Antiepileptic Drugs, 5th Edition

Lamotrigine

37

Clinical Efficacy and Use in Epilepsy

Linda J. Stephen MBChB, MRCGP*

Martin J. Brodie MD**

* Honorary Clinical Teacher, Department of Medicine and Therapeutics, University of Glasgow; and Deputy Director, Epilepsy Unit, Western Infirmary, Glasgow, Scotland, United Kingdom

** Professor of Medicine and Clinical Pharmacology, University Department of Medicine and Therapeutics, Glasgow, Scotland, United Kingdom

In the 1960s, some antiepileptic drugs were observed to give rise to abnormalities in folate metabolism, and later folate itself was shown to be proconvulsant in rodents. Around that time, Reynolds and colleagues proposed that antifolate drugs would have anticonvulsant properties (1). Lamotrigine, a phenyltriazine compound among a group having antifolate properties, was born out of this suggestion. Lamotrigine is now licensed worldwide for use as monotherapy in adults and as add-on treatment in adults and children for partial and generalized tonic-clonic seizures and for seizures associated with Lennox-Gastaut syndrome.

CLINICAL EFFICACY

Evidence from Randomized, Controlled Clinical Trials

Partial-Onset Seizures

Eleven placebo-controlled, double-blind, crossover, and parallel-group trials (Table 37.1) involving 1,052 patients have confirmed the efficacy of lamotrigine for partial seizures with or without secondary generalization (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12).

In the preliminary report by Binnie and colleagues (2), 10 patients with treatment-resistant partial seizures were recruited and all completed the study. There was a significant decrease in seizure counts with lamotrigine compared with placebo. Six noted a decrease in seizure frequency of at least 50% on lamotrigine, with one patient remaining seizure free throughout the 7-day treatment period.

Jawad and colleagues (3) maintained trough levels of lamotrigine between 1.5 and 2 mg/L. They found a significant reduction in seizure days and number of seizures among their 21 patients over 12 weeks of therapy. Two-thirds of patients had their total seizure count more than halved. Seventy-five percent of patients with partial seizures responded to lamotrigine, compared with 44% with secondary generalization.

In Binnie and colleagues' later study (4), 30 patients were given lamotrigine as add-on therapy. In seven patients, the lamotrigine dosage was reduced, mostly because of headache and dizziness. Twelve patients had their total seizure count reduced by more than 25% with lamotrigine, compared with only four taking placebo. Twenty of the 22 patients with partial seizures noted an improvement in seizure numbers. This exceeded 50% in just two.

The results from Sander and colleagues' study (5) were the least conclusive. Eighteen of 21 patients completed the trial. There was an overall reduction in seizure numbers, which was greater for secondary generalized events in the later stages of the lamotrigine treatment period. Partial seizures appeared unaffected. Tolerability was not a problem, with similar numbers of adverse events reported on lamotrigine and placebo. Modest efficacy, however, was most likely due to a combination of low-dose lamotrigine and severity of the epilepsy.

Loiseau and coworkers (6) found that over an 8-week period, 15 of 23 patients reported a reduction in total seizures while taking lamotrigine compared with placebo. Fourteen had the frequency of their partial seizures reduced, eight by more than 50%.

Over a 6-month treatment period, Matsuo and colleagues (7) studied 216 patients. Equal numbers were randomized to 300 or 500 mg/day of lamotrigine or placebo. Efficacy was greatest in the 500-mg arm, with a reduction in median seizure frequency of 36%. Patients taking placebo had a reduction of 8%, and those on 300 mg, 20%. One-third of patients taking 500 mg/day experienced a ≥50% reduction in seizure number, and one-fourth of these patients had a similar reduction in seizure days. Frequency of partial seizures was significantly reduced compared with baseline in patients taking 500 mg lamotrigine. Thirteen patients on active treatment were withdrawn as a result of adverse events, most of whom were in the 500-mg arm.

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TABLE 37.1. PLACEBO-CONTROLLED EFFICACY TRIALS WITH ADJUNCTIVE LAMOTRIGINE

Reference

Patients Recruited

Patients Completed

Duration of Treatment (wk)

Dose range (mg/day)

Decrease in Total Seizure Frequency (%)

Patients with >50% Decrease in Total Seizures

Patients with >50% Decrease in Generalized Seizures

Patients with >50% Decrease in Other Seizure Types

Binnie et al., 1987

10a

10

1

100-300

NA

60

5/5 (100%)

5/8 (62.5%)c

Jawad et al., 1989

24a

21

12

75-400

59 (median)

66

7/15 (47%)

12/17 (71%)c

Binnie et al., 1989

34a

30

12

50-150 (VPA)

17 (median)

7

2/19 (9%)

2/20 (10%)c

       

50-400 (non-VPA)

       

Sander et al., 1990

21a

18

12

100-300

18 (mean)

11

NA

NA

Loiseau et al., 1990

25a

23

8

75-300

23 (median)

30

NA

8/23 (35%)c

Matsuo et al., 1993

216b

191

24

300

20 (median)

20

NA

NA

       

500

36 (median)

34

NA

NA

Schapel et al., 1993

41a

41

12

150 (VPA)

24 (median)

22

9/32 (28%)

8/41 (20%)c

       

300 (non-VPA)

       

Smith et al., 1993

81a

62

18

100-400

30 (mean)

18

10/36 (28%)

12/62 (19%)c

Messenheimer et al., 1994

98a

88

14

100-400

25 (median)

20

NA

NA

Schachter et al., 1995

446b

374

24

100-500

NA

NA

NA

NA

Boas et al., 1996

56a

38

12

75-400

30 (mean)

24

12/19 (63%)

10/46 (22%)c

Beran et al., 1998

26a

22

8

75 (VPA)

NA

NA

7/14 (50%)

5/15 (33%)d

       

150 (non-VPA)

       

NA, data not available; VPA, valproic acid.

a Crossover trials.

b Parallel groups.

c Partial seizures.

d Absence seizures.

