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Dolutegravir Sodium and Rilpivirine Hydrochloride

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
Brands: Juluca

Medically reviewed on Oct 1, 2018

Introduction

See also: Atripla

Antiretroviral; fixed combination of dolutegravir and rilpivirine (dolutegravir/rilpivirine).1 Dolutegravir is an HIV integrase strand transfer inhibitor (INSTI) and rilpivirine is an HIV nonnucleoside reverse transcriptase inhibitor (NNRTI).1 3 5

Uses for Dolutegravir Sodium and Rilpivirine Hydrochloride

Treatment of HIV Infection

Treatment of HIV-1 infection in certain antiretroviral-experienced (previously treated) adults.1 2

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.1

Used alone as a complete regimen for treatment of HIV-1 infection in these antiretroviral-experienced adults;1 manufacturer states concomitant use with other antiretrovirals not recommended.1

Dolutegravir Sodium and Rilpivirine Hydrochloride Dosage and Administration

Administration

Oral Administration

Administer orally once daily with a meal.1 A protein drink alone does not constitute a meal.1 (See Food under Pharmacokinetics.)

Dosage

Available as fixed-combination tablets containing dolutegravir sodium and rilpivirine hydrochloride;1 dosages expressed in terms of dolutegravir and rilpivirine, respectively.1

Each fixed-combination tablet contains 50 mg of dolutegravir and 25 mg of rilpivirine.1

Adults

Treatment of HIV Infection in 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).1

Treatment of HIV Infection in Antiretroviral-experienced Adults Receiving Rifabutin
Oral

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

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment (Child-Pugh class A or B): Dosage adjustments not needed.1

Severe hepatic impairment (Child-Pugh class C): Manufacturer makes no specific recommendations.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild or moderate renal impairment (Clcr ≥30 mL/minute): Dosage adjustments not needed.1

Severe renal impairment (Clcr <30 mL/minute) or end-stage renal disease: Manufacturer makes no specific dosage recommendations;1 increased monitoring for adverse effects recommended.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations;1 use with caution because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.1 (See Geriatric Use under Cautions.)

Cautions for Dolutegravir Sodium and Rilpivirine Hydrochloride

Contraindications

  • Previous hypersensitivity reaction to dolutegravir or rilpivirine.1

  • Concomitant use with dofetilide, certain drugs that induce CYP3A, or certain drugs that elevate gastric pH.1 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]).1 (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.1

Severe skin and hypersensitivity reactions, including cases of drug reaction with eosinophilia and systemic symptoms (DRESS), reported during postmarketing experience with rilpivirine-containing regimens.1 Some skin reactions were accompanied by constitutional symptoms; other skin reactions were associated with organ dysfunction, including elevated hepatic enzyme concentrations.1

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).1 Monitor clinical status, including laboratory parameters with liver aminotransferases, and initiate appropriate therapy.1 Delay in stopping dolutegravir/rilpivirine treatment after onset of hypersensitivity reaction may result in a life-threatening reaction.1

Hepatic Effects

Adverse hepatic effects reported in patients receiving dolutegravir- or rilpivirine-containing regimens.1

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.1 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.1

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.1

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).1

Monitor for hepatotoxicity.1

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.1

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.1

Fetal/Neonatal Morbidity and Mortality

Neural tube defects involving brain, spine, and spinal cord reported rarely in infants born to women who received dolutegravir.35 203 Preliminary results from an ongoing observational study indicate higher risk of neural tube defects in infants born to women who were receiving dolutegravir at time of conception or early in first trimester of pregnancy.35 203

Pending further accumulation of data, FDA and other experts recommend that women of childbearing potential undergo pregnancy testing before a dolutegravir-containing regimen is initiated and take measures to avoid pregnancy during treatment with such regimens.35 203 (See Pregnancy under Cautions.)

Interactions

Consider potential for drug interactions prior to and during treatment with dolutegravir/rilpivirine and monitor for adverse effects associated with concomitant drugs.1

Concomitant use with certain drugs may result in drug interactions.1 May lead to loss of therapeutic effects and possible development of resistance or possible adverse effects from increased exposures of concomitant drugs.1

Because rilpivirine may prolong QT interval corrected for rate (QTc), consider alternatives to dolutegravir/rilpivirine in patients receiving drugs with known risk of torsades de pointes.1

HIV-infected Individuals Coinfected with HBV or HCV

Risk for elevated aminotransferase concentrations may be increased during dolutegravir/rilpivirine therapy.1 (See Hepatic Effects under Cautions.)

