Public Assessment Report. Decentralised Procedure

Transcription

1 Public Assessment Report Decentralised Procedure PRAZEPAM EG 10 mg & 20 mg tablets 15 mg/ml oral drops (30 drops/ml) Prazepam BE licence no: BE BE BE Applicant: Eurogenerics NV Date: 26/08/

2 This assessment report is published by the Federal Agency for Medicines and Health Products following Article 21 (3) and (4) of Directive 2001/83/EC, amended by Directive 2004/27/EC. The report comments on the registration dossier that was submitted to the Federal Agency for Medicines and Health Products and its fellow organisations in all concerned EU member states. It reflects the scientific conclusion reached by the Federal Agency for Medicines and Health Products and all concerned member states at the end of the evaluation process and provides a summary of the grounds for approval of a marketing authorisation. This report is intended for all those involved with the safe and proper use of the medicinal product, i.e. healthcare professionals, patients and their family and carers. Some knowledge of medicines and diseases is expected of the latter category as the language in this report may be difficult for laymen to understand. This assessment report shall be updated by a following addendum whenever new information becomes available. To the best of the Federal Agency for Medicines and Health Products knowledge, this report does not contain any information that should not have been made available to the public. The MAH has checked this report for the absence of any confidential information

3 LAY SUMMARY The Federal Agency for Medicines and Health Products granted Eurogenerics NV Marketing Authorisation for the medicinal product Prazepam EG 10mg tablets, Prazepam EG 20mg tablets and Prazepam EG 15mg/mL oral drops (BE , BE and BE ) on 08/06/2009. This pharmacy-only/prescription-only medicine is used for the symptomatic treatment of anxiety and in the event of a severe incapacitating disorder or if it is causing extreme suffering to the patient. This is a decentralised application for Prazepam EG 10mg tablets, Prazepam EG 20mg tablets and Prazepam EG 15mg/mL oral drops submitted under Article 10(1) of Directive 2001/83/EC (generic application). Prazepam is a benzodiazepine. Benzodiazepines act on the limbic, thalamic and hypothalamic regions of the CNS and are capable of producing the required level of CNS depression, notably sedation, hypnosis, relaxation of skeletal muscles and anticonvulsant activity. Prazepam is a prodrug and owes its in vivo activity to its parent compound N-desmethyldiazepam. The data submitted in support of the application for Prazepam EG 10 mg tablets, Prazepam EG 20mg tablets and Prazepam EG 15mg/mL oral drops raised no clinically significant safety concerns and it was therefore judged that the benefits of using these products outweigh the risks; hence a Marketing Authorisation has been granted

4 TABLE OF CONTENTS Module 1: Information about the initial procedure Page 5 Module 2: Summary of Product Charcteristics Page 7 Module 3: Package Leaflets Page 17 Module 4: Labelling Page 25 Module 5: Scientific Discussion Page Introduction 2. Quality aspects 3. Non-clinical aspects 4. Clinical aspects 5. Overall conclusion, benefit/risk assessment and recommendation Module 6: Public Assessment Report Update Page

5 1. Type of application MODULE 1 INFORMATION ABOUT THE INITIAL PROCEDURE This application is being made according to Article 28 of Directive 2001/83/EC as amended, granted by the Belgian Health Authorities on 8/6/2009. (MA number: BE , BE and BE ). This application concerns an abridged application, submitted according to Article 10 (1) Directive 2001/83/EC as amended. This type of application refers to information that is contained in the dossier of the authorisation of the reference product. A reference product is a medicinal product authorised and marketed on the basis of a full dossier, i.e. including chemical, biological, pharmaceutical, pharmacological- toxicological and clinical data. This information is not fully available in the public domain. Authorisations for generic products are therefore linked to the original authorised medicinal product, which is legally allowed once the data protection time of the dossier of the reference product has expired. For this kind of applications, it has to be demonstrated that the pharmacokinetic profile of the product is similar to the pharmacokinetic profile of the reference product. To this end a bioequivalence study has to be submitted. A bioequivalence study is the widely accepted means of demonstrating that the therapeutic equivalence and the use of different excipients and different methods of manufacture has no influence on efficacy and safety. A generic product can be used instead of its innovator product. No new pre-clinical and clinical studies were conducted, which is acceptable for this abridged application. This medicinal product Prazepam EG 10 mg tablets, Prazepam EG 20 mg tablets and Prazepam EG 15 mg/ml oral drops claims essential similarity with the innovator product Prazene 10mg tablets, Prazene 20mg tablets and Prazene 15mg/ml drops which has been registered in Italia by Pfizer Italia since 26/01/1979 (10mg tablets) and 20/12/1984 (20mg tablets and drops). In addition reference is also made to Lysanxia 10mg tablets, Lysanxia 20mg tablets and Lysanxia 15mg/mL drops authorizations in the individual Member States (reference product). The reference product used for bioequivalence study is Prazene 10mg and 20mg tablets registered by Pfizer Italia in Italia. 2. Active Substance Prazepam 3. Form tablets oral drops 4. Strength 10mg 20mg 15mg/ml 5. MA Holder Eurogenerics NV Heizel Esplanade b Brussel, Belgium - 5 -

6 6. RMS The Reference Member State is Belgium. 7. CMS The following member states were concerned: FR, IT, LU 8. Procedure-number 9. Timetable Day 0: 28/02/2008 Day 70: 08/05/2008 Day 100: 07/06/2008 Day 105: 12/06/2008 Day 120: 23/01/2009 Day 180: 24/03/2009 Day 205: 18/04/2009 Day 210: 23/04/

