Frisium (Clobazam)


Hoechst Marion Roussel


Anticonvulsant for Adjunctive Therapy

Action And Clinical Pharmacology: Clobazam is a 1,5-benzodiazepine with anticonvulsant properties.

In general, the mode of antiepileptic action of clobazam is probably largely analogous to that of the 1,4-benzodiazepines . The differences between clobazam (a 1,5-benzodiazepine) and the 1,4-benzodiazepines in terms of therapeutic efficacy and neurotoxicity are possibly due to the variation in degree of the agonist action at the high affinity benzodiazepine receptor or to differing relative action at the high and low affinity benzodiazepine receptors.

Regarding the mechanism of action it is likely that modifications to the function of gamma-aminobutyric acid (GABA) as an important inhibitory neurotransmitter underlie the pharmacological effects of the benzodiazepines. Electrophysiologic studies have shown that benzodiazepines potentiate GABA-ergic transmission at all levels of the neuroaxis, including the spinal cord, hypothalamus, hippocampus, substantia nigra, cerebellar cortex and cerebral cortex. The changes induced by the interaction of GABA with its receptors is enhanced by benzodiazepines, resulting in a decrease in the firing rate of critical neurons in many regions of the brain.

The oral absorption of clobazam, like that of all benzodiazepines, is fast and complete. The time to peak concentration ranges from 1 to 4 hours. The administration of food with the drug has variable effects on the rate of absorption. The drug is highly lipophilic and is rapidly distributed in fat and cerebral grey matter. Within 1 to 4 hours of administration it has accumulated in white matter and is then redistributed widely. The volume of distribution is large.

Clobazam is extensively metabolized and is not excreted in unchanged form by any species studied. Clobazam forms a number of metabolites with N-desmethylclobazam being the most important. The half-life of N-desmethylclobazam is much longer (mean 42 hours; range 36 to 46 hours) than for clobazam (mean 18 hours; range 10 to 30 hours). N-desmethylclobazam reaches higher serum levels, especially with long-term administration of clobazam. The half-life increases with the patient’s age. The drug is about 85% protein-bound; hepatic disease may alter both the metabolism of the drug and its protein binding thus affecting plasma clobazam levels. There have been no studies that have demonstrated a clear-cut correlation between serum levels of clobazam or of N-desmethylclobazam to clobazam efficacy.

Most reports indicate there is no, or only a very weak, correlation between the clobazam dose, or blood levels, and its clinical effects. Therapeutic blood levels for clobazam are in the range of 50 to 300 ng/mL with the corresponding range for N-desmethylclobazam being from 1 000 to 4 000 ng/mL. The serum levels at which anticonvulsant effects can be expected are not yet known but it can be assumed that the therapeutic range lies in the order of the figures given above. Since N-desmethylclobazam blood levels are 10 to 20 times higher than those for clobazam, and this metabolite also has antiepileptic effects, it may be more important to the anti-epileptic efficacy of clobazam than the parent compound itself.

After oral administration of 4-labeled clobazam to man, approximately 90% of the radioactivity was recovered in urine.

Seven double-blind studies have been reported in which clobazam was given as adjunctive therapy versus placebo within an established antiepileptic regimen; clobazam was shown to be significantly superior to placebo.

Indications And Clinical Uses: Clobazam has been found to be of value as adjunctive therapy in patients with epilepsy who are not adequately stabilized with their current anticonvulsant therapy.

Contra-Indications: Hypersensitivity to clobazam, severe muscle weakness (myasthenia gravis) and narrow-angle glaucoma.

Manufacturers’ Warnings In Clinical States: Geriatrics: Clobazam should be used with caution in elderly and debilitated patients, and those with organic brain disorders, with treatment initiated at the lowest possible dose (see Precautions).

Potentiation of Drug Effects: Patients should be cautioned about the possibility of additive effects when clobazam is combined with alcohol or other drugs with CNS depressant effects. Patients should be advised against consumption of alcohol during treatment with clobazam (see Precautions).

Physical and Psychological Dependence: Physical and psychological dependence are known to occur in persons taking benzodiazepines. Caution must be exercised if it is at all necessary to administer clobazam to individuals with a history of drug misuse or those who may increase the dose on their own initiative. Such patients must be placed under careful surveillance. Signs and symptoms of withdrawal may follow discontinuation of use of clobazam; thus it should not be abruptly discontinued after prolonged use (see Precautions).

Pregnancy and Lactation: Clobazam should not be used in the first trimester of pregnancy and thereafter only if strictly indicated. Nursing mothers in whom therapy with clobazam is indicated should cease breast-feeding, since clobazam passes into breast milk.

Several studies have suggested an increased risk of congenital malformations associated with the use of minor tranquilizers (chlordiazepoxide, diazepam and meprobamate) during the first trimester of pregnancy. If clobazam is prescribed to a woman of childbearing potential she should be warned to consult her physician regarding the discontinuation of the drug if she intends to become, or suspects she might be, pregnant.

Anterograde Amnesia: Anterograde amnesia is known to occur after administration of benzodiazepines.

Patients with Depression or Psychosis: Clobazam is not recommended for use in patients with depressive disorders or psychosis.

Precautions: Occupational Hazards: Clobazam possesses a mild CNS depressant effect; therefore, patients should be cautioned against driving, operating dangerous machinery or engaging in other hazardous activities, particularly in the dose adjustment period, or until it has been established that they do not become drowsy or dizzy.

Geriatrics: Elderly and debilitated patients, or those with organic brain syndrome, have been found to be prone to the CNS depressant activity of benzodiazepines even after low doses. Manifestations of this CNS depressant activity include ataxia, oversedation and hypotension. Therefore, medication should be administered with caution to these patients, particularly if a drop in blood pressure might lead to cardiac complications. Initial doses should be low and increments should be made gradually, depending on the response of the patient, in order to avoid oversedation, neurological impairment and other possible adverse reactions.

Dependence Liability: Clobazam should not be administered to individuals prone to drug abuse. Caution should be observed in all patients who are considered to have potential for psychological dependence. Withdrawal symptoms have been observed after abrupt discontinuation of benzodiazepines. These include irritability, nervousness, insomnia, agitation, tremors, convulsions, diarrhea, abdominal cramps, vomiting and mental impairment. As with other benzodiazepines, clobazam should be withdrawn gradually.

Tolerance: Loss of part or all of the anticonvulsant effectiveness of clobazam has been described in patients who have been receiving the drug for some time. There is no absolute or universal definition for the phenomenon and reports vary widely on its development. The reported success of clobazam in intermittent therapy in catamenial epilepsy implies that tolerance may be minimized by intermittent treatment, but long-term follow-up is unreported. No studies have identified or predicted which patients are likely to develop tolerance or precisely when this might occur.

Mental and Emotional Disorders: It should be recognized that suicidal tendencies may be present in patients with emotional disorders; particularly those depressed. Protective measures and appropriate treatment may be necessary and should be instituted without delay.

Since excitement and other paradoxical reactions can result from the use of benzodiazepines in psychotic patients, clobazam should not be used in patients suspected of having psychotic tendencies.

Patients with Impaired Renal or Hepatic Function: Clobazam requires dealkylation and hydroxylation before conjugation. Usual precautions should be taken if clobazam is used in patients who may have some impairment of renal or hepatic function. It is suggested that the dose in such cases be carefully titrated. In patients for whom prolonged therapy with clobazam is indicated, blood counts and liver function should be monitored periodically.

Patients with Acute, Severe Respiratory Insufficiency: In patients with acute, severe respiratory insufficiency, respiratory function should be monitored.

Laboratory Tests: If clobazam is administered for repeated cycles of therapy, periodic blood counts and liver and thyroid function tests are advisable.

Drug Interactions: Most studies of the potential interactions of clobazam with other antiepileptic agents have failed to demonstrate significant interactions with phenytoin, phenobarbital or carbamazepine. However, one study noted that the addition of clobazam caused a 25% increase in serum drug levels in 29% of patients taking carbamazepine, 63% of patients taking phenytoin, 13% of those taking valproate and 14% of those on phenobarbital. The contradictory findings in different studies are presumably due to variations in patient susceptibility, and although clinically significant interactions are unusual, they may occur. Alcohol may also significantly increase plasma clobazam levels.

