Seizure 2000; 9: 8087

doi: 10.1053/seiz.2000.0380, available online at http://www.idealibrary.com on

A multicentre, double-blind, randomized, parallel group

study to evaluate the tolerability and efficacy of two
oral doses of levetiracetam, 2000 mg daily and 4000 mg
daily, without titration in patients with refractory
epilepsy

T. BETTS , T. WAEGEMANS & P. CRAWFORD

Birmingham University Seizure Clinic, Birmingham, UK; UCB Pharma, Brussels, Belgium; York
District Hospital, York, UK
Correspondence to: Tim Betts, Birmingham University Seizure Clinic, Queen Elizabeth Psychiatric Hospital, Birmingham B15 2QZ, UK
Request for reprints: Betty van Vleyman, UCB Pharma, Researchdreef 60, B-1070 Brussels, Belgium

The aim of this study was to determine the tolerability and efficacy of two oral regimens of levetiracetam, 1000 mg and 2000 mg
twice daily, as add-on treatment without titration in patients with refractory epilepsy.
After a 1- to 4-week baseline, 119 patients were randomized to receive levetiracetam 2000 mg daily, 4000 mg daily, or
placebo for a 24-week double-blind period, then levetiracetam 4000 mg daily in a 24-week open-label phase.
Somnolence was the most common reason for discontinuation, and along with asthenia, occurred more frequently with
levetiracetam than placebo. Responder rates were higher with levetiracetam 2000 mg and 4000 mg daily (48.1% [P < 0.05]
and 28.6% [NS], respectively) than placebo (16.1%). In the open-label phase, the overall responder rate was 43.0%. Switching
from placebo to levetiracetam increased the overall responder rate from 16.7% to 44.0%. No such increase was observed with
patients initiated on levetiracetam 2000 mg daily.
Levetiracetam initiated at doses of 2000 mg or 4000 mg daily without titration is well-tolerated and effective as add-on therapy
in patients with partial and/or generalized seizures. The higher dose may be related to an increased incidence of somnolence
and is not necessarily more effective than the lower dose.
c 2000 BEA Trading Ltd

Key words: antiepileptic drugs; seizures; refractory epilepsy; levetiracetam; add-on therapy; titration.

INTRODUCTION
Between 30% and 50% of patients with epilepsy either fail to respond adequately to, or are unable to
fully comply with, standard antiepileptic therapy1, 2 .
Approximately one-third of patients treated with currently available antiepileptic drugs have seizures that
are refractory to therapy3 . In addition, adverse effects
prevent adequate seizure control in a reported 20
30% of patients taking antiepileptic drugs4 . Individualized upward dose titration to an effective dose is one
method employed to avoid unnecessary dose-related
adverse effects5 . Currently, antiepileptic drug development is focused on providing an agent with a broad
spectrum of antiepileptic activity and with an over10591311/00/020080 + 08

$35.00/0

all improved safety, tolerability, and efficacy profile to

maximize seizure control.
Levetiracetam, an S-enantiomer derivative of pyrrolidine acetamide, is a novel agent with a broadspectrum effect in animal models of partial and generalized epilepsy68 . Levetiracetam has both antiepileptic and antiepileptogenic properties6, 8, 9 . Although the
mechanism of action of levetiracetam has not been
fully elucidated, the drug does not appear to act at any
recognized site of antiepileptic drug activity. Instead,
in vitro studies suggest a brain-specific binding site10 .
Compared with other antiepileptic drugs, levetiracetam has a wide margin of safety. Results of
pre-clinical studies show no evidence for carcinogenic, mutagenic, or teratogenic potential7 . Levec 2000 BEA Trading Ltd

