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5/19/2001

Oral Prodrug of Ganciclovir Approved for CMV Retinitis

Tzipora R. Lieder

Twelve years after the introduction of ganciclovir, Roche has obtained FDA approval for valganciclovir (Valcyte), an oral prodrug of the antiviral agent. Like intravenous (i.v.) ganciclovir, valganciclovir is indicated for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS. The oral dosage form of ganciclovir is indicated for use in these patients as maintenance therapy after retinitis has been stabilized by appropriate induction therapy or as treatment when the risk of more rapid disease progression is balanced by the benefit of avoiding daily i.v. infusions.

Both dosage forms of ganciclovir are also indicated for prevention of CMV infection in high-risk solid-organ-transplant recipients. Postmarketing research is evaluating the use of valganciclovir in these patients.

In an open-label study that led to the prodrug’s approval, 160 AIDS patients newly diagnosed with CMV retinitis were randomized to receive induction therapy with oral valganciclovir or i.v. ganciclovir. Patients in the valganciclovir group received 900 mg twice daily for 21 days, followed by 900 mg once daily for 7 days, while patients in the i.v. ganciclovir group received 5 mg/kg twice daily for 21 days, followed by 5 mg/kg once daily for 7 days. Progression of retinitis was determined on the basis of masked review of retinal photographs taken at baseline and week 4. After four weeks, the retinitis had not worsened in 64 of the 80 patients who took valganciclovir, compared with 63 of the 80 patients who received i.v. ganciclovir.

All of the patients in the study received valganciclovir after the fourth week; therefore, no comparative clinical data is available on the use of valganciclovir as maintenance therapy for CMV retinitis. However, pharmacokinetic studies have found that the area under the time-versus-ganciclovir-concentration curve (AUC) after the administration of 900 mg of valganciclovir is similar to the AUC after the administration of 5 mg/kg of i.v. ganciclovir. Ingestion of valganciclovir results in a lower maximum plasma concentration (Cmax) of ganciclovir than i.v. administration of ganciclovir produced but a higher Cmax than ganciclovir capsules produce.

Valganciclovir is rapidly converted to ganciclovir by esterases in the intestinal wall and liver. The bioavailability of valganciclovir is increased by a high-fat meal; therefore, the drug should be taken with food. Valganciclovir is eliminated renally as ganciclovir through glomerular filtration and active tubular secretion. In patients with impaired renal function, the half-life of ganciclovir is increased. Dosage adjustments for these patients must be based on creatinine clearance. Patients receiving hemodialysis cannot take valganciclovir because the daily dose they require is smaller than the contents of the available dosage form.

Valganciclovir’s labeling, like ganciclovir’s, carries a black-box warning concerning the risks of granulocytopenia, anemia, and thrombocytopenia. Patients’ blood counts should be closely monitored during therapy. Valganciclovir should not be used in pregnant or breastfeeding women, and women of childbearing potential should use effective contraception during treatment. Men should also be advised to practice barrier contraception during valganciclovir treatment and for at least 90 days afterward.

Other adverse events reported in clinical studies of valganciclovir include diarrhea, nausea, headache, vomiting, abdominal pain, pyrexia, insomnia, peripheral neuropathy, paresthesia, and retinal detachment. In the study comparing valganciclovir with i.v. ganciclovir, all adverse effects occurred at similar rates, with the exception of catheter-related infections, which were more common in patients who received i.v. ganciclovir.

Because of valganciclovir’s potential toxicities, care should be taken in handling valganciclovir tablets, and the tablets should not be broken or crushed.

The bioavailability of ganciclovir from valganciclovir tablets is significantly higher than from ganciclovir capsules. Patients should be cautioned not to substitute valganciclovir tablets for ganciclovir capsules on a one-to-one basis. The recommended dosage of valganciclovir for induction therapy in patients with active CMV retinitis is 900 mg twice daily with food. Patients with inactive CMV retinitis and those with active disease who have completed induction therapy should receive 900 mg once daily with food.

Valcyte is supplied as 450-mg tablets.