Dolutegravir and Rilpivirine (Monograph)

Brand name: Juluca
Drug class: HIV Integrase Inhibitors
Chemical name: (4R,12aS)-N-[(2,4-Difluorophenyl)methyl]-3,4,6,8,12,12a-hexahydro-7-hydroxy-4-methyl-6,8-dioxo-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide sodium salt
Molecular formula: C₂₀H₁₈F₂N₃NaO₅C₂₂H₁₈N₆•HCl
CAS number: 1051375-19-9

Medically reviewed by Drugs.com on Jul 18, 2022. Written by ASHP.

Introduction

Antiretroviral; fixed combination of dolutegravir and rilpivirine (dolutegravir/rilpivirine). Dolutegravir is an HIV integrase strand transfer inhibitor (INSTI) and rilpivirine is an HIV nonnucleoside reverse transcriptase inhibitor (NNRTI).

Uses for Dolutegravir and Rilpivirine

Treatment of HIV Infection

Treatment of HIV type 1 (HIV-1) infection in antiretroviral-experienced (previously treated) adults.

Use to replace the current regimen only in antiretroviral-experienced adults who are virologically suppressed (i.e., plasma HIV-1 RNA levels <50 copies/mL) on a stable antiretroviral regimen for ≥6 months, have no known history of treatment failure, and are infected with HIV-1 with no known substitutions associated with resistance to dolutegravir or rilpivirine.

Dolutegravir/rilpivirine fixed combination is used alone as a complete regimen for treatment of HIV-1 infection in antiretroviral-experienced adults; manufacturer states concomitant use with other antiretrovirals not recommended.

When considering a change to a 2-drug antiretroviral regimen in antiretroviral-experienced adults who are virologically suppressed on an effective regimen, experts state that a regimen of dolutegravir and rilpivirine is a reasonable option when use of HIV nucleoside reverse transcriptase inhibitors (NRTIs) is not desirable and when there is no evidence of resistance to dolutegravir or rilpivirine. However, these experts state do not use in patients with HBV coinfection.

Dolutegravir/rilpivirine not evaluated for treatment of HIV-1 infection in antiretroviral-naive (have not previously received antiretroviral therapy) patients and is not recommended for initial antiretroviral therapy.

Most appropriate antiretroviral regimen cannot be defined for every clinical scenario; select regimen based on information regarding antiretroviral potency, potential rate of resistance development, known toxicities, potential for pharmacokinetic interactions, and patient's virologic, immunologic, and clinical characteristics. Guidelines for the management of HIV infection, including specific recommendations for initial treatment in antiretroviral-naive patients and recommendations for changing antiretroviral regimens, are available at [Web].

Dolutegravir and Rilpivirine Dosage and Administration

General

• Test for HBV infection prior to initiation of dolutegravir/rilpivirine. (See Hepatic Effects under Cautions.)

• Perform pregnancy testing prior to initiation of dolutegravir/rilpivirine in women of childbearing potential. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Administration

Oral Administration

Administer orally once daily with a meal. A protein drink alone does not constitute a meal. (See Food under Pharmacokinetics.)

Dosage

Available as fixed-combination tablets containing dolutegravir sodium and rilpivirine hydrochloride; dosages expressed in terms of dolutegravir and rilpivirine, respectively.

Each fixed-combination tablet contains 50 mg of dolutegravir and 25 mg of rilpivirine.

Adults

Treatment of HIV-1 Infection

Antiretroviral-experienced Adults

Oral

1 tablet of dolutegravir/rilpivirine (dolutegravir 50 mg and rilpivirine 25 mg) once daily when used to replace a current regimen in certain adults (see Treatment of HIV Infection under Uses).

Antiretroviral-experienced Adults Receiving Rifabutin

Oral

1 tablet of dolutegravir/rilpivirine (dolutegravir 50 mg and rilpivirine 25 mg) and a 25-mg tablet of single-entity rilpivirine once daily to provide a total rilpivirine dosage of 50 mg daily. (See Specific Drugs under Interactions.)

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): Dosage adjustments not needed.

Severe hepatic impairment (Child-Pugh class C): Manufacturer makes no specific recommendations. (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild or moderate renal impairment (Cl_cr ≥30 mL/minute): Dosage adjustments not needed.

Severe renal impairment (Cl_cr <30 mL/minute) or end-stage renal disease: Manufacturer makes no specific dosage recommendations; increased monitoring for adverse effects recommended. (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations; use with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy. (See Geriatric Use under Cautions.)

Cautions for Dolutegravir and Rilpivirine

Contraindications

• Previous hypersensitivity reaction to dolutegravir or rilpivirine.

