Summary of Product Characteristics

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1 Approved by SAM (State Agency of Medicines) on NAME OF THE MEDICINAL PRODUCT 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Active substanc clonazepam (Clonazepanum). Each tablet contains 2 mg of clonazepam. The list of excipients see in section PHARMACEUTICAL FORM Tablets. Description: white or almost white, round, flat tablets with bevelled sides and a breaking line on one side of a tablet. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications All clinical forms of epileptic disease. Panic attacks in adults. 4.2 Posology and method of administration The dose and duration of treatment should be adjusted individually. Epilepcy Adults are not suitable for initial treatment and dosage gradual increase during the period. In these cases, final dosage forms with a lower clonazepam dosage per unit should be used. Usually the therapeutic dose is 4-8 mg per day divided in 2-3 single doses. In case a daily dose cannot be divided into equal single doses, the larger dose should be used at bedtime. The maximum dose is 20 mg per day. Concomitant use of clonazepam and other anticonvulsants is permitted, however the interaction of the medicines may result in increased central nervous system depression and other side-effects. To obtain optimal seizure control doses need to be adjusted. In order to control cases of seizures when other anticonvulsants are replaced by clonazepam, clonazepam dose is gradually increased, but previously administered drug s dose is gradually reduced. If clonazepam is started to use as an additional drug, clonazepam dose should be gradually increased till the seizures are controlled. For elderly and debilitated patients are not suitable for initial treatment and dosage gradual increase during the period. In these cases, final dosage forms with a lower clonazepam dosage per unit should be used. Therapeutic dose in elderly and debilitated patients is generally half of the adult dose, 2-4 mg per day divided into 2-3 single doses. For children till 5 years are not suitable due to high dosage.

2 2 of 10 are not suitable for initial treatment and dosage gradual increase during the period for children 5 to12 years. In these cases final dosage forms with a lower clonazepam dosage per unit should be used. For children 5-12 years therapeutic dose is 3-6 mg divided into 2-3 single doses. For patients with a light or moderate renal and/or liver failure treatment is started with a lowest dose and cautiously taking into account clinical state of the patient gradually increasing the dose. In cases of severe failure treatment is contraindicated. Panic seizures Adults: are not suitable for initial treatment and dosage gradual increase during the period. Usual daily dose is 1 mg, which is sufficient for the most part of patients. Daily dose should not be overdosed, because the efficacy is not intensified if the dose is increased. In single cases the dose can be gradually increased till the maximum dose to treat panic seizures 4 mg a day. To control somnolence during day time the daily dose may be used once before bedtime. It should be periodically considered if there are indications for treatment proceeding with clonazepam. Children till 18 years: are not recommended to use for the treatment of panic seizures as there is no sufficient information of its safety and efficacy in children. Mode of administration The medicine is used orally with water. In case a daily dose cannot be divided into equal single doses, the larger dose should be used at bedtime. Clonazepam should not be used more than 3-6 months. Interruption of administration Administration must not be interrupted abruptly, even if the drug is used for a short period. Abrupt withdrawal of the drug may cause withdrawal syndrome (sleep and mood disorders, psychiatric disorders, an increased incidence of epileptic seizures, dysphoria, movement stimulation, tachycardia). Clonazepam should not be taken longer than 3-6 months.

3 3 of 10 Clonazepam should be discontinued if using on a regular basis, its efficacy has decreased (developed tolerance) Contraindications - Hypersensitivity to clonazepam and / or any of the excipients, as well as other benzodiazepines - A central origin of respiratory disorders - Acute lung failure - Severe respiratory failure - Sleep apnea syndrome - Severe liver failure - Severe renal insufficiency - Myasthenia gravis - Closed-angle glaucoma - Pregnancy and lactation Co-administration of clonazepam with sodium oxybate and ritonavir should be avoided Special warnings and special precautions for use Tolerance: after several weeks of regular benzodiazepines use (including clonazepam) drug addiction can occur, as a result drugs effects are diminished. Dependence: benzodiazepines (including clonazepam) may lead to mental and physical dependence. Increasing the dose and extending the duration of use, risk of dependence increases. If there is dependence, abrupt discontinuation may lead to drug withdrawal syndrome. Typical symptoms include headache, muscle pain, agitation, unsteady gait, confusion, disorientation, anxiety, emotional stress, insomnia. In severe cases there can be a sense of reality loss, personality changes, increased sensitivity to touch, sound and light, tingling in the limbs, limb numbness, hallucinations, seizures. Anterograde amnesia: clonazepam, like other benzodiazepines may induce anterograde amnesia. More often this state occurs within several hours after administration, particularly when high doses of medicine are used. If you develop symptoms of anterograde amnesia, clonazepam use should be discontinued. Paradoxical reactions: clonazepam like other benzodiazepines can cause paradoxical reactions. These may include agitation, aggression, delusions, hallucinations, insomnia, inadequate behavior. Such reactions often occur in elderly patients or from alcohol dependent patients. In some cases clonazepam can cause tonic / clonic seizures.

