Dolutegravir and Rilpivirine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Juluca: Dolutegravir 50 mg and rilpivirine 25 mg

Pharmacology

Mechanism of Action

Dolutegravir, an integrase inhibitor, inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration. Rilpivirine, a non-nucleoside reverse transcriptase inhibitor, binds to reverse transcriptase and blocks the RNA-dependent and DNA-dependent polymerase activities, including HIV-1 replication.

Use: Labeled Indications

HIV-1 infection, treatment: Treatment of HIV-1 infection in adults virologically suppressed on a stable antiretroviral regimen for ≥6 months with no history of treatment failure and no known resistance to the individual components

Contraindications

Hypersensitivity to dolutegravir, rilpivirine, or any component of the formulation; concurrent use with dofetilide, carbamazepine, systemic dexamethasone (>1 dose), oxcarbazepine, phenobarbital, phenytoin, proton pump inhibitors (PPIs) (eg, esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole), rifampin, rifapentine, and/or St John's wort.

Dosage and Administration

Dosing: Adult

HIV-1 infection, treatment: Oral: One tablet (dolutegravir 50 mg/rilpivirine 25 mg) once daily. Note: Prior to switching to dolutegravir/rilpivirine, patients must be virologically suppressed on a stable antiretroviral regimen for ≥6 months with no history of treatment failure and no known resistance to dolutegravir or rilpivirine.

Dose adjustment for concomitant therapy with rifabutin: One tablet (dolutegravir 50 mg/rilpivirine 25 mg) once daily, with an additional rilpivirine 25 mg tablet once daily for the duration of rifabutin coadministration.

Dosing: Geriatric

Refer to adult dosing.

Administration

Administer with a meal; a protein supplement drink alone does not replace a meal. Administer 4 hours before or 6 hours after cation-containing antacids or laxatives, sucralfate, oral supplements containing iron or calcium, or buffered medications. Alternatively, may be administered with supplements containing calcium or iron at the same time if administered together with food.

Dietary Considerations

Take with a meal (not a protein supplement drink alone). Take 4 hours before or 6 hours after cation-containing antacids or laxatives, sucralfate, oral supplements containing iron or calcium, or buffered medications. Alternatively, may be taken with supplements containing calcium or iron at the same time if taken together with food.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Keep in original container; protect from moisture and do not remove desiccant.

Drug Interactions

Aluminum Hydroxide: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral aluminum hydroxide. Administer the dolutegravir/rilpivirine combination product at least 4 hours before or 6 hours after oral aluminum hydroxide. Consider therapy modification

Antacids: May decrease the serum concentration of Rilpivirine. Management: Administer antacids at least 2 hours before or 4 hours after rilpivirine. Administer antacids at least 6 hours before or 4 hours after the rilpivirine/dolutegravir combination product. Consider therapy modification

Antihepaciviral Combination Products: May increase the serum concentration of Rilpivirine. Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Calcium Salts: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral calcium. Administer dolutegravir/rilpivirine at least 4 hours before or 6 hours after oral calcium salts. Alternatively, dolutegravir and oral calcium can be taken together with food. Consider therapy modification

CarBAMazepine: May decrease the serum concentration of Rilpivirine. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Rilpivirine. Monitor therapy

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Darunavir: May increase the serum concentration of Rilpivirine. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

DexAMETHasone (Systemic): May decrease the serum concentration of Rilpivirine. Avoid combination

Didanosine: Rilpivirine may decrease the absorption of Didanosine. More specifically, simultaneous coadministration of these drugs creates a conflict between recommendations to administer with (rilpivirine) and without (didanosine) food. Didanosine may decrease the absorption of Rilpivirine. More specifically, simultaneous coadministration of these drugs creates a conflict between recommendations to administer with (rilpivirine) and without (didanosine) food. Management: Administer didanosine on an empty stomach at least 2 hours before or 4 hours after rilpivirine, due to the requirement that rilpivirine be administered with food. Consider therapy modification

Dofetilide: Dolutegravir may increase the serum concentration of Dofetilide. Avoid combination

