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CLONAZEPAM 2 MG TABLETS

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Clonazepam 2 mg Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 2 mg clonazepam . Lactose monohydrate For a full list of excipients, see section 6.1.

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PHARMACEUTICAL FORM
Tablet Round white tablets with cross-score break line, marked CLN 2.

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4.1

CLINICAL PARTICULARS
Therapeutic indications
All clinical forms of epileptic disease and seizures in infants, children and adults, especially absence seizures (petit mal), including atypical absence; primary or secondarily generalised tonic-clonic seizures (grand mal); partial (focal) seizures with elementary or complex symptomatology; various forms of myoclonic seizures, myoclonus and associated abnormal movements.

4.2

Posology and method of administration
Method of administration: Oral use. Mode of administration: Treatment should be started with low doses. The dose may be increased progressively until the maintenance dose suited to the individual patient has been found. The crossscored tablets facilitate the administration of lower daily doses in the initial stages of treatment. The dosage of clonazepam must be adjusted to the needs of each individual and depends on the individual response to therapy. The maintenance dosage must be determined according to clinical response and tolerance. The daily dose should be divided into 3 or 4 doses throughout the day. If doses are not equally divided, the largest dose should be given before retiring. Once the maintenance dose level has been reached, the daily amount may be given in a single dose in the evening.

Simultaneous administration of more than one antiepileptic drug is a common practice in the treatment of epilepsy and may be undertaken with clonazepam. The dosage of each drug may be required to be adjusted to obtain the optimum effect. If status epilepticus occurs in a patient receiving oral clonazepam, intravenous clonazepam may still control the status. 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. If necessary, larger doses may be given at the discretion of the physician, up to a maximum of 20 mg daily. The maintenance dose should be attained after 2-4 weeks of treatment. Adults Initial dose not to exceed 1 mg/day. The maintenance dosage for adults normally falls with the range 4 8 mg. Elderly Initial dose should not exceed 0.5 mg/day. The elderly are particularly sensitive to the effects of centrally depressant drugs and may experience confusion. Children and Infants Children should receive the 0.5 mg tablets to ensure optimum dosage adjustment. Initial dose should not exceed 0.25 mg/day for infants and small children (1-5 yrs). Initial dose should not exceed 0.5 mg/day for older children. The maintenance dosage normally falls within the ranges: Infants (0 - 1 year) Small children (1 5 years) School children (5-12 years) 0.5 1 mg/day 1 3 mg/day 3 6 mg/day

In some forms of childhood epilepsy, certain patients may cease to be adequately controlled by clonazepam. Control may be re-established by increasing the dose or interrupting treatment with clonazepam for 2 or 3 weeks. During the interruption in therapy, careful observation and other drugs may be needed. Hepatic Impairment In patients with mild to moderate hepatic impairment the dose should be adjusted to individual requirements and will probably be lower.

4.3

Contraindications
Known sensitivity to benzodiazepines, such as clonazepam, or to any of the drugs excipients. Acute pulmonary insufficiency; severe respiratory insufficiency, sleep apnoea syndrome, myasthenia gravis, severe hepatic insufficiency.

4.4

Special warnings and precautions for use

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic drugs has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for clonazepam. Therefore patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge. Patients with a history of depression and/or suicide attempts should be kept under close supervision. Use with caution in patients with chronic pulmonary insufficiency, or with renal or hepatic function impairment, and in the elderly or debilitated. In these cases dosage should generally be reduced. Carefully adjust dosage to individual requirements in patients with pre-existing disease of the liver or the respiratory system (e.g. chronic obstructive pulmonary disease) and in patients undergoing treatment with other centrally acting medications or anticonvulsant (antiepileptic) agents (see Section 4.5. Interaction with other medicinal products and other forms of interaction). Do not interrupt treatment abruptly. As with all other antiepileptic drugs, treatment must be withdrawn gradually, by reducing the dose due to the risk of precipitating status epilepticus. This precaution must also be taken when withdrawing another drug while the patient is still receiving clonazepam therapy. Prolonged use of benzodiazepines may result in dependence with withdrawal symptoms on cessation of use. Use 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). Use with extreme caution in patients with a history of alcohol or drug abuse. Clonazepam may cause increased production of saliva and bronchial secretion in infants and small children. Therefore special attention must be paid to maintaining patency of the airways. Like all drugs of this type, clonazepam may, depending on dosage, administration and individual susceptibility, modify the patients reactions (e.g. driving ability, behaviour in traffic). In cases of loss or bereavement, psychological adjustment may be inhibited by benzodiazepines.

In rare cases, clonazepam has induced convulsions in patients with porphyria. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency of glucose-galactose malabsorption should not take this medicine.

