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Juluca

Generic Name: Dolutegravir Sodium and Rilpivirine Hydrochloride
Class: HIV Integrase Inhibitors
Chemical Name: (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-3,4,12,12a-tetrahydro-2H-pyrido[5,6]pyrazino[2,6-b][1,3]oxazine-9-carboxamide
Molecular Formula: C20H19F2N3O5C22H18N6
CAS Number: 1051375-16-6

Medically reviewed on December 4, 2017.

Introduction

Dolutegravir sodium and rilpivirine hydrochloride is an antiretroviral agent.

Uses for Juluca

Dolutegravir sodium and rilpivirine hydrochloride has the following uses:

Dolutegravir sodium and rilpivirine hydrochloride is a fixed-dose combination of dolutegravir, a human immunodeficiency virus type 1 (HIV-1) integrase strand transfer inhibitor (INSTI), and rilpivirine, a HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI), is indicated as a complete regimen for the treatment of HIV-1 infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen for at least 6 months with no history of treatment failure and no known substitutions associated with resistance to the individual components of dolutegravir sodium and rilpivirine hydrochloride.1

Juluca Dosage and Administration

General

Dolutegravir sodium and rilpivirine hydrochloride is available in the following dosage form(s) and strength(s):

Each tablet contains: 50 mg of dolutegravir (equivalent to 52.6 mg dolutegravir sodium) and 25 mg of rilpivirine (equivalent to 27.5 mg rilpivirine hydrochloride).1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

  • One tablet taken orally once daily with a meal.1

  • Rifabutin coadministration: Take an additional 25-mg tablet of rilpivirine with the dolutegravir/rilpivirine fixed-combination tablet once daily with a meal for the duration of the rifabutin coadministration.1

Cautions for Juluca

Contraindications

  • Previous hypersensitivity reaction to dolutegravir or rilpivirine.1

  • Coadministration with dofetilide.1

  • Coadministration with drugs where significant decreases in rilpivirine plasma concentrations may occur, which may result in loss of virologic response.1

Warnings/Precautions

Skin and Hypersensitivity Reactions

Hypersensitivity reactions have been reported with dolutegravir and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. These events were reported in less than 1% of subjects receiving dolutegravir in Phase 3 clinical trials.1

Severe skin and hypersensitivity reactions have been reported during postmarketing experience, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), with rilpivirine-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. During the Phase 3 clinical trials of rilpivirine, treatment-related rashes with at least Grade 2 severity were reported in 3% of subjects. No Grade 4 rash was reported.1

Discontinue dolutegravir sodium and rilpivirine hydrochloride immediately if signs or symptoms of severe skin or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters or peeling of the skin, mucosal involvement [oral blisters or lesions], conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including laboratory parameters with liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with dolutegravir sodium and rilpivirine hydrochloride after the onset of hypersensitivity may result in a life-threatening reaction. 1

Hepatotoxicity

Hepatic adverse events have been 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. Additionally, in some patients receiving dolutegravir-containing regimens, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Cases of hepatic toxicity including elevated serum liver biochemistries and hepatitis have also been reported in patients receiving a dolutegravir- or rilpivirine-containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Drug-induced liver injury leading to acute liver failure has been reported with dolutegravir-containing products, including liver transplant with the fixed combination of abacavir, dolutegravir, and lamivudine. Monitoring for hepatotoxicity is recommended.1

Depressive Disorders

Depressive disorders (including depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, and suicidal ideation) have been reported with rilpivirine. Promptly evaluate patients with severe depressive symptoms to assess whether the symptoms are related to dolutegravir sodium and rilpivirine hydrochloride and to determine whether the risks of continued therapy outweigh the benefits.1

Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

The concomitant use of dolutegravir sodium and rilpivirine hydrochloride and other drugs may result in known or potentially significant drug interactions, some of which may lead to:1

  • Loss of therapeutic effect of dolutegravir sodium and rilpivirine hydrochloride and possible development of resistance. 1

  • Possible clinically significant adverse reactions from greater exposures of concomitant drugs.1

In healthy subjects, 75 mg once daily rilpivirine (3 times the dose in dolutegravir sodium and rilpivirine hydrochloride) and 300 mg once daily (12 times the dose in dolutegravir sodium and rilpivirine hydrochloride) have been shown to prolong the QTc interval of the electrocardiogram. Consider alternatives to dolutegravir sodium and rilpivirine hydrochloride when coadministered with a drug with a known risk of torsades de pointes.1

Consider the potential for drug interactions prior to and during therapy with dolutegravir sodium and rilpivirine hydrochloride; review concomitant medications during therapy with dolutegravir sodium and rilpivirine hydrochloride; and monitor for the adverse reactions associated with the concomitant drugs.1

