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CLONAZEPAM AUDEN 2MG TABLETS

Active substance(s): CLONAZEPAM

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Clonazepam Auden 2mg Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 2 mg clonazepam .
Lactose monohydrate
For a full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Tablet
Round white tablets with cross-score break line, marked ‘CLN 2’.

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 seizures (grand mal); 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
Method of administration: Oral use.
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 crossscored tablets facilitate the administration of lower daily doses in the initial stages of
treatment.
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 or 4 doses throughout the day. 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.
If necessary, larger doses may be given at the discretion of the physician, up to a
maximum of 20 mg daily. The maintenance dose should be attained after 2-4 weeks
of treatment.
Adults
Initial dose not to exceed 1 mg/day.
The maintenance dosage for adults normally falls with the range 4 – 8 mg.
Elderly
Initial dose should not exceed 0.5 mg/day. The elderly are particularly sensitive to
the effects of centrally depressant drugs and may experience confusion.
Children and Infants
Children should receive the 0.5 mg tablets to ensure optimum dosage adjustment.
Initial dose should not exceed 0.25 mg/day for infants and small children (1-5 yrs).
Initial dose should not exceed 0.5 mg/day for older children.
The maintenance dosage normally falls within the ranges:
Infants (0 - 1 year)

0.5 – 1 mg/day

Small children (1 – 5 years)

1 – 3 mg/day

School children (5-12 years)

3 – 6 mg/day

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.
Hepatic Impairment
In patients with mild to moderate hepatic impairment the dose should be adjusted to
individual requirements and will probably be lower.

4.3

Contraindications
Known sensitivity to benzodiazepines, such as clonazepam, or to any of the drug’s
excipients.
Acute pulmonary insufficiency; severe respiratory insufficiency, sleep apnoea
syndrome, myasthenia gravis, severe hepatic insufficiency.

Clonazepam must not be used in patients in a coma, or in patients known to be
abusing pharmaceuticals, drugs or alcohol.

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.
Use with caution in patients with chronic pulmonary insufficiency, or with renal or
hepatic function impairment, and in the elderly or debilitated. In these cases dosage
should generally be reduced.
Carefully adjust dosage to individual requirements in patients with pre-existing
disease of the liver or the respiratory system (e.g. chronic obstructive pulmonary
disease) and in patients undergoing treatment with other centrally acting medications
or anticonvulsant (antiepileptic) agents (see Section 4.5. Interaction with other
medicinal products and other forms of interaction).
Do not interrupt treatment abruptly. As with all other antiepileptic drugs, treatment
must be withdrawn gradually, by reducing the dose due to 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 with withdrawal
symptoms on cessation of use.
Use 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).
Use with extreme caution in patients with a history of alcohol or drug abuse.

Clonazepam may cause increased production of saliva and bronchial secretion in
infants and small children. 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.
Clonazepam is considered to be probably non porphyrinogenic, although there is
some conflicting evidence. In rare cases, clonazepam has induced convulsions in
patients with porphyria.
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) (See section 4.7).
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.
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 of glucose-galactose malabsorption should not take this medicine.
Dependence
Use of benzodiazepines may lead to the development of physical and psychological
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 double 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
Alcohol in combination with clonazepam may modify the effects of the drug,
compromise the success of therapy or give rise to unpredictable side-effects. Under
no circumstances should alcohol be consumed while under treatment with
clonazepam.
When 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
increase the clearance of clonazepam thereby decreasing the plasma concentrations of
the latter during combined treatment.
Pharmacokinetic interactions: Clonazepam itself does not induce the enzymes
responsible for its own metabolism.
The SSRI (selective serotonin reuptake inhibitors) sertraline and fluoxetine do not
affect the pharmacokinetics of clonazepam when administered concomitantly.
The plasma concentration of clonazepam is often reduced by carbamazepine,
phenobarbital, phenytoin or primidone, and possibly by theophylline.
Concurrent treatment with phenytoin or primidone can change the plasma
concentration of phenytoin or primidone (usually increases).
There is an increased risk of prolonged sedation and respiratory depression when
clonazepam is given with amprenavir.
Metabolism of clonazepam is inhibited (i.e. increased plasma concentration) by
cimetidine, disulfiram, fluvoxamine and ritonavir.
Metabolism of clonazepam may possibly be accelerated by rifampicin.
Clonazepam may possibly antagonise effects of levodopa.
There are enhanced hypotensive and sedative effects when clonazepam is given with
alpha-blockers or with moxonidine.
There is an enhanced hypotensive effect when clonazepam is given with ACE
inhibitors, adrenergic neurone blockers, angiotensin-II receptor antagonists, betablockers, calcium channel blockers, clonidine, diazoxide, diuretics, hydralazine,
methyldopa, minoxidil, nitrates or nitroprusside.

