Antiepileptic Drugs, 5th Edition

Topiramate

80

Clinical Efficacy and Use in Epilepsy

Michael D. Privitera MD*

Roy E. Twyman MD**

* Professor and Vice Chair, Department of Neurology, University of Cincinnati Medical Center, Cincinnati, Ohio

** Senior Director, Department of Clinical Development, Neurology, R. W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey

Topiramate, a structurally unique anticonvulsant, exhibits multiple mechanisms of action, a feature suggestive of a broad spectrum of antiseizure activity. To characterize the pharmacologic and clinical properties of topiramate further, the agent has been investigated in a comprehensive drug development program. This chapter reviews certain key studies, conducted as part of the clinical development program, together with other investigator-driven studies, that provide evidence for the clinical efficacy of topiramate in epilepsy. This chapter also outlines current recommendations regarding the use of topiramate in clinical practice and lessons learned from the clinical trials program. Many of the studies reviewed in this chapter also investigated the safety and tolerability of topiramate, which are reviewed separately elsewhere in this publication.

Clinical testing was initially carried out with topiramate, administered as adjunctive therapy, in adults with refractory partial-onset seizures. In these controlled regulatory trials, a high starting dose of topiramate was given, and a relatively fast titration schedule was followed. Despite the drug's significant demonstrated efficacy, investigators believed that side effects could be minimized with lower doses and slower titration. In a subsequent study, the benefit of slower titration was substantiated, and dosing recommendations were been adjusted accordingly.

After evaluation as adjunctive therapy in adults with partial-onset seizures, the development program for topiramate followed a traditional route into pediatrics, secondary generalized seizures, primary generalized seizures, and, more recently, monotherapy in adults and children with newly diagnosed or therapy-resistant epilepsy. As reviewed in this chapter, an extensive body of data has accumulated from both clinical trials and postmarketing experience to indicate that topiramate, used adjunctively or as monotherapy, is a highly efficacious, broad-spectrum anticonvulsant in adults and children.

The following sections review the efficacy and clinical use of topiramate in patients with different types of seizures. Special emphasis is placed on randomized controlled trials. When results from long-term follow-up studies are reported, these represent intent-to-treat analyses, with the stipulation that the patient's entry date into open-label treatment had to be at least 3 months or 6 months before data cutoff, depending on whether the analysis called for 3-month data or 6-month data. When a patient's entry into open-label treatment was >3 months before data cutoff, but treatment was discontinued, the patient's last seizure information was carried forward.

SPECTRUM OF EFFICACY

Evidence from Placebo-Controlled Clinical Trials: Adjunctive Therapy

Refractory Partial-Onset Seizures, with or without Secondarily Generalized Seizures, in Adults

Topiramate was evaluated as adjunctive therapy in adults with refractory partial-onset seizures, with or without secondary generalization, in eight double-blind, randomized, placebo-controlled trials (2,11,23,29,34,39,41,44). These trials investigated a single target dose (2,34,39,41) or a range of target doses (11,29) of topiramate. In addition, several pooled analyses and meta-analyses further examined the efficacy of topiramate in treating partial-onset seizures in adults. In all trials, topiramate was administered on a twice-daily schedule, and concomitant medication was kept unchanged.

P.741

Trials Exploring One Target Dosage

Six double-blind, placebo-controlled trials studied a single target dosage of topiramate as adjunctive therapy in patients with partial-onset seizures (Table 80.1). In the study reported by Rosenfeld et al. (34), 167 of 209 patients received topiramate at doses up to 1,000 mg/day (or maximum tolerated dose) over an 11-week titration period, followed by an 8-week maintenance period. The mean actual dose achieved was 799 mg/day. The median reduction in seizure frequency versus baseline was 51% after topiramate treatment compared with 1% reduction after placebo (p < .001). Freedom from seizures was achieved in 6% of topiramate-treated patients but in none of the placebo recipients. These findings were corroborated by five subsequent single-dosage trials, studying different target dosages of 300, 400, 600 (two studies), or 800 mg/day.

TABLE 80.1. MEDIAN PERCENTAGE REDUCTION IN SEIZURE FREQUENCY AND RESPONSE RATES (INTENT-TO-TREAT ANALYSIS) IN EIGHT MULTICENTER, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED TRIALS OF ADJUNCTIVE TOPIRAMATE (SINGLE AND MULTIPLE DOSE) IN ADULTS WITH REFRACTORY PARTIAL-ONSET SEIZURES, WITH OR WITHOUT SECONDARY GENERALIZED SEIZURESa

Reference

Variable

Placebo

Target Topiramate Dosage (mg/day)

200

300

400

600

800

1,000

Studies exploring a single target dosage

               
 

Rosenfeld et al., 1996 (34)

n

42

         

167

   

Median % reduction

1

         

51b

   

≥50% reduction

19

         

52b

   

≥75% reduction

5

         

25

   

100% reduction

0

         

6

 

Sharif et al., 1996 (39)

n

24

   

23

     
   

Median % reduction

1

   

41

     
   

≥50% reduction

8

   

35b

     
   

≥75% reduction

4

   

22

     
   

100% reduction

0

   

9

     
 

Tassinari et al., 1996 (41)

n

30

     

30

   
   

Median % reduction

12 (increase)

     

46b

   
   

≥50% reduction

10

     

47b

   
   

≥75% reduction

3

     

23b

   
   

100% reduction

0

     

0

   
 

Ben-Menachem et al., 1996 (2)

n

28

       

28

 
   

Median % reduction

18 (increase)

       

36b

 
   

≥50% reduction

0

       

43b

 
   

≥75% reduction

0

       

36b

 
   

100% reduction

0

       

7

 
 

Korean et al., 1999 (23)

n

86

     

91

   
   

Median % reduction

9

     

51

   
   

≥50% reduction

13

     

51

   
   

100% reduction

1

     

8

   
 

Yen et al., 2000 (44)

n

23

23

         
   

Median % reduction

7

44

         
   

≥50% reduction

13

48b

         

Studies exploring a range of target dosages

               
 

Faught et al., (1996) (11)

n

45

 

45

45

46

   
   

Median % reduction

13

 

30

48b

45b

   
   

≥50% reduction

18

 

27

47b

46b

   
   

≥75% reduction

9

 

9

27

25

   
   

100% reduction

0

 

0

4

4

   
 

Privitera et al., 1996 (29)

n

47

     

48

48

47

   

Median % reduction

1

     

41b

41b

38b

   

≥50% reduction

9

     

44b

40b

38b

   

≥75% reduction

0

     

23

13

13

   

100% reduction

0

     

10

2

0

aResponder rates are expressed as percentage of patients showing the indicated degree of seizure reduction compared with a prospective baseline.

Significantly different from placebo (p ≤ .05)

P.742

 

In a small trial conducted in Taiwan (44), 46 patients were randomized to receive topiramate (300 mg/day) or placebo, using a 6-week titration and an 8-week maintenance period. Mean reduction in seizure frequency was 44% in the topiramate group and 7% in the placebo group (p < .01), and 48% of patients receiving topiramate compared with 13% receiving placebo (p = .01) had a >50% seizure reduction.