Precautions Related to Use of Fixed Combinations

When dolutegravir/rilpivirine used, consider cautions, precautions, contraindications, and drug interactions associated with both drugs in the fixed combination.1 Consider cautionary information applicable to specific populations (e.g., pregnant or nursing women, individuals with hepatic or renal impairment, geriatric patients) for each drug.1

Specific Populations

Pregnancy

Antiretroviral Pregnancy Registry at 800-258-4263 or [Web].1 202

Dolutegravir crosses placenta;202 results of an ex vivo perfusion model indicate high fetal-to-maternal ratio (0.6).202 Rilpivirine also crosses placenta.202

Preliminary results from an ongoing observational study in Botswana indicate higher risk of neural tube defects in infants born to women receiving a dolutegravir-containing regimen at time of conception or early in first trimester of pregnancy.35 203 To date, no reported cases of neural tube defects in infants born to women who received dolutegravir initiated later in pregnancy.35 FDA is conducting a comprehensive review of these results and any other data that become available.35

Pending further accumulation of data, FDA and other experts recommend advising women of childbearing potential (including those already receiving a dolutegravir-containing regimen) about potential risk of neural tube defects if dolutegravir is taken near time of conception or early in first trimester of pregnancy and instructing such women to use effective contraception to avoid pregnancy during treatment.35 203 Neural tube defects can occur early in pregnancy35 within first 4 weeks (28 days) after conception or 6 weeks from last menstrual period.203

FDA and other experts recommend that a pregnancy test be performed in all women of childbearing potential prior to initiation of a dolutegravir-containing regimen.35 203 Experts recommend that dolutegravir not be initiated in pregnant women within 8 weeks of their last menstrual period.203 If a pregnant woman is already receiving a dolutegravir-containing regimen and is within 8 weeks of her last menstrual period, these experts recommend the healthcare provider counsel the woman about risks and benefits of current regimen; if other options are available, a switch to a regimen that does not contain dolutegravir is recommended.203 If a woman is pregnant and ≥8 weeks past her last menstrual period, these experts state that initiating or continuing a dolutegravir-containing regimen or initiating or switching to a regimen that does not contain dolutegravir can be considered after weighing risks and benefits.203 Consult National Perinatal HIV Hotline at 888-448-8765 for additional guidance.203

Manufacturer states data insufficient to adequately assess risk of birth defects and miscarriage if dolutegravir/rilpivirine used in pregnant women.1

Lactation

Dolutegravir/rilpivirine: Not known if distributed into human milk, affects human milk production, or affects breast-fed infant.1

Dolutegravir: Some reports that dolutegravir distributed in human milk in low concentrations;202 distributed into milk in rats.1

Rilpivirine: Not known whether distributed into human milk;202 detected in plasma of rat pups exposed to rilpivirine through milk of lactating rats.1

Instruct HIV-infected women not to breast-feed because of risk of HIV transmission and risk of adverse effects in the infant.1 202

Pediatric Use

Safety and efficacy not established in pediatric patients.1 Pharmacokinetics not evaluated.1

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether they respond differently to dolutegravir/rilpivirine compared with younger adults.1 Population pharmacokinetic analyses indicate age has no clinically important effect on pharmacokinetics of dolutegravir or rilpivirine.1

Caution advised because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Hepatic Impairment

Dosage adjustments not needed in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1 Effect of severe hepatic impairment on pharmacokinetics not known.1

Renal Impairment

Dosage adjustments not needed in patients with mild or moderate renal impairment (Clcr ≥30 mL/minute).1

Increased monitoring for adverse effects recommended in patients with severe renal impairment (Clcr <30 mL/minute) or end-stage renal disease.1

Common Adverse Effects

Diarrhea,1 headache.1

Interactions for Dolutegravir Sodium and Rilpivirine Hydrochloride

CYP3A plays minor role in dolutegravir metabolism;1 rilpivirine primarily metabolized by CYP3A4.1

Dolutegravir: Does not inhibit CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A;1 does not induce CYP1A2, 2B6, or 3A4.1

Dolutegravir: Metabolized by UGT1A1 and also is a substrate for UGT1A3 and UGT1A9.1 Does not inhibit UGT1A1 or UGT2B7.1

Dolutegravir: Substrate of P-glycoprotein (P-gp) transport system;1 does not inhibit P-gp-mediated transport.1

Dolutegravir: Substrate of breast cancer resistance protein (BCRP);1 does not inhibit BCRP.1

Dolutegravir: Inhibits multidrug and toxin extrusion transporter (MATE) 1.1

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

Dolutegravir: Inhibits renal organic cation transporter (OCT) 2;1 does not inhibit OCT1.1

Dolutegravir: Does not inhibit bile salt export pump (BSEP) or multidrug resistance protein (MRP) 2 or MRP4.1

The following drug interactions are based on studies using the individual components of dolutegravir/rilpivirine or are predicted to occur with the fixed combination.1 When dolutegravir/rilpivirine used, consider interactions associated with both drugs in the fixed combination.1

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.1

CYP3A inhibitors: Possible increased dolutegravir and rilpivirine plasma concentrations.1

Drugs Affecting Uridine Diphosphate-glucuronosyltransferases

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

UGT1A1 inhibitors: Possible increased dolutegravir concentrations.1

Drugs Affecting P-glycoprotein Transport

P-gp inducers: Possible decreased dolutegravir plasma concentrations.1

P-gp inhibitors: Possible increased dolutegravir plasma concentrations.1

Drugs Affecting Breast Cancer Resistance Protein

BCRP inducers: Possible decreased dolutegravir plasma concentrations.1

BCRP inhibitors: Possible increased dolutegravir plasma concentrations.1

Drugs Affected by Multidrug and Toxin Extrusion Transporter

Drugs eliminated by MATE1: Possible increased plasma concentrations of these drugs.1

Drugs Affected by Renal Organic Cation Transporters

Drugs eliminated by OCT2: Possible increased plasma concentrations of these drugs.1

Specific Drugs

Drug

Interaction

Comments

Acetaminophen

Rilpivirine: No clinically important pharmacokinetic interactions1

Aluminum preparations

Possible decreased absorption and decreased dolutegravir concentrations1

Give dolutegravir/rilpivirine ≥4 hours before or ≥6 hours after aluminum1

Antacids, aluminum-, calcium-, or magnesium-containing

Decreased rilpivirine concentrations expected, may result in loss of therapeutic response and lead to resistance to rilpivirine or other HIV NNRTIs;1 decreased dolutegravir concentrations and AUC1

Give dolutegravir/rilpivirine ≥4 hours before or ≥6 hours after aluminum-, calcium-, or magnesium-containing antacids1

Antiarrhythmic agents (dofetilide)

Dofetilide: Possible increased dofetilide concentrations and increased risk of serious and/or life-threatening adverse effects1

Dofetilide: Concomitant use with dolutegravir/rilpivirine contraindicated1

Anticonvulsants (carbamazepine, oxcarbazepine, phenobarbital, phenytoin)

Carbamazepine: Decreased dolutegravir concentrations and AUC;1 substantially decreased rilpivirine exposures expected, which may lead to loss of virologic response1

Oxcarbazepine, phenobarbital, phenytoin: Possible decreased dolutegravir and rilpivirine exposures;1 possible loss of virologic response1

Carbamazepine, oxcarbazepine, phenobarbital, phenytoin: Concomitant use with dolutegravir/rilpivirine contraindicated1

Antidiabetic agents (metformin)

Dolutegravir: Increased metformin concentrations and AUC1

If dolutegravir/rilpivirine initiated or discontinued in patient receiving metformin, monitor blood glucose concentrations and adjust metformin dosage if needed;1 do not exceed metformin hydrochloride dosage of 1 g daily during concomitant therapy1

Antimycobacterial agents (rifabutin, rifampin, rifapentine)

Rifabutin: Concomitant use with rilpivirine decreases rilpivirine concentrations and AUC;1 no clinically important effect on dolutegravir pharmacokinetics1

Rifampin: Concomitant use with dolutegravir decreases dolutegravir concentrations and AUC;1 concomitant use with rilpivirine decreases rilpivirine concentrations and AUC and may result in loss of virologic response1

Rifapentine: Decreased dolutegravir and rilpivirine concentrations expected;1 may result in loss of rilpivirine virologic response1

Rifabutin: Manufacturer recommends 1 tablet of the fixed combination (50 mg of dolutegravir and 25 mg of rilpivirine) and a 25-mg tablet of single-entity rilpivirine once daily to provide total rilpivirine dosage of 50 mg daily1

Rifampin, rifapentine: Concomitant use with dolutegravir/rilpivirine contraindicated1

