AHFS Class:

• HIV Integrase Inhibitors 8:18.08.12

Generic Name(s):

• Dolutegravir Sodium and Rilpivirine Hydrochloride

Dolutegravir sodium and rilpivirine hydrochloride (dolutegravir/rilpivirine) is a fixed-combination antiretroviral agent containing dolutegravir (human immunodeficiency virus [HIV] integrase strand transfer inhibitor [INSTI]) and rilpivirine (HIV nonnucleoside reverse transcriptase inhibitor [NNRTI]).1

Treatment of HIV Infection

The fixed combination of dolutegravir sodium and rilpivirine hydrochloride (dolutegravir/rilpivirine) is used as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in antiretroviral-experienced (previously treated) adults to replace the current antiretroviral regimen in those 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

Dolutegravir and rilpivirine are available as a fixed-combination preparation (dolutegravir/rilpivirine) and as separate single-entity products.1,226,236 Refer to the full prescribing information of the single-entity products for information on specific uses.226,236

Clinical Experience

Antiretroviral-experienced Adults

Efficacy of a 2-drug antiretroviral regimen of dolutegravir and rilpivirine in antiretroviral-experienced adults was evaluated in 2 identically designed, randomized, open-label, active-control, phase 3, noninferiority studies (SWORD-1; NCT02429791 and SWORD-2; NCT02422797).1,2,6 Patients enrolled in these studies were adults with plasma HIV-1 RNA levels <50 copies/mL for ≥6 months (median age 43 years, 22% female, 20% non-white, 11% with baseline CD4+ T-cell count <350 cells/mm³).1,2 At initial screening, all patients were on a stable suppressive antiretroviral regimen (i.e., an INSTI, NNRTI, or PI in conjunction with 2 HIV nucleoside reverse transcriptase inhibitors [NRTIs]) for ≥6 months and had no known history of resistance to dolutegravir or rilpivirine.1,2 Patients were randomized in a 1:1 ratio to either switch to the 2-drug regimen of dolutegravir and rilpivirine (dolutegravir 50 mg and rilpivirine 25 mg) once daily (early-switch group) or stay on their current antiretroviral regimen for 52 weeks before switching to the 2-drug regimen (late-switch group).1,2,6 The primary end point was virologic response (defined as plasma HIV-1 RNA levels <50 copies/mL) at 48 weeks.1,2 Pooled virologic outcomes at 48 weeks (95% of patients in each treatment group had plasma HIV-1 RNA levels <50 copies/mL) indicated that the switch to a 2-drug regimen of dolutegravir and rilpivirine was noninferior to continuing the 3-drug antiretroviral regimen.1,2 At week 52, all 513 study participants in the early-switch group continued with the 2-drug regimen of dolutegravir and rilpivirine and 477 of the 511 patients in the late-switch group changed to the 2-drug regimen.6 At week 100, 89% of patients in the early-switch group and 93% of patients in the late-switch group were still virologically suppressed (i.e., plasma HIV-1 RNA levels <50 copies/mL).6 At week 148, 84% of patients in the early-switch group and 90% of patients in the late-switch group were still virologically suppressed (i.e., plasma HIV-1 RNA levels <50 copies/mL).1,11

Clinical Perspective

Therapeutic options for the treatment and prevention of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving.200,201,202 Antiretroviral therapy is recommended for all individuals with HIV regardless of CD4 counts, and should be initiated as soon as possible after diagnosis of HIV and continued indefinitely.200,201,202 The primary goals of antiretroviral therapy are to achieve and maintain durable suppression of HIV viral load (as measured by plasma HIV-1 RNA levels) to a level below which drug-resistance mutations cannot emerge (i.e., below detectable limits), restore and preserve immunologic function, reduce HIV-related morbidity and mortality, improve quality of life, and prevent transmission of HIV.200,202 While the most appropriate antiretroviral regimen cannot be defined for each clinical scenario, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents, HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, and HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, have developed comprehensive guidelines that provide information on selection and use of antiretrovirals for the treatment or prevention of HIV infection.200,201,202 Because of the complexity of managing patients with HIV, it is recommended that clinicians with HIV expertise be consulted when needed.200,201,202

The use of combination antiretroviral regimens that generally include 3 drugs from 2 or more drug classes is currently recommended to achieve viral suppression.200,201 In both treatment-naïve adults and children, an initial antiretroviral regimen generally consists of 2 NRTIs administered in combination with a third active antiretroviral drug from 1 of 3 drug classes: an INSTI, an NNRTI, or a PI with a pharmacokinetic enhancer (also known as a booster; the 2 drugs used for this purpose are cobicistat and ritonavir).200,201,202 Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance-test results, comorbid conditions, access, and cost.3,200,201,202 In patients with comorbid infections (e.g., hepatitis B, tuberculosis), antiretroviral regimen selection should also consider the potential for activity against other present infections and timing of initiation relative to other anti-infective regimens.200