4.5

Interaction with other medicinal products and other forms of interaction
Alcohol in combination with clonazepam may modify the effects of the drug, compromise the success of therapy or give rise to unpredictable side-effects. Under no circumstances should alcohol be consumed while under treatment with clonazepam. When used in conjunction with other antiepileptic drugs, side-effects such as sedation and apathy, and toxicity may be more evident, particularly with hydantoins or phenobarbital and combinations including them. This requires extra care in adjusting dosage in the initial stages of treatment. The combination of clonazepam and sodium valproate has, rarely, been associated with the development of absence status epilepticus. Although some patients tolerate and benefit from this combination of drugs, this potential hazard should be borne in mind when its use is considered. The plasma concentration of clonazepam is often reduced by carbamazepine, phenobarbital, phenytoin or primidone, and possibly by theophylline. Concurrent treatment with phenytoin or primidone can change the plasma concentration of phenytoin or primidone (usually increases). There is an increased risk of prolonged sedation and respiratory depression when clonazepam is given with amprenavir. Metabolism of clonazepam is inhibited (i.e. increased plasma concentration) by cimetidine, disulfiram, fluvoxamine and ritonavir. Metabolism of clonazepam may possibly be accelerated by rifampicin. Clonazepam may possibly antagonise effects of levodopa. There are enhanced hypotensive and sedative effects when clonazepam is given with alpha-blockers or with moxonidine. There is an enhanced hypotensive effect when clonazepam is given with ACE inhibitors, adrenergic neurone blockers, angiotensin-II receptor antagonists, betablockers, calcium channel blockers, clonidine, diazoxide, diuretics, hydralazine, methyldopa, minoxidil, nitrates or nitroprusside. There is an increased sedative effect when clonazepam is given with alcohol, general anaesthetics, tricyclic and tricyclic-related antidepressants, antihistamine (less so for non-sedating antihistamines and not usually for topically applied antihistamines), antipsychotics, baclofen, lofexidine, mirtazapine, nabilone, opioid analgesics, tizanidine.

4.6

Pregnancy and lactation
Pregnancy Clonazepam has harmful pharmacological effects on pregnancy and the foetus/newborn child.

Clonazepam should not be used during pregnancy unless clearly necessary. Administration of high doses in the last trimester of pregnancy or during labour can cause irregularities in the heart beat of the unborn child and hypothermia, hypotonia, mild respiratory depression and poor sucking in the neonate. Infants born to mothers who took benzodiazepines chronically during the later stages of pregnancy may have developed physical dependence and may be at some risk for developing withdrawal symptoms in the post-natal period. Lactation Clonazepam passes into the maternal milk in small amounts. Therefore, clonazepam should not be used in mothers who breastfeed unless clearly necessary.

4.7

Effects on ability to drive and use machines
Driving, operating machinery and other hazardous activities should be avoided when using clonazepam especially during the first few days of treatment. Even when adequately controlled on clonazepam, increases in dosage or alteration in timings of dosage may modify patients reactions, depending on individual susceptibility. Clonazepam can slow reaction to such an extent that the ability to drive a vehicle or operate machinery is impaired. The decision for allowing the patient to drive rests with their doctor and should be based on the patients response to treatment and the dosage involved.

4.8

Undesirable effects
The side effects marked with an asterisk (*) are usually transitory and disappear spontaneously as treatment continues or with dose reduction. They tend to occur early in treatment and can be greatly reduced, if not avoided, by commencing with low dosages followed by progressive increases. Blood and the lymphatic system disorders Isolated cases of blood dyscrasias. Immune system disorders Allergic reaction and a very few cases of anaphylaxis and angioedema. Endocrine disorders Isolated cases of reversible development of premature secondary sex characteristics in children (incomplete precocious puberty) have been reported. Psychiatric disorders Anterograde amnesia (risk increases at higher dosages). Amnestic effects may be associated with inappropriate behaviour. Depression, loss of libido, impotence. 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. Paradoxical effects such as aggressiveness, excitability, nervousness, hostility, anxiety, sleep disturbances, nightmares, vivid dreams, irritability, agitation, psychotic disorders and activation of new types of seizures may occur. If these occur, the benefit of continuing the drug should be weighed against the adverse effect. It may

be necessary to add another suitable drug to the regimen or to discontinue clonazepam therapy. Nervous system disorders Dizziness*, light-headedness*, somnolence*, fatigue*, co-ordination disturbances*, poor concentration, restlessness, confusion and disorientation, headache. Dysarthria and ataxia* are reversible disorders and occur particularly in long-term or high-dose treatment. With certain forms of epilepsy, an increase in the frequency of seizures during longterm treatment is possible. Rarely, convulsions may be induced in patients with porphyria. Eye disorders Double vision and nystagmus are reversible disorders and occur particularly in longterm or high-dose treatment. Respiratory, thoracic and mediastinal disorders Rarely respiratory depression may occur with intravenous clonazepam, particularly if other depressant drugs have been administered. This effect can usually be avoided by careful adjustment of the dose to individual requirements. In infants and small children, and particularly those with a degree of mental impairment, salivary or bronchial hypersecretion with drooling may occur. Supervision of the airway may be required. Gastrointestinal disorders Rarely: nausea, gastrointestinal symptoms. Hepato-biliary disorders Isolated cases of abnormal liver function tests have been reported. Skin and subcutaneous tissue disorders Rarely: urticaria, pruritus, transient hair loss, pigmentation changes. Musculoskeletal, connective tissue and bone disorders Muscle weakness*, occasional muscular hypotonia* Renal and urinary disorders Rarely: urinary incontinence. General disorders and administration site conditions Withdrawal: Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. During long-term treatment, withdrawal symptoms may develop, especially withdrawing from 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: derealisation, depersonalisation, 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, discontinuation should be carried out by gradually reducing the daily dose.

