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Tablet 0.5 mg: peach, flat bevelled edged, 8mm in diameter, debossed "CN" over "0.5" on one side and cross scored on the other.
Tablet 2 mg: white, flat bevelled edged, 8mm in diameter, debossed "CN" over "2" on one side and cross scored on the other.
Clonazepam exhibits pharmacological properties which are common to benzodiazepines and include anticonvulsive, sedative, muscle relaxing and anxiolytic effects. As with other benzodiazepines these effects are thought to be mediated mainly by post-synaptic GABA mediated inhibition, although there are animal data showing in addition 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.
Clonazepam is quickly and completely absorbed after oral administration of clonazepam. Peak plasma concentrations are reached in most cases within 1-4 hours after an oral dose. Bioavailability is 90% after oral administration. At a daily dose of 6 mg, divided in 3 doses, steady-state plasma concentrations are 25-75 ng/ml. Steady-state plasma concentrations following repeat doses may be four times (following once daily dosing) to eight times (following 3 doses/day) higher than those observed after a single dose.
After i.m. administration Tmax is approximately 3 hours and the bioavailability is 93%.
The plasma concentrations of clonazepam which achieve the optimum effect are between 20 and 70 ng/ml (on average about 55 ng/ml).
The mean volume of distribution of clonazepam is estimated at about 3 l/kg. The plasma protein binding of clonazepam is 85%. 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, with formation of 7-amino or 7-acetylamino compounds, which may be further conjugated. The main metabolite is 7-amino-clonazepam, which has shown only slight anticonvulsant activity. Four other metabolites present in very small proportions have also been identified.
Within 4-10 days 50-70% of the total radioactivity of a radiolabeled 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.
The elimination half-life is between 20 and 60 hours (mean 30 hours).
Based on kinetic criteria no dose adjustment is required in patients with renal failure. The elimination half-life in neonates is within the range reported for adults.
Most clinical forms of epilepsy in infants and children, in particular typical and atypical absences (Lennox-Gastaut syndrome), nodding spasms, primary or secondary generalised tonic-clonic seizures.
Clonazepam may also be used in epilepsy of adults and in focal seizures.
The dosage of clonazepam must be individually adjusted according to the patient's clinical response, tolerance of the medicine and the patient's age. To ensure optimum dosage adjustment, children should be given the 0.5 mg tablets. The cross-scored 0.5 mg tablets facilitate the administration of lower daily doses to adults in the initial stages of treatment.
As a general rule, clonazepam is given as low-dose, single-agent therapy in new, non-therapy-resistant cases.
A single oral dose of clonazepam begins to take effect within 30-60 minutes and remains effective for 6-8 hours in children and 8-12 hours in adults.
To avoid adverse reactions at the beginning of therapy, it is essential to start treatment with clonazepam at a low dose and increase the daily dose progressively until the maintenance dose suited to the individual patient has been reached.
The initial dose for infants and children up to the age of 10 years (or up to 30 kg bodyweight) is 0.01-0.03 mg/kg daily given in 2-3 divided doses. The dose should be increased by no more than 0.25-0.5 mg every third day until either a daily maintenance dose of approximately 0.1 mg/kg of bodyweight daily has been reached or seizures are controlled or undesired effects preclude further increase. The daily maximum dose in children is 0.2 mg/kg of bodyweight and should not be exceeded.
Based on established dosages for children up to 10 years (see above) and those for adults (see below) the following can be recommended for children between 10 and 16 years: The initial dose is 1-1.5 mg/day given in 2-3 divided doses. The dose may be increased by 0.25-0.5 mg every third day until the individual maintenance dose (usually 3-6 mg/day) is reached.
The initial dose for adults should not exceed 1.5 mg/day divided into 3 doses. The dose may be increased in increments of 0.5 mg every three days until either seizures are adequately controlled or undesired effects preclude any further increase. The maintenance dose must be individualized for each patient depending upon response. Usually a maintenance dose of 3-6mg per day is sufficient. The maximum therapeutic dose for adults is 20 mg daily and should not be exceeded.
The daily dose should be divided into 3 equal doses. If doses are not equally divided, the largest dose should be given before retiring. The maintenance dose level is best attained after 1-3 weeks of treatment. Once the maintenance dose level has been reached, the daily amount may be given in a single dose in the evening.
