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
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
Oral1 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
Oral1 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 (Clcr ≥30 mL/minute): Dosage adjustments not needed.
Severe renal impairment (Clcr <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 (QTc), 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 (Clcr ≥30 mL/minute).
Increased monitoring for adverse effects recommended in patients with severe renal impairment (Clcr <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
Drug |
Interaction |
Comments |
---|---|---|
Acetaminophen |
Rilpivirine: No clinically important pharmacokinetic interactions |
|
α1-Adrenergic blocking agents (alfuzosin, doxazosin, silodosin, tamsulosin, terazosin) |
Dolutegravir or rilpivirine: Not expected to affect α1-adrenergic blocking agent concentrations |
Dosage adjustments not needed if used with dolutegravir or rilpivirine |
β-Adrenergic blocking agents |
Metoprolol, timolol: Dolutegravir not expected to affect β-adrenergic blocking agent concentrations |
Metoprolol, timolol: Dosage adjustments not needed if used with dolutegravir |
Aluminum preparations |
Possible decreased dolutegravir absorption and decreased dolutegravir concentrations |
Give dolutegravir/rilpivirine ≥4 hours before or ≥6 hours after aluminum |
Antacids, aluminum-, calcium-, or magnesium-containing |
Decreased dolutegravir concentrations and AUC; decreased rilpivirine concentrations expected, may result in loss of therapeutic response and lead to resistance to rilpivirine or other HIV NNRTIs |
Give dolutegravir/rilpivirine ≥4 hours before or ≥6 hours after aluminum-, calcium-, or magnesium-containing antacids |
Antiarrhythmic agents |
Amiodarone, digoxin, dronedarone, flecainide, systemic lidocaine, mexiletine, propafenone, quinidine: Dolutegravir not expected to affect concentrations of these antiarrhythmic agents Disopyramide: Possible increased disopyramide concentrations if used with dolutegravir Dofetilide: Possible increased dofetilide concentrations and increased risk of serious and/or life-threatening adverse effects if used with dolutegravir/rilpivirine |
Amiodarone, digoxin, dronedarone, flecainide, systemic lidocaine, mexiletine, propafenone, quinidine: Dosage adjustments not needed if used with dolutegravir Disopyramide: Monitor for disopyramide-associated adverse effects if used with dolutegravir Dofetilide: Concomitant use with dolutegravir/rilpivirine contraindicated |
Anticoagulants |
Apixaban, betrixaban, dabigatran, edoxaban, rivaroxaban: Dolutegravir or rilpivirine not expected to affect concentrations of these anticoagulants Warfarin: Dolutegravir or rilpivirine not expected to affect warfarin concentrations |
Apixaban, betrixaban, dabigatran, edoxaban, rivaroxaban: Dosage adjustments not needed if used with dolutegravir or rilpivirine Warfarin: Dosage adjustments not needed if used with dolutegravir or rilpivirine |
Anticonvulsants |
Carbamazepine: Decreased dolutegravir concentrations and AUC; substantially decreased rilpivirine exposures expected, which may lead to loss of virologic response Eslicarbazepine: Possible decreased dolutegravir or rilpivirine concentrations Ethosuximide, lamotrigine: Dolutegravir not expected to affect concentrations of these anticonvulsants Ethosuximide, lacosamide, lamotrigine, tiagabine, zonisamide: Rilpivirine not expected to affect concentrations of these anticonvulsants Oxcarbazepine, phenobarbital, phenytoin: Possible decreased dolutegravir and rilpivirine exposures; possible loss of virologic response Valproic acid: Data not available |
Carbamazepine, oxcarbazepine, phenobarbital, phenytoin: Concomitant use with dolutegravir/rilpivirine contraindicated Eslicarbazepine: Some experts state consider alternative anticonvulsant or alternative antiretroviral agents Ethosuximide, lamotrigine: Dosage adjustments not needed if used with dolutegravir Ethosuximide, lacosamide, lamotrigine, tiagabine, zonisamide: Dosage adjustments not needed if used with rilpivirine Valproic acid: Some experts recommend monitoring valproic acid concentrations and virologic response if used with dolutegravir |
