, Volume 3, Issue 4, pp 293-319
Date: 18 Dec 2012

Topiramate

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Summary

Abstract

Topiramate is an antiepileptic drug (AED) which appears to have a broad range of antiseizure activity in humans. A previous overview focused primarily on results of trials of topiramate in adults with epilepsy, and this review highlights the use of topiramate in children. Clinical trials have shown that topiramate is effective when used adjunctively in children with refractory partial-onset seizures and generalised tonic-clonic seizures. The drug significantly reduced seizure frequency compared with placebo in children with partial-onset epilepsy after 16 weeks of double-blind adjunctive treatment (33.1 vs 10.5%); the frequency of secondarily generalised seizures was also markedly reduced. During a nonblind extension of this trial, the mean dosage was titrated from 4.8 to 9 mg/kg/day and further reductions in the frequency of seizures were observed (71% compared with prestudy levels).

In 2 mixed adult/paediatric populations with primary generalised tonic-clonic seizures, topiramate (target dosage 5.2 to 9.3 mg/kg/day) reduced the seizure rate compared with those receiving placebo. This difference was significant in one trial (56.7 vs 9%) but not in another (57.1 vs 33.2%). A subanalysis of the paediatric patients found that the favourable effect of topiramate on seizure rates was not age-related.

Topiramate (median average dosage 5.1 mg/kg/day) was also found to be useful as adjunctive therapy in the management of Lennox-Gastaut syndrome and significantly reduced the mean frequency of drop attacks by 14.8% compared with an increase of 5.1% with placebo. Further gains in seizure control were made in a nonblind extension of this trial where the mean topiramate dosage was 10 mg/kg/day.

Nine of 11 patients in 1 pilot trial of children with otherwise intractable West syndrome, and 5 of 10 in another, achieved a ≥50% reduction in seizure rate with topiramate (target dosage up to 24 mg/kg/day). In an 18-month extension of the former trial (mean dosage 29 mg/kg/day) a ≥50% reduction in seizures was maintained in 7 of 11 children.

Adverse events associated with adjunctive topiramate therapy in children were predominantly neuropsychiatric and generally mild to moderate in severity. Behavioural and cognitive problems do occur and are a limiting factor in some children. Also, weight loss can be problematical in some individuals. Withdrawal rates were low in the controlled trials (4.8%), but appear to be more frequent in noncomparative and post-marketing studies.

Conclusion: Well controlled studies have demonstrated that topiramate is an effective agent for the adjunctive therapy of partial and generalised tonic-clonic seizures in children. Treatment-limiting adverse events do occur, but these may be managed by slow titration. Although comparative studies with the other newer AEDs used in adjunctive therapy are required, topiramate is an important extension to the range of drugs that may be used to treat refractory epilepsy in children.

Pharmacodynamic Properties

Topiramate is a structurally novel anticonvulsant derived from the naturally occurring monosaccharide D-fructose and contains a sulfamate moiety essential for pharmacological activity. In vitro experiments have identified several molecular activities that may contribute to its anticonvulsant activity: inhibition of voltage-sensitive sodium and/or calcium channels, potentiation of γ-aminobutyric acid, selective blockade of kainate-activated glutamate receptors, and inhibition of carbonic anhydrase. For many antiepileptic drugs (AEDs) there are strong correlations between results obtained in animal models of epilepsy and efficacy in humans. In vivo animal studies with topiramate have demonstrated the following: suppression of the hindlimb tonic-extensor component of the maximal electro-shock seizure test in rodents; regression of amygdaloid kindled seizures in rats, rabbits and cats; suppression of tonic and absence-like seizures in spontaneously epileptic rats; inhibition of audiogenic tonic convulsions and clonic seizures in rats and lowering of neurodeficit score; control of tonic-clonic seizures in a rat model of global ischaemia-induced epilepsy; inhibition of seizures in hypoxic neonatal rats.

Overall, these in vivo studies suggest that topiramate has a broad spectrum of antiseizure activity and supports the clinical findings where topiramate has been found to be effective in both partial and generalised seizures.

