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Clonazepam, 2 mg tablets

Drug formTablets

ATC categoryNeurology. Psychiatry

ATC subcategoryAntiepileptics

Brand nameClonazepam

Generic nameClonazepam

Composition

Each tablet contains:

active ingredient: clonazepam – 2 mg;

excipients: microcrystalline cellulose, lactose monohydrate, maize (corn) starch, povidone, sodium starch glycolate, magnesium stearate, talc purified.

Pharmacological group and ATC code

Antiepileptics; N03AE01.

Chemical name and CAS number

5-(2-chlorophenyl)-7-nitro-2, 3-dihydro-1H-1,4-benzodiazepin-2-one; 1622-61-3.

Pharmacology

Clonazepam is a benzodiazepine derivative similar to diazepam, with marked antiepileptic properties.

The precise mechanism by which clonazepam exerts its antiseizure 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. Convulsions produced in rodents by pentylenetetrazol or, to a lesser extent, electrical stimulation are antagonized, as are convulsions produced by photic stimulation in susceptible baboons. A taming effect in aggressive primates, muscle weakness and hypnosis are also produced. In humans, clonazepam is capable of suppressing the spike and wave discharge in absence seizures (petit mal) and decreasing the frequency, amplitude, duration, and spread of discharge in minor motor seizures.

Pharmacokinetics

Clonazepam is well absorbed after oral doses and peak plasma concentrations have been reported to occur within 4 hours. It is extensively metabolised in the liver, its principal metabolite being 7-aminoclonazepam, which probably has little antiepileptic activity; minor metabolites are the 7-acetamido- and 3-hydroxy-derivatives. It is excreted mainly in the urine almost entirely as its metabolites in free or conjugated form. It is about 86% bound to plasma proteins and estimations of its plasma half-life range from about 20 to 40 hours, and occasionally more.

A therapeutic range of plasma concentrations has not been established.

Clonazepam crosses the placental barrier and is distributed into breast milk.

Uses and administration
Clonazepam may be used in the treatment of all types of epilepsy and seizures. It may also be used in myoclonus and associated abnormal movements. Clonazepam is also employed for the treatment of panic disorder.

Administration

For epilepsy and myoclonus treatment is started with small doses that are progressively increased to an optimum dose according to the response of the patient. Оnce the maintenance dose has been reached, the daily amount may be given as a single dose at night. The initial adult dose is 1 mg by mouth at night for 4 nights gradually increased over 2 to 4 weeks to a usual maintenance dose of 4 to 8 mg daily; it is recommended that the total dose should not exceed 20 mg daily.

Child 5–12 years: initially 1 mg at night for 4 nights increased over 2–4 weeks to usual maintenance dose of 3–6 mg daily in 3–4 divided doses; may be given as a single bedtime dose when maintenance dose established.

Child 12–18 years: initially 1 mg at night for 4 nights increase over 2–4 weeks to usual maintenance dose of 4–8 mg daily, maximum 20 mg daily; may be given as a single bedtime dose when maintenance dose established.

As with other antiepileptics, withdrawal of Clonazepam therapy or transition to or from another type of antiepileptic therapy should be made gradually to avoid precipitating an increase in the frequency of seizures.

In the treatment of panic disorder, Clonazepam is given in maintenance dose of 1 mg daily; a few patients may benefit from further increases, up to a maximum of 4 mg daily.

In order to minimise drowsiness, Clonazepam may be taken as a single dose at bedtime. Withdrawal should again be gradual.

Overdosage

Impairment of consciousness is fairly rapid in poisoning by benzodiazepines. Deep coma or other manifestations of severe depression of brainstem vital functions are rare; more common is a sleep-like state from which the patient can be temporarily roused by appropriate stimuli. There is usually little or no respiratory depression, and cardiac rate and rhythm remain normal in the absence of anoxia or severe hypotension. Since tolerance to benzodiazepines develops rapidly, consciousness is often regained while concentrations of drug in the blood are higher than those which induced coma. Anxiety and insomnia can occur during recovery from acute overdosage, while a full-blown withdrawal syndrome, possibly with major convulsions, can occur in patients who have previously been chronic users.

Contraindications
Patients with known sensitivity to benzodiazepines; or any of the drug’s excipients; acute pulmonary insufficiency; severe respiratory insufficiency, sleep apnoea syndrome, myasthenia gravis, severe hepatic insufficiency, pregnancy and breast feeding, angle-closure glaucoma.