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Schapel and colleagues (8) undertook 12 weeks of treatment with lamotrigine and matched placebo in 41 patients, all of whom completed the study. Those on enzyme-inducing antiepileptic drugs were titrated to 300 mg lamotrigine daily; those on sodium valproate and an enzyme inducer received 150 mg/day. Twenty-six patients reported a decrease in total seizure numbers, by more than half in nine (22%). Overall, 20% and 47% of patients with partial and secondary generalized seizures had these reduced by more than 50% with lamotrigine, compared with 16% on placebo. Although the decrease in secondary generalized seizures did not reach statistical significance, it became more marked when patients with less than four seizures a month were excluded.

Smith and coworkers (9) reported 18-week lamotrigine and placebo treatment periods. Of 81 patients recruited, 62 completed the trial. Lamotrigine dosages were relatively high compared with other crossover studies—200 mg/day for patients on non-enzyme-inducing drugs and 400 mg/day for those taking enzyme-inducing antiepileptic drugs. Eleven patients withdrew because of adverse events, mostly headache, diplopia, and dizziness. Eighteen of the completing patients had a modest response, reporting a reduction in total seizures of 25% to 49% compared with placebo. A further 11 were regarded as responders (reduction >50%). On analysis by seizure type, 12 of 62 patients experienced a significant reduction in partial seizures, with 10 of 36 demonstrating a similar response for secondary generalized seizure frequency. Seizure severity was ameliorated by lamotrigine. For the first time, quality-of-life factors were monitored in an antiepileptic drug study. Although most of the tests revealed no difference between lamotrigine and placebo, there were significant improvements in mastery (perceived internal control) and happiness scores. Forty-two of the completing patients chose to remain on lamotrigine, some despite little change in seizure pattern.

Messenheimer and colleagues (10) undertook a study comparing 14 weeks of lamotrigine treatment with placebo. A total of 98 patients, 75% of whom were taking carbamazepine, entered the trial. Lamotrigine dosage was titrated to a maximum of 400 mg/day. Efficacy data were evaluated in 88 patients, 44% of whom had a >25% decrease and 20% of whom had a ≥50% decrease in seizure frequency on lamotrigine compared with placebo. The number of seizure days was reduced by 18% during the active treatment period.

Schachter and colleagues (11) conducted the largest American parallel group study in 446 patients, 112 of whom received placebo. The remaining 334 took up to 500 mg/day of lamotrigine for 6 months. Efficacy data were scanty, although investigators rated 65% of patients who received lamotrigine “improved” compared with 35% of those on placebo. The withdrawal rate was 8% for both groups because of side effects.

Boas and colleagues (12) assessed the antiepileptic effect of lamotrigine in 56 patients over a 12-week period. Those not receiving sodium valproate were titrated to 400 mg lamotrigine daily and those taking valproate to 200 mg/day. Thirty-eight patients completed the study. Significant reductions in mean seizure count (30.3%) and in mean seizure days (27.5%) occurred with lamotrigine. Two patients withdrew from the active treatment arm because of lack of efficacy, and six because of adverse effects.

Generalized Seizures

Beran and colleagues (13) performed the first double-blind, placebo-controlled, crossover study of adjunctive lamotrigine in 26 patients with generalized epilepsies (Table 37.1). Twenty-one had idiopathic generalized epilepsy, two had symptomatic epilepsy, and three patients were unclassifiable. Twenty-two patients were included in the efficacy analysis, with tonic-clonic and absence seizure rates being at least halved in 50% and 30%, respectively, compared with placebo. Two patients had myoclonic seizures, one of whom became worse and the other experiencing no change.

Monotherapy Studies

Four randomized, comparative trials have supported the efficacy of lamotrigine as monotherapy for partial-onset and generalized tonic-clonic seizures in adults (14, 15, 16) and in elderly patients (17) with newly diagnosed epilepsy (Table 37.2).

Brodie and colleagues (14) randomized 260 patients with partial-onset or primary generalized tonic-clonic seizures to receive lamotrigine or carbamazepine during 48 weeks of treatment in a double-blind study. Baseline seizure counts were similar for both treatment arms. No significant difference was noted for seizure freedom at 6 weeks or in time to first seizure, but patients taking lamotrigine were significantly more likely to remain on antiepileptic medication than their carbamazepine-treated counterparts. More patients on carbamazepine withdrew because of rash (13% carbamazepine; 9% lamotrigine) and other side effects. Somnolence was significantly more common in carbamazepine-treated patients.

Ruenanen and coworkers (15) studied the efficacy of lamotrigine and carbamazepine in a randomized open-label trial. In equal numbers, 343 patients were randomized to receive lamotrigine 100 mg/day, lamotrigine 200 mg/day, or carbamazepine 600 mg/day. After 30 weeks of treatment, data from the 223 completers were analyzed. A higher proportion of patients taking 200 mg/day of lamotrigine (60.4%) remained seizure free for the last 24 weeks compared with those taking 100 mg/day (51.3%) and carbamazepine (54.7%). There were no differences among the three study arms in the number of patients seizure free at 6 weeks, in time to first seizure, or in time to treatment withdrawal.

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TABLE 37.2. RANDOMIZED COMPARATIVE MONOTHERAPY TRIALS OF LAMOTRIGINE IN PATIENTS WITH NEWLY DIAGNOSED PARTIAL-ONSET AND GENERALIZED TONIC-CLONIC SEIZURES

Reference

Comparative Antiepileptic Drug

Dose Range (mg/day)

Patients Recruited

Patients Completed

Duration of Treatment (wk)

Seizure Freedom Comparison at 6 Wk

Time to First Seizure

Time to Withdrawal

Brodie et al., 1995

CBZ

LTG 100-300

260a

151

48

No significant difference

No significant difference

Significantly longer for LTG patients

   

CBZ 300-1400

131 LTG

85 (65%) LTG

     
     

129 CBZ

66 (51%) CBZ

       

Reunanen et al., 1996

CBZ

LTG 100

343b

223

30

No significant difference

No significant difference

No significant difference

 

LTG 200

115 LTG 100 mg

71 (61.7%) LTG 100 mg

 
   

CBZ 600

111 LTG 200 mg

76 (68.5% LTG 200 mg

       
     

117 CBZ

76 (64.7%) CBZ

       

Steiner et al., 1999

PHT

LTG NA-400

181a

174

48

No significant difference

Cumulative trend favored LTG

PHT favored during titration period

   

PHT NA-600

86 LTG

81 (94%) LTG

 
     

95 PHT

93 (98%) PHT

       

Brodie et al., 1999

CBZc

LTG 75-300

150a

92

24

No significant difference

NA

Significantly longer for LTG patients (p < .001)

   

CBZ 200-800

102 LTG

72 (71%) LTG

   
     

48 CBZ

20 (42%) CBZ

     

CBZ, carbamazepine; LTG, lamotrigine; NA, data not available; PHT, phenytoin.

a Double-blind trial.

b Open-label trial.

c Elderly patients.

