SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Clonazepam LIME 2mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each Tablet contains 2mg of clonazepam.

Also contains 73.0mg of Lactose per tablet.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablets.

White to off white flat circular bevelled tablets cross-scored on one side and plain on the other side

The tablets can be divided in to equal quarters.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

All clinical forms of epileptic disease and seizures in infants, children and 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

Route of administration Oral

Recommended dosage

The scored 0.5mg tablets facilitate the administration of lower daily doses in the initial stages of treatment.

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 3 or 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.

Infants and children

To ensure optimum dosage adjustment, children should be given the 0.5mg tablets.

Initial dosage should not exceed 0.25mg/day for infants and small children (1 to 5 years) and 0.5mg/day for older children. The maintenance dosage normally falls within the ranges:

School children (5 to 12 years) 3 to 6mg Small children (1 to 5 years) 1 to 3mg Infants (0 to 1 year) 0.5 to 1mg

In some forms of childhood epilepsy, certain patients may cease to be adequately controlled by clonazepam. Control may be re-established by increasing the dose, or interrupting treatment with clonazepam for 2 or 3 weeks. During the interruption in therapy, careful observation and other drugs may be needed.

Mode of administration

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 3 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, intravenous clonazepam 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 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 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. In such cases, a combination with other antiepileptics is indicated. 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).

The concomitant use of Clonazepam with alcohol or/and CNS depressants should be avoided. Such concomitant use has the potential to increase the clinical effects of Clonazepam, possibly including severe sedation, clinically relevant respiratory and/or cardio-vascular depression (see 4.5).

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

In infants and small children clonazepam may cause increased production of saliva and bronchial secretion. Therefore special attention must be paid to maintaining patency of the airways.

Effects on the respiratory system may be aggravated by pre-existing airways obstruction or brain damage or if other medications which depress respiration have been given. As a rule, this effect can be avoided by careful adjustment of the dose to individual requirements.

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).

Clonazepam is considered to be probably nonporphyrinogenic, although there is some conflicting evidence. Therefore in patients with porphyria, clonazepam should be used with care.

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.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption, should not take this medicine.

Dependence

Use of benzodiazepines may lead to the development of physical and psychic dependence upon these products (see 4.8). In particular long-term or high-dose treatment, may lead to reversible disorders such as dysarthria, reduced coordination of movements and gait disorder (ataxia), nystagmus and vision (diplopia).

Furthermore, the risk of anterograde amnesia, which may occur using benzodiazepines at therapeutic dosages, increases at higher dosages. Amnestic effects may be associated with inappropriate behaviour. With certain forms of epilepsy, an increase in the frequency of seizures (see 4.8) during long-term treatment is possible. The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a medical history of alcohol and/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 after a lengthy period of use, 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. The risk of withdrawal symptoms is increased when benzodiazepines are used together with day-time sedatives (crossed tolerance).

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 serotonine 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 foetus/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

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

Clonazepam is well tolerated and adverse reactions have generally been mild and reversible. The following have been reported as adverse events in clinical trials or reported from routine use, but in many cases a relationship to treatment with clonazepam has not been established.

The following definitions of frequencies are used:

Uncommon	> 1/1000 and < 1/100
Rare	< 1/1000

Common:

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

Neurological: dizziness, ataxia, somnolence, and co-ordination disturbances; Musculoskeletal: muscle weakness and occasional muscular hypotonia.

General: fatigue, light-headedness.

Neurological, musculoskeletal, and general effects are usually transient 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.

Eye Disorders: nystagmus.

Uncommon:

Psychiatric: 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.

Rare:

Haematological: as with other benzodiazepines, isolated cases of blood dyscrasias have been reported.

Psychiatric: depression may occur in patients treated with clonazepam, but it may be also associated with the underlying disease

Neurological: particularly in long-term use, or with high-dose treatment, there are reports of reversible disorders such as a slowing or slurring of speech (dysarthria), reduced co-ordination of movements and gait (ataxia). Seizures may also occur in pre-disposed patients (see Special Warnings and Precautions for Use).

Eye Disorders: double vision.

Gastrointestinal: gastrointestinal symptoms including nausea.

Cardiac disorders: cardiac failure including cardiac arrest has been reported.

Respiratory: respiratory depression may occur with intravenous clonazepam, this effect may be aggravated by pre-existing airways obstruction or brain damage or if other medications which depress respiration have been given. As a rule, this effect can be avoided by careful adjustment of the dose in individual requirements.

Hepatic: abnormal liver function tests have been reported.

Skin: there are a few reports of urticaria, pruritus, transient hair loss and pigmentation changes. Allergic reactions including a very few cases of anaphylaxis and angioedema have been reported to occur with benzodiazepines.

Urinary: urinary incontinence.

Reproductive: decrease in sexual drive (loss of libido), and impotence have been reported. Isolated cases of reversible development of premature secondary sex characteristics in children (incomplete precocious puberty) have also been reported.

General: headache.

Withdrawal symptoms: 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 which may be extreme, headaches, muscle pain, 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.

Special Warnings and Special Precautions for Use.

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

With certain forms of epilepsy, an increase in the frequency of seizures during longterm treatment is possible. 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, there are rare reports of induced convulsions in these patients.

An increased risk of falls and fractures has been recorded in benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

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:

Maintain a clear airway and adequate ventilation if indicated.

1.    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.

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

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

4.    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.

5.    Flumazenil (Anexate), 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

Pharmcotherapeutic group: benzodiazepine derivative ATC Code: N03AE01

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 of clonazepam. 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

In preclinical murine studies there was at least a two fold increase in birth defects at dose levels of 3, 9 and 18 times the human therapeutic dose compared to the controls.

6.1    List of excipients

Anhydrous Lactose Pregelatinised Starch Microcrystalline Cellulose Magnesium Stearate

6.2    Incompatibilities

Not applicable

6.3    Shelf life

Shelf life of the medicinal product as packaged for sale: 3 years

6.4    Special precautions    for    storage

Do not store above 25°C. Store in the original packaging.

6.5    Nature and contents of    container

Tablets are packed in Clear PVC-PVDC/Aluminium blisters containing 30 or 100 tablets. Not all pack sizes will be marketed.

6.6    Special precautions    for    disposal

No special requirements.

MARKETING AUTHORISATION HOLDER

Lime Pharma Ltd. Mckenzie House, Bury Street, Ruislip, Middlesex,

HA4 7TL UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 20620/0091

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

29/06/2010

10    DATE OF REVISION OF THE TEXT

28/07/2016