dolutegravir/rilpivirine

Dolutegravir

Absorption: Absorption follows oral administration; bioavailability is unknown.

Distribution: Enters CSF.

Protein Binding: >98.9%.

Metabolism/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/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 ⬆ ⬇

(blood levels)

ROUTE	ONSET	PEAK	DURATION
Dolutegravir (PO)	unknown	2–3 hr	12–24 hr‡
Rilpivirine (PO)	unknown	4–5 hr	24 hr

‡Depends on concurrent use of metabolic inducers.

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Hypersensitivity;
Concurrent use of carbamazepine, dexamethasone, dofetilide, oxcarbazepine, phenobarbital, phenytoin, proton pump inhibitors, rifampin, rifapentine, and St. John's wort;
OB: Avoid use through first trimester of pregnancy (may risk of neural tube defects);
Lactation: Breast feeding not recommended in patients with HIV.

Use Cautiously in:

Underlying hepatic disease, including hepatitis B or C (↑ risk for hepatotoxicity);
Severe renal impairment;
History of depression or suicide attempt;
OB: Can consider use during second or third trimester if potential maternal benefit justifies potential fetal risk;
Rep: Women of reproductive potential;
Pedi: Safety and effectiveness in children not established;
Geri: Consider age-related in cardiac, renal and hepatic function, chronic disease states and concurrent medications.

Adv. Reactions/Side Effects ⬆ ⬇

CV: QTc 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

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 torsade 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.Verify negative pregnancy test prior to starting 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 one daily with a meal.
- Administer dolutegravir/rilpivirine ≥4 hr before or ≥6 hr after antacids and ≥4 hr before or ≥12 hrs 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 the HIV virus 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 patients to use effective contraception, especially during conception and the 1st trimester and to notify health care professional if pregnancy is planned or suspected. Advise patient to avoid breast feeding during therapy. Enroll women who become pregnant during therapy in Antiviral Pregnancy Registry by calling 1-800-258-4263.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇

Action ⬆ ⬇

Pharmacokinetics ⬆ ⬇