SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL    PRODUCT

Clobazam Auden 10mg Tablets

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Clobazam 10 mg

Clobazam 10mg Tablets contain lactose. For fUll list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablet

White to off-white, circular tablet, one-side scored and the other marked ‘CB 10’.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Clobazam is a 1,5-benzodiazepine indicated for the short-term relief (2-4 weeks) only of anxiety that is severe, disabling or subjecting the individual to unacceptable distress, occurring alone or in association with insomnia or short term psychosomatic, organic or psychotic illness. The use of clobazam to treat short-term “mild” anxiety is inappropriate and unsuitable.

Before treatment of anxiety states associated with emotional instability, it must first be determined whether the patient suffers from a depressive disorder requiring adjunctive or different treatment. Indeed, in patients with anxiety associated with depression, clobazam must be used only in conjunction with adequate concomitant treatment. Use of benzodiazepine (such as clobazam) alone, can precipitate suicide in such patients.

In patients with schizophrenic or other psychotic illnesses, use of benzodiazepines is recommended only for adjunctive, i.e. not for primary treatment.

Clobazam may be used as adjunctive therapy in epilepsy.

4.2    Posology and method of administration

Treatment of anxiety

The usual anxiolytic dose for adults is 20-30mg daily in divided doses or as a single dose given at night. Doses up to 60mg daily have been used in the treatment of adult in-patients with severe anxiety.

The lowest dose that can control symptoms should be used. After improvement of the symptoms, the dose may be reduced.

It should not be used for longer than 4 weeks. Long term chronic use as an anxiolytic is not recommended. In certain cases, extension beyond the maximum treatment period may be necessary; treatment must not be extended without re-evaluation of the patient's status using special expertise. It is strongly recommended that prolonged periods of uninterrupted treatment be avoided, since they may lead to dependence. Treatment should always be withdrawn gradually. Patients who have taken Clobazam for a long time may require a longer period during which doses are reduced.

Anxiolytic treatment should be limited to the lowest possible dose for the shortest possible time (see CSM advice). Dependence is particularly likely in patients with a history of alcohol or drug abuse and in patients with marked personality disorders.

CSM advice:

1.    Benzodiazepines are indicated for the short-term relief (two to four weeks only) of anxiety that is severe, disabling or subjecting the individual to unacceptable distress, occurring alone or in association with insomnia or short-term psychosomatic, organic or psychotic illness.

2.    Benzodiazepines should be used to treat insomnia only when it is severe, disabling, or subjecting the individual to extreme distress.

Withdrawal of a benzodiazepine should be gradual because abrupt withdrawal may produce confusion, toxic psychosis, convulsions, or a condition resembling delirium tremens. The benzodiazepine withdrawal syndrome may develop at any time up to 3 weeks after stopping a long-acting benzodiazepine, but may occur within a few hours in the case of a short-acting one. It is characterised by insomnia, anxiety, loss of appetite and of body-weight, tremor, perspiration, tinnitus, and perceptual disturbances. These symptoms may be similar to the original complaint and encourage further prescribing; some symptoms may continue for weeks or months after stopping benzodiazepines.

A benzodiazepine can be withdrawn in steps of about one-eighth (range one-tenth to one-quarter) of the daily dose every fortnight. A suggested withdrawal protocol for patients who have difficulty is as follows:

1.    Transfer patient to equivalent daily dose of diazepam preferably taken at night

2.    Reduce diazepam dose in fortnightly steps of 2 or 2.5mg; if withdrawal symptoms occur, maintain this dose until symptoms improve

3.    Reduce dose further, if necessary in smaller fortnightly steps; it is better to reduce too slowly rather than too quickly

4.    Stop completely; time needed for withdrawal can vary from about 4 weeks to a year or more

Counselling may help; beta-blockers should only be tried if other measures fail; antidepressants should be used only for clinical depression or for panic disorder; avoid antipsychotics (which may aggravate withdrawal symptoms).

Elderly: Doses of 10-20mg daily in anxiety may be used in the elderly, who are more sensitive to the effects of psychoactive agents. Treatment requires low initial doses and gradual dose increments under careful observation.

Treatment of epilepsy in association with one or more other anticonvulsants

By mouth

Adults: In epilepsy a starting dose of 20-30mg daily is recommended, increasing as necessary up to a maximum of 60mg daily.

