- Email: [email protected]
Add-on levetiracetam in children and adolescents with refractory epilepsy: Results of an open-label multi-centre study
ARTICLE IN PRESS E U R O P E A N J O U R N A L O F PA E D I AT R I C N E U R O L O G Y
12 (2008) 321 – 327
Official Journal of the European Paediatric Neurology Society
Original article
Add-on levetiracetam in children and adolescents with refractory epilepsy: Results of an open-label multi-centre study Petra M.C. Callenbacha,, Willem Frans M. Artsb, Robert ten Houtenc, Paul Augustijnd, W. Boudewijn Gunninge, Els A.J. Peetersf, Alma M. Webere, Hans Stroinkg, Yvette Geertsd, Ada T. Geertsh, Oebele F. Brouwera a
Department of Neurology, University Medical Centre Groningen, University of Groningen, P.O. Box 30 001, 9700 RB Groningen, The Netherlands b Department of Paediatric Neurology, Erasmus University Medical Centre, Rotterdam, The Netherlands c Department of Neurology, Medical Centre Alkmaar, Alkmaar, The Netherlands d Dutch Epilepsy Clinics Foundation (S.E.I.N.), Heemstede and Zwolle, The Netherlands e Epilepsy Centre Kempenhaeghe, Heeze and Oosterhout, The Netherlands f Department of Neurology, Juliana Children’s Hospital and Westeinde Hospital, The Hague, The Netherlands g Department of Neurology, St. Elisabeth and TweeSteden Hospital, Tilburg, The Netherlands h Department of Neurology, Erasmus University Medical Centre, Rotterdam, The Netherlands
art i cle info
ab st rac t
Article history:
Purpose: To study the efficacy and tolerability of add-on levetiracetam in children and
Received 31 July 2007
adolescents with refractory epilepsy.
Received in revised form
Methods: In this prospective multi-centre, open-label, add-on study, 33 children
6 September 2007
aged 4–16 years (median 8.5 years) with epilepsy refractory to at least two antiepileptic
Accepted 6 September 2007
drugs were treated with levetiracetam in addition to their present treatment regimen with a follow-up of 26 weeks. The starting dose of 10 mg/kg/day was increased with 2-week steps
Keywords:
of 10 mg/kg/day, if necessary, up to a maximum dose of 60 mg/kg/day.
Levetiracetam
Results: Retention rate was 69.7% after 26 weeks on a median levetiracetam dosage of
Add-on
22 mg/kg/day. Four children dropped-out because levetiracetam was ineffective, four
Children
because seizure frequency increased and/or seizures became more severe, and two because
Refractory epilepsy
they developed aggressive behaviour. Compared to their baseline seizure frequency,
Efficacy
13 children (39.4%) had a 450% seizure reduction 12 weeks after initiation of levetiracetam,
Tolerability
and 17 children (51.5%) at 26 weeks. At 26 weeks, nine children (27.3%) had been seizurefree for at least the last 4 weeks, terminal remission ranged from 0 to 187 days (mean 46 days). Levetiracetam was effective in both partial and primary generalized seizures, but had most effect in partial seizures. Most reported side effects were hyperactivity (48.5%), somnolence (36.4%), irritability (33.3%) and aggressive behaviour (27.3%). Severity of most side effects was mild. Five
Corresponding author. Tel.: +31 50 3612430; fax: +31 50 3611707.
E-mail address: [email protected] (P.M.C. Callenbach). 1090-3798/$ - see front matter & 2007 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2007.09.004
ARTICLE IN PRESS 322
E U R O P E A N J O U R N A L O F PA E D I AT R I C N E U R O L O G Y
12 (2008) 321 – 327
children had a serious adverse event, which all concerned hospital admissions that were not related to levetiracetam use. Conclusion: Levetiracetam proved to be an effective and well-tolerated add-on treatment in this group of children with refractory epilepsy. & 2007 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
1.
Introduction
Levetiracetam is a newly developed antiepileptic drug (AED) that has been approved in Europe and the United States as adjunctive therapy in the treatment of partial onset seizures in adults since 2000 and in children of 4 years and older since 2005. It has linear pharmacokinetics, an almost complete oral absorption and a low extent of metabolism, and is unlikely to interact with other drugs such as lamotrigine, valproic acid and carbamazepine.1–3 Levetiracetam binds to and modulates the synaptic vesicle protein 2A (SV2A), but the exact mechanism of action is still unknown.4 Several trials with levetiracetam as add-on therapy in children and adolescents with refractory epilepsy have shown efficacy in both partial and generalized seizures.5–15 Furthermore, levetiracetam was well tolerated in children, leading to low discontinuation rates due to adverse events. The most common reported adverse events were behavioural changes (e.g. irritability, agitation, hyperactivity, cognitive slowing) and somnolence. All adverse events were reversible and disappeared when levetiracetam therapy was discontinued. Most studies had a short follow-up period or children were not followed for a fixed period, leading to marked variability of the follow-up periods within studies (Table 1). We have prospectively studied the efficacy and tolerability of add-on levetiracetam in children aged 4–16 years with refractory epilepsy during 26 weeks of treatment. Additional aims were to investigate whether levetiracetam has different efficacy in various seizure types or epilepsy syndromes and to determine side effects more carefully with a standardized questionnaire.
2.
Methods
2.1.
Patients
Eleven centres in the Netherlands participated in this multicentre, open-label, add-on study. Included were children aged four until and including 15 years with epilepsy that did not respond to at least two AEDs. All children needed to have had at least four seizures in the last 4 weeks before inclusion and had to use at least one other AED at the time of inclusion. Children were not eligible if they had serious pre-existing behavioural disturbances (according to clinician’s judgment), were participating in another clinical trial with an investigational drug or device within 12 weeks of inclusion or at any time during the study, had a known presence or history of allergy to the components of the study medication (levetiracetam, lactose and excipients) or other pyrrolidine derivates, or had a known disorder or condition that might interfere with the absorption, distribution, metabolization or excretion of drugs. Females were excluded if they were pregnant or breast-feeding and if they were of childbearing potential and were not using adequate contraceptive measures. The study was approved by the medical ethical committees of all participating centres. All legal representatives and subjects aged 12 years or older gave written informed consent.
2.2.
Study medication
Each child was treated with levetiracetam with a follow-up duration of 26 weeks. The initial dose was 10 mg/kg/day in
Table 1 – Add-on studies of levetiracetam in children with epilepsy Study
Study design
Study duration
Dosage (mg/kg/day)
Age (yrs)
N
Seizure type
Glauser5 Wheless6 Nakken7 Lagae8 Tan9 Lagae10,a Grosso11 Opp12 Glauser13,a Peake14 Grosso15 This study
Prospective Prospective Prospective Prospective Retrospective Prospective Prospective Prospective Prospective, PC Retrospective Retrospective Prospective
6W titration, 8W evaluation p9 M (mean 5 M) 3–14 M (mean 8 M) 12 W 1–30 M (mean 8 M) 20 W 2–20 M (median 7 M) 12–86 W (median 33 W) 14 W 12 M 3–42 M (mean 9 M) 26 W
10-40 (median 39) Mean 53 10–40 17–60 (median 37) 14–69 (mean 37) 10–60 (median 33) 10–60 (median 38) 6–140 (mean 48) 40–60 8–100 (mean 39) 25–62 (mean 41) 10–60 (median 22)
6–12 0.5–14 3–17 0.9–14 1.2–10 0.5–16 0.5–16 0–18 4–16 0.3–19 o4 4–16
24 39 44 21 26 67 110 209 101 200 81 33
R PS R PS, GS R PS, GS R PS, GS R PS, GS PS, GS R PS, GS R PS, GS R PS R PS, GS R PS, GS R PS, GS
GS ¼ generalized seizures, M ¼ months, N ¼ number of children studied, PC ¼ placebo-controlled, PS ¼ partial seizures, R ¼ refractory, W ¼ weeks, yrs ¼ years. a Only the part of the study is stated where children were treated with add-on levetiracetam.
