Drug Information

Abacavir

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.

  • Ziagen®
Brand Names: Canada

  • Ziagen®
Medication GuideAn FDA-approved patient medication guide, which is available with the product information and at file://www.fda.gov/downloads/Drugs/DrugSafety/ucm089831.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: 300 mg twice daily or 600 mg once daily in combination with other antiretroviral agents

Dosing: PediatricHIV treatment: Oral: 3 months to 16 years: 8 mg/kg body weight twice daily (maximum: 300 mg twice daily) in combination with other antiretroviral agents

Dosing: GeriatricRefer to adult dosing.

Dosing: Hepatic ImpairmentMild dysfunction (Child-Pugh score 5-6): 200 mg twice daily (oral solution is recommended)

Moderate-to-severe dysfunction (Child-Pugh score >6): Use is contraindicated by the manufacturer.

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

Solution, oral:

Ziagen®: 20 mg/mL (240 mL [DSC] ) [strawberry-banana flavor]

Ziagen®: 20 mg/mL (240 mL) [contains propylene glycol; strawberry-banana flavor]

Tablet, oral:

Ziagen®: 300 mg [DSC]

Ziagen®: 300 mg [scored]

Generic Equivalent Available: U.S.No

AdministrationMay be administered with or without food.

UseTreatment of HIV infections in combination with other antiretroviral agents

Adverse Reactions SignificantHypersensitivity reactions (which may be fatal) occur in ~5% of patients (see Warnings/Precautions). Symptoms may include anaphylaxis, fever, rash (including erythema multiforme), fatigue, diarrhea, abdominal pain; respiratory symptoms (eg, pharyngitis, dyspnea, cough, adult respiratory distress syndrome, or respiratory failure); headache, malaise, lethargy, myalgia, myolysis, arthralgia, edema, paresthesia, nausea and vomiting, mouth ulcerations, conjunctivitis, lymphadenopathy, hepatic failure, and renal failure.

Note: Rates of adverse reactions were defined during combination therapy with other antiretrovirals (lamivudine and efavirenz or lamivudine and zidovudine). Only reactions which occurred at a higher frequency in adults (except where noted) than in the comparator group are noted. Adverse reaction rates attributable to abacavir alone are not available.

>10%:

Central nervous system: Headache (7% to 13%)

Gastrointestinal: Nausea (7% to 19%, children 9%)

1% to 10%:

Central nervous system: Depression (6%), fever/chills (6%, children 9%), anxiety (5%)

Dermatologic: Rash (5% to 6%, children 7%)

Endocrine & metabolic: Triglycerides increased (2% to 6%)

Gastrointestinal: Diarrhea (7%), vomiting (children 9%), amylase increased (2%)

Hematologic: Thrombocytopenia (1%)

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Hepatic: AST increased (6%)

Neuromuscular & skeletal: Musculoskeletal pain (5% to 6%)

Miscellaneous: Hypersensitivity reactions (2% to 9%; may include reactions to other components of antiretroviral regimen), infection (ENT 5%)

<1% (Limited to important or life-threatening): Erythema multiforme, fat redistribution, GGT increased, hepatic steatosis, hepatomegaly, hepatotoxicity, lactic acidosis, MI, pancreatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis

ContraindicationsHypersensitivity to abacavir or any component of the formulation (do not rechallenge patients who have experienced hypersensitivity to abacavir regardless of HLA-B*5701 status); moderate-to-severe hepatic impairment

Warnings/PrecautionsBoxed warnings:

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

• Lactic acidosis/hepatomegaly: 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).

• Hypersensitivity reactions: [U.S. Boxed Warning] : Serious and sometimes fatal hypersensitivity reactions have occurred. 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 therapy or reinitiating therapy in patients of unknown status, including patients who previously tolerated therapy. Therapy is not recommended in patients testing positive for the HLA-B*5701 allele. An allergy to abacavir should be reported in the patient’s medical record (DHHS, 2011). Reactions usually occur within 9 days of starting abacavir; ~90% occur within 6 weeks. Patients exhibiting symptoms from two or more of the following: Fever, skin rash, constitutional symptoms (malaise, fatigue, aches), respiratory symptoms (eg, pharyngitis, dyspnea, cough), and GI symptoms (eg, abdominal pain, diarrhea, nausea, vomiting) should discontinue therapy immediately and call for medical attention. Abacavir should be permanently discontinued if hypersensitivity cannot be ruled out, even when other diagnoses are possible and regardless of HLA-B*5701 status. Abacavir 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 (ie, interruption in drug supply, temporary discontinuation while treating other conditions). 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 abacavir is restarted following an interruption in therapy, evaluate the patient for previously unsuspected symptoms of hypersensitivity. To report these events on abacavir 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).

Disease-related concerns:

• 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.

• Hepatic impairment: Use with caution in patients with mild hepatic dysfunction (contraindicated in moderate-to-severe dysfunction).

• HIV: Appropriate use: Abacavir should always be used as a component of a multidrug regimen. Use with caution in patients with plasma HIV RNA levels ≥100,000 copies/mL as earlier virologic failure has been observed in one study (DHHS, 2011).

Special populations:

• Pediatrics: Safety and efficacy have not been established in children <3 months of age.

Dosage form specific issues:

• Propylene glycol: Products may contain propylene glycol.

Drug Interactions

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

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

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

Pregnancy Risk FactorC

Pregnancy ImplicationsAdverse events have been observed in some animal reproduction studies. It is not known if abacavir crosses the human placenta. No increased risk of overall birth defects has been observed following first trimester exposure according to data collected by the antiretroviral pregnancy registry. Cases of lactic acidosis/hepatic steatosis syndrome related to mitochondrial toxicity have been reported in pregnant women receiving nucleoside analogues. It is not known if pregnancy itself potentiates this known side effect; however, women may be at increased risk of lactic acidosis and liver damage. In addition, these adverse events are similar to other rare but life-threatening syndromes which occur during pregnancy (eg, HELLP syndrome). Hepatic enzymes and electrolytes should be monitored frequently during the third trimester of pregnancy in women receiving nucleoside analogues and clinicians should watch for early signs of the syndrome. The pharmacokinetics of abacavir are not significantly changed by pregnancy and dose adjustment is not needed for pregnant women. The Perinatal HIV Guidelines Working Group considers abacavir to be an alternative NRTI in dual nucleoside combination regimens.

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Healthcare providers are encouraged to enroll pregnant women exposed to antiretroviral medications in the Antiretroviral Pregnancy Registry (1-800-258-4263 or www.APRegistry.com). Healthcare providers caring for HIV-infected women and their infants may contact the National Perinatal HIV Hotline (888-448-8765) for clinical consultation.

LactationExcretion in breast milk unknown/contraindicated

Breast-Feeding ConsiderationsIn infants born to mothers who are HIV positive, HAART while breast-feeding may decrease postnatal infection. However, maternal or infant antiretroviral therapy does not completely eliminate the risk of postnatal HIV transmission. In addition, multiclass-resistant virus has been detected in breast-feeding infants despite maternal therapy.

In the United States where formula is accessible, affordable, safe, and sustainable, complete avoidance of breast-feeding by HIV-infected women is recommended to decrease potential transmission of HIV.

Dietary ConsiderationsMay be taken with or without food.

Pricing: U.S. (www.drugstore.com)Solution (Ziagen)

20 mg/mL (240): $143.99

Monitoring ParametersCBC with differential, serum creatine kinase, CD4 count, HIV RNA plasma levels, 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

International Brand Names

  • Abamune (IN, UY);
  • Ampi-quim (MX);
  • Filabac (AR);
  • Zepril (AR);
  • Ziagen (AT, AU, BB, BE, BG, BM, BS, BZ, CH, CL, CN, CO, CR, CZ, DE, DK, DO, ES, FI, FR, GB, GR, GT, GY, HK, HN, IE, IL, IT, JM, KP, NI, NL, NO, PA, PE, PL, PT, RU, SE, SG, SR, SV, TR, TT, TW, VE);
  • Ziagenavir (AR, BR, MX, TH, UY)
Mechanism of ActionNucleoside reverse transcriptase inhibitor. Abacavir is a guanosine analogue which is phosphorylated to carbovir triphosphate which interferes with HIV viral RNA-dependent DNA polymerase resulting in inhibition of viral replication.

Pharmacodynamics/KineticsAbsorption: Rapid and extensive absorption

Distribution: Vd: 0.86 L/kg

Protein binding: 50%

Metabolism: Hepatic via alcohol dehydrogenase and glucuronyl transferase to inactive carboxylate and glucuronide metabolites

Bioavailability: 83%

Half-life elimination: 1.5 hours

Time to peak: 0.7-1.7 hours

Excretion: Primarily urine (as metabolites, 1.2% as unchanged drug); feces (16% total dose)

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