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Steiner and coworkers (16) compared lamotrigine and phenytoin monotherapy in 181 patients. The efficacy analysis included 81 patients taking lamotrigine and 93 on phenytoin. There was no significant difference during the last 24 and 40 weeks of treatment in the percentage of patients remaining on treatment and seizure free, the numbers of seizures, and the changes in seizure frequency from baseline. Time to first seizure analysis favored lamotrigine for all seizure types considered together. Time to study discontinuation showed a trend favoring phenytoin during the titration period, but not subsequently. A total of 31 patients were discontinued because of adverse events, 13 (15%) with lamotrigine and 18 (19%) with phenytoin.

To compare efficacy of lamotrigine and carbamazepine in elderly patients, Brodie and associates (17) randomized 150 patients aged 65 years and older to receive lamotrigine or carbamazepine in a 2:1 ratio. The study was completed by 71% of lamotrigine-treated patients and 42% of those taking carbamazepine. There was no statistical difference in seizure freedom rates at 6 weeks, but analysis excluded the 58% of patients on carbamazepine who withdrew prematurely. A higher percentage of patients on lamotrigine remained seizure free for the last 4 months because of the greater dropout rate in the carbamazepine arm (lamotrigine 39%, carbamazepine 21%). Of those discontinuing, 42% on carbamazepine and 18% taking lamotrigine did so because of adverse events. Significantly fewer patients on lamotrigine (3%) withdrew because of rash compared with those taking carbamazepine (19%). Significantly more patients taking carbamazepine reported somnolence.

A double-blind, double-dummy, active-control study was undertaken by Gilliam and colleagues (18) to evaluate the efficacy and safety of lamotrigine as monotherapy. In equal numbers, 156 patients taking carbamazepine or phenytoin were randomly assigned to receive adjunctive lamotrigine or sodium valproate during 20 weeks' treatment. Lamotrigine was titrated to 500 mg/day or the maximally tolerated dosage over 3 weeks. Sodium valproate was titrated over 8 days to 1,000 mg/day or the maximally tolerated dosage. Initial antiepileptic medications were then withdrawn. Significantly more patients taking lamotrigine (56%) completed the study compared with those on valproate (20%). The time to escape was statistically longer in lamotrigine-treated patients. The lamotrigine daily dosage of 500 mg was achieved in 95% of patients treated for at least 5 weeks.

To compare adjunctive treatment and withdrawal to monotherapy with lamotrigine or carbamazepine, Fakhoury and associates (19) randomized 143 patients with uncontrolled epilepsy to receive the drugs in a 2:1 ratio as add on therapy. Each drug was added over 12 weeks, after which existing therapy was withdrawn. Patients taking monotherapy remained on lamotrigine for longer, with more becoming seizure free or having a reduction in seizure frequency. Fewer lamotrigine-treated patients withdrew because of drug-related adverse events.

Gazda and colleagues (20) compared adjunctive treatment and monotherapy with lamotrigine and sodium valproate in 154 patients with uncontrolled epilepsy. Patients were randomized in a 2:1 ratio to receive lamotrigine or valproate. The drugs were added to current therapy for 12 weeks, after which existing treatment was withdrawn and patients entered an 8-week monotherapy phase. After conversion to monotherapy, seizure freedom and reduction rates were greater for lamotrigine than for valproate. More patients on lamotrigine were successfully withdrawn to monotherapy.

Martinez and coworkers (21) compared lamotrigine with conventional antiepileptic monotherapies in 115 patients who had failed on carbamazepine, phenytoin, or sodium valproate. Fifty-seven patients were randomized to be converted from their original antiepileptic drugs to lamotrigine and 58 were randomized to receive carbamazepine, phenytoin, or sodium valproate, according to the physician's choice. More patients on lamotrigine (65%) completed the study than those taking conventional antiepileptic drugs (57%), with the former having improvements in seizure frequency, seizure intensity, intellectual functioning, adverse events, overall status, and global self-assessment. The extent of reduction in seizure frequency was comparable in both groups.

Children: Partial-Onset Seizures

Two placebo-controlled studies of lamotrigine in children with partial-onset seizures have been conducted (22,23).

Schlumberger and colleagues (22) evaluated the efficacy of adjunctive lamotrigine in 120 children, 63% of whom had learning disabilities, over 3 months to 3 years. Sixty patients participated in a single-blind study, receiving placebo for 1 month before switching to lamotrigine in a dose-ranging phase. Patients were started on 0.5, 1, or 2 mg/kg/day according to whether they were taking enzyme-inhibiting, balanced, or enzyme-inducing comedication, respectively. The dosage was doubled during the second month, tripled during the third, and increased thereafter if required. Of the other 60 children in whom efficacy was evaluated, 23 participated in a pharmacokinetic study and 37 received lamotrigine on a compassionate basis with dosing schedules based on results from the single-blind study. No difference was seen between baseline and placebo in the single-blind study. Fourteen patients, 13 with generalized epilepsy, became seizure free for more than 6 months. Treatment could be reduced to monotherapy in 12 patients, 11

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of whom had generalized epilepsy. Ten remained seizure free. The best results were obtained for the nine patients with absence epilepsy, of whom three became seizure free, four had a >50% improvement, and none worsened. Of the 10 patients with the Lennox Gastaut syndrome, 3 became seizure free, 3 had a >50% improvement, and none worsened.