Pharmacokinetic Properties

In a study of 18 children (aged 4 to 17 years) with epilepsy who received oral topiramate for 4 weeks (titrated to a target dose of 9 mg/kg/day) peak plasma topiramate concentration (Cmax) and area under the plasma concentration-time curve (AUC) were linearly related to dose regardless of age. Cmax and AUC were lower, and the time to Cmax shorter, in younger children. Plasma topiramate concentrations in patients receiving the same dosage (on a mg/kg basis) are likely to be about 33% lower in children than in adults because of more rapid clearance, so higher dosages may be required to achieve seizure control in children.

The bioavailability of topiramate in adults is ≈80% and is unaffected by food. Paediatric patients frequently receive topiramate as a ‘sprinkle’ formulation with food and the relative bioavailabilities of 2 sprinkle formulations and immediate release tablets has been shown to be equivalent in 9 healthy adult male volunteers.

Data obtained in healthy adult male volunteers indicate that topiramate distributes primarily into body water and the volume of distribution was 0.6 to 0.8 L/kg after a single oral dose of 100 to 1200mg. The extent of plasma protein binding of topiramate is 13 to 17%.

Topiramate is not extensively metabolised after oral administration. After administration of a single radiolabelled topiramate 100mg dose 78% of the radioactivity in the plasma was unchanged drug while <5% appeared as metabolites. Topiramate is excreted primarily by the kidneys; after 10 days, 80.6% of the radiolabelled dose was recovered from the urine and 0.7% from the faeces. The clearance of topiramate from plasma during haemodialysis is about 9 times faster than in patients with normal renal function.

The oral clearance (CL/F) and terminal elimination half-life (t½) of topiramate were both independent of dose in children, but CL/F was somewhat higher in patients ≤7years of age, resulting in lower Cmax and AUC values in this group. However, it is not possible to attribute this observation to age differences because an unequal number of patients in each age group were receiving enzyme-inducing AEDs (which increase clearance of topiramate). Subgroup analysis showed that those patients receiving enzyme-inducing AEDs had a significantly higher CL/F, than those receiving AEDs which do not induce enzymes. Consequently, the t½ was significantly shorter in the former group. A comparison between these results in children and historical data in adults suggests that CL/F in children is approximately 50% higher than in adults.

Topiramate interacts with other AEDs and the plasma concentration of topiramate is reduced when it is administered with carbamazepine (↓≈40), phenytoin (↓ 33 to 50%) or valproic acid (sodium valproate) [↓ 15%]. The plasma concentration of phenytoin is increased by 25% when administered with topiramate, while that of valproic acid is decreased by 11% in the presence of topiramate. Three cases of hyperammonaemic encephalopathy have been reported in patients who had topiramate added to previously well-tolerated valproic acid therapy.

Serum ethinylestradiol concentrations were reduced by 18 to 30% and CL/F values by 15 to 33% in 12 women with epilepsy taking ethinylestradiol 35µg plus norethisterone (norethindrone) 1mg for contraception and topiramate 200 to 800 mg/day. To ensure adequate contraception the investigators recommended that the daily dosage of ethinylestradiol should be increased when this contraceptive combination is used in conjunction with topiramate. Administration of topiramate 200 mg/day for 6 days was associated with reduced digoxin Cmax and AUC values after a single oral dose of digoxin 0.6mg.

Efficacy in Children with Seizures

Placebo-controlled studies of topiramate have been conducted in children with partial seizures and generalised tonic-clonic seizures [mixed adult/paediatric populations; also in Lennox-Gastaut syndrome (LGS)], and small pilot studies in children with West syndrome (infantile spasms) have also been completed.

Partial Seizures

A statistically significant reduction in seizure frequency was demonstrated in a placebo-controlled trial of adjunctive topiramate (mean final dosage 4.8 mg/kg/day) in 86 children with partial-onset epilepsy. After 16 weeks of double-blind treatment, topiramate caused a median 33.1% reduction in monthly seizure frequency compared with a reduction of 10.5% in those who received placebo. A subgroup of patients (20 in each group) who experienced secondarily generalised seizures also exhibited a marked reduction in seizure rate when receiving topiramate. During a nonblind extension, the mean topiramate dosage was titrated according to clinical response to a mean of 9 mg/kg/day. Further reductions in the frequency of seizures were observed (71% compared with prestudy levels).