Topiramate, 400 mg/day, resulted in a median percentage reduction in seizure rate of 40.7% versus 1.1% in those receiving placebo in a similarly small European trial (39). In this trial, the titration period was 3 weeks, and the maintenance period was 8 weeks. There were significantly more responders (≥50% reduction in seizure rate relative to baseline) in the topiramate-treated group than in the placebo group (35% versus 8%, p < .05). Seizures were eliminated in 9% of those receiving topiramate but in none of those receiving placebo.

Tassinari et al. (41) reported a European comparison of topiramate (n = 30; patients titrated up to a target dose of 600 mg/day, or maximum tolerated dose, over a 4-week period) with placebo (n = 30). Again, the maintenance period was 8 weeks, and the actual mean dosage of topiramate achieved was 519 mg/day. The median percentage reduction in seizure rate was 46.4% in topiramate-treated patients. This compared with a rise of 12.2% among placebo recipients (p < .005). There were more treatment responders (≥50% reduction) in the topiramate group (47%) than in the placebo group (10%; p < .001). A trial in Korea compared 600 mg topiramate (or highest tolerated dose) with placebo in 177 patients. Titration and maintenance periods were 10 and 8 weeks, respectively, and the actual mean achieved dose was 449 mg/day, with only 51 of 91 patients randomized to topiramate achieving the target dose. Median reduction in seizure frequency was 51% in patients receiving topiramate and 9% in those receiving placebo, and 51% of patients receiving topiramate (versus 13% receiving placebo, p < .01) achieved a ≥50% seizure reduction (23).

Ben-Menachem and colleagues studied a topiramate target dose of 800 mg/day (n = 8) versus placebo (n = 28) (2). Titration and maintenance periods were 5 and 8 weeks, respectively. The mean daily dose of topiramate achieved was 568 mg/day. There was a significant reduction in average monthly seizure rate in the topiramate group compared with placebo (35.8% versus 17.8%, respectively; p < .001). In addition, 43% of topiramate recipients were rated as responders (≥50% reduction), whereas none of the placebo-treated patients achieved this level of response (p < .001).

Trials Exploring Multiple Target Dosages

Two dose-ranging trials were included in the topiramate clinical development program. Each evaluated three doses of topiramate: 200, 400, and 600 mg/day with 4-week titration (11); and 600, 800, and 1,000 mg/day with 6-week titration (29). Maintenance periods were 12 versus in both studies. In the study by Faught et al., mean doses achieved in the three treatment arms were 200, 391, and 556 mg/day. Results are summarized in Table 80.1. The median percentage reduction in seizure rate, relative to baseline, was significantly greater with topiramate than placebo in the 400 and 600 mg/day groups, and it was of borderline significance in the 200 mg/day group (p = .051). There were significantly more responders (≥50% reduction) in the topiramate 400 and 600 mg/day groups than in the placebo recipients. A significant dose-response relationship was observed for both seizure reduction (p < .005 excluding the placebo group) and the percentage of treatment responders (p < .05 excluding the placebo group).

Privitera and colleagues (29) extended the highest dosage (600 mg/day) studied by Faught et al. (11) to 800 and 1,000 mg/day and thereby covered the full anticipated dosage range encountered in clinical practice. The mean daily doses achieved in the three topiramate arms of the study were 544, 739, and 799 mg. There were statistically significant differences between each topiramate group and placebo with respect to median percentage reduction in seizure rate relative to baseline. A significantly higher percentage of patients in each topiramate group than placebo were considered responders (≥50% reduction): 44%, 40%, and 38% for the 600, 800, and 1,000 mg/day groups, respectively, compared with 9% in placebo recipients (p < .001 for all groups versus placebo). Although statistical comparisons were reported between the three treatment groups, the authors commented that doses >600 mg/day did not appear to be associated with any significant efficacy advantage.

Meta-Analyses and Pooled Analyses

Additional information on the efficacy of topiramate has been provided by pooled analyses of the data generated in the six trials conducted in Europe and the United States. Because the studies involved similar protocols, patient populations, and efficacy end points, the pooled data are an important source of information on treatment response in different patient subgroups. Overall, 527 patients were treated with topiramate and 216 with placebo (31). Seizures were reduced by ≥50% from baseline in 43% of topiramate-treated patients and in 12% of placebo-treated patients (p < .001). Freedom from seizures was achieved in 5% of topiramate recipients but in none of the placebo-treated patients during the 11 to 19 weeks of double-blind therapy (p < .001) (Figure 80.1). The therapeutic effect of topiramate was consistent regardless of gender, age, baseline seizure frequency, and concomitant antiepileptic drug therapy.

P.743

 

 

FIGURE 80.1. Response rates (≥50%, ≥75%, and 100% reduction in seizures compared with baseline) in the pooled analysis of six multicenter trials of adjunctive topiramate conducted in Europe and the United States; all dosage groups are combined (topiramate 200 to 1,000 mg/day).

Refractory Partial-Onset Seizures, with or without Secondarily Generalized Seizures, in Children

Topiramate has also been studied in children with epilepsy. A multicenter, double-blind, adjunctive-therapy, 16-week placebo-controlled trial was conducted to study the efficacy of topiramate in children ≤16 years of age with refractory partial-onset seizures, with or without secondarily generalized seizures (10). Of a total of 86 patients, 41 were randomized to topiramate and 45 to placebo. Topiramate was titrated upward to a target dose of 125 to 400 mg/day, depending on the patient's body weight (125 mg/day for 16 to 24.9 kg; 175 mg/day for 25 to 33.9 kg; 225 mg/day for 34 to 42.9 kg; 400 mg/day for ≥43 kg). Topiramate treatment was associated with a 33.1% reduction in the median percentage seizure frequency relative to baseline, compared with a 10.5% reduction in the placebo group (p < .05). More topiramate than placebo recipients achieved ≥50% reduction in seizure frequency (39% versus 20%, respectively). This difference was of borderline statistical significance. However, topiramate was associated with a statistically superior response when evaluated against the higher response rate of ≥75% reduction (17% versus 2%; p < .05), and it was also favored over placebo by the patients' parents; 69% of patients were rated by parents as showing improvement with topiramate compared with 33% with placebo (p < .05).

Children who participated in this double-blind trial were eligible for entry into a long-term open-label extension study in which the dose of topiramate could be raised to a maximum of 30 mg/kg/day and concomitant medication adjusted according to patient response (32). The mean topiramate dose was 9 mg/kg/day. Open-label topiramate was received by a total of 83 patients for ≥3 months and by 73 patients for ≥6 months. The median percentage reduction in seizures at ≥3 and ≥6 months was 65% and 71%, respectively. Of those who received ≥6 months treatment, seizure reductions of ≥50%, ≥75%, and 100% were achieved by 64%, 40%, and 14% of patients, respectively. Ritter and colleagues (32) noted that seizure control in this open-label extension, in which the mean dose was 9 mg/kg/day, was greater than that observed during double-blind treatment, in which topiramate was given at a mean dose of 4.8 mg/kg/day. The increase in seizure control appears to reflect the dosage adjustment. Ritter and colleagues (32) pointed out that the magnitude of the therapeutic effect observed in the double-blind trial may have been underestimated because of the higher plasma clearance of topiramate (~50% higher) in children compared with adults (35). This would imply that the mean target dose of topiramate in the controlled trial (6 mg/kg/day) would actually be equivalent to an adult dose of approximately 270 mg/day. In adults, however, maximum control of partial-onset seizures was achieved at 400 mg/day (11,39).