Efavirenz: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Efavirenz. Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Efavirenz. Avoid combination

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Ergonovine: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Ergonovine. Specifically, this would be most likely with delavrdine, while other Non-Nucleoside Reverse Transcriptase Inhibitors may be more likely to decrease the concentration of Ergonovine. Avoid combination

Etravirine: Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Etravirine. This has been observed with the NNRTIs efavirenz and nevirapine. Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the serum concentration of Etravirine. This has been observed with delavirdine. Avoid combination

Fosamprenavir: May decrease the serum concentration of Dolutegravir. Specifically, Fosamprenavir/Ritonavir may decrease the serum concentration of Dolutegravir. The individual contributions of Fosamprenavir and Ritonavir to this effect are unknown. Management: Increase dolutegravir to 50 mg twice daily in adults and pediatric patients (12 yrs or older and at least 40 kg). Seek alternatives to fosamprenavir/ritonavir in INSTI-experienced patients with suspected or certain INSTI resistance. Consider therapy modification

Fosphenytoin: May decrease the serum concentration of Rilpivirine. Avoid combination

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Monitor therapy

Histamine H2 Receptor Antagonists: May decrease the serum concentration of Rilpivirine. Management: Administer histamine H2 receptor antagonists at least 12 hours before or 4 hours after rilpivirine. Consider therapy modification

Iron Preparations: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral iron. Administer dolutegravir/rilpivirine at least 4 hours before or 6 hours after oral iron. Alternatively, dolutegravir and oral iron can be taken together with food. Exceptions: Ferric Carboxymaltose; Ferric Derisomaltose; Ferric Gluconate; Ferric Hydroxide Polymaltose Complex; Ferric Pyrophosphate Citrate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Consider therapy modification

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Ketoconazole (Systemic): May increase the serum concentration of Rilpivirine. Rilpivirine may decrease the serum concentration of Ketoconazole (Systemic). Monitor therapy

Levomethadone: Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Levomethadone. Management: Levomethadone dosage adjustments will likely be required with efavirenz and nevirapine, and may be necessary with rilpivirine as well. Monitor therapy

Lopinavir: May increase the serum concentration of Rilpivirine. Monitor therapy

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Macrolide Antibiotics: May increase the serum concentration of Rilpivirine. Management: Consider the use of azithromycin or another non-macrolide alternative when appropriate to avoid this potential interaction. Exceptions: Azithromycin (Systemic); Fidaxomicin; Roxithromycin; Spiramycin. Consider therapy modification

Magnesium Salts: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral magnesium salts. Administer the dolutegravir/rilpivirine combination product at least 4 hours before or 6 hours after oral magnesium salts. Consider therapy modification

MetFORMIN: Dolutegravir may increase the serum concentration of MetFORMIN. Management: Consider the risks and benefits of this combination. If combined, limit the daily metformin dose to 1,000 mg when used with dolutegravir. Monitor for increased metformin effects/toxicities (including lactic acidosis) during concomitant use. Consider therapy modification

Methadone: Reverse Transcriptase Inhibitors (Non-Nucleoside) may increase the metabolism of Methadone. Management: Methadone dosage adjustments will likely be required with efavirenz and nevirapine, and may be necessary with rilpivirine as well. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after multivitamins. Administer the dolutegravir/rilpivirine product at least 4 hours before or 6 hours multivitamins. Alternatively, dolutegravir and multivitamins can be taken together with food Consider therapy modification

Multivitamins/Minerals (with AE, No Iron): May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after multivitamins. Administer the dolutegravir/rilpivirine product at least 4 hours before or 6 hours multivitamins. Alternatively, dolutegravir and multivitamins can be taken together with food Consider therapy modification

Nevirapine: May decrease the serum concentration of Dolutegravir. Avoid combination

Orlistat: May decrease the serum concentration of Antiretroviral Agents. Monitor therapy

OXcarbazepine: May decrease the serum concentration of Rilpivirine. Avoid combination