ARTICLE IN PRESS E U R O P E A N J O U R N A L O F PA E D I AT R I C N E U R O L O G Y
two dosages. If the dose was well tolerated but there was insufficient seizure control, the dose could be increased with 10 mg/kg/day per two weeks, with a maximum dose of 60 mg/kg/day. Two formulations were available, tablets (250 mg) and oral solution (100 mg/ml). If the study treatment was not tolerated by the child, if the child had no substantial benefit from the study treatment at the maximum dosage of 60 mg/kg/day, or if the investigator decided to withdraw the child for safety reasons, the study drug was gradually reduced with 10 mg/kg/day weekly. The dosage of the concomitant AED(s) had to remain stable throughout the study period.
2.3.
Study design
The trial consisted of a pre-selection visit (4 weeks before initiation of levetiracetam), an initiation visit, visits in week 4, week 12 and week 26, and a phone call in week 8. During the pre-selection visit, the eligibility of the child for the trial was checked and a daily record card was given to the child to record date, number, and type of his/her seizures during the next 4 weeks. At the initiation visit, the study medication was prescribed if the child was still eligible. From the initiation visit onwards, the updated daily record card was checked by the investigator at each visit and the occurrence of seizures since the preceding visit was evaluated, a physical examination was performed, and any changes in study medication dosage or in concomitant non-AED and AED medications were verified. The occurrence of adverse events was checked with help of a standardized side effects questionnaire, and the possible relationship between each complaint and levetiracetam therapy was evaluated by the treating physician. The questionnaire contained 33 queries covering the presence and severity of behavioural changes, sleep-related problems, cognitive problems, and physical problems. The seizures and epileptic syndrome were classified according to the revised classifications of the International League Against Epilepsy (ILAE).16,17
2.4.
Data analysis
The primary outcome parameter of our study was the retention rate after 26 weeks of treatment. Secondary outcome parameters were: (1) the number of children with seizure reduction of more than 50% (as compared to the mean number of seizures per week in the last 4 weeks before inclusion) in the period between obtaining a stable dose and 12 weeks after initiation of levetiracetam; (2) the number of children with seizure reduction of more than 50% (as compared to the mean number of seizures per week in the last 4 weeks before inclusion) in the period between obtaining a stable dose and 26 weeks after initiation of levetiracetam; and (3) terminal remission, the period of time the child was seizure-free (SF) counting back from visit 4 (26 weeks after initiation of levetiracetam). A dose was considered stable if it remained the same during at least 4 weeks. To assess safety, the adverse events that were reported by every individual in the standardized side effects questionnaires during the study were recorded. All statistical analyses were performed using SPSS 14.0.2. Nonparametric tests (Kruskal Wallis and Mann–Whitney)
12 (2008) 321 – 327
323
were used to compare efficacy between children with and without mental retardation, between partial and generalized seizure types, between epilepsy syndromes, and between different administration routes. A chi-square test was used to compare drop-out rate in the same, abovementioned, subgroups.
3.
Results
Between March 2005 and July 2006, 33 children with refractory epilepsy were included in the study. Patient demographics are listed in Table 2. Median number of seizures was 14 per week in the period between the pre-selection visit and the initiation visit. Nineteen children (57.6%) had partial seizures with or without secondary generalization, nine (27.3%) generalized seizures, four (12.1%) both partial and generalized seizures, and in one child seizures could not be classified. Of the six children with absences, three had atypical absences and were classified as having symptomatic generalized epilepsy. Most children had one (57.6%) or two (36.4%) seizure types (Table 2). In three children (9.1%) the epilepsy syndrome was classified as idiopathic, in 20 (60.6%) as symptomatic, in eight (24.2%) as cryptogenic, and in two the syndrome could not be determined (Table 2). The following AEDs were used at intake in the study: valproic acid (45.5%), lamotrigine (33.3%), carbamazepine (27.3%), oxcarbazepine (15.2%), clobazam (15.2%), ethosuximide (9.1%), topiramate (9.1%), clonazepam (6.1%), and phenytoin (3.0%).
3.1.
Efficacy
After 26 weeks, 23 of the 33 included children still used levetiracetam (retention rate 69.7%). Four children droppedout because levetiracetam was ineffective (these children used a maximum dose of 30–60 mg/kg/day), four because seizure frequency increased and/or seizures became more severe, and two because they developed aggressive behaviour. Twelve weeks after initiation of levetiracetam, 21 children had reached a stable dose. Thirteen of these children (39.4% of the total group) had a seizure reduction of more than 50% since obtaining a stable dose as compared to the last 4 weeks before inclusion. Seventeen children (51.5%) had a seizure reduction of more than 50% in the period between obtaining a stable dose and 26 weeks after initiation of levetiracetam (12 of them also had 450% seizure reduction at 12 weeks). Of these 17 children, six (18.2%) became SF immediately after obtaining a stable dose and remained so during the entire follow-up, and three other children (9.1%) were SF for at least the last 4 weeks at 26 weeks (mean duration of seizure-freedom of these nine children: 15.7 weeks, range 5.7–26 weeks); in another three children (9.1%) the period of seizure-freedom varied from 2 to 4 weeks at 26 weeks. Terminal remission in the 23 children who completed the study ranged from 0 to 187 days (mean 46 days, median 14 days). Efficacy and drop-out rate did not differ significantly between children with mental retardation and those without mental retardation.
