General

Pronunciation:
doe-loo-teg-ra-vir/ril-pi-vir-een

Trade Name(s)

• Juluca

Ther. Class.

antiretrovirals

Pharm. Class.

integrase strand transfer inhibitors

non nucleoside reverse transcriptase inhibitors

Indications

Treatment of HIV-1 infection in patients who are virologically suppressed (HIV-1 RNA < 50 copies/mL) on a stable antiretroviral regimen for ≥6 mo with no history of treatment failure and no known resistance to dolutegravir or rilpivirine.

Action

Dolutegravir: inhibits HIV-1 integrase, which is required for viral replication.  Rilpivirine: inhibits HIV-replication by noncompetitively inhibiting HIV reverse transcriptase.

Therapeutic Effect(s):

Increased CD4 cell counts and decreased viral load with subsequent slowed progression of HIV infection and its sequelae.

Pharmacokinetics

Dolutegravir

Absorption: Absorption follows oral administration; bioavailability is unknown.

Distribution: Enters CSF.

Protein Binding: >98.9%.

Metabolism and Excretion: Metabolized primarily by the UGT1A1 enzyme system with some metabolism by CYP3A4.  Poor UGT1A1 metabolizers have ↑ dolutegravir concentrations and an ↑ risk of adverse effects. 53% excreted unchanged in feces. Metabolites are renally excreted; minimal renal elimination of unchanged drug.

Half-life: 14 hr.

Rilpivirine

Absorption: Well absorbed following oral administration.

Distribution: Unknown.

Protein Binding: 99.7%.

Metabolism and Excretion: Mostly metabolized by the liver via CYP3A; 25% excreted in feces unchanged, <1% excreted unchanged in urine.

Half-life: 50 hr.

TIME/ACTION PROFILE (plasma concentrations)

Contraindication/Precautions

Contraindicated in:

• Hypersensitivity;
• Concurrent use of carbamazepine, dexamethasone, dofetilide, oxcarbazepine, phenobarbital, phenytoin, proton pump inhibitors, rifampin, rifapentine, and St. John's wort.

Use Cautiously in:

• Underlying hepatic disease, including hepatitis B or C (↑ risk for hepatotoxicity);
• Severe renal impairment;
• History of depression or suicide attempt;
• OB:  The Health and Human Services perinatal HIV guidelines do not recommend use of this fixed-dose 2-drug combination as a complete regimen in pregnant patients with HIV who are antiretroviral-naive, who have had antiretroviral therapy (ART) in the past but are restarting, or who require a new ART regimen (due to poor tolerance or poor virologic response of current regimen). Use may continue in pregnant patients who are virologically suppressed and are already using this 2-drug regimen;
• Lactation: Safety not established in breastfeeding; breastfeeding should be supported in people with HIV who are taking ART as prescribed and are maintaining an undetectable amount of virus in the body;
• Pedi:   Safety and effectiveness not established in children;
• Geri:  Consider age-related ↓ in cardiac, renal, and hepatic function; chronic disease states; and concurrent medications.

Adverse Reactions/Side Effects

CV: QT interval prolongation

Derm: DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS), pruritus, rash

Endo: hyperglycemia

GI: ↑ lipase, HEPATOTOXICITY

GU: ↑ serum creatinine

MS: ↓ bone mineral density

Neuro: depression, headache, dizziness, SUICIDAL THOUGHTS

Misc: hypersensitivity reactions (including rash, constitutional symptoms, and liver injury), fatigue, immune reconstitution syndrome