Specific Populations

Pregnancy

Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to dolutegravir sodium and rilpivirine hydrochloride during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.1

Risk Summary: There is insufficient prospective pregnancy data from the APR to adequately assess the risk of birth defects and miscarriage. Given the limited number of pregnancies exposed to dolutegravir-containing regimens reported to the APR, no definitive conclusions can be drawn on the safety of dolutegravir in pregnancy, and continued monitoring is ongoing through the APR. 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. The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. The APR uses the MACDP as the US reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ gestation.1

In animal reproduction studies, no evidence of adverse developmental outcomes was observed with the components of dolutegravir sodium and rilpivirine hydrochloride . 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 pre- and post-natal development studies, maternal systemic exposures (AUC) to dolutegravir and rilpivirine were approximately 32 and 63 times, respectively, the exposures of each component in humans at the RHD.1

Human Data: Based on prospective reports to the APR of 202 exposures to rilpivirine during pregnancy resulting in live births, there was no difference between the overall risk of birth defects for rilpivirine compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in live births was 0.5% (95% CI: 0.0% to 2.7%) and 0.8% (95% CI: 0.0% to 4.4%) following first and second/third trimester exposure, respectively, to rilpivirine-containing regimens.1

Animal Data: Dolutegravir: Dolutegravir was administered orally at up to 1,000 mg per kg daily to pregnant rats and rabbits on gestation Days 6 to 17 and 6 to 18, respectively, and also to rats on gestation Day 6 to lactation/post-partum Day 20. No adverse effects on embryo-fetal (rats and rabbits) development were observed at up to the highest dose tested. During organogenesis systemic exposures (AUC) to dolutegravir in rabbits were less than the exposure in humans and in rats were approximately 38 times the exposure in humans (50 mg once daily). In the rat pre/post-natal development study, decreased body weight of the developing offspring was observed during lactation at a maternally toxic dose (approximately 32 times the human exposure with 50 mg once daily). 1

Animal Data: Rilpivirine: Rilpivirine was administered orally to pregnant rats (40, 120, or 400 mg per kg per day) and rabbits (5, 10, or 20 mg per kg per day) through organogenesis (on gestation Days 6 through 17, and 6 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with rilpivirine in rats and rabbits at exposures 15 (rats) and 70 (rabbits) times higher than the exposure in humans at the recommended dose of 25 mg once daily. In a pre/postnatal development study with rilpivirine, where rats were administered up to 400 mg per kg per day through lactation, no significant adverse effects directly related to drug were noted in the offspring.1

Lactation

Risk Summary: The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. 1

It is not known whether dolutegravir sodium and rilpivirine hydrochloride or components of dolutegravir sodium and rilpivirine hydrochloride 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.1

Because of the potential for HIV-1 transmission (in HIV-negative infants), developing viral resistance (in HIV-positive infants), and adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving dolutegravir sodium and rilpivirine hydrochloride.1

Animal Data: Dolutegravir: Dolutegravir was the primary drug-related component excreted into the milk of lactating rats following a single oral dose of 50 mg per kg on lactation Day 10, with milk concentrations of up to approximately 1.3 times that of maternal plasma concentrations observed 8 hours post-dose. 1

Animal Data: Rilpivirine: In animals, no studies have been conducted to assess the excretion of rilpivirine into milk directly; however, rilpivirine was present in plasma of rat pups exposed through the milk of lactating rats (dosed up to 400 mg per kg per day).1

Pediatric Use

The safety and efficacy of dolutegravir sodium and rilpivirine hydrochloride have not been established in pediatric patients.1

Geriatric Use

Clinical trials of dolutegravir sodium and rilpivirine hydrochloride did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised in administration of dolutegravir sodium and rilpivirine hydrochloride in elderly patients reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.1

Renal Impairment

No dosage adjustment is necessary for patients with mild or moderate renal impairment (creatinine clearance greater than or equal to 30 mL/min). In patients with severe renal impairment (creatinine clearance less than 30 mL/min) or end-stage renal disease, increased monitoring for adverse effects is recommended.1

Hepatic Impairment

No dosage adjustment is necessary for patients with mild to moderate hepatic impairment (Child-Pugh Score A or B). The effect of severe hepatic impairment (Child-Pugh Score C) on the pharmacokinetics of dolutegravir or rilpivirine is unknown.1

Common Adverse Effects

The most common adverse reactions (all Grades) observed in at least 2% of subjects were diarrhea and headache.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Because dolutegravir sodium and rilpivirine hydrochloride is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended.1