Dolutegravir/rilpivirine is a co-formulation of an INSTI (dolutegravir) and an NNRTI (rilpivirine).200 In the HHS adult and adolescent HIV treatment guideline, the 2-drug regimen of dolutegravir/rilpivirine is not recommended for initial therapy because it has not been studied for use in this setting.200 Growing evidence suggests that some 2-drug regimens are effective in maintaining virologic control in patients who have initiated therapy and achieved sustained virologic suppression; however, 2-drug regimens are not recommended for patients with hepatitis B virus (HBV) coinfection, unless the patient is also on a specific anti-HBV active regimen.200

In the HHS pediatric HIV treatment guideline, dolutegravir/rilpivirine is not a recommended regimen for children with HIV; data are insufficient to support the use of 2-drug regimens in children at this time.201

In the HHS perinatal HIV treatment guideline, dolutegravir is included in various antiretroviral regimens.202 The 2-drug regimen of dolutegravir/rilpivirine is not recommended for use in pregnant patients due to a lack of data in this patient population.202 However, if a pregnant patient presents to care on dolutegravir/rilpivirine and demonstrates successful maintenance of viral suppression, they can continue the 2-drug regimen with more frequent viral load monitoring (every 1-2 months throughout pregnancy).202

General

Pretreatment Screening

• Perform testing for hepatitis B virus (HBV) infection prior to initiation of dolutegravir/rilpivirine.200

Patient Monitoring

• Monitor for hepatotoxicity during treatment with dolutegravir/rilpivirine.1
• Monitor for signs or symptoms of severe skin or hypersensitivity reactions based on clinical status and laboratory parameters; discontinue dolutegravir/rilpivirine immediately if signs or symptoms develop.1
• Evaluate patients with severe depressive symptoms to determine relationship to treatment with dolutegravir/rilpivirine and whether continued treatment is warranted.1
• Monitor more frequently for adverse effects in patients with severe renal impairment (creatinine clearance <30 mL/minute) or end-stage renal disease.1

Administration

The fixed combination dolutegravir/rilpivirine is administered orally once daily with a meal.1 The manufacturer states that a protein drink alone does not constitute a meal.1

Store dolutegravir/rilpivirine at room temperature of 20-25ºC (excursions permitted to 15-30ºC).1 Store and dispense in the original package, protect from moisture, and keep the bottle tightly closed; do not remove the desiccant.1

Dosage

Fixed-combination tablets of dolutegravir/rilpivirine contain dolutegravir sodium and rilpivirine hydrochloride; dosages are expressed in terms of dolutegravir and rilpivirine, respectively.1

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

Adult Dosage

Treatment of HIV-1 Infection in Antiretroviral-experienced Adults

For the treatment of human immunodeficiency virus type 1 (HIV-1) infection in certain antiretroviral-experienced adults, the usual dosage of dolutegravir/rilpivirine is 1 tablet (50 mg of dolutegravir and 25 mg of rilpivirine) once daily with a meal.1

Treatment of HIV-1 Infection in Antiretroviral-experienced Adults Receiving Rifabutin

If dolutegravir/rilpivirine is used for the treatment of HIV-1 infection in certain antiretroviral-experienced adults receiving rifabutin, patients should receive 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 with a meal to provide a total rilpivirine dosage of 50 mg daily for the duration of rifabutin coadministration.1

Special Populations

Hepatic Impairment

Dosage adjustment of dolutegravir/rilpivirine is not necessary in adults with mild or moderate hepatic impairment (Child-Pugh class A or B).1

The effect of severe hepatic impairment (Child-Pugh class C) on the pharmacokinetics of dolutegravir/rilpivirine is not known and the manufacturer makes no specific dosage recommendations for such patients.1

Renal Impairment

Dosage adjustment of dolutegravir/rilpivirine is not necessary in adults with mild or moderate renal impairment (creatinine clearance ≥30 mL/minute).1

The manufacturer makes no specific dosage recommendations for those with severe renal impairment (creatinine clearance <30 mL/minute) or end-stage renal disease; increased monitoring for adverse effects is recommended in such individuals.1

Geriatric Patients

The manufacturer makes no specific dosage recommendations for dolutegravir/rilpivirine in geriatric patients, but recommends caution because of possible age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1

Contraindications

• Previous hypersensitivity reaction to dolutegravir or rilpivirine.1
• Concomitant use with dofetilide due to potential for serious and/or life-threatening adverse effects resulting from increased dofetilide plasma concentrations.1
• Concomitant use with drugs that induce cytochrome P-450 (CYP) isoenzyme 3A or drugs that elevate gastric pH since substantially decreased plasma rilpivirine concentrations may occur and may result in loss of virologic response; these drugs include 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 St. John's wort ( Hypericum perforatum ).1