A multicentre, double-blind, randomized, parallel group study

tiracetam has a favourable pharmacokinetic profile

in humans. Following oral administration, levetiracetam undergoes rapid and almost complete absorption;
steady-state plasma levels are attained approximately
48 hours after administration. Levetiracetam exhibits
linear kinetics, is minimally protein bound, and has
no effect on hepatic cytochrome P450 enzymes. It is
partly metabolized in blood and fully excreted in urine,
mostly as unchanged drug11 .
The clinical effects of levetiracetam have been evaluated in three placebo-controlled clinical studies of
patients with epilepsy. In these studies, levetiracetam,
initiated at 1000 mg daily and then increased up to
2000 mg or 3000 mg daily in 1000 mg increments,
effectively reduced the frequency of seizures in patients with partial seizures12 . It was well-tolerated,
and the most commonly reported adverse events, reported for more than 3% of patients and with a difference of more than 3% between levetiracetam and
placebo, were somnolence, asthenia, and dizziness
(<15% of patients). Single-blind and open-label studies have shown encouraging results when levetiracetam is titrated upward to 4000 mg daily13 . The purpose of the present study was to ascertain the tolerability and efficacy of levetiracetam at doses of 2000 mg
and 4000 mg daily as add-on therapy in patients with
refractory epilepsy, administered without titration.

PATIENTS AND METHODS

Study population
Eligible patients were men or women between the ages
of 16 and 70 years with well-characterized refractory
epilepsy and any seizure type (partial [type I] or secondarily generalized or primary generalized tonicclonic
seizures [type II]) classified according to the International League Against Epilepsy (ILAE) criteria14 . Patients had to have been maintained on a stable dosage
regimen of up to three antiepileptic drugs for at least
3 months prior to study entry. In addition, they were required to have experienced at least four seizures in the
24 weeks prior to study entry. Women of childbearing
potential were eligible only if they were using a reliable method of contraception. All patients provided
written informed consent prior to enrolment, and the
study was approved by the individual ethical review
procedures of the participating centres.
Patients were excluded if they had a history of allergy, alcohol or drug abuse, a serious medical condition that could interfere with the assessment of safety
and efficacy, psychotic conditions, problems with absorption, metabolism, or elimination of drugs, including gastrointestinal dysfunction, or renal or hepatic insufficiency.

81

Study design

This was a multicentre, double-blind, randomized

study with three parallel groups designed to evaluate the tolerability and efficacy of two oral doses of
levetiracetam (2000 mg and 4000 mg daily) as addon therapy in patients with refractory epilepsy of any
type. The study was conducted at 37 sites in Belgium
and the United Kingdom between September 1993 and
March 1997. The study consisted of four phases: a
1- to 4-week baseline period, a 24-week double-blind
treatment period, a 24-week open-label treatment period, and a 4-week run-out/downtitration period (or
entry into an open follow-up study) (Fig. 1).
Patients were seen at an initial screening visit, and if
eligible, were randomized within 4 weeks (baseline) to
2000 mg daily (1000 mg twice daily) or 4000 mg daily
(2000 mg twice daily) of levetiracetam, or matching
placebo tablets for 24 weeks. Randomization occurred
in blocks of three, defining the treatment numbers per
investigator. In each block, a random procedure (generated by the RANUNI function of SAS software) performed the permutation of the three treatment numbers. Patients in each study centre were assigned treatment numbers according to the number of the country/principal investigator and the chronological order
of their entry into the study. Levetiracetam was provided as white 500 mg tablets and placebo as matching
tablets, equal in appearance and taste. Both levetiracetam and placebo were supplied by UCB S.A. Pharma
Sector.
The assigned dose was initiated at the start of
active treatment. Visits were scheduled after 4, 12,
and 24 weeks of double-blind treatment. At the end
of this period, seizure-free patients continued on
their assigned dose of levetiracetam for an additional
24 weeks in the open-label treatment period with visits after 12 and 24 weeks. All patients who were not
seizure free at the end of the double-blind treatment
period received 4000 mg daily of levetiracetam (without uptitration) in an open-label fashion. At the final visit of the study, levetiracetam was discontinued
abruptly (run-out) or decreased by 1000 mg per week,
or patients entered an open follow-up study. The investigator could withdraw patients from the study if consent was withdrawn, the double-blind code was broken, if an adverse event occurred that was considered
by the investigator to require discontinuation, or if the
patient became pregnant.
The primary
assessment was the tolerability and safety of levetiracetam initiated at high therapeutic doses without
titration. Complete physical and neurological examiMeasurement of safety and tolerability.