  • Refer to the full prescribing information for important drug interactions with dolutegravir sodium and rilpivirine hydrochloride.1

  • Drugs that induce or inhibit CYP3A4 or UGT1A1 may affect the plasma concentrations of the components of dolutegravir sodium and rilpivirine hydrochloride.1

  • Drugs that increase gastric pH or contain polyvalent cations may decrease plasma concentrations of the components of dolutegravir sodium and rilpivirine hydrochloride.1

  • Consider alternatives to prescribing dolutegravir sodium and rilpivirine hydrochloride with drugs with a known risk of torsades de pointes.1

Actions and Spectrum

Mechanism Of Action

Dolutegravir sodium and rilpivirine hydrochloride is a fixed-dose combination of the HIV-1 antiretroviral agents, dolutegravir and rilpivirine.1

Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration, which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified HIV-1 integrase and pre-processed substrate DNA resulted in IC50 values of 2.7 nM and 12.6 nM.1

Rilpivirine is a diarylpyrimidine NNRTI of HIV-1 and inhibits HIV-1 replication by non-competitive inhibition of HIV-1 reverse transcriptase (RT). Rilpivirine does not inhibit the human cellular DNA polymerases α, β, and γ.1

Spectrum

Antiviral Activity in Cell Culture: Dolutegravir exhibited antiviral activity against laboratory strains of wild-type HIV-1 with mean EC50 values of 0.5 nM to 2.1 nM (0.21 to 0.85 ng per mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells. Dolutegravir exhibited antiviral activity against 13 clinically diverse clade B isolates with a mean EC50 value of 0.52 nM in a viral integrase susceptibility assay using the integrase coding region from clinical isolates. Dolutegravir demonstrated antiviral activity in cell culture against a panel of HIV-1 clinical isolates (3 in each group of M [clades A, B, C, D, E, F, and G] and 3 in group O) with EC50 values ranging from 0.02 nM to 2.14 nM.1

Rilpivirine exhibited activity against laboratory strains of wild-type HIV-1 in an acutely infected T-cell line with a median EC50 value for HIV-1IIIB of 0.73 nM (0.27 ng per mL). Rilpivirine demonstrated antiviral activity against a broad panel of HIV-1 group M (clades A, B, C, D, F, G, H) primary isolates with EC50 values ranging from 0.07 nM to 1.01 nM (0.03 to 0.37 ng/mL) and was less active against group O primary isolates with EC50 values ranging from 2.88 to 8.45 nM (1.06 to 3.10 ng/mL).1

Antiviral Activity in Combination with Other Antiviral Agents: Neither dolutegravir nor rilpivirine were antagonistic to all tested anti-HIV agents or with each other when tested in combination.1

Resistance

Cell Culture: Dolutegravir-resistant viruses were selected in cell culture starting from different wild-type HIV-1 strains and clades. Amino acid substitutions E92Q, G118R, S153F or Y, G193E, or R263K emerged in different passages and conferred decreased susceptibility to dolutegravir of up to 4-fold.1

Rilpivirine-resistant strains were selected in cell culture starting from wild-type HIV-1 of different origins and clades as well as NNRTI-resistant HIV-1. The frequently observed amino acid substitutions that emerged and conferred decreased phenotypic susceptibility to rilpivirine included: L100I; K101E; V106I and A; V108I; E138K and G, Q, R; V179F and I; Y181C and I; V189I; G190E; H221Y; F227C; and M230I and L.1

Virologically Suppressed Subjects: In the pooled SWORD-1 and SWORD-2 trials, 2 subjects in each treatment arm had confirmed virologic failure at any time through Week 48. The 2 subjects in the dolutegravir/rilpivirine arm had detectable resistance substitutions at rebound. One subject had the NNRTI-resistance-associated substitution K101K/E with no decreased susceptibility to rilpivirine (fold-change = 1.2) at Week 36, had no INSTI resistance-associated substitutions or decreased susceptibility to dolutegravir (fold-change less than 2), and had HIV-1 RNA less than 50 copies per mL at the withdrawal visit. The other subject had the dolutegravir resistance-associated substitution G193E at baseline (by exploratory HIV proviral DNA archive sequencing) and Week 24 (by conventional sequencing) without decreased susceptibility to dolutegravir (fold-change = 1.02) at Week 24. No resistance-associated substitutions were observed for the other 2 subjects in the comparative current antiretroviral regimen arms.1