Generalised Tonic-Clonic Seizures

Trials of adjunctive topiramate for the treatment of primary generalised tonic-clonic seizures have not been performed in an exclusively paediatric population; however, 2 well controlled trials in a mixed population have been completed. While the seizure rate decreased in topiramate-treated patients (target dosage 5.2 to 9.3 mg/kg/day) compared with placebo in both trials, this difference was significant in one trial (56.7 vs 9%), but not the other (57.1 vs 33.2%). A subanalysis of the paediatric patients found a favourable effect of topiramate on seizure rate that did not appear to be age-related. An unpublished post-hoc analysis of the pooled data from both trials added further support to the contention that topiramate is an effective adjunctive treatment of both adults and children with primary generalised tonic-clonic seizures.

Topiramate was also found to be useful as adjunctive therapy in the management of LGS. In a well controlled double-blind 11-week trial of 98 adults and children with LGS, the addition of topiramate (median average dosage 5.1 mg/kg/day) to therapy significantly reduced the mean frequency of drop attacks by 14.8% compared with an increase of 5.1% in the placebo group. During a nonblind follow-up in which the topiramate dosage was titrated to a mean of 10 mg/kg/day, further gains in seizure control were made (the mean percentage reduction in drop attacks after ≥6 months of treatment was 56% and 15% of patients achieved complete control of seizures).

Two small pilot studies in children with West syndrome, 1 with an 18-month extension, have been completed. Nine of 11 patients in one trial and 5 of 10 in the other achieved a ≥50% reduction in seizure rate with topiramate (target dosage up to 24 mg/kg/day). In the 18-month extension of 1 trial a ≥50% reduction in seizures was maintained in 7 of 11 children with a mean dosage of 29 mg/kg/day; however, this efficacy measure is not regarded as reliable in West syndrome and further trials are required.

Topiramate has been compared with carbamazepine or valproic acid in a 119 children (aged 6 to 16 years) with newly diagnosed epilepsy of all types. After ≥6 months of therapy 63, 59, 39 and 53% of children treated with topiramate 100 or topiramate 200 mg/day, carbamazepine or valproic acid, respectively, were seizure free. The time to first seizure or drug-related withdrawal did not differ between treatments.

Tolerability

Somnolence, anorexia, fatigue, nervousness, concentration/attention/memory difficulties, aggression and weight loss were the most frequently reported events (incidence at least 5% higher than that in placebo recipients) in a pooled analysis of placebo-controlled studies involving 199 children with partial or generalised seizures who received topiramate (mean dosage 6.2 mg/kg/day) for a mean 107 days.

In a retrospective analysis of the factors associated with behavioural and cognitive abnormalities in children receiving topiramate, 11 of 75 (14.7%) children experienced behavioural or cognitive abnormalities 2 to 16 weeks after initiation of therapy. Nearly 50% of these 11 children had a previous history of these problems but 14% did not (p = 0.03). Concurrent use of lamotrigine was also associated with behavioural or cognitive abnormalities (p = 0.05). On occasion, behavioural problems can be severe and are likely to be a cause of withdrawal.

Most adverse events occurring in topiramate-treated children taking part in double-blind trials were regarded as mild or moderate in severity and the withdrawal rate was low (4.8%). However, the withdrawal rate in some noncomparative studies has been much higher. In 2 retrospective studies of paediatric patients with intractable epilepsy 41.4 and 39% discontinued topiramate because of adverse events. Other noncomparative studies have reported withdrawal rates of 11, 7.2 and 4.5%.

Dose-related weight loss is a common event in topiramate-treated individuals. In placebo-controlled, double-blind trials of children with epilepsy, weight loss in those treated with topiramate for 11 to 16 weeks (n = 98) was 0.4kg compared with a weight gain of 1.2kg in those receiving placebo (n = 101). A subanalysis of patients treated with topiramate for ≥2 years showed a slight decrease in body-weight during the first 6 months (0.3kg), but a gain of 3.2kg by 2 years. In a retrospective study, the height of topiramate-treated (n = 77) and non-topiramate-treated (n = 67) age- and seizure-matched patients was measured at initiation of treatment and after a mean of 21 months’ therapy. No statistical difference in the rate of linear growth was found.