82

T. Betts et al.
Double-blind
treatment period
(24 weeks)

Baseline
(1 4 weeks)

Open-label
treatment period
(24 weeks)

Run-out
downtitration
period
(4 weeks)

LEV 4000 mg/d + AEDs

or open
folllow-up
study

Not seizure-free: LEV 4000 mg/d

LEV 2000 mg/d + AEDs
Seizure-free: maintain blind
Randomization
(no titration)
Visit
1
4
Week

LEV 1000 mg/d

per week

Placebo + AEDs

2
0

3
4

4
12

5
24

6
36

7
48

8
52

Fig. 1: Study design illustrating timeline and components for each period of the study. AED = antiepileptic drug; LEV =
levetiracetam.

nations, haematological and blood chemistry parameters, urinalyses, and antiepileptic drug plasma levels
were carried out at each study visit. Adverse events
were recorded in detail and rated by investigators
as mild, moderate, or severe. A causal relationship
to study treatment was assessed by investigators as
highly probable, probable, possible, unlikely, or no relationship.
Throughout the study, all
patients completed daily record cards on which they
logged the number, duration, description, and date of
each seizure. At each visit, the investigator recorded
the number of seizures and classified each seizure according to ILAE criteria. The main efficacy assessment was the responder rate, defined as the proportion
of patients achieving a 50% reduction in total seizure
frequency after having completed 24 weeks of doubleblind treatment compared with baseline. Other efficacy variables included responder rates after 4 weeks
of double-blind treatment, and seizure frequency by
seizure type and number of seizure-free patients.
Measurement of efficacy.

Statistical methods
The intention-to-treat population included all randomized patients who had received at least one dose of
study medication. The inferential intention-to-treat
population consisted of the set of patients from the
intention-to-treat population who provided data for
the relevant treatment period(s). All treatment comparisons were made using two-tailed tests at the 0.05
significance level. The responder rate analyses were
performed by means of logistic regression. Odds ratios for obtaining a 50% seizure reduction and 95%

confidence interval were calculated. Median percentage reduction of weekly seizure frequency per seizure
type (I and II) were analysed using the Wilcoxon rank
sum test.
Adverse events were tabulated by body system, preferred COSTART term, severity, and relationship to
the study drug. The numbers of patients who experienced at least one adverse event were compared using
logistic regression. Baseline and study results of laboratory tests, vital signs, and mean trough antiepileptic drug plasma levels were compared among treatment groups using the KruskalWallis test on difference from baseline.

RESULTS
Patient demographics
A total of 136 patients were screened; 119 patients
were randomized to double-blind treatment and comprised the intention-to-treat population: 39 in the
placebo group, 42 in the group receiving levetiracetam
2000 mg daily, and 38 in the group receiving levetiracetam 4000 mg daily (Fig. 2). Treatment groups
were comparable with respect to baseline characteristics (Table 1). Across all treatment groups, the mean
age was 38 years, the duration of epilepsy ranged from
0.4 to 57.6 years, and the mean age of epilepsy onset was 14.4 years. Median seizure frequency was determined for the set of patients from the intention-totreat population who had adequate data (non-missing
and properly completed) at both baseline and following randomization. At baseline, it was 1.24 (N = 36),
1.21 (N = 34), and 1.34 (N = 36) per week for the
placebo, 2000 mg daily, and 4000 mg daily treatment

