Source: Υπουργείο Υγείας (CY) Revision Year: 2018 Publisher: MEDOCHEMIE LTD., 1-10 Constantinoupoleos street, 3011 Limassol, Cyprus
Hypersensitivity to benzodiazepines or to any of the excipients listed in section 6.1.
Patients with acute pulmonary insufficiency; severe respiratory insufficiency, sleep apnoea syndrome, myasthenia gravis, severe hepatic insufficiency.
Aklonil must not be used in patients in a coma, or in patients known to be abusing pharmaceuticals, drugs or alcohol.
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents in several indications. A meta-analysis of randomized 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.
Aklonil 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antiepileptic drugs, treatment with Aklonil even if of short duration, must not be abruptly interrupted, but must be withdrawn by gradually reducing the dose in view of the risk of precipitating status epilepticus.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 Aklonil therapy.
Prolonged use of benzodiazepines may result in dependence development with withdrawal symptoms on cessation of use.
Aklonil 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 Aklonil 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 section 4.5).
Aklonil 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.
The dosage of Aklonil 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). Effects on the respiratory system may be aggravated by preexisting 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 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) (see section 4.7).
As a general rule, epileptic patients are not allowed to drive. Even when adequately controlled on Aklonil, 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.
Use of benzodiazepines may lead to the development of physical and psychic dependence upon these products (see section 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 section 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).
Concomitant use of clonazepam and opioids may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of sedative medicines such as benzodiazepines or related drugs such as clonazepam with opioids should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe clonazepam concomitantly with opioids, the lowest effective dose should be used, and the duration of treatment should be as short as possible (see also general dose recommendation in section 4.2).
The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers (where applicable) to be aware of these symptoms (see section 4.5).
Aklonil tablets contain lactose monohydrate.
Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
In combination with clonazepam, alcohol may modify the effects of the drug, compromise the success of therapy or give rise to unpredictable side-effects (see also section 4.4).
See section 4.9 for warning of other central nervous system depressants, including alcohol.
Enhanced effects on sedation, respiration and haemodynamics may occur when clonazepam is co-administered with any centrally acting depressants e.g. alcohol, and other anticonvulsant (antiepileptic) agents, anaesthetics, hypnotics, psychoactive drugs and some analgesics as well as muscle relaxants and may result in mutual potentiation of drug effects (see also section 4.9).
In combination therapy with centrally-acting medications, the dosage of each drug must be adjusted to achieve the optimum effect.
The concomitant use of sedative medicines such as benzodiazepines or related drugs such as clonazepam with opioids increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dosage and duration of concomitant use should be limited (see section 4.4).
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 increase the clearance of clonazepam thereby decreasing the plasma concentrations of the latter during combined treatment.
Clonazepam itself does not induce the enzymes responsible for its own metabolism.
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.
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). 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. Aklonil should only be administered to pregnant women if the potential benefits outweigh the risk to the foetus.
During pregnancy, Aklonil may be administered only if there is a compelling indication. 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 feeding in the neonate. Infants born to mothers who took benzodiazepines chronically during the later stages of pregnancy may have developed a 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.
Although, the active ingredient of Aklonil has been found to pass into the maternal milk in small amounts only, mothers undergoing treatment with this medicine should not breastfeed. If there is a compelling indication for Aklonil, breastfeeding should be discontinued.
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 patients physician and should be based on the patient’s response to treatment and the dosage involved.
The following have been observed:
Immune system disorders
Allergic reactions and very rare cases of anaphylaxis have been reported to occur with benzodiazepines. Angioedema may occur in rare cases.
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:
Impaired concentration, restlessness, confusional state, disorientation have been observed. Depression may occur in patients treated with clonazepam, but it may be also associated with the underlying disease.
The following paradoxical reactions have been observed: excitability, irritability, aggression, agitation, nervousness, hostility, anxiety, sleep disturbances, nightmares, vivid dreams and 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.
Nervous System Disorders:
Somnolence, slowed reaction, muscular hypotonia, dizziness and ataxia. 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.
With certain forms of epilepsy, an increase in the frequency of seizures during long-term treatment is possible.
Although clonazepam has been given uneventfully to patients with porphyria, rarely it may induce convulsions in these patients.
Eye Disorders:
Particularly in long-term or high-dose treatment, reversible disorders of vision (diplopia) may occur.
Common: nystagmus
Cardiac Disorders:
Cardiac failure including cardiac arrest has been reported.
Respiratory, thoracic and mediastinal system disorders:
Respiratory depression may occur, particularly on i.v. administration of 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 to individual requirements.
Increased salivation or bronchial secretion may occur in infants or young children (see also section 4.4).
Gastrointestinal disorders:
The following effects have been reported in rare cases: nausea, gastrointestinal and epigastric symptoms.
Skin and subcutaneous tissue disorders:
The following effects may occur in rare cases: urticaria, pruritus, rash, transient hair loss and pigmentation changes.
Musculoskeletal and connective tissue disorders:
Muscle weakness, this undesirable effect occurs relatively frequently and is usually transient and generally disappears spontaneously in the course of the treatment or on reduction of the dosage. It can be partially prevented by increasing the dose slowly at the start of treatment.
Renal and urinary disorders:
In rare cases urinary incontinence may occur.
Reproductive system and breast disorders:
In rare cases erectile dysfunction or loss of libido may occur.
General disorders and administration site conditions:
Fatigue (tiredness, lassitude), this undesirable effect occurs relatively frequently and is usually transient and generally disappears spontaneously in the course of the treatment or on reduction of the dosage. It can be partially prevented by increasing the dose slowly at the start of treatment.
Injury, poisoning and procedural complications:
There have been reports of falls and fractures in benzodiazepine users. The risk is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.
Investigations:
In rare cases decreased platelet count may occur. As with other benzodiazepines, isolated cases of blood dyscrasias and abnormal liver function tests have been reported.
Dependence and withdrawal, (see section 4.4).
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 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 to Pharmaceutical Services, Ministry of Health, CY-1475, www.moh.gov.cy/phs, Fax: +35722608649.
None known.
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