Abacavir (Systemic)
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VA CLASSIFICATION
Primary: AM840
Commonly used brand name(s): Ziagen.
Another commonly used name is
ABC{05}
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Antiviral (systemic)—
Indications
General considerations
Human immunodeficiency virus (HIV-1) isolates with reduced susceptibility to abacavir have been recovered in vitro , as well as from some patients treated with this medication. Genetic analysis of isolates from patients treated with abacavir alone has found point mutations in the reverse transcriptase gene that resulted in amino acid substitutions at positions K65R, L74V, Y115F, and M184V; M184V and L74V mutations were observed most frequently in clinical isolates. Phenotypic analysis of HIV-1 isolates with abacavir-associated mutations from 17 patients after 12 weeks of monotherapy with abacavir found a threefold decrease in susceptibility to abacavir in vitro . However, the clinical significance of these genotypic and phenotypic findings has not been established. {01}
In vitro, cross-resistance has been observed with other nucleoside reverse transcriptase inhibitors; recombinant laboratory strains of HIV-1 (HXB2) containing multiple reverse transcriptase mutations conferring abacavir resistance exhibited cross-resistance to lamivudine, didanosine, and zalcitabine.
Cross-resistance between abacavir and HIV-protease inhibitors is unlikely because the enzyme targets involved are different. Cross-resistance between abacavir and non-nucleoside reverse transcriptase inhibitors is unlikely because the binding sites on reverse transcriptase are different. {01}
Accepted
Human immunodeficiency virus (HIV) infection (treatment)—Abacavir is indicated, in combination with other agents, for treatment of HIV-1 infection {01}.
Note: This indication is based on analyses of surrogate markers in controlled studies of up to 24 weeks duration {01}. Currently, there are no data from controlled clinical trials evaluating long-term suppression of HIV RNA or disease progression with abacavir therapy {01}.
Patients may continue to experience illness associated with HIV infection, including opportunistic infections {01}.
Treatment with abacavir does not reduce the risk of transmission of HIV to others through sexual contact or blood contamination {01}.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Source—
Synthetic {01}.
Chemical group—
Carbocyclic synthetic nucleoside analog {01}.
Molecular weight—
670.76 daltons {01}
Mechanism of action/Effect:
Reverse transcriptase inhibitor. Activity follows intracellular conversion by cellular enzymes to the active metabolite, carbovir triphosphate, which is an analog of deoxyguanosine-5´-triphosphate (dGTP). Carbovir triphosphate competes with the natural substrate dGTP and is incorporated into viral DNA, inhibiting the activity of HIV-1 reverse transcriptase. The incorporated nucleoside analog lacks a 3´-OH group, and thus prevents formation of the 5´ to 3´ phosphodiester linkage that is essential for DNA chain elongation, terminating viral DNA growth. {01}
Absorption:
Rapid and extensive {01}. The geometric absolute bioavailability of the tablet is 83% and is not affected by food; systemic exposure to the oral solution is comparable {01}.
Distribution:
Vol D= 0.86 ± 0.15 liter per kg (L/kg), following intravenous administration. {01}
Concentrations in cerebrospinal fluid (CSF) range from 27 to 33% of those in plasma {01}. Readily distributed into erythrocytes, as indicated by identical total blood and plasma drug-related radioactivity concentrations {01}.
Protein binding:
Moderate (approximately 50%); unrelated to concentration {01}.
Biotransformation:
Hepatic, by alcohol dehydrogenase (to the 5´-carboxylic acid metabolite) and glucuronosyltransferase (to the 5´-glucuronide metabolite). Metabolites do not have antiviral activity. Not significantly metabolized by cytochrome P450 enzymes. {01}
Half-life:
Elimination—1.54 ± 0.63 hours {01}.
Steady-state
Adults—3 ± 0.89 mcg per mL following oral administration of 300 mg twice daily {01}.
