store at room temperature, 20-25°C (68-77°F); excursions permitted 15-30°C (59-86°F)
            • Store and dispense in original package, protect from moisture, and keep bottle tightly closed
            • Do not remove desiccant
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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
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            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
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