7 MODULE 2 SUMMARY OF PRODUCT CHARACTERISTICS 1. NAME OF THE MEDICINAL PRODUCT PRAZEPAM EG 10 mg tablets PRAZEPAM EG 20 mg tablets PRAZEPAM EG 15 mg/ml oral drops, solution 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Prazepam EG 10 mg tablets: each tablet contains 10 mg prazepam. Excipients: Lactose: 119,60 mg Prazepam EG 20 mg tablets: each tablet contains 20 mg prazepam. Excipients: Lactose: 83,80 mg Prazepam EG 15 mg/ml oral drops, solution: each ml contains 15 mg prazepam (equivalent to 30 drops). For a full list of excipients, see section PHARMACEUTICAL FORM Tablets. Prazepam EG 10 mg tablets: Blue, round, flat tablets, scored on one side. Prazepam EG 20 mg tablets: White, round, flat tablets, scored on one side. The tablet can be divided into equal halves. Oral drops, solution. Prazepam EG 15 mg/ml oral drops, solution: Blue solution characterised by mint and anethole odour and taste. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Symptomatic treatment of anxiety. Benzodiazepines are indicated in the event of severe incapacitating symptoms or if these symptoms lead to an extreme suffering for the patient. 4.2 Posology and method of administration Adults The recommended dose should be of mg/day, and higher doses up to 60 mg should be reserved for most severe anxious conditions in psychiatric patients. This dosage can be administered in one or several doses every 24 hours, e.g.: a.) a full dose at night or - 7 -

8 b.) ¼ of the dose in the morning, ¼ at midday and ½ at night or c.) ½ of the dose in the morning and ½ at night. Elderly patients. In elderly or debilitated patients, it is advisable to start treatment with a 10 or 15 mg dose of prazepam, distributed over the day, and to subsequently increase it if necessary. Usually the therapeutic response can be obtained with half dose (see section 4.4). Adolescents (12-17 years of age). Under 18 years of age, it is advisable to adjust the dosage depending on the age and weight of the patient and to not exceed 1 mg per kg body weight per day. Children. There are no clinical data on the use of prazepam in children under 6 years of age (see section 4.3, 4.4) For all patients In some cases the patient s state of health may necessitate longer-term administration. Each case where benzodiazepines are used over a prolonged period should be regularly re-evaluated by the doctor. Caution is advised when treatment is stopped. A decrease in dose should be considered in patients with impaired renal or mild to moderate impaired hepatic function. Duration of treatment. Treatment should be as short as possible. The patient s state of health should be regularly re-evaluated and the need for continued treatment re-examined, especially if the patient has no symptoms. Total duration of treatment should normally not exceed 8-12 weeks, including the dose withdrawal phase. In some cases, it may be necessary to prolong treatment beyond the maximum recommended period; if this happens, the patient s state of health should be re-evaluated first by a doctor. Treatment should be initiated at the minimum recommended dose. The maximum dose should not be exceeded. 4.3 Contraindications Patients with a history of hypersensitivity to the active substance or to any of the excipients. Patients with a history of hypersensitivity to other benzodiazepines. Cases of glaucoma and myasthenia gravis. Children under 6 years of age. Patients with severe respiratory insufficiency. Sleep apnoea syndrome. Benzodiazepines are contraindicated in patients with severe hepatic insufficiency as it may precipitate encephalopathy. 4.4 Special warnings and precautions for use Prazepam EG is not recommended in psychiatric disorders and psychotic states where anxiety is not one of the major factors. As a result, prazepam should only be used as an adjuvant in psychoses. Elderly patients. Minor drowsiness and/or a decrease in ability to concentrate, as well as a reduction in muscle tone may present in the elderly or in those with weak muscles. In the elderly or very weak, it is advisable to start treatment at a lower dose e.g. 10 or 15 mg dose of prazepam, distributed over the day, and to subsequently increase it if necessary

9 Adolescents (12-17 years of age). In adolescents it is advisable to decrease the dosage, depending on the age and weight of the patient. Children. There are no clinical data on the use of prazepam in children under 6 years of age. Renal impairment. A decrease in dose should be considered in patients with impaired renal function. Hepatic impairment. A decrease in dose should be considered in patients with mild to moderate impaired hepatic function. Tolerance. Benzodiazepines can induce symptoms of tolerance. Dependence. Administration of benzodiazepines can lead to the development of physical and psychological dependence. The risk of dependence increases with the dose and duration of treatment. Furthermore, it is greater in patients with a history of alcoholism or drug dependence. Once a person has become physically dependent, sudden withdrawal of treatment is accompanied by symptoms of withdrawal (for a list of these symptoms see section 4.8). Rebound anxiety: when treatment is stopped a temporary syndrome may occur, in which the symptoms that led to benzodiazepines being prescribed reappear in an amplified form. As the risk of withdrawal or rebound symptoms is greater after sudden withdrawal of treatment, a gradual reduction in dose is recommended. For a list of withdrawal symptoms see section 4.8 Progressive discontinuation of treatment The procedure should be clearly detailed to the patient. Besides the need of progressive dose tapering phase, patients should be informed of the risk of rebound phenomena in order to minimise the anxiety that might follow the symptoms linked with discontinuation, even if progressive. The patient should be informed about the possibly uncomfortable nature of this period. Duration of treatment. Duration of treatment should be as short as possible (see Posology and Method of Administration ) and should not exceed 8-12 weeks, including the dose withdrawal phase. If the treatment is to be extended beyond this period, the situation should be re-evaluated. For patients with a history of dependence, see the section Undesirable effects. Amnesia. Benzodiazepines can cause anterograde amnesia which generally occurs within a few hours after ingestion of the product. For patients with a history of dependence, see the section Undesirable effects. Epilepsy Although epileptic fits may occur following the abrupt withdrawal of treatment, this risk will probably be greater with benzodiazepines that have a short half-life. One should bear this in mind when treating patients who have already suffered from epilepsy. Psychiatric and paradoxical reactions