ARTICLE IN PRESS 324
E U R O P E A N J O U R N A L O F PA E D I AT R I C N E U R O L O G Y
Table 2 – Baseline demographics and clinical characteristics of our study population (n ¼ 33) Sex (%) Male Female
17 (51.5) 16 (48.5)
Median age in years (range)
8.5 (4.2–15.6)
Mental retardation (%)
14 (42.4)
Number of seizures per week (%) 1–2 3–10 11–50 450 Seizure typea (%) Simple partial seizures Complex partial seizures Partial onset with secondary generalization Generalized tonic-clonic Tonic Atonic Clonic Myoclonic Absences Unclassified seizures Epilepsy syndromeb (%) Symptomatic localization-related epilepsy not further defined (1.2.c) Cryptogenic localization-related epilepsy (1.3) Juvenile absence epilepsy (2.1.e) Idiopathic generalized epilepsy not further defined (2.1.h) Epilepsy with myoclonic-astatic seizures (2.2.c) Symptomatic generalized epilepsy not further defined (2.3.1.c) Epilepsy undetermined whether focal or generalized (3.1.e) Not known Number of AEDs at initiation of levetiracetam (%) One Two Three
7 (21.2) 8 (24.2) 8 (24.2) 10 (30.3) 2 (6.1) 19 (57.6) 10 (30.3) 2 (6.1) 4 (12.1) 1 (3.0) 0 4 (12.1) 6 (18.2) 1 (3.0)
11 (33.3) 8 (24.2) 1 (3.0) 2 (6.1) 1 (3.0) 8 (24.2) 1 (3.0) 1 (3.0)
16 (48.5) 13 (39.4) 4 (12.1)
a
According to the revised classification of epileptic seizures of the ILAE.16 b According to the revised classification of epilepsies and epileptic syndromes of the ILAE.17
Levetiracetam was effective in various seizure types (Fig. 1). Overall, levetiracetam was more effective in partial seizures than in generalized seizures (p ¼ 0.036): twenty children had 450% seizure reduction in one or two seizure types (in total 29 seizure types), of which 20 seizure types (69%) had partial onset (Fig. 1). Fourteen (48%) of these partial-onset seizure types disappeared completely with levetiracetam treatment. In eight children a 450% increase in seizure-frequency of one or two seizure types was observed. Four of these children dropped-out, whereas the other four children had an increased number of one seizure type combined with a markedly reduced number (95–100%) of the other seizure types. Two of these last four patients had an overall seizure
12 (2008) 321 – 327
reduction of more than 50%, the other two had 0–50% seizure reduction. The number of patients dropping out did not differ significantly between seizure types. Fig. 2 shows the efficacy per epilepsy syndrome, classified according to the ILAE in 1989.17 Levetiracetam was effective in different syndromes. Eleven of the 17 children (64.7%) with more than 50% seizure reduction at 26 weeks and seven of the nine children (77.8%) who were SF for at least 4 weeks at 26 weeks had localization-related epilepsy. One additional child had more than 50% seizure reduction, but he dropped-out because of aggressive behaviour. The efficacy or drop-out rate did not differ significantly between epilepsy syndromes, between localization-related and generalized epilepsy syndromes, or between symptomatic, idiopathic and cryptogenic epilepsy. The final dosage of levetiracetam after 26 weeks ranged from 9 to 53 mg/kg/day (median 22 mg/kg/day; mean 26.5 mg/ kg/day). Nine children had a final dosage p15 mg/kg/day, of whom seven had more than 50% seizure reduction (three of them became SF). Twenty-three children (69.7%) used oral solution until their final visit, seven (21.2%) used tablets, and three (9.1%) changed from oral solution to tablets during the trial at the moment they started to use a dose that could also be administered with tablets. Eleven of the 23 children (47.8%) on oral solution and five of the seven children (71.4%) on tablets had more than 50% seizure reduction between initiation of levetiracetam and the last completed visit (eight of the patients on oral solution and one on tablets droppedout). Efficacy or the number of children dropping out did not differ significantly between the children using tablets and those on oral solution. After the fixed follow-up period of the study, 21 children (63.6%) continued to use levetiracetam, in one levetiracetam was withdrawn because it was not effective and in one because of side effects (behavioural problems and diplopia). Despite the fact that concomitant AEDs had to remain stable throughout the study period, concomitant AEDs were changed during the trial in eight children. In four children concomitant AEDs were reduced or stopped because of side effects (two of these were SF at week 26, two had 450% seizure reduction), in two children a physician that was consulted for a second opinion advised to reduce or stop concomitant AEDs (one was SF at week 26, one had 0–50% seizure reduction), and two children were temporarily treated with other AEDs (midazolam and phenytoin) because of a status epilepticus during pneumonia in one and a cluster of seizures during 1 day in the other (the first was SF at week 26, the other had 0–50% seizure reduction). Due to these adjustments in concomitant AEDs, two children had had levetiracetam monotherapy for 3 months at the end of the trial (one was SF, one had 0–50% seizure reduction).
3.2.
Tolerability
All children reported at least one behavioural, sleep-related, cognitive or physical problem in the standardized side effects questionnaire that was either not present before the start of levetiracetam treatment or worsened during the study (Table 3). Most common complaints were hyperactivity (48.5%), somnolence (36.4%), irritability (33.3%) and aggressive
ARTICLE IN PRESS E U R O P E A N J O U R N A L O F PA E D I AT R I C N E U R O L O G Y
12 (2008) 321 – 327
325
Fig. 1 – Seizure reduction by seizure type (from baseline to the last completed visit for all 33 children), classified according to the revised clinical and electroencephalographic classification of epileptic seizures of the ILAE.16 Sec. ¼ secondary, GTC ¼ primary generalized tonic-clonic.
Fig. 2 – Seizure reduction by epilepsy syndrome (from baseline to the last completed visit for all 33 children), classified according to the revised classification of epilepsies and epileptic syndromes of the ILAE.17 1.2.c ¼ symptomatic localizationrelated epilepsy not further defined, 1.3 ¼ cryptogenic localization-related epilepsy, 2.1.e ¼ juvenile absence epilepsy, 2.1.h ¼ idiopathic generalized epilepsy not further defined, 2.2.c ¼ epilepsy with myoclonic-astatic seizures, 2.3.1.c ¼ symptomatic generalized epilepsy not further defined, 3.1.e ¼ epilepsy undetermined whether focal or generalized.
behaviour (27.3%). Severity of most complaints was mild and they were rarely a reason for discontinuation of levetiracetam. Two children dropped out because of aggressive behaviour (one of them had 450% seizure reduction). Five children had a serious adverse event during the trial, which all concerned hospital admissions for reasons considered not to be related to the use of levetiracetam by the treating physician, being status epilepticus during fever and pneumonia; gastroenteritis; percutaneous gastrostomy; orthopaedic surgery; and planned oesophagoscopy. One severely retarded child with tetraplegia and pre-existing
constipation died 2 months after completing the trial due to complications of a perforated colon.
4.
Discussion
This prospective open-label trial showed that add-on therapy with levetiracetam is effective and well-tolerated in children aged 4–16 years with refractory epilepsy. More than 50% of the children had a seizure reduction of more than 50% after 26 weeks of treatment, and 27% were SF for at least 4 weeks at
ARTICLE IN PRESS 326
E U R O P E A N J O U R N A L O F PA E D I AT R I C N E U R O L O G Y
Table 3 – Number of children reporting complaints as stated in the standardized side effects questionnaire Frequency (%)
(Possibly) related to levetiracetam (%)a
Behavioural Hyperactivity Irritability Aggressive behaviour Behavioural problems Nervousness
23 (69.7) 16 (48.5) 11 (33.3) 9 (27.3)
11 (33.3) 10 (30.3) 9 (27.3)
6 (18.2)
4 (12.1)
5 (15.2)
3 (9.1)
Sleep-related Somnolence Tiredness Lethargy
16 (48.5) 12 (36.4) 8 (24.2) 6 (18.2)
9 (27.3) 7 (21.2) 4 (12.1)
Cognitive Concentration disturbance Impaired school performance
10 (30.3) 7 (21.2)
4 (12.1)
6 (18.2)
4 (12.1)
Physical Decreased appetite Constipation Trembling Increased weight Drooling Gums problems Nausea Hair loss Headache Itch
25 (75.8) 7 (21.2)
6 (18.2)
6 6 6 6 5 5 4 4 4
4 (12.1) 3 (9.1) 3 (9.1) 3 (9.1) 4 (12.1) 4 (12.1) 3 (9.1) 3 (9.1) 3 (9.1)
(18.2) (18.2) (18.2) (18.2) (15.2) (15.2) (12.1) (12.1) (12.1)
Only complaints that were reported by at least 10% of the children and occurred or worsened during the use of levetiracetam are listed. a According to the judgment of the treating physician.
