TRIUMEQ- dolutegravir sodium, abacavir sulfate and lamivudine tablet, film coated
WARNING: HYPERSENSITIVITY REACTIONS, LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY, and EXACERBATIONS OF HEPATITIS B
Hypersensitivity Reactions
Serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with abacavir, a component of TRIUMEQ� (abacavir, dolutegravir, and lamivudine). Patients who carry the HLA‑B*5701 allele are at a higher risk of a hypersensitivity reaction to abacavir; although, hypersensitivity reactions have occurred in patients who do not carry the HLA ‑B*5701 allele [see Warnings and Precautions (5.1)].
TRIUMEQ is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA ‑B*5701-positive patients [see Contraindications (4), Warnings and Precautions (5.1)]. All patients should be screened for the HLA‑B*5701 allele prior to initiating therapy with TRIUMEQ or reinitiation of therapy with TRIUMEQ, unless patients have a previously documented HLA ‑B*5701 allele assessment. Discontinue TRIUMEQ immediately if a hypersensitivity reaction is suspected, regardless of HLA-B*5701 status and even when other diagnoses are possible [see Contraindications (4), Warnings and Precautions (5.1)].
Following a hypersensitivity reaction to TRIUMEQ, NEVER restart TRIUMEQ or any other abacavir ‑containing product because more severe symptoms, including death can occur within hours. Similar severe reactions have also occurred rarely following the reintroduction of abacavir-containing products in patients who have no history of abacavir hypersensitivity [see Warnings and Precautions (5.1)].
Lactic Acidosis and Severe Hepatomegaly with Steatosis
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination, including abacavir, lamivudine, and other antiretrovirals. Discontinue TRIUMEQ if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur [see Warnings and Precautions (5.2)].
Exacerbations of Hepatitis B
Severe acute exacerbations of hepatitis B have been reported in patients who are co ‑infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine, a component of TRIUMEQ. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue TRIUMEQ and are co-infected with HIV-1 and HBV. If appropriate, initiation of anti ‑hepatitis B therapy may be warranted [see Warnings and Precautions (5.3)].
1 INDICATIONS AND USAGE
TRIUMEQ is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection.
Limitations of Use
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TRIUMEQ alone is not recommended for use in patients with current or past history of resistance to any components of TRIUMEQ [see Microbiology (12.4)].
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TRIUMEQ alone is not recommended in patients with resistance-associated integrase substitutions or clinically suspected integrase strand transfer inhibitor resistance because the dose of dolutegravir in TRIUMEQ is insufficient in these subpopulations. See full prescribing information for dolutegravir.
2 DOSAGE AND ADMINISTRATION
2.1 Screening for HLA-B*5701 Allele prior to Starting TRIUMEQ
Screen for the HLA‑B*5701 allele prior to initiating therapy with TRIUMEQ [see Boxed Warning, Warnings and Precautions (5.1)].
2.2 Recommended Dosage
TRIUMEQ is a fixed-dose combination product containing 600 mg of abacavir, 50 mg of dolutegravir, and 300 mg of lamivudine. The recommended dosage regimen of TRIUMEQ in adults is one tablet once daily orally with or without food.
2.4 Not Recommended Due to Lack of Dosage Adjustment
Because TRIUMEQ is a fixed-dose tablet and cannot be dose adjusted, TRIUMEQ is not recommended in:
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patients with creatinine clearance less than 50 mL per minute [see Use in Specific Populations (8.6)].
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patients with mild hepatic impairment. TRIUMEQ is contraindicated in patients with moderate or severe hepatic impairment [see Contraindications (4), Use in Specific Populations (8.7)].
3 DOSAGE FORMS AND STRENGTHS
TRIUMEQ tablets are purple, biconvex, oval, and debossed with "572 Trı" on one side. Each film-coated tablet contains abacavir sulfate equivalent to 600 mg of abacavir, dolutegravir sodium equivalent to 50 mg of dolutegravir, and 300 mg of lamivudine [see Description (11)].
4 CONTRAINDICATION
TRIUMEQ is contraindicated in patients:
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who have the HLA-B*5701 allele [see Warnings and Precautions (5.1)].
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with prior hypersensitivity reaction to abacavir, dolutegravir [see Warnings and Precautions (5.1)] , or lamivudine.
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r eceiving dofetilide, due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events with concomitant use of dolutegravir [see Drug Interactions (7)].
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with moderate or severe hepatic impairment [see Use in Specific Populations (8.7)].
DESCRIPTION
TRIUMEQ
TRIUMEQ contains an INSTI (dolutegravir) and 2 nucleoside analogues (abacavir and lamivudine) with inhibitory activity against HIV.
Each film-coated tablet contains abacavir sulfate equivalent to 600 mg of abacavir, dolutegravir sodium equivalent to 50 mg of dolutegravir, and 300 mg of lamivudine. TRIUMEQ tablets are purple, biconvex, oval, debossed with "572 Trı" on one side and contain the inactive ingredients D-mannitol, magnesium stearate, microcrystalline cellulose, povidone, and sodium starch glycolate. The tablet film-coating (OPADRY� II Purple 85F90057) contains the inactive ingredients iron oxide black, iron oxide red, macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, and titanium oxide.
Abacavir Sulfate
The chemical name of abacavir sulfate is ( 1S,cis)- 4-[2-amino-6-(cyclopropylamino)-9H -purin-9-yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). It has a molecular formula of (C14 H18 N6 O)2� H2 SO4 and a molecular weight of 670.76 g per mol.
Abacavir sulfate is a white to off-white solid and is soluble in water.
Dolutegravir
The chemical name of dolutegravir sodium is sodium (4R ,12aS)-9-{[(2,4-difluorophenyl)methyl]carbamoyl}-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H -pyrido[1',2':4,5]pyrazino[2,1-b ][1,3]oxazin-7-olate. The empirical formula is C20 H18 F2 N3 NaO5 and the molecular weight is 441.36 g per mol.
Dolutegravir sodium is a white to light yellow powder and is slightly soluble in water.
Lamivudine
The chemical name of lamivudine is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)-(1H)-pyrimidin-2-one. Lamivudine is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. It has a molecular formula of C8 H11 N3 O3 S and a molecular weight of 229.3 g per mol
Lamivudine is a white to off-white crystalline solid and is soluble in water.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
TRIUMEQ is an HIV-1 antiviral agent.
Microbiology
Mechanism of Action
Dolutegravir: Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified recombinant HIV-1 integrase and pre-processed substrate DNA resulted in IC50 values of 2.7 nM and 12.6 nM.
Abacavir: Abacavir is a carbocyclic synthetic nucleoside analogue. Abacavir is converted by cellular enzymes to the active metabolite, carbovir triphosphate (CBV-TP), an analogue of deoxyguanosine-5′-triphosphate (dGTP). CBV-TP inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA.
Lamivudine: Lamivudine is a synthetic nucleoside analogue. Intracellularly lamivudine is phosphorylated to its active 5′-triphosphate metabolite, lamivudine triphosphate (3TC-TP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue
