Pharmacology - Clobazam (Frisium)

[Jatelka]

Clobazam is 7-Chloro-1,5-dihydro-1-methyl-5-phenyl-1,5-benzodiazepine-2,4(3H)-dione.

It's chemical formula is C16H13ClN2O2 and it’s molecular mass is 300.74.



It is a white crystalline powder, very slightly soluble in water and freely soluble in alcohol.

Pharmacokinetics

After oral administration absorption is rapid and bioavailability at least 90%. Concomitant administration of alcohol increases bioavailability by up to 50%. There is marked interindividual variability in peak plasma concentration, which can occur at 0.25 to 4 hours. The elimination half life is about 20 hours, again, with marked variation. Clobazam is primarily metabolized by the liver. It has 2 major metabolites,N-desmethyl-clobazam and 4'-hydroxyclobazam, the former of which is active. N-desmethyl-clobazam attains maximal plasma concentration after 24 to 72 hours. It’s elimination half-life is approximately 50 hours. Clobazam is heavily protein bound (90%).

In patients with hepatic impairment the half-life is prolonged. In patients with renal failure the plasma level of Clobazam is reduced, possibly because of impaired absorption.

In a carcinogenecity study a significant increase in follicle cell adenoma was found in rats at a dose of 100mg/kg. Clobazam also leads to thyroid activation in rats (although this has not been documented in other species).

Indications

Clobazam is indicated for the short term treatment (less than 4 weeks) of anxiety and as an adjunct in the treatment of certain types of epilepsy

Dosage

Usual therapeutic dose (in anxiety) is 20mg daily, maximal recommended 30mg. The usual therapeutic dose in epilepsy is higher, generally the maximum is 60mg daily (divided doses)

Contraindications

It is contraindicated in those that are hypersensitive to Clobazam, in those with a histroy of drug or alcohol dependence, in myasthenia gravis, in severe respiratory failure and obstructive sleep apnoea. It is also contraindicated in severe hepatic failure (risk of precipitating encephalopathy) and in pregnancy and lactation.

Adverse effects

Anterograde amnesia can occur with even therapeutic doses, apparently this is more likely in the elderly. Over-sedation and hangover effect are often reported along with reduced reaction times (patients should not drive or operate heavy machinery).

Common: Confusion, dry mouth, constipation, headaches, anorexia, nausea, dizziness, muscle weakness, ataxia and tremor

Less common: Slurred speech, weight gain, loss of libido. Paradoxical reactions with agitation, hallucinations, suicidal ideation and muscle spasm can occur (and are more common in children and the elderly).

Rare: Anaphylaxis, Urticaria,

As with all benzodiazepines a physical tolerance can develop with even short term use. Clobazam should not be discontinued suddenly. When used in epilepsy, tolerance to the anti-convulsant effects can require ever escalating doses.

Over- dosage

Drowsiness, confusion and ataxia progressing to respiratory depression, eventual coma and hypotension. There is a case report in the literature of an overdose of 880mg, which result in deep coma (unresponsive to pain) for 5 days, with total length of coma 24 days.