the end of the study. Levetiracetam was effective in both partial and generalized seizures and in both localizationrelated and generalized epilepsy syndromes, with most effect in partial seizures and localization-related epilepsy syndromes. This is the first study in which children were treated with levetiracetam oral solution, which has previously been shown to be bioequivalent to the tablet formulation.18 Efficacy did not differ significantly between oral solution and tablets. Our results are overall in line with earlier studies on the efficacy of levetiracetam as add-on therapy in children and adolescents (Table 4).5–15 Retention rate was 70% in our study compared to 33–95% in other studies; it was in general inversely correlated with the duration of follow-up (Table 4). The percentage of children with more than 50% reduction in seizure-frequency ranged from 20% to 61% in these studies versus 52% in our study. Particularly, relatively more children became SF in our study than in other published studies (27% versus 4–12%, Table 4). All but one of the studies included children with refractory epilepsy, and baseline characteristics were overall comparable with respect to median age at intake,
12 (2008) 321 – 327
seizure types, seizure frequency at baseline, and concomitant AEDs. The only difference between our and earlier studies is that fewer children in our study had mental retardation (42% in our study versus 72–100% in other studies).6–12,15 We observed no difference in efficacy between children with mental retardation and those without mental retardation, and the presence of fewer children with mental retardation in our study can, therefore, not explain this higher percentage of children being SF at the end of the trial. Most studies did not define the duration of seizure-freedom.6,7,9–12,14,15 Two studies only counted children that became SF after obtaining a stable dose and remained so during follow-up (both 8 weeks),5,8 and the double-blind placebo-controlled study only counted children who were SF during the entire double-blind treatment period of 14 weeks.13 In these three studies 5–9% of the children had no seizures during the complete follow-up versus 18% in our cohort. Peake et al.14 and Grosso et al.15 observed a decreasing number of children being SF during follow-up (Peake et al.: 14% after both two and six months and 5% after 12 months, Grosso et al.: 31% after three months, 15% after 12 months). Based on these studies it could be assumed that the percentage of children being SF is dependent on the duration of follow-up, but no relation between these two parameters can be observed in Table 4 if the studies are compared. In our cohort, the median dosage of levetiracetam (22 mg/kg/day) at the end of the trial was lower than in other studies (33–39 mg/kg/day, Table 1).5,8,10,11 The same holds for the mean dosage (26.5 mg/kg/day versus 37–53 mg/kg/day).6,9,12,14,15 In the study of Glauser et al., the dosage was increased to 40 mg/kg/day, unless an excellent clinical response was seen at 20 mg/kg/day.5 This may explain the higher median dosage in that study (Table 1). The titration schedules of the other studies cannot explain the higher mean and median dosages while they were comparable to the titration schedule of our study, with increasing the dosage with 5–10 mg/kg/day every four days,8 week,10,11,15 or fortnight.7,9 No titration schedule was described in three studies.6,12,14 The fact that in our study relatively more children became SF seems to be no explanation as well, since we found no relationship between efficacy and final dosage of levetiracetam in our cohort. An explanation for the lower daily dosage of levetiracetam used in our cohort might be that the investigators participating in the trial were more careful in up titrating in order to find a good balance between tolerability and efficacy. The most frequently reported adverse events in our cohort are identical to those reported in other trials (Table 4). The percentage of children and/or their parents reporting these adverse events was, however, higher than in most other studies. A possible explanation is that we used a standardized side effects questionnaire and that more children and/or their parents mention a certain complaint if specifically asked than if they have to report the complaint spontaneously. Most reported complaints were mild in our study and were rarely a reason for discontinuation of levetiracetam. In conclusion, our results confirm that levetiracetam is an effective and in general well-tolerated treatment as add-on therapy in children aged 4–16 years with refractory partial or generalized epilepsy, with most effect in partial epilepsy.
ARTICLE IN PRESS E U R O P E A N J O U R N A L O F PA E D I AT R I C N E U R O L O G Y
12 (2008) 321 – 327
327
Table 4 – Efficacy and adverse events in add-on studies of levetiracetam in children with epilepsy Authors
FU
Retention (%)
SF (%)
450% red (%)
Increase (%)
Most common AE (% of children reporting this AE)
Glauser5
8W
92
9
52
17
Lagae8
12 W
95
5
48
14
Glauser13,a
14 W
93
7
45
NI
20 W Avg 5 M
73 64
4 8
49 33
15 10
26 W
70
27
52
9
Grosso11 Opp12
Avg 7 M Avg 33 W
41 33
9 6
39 25
11 10
Tan9 Nakken7 Grosso15
Avg 8 M Avg 8 M Avg 9 M
81 34 46
8 7 12
61 20 30
12 43 18
Peake14
12 M
49
5
32
11
Headache (33), infection (33), anorexia (25), somnolence (25) Somnolence (10), headache (5), behavioural problems (5) Somnolence (23), accidental injury (17), vomiting (15) Tiredness (9), aggression (6) Sedation (15), aggression (13), hyperactivity (10) Hyperactivity (49), somnolence (36), irritability (33) aggression (27) Somnolence, irritability Somnolence (24), behavioural problems (26) NI Somnolence (7), dizziness (7), ataxia (7) Drowsiness (45), nervousness (36), cognitive disturbances (29) Behavioural problems (9), emotional lability (8)
Lagae10,a Wheless6 This study
Studies are stated in order of duration of follow-up. AE ¼ adverse events, avg ¼ mean/median duration, FU ¼ duration of follow-up, Increase ¼ percentage of children with 450% increased seizure-frequency, M ¼ months, NI ¼ not indicated, 450% red ¼ 50–100% seizure reduction, SF ¼ seizure-free, W ¼ weeks. a Only the part of the study is stated where children were treated with add-on levetiracetam.
Acknowledgements This study was financially supported by UCB Pharma BV, The Netherlands. R E F E R E N C E S
1. Patsalos PN. Pharmacokinetic profile of levetiracetam: toward ideal characteristics. Pharmacol Ther 2000;85:77–85. 2. Pellock JM, Glauser TA, Bebin EM, et al. Pharmacokinetic study of levetiracetam in children. Epilepsia 2001;42:1574–9. 3. Fountain NB, Conry JA, Rodriguez-Leyva I, et al. Prospective assessment of levetiracetam pharmacokinetics during dose escalation in 4- to 12-year-old children with partial-onset seizures on concomitant carbamazepine or valproate. Epilepsy Res 2007;74:60–9. 4. Lynch BA, Lambeng N, Nocka K, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci USA 2004;101:9861–6. 5. Glauser TA, Pellock JM, Bebin EM, et al. Efficacy and safety of levetiracetam in children with partial seizures: an open-label trial. Epilepsia 2002;43:518–24. 6. Wheless JW, Ng YT. Levetiracetam in refractory pediatric epilepsy. J Child Neurol 2002;17:413–5. 7. Nakken KO, Eriksson AS, Lossius R, Johannessen SI. A paradoxical effect of levetiracetam may be seen in both children and adults with refractory epilepsy. Seizure 2003;12:42–6. 8. Lagae L, Buyse G, Deconinck A, Ceulemans B. Effect of levetiracetam in refractory childhood epilepsy syndromes. Eur J Paediatr Neurol 2003;7:123–8.
9. Tan MJ, Appleton RE. Efficacy and tolerability of levetiracetam in children aged 10 years and younger: a clinical experience. Seizure 2004;13:142–5. 10. Lagae L, Buyse G, Ceulemans B. Clinical experience with levetiracetam in childhood epilepsy: an add-on and monotherapy trial. Seizure 2005;14:66–71. 11. Grosso S, Franzoni E, Coppola G, et al. Efficacy and safety of levetiracetam: an add-on trial in children with refractory epilepsy. Seizure 2005;14:248–53. 12. Opp J, Tuxhorn I, May T, et al. Levetiracetam in children with refractory epilepsy: a multicenter open label study in Germany. Seizure 2005;14:476–84. 13. Glauser TA, Ayala R, Elterman RD, et al. Double-blind placebocontrolled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology 2006;66:1654–60. 14. Peake D, Mordekar S, Gosalakkal J, et al. Retention rate of levetiracetam in children with intractable epilepsy at 1 year. Seizure 2007;16:185–9. 15. Grosso S, Cordelli DM, Franzoni E, et al. Efficacy and safety of levetiracetam in infants and young children with refractory epilepsy. Seizure 2007;16:345–50. 16. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489–501. 17. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389–99. 18. Coupez R, Straetemans R, Sehgal G, Stockis A, Lu ZS. Levetiracetam: relative bioavailability and bioequivalence of a 10% oral solution (750 mg) and 750-mg tablets. J Clin Pharmacol 2003;43:1370–6.
