Abacavir, Dolutegravir, and Lamivudine

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Triumeq: Abacavir 600 mg, dolutegravir 50 mg, and lamivudine 300 mg

Pharmacology

Mechanism of Action

Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration. 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. 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 reverse transcriptase via DNA chain termination after incorporation of the nucleotide analogue.

Use: Labeled Indications

HIV infection, treatment: Treatment of HIV-1 infection in adult and pediatric patients weighing ≥40 kg.

Limitations of use: Not recommended for use in patients with known or clinically suspected integrase strand transfer inhibitor resistance because the dose of dolutegravir is insufficient in these subpopulations.

Contraindications

Hypersensitivity to abacavir, dolutegravir, lamivudine, or any component of the formulation; patients with HLA-B*5701 allele; concomitant dofetilide; moderate or severe hepatic impairment

Dosage and Administration

Dosing: Adult

HIV-1 infection, treatment: Oral: One tablet (abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg) once daily

Dosage adjustment for concomitant therapy: With efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, carbamazepine, or rifampin: One tablet (abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg) once daily, with an additional dolutegravir 50 mg tablet daily administered 12 hours after Triumeq

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

HIV-1 infection, treatment:

Children and Adolescents weighing <40 kg: Not recommended; product is a fixed-dose combination

Children and Adolescents weighing ≥40 kg: Oral: One tablet (abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg) once daily

Dosing adjustment for concomitant therapy with efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, carbamazepine, or rifampin: Limited data available: Children and Adolescents weighing ≥40 kg: Oral: One tablet once daily, with an additional dolutegravir 50 mg tablet daily administered 12 hours after Triumeq

Administration

Oral: Administer with or without food. If patient is on concomitant therapy with efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, carbamazepine, or rifampin an additional daily single-component dolutegravir tablet should be administered 12 hours after Triumeq. Administer 2 hours before or 6 hours after cation-containing antacids or laxatives, sucralfate, oral supplements containing iron or calcium, or buffered medications. Alternatively, may be administered with supplements containing calcium or iron at the same time if administered together with food.

Storage

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Dispense in original container; protect from moisture.

Drug Interactions

Aluminum Hydroxide: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral aluminum hydroxide. Administer the dolutegravir/rilpivirine combination product at least 4 hours before or 6 hours after oral aluminum hydroxide. Consider therapy modification

Cabozantinib: MRP2 Inhibitors may increase the serum concentration of Cabozantinib. Monitor therapy

Calcium Salts: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral calcium. Administer dolutegravir/rilpivirine at least 4 hours before or 6 hours after oral calcium salts. Alternatively, dolutegravir and oral calcium can be taken together with food. Consider therapy modification

CarBAMazepine: May decrease the serum concentration of Dolutegravir. Management: Increase dolutegravir dose to 50 mg twice daily when used together with carbamazepine. Patients with known or suspected integrase strand inhibitor resistance should use an alternative to carbamazepine when possible. Consider therapy modification

Cladribine: Agents that Undergo Intracellular Phosphorylation may diminish the therapeutic effect of Cladribine. Avoid combination

Dofetilide: Dolutegravir may increase the serum concentration of Dofetilide. Avoid combination

Efavirenz: May decrease the serum concentration of Dolutegravir. Management: Increase dolutegravir dose to 50 mg twice daily in adults or children. Consider alternatives to efavirenz for INSTI experienced patients with clinically suspected INSTI resistance or certain INSTI associated resistance substitutions. Consider therapy modification

Emtricitabine: LamiVUDine may enhance the adverse/toxic effect of Emtricitabine. Avoid combination

Etravirine: May decrease the serum concentration of Dolutegravir. Management: Avoid etravirine with dolutegravir unless with atazanavir/ritonavir, darunavir/ritonavir or lopinavir/ritonavir; avoid use with Dovato brand combination. Canada recommends using dolutegravir 50 mg twice daily when with etravirine without a boosted PI. Consider therapy modification

Fosamprenavir: May decrease the serum concentration of Dolutegravir. Specifically, Fosamprenavir/Ritonavir may decrease the serum concentration of Dolutegravir. The individual contributions of Fosamprenavir and Ritonavir to this effect are unknown. Management: Increase dolutegravir to 50 mg twice daily in adults and pediatric patients (12 yrs or older and at least 40 kg). Seek alternatives to fosamprenavir/ritonavir in INSTI-experienced patients with suspected or certain INSTI resistance. Consider therapy modification

Fosphenytoin-Phenytoin: May decrease the serum concentration of Dolutegravir. Avoid combination

Iron Preparations: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral iron. Administer dolutegravir/rilpivirine at least 4 hours before or 6 hours after oral iron. Alternatively, dolutegravir and oral iron can be taken together with food. Exceptions: Ferric Carboxymaltose; Ferric Derisomaltose; Ferric Gluconate; Ferric Hydroxide Polymaltose Complex; Ferric Pyrophosphate Citrate; Ferumoxytol; Iron Dextran Complex; Iron Sucrose. Consider therapy modification

Magnesium Salts: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral magnesium salts. Administer the dolutegravir/rilpivirine combination product at least 4 hours before or 6 hours after oral magnesium salts. Consider therapy modification

MetFORMIN: Dolutegravir may increase the serum concentration of MetFORMIN. Management: Consider the risks and benefits of this combination. If combined, limit the daily metformin dose to 1,000 mg when used with dolutegravir. Monitor for increased metformin effects/toxicities (including lactic acidosis) during concomitant use. Consider therapy modification

Methadone: May diminish the therapeutic effect of Abacavir. Abacavir may decrease the serum concentration of Methadone. Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after multivitamins. Administer the dolutegravir/rilpivirine product at least 4 hours before or 6 hours multivitamins. Alternatively, dolutegravir and multivitamins can be taken together with food Consider therapy modification

Multivitamins/Minerals (with AE, No Iron): May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after multivitamins. Administer the dolutegravir/rilpivirine product at least 4 hours before or 6 hours multivitamins. Alternatively, dolutegravir and multivitamins can be taken together with food Consider therapy modification

Nevirapine: May decrease the serum concentration of Dolutegravir. Avoid combination

Orlistat: May decrease the serum concentration of Antiretroviral Agents. Monitor therapy

OXcarbazepine: May decrease the serum concentration of Dolutegravir. Avoid combination

PHENobarbital: May decrease the serum concentration of Dolutegravir. Avoid combination

Primidone: May decrease the serum concentration of Dolutegravir. Specifically, the Primidone metabolite phenobarbital may decrease Dolutegravir serum concentrations. Avoid combination

Protease Inhibitors: May decrease the serum concentration of Abacavir. Monitor therapy

RifAMPin: May decrease the serum concentration of Dolutegravir. Management: Increase dolutegravir dose to 50 mg twice daily in adults or children. Consider alternatives to rifampin for INSTI experienced patients with clinically suspected INSTI resistance or certain INSTI associated resistance substitutions. Consider therapy modification

Selenium: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral selenium. Administer the dolutegravir/rilpivirine combination product at least 4 hours before or 6 hours after oral selenium. Consider therapy modification

Sorbitol: May decrease the serum concentration of LamiVUDine. Management: When possible, avoid chronic coadministration of sorbitol-containing solutions with lamivudine, but if this combination cannot be avoided, monitor patients more closely for possible therapeutic failure associated with decreased lamivudine exposure. Consider therapy modification

St John's Wort: May decrease the serum concentration of Dolutegravir. Avoid combination

Sucralfate: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after sucralfate. Administer the dolutegravir/rilpivirine combination product at least 4 hours before or 6 hours after sucralfate. Consider therapy modification

Tipranavir: May decrease the serum concentration of Dolutegravir. Specifically, Tipranavir/Ritonavir may decrease the serum concentration of Dolutegravir. The individual contributions of Tipranavir and Ritonavir to this effect are unknown. Management: Increase dolutegravir dose to 50 mg twice daily in patients receiving tipranavir/ritonavir. Seek alternatives to tipranavir/ritonavir in INSTI experienced patients with suspected INSTI resistance or certain INSTI associated resistance substitutions. Consider therapy modification

Trimethoprim: May increase the serum concentration of LamiVUDine. Monitor therapy

Zinc Salts: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral zinc salts. Administer the dolutegravir/rilpivirine combination product at least 4 hours before or 6 hours after oral zinc salts. Consider therapy modification

Adverse Reactions

See individual agents as well as other combination products for additional information.