Refractory Primary Generalized Tonic-Clonic Seizures in Adults and Children

A multicenter, randomized, placebo-controlled, doubleblind trial was conducted in 80 patients to evaluate the efficacy of topiramate in adults and children with primary generalized tonic-clonic seizures (GTCS) (4, 5, 6). Patients were required to have previously experienced tonic-clonic seizures (or at least three over an 8-week baseline) with or without other generalized seizure types and electroencephalographic (EEG) recordings consistent with generalized-onset seizures (normal or generalized epileptiform abnormalities). Patients with Lennox-Gastaut syndrome

P.744


were excluded from the study. Enrolled patients were therefore most likely to present with idiopathic generalized epilepsy syndromes. However, some patients with partial-onset epilepsy often present with normal EEG readings or with what appear to be generalized epileptiform abnormalities (sometimes called secondary bilateral synchrony), and seizures in these patients may rapidly generalize into tonic-clonic seizures. It is therefore probable that a few patients with symptomatic generalized epilepsy syndromes or partial-onset seizures with rapid secondary generalization were also included in the study. In this trial, >70% of patients had at least one other type of generalized seizure (absence, myoclonic, or tonic), a finding indicating that the proportion of patients with misdiagnosed partial seizures was probably small.

Of the 80 patients enrolled, 39 were assigned to treatment with topiramate (mean age, 26.8 years) and 41 to placebo (mean age, 25.6 years), with titration and maintenance periods of 8 and 12 weeks, respectively. The study included a wide age range, with some very young children (3 to 59 years). Titration and target doses (175, 225, or 400 mg/day) were determined by patient body weight (25 to 33.9, 34 to 42.9, and ≥43 kg, respectively). Treatment with topiramate resulted in a median percentage reduction in the frequency of primary GTCS of 56.7% compared with 9.0% after placebo (p < .05). For all generalized seizure types, the difference between topiramate and placebo response was further increased (42.1 % reduction for topiramate and 0.9% reduction for placebo; p < .005). A statistically significantly higher number of topiramate-treated patients than placebo recipients were rated as responders on both ≥50% (p < .001) and ≥75% (p < .05) reduction of tonic-clonic and all generalized seizures (based on analysis of double-blind completers). The data generated in this study were further analyzed to determine whether any differences in treatment effect existed with regard to patient age, that is, ≤16 years or >16 years. The superiority of topiramate to placebo in terms of median percentage reduction in seizure frequency and percentage of patients with ≥50% reduction in seizures was maintained, regardless of patient age, for both tonic-clonic and all generalized seizure types. Despite the relative limitations of the inclusion criteria, this was the first trial to demonstrate under double-blind, placebo-controlled conditions a statistically significant therapeutic effect of an antiepileptic drug against primary GTCS.

Twelve patients who participated in the double-blind study were selected to continue topiramate treatment in a 20-week open extension (37). Compared with baseline, the frequency of GTCS was reduced by ≥50% in 11 of 12 patients (91%). Freedom from seizures was achieved by seven of 12 patients (58.3%).

An additional open-label extension of the double-blind study (4, 5, 6) was conducted to investigate the effect of longterm topiramate in children with primary GTCS without focal onset. Adjunctive topiramate was given to 33 patients for ≥3 months (18). Compared with baseline of the doubleblind trial, 67% of patients showed a reduction in seizure frequency of ≥50%, whereas 6% were seizure free during the 3-month period.

A second double-blind trial of topiramate in patients with GTCS was completed, but the results have not been published. The study protocol and patient entry criteria were essentially identical to those of the trial published by Biton et al. (6).

A long-term open-label investigation of topiramate in GTCS was also undertaken as a pooled extension of both of the double-blind, placebo-controlled trials discussed earlier (3, 6). Adults and children who completed these trials (n = 131) entered the open-label extension (25). The mean duration of open-label topiramate treatment was 387 days, and the mean dose was 7 mg/kg/day. Long-term adjunctive topiramate was effective in controlling GTCS; of those patients who received open-label topiramate for ≥6 months (n = 96), GTCS were reduced ≥50% from baseline in 63% of patients and ≥75% from baseline in 44%. Although they had previously had a median pretreatment seizure rate of one GTCS a week, 16% of patients became free of GTCS over a period of ≥6 months.

Juvenile Myoclonic Epilepsy

Biton et al. reported data on a subset of 22 patients from the two primary generalized epilepsy trials noted above (4,6) who likely had juvenile myoclonic epilepsy. These data are the only comparative data of an antiepileptic drug and placebo given as adjunctive therapy in juvenile myoclonic epilepsy. Primary GTCS were reduced by at least half in 73% of topiramate-treated patients and in 18% of placebo-treated patients (p = .03). Although the patient populations were not sufficiently large to detect statistically significant differences in other seizure types, myoclonic seizure frequency was also reduced with topiramate. The number of weeks free of myoclonic seizures increased by 171% in topiramate-treated patients and by 130% in placebo-treated patients. For absence seizures, the median percentage increase in seizure-free weeks was 15% for topiramate-treated patients, whereas in placebo-treated patients, there was a decrease of 7%.

Lennox-Gastaut Syndrome

Topiramate was also evaluated as an adjunctive treatment for patients with Lennox-Gastaut syndrome. In this trial, Lennox-Gastaut syndrome was confirmed by EEG (i.e., slow spike-and-wave pattern) and multiple seizure types including drop attacks and a history of atypical absence seizures. A multicenter, double-blind, placebo-controlled trial enrolled patients with multiple seizure types (tonic or atonic drop attacks) and atypical absence seizures plus an

P.745


EEG pattern typical of Lennox-Gastaut syndrome and a history of ≥60 seizures in the month before baseline (38). Overall, 98 patients were enrolled in the trial (48 randomized to topiramate and 50 to placebo). Age ranged from 2 to 42 years, with a mean age of 11 years in each group. The average topiramate dose during the double-blind treatment phase was 4.8 mg/kg/day. The median percentage reduction in drop attacks relative to baseline in topiramate-treated patients was 14.5%, whereas the placebo group experienced a median increase of 5% (p < .05). A combined measure of drop attacks and tonic-clonic seizures was reduced by 26% with topiramate, but it increased by 5% with placebo (p = .015). Of the parents or guardians of patients in the topiramate group, 53% believed there had been some degree of improvement in seizure severity compared with baseline. This finding compared with 28% in the placebo group (p < .05). The study continued into a long-term open-label extension phase. Topiramate effectiveness in Lennox-Gastaut syndrome compared favorably to that reported in a controlled trial of lamotrigine (27). The placebo-adjusted responder rate for drop attacks was 14% for topiramate and 15% for lamotrigine; that for major motor seizures was 25% with topiramate and 17% with lamotrigine.

