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Abacavir Sulfate / Lamivudine / Zidovudine

Pronunciation: a-BAK-a-vir SUL-fate/la-MIV-ue-deen/zye-DOE-vue-deen
Class: Nucleoside analog reverse transcriptase inhibitor combination

Trade Names

Trizivir
- Tablets abacavir sulfate 300 mg/lamivudine 150 mg/zidovudine 300 mg

Pharmacology

Inhibits replication of HIV by incorporation into HIV DNA and production of incomplete, nonfunctional DNA.

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

Abacavir

Rapidly absorbed and extensively distributed. Oral bioavailability 86%.

Lamivudine

Rapidly absorbed and extensively distributed. Oral bioavailability 86%.

Zidovudine

Rapidly absorbed and extensively distributed. Oral bioavailability 64%.

Distribution

Abacavir

Binding of abacavir to human plasma proteins is approximately 50%. Binding of abacavir to plasma proteins was independent of concentration. Vd approximately 0.86 L/kg.

Lamivudine

Binding to plasma protein is low. Vd approximately 1.3 L/kg.

Zidovudine

Binding to plasma protein is low. Vd approximately 1.6 L/kg.

Metabolism

In humans, abacavir, lamivudine, and zidovudine are not significantly metabolized by CYP-450 enzymes.

Abacavir

The primary routes of elimination of abacavir are metabolism by alcohol dehydrogenase to form the 5'-carboxylic acid and glucuronyl transferase to form the 5'-glucuronide.

Lamivudine

Approximately 70% of an intravenous dose of lamivudine is recovered as unchanged drug in the urine. Metabolism of lamivudine is a minor route of elimination. In humans, the only known metabolite is the trans-sulfoxide metabolite (approximately 5% of an oral dose after 12 hours).

Zidovudine

Zidovudine is eliminated primarily by hepatic metabolism. The major metabolite of zidovudine is 3'-azido-3'-deoxy-5'-O-β-D-glucopyranuronosylthymidine (GZDV). GZDV AUC is about 3-fold greater than the zidovudine AUC.

Elimination

Systemic Cl

Abacavir approximately 0.8 L/h/kg; lamivudine approximately 0.33 L/h/kg; zidovudine approximately 1.6 L/h/kg.

Renal Cl

Abacavir approximately 0.007 L/h/kg; lamivudine approximately 0.22 L/h/kg; zidovudine approximately 0.34 L/h/kg.

Elimination half-life

Abacavir approximately 1.45 h; lamivudine 5 to 7 h; zidovudine 0.5 to 3 h.

Food effects

Administration of abacavir/lamivudine/zidovudine with food did not alter the extent of abacavir, lamivudine, and zidovudine absorption (AUC), as compared with administration under fasted conditions.

Indications and Usage

Use alone or in combination with other antiretroviral agents for the treatment of HIV-1 infection.

Contraindications

Patients with hepatic impairment; patients with previously demonstrated hypersensitivity to abacavir or any component of the product; never restart any abacavir-containing product following a hypersensitivity reaction, regardless of HLA-B*570 status.

Dosage and Administration

Adults and Adolescents (at least 40 kg)

PO 1 tablet twice daily.

General Advice

  • May be used alone or in combination with other antiretrovirals.
  • Administer without regard to meals. Administer with food if GI upset occurs.
  • If a dose is missed, administer the missed dose as soon as noted and then administer the next dose at the regularly scheduled time.

Storage/Stability

Store at controlled room temperature (59° to 86°F).

Drug Interactions

Acetaminophen, nelfinavir, rifamycins (eg, rifampin), ritonavir

Zidovudine plasma concentrations may be reduced, decreasing the pharmacologic effects.

Atovaquone, fluconazole, methadone, probenecid, valproic acid

Zidovudine plasma concentrations may be elevated, increasing the pharmacologic and adverse reactions.

Doxorubicin, ribavirin, stavudine

Antagonistic relationship has been demonstrated between these agents and zidovudine.

Ethanol

Abacavir plasma concentrations may be elevated, increasing the pharmacologic and adverse reactions.

Food

When administered with a high-fat meal, the abacavir, lamivudine, and zidovudine C max may be decreased; however, Trizivir may be given with or without food.

Ganciclovir, interferon-alpha, other bone marrow suppressive or cytotoxic agents

May increase the hematologic toxicity of zidovudine.

Methadone

Abacavir may increase methadone Cl, necessitating a dosage increase in some patients.

Phenytoin

Zidovudine Cl may be decreased. Phenytoin levels may increase, decrease, or not change.

Trimethoprim/sulfamethoxazole

Serum concentrations of lamivudine may be elevated, increasing the pharmacologic and adverse reactions.

Zalcitabine

Lamivudine and zalcitabine may inhibit the intracellular phosphorylation of each other.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Cardiomyopathy (postmarketing).

CNS

Headache (13%); fatigue, malaise (12%); depression (6%); anxiety (5%); dizziness, insomnia and other sleep disorders, paresthesia, peripheral neuropathy, seizures (postmarketing).

Dermatologic

Skin rash (5%); alopecia, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria (postmarketing).

