Chemical formula: C₁₅H₁₀ClN₃O₃ Molecular mass: 315.711 g/mol PubChem compound: 2802
Clonazepam exhibits pharmacological properties which are common to benzodiazepines and include anticonvulsive, sedative, muscle relaxing and anxiolytic effects. Animal data and electroencephalographic investigations in man have shown that clonazepam rapidly suppresses many types of paroxysmal activity including the spike and wave discharge in absence seizures (petit mal), slow spike wave, generalised spike wave, spikes with temporal or other locations as well as irregular spikes and waves.
Generalised EEG abnormalities are more readily suppressed by clonazepam than are focal EEG abnormalities such as focal spikes. Clonazepam has beneficial effects in generalised and focal epilepsies.
Clonazepam is quickly and completely absorbed after oral administration. Peak plasma concentrations are reached in most cases within 1–4 hours after an oral dose. Bioavailability is 90% after oral administration.
Routine monitoring of plasma concentrations of clonazepam is of unproven value since this does not appear to correlate well with either therapeutic response or side-effects.
The mean volume of distribution of clonazepam is estimated at about 3 l/kg. Clonazepam must be assumed to cross the placental barrier and has been detected in maternal milk.
The biotransformation of clonazepam involves oxidative hydroxylation and reduction of the 7-nitro group by the liver with formation of 7-amino or 7-acetylamino compounds, with trace amounts of 3-hydroxy derivatives of all three compounds, and their glucuronide and sulphate conjugates. The nitro compounds are pharmacologically active, whereas the amino compounds are not.
The elimination half-life is between 20 and 60 hours (mean 30 hours).
Within 4-10 days 50-70% of the total radioactivity of a radiolabelled oral dose of clonazepam is excreted in the urine and 10-30% in the faeces, almost exclusively in the form of free or conjugated metabolites. Less than 0.5% appears as unchanged clonazepam in the urine.
Based on kinetic criteria no dose adjustment is required in patients with renal failure.
Conventional studies of carcinogenic potential have not been conducted with clonazepam. However, in an 18-month chronic study in rats no treatment-related histopathological changes were seen up to the highest tested dose of 300mg/kg/day.
Genotoxicity tests using bacterial systems with in vitro or host mediated metabolic activation did not indicate a genotoxic liability for clonazepam.
Studies assessing fertility and general reproductive performance in rats showed a reduced pregnancy rate and impaired pup survival at doses of 10 and 100mg/kg/day.
No adverse maternal or embryo-foetal effects were observed in either mice or rats following administration of oral clonazepam during organogenesis, at doses of up to 20 or 40mg/kg/day, respectively.
In several rabbit studies following doses of clonazepam of up to 20mg/kg/day, a low, non-dose-related incidence of a similar pattern of malformations (cleft palate, open eyelids, fused sternebrae and limb defects) was observed.
As toxicokinetic evaluations have not been performed with clonazepam, it is not possible to determine the safety margin for the adverse effects observed in the non-clinical studies. The relevance of these findings to the patient population is unclear therefore a potential risk to man cannot be ruled out.
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