• Concomitant use with dofetilide, certain drugs that induce CYP3A, or certain drugs that elevate gastric pH. This includes certain anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin), certain antimycobacterials (rifampin, rifapentine), systemic dexamethasone (given in multiple doses), proton-pump inhibitors (e.g., esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole), and certain herbal supplements (St. John’s wort [Hypericum perforatum]). (See Specific Drugs under Interactions.)

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Hypersensitivity reactions (e.g., rash, constitutional findings, and sometimes organ dysfunction including liver injury) reported in patients receiving dolutegravir.

Severe skin and hypersensitivity reactions, including cases of drug reaction with eosinophilia and systemic symptoms (DRESS), reported during postmarketing experience with rilpivirine-containing regimens. Some skin reactions were accompanied by constitutional symptoms; other skin reactions were associated with organ dysfunction, including elevated hepatic enzyme concentrations.

Immediately discontinue dolutegravir/rilpivirine if signs or symptoms of severe skin or hypersensitivity reactions occur (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). Monitor clinical status, including laboratory parameters with liver aminotransferases, and initiate appropriate therapy. Delay in stopping dolutegravir/rilpivirine treatment after onset of hypersensitivity reaction may result in a life-threatening reaction.

Hepatic Effects

Adverse hepatic effects reported in patients receiving dolutegravir- or rilpivirine-containing regimens.

HIV-infected patients with HBV or HCV coinfection or markedly elevated serum aminotransferase concentrations prior to initiation of dolutegravir/rilpivirine may be at increased risk for development or worsening of aminotransferase elevations. In some patients receiving a dolutegravir-containing regimen, serum aminotransferase elevations were consistent with immune reconstitution syndrome or HBV reactivation, particularly in the setting where HBV therapy had been discontinued.

Cases of hepatic toxicity, including elevated serum liver biochemistries and hepatitis, also reported in patients receiving dolutegravir- or rilpivirine-containing regimens who had no preexisting hepatic disease or other identifiable risk factors.

Drug-induced liver injury leading to acute liver failure reported with dolutegravir-containing regimens; drug-induced liver injury leading to liver transplant reported with the fixed combination of abacavir, dolutegravir, and lamivudine (abacavir/dolutegravir/lamivudine).

Monitor for hepatotoxicity.

Depressive Disorders

Depressive disorders (depressed mood, depression, dysphoria, major depression, altered mood, negative thoughts, suicide attempt, suicidal ideation) reported in patients receiving dolutegravir and/or rilpivirine.

Promptly evaluate patients experiencing severe depressive symptoms to determine the likelihood that symptoms are related to dolutegravir/rilpivirine and to determine if benefits of continued dolutegravir/rilpivirine therapy outweigh risks.

Fetal/Neonatal Morbidity and Mortality

Data from an observational study in Botswana showed an association between dolutegravir and an increased risk of neural tube defects when the drug is administered at the time of conception and during early pregnancy.

Because there is only a limited understanding of reported types of neural tube defects associated with dolutegravir use and because the date of conception may not be determined with precision, manufacturer states consider an alternative to dolutegravir/rilpivirine for women at the time of conception through the first trimester of pregnancy. Manufacturer also states initiation of dolutegravir/rilpivirine not recommended in women actively trying to become pregnant, unless there is no suitable alternative. (See Pregnancy under Cautions.)

Interactions

Concomitant use with certain drugs may result in drug interactions. May lead to loss of therapeutic effects and possible development of resistance or possible adverse effects from increased exposures of concomitant drugs.

Because rilpivirine may prolong QT interval corrected for rate (QT_c), consider alternatives to dolutegravir/rilpivirine in patients receiving drugs with known risk of torsades de pointes.

Consider potential for drug interactions prior to and during treatment with dolutegravir/rilpivirine and monitor for adverse effects associated with concomitant drugs.

HIV-infected Individuals Coinfected with HBV or HCV

Risk for elevated aminotransferase concentrations may be increased during dolutegravir/rilpivirine therapy. (See Hepatic Effects under Cautions.)

Use of Fixed Combinations

Consider cautions, precautions, contraindications, and interactions associated with both components of dolutegravir/rilpivirine.

Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug in the fixed combination.

Specific Populations

Pregnancy

Antiretroviral Pregnancy Registry at 800-258-4263 or [Web].