Several of the established antiepileptic agents: carbamazepine, phenytoin, phenobarbital, valproic acid, cause the blood levels of clobazam to decrease slightly. Findings are less consistent with regard to N-desmethylclobazam: serum levels are lower with concurrent valproic acid, but higher with carbamazepine and phenytoin.

Toxicologic Studies: In mouse, clobazam was associated with hepatomas in high-dose males. In rat, an increased incidence of thyroid adenomas was seen in males. There were 3 malignancies: 2 (male and female) in the thyroid and 1 (female) in the liver. The relevance of these findings to man has not been established.

Adverse Reactions: From 19 published studies of clobazam use in epileptic patients, the overall incidence of side effects was 33% of which drowsiness, dizziness and fatigue were most frequently reported. Canadian experience provides a similar overall incidence (32%) with drowsiness reported in 17.3% of patients, and 12% of patients terminating treatment because of side effects.

The incidence of side effects was lower in patients under 16 years of age (23.7%) than the incidence in adults (43.1%): p
Symptoms of tiredness may sometimes appear, especially at the beginning of treatment with clobazam and when higher doses are used. Also in rare instances and usually only temporarily, the patient may experience dryness of the mouth, constipation, loss of appetite, nausea, dizziness, muscle weakness, disorientation, tiredness, or a fine tremor of the fingers, but also paradoxical reactions, e.g., restlessness and irritability.

After prolonged use of benzodiazepines, impairment of consciousness combined with respiratory disorders has been reported in very rare cases, particularly in elderly patients; it sometimes persisted for some length of time.

Occupational Hazards: Under experimental conditions, impairment of alertness has been observed to be less pronounced after therapeutic doses of clobazam than after other benzodiazepines. Nevertheless, even when used as directed, the drug may alter reactivity to such an extent as to impair driving performance or the ability to operate machinery, especially when it is taken in conjunction with alcohol.

As with other drugs of this type (benzodiazepines), the therapeutic benefit must be balanced against the risk of habituation and dependence during prolonged use.

Isolated cases of skin reactions such as rashes or urticaria have been observed.

Symptoms And Treatment Of Overdose: Symptoms: The cardinal manifestations are drowsiness, confusion, reduced reflexes, increasing sedation and coma.

Effects on respiration, pulse and blood pressure are noticed with large overdoses. Patients exhibit some jitteriness and overstimulation usually when the effects of the drug begin to wear off.

Treatment: Immediate gastric lavage may be beneficial if performed soon after ingestion of clobazam. Given the route of excretion, (see Pharmacology) forced diuresis by short-acting loop diuretic may be useful some hours post-ingestion. If respiratory depression and/or coma are observed, the presence of other CNS depressants should be suspected. Respirations, pulse and blood pressure should be monitored. General supportive measures aimed at maintaining cardiopulmonary function should be instituted and administration of i.v. fluids started. Hypotension and CNS depression are managed by the usual means.

Dosage And Administration: As with other benzodiazepines, the possibility of a decrease in anticonvulsant efficacy in the course of treatment must be borne in mind.

In patients with impaired liver and kidney function, clobazam should be used in reduced dosage.

Adults: Small doses, 5 to 15 mg/day, should be used initially, gradually increasing to a maximum daily dose of 80 mg as necessary.

As with all benzodiazepines, abrupt withdrawal may precipitate seizures. It is therefore recommended that clobazam be gradually reduced in dose before treatment is discontinued.

If the daily dose is divided, the higher portion should be taken at night. Daily doses up to 30 mg may be taken as a single dose at night.

Availability And Storage: Each white, uncoated, bevelled, round tablet, 7 mm diameter, marked with “BGL” above and below the scorebreak on the obverse and the “Hoechst Tower and Bridge” logo on the reverse, contains: clobazam 10 mg. Nonmedicinal ingredients: colloidal silicon dioxide, cornstarch, lactose, magnesium stearate and talc. Blister packs (PVC film and aluminum foil) of 30 (3´10). Store in original containers at room temperature, below 25°C.

FRISIUM® Hoechst Marion Roussel Clobazam Anticonvulsant for Adjunctive Therapy

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