Classification
Therapeutic: antiretrovirals (combination)
Pharmacologic: integrase strand transfer
inhibitors (INSTI) (dolutegravir), nucleoside
reverse transcriptase inhibitors (abacavir,
lamivudine)
Indications
Treatment of HIV-1 infection.
Action
Abacavir—Converted inside cells to carbovir triphosphate,
its active metabolite. Carbovir triphosphate inhibits
the activity of HIV-1 reverse transcriptase, which
in turn terminates viral DNA growth. Dolutegravir—
Inhibits HIV-1 integrase, which is required for viral replication.
Lamuvudine—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
Abacavir
Absorption: Rapidly and extensively (83%) absorbed.
Distribution: Distributes into extravascular space
and readily distributes into erythrocytes.
Metabolism and Excretion: Mostly metabolized
by the liver; 1.2% excreted unchanged in urine.
Half-life: 1.5 hr.
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. 53% excreted unchanged in feces. Metabolites
are renally excreted, minimal renal
elimination of unchanged drug. Poor metabolizers of
dolutegravir haveqlevels andpclearance.
Half-life: 14 hr.
Lamivudine
Absorption: Well absorbed after oral administration
(86% in adults, 66% in infants and children).
Distribution: Distributes into the extravascular
space. Some penetration into CSF; remainder of distribution
unknown.
Metabolism and Excretion: Mostly excreted unchanged
in urine; 5% metabolized by the liver.
Half-life: Adults—3.7 hr; children—2 hr.
TIME/ACTION PROFILE (blood levels)
ROUTE ONSET PEAK DURATION
PO unknown unknown 24 hr
Contraindications/Precautions
Contraindicated in: Hypersensitivity to any component
(especially abacavir, rechallenge may be fatal);
Resistance to any component; Presence of HLA-B*5701
allele; Concurrent use of dofetilide; Concurrent administration
of lamivudine or abacavir alone or in other
combination antiretroviral dose forms; Lactation:
Breast feeding not recommended for HIV-infected patients;
Moderate to severe liver impairment; CCr 50
mL/min.
Use Cautiously in: Underlying hepatitis B or C
(may worsen liver function); Patients with HIV-1/HCV
coinfection receiving interferon alfa with/without ribavirin
(may be at risk for hepatic decompensation, dose
alteration or discontinuation of interferon and/or ribavirin
may be necessary); Mild hepatic impairment (if
dosepof abacavir is necessary, combination should be
given as individual components); Underlying cardiovascular
disease, including history of hypertension, hyperlipidema,
smoking history, or diabetes mellitus; OB:
Use only if potential benefit justifies potential risk to the
fetus; Pedi: Safety and effectiveness not established.
Adverse Reactions/Side Effects
Abacavir/dolutegravir/lamivudine.
CNS: fatigue, headache, insomnia. CV: MYOCARDIAL INFARCTION.
GI: HEPATOMEGALY (WITH STEATOSIS), HEPATOTOXICITY
(qWITH HEPATITIS B OR C), exacerbation of
Hepatitis B. F and E: LACTIC ACIDOSIS. Misc: HYPERSENSITIVITY REACTIONS, immune reconstitution syndrome,
redistribution/accumulation of body fat.
Interactions
Drug-Drug: Abacavir: Alcoholqblood levels. May
qmethadone metabolism in some patients; slightqin
methadone dosing may be needed. Dolutegravir:
Mayqblood levels and toxicity from dofetilide; concurrent
use contraindicated. Blood levels and effectiveness
arepby etravirine (should not be used concurrently
without atazanavir/ritonavir, darunavir/ritonavir
or lopinavir/ritonavir). Blood levels and effectiveness
arepby efavirenz, fosamprenavir/ritonavir, tipranavir/
ritonavir, carbamazepine, and rifampin;
qdosage of dolutegravir recommended. Blood levels
and effectiveness may bepby nevirapine; avoid concurrent
use. Mayqblood levels and toxicity from metformin;
do not exceed metformin dose of 1000 mg/
day. Blood levels and effectiveness may bepby other
metabolic inducers including oxcarbazepine, phenobarbital,
and phenytoin; avoid concurrent use.
Absorption and effectiveness may bepby cation-containing
antacids, buffered medications, oral calcium
supplements, oral iron supplements, laxatives,
or sucralfate; dolutegravir should be taken 2 hr
before or 6 hr after; may also take dolutegravir and calcium
or iron supplements with food. Lamivudine:
Trimethoprim/sulfamethoxazoleqlevels (dose alteration
may be necessary in renal impairment).qrisk
of pancreatitis with concurrent use of other drugs
causing pancreatitis.qrisk of neuropathy with concurrent
use of other drugs causing neuropathy.
Combination therapy with tenofovir and abacavir
may lead to virologic nonresponse; avoid use.
Drug-Natural Products: Blood levels and effectiveness
may bepSt. John’s wort; avoid concurrent
use.
Route/Dosage
PO (Adults): One tablet (abacavir 600 mg/dolutegravir
50 mg/lamivudine 300 mg) daily; Concurrent efavirenz,
fosamprenavir/ritonavir, tipranavir/ritonavir,
carbamazepine, or rifampin—additional 50–
mg dose of dolutegravir is required separated by 12 hr.
Availability
Tablets: abacavir 600 mg/dolutegravir 50 mg/lamivudine
300 mg per tablet.
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