Duchowny and colleagues (23) examined the efficacy and safety of adjunctive lamotrigine in 201 children and adolescents with partial-onset seizures during a placebo-controlled, parallel-group trial. After a 6-week titration period, patients received an unchanged dosage of lamotrigine or placebo for 12 weeks. A total of 167 patients completed the study, 84 on lamotrigine and 83 on placebo. Patients taking lamotrigine had a significant reduction in partial and secondary generalized seizure numbers from baseline (44%) compared with those on placebo (13%). Significantly more patients with partial and secondary generalized seizures taking lamotrigine had at least a 50% reduction in seizure frequency and seizure-free days compared with placebo. Adverse events were no different from those reported in adults.

Children: Generalized Seizures

Eriksson and coworkers (24) undertook a randomized, double-blind, crossover study of adjunctive lamotrigine in 30 children and adolescents with refractory generalized epilepsy. Twenty had the Lennox-Gastaut syndrome. After an 8-week baseline phase, lamotrigine was added to current antiepileptic drugs during a 2- to 12-month open-label phase. At the end of this time, children who had a ≥50% reduction in seizure frequency, seizure severity or both, or definite improvements in behavior, motor skills, or both were classified as responders. These children entered two 12-week double-blind phases during which their previous dosage of lamotrigine or placebo was administered in random order. The open phase was completed by 27 patients, all of whom had a significantly lower monthly seizure rate compared with baseline. Atypical absences and myoclonic events were excluded from analysis because of difficulty in counting them. Lamotrigine was found to be significantly more effective than placebo. A total of 17 children were classified as responders, with 7 having a ≥50% reduction in seizure frequency and 2 having a ≥75% reduction. Fifteen children completed the double-blind phase, showing a ≥50% reduction in seizure frequency on lamotrigine. One child became seizure-free and one had a ≥75% reduction in seizures. Seven of the 20 patients with the Lennox-Gastaut syndrome had a >50% reduction in seizure frequency, with 2 becoming seizure free and 3 having a >75% decrease in seizures. Eight (47%) of the 17 children with tonic-clonic seizures, 6 (55%) of 11 with atonic seizures, and 13 (62%) of 21 with tonic seizures had a >50% reduction in seizure frequency.

Children: Monotherapy Studies

To evaluate whether lamotrigine monotherapy was efficacious and safe for children with typical absence epilepsy, Frank and colleagues (25) undertook a study in 45 newly diagnosed children using an enrichment design. Patients received escalating doses of open-label medication for ≥5 weeks, with the 29 who became seizure free subsequently being randomized in a double-blind phase to receive lamotrigine or placebo for ≥10 weeks. This phase was completed by 28 patients, 14 each taking lamotrigine and placebo. During the double-blind phase, significantly more patients on lamotrigine (64%) became seizure free compared with those taking placebo (21%). Overall, 30 (71%) of the 42 patients who completed the dose escalation phase became seizure free at a median lamotrigine dosage of 5 mg/kg/day (range, 2 to 15 mg/kg/day). Twenty-two patients who continued to seize on 7 mg/kg/day had their dosage increased to a maximal dosage of 15 mg/kg/day and, of these, 18 (82%) became seizure free.

Lennox-Gastaut Syndrome

Motte and colleagues (26) undertook a double-blind study of adjunctive lamotrigine in 169 children and adults with the Lennox-Gastaut syndrome. During a 4-week baseline period, all patients received placebo together with their standard antiepileptic drug regimens. In total, 169 eligible patients entered a 16-week treatment period, receiving either active drug or placebo. The study was completed by 148 patients. The median reduction in seizure count from baseline for those taking lamotrigine (34%) was significantly greater than for those taking placebo (9%). Statistically more lamotrigine-treated patients had a reduction of at least 50% in the frequency of all types of major seizures, drop attacks, and tonic-clonic seizures. No significant difference was found for atypical absences. Three patients taking lamotrigine withdrew because of adverse events, one because of worsening seizures and two, who also were taking sodium valproate, because of rash.

Patients with Learning Disabilities

An interim analysis from Veendrick-Meekes and colleagues (27) reports on their placebo-controlled trial of adjunctive lamotrigine in 48 adults with learning disabilities. Seizure counts more than halved in 30 (37%) of the patients on lamotrigine compared with 18 (22%) of those taking placebo. Seizure freedom occurred in 11% of lamotrigine patients, but in none on placebo. Investigator global evaluation showed that 52% of patients on lamotrigine improved, 41% had no change, and 7% deteriorated, compared with those on placebo, of whom 6% improved, 88% had no change, and 6% deteriorated. Using the Hague Seizure Severity Scale, carers reported a significant decrease

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in seizure severity in lamotrigine-treated patients compared with those taking placebo.

Evidence from Other Studies

Partial-Onset and Generalized Seizures

A number of open-label studies with lamotrigine in patients with a variety of seizure types have played a valuable role in exploring dose requirements and identifying common side effects.

Jawad and coworkers (28) gave 23 patients adjunctive lamotrigine for 7 days. Of the 20 who completed the study, 18 took 2 other drugs, the remainder receiving 3. Eight patients (40%) had a reduction in seizure frequency exceeding 50%, whereas a similar number noted a less striking improvement.

Sander and colleagues' open-label study (29) also supported efficacy for adjunctive lamotrigine. A total of 104 patients completed 12 months of treatment with lamotrigine, with 25% experiencing a reduction in seizure count by more than half. The dropout rate was 15%. Six to 8 years later, these patients were followed up (30). It was reported that 21% had a >50% reduction in seizure frequency, with only one being seizure free.

Timmings and Richens (31) reviewed records from 82 patients started on lamotrigine. The drug was withdrawn in 22 because of lack of efficacy or adverse events. Of the remaining patients, 19 had primary generalized epilepsy, 29 had partial-onset seizures, and 12 had mixed or unclassifiable seizure types. Seizure frequency more than halved in 79% of patients with primary generalized epilepsy and in 48% of those with partial-onset seizures. Six patients became seizure free. Concomitant antiepileptic drugs could be successfully withdrawn in 33%.

Stewart and associates (32) reported results in 72 patients with refractory epilepsy, 63 with partial-onset, 4 with primary generalized, and 5 with unclassifiable seizures. The addition of lamotrigine resulted in 30% of those with partial-onset seizures having a ≥50% improvement in seizure control, with one patient becoming seizure free. Two patients with primary generalized seizures had their seizures abolished and two had a >75% improvement in control.