10 Reactions like restlessness, agitation, irritability, aggressiveness, delirium, rage, nightmares, delusions, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines. If these paradoxical reactions occur, Prazepam EG should be discontinued. These reactions are more likely to occur in children and the elderly. Benzodiazepines are not indicated in the primary treatment of psychotic disorders. Benzodiazepines should not be used as monotherapy in the treatment of depression or anxiety associated with depression (as they may trigger suicide in these patients). Alcohol. Benzodiazepines should be used with extreme caution in patients with a history of alcoholism or drug dependence. As far as the concomitant intake of alcohol is concerned, see the section Interaction with other medicinal products and other forms of interaction. Patients with respiratory conditions. Owing to the risk of severe respiratory depression, a lower dose is recommended in patients presenting with chronic, non-specific respiratory conditions or respiratory insufficiency. See the section Contraindications. Lactose. Prazepam EG tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. 4.5 Interaction with other medicinal products and other forms of interaction It is not advisable to use Prazepam EG at the same time as other substances that have a CNSdepressant action (e.g. narcotics, anaesthetics, anticonvulsants, sedating antihistamines, barbiturates, MAO inhibitors, antidepressants, antipsychotics, hypnotics, anxiolytics/sedatives, analgesics and alcohol). Simultaneous intake of alcohol is not recommended. The sedative effect may be potentiated by the simultaneous intake of the product with alcohol, which may affect the ability to drive and use machines. Simultaneous intake of narcotic analgesics may also amplify the feeling of euphoria, which results in increasing psychological dependence. The concomitant use of benzodiazepines and valproic acid appears to increase the risk of psychoses. The concomitant use of cimetidine and/or omeprazole increases the concentration of benzodiazepines in the plasma. Pharmacokinetic interactions, the clinical impact of which is not at all clear, have been described between several benzodiazepines and the following medications: barbiturates, rifampicin, phenytoin, oral contraceptives, isoniazide and disulphiram. The inhibitors CYP3A4 and CYP450 can reduce the metabolism of prazepam and increase the potential for toxicity. Theophylline antagonises the pharmacological effect of benzodiazepines. Oral contraceptives and hormone substitution treatments can increase the effects of prazepam as they inhibit oxidative metabolism, and therefore increase serum concentrations of concomitantly administered benzodiazepines which are undergoing oxidation. Patients taking oral contraception should be monitored to determine any increase in the effects of prazepam. Caution is advised when administering benzodiazepines at the same time as clozapine as they can cause additional CNS-depressant effects. Severe confusion, hypotension and respiratory depression have been observed on rare occasions in patients receiving clozapine at the same time or after

11 benzodiazepine treatment. Patients treated simultaneously with clozapine should initially be given half the normal dose of benzodiazepine until there is sufficient experience with that patient. When buprenorphine is given concomitantly with prazepam, the risk of a possibly fatal respiratory depression is increased. Therefore a careful benefit/risk evaluation of this association should be performed and the patient should be informed of the necessity to respect the prescribed doses. 4.6 Pregnancy and lactation Administration of benzodiazepines is not recommended in the event of suspected or confirmed pregnancy and while breast-feeding. Pregnancy. When prazepam is prescribed to a woman of child-bearing age, the woman should be advised to inform her doctor if she wishes to become or is already pregnant, so that the doctor can take the decision to discontinue treatment. Studies carried out to date on prazepam have not yet established whether there is a risk of congenital malformation when this product is used during pregnancy. However, some studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. As the indications are rarely vitally urgent, it is preferable not to administer prazepam during the first trimester of pregnancy. When the product is administered for medical reasons during the last part of pregnancy or during labour, hypothermia, hypotension and respiratory depression may develop in the newborn. Since infants whose mothers have taken benzodiazepines during pregnancy may develop physical dependency, withdrawal symptoms may occur during postnatal development. Lactation. Administration of prazepam is not advisable during labour and while breast-feeding, because of the risk of hypotension, hypothermia and even withdrawal symptoms in the newborn. Benzodiazepines cross the foeto-placental barrier and are excreted in the mother s milk. 4.7 Effects on ability to drive and use machines Depending on the individual sensitivity to benzodiazepines which is unpredictable, patients may develop drowsiness and/or reduction in ability to concentrate, amnesia, deterioration in concentration and muscle function as well as reduced muscle tone and slowing of reflexes. These reactions may affect the ability to drive or operate machinery. If sleeping time is inadequate, this may increase the risk of impaired vigilance (see Interaction with other medicinal products and other forms of interaction ). Therefore, caution is advised when the patient is driving a vehicle or operating dangerous machinery, especially at the start of treatment. 4.8 Undesirable effects Reported side-effects are summarised in the following table, by system and frequency. The frequencies are defined as follows: very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1,000, < 1/100), rare (> 1/10,000, < 1/1,000) and very rare (< 1/10,000). MedDRa SOC Psychiatric disorders Very common 1/10 Common 1/100, <1/10 confusion, abnormal dreams Uncommon 1/1000, <1/100 Rare 1/10000, <1/1000 Very rare <1/