Children—3.71 ± 1.36 mcg per mL following oral administration of 8 mg per kg of body weight (mg/kg) twice daily {01}.
Elimination:
Renal, 1.2% as abacavir, 30% as the 5´-carboxylic acid metabolite, 36% as the 5´-glucuronide metabolite, and 15% as other unidentified minor metabolites {01}.
Fecal, 16% {01}.
In dialysis—
It is not known whether abacavir is removable by hemodialysis or peritoneal dialysis {01}.
Note: Total clearance after intravenous administration is 0.8 ± 0.24 liters per hour per kg of body weight (L/hr/kg) (mean ± SD) {01}.
Precautions to Consider
Mutagenicity
Abacavir was found to induce chromosomal aberrations both in the presence and absence of metabolic activation in an in vitro cytogenicity study in human lymphocytes. It was mutagenic in the absence of metabolic activation, although it was not mutagenic in the presence of metabolic activation in an L5178Y mouse lymphoma assay. Abacavir was clastogenic in males and not clastogenic in females in an in vivo mouse bone marrow micronucleus assay at systemic exposures approximately nine times higher than that in humans at the therapeutic dose. Abacavir was not found to be mutagenic in bacterial mutagenicity assays in either the presence or the absence of metabolic activation. {01}
Pregnancy/Reproduction
Fertility—
No adverse effects on the mating performance or fertility of male and female rats were observed with abacavir at doses of up to 500 mg per kg of body weight (mg/kg) per day (producing exposures approximately eightfold higher than that in humans at the therapeutic dose based on body surface area comparisons). {01}
Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}.
Studies in rats revealed that abacavir crosses the placenta. At doses of 1000 mg/kg (35 times the human exposure, based on area under the curve [AUC]) during organogenesis, developmental toxicity (depressed fetal body weight and reduced crown-rump length) and increased incidences of fetal anasarca and skeletal malformations were found. In a fertility study, doses of 500 mg/kg per day were associated with evidence of toxicity to the developing embryos and fetuses (increased resorptions and decreased fetal body weights). Studies in female rats at doses of 500 mg/kg (beginning at embryo implantation and ending at weaning) showed an increased incidence of stillbirths and lower body weights throughout life. Studies in rabbits at doses of up to 700 mg/kg (8.5 times the human exposure at the recommended dose, based on AUC) found no evidence of drug-related developmental toxicity or increases in fetal malformations. {01}
Risk-benefit should be considered before use of abacavir during pregnancy {01}.
An Antiretroviral Pregnancy Registry has been established to monitor the outcomes of pregnant women exposed to abacavir. Physicians are encouraged by the manufacturer to register patients by calling (800) 258-4263. {01}
FDA Pregnancy Category C {01}.
Breast-feeding
It is not known whether abacavir is distributed into human breast milk {01}. However, it is distributed into the milk in lactating rats {01}. In addition, the Centers for Disease Control and Prevention recommends that HIV-infected mothers refrain from breast-feeding their infants to avoid risking postnatal transmission of HIV. Breast-feeding is not recommended during therapy with abacavir. {01}
Pediatrics
Safety and efficacy in children between the ages of 3 months and 13 years have been established in adequate and well-controlled studies {01}.
Geriatrics
No information is available on the relationship of age to the effects of abacavir in geriatric patients {01}.
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing the following medication, depending on the amount present, may also interact with this medication.