Ninety-seven patients (mean age, 11 years) continued open-label topiramate for a mean treatment duration of 539 days at a mean dose of 10 mg/kg/day (21). Of those patients who received topiramate for ≥6 months and who experienced drop attacks (n = 82), 55% had a reduction in drop attacks of ≥50%. A reduction of ≥75% was experienced by 35% of these patients, and 15% were free of drop attacks for at least 6 months. Of those patients who started open-label topiramate treatment, 71% continued therapy for at least 3.4 years.

Evidence from Randomized Controlled Clinical Trials: Monotherapy

As the clinical development program for topiramate has evolved, the drug has been increasingly evaluated as monotherapy. Two randomized controlled trials established the efficacy of topiramate monotherapy in patients with partial-onset seizures with or without secondary generalized seizures: (a) a multicenter trial in patients with recently diagnosed epilepsy (14) and (b) a single-center study in patients with chronic, refractory epilepsy (36).

Monotherapy trials of antiepileptic drugs are typically designed either to demonstrate superiority of the tested drug over some alternative treatment or to demonstrate equivalence of the newer medication to an established standard. The United States Food and Drug Administration has made it clear that it will not accept as evidence of efficacy the latter type of study showing that a new antiepileptic drug is equivalent to a standard antiepileptic drug. This regulatory requirement is based on the possibility that, in the particular study being evaluated, both treatments could have been equally ineffective. In epilepsy monotherapy trials, in which a placebo control would usually be considered unethical, novel trial designs have evolved to demonstrate superiority of a new antiepileptic drug over a control treatment. The control treatment is typically a lower dose of the test drug or a relatively low dose of a standard drug. The ethical issues related to this trial design have been discussed (8). For patients and their clinicians, however, the most relevant type of monotherapy study is one that compares clinical outcomes, such as freedom from seizures, retention time in the study, and intolerable adverse events, with a new versus an old antiepileptic drug both used at optimal dosages. Such studies are designed to establish equivalence, rather than differences, as an outcome, and they require large numbers of patients with a prior definition of equivalence based on confidence intervals. The approach increasingly being taken by European regulatory authorities is to license antiepileptic drugs for monotherapy after the demonstration of equivalence, with the active control used in clinical situations for which it is approved and known to be effective. The optimal monotherapy trial design that satisfies both regulatory requirements in Europe and in the United States and provides ethically acceptable “best treatment” for patients remains a topic of discussion.

Recently Diagnosed Epilepsy

This multicenter trial was conducted at 76 sites throughout North America and Europe (14). Topiramate was administered at a low dose (25 or 50 mg/day) or a high dose (200 or 500 mg/day) according to body weight, so those patients weighing ≤50 kg received either 25 or 200 mg/day and those weighing >50 kg received either 50 or 500 mg/day (or highest tolerated dose). A total of 252 patients (aged 6 to 85 years) with recently diagnosed (within 3 years) partial-onset epilepsy or GTCS were randomized to either the low- or high-dose arm of the trial. Forty-five percent of patients received anticonvulsant medication at the time of recruitment, and this medication was discontinued over the initial 6 weeks (titration period) of the trial. Virtually all patients randomized to the low-dose group achieved the target dose, compared with 72% of patients randomized to the high-dose group.

A significant difference was observed between the lowand high-dose groups with respect to seizure frequency. After achieving the target dose of topiramate, 65% of the high-dose group compared with 39% of the low-dose group became seizure free (p = .001).

The median time to first seizure was greater in the high-dose group (317 days) than in the low-dose group (108 days; p = .06). The median time to exit because of a second seizure was also longer in the high-dose group (422 days) than in the low-dose group (293 days), although this did not reach statistical significance. However, using a bivariate analysis taking into account the dependence of the time to

P.746


second seizure on the occurrence of a first seizure, the difference in time to exit resulting from a second seizure was significant and favored the higher dose (p = .01) (Figure 80.2).

 

FIGURE 80.2. Median time to first seizure and to exit resulting from second seizure after high-dose (200/500 mg/day) and low-dose (25/50 mg/day) topiramate monotherapy in patients with recently diagnosed partial epilepsy. Data are based on bivariate analysis allowing for the dependence of the occurrence of a second seizure on the occurrence of a first seizure.

A correlation between plasma level of topiramate and time to first seizure was observed; those patients who had the highest plasma concentrations (>9.91 µg/mL) had the longest time to first seizure. The median time to first seizure was 451 days in patients with a plasma topiramate concentration of >9.91 µg/mL, 194 days in patients with a plasma topiramate concentration of 1.77 to 9.91 µg/mL, and 84 days in those with a plasma topiramate concentration of ≤1.76 µg/mL (p = .015).

Chronic Refractory Epilepsy

Sachdeo and colleagues (36) reported a double-blind, single-center study comparing high (1,000 mg/day; n = 24) and low (100 mg/day; n = 24) doses of topiramate in patients ≥14 years of age with refractory partial-onset seizures, with or without secondary GTCS. Preexisting treatment was gradually tapered and was finally withdrawn over a 5-week conversion period as the dose of topiramate was titrated upward to 1,000 mg/day (or the maximum tolerated dose) or 100 mg/day. Topiramate monotherapy was subsequently stabilized at the high- or low-dose level for a further 11 weeks. The primary efficacy variable was time to exit, mainly resulting from seizure deterioration. Patients in the high-dose group remained in the study significantly longer than those in the low-dose group (p = .002). Of those patients who received high-dose topiramate, 13 of 24 (54%) did not leave the study for any of the predefined reasons for exit, whereas four of 24 (17%) patients in the low-dose group did not leave the study (p = .015).

A reduction in seizure frequency of ≥50% was achieved in 46% of patients who received 1,000 mg/day topiramate compared with 13% of those receiving 100 mg/day. Freedom from seizures was achieved in 13% of the high-dose group compared with none of the low-dose group. Patient and investigator global ratings also confirmed the greater efficacy of the high-dose treatment, with marked improvement noted in 46% of high-dose compared with 8% of low-dose patients.

In an open-label extension phase, 19 of 20 patients experienced a reduction in seizures of ≥50% at an average dose of 555 mg/day (range, 100 to 800 mg/day). Freedom from seizures was achieved in 14 patients for periods ranging from 3 months to >2 years (37).

Topiramate Monotherapy versus Standard Monotherapy in Newly Diagnosed Epilepsy

Monotherapy is the preferred treatment choice in patients presenting with newly diagnosed epilepsy. However, the exact classification of seizure type and syndromes in this patient population can be difficult and relies on clear information at the time of diagnosis. Over time, the initial classification can be found to be incomplete or inaccurate, and thus, treatment of this patient group represents a particular clinical problem. Topiramate represents a good candidate for use in patients with newly diagnosed epilepsy because it has demonstrated efficacy in many seizure types and syndromes, as well as proven effectiveness as monotherapy.