Adjunctive therapy for epilepsy

Monotherapy under specialist supervision for catamenial (menstruation) seizures (usually for 7-10 days just before and during menstruation)

Cluster seizures

Paediatric patients aged 6years and above:

When prescribed for children treatment requires low initial doses and gradual dose increments under careful observation. It is recommended that normally treatment should be started at 5mg daily. A maintenance dose of 0.3 to 1mg/kg body weight daily is usually sufficient.

As there is no age appropriate formulation to enable safe and accurate dosing, no dosage recommendations can be made in children under 6 years of age.

Tablets should be swallowed without chewing with sufficient amount of liquid (1/2 glass)

The patient must be re-assessed after a period not exceeding 4 weeks and regularly thereafter in order to evaluate the need for continued treatment. A break in therapy may be beneficial if drug exhaustion develops, recommencing therapy at a low dose. At the end of treatment (including in poor-responding patients), since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended to gradually decrease the dosage.

4.3 Contraindications

Clobazam 10mg Tablets must not be used:

-    in patients with hypersensitivity to benzodiazepines or any of the excipients of Clobazam 10 mg Tablets - see section 6.1

-    In patients with any history of drug or alcohol dependence (increased risk of development of dependence).

-    In patients with myasthenia gravis (risk of aggravation of muscle weakness).

-    In patients with severe respiratory insufficiency (risk of deterioration).

-    In patients with sleep apnoea syndrome (risk of deterioration).

-    In patients with severe hepatic insufficiencies (risk of precipitating encephalopathy).

-    During the first trimester of pregnancy (for use during second and third trimester, see section 4.6 Pregnancy and Lactation).

-    In breast-feeding women.

Benzodiazepines must not be given to children without careful assessment of the need

for their use. Clobazam must not be used in children between the ages of 6 months

and 3 years, other than in exceptional cases for anticonvulsant treatment where there

is a compelling indication.

4.4 Special warnings and precautions for use

•    Amnesia

Amnesia may occur with benzodiazepines. In case of loss or bereavement psychological adjustment may be inhibited by benzodiazepines.

Special caution is necessary if clobazam is used in patients with myasthenia gravis, spinal or cerebellar ataxia or sleep apnoea. A dose reduction may be necessary.

•    Muscle weakness

Clobazam can cause muscle weakness. Therefore, in patients with pre-existing muscle weakness or spinal or cerebellar ataxia or sleep apnoea, special observation is required and a dose reduction may be necessary. Clobazam is contraindicated in patients with myasthenia gravis.

•    Depression and personality disorders

Disinhibiting effects may be manifested in various ways. Suicide may be precipitated in patients who are depressed and aggressive behaviour towards self and others may be precipitated. Extreme caution should therefore be used in prescribing benzodiazepines in patients with personality disorders.

•    Dependence

Use of benzodiazepines - including clobazam - may lead to the development of physical and psychic dependence upon these products. The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a history of alcohol or drug abuse. Therefore the duration of treatment should be as short as possible (see Posology).

Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms (or rebound phenomena). Rebound phenomena are characterised by a recurrence in enhanced form of the symptoms which originally led to clobazam treatment. This may be accompanied by other reactions including mood changes, anxiety or sleep disturbances and restlessness.

A withdrawal syndrome may also occur when abruptly changing over from a benzodiazepine with a long duration of action (for example, Clobazam) to one with a short duration of action.

•    Respiratory Depression

Respiratory function should be monitored in patients with chronic or acute severe respiratory insufficiency and a dose reduction of clobazam may be necessary.

•    Renal and hepatic impairment

In patients with impairment of renal or hepatic function, responsiveness to clobazam and susceptibility to adverse effects are increased, and a dose reduction may be necessary. In long-term treatment renal and hepatic function must be checked regularly.

•    Elderly patients

In the elderly, due to the increased sensitivity to adverse reactions such as drowsiness, dizziness, muscle weakness, there is an increased risk of fall that may result in serious injury. A dose reduction is recommended.

•    Tolerance in epilepsy

In the treatment of epilepsy with benzodiazepines - including clobazam -consideration must be given to the possibility of a decrease in anticonvulsant efficacy (development of tolerance) in the course of treatment.