Warnings/Precautions

Skin and Hypersensitivity Reactions

Hypersensitivity reactions (e.g., rash, constitutional findings, and sometimes organ dysfunction, including liver injury) have been reported in patients receiving dolutegravir.1 These adverse effects were reported in <1% of patients receiving dolutegravir in phase 3 clinical trials.1

Severe skin and hypersensitivity reactions, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported during postmarketing experience with rilpivirine-containing regimens.1 Some skin reactions were accompanied by constitutional symptoms such as fever; other skin reactions were associated with organ dysfunction, including elevated hepatic enzyme concentrations.1 During phase 3 clinical trials evaluating rilpivirine, treatment-associated rash with at least grade 2 severity was reported in 3% of patients.1

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

Hepatotoxicity

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

Patients with human immunodeficiency virus (HIV) infection and with hepatitis B virus (HBV) or hepatitis C virus (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 have been 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 has been reported with dolutegravir-containing regimens; drug-induced liver injury leading to liver transplant has been reported with the fixed combination of abacavir, dolutegravir, and lamivudine (abacavir/dolutegravir/lamivudine).1

Monitor for hepatotoxicity in patients receiving dolutegravir/rilpivirine.1

Depressive Disorders

Depressive disorders (depressed mood, depression, dysphoria, major depression, altered mood, negative thoughts, suicide attempt, suicidal ideation) have been 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 the benefits of continued therapy outweigh the risks.1

Drug Interactions

Concomitant use of dolutegravir/rilpivirine and certain other drugs may result in known or potentially clinically important drug interactions, some of which may lead to loss of therapeutic effect of dolutegravir/rilpivirine and possible development of resistance or result in possible adverse effects from increased exposures of concomitant drugs.1

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

Because prolongation of the QT interval corrected for rate (QT_c) has been reported in healthy individuals receiving rilpivirine in a dosage of 75 or 300 mg once daily (3 or 12 times higher, respectively, than the rilpivirine dose in dolutegravir/rilpivirine), consider use of alternative antiretrovirals in patients receiving a drug with a known risk of torsades de pointes.1

Use of Fixed Combinations

When dolutegravir/rilpivirine is used, consider the 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

The Antiretroviral Pregnancy Registry (APR) monitors pregnancy outcomes in women exposed to dolutegravir/rilpivirine during pregnancy.1 Clinicians are encouraged to register patients in the APR by calling 800-258-4263 or visiting [Web].1,202

Data regarding the use of dolutegravir/rilpivirine in pregnant women are insufficient to date to definitively assess a drug-associated risk for birth defects and miscarria however, human data from the APR do not indicate an increased birth defect risk.1 Of 1,377 dolutegravir exposures during pregnancy resulting in live births, the prevalence of birth defects was 3.3% following first trimester exposure and 5% following second-/third-trimester exposure.1 Of 870 rilpivirine exposures during pregnancy resulting in live births, the prevalence of birth defects was 2.1% following first trimester exposure and 0.9% following second-/third-trimester exposure.1

There has been a concern regarding the development of neural tube defects in infants exposed to dolutegravir during pregnancy.1 The first interim analysis from an ongoing birth outcome surveillance study in Botswana identified an association between dolutegravir and an increased risk of neural tube defects when dolutegravir was administered at the time of conception and in early pregnancy.1 In a larger subsequent analysis, the prevalence of neural tube defects in infants delivered to individuals taking dolutegravir at conception was 0.11%, which did not differ significantly from that of infants delivered to HIV-positive individuals not administered dolutegravir (0.11%) or to HIV-negative individuals (0.06%).1

Results from an Eswatini birth outcome surveillance study revealed similar outcomes; the prevalence of neural tube defects in infants delivered to individuals taking dolutegravir at conception was 0.08%, which did not differ significantly from that of infants delivered to individuals taking non-dolutegravir-containing regimens (0.22%) or to HIV-negative individuals (0.08%).1

Lactation

Dolutegravir is distributed into human milk.1 It is not known whether rilpivirine is distributed into human milk;226 the drug was present in milk when administered to lactating rats.1

It is not known whether dolutegravir or rilpivirine affects human milk production or the breastfed infant.1,226

The HHS perinatal HIV transmission guideline provides updated recommendations on infant feeding.202 The guideline states that patients with HIV should receive evidence-based, patient-centered counseling to support shared decision making about infant feeding.202 During counseling, patients should be informed that feeding with appropriate formula or pasteurized donor human milk from a milk bank eliminates the risk of postnatal HIV transmission to the infant.202 Additionally, achieving and maintaining viral suppression with antiretroviral therapy during pregnancy and postpartum reduces the risk of breastfeeding HIV transmission to <1%, but does not completely eliminate the risk.202 Replacement feeding with formula or banked pasteurized donor milk is recommended when patients with HIV are not on antiretroviral therapy and/or do not have a suppressed viral load during pregnancy (at a minimum throughout the third trimester), as well as at delivery.202

