abacavir/dolutegravir/lamivudine (Rx)

Brand and Other Names:Triumeq
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

abacavir/dolutegravir/lamivudine

tablet

  • 600mg/50mg/300mg

HIV Infection

Indicated for human immunodeficiency virus type 1 (HIV-1) infection in patients weighing ≥40 kg

1 tablet PO qDay

Dosage Modifications

Coadministration with efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin: Take an additional dolutegravir (as single-entity) 50-mg tablet, separated by 12 hr from abacavir/dolutegravir/lamivudine dose

Coadministration with dofetilide: Contraindicated

Renal impairment

  • CrCl ≥50 mL/min: No dosage adjustment required
  • CrCl <50 mL/min: Not recommended; fixed-dose tablet cannot be dose adjusted

Hepatic impairment

  • Mild: Not recommended; fixed-dose tablet cannot be dose adjusted
  • Moderate-to-severe: Contraindicated

Dosing Considerations

Not recommended alone for use in patients with current or past history of resistance to any components of abacavir/dolutegravir/lamivudine

Before initiating treatment with abacavir-containing products, screening for the presence of a genetic marker, the HLA-B*5701 allele, should be performed in any HIV-infected patient, irrespective of racial origin

Products containing abacavir should not be used in patients known to carry the HLA-B*5701 allele; these patients are at high risk for hypersensitivity reactions

Limitations of Use

  • Monotherapy is not recommended in patients with resistance-associated integrase substitutions or clinically suspected integrase strand transfer inhibitor resistance because the dose of dolutegravir in abacavir/dolutegravir/lamivudine is insufficient in these subpopulations

Dosage Forms & Strengths

abacavir/dolutegravir/lamivudine

tablet

  • 600mg/50mg/300mg

HIV Infection

Indicated for human immunodeficiency virus type 1 (HIV-1) infection in patients weighing ≥40 kg

<40 kg: Safety and efficacy not established

≥40 kg: 1 tablet PO qDay

Dosage Modifications

Coadministration with efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, or rifampin: Take an additional dolutegravir (as single-entity) 50-mg tablet, separated by 12 hr from abacavir/dolutegravir/lamivudine dose

Coadministration with dofetilide: Contraindicated

Renal impairment

  • CrCl ≥50 mL/min: No dosage adjustment required
  • CrCl <50 mL/min: Not recommended; fixed-dose tablet cannot be dose adjusted

Hepatic impairment

  • Mild: Not recommended; fixed-dose tablet cannot be dose adjusted
  • Moderate-to-severe: Contraindicated

Dosing Considerations

Not recommended alone for use in patients with current or past history of resistance to any components of abacavir/dolutegravir/lamivudine

Before initiating treatment with abacavir-containing products, screening for the presence of a genetic marker, the HLA-B*5701 allele, should be performed in any HIV-infected patient, irrespective of racial origin

Products containing abacavir should not be used in patients known to carry the HLA-B*5701 allele; these patients are at high risk for hypersensitivity reactions

Limitations of Use

  • Monotherapy is not recommended in patients with resistance-associated integrase substitutions or clinically suspected integrase strand transfer inhibitor resistance because the dose of dolutegravir in abacavir/dolutegravir/lamivudine is insufficient in these subpopulations
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Interactions

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            Adverse Effects

            1-10%

            Lipase (4-9%)

            Hyperglycemia (2-7%)

            Creatinine kinase (4-5%)

            Insomnia (3%)

            Decreased neutrophils (2-3%)

            Increased AST (<1 to 3%)

            Headache (2%)

            Fatigue (2%)

            Increased ALT (<1 to 2%)

            Depression (1%)

            <1%

            Abnormal dreams

            Dizziness

            Nausea

            Diarrhea

            Rash

            Postmarketing Reports

            Digestive: Stomatitis

            Gastrointestinal: Pancreatitis

            General: Weakness

            Blood and Lymphatic Systems: Aplastic anemia, anemia (eg, pure red cell aplasia and severe anemias progressing on therapy), lymphadenopathy, splenomegaly

            Hepatobiliary Disorders: Acute liver failure, liver transplant Hypersensitivity: Sensitization reactions (eg, anaphylaxis), urticaria

            Metabolism and nutrition disorders: Hyperlactemia, lactic acidosis and severe hepatomegaly with steatosis

