Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties
Pharmacotherapeutic group: Antiepileptic agent, antipanic agent. ATC code: N03AE01.
Mechanism of action
Clonazepam is an anticonvulsant which exhibits several pharmacological properties characteristic of the benzodiazepine class of medicines.


The exact site and mode of action of the anticonvulsant action of clonazepam is unknown.
Benzodiazepines enhance the polysynaptic inhibitory processes at all levels of the central nervous system. Clonazepam is more effective in blocking spread of electrical activity in the lesion itself.

Antipanic: The precise mechanism by which clonazepam exerts its antipanic effects is unknown, although it is believed to be related to its ability to enhance the activity of gamma aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system.
Clinical trials
Seizure Disorders: No data available.
Panic Disorder: The effectiveness of Rivotril in the treatment of panic disorder was demonstrated in two double-blind, placebo-controlled studies of adult outpatients who had a primary diagnosis of panic disorder (DSM-IIIR) with or without agoraphobia. In these studies, Rivotril was shown to be significantly more effective than placebo in treating panic disorder on change from baseline in panic attack frequency, the Clinician’s Global Impression Severity of Illness Score and the Clinician’s Global Impression Improvement Score.
Study 1 was a 9-week, fixed-dose study involving Rivotril doses of 0.5, 1, 2, 3 or 4 mg/day or placebo. This study was conducted in four phases: a 1-week placebo lead-in, a 3-week upward titration, a 6-week fixed dose, and a 7-week discontinuance phase. A significant difference from placebo was observed consistently only for the 1 mg/day group. The difference between the 1 mg dose group and placebo in reduction from baseline in the number of full panic attacks was approximately 1 panic attack per week. At endpoint, 74% of patients receiving clonazepam 1 mg/day were free of full panic attacks, compared to 56% of placebo-treated patients.
Study 2 was a 6-week, flexible-dose study involving Rivotril in a dose range of 0.5 to 4 mg/day or placebo. This study was conducted in three phases: a 1-week placebo lead-in, a 6-week optimal-dose, and a 6-week discontinuance phase. The mean clonazepam dose during the optimal dosing period was 2.3 mg/day. The difference between Rivotril and placebo in reduction from baseline in the number of full panic attacks was approximately 1 panic attack per week. At endpoint, 62% of patients receiving clonazepam were free of full panic attacks, compared to 37% of placebo-treated patients.
Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of race or gender.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

Absorption
Clonazepam is rapidly and almost completely (82 - 98%) absorbed after oral administration of Rivotril tablets, with peak serum levels being reached between 2 - 3 hours. The absorption half-life is 24 min. Rivotril tablets are similar to an oral solution with respect to the extent of clonazepam absorption, whereas the rate of absorption is different (slightly slower for the tablets). With continuous therapy, accumulation occurs and although values differ in different reports, the therapeutic serum level appears to be between 10 and 80 n-anogram/mL.
In one study with increase in dosage to 5 mg/day the average level of clonazepam after 15 days was 54 nanogram/mL. A steady state is usually reached within 2 - 3 weeks.


Plasma concentrations of clonazepam at steady states for once daily dosage regimens are 3- fold higher than those after single oral doses. Following multiple oral doses of 2 mg three times daily steady-state pre-dose plasma concentrations of clonazepam ranged from 30 - 80 nanogram/mL. The plasma concentration-dose relationship of clonazepam is linear. Severe toxic effects, resulting in increased frequency of seizures for some patients, have been reported at steady state plasma concentrations above 100 nanogram/mL.

The absolute bioavailability is 90%.
Distribution
Clonazepam enters the cerebral tissues rapidly.The distribution half-life is approximately between 0.5- 1 hours. The apparent volume of distribution, 3 L/kg, suggests concentration in some tissues.
The plasma protein binding of clonazepam ranges from 82-86%.
Metabolism
Clonazepam is metabolised in the liver. The metabolic pathways include hydroxylation, reduction of the nitro groups to an amine and addition of acetate to the amino grouping. Clonazepam is extensively metabolised by reduction to 7-amino-clonazepam and by N-acetylation to 7- acetamido-clonazepam. Hydroxylation at the C-3 position also occurs. Hepatic cytochrome P450 3A4 is implicated in the nitroreduction of clonazepam to pharmacologically inactive metabolites.
Excretion
The mean elimination half-life is 39.0 ± 8.3 hours.

50- 70% of the dose is excreted in the urine and 10- 30% in the faeces as metabolites. The urinary excretion of unchanged clonazepam is usually less than 2% of the administered dose.
The metabolites are present in urine both as free and conjugated (glucuronide and sulphate) compounds.

Clinical significance of pharmacokinetics
With chronic dosing, accumulation occurs. However, there is a wide variation in therapeutic plasma levels and a correlation between adverse effects with plasma levels or the rate of increase in plasma concentration of clonazepam and its metabolites has not been established.
Consequently, monitoring of plasma levels, as is often done with some anticonvulsants, would be valuable.

It should be emphasised that because of the effect of clonazepam on plasma levels of other anticonvulsants administered concomitantly (and vice versa) the patient should be monitored carefully in the initial stages for clinical response and occurrence of side effects.

Pharmacokinetics in Special Populations
Renal Impairment
Renal impairment does not affect the pharmacokinetics of clonazepam. Therefore, based on pharmacokinetic considerations, no dosage adjustment may be required in patients with renal impairment. The pharmacodynamics of probable accumulated clonazepam metabolites may necessitate dosage review in these patients.

Hepatic Impairment
The influence of hepatic disease on clonazepam pharmacokinetics has not been investigated.

However, due to the sole hepatic metabolism of clonazepam, the pharmacokinetics of clonazepam are expected to be affected on theoretical grounds.

Elderly Patients
The pharmacokinetics of clonazepam in the elderly has not been established.

Neonates
Although the elimination half-life (41.9 ± 29.8 hours) and clearance values in neonates pre- treated with phenobarbital are the same order of magnitude as those reported in non- pretreated adults, postnatal age does, however, affect the clearance of clonazepam under normal conditions.