12 (2008) 321 – 327
Official Journal of the European Paediatric Neurology Society
Original article
Add-on levetiracetam in children and adolescents with refractory epilepsy: Results of an open-label multi-centre study Petra M.C. Callenbacha,, Willem Frans M. Artsb, Robert ten Houtenc, Paul Augustijnd, W. Boudewijn Gunninge, Els A.J. Peetersf, Alma M. Webere, Hans Stroinkg, Yvette Geertsd, Ada T. Geertsh, Oebele F. Brouwera a
Department of Neurology, University Medical Centre Groningen, University of Groningen, P.O. Box 30 001, 9700 RB Groningen, The Netherlands b Department of Paediatric Neurology, Erasmus University Medical Centre, Rotterdam, The Netherlands c Department of Neurology, Medical Centre Alkmaar, Alkmaar, The Netherlands d Dutch Epilepsy Clinics Foundation (S.E.I.N.), Heemstede and Zwolle, The Netherlands e Epilepsy Centre Kempenhaeghe, Heeze and Oosterhout, The Netherlands f Department of Neurology, Juliana Children’s Hospital and Westeinde Hospital, The Hague, The Netherlands g Department of Neurology, St. Elisabeth and TweeSteden Hospital, Tilburg, The Netherlands h Department of Neurology, Erasmus University Medical Centre, Rotterdam, The Netherlands
art i cle info
ab st rac t
Article history:
Purpose: To study the efficacy and tolerability of add-on levetiracetam in children and
Received 31 July 2007
adolescents with refractory epilepsy.
Received in revised form
Methods: In this prospective multi-centre, open-label, add-on study, 33 children
6 September 2007
aged 4–16 years (median 8.5 years) with epilepsy refractory to at least two antiepileptic
Accepted 6 September 2007
drugs were treated with levetiracetam in addition to their present treatment regimen with a follow-up of 26 weeks. The starting dose of 10 mg/kg/day was increased with 2-week steps
Keywords:
of 10 mg/kg/day, if necessary, up to a maximum dose of 60 mg/kg/day.
Levetiracetam
Results: Retention rate was 69.7% after 26 weeks on a median levetiracetam dosage of
Add-on
22 mg/kg/day. Four children dropped-out because levetiracetam was ineffective, four
Children
because seizure frequency increased and/or seizures became more severe, and two because
Refractory epilepsy
they developed aggressive behaviour. Compared to their baseline seizure frequency,
Efficacy
13 children (39.4%) had a 450% seizure reduction 12 weeks after initiation of levetiracetam,
Tolerability
and 17 children (51.5%) at 26 weeks. At 26 weeks, nine children (27.3%) had been seizurefree for at least the last 4 weeks, terminal remission ranged from 0 to 187 days (mean 46 days). Levetiracetam was effective in both partial and primary generalized seizures, but had most effect in partial seizures. Most reported side effects were hyperactivity (48.5%), somnolence (36.4%), irritability (33.3%) and aggressive behaviour (27.3%). Severity of most side effects was mild. Five
Corresponding author. Tel.: +31 50 3612430; fax: +31 50 3611707.
E-mail address: [email protected] (P.M.C. Callenbach). 1090-3798/$ - see front matter & 2007 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpn.2007.09.004
ARTICLE IN PRESS 322
E U R O P E A N J O U R N A L O F PA E D I AT R I C N E U R O L O G Y
12 (2008) 321 – 327
children had a serious adverse event, which all concerned hospital admissions that were not related to levetiracetam use. Conclusion: Levetiracetam proved to be an effective and well-tolerated add-on treatment in this group of children with refractory epilepsy. & 2007 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
1.
Introduction
Levetiracetam is a newly developed antiepileptic drug (AED) that has been approved in Europe and the United States as adjunctive therapy in the treatment of partial onset seizures in adults since 2000 and in children of 4 years and older since 2005. It has linear pharmacokinetics, an almost complete oral absorption and a low extent of metabolism, and is unlikely to interact with other drugs such as lamotrigine, valproic acid and carbamazepine.1–3 Levetiracetam binds to and modulates the synaptic vesicle protein 2A (SV2A), but the exact mechanism of action is still unknown.4 Several trials with levetiracetam as add-on therapy in children and adolescents with refractory epilepsy have shown efficacy in both partial and generalized seizures.5–15 Furthermore, levetiracetam was well tolerated in children, leading to low discontinuation rates due to adverse events. The most common reported adverse events were behavioural changes (e.g. irritability, agitation, hyperactivity, cognitive slowing) and somnolence. All adverse events were reversible and disappeared when levetiracetam therapy was discontinued. Most studies had a short follow-up period or children were not followed for a fixed period, leading to marked variability of the follow-up periods within studies (Table 1). We have prospectively studied the efficacy and tolerability of add-on levetiracetam in children aged 4–16 years with refractory epilepsy during 26 weeks of treatment. Additional aims were to investigate whether levetiracetam has different efficacy in various seizure types or epilepsy syndromes and to determine side effects more carefully with a standardized questionnaire.
2.
Methods
2.1.
Patients
Eleven centres in the Netherlands participated in this multicentre, open-label, add-on study. Included were children aged four until and including 15 years with epilepsy that did not respond to at least two AEDs. All children needed to have had at least four seizures in the last 4 weeks before inclusion and had to use at least one other AED at the time of inclusion. Children were not eligible if they had serious pre-existing behavioural disturbances (according to clinician’s judgment), were participating in another clinical trial with an investigational drug or device within 12 weeks of inclusion or at any time during the study, had a known presence or history of allergy to the components of the study medication (levetiracetam, lactose and excipients) or other pyrrolidine derivates, or had a known disorder or condition that might interfere with the absorption, distribution, metabolization or excretion of drugs. Females were excluded if they were pregnant or breast-feeding and if they were of childbearing potential and were not using adequate contraceptive measures. The study was approved by the medical ethical committees of all participating centres. All legal representatives and subjects aged 12 years or older gave written informed consent.
2.2.
Study medication
Each child was treated with levetiracetam with a follow-up duration of 26 weeks. The initial dose was 10 mg/kg/day in
Table 1 – Add-on studies of levetiracetam in children with epilepsy Study
Study design
Study duration
Dosage (mg/kg/day)
Age (yrs)
N
Seizure type
Glauser5 Wheless6 Nakken7 Lagae8 Tan9 Lagae10,a Grosso11 Opp12 Glauser13,a Peake14 Grosso15 This study
Prospective Prospective Prospective Prospective Retrospective Prospective Prospective Prospective Prospective, PC Retrospective Retrospective Prospective
6W titration, 8W evaluation p9 M (mean 5 M) 3–14 M (mean 8 M) 12 W 1–30 M (mean 8 M) 20 W 2–20 M (median 7 M) 12–86 W (median 33 W) 14 W 12 M 3–42 M (mean 9 M) 26 W
10-40 (median 39) Mean 53 10–40 17–60 (median 37) 14–69 (mean 37) 10–60 (median 33) 10–60 (median 38) 6–140 (mean 48) 40–60 8–100 (mean 39) 25–62 (mean 41) 10–60 (median 22)
6–12 0.5–14 3–17 0.9–14 1.2–10 0.5–16 0.5–16 0–18 4–16 0.3–19 o4 4–16
24 39 44 21 26 67 110 209 101 200 81 33
R PS R PS, GS R PS, GS R PS, GS R PS, GS PS, GS R PS, GS R PS, GS R PS R PS, GS R PS, GS R PS, GS
GS ¼ generalized seizures, M ¼ months, N ¼ number of children studied, PC ¼ placebo-controlled, PS ¼ partial seizures, R ¼ refractory, W ¼ weeks, yrs ¼ years. a Only the part of the study is stated where children were treated with add-on levetiracetam.
ARTICLE IN PRESS E U R O P E A N J O U R N A L O F PA E D I AT R I C N E U R O L O G Y
two dosages. If the dose was well tolerated but there was insufficient seizure control, the dose could be increased with 10 mg/kg/day per two weeks, with a maximum dose of 60 mg/kg/day. Two formulations were available, tablets (250 mg) and oral solution (100 mg/ml). If the study treatment was not tolerated by the child, if the child had no substantial benefit from the study treatment at the maximum dosage of 60 mg/kg/day, or if the investigator decided to withdraw the child for safety reasons, the study drug was gradually reduced with 10 mg/kg/day weekly. The dosage of the concomitant AED(s) had to remain stable throughout the study period.
2.3.
Study design
The trial consisted of a pre-selection visit (4 weeks before initiation of levetiracetam), an initiation visit, visits in week 4, week 12 and week 26, and a phone call in week 8. During the pre-selection visit, the eligibility of the child for the trial was checked and a daily record card was given to the child to record date, number, and type of his/her seizures during the next 4 weeks. At the initiation visit, the study medication was prescribed if the child was still eligible. From the initiation visit onwards, the updated daily record card was checked by the investigator at each visit and the occurrence of seizures since the preceding visit was evaluated, a physical examination was performed, and any changes in study medication dosage or in concomitant non-AED and AED medications were verified. The occurrence of adverse events was checked with help of a standardized side effects questionnaire, and the possible relationship between each complaint and levetiracetam therapy was evaluated by the treating physician. The questionnaire contained 33 queries covering the presence and severity of behavioural changes, sleep-related problems, cognitive problems, and physical problems. The seizures and epileptic syndrome were classified according to the revised classifications of the International League Against Epilepsy (ILAE).16,17
2.4.
Data analysis
The primary outcome parameter of our study was the retention rate after 26 weeks of treatment. Secondary outcome parameters were: (1) the number of children with seizure reduction of more than 50% (as compared to the mean number of seizures per week in the last 4 weeks before inclusion) in the period between obtaining a stable dose and 12 weeks after initiation of levetiracetam; (2) the number of children with seizure reduction of more than 50% (as compared to the mean number of seizures per week in the last 4 weeks before inclusion) in the period between obtaining a stable dose and 26 weeks after initiation of levetiracetam; and (3) terminal remission, the period of time the child was seizure-free (SF) counting back from visit 4 (26 weeks after initiation of levetiracetam). A dose was considered stable if it remained the same during at least 4 weeks. To assess safety, the adverse events that were reported by every individual in the standardized side effects questionnaires during the study were recorded. All statistical analyses were performed using SPSS 14.0.2. Nonparametric tests (Kruskal Wallis and Mann–Whitney)
12 (2008) 321 – 327
323
were used to compare efficacy between children with and without mental retardation, between partial and generalized seizure types, between epilepsy syndromes, and between different administration routes. A chi-square test was used to compare drop-out rate in the same, abovementioned, subgroups.
3.
Results
Between March 2005 and July 2006, 33 children with refractory epilepsy were included in the study. Patient demographics are listed in Table 2. Median number of seizures was 14 per week in the period between the pre-selection visit and the initiation visit. Nineteen children (57.6%) had partial seizures with or without secondary generalization, nine (27.3%) generalized seizures, four (12.1%) both partial and generalized seizures, and in one child seizures could not be classified. Of the six children with absences, three had atypical absences and were classified as having symptomatic generalized epilepsy. Most children had one (57.6%) or two (36.4%) seizure types (Table 2). In three children (9.1%) the epilepsy syndrome was classified as idiopathic, in 20 (60.6%) as symptomatic, in eight (24.2%) as cryptogenic, and in two the syndrome could not be determined (Table 2). The following AEDs were used at intake in the study: valproic acid (45.5%), lamotrigine (33.3%), carbamazepine (27.3%), oxcarbazepine (15.2%), clobazam (15.2%), ethosuximide (9.1%), topiramate (9.1%), clonazepam (6.1%), and phenytoin (3.0%).
3.1.
Efficacy
After 26 weeks, 23 of the 33 included children still used levetiracetam (retention rate 69.7%). Four children droppedout because levetiracetam was ineffective (these children used a maximum dose of 30–60 mg/kg/day), four because seizure frequency increased and/or seizures became more severe, and two because they developed aggressive behaviour. Twelve weeks after initiation of levetiracetam, 21 children had reached a stable dose. Thirteen of these children (39.4% of the total group) had a seizure reduction of more than 50% since obtaining a stable dose as compared to the last 4 weeks before inclusion. Seventeen children (51.5%) had a seizure reduction of more than 50% in the period between obtaining a stable dose and 26 weeks after initiation of levetiracetam (12 of them also had 450% seizure reduction at 12 weeks). Of these 17 children, six (18.2%) became SF immediately after obtaining a stable dose and remained so during the entire follow-up, and three other children (9.1%) were SF for at least the last 4 weeks at 26 weeks (mean duration of seizure-freedom of these nine children: 15.7 weeks, range 5.7–26 weeks); in another three children (9.1%) the period of seizure-freedom varied from 2 to 4 weeks at 26 weeks. Terminal remission in the 23 children who completed the study ranged from 0 to 187 days (mean 46 days, median 14 days). Efficacy and drop-out rate did not differ significantly between children with mental retardation and those without mental retardation.
ARTICLE IN PRESS 324
E U R O P E A N J O U R N A L O F PA E D I AT R I C N E U R O L O G Y
Table 2 – Baseline demographics and clinical characteristics of our study population (n ¼ 33) Sex (%) Male Female
17 (51.5) 16 (48.5)
Median age in years (range)
8.5 (4.2–15.6)
Mental retardation (%)
14 (42.4)
Number of seizures per week (%) 1–2 3–10 11–50 450 Seizure typea (%) Simple partial seizures Complex partial seizures Partial onset with secondary generalization Generalized tonic-clonic Tonic Atonic Clonic Myoclonic Absences Unclassified seizures Epilepsy syndromeb (%) Symptomatic localization-related epilepsy not further defined (1.2.c) Cryptogenic localization-related epilepsy (1.3) Juvenile absence epilepsy (2.1.e) Idiopathic generalized epilepsy not further defined (2.1.h) Epilepsy with myoclonic-astatic seizures (2.2.c) Symptomatic generalized epilepsy not further defined (2.3.1.c) Epilepsy undetermined whether focal or generalized (3.1.e) Not known Number of AEDs at initiation of levetiracetam (%) One Two Three
7 (21.2) 8 (24.2) 8 (24.2) 10 (30.3) 2 (6.1) 19 (57.6) 10 (30.3) 2 (6.1) 4 (12.1) 1 (3.0) 0 4 (12.1) 6 (18.2) 1 (3.0)
11 (33.3) 8 (24.2) 1 (3.0) 2 (6.1) 1 (3.0) 8 (24.2) 1 (3.0) 1 (3.0)
16 (48.5) 13 (39.4) 4 (12.1)
a