•    CYP2C19 poor metabolisers

In patients who are CYP2C19 poor metabolisers, levels of the active metabolite N-desmethylclobazam are expected to be increased as compared to extensive metabolisers. As this may lead to increased side effects, dosage adjustment of clobazam may be necessary (e.g. low starting dose with careful dose titration (please refer to section 5.2)).

•    Alcohol

It is recommended that patients abstain from drinking alcohol during treatment with clobazam (increased risk of sedation and other adverse effects) (please refer to section 4.5).

Clobazam 10mg Tablets contain lactose; patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

•    Central nervous system depressant drugs

Especially when clobazam is administered at higher doses, an enhancement of the central depressive effect may occur in cases of concomitant use with antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressant agents, narcotic analgesics, anticonvulsant drugs, anaesthetics and sedative antihistamines. Special caution is also necessary when clobazam is administered in cases of intoxication with such substances or with lithium.

•    Alcohol

Concomitant consumption of alcohol can increase the bioavailability of clobazam by 50% and therefore increase the effects of clobazam (e.g.; sedation). This affects the ability to drive or use machines.

•    Anticonvulsants

Addition of clobazam to established anticonvulsant medication (e.g., phenytoin, valproic acid) may cause a change in plasma levels of these drugs. If used as an adjuvant in epilepsy the dosage of Clobazam should be determined by monitoring the EEG and the plasma levels of the other drugs checked.

Phenytoin and carbamazepine may cause an increase in the metabolic conversion of clobazam to the active metabolite N-desmethyl clobazam. Stiripentol increases plasma levels of clobazam and its active metabolite N-desmethylclobazam, through inhibition of CYP3A and CYP2C19. Monitoring of blood levels is recommended, prior to initiation of stiripentol, and then once new steady-state concentration has been reached, i.e. after 2 weeks approximately.

•    Narcotic analgesics

If clobazam is used concomitantly with narcotic analgesics, possible euphoria may be enhanced; this may lead to increased psychological dependence.

•    Muscle relaxants

The effects of muscle relaxants, analgesics and nitrous oxide may be enhanced.

•    CYP 2C19 inhibitors

Strong and moderate inhibitors of CYP2C19 may result in increased exposure to N-desmethylclobazam (N-CLB), the active metabolite of clobazam. Dosage adjustment of clobazam may be necessary when co-administered with strong (e.g. fluconazole, fluvoxamine, ticlopidine) or moderate (e.g. omeprazole) CYP2C19 inhibitors (please refer to Section 5.2).

•    CYP 2D6 substrates

Clobazam is a weak CYP2D6 inhibitor. Dose adjustment of drugs metabolized by CYP2D6 (e.g. dextromethorphan, pimozide, paroxetine, nebivolol may be necessary.

Concurrent treatment with drugs that inhibit the cytochrome P-450 enzyme (mono-oxygenase) system (e.g. cimetidine) may enhance and prolong the effect of clobazam.

4.6 Pregnancy and lactation

If the product is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding discontinuation of the product if she intends to become pregnant or suspects that she is pregnant.

If, for compelling medical reasons, the product is administered during the late phase of pregnancy, or during labour at high doses, effects on the neonate such as hypothermia, hypotonia, moderate respiratory depression and difficulties in drinking (signs and symptoms of so-called “floppy infant syndrome”), can be expected due to the pharmacological action of the compound.

Moreover, infants born to mothers who took benzodiazepines during the latter stage of pregnancy may have developed physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period. Appropriate monitoring of the newborn in the postnatal period is recommended.

Since benzodiazepines are found in the breast milk, benzodiazepines should not be given to breast feeding mothers.

4.7 Effects on ability to drive and use machines

Sedation, amnesia, impaired concentration and impaired muscular function may adversely affect the ability to drive or to use machines. If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased (see also Interactions).

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

-    The medicine is likely to affect your ability to drive

-    Do not drive until you know how the medicine affects you

-    It is an offence to drive while under the influence of this medicine

-    However, you would not be committing an offence (called ‘statutory defence’) if:

o The medicine has been prescribed to treat a medical or dental problem and o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and o It was not affecting your ability to drive safely

4.8 Undesirable effects

Nervous system disorders

Clobazam may cause sedation, leading to fatigue and sleepiness, especially at the beginning of treatment and when higher doses are used. Side-effects such as slowing of reaction time, muscle weakness, ataxia, confusion, drowsiness, dizziness, numbed emotions and headaches, or a fine tremor of the fingers have been reported. These are more likely to occur at the beginning of treatment and often disappear with continued treatment or a reduction in dose.