A multicentre, double-blind, randomized, parallel group study

83

Patients screened
N = 136
Patients excluded
N = 17
Double-blind period
N = 119

LEV 2000 mg/day

N = 42a
Terminated prematurely
N = 14

LEV 4000 mg/day

N = 38a
Terminated prematurely
N=9

Placebo
N = 39a
Terminated prematurely
N = 10

Open-label period
N = 86

LEV 2000 mg/day then

4000 mg/day
N = 28

LEV 4000 mg/day then

4000 mg/day
N = 29

Placebo then LEV

4000 mg/day
N = 29

Terminated prematurely
N=1

Terminated prematurely
N=3

Terminated prematurely
N=4

a Patients

evaluated for primary assessment of safety.

Fig. 2: Patient disposition. LEV = levetiracetam.

groups, respectively. Sixteen patients were completely

seizure free during the baseline period, and in the efficacy analysis, these patients were treated as nonresponders. The most common antiepileptic drug regimens at baseline included carbamazepine (N = 69),
valproate (N = 38), phenytoin (N = 37), or phenobarbitone (N = 25).

Patient disposition
Among the 119 patients randomized to drug treatment, 33 (placebo, N = 10; levetiracetam 2000 mg
daily, N = 14; levetiracetam 4000 mg daily, N = 9)
discontinued during the double-blind treatment period
(Fig. 2). The number of patients who discontinued was
comparable among treatment groups. Most patients
who discontinued in the first month did so because
of adverse events (Fig. 3). Somnolence was the most
commonly reported reason for study discontinuation.
A total of 86 patients continued into the open-label
treatment period (Table 2).

Safety and tolerability

The incidence of adverse events was similar among
study groups (placebo, 84.6%, 33/39; levetiracetam
2000 mg daily, 83.3%, 35/42; levetiracetam 4000 mg
daily, 84.2%, 32/38). In the double-blind treatment
period, the most frequently reported adverse events
were somnolence and asthenia (COSTART term for
fatigue or tiredness) (Table 3). The incidence of somnolence was highest in patients receiving 4000 mg
daily of levetiracetam (44.7%, 17/38), but was comparable between the 2000 mg daily treatment group
and placebo (26.2%, 11/42 and 25.6%, 10/39, respectively). Asthenia was most commonly reported by
patients in the 2000 mg daily treatment group (31.0%,
13/42), but was similar between the 4000 mg daily
treatment group and placebo group (13.2%, 5/38 and
15.4%, 6/39, respectively). Other frequently reported
adverse events (10% incidence in at least one of
the levetiracetam treatment groups) were accidental
injury (more frequent in the placebo group), infection, nausea, dizziness, and urinary tract infection. Adverse events generally appeared within the first month

84

T. Betts et al.

Table 1: Patient demographics and history of epilepsy (intention-to-treat population).

Variable
Mean age (y) SD
Gender, (%) male/female
Mean age at epilepsy onset (y) SD
Mean duration of epilepsy (y) SD
Unknown aetiology of epilepsy, N (%)
Patients with 1 seizure reported over baseline perioda , N (%)
Partial onset (I)
Generalized (II)
All seizures (I+II+III)

Placebo
(N = 39)

Levetiracetam
2000 mg/d
(N = 42)

Levetiracetam
4000 mg/d
(N = 38)

35 12
62/38
9.3 9.0
26.0 13.2
24 (61.5)

39 13
69/31
18.3 14.8
21.1 14.4
29 (69.0)

40 12
53/47
15.4 13.3
24.6 15.6
20 (52.6)

19 (48.7)
16 (41.0)
32 (82.1)

20 (47.6)
17 (40.5)
35 (83.3)

19 (50.0)
17 (44.7)
32 (84.2)

SD = standard deviation.
a 16 patients were seizure free during the 4-week baseline period (six in the placebo group; four in the levetiracetam 2000 mg/day group;
six in the levetiracetam 4000 mg/day group; four other patients had missing information).

