Original Article

Intermittent Clobazam Therapy in Febrile Seizures

Winsley Rose, Chellam Kirubakaran and Julius Xavier Scott

Christian Medical College and Hospita, Vellore, Tamil Nadu, India

Abstract. Objective: To evaluate the efficacy of intermittent clobazam therapy in preventing the recurrence of febrile seizures
and to assess its safety. Methods: The study was a prospective, randomized, double-blind placebo-controlled trial conducted
in the Department of Child Health, Christian Medical College Hospital, Vellore between July 2001 and September 2002.
Neurologically normal children between 6 months and 3 years of age with a history of febrile seizures and no evidence of acute
CNS infection or EEG abnormality were included into the study. 19 children in a clobazam group and 20 in the placebo group
were randomly allocated. Temperature reduction measures with paracetamol and tepid sponging were advised to all children.
In addition the dispensed medication was to be administered at the onset of fever and continued for 48 hours irrespective of
the duration of fever. The children were then monitored for seizures and adverse effects of clobazam. The children were
followed up for a mean period of 9.9 months. The analysis was done on the number of febrile episodes in both the groups.
Results: There were a total of 110 episodes of fever during the study period. Mean number of febrile episodes in the clobazam
group was 3.1 and in placebo group 2.56. Six (12.5%) of the 48 episodes in placebo group and one (1.7%) of 60 episodes in
clobazam group had seizure recurrence. This was statistically significant (p = 0.01). Drowsiness and weakness were present
equally in both clobazam and placebo groups whereas ataxia was present only in the clobazam group, the difference being
statistically significant (p=0.04). Conclusion: Intermittent clobazam therapy is an effective measure in the prevention of
recurrence of febrile seizures. The ataxia due to clobazam was much lower than that reported with diazepam.
[Indian J Pediatr 2005; 72 (1) : 31-33] E-mail: child2@cmcvellore.ac.in

Key words : Intermittent clobazam therapy; Febrile seizures

Febrile seizures are the most c o m m o n types of seizure MATERIALS AND M E T H O D S

w i t h a p r e v a l e n c e on 3 to 4 p e r c e n t . ~ T h e y are age
dependent and are rare before 9 months and after 5 years
of age. 2 Febrile s e i z u r e s f r e q u e n t l y recur, w i t h a
recurrence rate of 33 percent overall and 50% w h e n the
first febrile seizure occurs before one year of age) Half the
recurrences occur within six months of the first febrile
seizure, three quarters within a year and 90% within two
years. 3 P r e v e n t i o n of the febrile s e i z u r e s is h i g h l y
desirable. For the past 3 decades various regimes such as
daily phenobarbitone, daily sodium valproate,
intermittent rectal or oral diazepam have been tried with
various degrees of success. 3'4'5'6 Clobazam is the first and
only 1,5 benzodiazepine to be used in the management of
epilepsy. It is an effective anti-epileptic drug in adults
and children. 7 The side effects of clobazam are typical of
benzodiazepines: drowsiness, psychomotor retardation,
muscular weakness and pseudoataxia. These side effects
are however, less marked than those occurring with 1,4
b e n z o d i a z e p i n e s 2 As c l o b a z a m is a s u p e r i o r
b e n z o d i a z e p i n e with fewer side effects, this s t u d y if
a i m e d at e v a l u a t i n g the use of intermittent c l o b a z a m
therapy in the prevention of recurrence of febrile seizures.
Correspondenceand Reprint requests : Dr. Chellam Kirubakaran,
Professor & Head, Department of Child Health & Pediatric
Haemato-Oncology, Christian Medical College, Vellore - 632 004,
India. Fax : 91-0416-2232035
The s t u d y was prospective, r a n d o m i z e d , double-blind
placebo controlled trial conducted in the Department of
Child Health, Christian Medical Collage Hospital, Vellore
between July 2001 and September 2002. It has been found
in previous studies that the recurrence of febrile seizures
with the use of antipyretic administration only, is 24%
and 6% with intermittent d i a z e p a m therapy within one
year. A s s u m i n g that intermittent clobazam therapy is
atleast as effective as intermittent d i a z e p a m therapy,
statistical a n a l y s i s was d o n e to find the n u m b e r of
e p i s o d e s that n e e d to be s t u d i e d to be s t a t i s t i c a l l y
significant. With an alpha error of 5% and power of 80%
the sample size was calculated to be 62 febrile episodes in
each arm. With an average of 3 episodes of fever per
person per year, the n u m b e r of children to be studied
would be 21 in each arm.
As the study was double-blind, the clobazam and the
placebo were randomized and blinded. The pharmacists
had the r a n d o m i z a t i o n codes and p r e p a r e d the d r u g
accordingly. Only the pharmacist, till the completion of
the study, k n e w the code. The investigator was given
only random numbers to be assigned to the patients.
Clobazam is available only in tablet form. As a suitable
placebo tablet to blind the study could not be procured, a
suspension of the clobazam was prepared, with a suitable
placebo s u s p e n s i o n w i t h o u t the active c o m p o n e n t of