12 MedDRa SOC Nervous system disorders Eye disorders Very common 1/10 Common 1/100, <1/10 somnolence drowsiness, dizziness, ataxia, headache, tremor, speech disturbances Uncommon 1/1000, <1/100 syncope impaired vision Rare 1/10000, <1/1000 Very rare <1/10000 Cardiac disorders Gastrointestina l disorders Skin and subcutaneous tissue disorders Musculoskelet al and connective tissue disorders Renal and urinary disorders Reproductive system and breast disorders General disorders and administration site conditions palpitations dry mouth, various gastro-intestinal complaints diaphoresis, rash pruritis anaphylactic shock athralgy Fatigue, asthenia oedema of the feet several genital and urinary symptoms menstruation, ovulation and sexual disturbances gynecomastia The following undesirable effects are typical for benzodiazepines. They mostly occur at the start of treatment and generally disappear as treatment progresses. Decreasing the dose can relieve symptoms. General disorders: asthenia, muscle weakness, changes in libido, feeling drunk. Nervous system disorders. Uncommon: Altered state of consciousness, memory disorders (especially in the elderly), possibility of paradoxical reactions (especially in the elderly, e.g. increased insomnia, aggression, agitation, increased anxiety and epileptic fits), irritability, reduced vigilance, confusion. Rare psychiatric disorders, such as depersonalisation, psychosis, frozen emotions or paradoxical reactions may present due to rapid fluctuations in blood levels of benzodiazepines. Hepatobiliary disorders: cholestasis and jaundice (rare). Respiratory disorders: respiratory depression in patients suffering from a non-specific chronic respiratory condition. Blood and lymphatic system disorders: rarely, agranulocytosis. Eye disorders: diplopia. Amnesia

13 Anterograde amnesia can occur at therapeutic doses. The risk increases with increasing dose. Effects of amnesia may be associated with inappropriate behaviour (see section Special warnings and precautions for use ). Depression. Pre-existing depression may become apparent during benzodiazepine treatment. Psychiatric and paradoxical reactions. Agitation, irritability, aggression, delirium, rage, nightmares, hallucinations, psychoses, inappropriate behaviour and other behavioural effects are known reactions of treatment with benzodiazepines or benzodiazepine-type products. These reactions can be relatively serious and are more likely to occur in the elderly. Dependence. Administration of benzodiazepines (even at therapeutic doses) can lead to the development of physical dependence. As a result, stopping treatment might induce a withdrawal or rebound effect (see section Special warnings and precautions for use ). Psychological dependence may also develop. Cases of benzodiazepine abuse have been reported. Prolonged use can undeniably cause physical and psychological dependence. Since the half-life of the active metabolite of prazepam in the blood is very long, the risk of withdrawal symptoms appearing is relatively small. Symptoms that may present following abrupt withdrawal of prolonged benzodiazepine treatment include: mood swings, (extreme) anxiety or sleeping disorders, agitation, convulsions, tremor, muscle and abdominal cramps, vomiting, sweating, headaches, muscle pain, tension, confusion and irritability. In severe cases, the following symptoms may present: derealisation, depersonalisation, hyperacousia, numbness and tingling in the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic fits. 4.9 Overdose Symptoms of benzodiazepine overdose include: fatigue which may be accompanied by ataxia, inability to coordinate movements and confusion. As in all cases of overdose, one should consider that other substances may have been taken simultaneously. A benzodiazepine overdose taken in conjunction with alcohol, another medication or in the presence of an underlying illness, can prove life-threatening. If large doses have been absorbed, vomiting must be induced if this does not occur spontaneously, a gastric lavage performed or activated charcoal administered immediately and patient s vital functions monitored adequately. If the patient suffers from hypotension (although unlikely), this is to be controlled by injecting L- noradrenaline bitartrate or vasopressor drugs (e.g. metaraminol bitartrate). Flumazenil is a specific antagonist of benzodiazepine receptors that can be used as an adjuvant with resuscitation measures in the event of severe intoxication with coma. The use of flumazenil as an antidote is contraindicated in the following cases: when taking tricyclic antidepressants, the concomitant administration of medications that induce epileptic fits, ECG anomalies such as prolongation of the QRS interval or QT interval (suggesting the concomitant intake of tricyclic antidepressants). Patients treated with flumazenil must be followed up for a fixed time after treatment in case sedation, respiratory depression or any other residual effect associated with benzodiazepines reappears. The doctor should be aware of the risk of convulsions when flumazenil is combined with benzodiazepines, particularly in long-term users of benzodiazepines or in the event of an overdose of cyclic antidepressants

