Clonazepam Rosemont 2mg/5ml Oral Solution

NAME OF THE MEDICINAL PRODUCT

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5ml contains 2mg Clonazepam

Excipients: Ethanol - 100mg/5ml

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Oral solution

A clear, pale straw coloured oily solution

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

All clinical forms of epileptic disease and seizures in adults, especially absence seizures (petit mal) including atypical absence; primary or secondarily generalised tonic-clonic (grand mal), tonic or clonic seizures; partial (focal) seizures with elementary or complex symptomatology; various forms of myoclonic seizures, myoclonus and associated abnormal movements.

4.2 Posology and method of administration

Posology

The 0.5mg/5ml oral solution may facilitate the administration of lower daily doses in the initial stages of treatment or treatment for the elderly.

The 2mg/5ml oral solution should be used for maintenance and maximum dosage regimens.

Adults

Initial dosage should not exceed 1mg/day. The maintenance dosage for adults normally falls within the range 4 to 8mg.

Elderly

The elderly are particularly sensitive to the effects of centrally depressant drugs and may experience confusion. It is recommended that the initial dosage of clonazepam should not exceed 0.5mg/day.

These are total daily dosages which should be divided into 4 doses taken at intervals throughout the day. If necessary, larger doses may be given at the discretion of the physician, up to a maximum of 20mg daily. The maintenance dose should be attained after 2 to 4 weeks of treatment.

Paediatric Population

Due to the presence of ethanol in the formulation, this product is not indicated for paediatric use.

Method of administration

A 2.5ml/ 5ml double ended spoon with a further 1.25ml graduation is supplied with the pack.

Suitable for administration via non-PVC nasogastric (NG) or percutaneous endoscopic gastrostomy (PEG) tubes. For further instructions see section 6.6.

When these instructions are followed over 95% of the dose is delivered.

The product is incompatible with polystyrene or PVC and therefore, other devices may react with the product.

It should be noted that for oral syringes, the product may cause the plunger to stop moving smoothly or the markings may fade over time.

Treatment should be started with low doses. The dose may be increased progressively until the maintenance dose suited to the individual patient has been found.

The dosage of clonazepam must be adjusted to the needs of each individual and depends on the individual response to therapy. The maintenance dosage must be determined according to clinical response and tolerance.

The daily dose should be divided into 4 equal doses. If doses are not equally divided, the largest dose should be given before retiring. Once the maintenance

dose level has been reached, the daily amount may be given in a single dose in the evening.

Simultaneous administration of more than one antiepileptic drug is a common practice in the treatment of epilepsy and may be undertaken with clonazepam. The dosage of each drug may be required to be adjusted to obtain the optimum effect. If status epilepticus occurs in a patient receiving oral clonazepam, administration of an intravenous clonazepam injection may still control the status. Before adding clonazepam to an existing anticonvulsant regimen, it should be considered that the use of multiple anticonvulsants may result in an increase of undesired effects.

4.3 Contraindications

Patients with known sensitivity to benzodiazepines; or any of the drugs excipients; acute pulmonary insufficiency; severe respiratory insufficiency, sleep apnoea syndrome, myasthenia gravis, severe hepatic insufficiency.

4.4 Special warnings and precautions for use

Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic 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 clonazepam.

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.

Patients with a history of depression and/or suicide attempts should be kept under close supervision.

Clonazepam should be used with caution in patients with chronic pulmonary insufficiency, or with impairment of renal or hepatic function, and in the elderly or the debilitated. In these cases dosage should generally be reduced.

As with all other antiepileptic drugs, treatment with clonazepam even if of short duration, must not be abruptly interrupted, but must be withdrawn by gradually reducing the dose in view of the risk of precipitating status epilepticus. This precaution must also be taken when withdrawing another drug while the patient is still receiving clonazepam therapy.

Prolonged use of benzodiazepines may result in dependence development with withdrawal symptoms on cessation of use.

