CLOBAZAM ACCORD 10 MG TABLETS - summary of medicine characteristics

Clobazam Accord 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 Treatment should always be withdrawn gradually.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 onetenth 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 6 years 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). Tablets can be administered whole, or crushed and mixed in apple sauce (see section 5.2). Clobazam can be given with or without food.

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. 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 (see section 4.2).

4.4 Special warnings and precautions for use Amnesia

CYP2C19 poor metabolisers

4.5 Interaction with other medicinal products and other forms of interaction Central nervous system depressant drugs

4.6 Fertility, pregnancy and lactation

Pregnancy

There are limited amount of data from the use of clobazam in pregnant women.

Nevertheless, a large amount of data collected from cohort studies has not demonstrated evidence of the occurrence of major malformations following exposure to benzodiazepines during the first trimester of pregnancy, although incidence of cleft lip and palate were observed in case-control studies.

Clobazam is not recommended during pregnancy and in women of childbearing potential not using contraception.

Clobazam crosses the placenta. Animal studies have demonstrated reproductive toxicity (see section 5.3).

Women of childbearing potential should be informed of the risks and benefits of the use of clobazam during pregnancy.

Women of childbearing potential should be informed to contact her physician regarding discontinuation of the product if they are pregnant or intend to become pregnant. If clobazam treatment is to be continued, use clobazam at the lowest effective dose.

Cases of reduced fetal movement and fetal heart rate variability have been described after administration of benzodiazepines during the second and/or third trimester of pregnancy.

If clobazam is administered during the late phase of pregnancy or during childbirth effects on the neonate, such as respiratory depression (including respiratory distress and apnoea), sedation signs, hypothermia, hypotonia, and feeding difficulties in the newborn (so-called “floppy infant syndrome”) are to be expected.

Moreover, infants born to mothers who have taken benzodiazepines over longer periods during the later stages of pregnancy may have developed physical dependence and may be at risk of developing a withdrawal syndrome in the postnatal period. Appropriate monitoring of the newborn in the postnatal period is recommended.

Breast-feeding

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

Fertility

No clinical data on fertility are available. In a fertility study in male and female rats no effect on fertility was observed (see section 5.3).

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

The following CIOMS frequency rating is used, when applicable: Very common (> 1/10); common (> 1/100 to < 1/10); uncommon (> 1/1,000 to < 1/100); rare (> 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data).

Metabolism and nutrition disorders

Common: decreased appetite

Psychiatric disorders

Common: irritability, aggression, restlessness, depression (pre-existing depression may be unmasked), drug tolerance (especially during prolonged use) (see section 4.4), agitation

Uncommon: abnormal behaviour, confusional state, anxiety, delusion, nightmare, loss of libido (particularly with high doses or in long-term treatment, and is reversible)

Not known: dependence (especially during prolonged use) (see section 4.4), initial insomnia, anger, hallucinations, psychotic disorder, poor sleep quality, suicidal ideation

Nervous system disorders

Very common: somnolence, especially at the beginning of treatment and when higher doses are used

Common: sedation, dizziness, disturbance in attention, slow speech/dysarthri­a/speech disorder (particularly with high doses or in long-term treatment, and is reversible), headache, tremor, ataxia

Uncommon: numbed emotions, amnesia effects may be associated with abnormal behaviour, memory impairment, anterograde amnesia (in the normal dose range but especially at higher dose levels)

Not known: cognitive disorder, altered state of consciousness (particularly in elderly patients, may be combined with respiratory disorders), nystagmus (particularly with high doses or in long-term treatment), disorders of articulation, gait disturbance and other motor functions (particularly with high doses or in long-term treatment, and are reversible), fine tremor of the fingers more likely to occur at the beginning of treatment and often disappear with continued treatment or a reduction in dose)

Eye disorders

Uncommon: diplopia, (particularly with high doses or in long-term treatment, and is reversible)

Respiratory, thoracic and mediastinal disorders

Not known: respiratory depression, respiratory failure (especially if administered in high doses), particularly in patients with pre-existing compromised respiratory function (e.g. in patients with bronchial asthma or brain damage) (see section 4.3 and 4.4)

Gastrointestinal disorders

Common: dry mouth, nausea, constipation

Skin and subcutaneous tissue disorders

Uncommon: rash

Not known: photosensitivity reaction, urticarial, Stevens-Johnson syndrome, toxic epidermal necrolysis (including some cases with fatal outcome)

Musculoskeletal and connective tissue disorders

Not known: muscle spasms, muscle weakness

General disorders and administration site conditions

Very common: fatigue, especially at the beginning of treatment and when higher doses are used

Uncommon: weight increased (particularly with high doses or in long-term treatment, and is reversible)

Not known: slow response to stimuli, hypothermia

Injury, poisoning and procedural complications

Uncommon: fall

Discontinuation of the therapy may result in withdrawal or rebound phenomena (see section 4.4). 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.