Before adding clonazepam to an existing anticonvulsant regimen, it should be considered that the use of multiple anticonvulsants may result in an increase of undesired effects.
Clonazepam can be administered concurrently with one or several other antiepileptic agents, in which case the dosage of each agent must be adjusted to achieve the optimum effect.
As with all antiepileptic agents, treatment with clonazepam must not be stopped abruptly, but must be reduced in a stepwise fashion (see Undesirable Effects).
Clonazepam must not be used in patients with known hypersensitivity to clonazepam or any of the medicine's excipients or those with severe respiratory insufficiency.
Clonazepam may be used only with particular caution in patients with spinal or cerebellar ataxia, in the event of acute intoxication with alcohol or drugs and in patients with severe liver damage (e.g. cirrhosis of the liver).
Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse.
In infants and small children clonazepam may cause increased production of saliva and bronchial secretion. Therefore special attention must be paid to maintaining patency of the airways.
The dosage of clonazepam must be carefully adjusted to individual requirements in patients with pre-existing disease of the respiratory system (e.g. chronic obstructive pulmonary disease) or liver and in patients undergoing treatment with other centrally acting medications or anticonvulsant (antiepileptic) agents (see Interactions).
Like all medicines of this type, clonazepam may, depending on dosage, administration and individual susceptibility, modify the patient's reactions (e.g. driving ability, behaviour in traffic).
Anticonvulsants, including clonazepam, should not be discontinued abruptly in epileptic patients as this may precipitate status epilepticus. When, in the judgement of the clinician, the need for dosage reduction or discontinuation arises, this should be done gradually.
Patients with a history of depression and/or suicide attempts should be kept under close supervision.
From preclinical studies it cannot be excluded that clonazepam possesses the possibility of producing congenital malformations. From epidemiological evaluations there is evidence that anticonvulsants act as teratogens. However, it is difficult to determine from published epidemiological reports which medicine or combination of medicines is responsible for defects in the newborn. The possibility also exists that other factors e.g. genetic factors or the epileptic condition itself may be more important than the medication in leading to birth defects. Under these circumstances, clonazepam should only be administered to pregnant women if the potential benefits outweigh the risk to the foetus.
During pregnancy, clonazepam may be administered only if there is a compelling indication. Administration of high doses in the last trimester of pregnancy or during labour can cause irregularities in the heartbeat of the unborn child and hypothermia, hypotonia, mild respiratory depression and poor feeding in the neonate. It should be borne in mind that both pregnancy itself and abrupt discontinuation of the medication can cause exacerbation of epilepsy.
Although the active ingredient of clonazepam has been found to pass into the maternal milk in small amounts only, mothers undergoing treatment with clonazepam should not breastfeed. If there is a compelling indication for clonazepam, breastfeeding should be discontinued.
The following undesirable effects occur relatively frequently: tiredness, sleepiness, lassitude, muscular hypotonia, muscle weakness, dizziness, light-headedness, ataxia, slowed reaction. These effects are usually transient and generally disappear spontaneously in the course of the treatment or on reduction of the dosage. They can be partially prevented by increasing the dose slowly at the start of treatment.
Poor concentration, restlessness, confusion and disorientation have been observed. Anterograde amnesia may occur using benzodiazepines at therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behaviour.
With certain forms of epilepsy, an increase in the frequency of seizures during long-term treatment is possible.
Depression may occur in patients treated with clonazepam, but it may be also associated with the underlying disease.
The following paradoxical reactions have been observed: excitability, irritability, aggressive behaviour, agitation, nervousness, hostility, anxiety, sleep disturbances, nightmares and vivid dreams.
In rare cases, urticaria, pruritis, rash, transient hair loss, pigmentation changes, nausea, epigastric symptoms, headache, reduction in blood platelets (thrombocytopenia), decrease in sexual drive (loss of libido), impotence and urinary incontinence may occur. Isolated cases of reversible development of premature secondary sex characteristics in children (incomplete precocious puberty) have been reported. Allergic reactions and a very few cases of anaphylaxis have been reported to occur with benzodiazepines.
Particularly in long-term or high-dose treatment, reversible disorders such as a slowing or slurring of speech (dysarthria), reduced co-ordination of movements and gait (ataxia) and disorders of vision (double vision, nystagmus) may occur.