OXcarbazepine: May decrease the serum concentration of Dolutegravir. Avoid combination

PHENobarbital: May decrease the serum concentration of Rilpivirine. Avoid combination

PHENobarbital: May decrease the serum concentration of Dolutegravir. Avoid combination

Phenytoin: May decrease the serum concentration of Rilpivirine. Avoid combination

Primidone: May decrease the serum concentration of Rilpivirine. Avoid combination

Primidone: May decrease the serum concentration of Dolutegravir. Specifically, the Primidone metabolite phenobarbital may decrease Dolutegravir serum concentrations. Avoid combination

Proton Pump Inhibitors: May decrease the serum concentration of Rilpivirine. Avoid combination

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

Reverse Transcriptase Inhibitors (Non-Nucleoside): May increase the serum concentration of Rilpivirine. This mechanism applies to coadministration of delavirdine. Reverse Transcriptase Inhibitors (Non-Nucleoside) may decrease the serum concentration of Rilpivirine. This mechanism applies to coadministration of efavirenz, etravirine, and nevirapine. Avoid combination

Rifabutin: May decrease the serum concentration of Rilpivirine. Management: Increase the rilpivirine adult dose to 50 mg/day during rifabutin treatment. Decrease back to 25 mg/day following rifabutin discontinuation. Use of rifabutin with the emtricitabine/rilpivirine/tenofovir alafenamide combination product is not recommended. Consider therapy modification

Rifamycin Derivatives: May decrease the serum concentration of Rilpivirine. Exceptions: Rifabutin. Avoid combination

Saquinavir: May enhance the arrhythmogenic effect of Rilpivirine. Saquinavir may increase the serum concentration of Rilpivirine. Avoid combination

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Selenium: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral selenium. Administer the dolutegravir/rilpivirine combination product at least 4 hours before or 6 hours after oral selenium. Consider therapy modification

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

St John's Wort: May decrease the serum concentration of Dolutegravir. Avoid combination

Sucralfate: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after sucralfate. Administer the dolutegravir/rilpivirine combination product at least 4 hours before or 6 hours after sucralfate. Consider therapy modification

Tipranavir: May decrease the serum concentration of Dolutegravir. Specifically, Tipranavir/Ritonavir may decrease the serum concentration of Dolutegravir. The individual contributions of Tipranavir and Ritonavir to this effect are unknown. Management: Increase dolutegravir dose to 50 mg twice daily in patients receiving tipranavir/ritonavir. Seek alternatives to tipranavir/ritonavir in INSTI experienced patients with suspected INSTI resistance or certain INSTI associated resistance substitutions. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Zinc Salts: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral zinc salts. Administer the dolutegravir/rilpivirine combination product at least 4 hours before or 6 hours after oral zinc salts. Consider therapy modification

Adverse Reactions

Also see individual agents.

1% to 10%:

Central nervous system: Headache (2%)

Endocrine & metabolic: Hyperglycemia (4%)

Gastrointestinal: Increased serum lipase (5%), diarrhea (2%)

Hepatic: Increased serum ALT (2%), increased serum bilirubin (2%)

Neuromuscular & skeletal: Decreased bone mineral density (2%), increased creatine phosphokinase (≤1%)

<1%, postmarketing, and/or case reports: Bone fracture, increased serum AST

Warnings/Precautions

Concerns related to adverse effects:

• Depressive disorders: Rilpivirine may cause depression, depressed mood, dysphoria, mood changes, negative thoughts, suicide attempts, or suicidal ideation. Promptly evaluate patients with severe depressive symptoms and/or if changes are noted and reevaluate risk versus benefit of continued combination therapy.
• Hepatotoxicity: Hepatic adverse events, including elevated transaminases, hepatitis, and acute liver failure (sometimes requiring liver transplant) have been reported with regimens containing dolutegravir or rilpivirine. Risk may be increased in patients with significant transaminase elevations or hepatitis B or C prior to treatment, however, hepatotoxicity has been reported in patients with no preexisting hepatic disease or other risk factors. In some patients receiving dolutegravir-containing regimens, elevations in transaminases may be concurrent with development of immune reconstitution syndrome or hepatitis B reactivation (especially if antihepatitis therapy has been discontinued). Baseline and periodic laboratory LFT evaluation during therapy is recommended for patients with preexisting risk factors; also consider LFT monitoring in patients without identifiable hepatic disease risk.
• Hypersensitivity reactions: Rash, constitutional findings, and organ dysfunction (eg, liver injury) have been reported with dolutegravir. Hypersensitivity and severe skin reactions have been reported with rilpivirine, including severe rash or rash accompanied by fever, blisters, mucosal involvement, conjunctivitis, facial edema, angioedema, hepatitis or eosinophilia, or drug reaction with eosinophilia and systemic symptoms (DRESS). Most rashes were grade 1 or 2 and occurred within the first 4 to 6 weeks of therapy; no grade 4 rashes were reported. Discontinue treatment immediately if severe skin or hypersensitivity reactions occur; life-threatening reactions may occur if there is a delay in discontinuing therapy after onset of hypersensitivity. Monitor clinical status and liver function tests, and initiate supportive therapy as appropriate. Do not restart therapy with any dolutegravir or rilpivirine-containing product if hypersensitivity occurs.
• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves’ disease, polymyositis, Guillain-Barré syndrome) later in therapy; further evaluation and treatment may be required.
• QTc prolongation: In healthy subjects, supratherapeutic doses of rilpivirine (ie, 75 mg daily, 300 mg daily) have been associated with QTc prolongation; use caution and/or consider alternative therapy when coadministering with a drug with a known risk of torsades de pointes.

Disease-related concerns:

• Hepatic impairment: Not recommended for use in patients with severe hepatic impairment (has not been studied). Patients with underlying hepatic disease (such as hepatitis B or C coinfection) may be at increased risk of development or worsening of transaminase elevations; use with caution. Monitor transaminases at baseline and during therapy.
• Renal impairment: Use with caution and increased monitoring for adverse reactions in patients with CrCl <30 mL/minute or end-stage renal disease (ESRD). In addition, in INSTI-experienced patients with severe renal impairment, decreases in dolutegravir concentrations were observed and may result in loss of therapeutic effect and development of resistance to dolutegravir or other coadministered antiretroviral agents.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Other warnings/precautions:

• Appropriate use: Indicated for virologically suppressed patients with no history of treatment failure and/or resistance to dolutegravir or rilpivirine; has not been studied as initial or salvage therapy for patients with detectable HIV-1 viral load.
• Changes in serum creatinine: Dolutegravir and rilpivirine may increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function or effective renal plasma flow (Gutierrez 2014). Increased serum creatinine occurred within the first 4 weeks of treatment with dolutegravir and rilpivirine and remained stable through 48 weeks of treatment.

Monitoring Parameters

HIV viral load, CD4 count, lipid profile, hepatic transaminases (baseline and during therapy), signs of skin rash, fever, and/or hypersensitivity reactions, signs and symptoms of infection.

Pregnancy

Pregnancy Considerations

The Health and Human Services (HHS) Perinatal HIV Guidelines do not recommend use of this fixed-dose 2-drug combination in pregnant females living with HIV who are antiretroviral-naive, who have had antiretroviral therapy (ART) in the past but are restarting, who require a new ART regimen (due to poor tolerance or poor virologic response of current regimen), and who are not yet pregnant but are trying to conceive. For females who become pregnant while taking this combination as a complete regimen, the regimen should be changed or additional agents added (2-drug regimens are not recommended during pregnancy) (HHS [perinatal] 2019).

Refer to individual monographs for additional information.

Patient Education

What is this drug used for?

• It is used to treat HIV infection.

Frequently reported side effects of this drug

• Headache
• Diarrhea

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Depression like thoughts of suicide, anxiety, emotional instability, or confusion
• Agitation
• Muscle pain
• Joint pain
• Shortness of breath
• Severe loss of strength and energy
• Trouble swallowing
• Infection
• Severe skin problems like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.