Benzodiazepines (midazolam)

Midazolam: Dolutegravir does not have clinically important effect on midazolam AUC1

Buffered preparations

Buffered preparations containing polyvalent cations: Possible decreased absorption and decreased dolutegravir concentrations1

Buffered preparations containing polyvalent cations: Give dolutegravir/rilpivirine ≥4 hours before or ≥6 hours after such preparations1

Calcium supplements

Possible decreased dolutegravir concentrations when given concomitantly in fasted state1

Give dolutegravir/rilpivirine ≥4 hours before or ≥6 hours after oral calcium supplements;1 alternatively, may be given concomitantly if taken with food1

Chlorzoxazone

Rilpivirine: No clinically important pharmacokinetic interactions1

Corticosteroids (dexamethasone, prednisone)

Dexamethasone (multiple systemic doses): Possible decreased rilpivirine concentrations and possible loss of virologic response1

Prednisone: No clinically important effect on dolutegravir pharmacokinetics1

Dexamethasone: Concomitant use of more than a single dose of dexamethasone with dolutegravir/rilpivirine contraindicated1

Daclatasvir

Dolutegravir: No clinically important pharmacokinetic interactions1

Digoxin

Rilpivirine: No clinically important effect on digoxin pharmacokinetics1

Estrogens/progestins

Dolutegravir: No clinically important effect on norelgestromin pharmacokinetics1

Rilpivirine: Concomitant use with ethinyl estradiol and norethindrone has no clinically important effect on rilpivirine, ethinyl estradiol, or norethindrone pharmacokinetics1

Histamine H2-receptor antagonists

Rilpivirine: Concomitant famotidine decreases rilpivirine concentrations and AUC;1 other H2-receptor antagonists (e.g., cimetidine, nizatidine, ranitidine) may decrease rilpivirine concentrations, result in loss of therapeutic response, and lead to resistance to rilpivirine or other HIV NNRTIs1

Dolutegravir: Pharmacokinetic interactions not expected1

Give dolutegravir/rilpivirine ≥4 hours before or ≥12 hours after H2-receptor antagonist1

HMG-CoA reductase inhibitors (statins)

Atorvastatin: When used with rilpivirine, no clinically important pharmacokinetic interactions1

Iron preparations

Possible decreased dolutegravir concentrations when given concomitantly in fasted state1

Give dolutegravir/rilpivirine ≥4 hours before or ≥6 hours after oral iron;1 alternatively, may be given concomitantly if taken with food1

Laxatives containing polyvalent cations

Possible decreased absorption and decreased dolutegravir concentrations1

Give dolutegravir/rilpivirine ≥4 hours before or ≥6 hours after laxatives containing polyvalent cations1

Macrolides

Clarithromycin, erythromycin, telithromycin: Possible increased rilpivirine concentrations;1 no effect on dolutegravir concentrations expected1

Clarithromycin, erythromycin, or telithromycin: Consider alternative macrolides (e.g., azithromycin)1

Magnesium preparations

Possible decreased absorption and decreased dolutegravir concentrations1

Give dolutegravir/rilpivirine ≥4 hours before or ≥6 hours after magnesium1

Methadone

Dolutegravir: No clinically important effect on methadone pharmacokinetics1

Rilpivirine: Decreased methadone concentrations; no clinically important effect on rilpivirine concentrations or AUC1

Adjustment of initial methadone dosage not needed;1 closely monitor clinically and adjust methadone maintenance dosage if needed1

Multivitamins

Possible decreased dolutegravir concentrations when given concomitantly in fasted state1

Give dolutegravir/rilpivirine ≥4 hours before or ≥6 hours after multivitamins;1 alternatively, may be given concomitantly if taken with food1

Phosphodiesterase type 5 inhibitors

Sildenafil: When used with rilpivirine, no clinically important pharmacokinetic interactions1

Proton-pump inhibitors

Rilpivirine: Concomitant omeprazole decreases rilpivirine concentrations and AUC;1 other proton-pump inhibitors (e.g., esomeprazole, lansoprazole, pantoprazole, rabeprazole) also may decrease rilpivirine concentrations, result in loss of therapeutic response, and lead to resistance to rilpivirine or other HIV NNRTIs1

Dolutegravir: Omeprazole does not have clinically important effect on dolutegravir pharmacokinetics1

Concomitant use with dolutegravir/rilpivirine contraindicated1

St. John's wort (Hypericum perforatum)