Cocito and colleagues (33) gave add-on lamotrigine to 13 patients with refractory partial-onset seizures and to 3 with uncontrolled primary generalized epilepsy. Ten patients completed 1 year of treatment, with six having their seizure frequency more than halved compared with baseline.

Schapel and Chadwick (34) undertook a retrospective analysis comparing the efficacy and tolerability of adjunctive lamotrigine and vigabatrin in 333 patients with refractory epilepsy. One hundred sixteen patients were exposed to lamotrigine only, 108 to vigabatrin only, and 109 to both drugs, together or in combination. Lamotrigine was continued in preference to vigabatrin by 36 patients, and vigabatrin was continued in preference to lamotrigine by 17 patients. Both drugs were continued in combination by 31 patients. After 40 months, the probability of patients remaining on lamotrigine was 57%, and on vigabatrin, 43%. With lamotrigine, 10% of patients became seizure free, and 45% had a 50% improvement in seizure frequency.

Buchanan (35) followed up 200 patients of all ages with different seizure types who had taken lamotrigine for at least 6 months. Introduction of the drug resulted in seizure freedom for 70 (35%) patients, with 54% of those with primary generalized and 26% of those with partial-onset seizures becoming seizure free. Of the 67 patients with cerebral palsy or brain injury, 67% were reported to have a marked improvement in alertness, cognition, and quality of life. Eleven (73%) patients with juvenile myoclonic epilepsy were seizure free, although 13 patients switched to lamotrigine because of side effects rather than poor control. Of patients with absences or tonic-clonic seizures, 18 (69%) became fully controlled. One (14%) patient with tonic seizures and three (21%) with the Lennox-Gastaut syndrome became seizure free.

Kilpatrick and colleagues (36) undertook a prospective study of adjunctive lamotrigine in 27 patients with newly diagnosed and 42 patients with refractory epilepsy. Overall, 26 patients had idiopathic generalized and 43 had partial-onset seizures. The drug was started in a dosage of 25 or 50 mg/day with an increase in 50-mg monthly increments until seizure freedom or unacceptable side effects occurred. The study was completed by 50 patients, 32 of whom became seizure free on a median lamotrigine dose of 200 mg (range, 50 to 850 mg). No useful concentration-toxicity effect relationship was demonstrated.

Gericke and coworkers (37) examined the efficacy of lamotrigine as add-on therapy or monotherapy in 46 patients with idiopathic generalized epilepsy. Lamotrigine was started because of poor seizure control, and concomitant antiepileptic drugs were withdrawn if patients subsequently developed side effects. After 5 months' follow-up, 32 (70%) patients became seizure free—9 of 12 (75%) with childhood absence epilepsy, 10 of 12 (83%) with juvenile absence epilepsy, 7 (50%) with juvenile myoclonic epilepsy, 3 (60%) as with generalized tonic-clonic seizures on awakening, and 3 (100%) with photosensitive epilepsy. An improvement of >50% was seen in one-fourth. Patients who were not controlled had either absences with a mild atonic component, absences with eyelid myoclonia, a longstanding history of epilepsy, or poor compliance. In seven patients with juvenile myoclonic epilepsy, tonic-clonic and absence seizures were abolished, but myoclonic seizures persisted. Eleven of the 16 patients on lamotrigine monotherapy became seizure free, 3 with childhood absence epilepsy, 4 with juvenile absence epilepsy, 2 with juvenile myoclonic epilepsy, and 2 with pure photosensitive epilepsy.

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Collins and coworkers (38) conducted a retrospective review of 61 patients with uncontrolled partial-onset seizures, comparing add-on treatment with lamotrigine in 37, gabapentin in 36, topiramate in 28, and vigabatrin in 26. The median time to 50% dropout was >43 months for lamotrigine, compared with 13, 28, and 26 months for gabapentin, topiramate, and vigabatrin, respectively. Sixty percent of patients taking lamotrigine, 19% of those on gabapentin, 50% of those on topiramate, and 27% of those on vigabatrin continued on treatment.

Faught (39) reported that four adult patients with startle-induced seizures who had been resistant to almost every other antiepileptic drug improved with lamotrigine.

Status Epilepticus

A report of its intravenous use in status epilepticus suggests that lamotrigine also possesses acute anticonvulsant properties (40). This also may be the case in children. Besag (41) studied the use of lamotrigine in 12 children with intermittent nonconvulsive status epilepticus using an automatic spike-and-wave recording system. Half the patients had a significant reduction in seizure frequency over a 48-week period. A decrease in episode frequency of 80% or more was reported. Increased well-being was postulated to be due to a reduction in subclinical seizures.

Children: Partial-Onset Seizures

A number of open-label trials of lamotrigine in children have been performed. Several studies have included children with different seizure types and those with and without learning disabilities.

Battino and coworkers (42) administered adjunctive lamotrigine over a 12-month period to 14 children with refractory epilepsy, half of whom had structural brain lesions. Of the seven patients who completed the study, two became seizure free, four had their seizure frequency more than halved, and one had no change.

Uvebrant and Bauziené (43) treated 50 children and adolescents with adjunctive lamotrigine. Several had multiple seizure types, with 40 (36%) having partial-onset seizures and 71 (64%) having generalized epilepsy. Eight children had infantile spasms, eight had the Lennox-Gastaut syndrome, four had myoclonic astatic epilepsy, three had electrical status epilepticus during slow sleep (ESES), two had gelastic epilepsy with hypothalamic hamartoma, and two had absence seizures. Children were followed up for 4 to 35 months (mean 14 months), after which 30 continued on lamotrigine. Five (11%) of these became seizure free and 16 (36%) had more than a 30% improvement in their seizure frequency. The situation did not improve in 24 (53%). Myoclonic, tonic, and tonic-clonic seizures were the most resistant. Seizure frequency in 60% of the children with the Lennox-Gastaut syndrome improved by more than half. One of the two children with gelastic epilepsy improved, as did one with myoclonic astatic epilepsy. None of those with ESES improved. Fifty-three percent of parents reported an improvement in the mental state of their child.

Besag and coworkers (44) analyzed pooled data from five open add-on studies of adjunctive lamotrigine in 285 children with refractory epilepsy. Most had two or more seizure types. Assessments were made at the end of four 12-week treatment periods. Seizure frequency was reduced by 50% or more in one-third of patients. Lamotrigine was effective in partial, generalized tonic-clonic, myoclonic, and atonic seizures, but was particularly so for typical and atypical absences.

