abacavir/dolutegravir/lamivudine (Rx)

Dosage Forms & Strengths

abacavir/dolutegravir/lamivudine

tablet

600mg/50mg/300mg

HIV-1 Infection

<40 kg: Safety and efficacy not established

≥40 kg: 1 tablet PO qDay

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

Dosage Modifications

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

Current or past history of resistance to components abacavir/dolutegravir/lamivudine: Not recommended

Screen for presence of genetic marker HLA-B*5701 allele before initiating treatment with abacavir-containing products in HIV-infected patients irrespective of racial origin

Patients known to carry HLA-B*5701 allele should not use products containing abacavir; risk for hypersensitivity reactions high

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

Contraindicated

dofetilide

elvitegravir/cobicistat/emtricitabine/tenofovir DF

emtricitabine

Serious - Use Alternative

aluminum hydroxide/magnesium carbonate

carbamazepine

efavirenz

etravirine

fosamprenavir

fosphenytoin

ganciclovir

nevirapine

oxcarbazepine

phenobarbital

phenytoin

ribavirin

rifampin

sorbitol

St John's Wort

tafenoquine

tipranavir

valganciclovir

abacavir

Monitor Closely

aluminum hydroxide

atazanavir

cabozantinib

calcium acetate

calcium carbonate

calcium citrate

didanosine

efavirenz

emtricitabine

enfuvirtide

erdafitinib

fosamprenavir

ganciclovir

indinavir

interferon alfa 2b

lamivudine

metformin

methadone

nelfinavir

nevirapine

orlistat

peginterferon alfa 2a

ribavirin

ritonavir

saquinavir

stavudine

tenofovir DF

tipranavir

trimethoprim

valganciclovir

zidovudine

Minor

ethanol

sulfamethoxazole

zidovudine

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

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)

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

Initiation of therapy is not recommended in individuals actively trying to become pregnant unless there is no suitable alternative; a benefit-risk assessment should consider factors such as feasibility of switching, tolerability, ability to maintain viral suppression, and risk of transmission to infant against risk of neural tube defects

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 Category Definitions

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.

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

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

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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