Topiramate is a unique antiseizure medication that is used in treatment of partial and generalized seizures. Topiramate has been rarely associated with hepatic injury and largely when used in combination with other anticonvulsant medications.
Topiramate (toe pyre' a mate) is a sulfamate-substituted monosaccharide and belongs to an anticonvulsant class of its own. Topiramate is believed to act by reducing sodium channel currents and enhancing gamma aminobutyric acid (GABAA) receptor activity. Topiramate was approved for use in epilepsy in the United States in 1996 and it is still widely used. Its current indications are for prevention and management of partial and generalized seizures used either as monotherapy or in combination with other anticonvulsants. Topiramate is also used for migraine and for bipolar disorder. The recommended starting dose in adults is 25 mg twice daily, escalating at weekly intervals to a maximum of 200 mg twice daily. Topiramate is available in 25, 100 and 200 mg tablets in multiple generic forms and under the brand name Topromax. Pediatric formulations as sprinkle capsules are available in doses of 15 and 25 mg. Common side effects include dizziness, somnolence, paresthesias, change in taste, anorexia, weight loss, itching, difficulty concentrating and nervousness.
Prospective studies suggest that less than 1% of subjects develop elevations in serum aminotransferase levels during long term topiramate therapy. Clinically apparent hepatotoxicity from topiramate is quite rare and usually arises in patients receiving multiple other anticonvulsants. Topiramate is metabolized by CYP 3A4 and may increase risk of valproate or other anticonvulsant hepatotoxicity. A distinctive syndrome is the development of lethargy, weakness with marked serum aminotransferase elevations and hyperammonemia arising within 2 to 3 weeks of the addition (or dose increase) of topiramate to long term valproate therapy. While valproate alone can cause a similar syndrome, it appears much more common (~1%) with the combination than with valproate alone (~0.1%). This syndrome has several features suggestive of Reye syndrome (hyperammoniemia, hypoglycemia, rapid reversal of injury) and in many instances is preceded by a acute viral illness. Topiramate by itself has only rarely been linked to clinically apparent liver injury and the clinical features and course of injury have not been well defined. Topiramate has not been linked to cases of the anticonvulsant hypersensitivity syndrome and is considered a safe alternative in patients with that syndrome.
Mechanism of Injury
The mechanism of topiramate hepatotoxicity is thought to be due to its effects in inducing CYP 3A4 or inhibiting CYP 2C19 and possibly through the effects of a toxic metabolic intermediate.
Outcome and Management
Topiramate hepatotoxicity is usually attributed to its effects on the metabolism of other anticonvulsants, and as such is rapidly reversible within a few days of either drug being stopped. Acute liver failure and chronic injury from topiramate therapy has not been reported.
REPRESENTATIVE TRADE NAMES
Topiramate – Generic, Topamax®
Product labeling at DailyMed, National Library of Medicine, NIH
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References updated: 16 December 2013
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review of indications and side effects of anticonvulsants; topiramate is used for partial and primary generalized tonic-clonic seizures, both as monotherapy and adjunctive therapy in adults and children; adverse events include drowsiness, dizziness, headache and ataxia; mentions that liver failure has been reported).
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