Abacavir

U.S. BRAND NAMES — Ziagen®

PHARMACOLOGIC CATEGORY
Antiretroviral Agent, Reverse Transcriptase Inhibitor (Nucleoside)

DOSING: ADULTS — HIV treatment: Oral: 300 mg twice daily or 600 mg once daily in combination with other antiretroviral agents

DOSING: PEDIATRIC — HIV 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

(For additional information see "Abacavir: Pediatric drug information")

DOSING: ELDERLY — Refer to adult dosing.

DOSING: HEPATIC IMPAIRMENT
Mild dysfunction (Child-Pugh score 5-6): 200 mg twice daily (oral solution is recommended)

Moderate-to-severe dysfunction: Use is contraindicated by the manufacturer

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

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

Tablet:
Ziagen®: 300 mg

DOSAGE FORMS: CONCISE
Solution, oral:
Ziagen®: 20 mg/mL

Tablet:
Ziagen®: 300 mg

GENERIC EQUIVALENT AVAILABLE — No

ADMINISTRATION — May be administered with or without food.

USE — Treatment of HIV infections in combination with other antiretroviral agents

ADVERSE REACTIONS SIGNIFICANT — Hypersensitivity 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%)
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

CONTRAINDICATIONS — Hypersensitivity 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 / PRECAUTIONS
Boxed 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. 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). 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 abacavir is restarted following an interruption in therapy, evaluate the patient for previously unsuspected symptoms of hypersensitivity. Do not restart if hypersensitivity is suspected or if hypersensitivity cannot be ruled out regardless of HLA-B*5701 status. 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. 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 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. 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.

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

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 INTERACTIONS — Ethanol: Ethanol may increase the risk of toxicity.

PREGNANCY RISK FACTOR — C (show table)

PREGNANCY IMPLICATIONS — Adverse 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 1st trimester exposure according to data collected by the antiretroviral pregnancy registry. Cases of lactic acidosis/hepatic steatosis syndrome have been reported in pregnant women receiving nucleoside analogues. It is not known if pregnancy itself potentiates this known side effect; however, pregnant women may be at increased risk of lactic acidosis and liver damage. Hepatic enzymes and electrolytes should be monitored frequently during the 3rd trimester of pregnancy in women receiving nucleoside analogues. Dose adjustment is not needed for pregnancy. The Perinatal HIV Guidelines Working Group considers abacavir to be an alternative NRTI in dual nucleoside combination regimens. Health professionals are encouraged to contact the antiretroviral pregnancy registry to monitor outcomes of pregnant women exposed to antiretroviral medications (1-800-258-4263 or www.APRegistry.com).

LACTATION — Excretion in breast milk unknown/contraindicated

BREAST-FEEDING CONSIDERATIONS — In 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 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 CONSIDERATIONS — May be taken with or without food.

PRICING — (data from drugstore.com)
Solution (Ziagen)
20 mg/mL (240): $132.55

Tablets (Ziagen)
300 mg (60): $545.02

MONITORING PARAMETERS — CBC 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

CANADIAN BRAND NAMES — Ziagen®

INTERNATIONAL BRAND NAMES — Abamune (IN); 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 ACTION — Nucleoside 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 / KINETICS
Absorption: 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)

PATIENT INFORMATION — If you experience any of the following: Fever, skin rash, fatigue, nausea, vomiting, diarrhea, abdominal pain, contact your prescriber immediately. This drug is not a cure for HIV infection, nor will it reduce the risk of transmission to others. You will need frequent blood tests to adjust dosage for maximum therapeutic effect. Take as directed; do not discontinue (even if feeling better). You may experience headache or muscle pain or weakness. If you are instructed to stop the medication, do not take this medication in the future. Do not restart without specific instructions by your prescriber