A uniquely designed, double-blind study was conducted to compare the efficacy of topiramate monotherapy with the physician's preferred choice of initial standard antiepileptic drug monotherapy (carbamazepine or valproate) in patients with newly diagnosed epilepsy, regardless of seizure type or syndrome (30). At study entry, patients were assigned to either a carbamazepine or a valproate comparative treatment arm, based on the investigator's assessment of the best treatment choice. These patients were subsequently randomized to receive topiramate under double-blind conditions, either 100 or 200 mg/day, or the investigator's choice at doses effective for patients with newly diagnosed epilepsy (600 mg/day carbamazepine or

P.747


1,250 mg/day valproate). After a 35-day titration period, patients received their assigned treatment until exit or for 6 months after the last patient was enrolled (Figure 80.3).

 

FIGURE 80.3. Patients with newly diagnosed epilepsy were assigned to either a carbamazepine or valproate comparative treatment arm according to the investigator's “best choice” of treatment and were then randomized to receive under doubleblind conditions topiramate (100 or 200 mg/day) or the investigator's best choice of carbamazepine (600 mg/day) or valproate (1,250 mg/day). After a 35-day titration period, patients received their assigned treatment until exit or for 6 months after the last patient was enrolled.

A total of 623 patients aged 6 to 84 years entered the trial, with 395 assigned to the carbamazepine-topiramate arm and 228 assigned to the valproate-topiramate arm. In total, 52% and 49% of patients in the carbamazepine and valproate treatment arms, respectively, completed the study. There were no statistically significant between-group differences for topiramate and carbamazepine or valproate in terms of time to exit, time to first seizure, and the proportion of patients who were free of seizures during the last 6 months of treatment. Discontinuation rates because of adverse events were not different among the three treatments. These results suggest that topiramate is at least as effective as carbamazepine or valproate in patients with newly diagnosed epilepsy. Topiramate, at a dose of 100 mg/day, had comparable efficacy but tended to be better tolerated than 200 mg/day, and it was at least as well tolerated as 600 mg/day carbamazepine and 1,250 mg/day valproate (30). In addition, topiramate monotherapy was associated with a lower incidence of cognitive effects such as speech disorders, related speech problems, and psychomotor slowing than reported in trials using adjunctive topiramate therapy

Evidence from Other Studies—Open Trials and Case Reports: Adjunctive Therapy

In addition to the randomized controlled trials described earlier, the clinical efficacy of topiramate has been evaluated in numerous open investigator studies and case reports. Several of these are summarized in the following discussion.

A series of open-label studies investigated the efficacy of topiramate against refractory partial seizures. The combined results of nine of these studies suggest that 80 of 173 patients who received topiramate were responders (46.2%). In seven of the studies, response was defined as median percentage reduction in seizure frequency ≥50%. This was achieved by 94 of 123 patients (76.4%). The remaining two studies defined response as percentage reduction in seizure frequency for the whole group, and the investigators reported response rates of 47% and 69% (28).

Several open-label studies have also been conducted to evaluate the therapeutic effect of topiramate as long-term adjunctive therapy further and thereby to obtain a more accurate indication of the drug's likely effectiveness as maintenance therapy. Abou-Khalil and colleagues (1) reported an open-label study in which topiramate was given to 292 adult patients with previously refractory partial and/or generalized seizures. Seizure reductions were calculated for two subsets of patients: (a) those completing ≥84 days (3 months of topiramate therapy; n = 241); and (b) those completing ≥168 days (6 months of therapy; n = 196). Overall, the mean treatment duration was 413 days, and the mean topiramate dose was 503 mg/day.

A reduction in seizure frequency of ≥50% was experienced by 54% of patients, and a reduction of ≥75% was experienced by 36% of patients. In those patients receiving adjunctive topiramate for ≥3 months, freedom from seizures was achieved in 11%, 10%, and 34% for all seizures, partial seizures, and generalized seizures, respectively. Seizure control was sustained at 6 months, with seizure reductions almost identical to findings at 3 months (10%, 9%, and 35%, respectively).

Other studies provide support for the use of topiramate in the long-term treatment of patients with partial-onset seizures. For example, Canger and colleagues (7) observed continued efficacy in the treatment of partial-onset epilepsy over a 4-year period. Michelucci et al. (24) noted that the response to topiramate was sustained for at least 5 years in those patients who previously had refractory partial seizures but who experienced an initial response.

These results are consistent with data from long-term extensions of randomized clinical trials in which 467 patients received topiramate for >6 months (unpublished data, Ortho-McNeil Pharmaceutical). In these trials, the percentage of patients discontinuing because of the drug's lack of effectiveness peaked at 6% in those patients who received topiramate for between 6 and 18 months. In patients who received topiramate for longer still (some patients received topiramate for >48 months), the percentage who discontinued treatment because of ineffectiveness declined to between 3% and 4%. These results suggest fairly convincingly that tolerance to topiramate does not develop over time.

P.748

 

Evidence from Other Studies—Open Trials and Case Reports: Monotherapy in Adults

Several investigators have reported continued good response rates to topiramate in patients with refractory partial-onset seizures after the withdrawal of concomitant antiepileptic medication (17,33,42). Some studies have subsequently investigated these observations in larger patient groups. A retrospective analysis of combined open extension data from randomized controlled trials (35) identified 45 patients from a total of 136 (33%) who had successfully been converted to monotherapy with topiramate for a mean duration of 22 months (3 to 44 months). Of these, 28 (62%) were seizure free during the last 3 months of observation.

Further long-term monotherapy data were generated in a prospective observational study of 170 patients with refractory localization-related or idiopathic generalized epilepsy (40). Thirty patients had concomitant medication discontinued, 12 had established topiramate monotherapy, and eight remained seizure free at 6 months. The authors concluded that topiramate was “efficacious as add-on and monotherapy in patients with refractory partial and generalized seizures in everyday clinical use.” They also pointed out that, in many patients, good response rates were achieved with topiramate doses that were considerably lower than those used in the regulatory clinical trials; of the total study population, 16 responders and 13 seizure-free patients were receiving ≤100 mg/day topiramate.

Evidence from Other Studies—Open Trials and Case Reports: Monotherapy in Pediatrics

Refractory Partial-Onset and Primary Generalized Seizures

To date, studies investigating the use of topiramate as monotherapy in children have followed an open-label design. A pilot trial was conducted by Glauser and colleagues (19) to investigate topiramate monotherapy for partial-onset seizures in five children (3 to 12 years of age). Two patients, who were titrated up to 3 mg/kg/day over a 3-week period, remained seizure free at the time the report was published.

Further studies conducted by Moreland et al. (26) found topiramate monotherapy to be effective in children with complex partial seizures over a dose range of 2.5 to 5.0 mg/kg/day. Efficacy was also demonstrated in children with generalized epilepsy. However, the study population was too small for statistical analysis.

West's Syndrome (Infantile Spasms)

In a pilot study of West's syndrome, 11 children, aged 3 to 48 months, received topiramate (up to a target level of 24 mg/kg/day) with tapering of other antiepileptic drugs (20). Topiramate monotherapy was achieved in seven patients. A ≥50% reduction in seizure frequency was achieved by nine patients (82%), and five (45%) children became spasm free. All 11 children who participated in this study entered a long-term extension phase. The mean duration of treatment was 18 months, and the mean topiramate dosage was 29 mg/kg/day (22). At data analysis (October, 1998), eight patients (73%) were continuing topiramate treatment. Of these, four (50%) remained spasm free, and seven (88%) continued to experience a ≥50% reduction in spasm frequency. Three of the eight children (38%) who continued to take topiramate at data analysis were able to receive topiramate monotherapy (all were spasm free).