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

• May ↑ levels and risk of toxicity of  dofetilide ; concurrent use contraindicated.
•  CYP3A inducers, including  carbamazepine,  dexamethasone  (more than a single dose),  oxcarbazepine,  phenobarbital,  phenytoin,  rifampin, or  rifapentine, may ↓ levels and effectiveness and promote virologic resistance; concurrent use contraindicated.
• By causing an ↑ in gastric pH,  proton pump inhibitors  ↓ rilpivirine levels and effectiveness and may promote virologic resistance; concurrent use contraindicated.
• May ↑ blood levels and toxicity from  metformin ; do not exceed metformin dose of 1000 mg/day.
• Cation-containing products, including  calcium supplements  (oral),  iron supplements  (oral),  laxatives,  buffered medications, or  sucralfate, may ↓ dolutegravir levels and effectiveness; give 4 hr before or 6 hr after products containing polyvalent cations.
• Concurrent use with  antacids  may ↓ rilpivirine levels and effectiveness; administer ≥4 hr before or ≥6 hr after antacids.
• Concurrent use with  H₂  receptor antagonists  may ↓ rilpivirine levels and effectiveness; administer ≥4 hr before or ≥12 hr after H₂  receptor antagonist.
•  Rifabutin  may ↓ rilpivirine levels; give additional rilpivirine 25-mg tablet once daily with a meal during concurrent use.
•  Clarithromycin  or  erythromycin  may ↑ rilpivirine levels; consider azithromycin.
• Concurrent use with  QT interval prolonging drugs  may ↑ risk of torsades de pointes.
• May ↓  methadone  levels; monitor clinical effects.
• May ↑ levels of and risk of seizures from  dalfampridine ; consider potential benefit vs. risk of concurrent use.

Drug-Natural Products:

 St. John's wort  may ↓ levels and effectiveness and promote virologic resistance; concurrent use contraindicated.

Route/Dosage

PO (Adults): One tablet once daily.

Availability

Tablets: dolutegravir 50 mg/rilpivirine 25 mg

Assessment

• Assess for change in severity of HIV symptoms and for symptoms of opportunistic infections during therapy.
• Monitor for signs and symptoms of DRESS (fever, rash, lymphadenopathy, and/or facial swelling), associated with involvement of other organ systems (hepatitis, nephritis, hematologic abnormalities, myocarditis, myositis) during therapy. May resemble an acute viral infection. Eosinophilia is often present. Discontinue therapy if signs occur.
• Assess mental status (orientation, mood, behavior) before and periodically during therapy. Monitor closely for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.
• Monitor for signs and symptoms of hypersensitivity reactions (rash, fever, malaise, fatigue, muscle or joint aches, blisters or peeling of skin, oral blisters or lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Discontinue therapy and do not restart.
• Assess mental status (orientation, mood, behavior) before and periodically during therapy. Monitor closely for notable changes in behavior that could indicate the emergence or worsening of suicidal thoughts or behavior or depression.

Lab Test Considerations:

Monitor viral load and CD4 counts regularly during therapy.

• Monitor liver function tests before and periodically during therapy, especially in patients with underlying liver disease or marked ↑ transaminase. May cause ↑ AST, ALT, and total bilirubin.

Implementation

• PO Administer once daily with a meal.
  • Administer dolutegravir/rilpivirine ≥4 hr before or ≥6 hr after antacids and ≥4 hr before or ≥12 hr after H₂  receptor antagonists.

Patient/Family Teaching

• Emphasize the importance of taking dolutegravir/rilpivirine as directed. Do not take more than prescribed amount, and do not stop taking without consulting health care professional. Take missed doses as soon as remembered unless with a meal. Do not double doses. Advise patient to read  Patient Information  before starting therapy and with each Rx renewal in case of changes.
• Inform patient that dolutegravir/rilpivirine does not cure HIV or prevent associated or opportunistic infections. Dolutegravir/rilpivirine may reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Caution patient to use a condom during sexual contact and to avoid sharing needles or donating blood to prevent spreading HIV to others. Advise patient that the long-term effects of dolutegravir/rilpivirine are unknown at this time.
• Advise patient to notify health care professional if signs and symptoms of skin rash and allergic reactions and hepatotoxicity (skin or white of eyes turns yellow/jaundice; dark urine; light-colored stools; nausea or vomiting; loss of appetite; pain, aching, or tenderness on the right side of stomach).
• Inform patients and families of risk of suicidal thoughts and behavior and advise that behavioral changes, emergent or worsening signs and symptoms of depression, unusual changes in mood, or emergence of suicidal thoughts, behavior, or thoughts of self-harm should be reported to health care professional immediately.
• Immune reconstitution syndrome may trigger opportunistic infections or autoimmune disorders. Notify health care professional if symptoms (signs and symptoms of an infection) occur.
• Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications, especially St. John's wort.
• Rep:  Advise females of reproductive potential to notify health care professional if pregnancy is planned or suspected or if breastfeeding is planned. Enroll pregnant patients in the Antiretroviral Pregnancy Registry by calling 1-800-258-4263.

Evaluation/Desired Outcomes

Delayed progression of HIV and decreased opportunistic infections in patients with HIV.