Extended Release Topiramate Formulations in Epilepsy

Review Article

Austin J Clin Neurol 2015;2(8): 1066.

Extended Release Topiramate Formulations in Epilepsy

Pegah Afra¹* and Bola Adamolekun²

¹Department of Neurology, School of Medicine, University of Utah, USA

²Department of Neurology, University of Tennessee Health Science Center, USA

*Corresponding author: Pegah Afra, Department of Neurology, University of Utah, 175 N. Medical Drive East, 5th Floor, Salt Lake City, UT 84132, USA

Received: April 08, 2015; Accepted: June 12, 2015; Published: June 26, 2015


Topiramate is a novel antiepileptic medication with multiple mechanisms of actions. It is a broad spectrum antiepileptic drug and it is indicated for adjunctive treatment, conversion to monotherapy and initial monotherapy of partial onset and primary generalized epilepsies, the Lennox-Gastaut syndrome as well as for treatment of migraine headaches. It is also used clinically for a variety of neurologic and psychiatric disorders as well as for obesity. Recently, two extended release formulations of topiramate were approved by the FDA for treatment of epilepsy. We review these two formulations in this paper.

Keywords: Topiramate; Extended release formulations; Epilepsy


Topiramate (2,3:4,5-bis-O-(1-methylethylidende)-beta-Dfructopyranose- sulfamate) is a novel antiepileptic drug (AED) derived from the naturally occurring monosaccharide D-fructose. It is not structurally related to other antiepileptic drugs and was originally synthesized as part of a search for fructose-related compounds with hypoglycemic activity [1]. Its anticonvulsant activity was discovered in animal experimental seizure models in the 1980’s [2]. Topiramate (TPM) has since been shown to be effective in the rodent maximal electroshock model [3], in the amygdala kindling model [4] and in genetic models of epileptogenicity [5].

Topiramate has multiple mechanisms of action [6,7]. These include: 1) Sodium channel blockade/modulation: Topiramate inhibits sustained repetitive firing in a use and concentrationdependent manner in cultured hippocampal neurons and reduces voltage-activated sodium currents in cultured neocortical neurons. 2) Calcium channel blockade: Topiramate inhibits N-, P- and L-type calcium currents [8]. 3) Potassium channel activation: Topiramate activates potassium currents which may contribute to membrane hyperpolarization. 4) Glutamate receptor antagonism (Kainate/ AMPA): Topiramate also has inhibitory effects on the Kainate/AMPA subtype (GluR5) of the glutamate receptor. It reduces kainate-evoked inward currents, blocks kainate-evoked cobalt influx, and blocks kainate acid receptor-mediated postsynaptic currents. The effects of topiramate on kainate-evoked currents are unique to this compound among the AEDs. 5) GABA potentiation: Topiramate enhances GABA-evoked single-channel chloride currents by increasing the frequency of opening and burst frequency, without affecting the open channel duration or burst duration. Although the enhancement of GABA-A by topiramate is similar to that of the benzodiazepines, it is not reversed by flumazenil. 6) Carbonic anhydrase inhibition: Topiramate inhibits certain carbonic anhydrase isoforms and results in alteration of bicarbonate homeostasis.

Immediate-release Topiramate was FDA-approved for prescription use in the United States in December 1996 under the brand name Topamax (Janssen pharmaceuticals, Titusville NJ USA). Perhaps as a result of its multiple mechanisms of action, Topiramate is effective against many seizure types. It is currently indicated for adjunctive treatment of partial onset epilepsy, primary generalized epilepsy, and the Lennox-Gastaut syndrome in adults and children ages 2 to 16 years, as well as for conversion to monotherapy and initial monotherapy. It is efficacious as an add-on treatment for drug resistant partial onset epilepsy [9] and is three times more effective compared to placebo in reducing seizures [10]. It is also indicated for the prophylaxis of migraine headache in adults [11]. Topiramate has also been used for the treatment of hyperkinetic movement disorders[12], trigeminal neuralgia [13], obesity [14], antipsychotic medication-induced weight gain [15], eating disorders [16], a variety of psychiatric and mood disorders [17-19] as well as drug and alcohol addiction [20,21].

Immediate-release Topiramate is dosed twice daily. It is rapidly absorbed from the gastrointestinal tract, and its absorption is not significantly affected by food. It is characterized by a plasma elimination half-life ranging from 21-42hrs and by dose-proportional pharmacokinetics from 200-800mg. Ninety percent of the maximal plasma concentration (Cmax) is achieved within 2 hours after oral administration [22].

The most significant dose-limiting adverse effects of immediaterelease TPM are its effects on cognition, particularly language function [23]. The serious side effects of topiramate include acute myopia and secondary angle closure glaucoma, reversible visual field defects (independent of elevated intraocular pressure), oligo/ anhydrosis and hyperthermia, kidney stones, acute pancreatitis, nonanion gap metabolic acidosis and fetal toxicity (Pregnancy Category D). Other serious side effects include hyperammonemia and encephalopathy with or without concomitant valproic acid (VPA) therapy, hypothermia with concomitant VPA use, paresthesias, suicidal behavior and ideation [11].

Recently, two extended release formulations of topiramate were approved by the FDA for the treatment of epilepsy with once daily dosing: Trokendi XR (Supernus Pharmaceuticals) in August 2013, followed by Qudexy XR (Upsher-Smith Laboratories, Inc) in March 2014. An authorized generic of Qudexy XR was launched in July 2014 by Upsher-Smith Laboratories. Table one summarizes all the brand formulations of topiramate.

Citation: Afra P and Adamolekun B. Extended Release Topiramate Formulations in Epilepsy. Austin J Clin Neurol 2015;2(8): 1066. ISSN : 2381-9154