Adverse effects
The principal adverse effect of Clonazepam is drowsiness, which occurs in about 50% of all patients when starting therapy. Salivary or bronchial hypersecretion may cause respiratory problems in children.

Drowsiness, sedation, muscle weakness, and ataxia are the most frequent adverse effects of Clonazepam use. They generally decrease on continued dosage and are a consequence of CNS depression. Less frequent effects include vertigo, headache, confusion, depression, slurred speech or dysarthria, changes in libido, tremor, visual disturbances, urinary retention or incontinence, gastrointestinal disturbances, changes in salivation, and amnesia. Some patients may experience a paradoxical excitation which may lead to hostility, aggression, and disinhibition. Jaundice, blood disorders, and hypersensitivity reactions have been reported rarely. Respiratory depression and hypotension occasionally occur with high dosage and parenteral use.

Overdosage can produce CNS depression and coma or paradoxical excitation. However, fatalities are rare when taken alone.

Treatment of adverse effects

The treatment of benzodiazepine overdosage is generally symptomatic and supportive. Activated charcoal may be given orally within one hour of ingestion, provided they are not too drowsy. Gastric lavage is generally not advocated in overdoses of benzodiazepines alone. The specific benzodiazepine antagonist, flumazenil, is rarely required and can be hazardous, particularly in mixed overdoses involving tricyclic antidepressants or in benzodiazepine-dependent patients. The BNF recommends that flumazenil should be used on expert advice only.

Drug interactions

Hepatic enzyme inducers, such as carbamazepine, phenobarbital, or phenytoin, may accelerate the metabolism of Clonazepam. Alcohol may affect the patient’s response to Clonazepam. Clonazepam may be expected to have the sedative interactions associated with benzodiazepines in general.

Enhanced sedation or respiratory and cardiovascular depression may occur if Clonazepam is given with other drugs that have CNS-depressant properties; these include alcohol, antidepressants, antihistamines, antipsychotics, general anaesthetics, other hypnotics or sedatives, and opioid analgesics. The sedative effect of benzodiazepines may also be enhanced by cisapride. Adverse effects may also be produced by concomitant administration with drugs, which interfere with the metabolism of benzodiazepines.

Precautions

Clonazepam should be avoided in patients with pre-existing CNS depression or coma, respiratory depression, acute pulmonary insufficiency, myasthenia gravis, or sleep apnoea, and used with care in those with chronic pulmonary insufficiency. Clonazepam should be given with care to elderly or debilitated patients who may be more prone to adverse effects. Caution is required in patients with muscle weakness, or those with hepatic or renal impairment, who may require reduced doses; its use should be avoided in severe hepatic impairment. The sedative effects of Clonazepam are most marked during the first few days of use; affected patients should not drive or operate machinery. Monitoring of cardiorespiratory function is generally recommended when benzodiazepines are used for deep sedation.

Clonazepam is not appropriate for the treatment of chronic psychosis or for phobic or obsessional states. Clonazepam-induced disinhibition may precipitate suicide or aggressive behaviour and it should not, therefore, be used alone to treat depression or anxiety associated with depression; it should also be used with care in patients with personality disorders. Caution is required in patients with organic brain changes particularly arteriosclerosis. In cases of bereavement, psychological adjustment may be inhibited by Clonazepam.

Dependence characterised by a withdrawal syndrome may develop after regular use of Clonazepam, even in therapeutic doses for short periods; because of the risk of dependence, Clonazepam should be used with caution in patients with a history of alcohol or drug addiction.

The elderly

Old age may alter the distribution, elimination, and clearance of benzodiazepines. Metabolic clearance of benzodiazepines metabolised principally by oxidation appears to be reduced but not clearance of those biotransformed by glucuronide conjugation or nitroreduction. Prolonged half-life in the elderly may be a result of such a decrease in clearance or of an increase in the volume of distribution. The clinical consequence of these changes depends on factors such as dosage schedule and extent of first-pass extraction by the liver.

Irrespective of pharmacokinetic changes, the elderly may exhibit increased sensitivity to acute doses of benzodiazepines. Impairment of memory, cognitive function, and psychomotor performance and behaviour disinhibition may be more common than with younger patients. Long-term use commonly exacerbates underlying dementia in elderly patients.