Pediatric Use

Safety and efficacy of dolutegravir/rilpivirine have not been established in pediatric patients.1 Pharmacokinetics of the drug have not been evaluated in pediatric patients.1

Geriatric Use

Clinical studies of dolutegravir/rilpivirine did not include a sufficient number of patients ≥65 years of age to determine whether they respond differently compared with younger patients.1 Population pharmacokinetic analyses indicate that age has no clinically important effect on the pharmacokinetics of dolutegravir or rilpivirine.1

Use dolutegravir/rilpivirine with caution in geriatric patients because of age-related decreases in hepatic, renal, and/or cardiac function and potential for concomitant disease and drug therapy.1

Hepatic Impairment

Dosage adjustments are not necessary if dolutegravir/rilpivirine is used in patients with mild or moderate hepatic impairment (Child-Pugh class A or B).1

Dolutegravir exposures in individuals with moderate hepatic impairment (Child-Pugh class B) were similar to those observed in healthy individuals.1 The effect of severe hepatic impairment (Child-Pugh class C) on dolutegravir exposures has not been evaluated.1

Rilpivirine exposures were 47 or 5% higher in individuals with mild or moderate hepatic impairment (Child-Pugh class A or B), respectively, compared with healthy individuals.1 The effect of severe hepatic impairment (Child-Pugh class C) on rilpivirine exposures has not been evaluated.1

Renal Impairment

Dosage adjustments are not necessary if dolutegravir/rilpivirine is used in patients with mild or moderate renal impairment (creatinine clearance ≥30 mL/minute).1 Increased monitoring for adverse effects is recommended if dolutegravir/rilpivirine is used in patients with severe renal impairment (creatinine clearance <30 mL/minute) or end-stage renal disease.1

Population pharmacokinetic analyses indicate that mild and moderate renal impairment do not have a clinically important effect on dolutegravir pharmacokinetics.1 In individuals with severe renal impairment, dolutegravir AUC, peak plasma concentrations, and plasma concentrations measured 24 hours after dosing were 40, 23, and 43% lower, respectively, compared with healthy individuals.1 The pharmacokinetics of dolutegravir have not been evaluated in individuals requiring dialysis.1

Population pharmacokinetic analyses indicate that mild renal impairment does not have a clinically important effect on rilpivirine pharmacokinetics.1 The pharmacokinetics of rilpivirine have not been evaluated in individuals with moderate or severe renal impairment, end-stage renal disease, or renal disease requiring dialysis.1

Common Adverse Effects

Adverse effects reported in ≥2% of patients receiving dolutegravir/rilpivirine include diarrhea, headeache, and nausea.1

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

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Cytochrome P-450 (CYP) isoenzyme 3A plays a minor role in the metabolism of dolutegravir; rilpivirine is primarily metabolized by CYP3A4.1 Concomitant use with drugs that induce CYP3A may decrease dolutegravir and rilpivirine plasma concentrations, decrease therapeutic effect of the drugs, and may lead to resistance to rilpivirine or other HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs).1 Concomitant use with drugs that inhibit CYP3A may increase dolutegravir and rilpivirine plasma concentrations.1

In vitro studies indicate that dolutegravir does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A and does not induce CYP1A2, 2B6, or 3A4.1 Rilpivirine is not likely to have a clinically important effect on exposures of drugs metabolized by CYP isoenzymes.1

Drugs Affecting or Metabolized by Uridine Diphosphate-glucuronosyltransferases

Dolutegravir is metabolized by uridine diphosphate-glucuronosyltransferase (UGT) 1A1, and in vitro studies indicate the drug also is a substrate for UGT1A3 and UGT1A9.1 Pharmacokinetic interactions are possible with inducers of these enzymes (decreased plasma concentrations of dolutegravir and decreased therapeutic effect of the drug) or with inhibitors of these enzymes (increased plasma concentrations of dolutegravir).1

Dolutegravir does not inhibit UGT1A1 or UGT2B7 in vitro.1

Drugs Affecting or Affected by P-glycoprotein Transport

Dolutegravir is a substrate of the P-glycoprotein (P-gp) transport system in vitro; dolutegravir does not inhibit P-gp-mediated transport in vitro.1

Pharmacokinetic interactions are possible with inducers of P-gp (decreased plasma concentrations of dolutegravir and decreased therapeutic effect of the drug) or with inhibitors of P-gp (increased plasma concentrations of dolutegravir).1