Antidiabetic agents |
Canagliflozin, dapagliflozin, empagliflozin: Rilpivirine not expected to affect concentrations of these antidiabetic agents Linagliptin, saxagliptin, sitagliptin: Rilpivirine not expected to affect concentrations of these antidiabetic agents Metformin: Increased metformin concentrations and AUC if used with dolutegravir Saxagliptin or fixed combination of dapagliflozin and saxagliptin (dapagliflozin/saxagliptin): Dolutegravir not expected to affect concentrations of these antidiabetic agents |
Canagliflozin, dapagliflozin, empagliflozin: Dosage adjustments not needed if used with rilpivirine Linagliptin, saxagliptin, sitagliptin: Dosage adjustments not needed if used with rilpivirine Metformin: If dolutegravir/rilpivirine initiated or discontinued in patients receiving metformin, monitor blood glucose concentrations and adjust metformin dosage if needed; do not exceed metformin hydrochloride dosage of 1 g daily during concomitant therapy Saxagliptin or dapagliflozin/saxagliptin: Dosage adjustments not needed if used with dolutegravir |
Antifungals, azoles |
Fluconazole, isavuconazonium (prodrug of isavuconazole), itraconazole, posaconazole, voriconazole: Possible decreased rilpivirine concentrations Itraconazole, posaconazole, voriconazole: Pharmacokinetic interactions not expected if used with dolutegravir |
Fluconazole, isavuconazonium, itraconazole, posaconazole, voriconazole: Dosage adjustments not needed if used with rilpivirine Itraconazole, posaconazole, voriconazole: Dosage adjustments not needed if used with dolutegravir |
Antimalarial and antiprotozoal agents |
Fixed combination of artemether and lumefantrine (artemether/lumefantrine): Rilpivirine not expected to affect concentrations of the antimalarial agents Atovaquone: Data not available regarding use with rilpivirine Fixed combination of atovaquone and proguanil (atovaquone/proguanil): Data not available regarding use with rilpivirine |
Artemether/lumefantrine: Dosage adjustments not needed if used with rilpivirine Atovaquone: Monitor for atovaquone efficacy if used with rilpivirine Atovaquone/proguanil: Monitor for antimalarial efficacy if used with rilpivirine |
Antimycobacterial agents (bedaquiline, rifabutin, rifampin, rifapentine) |
Bedaquiline: Rilpivirine not expected to affect bedaquiline concentrations Rifabutin: Concomitant use with rilpivirine decreases rilpivirine concentrations and AUC; no clinically important effect on dolutegravir pharmacokinetics Rifampin: Concomitant use with rilpivirine decreases rilpivirine concentrations and AUC and may result in loss of virologic response; concomitant use with dolutegravir decreases dolutegravir concentrations and AUC Rifapentine: Decreased dolutegravir and rilpivirine concentrations expected; may result in loss of rilpivirine virologic response |
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 daily Rifampin, rifapentine: Concomitant use with dolutegravir/rilpivirine contraindicated |
Antiplatelet agents |
Clopidogrel, prasugrel, ticagrelor, vorapaxar: Dolutegravir or rilpivirine not expected to affect concentrations of these antiplatelet agents |
Clopidogrel, prasugrel, ticagrelor, vorapaxar: Dosage adjustments not needed if used with dolutegravir or rilpivirine |
Antipsychotic agents |
Aripiprazole, brexpiprazole, cariprazine, iloperidone, lurasidone, pimavanserin, pimozide, quetiapine: Dolutegravir or rilpivirine not expected to affect concentrations of these antipsychotic agents |
Aripiprazole, brexpiprazole, cariprazine, iloperidone, lurasidone, pimavanserin, pimozide, quetiapine: Dosage adjustments not needed if used with dolutegravir or rilpivirine |
Benzodiazepines |
Alprazolam, diazepam, lorazepam, midazolam, triazolam: Rilpivirine not expected to affect concentrations of these benzodiazepines Clonazepam, clorazepate, diazepam, estazolam, flurazepam, midazolam, triazolam: Dolutegravir not expected to affect concentrations of these benzodiazepines |
Alprazolam, diazepam, lorazepam, midazolam, triazolam: Dosage adjustments not needed if used with rilpivirine Clonazepam, clorazepate, diazepam, estazolam, flurazepam, triazolam: Dosage adjustments not needed if used with dolutegravir |