Possible decreased dolutegravir and rilpivirine concentrations;1 may lead to loss of rilpivirine virologic response1

Concomitant use with dolutegravir/rilpivirine contraindicated1

Simeprevir

Rilpivirine: No clinically important pharmacokinetic interactions1

No clinically important interactions in cirrhotic patients with HIV and HCV coinfection receiving dolutegravir and rilpivirine concomitantly with simeprevir and sofosbuvir (with or without ribavirin)4

Sofosbuvir

No clinically important interactions in cirrhotic patients with HIV and HCV coinfection receiving dolutegravir and rilpivirine concomitantly with simeprevir and sofosbuvir (with or without ribavirin)4

Sucralfate

Possible decreased absorption and decreased dolutegravir concentrations1

Give dolutegravir/rilpivirine ≥4 hours before or ≥6 hours after sucralfate1

Dolutegravir Sodium and Rilpivirine Hydrochloride Pharmacokinetics

Absorption

Food

Dolutegravir: Administration with moderate- or high-fat meal increases AUC by 1.9-fold.1

Rilpivirine: Administration with moderate- or high-fat meal increases AUC by 1.6- or 1.7-fold, respectively.1 If taken with only a protein-rich nutritional drink, exposures are 50% lower than when taken with a meal.1

Plasma Concentrations

Dolutegravir: Peak plasma concentrations attained 3 hours after a dose.1

Rilpivirine: Peak plasma concentrations attained 4 hours after a dose.1

Distribution

Extent

Dolutegravir: Crosses placenta.202 Appears to be distributed into human milk in low concentrations;202 distributed into milk in rats.1

Rilpivirine: Crosses placenta.202 Not known whether distributed into human milk;202 detected in plasma of rat pups exposed to rilpivirine through the milk of lactating rats.1

Plasma Protein Binding

Dolutegravir: Approximately 99%.1

Rilpivirine: Approximately 99%.1

Elimination

Metabolism

Dolutegravir: Primarily metabolized by UGT1A1;1 CYP3A plays a minor role.1

Rilpivirine: Primarily metabolized by CYP3A.1

Elimination Route

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

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

Half-life

Dolutegravir: 14 hours.1

Rilpivirine: 50 hours.1

Special Populations

Mild hepatic impairment (Child-Pugh class A): Rilpivirine exposures 47% higher than matched controls.1

Moderate hepatic impairment (Child-Pugh class B): Dolutegravir exposures similar to those in healthy individuals;1 rilpivirine exposures 5% higher than matched controls.1

Severe hepatic impairment (Child-Pugh class C): Effect on dolutegravir and rilpivirine pharmacokinetics not evaluated.1

Mild renal impairment: No clinically important effect on dolutegravir or rilpivirine pharmacokinetics.1

Moderate renal impairment: No clinically important effect on dolutegravir pharmacokinetics;1 effect on rilpivirine pharmacokinetics not known.1

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;1 effect on rilpivirine pharmacokinetics not known.1

End-stage renal disease: Effect on rilpivirine pharmacokinetics not known.1

Dialysis: Effect on dolutegravir or rilpivirine pharmacokinetics not known.1

Age, race, gender: No clinically important effects on dolutegravir or rilpivirine pharmacokinetics.1

HCV coinfection: No clinically important effects on dolutegravir or rilpivirine exposures.1

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).1

Store and dispense in original package;1 do not remove desiccant;1 protect from moisture.1

Actions and Spectrum

  • Dolutegravir/rilpivirine is a fixed-combination antiretroviral containing dolutegravir and rilpivirine.1

  • Dolutegravir is an HIV INSTI antiretroviral.1 3 5 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.1 3 5

  • Rilpivirine is a diarylpyrimidine HIV NNRTI.1 3 5 The drug noncompetitively inhibits HIV-1 reverse transcriptase.1 3 5

  • HIV-1 resistant to dolutegravir or rilpivirine produced in vitro and have emerged during clinical use.1 2

  • 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.1 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.1

  • HIV-1 resistant to some other HIV INSTIs (e.g., elvitegravir, raltegravir) may have reduced susceptibility or resistance to dolutegravir.236

  • Cross-resistance occurs among HIV NNRTIs;1 cross-resistance to efavirenz, etravirine, and/or nevirapine likely after virologic failure and development of resistance to rilpivirine.1

  • No in vitro evidence of antagonistic anti-HIV effects between dolutegravir and rilpivirine.1