Drugs Affecting or Affected by Bile Salt Export Pump

Dolutegravir does not inhibit the bile salt export pump (BSEP) in vitro.1

Drugs Affecting or Affected by Breast Cancer Resistance Protein

Dolutegravir is a substrate of breast cancer resistance protein (BCRP) in vitro; dolutegravir does not inhibit BCRP in vitro.1

Pharmacokinetic interactions are possible with inducers of BCRP (decreased plasma concentrations of dolutegravir and decreased therapeutic effects of the drug) or with inhibitors of BCRP (increased plasma concentrations of dolutegravir).1

Drugs Affecting or Affected by Multidrug and Toxin Extrusion Transporter

Dolutegravir inhibits multidrug and toxin extrusion transporter (MATE) 1 in vitro.1 Therefore, dolutegravir may increase plasma concentrations of drugs eliminated by MATE1 (e.g., dalfampridine, dofetilide, metformin).1

Drugs Affecting or Affected by Multidrug Resistance Protein

Dolutegravir does not inhibit multidrug resistance protein (MRP) 2 or MRP4 in vitro.1

Drugs Affecting or Affected by Organic Anion Transporters

In vitro, dolutegravir inhibits renal organic anion transporter (OAT) 1 and OAT3.1 In vivo, dolutegravir does not alter plasma concentrations of OAT1 or OAT3 substrates (e.g., tenofovir, aminohippurate).1

Dolutegravir does not inhibit organic anion transporter polypeptide (OATP) 1B1 or OATP1B3 in vitro; dolutegravir is not a substrate of OATP1B1 or 1B3 in vitro.1

Drugs Affecting or Affected by Organic Cation Transporters

In vitro, dolutegravir inhibits renal organic cation transporter (OCT) 2; dolutegravir does not inhibit OCT1 in vitro.1

Dolutegravir may increase plasma concentrations of drugs eliminated by OCT2 (e.g., dalfampridine, dofetilide, metformin).1

Drugs that Prolong the QT Interval

Because rilpivirine can prolong the QT interval corrected for rate (QT_c), consider an alternative to dolutegravir/rilpivirine in patients receiving drugs with a known risk of torsades de pointes.1

Acetaminophen

Concomitant use of rilpivirine and acetaminophen does not have a clinically important effect on the pharmacokinetics of either drug.1

Anticonvulsants

Carbamazepine

Concomitant use of carbamazepine (300 mg twice daily) and dolutegravir (50 mg once daily) decreases peak plasma concentrations and AUC of dolutegravir.1 Concomitant use of carbamazepine and rilpivirine is expected to substantially decrease rilpivirine exposures, which may lead to loss of virologic response.1

Concomitant use of carbamazepine and dolutegravir/rilpivirine is contraindicated.1

Oxcarbazepine, Phenobarbital, and Phenytoin

Oxcarbazepine, phenobarbital, and phenytoin are expected to decrease dolutegravir and rilpivirine exposures, which may lead to loss of virologic response.1

Concomitant use of oxcarbazepine, phenobarbital, or phenytoin and dolutegravir/rilpivirine is contraindicated.1

Antilipemic Agents

HMG-CoA Reductase Inhibitors

Concomitant use of rilpivirine and atorvastatin does not have a clinically important effect on the pharmacokinetics of either drug.1 Concomitant use of rilpivirine and other statins (e.g., fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin) is not expected to affect concentrations of the statin.200 Dosage adjustments are not needed if rilpivirine is used concomitantly with any of these statins.200

Antimycobacterial Agents

Rifabutin

Rifabutin does not have a clinically important effect on the pharmacokinetics of dolutegravir.1 Concomitant use of rilpivirine and rifabutin results in decreased rilpivirine plasma concentrations and AUC.1

If dolutegravir/rilpivirine is used concomitantly with rifabutin, the manufacturer recommends that patients receive 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 with a meal to provide a total rilpivirine dosage of 50 mg daily.1

Rifampin

Concomitant use of dolutegravir and rifampin decreases plasma concentrations and AUC of dolutegravir.1 Concomitant use of rilpivirine and rifampin decreases plasma concentrations and AUC of rilpivirine and may result in loss of virologic response.1

Concomitant use of rifampin and dolutegravir/rilpivirine is contraindicated.1

Rifapentine

Concomitant use of rifapentine and dolutegravir/rilpivirine is expected to result in clinically important decreases in rilpivirine plasma concentrations and may lead to loss of virologic response;1 clinically important decreases in dolutegravir plasma concentrations also are expected.1,200

Concomitant use of rifapentine and dolutegravir/rilpivirine is contraindicated.1

Antiretroviral Agents

Dolutegravir/rilpivirine is a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in certain antiretroviral-experienced adults, and the manufacturer states that concomitant use with other antiretroviral agents is not recommended.1

There is no in vitro evidence of antagonistic antiretroviral effects between dolutegravir and rilpivirine.1

Calcium, Iron, Multivitamins, and Other Preparations Containing Polyvalent Cations

