The FDA has granted marketing approval to valacyclovir hydrochloride (Valtrex/Glaxo Wellcome) for treating herpes zoster (shingles) in immunocompetent adults. The manufacturer describes Valtrex as the successor to its acyclovir (Zovirax).
Valacyclovir HCl is the hydrochloride salt of the L-valyl ester of acyclovir. The molecule was designed to improve on the relatively low bioavailability of acyclovir after oral administration. Valacyclovir, which is administered orally, is rapidly absorbed from the gastrointestinal tract. The compound is rapidly and almost totally converted to acyclovir and L-valine by first-pass metabolism in the intestines, liver, or both. Phase I trials examined the pharmacokinetics of valacyclovir with single doses of 100 to 1000 mg and multiple doses of 250 to 2000 mg. The bioavailability of acyclovir after administration of valacyclovir was roughly three to five times that previously observed after oral administration of 800 mg acyclovir. The higher valacyclovir doses produced maximum plasma concentrations and areas under the concentration-time curve (AUC) that were equivalent to those produced by intravenously administered acyclovir. (Weller S et al. Clin Pharmacol Ther. 1993; 54: 595-605.) The enhanced pharmacokinetics of valacyclovir suggest the potential for superior clinical efficacy over oral acyclovir. (Darby G. J Int Med Res. 1994; 22(suppl 1): 33A-42A.)
Acyclovir has a high affinity for the viral enzyme thymidine kinase, which is encoded by herpes simplex virus, varicella zoster virus, and Epstein-Barr virus. The enzyme converts the drug to acyclovir monophosphate, and cellular enzymes further convert it to the diphosphate and then the triphosphate. The triphosphate molecule blocks replication of viral DNA by competitive inhibition of viral DNA polymerase, incorporation and termination of the growing viral DNA chain, and inactivation of viral DNA polymerase.
FDA approval was based on data from two randomized, double- blind clinical trials involving immunocompetent patients with localized herpes zoster. One trial compared valacyclovir with placebo in patients less than 50 years of age. The other compared valacyclovir with acyclovir in patients older than 50 years. In both trials, treatment began within 72 hours after shingles rash appeared. In the trial with the younger patients, those receiving valacyclovir had a median time of 2 days to cessation of new lesion formation, compared with 3 days for the placebo group. In the trial with the older patients, formation of new lesions ceased after a median 3 days in both the valacyclovir and acyclovir groups. No significant difference in the duration of post-herpetic neuralgia was found between valacyclovir and placebo. In the valacyclovir-acyclovir comparison, a statistically nonsignificant trend toward a shorter duration of post- herpetic neuralgia was evident in the valacyclovir group (40 to 43 days vs 59 days).
In the comparison with acyclovir, the most common adverse events in the valacyclovir group were nausea (16% of patients), headache (13%), vomiting (7%), diarrhea (5%), constipation (5%), asthenia (4%), dizziness (4%), abdominal pain (3%), and anorexia (3%). In the comparison with placebo, the most common adverse events in the valacyclovir group were headache (17%), nausea (10%), vomiting (4%), diarrhea (4%), asthenia (3%), dizziness (2%), abdominal pain (2%), constipation (1%), and anorexia (less than 1%). Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome has been reported in patients with advanced HIV disease and in recipients of renal and bone marrow transplants. However, use of Valtrex is not indicated for immunocompromised patients.
Valtrex is supplied as film-coated caplets containing 500 mg valacyclovir. The manufacturer recommends a dosage for herpes zoster of 1 g (two caplets) by mouth three times a day for 7 days. Patients should begin taking the drug at the earliest sign of shingles (the medication is most effective when started within 48 hours of the appearance of rash). Efficacy when treatment starts more than 72 hours after onset of rash has not been determined. Dosage modification may be required for patients with renal impairment and for the elderly (depending on renal function). Valacyclovir use has not been evaluated for children. Concomitant administration of cimetidine, probenecid, or both may reduce the rate but not the extent of conversion of valacyclovir to acyclovir. (FDC Reports. 1995;17 Jul: p. T&G3. Additional information requested of and supplied by the manufacturer.)
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