Abstracts

Usually, valproate (VPA) therapy is started orally with an increase of 300mg every 2-3 days and a target dose of 1200-1800mg daily, which is established after 8-18 days. Meanwhile, no sufficient anticonvulsive effect is ensured. In patients with high seizure frequency, rapid achievement of therapeutic serum levels is essential. We evaluated the efficacy, tolerability, safety and pharmacokinetics of a 4-day i.v./oral VPA loading scheme. 49 patients with epilepsy or a first seizure under conditions that required anticonvulsive treatment, received 20mg/kg sodium valproate i.v within 10 minutes every 12h for 2 days (n=42). In patients with additional administration of enzyme inductors the dose was increased to 25mg/kg (n=7). Starting from day 3 the patients received 10mg/kg p.o. of slow-release VPA every 12h (12,5mg/kg in case of inductors). Serum levels of valproate were repetitively analyzed on day 1 and 4 at short intervals. Clinical data concerning efficacy and safety was collected on standardized case report forms. Follow-up visits took place 14 and 90 days after beginning of treatment. 6 patients were excluded, mainly due to incompliance or drug abuse. Highest VPA serum concentrations (cmax) typically were reached directly after i.v. administration (cmax/i.v. 93.8 to 213.8 mg/L, mean 140 mg/L). Lowest levels (cmin) were reached 12 h after i.v. administration (cmin/i.v. 20.3 to 57.2 mg/L, mean 39.0 mg/L). Cmax/p.o. after oral VPA administration was 52.3 to 142.5 mg/L, mean 90.6 mg/L. Cmin/p.o. was measured at day 4 prior to the morning dose (41.6 to 128.4 mg/L, mean 75.9 mg/L). The desired VPA level of 50-120 mg/L was reached in 37 of 43 patients. Subgroup analysis showed that despite of a higher dosing scheme patients additionally taking enzyme inductors reached lower concentrations, which accounts for 3 patients with serum levels below 50 mg/L. Adverse effects (day 1-4) were fatigue (n=9, 20.9%), injection site discomfort (n=6, 13.9%), dizziness (n=6, 13.9%), drowsiness (n=5, 11.6%), oral paresthesias and taste disturbances (n=4, 9.3%), headache (n=3, 6.9%), nausea (n=2, 4.7%), stomach pain (n=2, 4.7%), limb paresthesias (n=2, 4.7%), reversible toxic CNS reaction (n=2, 4.7%), vomiting (n=1, 2.3%), blurred or double vision (n=1, 2.3%), tinnitus (n=1, 2.3%). At follow-up visits, the quantity of adverse effects was not different from those reported in the literature. All patients except one experienced complete seizure control or reduction of seizure frequency. Intravenous VPA loading is an effective, rapid, well tolerated, and practicable way of VPA administration in patients at high risk of recurrent seizures. Adverse effects during i.v. VPA loading are comparable to those known from oral administration, except the occurrence of pain at the injection site and oral paresthesias with taste disturbances. (Supported by a grant from Sanofi-Synthelabo GmbH, Germany)