Bosentan |
Possible decreased dolutegravir concentrations |
Dosage adjustments not needed if used with dolutegravir |
Buffered preparations |
Buffered preparations containing polyvalent cations: Possible decreased dolutegravir absorption and decreased dolutegravir concentrations |
Buffered preparations containing polyvalent cations: Give dolutegravir/rilpivirine ≥4 hours before or ≥6 hours after such preparations |
Buprenorphine |
Buprenorphine (buccal, sublingual, subdermal implant): Dolutegravir or rilpivirine not expected to affect buprenorphine or norbuprenorphine concentrations |
Dosage adjustments not needed if used with dolutegravir or rilpivirine |
Bupropion |
Dolutegravir or rilpivirine: Not expected to affect bupropion concentrations |
Dosage adjustments not needed if used with dolutegravir or rilpivirine |
Buspirone |
Dolutegravir not expected to affect buspirone concentrations |
Dosage adjustments not needed if used with dolutegravir |
Calcifediol |
Dolutegravir not expected to affect calcifediol concentrations |
Dosage adjustments not needed if used with dolutegravir |
Calcium-channel blocking agents |
Dolutegravir or rilpivirine: Not expected to affect concentrations of calcium-channel blocking agents |
Dosage adjustments not needed if used with dolutegravir or rilpivirine |
Calcium supplements |
Possible decreased dolutegravir concentrations when given concomitantly in fasted state |
Give dolutegravir/rilpivirine ≥4 hours before or ≥6 hours after oral calcium supplements; alternatively, may be given concomitantly if taken with food |
Chlorzoxazone |
Rilpivirine: No clinically important pharmacokinetic interactions |
|
Colchicine |
Dolutegravir not expected to affect colchicine concentrations |
Dosage adjustments not needed if used with dolutegravir |
Corticosteroids (dexamethasone, prednisone) |
Dexamethasone (multiple systemic doses): Possible decreased rilpivirine concentrations and possible loss of virologic response Prednisone: No clinically important effect on dolutegravir pharmacokinetics |
Dexamethasone: Concomitant use of more than a single dose of dexamethasone with dolutegravir/rilpivirine contraindicated |
Dalfampridine |
Possible increased dalfampridine concentrations and increased risk of seizures if used with dolutegravir |
Weigh potential benefits of concomitant dalfampridine and dolutegravir therapy against risk of seizures |
Dronabinol |
Dolutegravir not expected to affect dronabinol concentrations |
Dosage adjustments not needed if used with dolutegravir |
Elbasvir and grazoprevir |
Fixed combination of elbasvir and grazoprevir (elbasvir/grazoprevir): Concomitant use with dolutegravir or rilpivirine not expected to alter concentrations of the antiretrovirals or HCV antivirals |
Elbasvir/grazoprevir: Dosage adjustments not needed if used with dolutegravir or rilpivirine |
Eluxadoline |
Dolutegravir not expected to affect eluxadoline concentrations |
Dosage adjustments not needed if used with dolutegravir |
Eplerenone |
Dolutegravir not expected to affect eplerenone concentrations |
Dosage adjustments not needed if used with dolutegravir |
Ergot alkaloids (dihydroergotamine, ergotamine, methylergonovine) |
Dolutegravir not expected to affect concentrations of ergot alkaloids |
Dosage adjustments not needed if used with dolutegravir |
Estrogens and progestins |
Estradiol, estrogen, conjugated estrogens: Dolutegravir not expected to affect concentrations of these estrogens Drospirenone, medroxyprogesterone, micronized progesterone: Dolutegravir not expected to affect concentrations of these hormones Oral contraceptives containing ethinyl estradiol and norgestimate: Dolutegravir has no effect on pharmacokinetics of ethinyl estradiol or norgestimate Oral contraceptives containing ethinyl estradiol and norethindrone: Concomitant rilpivirine does not have a clinically important effect on rilpivirine, ethinyl estradiol, or norethindrone pharmacokinetics |
Estradiol, estrogen, conjugated estrogens: Dosage adjustments not needed if used with dolutegravir Drospirenone, medroxyprogesterone, progesterone: Dosage adjustments not needed if used with dolutegravir Oral contraceptives containing ethinyl estradiol and norgestimate: Dosage adjustments not needed |