4 4 of 10 Specific patient groups Elderly patients with adverse events, mainly due to disorientation and coordination problems (falls, injuries), should take lower doses of clonazepam. The dose is reduced in patients with hepatic insufficiency (in case of acute liver failure, the use is contraindicated). Benzodiazepines can cause the development of hepatic encephalopathy. Liver failure can cause unwanted side effects of benzodiazepines. In case of renal insufficiency, the dose should be decreased. Clonazepam should be used with caution in patients with chronic pulmonary insufficiency because it has inhibiting effect on the respiratory system. Patients with spinocerebellar ataxia and myasthenia: clonazepam should be used with caution. In case of porphyria clonazepam should be used with caution. Clonazepam use may cause worsening of symptoms of this disease. Patients with depression and / or a history of suicidal ideation: clonazepam should be used with caution. Due to risk of overdose clonazepam should be indicated at possible lowest doses and quantity. Patients who are or have been dependent on alcohol or other drugs (including drug abuse): clonazepam should be used with caution. Clonazepam use should be closely monitored as this group of patients is at high risk of developing psychological dependence. Salivation, respiratory tract secretion may increase when clonazepam is used in children. The permeability of the respiratory tract should be controlled. During long term use mental and physical disabilities may occur. While using clonazepam for a prolonged time periodic monitoring of blood counts and liver function tests is recommended. During treatment and 3 days after treatment discontinuation drinks containing alcohol should not be used. contain lactose monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine Interaction with other medicinal products and other forms of interaction Clonazepam and Amprenavir: when used concomitantly respiratory depression and sedation prolongation risk increase Carbamazepine: carbamazepine often reduces clonazepam plasma concentration Phenobarbital: phenobarbital often reduces clonazepam plasma concentration

5 5 of 10 Phenytoin: phenytoin often reduces clonazepam plasma concentration Primidone: primidone often reduces clonazepam plasma concentration Valproic acid: concomitant use increases the risk of side effects, in some cases may provoke seizures Benzodiazepine derivatives, including clonazepam and Cimetidine: cimetidine inhibits metabolism of benzodiazepines (clonazepam sedative effect increases) Disulfiram: disulfiram prevents the metabolism of benzodiazepines (clonazepam sedative effect increases) Fluvoxamine: fluvoxamine increases plasma concentrations of some benzodiazepines Levodopa: benzodiazepines can antagonize levodopa action Moxonidine: concomitant use may increase sedative effect Rifampicin: rifampicin may accelerate the metabolism of benzodiazepines (reduces clonazepam plasma concentration) Sodium oxybate: benzodiazepines reinforce the action of sodium oxybate (the concomitant use should be avoided) Theophylline: theophylline may reduce the benzodiazepine effect Anxiolytics and hypnotics including clonazepam, and ACE inhibitors: concomitant use enhances antihypertensive effect Adrenergic neurons blockers: concomitant use enhances antihypertensive effect Alcohol: concomitant use enhances sedative effects Alpha-blockers: concomitant use intensifies antihypertensive and sedative effects Anesthetic (general) agents: co-administration intensifies sedative effects Angiotensin II receptor antagonists: concomitant use enhances antihypertensive effect Antidepressants (tricyclic antidepressants, drugs similar to tricyclic antidepressants): concomitant use enhances sedative effects Antihistamines: co-administration enhances sedative effects, interactions are less expressed in a non-sedating antihistamines. Interaction is not observed when antihistamines with local effects are used (including inhalation) Antipsychotic drugs: co-administration enhances sedative effects. Toxicity is possible when used in combination with myelosuppressive drugs Baclofen: co-administration enhances sedative effects Beta-blockers: co-administration enhances antihypertensive effect Calcium channel blockers: co-administration enhances antihypertensive effect (dihydropyridine calcium channel blockers: including amlodipine, felodipine, isradipine, lacidipine, lercanidipine, nicardipine, nifedipine, nimodipine and nisoldipine) Clonidine: co-administration enhances antihypertensive effect Diazoxide: co-administration enhances antihypertensive effect

6 6 of 10 Diuretics: co-administration enhances antihypertensive effect Hydralazine: co-administration enhances antihypertensive effect Lofexidine: co-administration enhances sedative effect Methyldopa: co-administration enhances antihypertensive effect Minoxidil: co-administration enhances antihypertensive effect Mirtazapine: co-administration enhances sedative effect Moxonidine: co-administration enhances antihypertensive effect Nabilon: co-administration enhances sedative effect Nitrates: co-administration enhances antihypertensive effect Nitroprusside: co-administration enhances antihypertensive effect Opioid analgesics: co-administration enhances sedative effects Ritonavir: ritonavir may increase the anxiolytics and hypnotics concentrations in plasma Tizanidine: co-administration enhances sedative effects 4.6. Pregnancy and lactation Administration of the drug is contraindicated. Absolute contraindication during the first three months of pregnancy. During the other period of pregnancy the use is possible only in cases of emergency, if use of safer drugs is not possible. Benzodiazepines (including clonazepam) in a newborn can cause dependence, withdrawal syndrome. If mother during the last three months of pregnancy or a few days before birth has used clonazepam, a newborn will have hypothermia, hypotension, respiratory failure, impaired sucking reflex. Clonazepam is excreted into breast milk. If mother requires treatment with clonazepam, child breast-feeding should be discontinued Effects on ability to drive and use machines It is prohibited to drive during treatment and three days after clonazepam use discontinuation because the drug causes drowsiness, impairs memory and ability to concentrate. During treatment it is necessary to refrain from potentially dangerous activities that require increased attention and rapid psychomotor reactions Undesirable effects Classification of frequency of side effects: very common (> 1/10); common (> 1/100, < 1/10); uncommon (> 1/1 000, < 1/100); rare (> 1/10 000, < 1/1 000); very rare (< 1/10 000). Undesirable effects are transient in most cases and they are observed in the first weeks of treatment. Side effects are possible more often in elderly. Blood and lymphatic system disorders: very rare - anemia, leukopenia, thrombocytopenia, eosinophilia. Nervous system disorders: common - drowsiness, dizziness, fatigue, motion coordination and

7 7 of 10 attention disorders, confusion; long term use of high doses -memory impairment, dependence and withdrawal syndrome; uncommon - headaches, speech problems (slow, slurred speech), hemiparesis. Long-term use: rare - visual disturbances (blurred vision, diplopia, nystagmus). Respiratory, thoracic and mediastinal disorders: common - increased bronchial secretions formation, particularly in children, very rare - respiratory depression, usually in combination with other respiratory system-inhibiting drugs. Gastrointestinal disorders: uncommon - dry mouth, nausea, anorexia, diarrhea, constipation and abdominal pain. Renal and urinary disorders: rare - enuresis or urinary retention, nocturia. Skin and subcutaneous tissue disorders: rare - hives, itching, transient hair loss, skin pigmentation changes. Musculoskeletal and connective tissue disorders: uncommon-low muscle tone. General disorders rare - palpitations, fever, dehydration, lymphadenopathy, weight gain or loss. In some cases - angioedema, anaphylactic reaction. Liver and/or biliary disorders: rare - enlarged liver, mild and transient transaminase alkaline phosphatase activity in the blood. Reproductive system disorders: uncommon - menstrual disorders, decreased libido, rare - impotence. Psychiatric disorders: uncommon consciousness disorders, depression, very rare - paradoxical reactions (incl. aggression and anxiety). 4.9 Overdose Symptoms: stupor, drowsiness, fatigue, diplopia, ataxia, at high doses - hypotension and deep sleep, coma, very rare - respiratory depression. Measures: the patient must be hospitalized. Within one hour after overdose patients without impaired consciousness are given activated charcoal, activated charcoal is administered through the probe in unconscious patients. Patients with less severe symptoms of intoxication are allowed to sleep monitoring breathing. In case of severe intoxication, breathing, pulse and blood pressure are controlled. If necessary, caffeine and sodium benzoate are administered for CNS stimulation. Respiratory failure can be also caused by peripheral myorelaxation; therefore it is necessary to carry out mechanical lung ventilation. Levarterenol bitartrate or metaraminol bitartrate are used to prevent hypotension. Flumazenil (benzodiazepine derivatives antagonist) is a specific antidote that can be used intravenously in emergency situations. Flumazenil should not be used in patients taking clonazepam independently and for a long time. Rapid blocking action of benzodiazepines in patients with epilepsy can cause an attack. These patients should never be given flumazenil in the treatment of benzodiazepine overdose. Dialysis is not effective.