>10%:

Endocrine & metabolic: Hyperglycemia (≥126 mg/dL)

Gastrointestinal: Increased serum lipase (>1.5 x ULN)

Neuromuscular & skeletal: Increased creatine phosphokinase (≥6.0 x ULN)

1% to 10%:

Central nervous system: Drowsiness (<2%), lethargy (<2%), nightmares (<2%), sleep disorder (<2%), suicidal ideation (<2%), depression, fatigue, headache, insomnia

Dermatologic: Pruritus (<2%)

Endocrine & metabolic: Hypertriglyceridemia (<2%)

Gastrointestinal: Abdominal distention (<2%), abdominal distress (<2%), abdominal pain (<2%), anorexia (<2%), dyspepsia (<2%), flatulence (<2%), gastroesophageal reflux disease (<2%), upper abdominal pain (<2%), vomiting (<2%)

Hematologic & oncologic: Decreased neutrophils

Hepatic: Hepatitis (<2%), increased serum ALT (>2.5 x ULN), increased serum AST (>2.5 x ULN)

Neuromuscular & skeletal: Arthralgia (<2%), myositis (<2%)

Renal: Renal insufficiency (<2%)

Miscellaneous: Fever (<2%)

<1%, postmarketing, and/or case reports: Abnormal dreams, diarrhea, dizziness, hypersensitivity reaction, immune reconstitution syndrome, nausea, skin rash

Warnings/Precautions

Concerns related to adverse effects:

• Hepatotoxicity: Hepatic adverse events, including elevated transaminases, hepatitis, and acute liver failure (sometimes requiring liver transplant), have been reported with regimens containing dolutegravir. Risk may be increased in patients with significant transaminase elevations or hepatitis B or C prior to treatment; however, hepatotoxicity has been reported in patients with no preexisting hepatic disease or other risk factors. In some patients receiving dolutegravir-containing regimens, elevations in transaminases may be concurrent with development of immune reconstitution syndrome or hepatitis B reactivation (especially if antihepatitis therapy has been discontinued). Baseline and periodic laboratory LFT evaluation during therapy is recommended for patients with preexisting risk factors; also consider LFT monitoring in patients without identifiable hepatic disease risk.
• Hypersensitivity reactions: [US Boxed Warning]: Serious hypersensitivity reactions (sometimes fatal) have occurred in patients taking abacavir (in Triumeq). Patients who carry the HLA-B*5701 allele are at a higher risk for a hypersensitivity reaction to abacavir, although hypersensitivity reactions have occurred in patients who do not carry the HLA-B*5701 allele. 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 had a previously documented HLA-B*5701 allele assessment. Discontinue Triumeq if a hypersensitivity reaction is suspected. Triumeq is contraindicated in patients who have the HLA-B*5701 allele or in patients with a prior hypersensitivity reaction to abacavir. Reintroduction of Triumeq or any other abacavir-containing product can result in life-threatening or fatal hypersensitivity reactions, even in patients who have no history of hypersensitivity to abacavir therapy. Such reactions can occur within hours. Additionally, allele-positive patients (including abacavir treatment naive) should have an allergy to abacavir documented in their medical record. Reactions usually occur within 9 days of starting abacavir; ~90% occur within 6 weeks, although these reactions may occur at any time during therapy (HHS [adult] 2017). These reactions usually include signs or symptoms in 2 or more of the following groups: fever, skin rash, GI symptoms (eg, abdominal pain, nausea, vomiting, diarrhea), constitutional (eg, generalized malaise, fatigue or achiness), or respiratory symptoms (eg, pharyngitis, dyspnea, cough). Other signs and symptoms include lethargy, headache, myalgia, edema, abnormal chest x-ray findings, arthralgia and paresthesia. Anaphylaxis, liver failure, renal failure, hypotension, adult respiratory distress syndrome, respiratory failure, myolysis, and death have occurred in association with hypersensitivity reactions. Physical findings (lymphadenopathy, mucous membrane lesions, and rash [maculopapular, urticarial or variable]) may occur. Erythema multiforme has also been reported. Laboratory abnormalities (eg, elevated liver function tests, elevated creatine phosphokinase, elevated creatinine, and lymphopenia) may occur. Triumeq should be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible. Following a hypersensitivity reaction, Triumeq SHOULD NOT be restarted because more severe symptoms may occur within hours, including LIFE-THREATENING HYPOTENSION AND DEATH. If Triumeq is to be restarted following an interruption in therapy not associated with symptoms of a hypersensitivity reaction, carefully evaluate the patient for previously unsuspected symptoms of hypersensitivity. Do not restart if hypersensitivity is suspected or cannot be ruled out regardless of HLA-B*5701 status. If Triumeq is restarted, continually monitor for symptoms of a hypersensitivity reaction. Make the patient aware that reintroduction should only take place if medical care is readily accessible.

- Hypersensitivity reactions reported with dolutegravir include rash, constitutional findings, and organ dysfunction (eg, liver injury). Discontinue immediately if signs of hypersensitivity (eg, severe rash, rash with fever, malaise, fatigue, muscle/joint aches, blistering or peeling of skin, oral blisters/lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing) occur. Monitor clinical status, liver function tests and initiate supportive therapy as appropriate. If hypersensitivity occurs, do not reinitiate therapy. Do not restart Triumeq or any other abacavir or dolutegravir-containing product in patients who have stopped Triumeq therapy due to a hypersensitivity reaction.

• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection during initial HIV treatment or activation of autoimmune disorders (eg, Graves disease, polymyositis, Guillain-Barré syndrome) later in therapy; further evaluation and treatment may be required.
• Lactic acidosis/hepatomegaly: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with nucleoside analogues alone or in combination, including abacavir, lamivudine and other antiretrovirals. Female gender and obesity may increase the risk for development. Suspend treatment in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or hepatotoxicity (transaminase elevation may/may not accompany hepatomegaly and steatosis).
• Pancreatitis: Pancreatitis has been observed with lamivudine and abacavir. Discontinue use if pancreatitis is suspected and resume only after pancreatitis has been ruled out.

Disease-related concerns:

• Chronic hepatitis B: [US Boxed Warning]: Exacerbation of hepatitis B has been reported with discontinuation of lamivudine in coinfected HIV/HBV patients; monitor hepatic function with clinical and laboratory evaluations closely for at least several months after discontinuing Triumeq in coinfected patients. Antihepatitis B therapy initiation may be warranted, if appropriate.
• Coronary heart disease: Use has been associated with an increased risk of MI in some cohort studies (Elion 2018; HHS [adult] 2017). Consider using with caution in patients with risks for coronary heart disease and minimizing modifiable risk factors (eg, hypertension, hyperlipidemia, diabetes mellitus, smoking) prior to use.
• Emergence of lamivudine-resistant hepatitis B: HIV/HBV coinfected patients receiving lamivudine-containing antiretroviral regimens have developed lamivudine resistant HBV variants.
• Hepatic impairment: Triumeq, as a fixed-dose combination tablet, should not be used in patients with mild hepatic impairment; use is contraindicated in moderate to severe hepatic impairment.
• Renal impairment: Triumeq, as a fixed-dose combination tablet, should not be used in patients with CrCl <50 mL/minute.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
• Duplicate therapy: Concomitant use of other abacavir-, lamivudine-, or dolutegravir-containing products with the fixed-dose combination product should be avoided.

Other warnings/precautions:

• Appropriate use: Triumeq, as a fixed-dose combination tablet, should not be used in patients requiring dosage adjustment.
• Changes in serum creatinine: Dolutegravir may increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function or effective renal plasma flow (Gutierrez 2014). Increased serum creatinine occurred within the first 4 weeks of treatment with dolutegravir and remained stable through 144 weeks of treatment.

Monitoring Parameters

Baseline HLA-B*5701 allele screening, hypersensitivity reactions, liver aminotransferases, renal and hepatic function, hepatotoxicity, treatment-associated toxicities including hepatic decompensation, hepatitis exacerbation, or lamivudine resistance in coinfected patients

Pregnancy

Pregnancy Considerations

The Health and Human Services (HHS) perinatal HIV guidelines consider this fixed-dose combination a preferred regimen in pregnant females living with HIV who are antiretroviral naive, who have had antiretroviral therapy (ART) in the past but are restarting, and who require a new ART regimen (due to poor tolerance or poor virologic response of current regimen). In addition, females who become pregnant while taking this regimen may continue if viral suppression is effective and the regimen is well tolerated. This fixed-dose combination is recommended as an alternative regimen for women who are not yet pregnant but are trying to conceive (HHS [perinatal] 2019).

Refer to individual monographs for additional information.

Patient Education

What is this drug used for?

• It is used to treat HIV infection.

Frequently reported side effects of this drug

• Headache
• Trouble sleeping
• Loss of strength and energy

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Allergic reaction with organ failure like fever, rash, fatigue, flu-like signs, nausea, vomiting, diarrhea, abdominal pain, sore throat, cough, or difficulty breathing.
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Lactic acidosis like fast breathing, fast heartbeat, abnormal heartbeat, vomiting, fatigue, shortness of breath, severe loss of strength and energy, severe dizziness, feeling cold, or muscle pain or cramps.
• Kidney problems like unable to pass urine, blood in the urine, change in amount of urine passed, or weight gain.
• Pancreatitis like severe abdominal pain, severe back pain, severe nausea, or vomiting.
• Severe dizziness
• Passing out
• Chest pain
• Mouth sores
• Eye irritation
• Muscle pain
• Muscle weakness
• Joint pain
• Burning or numbness feeling
• Edema
• Shortness of breath
• Swollen glands
• Infection
• Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.