TRIUMEQ (abacavir, dolutegravir, and lamivudine tablets)

TRIUMEQ (abacavir, dolutegravir, and lamivudine tablets)

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TRIUMEQ (abacavir, dolutegravir, and lamivudine tablets)

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, USP: The chemical name of abacavir sulfate, USP is (1 S,cis)-4-[2-amino-6-(cyclopropylamino)-9 H-purin-9- yl]-2-cyclopentene-1-methanol sulfate (salt) (2:1). Abacavir sulfate, USP is the enantiomer with 1S, 4R absolute configuration on the cyclopentene ring. It has a molecular formula of (C14H18N6O)2 •H2SO4 and molecular weight of 670.74 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-2Hpyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]oxazin-7-olate. The empirical formula is C20H18F2N3NaO5 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, USP: The chemical name of lamivudine, USP is (2R,cis)-4-amino-1-(2-hydroxymethyl-1,3-oxathiolan-5-yl)- (1H)-pyrimidin-2-one. Lamivudine, USP is the (-)enantiomer of a dideoxy analogue of cytidine. Lamivudine, USP has also been referred to as (-)2′,3′-dideoxy, 3′-thiacytidine. It has a molecular formula of (C8H11N3O3S and molecular weight of 229.3.

Indications and usage

TRIUMEQ is indicated for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults and in pediatric patients weighing at least 40 kg.

Limitations of Use:

  • 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 TIVICAY (dolutegravir).

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 HIV1 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 (3TCTP). The principal mode of action of 3TC-TP is inhibition of RT via DNA chain termination after incorporation of the nucleotide analogue.

Dosage and administration

  • Screen for the HLA-B*5701 allele prior to initiating therapy with TRIUMEQ
  • Pregnancy testing is recommended before initiation of TRIUMEQ in adolescents and adults of childbearing potential

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 and in pediatric patients weighing at least 40 kg is one tablet once daily orally with or without food.

Because TRIUMEQ is a fixed-dose tablet and cannot be dose adjusted, TRIUMEQ is not recommended in:

  • patients with creatinine clearance less than 30 mL per minute.
  • patients with mild hepatic impairment. TRIUMEQ is contraindicated in patients with moderate or severe hepatic impairment.

Contraindications

  • who have the HLA-B*5701 allele.
  • with prior hypersensitivity reaction to abacavir, dolutegravir, lamivudine.
  • receiving 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.
  • with moderate or severe hepatic impairment

Warnings and precautions

Hypersensitivity Reactions: Hypersensitivity reactions have been reported with the use of abacavir or dolutegravir, components of TRIUMEQ.

  • Abacavir

Serious and sometimes fatal hypersensitivity reactions have occurred with abacavircontaining regimens. See full prescribing information for ZIAGEN (abacavir).

Abacavir hypersensitivity reactions have included multi-organ failure and anaphylaxis and typically occurred within the first 6 weeks of treatment with abacavir (median time to onset was 9 days); although abacavir hypersensitivity reactions have occurred any time during treatment. Patients who carry the HLA-B*5701 allele are at a higher risk of abacavir hypersensitivity reactions; although, patients who do not carry the HLA-B*5701 allele have developed hypersensitivity reactions.

  • Dolutegravir

Hypersensitivity reactions have been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. The events were reported in less than 1% of subjects receiving TIVICAY in Phase 3 clinical trials. Discontinue TRIUMEQ and other suspect agents immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters or peeling of the skin, oral blisters or lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with TRIUMEQ or other suspect agents after the onset of hypersensitivity may result in a lifethreatening reaction.

Posttreatment Exacerbations of Hepatitis in Patients with Hepatitis B Coinfection

Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine. See full prescribing information for EPIVIR (lamivudine). Patients should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment.

Emergence of Lamivudine-Resistant HBV

Safety and efficacy of lamivudine have not been established for treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV. Emergence of hepatitis B virus variants associated with resistance to lamivudine has been reported in HIV-1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with hepatitis B virus. See full prescribing information for EPIVIR-HBV (lamivudine).

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Hepatotoxicity

Hepatic adverse events have been reported in patients receiving a dolutegravircontaining regimen. Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of TRIUMEQ. In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Cases of hepatic toxicity, including elevated serum liver biochemistries, hepatitis, and acute liver failure, have also been reported in patients receiving a dolutegravir-containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Drug-induced liver injury leading to liver transplant has been reported with TRIUMEQ. Monitoring for hepatotoxicity is recommended.

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, including abacavir and lamivudine (components of TRIUMEQ). A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. See full prescribing information for ZIAGEN (abacavir) and EPIVIR (lamivudine). Treatment with TRIUMEQ should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.

Embryo-Fetal Toxicity

An ongoing observational study showed an association between dolutegravir and an increased risk of neural tube defects when dolutegravir was administered at the time of conception and in early pregnancy. As there is limited understanding of the association of reported types of neural tube defects with dolutegravir use, inform adolescents and adults of childbearing potential, including those actively trying to become pregnant, about the potential increased risk of neural tube defects with TRIUMEQ.

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including TRIUMEQ. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.

Myocardial Infarction

Several prospective, observational, epidemiological studies have reported an association with the use of abacavir and the risk of myocardial infarction (MI). Meta-analyses of randomized, controlled clinical trials have observed no excess risk of MI in abacavirtreated subjects as compared with control subjects. To date, there is no established biological mechanism to explain a potential increase in risk. In totality, the available data from the observational studies and from controlled clinical trials show inconsistency; therefore, evidence for a causal relationship between abacavir and the risk of MI is inconclusive.

Adverse reactions

The most commonly reported adverse reactions of at least moderate intensity and incidence at least 2% (in those receiving TRIUMEQ) were insomnia, headache, and fatigue.

Drug interactions

Coadministration of TRIUMEQ with other drugs can alter the concentration of other drugs and other drugs may alter the concentrations of TRIUMEQ. The potential drug-drug interactions must be considered prior to and during therapy.

Use in specific populations

Pregnancy: Data from an ongoing birth outcome surveillance study has identified an increased risk of neural tube defects when dolutegravir, a component of TRIUMEQ, is administered at the time of conception. As defects related to closure of the neural tube occur from conception through the first 6 weeks of gestation, embryos exposed to dolutegravir from the time of conception through the first 6 weeks of gestation are at potential risk.

Lactation: The Centers for Disease Control and Prevention recommends that HIV-1-infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection.

Abacavir and lamivudine are present in human milk. When administered to lactating rats, dolutegravir was present in milk (see Data). There is no information on the effects of TRIUMEQ or its components on the breastfed infant or the effects of the drug on milk production.

Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving TRIUMEQ.

Females and Males of Reproductive Potential: In adolescents and adults of childbearing potential currently on TRIUMEQ who are actively trying to become pregnant or if pregnancy is confirmed in the first trimester, assess the risks and benefits of continuing TRIUMEQ and discuss with the patient if an alternative treatment should be considered.

Overdosage

There is no known specific treatment for overdose with TRIUMEQ. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required.

Dolutegravir: As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis.

Abacavir: It is not known whether abacavir can be removed by peritoneal dialysis or hemodialysis.

Lamivudine: Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event.

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