What are the key aspects of topiramate (an antiepileptic medication) to know for board relevance?

From the Guidelines

Topiramate is a viable option for weight loss in adults with obesity, particularly when used in combination with phentermine, as evidenced by the FDA approval of the combination of phentermine and topiramate extended release for chronic weight management in adults with an initial BMI of 30 kg/m2 or 27 kg/m2 in the presence of at least 1 weight-related complication 1. When considering topiramate for weight loss, it is essential to note that its exact mechanism of action is unknown, but it is thought to reduce energy consumption through modulation of gamma-aminobutyric acid receptors in relevant CNS structures 1. Key points to consider when prescribing topiramate for weight loss include:

• The typical dosing of topiramate in combination with phentermine is lower than the dose usually prescribed as phentermine monotherapy, with a maximum dose of 15 mg of phentermine in the combination therapy 1
• Topiramate has been shown to increase energy expenditure in rodents, but this effect has not been demonstrated in humans 1
• Prospective, randomized, placebo-controlled trials have demonstrated the efficacy of topiramate in patients with overweight and obesity, although most of these trials have been less than 12 months in duration 1
• Topiramate is not FDA-approved as a monotherapy for weight loss, but it is often used off-label for this purpose 1
• The magnitude of weight loss with phentermine-topiramate ER 15 mg/92 mg is moderate to large, with a higher rate of treatment discontinuation, but rare serious adverse events 1

From the FDA Drug Label

CLINICAL PHARMACOLOGY Mechanism of Action The precise mechanisms by which topiramate exerts its anticonvulsant effects are unknown; however, preclinical studies have revealed four properties that may contribute to topiramate’s efficacy for epilepsy Electrophysiological and biochemical evidence suggests that topiramate, at pharmacologically relevant concentrations, blocks voltage-dependent sodium channels, augments the activity of the neurotransmitter gamma-aminobutyrate at some subtypes of the GABA-A receptor, antagonizes the AMPA/kainate subtype of the glutamate receptor, and inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV. Pharmacokinetics The sprinkle formulation is bioequivalent to the immediate release tablet formulation and, therefore, may be substituted as a therapeutic equivalent. The mean plasma elimination half-life is 21 hours after single or multiple doses Steady state is thus reached in about 4 days in patients with normal renal function.

Key Points about topiramate:

• Mechanism of Action: blocks voltage-dependent sodium channels, augments GABA activity, antagonizes glutamate receptors, and inhibits carbonic anhydrase
• Pharmacokinetics:
  • Bioequivalence between sprinkle and immediate release formulations
  • Mean plasma elimination half-life: 21 hours
  • Steady state reached in approximately 4 days with normal renal function 2

From the Research

Topiramate Overview

• Topiramate is a widely-used drug for the treatment of epilepsy, effective for several types of partial-onset and generalized-onset seizures 3.
• It is also used as a prophylactic against migraine headaches 3, 4, 5.
• Topiramate was first approved for prescription use in 1996 3.

Dosage and Administration

• The recommended target dose of topiramate for initial monotherapy of new-onset seizures is 100 mg/day for adults 3.
• Adjunctive use with enzyme-inducing drugs and use for refractory seizures requires higher dosages, though the optimum dose for most patients does not exceed 400 mg/day 3.
• A starting dose of 25 mg/d, with weekly increases of 25 mg, and an initial monotherapy target dose of 100 mg/d is commonly used for migraine prevention 4.

Efficacy

• Topiramate has been shown to be effective in the treatment of partial-onset and generalized seizures, with 75% of epilepsy patients treated with 400 mg/d remaining seizure-free at 1 year 4.
• It is also effective in the prevention of migraine, with 49% to 54% of patients experiencing a > or =50% reduction in monthly migraine frequency 4.
• A comparative study found that low-dose topiramate (50 mg/day) was as effective as sodium valproate (400 mg/day) in migraine prophylaxis, with a responder rate of 71.6% and 64.3%, respectively 6.

Safety and Side Effects

• Topiramate is generally safe and well-tolerated, but adverse effects limit use in about 25% of patients 3.
• Common side effects include paresthesia, weight loss, and other centrally mediated symptoms, which may be ameliorated by proper titration and dosing 3, 4.
• Valproate, topiramate, carbamazepine, and phenytoin may lead to adverse outcomes for infants of exposed mothers, and valproate should not be given to women of childbearing potential for migraine prevention 7.