Table 2: Patient number and reasons for premature discontinuation (intention-to-treat population).
Reason for
discontinuation,
N (%)

Placebo
(N = 39)

Total
Adverse events
somnolence
Withdrew consent
Othera

10 (25.6)
6 (15.4)
1 (2.6)
2 (5.1)
2 (5.1)

Double-blind period
Levetiracetam
2000 mg
(N = 42)
14 (33.3)
11 (26.2)
5 (11.9)
1 (2.4)
2 (4.8)

Levetiracetam
4000 mg
(N = 38)

Open-label
Levetiracetam
4000 mg
(N = 86)

9 (23.7)
5 (13.2)
4 (10.5)
2 (5.3)
2 (5.3)

8 (9.3)
5 (5.8)
1 (1.2)
0 (0)
3 (3.5)

a Includes protocol violation, lack or loss of efficacy.

Table 3: Most commonly reported adverse events in the

double-blind treatment period (incidence 10% in at least
one of the levetiracetam treatment groups) (intention-to-treat
population).

Adverse event

Placebo
(N = 39)

Somnolence
10 (25.6%)
Asthenia
6 (15.4%)
Accidental injury
6 (15.4%)
Infection
3 (7.7%)
Nausea
1 (2.6%)
Dizziness

Urinary tract infection 1 (2.6%)

Levetiracetam Levetiracetam
2000 mg/d
4000 mg/d
(N = 42)
(N = 38)
11 (26.2%)
13 (31.0%)
1 (2.4%)
1 (2.4%)

2 (4.8%)

17 (44.7%)
5 (13.2%)
5 (13.2%)
6 (15.8%)
5 (13.2%)
4 (10.5%)
4 (10.5%)

N = 5 (17.2%); levetiracetam 2000 mg daily, N = 3

(10.7%); and levetiracetam 4000 mg daily, N = 1
(3.4%). Three patients had serious adverse events during the open-label period that were considered to be
related to levetiracetam (convulsion in two patients
and hallucination in one patient). Three patients reported serious adverse events during the placebo runout/downtitration period.
There were no significant changes in clinical laboratory parameters nor in any physical or neurological examination among the three treatment groups throughout the study. No changes were observed in concomitant antiepileptic trough drug concentrations.

No significant difference compared with placebo.

of treatment. During the open-label treatment period,

somnolence occurred in 8.1% (N = 7) and asthenia in
3.5% (N = 3) of the 86 patients.
Ten patients reported serious adverse events during
the double-blind period: placebo, N = 3 (7.7%); levetiracetam 2000 mg daily, N = 3 (7.1%); levetiracetam 4000 mg daily, N = 4 (10.5%). None of these
was considered by the investigator to be related to
drug treatment. Nine patients reported serious adverse
events during the open-label period when receiving
4000 mg daily of levetiracetam. They had been randomized during the double-blind period to placebo,

Efficacy
A total of 86 patients
completed 24 weeks of double-blind treatment and
had adequate seizure data at both baseline and week 24
for efficacy assessment. After 24 weeks of treatment,
the responder rate of the inferential intention-totreat population (N = 86) was 48.1% (13/27) and
28.6% (8/28) in patients treated with levetiracetam
2000 mg and 4000 mg daily, respectively, compared
with placebo (16.1%, 5/31) (Fig. 4). The difference
in response was statistically significant between the
Double-blind treatment period.

A multicentre, double-blind, randomized, parallel group study

Total discontinuation during double-blind period

Discontinuation < 28 days
Discontinuation < 28 days for AE
40
33.3
30
Patients (%)

25.6
23.7
20
13.2
10

10.3

10.5

9.5
7.7

7.1

Placebo

LEV 2000 mg daily

LEV 4000mg daily

(N = 39)

(N = 42)

(N = 38)

Fig. 3: The percentage of patients discontinuing within

28 days of double-blind treatment in comparison with the
total percentage of discontinuations during the double-blind
period. Differences vs. placebo were not significant. AE =
adverse event; LEV = levetiracetam.