After this study, Besag and colleagues (45) evaluated the safety, tolerability, and efficacy of lamotrigine at 2 or 3 years in 155 children and adolescents with epilepsy who had already completed a 12-month add-on trial. Patients entered the study on their optimal dose of lamotrigine from the previous trial. Twenty-two were on monotherapy. Change in seizure control was evaluated using a numerical scale of 1 (marked deterioration) to 7 (marked improvement). The study was completed by 109 patients. The overall percentage with improved or unchanged seizure control was maintained throughout the trial, ranging from 73% to 80% and 11% to 16%, respectively. Thirteen of the 22 patients on monotherapy remained on lamotrigine.

Herranz and coworkers (46) reported on efficacy and tolerability of adjunctive lamotrigine over a period of 144 weeks in 13 children with refractory epilepsy. Seven patients continued on lamotrigine, two becoming seizure free and four having a >50% reduction in seizure frequency.

Buoni and colleagues (47) studied the response to lamotrigine in 63 children with drug-resistant epilepsies over 1 to 3 years. Sixteen (25%) patients, six with typical absence seizures, four with myoclonic astatic seizures, three with the Lennox-Gastaut syndrome, and three with complex partial seizures, became seizure free. A significant long-standing response to lamotrigine treatment occurred in six (10%) children. Eleven (17.4%) patients showed an initial unsustained improvement. No response occurred in 30 (47.6%) patients.

Three studies compared outcomes in children taking adjunctive lamotrigine and vigabatrin (48, 49, 50).

Schapel and colleagues (48) surveyed 109 children with poorly controlled epilepsy treated with add-on lamotrigine or vigabatrin. Localization-related epilepsy was present in 65%, with the remainder having generalized seizures. There were 79 patient exposed to lamotrigine and 86 with vigabatrin. Forty-two patients received lamotrigine, 52 received vigabatrin, and 20 were treated with both drugs simultaneously. Fifteen patients were treated with both drugs serially, 12 continuing on lamotrigine and 3 continuing on vigabatrin. It was estimated from a Kaplan-Meier curve that 71% and 62% of patients would be expected to take lamotrigine or vigabatrin, respectively, after 40 months. Seizure control

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had improved by 50% or more in 65% of patients on lamotrigine and in 58% of patients on vigabatrin. Lamotrigine was more successful than vigabatrin for generalized seizures, with the converse found for partial seizures. The drugs appeared equally effective for the Lennox-Gastaut syndrome, but more patients with myoclonic astatic epilepsy improved with lamotrigine. All five patients with epilepsy with myoclonic absences responded to lamotrigine.

Bélanger and colleagues (49) reviewed medical records from 105 children with a variety of seizure types and syndromes who had been prescribed lamotrigine, vigabatrin, or both for at least 1 year. Fifty-eight patients had generalized epilepsy, including 23 with infantile spasms. Forty-seven patients had localization-related epilepsy. Of these, 42 had lamotrigine added to their antiepileptic drug regimen, whereas 83 received vigabatrin. Eight patients received both drugs. The authors concluded that lamotrigine was more effective for generalized epilepsies and vigabatrin was significantly more effective in partial epilepsies. Lamotrigine was statistically more efficacious in children whose electroencephalograms (EEGs) showed a primary generalized pattern compared with those with multifocal spikes or secondarily generalized activity.

Dimova and Korinthenberg (50) undertook a retrospective comparison of the efficacy and side effects of add-on lamotrigine and vigabatrin in 134 children with refractory partial-onset and primary generalized seizures. Lamotrigine was given to 57 patients. A >50% reduction in seizure frequency was observed in 33% on lamotrigine and 41% on vigabatrin for patients with partial-onset seizures, and in 34% of patients on lamotrigine and 33% of patients on vigabatrin for those with generalized seizures.

Children: Generalized Seizures

Buchanan (51) examined the use of lamotrigine in 12 girls with juvenile myoclonic epilepsy who either had side effects with or did not wish to take sodium valproate. Four were seizure free at the start of the study. Attempts to withdraw sodium valproate were made in the seven patients taking this drug. Five patients became completely controlled on lamotrigine monotherapy. Five patients remained on a combination of valproate and lamotrigine. Reduction in valproate led to breakthrough of myoclonic jerks in three.

Farrell and colleagues (52) evaluated the efficacy and adverse effects of adjunctive lamotrigine in 56 children with uncontrolled generalized epilepsies, 46 of whom had learning disabilities and 36 of whom had two or more seizure types. Patients were reviewed at three monthly intervals for 25 weeks. Six (11%) patients became seizure free and 24 (43%) had a >50% reduction in seizure frequency. Three of the 15 children with the Lennox-Gastaut syndrome became seizure free and 8 had a >50% improvement in their seizure frequency.

Buoni and colleagues (53) studied the effects of lamotrigine in 15 children with absence epilepsy. Five already were taking sodium valproate, three were taking sodium valproate and ethosuximide, and seven had untreated seizures. Patients were followed up from 1.8 to 4.3 years. Absence seizures became controlled in all patients started on lamotrigine monotherapy, although rash led to treatment withdrawal in one. Seizure control in the others was significantly more likely with lamotrigine and sodium valproate duotherapy, compared with lamotrigine monotherapy. Normalization of the surface EEG with lamotrigine occurred in 13 patients.

Infantile Seizures

Lamotrigine has demonstrated efficacy for seizures in infants.

Veggiotti and colleagues (54) studied 30 infants with refractory infantile spasms who had lamotrigine added to their antiepileptic drug regimen. After 3 months' treatment, spasms had ceased in 5 (16.6%) patients also taking sodium valproate, improved in 4 (13.3%), worsened in 2 (6.6%) and remained unchanged in 19 (63.5%). Asymmetric spasms were significantly associated with a favorable outcome.

Barr and coworkers (55) reported that a newborn infant with seizures of unknown etiology refractory to conventional antiepileptic drugs had a rapid and sustained cessation with lamotrigine 4.4 mg/kg/day. The drug was well tolerated and allowed discontinuation of phenobarbital and phenytoin, leaving the neonate on lamotrigine and vigabatrin.