14 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: anxiolytics, ATC code: N05BA11. Mode of action. Prazepam is a derivative of the benzodiazepines. Benzodiazepines act on the limbic, thalamic and hypothalamic regions of the CNS and are capable of producing the required level of CNS depression, notably sedation, hypnosis, relaxation of skeletal muscles and anticonvulsant activity. Recent data indicate that benzodiazepines act by stimulating the GABA (gamma-aminobutyric acid) - benzodiazepine receptor complex. GABA is an inhibitory neurotransmitter that acts on specific subtypes of receptors designated by GABA-A and GABA-B. GABA-A is the main CNS receptor subtype and it is supposed to mediate anxiolytic and sedative actions. It is thought that specific subtypes of the benzodiazepine (BNZ) receptors are coupled to GABA-A receptors. Three types of BNZ receptor have been observed in the CNS and other tissues; BNZ 1 receptors are situated in the cerebellum and cerebral cortex, BNZ 2 receptors are situated in the cerebral cortex and the spinal cord and BNZ 3 receptors are situated in the peripheral tissues. Activation of the BNZ 1 receptor is supposed to mediate sleep, while the BNZ 2 receptor encourages muscle relaxation, anticonvulsant activity, motor coordination and memory. Benzodiazepines are bound to BNZ 1 and BNZ 2 receptors, which stimulate the GABA effects. Unlike barbiturates, which increase the GABA responses by prolonging the time the chloride channels are open, benzodiazepines stimulate the effects of GABA by increasing the affinity of GABA for the GABA receptor. Binding the GABA to the receptor site causes the chloride channel to open, resulting in a hyperpolarised cell membrane that prevents any subsequent excitement of the cell. 5.2 Pharmacokinetic properties Absorption/biotransformation. After absorption, practically no prazepam is recovered in the blood. The metabolite, obtained by enzymatic transformation, is N-desalkylprazepam. This is responsible for the pharmacodynamic activity of the product. N-desalkylprazepam is strongly bound to plasma proteins, the free fraction accounting for approximately 3.5%. The peak plasma concentration of this metabolite is achieved after 4-6 hours, and the mean half-life is of the order of +/- 65 hours. Elimination. Excretion of this metabolite is mainly by renal route in the form of 3-hydroxyprazepam glucuronide and oxazepam. 5.3 Preclinical safety data Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use. However, in rats, oral administration of 10 mg/kg prazepam increased the frequency of foetal hydrops, tail skeletal anomalies, and reduced the body weight and the weight of the most important internal organs of offspring. In rabbits, no congenital defects with oral dosages of prazepam between 5 and 50 mg/kg have been observed. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients Prazepam EG 10 mg tablets

15 Lactose monohydrate Microcrystalline cellulose Maize starch Magnesium stearate Indigotin Lake (E 132) Prazepam EG 20 mg tablets. Lactose monohydrate Microcrystalline cellulose Maize starch Magnesium stearate Colloidal silica Prazepam EG 15 mg/ml oral drops, solution Propylene glycol Diethylene glycol monoethyl ether Sodium saccharin Polysorbate 80 Menthol Anethol E 131 Patent blue V 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years. Drops: Prazepam EG 15 mg/ml oral drops, solution should be used within 30 days after first opening. 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container Prazepam EG 10 mg tablets: 20, 30, 40 and 50 tablets packed in blisters (Alu/PVC). Prazepam EG 20 mg tablets: 20 and 50 tablets for packed in blisters (Alu/PVC). Prazepam EG drops: 20 ml solution packed in a dropper container. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling No special requirements. 7. MARKETING AUTHORISATION HOLDER < to be completed nationally> 8. MARKETING AUTHORISATION NUMBER(S) Prazepam EG 10 mg tablets:

16 Prazepam EG 20 mg tablets: Prazepam EG 15 mg/ml oral drops, solution: 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION Prazepam EG 10 mg tablets: Prazepam EG 20 mg tablets: Prazepam EG 15 mg/ml oral drops, solution: 10. DATE OF REVISION/APPROVAL OF THE TEXT Date of revision of the text: Date of approval of the text:

17 MODULE 3 PACKAGE LEAFLET: INFORMATION FOR THE USER PRAZEPAM EG 10 mg tablets PRAZEPAM EG 20 mg tablets PRAZEPAM EG 15 mg/ml oral drops, solution prazepam Read all of this leaflet carefully before you start taking this medicine. Keep this leaflet. You may need to read it again. If you have any further questions, ask your doctor or pharmacist. This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. In this leaflet: 1. What Prazepam EG is and what it is used for 2. Before you take Prazepam EG 3. How to take Prazepam EG 4. Possible side effects 5. How to store Prazepam EG 6. Further information 1. What Prazepam EG is and what it is used for The active substance of Prazepam EG is prazepam. Prazepam is a benzodiazepine derivative and is indicated to treat symptoms of anxiety. Benzodiazepines are used to treat severe incapacitating symptoms or symptoms leading to an extreme suffering for the patient. Prazepam EG is used to treat anxiety and nervous tension requiring sedative treatment. 2. Before you take Prazepam EG DO NOT take Prazepam EG if you are allergic (hypersensitive) to prazepam or to any of the other ingredients of Prazepam EG. if you have experienced an allergic reaction to other benzodiazepines in the past if you suffer from glaucoma (an eye disorder, characterised by increased pressure within the eye) or severe myasthenia (muscle weakness) if you have severe breathing difficulties in children below 6 years of age if you have sleep apnoea syndrome (when you stop breathing for a short time during your sleep) if you have severe hepatic insufficiency (severe liver disease) Take special care with Prazepam EG

