Topiramate - A review of its use in the treatment of epilepsy

Topiramate (Topamax) is a structurally novel broad-spectrum antiepileptic drug (AED) with established efficacy as monotherapy or adjunctive therapy in the treatment of adult and paediatric patients with generalised tonic-clonic seizures, partial seizures with or without generalised seizures, and seizures associated with Lennox-Gastaut syndrome. The incidence and severity of many adverse events, including CNS-related events, may be reduced through the use of slow titration to effective and well tolerated dosages. It is associated with few clinically significant interactions with other drugs, is effective when used with other AEDs, is not associated with drug-induced weight gain and, at lower dosages, does not interfere with the effectiveness of oral contraceptives. Therefore, topiramate is a valuable option as monotherapy or adjunctive therapy in the treatment of epilepsy in adult and paediatric patients. Pharmacological Properties Topiramate, a sulfamate-substituted derivative of the monosaccharide D-fructose, has been associated with a broad spectrum of antiepileptic activity in in vitro and animal studies. Although its precise mechanism of action is unknown, topiramate is considered to produce its antiepileptic effects through enhancement of GABAergic activity, inhibition of kainate/alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid-type glutamate receptors, inhibition of voltage-sensitive sodium and calcium channels, increases in potassium conductance and inhibition of carbonic anhydrase. Oral topiramate is rapidly absorbed in patients with epilepsy, with a relative bioavailability of approximate to 80%. The pharmacokinetics of topiramate are dose proportional, with steady state usually being reached in 4-8 days. Although approximate to 20-30% of topiramate is metabolised when it is administered as monotherapy, the metabolised proportion of the dose increases to 50-70% in patients receiving enzyme-inducing AEDs (e.g. carbamazepine and phenytoin). The rate of clearance is greater in paediatric patients than in adult patients, and in patients receiving enzyme-inducing AEDs than in those not receiving such AEDs. Therapeutic Efficacy In clinical trials, approved dosages (i.e. <= 400 mg/day) of topiramate as monotherapy or adjunctive therapy were effective in reducing the frequency of seizures in patients with primary generalised tonic-clonic seizures, partial seizures or seizures associated with Lennox-Gastaut syndrome. After 6 or 7 months of topiramate monotherapy in dosage comparison and noncomparative trials, 44-83% of patients were seizure free and, after 12 or 13 months, 41-76% of patients were seizure free. In subgroup analyses, topiramate was shown to be effective in paediatric and elderly populations and in treating both partial and generalised epilepsy. In comparative randomised trials, the efficacy of topiramate was generally similar to that of standard therapy with valproic acid (valproate) or carbamazepine, and to that of the newer AEDs gabapentin, lamotrigine and oxcarbazepine, with the exception of less favourable results with regard to time to treatment failure versus valproic acid in patients with generalised or unclassified epilepsy and lamotrigine in patients with partial epilepsy. Topiramate is also effective as an adjunctive AED. In randomised, double-blind trials of 8-12 weeks' duration in adult and/or paediatric patients with primary generalised tonic-clonic seizures or partial seizures, approved dosages of topiramate were generally significantly more effective than placebo in reducing the median seizure frequency from baseline (reduction of 30-57% vs 9-13%). In patients with Lennox-Gastaut syndrome, the frequency of drop seizures decreased by 15% in topiramate recipients and increased by 5% in placebo recipients. Topiramate provides long-term seizure control; patients with epilepsy receiving topiramate had 41-71% reductions from baseline in seizures in noncomparative trials of >= 6 months' duration. Pharmacoeconomic and Other Considerations In 2-year cost-utility analyses that included direct medical and social services costs in the UK, topiramate was predicted to be cost effective relative to standard treatment with valproic acid in adults with generalised or unclassified epilepsy across a range of thresholds for the cost per quality-adjusted life-year (QALY) gained and was preferred over lamotrigine. However, in adults with partial epilepsy, lamotrigine appeared to be cost effective relative to standard treatment with carbamazepine and was preferred over gabapentin and topiramate. In an observational 6-month UK study comparing adjunctive treatment with topiramate, vigabatrin, lamotrigine, gabapentin and clobazam in patients with refractory epilepsy, topiramate had high probability of being the optimal adjunctive AED treatment across a range of cost per QALY gained thresholds. Tolerability In patients with epilepsy, treatment with topiramate is commonly associated with CNS- and peripheral nervous system-related adverse events, including dizziness, ataxia, speech difficulty, paraesthesia, coordination abnormality, involuntary muscle contraction, stupor and vertigo. Tolerability to topiramate may improve with slower titration and dosage adjustments. Cognitive dysfunction associated with topiramate is generally mild to moderate in severity and primarily affects cognitive language and working memory. The carbonic anhydrase inhibitory effects of topiramate may result in metabolic acidosis, renal calculi and hypohidrosis. Topiramate is associated with weight loss in many patients, with obese patients experiencing the greatest loss during continued therapy.