Zidovudine
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Zidovudine |
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The information represented on this drug does not necessarily correspond
with the information that can be found in the Belgian scientific
leaflet.
Zidovudine was approved by the FDA in 1987 as the first antiretroviral
drug. (It was originally developed in the 1960s as an anticancer drug).
Zidovudine is sequentially phosphorylated by cellular enzymes until
it is activated to Zidovudine-triphosphate. This acts as a competitive
inhibitor of the viral reverse transcriptase, and, when incorporated
into growing viral RNA strands, causes chain termination. It is one
of the few drugs that has been proven to retard or prevent HIV-1-associated
central nervous system disease. (100)
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USA (FDA)
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| Pharmaceutical co.: Glaxo Wellcome Inc. | Belgium:
Reimbursable since: Capsules 100MG: May 1987 Capsules 250MG: December 1988 Syrup : January 1994 Others : April 1997 |
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| Active
Ingredient |
Dosage form;
Route |
Strength | ||||||
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Zidovudine | Capsule; Oral | 100MG | |||||
| Zidovudine | Capsule; Oral | 250MG | ||||||
| Zidovudine | Injectable; Injection | 10MG/ML | ||||||
| Zidovudine | Syrup; Oral | 10MG/ML | ||||||
| Zidovudine | Tablet; Oral | 200MG | ||||||
| Zidovudine | Tablet; Oral | 300MG | ||||||
In its oral formulation, zidovudine is well absorbed, with approximately 60% oral bioavailability. Because its intracellular half-life is approximately 3 to 4 hours, multiple doses are required each day. Zidovudine can be administered with food or while fasting. Because zidovudine is metabolized in part by the kidney, the dose should be reduced in patients with significant renal disease. Dose reductions are not necessary in patients with hepatic insufficiency. Zidovudine penetrates the cerebrospinal fluid to levels 20 to 30% of those in plasma. (106)
The standard dosage of zidovudine is 600 mg daily. (100) The FDA has approved a 300-mg formulation, which allows for convenient twice daily dosing and should improve compliance. (106)
Maternal dosing: (111)
- Prepartum: Staring after 14 weeks of pregnancy, 100 mg five times daily until start of labor.
- Intrapartum: Administer intravenous zidovudine at 2 mg/kg over 1 hour followed by a continuous intavenous infusion of & mg/kg/hour until clamping of the umbilical cord.
Pediatric dose: (111)
- 3months to 12 years: 180 mg/m²/dose every 6 hours, not exeed 200 mg every 6 hours.
- Infants: 2 mg/kg orally every 6 hours starting within 12 hours after brith and continuing through 6 weeks of age. Infants unable to receive oral dosing may be given zidovudine at 1,5 mg/kg, infused over 30 minutes, every 6 hours.
When used at current doses in asymptomatic patients, zidovudine is relatively well tolerated. Most side effects occur in patients with advanced HIV disease. All side effects associated with zidovudine are reversible on drug discontinuation. The primary toxicities associated with zidovudine are neutropenia and anemia. (113) These are inversely related to the starting CD4 lymphocyte count, hemoglobin concentration, and granulocyte count, and directly related to dosage and duration of therapy. Significant anemia most commonly occurs after 4 to 6 weeks of therapy. Myopathy is a relatively uncommon, potentially serious complication of zidovudine therapy (and may be difficult to distinguish from primary HIV myopathy (100)). Nausea is the most common gastrointestinal side effect, occurring in approximately 5% of asymptomatic patients and up to 50% of patients with more advanced HIV disease. Zidovudine has also been associated with seizures, macular edema, and the Stevens-Johnson syndrome, although the casual relationship remains uncertain. Other side effects are fatigue, malaise, insomnia, headache, restlessness, and hyperpigmentation of the nails and skin. (106,114)
The combination of zidovudine and ganciclovir is poorly tolerated in
patients with advanced HIV disease and serious cytomegalovirus disease,
with 82% developing severe to life-threatening hematologic toxicity.(127)
The toxicity probably is not a pharmacologic interaction but represents
combined myelosuppression of the two drugs. Extreme caution is necessary
when zidovudine and ganciclovir are co-administered. Probenecid inhibits
hepatic glucuronidation and secretion of zidovudine through the renal tubules,
resulting in increased serum concentrations and a prolonged elimination
half-life. This may increase the risk of toxicity or possibly permit a
reduction in daily zidovudine dosage. Anemia and neutropenia are more common
when zidovudine and trimethoprim are combined. Trimethoprim can decrease
the renal clearance of zidovudine and possibly increase the serum concentration
of zidovudine. Zidovudine can either decrease or increase phenytoin concentrations;
therefore, phenytoin concentrations should be monitored in patients receiving
both agents. Methadone has been shown to decrease zidovudine metabolism,
however, no dosage adjustment is currently recommended. (114)
| Interactions with other antiretroviral agents | |
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