Type of Dosage Form • Tablets Route of Administration: • Oral: Tablets Sterile / Radioactive Statement: Tablets: Not applicable. Active ingredient: Clonazepam
PHARMACOLOGICAL PROPERTIES AND EFFECTS
Mechanism of Action: Clonazepam exhibits pharmacological properties which are common to benzodiazepines and include anticonvulsive, sedative, muscle relaxing and anxiolytic effects. The central actions of benzodiazepines are mediated through an enhancement of the GABAergic neurotransmission at inhibitory synapses. In the presence of benzodiazepines the affinity of the GABA receptor for the neurotransmitter is enhanced through positive allosteric modulation resulting in an increased action of released GABA on the postsynaptic transmembrane chloride ion flux. There are also animal data showing an effect of clonazepam on serotonin. 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 absences seizures (petit mal), slow spike wave, generalized spike wave, spikes with temporal or other locations as well as irregular spikes and waves. Generalized EEG abnormalities are more regularly suppressed than focal abnormalities. According to these findings clonazepam has beneficial effects in generalized and focal epilepsies.
Clinical / Efficacy Studies: No text.
Absorption Clonazepam is rapidly and almost completely absorbed after oral administration of Rivotril tablets. Peak plasma concentrations of clonazepam are reached in 1-4 hours. The absorption half-life is around 25 min. The absolute bioavailability is around 90% with large differences between individuals. Rivotril tablets are bioequivalent to an oral solution with respect to the extent of clonazepam absorption, whereas the rate of absorption is slightly slower for the tablets. Plasma concentrations of clonazepam at steady state for a once-daily dosage regimen are 3-fold higher than those after a single oral dose; the predicted accumulation ratios for two times and three times daily regimens are 5 and 7, respectively. Following multiple oral doses of 2 mg three times daily steady-state pre-dose plasma concentrations of clonazepam averaged 55 ng/ml. The plasma concentration-dose relationship of clonazepam is linear. The target anticonvulsant plasma concentrations of clonazepam range from 20 to 70 ng/ml. Severe toxic effects including increased frequency of seizures developed in the majority of patients with steady state plasma concentrations above 100 ng/ml. In patients with panic disorders; effective concentrations of clonazepam for reducing the frequency of panic attacks were around 20 ng/ml.
Clonazepam distributes very rapidly to various organs and body tissues with preferential uptake by brain structures. The distribution half-life is approximately 0.5-1 hour. The volume of distribution is 3l/kg. The plasma protein binding is 82- 86%.
Metabolism: Clonazepam is extensively metabolized by reduction to 7-amino-clonazepam and by N-acetylation to 7-acetamido-clonazepam. Hydroxylation at the C-3 position also occurs. Hepatic cytochrome P-450 3A4 is implicated in the nitroreduction of clonazepam to pharmacologically inactive or weakly active metabolites. The metabolites are present in urine both as free and conjugated (glucuronide and sulphate) compounds.
Elimination: The mean elimination half-life is 30-40 hours and is independent of the dose. The clearance is close to 55 ml/min irrespective of gender, but weight-normalized values declined with increasing body weight. 50-70% of the dose is excreted in the urine and 10-30% in faeces as metabolites. The urinary excretion of unchanged clonazepam is usually less than 2% of the administered dose.
Pharmacokinetics in Special Populations
Renal Impairment: Renal impairment does not affect the pharmacokinetics of clonazepam. Based on pharmacokinetic criteria, no dose adjustment is required in patients with renal impairment.
Hepatic Impairment: Plasma protein binding of clonazepam in cirrhotic patients is significantly different from that in healthy subjects (free fraction 17.1±1.0% vs 13.9±0.2%). Although the influence of hepatic impairment on clonazepam pharmacokinetics has not been further investigated, experience with another closely related nitrobenzodiazepine (nitrazepam) indicates that clearance of unbound clonazepam might be reduced in liver cirrhosis.
Elderly Patients: The pharmacokinetics of clonazepam in old age has not been established.
Pediatric Patients: Overall the elimination kinetics in children are similar to those observed in adults. After therapeutic doses to children (0.03-0.11 mg/kg) the serum concentrations were in the same range (13-72 ng/ml) as effective concentrations in adults. In neonates 0.10 mg/kg doses led to concentrations between 28-117 ng/ml at the end of a short infusion, dropping to 18 – 60 ng/ml 30 minutes later; these were tolerated with no appreciable side effects. In neonates clearance values are dependent on post-natal age. Elimination half-life values in neonates are of the same magnitude as those reported in adults. In children clearance values of 0.42+/- 0.32 ml/min/kg (ages 2-18 years ) and 0.88 +/- 0.4 ml/min/kg (ages 7-12 years ) were reported; these values decreased with increasing body weight. Ketogenic diet in children does not affect clonazepam concentrations.
Carcinogenicity: No 2-year carcinogenicity studies have 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 300 mg/kg/day.
Mutagenicity: Genotoxicity tests using bacterial systems with in vitro or host mediated metabolic activation did not indicate a genotoxic liability for clonazepam.
Impairment of Fertility: Studies assessing fertility and general reproductive performance in rats showed a reduced pregnancy rate and impaired pup survival at doses of 10 and 100 mg/kg/day.
Teratogenicity 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 40 mg/kg/day, respectively. In several rabbit studies following doses of clonazepam of up to 20 mg/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 (see 2.5.1 Pregnancy).