Ethanol (concurrent use with abacavir may result in increased concentrations and half-life of abacavir as a result of competition for common metabolic pathways via alcohol dehydrogenase {01})
Methadone (methadone clearance increased 22% in patients stabilized on oral methadone maintenance therapy who started abacavir therapy with 600 mg twice daily; increase in clearance will not be clinically significant in the majority of patients; methadone dosage increase may be required in a small number of patients )
{04}
Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Aspartate aminotransferase (AST [SGOT])
Gamma-glutamyltransferase (GGT) (values may be increased {01})
Creatine kinase (CK) or
Creatinine (serum values may be increased {01})
Glucose and
Triglycerides (mild increases in blood concentrations have been reported {01})
Hemoglobin and
Leukocytes (blood concentrations may be decreased {01})
Lactate, serum (plasma concentrations may be increased, indicating lactic acidosis, which has been reported in association with severe hepatomegaly with steatosis {01})
Lymphocytes (blood concentrations may be decreased {01})
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hypersensitivity reaction to abacavir (life-threatening hypersensitivity reactions can occur at any time during abacavir therapy and will recur with repeated exposure to abacavir following a previous hypersensitivity reaction {01}; patients developing symptoms of hypersensitivity should discontinue therapy as soon as a reaction is suspected {03})
Risk-benefit should be considered when the following medical problems exist
Hepatic disease or
Risk factors for hepatic disease (lactic acidosis and severe hepatomegaly with steatosis may occur in patients with liver disease or a predisposition toward liver dysfunction; fatal cases have been reported; treatment should be stopped in patients with evidence of lactic acidosis or hepatomegaly{03})
Side/Adverse Effects
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of antiretroviral nucleoside analogs, including abacavir, alone or in combination {01}.
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence less frequent
Hypersensitivity reaction {01}{02} (abdominal or stomach pain; cough; diarrhea; difficult or labored breathing ; fever; headache; joint or muscle pain; nausea; numbness or tingling of face, hands, or feet; redness and soreness of eyes; skin rash; shortness of breath; sore throat; sores in mouth; swelling of feet or lower legs; vomiting; unusual feeling of discomfort or illness; unusual tiredness)
Note: Symptoms of the hypersensitivity reaction usually occur within the first 6 weeks of treatment, although they may occur at any time, and indicate multi-organ/body involvement {01}. The reaction may be severe, progressing to anaphylaxis, hepatic failure, renal failure, hypotension, and death {01}. Symptoms worsen with continued therapy but frequently resolve on withdrawal of abacavir {01}. However, re-exposure to abacavir following a previous hypersensitivity reaction will produce more severe symptoms within hours, possibly including life-threatening hypotension and death {01}.
The skin rash is usually maculopapular or urticarial, but the appearance varies and hypersensitivity reactions have occurred without skin rash {01}.
The diagnosis of hypersensitivity reaction should be carefully considered for patients presenting with acute onset respiratory disease symptoms, even if alternative respiratory diagnoses (pneumonia, bronchitis, pharyngitis, or flu-like illness) are possible {02}.
Other physical findings with the hypersensitivity reaction include lymphadenopathy and mucous membrane lesions {01}. Laboratory value alterations may include elevated hepatic function values, creatine kinase, or creatinine, and lymphopenia {01}.
An Abacavir Hypersensitivity Registry has been established to facilitate the reporting of hypersensitivity reactions and to collect information about each case. Physicians are encouraged by the manufacturer to register patients by calling (800) 270-0425.
A warning card which provides information about recognition of abacavir hypersensitivity reactions should be dispensed to the patient with each new prescription and refill {02}.
Incidence rare
Hepatotoxicity {01} , including lactic acidosis ( abdominal discomfort; nausea; decreased appetite; general feeling of discomfort; diarrhea; fast, shallow breathing; muscle pain or cramping; shortness of breath; sleepiness; unusual tiredness or weakness)
pancreatitis (abdominal pain and distention ; fever; nausea; vomiting )
Note: Hepatotoxicity, consisting of lactic acidosis and severe hepatomegaly with steatosis, has been reported with nucleoside therapy (including abacavir), alone or in combination {01}. Fatalities have occurred {01}. The majority of cases have occurred in women {01}. Possible risk factors include obesity and prolonged nucleoside exposure, as well as other risk factors for liver disease, although cases have occurred in the absence of any known risk factors {01}.