18 Prazepam EG is only recommended for nervous disorders in which anxiety is a main feature. As a result, if you have severe mental illness, you should only be given prazepam as an additional ( add-on ) treatment. if you are elderly or you are physically weakened, you may develop slight drowsiness and/or reduced mental sharpness in what you undertake as well as reduced muscle tone if you are elderly or severely weakened, you should start treatment at a dose of 10 or 15 mg prazepam (divided throughout the day), and increase this dose later on, if necessary. If you have non-specific, chronic breathing difficulties and dyspnoea (shortness of breath) your doctor should recommend a lower dose. Adolescents between years of age, will be given a reduced dose, depending on the adolescent s age and body weight. You should tell your doctor if you have a kidney or liver disorder (see section Do not take Prazepam EG ). Benzodiazepines can lead to dependency. The risk of dependency increases with the dose and duration of treatment and in patients with a history of alcoholism or dependency on other substances. In this case, any abrupt discontinuation of treatment can lead to the withdrawal symptoms: headache, muscle pain, extreme anxiety, tension, confusion and irritability. In severe cases, the following symptoms may appear: derealisation (when things seem strange or unreal), depersonalisation (when you have an altered perception of yourself), hyperacusis (when you are unable to tolerate everyday sounds), numbness and tingling in the hands and feet (pins and needles), hypersensitivity to light, sound and physical contact, hallucinations (when you sense things that are not real), epileptic fits. Stopping treatment may trigger a short-lasting syndrome, causing your original symptoms to reoccur in exaggerated form. Other reactions may occur, e.g. mood swings, sleep disorders, convulsions, tremor, muscle and abdominal cramps, vomiting, sweating and agitation. The risk of withdrawal symptoms or rebound phenomenon is significantly increased if you suddenly stop your treatment, so your doctor will reduce your dose gradually. You may suffer from rebound anxiety when stopping Prazepam EG. You should take Prazepam EG for as short a time as possible, depending on your illness, and no longer than 8-12 weeks, including the dose-reduction ( tapering-off ) phase. You should not take Prazepam EG for longer than this until your doctor has reassessed your condition. Benzodiazepines may lead to short-term memory loss, which usually occurs within a few hours after you have taken your medicine. If you suffer from alcoholism or a dependency on other substances, you should take great care. If you are already taking other medicines, please also read the section Taking other medicines. Taking other medicines Prazepam EG should not be used together with other medicines that may decrease brain activity, e.g.: narcotics anaesthetics anticonvulsants sedative antihistamines barbiturates antidepressants antipsychotics monoamine oxidase inhibitors hypnotics anxiolytics/sedatives painkillers Combined use of benzodiazepines and valproic acid increases the risk of psychosis (a loss of contact with reality)

19 Any combined use of benzodiazepines and clozapine should be carefully considered. In this case, your doctor may decide to reduce the benzodiazepine dose at the start of treatment. The effect of Prazepam EG may be prolonged if used together with cimetidine or omeprazole (medicines used to treat ulcers). The effect of Prazepam EG may be increased if used together with oral contraceptives (the Pill) and supplementary hormonal treatments, e.g. hormone replacement therapy (HRT). Use of narcotic analgesics (e.g. morphine) can increase euphoria, resulting in increased psychological dependence (addiction). Theophylline (an asthma medicine) works against the pharmacological effect of benzodiazepines. Association of prazepam and buprenorphin is only possible after a careful benefit/risk evaluation. Contact your doctor before taking Prazepam EG. Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription. Using Prazepam EG with food and drink Prazepam EG should not be used at the same time as other medicines which may decrease brain activity, including alcohol. Do not drink any alcohol during treatment. The sedative effect of Prazepam EG can be increased by the consumption of alcohol during treatment, which may affect your ability to drive and use machines. Pregnancy and breast-feeding You should not take Prazepam EG if you are pregnant or you think you may be pregnant. Inform your doctor if you become pregnant, or if you wish to become pregnant. In particular, Prazepam EG should not be taken in the first three months of pregnancy. Prazepam should not be taken during childbirth. Please tell your doctor if you are breastfeeding. If you are breast-feeding you should not take prazepam. Ask your doctor or pharmacist for advice before taking any medicine. Driving and using machines Depending on your individual sensitivity, the following side-effects may occur: drowsiness and/or reduced ability to concentrate amnesia (memory loss) a lack of concentration impaired muscle function reduced muscle tone slower reflexes. Such effects can influence your ability to drive or use machines. If you are suffering from a lack of sleep you are at greater risk of reduced alertness. You should therefore be careful when driving vehicles or using dangerous tools, especially at the start of treatment. Important information about some of the ingredients of Prazepam EG Prazepam EG tablets contain lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product

20 3. How to take Prazepam EG Always take Prazepam EG exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. All Prazepam EG formulations are intended for oral use. Your doctor will decide on the daily dose that you should take. The usual dose is between 10 and 60 mg prazepam, depending on your response. For elderly patients If you are elderly or severely weakened, you should start treatment at a dose of 10 or 15 mg prazepam (divided throughout the day), and increase this dose later on, if necessary. For adolescents (12 to 17 years of age) If you are less than 18 years old your dose will be adjusted according to your age and body weight. The maximum dose is 1 mg per kg of body weight per day. Duration of treatment Your doctor will tell you how long you should go on taking Prazepam EG. In many cases, benzodiazepines need only be taken on an occasional or temporary basis, i.e. over a short period. Sometimes, your state of health requires the use of Prazepam EG over longer periods. Whenever benzodiazepines are used over longer periods, your doctor will regularly assess if you need to continue treatment. It is important to exercise caution when stopping treatment. Patients with liver or kidney disease Reduced doses must be considered for patients with impaired liver or kidney function. If you take more Prazepam EG than you should The visible signs of overdose are tiredness, sometimes with uncoordinated movements and confusion. As in all cases of overdose, the possibility of multiple drug involvement (i.e. that other drugs have also been taken) must be considered. If you forget to take Prazepam EG If you have forgotten your dose, take the next dose at your scheduled time. Do not take a double dose of Prazepam EG to make up for a forgotten dose. If you stop taking Prazepam EG Do not stop taking Prazepam EG suddenly under any circumstances, especially if you have been taking Prazepam EG for a long time. Symptoms may appear after suddenly stopping long-term benzodiazepine treatment (see Take special care with Prazepam EG ). Always consult your doctor, who will explain how to reduce your dose gradually. If you have any further questions on the use of this product, ask your doctor or pharmacist. 4. Possible side effects Like all medicines, Prazepam EG can cause side effects, although not everybody gets them. Reported side-effects are summarised in the following table, by system and frequency. The frequencies are defined as follows: very common: affects more than 1 user in 10 common: affects 1 to 10 users in 100 uncommon: affects 1 to 10 users in 1,

21 rare: affects 1 to 10 users in 10,000 very rare: affects less than 1 user in 10,000 not known: frequency cannot be estimated from the available data The following side effects have been identified with benzodiazepine use in general. They mainly occur at the start of treatment and mostly disappear as treatment continues. Blood and lymphatic system disorders: Rare: Blood disorders (agranulocytosis). Cardiac disorders: Common: Eye disorders: Uncommon: Gastrointestinal disorders; Common: Heart palpitations Blurred vision, double vision Dry mouth, various gastrointestinal complaints General disorders and administration site conditions: Common: Tiredness, weakness, altered libido, feeling drunk Hepatobiliary disorders: Rare: Investigations: Rare: Jaundice Bile output decreased Musculoskeletal and connective tissue disorders: Common: Painful joints Uncommon: Swollen feet Nervous system disorders: Very common: Common: Uncommon: Somnolence Drowsiness, dizziness, bouts of giddiness, uncoordinated movements, headache, trembling, problems of self-expression Fainting, altered state of consciousness, memory impairment (especially if you are elderly), epileptic fits, alertness decreased Psychiatric disorders: Common: Uncommon: Rare: Renal and urinary disorders: Uncommon: Confusion, vivid dreams Agitation, irritability, increased insomnia, aggressiveness, increased anxiety, confusion Multiple personality, depression, psychosis, apathy or paradoxical reactions, delusion of persecution Several genital and urinary disorders Reproductive system and breast disorders: Rare: Menstruation, ovulation and sexual disturbances Very rare: Enlargement of breasts in males (gynaecomastia) Respiratory, thoracic and mediastinal disorders: Not known: Depressed breathing in patients with non-specific chronic respiratory disease

22 Skin and subcutaneous tissue disorders: Common: Severe bouts of sweating, temporary skin rash Uncommon: Itching Very rare: Hypersensitivity to foreign substances, anaphylactic shock Amnesia: Memory loss after taking Prazepam EG (anterograde amnesia) may occur at therapeutic doses. This risk increases with the dose. The effects of memory loss may be associated with inappropriate behaviour (see section Take special care with Prazepam EG ). Depression: Hidden depression may become obvious during treatment with benzodiazepines. Psychiatric and paradoxical reactions: Reactions, such as: agitation irritability aggressiveness delirium (sudden lack of ability to focus your attention) bouts of rage nightmares hallucinations (sensing things that are not really there) psychoses (mental disorders) inappropriate behaviour and other behavioural problems are known reactions during treatment with benzodiazepines or benzodiazepine-like products. Such reactions may also be relatively dangerous and are generally more common in the elderly. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist. 5. How to store Prazepam EG Keep out of the reach and sight of children. This medicinal product does not require any special storage conditions. Drops: Prazepam EG 15 mg/ml oral drops, solution should be used within 30 days after first opening. Do not use Prazepam EG after the expiry date which is stated on the carton, blister or bottle after EXP. The expiry date refers to the last day of that month. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. 6. Further information What Prazepam EG contains The active substance is prazepam. Each tablet contains 10 mg or 20 mg prazepam. 1 ml of solution contains 15 mg prazepam (equivalent to 30 drops). The other ingredients are: Prazepam EG 10 mg tablets:

23 lactose monohydrate microcrystalline cellulose maize starch magnesium stearate indigotin Lake (E132) Prazepam EG 20 mg tablets: lactose monohydrate microcrystalline cellulose maize starch magnesium stearate colloidal silica Prazepam EG 15 mg/ml oral drops, solution: propylene glycol diethylene glycol monoethyl ether sodium saccharin polysorbate 80 menthol anethol E 131 Patent blue V What Prazepam EG looks like and contents of the pack Prazepam EG 10 mg tablets are scored blue tablets and are available in Aluminium/PVC blister packs of 20, 30, 40 and 50 tablets. The tablet can be divided into equal halves. Prazepam EG 20 mg tablets are scored white tablets and are available in Aluminium/PVC blister packs of 20 and 50 tablets. The tablet can be divided into equal halves. Prazepam EG 15 mg/ml oral drops, solution is available in 20 ml dropper containers. 30 drops of the solution correspond with 1 ml and thus 15 mg prazepam. Not all pack sizes may be marketed. Marketing Authorisation Holder <to be completed nationally> Manufacturer Prazepam EG 10 mg tablets: Cosmo S.p.A. Via C. Colombo, Lainate (MI) Italy Sanico NV Industrieterrein 4 Veedijk Turnhout Belgium Laboratoires BTT Zone Industrielle de Kraft Erstein France

