• synthesized in 1972 by modification of the
• The resulting 1,5 structure retained 20% of
the the anxiolytic activity of diazepam,10-15 %
of diazepam's sedative effects .
• introduced as an anti-anxiety agent about
half as potent as diazepam and producing less
psychomotor side-effects than diazepam.
• later found to have major antiepileptic effects
• white hygroscopic powder with MW 300.73.
• It has a bitter taste, is relatively insoluble in
• cannot be given as intravenous or intramuscular
• It is a weak organic acid and forms water-soluble
salts at acidic pH.
• At physiological pH its lipid solubility is about 40%
of that of diazepam
Mode of action
• Clobazam exerts its anxiolytic and
anticonvulsant action at the benzodiazepine
binding site of the Gamma-aminobutyric acid
A (GABA -A) receptor complex by increasing
the likelihood of opening of the ligand-gated
Cl~ ion channel in response to given
concentration of GABA.
• less affinity for the ω1-allosteric binding site on the
GABAA receptor compared to the 1,4-benzodiazepines.
• selective affinity for the ω2 site, where it has agonistic
• action at a lower affinity membrane site which
probably involves an increase in the population of
sodium channels in the inactive state, limiting the
repetitive firing of neurones.
• A decrease of voltage-sensitive Ca conductance is also
observed, limiting Ca(++) entry presynaptically and
decreasing neurotransmitter release
• absorbed rapidly and almost completely.
• Mean absorption half-life is 20 min.
• It is unaffected by age or sex.
• The rate of absorption is reduced when the drug
is taken with or after meals, but the extent of
absorption is not .
• The drug is highly lipophilic and, after
absorption, is rapidly distributed in fat and
cerebral grey matter.
• Maximal plasma concentration after a single dose is seen
after 1-4 h
• half-lives varies from 11 to 77 h in healthy subjects, with
the longest half-life in the elderly .
• The half-life of clobazam's major
metabolite, Ndesmethylclobazam is even longer, about 50
• At clinical doses , plasma concentration of the metabolite
(300-3500ng/mL) is usually 10-fold greater than clobazam
concentrations (20-350 ng/mL) .
• good correlation between plasma concentration and dose
in the individual patient but large interindividual variations.
• Measurements of serum levels, however, have not been
found useful clinically.
• Plasma protein binding of the benzodiazepines
varies from nearly 99% for diazepam to 70% for
• Clobazam protein binding is 83%.
• The protein bound fraction is independent of
plasma concentration of clobazam
• only changed by lowered protein content, which
may be of importance in hepatic and renal
diseases and other conditions with lowered
protein, e.g. in the elderly.
• has a complex pattern of interactions, with marked interindividual
• increase or decrease in the blood levels of
phenobarbital, phenytoin or carbamazepine .
• Phenytoin toxicity in patients on maximal tolerable phenytoin
doses when clobazam was added
• levels of all enzyme-inducing antiepileptic drugs can alter in
• The combination of valproate in doses of 1500-2000 mg and
clobazam leads to an increase in serum valproate levels often with
• These rather unpredictable interactions may be the explanation
for the aversion to clobazam shown by some patients with chronic
epilepsy on antiepileptic polytherapy.
• Clobazam levels are generally lower and norclobazam
levels higher in patients who are comedicated with
enzyme-inducing antiepileptic drugs.
• Comedication with carbamazepine seems to induce
the epoxidation of this drug
• Conversely, it has also been reported that clobazam
levels can be raised in bitherapy with
phenobarbital, phenytoin and carbamazepine .
• Concomitant administration of alcohol and cimetidine
can also lead to a significant increase in clobazam
• Clobazam is metabolized to least 12 metabolites.
• biotransformation of clobazam is by oxidation in the liver to
desmethylclobazam (norclobazam), an active metabolite.
• Norclobazam may be responsible for the effects of clobazam .
serum concentrations are usually over 10-fold higher than the
• Studies in baboons have shown antiepileptic effects 5-6 h after IV
infusion, by which time clobazam plasma concentrations have fallen
to low levels.
• the lipophilicity of norclobazam is lower than that of
clobazam, and the affinity for the benzodiazepine receptor is more
than 10-fold lower than that of clobazam.
• Desmethylclobazam is further metabolized by conjugation and
excreted in bile as glucuronate and in bile and urine as the sulphate
• sedation, development of tolerance and
withdrawal symptoms can limit the use of 1,4
benzodiazepines in chronic treatment of epilepsy,
• clobazam has less detrimental effects on
psychomotor performance than these drugs .
• Impairment on a few cognitive tests, mainly
retrieval processes and mental rapidity has been
• Muscle fatigue or weakness is an effect apparent
in dynamic work situations where a disorderly
recruitment of motor units is seen .
• Significant toxicity includes
sedation, dizziness, headache, nausea, amnesia, ataxia and
blurred vision or diplopia.
• In chronic institutionalized patient populations increased
irritability, depression and disinhibition occurs and
behaviour disturbance may be seen. .
• Drowsiness and dizziness were the most common side-
• Gelastic seizures,Urticaria ,Rashes,are rare side effects
• side-effects were mild and transient, and seems well
• The plasma concentration of the metabolite norclobazam is
increased significantly in polytherapy, and this may be the
cause of some of the sedative side-effects
• Tolerance or 'escape' is usually measured as an increase of
seizure frequency in the last half of a treatment period,
• Tolerance is increased by high doses, and decreased by
• In patients with temporal lobe epilepsy tolerance was
found to be increasing slowly from 3% after 1 month to
35% after 2 years and did not seem to increase further
• Used as monotherapy in childhood epilepsy, tolerance was
noted in7 .5%, as compared to 4.3% for carbamazepine and
6.7% for phenytoin monotherapy .
• Tolerance to sedation develops more quickly than
tolerance to the anticonvulsant or anxiolytic effects
• Withdrawal symptoms with
irritability, restlessness and difficulty to
concentrate appears in 5-10% during the first
14 days after termination of treatment.
• Tapering will in most cases prevent this.
• tried in patients with refractory epilepsy of long standing
as an addition to other antiepileptic treatment.
• Patients of all ages, aetiologies and seizure types
• Some consider partial seizures to do best, and others
secondarily generalized attacks.
• It has been claimed that patients with symptomatic
epilepsy, most often with partial seizures without
secondary generalization and without mental
retardation, respond best to clobazam , but this is an
uncontrolled observation which has not been replicated
Open studies reported a beneficial and even
astounding effect in
• non-convulsive status,
• startle seizures ,
• Lennox-Gastaut syndrome
• alcoholic withdrawal seizures ,
Studies of clobazam used as monotherapy are
Clobazam has, however, been used in open
studies as the only drug in benign childhood
partial epilepsy and found of value even in
carbamazepine-resistant cases .
Uncontrolled observations (as well as routine clinical
experience) show good efficacy
• acute epilepsy,
• serial seizures
• prophylaxis (e.g. on days when it is important to avoid
a seizure such as when travelling, taking
examinations, interviews, etc.).
• Clobazam is the drug of first choice for such
• intermittent therapy in catamenial epilepsy
Dose and clinical therapeutics
• 5 to 140 mg/day.
• There is now general agreement that doses between 10
and 20 mg/day (in adults) are usually best,
• few patients who continue to have seizures respond better
to higher doses,
• Dose adjustments are not usually needed in patients
comedicated with other antiepileptic drugs.
• The frequency of side-effects increases sharply with higher
doses (above 30mg/day).
• The usual daily dose for acute prophylaxis is lOmg.
• Clobazam withdrawal should be carried out slowly in a