EENT

Ear/nose/throat infections (5%).

Endocrine

Gynecomastia (postmarketing).

GI

Nausea (19%); nausea/vomiting (10%); diarrhea (7%); abdominal pain, anorexia, decreased appetite, dyspepsia, oral mucosal pigmentation, stomatitis (postmarketing).

Hematologic-Lymphatic

Anemia, aplastic anemia, lymphadenopathy, splenomegaly, thrombocytopenia (postmarketing).

Hepatic

Elevated bilirubin, elevated transaminases, hepatic steatosis, lactic acidosis, pancreatitis, posttreatment exacerbation of hepatitis (postmarketing).

Lab Tests

Elevated CPK (7%); increased ALT (6%); neutropenia (5%); hyperamylasemia, hypertriglyceridemia (2%).

Metabolic

Body accumulation/fat redistribution, hyperglycemia (postmarketing).

Musculoskeletal

Musculoskeletal pain (5%); arthralgia, muscle weakness, myalgia, rhabdomyolysis (postmarketing).

Respiratory

Viral respiratory infections (5%); abnormal breath sounds/wheezing (postmarketing).

Miscellaneous

Hypersensitivity (8%); fever/chills (6%); anaphylaxis, vasculitis, weakness (postmarketing).

Precautions

Warnings

Intended only for patients whose regimen would otherwise include abacavir, lamivudine, and zidovudine.

Hypersensitivity reactions

Serious and sometimes fatal hypersensitivity reactions have been associated with abacavir. The reaction is a multi-organ clinical syndrome usually characterized by a sign or symptom in 2 or more of the following groups: (1) fever; (2) rash; (3) GI, including abdominal pain, diarrhea, nausea, or vomiting; (4) constitutional, including achiness, fatigue, or generalized malaise; (5) respiratory, including cough, dyspnea, or pharyngitis. Discontinue Trizivir as soon as a hypersensitivity reaction is suspected. Permanently discontinue Trizivir if hypersensitivity cannot be ruled out, even when other diagnoses are possible. Patients carrying the HLA-B*5710 allele are at a high risk for experiencing a hypersensitivity reaction to abacavir.

Following a hypersensitivity reaction to abacavir, never restart Trizivir or any other abacavir-containing product because more severe symptoms can occur within hours and may include life-threatening hypotension and death.

Reintroduction of Trizivir or any other abacavir-containing product, even in patients who have no identified history or unrecognized symptoms of hypersensitivity to abacavir therapy, can result in serious or fatal hypersensitivity reactions.

Hematologic toxicity

Zidovudine has been associated with hematologic toxicity, including neutropenia and severe anemia. Prolonged zidovudine use has been associated with symptomatic myopathy.

Lactic acidosis and severe hepatomegaly

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with use of nucleoside analogues alone or in combination.

Exacerbations of hepatitis B

Severe acute exacerbations of hepatitis B have been reported in patients coinfected with hepatitis B virus (HBV) and HIV who have discontinued lamivudine. Closely monitor hepatic function with clinical and laboratory follow-up for at least several months in patients who discontinue Trizivir and are coinfected with HIV and HBV. Initiation of anti–hepatitis B therapy may be warranted.


Monitor

Hematologic

Frequently monitor blood cell counts in patients with advanced HIV disease and in patients receiving combination therapy with Trizivir , interferon alpha, and ribavirin. Periodically monitor blood cell counts in HIV-infected patients with asymptomatic or early HIV disease.

Hepatic

Monitor patients with coinfection with HBV and HIV for posttreatment exacerbations of hepatitis B for several months after stopping treatment. Closely monitor patients receiving combination therapy with Trizivir , interferon alpha, and ribavirin; hepatic decompensation has been reported.

Hypersensitivity reaction

Monitor patient for signs/symptoms of allergic reaction to abacavir. Discontinue use if a sign or symptom in 2 or more of the following groups is noted: fever; rash; GI, including abdominal pain, diarrhea, nausea, or vomiting; constitutional, including achiness, fatigue, or generalized malaise; and respiratory, including cough, dyspnea, or pharyngitis. If hypersensitivity reaction is documented, ensure the reaction is reported to Abacavir Hypersensitivity Registry as noted in the package insert.

Lactic acidosis

Monitor patient for signs/symptoms of lactic acidosis (profound weakness or tiredness; unexpected stomach discomfort; feeling cold, dizzy, or light-headed; slow or irregular heartbeat). Withhold drug if suspected.


Pregnancy

Category C .

Lactation

HIV-infected mothers should not breast-feed their infants.

Abacavir

Undetermined.

Lamivudine and zidovudine

Excreted in breast milk.

Children

Not intended for use in children. Do not administer to adolescents who weigh less than 40 kg (88 lb) because it is a fixed-dose tablet that cannot be adjusted for this population.

Elderly

Use with caution, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and comorbidity.

Hypersensitivity

Fatal hypersensitivity reactions have been associated with abacavir use and have occurred within hours after reintroduction of abacavir in patients who have no identified history or unrecognized symptoms of hypersensitivity.