Dependance and withdrawal

The development of dependence is common after regular use of benzodiazepines, even in therapeutic doses for short periods. Dependence is particularly likely in patients with a history of alcohol or drug abuse and in those with marked personality disorders. Benzodiazepines should
therefore be withdrawn by gradual reduction of the dose after regular use for even a few weeks; the time needed for withdrawal can vary from about 4 weeks to a year or more. The extent to which tolerance occurs has been debated but appears to involve psychomotor performance more often than anxiolytic effects. Drug-seeking behaviour is uncommon with therapeutic doses of benzodiazepines.

Benzodiazepine withdrawal syndrome

Development of dependence to benzodiazepines cannot be predicted but risk factors include high dosage, regular continuous use, the use of benzodiazepines with a short half-life, use in patients with dependent personality characteristics or a history of drug or alcohol dependence, and the development of tolerance. The mechanism of dependence is unclear but may involve reduced gamma-aminobutyric acid (GABA) activity resulting from down-regulation of GABA receptors.

Symptoms of benzodiazepine withdrawal include anxiety, depression, impaired concentration, insomnia, headache, dizziness, tinnitus, loss of appetite, tremor, perspiration, irritability, perceptual disturbances such as hypersensitivity to physical, visual, and auditory stimuli and abnormal taste, nausea, vomiting, abdominal cramps, palpitations, mild systolic hypertension, tachycardia, and orthostatic hypotension. Rare and more serious symptoms include muscle twitching, confusional or paranoid psychosis, convulsions, hallucinations, and a state resembling delirium tremens. Broken sleep with vivid dreams and increased REM sleep may persist for some weeks after withdrawal of benzodiazepines.

Symptoms typical of withdrawal have occurred despite continued use of benzodiazepines and have been attributed either to the development of tolerance. Pseudowithdrawal has been reported in patients who believed incorrectly that their dose of benzodiazepine was being reduced. Benzodiazepine withdrawal syndrome can theoretically be distinguished from these reactions and from rebound phenomena (return of original symptoms at greater than pretreatment severity) by the differing time course. A withdrawal syndrome is characterised by its onset, by the development of new symptoms, and by a peak in intensity followed by resolution. Onset of withdrawal symptoms depends on the half-life of the drug and its active metabolites. Symptoms can begin within a few hours after withdrawal of a short-acting benzodiazepine, but may not develop for up to 3 weeks after stopping a longer-acting benzodiazepine. Resolution of symptoms may take several days or months.

With increased awareness of the problems of benzodiazepine dependence, emphasis has been placed on prevention by proper use and careful patient selection. For example, the UK CSM has recommended that benzodiazepines should be reserved for the short-term relief (2 to 4 weeks only) of anxiety that is severe, disabling, or subjecting the individual to unacceptable distress and is occurring alone or in association with insomnia or short-term psychosomatic, organic, or psychotic illness.

Withdrawal from long-term benzodiazepine use should generally be encouraged. Established dependence can be difficult to treat; the patient should have professional and family support and behavioural therapy may be helpful. Withdrawal in a specialist centre may be required for some patients. Since abrupt withdrawal of benzodiazepines may result in severe withdrawal symptoms dosage should be tapered. The BNF considers that benzodiazepines can be withdrawn in steps of about one-eighth of the daily dose every fortnight (range one-tenth to one-quarter). There are no comparative studies of the efficacy of various withdrawal schedules and in practice the protocol should be titrated against the response of the patient.

The daily dosage of clonazepam can then be reduced in steps of 0.1 to 0.5 mg at fortnightly intervals. If troublesome abstinence effects occur the dose should be held level for a longer period before further reduction; increased dosage should be avoided if possible. It is better to reduce too slowly than too quickly. Time required for withdrawal can vary from about 4 weeks to a year or longer. In many cases the rate of withdrawal is best decided by the patient.

Adjuvant therapy should generally be avoided. Although a beta blocker may be given for prominent sympathetic overactivity the BNF recommends that this be tried only if other measures fail; antidepressants should be used only for clinical depression or panic attacks. Antipsychotic drugs should be avoided as they may aggravate symptoms.

Symptoms gradually improve after withdrawal but postwithdrawal syndromes lasting for several weeks or months have been described. Continued support may be required for the first year after withdrawal to prevent relapse.

Identification

White scored cylindrical tablets, the end surface of which are flat.

Presentation

1 blister packet with 24 tablets in the cardboard box.

Expiry date

3 years. Do not use after the expiration date.

Storage conditions

Store at a room temperature (15-250C), in a dry place, out of the reach of children. Protect from light.