CLOBAZAM TENPHARMA 10 MG / 5ML ORAL SUSPENSION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Clobazam TenPharma 10 mg/5mL Oral Suspension

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of oral suspension contains 2 mg of clobazam

Each 5 ml of oral suspension contains 10 mg of clobazam

Excipient(s) with known effect:

Each 5 ml of suspension contains

Sodium methyl parahydroxybenzoate (E219): 5.31 mg

Sodium propyl parahydroxybenzoate (E217): 0.566 mg

Liquid Maltitol (E965): 1500 mg

This medicinal product contains 0.628mmol (or 14.4 mg) sodium per 5ml dose.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Oral Suspension

A uniform white to off-white suspension with an odour of raspberry.

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

If low doses are required, the 5 mg/5ml strength product is the more suitable presentation. If high doses are required, the 10 mg/5ml strength product is the more suitable presentation.

Posology

Treatment of anxiety

Adults:

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 clobazam for a long time may require a longer period during which doses are reduced.

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.

Treatment of epilepsy in association with one or more other anticonvulsants

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.

Adults:

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

Elderly:

Treatment requires low initial doses and gradual dose increments under careful observation.

Paediatric patients aged 6 years and over:

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 5 mg daily. A maintenance dose of 0.3 to 1mg/kg body weight daily is usually sufficient.

No dosage recommendations can be made in children under 6 years of age.

Hepatic and renal failure

Treatment requires low initial doses and gradual dose increments under careful observation (please refer to section 4.3 Contraindi­cations and section 4.4 Renal and hepatic impairment sub-section).

Method of administration

For oral use only.

Once titrated to an effective lowest dose of clobazam, patients should remain on their treatment and care should be exercised when changing between different formulations.

The oral suspension is particularly recommended for children and adults with swallowing difficulties, as it allows a secure and precise dosage.

Invert the bottle two or three times before use.

Can be taken with or without food. It is recommended that the dose be followed with a glass (approximately 200ml) of water.

4.3 Contraindi­cations

Clobazam must not be used:

– In patients with hypersensitivity to benzodiazepines or any of the excipients listed in 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).

– 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

In some individuals taking clobazam, the drug reaches higher plasma levels than the same dose taken as a tablet. This may lead to an increased risk of respiratory depression and sedation which may be most noticeable when switching to this medicine from tablets. Therefore, caution must be taken when switching between clobazam products as the mean Cmax on single dose administration for the suspension is higher than that observed for the tablet formulation.

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 alone, can precipitate suicide in such patients.

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

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.

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 section 4.2).

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 to one with a short duration of action.

Serious skin reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported with clobazam in both children and adults during the post-marketing experience. A majority of the reported cases involved the concomitant use of other drugs, including antiepileptic drugs that are associated with serious skin reactions.

SJS/TEN could be associated with a fatal outcome. Patients should be closely monitored for signs or symptoms of SJS/TEN, especially during the first 8 weeks of treatment. Clobazam should be immediately discontinued when SJS/TEN is suspected. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered (see section 4.8).

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

Clobazam is contraindicated in patients with severe respiratory insufficiency (see section 4.3).

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 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.

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.

Benzodiazepines are not recommended for the primary treatment of psychotic illness.

Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines. (See section 4.8). Should this occur, use of the medicinal product should be discontinued.

They are more likely to occur in children and the elderly.

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 clobazam.

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.

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 (see 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) (see section 4.5)

Concomitant use of opioids and benzodiazepines, including clobazam, may result in sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of opioids and benzodiazepines for use in patients for whom alternative treatment options are inadequate.

If a decision is made to prescribe clobazam concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation (see section 4.5).

The medicine contains:

Sodium methyl parahydroxybenzoate and sodium propyl parahydroxyben­zoate: May cause allergic reactions (possibly delayed).

Sodium: This medicinal product contains 2.9 mg sodium per mL, equivalent to 0.1% of the WHO recommended maximum daily intake of 2g sodium for an adult.

Liquid Maltitol: Patients with rare hereditary problems of fructose intolerance should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant consumption of alcohol can increase the bioavailability of clobazam by 50% (see Section 5.2) and therefore increase the effects of clobazam e.g. sedation (see section 4.7). This affects the ability to drive or use machines. Benzodiazepines, including clobazam, should be used with extreme caution in patients with a history of alcohol or drug abuse.

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.

The concomitant use of benzodiazepines, including clobazam, and opioids increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. Limit dosage and duration of concomitant use of benzodiazepines and opioids (see section 4.4).

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 of clobazam and active metabolite is recommended, prior to initiation of stiripentol, and then once new steady-state concentration has been reached, i.e. after 2 weeks approximately. Clinical monitoring is recommended and dose adjustment may be necessary.

Concomitant administration of drugs, inhibit the monooxygenase system, such as cimetidine and erythromycin, can enhance the effects of clobazam.

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

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

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 (see Section 5.2).

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

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 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 apnea), 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 must 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

Clobazam has major influence on the 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 section 4.5).

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

5   PHARMACOLOGICAL PROPERTIES

Hepatic metabolism decreases and total clearance with increasing concentrations at equilibrium, the free-fraction and half-lives. It is important to reduce the dose.

There is a decrease in total clearance.

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.

6.1 List of excipients

Purified water

Liquid Maltitol (E965)

Disodium phosphate dihydrate (E339)

Citric acid monohydrate (E330)

Xanthan gum (E415)

Sodium methyl parahydroxybenzoate (E219)

Raspberry flavour

Acesulfame potassium (E950)

Sodium propyl parahydroxybenzoate (E217)

6.2 Incompati­bilities

In the absence of compatibility studies, this product must not be mixed with other medicinal products or beverages.

6.3

6.4

Shelf life

Unopened: 3 years

After first opening: 28 days

Special precautions for storage

Do not store above 25°C.

Do not freeze.

Keep the bottle in the outer carton in order to protect from light.

6.5 Nature and contents of container

Amber glass bottle (Type III glass) containing 150 ml, closed with a tamper evident, child-resistant screw cap with polyethylene liner.

The bottle is supplied with a CE-marked 5 ml dosing pipette (oral syringe) made from PP and HDPE (with 0.2 ml graduations), and a separate LDPE ‘bung’ adaptor which is fitted to the neck of the bottle at first use (i.e. after opening), to ensure proper use of the dosing pipette.

Where higher doses are to be administered, dosing cups should be considered.

6.6 Special precautions for disposal

Invert the bottle two or three times before use.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

BCM Specials Limited trading as Ten Pharma

1 Thane Road West,

Nottingham,

England, NG2 3AA,

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 34777/0007

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

02/07/2021