Disorders of articulation, unsteadiness of gait and other motor functions, or loss of libido may occur, particularly with high doses or in long-term treatment. These reactions are reversible.

After prolonged use of benzodiazepines, impairment of consciousness, sometimes combined with respiratory disorders, has been reported in very rare cases, particularly in elderly patients: it sometimes persists for some length of time. These disorders have not been seen so far under clobazam treatment.

Anterograde amnesia may occur, especially at higher dose levels. Amnesia effects may be associated with inappropriate behaviour.

Psychiatric disorders

Paradoxical reactions, such as restlessness, irritability, difficulty in falling asleep or sleeping through, acute agitational states, , anxiety, aggressiveness , delusion, fits of rage, nightmare, hallucinations, psychotic reactions suicidal tendencies or frequent muscle spasms may occur, especially in elderly and in children. In the event of such reactions, treatment with clobazam must be discontinued.

Pre-existing depression may be unmasked during benzodiazepine use.

Tolerance and physical and/or psychic dependence may develop, especially during prolonged use. Discontinuation of the therapy may result in withdrawal or rebound phenomena (see Warnings and Precautions). Abuse of benzodiazepines has been reported.

When used as an adjuvant in the treatment of epilepsy, this preparation may in rare cases cause restlessness and muscle weakness.

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

Eye disorders

Visual disorders (e.g., double vision). Such reactions occur particularly with high doses or in long-term treatment, and are reversible.

Respiratory, thoracic and mediastinal disorders

Clobazam may cause respiratory depression, especially if administered in high doses. Therefore, particularly in patients with pre-existing compromised respiratory function (i.e., in patients with bronchial asthma) or brain damage, respiratory insufficiency may occur or deteriorate.

Gastrointestinal disorders

Dryness of the mouth, constipation, loss of appetite, nausea

Skin and subcutaneous tissue disorders

Cutaneous reactions, such as rash or urticaria may develop in very rare cases. Stevens-Johnson syndrome, Toxic Epidermal Necrolysis

Metabolism and nutrition disorders

Weight gain, may occur particularly with high doses or in long-term treatment. This reaction is reversible.

General disorders

Fall

Reporting of Suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme, Website:www.mhra.gov.uk/yellowcard

4.9 Overdose

Overdose of benzodiazepines is usually manifested by degrees of central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, mental confusion and lethargy, in more serious cases, symptoms may include ataxia, hypotonia, hypotension, respiratory depression, rarely coma and very rarely death. As with other benzodiazepines, overdose should not present a threat to life unless combined with other CNS depressants (including alcohol).

In the management of overdose, it is recommended that the possible involvement of multiple agents be taken into consideration.

Following overdose with oral benzodiazepines, vomiting should be induced (within one hour) if the patient is conscious, or gastric lavage undertaken with the airway protected if the patient is unconscious. If there is no advantage in emptying the stomach, activated charcoal should be given to reduce absorption. Special attention should be paid to respiratory and cardiovascular functions in intensive care.

Secondary elimination of clobazam (by forced diuresis or haemodialysis) is ineffective.

Consideration should be given to the use of flumazenil as a benzodiazepine antagonist.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

ATC Code: N05BA09 (Nervous System, Psycholeptics, Anxiolytics, Benzodiazepine derivatives, Clobazam)

Clobazam is a 1,5-benzodiazepine. In single doses up to 20mg or in divided doses up to 30mg, clobazam does not affect psychomotor function, skilled performance, memory or higher mental functions.

5.2    Pharmacokinetic properties

Absorption of clobazam is virtually complete after oral administration. Approximately 85% is protein bound in man. It is metabolised by demethylation and hydroxylation. It is excreted unchanged and as metabolites in the urine (87%) and faeces.

5.3    Preclinical safety data

None applicable

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose monohydrate

Cellulose microcrystalline Sodium starch glycolate Talc

Magnesium stearate.

6.2    Incompatibilities

None known

6.3    Shelf life

3 years

6.4    Special precautions for storage

The medicinal product does not require any special storage instructions.