Renal Function

Because this is a fixed-dose combination, do not use for patients requiring dose adjustments (eg, CrCl less than 50 mL/min).

Hepatic Function

Contraindicated in patients with impaired hepatic function because this is a fixed-dose combination that cannot be adjusted for hepatically impaired patients.

Bone marrow suppression

Use with caution in patients who have bone marrow compromise evidenced by granulocyte count less than 1,000 cells/mm 3 or Hgb less than 9.5 g/dL.

Fat redistribution

Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast enlargement, and cushingoid appearance have been reported. Mechanism and long-term consequences of these events is unknown.

Fixed-dose combination

Contains abacavir, lamivudine, and zidovudine in a fixed-dose tablet. Ensure patient is not receiving abacavir, lamivudine, or zidovudine in any other doseforms. Because the dose cannot be adjusted, do not administer to patients who weigh less than 40 kg or other patients who may require a dose adjustment (eg, dose-related toxicity, hepatic or renal impairment).

Immune reconstitution syndrome

Has been reported in patients treated with combination antiretroviral therapy.

MI

Use of abacavir within the 6 months prior to combined antiretroviral therapy may increase the risk of MI.

Myopathy

Myopathy and myositis, with pathological changes similar to that produced by HIV disease, have been associated with prolonged use of zidovudine.

Posttreatment exacerbations of hepatitis

In patients treated with lamivudine for chronic HBV, there is clinical and laboratory evidence of hepatitis exacerbations after discontinuation of lamivudine.

Therapy-experienced patients

Patients with prolonged prior nucleoside reverse transcriptase inhibitor (NRTI) exposure or who have HIV-1 isolates containing multiple mutations conferring NRTI resistance have limited response to abacavir. Thus, potential cross-resistance between abacavir and other NRTIs should be considered when selecting new regimens for therapy-experienced patients.

Overdosage

Symptoms

Confusion, dizziness, drowsiness, headache, lethargy, nausea, vomiting.

Patient Information

  • Caution patient not to take any other HIV medications that contain abacavir, lamivudine, or zidovudine.
  • Advise patient to review Medication Guide before starting therapy and to read and check for new information each time the medication is refilled.
  • Advise patient to review, and carry with them at all times, the Warning Card summarizing the symptoms of abacavir hypersensitivity reaction.
  • Advise patient that this drug may be used alone or in combination with other HIV medications. Instruct patient taking other HIV medications to continue to take them as prescribed by health care provider.
  • Instruct patient to take exactly as prescribed and not to change the dose or discontinue therapy unless advised by health care provider.
  • Instruct patient to take 1 tablet twice daily without regard to meals but to take with food if stomach upset occurs.
  • Instruct patient to discontinue use and notify health care provider immediately if 2 or more of the following symptoms occur: (1) fever; (2) rash; (3) diarrhea, nausea, stomach area pain, or vomiting; (4) achiness, extreme tiredness, or generalized body discomfort; (5) cough, shortness of breath, or sore throat.
  • Caution patient not to restart this medication or any other abacavir-containing medication if they experience a hypersensitivity reaction to this medication. Explain to patient that restarting abacavir or an abacavir-containing product could cause a more serious, and possibly fatal, reaction.
  • Caution patient that if therapy is interrupted for a few days for reasons other than a hypersensitivity reaction (eg, interruption in drug supply) and is then restarted, there is a risk of experiencing a serious or fatal hypersensitivity reaction. Advise patient to talk with health care provider before restarting the medication on their own. Advise patient that if health care provider tells them they can take the medication again, to start taking it when they are around medical help or people who can call a health care provider if necessary.
  • Caution patient that medication can cause a rare but serious condition called lactic acidosis with liver enlargement, and that profound weakness or tiredness; unexpected stomach discomfort; feeling cold, dizzy, or light-headed; or slow or irregular heartbeat may be symptoms of this condition. Instruct patient to immediately inform health care provider if these symptoms develop.
  • Caution patient who has concurrent infection with HBV that their hepatitis may worsen if therapy is stopped and that their liver function should be followed closely for several months after stopping the medication. Advise patient that they may need to begin taking anti-HBV medications.
  • Advise patient that medication may cause changes in body fat distribution (eg, increased amount of fat in upper back and neck, breasts, and around the back, chest, and stomach area; loss of fat from arms, legs, and face) and that the cause and long-term health effects of these changes are not known at this time. Advise patient to report changes in body fat distribution to health care provider.
  • Advise patient that long-term use can cause muscle weakness and to report this to health care provider immediately if noted or suspected.
  • Inform patient that drug does not completely eliminate HIV virus and does not reduce the risk of transmitting HIV to others through sexual contact or blood contamination. Instruct patient that appropriate precautions must still be followed.
  • Advise patient that drug is not a cure for HIV infection and that they may continue to acquire illnesses associated with HIV infection, including opportunistic infections, and that they should remain under a health care provider's care.
  • Instruct mother not to breast-feed her infant because of the risk of transmitting the HIV virus to the infant and the potential for serious adverse reactions from medication transmitted to her infant through breast milk.

Copyright © 2009 Wolters Kluwer Health.

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