Other Childhood Epilepsies

Two small, open-label reports documented topiramate's effect in some less common syndromes. In five patients diagnosed with Angelman's syndrome and treated with topiramate (12,13), two patients were seizure free, one for 8 months and the other for 12 months. Two patients had resolution of GTCS. On patient discontinued treatment because of adverse effects. Of 14 patients with tuberous sclerosis who were treated with topiramate (12,13), nine patients had a ≥50% reduction in seizures, and three remained seizure free, whereas five were considered nonresponders. Some, but not all, of these patients had infantile spasms at some time in the past, but none of the reported cases of tuberous sclerosis or Angelman's syndrome had active spasms at the time of these studies.

Additional Studies in the Topiramate Clinical Development Program

In addition to the randomized controlled trials and longterm open-label studies described earlier, several other investigations were conducted to evaluate other aspects of topiramate—for example, optimal dose and titration rate; tolerability profile—as clinical development has evolved through adjunctive therapy, monotherapy, and, more recently, low-dose monotherapy.

To determine the optimal dose and titration rate of topiramate in the treatment of epilepsy, a multicenter, randomized, double-blind, parallel group trial was conducted in 188 patients (9). Patients were randomized to either slow titration of topiramate (n = 95) or a faster titration rate (n = 93), similar to that used in the regulatory trials of adjunctive therapy in adults. Patients in the slow-titration group received starting doses of 50 mg/day that were increased by weekly increments of 50 mg/day over an 8-week period to a maximum dose of 400 mg/day. The faster-titration group received starting doses of 100 mg/day that were increased to 200 mg/day and then to 400 mg/day over a 3-week period. Although the efficacy of topiramate was similar in the two

P.749


dosage groups (according to median percentage reduction from baseline in seizure rate, percentage of responders, and percentage seizure free), the proportion of patients who discontinued treatment because of adverse events was significantly lower in the slower-titration group than in the faster-titration group (10 of 95 versus 20 of 93, respectively; p = .036). These data suggest that some of the adverse events reported in the controlled clinical trials may have been caused by excessively fast titration. Clinical experience certainly indicates that an initial low dose and slower titration to clinical response (which may be achieved with doses as low as 100 mg/day monotherapy) is associated with a good tolerability profile.

In addition, preliminary results of a recently completed trial of topiramate monotherapy in newly diagnosed epilepsy suggest that a dose of 100 mg/day is at least as effective and as well tolerated as the investigator's choice of standard antiepileptic drugs for this population (600 mg/day carbamazepine or 1,250 mg/day valproate) (30). The tolerability and safety of topiramate are discussed elsewhere in this publication.

MODE OF USE

Indications

Topiramate is indicated as adjunctive therapy for adults and children (≥2 years of age) with partial-onset seizures in 86 countries, for GTCS in 20 countries, and as monotherapy in eight countries. Topiramate is also indicated in 15 countries as adjunctive therapy in adults and children for seizures associated with Lennox-Gastaut syndrome.

Dosing Recommendations

Based on clinical experience and randomized, controlled trials, clinicians and investigators appear to agree that topiramate produces equal seizure control and is better tolerated when it is given at a low starting dose and is titrated slowly to clinical response.

Adults

Monotherapy.

In adults, it is recommended that topiramate be given at a starting dose of 25 mg nightly for 1 week. Dosage should then be increased at 1- or 2-week intervals by increments of 25 or 50 mg/day, administered in two divided doses. The dose and titration rate should be guided by clinical outcome. Smaller increments or longer intervals between increments may be used if the patient is unable to tolerate the titration regimen. The initial target dose range for monotherapy appears to be 100 to 200 mg/day, and the maximum recommended daily dose is 500 mg. These recommendations apply to all adults, including the elderly, in the absence of underlying renal disease.

Adjunctive Therapy.

As for monotherapy, it is recommended that titration be initiated at 25 mg nightly for 1 week and increased at 1- or 2-week intervals by 25 mg/day in two divided doses. The minimum effective dose is 200 mg/day, and the usual total daily dose as adjunctive therapy is 200 to 400 mg/day in two divided doses.

Children (≥2 Years)

Monotherapy.

It is recommended that topiramate be given at a starting dose of 1 to 3 mg/kg nightly for the first week and then increased at 1- or 2-week intervals by increments of 1 to 3 mg/kg/day, administered in two divided doses.

Adjunctive Therapy.

The recommended total daily dosage of adjunctive topiramate for children is 5 to 9 mg/kg/day in two divided doses. Titration should begin at 15 to 25 mg (or less, based on a range of 1 to 3 mg/kg/day) nightly for the first week. Dosage may then be increased by increments of 1 to 3 mg/kg/day (in two divided doses) at 1- or 2-week intervals.

In both adults and children, the tolerability of topiramate is significantly improved by slower titration without compromising clinical efficacy (9). Tolerability is therefore improved by using lower doses or by extending the time interval between dose increments in the upward titration period.

Current Role in Epilepsy Management

The clinical trial program for topiramate in epilepsy has generated a large body of data (approximately 2,600 patients, including >350 children) regarding the efficacy and safety of the anticonvulsant across a broad range of seizure types and in a wide age range. These epilepsy trials have provided some important insights into the optimal use of topiramate in clinical practice. For example, efficacy has been demonstrated with topiramate at a wide range of doses, including doses that are substantially lower than those initially employed in the controlled regulatory trials of adjunctive therapy in adults. Likewise, further investigation indicates that the titration rates used in these first controlled trials were not optimal for many patients. By using a slower titration schedule, fewer side effects are reported without compromising efficacy. Data from monotherapy trials have indicated that some side effects previously associated with adjunctive topiramate use may reflect, at least in part, pharmacodynamic interactions with other antiepileptic drugs. When topiramate is administered as monotherapy, the incidence of several adverse events, including psychomotor slowing, speech disorders, memory difficulty, and confusion, is reduced. Further investigation of topiramate use as monotherapy has also revealed that a 100 mg/day dose of topiramate had similar efficacy to 200 mg/day in newly diagnosed epilepsy, and it was better tolerated.

P.750

 

There is now considerable postmarketing experience with topiramate. As of October 1, 2000, 750,000 patients with epilepsy had been treated with topiramate, representing more than 400,000 patient-years of exposure. The efficacy seen in clinical practice appears to reflect the results of the clinical trials.

Use in Special Populations

The pharmacokinetics of topiramate may be affected by individual patient characteristics, such as age and coexisting medical conditions. Dosage and titration should follow the recommended guidelines, but they should also be guided by clinical outcome. In patients with renal impairment, a few additional considerations apply, as outlined in the next section.

Impaired Renal Function

Decreased renal function can alter the pharmacokinetics of drugs such as topiramate that are renally eliminated. The clearance of topiramate has been found to be reduced by 42% in patients with moderate renal impairment and 54% in those with severe renal impairment (15). It is therefore recommended that the usual topiramate dose be halved in such patients.