2000 mg daily treatment group and placebo (P =

0.01). After 24 weeks, the odds of obtaining a reduction in seizure frequency of 50% with levetiracetam
2000 mg and 4000 mg daily were 4.9 (95% confidence interval [CI]: 1.4; 16.8) and 2.0 (95% CI:0.6;
7.2) higher than the odds of obtaining the same response with placebo, respectively. Responder rates after 4 weeks of double-blind treatment were consistent
with the 24-week findings. Differences in responder
rates were statistically significant between the levetiracetam 2000 mg daily treatment group and placebo,
44.1% vs. 19.4%, respectively, (P < 0.05). The responder rate in patients who received 4000 mg daily
of levetiracetam was 33.3%.
For all seizure types, an overall reduction in median seizure frequency was observed for the levetiracetam treatment groups compared with baseline. Median seizure frequency was 0.62 and 0.59 per week
with levetiracetam 2000 mg and 4000 mg daily, respectively (1.21 and 1.34 at baseline, respectively). In
contrast, median seizure frequency increased for patients who received placebo (1.40 vs. 1.24 at baseline). In the levetiracetam treatment groups, the median percentage reductions in seizure frequency were
similar between seizure types I and II, and were higher
when compared with placebo, although differences
were not significant (Fig. 5). Throughout the entire
double-blind treatment period, seven patients were
completely seizure free; of these, four patients had received 2000 mg daily, two received 4000 mg daily of
levetiracetam, and one received placebo.

85

In the open-label treatment period, all treatment groups received 4000 mg

daily of levetiracetam, except for five patients
(placebo, N = 1; levetiracetam 2000 mg daily, N =
4) who continued with their double-blind treatment
because they were seizure free throughout the doubleblind period. Overall, according to analysis using the
last available observation under treatment, 43% of the
79 patients had a 50% reduction in seizure frequency
following open-label treatment compared with baseline. The percentage of responders was 44.0% in patients initially treated with placebo, 46.2% in patients
initially treated with levetiracetam 2000 mg daily, and
39.3% in patients initially treated with levetiracetam
4000 mg daily (Fig. 4). Importantly, an increase in
response was observed in patients who had received
placebo in the double-blind treatment period but were
subsequently switched to treatment with 4000 mg
daily of levetiracetam in the open-label treatment period (response rose from 16.7% to 44.0% [11/25], respectively). The responder rate of patients switched
from 2000 mg to 4000 mg daily of levetiracetam was
similar (46%; 12/26).
Open-label treatment period

DISCUSSION
Results of this placebo-controlled study demonstrate
that levetiracetam was well tolerated at doses of
2000 mg and 4000 mg daily without titration in patients with refractory epilepsy. The most frequent adverse effects were somnolence and asthenia. Somnolence was most often cited as the reason for study discontinuation. In this study, the occurrence of somnolence was more pronounced at the initiation of treatment with levetiracetam and with the higher dose. This
study supports pre-clinical findings68 by demonstrating that levetiracetam could have a broad-spectrum
potential because it decreased the frequency of partial and secondarily and primary generalized seizures.
Specific studies in generalized seizures are ongoing.
A clinical response was achieved early in the course
of treatment. Responder rates after 4 and 24 weeks
were similar. Throughout the double-blind treatment
period, four patients receiving levetiracetam 2000 mg
daily and two receiving 4000 mg daily of levetiracetam remained seizure free compared with the one receiving placebo.
Levetiracetam has been evaluated in three other
larger clinical trials at doses ranging from 1000 mg
to 3000 mg daily12 . Based on pooled efficacy data,
at all doses tested (1000 mg, 2000 mg, and 3000 mg
daily) levetiracetam was more effective than placebo
in reducing the weekly partial seizure frequency12 .
A distinct doseresponse relationship was observed,