Clonazepam may be used only with particular caution in patients with spinal or cerebellar ataxia, in the event of acute intoxication with alcohol or drugs and in patients with severe liver damage (e.g. cirrhosis of the liver).

Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse.

The dosage of clonazepam must be carefully adjusted to individual requirements in patients with pre-existing disease of the respiratory system (e.g. chronic obstructive pulmonary disease) or liver and in patients undergoing treatment with other centrally acting medications or anticonvulsant (antiepileptic) agents (see section 4.5).

Like all drugs of this type, clonazepam may, depending on dosage, administration and individual susceptibility, modify the patient's reactions (e.g. driving ability, behaviour in traffic).

In cases of loss or bereavement, psychological adjustment may be inhibited by benzodiazepines.

Due to the oily nature of this medicine caution should be used when administering this medicine via a nasogastric (NG) or percutaneous endoscopic gastrostomy (PEG) tubes.

This could lead to under dosing due to medicine remaining in the tube. For accurate delivery the instructions in section 6.6 should be followed.

Excipient warnings:

This product contains the following excipients:

Ethanol: This medicinal product contains 2.6% (v/v) ethanol (alcohol), i.e. up to 100mg per 5ml dose.

Harmful for those suffering from alcoholism.

To be taken into account in pregnant or breast-feeding women and high-risk groups such as patients with liver disease, or epilepsy.

As this product is indicated for epilepsy, special consideration should be given to the amount of ethanol administered in the dose (see section 4.2).

4.5

Interaction with other medicinal products and other forms of interaction

Since alcohol can provoke epileptic seizures, irrespective of therapy, patients must under no circumstances drink alcohol while under treatment. In combination with clonazepam, alcohol may modify the effects of the drug, compromise the success of therapy or give rise to unpredictable side-effects.

When clonazepam is used in conjunction with other antiepileptic drugs, side-effects such as sedation and apathy, and toxicity may be more evident, particularly with hydantoins or phenobarbital and combinations including them. This requires extra care in adjusting dosage in the initial stages of treatment. The combination of clonazepam and sodium valproate has, rarely, been associated with the development of absence status epilepticus.

Although some patients tolerate and benefit from this combination of drugs, this potential hazard should be borne in mind when its use is considered.

The antiepileptic drugs phenytoin, phenobarbital, carbamazepine and valproate may induce the metabolism of clonazepam causing higher clearance and lower plasma concentrations of the latter during combined treatment.

The selective serotonin reuptake inhibitors sertraline and fluoxetine do not affect the pharmacokinetics of clonazepam when administered concomitantly.

Known inhibitors of hepatic enzymes, e.g. cimetidine, have been shown to reduce the clearance of benzodiazepines and may potentiate their action and known inducers of hepatic enzymes, e.g. rifampicin, may increase the clearance of benzodiazepines.

In concurrent treatment with phenytoin or primidone, a change, usually a rise in the serum concentration of these two substances has occasionally been observed.

Concurrent use of clonazepam and other centrally acting medications, e.g. other anticonvulsant (antiepileptic) agents, anaesthetics, hypnotics, psychoactive drugs and some analgesics as well as muscle-relaxants may result in mutual potentiation of drug effects. This is especially true in the presence of alcohol. In combination therapy with centrally-acting medications, the dosage of each drug must be adjusted to achieve the optimum effect.

4.6 Fertility, Pregnancy and lactation

Preclinical studies in animals have shown reproductive toxicity (see section 5.3 Preclinical safety data). From epidemiological evaluations there is evidence that anticonvulsant drugs act as teratogens.

Clonazepam has harmful pharmacological effects on pregnancy and the fetus/newborn child. Administration of high doses in the last trimester of pregnancy or during labour can cause irregularities in the heart beat of the unborn child and hypothermia, hypotonia, mild respiratory depression and poor sucking in the neonate. Infants born to mothers who took benzodiazepines chronically during the later stages of pregnancy may have developed physical dependence and may be at some risk for developing withdrawal symptoms in the post-natal period. Therefore clonazepam should not be used in pregnancy unless clearly necessary.