Calcium, Iron, and Multivitamins

Oral calcium supplements, oral iron preparations, or other oral supplements containing calcium or iron (e.g., multivitamins) may decrease plasma concentrations of dolutegravir when used concomitantly with dolutegravir/rilpivirine in the fasted state.1

Administer dolutegravir/rilpivirine at least 4 hours before or 6 hours after oral supplements containing calcium or iron.1 Alternatively, if dolutegravir/rilpivirine is administered with food, the drug can be used concomitantly with oral supplements containing calcium or iron.1

Preparations Containing Polyvalent Cations

Concomitant use of dolutegravir/rilpivirine and drugs containing polyvalent cations (e.g., magnesium, aluminum, laxatives, buffered medications, cation-containing products) may decrease absorption of dolutegravir resulting in decreased plasma concentrations of the drug.1

Administer dolutegravir/rilpivirine at least 4 hours before or 6 hours after drugs or preparations containing polyvalent cations.1

Cardiac Drugs

Antiarrhythmic Agents

Dofetilide

Concomitant use of dofetilide and dolutegravir/rilpivirine may increase dofetilide plasma concentrations and increase the risk of serious and/or life-threatening adverse effects.1

Concomitant use of dofetilide and dolutegravir/rilpivirine is contraindicated.1

Corticosteroids

Dexamethasone

Concomitant use of systemic dexamethasone (multiple doses) with dolutegravir/rilpivirine may result in decreased plasma concentrations of rilpivirine and may lead to loss of virologic response.1

Concomitant use of more than a single dose of dexamethasone with dolutegravir/rilpivirine is contraindicated.1

Prednisone

Prednisone does not have a clinically important effect on the pharmacokinetics of dolutegravir.1,200

Dalfampridine

Concomitant use of dolutegravir and dalfampridine may result in increased dalfampridine concentrations and may increase the risk of seizures.1 Weigh the potential benefits of concomitant use of dalfampridine and dolutegravir against the risk of seizures.1

Estrogens and Progestins

Ethinyl Estradiol and Norethindrone or Norgestimate

Dolutegravir does not have a clinically important effect on the pharmacokinetics of hormonal contraceptives containing ethinyl estradiol or norgestimate.1,200 Dosage adjustments are not needed if oral contraceptives containing ethinyl estradiol and norgestimate are used in patients receiving dolutegravir.1,200

Concomitant use of rilpivirine with ethinyl estradiol and norethindrone does not have a clinically important effect on rilpivirine, ethinyl estradiol, or norethindrone pharmacokinetics.1

GI Drugs

Antacids

Antacids containing aluminum, calcium, or magnesium are expected to decrease plasma concentrations of rilpivirine and may result in loss of therapeutic response and lead to resistance to rilpivirine or other HIV NNRTIs.1 Antacids also decrease plasma concentrations and AUC of dolutegravir.1

Administer dolutegravir/rilpivirine at least 4 hours before or 6 hours after antacids containing aluminum, calcium, or magnesium.1

Histamine H2-receptor Antagonists

Concomitant use of rilpivirine (single dose) and famotidine (single dose taken 2 hours before rilpivirine) results in decreased rilpivirine plasma concentrations and AUC.1 Concomitant use of other histamine H₂-receptor antagonists (e.g., cimetidine, nizatidine) also may result in decreased rilpivirine plasma concentrations and loss of therapeutic response and may lead to resistance to rilpivirine or other HIV NNRTIs.1 Concomitant use of histamine H₂-receptor antagonists and dolutegravir is not expected to affect dolutegravir exposures.1

Administer dolutegravir/rilpivirine at least 4 hours before or 12 hours after a histamine H₂-receptor antagonist.1

Proton-pump Inhibitors

Concomitant use of omeprazole and rilpivirine results in decreased rilpivirine plasma concentrations and AUC.1 Concomitant use of other proton-pump inhibitors (e.g., esomeprazole, lansoprazole, pantoprazole, rabeprazole) also may result in decreased rilpivirine plasma concentrations and loss of therapeutic response and may lead to resistance to rilpivirine or other HIV NNRTIs.1 Concomitant use of omeprazole and dolutegravir does not have a clinically important effect on the pharmacokinetics of dolutegravir.1

Concomitant use of dolutegravir/rilpivirine and proton-pump inhibitors (e.g., esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole) is contraindicated.1

Sucralfate

Sucralfate may decrease plasma concentrations of dolutegravir.1

Administer dolutegravir/rilpivirine at least 4 hours before or 6 hours after sucralfate.1

HCV Antivirals

HCV Polymerase Inhibitors

Sofosbuvir

In cirrhotic patients with HIV and hepatitis C virus (HCV) coinfection receiving dolutegravir and rilpivirine (with or without HIV nucleoside reverse transcriptase inhibitors [NRTIs]) concomitantly with simeprevir (no longer commercially available in the US) and sofosbuvir (with or without ribavirin), no clinically important drug interactions were observed.4

Macrolides

Concomitant use of dolutegravir/rilpivirine and clarithromycin or erythromycin may result in increased rilpivirine plasma concentrations, but is not expected to affect dolutegravir concentrations.1 Consider an alternative to these macrolides (e.g., azithromycin) whenever possible in patients receiving dolutegravir/rilpivirine.1

Metformin

Concomitant use of metformin hydrochloride (500 mg twice daily) and dolutegravir (50 mg once or twice daily) increases peak plasma concentrations and AUC of metformin.1

Assess the benefit and risk of concomitant use of dolutegravir/rilpivirine and metformin.1

Some experts state that the lowest metformin dosage should be used initially and dosage of the antidiabetic agent should be titrated to achieve glycemic control while monitoring for metformin-associated adverse effects in patients receiving dolutegravir.200 Metformin dosage may need to be adjusted when initiating or discontinuing dolutegravir.200

Concomitant use of rilpivirine and metformin is not expected to affect metformin concentrations; dosage adjustments are not needed if rilpivirine and metformin are used concomitantly.200

Methadone

Dolutegravir does not have a clinically important effect on the pharmacokinetics of methadone.1 Concomitant use of methadone and rilpivirine results in decreased methadone concentrations, but does not have a clinically important effect on rilpivirine concentrations or AUC.1

Although adjustment of initial methadone dosage is not needed when methadone and dolutegravir/rilpivirine are used concomitantly, close clinical monitoring is recommended and adjustment of methadone maintenance dosage may be required in some patients.1

St. John's Wort

Concomitant use of St. John's wort ( Hypericum perforatum ) and dolutegravir/rilpivirine may result in clinically important decreases in rilpivirine plasma concentrations and may lead to loss of virologic response to the drug; dolutegravir plasma concentrations also may be decreased.1

Concomitant use of St. John's wort and dolutegravir/rilpivirine is contraindicated.1

Description

Dolutegravir sodium and rilpivirine hydrochloride (dolutegravir/rilpivirine) is a fixed combination containing 2 human immunodeficiency virus (HIV) antiretrovirals.1 Dolutegravir is an HIV integrase strand transfer inhibitor (INSTI) and rilpivirine is a diarylpyrimidine HIV nonnucleoside reverse transcriptase inhibitor (NNRTI).1,3,5 There is no in vitro evidence of antagonistic anti-HIV effects between dolutegravir and rilpivirine.1

Dolutegravir 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 Dolutegravir is active against HIV type 1 (HIV-1)1 and also has in vitro activity against HIV type 2 (HIV-2).200

Rilpivirine noncompetitively inhibits HIV-1 reverse transcriptase.1,3,5 HIV-2 is intrinsically resistant to NNRTIs.200

Strains of HIV-1 resistant to dolutegravir or rilpivirine have been produced in vitro and have emerged during clinical use.1,2 In clinical studies evaluating a 2-drug regimen of dolutegravir and rilpivirine in antiretroviral-experienced adults, virologic failure during treatment with the regimen was reported in 12 patients, of which 10 had post-baseline resistance data.1 Six isolates showed genotypic and/or phenotypic resistance to rilpivirine with emergent NNRTI resistance substitutions E138E/A, M230M/L, L100L/I, K101Q, E138A, K101K/E, M230M/L, L100L/V/M, and M230M/L.1 In addition, 1 patient had NNRTI-resistance substitutions K103N and V179I with rilpivirine phenotypic fold change of 5.2 but had no baseline sample.1 Two isolates showed evidence of dolutegravir resistance substitutions.1 One isolate had emergent INSTI-resistance substitution V151V/I present post-baseline with baseline INSTI-resistance substitutions N155N/H and G163G/R, but no integrase phenotypic data were available at virologic failure.1 The other patient had the dolutegravir-resistance substitution G193E at baseline and virologic failure, but no detectable phenotypic resistance.1 Cross-resistance occurs among HIV NNRTIs.1 Cross-resistance to efavirenz, etravirine, and/or nevirapine is likely after virologic failure and development of resistance to rilpivirine.1

The effect of dolutegravir/rilpivirine on the QT interval has not been studied.1 Following oral administration of dolutegravir, peak plasma concentrations of the drug are attained 3 hours after a dose.1 Administration with a moderate- or high-fat meal increases the AUC of dolutegravir by approximately 1.9-fold; this effect is not considered clinically important.1 Dolutegravir is metabolized primarily by uridine diphosphate-glucuronosyltransferase (UGT) 1A1; cytochrome P-450 (CYP) isoenzyme 3A plays only a minor role in metabolism of the drug.1 Following an oral dose of dolutegravir, 64% of the dose is eliminated in feces (53% as unchanged drug) and 31% is eliminated in urine as metabolites (<1% as unchanged drug).1 Dolutegravir has a plasma elimination half-life of 14 hours.1 In vitro studies indicate that dolutegravir is approximately 99% bound to plasma proteins.1