Cross-Resistance: Dolutegravir: The susceptibility of dolutegravir was tested against 60 INSTI-resistant site-directed mutant HIV-1 viruses (28 with single substitutions and 32 with 2 or more substitutions). The single INSTI-resistance substitutions T66K, I151L, and S153Y conferred a greater than 2-fold decrease in dolutegravir susceptibility (range: 2.3-fold to 3.6-fold from reference). Combinations of multiple substitutions T66K/L74M; E92Q/N155H; G140C/Q148R; G140S/Q148H, R or K; Q148R/N155H; T97A/G140S/Q148, and substitutions at E138/G140/Q148 showed a greater than 2-fold decrease in dolutegravir susceptibility (range: 2.5-fold to 21-fold from reference).1

Cross-Resistance: Rilpivirine: Considering all of the available cell culture and clinical data, any of the following amino acid substitutions, when present at baseline, are likely to decrease the antiviral activity of rilpivirine: K101E, K101P, E138A, E138G, E138K, E138R, E138Q, V179L, Y181C, Y181I, Y181V, Y188L, H221Y, F227C, M230I, or M230L.1

Cross-resistance in site-directed mutant virus has been observed among NNRTIs. The single NNRTI substitutions K101P, Y181I, and Y181V conferred 52 times, 15 times, and 12 times decreased susceptibility to rilpivirine, respectively. The combination of E138K and M184I showed 6.7 times reduced susceptibility to rilpivirine compared with 2.8 times for E138K alone. The K103N substitution did not show reduced susceptibility to rilpivirine by itself. However, the combination of K103N and L100I resulted in a 7 times reduced susceptibility to rilpivirine. In another study, the Y188L substitution resulted in a reduced susceptibility to rilpivirine of 9 times for clinical isolates and 6 times for site-directed mutants. Combinations of 2 or 3 NNRTI resistance-associated substitutions gave decreased susceptibility to rilpivirine (fold-change range: 3.7 to 554) in 38% and 66% of mutants, respectively.1

Cross-resistance to efavirenz, etravirine, and/or nevirapine is likely after virologic failure and development of rilpivirine resistance.1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).1

Severe Skin and Hypersensitivity Reactions: Advise patients to immediately contact their healthcare provider if they develop a rash. Instruct patients to immediately stop taking dolutegravir sodium and rilpivirine hydrochloride and seek medical attention if they develop a rash associated with any of the following symptoms, as it may be a sign of a more serious reaction such as DRESS severe hypersensitivity: fever; generally ill feeling; extreme tiredness; muscle or joint aches; blisters or peeling of the skin; oral blisters or lesions; eye inflammation; facial swelling; swelling of the eyes, lips, tongue, or mouth; breathing difficulty; and/or signs and symptoms of liver problems (e.g., yellowing of the skin or whites of the eyes; dark or tea-colored urine; pale-colored stools or bowel movements; nausea; vomiting; loss of appetite; or pain, aching, or sensitivity on the right side below the ribs). Advise patients that if hypersensitivity occurs, they will be closely monitored, laboratory tests will be ordered, and appropriate therapy will be initiated.1

Hepatotoxicity: Inform patients that hepatotoxicity has been reported with the components of the fixed combination of dolutegravir sodium and rilpivirine hydrochloride. Inform patients that monitoring for hepatotoxicity is recommended.1

Depressive Disorders: Inform patients that depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) have been reported with the components of dolutegravir sodium and rilpivirine hydrochloride. Advise patients to seek immediate medical evaluation if they experience depressive symptoms.1

Drug Interactions: Dolutegravir sodium and rilpivirine hydrochloride may interact with many drugs; therefore, advise patients to report to their healthcare provider the use of any other prescription or non-prescription medication or herbal products, including St. John’s wort.1

Administration Instruction: Inform patients that it is important to take dolutegravir sodium and rilpivirine hydrochloride once daily on a regular dosing schedule with a meal and to avoid missing doses, as it can result in development of resistance. Instruct patients that if they miss a dose of dolutegravir sodium and rilpivirine hydrochloride, to take it as soon as they remember with a meal. Advise patients not to double their next dose. Advise the patient that a protein drink alone does not replace a meal.1

Pregnancy Registry: Inform patients that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to dolutegravir sodium and rilpivirine hydrochloride.1

Lactation: Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in the breast milk.1

Storage: Instruct patients to store dolutegravir sodium and rilpivirine hydrochloride in the original bottle to protect from moisture and keep the bottle tightly closed. Do not remove desiccant.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Dolutegravir Sodium and Rilpivirine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet, Film Coated

50 mg dolutegravir, 25 mg rilpivirine

Juluca

ViiV Healthcare Company

AHFS Drug Information. © Copyright 2018, Selected Revisions December 4, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. ViiV Healthcare Company. Juluca (dolutegravir sodium and rilpivirine hydrochloride) ORAL prescribing information. 2017 Nov.

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