Patients with Learning Disabilities

Timmings and Richens (56) reported on 11 patients with the Lennox-Gastaut syndrome who had been treated with adjunctive lamotrigine for 3 months. Ten (91%) patients had a ≥50% improvement in seizure frequency, with one becoming seizure free. The drug was well tolerated, allowing withdrawal of other antiepileptic drugs in six patients.

Buchanan (57) studied the outcomes of 6 months of add-on lamotrigine in 34 children and adults with brain injury. Overall, 35.3% of patients became seizure free and 76.6% had a >50% reduction in seizure frequency.

Donaldson and associates (58) conducted a retrospective review of adjunctive lamotrigine in 16 adults and children with the Lennox-Gastaut syndrome over 18 months. Efficacy data were derived from 15 patients, 53% of whom experienced a >50% reduction in total seizure frequency, with 20% having a >90% reduction. At the end of the study, 53% of parents reported that their child's quality of life was much or very much improved, 33% reported minimal improvement or no change, and 13% said that quality of life had worsened since lamotrigine had been initiated. Myoclonic seizures were the least responsive.

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Bhaumik and coworkers (59) undertook a retrospective analysis of outcomes for adults with learning disabilities treated with lamotrigine, vigabatrin, and gabapentin. Twenty-five treatment episodes were identified for lamotrigine, with 10 patients on monotherapy. Nine (36%) patients experienced a >50% reduction in seizure frequency.

Huber and colleagues (60) studied the effect of add-on lamotrigine in 125 patients with refractory seizures and multiple additional handicaps during a mean treatment period of 21.9 months. Lamotrigine was continued by 71.4% of patients, one-third of whom had a ≥50% reduction in their seizure frequency. Responder rates were 35.6% for patients with focal epilepsies, 26.7% for patients with generalized epilepsies, and 22.4% for patients with both. Patients taking concomitant valproate (51.5%) were significantly more likely to respond than those not taking the drug (20.7%).

Coppola and Pascotto (61) studied the outcome of 7 months of adjunctive lamotrigine in 37 children and adolescents with refractory epilepsy and mental delay. Thirteen (35.1%) patients showed a >50% decrease in seizure frequency. Of the eight (21.6%) patients who became seizure free, four had typical absences, two atypical absences, and two atonic seizures. The authors commented that lamotrigine seemed to be more efficacious in patients with a shorter duration and later onset of epilepsy.

Gidal and associates (62) retrospectively analyzed the efficacy of adjunctive lamotrigine in 44 institutionalized, developmentally disabled patients with epilepsy. Twenty-four patients had generalized seizures, 15 had partial seizures, and 5 were classified as having mixed seizure disorders. A significant reduction in total and generalized seizures occurred. A decrease in seizures of >75% was seen in 14 (32%) patients.

Lamotrigine has been reported to be efficacious in Rett's syndrome (63,64). Uldall and colleagues (63) gave the drug to four girls with the syndrome who all improved with a >50% reduction in seizures. Stenbom and associates (64) also found that four girls with Rett's syndrome had improved behavior, mood, and alertness on lamotrigine.

TABLE 37.3. LAMOTRIGINE DOSAGE SCHEDULES

Antiepileptic Drug Group

Weeks 1-2

Weeks 3-4

Increase Per 1-2 Weeks

Maintenance

Adult on monotherapy

25 mg/day

50 mg/day

50-100 mg/day

100-200 mg/daya

Adult on enzyme-inducer(s)

50 mg/day

100 mg/day

100 mg/day

300-500 mg/daya

Adult on valproate

12.5 mg/day

25 mg/day

25-50 mg/day

100-200 mg/daya

Child on enzyme inducer(s)

0.6 mg/kg/day

1.2 mg/kg/day

1.2 mg/kg/day

5-15 mg/kg/daya

Child on valproate

0.15 mg/kg/day

0.3 mg/kg/day

0.3 mg/kg/day

1-5 mg/kg/daya

a Higher doses can be tried if seizures persist and the patient is tolerating the drug without complaint.

MODE OF USE

Indications

Lamotrigine is available as adjunctive treatment for partial seizures, primary and secondary generalized seizures, and seizures associated with the Lennox-Gastaut syndrome for adults and children 2 years of age and older. The drug also is licensed as monotherapy for these indications in adults.

Dosing Recommendations

Starting Dose and Titration Rate

Recommended dosing schedules for lamotrigine are outlined in Table 37.3. Long-term studies have revealed no evidence of tolerance (65). The low starting dose and slow titration rate for adjunctive therapy depend on existing treatment, the aim of which is to reduce the likelihood of rash (66). Tablets containing 25, 50, 100, and 200 mg lamotrigine are available. Dispersible chewable tablets containing 5, 25, and 100 mg provide an alternative preparation for children and for patients who have difficulty swallowing. These also can be dispersed in water. Lamotrigine usually is prescribed twice daily, but a single daily dose can be used in patients taking the drug with sodium valproate or as monotherapy.

Initial Target and Optimal Range of Maintenance Dosages

Seizures are controlled in most patients receiving monotherapy at dosages of 100 to 300 mg/day, although some need higher amounts. Higher dosages of 400 to 800 mg/day may be required in refractory epilepsy when lamotrigine is used with an enzyme-inducing antiepileptic drug. Substantially lower dosages of 50 to 200 mg/day are advised when lamotrigine is combined with sodium valproate. Withdrawal of enzyme-inducing antiepileptic drugs causes a rise in circulating concentrations of lamotrigine, whereas discontinuing sodium valproate produces a fall.

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CURRENT ROLE IN EPILEPSY MANAGEMENT

Lamotrigine has a broad range of efficacy against partial-onset and primary generalized seizures and seizures associated with the Lennox-Gastaut syndrome. The drug is widely prescribed as monotherapy and add-on treatment for these indications in adults and as adjunctive therapy in children. Its efficacy for tonic-clonic and typical absence seizures is better documented than for juvenile myoclonic epilepsy and other myoclonic syndromes. Because lamotrigine does not influence the metabolism of lipid-soluble drugs such as warfarin and the combined oral contraceptive pill, its use with other agents generally is straightforward. It usually is well tolerated and has a wide therapeutic ratio.