In contrast, a supplemental dose of topiramate is recommended for patients undergoing hemodialysis. The mean hemodialysis plasma clearance of topiramate in patients with end-stage renal disease was found to be four to six times greater than in persons with normal renal function (16). It is suggested that the supplemental dose be equivalent to one-half of the daily dose, administered in divided doses at beginning and completion of hemodialysis.

Precautions

Nephrolithiasis

Some patients who receive topiramate may be at increased risk of renal stone formation. Adequate hydration is recommended to reduce this risk, particularly in patients with a family history of nephrolithiasis, prior stone formation, or hypercalciuria.

The incidence of nephrolithiasis observed with topiramate in clinical trials was 1.5%, approximately two to four times higher than expected in a similar untreated population. Stones passed spontaneously in two-thirds of those affected, and 75% of patients decided to continue topiramate therapy despite this occurrence (31,43).

Pregnancy

Insufficient data exist at this time to assess accurately whether topiramate is more or less teratogenic than the standard antiepileptic drugs. Topiramate is teratogenic in mice, rats, and rabbits, and it leads primarily to craniofacial defects as well as limb and vertebral malformations. Teratogenic effects associated with carbonic anhydrase inhibitors are not, however, seen in humans, based on information provided to the Food and Drug Administration, but exposure to these drugs has been limited. To date, there have been no studies of topiramate in pregnant women. It is therefore recommended that topiramate be used in pregnancy only if the potential benefit outweighs the potential risk to the fetus.

The current data on pregnancies in women receiving topiramate include some retrospective and some prospective cases. Retrospective data should always be evaluated with caution, because substantial selection bias may overestimate malformation rates. For pregnancies reported prospectively, information on birth status and outcome have been collected on 27. Of these, there were no major anomalies, one minor anomaly (harelip with exposure to phenytoin and topiramate), 11 births with no anomalies, seven spontaneous abortions (consistent with the incidence of spontaneous abortion report in other data in epilepsy), one ectopic pregnancy, and seven therapeutic abortions (dysmorphic features on autopsy). Of the retrospective data, there are 40 cases with information. Of these, there were five major anomalies, three minor anomalies, 16 live births with no anomalies, eight spontaneous abortions, six therapeutic abortions (one with an abnormal finding of spina bifida and hydrocephalus; the mother had received valproate and topiramate), one fetal death, one “blighted ovum,” and one not specified in terms of outcome.

Women with epilepsy who become pregnant and the physicians who treat these women should be encouraged to report and enroll in the Antiepileptic Drug Pregnancy Register of North America, a pharmaceutical company-driven registry, or in the European Registry of Antiepileptic Drugs and Pregnancy (EURAP), set up by a consortium of independent research groups and now extended to several non-European countries. The aim of both of these registries is to improve the analysis and assessment of pregnancy outcome, in terms of fetal risk, after prenatal antiepileptic drug exposure.

Oral Contraception

Topiramate has been found to increase the clearance of the estrogenic component of oral contraceptives in a dose-related manner. Therefore, the efficacy of low-dose (i.e., 20 or 30 µg) oral contraceptives may be reduced in the presence of topiramate. This effect is currently under further investigation in an ongoing steady-state monotherapy oral contraceptive study. Women receiving topiramate should be warned of the possibility of oral contraceptive failure. Clinicians should recommend that additional contraceptive measures be taken.

P.751

 

Contraindications

Topiramate is contraindicated in patients with a history of hypersensitivity to any component of the product.

SUMMARY

The clinical trials program for topiramate in epilepsy and considerable postmarketing experience (750,000 patients treated for ≤400,000 patient-years of exposure) indicate that topiramate is an efficacious, broad-spectrum anticonvulsant. Efficacy has been demonstrated in partial-onset seizures and primary GTCS in adults and children, as both monotherapy and adjunctive therapy. Topiramate has also demonstrated efficacy in treating the refractory and multiple seizure types of Lennox-Gastaut syndrome. Preliminary data are promising for use in treatment-resistant infantile spasms of West's syndrome. The multiple mechanisms of action exhibited by the drug (Chapter 77) may help to explain the agent's apparent broad activity in epilepsy, in both the short term and the longer term. Good clinical responses to topiramate (~10% to 30% of previously treatment-refractory patients becoming seizure free) have now been maintained in some patients for periods of ≤5years, both as adjunctive treatment and as monotherapy.

Topiramate is currently indicated in 19 countries as adjunctive therapy for children as young as 2 years of age, the lowest child age approval of all antiepileptic agents. Use of topiramate across such a wide age range has provided valuable information, not only about efficacy and tolerability, but also about pharmacokinetics, dosing, and titration. Because of increased plasma clearance of topiramate in children compared with adults, it has been suggested that suboptimal doses were given to children under double-blind conditions (4.8 to 6 mg/kg/day). Higher dose levels (>9 mg/kg/day, as administered during open-label extension trials) are now preferred to achieve optimal clinical outcome in children.

Use of topiramate in clinical practice and subsequent clinical testing has also provided valuable information about optimal dosing in adults. The benefit of a lower starting dose and slower titration than that used in the initial regulatory trials has been substantiated.

Finally, preliminary findings of one study suggest that topiramate monotherapy is no less effective than standard carbamazepine or valproate monotherapy in patients with newly diagnosed epilepsy. Furthermore, the optimal monotherapy dose in this patient population was reported to be 100 mg/day. This dosage was as efficacious but better tolerated than 200 mg/day topiramate and at least as well tolerated as 600 mg/day carbamazepine monotherapy or 1,250 mg/day valproate monotherapy, with a notable lack of cognitive side effects reported with topiramate add-on therapy.

Although additional studies are required to investigate and define the role of topiramate further as monotherapy for adults and children with epilepsy, early indications are promising. Optimal dosing and titration as employed in recent clinical trials may substantially improve the agent's tolerability without compromising efficacy.