4.9

Overdose
As with other benzodiazepine drugs, overdosage should not present undue problems of management or threat to life. Patients have recovered from overdoses in excess of 60mg without special treatment. Severe somnolence with muscle hypotonia will be present. Symptoms: The symptoms of overdosage or intoxication vary greatly from person to person depending on age, bodyweight and individual response. Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Coma, hypotension and respiratory depression occasionally occur but are seldom serious if these drugs are taken alone. Coma usually lasts only a few hours but in elderly people it may be more protracted and cyclical. Benzodiazepine respiratory depressant effects are more serious in patients with severe chronic obstructive airways disease. Benzodiazepines potentiate the effects of other central nervous system depressants, including alcohol. Management: 1. Maintain a clear airway and adequate ventilation if indicated. 2. The benefit of gastric decontamination is uncertain. Consider activated charcoal (50g for an adult, 10-15g for a child) in adults or children who have taken more than 0.4mg/kg within 1 hour, provided they are not too drowsy. 3. Gastric lavage is unnecessary if these drugs have been taken alone. 4. Patients who are asymptomatic at 4 hours are unlikely to develop symptoms. 5. Supportive measures as indicated by the patient's clinical state. 6. Flumazenil (Anexate), a benzodiazepine antagoinist is available but should rarely be required. It has a short half-life (about an hour). Flumazenil is NOT TO BE USE IN MIXED OVERDOSE OR AS A DIAGNOSTIC TEST (see separate prescribing information). Warning The use of flumazenil is not recommended in epileptic patients who have been receiving benzodiazepine treatment for a prolonged period. Although flumazenil exerts a slight intrinsic anticonvulsant effect, its abrupt suppression of the protective effect of a benzodiazepine agonist can give rise to convulsions in epileptic patients. If excitation occurs, barbiturates should not be used.

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5.1

PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
ATC code: N03AE01 Clonazepam exhibits pharmacological properties which are common to benzodiazepines and include anticonvulsive, sedative, muscle relaxing and anxiolytic effects. 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 absence seizures (petit mal), slow spike wave,

generalised spike wave, spikes with temporal or other locations as well as irregular spikes and waves. Generalised EEG abnormalities are more readily suppressed by clonazepam than are focal EEG abnormalities such as focal spikes. Clonazepam has beneficial effects in generalised and focal epilepsies.

5.2

Pharmacokinetic properties
Absorption Clonazepam is quickly and completely absorbed after oral administration. Peak plasma concentrations are reached in most cases within 1 - 4 hours after an oral dose. Bioavailability is 90% after oral administration. Routine monitoring of plasma concentrations of clonazepam is of unproven value since this does not appear to correlate well with either therapeutic response or sideeffects. Distribution The mean volume of distribution of clonazepam is estimated at about 3 l/kg. Clonazepam must be assumed to cross the placental barrier and has been detected in maternal milk. Metabolism The biotransformation of clonazepam involves oxidative hydroxylation and reduction of the 7-nitro group by the liver with formation of 7-amino or 7-acetylamino compounds, with trace amounts of 3-hydroxy derivatives of all three compounds, and their glucuronide and sulphate conjugates. The nitro compounds are pharmacologically active, whereas the amino compounds are not. Within 4 - 10 days 50 - 70% of the total radioactivity of a radiolabelled 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. Elimination The elimination half-life is between 20 and 60 hours (mean 30 hours). Pharmacokinetics in special clinical situations Based on kinetic criteria no dose adjustment is required in patients with renal failure.

5.3

Preclinical safety data
In preclinical murine studies there was at least a two fold increase in teratogenic birth defects at dose levels of 3, 9 and 18 times the human therapeutic dose compared to the controls.

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6.1

PHARMACEUTICAL PARTICULARS
List of excipients
Lactose monohydrate

Magnesium stearate Cellulose microcrystalline Sodium starch glycolate

6.2

Incompatibilities
Not applicable.

6.3

Shelf life 3 Years.

6.4

Special precautions for storage
Store in the original package.

6.5

Nature and contents of container
PVC/PVDC/aluminium blister pack. Pack size: 100 tablets

6.6

Special precautions for disposal and other handling
None.

7.

MARKETING AUTHORISATION HOLDER

Auden Mckenzie (Pharma Division) Ltd Mckenzie House Bury Street Ruislip Middlesex HA4 7TL UK 8 MARKETING AUTHORISATION NUMBER(S)
PL 17507/0080

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DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10/03/2008

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DATE OF REVISION OF THE TEXT
15/06/2011

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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