This information is intended for use by health professionals

1. Name of the medicinal product

Clobazam Atnahs 5mg/5ml Oral Suspension

Clobazam Atnahs 10mg/5ml Oral Suspension

2. Qualitative and quantitative composition

Each 5 ml of suspension contains 5 mg or 10mg of clobazam

Excipients with known effect

Each 5 ml of suspension contains 875mg of sorbitol, 15.25mg of sodium, 10.25mg of sodium methyl parahydroxybenzoate (E219) and 1.12mg of sodium propyl parahydroxybenzoate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical form

Oral Suspension

An off white viscous 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

Posology

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

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

Adults

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

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.

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, regardless of the age group of the patient.

Method of administration

For oral use only.

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

4.3 Contraindications

Clobazam must not be used:

• In patients with hypersensitivity to benzodiazepines or any of the excipients of Clobazam Oral Suspension 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 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.

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 psychological 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 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.

Serious Skin Reaction

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 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).

Excipient warnings in the formulation

Clobazam Oral Suspension contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine.

The medicine also contains sodium methyl and propyl parahydroxybenzoates which may cause allergic reactions. The signs may include a rash, swallowing or breathing problems and swelling of the lips, face, throat or tongue.

Sodium - contains 3.05 mg/ml. this should be taken into account by patients on a low sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

Alcohol

Concomitant consumption of alcohol can increase the bioavailability of clobazam by 50% (please refer to Section 5.2) and therefore increase the effects of clobazam e.g. sedation (please refer to section 4.5). This affects the ability to drive or use machines.

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.

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-desmethylclobazam.

Muscle relaxants

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

Narcotic analgesics

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

MAOIs

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.

CYP2C19 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).

CYP2D6 substrates

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.

In the post-marketing safety database, limited data on exposed pregnancies are available with clobazam. Some of those cases reported fatal or neonatal disorders.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. In animal studies, no congenital malformations have been found in mice, rats and rabbits.

Administration of clobazam before or during childbirth can result in the occurrence of respiratory depression (including respiratory distress and apnea), which may be associated with other disorders such as sedation signs, hypothermia, hypotonia, and feeding difficulties in the new born (signs and symptoms of the so-called “floppy infant syndrome”).

In the later stages of pregnancy, it must only be used if there are compelling indications.

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 for developing withdrawal symptoms in the postnatal period. Appropriate monitoring of the new-born in the postnatal period is recommended.

Woman of childbearing potential

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.

Breast Feeding

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

Fertility

No effects on fertility were observed in animals (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

Nervous system disorders

Clobazam may cause sedation, leading to fatigue and sleepiness, especially at the beginning of treatment and when higher doses are used. Slowing of reaction time, drowsiness, numbed emotions, confusion, headaches, dizziness, muscle weakness, ataxia or a fine tremor of the fingers may occur.

Slowed or indistinct speech (disorders of articulation), unsteadiness of gait and other motor functions or loss of libido may occur. Such reactions occur particularly with high doses or in long-term treatment, and are reversible.

After prolonged use of benzodiazepines, impairment of consciousness, sometimes combined with respiratory disorders, may occur in very rare cases, particularly in elderly patients: these effects sometimes persist 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

Especially in the elderly and in children, paradoxical reactions, may occur such as restlessness, irritability, difficulty in falling asleep or sleeping through, acute agitation states, anxiety, aggressiveness, delusion, fits of rage, nightmares, hallucinations, psychotic reactions, suicidal tendencies or frequent muscle spasms. 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 (diplopia, nystagmus). 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

Dry mouth, constipation, decreased appetite, nausea.

Skin and subcutaneous tissue disorders

Cutaneous reactions, such as rash or urticarial 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 the Yellow Card Scheme at 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

Pharmacotherapeutic group: Anxiolytics, Benzodiazepine derivates, ATC code: N05BA09

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 peak plasma level of clobazam after oral administration of Clobazam Oral Suspension 10mg/5ml was similar to that observed after administration of a reference 10 mg tablet in a single dose, randomised, crossover bioequivalence study (mean Cmax 238.52 ± 59.43 ng/ml and 243.25 ± 54.34 ng/ml, respectively).

Concomitant intake of alcohol can increase the bioavailability of clobazam by 50%.

Distribution

After a single dose of 20 mg clobazam, marked inter individual 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 metabolisers exhibit a 5-fold higher plasma concentration of N-CLB compared to extensive metabolisers.

Clobazam is a weak CYP2D6 inhibitor. Co-administration 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.

Elderly

Hepatic metabolism decreases and total clearance decreases with increasing concentrations at equilibrium, it is important to reduce the dose.

Hepatic Impairment

There is a decrease in total clearance.

5.3 Preclinical safety data

Repeat dose toxicity

In chronic toxicity studies in rats with daily oral clobazam administration of 12-1000 mg/kg, spontaneous activity was dose-dependently reduced, whereas respiratory depression and hypothermia were observed at the high dose level. Dose-dependent sedation, somnolence, ataxia and tremor were initially evident in dogs receiving daily oral doses of 2.5-80 mg/kg clobazam, which almost completely reversed in the course of the study. Similar dose-dependent effects were noted in monkeys after daily oral administration of 2.5-20 mg/kg.

Reproduction toxicity

In reproductive toxicity studies in rats and mice clobazam was reported to be without teratogenic or fertility disturbing effect (see section 4.6).

Genotoxicity and carcinogenicity

Clobazam is not genotoxic or tumorigenic. Follicular cell adenoma was significantly increased in rats at the 100 mg/kg clobazam high dose. In contrast to other species (mouse, dog, monkey), clobazam is known to activate the thyroid gland in rats like other benzodiazepine-containing agents. No effects on human thyroid function were noted at clinically relevant doses (20-80 mg).

6. Pharmaceutical particulars
6.1 List of excipients

Sorbitol (E420)

Xanthan Gum (E415)

Acesulfame Potassium (E950)

Raspberry Flavour

Sodium Propyl parahydroxybenzoate (E217)

Sodium Methyl parahydroxybenzoate (E219)

Disodium Hydrogen Phosphate Dihydrate (for pH-adjustment)

Sodium Dihydrogen Phosphate Dihydrate (for pH-adjustment)

Purified Water

6.2 Incompatibilities

None.

6.3 Shelf life

Unopened: 2 years.

Once opened: 28 days

6.4 Special precautions for storage

Do not store above 25°C. Keep the bottle in the outer carton in order to protect from light.

6.5 Nature and contents of container

Amber glass bottles sealed with tamper evident, child resistant plastic screw caps.

Each pack also contains a 5ml oral syringe (polypropylene body, HDPE plunger) graduated every 0.5ml, syringe adapter (LDPE) and 30ml measuring cup (polypropylene) graduated every 5ml.

Pack sizes: 150ml.

6.6 Special precautions for disposal and other handling

This product may settle during storage. Please shake the bottle thoroughly before use.

7. Marketing authorisation holder

Atnahs Pharma UK Limited

Sovereign House

Miles Gray Road

Basildon

Essex

SS14 3FR

United Kingdom

8. Marketing authorisation number(s)

Clobazam Atnahs 5mg/5ml Oral Suspension: PL 43252/0010

Clobazam Atnahs 10mg/5ml Oral Suspension: PL 43252/0011

9. Date of first authorisation/renewal of the authorisation

22/11/2016

10. Date of revision of the text

22/11/2016