REFERENCES

  1. Abou-Khalil B, Topiramate YOL Study Group. Topiramate in the long-term management of refractory epilepsy. Epilepsia2000; 41[Suppl 1]:S72-S76.
  2. Ben-Menachem E, Henriksen O, Dam M, et al. Double-blind, placebo-controlled trial of topiramate as add-on therapy in patients with refractory partial epilepsy. Epilepsia1996;37: 539-543.
  3. Ben-Menachem E, Topiramate YTC-E Study Group. A doubleblind trial of topiramate in patients with generalized tonic-clonic seizures of non-focal origin. Epilepsia1997;38[Suppl 3]:S60.
  4. Biton V, Montouris GD, Riviello JD, et al. Efficacy and safety of topiramate in generalized seizures of non-focal origin. Epilepsia1997;38[Suppl 8]:206-207.
  5. Biton V, Chadwick D, Montouris GD, et al. Topiramate as longterm therapy in patients with generalized tonic-clonic seizures without focal onset. Neurology1998;50:A311-A312.
  6. Biton V, Montouris GD, Ritter F, et al. A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Neurology1999;52:1330-1337.
  7. Canger R, Avanzini G, Tartara A, et al. Long-term efficacy and tolerability of topiramate add-on therapy: interim analysis after four years of treatment. Epilepsia1997;38[Suppl 3]:S59.
  8. Chadwick D, Privitera M. Placebo-controlled studies in neurology: where do they stop? Neurology1999;52:682-685.
  9. Edwards KR, Kamin M, Topiramate TPS-TR Study Group. The beneficial effect of slowing the initial titration rate of topiramate. Neurology1997;48[Suppl 2]:A39.
  10. Elterman RD, Glauser TA, Wyllie E, et al. A double-blind, randomized trial of topiramate as adjunctive therapy for partial-onset seizures in children. Neurology1999;52:1338-1344.
  11. Faught E, Wilder BJ, Ramsay RE, et al. Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy using 200-, 400-, and 600- mg daily dosages. Neurology1996;46: 1684-1690.
  12. Franz DN, Glauser TA, Tudor C, et al. Topiramate therapy of epilepsy associated with Angelman's syndrome. Neurology2000; 54:1185-1188.
  13. Franz DN, Tudor C, Leonard J. Topiramate as therapy for tuberous sclerosis complex-associated seizures. Epilepsia2000;41 [Suppl 7]:87.
  14. Gilliam FG, Reife R, Shu-Chen W. Topiramate monotherapy: randomized controlled trial in patients with recently diagnosed localization-related epilepsy. Neurology1999;52[Suppl 2]:A248.
  15. Gisclon LG, Riffitts JM, Sica DA, et al. The pharmacokinetics (PK) of topiramate (T) in subjects with renal impairment (RI) as compared to matched subjects with normal renal function (NRF). Pharm Res1993;10[Suppl]:S397.
  16. Gisclon LG, Curtin CR. The pharmacokinetics (PK) of topiramate (T) in subjects with end-stage renal disease undergoing hemodialysis. Clin Pharmacol Ther1994;55:196.
  17. Glauser TA, Olberding L, Clark P, et al. Topiramate monotherapy substitution in children with partial epilepsy. Epilepsia1996; 37[Suppl 4]:S98.
  18. Glauser TA. Topiramate. Semin Pediatr Neurol1997;4:34-42.

P.752

 

  1. Glauser TA, Elterman R, Wyllie E, Topiramate YP Study Team. Open-label topiramate in paediatric partial epilepsy. Epilepsia1997;38[Suppl 3]:S94.
  2. Glauser TA, Clark PO, Strawburg R. A pilot study of topiramate in the treatment of infantile spasms. Epilepsia1998;39: 1324-1328.
  3. Glauser TA, Levisohn PM, Ritter F, et al. Topiramate in Lennox-Gastaut syndrome: open-label treatment of patients completing a randomized controlled trial. Epilepsia2000;41 [Suppl 1]:S86-S90.
  4. Glauser TA, Clark PO, McGee K. Long-term response to topiramate in patients with West syndrome. Epilepsia2000;41 [Suppl 1]:S91-S94.
  5. Korean Topiramate Study Group. Topiramate in medically intractable partial epilepsies: double-blind placebo-controlled randomized parallel group trial. Epilepsia1999;40:1767-1774.
  6. Michelucci R, Passarelli D, Riguzzi P, et al. Long-term follow-up of TPM in refractory partial seizures. Epilepsia1998;39[Suppl 2]:S67.
  7. Montouris GD, Biton V, Rosenfeld WE, et al. Nonfocal generalized tonic-clonic seizures: response during long-term topiramate treatment. Epilepsia2000;41[Suppl 1]:S77-S81.
  8. Moreland EC, Griesemer DA, Holden KR. Topiramate for intractable childhood epilepsy. Seizure1999;8:38-40.
  9. Motte J, Trevathan E, Arvidsson JF, et al. Lamotrigine for generalized seizures associated with the Lennox-Gastaut syndrome. N Engl J Med1997;337:1807-1812.
  10. Perucca E. A phamacological and clinical review on topiramate, a new antiepileptic drug. Pharmacol Res1997;35:241-256.
  11. Privitera M, Fincham R, Penry J, et al. Topiramate placebo-controlled dose-ranging trial in refractory partial epilepsy using 600-, 800-, and 1000- mg daily dosages. Neurology1996;46: 1678-1683.
  12. Privitera MD, Brodie MJ, Neto W, et al. Monotherapy in newly diagnosed epilepsy: topiramate versus investigator choice of carbamazepine or valproate. Epilepsia2000;41 [Suppl F]:138.
  13. Reife R, Pledger G, Shu-Chen W. Topiramate as add-on therapy: pooled analysis of randomized controlled trials in adults. Epilepsia2000;41[Suppl 1]:S66-S71.
  14. Ritter F, Glauser TA, Elterman RD, et al. Effectiveness, tolerability and safety of topiramate in children with partial-onset seizures. Epilepsia2000;41 [Suppl 1]:S82-S85.
  15. Rosenfeld WE, Sachdeo RC, Wood R. Topiramate can be a successful monotherapy drug. Epilepsia1995;36[Suppl 4]:S56.
  16. Rosenfeld W, Abou-Khalil B, Morrell M, et al. Double-blind placebo-controlled trial of topiramate adjunctive therapy for partial onset epilepsy. Epilepsia1996;37[Suppl 4]:S5.
  17. Rosenfeld WE, Sachdeo RC, Faught RE, et al. Long-term experience with topiramate as adjunctive therapy and as monotherapy in patients with partial onset seizures: retrospective survey of open-label treatment. Epilepsia1997;38[Suppl 1]:S34-S36.
  18. Sachdeo RC, Reife RA, Lim P, et al. Topiramate monotherapy for partial onset seizures. Epilepsia1997;38:294-300.
  19. Sachdeo RC, Patel R, Rehman KU. Long-term experience with topiramate monotherapy. Epilepsia1997;38[Suppl 8]:S97.
  20. Sachdeo RC, Glauser TA, Ritter F, et al. A double-blind randomized trial of topiramate in Lennox-Gastaut syndrome: Topiramate YL Study Group. Neurology1999;52:1881-1887.
  21. Sharief M, Viteri C, Ben-Menachem E, et al. Double-blind, placebo-controlled study of topiramate in patients with refractory epilepsy. Epilepsy Res1996;25:217-224.
  22. Stephen LJ, Sills GJ, Brodie MJ. Topiramate in refractory epilepsy: a prospective observational study. Epilepsia2000;41:977-980.
  23. Tassinari CA, Michelucci R, Chauvel P, et al. Double-blind, placebo-controlled trial of topiramate (600 mg daily) for the treatment of refractory partial epilepsy. Epilepsia1996;37: 763-768.
  24. Tigaran S, Dam M. Topiramate monotherapy: patient with refractory complex partial seizures becomes seizure-free. Epilepsia1996;37[Suppl 4]:S62.
  25. Wasserstein A, Reife R, Rak I. Topiramate and nephrolithiasis. Epilepsia1995;36[Suppl 3]:S153.
  26. Yen D-J, Yu H-Y, You Y-C, et al. A double-blind, placebo controlled study of topiramate in adult patients with refractory partial epilepsy. Epilepsia2000;61:1162-1166.