Data from an observational birth outcome surveillance study in Botswana (Tsepamo study) showed an increased risk of neural tube defects associated with use of dolutegravir-containing regimens at time of conception and during early pregnancy compared with use of antiretroviral regimens that did not contain dolutegravir. From August 2014 through March 2019, 5 cases of neural tube defects (2 cases of myelomeningocele and 1 case each of encephalocele, anencephaly, and iniencephaly) were identified out of 1683 deliveries (0.3%) to women exposed to dolutegravir-containing regimens at time of conception; prevalence rate of neural tube defects was 0.1% (15/14,792 deliveries) when the mother was receiving an antiretroviral regimen that did not contain dolutegravir at time of conception and was 0.08% (70/89,372 deliveries) when the mother did not have HIV infection.

To date, data from the birth outcome surveillance study in Botswana and postmarketing sources including >1000 pregnancy outcomes have not shown evidence of increased risk of adverse birth outcomes from dolutegravir exposures occurring during second and third trimesters of pregnancy.

Human data regarding use of dolutegravir/rilpivirine in pregnant women insufficient to definitively assess a drug-associated risk for birth defects and miscarriage with the fixed combination.

Perform pregnancy testing in all women of childbearing potential before initiating dolutegravir/rilpivirine.

Manufacturer states do not use dolutegravir/rilpivirine during first trimester of pregnancy, but may consider use of the drug during second and third trimesters of pregnancy if expected benefits justify potential risks to the pregnant woman and fetus. Manufacturer also states initiation of dolutegravir/rilpivirine not recommended in women actively trying to become pregnant, unless there is no suitable alternative.

Experts state that a 2-drug regimen of dolutegravir/rilpivirine is not recommended in antiretroviral-naive or antiretroviral-experienced pregnant women or women of childbearing potential trying to conceive because data not available regarding use of 2-drug regimens for treatment of HIV-1 infection during pregnancy.

Advise women of childbearing potential to consistently use effective contraception during dolutegravir/rilpivirine therapy. If a woman is currently receiving dolutegravir/rilpivirine and is actively trying to become pregnant or if pregnancy is confirmed in the first trimester, inform the woman of potential risk to an embryo exposed to dolutegravir/rilpivirine from time of conception through first trimester of pregnancy. Assess risks and benefits of continuing the drug versus switching to a different antiretroviral regimen and consider switching to a regimen that does not contain dolutegravir. Benefit-risk assessment should address factors such as feasibility of switching to a different regimen, tolerability, ability to maintain viral suppression, and risk of HIV transmission to the infant versus risk of neural tube defects.

Lactation

Dolutegravir: Some reports that dolutegravir distributed in human milk in low concentrations; distributed into milk in rats.

Rilpivirine: Not known whether distributed into human milk; detected in plasma of rat pups exposed to rilpivirine through milk of lactating rats.

Dolutegravir/rilpivirine: Not known whether the fixed combination or individual components affect human milk production or affect breast-fed infant.

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.

Pediatric Use

Safety and efficacy not established in pediatric patients. Pharmacokinetics not evaluated.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently to dolutegravir/rilpivirine compared with younger adults. Population pharmacokinetic analyses indicate age has no clinically important effect on pharmacokinetics of dolutegravir or rilpivirine.

Caution advised because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Hepatic Impairment

Dosage adjustments not needed in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).

Effect of severe hepatic impairment on pharmacokinetics not known.

Renal Impairment

Dosage adjustments not needed in patients with mild or moderate renal impairment (Cl_cr ≥30 mL/minute).

Increased monitoring for adverse effects recommended in patients with severe renal impairment (Cl_cr <30 mL/minute) or end-stage renal disease.

Common Adverse Effects

Diarrhea, headache.

Interactions for Dolutegravir and Rilpivirine

CYP3A plays minor role in dolutegravir metabolism; rilpivirine primarily metabolized by CYP3A4.

Dolutegravir: Does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A; does not induce CYP1A2, 2B6, or 3A4.

Dolutegravir: Metabolized by UGT1A1; substrate for UGT1A3 and UGT1A9. Does not inhibit UGT1A1 or UGT2B7.

Dolutegravir: Substrate of P-glycoprotein (P-gp) transport system and breast cancer resistance protein (BCRP); does not inhibit P-gp or BCRP.

Dolutegravir: Inhibits multidrug and toxin extrusion transporter (MATE) 1.

Dolutegravir: Inhibits renal organic anion transporter (OAT) 1 and OAT3. Does not inhibit organic anion transporter polypeptide (OATP) 1B1 or OATP1B3; not a substrate of OATP1B1 or 1B3.

Dolutegravir: Inhibits renal organic cation transporter (OCT) 2; does not inhibit OCT1.

Dolutegravir: Does not inhibit bile salt export pump (BSEP) or multidrug resistance protein (MRP) 2 or MRP4.

The following drug interactions are based on studies using the individual components of dolutegravir/rilpivirine or are predicted to occur with the fixed combination. When dolutegravir/rilpivirine is used, consider interactions associated with both drugs in the fixed combination.

Drugs Affecting Hepatic Microsomal Enzymes

CYP3A inducers: Possible decreased dolutegravir and rilpivirine plasma concentrations; may lead to decreased therapeutic effects of the drugs and resistance to rilpivirine or other HIV NNRTIs.

CYP3A inhibitors: Possible increased dolutegravir and rilpivirine plasma concentrations.

Drugs Affecting UGT

UGT1A1, 1A3, or 1A9 inducers: Possible decreased dolutegravir plasma concentrations and decreased therapeutic effects of dolutegravir.

UGT1A1 inhibitors: Possible increased dolutegravir concentrations.

Drugs Affecting P-glycoprotein Transport

P-gp inducers: Possible decreased dolutegravir plasma concentrations and decreased therapeutic effects of dolutegravir.

P-gp inhibitors: Possible increased dolutegravir plasma concentrations and decreased therapeutic effects of dolutegravir.

Drugs Affecting Breast Cancer Resistance Protein

BCRP inducers: Possible decreased dolutegravir plasma concentrations.

BCRP inhibitors: Possible increased dolutegravir plasma concentrations.

Drugs Affected by Multidrug and Toxin Extrusion Transporter

Drugs eliminated by MATE1: Dolutegravir may increase plasma concentrations of MATE1 substrates.

Drugs Affected by Renal Organic Cation Transporters

Drugs eliminated by OCT2: Dolutegravir may increase plasma concentrations of OCT2 substrates.

Specific Drugs

Dolutegravir and Rilpivirine Pharmacokinetics

Absorption

Bioavailability

Dolutegravir: Absolute bioavailability not established.

Rilpivirine: Absolute bioavailability not established.

Food

Dolutegravir: Administration with moderate- or high-fat meal increases AUC by 1.9-fold; not considered clinically important.

Rilpivirine: Administration with moderate- or high-fat meal increases AUC by 1.6- or 1.7-fold, respectively. If taken with only a protein-rich nutritional drink, exposures are 50% lower than when taken with a meal.

Plasma Concentrations

Dolutegravir: Peak plasma concentrations attained 2–3 hours after a dose.

Rilpivirine: Peak plasma concentrations attained 4 hours after a dose.

Distribution

Extent

Dolutegravir: Crosses placenta. Appears to be distributed into human milk in low concentrations; distributed into milk in rats.

Rilpivirine: Crosses placenta. Not known whether distributed into human milk; distributed into milk in rats.

Plasma Protein Binding

Dolutegravir: Approximately 99%.

Rilpivirine: Approximately 99%.

Elimination

Metabolism

Dolutegravir: Primarily metabolized by UGT1A1; CYP3A plays only minor role.

Rilpivirine: Primarily metabolized by CYP3A.

Elimination Route

Dolutegravir: 64% of an oral dose eliminated in feces (53% as unchanged drug); 31% eliminated in urine(<1% as unchanged drug).

Rilpivirine: 85% of an oral dose eliminated in feces (25% as unchanged drug); 6.5% eliminated in urine (<1% as unchanged drug).

Half-life

Dolutegravir: Approximately 14 hours.

Rilpivirine: 50 hours.

Special Populations

Mild hepatic impairment (Child-Pugh class A): Rilpivirine exposures 47% higher than matched controls.

Moderate hepatic impairment (Child-Pugh class B): Dolutegravir exposures similar to those in healthy individuals; rilpivirine exposures 5% higher than matched controls.

Severe hepatic impairment (Child-Pugh class C): Effect on dolutegravir and rilpivirine pharmacokinetics not evaluated.

Mild renal impairment: No clinically important effect on dolutegravir or rilpivirine pharmacokinetics.

Moderate renal impairment: No clinically important effect on dolutegravir pharmacokinetics; effect on rilpivirine pharmacokinetics not known.

Severe renal impairment: Dolutegravir AUC, peak plasma concentrations, and plasma concentrations measured 24 hours after dosing are 40, 23, and 43% lower, respectively, compared with healthy individuals; effect on rilpivirine pharmacokinetics not known.

End-stage renal disease: Effect on rilpivirine pharmacokinetics not known.

Dialysis: Effect on dolutegravir or rilpivirine pharmacokinetics not known.

Age, race, gender: No clinically important effects on dolutegravir or rilpivirine pharmacokinetics.

HCV coinfection: No clinically important effects on dolutegravir or rilpivirine exposures.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).

Store and dispense in original package; do not remove desiccant; protect from moisture.

Actions and Spectrum

• Dolutegravir/rilpivirine is a fixed-combination antiretroviral containing dolutegravir and rilpivirine.

