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Abacavir, Dolutegravir, and Lamivudine

Pronunciation

(a BAK a veer, doe loo TEG ra vir, & la MI vyoo deen)

Index Terms

  • Abacavir Sulfate, Dolutegravir, and Lamivudine
  • Abacavir/Dolutegravir/Lamivudine
  • Dolutegravir, Lamivudine, and Abacavir
  • Lamivudine, Abacavir, and Dolutegravir

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

Brand Names: U.S.

  • Triumeq

Pharmacologic Category

  • Antiretroviral, Integrase Inhibitor (Anti-HIV)
  • Antiretroviral, Reverse Transcriptase Inhibitor, Nucleoside (Anti-HIV)

Pharmacology

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 of human immunodeficiency virus type 1 (HIV-1) infection

Limitations of use: Not recommended for use in patients with current or past history of resistance to abacavir, dolutegravir, or lamivudine; not recommended in patients with resistance-associated integrase substitutions 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

Dosing: Adult

HIV treatment: Oral: One tablet daily

Dosage adjustment for concomitant therapy:

US labeling: With efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, carbamazepine, or rifampin: One tablet daily, with an additional dolutegravir 50 mg tablet daily administered 12 hours after Triumeq

Canadian labeling: With efavirenz, etravirine (in addition to atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir in INI-resistant patients), fosamprenavir/ritonavir, tipranavir/ritonavir, oxcarbazepine , carbamazepine, phenytoin, phenobarbital, St. John's wort or rifampin: One tablet daily, with an additional single-component dolutegravir 50 mg tablet administered daily 12 hours after Triumeq

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≥50 mL/minute: No dosage adjustment necessary.

CrCl <50 mL/minute: Use is not recommended (use dose-adjusted individual component drugs).

Dosing: Hepatic Impairment

Mild impairment (Child-Pugh class A): Use is not recommended (use dose-adjusted individual component drugs).

Moderate to severe impairment (Child-Pugh class B or C):

U.S. labeling: Use is contraindicated.

Canadian labeling: Use is not recommended.

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.

Hazardous agent (abacavir); use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

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. 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. 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

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: US recommends avoiding the use of etravirine with dolutegravir unless used with atazanavir/ritonavir, darunavir/ritonavir or lopinavir/ritonavir. Canada recommends increasing dolutegravir to 50 mg twice daily when used 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

Ganciclovir-Valganciclovir: May enhance the adverse/toxic effect of Reverse Transcriptase Inhibitors (Nucleoside). Hematologic toxicity with zidovudine is of particular concern. Ganciclovir-Valganciclovir may increase the serum concentration of Reverse Transcriptase Inhibitors (Nucleoside). Management: Monitor patients receiving any of these combination closely for toxicity of the reverse transcriptase inhibitor. Avoid zidovudine. Intravitreal implants would not be affected. Consider therapy modification

Iron Salts: May decrease the serum concentration of Dolutegravir. Management: Administer dolutegravir at least 2 hours before or 6 hours after oral iron. Alternatively, dolutegravir and oral iron can be taken together with food. Exceptions: Ferric Carboxymaltose; 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. Consider therapy modification

MetFORMIN: Dolutegravir may increase the serum concentration of MetFORMIN. Management: Limit the daily metformin dose to 1,000 mg when used together with dolutegravir. Metformin dose adjustments may also be needed upon discontinuation of dolutegravir. Monitor patient response to metformin closely. 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 the dose of a multivitamin that contains polyvalent cations (e.g., calcium, iron, magnesium, selenium, zinc). 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 the dose of a multivitamin that contains polyvalent cations (e.g., calcium, iron, magnesium, selenium, zinc). 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

Ribavirin (Oral Inhalation): May enhance the hepatotoxic effect of Reverse Transcriptase Inhibitors (Nucleoside). Monitor therapy

Ribavirin (Systemic): May enhance the hepatotoxic effect of Reverse Transcriptase Inhibitors (Nucleoside). 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. 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. 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 decrease the excretion 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. Consider therapy modification

Adverse Reactions

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

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

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%)

Hepatic: Hepatitis (<2%)

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

Renal: Renal insufficiency (<2%)

Miscellaneous: Fever (<2%)

<1% (Limited to important or life-threatening): Hypersensitivity reaction

ALERT: U.S. Boxed Warning

Hypersensitivity reactions:

Serious and sometimes fatal hypersensitivity reactions, with multiple organ involvement, have occurred with abacavir. 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.

Abacavir/dolutegravir/lamivudine is contraindicated in patients with a prior hypersensitivity reaction to abacavir and in HLA-B*5701-positive patients. All patients should be screened for the HLA-B*5701 allele prior to initiating therapy with abacavir/dolutegravir/lamivudine or reinitiation of therapy with abacavir/dolutegravir/lamivudine unless patients have a previously documentedan HLA-B*5701 allele assessment. Discontinue abacavir/dolutegravir/lamivudine immediately if a hypersensitivity reaction is suspected, regardless of status and even when other diagnoses are possible.

Following a hypersensitivity reaction to abacavir/dolutegravir/lamivudine, never restart abacavir/dolutegravir/lamivudine or any other abacavir-containing product because more severe symptoms, including death, can occur within hours. Similar severe reactions have also occurred rarely following reintroduction of abacavir-containing products in patients who have no history of abacavir hypersensitivity.

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 abacavir/dolutegravir/lamivudine if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur.

Exacerbations of hepatitis B:

Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue abacavir/dolutegravir/lamivudine and are coinfected with HIV-1 and HBV. If appropriate, initiation of antihepatitis B therapy may be warranted.

Warnings/Precautions

Also see individual agents.

Concerns related to adverse effects:

• Fat redistribution: May cause redistribution of fat (eg, buffalo hump, peripheral wasting with increased abdominal girth, cushingoid appearance).

• 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] 2015). These reactions usualy 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. Clinically, it is not possible to determine whether a hypersensitivity reaction is due to abacavir or dolutegravir. 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: [US Boxed Warning]: 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. Discontinue if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity occur. 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 of abacavir within the previous 6 months was associated with an increased risk of myocardial infarction (MI) in observational studies; however, in a sponsor conducted pooled analysis of clinical trials, no excess risk of MI was observed. Available data are inconclusive. 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.

• Interferon alfa: Use with caution in combination with interferon alfa with or without ribavirin in HIV/HBV coinfected patients; monitor closely for hepatic decompensation (eg, Child-Pugh score >6), anemia, or neutropenia; dose reduction or discontinuation of interferon and/or ribavirin may be required if toxicity is evident.

Special handling:

• Hazardous agent: Abacavir is a hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 2]).

Other warnings/precautions:

• Appropriate use: Triumeq, as a fixed-dose combination tablet, should not be used in patients requiring dosage adjustment.

• Laboratory abnormalities: HIV/HBV and HIV/HCV coinfected patients may be at increased risk for worsening or development of transaminase elevations. Some cases were consistent with immune reconstitution syndrome or HBV reactivation (especially when antihepatitis therapy was withdrawn). Laboratory tests should be performed at baseline and monitored during therapy in coinfected patients and those with underlying hepatic disease.

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 Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have not been conducted with this combination. See individual agents.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, insomnia, or loss of strength and energy. Have patient report immediately to prescriber signs of allergic reaction with organ failure (fever, rash, fatigue, flu-like signs, nausea, vomiting, diarrhea, abdominal pain, pharyngitis, cough, or difficulty breathing), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of lactic acidosis (fast breathing, tachycardia, abnormal heartbeat, vomiting, fatigue, shortness of breath, severe loss of strength and energy, severe dizziness, feeling cold, or muscle pain or cramps), signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain), severe dizziness, passing out, angina, mouth sores, eye pain/strain, muscle pain, joint pain, burning or numbness feeling, edema, change in body fat, shortness of breath, enlarged lymph nodes, or signs of infection (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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