Topiramate is a weak carbonic anhydrase inhibitor with the potential to cause acidosis and the formation of renal calculi in adults. The incidence in children has not yet been established, but only 1 of 313 children taking part in clinical trials of topiramate developed a renal calculus.

Dosage and Administration

Oral topiramate is indicated for the adjunctive treatment of children (aged between 2 and 16 years) with partial onset seizures or primary generalised tonic-clonic seizures. The drug should be titrated to achieve an optimal clinical response (seizure control without intolerable adverse effects) using a ‘start low, go slow’ approach. The manufacturer recommends that titration begins at 25 mg/day (or less, based on a range of 0.5 to 3 mg/kg/day), given nightly for the first week. The dosage should then be increased at 1- or 2-week intervals by increments of 1 to 3 mg/kg/day (administered in divided doses). The recommended total daily maintenance dosage after titration is 5 to 9 mg/kg/day (as a divided dose). In clinical trials, the minimum effective dosage appeared to be 4 to 6 mg/kg/day. Although some patients respond to lower dosages, others may require in excess of 15 mg/kg/day, and higher dosages may be required when concomitant enzyme-inducing AEDs are used.

Topiramate is available as 25, 50, 100 and 200mg tablets (availability may vary among countries) or as bioequivalent 15 and 25mg ‘sprinkle’ capsules. The latter can be opened and the contents sprinkled on a teaspoon of soft food (such as apple sauce) and swallowed without chewing, a method of administration which can be useful in children.

Topiramate is cleared by the kidneys. Therefore, dosage should be adjusted in patients with renal impairment [creatinine clearance <4.2 L/h/1.73m2 (<70 ml/min/1.73m2)]. Studies of topiramate in children with renal impairment have not been conducted, but in adults with moderate renal failure 50% of the usual dosage is recommended. Topiramate is cleared by dialysis and supplementary doses of topiramate may be required in dialysed patients. In patients with significant hepatic impairment, plasma concentrations of topiramate may be increased.

Various sections of the manuscript reviewed by: O. Dulac, Department of Neuropaediatrics, Hospital St Vincent de Paul, Paris, France; C.E. Elger, Epilepsy Clinic, University of Bonn, Bonn, Germany; R.D. Elterman, Dallas Pediatric Neurology Associates, Dallas, Texas, USA; E. Faught, University of Alabama at Birmingham, Birmingham, Alabama, USA; P. Levisohn, Division of Child Neurology, The Childrens’ Hospital, Denver, Colorado, USA; S.D. Lhatoo, National Hospital for Neurology and Neurosurgery, University College, London, England; W.E. Rosenfeld, The Comprehensive Epilepsy Care Center for Children and Adults, Chesterfield, Missouri, USA; R.C. Sachdeo, Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA; P. Uldall, Dianalund Epilepsy Hospital, Dianalund, Denmark; H.S. White, Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah, USA.

Data Selection

Sources: Medical literature published in any language since 1966 on Topiramate and Epilepsy and (Infants or Children or Adolescents), identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International, Auckland, New Zealand). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: Medline search terms were ‘Topiramate’ and (‘epilepsy’ or ‘seizures’) and (‘infants’ or ‘children’ or ‘adolescents’ or ‘paediatric’ or ‘pediatric’). EMBASE search terms were ‘Topiramate’ and (‘epilepsy’ or ‘seizures’) and (‘infants’ or ‘children’ or ‘adolescents’ or ‘paediatric’ or ‘pediatric’). AdisBase search terms were ‘Topiramate’ and (‘epilepsy’ or ‘seizures’) and (‘infants’ or ‘children’ or ‘adolescents’ or ‘paediatric’ or ‘pediatric’). Searches were last updated 20 March 2001.
Selection: Studies in patients with epilepsy who received topiramate. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Topiramate, epliepsy, children, pharmacodynamics, pharmacokinetics, therapeutic use.