PERIZAM 1 MG / ML ORAL SUSPENSION - summary of medicine characteristics

Perizam 1mg/ml Oral Suspension

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of oral suspension contains 1mg Clobazam

Excipient(s) with known effect:

Sodium Methyl parahydroxybenzoate (E219) (1.32mg)

Sodium Propyl parahydroxybenzoate (E217) (0.33mg)

Liquid Maltitol (E965) (0.3g)

Propylene Glycol (E1520) (6.21mg)

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Oral Suspension

An off-white suspension.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Perizam is a 1,5-benzodiazepine indicated in adults for the short-term symptomatic treatment (2–4 weeks) only of anxiety that is severe, disabling or subjecting the individual to unacceptable distress.

In treatment of anxiety states associated with affective disorders, Perizam must only be used in conjunction with adequate treatments for the underlying disorder.

In patients with schizophrenic or other psychotic illnesses, use of benzodiazepines is recommended only for short term symptomatic management of hyperarousal and agitation. Benzodiazepines do not possess antipsychotic properties.

Perizam may be used as adjunctive therapy in epilepsy in adults or children over 2 years, if standard treatment with one or more anticonvulsants has failed: Treatment of simple or complex partial epilepsy with or without secondary generalisation and treatment of all types of generalised epilepsy (tonic/clonic, myoclonic, absence seizures).

4.2 Posology and method of administration

Posology

If low doses are required, the 1mg/ml strength product the most suitable presentation. If high doses are required, the 2mg/ml strength product is the most 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 Perizam for a long time may require a longer period during which doses are reduced.

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

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.

Perizam doses should be adapted individually. Doses can be taken once a day or divided in 2 – 3 times a day, keeping the same total dose.

The patient must be re-assessed after a period not exceeding 4 weeks and every 4 weeks 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.

When prescribed for children treatment requires low initial doses and gradual dose increments under careful observation. Clobazam is typically initiated at a low dose, often 5 mg/day or 0.1 mg/kg/day for younger patients, and increased by step of 0.1 to 0.2 mg/kg/day at 7 days intervals, until a minimum effective dose is reached or side effects occur. Studies have suggested that slow titration may help avoid adverse effects and that when present, side effects may be reduced or eliminated with dose reduction.

The following up-titration regimen has been proposed in the literature in order to take into account the high metabolism variability linked to the P450 system maturation – especially in the presence of inducers and inhibitors – and should be used with increase of the dose by 0.1 to 0.2 mg/kg every week up to the targeted dose.

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

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

Perizam should not be used as an anticonvulsivant treatment in children from 6 months to 2 years old, unless under exceptional situations, when there is a clear epilepsy indication. The starting dose in this exceptional circumstances should be the lowest one (0.1 mg/kg/day) and titration should be even more cautious, not more than 0.1 mg/kg/day as in this population the metabolic pathways for clobazam may not be fully mature. Up-to-date, no precise dosage recommendation can be made in this population.

Treatment requires low initial doses and gradual dose increments under careful observation, regardless of the age group of the patient.

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. (See section 4.4 – Switching between formulations)

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

Perizam can be taken with or without food.

4.3 Contraindications

Perizam must not be used:

– In patients with hypersensitivity to benzodiazepines or any of the excipients of Perizam.

– 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.

– Acute intoxication with alcohol and CNS-active substances.

Benzodiazepines must not be given to children without careful assessment of the need for their use.

Perizam should not be used in children from 6 months to 2 years old, unless under exceptional situations as an anticonvulsivant treatment, when there is a clear epilepsy indication.

4.4 Special warnings and precautions for use

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, Perizam must be used only in conjunction with adequate concomitant treatment. Use of benzodiazepine (such as Perizam) alone, can precipitate suicide in such patients.

In some individuals taking Perizam, 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.

CYP2C19 poor metabolizers

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 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:

The medicine has been prescribed to treat a medical or dental problem and

You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

It was not affecting your ability to drive safely.

4.8 Undesirable effects

The frequencies of adverse events are ranked according to the following:

Very common (> 1/10), Common (>1/100, < 1/10), Uncommon (>1/1000, < 1/100), Rare (>1/10,000, < 1/1000), Very Rare (< 1/10,000), not known (cannot be estimated from the available data).

Uncommon (affects less than 1 in 100 people)

clobazam may cause sedation, leading to fatigue, drowsiness and sleepiness, especially at the beginning of treatment and when higher doses are used. These are more likely to occur at the beginning of treatment and often disappear with continued treatment or a reduction in dose.

slowing of reaction time

dizziness

headache

ataxia

confusion

Rare (affects less than 1 in 1000 people)

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

Very Rare (affects less than 1 in 10000 people)

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.

Not known (can not be estimated from the data available)

side-effects such as dryness of mouth, constipation, loss of appetite, nausea or a fine tremor 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. Numbed emotions and fall.

Slowed or distinct speech (disorders of articulation), unsteadiness of gait and other motor functions, visual disorders (diplopia, nystagmus), 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.

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.

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

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.

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

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

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continuing 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.

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.

5.1 Pharmacodynamic properties

Pharmaco-therapeutic group: Anxiolytics

ATC code: N05BA09

Clobazam is a 1,5-benzodiazepine and the pharmacodynamic activity is qualitatively similar to that of other compounds of this class:

Muscle relaxant

Anxiolytic

Sedative

Hypnotic

Anticonvulsant

Amnesic.

These effects are related to a specific agonist action upon a central part of the receptor complex ‘Gaba-Omega’ macromolecular receptors’. Also known as BZ1 and BZ2 and modulating the opening of the chloride channel.

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 2mg/ml was higher than that observed after administration of a reference 10mg tablet in a single dose, randomised, crossover bioequivalence study (mean Cmax 263.1 ± 54.38 ng and 224.00 ± 22.96 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 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 steadystate 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. 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.

Populations at Risk

Elderly

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

Hepatic Impairment

There is a decrease in total clearance.

5.3 Preclinical safety data

Chronic toxicity

In chronic toxicity studies in rats with daily oral clobazam administration of 121000 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 fertility studies in mice with daily administration of 200 mg/kg clobazam and in rats receiving daily doses of 85 mg/kg, impairment of fertility and gravidity was observed. Reproduction toxicity studies in mice, rats and rabbits revealed no teratogenic potential after daily administration up to 100 mg/kg clobazam.

Genotoxicty and carcinogenicity

Clobazam is not genotoxic or tumorigenic. Follicular cell adenoma were 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

Aluminium Magnesium Silicate

Citric Acid Monohydrate (E330)

Disodium Hydrogen Phosphate Dihydrate

Simethicone Emulsion

Sucralose (E955)

Polysorbate 80 (E433)

Masking Flavour (contains propylene glycol (E1520))

Raspberry Flavour 545724E (contains propylene glycol (E1520))

Xanthan Gum (E415)

Sodium Methyl parahydroxybenzoate (E219) (Preservative)

Sodium Propyl parahydroxybenzoate (E217) (Preservative)

Liquid Maltitol (E965)

Purified Water

6.2 Incompatibilities

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

6.3 Shelf life

Unopened: 3 years

After opening: 28 days

6.4 Special precautions for storage

Do not store above 25°C. Do not refrigerate or freeze.

6.5 Nature and contents of container

Bottle: Amber (Type III glass)

Closure: HDPE, EPE wadded, child resistant closure

Pack size: 150ml

Syringe: Polypropylene body and HDPE plunger with a capacity of 5ml

Bottle adaptor: Low Density Polyethylene. The bottle adaptor is not pre-fitted.

6.6 Special precautions for disposal

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

7 MARKETING AUTHORISATION HOLDER

Rosemont Pharmaceuticals Ltd

Rosemont House

Yorkdale Industrial Park

Braithwaite Street

Leeds

LS11 9XE

UK

8 MARKETING AUTHORISATION NUMBER(S)

PL00427/0227