Pharmacology

Topiramate, a sulphamate-substituted monosaccharide, is structurally distinct from other antiepileptic drugs. It probably works by blocking sodium channels, so preventing the spread of seizure activity, and by increasing synaptic levels of the inhibitory neurotransmitter gaba-amino-butyric acid (GABA). Topiramate also blocks neurotransmission to selected glutamate receptors though the clinical significance of this effect in seizure prevention is not known. Topiramate is a weak inhibitor of carbonic anhydrase but this is not thought to contribute to any antiepileptic action.

About 80% of oral topiramate is absorbed with plasma levels peaking 2-4 hours after a dose is taken. Food may delay, but does not reduce, absorption. In healthy volunteers most unchanged topiramate and its metabolites (which are inactive) are excreted by the kidney. The elimination half-life of the drug is 19-23 hours.2 Around 15% of topiramate is bound to plasma proteins. Plasma concentrations of topiramate correlate poorly with the drug's efficacy3 therefore monitoring of topiramate blood levels for dose guidance is unhelpful.

Efficacy

In three randomised, double-blind, placebo-controlled trials,4–6 (two of which are published only as abstracts4^,5) a total of 163 patients with refractory partial epilepsy received topiramate 200-400mg twice daily or placebo, plus their usual antiepileptic medication. The seizure rate was more than halved in 35-47% of patients taking topiramate but in only 0-10% of those on placebo.

A meta-analysis of data from these and two other randomised placebo-controlled trials (total 534 patients), also published only as an abstract, concludes that topiramate (100-500mg twice daily) was also better than placebo in reducing the rates of secondarily generalised seizures (76% vs. 36% reduction, respectively), complex partial seizures (41% vs. 2%) and simple partial seizures (58% reduction vs. 15% increase). 7 More patients on topiramate (19%) than on placebo (3%) had a 75% reduction in seizures and more became seizure-free (4% vs. 0). A summary of the results from the five trials, which is published in the promotional brochure for topiramate shows that efficacy is unlikely to be increased by giving doses over 400mg/day.8

There are no published studies comparing topiramate with other adjunctive drugs such as lamotrigine or gabapentin. Topiramate is not licensed for use in children under 12 years.

Unwanted effects

The promotional brochure for topiramate presents the incidences of the commonest unwanted effects reported in clinical trials involving a total of 360 patients.8 The main effects were dizziness (32% of patients), fatigue (29%), drowsiness (24%), abnormal thinking, such as, 'mental slowing' and 'inability to think clearly' (23%), impaired concentration (14%), confusion (17%), ataxia (19%) and paraesthesia (15%). From these data, it is difficult to assess the overall effect on cognitive function. 14% of patients on topiramate compared with 3.5% of those on placebo withdrew from treatment in the first 4 months because of adverse effects. The data sheet states that topiramate may cause agitation, emotional lability and depression. The CSM has received reports of psychiatric symptoms, including aggression (3 reports), euphoria (2), abnormal behaviour (2) and psychosis (1).

A review of topiramate's unwanted effects, published as an abstract,9 reports that 80-90% of the effects occurred at the start of treatment during dose titration. The authors suggest that too rapid titration might have been the cause of some of the toxicity. However, many of our consultants find that some patients are unable to tolerate the drug even with titration slower than that recommended in the data sheet.

Weight loss of up to 7% occurred in some patients. The reason for this is not known. This typically began within the first 3 months of treatment. Renal stone formation has also been reported occasionally.10

Precautions

Topiramate is teratogenic in animals. In general, it should not be given to women who are pregnant or who have child-bearing potential and are not using effective contraception.11 It is not known if topiramate is excreted in breast milk but as a precaution lactating women should not breastfeed if on the drug.

Patients with a personal or family history of renal stones or hypercalciuria should be advised to drink plenty of fluids while on topiramate.

Drug interactions

Phenytoin12 and carbamazepine13 reduce topiramate plasma concentrations. Topiramate itself may increase plasma phenytoin concentrations (possibly through inhibition of the CYP2C19 isoform of cytochrome P450)14 and may lower serum digoxin concentrations. There appears to be no clinically significant interaction between sodium valproate and topiramate.15 The effectiveness of the combined oral contraceptive pill may be reduced by topiramate and women taking a contraceptive pill will probably need one containing at least 50µg of oestrogen.

Dosage

Topiramate is available in 25mg, 50mg, 100mg and 200mg tablets. In reported trials, most patients needed a maintenance dose of between 200 and 600mg daily in two divided doses. The data sheet recommends starting with 50mg twice daily, increasing after one week to 100mg twice daily and then increasing the total daily dose by 200mg each week until seizures are controlled or unwanted effects develop (up to a maximum of 800mg daily). If the patient is unable to tolerate the titration regimen, lower increments or longer intervals should be used. Many of our consultants use a slower titration for most patients: starting with 25-50mg daily, increasing the daily dose by 25-50mg weekly or fortnightly (up to 100mg twice daily) and then by 100mg each week or fortnight up to a maximum of 800mg daily. Patients with renal impairment and those not taking a liver enzyme-inducing drug will probably require the slower titration regimen (with increments every 2 weeks) and lower maintenance doses. Age and hepatic impairment have only minimal effects on topiramate kinetics. In general, when withdrawing topiramate, the total daily dose should be reduced by no more than 100mg each week to avoid the possibility of provoking rebound seizures. However, some patients tolerate faster withdrawal rates.

Conclusion

Topiramate is an effective adjunctive treatment for adults with refractory partial epilepsy. However, it can impair cognitive function, causing mental slowing and/or impaired concentration and occasionally causes renal stones. Topiramate has not been compared in clinical trials with other adjunctive antiepileptics. Until comparative studies are done, the place of topiramate as adjunctive treatment for epilepsy will remain unclear.