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

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

After oral administration, clobazam is rapidly and extensively absorbed.

Time to peak plasma concentrations (Tmax) is achieved from 0.5 – 4.0 hrs. The administration of clobazam tablets with food or crushed in applesauce slows the rate of absorption by approximately 1 hour, but it does not affect the overall extent of absorption. Clobazam can be given without regard to meals. Concomitant intake of alcohol can increase the bioavailability of clobazam by 50%.

Distribution

After a single dose of 20 mg clobazam, marked interindividual variability in maximum plasma concentrations (222 to 709 ng/ml) was observed after 0.25 to 4 hours. Clobazam is lipophilic and distributes rapidly throughout the body. Based on a population pharmacokinetic analysis, the apparent volume of distribution at steady state was approximately 102 L, and is concentration independent over the therapeutic range. Approximately 80 – 90% of clobazam is bound to plasma protein.

Clobazam accumulates approximately 2–3 fold to steady state while the active metabolite N-desmethylclobazam (N-CLB) accumulates approximately 20 fold following clobazam twice daily administration. Steady state concentrations are reached within approximately 2 weeks.

Metabolism

Clobazam is rapidly and extensively metabolized in the liver. Clobazam metabolism occurs primarily by hepatic demethylation to N-desmethylclobazam (N-CLB), mediated by CYP3A4 and to a lesser extent by CYP2C19. N-CLB is an active metabolite and the main circulating metabolite found in human plasma.

N-CLB undergoes further biotransformation in the liver to form 4-hydroxy-N-desmethylclobazam, primarily mediated by CYP2C19.

CYP2C19 poor metabolizers exhibit a 5-fold higher plasma concentration of N-CLB compared to extensive metabolizers.

Clobazam is a weak CYP2D6 inhibitor. Coadministration with dextromethorphan led to increases of 90% in AUC and 59% in Cmax values for dextromethorphan. Concomitant administration of 400 mg ketoconazole (CYP3A4 inhibitor) increased Clobazam AUC by 54% with no effect on Cmax. These changes are not considered clinically relevant.

Elimination

Based on a population pharmacokinetic analysis, plasma elimination half lives of clobazam and N-CLB were estimated to be 36 hours and 79 hours respectively.

Clobazam is cleared mainly by hepatic metabolism with subsequent renal elimination. In a mass balance study, approximately 80% of the administered dose was recovered in urine and about 11% in the faeces. Less than 1 % of unchanged clobazam and less than 10% of unchanged N-CLB are excreted through the kidneys.

5.3 Preclinical safety data

Teratogenicity

Oral administration of clobazam to pregnant rats and rabbits throughout the period of organogenesis resulted in increased embryofetal mortality and increased incidences of fetal skeletal variations. In rabbits clobazam also decreased fetal body weights and increased the incidence of fetal malformations (visceral and skeletal). Additionally, oral administration of clobazam to rats throughout pregnancy and lactation resulted in decreased pup survival and alterations in offspring behaviour (locomotor activity). The observed embryo-fetal effects were associated with plasma exposures for clobazam and its major active metabolite N-desmethylclobazam less than those in humans at the maximum recommended dose.

Impairment of fertility

A study in rats in which clobazam was orally administered to male and female rats prior to and during mating and continuing in females to gestation day 6 had no effect on fertility and early embryonic development. The study was limited as the highest dose was associated with plasma exposures for clobazam and N-desmethylclobazam less than those in humans at the maximum recommended dose.

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.

6.5 Nature and contents of container

Carton containing 30 tablets in 3 x PVC/aluminium blister strips each of 10 tablets.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Accord Healthcare Limited

Sage House

319 Pinner Road

North Harrow

Middlesex

HA1 4HF

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 20075/0671

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

13/03/2008