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Diarrhea
fatigue
headache
loss of appetite
nausea or vomiting {01}
Incidence less frequent
Insomnia {01} (trouble in sleeping)
Overdose
There is no specific information on overdose with abacavir {01}.
For information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing).
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Abacavir (Systemic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Sensitivity to abacavir
Pregnancy—Causes birth defects and slowed growth in animals; risk-benefit should be considered
Breast-feeding—Not recommended because of the potential for postnatal transmission of HIV and for adverse effects
Proper use of this medication
» Compliance with therapy
» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses {01}
» Proper storage
Precautions while using this medication
» Checking with physician immediately if signs or symptoms of a hypersensitivity reaction (cough, dyspnea, fever, skin rash, fatigue, gastrointestinal symptoms, or pharyngitis) occur
Carrying warning card for recognition of hypersensitivity reaction {02}
Side/adverse effects
Signs of potential side effects, especially hypersensitivity reaction, hepatotoxicity, including lactic acidosis, and pancreatitis
General Dosing Information
It is recommended that abacavir be permanently withdrawn at the first sign of a hypersensitivity reaction {01}. Therapy with abacavir should not be restarted because more severe symptoms will recur within hours, possibly including life-threatening hypotension and death {01}.
It is recommended that abacavir therapy be withdrawn if clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (possibly including hepatomegaly and steatosis, with or without marked transaminase elevations) occur {01}.
Oral Dosage Forms
Note: Dosing and strengths of the dosage forms available are expressed in terms of abacavir base (not the sulfate salt) {01}.
ABACAVIR SULFATE ORAL SOLUTION
Usual adult and adolescent {01} dose
Human immunodeficiency virus (HIV) infection
Oral, 300 mg (base) two times a day, in combination with other antiretroviral agents {01}.
Usual pediatric dose
Human immunodeficiency virus (HIV) infection
Children up to 3 months of age: Safety and efficacy have not been established. {01}
Children 3 months to 16 years of age: Oral, 8 mg (base) per kg of body weight (up to 300 mg) two times a day, in combination with other antiretroviral agents {01}.
Children 16 years of age and older: See Usual adult and adolescent dose{01}.
Usual pediatric prescribing limits
600 mg per day.
Strength(s) usually available
U.S.—
20 mg per mL (Rx) [Ziagen (methylparaben and propylparaben) (saccharin sodium) (sorbitol)]
Packaging and storage:
Store between 20 and 25 ºC (68 and 77 ºF) {01}, unless otherwise specified by manufacturer. Protect from freezing {01}. May be refrigerated. {01}
ABACAVIR SULFATE TABLETS
Usual adult and adolescent dose
Human immunodeficiency virus (HIV) infection
See Abacavir Sulfate Oral Solution{01}.
Usual pediatric dose
Human immunodeficiency virus (HIV) infection
See Abacavir Sulfate Oral Solution{01}.
Strength(s) usually available
U.S.—
300 mg (base) (Rx) [Ziagen]
Packaging and storage:
Store between 20 and 25 ºC (68 and 77 ºF) {01}, unless otherwise specified by manufacturer.
Developed: 06/14/1999
Revised: 02/10/2003
References
- Ziagen package insert (Glaxo Wellcome—US), Rev 12/98, Rec 1/99.
- Product Information: Ziagen®, abacavir sulfate tablets and oral solution. Glaxo Wellcome, Research Triangle Park, NC, (PI revised 1/2000) reviewed 4/2000.
- Product Information: Ziagen®, abacavir sulfate tablets and oral solution. Glaxo Wellcome, Research Triangle Park, NC, (PI revised 07/2000) reviewed 09/2000.
- Product Information: Ziagen®, abacavir sulfate tablets and oral solution. Glaxo Wellcome, Research Triangle Park, NC, (PI revised 12/2000) reviewed 05/2001.
- Feinberg, William, R.Ph.,M.B.A., 2002 Update Pharmacy Perspective: Acquired Immune Deficiency Disease. CE PRN®2002; 13-18.
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