            Musculoskeletal: CPK elevation, muscle weakness, myalgia, rhabdomyolysis

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            Warnings

            Black Box Warnings

            HLA‑B*5701 allele and hypersensitivity

            • Serious and sometimes fatal hypersensitivity reactions have been associated with abacavir-containing products
            • Hypersensitivity to abacavir is a multiorgan clinical syndrome
            • Patients who carry the HLA‑B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir
            • Discontinue as soon as a hypersensitivity reaction is suspected; regardless of HLA-B*5701 status, permanently discontinue Triumeq if hypersensitivity cannot be ruled out, even when other diagnoses are possible
            • Following a hypersensitivity reaction to abacavir, NEVER restart abacavir-containing products

            Hepatitis B exacerbation

            • Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with hepatitis B virus (HBV) and HIV-1 and have discontinued lamivudine, a component of Triumeq
            • Monitor hepatic function closely in these patients and, if appropriate, initiate antihepatitis B treatment

            Contraindications

            Presence of HLA-B*5701 allele

            Previous hypersensitivity reaction to abacavir, dolutegravir, or lamivudine

            Coadministration with dofetilide

            Moderate or severe hepatic impairment (see Dosage Modifications)

            Cautions

            Use in patients with underlying hepatitis B or C may be associated with increased risk for worsening or development of elevated hepatic transaminase; monitor LFTs

            Hepatic toxicity, including elevated serum liver biochemistries, hepatitis, and acute liver failure reported without pre-existing hepatic disease or other identifiable risk factors; drug-induced liver injury leading to liver transplant reported; monitoring for hepatotoxicity recommended

            Hepatic decompensation, some fatal, has occurred in HIV-1/hepatitis C virus (HCV) coinfected patients receiving combination antiretroviral therapy (ART) and interferon alfa with or without ribavirin; discontinue as medically appropriate and consider dose reduction or discontinuation of interferon alfa, ribavirin, or both

            Posttreatment exacerbation of hepatitis reported in patients coinfected with hepatitis B infection

            Immune reconstitution syndrome may occur; patients may develop an inflammatory response to indolent or residual opportunistic infections (eg, Mycobacterium avium infection, cytomegalovirus infection, Pneumocystis jirovecii pneumonia [PCP] infection, or tuberculosis)

            Administration is not recommended in patients receiving other products containing abacavir or lamivudine

            Abacavir use was correlated with an increased risk of myocardial infarction (MI) based on a prospective, observational, epidemiological trial, but not in a meta-analysis of 26 randomized trials; caution with risks for coronary heart disease and minimizing modifiable risk factors, including smoking, hypertension, and hyperlipidemia

            May 18, 2018: The FDA issued a safety alert regarding the potential risk of neural tube birth defects (see Pregnancy)

            Drug interactions overview

            • Coadministration with certain drugs may result in known or potentially significant drug interactions, some of which may lead to loss of therapeutic effect and possible resistance, or significant adverse reactions of other from increase systemic exposure
            • Inducers of UGT1A1 and CYP3A (eg, oxcarbazepine, phenytoin, phenobarbital, carbamazepine, St John’s wort, rifampin) decrease dolutegravir
            • Coadministration with medications containing polyvalent cations decrease dolutegravir systemic exposure; give dolutegravir 2 hr before or 6 hr after polyvalent cations (eg, antacids, laxatives, sucralfate, iron supplements, calcium supplements, buffered medications)
            • Dolutegravir may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 (dofetilide and metformin)
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            Pregnancy & Lactation

            Pregnancy

            Pregnancy exposure registry to register patients by calling the Antiretroviral Pregnancy Registry (APR) 1-800-258-4263

            Insufficient data related to abacavir/dolutegravir/lamivudine use during pregnancy to inform a drug associated risk of birth defects and miscarriage

            In animal reproduction studies, no evidence of adverse developmental outcomes was observed with dolutegravir; during organogenesis in rat and rabbit and a rat pre/postnatal developmental study, systemic exposures (AUC) to dolutegravir were less than (rabbits) and ~50 times (rats) the exposure in humans at recommended human dose (RHD)

            Oral administration of abacavir to pregnant rats during organogenesis resulted in fetal malformations and other embryonic and fetal toxicities at exposures 35 times the human exposure (AUC) at the RHD; no adverse developmental effects were observed following oral administration of abacavir to pregnant rabbits during organogenesis at exposures ~9 times the human exposure (AUC) at the RHD

            Oral administration of lamivudine to pregnant rabbits during organogenesis resulted in embryo lethality at a human exposure (AUC) similar to the RHD; no adverse development effects were observed with oral administration of lamivudine to pregnant rats during organogenesis at plasma concentrations (Cmax) 35 times RHD

            Potential risk of neural tube birth defects

            • Serious cases of neural tube birth defects involving the brain, spine, and spinal cord reported in babies born to women treated with dolutegravir
            • Preliminary results from an ongoing observational study in Botswana found women who had received dolutegravir at the time of becoming pregnant or early in the first trimester appear to be at higher risk for these defects; to date, in this observational study there are no reported cases of babies born with neural tube defects to women starting dolutegravir later in pregnancy
            • Recommendations
              • Patients should not discontinue dolutegravir without consulting a healthcare professional because stopping your medicine can cause the HIV infection to worsen
              • Pregnant women stopping dolutegravir-containing regimen without switching to alternative HIV medicines could cause the amount of virus to increase and spread HIV to your baby
              • Patients taking a dolutegravir-containing regimen at the time of becoming pregnant and during the first trimester of pregnancy, there is a potential risk of neural tube defects; neural tube defects happen early in pregnancy, before many women even know they are pregnant
              • Inform women of childbearing age about the potential risk of neural tube defects when a dolutegravir-containing regimen is used at the time of conception and early in pregnancy; women of childbearing age should consult their healthcare providers about other non-dolutegravir-containing antiretroviral medicine
              • Healthcare providers should weigh the benefits and the risks of dolutegravir when prescribing antiretroviral medicines to women of childbearing age; consider alternative antiretroviral medicines; discuss the relative risks and benefits of appropriate alternative antiretroviral therapies
              • Women of childbearing age who decide to take a dolutegravir-containing regimen should consistently use effective birth control (contraception) while on HIV treatment; women should discuss their healthcare professionals about an effective birth control method to use while taking a dolutegravir-containing regimen
              • Perform pregnancy testing before initiating a dolutegravir-containing regimen in women of childbearing age to exclude pregnancy

            Lactation

            The Centers for Disease Control and Prevention does not recommend HIV-1-infected mothers in the United States breastfeed their infants to avoid the risk of postnatal transmission of HIV-1 infection

            Abacavir and lamivudine are present in human milk

            When administered to lactating rats, dolutegravir was present in milk

            There is no information on the effects of abacavir/dolutegravir/lamivudine or its components on the breastfed infant or the effects of the drug on milk production; because of the potential for HIV-1 transmission in HIV-negative infants, developing viral resistance (in HIV-positive infants), and serious adverse reactions in a breastfed infant, instruct mothers not to breastfeed

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Abacavir: Nucleoside reverse transcriptase inhibitor (NRTI); guanosine analog that inhibits HIV-1 reverse transcriptase by competing with dGTP as substrate, which, in turn, inhibits viral replication

            Dolutegravir: Integrase strand transfer inhibitor (INSTI); inhibits catalytic activity of HIV-1 integrase, an HIV encoded enzyme required for viral replication

            Lamivudine: NRTI; following phosphorylation, inhibits HIV reverse transcriptase by viral DNA chain termination; cytosine analog

            Absorption

            Peak plasma concentration

            • Abacavir: 4.26 mcg/mL
            • Dolutegravir: 3.67 mcg/mL
            • Lamivudine: 2.04 mcg/mL

            Peak plasma time

            • Dolutegravir: 2-3 hr

            AUC

            • Abacavir: 11.95 mcg•hr/mL
            • Dolutegravir: 53.6 mcg•hr/mL
            • Lamivudine: 8.87 mcg•hr/mL

            Distribution

            Protein bound

            • Abacavir: 50%
            • Dolutegravir: ≥98.9%
            • Lamivudine: Low

            Vd

            • Dolutegravir: 17.4 L

            Metabolism

            Abacavir: Primarily metabolized by alcohol dehydrogenase to form the 5′-carboxylic acid and glucuronyl transferase to form the 5′-glucuronide

            Dolutegravir: Primarily metabolized via UGT1A1 with some contribution from CYP3A

            Lamivudine: Negligible

            Elimination

            Half-life

            • Abacavir: 1.54 hr
            • Dolutegravir: 14 hr
            • Lamivudine: 5-7 hr

            Total body clearance

            • Abacavir: 0.8 L/hr/kg
            • Dolutegravir: 1 L/hr
            • Lamivudine: 398.5 mL/min

            Excretion

            • Dolutegravir: 53% feces (unchanged); 31% urine
            • Lamivudine: 70% urine (unchanged)

            Pharmacogenomics

            Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir

            Prior to initiating therapy with abacavir, screen for the HLA-B*5701 allele

            For HLA-B*5701-positive patients, treatment with an abacavir-containing regimen is contraindicated

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            Administration

            Oral administration

            Take with or without food

            Missed dose

            • Take tablet as soon as possible
            • Do not to double dose or take more than prescribed dose

            Storage

            Store at room temperature, 25°C (77°F); excursions permitted 15-30°C (59-86°F)

            Store and dispense in original package, protect from moisture, and keep the bottle tightly closed

            Do not remove desiccant

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.