Topamax (Topiramate)

What Is Topiramate?

Epilepsy is a group of disorders of the brain characterized by recurring episodes of convulsive seizures, sensory disturbances, abnormal behavior, loss of consciousness, or all of these. In all types of epilepsy, an uncontrolled electrical discharge from the nerve cells in the cerebral cortex of the brain is evident. While the cause of most types of epilepsy is unknown, it can be associated with a head injury, infection, brain tumor, intoxication, or chemical imbalance.

Topiramate is a new drug that has shown promise in the treatment of epilepsy. Since preliminary evaluation has been encouraging, double-blind, placebo-controlled trials were established to better define the effectiveness, safety, and appropriate dose range of topiramate for refractory partial epilepsy. This study aimed to evaluate a medium-to-high dose range consisting of daily dosages of 600, 800, and 1,000 mg of topiramate.

The FDA has approved a novel antiepileptic agent – topiramate (Topamax/Ortho-McNeil)-for the adjunctive treatment of adults with partial-onset seizures. Topiramate was identified by scientists at the National Institutes of Health during random screening of promising drug candidates and was developed by the R.W. Johnson Pharmaceutical Research Institute. The drug blocks voltage-sensitive sodium channels, enhances the activity of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), and blocks the action of the excitatory neurotransmitter glutamate. It also inhibits carbonic anhydrase, although this may not contribute to anticonvulsant activity.

In five placebo-controlled, double-blind clinical trials, topiramate significantly reduced the frequency of epileptic seizures, including refractory partial seizures. In dosage studies, topiramate given at 200, 400, 600, 800, and 1,000 mg per day at 200-mg doses gave inconsistent results, and increasing the dose beyond 400 mg per day did not increase efficacy. One trial included 45 patients who received 400 mg/day; 44% responded with at least a 50% reduction in seizure frequency compared with baseline. In a second trial, 35% of 23 patients who received the 400-mg/day dose showed a 50% reduction in seizure rate. By comparison, 24% of patients receiving the 200-mg/day dose showed a seizure reduction rate of about 27%, and approximately 36 to 46% of patients responded to 600, 800, and 1,000 mg/day with a 36 to 46% reduction in seizure rates (response generally decreased as the dosage was increased). Placebo patients showed little or no response and often showed increases in seizure frequency. Based on overall clinical results, topiramate appears to be a more potent anticonvulsant than Warner Lambert’s gabapentin (with response rates of 22-26%) and Glaxo Wellcome’s lamotrigine (seizure reduction, 25-36%).

How to Take

Topiramate is initially given at 50 mg/day, gradually increasing during an 8-week titration period to 400 mg/day in two divided doses. Oral bioavailability is about 80%, and food has no clinically significant effect on absorption. At 200 to 800 mg dosages, serum concentrations are linearly dose-related, and there is little intersubject variability. Plasma protein binding is less than 20%. Single-dose studies in healthy adults have revealed that the drug is about 20% metabolized. However, with multiple dosing in patients taking other antiepileptic drugs, up to 50% of the dose is metabolized. Elimination is primarily renal, with 50 to 80% of the dose excreted as unchanged topiramate; elimination half-life is 20 to 30 hours. Age, gender, race, baseline seizure rate, and concomitant antiepileptic drugs do not appear to affect efficacy, although topiramate may interact with phenytoin (Dilantin/Warner-Lambert) and carbamazepine (Tegretol/Novartis). Adding topiramate to a regimen that includes phenytoin may require adjustment of the phenytoin dose; addition or withdrawal of phenytoin and/or carbamazepine to the topiramate regimen may require adjustment of the dose of topiramate.

Side Effects

At the 200- to 400-mg dose range, the most frequent adverse effects in clinical trials were psychomotor slowing (incidence about 17%), difficulty concentrating (8%), speech and language problems (about 6%), somnolence (30%), and fatigue (11-12%). These reactions were generally dose-related. Similar side effects (although less frequent) were seen with lamotrigine and gabapentin. During clinical studies, 1.5% of topiramate-treated patients developed kidney stones, which represents a two- to fourfold increase over the average rate of stone formation. This may be due to carbonic anhydrase inhibition and is managed by increasing fluid intake. Another side effect thought to be related to carbonic anhydrase inhibition is paresthesia. The use of topiramate with other carbonic anhydrase inhibitors should be avoided. Approximately 11% of patients withdrew from clinical trials because of adverse events, primarily central nervous system (CNS) effects, paresthesias, and, at higher dosages, anorexia and weight loss.

Although topiramate has been approved only for adults, Johnson & Johnson is studying the drug in pediatric patients with epileptic disorders, including generalized seizures and Lennox-Gastaut syndrome.

Is Topiramate Effective for All Types of Epilepsy?

The primary studies that have been completed and submitted to the U.S. FDA for approval were conducted in patients with refractory partial epilepsy. Open-label studies of this medication included patients who had other types of epilepsy, and anecdotal experience suggests the drug may be effective in other seizure types. There are currently ongoing studies looking at other seizure types, such as generalized epilepsies and the Lennox-Gastaut Syndrome. The Lennox-Gastaut syndrome is a severe form of epilepsy typically seen in childhood and is considered one of the most difficult epileptic syndromes to treat. The results of these studies may be presented at national meetings in the next year or two.

Is Topiramate Synthetic or Naturally Derived, and What Is Its Discovery Story?

Topiramate is a synthetic compound developed by the Johnson & Johnson Pharmaceutical Research Institute. Its effectiveness in epilepsy was discovered through the collaborative program of the National Institutes for Health Epilepsy Branch. The Epilepsy Branch program allows corporations to submit compounds that might be effective in epilepsy to be evaluated in a series of animal tests and compared to standard antiepileptic drugs. This program has screened thousands of compounds over the last two decades. Topiramate was one of the compounds found to be highly effective in animal models and so was moved on to testing in humans with epilepsy.

Planned Trials Comparing Topiramate’s Efficacy and Safety with Similar Drugs

Most experts in the field feel that such trials are necessary to compare the efficacy and tolerability of these medications. Unfortunately, these comparative trials require large numbers of patients, a tremendous effort to organize, and are incredibly costly. Several companies have preliminary plans for such comparative trials.

Long-Term Effects of Topiramate (Topamax)

In the database submitted to the FDA consisting of approximately 3,000 patients, there were no consistent abnormalities of the function of the liver or bone marrow, as seen with some other medications. Some patients at the University of Cincinnati Epilepsy Treatment Center have been on the medication for over eight years without significant problems.

Has Its Safety in Children Been Evaluated?

Trials evaluating topiramate’s safety and effectiveness in children are currently underway. Preliminary data are encouraging; however, we must wait for the final results of these efficacy and safety trials to fully determine their role in the treatment of children.

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Jennifer Bowles

Jennifer is a clinical pharmacologist. She helps doctors of all medical specialties choose medications. Jennifer consults about drug dosage, interactions, and side effects.