Respiratory depression may occur. This effect may be aggravated by pre-existing airways obstruction or brain damage or if other medications which depress respiration have been given. As a rule, this effect can be avoided by careful adjustment of the dose to individual requirements.
In infants and young children, clonazepam may cause increased production of saliva or of bronchial secretion. Particular attention should therefore be paid to maintaining patency of the airways.
Use of benzodiazepines may lead to the development of physical and psychological dependence upon these products. The risk of dependence increases with dose and duration of treatment and is particularly pronounced in predisposed patients with a history of alcoholism or drug abuse.
Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. During long-term treatment, withdrawal symptoms may develop after a lengthy period of use, especially with high doses or if the daily dose is reduced rapidly or abruptly discontinued. The symptoms include tremor, sweating, agitation, sleep disturbances and anxiety, headaches, muscle pain, extreme anxiety, tension, restlessness, confusion, irritability and epileptic seizures which may be associated with the underlying disease. In severe cases the following symptoms may occur: derealization, depersonalization, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact or hallucinations. Since the risk of withdrawal symptoms is greater after abrupt discontinuation of treatment, abrupt withdrawal of Clonazepam should therefore be avoided and treatment - even if only of short duration - should be terminated by gradually reducing the daily dose.
Even if taken as directed, clonazepam can slow reactions to such an extent that the ability to drive a vehicle or operate machinery is impaired. This effect is aggravated by consumption of alcohol. Driving, operating machinery and other hazardous activities should therefore be avoided altogether or at least during the first few days of treatment. The decision on this question rests with the patient's physician and should be based on the patient's response to treatment and the dosage involved.
Clonazepam can be administered concurrently with one or more antiepileptic agents. But adding an extra medicine to the patient's regimen should involve a careful evaluation of the response to the treatment, because unwanted effects, such as sedation and apathy are more likely to occur. In such cases, the dosage of each medicine must be adjusted to achieve the optimum desired effect.
Concurrent administration of liver enzyme inducers such as barbiturates, hydantoins or carbamazepine, may accelerate the biotransformation of clonazepam without affecting its protein binding. By contrast, clonazepam itself does not appear to induce the enzymes responsible for its own metabolism.
In concurrent treatment with phenytoin or primidone, a rise in the serum concentration of these two substances has occasionally been observed.
The combination of clonazepam with valproic acid may occasionally cause petit mal status epilepticus.
Concurrent use of clonazepam and other centrally acting medications, e.g. other anticonvulsant (anti-epileptic) agents, anaesthetics, hypnotics, psychoactive medicines and some analgesics as well as muscle-relaxants, may result in mutual potentiation of the medicinal effects. This is especially true in the presence of alcohol. In combination therapy with centrally acting medications, the dosage of each medicine must be adjusted to achieve the optimum effect.
Epileptic patients being treated with clonazepam must under no circumstances consume alcohol since it may alter the effect of the medicine, reduce the efficacy of treatment or produce unexpected unwanted effects.
The symptoms of overdosage or intoxication vary greatly from person to person depending on age, bodyweight and individual response. They range from drowsiness and light-headedness to ataxia, somnolence and stupor, and finally to coma with respiratory depression and circulatory collapse. Serious sequelae are rare unless other medicines, drugs or alcohol have been taken concomitantly.
In the management of overdose it should be borne in mind that multiple agents may have been taken. In addition to monitoring of respiration, pulse rate and blood pressure, gastric lavage, i.v. fluid replacement with general supportive measures and the provision of emergency facilities to deal with possible airways obstruction are indicated. Hypotension may be treated with sympathomimetic agents.
The benzodiazepine antagonist flumazenil is not indicated in patients with epilepsy who have been treated with benzodiazepines. Antagonism of the benzodiazepine effect in such patients may provoke seizures.
Store at or below 25°C.
Controlled Drug (C5).
Bottles of 100 tablets.
Tablets 0.5mg: lactose, microcrystalline cellulose, maize starch, magnesium
stearate and sunset yellow FCF.
Tablets 2mg: lactose, microcrystalline cellulose, maize starch and magnesium
stearate.
Pacific Pharmaceuticals Ltd
PO Box 11-183
Ellerslie
AUCKLAND
Telephone: 09-579-2792
28th February 2003