Following oral administration of rilpivirine, peak plasma concentrations of the drug are generally attained 4 hours after a dose.1 Administration with a moderate- or high-fat meal increases the AUC of rilpivirine by approximately 1.6- or 1.7-fold, respectively.1 If taken with only a protein-rich nutritional drink, rilpivirine exposures are 50% lower than when taken with a meal.1 Rilpivirine is primarily metabolized by CYP3A.1 Following an oral dose, 85% of the dose is eliminated in feces (25% as unchanged drug) and 6.5% is eliminated in urine (<1% as unchanged drug).1 The half-life of rilpivirine is 50 hours.1 In vitro studies indicate that rilpivirine is approximately 99% bound to plasma proteins.1

Population pharmacokinetic analyses from studies with the individual components of dolutegravir/rilpivirine have found that gender and race have no clinically important effect on the pharmacokinetics of either drug.1 Population pharmacokinetic analyses have not shown any clinically important effects on dolutegravir or rilpivirine exposures in HIV-infected individuals with HCV coinfection.1 Individuals with HBV coinfection were excluded from clinical studies evaluating dolutegravir/rilpivirine.

Advice to Patients

• Inform patients about the critical nature of compliance with HIV therapy and importance of remaining under the care of a clinician.200 Inform patients to take the antiretroviral regimen as prescribed, and to not alter or discontinue the antiretroviral regimen without consulting a clinician.1,200
• Advise patients to take dolutegravir/rilpivirine once daily with a meal; a protein drink alone does not constitute a meal.1
• If a dose of dolutegravir/rilpivirine is missed, inform patients to take the dose with a meal as soon as it is remembered.1 Inform patients not to double their next dose to make up for a missed dose.1
• Advise patients to immediately discontinue dolutegravir/rilpivirine and seek 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 or redness, 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 of the abdomen 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 Inform patients to immediately contact their 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 is recommended.1
• Advise women to inform their clinician if they plan to become pregnant, or if pregnancy is confirmed, during treatment with dolutegravir/rilpivirine.1 Inform patients that a registry exists that monitors outcomes in women exposed to dolutegravir/rilpivirine during pregnancy.1
• Advise women to inform their clinician if they plan to breastfeed.1
• Advise patients of the potential for serious drug interactions and to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal products, and any concomitant illnesses.1
• Advise patients of other important precautionary information.1

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. ViiV Healthcare. Juluca^® (dolutegravir and rilpivirine) tablets prescribing information. Research Triangle Park, NC; 2024 Apr.

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; [PubMed 29310899]

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.. [PubMed 29246084]

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.. [PubMed 27999010]

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. [PubMed 28854832]

6. Aboud M, Orkin C, Podzamczer D et al. Efficacy and safety of dolutegravir-rilpivirine for maintenance of virological suppression in adults with HIV-1: 100-week data from the randomised, open-label, phase 3 SWORD-1 and SWORD-2 studies. Lancet HIV . 2019; 6:e576-e587. [PubMed 31307948]

10. Zash R, Holmes L, Diseko M et al. Neural-tube defects and antiretroviral treatment regimens in Botswana. N Engl J Med . 2019; 381:827-840.. [PubMed 31329379]

11. van Wyk J, Orkin C, Rubio R, et al. Brief report: durable suppression and low rate of virologic failure 3 years after switch to dolutegravir + rilpivirine 2-drug regimen: 148-week results from the SWORD-1 and SWORD-2 randomized clinical trials. J Acquir Immune Defic Syndr. 2020;85(3):325-330.

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 HIV-1-infected adults and adolescents (March 23, 2023). Updates may be available at HIV.gov website. [Web]

201. Panel on Antiretroviral Therapy and Medical Management of HIV-infected Children, US Department of Health and Human Services (HHS). Guidelines for the use of antiretroviral agents in pediatric HIV infection (January 31, 2023). Updates may be available at HIV.gov website. [Web]

202. Panel on Treatment of HIV-infected Pregnant Women and Prevention of Perinatal Transmission, US Department of Health and Human Services (HHS). Recommendations for the use of antiretroviral drugs in pregnant women with HIV infection and interventions to reduce perinatal HIV transmission in the United States (January 31, 2024). Updates may be available at HIV.gov website. [Web]

226. Janssen. Edurant^® (rilpivirine) tablets prescribing information. Titusville, NJ; 2022 Oct.

236. ViiV Healthcare. Tivicay^® (dolutegravir) tablets prescribing information. Durham, NC; 2022 Oct.