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As well as inducing its own metabolism, carbamazepine can accelerate clearance of a number
of other lipid-soluble drugs including the oral contraceptive pill, necessitating, for most women,
a daily oestrogen dose of 50 µg or more. Other affected drugs include sodium valproate,
ethosuximide, corticosteroids, anticoagulants, antipsychotics and cyclosporin. Drugs that
inhibit carbamazepine metabolism and which may result in toxicity include phenytoin,
cimetidine, danazol, dextropropoxyphene, diltiazem, erythromycin, isoniazid, verapamil and
viloxazine. The less common neurotoxic interaction with lithium (confusion, disorientation,
drowsiness, ataxia, tremor, hyperreflexia) is not associated with altered concentrations of either
drug.

The substantial variation in carbamazepine concentrations in any given individual over the
course of the day  as much as 100% with twice-daily dosing using the regular release
formulations  makes the interpretation of levels problematical. In most people, the dosage can
be titrated adequately on clinical criteria alone. Exceptions include people with learning
disabilities, those in whom adherence to treatment is suspect, and those taking a cocktail of
AEDs likely to interact with each other.

Clobazam

Clobazam is a useful adjunctive drug in refractory epilepsy although the majority of responders
will develop tolerance to its antiepileptic action. Nevertheless, a useful proportion (up to 20–
30%) will become and stay seizure-free in the long term. There is some evidence that the
intermittent use of clobazam reduces the likelihood of tolerance. Short-term administration, e.g.
1020 mg daily for 37 days, can be useful in women with catamenial seizures and as ‘cover’
for special events such as holidays, weddings and surgery. A single dose of 2030 mg can have
a prophylactic action if taken immediately after the first seizure in people who suffer regular
clusters of complex partial or secondary generalised seizures.

Clobazam’s structure differs from that of other benzodiazepines, and this may account for its
lesser propensity to cause sedation. Nevertheless, tiredness, irritability and depression are
commonly reported. Occasionally deterioration in behaviour and mood disturbance can occur,
particularly in people with learning disabilities in whom clobazam should probably be avoided.
Withdrawal seizures can also be a problem.

Clonazepam

Clonazepam has efficacy against absences, myoclonic jerks and tonic-clonic seizures. Sedation
and tolerance, however, substantially reduce its usefulness. Few people respond well to this
drug but nearly 50% will have an exacerbation of seizures when it is withdrawn. Accordingly,
clonazepam now has a limited role in the management of epilepsy, possibly limited to refractory
myoclonic seizures. Like other benzodiazepines, clonazepam should only be prescribed as a
last resort in people with learning difficulties.

Ethosuximide

Ethosuximide is only indicated in the treatment of absence seizures. Slow introduction is
sensible to minimise the development of gastrointestinal and CNS side effects. In children over
six years, 500 mg daily is a reasonable starting dose, with further increments as necessary to a
maximum of 12 g per day. The dose can be increased every 24 weeks according to clinical
need.

Side effects usually involve the gastrointestinal tract (nausea, vomiting, abdominal pain) or
CNS (lethargy, dizziness, and ataxia). Blood dyscrasias have been reported rarely. Drug
monitoring is not indicated unless for checking of adherence to treatment. Ethosuximide itself