Lamotrigine's ability to suppress interictal spiking may be a factor in improving well-being (41). A double-blind comparison with carbamazepine in newly diagnosed epilepsy supported better health-related quality-of-life scores with lamotrigine (67). Other workers have shown better mood and quality of life in patients receiving lamotrigine than sodium valproate as monotherapy (68,69). In another study, randomly switching poorly controlled patients from carbamazepine, phenytoin, or valproate to one of these drugs or lamotrigine resulted in lamotrigine-treated patients having better cognitive functioning, energy, and other life-style factors (70). Improved behavior also has been observed when the drug was used in patients with learning disabilities (71).

The combination of lamotrigine and sodium valproate appears particularly efficacious for partial or tonic-clonic seizures (72,73). This effect also has been noted in patients with generalized absence or myoclonic seizures (74, 75, 76). The use of lamotrigine with topiramate or vigabatrin also has been reported to enhance its effectiveness (77, 78, 79).

No significant relationship has been found between lamotrigine plasma levels and its pharmacologic effect (36,80). A tentative concentration range of 2 to 4 mg/L was originally suggested (80,81). A wider range of 3 to 14 mg/L has been mooted more recently (82). Some patients, however, can tolerate lamotrigine concentrations of up to 18 mg/L, whereas side effects develop in others at levels of approximately 1 mg/L (36). Routine monitoring of lamotrigine concentrations therefore is not recommended. Exceptions may be during pregnancy and when switching patients to lamotrigine from carbamazepine, phenytoin, or sodium valproate (83).

USE IN SPECIAL POPULATIONS

The Elderly

Lamotrigine is effective and well tolerated in elderly patients (17). Because it does not induce hepatic enzymes, it can be used safely with drugs metabolized by monooxygenase and conjugation enzyme systems. Lamotrigine clearance is unaffected by renal impairment (84). Because peak concentrations can be elevated, older patients may respond to lower doses (85). As monotherapy, lamotrigine can be started at 25 mg/day for 2 weeks, increasing to 25 mg twice daily for 2 weeks, and 50 mg twice daily thereafter (17). If add-on treatment is required, combining lamotrigine with low-dose sodium valproate can be particularly effective (86).

Women

Lamotrigine is a good initial choice for young women with epilepsy because it has a wide spectrum of activity, is well tolerated, and does not interact with the combined oral contraceptive pill (87). Although not recommended for use in pregnancy, lamotrigine has not produced malformations in animal models sensitive to the teratogenic effects of sodium valproate and carbamazepine (88). Encouraging interim results from an 8-year study have shown the rate of birth defects in 79 live births from women exposed to lamotrigine monotherapy in the first trimester to be 3.8% (89). This is consistent with the frequency of major malformations expected in the general population (2.2%) and in women with epilepsy (6% to 9%).

Because the clearance of lamotrigine is increased in pregnancy, women should be monitored carefully during this time in case dose adjustment is required (90,91). Plasma concentrations tend to normalize after delivery (90,92). Because lamotrigine has antifolate properties, all women planning a pregnancy should be prescribed folic acid 5 mg/day until at least 12 weeks' gestation (88).

Children

Children tolerate lamotrigine well, although the incidence of rash is higher than in adults (66,93). For this reason, the drug should be introduced at low dosage and titrated slowly, especially if combined with sodium valproate (Table 37.3). Lamotrigine is not licensed as monotherapy in this age group, but good tolerability and efficacy against a range of generalized seizures make it a useful adjunct in a wide range of childhood epilepsies, including seizures associated with the Lennox-Gastaut and other syndromes. The drug also may be effective for infantile seizures, particularly when combined with sodium valproate.

Patients with Learning Disabilities

Because of its wide spectrum of activity and potential to improve mental state, lamotrigine can be useful for patients with learning disabilities (94). In addition, the drug has proved effective in some patients with Rett's syndrome. A low, slow titration schedule is recommended. Combining the drug with sodium valproate or topiramate can be efficacious in controlling refractory seizures (86,95).

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PRECAUTIONS

Lamotrigine usually is well tolerated, with rash being the most serious side effect. Most rashes are mild, but some patients have experienced severe, life-threatening skin eruptions with systemic toxicity. There is good evidence to suggest that a low starting dose with a slow titration schedule (Table 37.3) helps to minimize risk, especially in patients taking sodium valproate. If rash does occur, the drug should be withdrawn immediately and the patient monitored closely. Reintroduction at very low dosage may be possible at a later date, but this requires close supervision and should not be undertaken if the initial reaction was severe (96).

Some patients taking carbamazepine experience headache, dizziness, ataxia, and diplopia when lamotrigine is introduced. This is thought to be the result of a pharmacodynamic interaction between the two drugs (72,77,97). Symptoms usually resolve with a reduction in the carbamazepine dose.

Like other antiepileptic drugs, lamotrigine appears to exacerbate seizures in a small number of patients (98). In particular, there is evidence to suggest that the drug may aggravate severe myoclonic epilepsy (99, 100, 101, 102). A paradoxical reaction also was noted in a child with benign childhood epilepsy with centrotemporal spikes who became worse on lamotrigine (103). If exacerbation of seizures does occur, lamotrigine should be rapidly withdrawn.

CONTRAINDICATIONS

Because lamotrigine is metabolized in the liver, it is sensible to avoid its use in patients with end-stage hepatic impairment. Children with severe myoclonic epilepsy should not receive the drug.

CONCLUSION

Lamotrigine is a broad-spectrum antiepileptic drug that has been in widespread clinical use since the early 1900s. It has efficacy for most seizure types in adults and children, although it may worsen severe myoclonic epilepsy. The drug is useful in patients with coexistent learning disabilities. Its good tolerability makes it suitable as an alternative to traditional antiepileptic drugs as a first-line agent for adolescents and adults with newly diagnosed epilepsy. In polytherapy regimens, the drug is particularly effective when combined with sodium valproate. Outcomes from pregnant women taking lamotrigine hold out the possibility that it will prove to be nonteratogenic. Monotherapy trials in children and quality-of-life studies are underway, with encouraging preliminary results.

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