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Abacavir, lamivudine, and zidovudine

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U.S. BRAND NAMES — Trizivir®

PHARMACOLOGIC CATEGORY
Antiretroviral Agent, Reverse Transcriptase Inhibitor (Nucleoside)

DOSING: ADULTS — HIV treatment: Oral: 1 tablet twice daily. Note: Not recommended for patients <40 kg. DOSING: PEDIATRIC — HIV treatment: Adolescents: Refer to adult dosing (not recommended for patients <40 kg). (For additional information see “Abacavir, lamivudine, and zidovudine: Pediatric drug information”) DOSING: ELDERLY — Use with caution. DOSING: RENAL IMPAIRMENT — Clcr ≤ 50 mL/minute: Avoid use. DOSING: HEPATIC IMPAIRMENT — Use contraindicated. DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling. Tablet:
Trizivir®: Abacavir 300 mg, lamivudine 150 mg, and zidovudine 300 mg

DOSAGE FORMS: CONCISE
Tablet:
Trizivir®: Abacavir 300 mg, lamivudine 150 mg, and zidovudine 300 mg

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION — Administer without regard to food or water.

USE — Treatment 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 SIGNIFICANT — Fatal 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%)
Miscellaneous: Hypersensitivity (2% to 9% based on abacavir component), viral infection (5%)

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

CONTRAINDICATIONS — Hypersensitivity 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 / PRECAUTIONS
Boxed 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.

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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® is not recommended in patients testing positive for the HLA-B*5701 allele. 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. 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.

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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 may increase risk of myocardial infarction; use caution in patients with risks for coronary heart disease; modifiable risk factors (eg, hypertension, hyperlipidemia, diabetes mellitus, and smoking) should be minimized 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 t ablet, should not be used in children. DRUG INTERACTIONS
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

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

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

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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

Rifamycin Derivatives: May increase the metabolism of Zidovudine. Exceptions: Rifabutin. Risk D: Consider therapy modification

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

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

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

Zalcitabine: LamiVUDine may diminish the therapeutic effect of Zalcitabine. Risk D: Consider therapy modification

ETHANOL / NUTRITION / HERB INTERACTIONS — Ethanol: Ethanol may increase the risk of toxicity.

PREGNANCY RISK FACTOR — C

PREGNANCY IMPLICATIONS — See individual agents.

LACTATION — See individual agents.

BREAST-FEEDING CONSIDERATIONS — See individual agents.

DIETARY CONSIDERATIONS — May be taken without regard to food or water.

PRICING — (data from drugstore.com)
Tablets (Trizivir)
300-150-300 mg (60): $1431.91

MONITORING PARAMETERS — Blood 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

CANADIAN BRAND NAMES — Trizivir®

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 ACTION — The 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 / KINETICS — Bioavailability studies of Trizivir® show no difference in AUC or Cmax when compared to abacavir, lamivudine, and zidovudine given together as individual agents. See individual agents.

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