Drug Information

Abacavir, lamivudine, and zidovudine

Special Alerts

Abacavir: Update on the Risk of Myocardial InfarctionMarch 2011

In July 2008, the U.S. Food and Drug Administration (FDA) notified healthcare professionals of a possible increased risk of myocardial infarction (MI) in patients taking nucleoside reverse transcriptase inhibitors (NRTIs), including abacavir, based on observational study data. Subsequently, the FDA completed a meta-analysis of 26 abacavir randomized clinical trials conducted between 1996 and 2010. Although several observational studies and one randomized controlled trial showed an increased risk of MI, the FDA has concluded there is not an increased risk of MI with abacavir use based on the overall meta-analysis.

For additional information, please refer to file://www.fda.gov/Drugs/DrugSafety/ucm245164.htm.

ALERT: U.S. Boxed WarningThe FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.

Brand Names: U.S.

  • Trizivir®
Brand Names: Canada

  • Trizivir®
Medication GuideAn FDA-approved patient medication guide, which is available with the product information and at file://www.fda.gov/downloads/Drugs/DrugSafety/ucm089807.pdf, must be dispensed with this medication. A Warning Card (summarizing symptoms of hypersensitivity), which is available with the product information, must also be dispensed with this medication for each new outpatient prescription and refill.

Pharmacologic Category

  • Antiretroviral Agent, Reverse Transcriptase Inhibitor (Nucleoside)
Dosing: AdultHIV treatment: Oral: 1 tablet twice daily. Note: Not recommended for patients <40 kg.

Dosing: Pediatric(For additional information see "Abacavir, lamivudine, and zidovudine: Pediatric drug information")

HIV treatment: Adolescents: Refer to adult dosing (not recommended for patients <40 kg).

Dosing: GeriatricRefer to adult dosing.

Dosing: Renal ImpairmentClcr <50 mL/minute: Avoid use.

Dosing: Hepatic ImpairmentUse contraindicated.

Dosage Forms: U.S.Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, oral:

Trizivir®: Abacavir sulfate 300 mg, lamivudine 150 mg, and zidovudine 300 mg

Generic Equivalent Available: U.S.No

AdministrationAdminister without regard to food.

UseTreatment of HIV infection (either alone or in combination with other antiretroviral agents) in patients whose regimen would otherwise contain the components of Trizivir®

Adverse Reactions SignificantFatal hypersensitivity reactions have occurred in patients taking abacavir (in Trizivir®). If Trizivir® is to be restarted following an interruption in therapy, first evaluate the patient for previously unsuspected symptoms of hypersensitivity. Do not restart if hypersensitivity is suspected or if hypersensitivity cannot be ruled out.

The following information is based on CNA3005 study data concerning effects noted in patients receiving abacavir, lamivudine, and zidovudine. See individual agents for additional information.

>10%:

Central nervous system: Headache (13%), malaise (12%), fatigue (12%)

Gastrointestinal: Nausea (19%)

1% to 10%:

Central nervous system: Fever/chills (6%), depression (6%), anxiety (5%)

Dermatologic: Rash (5%)

Endocrine & metabolic: Triglycerides increased (2% grade 3-4)

Gastrointestinal: Nausea and vomiting (10%), diarrhea (7%), amylase increased (2%)

Hematologic: Neutropenia (5%)

Hepatic: ALT increased (6%)

Neuromuscular & skeletal: CPK increased (7%)

Otic: Ear infection (5%)

Respiratory: Nose/throat infection (5%)

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Miscellaneous: Hypersensitivity (2% to 9% based on abacavir component), viral infection (5%)

Other (frequency unknown): Pancreatitis, GGT increased, fat redistribution, immune reconstitution syndrome

ContraindicationsHypersensitivity to abacavir, lamivudine, zidovudine, or any component of the formulation; hepatic impairment. Do not rechallenge patients who have experienced hypersensitivity to abacavir regardless of HLA-B*5701 status.

Warnings/PrecautionsBoxed warnings:

• Chronic hepatitis B: See “Disease-related concerns” below.

• Hematologic toxicity: See “Concerns related to adverse effects” below.

• HIV: Appropriate use: See “Disease-related concerns” below.

• Hypersensitivity reactions: See “Concerns related to adverse effects” below.

• Lactic acidosis/hepatomegaly: See “Concerns related to adverse effects” below.

• Myopathy: See “Concerns related to adverse effects” below.

Concerns related to adverse effects:

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

• Hematologic toxicity:[U.S. Boxed Warning] : Zidovudine has been associated with hematologic toxicities (eg, neutropenia, anemia); use with caution in patients with bone marrow compromise.

• Hypersensitivity reactions: [U.S. Boxed Warning] : Fatal hypersensitivity reactions have occurred in patients taking abacavir (in Trizivir®). Patients testing positive for the presence of the HLA-B*5701 allele are at an increased risk for hypersensitivity reactions. Screening for HLA-B*5701 allele status is recommended prior to initiating abacavir-containing therapy or reinitiating therapy in patients of unknown status, including patients who previously tolerated abacavir therapy. Trizivir® should not be used in patients testing positive for the HLA-B*5701 allele. Additionally, allele-positive patients (including abacavir treatment naive) should have an allergy to abacavir documented in their medical record (DHHS, 2011). Reactions usually occur within 9 days of starting abacavir; ~90% occur within 6 weeks Patients exhibiting symptoms of fever, skin rash, fatigue, respiratory symptoms (eg, pharyngitis, dyspnea, cough) and/or GI symptoms (eg, abdominal pain, nausea, vomiting, diarrhea) should discontinue therapy immediately and call for medical attention. Trizivir® should be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible and regardless of HLA-B*5701 status. Trizivir® SHOULD NOT be restarted because more severe symptoms may occur within hours, including LIFE-THREATENING HYPOTENSION AND DEATH. Fatal hypersensitivity reactions have occurred following the reintroduction of abacavir in patients whose therapy was interrupted (eg, interruption in drug supply, temporary discontinuation while treating other conditions). Reactions occurred within hours. In some cases, signs of hypersensitivity may have been previously present, but attributed to other medical conditions (eg, acute onset respiratory diseases, gastroenteritis, reactions to other medications). If Trizivir® is to be restarted following an interruption in therapy, first 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. To report these events on Trizivir® hypersensitivity, a registry has been established (1-800-270-0425).

• Immune reconstitution syndrome: Patients may develop immune reconstitution syndrome resulting in the occurrence of an inflammatory response to an indolent or residual opportunistic infection; further evaluation and treatment may be required.

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• Lactic acidosis/hepatomegaly: [U.S Boxed Warning] : Lactic acidosis and severe hepatomegaly with steatosis have been reported with nucleoside analogues, including fatal cases; use with caution in patients with risk factors for liver disease (risk may be increased with female gender, obesity, pregnancy or prolonged exposure) and 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).

• Myopathy: [U.S. Boxed Warning] : Prolonged use of zidovudine has been associated with symptomatic myopathy and myositis.

Disease-related concerns:

• Chronic hepatitis B: [U.S. Boxed Warning] : Exacerbation of hepatitis B has been reported with discontinuation of lamivudine in coinfected HIV/HBV patients; monitor hepatic function closely for several months after discontinuing Trizivir® in coinfected patients.

• Coronary heart disease: Use has been associated with an increased risk of myocardial infarction (MI) in observational studies; however, based on a meta-analysis of 26 randomized trials, the FDA has concluded there is not an increased risk. Consider using with caution in patients with risks for coronary heart disease and minimizing modifiable risk factors (eg, hypertension, hyperlipidemia, diabetes mellitus, and smoking) prior to use.

• HIV: Appropriate use:[U.S. Boxed Warning] : This combination should only be used as part of a multidrug regimen for which the individual components are indicated.

• Renal impairment: Trizivir®, as a fixed-dose combination tablet, should not be used in patients with Clcr <50 mL/minute.

Concurrent drug therapy issues:

• Interferon alfa: Use with caution in combination with interferon alfa with or without ribavirin in HIV/HBV coinfected patients; monitor closely for hepatic decompensation, anemia, or neutropenia; dose reduction or discontinuation of interferon and/or ribavirin may be required if toxicity evident.

Special populations:

• Adolescents and Adults <40 kg: Trizivir®, as a fixed-dose combination tablet, should not be used in patients <40 kg or those requiring dosage adjustment.

• Pediatrics: Trizivir®, as a fixed-dose combination tablet, should not be used in children.

Drug Interactions

(For additional information:

Acyclovir-Valacyclovir: May enhance the CNS depressant effect of Zidovudine. Risk C: Monitor therapy

Clarithromycin: May enhance the myelosuppressive effect of Zidovudine. Clarithromycin may decrease the serum concentration of Zidovudine. Management: Monitor response to zidovudine closely when used with clarithromycin, and consider staggering zidovudine and clarithromycin doses when possible in order to minimize the potential for interaction. Risk D: Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (Low risk). Risk C: Monitor therapy

Divalproex: May decrease the metabolism of Zidovudine. Risk C: Monitor therapy

DOXOrubicin: May enhance the adverse/toxic effect of Zidovudine. DOXOrubicin may diminish the therapeutic effect of Zidovudine. Risk D: Consider therapy modification

DOXOrubicin (Liposomal): May enhance the adverse/toxic effect of Zidovudine. DOXOrubicin (Liposomal) may diminish the therapeutic effect of Zidovudine. Risk D: Consider therapy modification

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

Fluconazole: May decrease the metabolism of Zidovudine. Risk C: Monitor therapy

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Ganciclovir-Valganciclovir: May enhance the adverse/toxic effect of Reverse Transcriptase Inhibitors (Nucleoside). Hematologic toxicity is of specific concern. Risk D: Consider therapy modification

Interferons: May enhance the adverse/toxic effect of Zidovudine. Interferons may decrease the metabolism of Zidovudine. Risk C: Monitor therapy

Methadone: May increase the serum concentration of Zidovudine. Risk C: Monitor therapy

Probenecid: May decrease the metabolism of Zidovudine. Risk C: Monitor therapy

Protease Inhibitors: May decrease the serum concentration of Zidovudine. Risk C: Monitor therapy

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

Ribavirin: May enhance the hepatotoxic effect of Reverse Transcriptase Inhibitors (Nucleoside). Lactic acidosis may occur. Risk D: Consider therapy modification

Ribavirin: Zidovudine may enhance the adverse/toxic effect of Ribavirin. Specifically, the risk/severity of anemia may be increased. Management: Due to significantly increased risk of anemia, consider even closer monitoring for anemia than routinely recommended for ribavirin. Alternative therapies should be considered when clinically possible, particularly for patients with other risk factors. Risk D: Consider therapy modification

Rifamycin Derivatives: May decrease the serum concentration of Zidovudine. Exceptions: Rifabutin. Risk C: Monitor therapy

Stavudine: Zidovudine may diminish the therapeutic effect of Stavudine. Risk X: Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy

Trimethoprim: May decrease the excretion of LamiVUDine. Risk C: Monitor therapy

Valproic Acid: May decrease the metabolism of Zidovudine. Risk C: Monitor therapy

Ethanol/Nutrition/Herb InteractionsEthanol: Ethanol may increase the risk of toxicity.

Pregnancy Risk FactorC

Pregnancy ImplicationsSee individual agents.

LactationSee individual agents.

Breast-Feeding ConsiderationsSee individual agents.

Dietary ConsiderationsMay be taken without regard to food.

Pricing: U.S. (www.drugstore.com)Tablets (Trizivir)

300-150-300 mg (60): $1516.36

Monitoring ParametersBlood glucose, CBC with differential, serum creatine kinase, CD4 count, HIV RNA plasma levels, bilirubin, serum transaminases, triglycerides, serum amylase; HLA-B*5701 genotype status prior to initiation of therapy and prior to reinitiation of therapy in patients of unknown HLA-B*5701 status; signs and symptoms of hypersensitivity, particularly in patients untested for the HLA-B*5701 allele; signs and symptoms of pancreatitis; observe for appearance of opportunistic infections

International Brand Names

  • Tricivir (AR, CN);
  • Trivudin (AR);
  • Trizivir (AT, AU, BE, BG, CH, CL, CO, CR, CZ, DE, DK, FI, FR, GB, GR, HK, HN, IE, IL, IT, MX, NL, NO, PE, PT, RU, SE, TR, TW, UY, VE)
Mechanism of ActionThe combination of abacavir, lamivudine, and zidovudine is believed to act synergistically to inhibit reverse transcriptase via DNA chain termination after incorporation of the nucleoside analogue as well as to delay the emergence of mutations conferring resistance.

Pharmacodynamics/KineticsBioavailability studies of Trizivir® show no difference in AUC or Cmax when compared to abacavir, lamivudine, and zidovudine given together as individual agents

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