Clonazepam has been found to pass into the maternal milk in small amounts. Therefore clonazepam should not be used in mothers who breastfeed unless clearly necessary.

4.7 Effects on ability to drive and use machines

As a general rule, epileptic patients are not allowed to drive. Even when adequately controlled on clonazepam, it should be remembered that any increase in dosage or alteration in timings of dosage may modify patients’ reactions, depending on individual susceptibility. Even if taken as directed, clonazepam can slow reactions to such an extent that the ability to drive a vehicle or operate machinery is impaired. This effect is aggravated by consumption of alcohol. Driving, operating machinery and other hazardous activities should therefore be avoided altogether or at least during the first few days of treatment. The decision on this question rests with the patient’s physician and should be based on the patient’s response to treatment and the dosage involved.

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 side-effects observed consist of fatigue, muscle weakness, dizziness, ataxia, light-headedness, somnolence, occasional muscular hypotonia and co-ordination disturbances. Such effects are usually transitory and disappear spontaneously as treatment continues or with dosage reduction. They tend to occur early in treatment and can be greatly reduced, if not avoided, by commencing with low dosages followed by progressive increases.

Poor concentration, restlessness, confusion and disorientation have been observed. Anterograde amnesia may occur using benzodiazepines at therapeutic dosage, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behaviour.

Depression may occur in patients treated with clonazepam, but it may be also associated with the underlying disease.

In rare cases, urticaria, pruritus, transient hair loss, pigmentation changes, nausea, gastrointestinal symptoms, headache, decrease in sexual drive (loss of libido), impotence and urinary incontinence may occur. Isolated cases of reversible development of premature secondary sex characteristics in children (incomplete precocious puberty) have been reported. Allergic reactions and a very few cases of anaphylaxis and angioedema have been reported to occur with benzodiazepines.

Particularly in long-term or high-dose treatment, reversible disorders such as a slowing or slurring of speech (dysarthria), reduced co-ordination of movements and gait (ataxia) and disorders of vision (double vision, nystagmus) may occur.

Rarely respiratory depression may occur with intravenous clonazepam, particularly if other depressant drugs have been administered. As a rule, this effect can be avoided by careful adjustment of the dose in individual requirements.

Use of benzodiazepines may lead to the development of physical and psychological dependence upon these products. The risk of dependence increases with dose and duration of treatment and is particularly pronounced in predisposed patients with a history of alcoholism or drug abuse.

Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. During long-term treatment, withdrawal symptoms may develop, especially with high doses or if the daily dose is reduced rapidly or abruptly discontinued. The symptoms include tremor, sweating, agitation, sleep disturbances and anxiety, headaches, muscle pain, extreme anxiety, tension, restlessness, confusion, irritability and epileptic seizures which may be associated with the underlying disease. In severe cases the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact or hallucinations. Since the risk of withdrawal symptoms is greater after abrupt discontinuation of treatment, abrupt withdrawal of the drug should therefore be avoided and treatment - even if only of short duration - should be terminated by gradually reducing the daily dose.

In infants and small children, and particularly those with a degree of mental impairment, clonazepam may give rise to salivary or bronchial hypersecretion with drooling. Supervision of the airway may be required.

With certain forms of epilepsy, an increase in the frequency of seizures during long-term treatment is possible.

As with other benzodiazepines, isolated cases of blood dyscrasias and abnormal liver function tests have been reported.

Clonazepam generally has a beneficial effect on behaviour disturbances in epileptic patients. In certain cases, paradoxical effects such as aggressiveness, excitability, nervousness, hostility, anxiety, sleep disturbances, nightmares, vivid dreams, irritability, agitation, psychotic disorders and activation of new types of seizures may be precipitated. If these occur, the benefit of continuing the drug should be weighed against the adverse effect. The addition to the regimen of another suitable drug may be necessary or, in some cases, it may be advisable to discontinue clonazepam therapy.