8 8 of PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: antiepileptic drug. ATC code: N03AE01. Clonazepam is benzodiazepine derivative. It has an expressed anticonvulsive and sedative activity, anxiolytic and muscle relaxation activity is less expressed. Clonazepam acts at the level of the limbic, thalamic, and hypothalamic regions of the CNS, and can produce any level of CNS depression required including sedation, hypnosis, skeletal muscle relaxation, anticonvulsant activity. The precise mechanism of drug s activity at molecular level is not completely known. The action of this drug is considered to mediate through the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Central benzodiazepine receptors interact allosterically with GABA receptors, potentiating the effects of GABA and thereby increasing the inhibition of the ascending reticular activating system. All benzodiazepine receptors are functionally linked to GABA receptors and chlorine ion channels. Benzodiazepine receptors stimulation of GABA receptors is activated causing chlorine ion channels opening. Increased influx of chlorine ions in cells leads to the corresponding hyperpolarization of neurons reducing irritation. Medication tolerance to clonazepam is formed in about 30% of patients. Efficacy reduction develops in first three months of preparation administration. Tolerance occurrence varies depending on the type of seizure. In these cases adjust the dose or temporarily interrupt the drug s use, which helps to restore efficacy Pharmacokinetic properties Many factors may influence clonazepam pharmacokinetics, namely: patient s age, liver and kidneys functions disorders, drugs interaction. Absorption: clonazepam is well absorbed from gastrointestinal tract. Bioavailability of clonazepam is 90 %. Distribution: Maximal plasma concentration of active substance is achieved within 1-4 hours after single oral dose administration of the drug, in separate cases within 4-8 hours. Stable active substance plasma concentration is achieved during 5-6 days. Clonazepam is approximately 85 % bound to plasma proteins. Clonazepam is soluble in lipids, therefore is well distributed in all tissues. Volume of distribution is 3.2 l/kg. Metabolism: clonazepam almost completely is biotransformed by the liver, but pharmacologically active metabolites are not formed. Excretion: elimination half-life is hours. Less than 2% of clonazepam is excreted in the urine unchanged. Elimination occurs in the urine in the form of glucuronide and sulfate conjugates.

9 9 of 10 Elimination is decreased and clonazepam accumulation is possible in elderly patients, and patients with decreased hepatic and/or renal function. Clonazepam easily crosses the blood-brain barrier and the placenta, excretes with mother s milk Preclinical safety study. Carcinogenicity, mutagenicity and genotoxicity: carcinogenic, genotoxic and mutagenic potential of clonazepam has not been adequately studied. Teratogenicity and fertility: there were performed preclinical studies in rodents (rabbits, rats, mice), which received clonazepam at doses several times higher than the maximum therapeutic dose in humans. Teratogenic effect on the foetus was determined in the group of animals involved in the studies compared to control group. The reduced number of females and newborns were found in rodents of the experimental group.. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients: lactose, maize starch, microcrystalline cellulose, magnesium stearate. 6.2 Incompatibilities: Not applicable. 6.3 Shelf life 4 years. 6.4 Special precautions for storage: Do not store above 25 C. Protect from light and moisture. 6.5 Nature and contents of container 10 tablets in blister from PVC film and lacquered aluminium foil 3 blisters (30 tablets) with package leaflet in the carton pack Special precautions for disposal and other handling Any unused products should be disposed of in accordance with local requirements. 7. MARKETING AUTHORISATION HOLDER JSC Olainfarm Address: 5 Rupnicu St., Olaine, LV-2114, Latvia. Phone: ; fax: ; olainfarm@olainfarm.lv 8. MARKETING AUTHORISATION NUMBER

10 10 of DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION / DATE OF REVISION OF THE TEXT: