Frisium^TM

Clobazam 10 mg.

Tablet

Frisium 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 Frisium 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, Frisium must be used only in conjunction with adequate concomitant treatment. Use of benzodiazepine (such as Frisium) 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.

Frisium may be used as adjunctive therapy in epilepsy.

Treatment of anxiety

The usual anxiolytic dose for adults is 20-30 mg 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 Treatment should always be withdrawn gradually.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 Frisium for a long time may require a longer period during which doses are reduced.

Treatment of epilepsy in association with one or more other anticonvulsants

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

Elderly:

Doses of 10-20 mg 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.

Children:

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.

Frisium must not be used:

− In patients with hypersensitivity to benzodiazepines or any of the excipients of Frisium.

− 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. Frisium 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.

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.

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.

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, Frisium) to one with a short duration of action.

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

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.

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.

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.

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.

Addition of clobazam to established anticonvulsant medication (eg, phenytoin, valproic acid) may cause a change in plasma levels of these drugs. If used as an adjuvant in epilepsy the dosage of Frisium 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.

The effects of muscle relaxants, analgesics and nitrous oxide may be enhanced. If clobazam is used concomitantly with narcotic analgesics, possible euphoria may be enhanced; this may lead to increased psychological dependence.

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

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.

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

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).

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 drowsiness, dizziness or dryness of the mouth, constipation, loss of appetite, nausea, 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.

Paradoxical reactions, such as restlessness, irritability, difficulty in sleeping, anxiety, delusion, nightmare, hallucinations or suicidal tendencies may occur, especially in elderly and in children. In the event of such reactions, treatment with clobazam must be discontinued.

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

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.

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

Slowing of reaction time, ataxia, confusion and headaches may occasionally occur.

Disorders of articulation, unsteadiness of gait and other motor functions, visual disorders (e.g., double vision), weight gain, or loss of libido may occur, particularly with high doses or in long-term treatment. These reactions are reversible.

Pre-existing depression may be unmasked during benzodiazepine use.

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.

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.

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.

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.

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.

None applicable

Lactose monohydrate, maize starch, colloidal silicon dioxide, talc, magnesium stearate.

None.

Five years.

Store below 25°C.

Blister pack (Alufoil/PVC) containing 30 tablets.

None.

Sanofi-aventis

One Onslow Street

Guildford

Surrey

GU1 4YS

PL 04425/0214

15 January 2002

April 2011

POM