• Dolutegravir is an HIV INSTI. The drug binds to the active site of HIV integrase and blocks the strand transfer step of retroviral DNA integration, which is essential for HIV replication. Active against HIV-1; also has in vitro activity against HIV type 2 (HIV-2).

• Rilpivirine is a diarylpyrimidine HIV NNRTI. The drug noncompetitively inhibits HIV-1 reverse transcriptase. Active against HIV-1; HIV-2 are intrinsically resistant to NNRTIs.

• HIV-1 resistant to dolutegravir or rilpivirine produced in vitro and have emerged during clinical use.

• In clinical studies evaluating 2-drug regimen of dolutegravir and rilpivirine in antiretroviral-experienced adults, virologic failure during treatment with the regimen reported in 2 patients with detectable resistance substitutions at rebound. One patient had a dolutegravir resistance-associated substitution (G193E) at baseline without decreased susceptibility to dolutegravir; the other had an NNRTI resistance-associated substitution (K101K/E) without decreased susceptibility to rilpivirine and without INSTI-resistance-associated substitutions.

• HIV-1 resistant to some other HIV INSTIs (e.g., elvitegravir, raltegravir) may have reduced susceptibility or resistance to dolutegravir.

• Cross-resistance occurs among HIV NNRTIs; cross-resistance to efavirenz, etravirine, and/or nevirapine likely after virologic failure and development of resistance to rilpivirine.

• No in vitro evidence of antagonistic anti-HIV effects between dolutegravir and rilpivirine.

Advice to Patients

• Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician. Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.

• Dolutegravir/rilpivirine is used alone as a complete regimen for treatment of HIV-1 infection in certain antiretroviral-experienced adults.

• Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.

• Advise patients that early initiation of antiretroviral therapy and sustained decreases in plasma HIV RNA have been associated with reduced risk of progression to acquired immunodeficiency syndrome (AIDS) and death.

• Advise patients that effective antiretroviral regimens can decrease HIV levels in blood and genital secretions and strict adherence to such regimens in conjunction with risk-reduction measures may decrease, but cannot absolutely eliminate, the risk of secondary transmission of HIV to others. Importance of continuing to practice safer sex (e.g., using latex or polyurethane condoms to minimize sexual contact with body fluids) and reducing high-risk behaviors (e.g., reusing or sharing needles).

• Importance of reading patient information provided by the manufacturer.

• Importance of taking once daily with a meal; a protein drink alone does not constitute a meal.

• If a dose of dolutegravir/rilpivirine is missed, the dose should be taken with a meal as soon as it is remembered. A double dose should not be taken to make up for a missed dose.

• Importance of immediately discontinuing dolutegravir/rilpivirine and seeking medical attention if rash occurs and is associated with fever, generally ill feeling, extreme tiredness, muscle or joint aches, breathing difficulty, blisters or peeling skin, oral blisters or lesions, eye inflammation, swelling of the face, eyes, lips, or mouth, and/or signs and symptoms of liver problems (e.g., yellowing of skin or whites of the eyes, dark or tea-colored urine, pale stools/bowel movements, nausea, vomiting, loss of appetite, or pain, aching, or sensitivity on right side below ribs). Advise patients that close monitoring and appropriate laboratory testing or treatment may be required if a hypersensitivity reaction occurs.

• Advise patients that depressive disorders (depressed mood, depression, dysphoria, major depression, altered mood, negative thoughts, suicide attempt, suicidal ideation) have been reported in patients receiving the components of dolutegravir/rilpivirine. Importance of immediately contacting clinician if depressive symptoms (e.g., feeling sad, hopeless, anxious, or restless; hurting oneself; having thoughts of hurting oneself) occur.

• Advise patients that hepatotoxicity has been reported in patients receiving the components of dolutegravir/rilpivirine and that monitoring for hepatotoxicity is recommended.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal products, and any concomitant illnesses.

• Importance of women informing clinicians if they plan to become pregnant, become pregnant, or if pregnancy is suspected during treatment with dolutegravir/rilpivirine. Advise women of childbearing potential of risks to the fetus if dolutegravir/rilpivirine is used at time of conception through first trimester. Advise women of childbearing potential taking dolutegravir/rilpivirine to consistently use effective contraception during dolutegravir/rilpivirine treatment. (See Pregnancy under Cautions.)

• Importance of women informing clinicians if they plan to breast-feed. Advise HIV-infected women not to breast-feed.

• Importance of advising patients of other important precautionary information. (See Cautions.)

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.

Reload page with references included

Frequently asked questions

• What drugs are contained in HIV treatment Juluca?

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