dolutegravir/lamivudine

REMS

HIV-1 infection in patients with no antiretroviral treatment history and with no known substitutions associated with resistance to dolutegravir or lamivudine.
HIV-1 infection as a replacement for the current antiretroviral regimen in patients who are virologically suppressed (HIV-1 RNA <50 copies/mL), taking a stable antiretroviral regimen, have no history of treatment failure, and have no known substitutions associated with resistance to dolutegravir or lamivudine.

Action ⬆ ⬇

Dolutegravir: Inhibits HIV-1 integrase, which is required for viral replication. Lamivudine: After intracellular conversion to its active form (lamivudine-5-triphosphate), inhibits viral DNA synthesis by inhibiting the enzyme reverse transcriptase.

Therapeutic effects:

Evidence of decreased viral replication and reduced viral load with slowed progression of HIV and its sequelae.

Pharmacokinetics ⬆ ⬇

Dolutegravir

Absorption: Bioavailability unknown.

Distribution: Unknown.

Protein Binding: >98.9%.

Metabolism/Excretion: Metabolized primarily by the UGT1A1 enzyme system with some metabolism by the CYP3A4 isoenzyme. Poor UGT1A1 metabolizers have ↑ dolutegravir concentrations and an ↑ risk of adverse effects. 64% excreted in feces (53% as unchanged drug); 31% excreted in urine (<1% as unchanged drug).

Half-Life: 14 hr.

Lamivudine

Absorption: Well absorbed after oral administration.

Distribution: Unknown.

Metabolism/Excretion: Mostly excreted unchanged in urine (70% as unchanged drug).

Half-Life: 13–19 hr.

Time/Action Profile ⬆ ⬇

(plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
Dolutegravir (PO)	unknown	2.5 hr	24 hr
Lamivudine (PO)	unknown	1 hr	24 hr

Contraind./Precautions ⬆ ⬇

Contraindicated in:

Prior hypersensitivity reaction to dolutegravir;
Concurrent use of dofetilide;
Severe renal impairment;
Severe hepatic impairment.

Use Cautiously in:

Coinfected with hepatitis B virus (HBV) (severe acute exacerbations of HBV may recur after discontinuation of lamivudine)
;
Underlying hepatic disease, including HBV or hepatitis C (↑ risk of hepatotoxicity);
Women and obesity (↑ risk of lactic acidosis and severe hepatomegaly with steatosis);
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 antiretroviral therapy as prescribed and are maintaining an undetectable amount of virus in the body;
Pedi: Children <12 yr (safety and effectiveness not established);
Geri: Consider age-related ↓ in cardiac, renal and hepatic function, chronic disease states, and concurrent medications in older adults.

Adv. Reactions/Side Effects ⬆ ⬇

Endo: hyperglycemia

F and E: hypophosphatemia, LACTIC ACIDOSIS

GI: ↑lipase, ↑liver enzymes, diarrhea, HEPATOMEGALY WITH STEATOSIS, HEPATOTOXICITY ( WITH HBV OR HEPATITIS C), ↑ with HBV or hepatitis C), nausea

Metab: hyperlipidemia

MS: ↑CK

Neuro: dizziness, fatigue, headache, insomnia

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

Interactions ⬆ ⬇

Drug-drug:

May ↑ levels and risk of toxicity of dofetilide; concurrent use contraindicated.
May ↑ levels and risk of toxicity of metformin.
Carbamazepine and rifampin may ↓ levels and effectiveness of dolutegravir; additional 50-mg dose of dolutegravir should be given 12 hr after dose of dolutegravir/lamivudine.
Oxcarbazepine, phenobarbital, and phenytoin may ↓ levels and effectiveness of dolutegravir; avoid concurrent use.
Absorption and effectiveness may be ↓ by cation-containing antacids or laxatives, as well as buffered medications or sucralfate; dolutegravir should be taken 2 hr before or 6 hr after these medications.
Absorption and effectiveness may be ↓ by calcium supplements (oral) or iron supplements (oral); under fasting conditions, dolutegravir should be taken 2 hr before or 6 hr after these medications; when taken with food, dolutegravir and calcium or iron supplements may be taken at the same time.
May ↑ dalfampridine levels and risk of seizures.
Sorbitol may ↓ levels and effectiveness of lamivudine; avoid concurrent use.
May ↑ dalfampridine levels and risk of seizures.

Drug-Natural Products:

St. John's wort may ↓ levels and effectiveness of dolutegravir; avoid concurrent use.

Route/Dosage ⬆ ⬇

PO (Adults and Children ≥12 yr and ≥25 kg): One tablet (dolutegravir 50 mg/lamivudine 300 mg) once daily.

Availability ⬆ ⬇

Tablets: dolutegravir 50 mg/lamivudine 300 mg

Assessment ⬆ ⬇

Assess for change in severity of HIV symptoms and for symptoms of opportunistic infections during therapy.
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.

Lab Test Considerations:

Monitor viral load and CD4 counts regularly during therapy.
- Assess for HBV. Dovato is not approved for administration in patients with HIV and HBV. If therapy is discontinued, may cause severe exacerbation of HBV. Monitor liver function in coinfected patients for several months after stopping therapy.
- Monitor liver function periodically. May cause ↑ levels of AST, ALT, and alkaline phosphatase, which usually resolve after interruption of therapy. Patients with concurrent hepatitis B or C should be followed for at least several months after stopping therapy. Lactic acidosis may occur with hepatic toxicity, causing hepatic steatosis; may be fatal, especially in women.
- May cause ↑ LDL cholesterol, total cholesterol, and triglyceride concentrations.

Implementation ⬆ ⬇

PO: Administer once daily without regard to food.
- Iron and calcium supplements may be taken with dolutegravir/lamivudine and food. If taken separately, administer dolutegravir/lamivudine ≥2 hr before or ≥6 hr after iron and calcium supplements.

Patient/Family Teaching ⬆ ⬇

Instruct patient on the importance of taking medication as directed, even if feeling better. Take missed dose as soon as remembered; do not double doses. Do not take more than prescribed amount and do not stop taking without consulting health care provider. Advise patient to read Patient Information prior to starting therapy and with each Rx refill in case of changes. Caution patient not to share or trade Dovato with others.
Advise patient that discontinuing therapy may lead to severe exacerbations of HBV.
Inform patient of importance of HBV testing before starting antiretroviral therapy.
Inform patient that Dovato does not cure HIV and may ↓ the risk of transmission of HIV to others through sexual contact or blood contamination. Caution patient to use a condom and avoid sharing needles or donating blood to prevent spreading HIV to others.
Advise patient to notify health care provider immediately if symptoms of hypersensitivity reactions, lactic acidosis (nausea; vomiting; unusual or unexpected stomach discomfort; unusual muscle pain; difficulty breathing; feeling cold, especially in arms and legs; dizziness; fast or irregular heartbeat; weakness or tiredness), liver problems (yellow skin or whites of eyes, dark urine, light-colored stools, loss of appetite, nausea, stomach pain), or signs of immune reconstitution syndrome (signs and symptoms of an infection or inflammation) occur.
Instruct patient to notify health care provider of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care provider before taking any new medications, especially St. John's wort.
Rep: Advise women of reproductive potential to notify health care provider 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.
Emphasize the importance of regular follow-up exams and blood counts to determine progress and monitor for side effects.

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Pronunciation ⬇

Classifications ⬆ ⬇

Indications ⬆ ⬇