What is the role of topiramate in the treatment of epilepsy?

Updated: Jan 28, 2020
  • Author: Juan G Ochoa, MD; Chief Editor: Selim R Benbadis, MD  more...
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Topiramate is a very potent anticonvulsant that is structurally different from other AEDs. It is derived from D-fructose and initially was developed as an antidiabetic drug. In animal models, it was found to have potent antiepileptic effects. Topiramate has multiple mechanisms of action. It exerts an inhibitory effect on sodium conductance, decreasing the duration of spontaneous bursts and the frequency of generated action potentials, enhances GABA by unknown mechanisms, inhibits the AMPA subtype glutamate receptor, and is a weak inhibitor of carbonic anhydrase.

Topiramate is absorbed rapidly after oral administration and has a bioavailability close to 100%. When it is administered at regular doses, food delays but does not affect the extent of absorption. The time to peak blood levels is about 2 hours. The volume of distribution ranges from 0.6-1.0 L/kg. Plasma protein binding is approximately 15%.

Only 15% of topiramate is metabolized in the liver by the P-450 microsomal enzyme system. None of the metabolites has antiepileptic action, and the majority of the drug (ie, 85%) is excreted unchanged in the urine. However, metabolism is much more extensive in patients on polytherapy, presumably as a result of enzyme induction.

In patients with renal failure, doses may have to be reduced. The elimination half-life ranges from 18-23 hours and is independent of dose over the normal clinical range. In experimental settings, no tolerance to topiramate has been recorded.

Enzyme-inducing drugs, such as PHT and CBZ, decrease serum topiramate concentrations by approximately 50%. Topiramate generally does not affect the steady-state concentrations of the other drugs given in polytherapy, although PHT levels may rise occasionally. Topiramate reduces ethyl estradiol levels by 30% and may inactivate the low-dose contraceptive pill. It may cause a mild reduction in digoxin levels.

Topiramate has a marked antiepileptic effect, as demonstrated in 6 double-blind, parallel-group, placebo-controlled, add-on trials and in a variety of open studies. As many as 5% of the patients became seizure free in some trials, 44% had a greater than 50% reduction in seizure frequency (compared to 12% of patients on placebo), and 21% had a greater than 75% reduction in seizure frequency.

Meta-analysis of placebo-controlled parallel-group studies of topiramate and the other new AEDs has shown greater effects from topiramate than from any of the other drugs in comparison with placebo. Topiramate has also been effective as adjunctive therapy in drug-resistant generalized epilepsies, including juvenile myoclonic epilepsy, absence and generalized tonic-clonic seizures, and Lennox-Gastaut syndrome.

In the United States, topiramate currently is approved for (1) partial onset and secondarily generalized tonic-clonic seizures, (2) primary generalized tonic-clonic seizures, and (3) Lennox Gastaut syndrome.

Topiramate is available as 25 mg, 50 mg, 100 mg, and 200 mg tablets and as 15 mg and 25 mg sprinkle formulations. A parenteral form is not available.

Topiramate should be started at a low dosage and titrated slowly to prevent adverse effects. Recommended starting dosage is 25 mg/d; this is increased in weekly or biweekly increments of 25-50 mg. Maintenance dosage is 200-600 mg/d in 2 divided doses. In children, the usual starting dosage is 0.5-1 mg/kg/d with increments of 0.5-1 mg/kg/d every 2 weeks. In clinical trials, pediatric dosing in the range of 9-11 mg/kg/d produced optimal seizure control.

The most common adverse effects of topiramate include ataxia, impairment of concentration, confusion, dizziness, fatigue, paresthesia in the extremities, somnolence, disturbance of memory, depression, agitation, and slowness of speech. If the drug is continued, many adverse effects subside within a few weeks.

The most common adverse effects in children are somnolence, anorexia, fatigue, and nervousness. The drug causes weight loss in many patients, sometimes more than 10 kg, an effect that may lead to discontinuance. The weight loss appears to be related to appetite suppression. As a carbonic anhydrase inhibitor, topiramate also has a propensity to cause renal calculi; therefore, patients should be encouraged to drink plenty of fluids.

No idiosyncratic severe reactions or allergic rashes have been reported; however, in the author’s experience, several cases of pruritus have occurred, always associated with previous history of allergic rash to other medications. No hepatotoxicity, hematologic toxicity, serious gastrointestinal (GI) toxicity, or cardiotoxicity have been documented. Recently, acute myopia with angle-closure glaucoma has been reported as a rare adverse event associated with topiramate.

Most physicians agree that topiramate is a highly effective AED. The adverse cognitive effects occur more frequently at higher doses and with a rapid titration rate. These cognitive adverse effects can be reduced by using a slow titration rate of 25 mg every week, until 200 mg/d is reached. Subsequently the dose can be increased in weekly increments of 25-50 mg/d to a target dose of 400-600 mg/d. In the author’s experience, very slow titration, occasionally by increments of 25 mg/d biweekly, has improved tolerability in sensitive patients.

Obese patients with epilepsy may benefit from this drug because of its weight-loss–inducing effect. Topiramate is also indicated as a prophylactic agent in patients with migraine headaches. [73, 74, 75, 76, 77, 78, 79]

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