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.

Contraind./Precautions ⬆ ⬇

Contraindicated in:

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

Use Cautiously in:

Coinfection with hepatitis B virus (HBV) (hepatitis may recur after discontinuation of lamivudine and ↑ risk of lamivudine-resistant HBV);
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: ↑creatine kinase

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 from 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, andphenytoin 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 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.

Availability ⬆ ⬇

Tablets: dolutegravir 50 mg/lamivudine 300 mg

Route/Dosage ⬆ ⬇

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

US Brand Names ⬆ ⬇

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.

Classifications ⬆ ⬇

Therapeutic Classification: antiretrovirals

Pharmacologic Classification: integrase strand transfer inhibitors (INSTI), nucleoside reverse transcriptase inhibitors

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

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 professional. Discontinuing therapy may lead to severe exacerbations. 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.
Inform patient of importance of HBV testing before starting antiretroviral therapy.
Inform patient that Dovato does not cure HIV and may reduce 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 professional 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; and 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 professional of all Rx or OTC medications, vitamins, or herbal products being taken and consult health care professional before taking any new 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.
Emphasize the importance of regular follow-up exams and blood counts to determine progress and monitor for side effects.

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Indications ⬇