Indian Journal of Pediatrics, Volume 72--January, 2005 31

 Winsley Rose et al
clobazam. The clobazam suspension contained clobazam
in the concentration of 5 mg per 2.5 ml. Both the drug and
placebo were dispensed in similar looking brown bottles
and had the same taste and the flavouring agent. The
stability of the clobazam suspension was one month.
The therapeutic dosage of clobazam ranges from 0.3 to
1 m g / k g / d a y . 9 The dosage schedule for the purpose of
this study was allocated according to the subject's weight
as follows:
Upto 5 kg 5 mg per day
6 kg to 10 kg 5 mg twice daily (bd)
11 kg to 15 kg 7.5 mg twice daily bd
> 15 kg 10 mg twice daily bd
The d i s p e n s e d m e d i c i n e was to be a d m i n i s t e r e d
immediately at the onset of fever and continued for 48
hours and stopped after 48 hours irrespective of whether
the fever persisted or not.
Children with one or more episodes of febrile seizures
aged 6 months to 3 years were recruited. The seizures
sould be generalized should have occurred within 24
hours of onset of fever. Children with history of a febrile
seizure and p r o v e d acute CNS infection, a b n o r m a l
e l e c t r o e n c e p h a l o g r a m , d e v e l o p m e n t a l retardation,
proven CNS malformation, progressive neurological
disease, proven chromosomal abnormalities and those on
any other anticonvulsant were excluded.
The prospective candidates u n d e r w e n t a detailed
medical history. A general physical and neurological
examination was performed. EEG was performed in all
the patients and CSF analysis done in those children who
had clinical evidence to suspect an acute CNS infection. A
written consent was then obtained from the parent or
guardian of those who fulfilled all the inclusion criteria
and none of the exclusion criteria.
On inclusion into the study, each patient was then
allocated a study number. The parents then received a
diary and were instructed to annotate further febrile
e p i s o d e s , w i t h their degree, a s s o c i a t e d s y m p t o m s ,
medication used, adverse effects and seizure recurrence.
They were also instructed to administer the medication at
the beginning of each febrile episode for a period of 48
h o u r s from the start of fever. The parents were also
i n s t r u c t e d to a d m i n i s t e r p a r a c e t a m o l and institute
temperature control measures at the onset of fever and
continue it through the duration of the illness.
The children under the study were followed up every
m o n t h from the time of induction into the s t u d y till
September 2002. During each visit they were reviewed
along with their parents or guardians and the 'diary'
scrutinized and updated. As the stability of the clobazam
suspension was one month, their drug was also renewed
every month.
The a n a l y s i s was d o n e on the n u m b e r of febrile
episodes in both the groups to assess the effectiveness of
clobazam against placebo in prevention of febrile seizures
using the t-test of significance. The side effects were
32
evaluated and significance assessed statistically by the t-
test. The data was analysed on the principle of intention
to treat.
RESULTS
Of the 40 children recruited, one child in the clobazam
group was lost to follow up. So, the final analysis was on
39 children. Three each in both clobazam and placebo
groups were aged less than 24 months. Seven and six
children were above 24 months of age in clobazam and
placebo groups respectively. There were 13 males and 7
females in the c l o b a z a m g r o u p and 13 males and 6
females in the placebo group. The mean period of follow
up was 9.9 months, range (0-14 months). The 39 children
had 108 episodes of fever during the follow up period.
Sixty of those episodes were treated with clobazam and
48 with placebo. Mean number of febrile episodes during
the follow up was 3.4 episodes of fever per years. Mean
number of febrile episodes in the clobazam group was 3.1
and in placebo group 2.56. Six (12.5%) of the 48 episodes
treated with placebo had seizure recurrence. One (1.7%)
of 60 episodes in clobazam group had seizure recurrence.
This was statistically significant (P=0.01).