According to the revised classification of epileptic seizures of the ILAE.16 b According to the revised classification of epilepsies and epileptic syndromes of the ILAE.17
Levetiracetam was effective in various seizure types (Fig. 1). Overall, levetiracetam was more effective in partial seizures than in generalized seizures (p ¼ 0.036): twenty children had 450% seizure reduction in one or two seizure types (in total 29 seizure types), of which 20 seizure types (69%) had partial onset (Fig. 1). Fourteen (48%) of these partial-onset seizure types disappeared completely with levetiracetam treatment. In eight children a 450% increase in seizure-frequency of one or two seizure types was observed. Four of these children dropped-out, whereas the other four children had an increased number of one seizure type combined with a markedly reduced number (95–100%) of the other seizure types. Two of these last four patients had an overall seizure
12 (2008) 321 – 327
reduction of more than 50%, the other two had 0–50% seizure reduction. The number of patients dropping out did not differ significantly between seizure types. Fig. 2 shows the efficacy per epilepsy syndrome, classified according to the ILAE in 1989.17 Levetiracetam was effective in different syndromes. Eleven of the 17 children (64.7%) with more than 50% seizure reduction at 26 weeks and seven of the nine children (77.8%) who were SF for at least 4 weeks at 26 weeks had localization-related epilepsy. One additional child had more than 50% seizure reduction, but he dropped-out because of aggressive behaviour. The efficacy or drop-out rate did not differ significantly between epilepsy syndromes, between localization-related and generalized epilepsy syndromes, or between symptomatic, idiopathic and cryptogenic epilepsy. The final dosage of levetiracetam after 26 weeks ranged from 9 to 53 mg/kg/day (median 22 mg/kg/day; mean 26.5 mg/ kg/day). Nine children had a final dosage p15 mg/kg/day, of whom seven had more than 50% seizure reduction (three of them became SF). Twenty-three children (69.7%) used oral solution until their final visit, seven (21.2%) used tablets, and three (9.1%) changed from oral solution to tablets during the trial at the moment they started to use a dose that could also be administered with tablets. Eleven of the 23 children (47.8%) on oral solution and five of the seven children (71.4%) on tablets had more than 50% seizure reduction between initiation of levetiracetam and the last completed visit (eight of the patients on oral solution and one on tablets droppedout). Efficacy or the number of children dropping out did not differ significantly between the children using tablets and those on oral solution. After the fixed follow-up period of the study, 21 children (63.6%) continued to use levetiracetam, in one levetiracetam was withdrawn because it was not effective and in one because of side effects (behavioural problems and diplopia). Despite the fact that concomitant AEDs had to remain stable throughout the study period, concomitant AEDs were changed during the trial in eight children. In four children concomitant AEDs were reduced or stopped because of side effects (two of these were SF at week 26, two had 450% seizure reduction), in two children a physician that was consulted for a second opinion advised to reduce or stop concomitant AEDs (one was SF at week 26, one had 0–50% seizure reduction), and two children were temporarily treated with other AEDs (midazolam and phenytoin) because of a status epilepticus during pneumonia in one and a cluster of seizures during 1 day in the other (the first was SF at week 26, the other had 0–50% seizure reduction). Due to these adjustments in concomitant AEDs, two children had had levetiracetam monotherapy for 3 months at the end of the trial (one was SF, one had 0–50% seizure reduction).
3.2.
Tolerability
All children reported at least one behavioural, sleep-related, cognitive or physical problem in the standardized side effects questionnaire that was either not present before the start of levetiracetam treatment or worsened during the study (Table 3). Most common complaints were hyperactivity (48.5%), somnolence (36.4%), irritability (33.3%) and aggressive
ARTICLE IN PRESS E U R O P E A N J O U R N A L O F PA E D I AT R I C N E U R O L O G Y
12 (2008) 321 – 327
325
Fig. 1 – Seizure reduction by seizure type (from baseline to the last completed visit for all 33 children), classified according to the revised clinical and electroencephalographic classification of epileptic seizures of the ILAE.16 Sec. ¼ secondary, GTC ¼ primary generalized tonic-clonic.
Fig. 2 – Seizure reduction by epilepsy syndrome (from baseline to the last completed visit for all 33 children), classified according to the revised classification of epilepsies and epileptic syndromes of the ILAE.17 1.2.c ¼ symptomatic localizationrelated epilepsy not further defined, 1.3 ¼ cryptogenic localization-related epilepsy, 2.1.e ¼ juvenile absence epilepsy, 2.1.h ¼ idiopathic generalized epilepsy not further defined, 2.2.c ¼ epilepsy with myoclonic-astatic seizures, 2.3.1.c ¼ symptomatic generalized epilepsy not further defined, 3.1.e ¼ epilepsy undetermined whether focal or generalized.
behaviour (27.3%). Severity of most complaints was mild and they were rarely a reason for discontinuation of levetiracetam. Two children dropped out because of aggressive behaviour (one of them had 450% seizure reduction). Five children had a serious adverse event during the trial, which all concerned hospital admissions for reasons considered not to be related to the use of levetiracetam by the treating physician, being status epilepticus during fever and pneumonia; gastroenteritis; percutaneous gastrostomy; orthopaedic surgery; and planned oesophagoscopy. One severely retarded child with tetraplegia and pre-existing
constipation died 2 months after completing the trial due to complications of a perforated colon.
4.
Discussion
This prospective open-label trial showed that add-on therapy with levetiracetam is effective and well-tolerated in children aged 4–16 years with refractory epilepsy. More than 50% of the children had a seizure reduction of more than 50% after 26 weeks of treatment, and 27% were SF for at least 4 weeks at
ARTICLE IN PRESS 326
E U R O P E A N J O U R N A L O F PA E D I AT R I C N E U R O L O G Y
Table 3 – Number of children reporting complaints as stated in the standardized side effects questionnaire Frequency (%)
(Possibly) related to levetiracetam (%)a
Behavioural Hyperactivity Irritability Aggressive behaviour Behavioural problems Nervousness
23 (69.7) 16 (48.5) 11 (33.3) 9 (27.3)
11 (33.3) 10 (30.3) 9 (27.3)
6 (18.2)
4 (12.1)
5 (15.2)
3 (9.1)
Sleep-related Somnolence Tiredness Lethargy
16 (48.5) 12 (36.4) 8 (24.2) 6 (18.2)
9 (27.3) 7 (21.2) 4 (12.1)
Cognitive Concentration disturbance Impaired school performance
10 (30.3) 7 (21.2)
4 (12.1)
6 (18.2)
4 (12.1)
Physical Decreased appetite Constipation Trembling Increased weight Drooling Gums problems Nausea Hair loss Headache Itch
25 (75.8) 7 (21.2)
6 (18.2)
6 6 6 6 5 5 4 4 4
4 (12.1) 3 (9.1) 3 (9.1) 3 (9.1) 4 (12.1) 4 (12.1) 3 (9.1) 3 (9.1) 3 (9.1)
(18.2) (18.2) (18.2) (18.2) (15.2) (15.2) (12.1) (12.1) (12.1)
Only complaints that were reported by at least 10% of the children and occurred or worsened during the use of levetiracetam are listed. a According to the judgment of the treating physician.
the end of the study. Levetiracetam was effective in both partial and generalized seizures and in both localizationrelated and generalized epilepsy syndromes, with most effect in partial seizures and localization-related epilepsy syndromes. This is the first study in which children were treated with levetiracetam oral solution, which has previously been shown to be bioequivalent to the tablet formulation.18 Efficacy did not differ significantly between oral solution and tablets. Our results are overall in line with earlier studies on the efficacy of levetiracetam as add-on therapy in children and adolescents (Table 4).5–15 Retention rate was 70% in our study compared to 33–95% in other studies; it was in general inversely correlated with the duration of follow-up (Table 4). The percentage of children with more than 50% reduction in seizure-frequency ranged from 20% to 61% in these studies versus 52% in our study. Particularly, relatively more children became SF in our study than in other published studies (27% versus 4–12%, Table 4). All but one of the studies included children with refractory epilepsy, and baseline characteristics were overall comparable with respect to median age at intake,
12 (2008) 321 – 327
seizure types, seizure frequency at baseline, and concomitant AEDs. The only difference between our and earlier studies is that fewer children in our study had mental retardation (42% in our study versus 72–100% in other studies).6–12,15 We observed no difference in efficacy between children with mental retardation and those without mental retardation, and the presence of fewer children with mental retardation in our study can, therefore, not explain this higher percentage of children being SF at the end of the trial. Most studies did not define the duration of seizure-freedom.6,7,9–12,14,15 Two studies only counted children that became SF after obtaining a stable dose and remained so during follow-up (both 8 weeks),5,8 and the double-blind placebo-controlled study only counted children who were SF during the entire double-blind treatment period of 14 weeks.13 In these three studies 5–9% of the children had no seizures during the complete follow-up versus 18% in our cohort. Peake et al.14 and Grosso et al.15 observed a decreasing number of children being SF during follow-up (Peake et al.: 14% after both two and six months and 5% after 12 months, Grosso et al.: 31% after three months, 15% after 12 months). Based on these studies it could be assumed that the percentage of children being SF is dependent on the duration of follow-up, but no relation between these two parameters can be observed in Table 4 if the studies are compared. In our cohort, the median dosage of levetiracetam (22 mg/kg/day) at the end of the trial was lower than in other studies (33–39 mg/kg/day, Table 1).5,8,10,11 The same holds for the mean dosage (26.5 mg/kg/day versus 37–53 mg/kg/day).6,9,12,14,15 In the study of Glauser et al., the dosage was increased to 40 mg/kg/day, unless an excellent clinical response was seen at 20 mg/kg/day.5 This may explain the higher median dosage in that study (Table 1). The titration schedules of the other studies cannot explain the higher mean and median dosages while they were comparable to the titration schedule of our study, with increasing the dosage with 5–10 mg/kg/day every four days,8 week,10,11,15 or fortnight.7,9 No titration schedule was described in three studies.6,12,14 The fact that in our study relatively more children became SF seems to be no explanation as well, since we found no relationship between efficacy and final dosage of levetiracetam in our cohort. An explanation for the lower daily dosage of levetiracetam used in our cohort might be that the investigators participating in the trial were more careful in up titrating in order to find a good balance between tolerability and efficacy. The most frequently reported adverse events in our cohort are identical to those reported in other trials (Table 4). The percentage of children and/or their parents reporting these adverse events was, however, higher than in most other studies. A possible explanation is that we used a standardized side effects questionnaire and that more children and/or their parents mention a certain complaint if specifically asked than if they have to report the complaint spontaneously. Most reported complaints were mild in our study and were rarely a reason for discontinuation of levetiracetam. In conclusion, our results confirm that levetiracetam is an effective and in general well-tolerated treatment as add-on therapy in children aged 4–16 years with refractory partial or generalized epilepsy, with most effect in partial epilepsy.
ARTICLE IN PRESS E U R O P E A N J O U R N A L O F PA E D I AT R I C N E U R O L O G Y
12 (2008) 321 – 327
327
Table 4 – Efficacy and adverse events in add-on studies of levetiracetam in children with epilepsy Authors
FU
Retention (%)
SF (%)
450% red (%)
Increase (%)
Most common AE (% of children reporting this AE)
Glauser5
8W
92
9
52
17
Lagae8
12 W
95
5
48
14
Glauser13,a
14 W
93
7
45
NI
20 W Avg 5 M
73 64
4 8
49 33
15 10
26 W
70
27
52
9
Grosso11 Opp12
Avg 7 M Avg 33 W
41 33
9 6
39 25
11 10
Tan9 Nakken7 Grosso15
Avg 8 M Avg 8 M Avg 9 M
81 34 46
8 7 12
61 20 30
12 43 18
Peake14
12 M
49
5
32
11
Headache (33), infection (33), anorexia (25), somnolence (25) Somnolence (10), headache (5), behavioural problems (5) Somnolence (23), accidental injury (17), vomiting (15) Tiredness (9), aggression (6) Sedation (15), aggression (13), hyperactivity (10) Hyperactivity (49), somnolence (36), irritability (33) aggression (27) Somnolence, irritability Somnolence (24), behavioural problems (26) NI Somnolence (7), dizziness (7), ataxia (7) Drowsiness (45), nervousness (36), cognitive disturbances (29) Behavioural problems (9), emotional lability (8)
Lagae10,a Wheless6 This study
Studies are stated in order of duration of follow-up. AE ¼ adverse events, avg ¼ mean/median duration, FU ¼ duration of follow-up, Increase ¼ percentage of children with 450% increased seizure-frequency, M ¼ months, NI ¼ not indicated, 450% red ¼ 50–100% seizure reduction, SF ¼ seizure-free, W ¼ weeks. a Only the part of the study is stated where children were treated with add-on levetiracetam.
Acknowledgements This study was financially supported by UCB Pharma BV, The Netherlands. R E F E R E N C E S
1. Patsalos PN. Pharmacokinetic profile of levetiracetam: toward ideal characteristics. Pharmacol Ther 2000;85:77–85. 2. Pellock JM, Glauser TA, Bebin EM, et al. Pharmacokinetic study of levetiracetam in children. Epilepsia 2001;42:1574–9. 3. Fountain NB, Conry JA, Rodriguez-Leyva I, et al. Prospective assessment of levetiracetam pharmacokinetics during dose escalation in 4- to 12-year-old children with partial-onset seizures on concomitant carbamazepine or valproate. Epilepsy Res 2007;74:60–9. 4. Lynch BA, Lambeng N, Nocka K, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci USA 2004;101:9861–6. 5. Glauser TA, Pellock JM, Bebin EM, et al. Efficacy and safety of levetiracetam in children with partial seizures: an open-label trial. Epilepsia 2002;43:518–24. 6. Wheless JW, Ng YT. Levetiracetam in refractory pediatric epilepsy. J Child Neurol 2002;17:413–5. 7. Nakken KO, Eriksson AS, Lossius R, Johannessen SI. A paradoxical effect of levetiracetam may be seen in both children and adults with refractory epilepsy. Seizure 2003;12:42–6. 8. Lagae L, Buyse G, Deconinck A, Ceulemans B. Effect of levetiracetam in refractory childhood epilepsy syndromes. Eur J Paediatr Neurol 2003;7:123–8.
9. Tan MJ, Appleton RE. Efficacy and tolerability of levetiracetam in children aged 10 years and younger: a clinical experience. Seizure 2004;13:142–5. 10. Lagae L, Buyse G, Ceulemans B. Clinical experience with levetiracetam in childhood epilepsy: an add-on and monotherapy trial. Seizure 2005;14:66–71. 11. Grosso S, Franzoni E, Coppola G, et al. Efficacy and safety of levetiracetam: an add-on trial in children with refractory epilepsy. Seizure 2005;14:248–53. 12. Opp J, Tuxhorn I, May T, et al. Levetiracetam in children with refractory epilepsy: a multicenter open label study in Germany. Seizure 2005;14:476–84. 13. Glauser TA, Ayala R, Elterman RD, et al. Double-blind placebocontrolled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology 2006;66:1654–60. 14. Peake D, Mordekar S, Gosalakkal J, et al. Retention rate of levetiracetam in children with intractable epilepsy at 1 year. Seizure 2007;16:185–9. 15. Grosso S, Cordelli DM, Franzoni E, et al. Efficacy and safety of levetiracetam in infants and young children with refractory epilepsy. Seizure 2007;16:345–50. 16. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. Epilepsia 1981;22:489–501. 17. Commission on Classification and Terminology of the International League Against Epilepsy. Proposal for revised classification of epilepsies and epileptic syndromes. Epilepsia 1989;30:389–99. 18. Coupez R, Straetemans R, Sehgal G, Stockis A, Lu ZS. Levetiracetam: relative bioavailability and bioequivalence of a 10% oral solution (750 mg) and 750-mg tablets. J Clin Pharmacol 2003;43:1370–6.