There is an increased sedative effect when clonazepam is given with alcohol, general
anaesthetics, tricyclic and tricyclic-related antidepressants, antihistamine (less so for
non-sedating antihistamines and not usually for topically applied antihistamines),
antipsychotics, baclofen, lofexidine, mirtazapine, nabilone, opioid analgesics,
tizanidine.

4.6

Pregnancy and lactation
Preclinical studies in animals have shown reproductive toxicity and from preclinical
studies it cannot be excluded that clonazepam possesses the possibility of producing
congenital malformations (see section 5.3 Preclinical safety data).
From epidemiological evaluations there is evidence that anticonvulsant drugs act as
teratogens. However, it is difficult to determine from published epidemiological
reports which drug or combination of drugs is responsible for defects in the newborn.
The possibility also exists that other factors e.g. genetic factors or the epileptic
condition itself may be more important than drug therapy in leading to birth defects.
Clonazepam should only be administered to pregnant women if the potential benefits
outweigh the risk to the foetus.
Pregnancy
Clonazepam has harmful pharmacological effects on pregnancy and the
foetus/newborn child.
Clonazepam should not be used during pregnancy unless clearly necessary.
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.
It should be borne in mind that both pregnancy itself and abrupt discontinuation of the
medication can cause exacerbation of epilepsy.
Lactation
Clonazepam passes 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
Driving, operating machinery and other hazardous activities should be avoided when
using clonazepam especially during the first few days of treatment. Even when
adequately controlled on clonazepam, increases in dosage or alteration in timings of
dosage may modify patients’ reactions, depending on individual susceptibility.
Clonazepam can slow reaction 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 for allowing the patient to drive rests with their doctor 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

4.8



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”

Undesirable effects
The side effects marked with an asterisk (*) are usually transitory and disappear
spontaneously as treatment continues or with dose 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.
Blood and the lymphatic system disorders
Isolated cases of blood dyscrasias.
Immune system disorders
Allergic reaction and a very few cases of anaphylaxis and angioedema.
Endocrine disorders
Isolated cases of reversible development of premature secondary sex characteristics in
children (incomplete precocious puberty) have been reported.
Psychiatric disorders and Paradoxical Reactions
Anterograde amnesia (risk increases at higher dosages). Amnestic effects may be
associated with inappropriate behaviour. Depression, loss of libido, impotence.
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 (see section 4.4) .

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 occur. If these occur, the
benefit of continuing the drug should be weighed against the adverse effect. It may
be necessary to add another suitable drug to the regimen or to discontinue
clonazepam therapy.
Nervous system disorders
Dizziness*, light-headedness*, somnolence*, fatigue*, co-ordination disturbances*,
poor concentration, restlessness, confusion and disorientation, headache.
Dysarthria and ataxia* are reversible disorders and occur particularly in long-term or
high-dose treatment.
These undesirable effects occur relatively frequently and may disappear gradually in
the course of the treatment or on reduction of the dosage. They can be partially
prevented by increasing the dose slowly at the start of treatment.
Headache was observed in rare cases. Causing of generalised fits was observed very
rarely.
Particularly in long-term or high-dose treatment, reversible disorders such as
dysarthria, reduced coordination of movements and gait disorder (ataxia) and
nystagmus may occur. Anterograde amnesia may occur using benzodiazepines at
therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be
associated with inappropriate behaviour. Although Clonazepam has been given
uneventfully to patients with porphyria, rarely it may induce convulsions in these
patients
With certain forms of epilepsy, an increase in the frequency of seizures during longterm treatment is possible.
Rarely, convulsions may be induced in patients with porphyria.
Eye disorders
Double vision and nystagmus are reversible disorders and occur particularly in longterm or high-dose treatment.
Common: nystagmus

Cardiac Disorders
Cardiac failure including cardiac arrest has been reported.
Respiratory, thoracic and mediastinal disorders
Rarely respiratory depression may occur with intravenous clonazepam, particularly if
other depressant drugs have been administered. This effect may be aggravated by
pre-existing airways obstruction or brain damage or if other medications which
depress respiration have been given .This effect can usually be avoided by careful
adjustment of the dose to individual requirements.
In infants and small children, and particularly those with a degree of mental
impairment, salivary or bronchial hypersecretion with drooling may occur.
Supervision of the airway may be required.
Gastrointestinal disorders

Rarely: nausea, gastrointestinal symptoms.
Hepato-biliary disorders
Isolated cases of abnormal liver function tests have been reported.
Skin and subcutaneous tissue disorders
Rarely: urticaria, pruritus, transient hair loss, pigmentation changes.
Musculoskeletal, connective tissue and bone disorders
Muscle weakness*, occasional muscular hypotonia*
Renal and urinary disorders
Rarely: urinary incontinence.
Reproductive System and Breast Disorders
In rare cases erectile dysfunction or loss of libido may occur.
General disorders and administration site conditions
Withdrawal: Once physical dependence has developed, abrupt termination of
treatment will be accompanied by withdrawal symptoms. During long-term
treatment, withdrawal symptoms may develop, especially withdrawing from 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, discontinuation should be carried
out by gradually reducing the daily dose.
Injury, Poisoning and Procedural Complications
An increased risk for falls and fractures has been reported in elderly benzodiazepine
users.
Investigations
In rare cases decreased platelet count may occur. As with other benzodiazepines,
isolated cases of blood dyscrasias. Dependence and withdrawal, (see 4.4).
Paediatric population
For paediatric specific events please refer to the information listed under headings:
Endocrine Disorders and
Respiratory, Thoracic and Mediastinal System Disorders in section 4.8.

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. Coma, hypotension and
respiratory depression occasionally occur but are seldom serious if these drugs are
taken alone. 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. Further absorption should be prevented using an appropriate method e.g. treatment
within 1-2 hours with activated charcoal. If activated charcoal is used airway
protection is imperative for drowsy patients.
4. Gastric lavage is unnecessary if these drugs have been taken alone .In case of
mixed ingestion gastric lavage may be considered, however not as a routine measure.
5. Patients who are asymptomatic at 4 hours are unlikely to develop symptoms.
6. 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.
7. Flumazenil (Anexate), a benzodiazepine antagoinist is available but should rarely
be required. It has a short half-life (about an hour). If CNS depression is severe
consider the use of flumazenil. This should only be administered under closely
monitored conditionstherefore patients administered flumazenil will require
monitoring after its effects have worn off. Flumazenil is to be used with extreme
caution in the presence of drugs that reduce seizure threshold (e.g. tricyclic
antidepressants). Refer to the prescribing information for flumazenil, for further
information on the correct use of this drug.Flumazenil is NOT TO BE USE 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
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. 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 sideeffects.
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 sulfate 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 teratogenic birth
defects at dose levels of 3, 9 and 18 times the human therapeutic dose compared to
the controls.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Lactose monohydrate
Magnesium stearate
Cellulose microcrystalline
Sodium starch glycolate

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
3 Years.

6.4

Special precautions for storage
Store in the original package.

6.5

Nature and contents of container
PVC/PVDC/aluminium blister pack.
Pack size: 100 tablets

6.6

Special precautions for disposal and other handling
None.

7

MARKETING AUTHORISATION HOLDER
Auden Mckenzie (Pharma Division) Ltd
Whiddon Valley

Barnstaple
North Devon
EX32 8NS
United Kingdom.

8

MARKETING AUTHORISATION NUMBER(S)
PL 17507/0080

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
10/03/2008

10

DATE OF REVISION OF THE TEXT
14/04/2016

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