abacavir/dolutegravir/lamivudine

General

Genetic Implications:

Pronunciation:
ah-back-ah-veer/doe-loo-teg-ra-vir/la-mi-vyoo-deen

Trade Name(s)

Triumeq
Triumeq PD

Ther. Class.

antiretrovirals

(combination)

Pharm. Class.

integrase strand transfer inhibitors

(dolutegravir)

nucleoside reverse transcriptase inhibitors

(abacavir, lamivudine)

Indications

HIV-1 infection.

Action

Abacavir: Converted inside cells to carbovir triphosphate, its active metabolite. Carbovir triphosphate inhibits the activity of HIV-1 reverse transcriptase, which in turn terminates viral DNA growth.
Dolutegravir: Inhibits HIV-1 integrase, which is required for viral replication.
Lamivudine: After intracellular conversion to its active form (lamivudine-5-triphosphate), inhibits viral DNA synthesis by inhibiting the enzyme reverse transcriptase.

Therapeutic Effect(s):

Evidence of decreased viral replication and reduced viral load with slowed progression of HIV and its sequelae.

Pharmacokinetics

Abacavir

Absorption: Rapidly and extensively (83%) absorbed.

Distribution: Distributes into extravascular space and readily distributes into erythrocytes.

Metabolism and Excretion: Mostly metabolized by the liver; 1.2% excreted unchanged in urine.

Half-life: 1.5 hr.

Dolutegravir

Absorption: Absorption follows oral administration; bioavailability is unknown.

Distribution: Enters CSF.

Protein Binding: >98.9%.

Metabolism and Excretion: Metabolized primarily by the UGT1A1 enzyme system with some metabolism by the CYP3A4 isoenzyme. 53% excreted unchanged in feces. Metabolites are renally excreted; minimal renal elimination of unchanged drug. Poor metabolizers of dolutegravir have ↑ levels and ↓ clearance.

Half-life: 14 hr.

Lamivudine

Absorption: Well absorbed after oral administration (86% in adults, 66% in infants and children).

Distribution: Distributes into the extravascular space. Some penetration into CSF; remainder of distribution unknown.

Metabolism and Excretion: Mostly excreted unchanged in urine; <5% metabolized by the liver.

Half-life: 13–19 hr.

TIME/ACTION PROFILE (plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
PO	unknown	unknown	24 hr

Contraindication/Precautions

Contraindicated in:

Hypersensitivity to any component (especially abacavir; rechallenge may be fatal);
Resistance to any component;
Presence of HLA-B*5701 allele;
Concurrent use of dofetilide;
Concurrent administration of lamivudine or abacavir alone or in other combination antiretroviral dose forms;
Severe renal impairment;
Hepatic impairment;
OB: Avoid use through first trimester of pregnancy (may ↑ risk of neural tube defects);
Lactation: Breastfeeding not recommended for patients with HIV.

Use Cautiously in:

Underlying hepatitis B or C (may worsen liver function);
Women and obesity (↑ risk of lactic acidosis and severe hepatomegaly with steatosis);
Underlying cardiovascular disease, including history of hypertension, hyperlipidemia, smoking history, or diabetes mellitus;
OB: Can consider use during 2nd or 3rd trimester if potential maternal benefit justifies potential fetal risk;
Pedi: Children <3 mo and <6 kg (safety and effectiveness not established).

Adverse Reactions/Side Effects

CV: MI

F and E: LACTIC ACIDOSIS

GI: exacerbation of hepatitis B, HEPATOMEGALY (with steatosis), HEPATOTOXICITY (↑ with hepatitis B or C)

Neuro: fatigue, headache, insomnia

Misc: HYPERSENSITIVITY REACTIONS, immune reconstitution syndrome

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

Alcohol may ↑ abacavir levels and the risk of toxicity.
Abacavir may ↓ levels and effectiveness of methadone ; slight ↑ in methadone dosing may be needed.
Abacavir may ↑ levels and risk of toxicity of riociguat ; may need to ↓ riociguat dose.
Combination therapy with tenofovir and abacavir may lead to virologic nonresponse; avoid concurrent use.
Dolutegravir may ↑ levels and risk of toxicity of dofetilide ; concurrent use contraindicated.
Etravirine may ↓ levels and effectiveness of dolutegravir; should not be used concurrently without atazanavir/ritonavir, darunavir/ritonavir, or lopinavir/ritonavir.
Efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, carbamazepine, and rifampin may ↓ levels and effectiveness of dolutegravir; ↑ dosage of dolutegravir recommended.
Nevirapine may ↓ levels and effectiveness of dolutegravir; avoid concurrent use.
Dolutegravir may ↑ levels and risk of toxicity of metformin.
Oxcarbazepine, phenobarbital, and phenytoin may ↓ levels and effectiveness of dolutegravir; avoid concurrent use.
Cation-containing antacids or laxatives, as well as buffered medications and sucralfate, may ↓ absorption and effectiveness of dolutegravir; give dolutegravir 2 hr before or 6 hr after these medications.
Calcium supplements (oral) or iron supplements (oral) may ↓ absorption and effectiveness of dolutegravir; under fasting conditions, abacavir/dolutegravir/lamivudine should be taken 2 hr before or 6 hr after these medications; when taken with food, abacavir/dolutegravir/lamivudine and calcium or iron supplements may be taken at the same time.
Dolutegravir may ↑ dalfampridine levels and risk of seizures.
Trimethoprim/sulfamethoxazole ↑ levels and risk of toxicity of lamivudine; may need to alter dose of lamividine in renal impairment.
↑ risk of pancreatitis with concurrent use of other drugs causing pancreatitis.
↑ risk of neuropathy with concurrent use of other drugs causing neuropathy.
Sorbitol may ↓ levels and effectiveness of lamivudine; avoid concurrent use.

Drug-Natural Products:

St. John's wort may ↓ levels and effectiveness of dolutegravir; avoid concurrent use.

Route/Dosage

Tablets and tablets for oral suspension are NOT interchangeable on a milligram-per-milligram basis.

PO (Adults and Children ≥3 mo and ≥25 kg): Triumeq: One tablet (abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg) once daily; Concurrent efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, carbamazepine, or rifampin: additional 50-mg dose of dolutegravir (Tivicay) is required separated from Triumeq by 12 hr.

PO (Children ≥3 mo and 20–<25 kg): Triumeq PD: Six tablets once daily (total dose = abacavir 360 mg/dolutegravir 30 mg/lamivudine 180 mg). Concurrent efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, carbamazepine, or rifampin: additional 30-mg dose of dolutegravir (Tivicay PD) is required separated from Triumeq PD by 12 hr.

PO (Children ≥3 mo and 14–<20 kg): Triumeq PD: Five tablets once daily (total dose = abacavir 300 mg/dolutegravir 25 mg/lamivudine 150 mg). Concurrent efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, carbamazepine, or rifampin: additional 25-mg dose of dolutegravir (Tivicay PD) is required separated from Triumeq PD by 12 hr.

PO (Children ≥3 mo and 10–<14 kg): Triumeq PD: Four tablets once daily (total dose = abacavir 240 mg/dolutegravir 20 mg/lamivudine 120 mg). Concurrent efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, carbamazepine, or rifampin: additional 20-mg dose of dolutegravir (Tivicay PD) is required separated from Triumeq PD by 12 hr.

PO (Children ≥3 mo and 6–<10 kg): Triumeq PD: Three tablets once daily (total dose = abacavir 180 mg/dolutegravir 15 mg/lamivudine 90 mg). Concurrent efavirenz, fosamprenavir/ritonavir, tipranavir/ritonavir, carbamazepine, or rifampin: additional 15-mg dose of dolutegravir (Tivicay PD) is required separated from Triumeq PD by 12 hr.

Availability (generic available)

Tablets: abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg

Tablets for oral suspension: abacavir 60 mg/dolutegravir 5 mg/lamivudine 30 mg

Assessment

Assess patient for change in severity of HIV symptoms and for symptoms of opportunistic infections during therapy.
Assess for signs of hypersensitivity reactions (fever; rash; GI–nausea, vomiting, diarrhea, abdominal pain; constitutional–malaise, fatigue, achiness; respiratory–dyspnea, cough, pharyngitis). May also cause elevated liver function tests, ↑ CK or serum creatinine, and lymphopenia. Patients who carry the HLA-B*5701 allele are at high risk for hypersensitivity reaction. Discontinue promptly if hypersensitivity reaction is suspected. Regardless of HLA-B*5701 status, permanently discontinue if hypersensitivity cannot be ruled out, even when other diagnoses are possible. Following a hypersensitivity reaction, never restart abacavir-containing products. More severe symptoms may occur within hr and may include life-threatening hypotension and death. Symptoms usually resolve upon discontinuation.
May cause lactic acidosis and severe hepatomegaly with steatosis. Monitor patient for signs (↑ serum lactate levels, ↑ liver enzymes, liver enlargement on palpation). Therapy should be suspended if clinical or laboratory signs occur.
Monitor patient for signs and symptoms of peripheral neuropathy (tingling, burning, numbness, or pain in hands or feet); may be difficult to differentiate from peripheral neuropathy of severe HIV disease. May require discontinuation of therapy.

Lab Test Considerations:

Verify negative pregnancy test in adolescent and adult females of reproductive potential prior to starting therapy.

Monitor viral load and CD4 cell count regularly during therapy.
Screen for HLA-B*5701 allele prior to initiation of therapy to decrease risk of hypersensitivity reaction. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir.
Test for presence of hepatitis B virus (HBV) prior to or when starting therapy. Emergence of lamivudine-resistant HBV variants associated with lamivudine-containing antiretroviral regimens have been reported. Consider additional treatment for chronic HBV if used in patients coinfected with HIV-1 and HBV; or consider an alternative regimen.
Monitor liver function periodically. May cause ↑ levels of AST, ALT, and alkaline phosphatase, which usually resolve after interruption of therapy. Patients with concurrent hepatitis B or C should be followed for at least several mo after stopping therapy. Lactic acidosis may occur with hepatic toxicity, causing hepatic steatosis; may be fatal, especially in women.
May cause ↑ serum glucose, lipase, and triglyceride levels.

Implementation

Triumeq and Triumeq PD are not bioequivalent and are not interchangeable on a milligram-per-milligram basis. Dose adjustment is required when switching dose forms.
PO Administer without regard to food.
- DNC: Pediatric patients: Fully disperse Triumeq PD tablets for oral suspension in 20 mL of drinking water (if using 4, 5, or 6 tablets for oral suspension) or 15 mL (if using 3 tablets for oral suspension) in the supplied cup; swirl the suspension so that no lumps remain. After full dispersion, administer oral suspension within 30 min of mixing. Do not chew, cut, or crush the tablets.
- Administer Triumeq 2 hr before or 6 hr after antacids; laxatives; other medications containing aluminum, magnesium, sucralfate, or buffering agents; calcium; or iron. Supplements containing calcium or iron can be taken with Triumeq if taken with food.

Patient/Family Teaching

Emphasize the importance of taking Triumeq as directed. Must always be used in combination with other antiretroviral drugs. Do not take more than prescribed amount, and do not stop taking without consulting health care professional. Take missed doses as soon as remembered unless almost time for next dose; do not double doses. Advise patient to read the Medication Guide prior to starting therapy and with each Rx refill in case of changes.
Instruct patient or caregiver in how to disperse Triumeq PD tablets.
Instruct patient not to share medication with others.
Inform patient that medication does not cure HIV or prevent associated or opportunistic infections. Medication may reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Caution patient to use a condom, and avoid sharing needles or donating blood to prevent spreading HIV to others. Advise patient that the long-term effects of medication are unknown at this time.
Advise patient of potential for hypersensitivity reactions that may result in death. Instruct patient to discontinue medication and notify health care professional immediately if symptoms of hypersensitivity or signs of immune reconstitution syndrome (signs and symptoms of inflammation from previous infections) occur. A warning card summarizing symptoms of hypersensitivity is provided with each prescription; instruct patient to carry card at all times.
Instruct patient to notify health care professional immediately if symptoms of lactic acidosis (tiredness or weakness, unusual muscle pain, trouble breathing, stomach pain with nausea and vomiting, cold especially in arms or legs, dizziness, fast or irregular heartbeat) or if signs of hepatotoxicity (yellow skin or whites of eyes, dark urine, light-colored stools, lack of appetite for several days or longer, nausea, abdominal pain) occur. These symptoms may occur more frequently in patients that are female, obese, or have been taking medications for a long time.
Instruct patient to notify health care professional promptly if signs of peripheral neuropathy or pancreatitis occur.
Advise patient to avoid sugarless gum or candy due to sorbitol content; may ↓ medication effectiveness.
Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications, especially methadone, St. John's wort, and other antiretrovirals.
Rep: May cause fetal harm and increase risk of neural tube defects. Advise adolescent and adult females of reproductive potential to use effective contraception and to avoid breastfeeding during therapy. Notify care professional if pregnancy is planned or suspected. Switch to another antiviral regimen during 1st trimester; may increase risk of neural tube defects. May consider Triumeq during 2nd and 3rd trimesters of pregnancy if expected benefit justifies potential risk to pregnant woman and fetus. Pregnant patients should be encouraged to enroll in the Antiretroviral Pregnancy Registry by calling 1-800-258-4263.
Advise patient to carry hypersensitivity warning card with them at all times.
Emphasize the importance of regular follow-up exams and blood counts to determine progress and monitor for side effects.

Evaluation/Desired Outcomes

Delayed progression of HIV, and decreased opportunistic infections in patients with HIV.
Decrease in viral load and increase in CD4 cell counts.