24 Eurogenerics NV Heizel Esplanade b22 B-1020 Brussels Belgium Prazepam EG 20 mg tablets: Cosmo S.p.A. Via C. Colombo, Lainate (MI) Italy Sanico NV Industrieterrein 4 Veedijk Turnhout Belgium Eurogenerics NV Heizel Esplanade b22 B-1020 Brussels Belgium Prazepam EG drops Cosmo S.p.A.Via C. Colombo, Lainate (MI) Italy Sanico NV Industrieterrein 4 Veedijk Turnhout Belgium Eurogenerics NV Heizel Esplanade b22 B-1020 Brussels Belgium This medicinal product is authorised in the Member States of the EEA under the following names: < {Name of the Member State} > < {Name of the medicinal product} This leaflet was last approved in {MM/YYYY}

25 MODULE 4 LABELLING PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton/box 1. NAME OF THE MEDICINAL PRODUCT Prazepam EG 10 mg tablets Prazepam 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 10 mg prazepam. 3. LIST OF EXCIPIENTS Contains lactose. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Tablets 20 tablets 30 tablets 40 tablets 50 tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY - 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS

26 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER [To be completed nationally] 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Batch 14. GENERAL CLASSIFICATION FOR SUPPLY [To be completed nationally] 15. INSTRUCTIONS ON USE INFORMATION IN BRAILLE Prazepam EG 10 mg *** MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS Alu/PVC blister 1. NAME OF THE MEDICINAL PRODUCT Prazepam EG 10 mg tablets Prazepam 2. NAME OF THE MARKETING AUTHORISATION HOLDER [To be completed nationally] 3. EXPIRY DATE EXP

27 4. BATCH NUMBER Batch 5. OTHER

28 LABELLING PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton/box 1. NAME OF THE MEDICINAL PRODUCT Prazepam EG 20 mg tablets Prazepam 2. STATEMENT OF ACTIVE SUBSTANCE(S) Each tablet contains 20 mg prazepam. 3. LIST OF EXCIPIENTS Contains lactose. See leaflet for further information. 4. PHARMACEUTICAL FORM AND CONTENTS Tablets 20 tablets 50 tablets 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY - 8. EXPIRY DATE EXP 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

29 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER [To be completed nationally] 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Batch 14. GENERAL CLASSIFICATION FOR SUPPLY [To be completed nationally] 15. INSTRUCTIONS ON USE INFORMATION IN BRAILLE Prazepam EG 20 mg *** MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS Alu/PVC blister 1. NAME OF THE MEDICINAL PRODUCT Prazepam EG 20 mg tablets Prazepam 2. NAME OF THE MARKETING AUTHORISATION HOLDER [To be completed nationally] 3. EXPIRY DATE EXP 4. BATCH NUMBER Batch 5. OTHER

30 LABELLING PARTICULARS TO APPEAR ON THE OUTER PACKAGING Carton/box 1. NAME OF THE MEDICINAL PRODUCT Prazepam EG 15 mg/ml oral drops solution Prazepam 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 ml of solution contains 15 mg prazepam (equivalent to 30drops). 3. LIST OF EXCIPIENTS - 4. PHARMACEUTICAL FORM AND CONTENTS Oral drops solution 20 ml 5. METHOD AND ROUTE(S) OF ADMINISTRATION Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY - 8. EXPIRY DATE EXP The solution should be used within 30 days after first opening. 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

31 11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER [To be completed nationally] 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Batch 14. GENERAL CLASSIFICATION FOR SUPPLY [To be completed nationally] 15. INSTRUCTIONS ON USE INFORMATION IN BRAILLE Prazepam EG 15 mg/ml *** PARTICULARS TO APPEAR ON THE PRIMAIRY PACKAGING Label 1. NAME OF THE MEDICINAL PRODUCT Prazepam EG 15 mg/ml oral drops solution Prazepam 2. STATEMENT OF ACTIVE SUBSTANCE(S) 1 ml of solution contains 15 mg prazepam (equivalent to 30 drops). 3. LIST OF EXCIPIENTS - 4. PHARMACEUTICAL FORM AND CONTENTS Oral drops solution 20 ml 5. METHOD AND ROUTE(S) OF ADMINISTRATION

32 Oral use. Read the package leaflet before use. 6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN Keep out of the reach and sight of children. 7. OTHER SPECIAL WARNING(S), IF NECESSARY - 8. EXPIRY DATE EXP The solution should be used within 30 days after first opening. 9. SPECIAL STORAGE CONDITIONS 10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER [To be completed nationally] 12. MARKETING AUTHORISATION NUMBER(S) [To be completed nationally] 13. BATCH NUMBER Batch 14. GENERAL CLASSIFICATION FOR SUPPLY [To be completed nationally] 15. INSTRUCTIONS ON USE INFORMATION IN BRAILLE