Although clonazepam has been given uneventfully to patients with porphyria, rarely it may induce convulsions in these patients.

An increased risk of falls and fractures has been recorded in elderly benzodiazepine users.

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 national reporting systems.

United Kingdom

Yellow Card Scheme. www.mhra.gov.uk/yellowcard Ireland

IMB Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb. ie

4.9 Overdose

As with other benzodiazepine drugs, overdosage should not present undue problems of management or threat to life. Patients have recovered from overdoses in excess of 60mg without special treatment. Severe somnolence with muscle hypotonia will be present.

Symptoms:

The symptoms of overdosage or intoxication vary greatly from person to person depending on age, bodyweight and individual response. Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Overdose of clonazepam is seldom life-threatening if the drug is taken alone, but may lead to coma, areflexia, apnoea, hypotension and cardiorespiratory depression. Coma usually lasts only a few hours but in elderly people it may be more protracted and cyclical. Benzodiazepine respiratory depressant effects are more serious in patients with severe chronic obstructive airways disease.

Benzodiazepines potentiate the effects of other central nervous system depressants, including alcohol.

Management:

1. Maintain a clear airway and adequate ventilation if indicated.

2. The benefit of gastric decontamination is uncertain. Consider activated charcoal (50g for an adult, 10-15g for a child) in adults or children who have taken more than 0.4mg/kg within 1 hour, provided they are not too drowsy.

3. Gastric lavage is unnecessary if these drugs have been taken alone.

4. Patients who are asymptomatic at 4 hours are unlikely to develop symptoms.

5. Supportive measures as indicated by the patient's clinical state. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central nervous system effects.

6. Flumazenil, a benzodiazepine antagonist is available but should rarely be required. It has a short half-life (about an hour). Flumazenil is NOT TO BE USED IN MIXED OVERDOSE OR AS A “DIAGNOSTIC TEST” (see separate prescribing information).

Warning

The use of flumazenil is not recommended in epileptic patients who have been receiving benzodiazepine treatment for a prolonged period. Although flumazenil exerts a slight intrinsic anticonvulsant effect, its abrupt suppression of the protective effect of a benzodiazepine agonist can give rise to convulsions in epileptic patients.

If excitation occurs, barbiturates should not be used.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antiepileptics, Benzodiazepine derivatives ATC Code: N03 AE01

Clonazepam exhibits pharmacological properties which are common to benzodiazepines and include anticonvulsive, sedative, muscle relaxing and anxiolytic effects. Animal data and electroencephalographic investigations in man have shown that clonazepam rapidly suppresses many types of paroxysmal activity including the spike and wave discharge in absence seizures (petit mal), slow spike wave, generalised spike wave, spikes with temporal or other locations as well as irregular spikes and waves.

Generalised EEG abnormalities are more readily suppressed by clonazepam than are focal EEG abnormalities such as focal spikes. Clonazepam has beneficial effects in generalised and focal epilepsies.

5.2 Pharmacokinetic properties

Absorption

Clonazepam is quickly and completely absorbed after oral administration. Peak plasma concentrations are reached in most cases within 1 - 4 hours after an oral dose. Bioavailability is 90% after oral administration.

Routine monitoring of plasma concentrations of clonazepam is of unproven value since this does not appear to correlate well with either therapeutic response or side-effects.

Distribution

The mean volume of distribution of clonazepam is estimated at about 3 l/kg. Clonazepam must be assumed to cross the placental barrier and has been detected in maternal milk.

Metabolism

The biotransformation of clonazepam involves oxidative hydroxylation and reduction of the 7-nitro group by the liver with formation of 7-amino or 7-acetylamino compounds, with trace amounts of 3-hydroxy derivatives of all three compounds, and their glucuronide and sulphate conjugates. The nitro compounds are pharmacologically active, whereas the amino compounds are not.