Fentanyl |
Dolutegravir not expected to affect fentanyl concentrations |
Dosage adjustments not needed if used with dolutegravir |
Flibanserin |
Dolutegravir not expected to affect flibanserin concentrations |
Dosage adjustments not needed if used with dolutegravir |
Glecaprevir and pibrentasvir |
Fixed combination of glecaprevir and pibrentasvir (glecaprevir/pibrentasvir): If used with dolutegravir, no clinically important pharmacokinetic interactions expected; if used with rilpivirine, concentrations of rilpivirine increased (84%), but no effect on glecaprevir or pibrentasvir concentrations |
Glecaprevir/pibrentasvir: Experts state dosage adjustments not needed if used with dolutegravir or rilpivirine |
Goserelin |
Dolutegravir not expected to affect goserelin concentrations |
Dosage adjustments not needed if used with dolutegravir |
Histamine H2-receptor antagonists |
Rilpivirine: Concomitant famotidine decreases rilpivirine concentrations and AUC; 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 NNRTIs Dolutegravir: Pharmacokinetic interactions not expected |
Give dolutegravir/rilpivirine ≥4 hours before or ≥12 hours after H2-receptor antagonist |
HMG-CoA reductase inhibitors (statins) |
Atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin: Dolutegravir or rilpivirine not expected to affect concentrations of these statins |
Atorvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin: Dosage adjustments not needed if used with dolutegravir or rilpivirine |
Immunosuppressive agents |
Cyclosporine, everolimus, sirolimus, tacrolimus: Dolutegravir not expected to affect concentrations of these immunosuppressive agents |
Cyclosporine, everolimus, sirolimus, tacrolimus: Dosage adjustments not needed if used with dolutegravir |
Iron preparations |
Possible decreased dolutegravir concentrations when given concomitantly in fasted state |
Give dolutegravir/rilpivirine ≥4 hours before or ≥6 hours after oral iron; alternatively, may be given concomitantly if taken with food |
Ivabradine |
Dolutegravir not expected to affect ivabradine concentrations |
Dosage adjustments not needed if used with dolutegravir |
Laxatives containing polyvalent cations |
Possible decreased dolutegravir absorption and decreased dolutegravir concentrations |
Give dolutegravir/rilpivirine ≥4 hours before or ≥6 hours after laxatives containing polyvalent cations |
Ledipasvir and sofosbuvir |
Fixed combination of ledipasvir and sofosbuvir (ledipasvir/sofosbuvir): If used with dolutegravir, no effect on dolutegravir concentrations; if used with rilpivirine, no effect on rilpivirine, ledipasvir, or sofosbuvir concentrations |
Ledipasvir/sofosbuvir: Dosage adjustments not needed if used with dolutegravir or rilpivirine |
Leuprolide |
Dolutegravir not expected to affect leuprolide concentrations |
Dosage adjustments not needed if used with dolutegravir |
Lofexidine |
Dolutegravir not expected to affect lofexidine concentrations |
Dosage adjustments not needed if used with lofexidine |
Lomitapide |
Dolutegravir not expected to affect lomitapide concentrations |
Dosage adjustments not needed if used with dolutegravir |
Macrolides |
Clarithromycin, erythromycin: Possible increased rilpivirine concentrations; no effect on dolutegravir concentrations expected |
Clarithromycin, erythromycin: Consider alternative macrolides (e.g., azithromycin) |
Magnesium preparations |
Possible decreased dolutegravir absorption and decreased dolutegravir concentrations |
Give dolutegravir/rilpivirine ≥4 hours before or ≥6 hours after magnesium |
Methadone |
Dolutegravir: No clinically important effect on methadone pharmacokinetics Rilpivirine: Decreased methadone concentrations; no clinically important effect on rilpivirine concentrations or AUC |
Adjustment of initial methadone dosage not needed; closely monitor clinically and adjust methadone maintenance dosage if needed |
Multivitamins |
Possible decreased dolutegravir concentrations when given concomitantly in fasted state |
Give dolutegravir/rilpivirine ≥4 hours before or ≥6 hours after multivitamins; alternatively, may be given concomitantly if taken with food |
Nefazodone |