Advice to Patients

  • Critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.1 200 Importance of taking as prescribed; do not alter or discontinue antiretroviral regimen without consulting clinician.1 200

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

  • Antiretroviral therapy is not a cure for HIV infection; opportunistic infections and other complications associated with HIV disease may still occur.200

  • 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.200

  • 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.200 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).200

  • Importance of reading patient information provided by the manufacturer.1

  • Importance of taking once daily with a meal;1 a protein drink alone does not constitute a meal.1

  • If a dose of dolutegravir/rilpivirine is missed, the dose should be taken with a meal as soon as it is remembered.1 A double dose should not be taken to make up for a missed dose.1

  • 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).1 Advise patients that close monitoring and appropriate laboratory testing or treatment may be required if a hypersensitivity reaction occurs.1

  • 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.1 Importance of immediately contacting clinician if depressive symptoms (e.g., feeling sad, hopeless, anxious, or restless; hurting oneself; having thoughts of hurting oneself) occur.1

  • Advise patients that hepatotoxicity has been reported in patients receiving the components of dolutegravir/rilpivirine and that monitoring for hepatotoxicity recommended.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal products, and any concomitant illnesses.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 (See Pregnancy under Cautions.) Advise HIV-infected women not to breast-feed.1

  • Importance of advising patients of other important precautionary information.1 (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.

Dolutegravir Sodium and Rilpivirine Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Film-coated tablets

Dolutegravir Sodium 50 mg (of dolutegravir) and Rilpivirine Hydrochloride 25 mg (of rilpivirine)

Juluca

ViiV

AHFS DI Essentials™. © Copyright 2018, Selected Revisions October 1, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. ViiV Healthcare. Juluca (dolutegravir and rilpivirine) tablets prescribing information. Research Triangle Park, NC; 2017 Dec.

2. Llibre JM, Hung CC, Brinson C et al. Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies. Lancet. 2018; http://www.ncbi.nlm.nih.gov/pubmed/29310899?dopt=AbstractPlus

3. Capetti AF, Cossu MV, Paladini L et al. Dolutegravir plus rilpivirine dual therapy in treating HIV-1 infection. Expert Opin Pharmacother. 2018; 19:65-77. http://www.ncbi.nlm.nih.gov/pubmed/29246084?dopt=AbstractPlus

4. Merli M, Galli L, Marinaro L et al. Pharmacokinetics of dolutegravir and rilpivirine in combination with simeprevir and sofosbuvir in HIV/hepatitis C virus-coinfected patients with liver cirrhosis. J Antimicrob Chemother. 2017; 72:812-815. http://www.ncbi.nlm.nih.gov/pubmed/27999010?dopt=AbstractPlus

5. Capetti AF, Astuti N, Cattaneo D et al. Pharmacokinetic drug evaluation of dolutegravir plus rilpivirine for the treatment of HIV. Expert Opin Drug Metab Toxicol. 2017; 13:1183-1192. http://www.ncbi.nlm.nih.gov/pubmed/28854832?dopt=AbstractPlus

35. US Food and Drug Administration. FDA drug safety communication: FDA to evaluate potential risk of neural tube birth defects with HIV medicine dolutegravir (Juluca, Tivicay, Triumeq). 2018 May 18. From FDA website. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM608127.pdf

200. Panel on Antiretroviral Guidelines for Adults and Adolescents, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV (May 30, 2018). Updates may be available at HHS AIDS Information (AIDSinfo) website. http://www.aidsinfo.nih.gov

201. Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (May 22, 2018). Updates may be available at HHS AIDS Information (AIDSinfo) website. http://www.aidsinfo.nih.gov

202. Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for the use of antiretroviral drugs in women with HIV infection and interventions to reduce perinatal HIV transmission in the United States (May 20, 2018). Updates may be available at HHS AIDS Information (AIDSinfo) website. http://www.aidsinfo.nih.gov

203. HHS Antiretroviral Guideline Panels. Recommendations regarding use of dolutegravir in adults and adolescents with HIV who are pregnant or of child bearing potential (May 30, 2018). Updates may be available at HHS AIDS Information (AIDSinfo) website. https://aidsinfo.nih.gov/news/2109/recommendations-regarding-the-use-of-dolutegravir-in-adults-and-adolescents-with-hiv-who-are-pregnant-or-of-child-bearing-potential

236. ViiV Healthcare. Tivicay (dolutegravir) tablets prescribing information. Research Triangle Park, NC; 2017 Nov.

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