86

T. Betts et al.

Placebo/LEV 4000 mg daily

LEV 2000 mg daily/4000 mg daily
LEV 4000 mg daily/4000 mg daily

Placebo
LEV 2000 mg daily
LEV 4000 mg daily

48.1a

50

50
46.2

44.1b

44
40

Responder rate (%)c

40

39.3

33.3
28.6

30

20

30

19.4

20

16.1

10

10

0
N = 25 N = 26 N = 28

N = 25 N = 26 N = 28

24 weeks

4 weeks

N = 25 N = 26 N = 28
Overall
24 weeks

Double-blind treatment period

Open-label treatment periodc

aP = 0.01 vs. placebo

bP < 0.05 vs. placebo
cAll patients received 4000 mg/daily of levetiracetam

Fig. 4: Responder rates (percentage of patients with 50% reduction in seizure frequency) after 4 and 24 weeks in the
double-blind period and in the open-label period. LEV = levetiracetam.
Partial seizures
Generalized seizures

70

67.7

66.7

60

Median % reduction

50

46.8
41.2

43.4

44.6

40

30

20

19.8

10
5.6
0
n = 19 n = 15

n = 17 n = 15

n = 17 n = 17

n = 39 n = 38

Placebo

LEV 2000
mg daily

LEV 4000
mg daily

LEV 4000
mg daily
(open label)

(N = 39)

(N = 42)

(N = 38)

(N = 86)

Fig. 5: Percentage change from baseline in weekly seizure frequencies by seizure type. Differences vs. placebo were not
significant. N = intention-to-treat population; n = number of subjects available for analysis; LEV = levetiracetam.

A multicentre, double-blind, randomized, parallel group study

with responder rates of 27.7%, 31.6%, and 41.3% for

the 1000 mg, 2000 mg, and 3000 mg daily doses, respectively. In the present study, efficacy was higher
with levetiracetam 2000 mg daily than 4000 mg daily,
with responder rates of 48.1% and 28.6%. When patients receiving 2000 mg daily were switched to the
higher 4000 mg daily dose in the open-label period,
no additional efficacy was gained and the incidence
of somnolence was higher at the higher dose. Based
on these results, levetiracetam may have a therapeutic
window with optimal response achieved at 3000 mg
daily. However, the present study was not powered
to detect a significant difference between the levetiracetam treatment arms. The study population was
small and there was an overall low baseline seizure
frequency. In addition, the study consisted of a short
4-week baseline period. Results should therefore be
interpreted with care, and no firm conclusions can be
made about efficacy.

CONCLUSIONS
Levetiracetam can be safely initiated at high therapeutic doses from 20004000 mg daily and has broadspectrum potential. The higher dose may be used, possibly at the expense of an increased incidence of somnolence, but it is not necessarily more effective than
the lower one, suggesting a therapeutic window of efficacy. Seizure control is rapidly achieved without the
need for titration. Although not likely to be the general
recommendation for use, this represents an advantage
over other antiepileptic drugs in terms of ease of use
in clinical practice.

ACKNOWLEDGEMENTS
We would like to thank the following professionals for their contribution to this research: (Belgium)
G. Abrams, P. H. Aussems, M. Baonville, A. Boogers,
A. Collier, J. Delbecq, J. C. Depoorter, F. De Ridder, T. H. Dhaene, R. Dobbelaere, A. M. Dusaucy,
M. Foulon, V. Franceschi, G. Franck, D. Fuchs,
A. Gillet, A. Jesuran, D. Koulicher, P. Kremer,
P. Lens, N. Louette, P. Maquet, M. Marin, L. Mechler,
C. Monte, E. Peeters, M. G. Rucquoy, M. Salavracos,
C. Sluys, M. Soeur, S. Strul, P. Tugendhaft, P. Vancoillie, J. Van Mullem, R. Verbruggen; (UK) T. Babic,

87

K. Smith, C. Fox. This study was supported by a grant

from UCB.

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