Dolutegravir: Not expected to affect nefazodone concentrations Rilpivirine: Possible increased rilpivirine concentrations |
Dosage adjustments not needed if used with dolutegravir or rilpivirine |
Phosphodiesterase type 5 (PDE5) inhibitors |
Avanafil, sildenafil, tadalafil, vardenafil: Dolutegravir or rilpivirine not expected to affect PDE5 inhibitor concentrations |
Avanafil, sildenafil, tadalafil, vardenafil: Dosage adjustments not needed if used with dolutegravir or rilpivirine |
Proton-pump inhibitors |
Rilpivirine: Concomitant omeprazole decreases rilpivirine concentrations and AUC; 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 NNRTIs Dolutegravir: Omeprazole does not have clinically important effect on dolutegravir pharmacokinetics |
Concomitant use with dolutegravir/rilpivirine contraindicated |
Ranolazine |
Dolutegravir not expected to affect ranolazine concentrations |
Dosage adjustments not needed if used with dolutegravir |
Rilpivirine |
No in vitro evidence of antagonistic antiretroviral effects between dolutegravir and rilpivirine |
|
Selective β-adrenergic agonists |
Arformoterol, formoterol, indacaterol, olodaterol, salmeterol (orally inhaled): Dolutegravir not expected to affect concentrations of the β-adrenergic agonist |
Arformoterol, formoterol, indacaterol, olodaterol, salmeterol (orally inhaled): Dosage adjustments not needed if used with dolutegravir |
Sofosbuvir |
No clinically important interactions in cirrhotic patients with HIV and HCV coinfection receiving dolutegravir and rilpivirine concomitantly with simeprevir (no longer available in US) and sofosbuvir (with or without ribavirin) |
|
Sofosbuvir and velpatasvir |
Fixed combination of sofosbuvir and velpatasvir (sofosbuvir/velpatasvir): Pharmacokinetic interactions with dolutegravir or rilpivirine not expected |
Sofosbuvir/velpatasvir: Dosage adjustments not needed if used with dolutegravir or rilpivirine |
Sofosbuvir, velpatasvir, and voxilaprevir |
Fixed combination of sofosbuvir, velpatasvir, and voxilaprevir (sofosbuvir/velpatasvir/voxilaprevir): Pharmacokinetic interactions with dolutegravir or rilpivirine not expected |
Sofosbuvir/velpatasvir/voxilaprevir: Dosage adjustments not needed if used with dolutegravir or rilpivirine |
Spironolactone |
Dolutegravir not expected to affect spironolactone concentrations |
Dosage adjustments not needed if used with dolutegravir |
SSRIs |
Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline: No pharmacokinetic interactions with dolutegravir expected |
Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline: Dosage adjustments not needed if used with dolutegravir |
St. John's wort (Hypericum perforatum) |
Possible decreased dolutegravir and rilpivirine concentrations; may lead to loss of rilpivirine virologic response |
Concomitant use with dolutegravir/rilpivirine contraindicated |
Sucralfate |
Possible decreased dolutegravir concentrations |
Give dolutegravir/rilpivirine ≥4 hours before or ≥6 hours after sucralfate |
Suvorexant |
Dolutegravir not expected to affect suvorexant concentrations |
Dosage adjustments not needed if used with dolutegravir |
Testosterone |
Dolutegravir not expected to affect testosterone concentrations |
Dosage adjustments not needed if used with dolutegravir |
Tramadol |
Dolutegravir not expected to affect tramadol concentrations |
Dosage adjustments not needed if used with dolutegravir |
Trazodone |
Dolutegravir or rilpivirine not expected to affect trazodone concentrations |
Dosage adjustments not needed if used with dolutegravir or rilpivirine |
Tricyclic antidepressants |
Amitriptyline, desipramine, doxepin, imipramine, nortriptyline: Dolutegravir not expected to affect concentrations of these tricyclic antidepressants |
Amitriptyline, desipramine, doxepin, imipramine, nortriptyline: Dosage adjustments not needed if used with dolutegravir |
Zolpidem |
Dolutegravir not expected to affect zolpidem concentrations |
Dosage adjustments not needed if used with dolutegravir |
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.
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 2023, Selected Revisions July 27, 2020. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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