The three major side effects reported were drowsiness,
ataxia and w e a k n e s s . H o w e v e r , d r o w s i n e s s and
w e a k n e s s w e r e p r e s e n t a l m o s t equally in b o t h the
clobazam and the placebo group (drowsiness-46.8% and
52.1% and weakness --4.8% and 4.2% respectively). The
difference was not statistically significant. Ataxia was
present in 5 (8.3%) in clobazam group and none in the
placebo, the difference being statistically significant
(p=0.04).
DISCUSSION
Intermittent d i a z e p a m t h e r a p y for the p r e v e n t i o n of
recurrence of febrile seizures has been well studied and
p r o v e n to be effective. 6,1~This s t u d y was a i m e d at
evaluating clobazam, a 1,5 benzodiazepine with less side
effects than diazepam, in the prevention of recurrence of
febrile seizure.
The children recruited in this study were in the age
group between 6 months and 3 years with a majority of
them (57%) being in the ~ c o n d year of life. There was a
p r e d o m i n a n c e of b o y s (67.5%) in b o t h the g r o u p s .
H o w e v e r , the p r o p o r t i o n of the boys and girls were
similar in the clobazam (65%) and the placebo g r o u p
(70%). In the final analysis there were 39 children with
108 episodes of fever during the follow up period.
Sixty of those episodes were treated with clobazam
and 48 episodes with placebo. The mean n u m b e r of
febrile episodes during the follow up period was 3.4
episodes of fever per year.
Of the 108 e p i s o d e s of fever, 7 e p i s o d e s w e r e
associated with seizures in 7 different children. The other
children did not have any seizures in spite of febrile
Indian Journal of Pediatrics, Volume 72--January, 2005
 Intermittent Clobazam Therapy in Febrile Seizures
episodes. The r e c u r r e n c e rates in the p l a c e b o g r o u p
reported by Luiza et al and Berg et al over a period of one
year was 22.5% and 22.9% respectively. 11,~2 This is a high
incidence as c o m p a r e d to the present s t u d y w h e r e the
recurrence in the p l a c e b o g r o u p was 12.5%. Similarly
T h i l o t h a m m a l et al f r o m C h e n n a i in their s t u d y of the
efficacy of continuous phenobaritone against placebo with
a o n e - y e a r follow up, r e p o r t a very h i g h recurrence of
febrile seizures in the placebo group of the present study
there was a significant difference between those treated
with clobazam (1.7%) and placebo (12.5%) (p = 0.01).
Side effects w e r e n o t s i g n i f i c a n t l y d i f f e r e n t in the
c l o b a z a m a n d p l a c e b o g r o u p s e x c e p t for a t a x i a .
D r o w s i n e s s a n d w e a k n e s s w e r e p r e s e n t in b o t h the
g r o u p s w i t h n o s i g n i f i c a n t d i f f e r e n c e (P=0.58 for
d r o w s i n e s s a n d (p=0.88 for w e a k n e s s ) . T h e s e t w o
s y m p t o m s could be independent of the medication, as the
dull b e h a v i o u r of the children d u r i n g the time of fever
could have been interpreted as drowsiness and weakness
b y the parents. However, 5 (8.3%) treated with clobazam
had ataxia and none in the placebo group, the difference
being significant (p=0.04). The n u m b e r of e p i s o d e s of
ataxia observed in the present study is m u c h lower than
the 30% incidence of ataxia with intermittent d i a z e p a m
therapy reported by R o s m a n et al? Hence significant side
effects are p r e s e n t in o n l y a small g r o u p of c h i l d r e n
treated with c l o b a z a m a n d have significantly less side
effects w h e n c o m p a r e d to diazepam.
CONCLUSION
Seizure recurrence was 1.7% in the clobazam g r o u p and
12.5% in t h e p l a c e b o g r o u p , w h i c h is s t a t i s t i c a l l y
significant (P=0.01). The only significant side effect was
Indian Journal of Pediatrics, Volume 72--January, 2005
ataxia seen in 8.3% in the g r o u p treated with clobazam,
which is lower than that reported with diazepam.
RECOMMENDATIONS
I n t e r m i t t e n t oral c l o b a z a m t h e r a p y is a v e r y effective
preventive measures against recurrence of febrile seizures
with very minimal adverse effect.
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