Within 4 - 10 days 50 - 70% of the total radioactivity of a radiolabelled oral dose of clonazepam is excreted in the urine and 10 - 30% in the faeces, almost exclusively in the form of free or conjugated metabolites. Less than 0.5% appears as unchanged clonazepam in the urine.

Elimination

The elimination half-life is between 20 and 60 hours (mean 30 hours).

Pharmacokinetics in special clinical situations

Based on kinetic criteria no dose adjustment is required in patients with renal failure.

5.3 Preclinical safety data

Carcinogenicity

No 2-year carcinogenicity studies have been conducted with clonazepam. However, in an 18-month chronic study in rats no treatment-related histopathological changes were seen up to the highest tested dose of 300 mg/kg/day.

Mutagenicity

Genotoxicity tests using bacterial systems with in vitro or host mediated metabolic activation did not indicate a genotoxic liability for clonazepam.

Impairment of Fertility

Studies assessing fertility and general reproductive performance in rats showed a reduced pregnancy rate and impaired pup survival at doses of 10 and 100 mg/kg/day.

Teratogenicity

No adverse maternal or embryo-fetal effects were observed in either mice or rats following administration of oral clonazepam during organogenesis, at doses of up to 20 or 40 mg/kg/day, respectively.

In several rabbit studies following doses of clonazepam of up to 20 mg/kg/day, a low, non-dose-related incidence of a similar pattern of malformations (cleft palate, open eyelids, fused sternebrae and limb defects) was observed (see section 4.6 Pregnancy and Lactation).

6.1 List of excipients

Saccharin

Ethanol

Levomenthol

Medium chain triglycerides

6.2 Incompatibilities

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

This product should not be mixed with water.

This product is incompatible with polystyrene and PVC.

6.3 Shelf life

12 months 1 month once open

6.4 Special precautions for storage

Do not store above 25°C. Store in the original package in order to protect from light.

6.5 Nature and contents of container

Bottle: Amber (Type III) glass

Closure: HDPE, EPE wadded, tamper evident, child resistant closure

Pack size: 150ml

Dosing Device: 2.5ml/ 5ml double ended spoon with a 1.25ml graduation mark

6.6 Special precautions for disposal and other handling

Instruction for administration via nasogastric (NG) or percutaneous endoscopic gastrostomy (PEG) tubes:

Clonazepam Oral Solution is suitable for use with the following types of NG and PEG tubes:

Material	External Bore Size (Fr Unit)	Internal Diameter (mm)	Maximum Length ^(cm)
Silicone	6	1.0	125
Silicone	10	2.0	125
Polyurethane	8	1.5	100
	12	2.6	75
	18	4.0	75

This product is not compatible with PVC or polystyrene and therefore should not be used with NG or PEG tubes made from these materials.

Care should be taken during administration due to the oily nature of the product. It is recommended to administer the dose prior to delivering feed through the NG or PEG tub and to follow the instruction below:

Ensure that the enteral feeding tube is free from obstruction before administration.

1) Flush the enteral tube with water, a minimum flush volume of 10mL is required.

2) Administer the required dose of Clonazepam Oral Solution with a suitable measuring device.

3) Flush the enteral tube again by either of the methods below:

i) Flush the enteral tube 3 consecutive times, using a minimum volume of 5mL of water each time.

ii) Flush the enteral tube using a minimum volume of 5mL of water and then immediately deliver a minimum of 10ml of feed.

Healthcare professionals should be aware that if the instructions above cannot be followed (e.g. longer or wider tubes are used or in a specific clinical situations) there is a risk of under dosing (up to 15%) as the oily medicine may adsorb to the

wall of the feeding tube.. Extra flushing with water or feed may combat this. In these situations the patient should be monitored closely.

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

LS119XE

8 MARKETING AUTHORISATION NUMBER(S)

PL 00427/0158

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

20/12/2011

10 DATE OF REVISION OF THE TEXT

28/04/2016