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. Excipient with known effect: Lactose: 119,60 mg

Prazepam EG 20 mg tablets: each tablet contains 20 mg prazepam. Excipient with known effect: Lactose: 83,80 mg

Prazepam EG 15 mg/ml oral drops, solution: each ml contains 15 mg prazepam (equivalent to 30 drops).

For the full list of excipients, see section 6.1.

3. 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 doses.

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

Posology

Adults The recommended dose should be of 10-30 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.:

1/11 a.) a full dose at night or 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).

Paediatric population  Adolescents (12-17 years of age). It is advisable to decrease the dosage depending on the age and weight of the patient and to not exceed 1 mg per kg body weight per day. The recommended dose should be of 10-30 mg/day, and higher doses up to 60 mg should be reserved for most severe anxious conditions in psychiatric patients.

There are no clinical data on the use of prazepam in children under 6 years of age (see section 4.3, 4.4). The use of benzodiazepines in children below 6 years of age is only permitted after evaluation and under the surveillance of a specialist (neuropaediatrician, psychiatrist) who will decide on its posology. In many cases the administration of benzodiazepines meets an occasional or temporary need and so will be of short duration.

Renal impairment, hepatic impairment A decrease in dose should be considered in patients with impaired renal or mild to moderate impaired hepatic function.

Method of administration

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 listed in section 6.1.  Patients with a history of hypersensitivity to other benzodiazepines.  Cases of myasthenia gravis.

2/11  Children under 6 years of age; use in children below 6 years of age is intended for rare and specific indications after evaluation and under the surveillance of a specialist (neuropaediatrician, psychiatrist)  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.

Paediatric population There are no clinical data on the use of prazepam in children under 6 years of age.

Benzodiazepines must not be administered to children without careful evaluation of the need of such treatment. Duration of treatment should be as short as possible. The use of benzodiazepines in children below 6 years of age is intended for rare and specific indications after evaluation and under the surveillance of a specialist (neuropaediatrician, psychiatrist) (see section 4.3. Contraindications). In children 6 to 18 years of age, dose reduction is recommended depending on the patient’s age and body weight. Prazepam EG should only be prescribed to children after thourough evaluation of the indication. There are no clinical data as to the use of Prazepam EG in children below 6 years of age. Children are more sensitive to the effects of benzodiazepines on the CNS, because development of the metabolism scheme is still incomplete so that formation of inactive metabolites might not be possible or not be complete.

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. Benzodiazepines are contraindicated in patients suffering from severe hepatic impairment, as they may precipitate encephalopathy.

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. These might be headache, muscular pains, extreme anxiety, tension, agitation, confusion and irritability. In severe cases, following symptoms may appear:

3/11 derealisation, depersonalisation, hyperacusis, numbness and tingling in the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic fits.

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. It may be accompanied by other reactions including mood changes, anxiety or sleep disturbances and restlessness. As the risk of withdrawal or rebound symptoms is greater after sudden withdrawal of treatment, a gradual reduction in dose is recommended.

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. As a consequence, in order to minimise this risk, patients need to be sure that they will have 7 to 8 hours of uninterrupted sleep following intake of the medicinal product (see also section “Indesirable effects”).

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. 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”.

4/11 Risk from concomitant use of opioids Concomitant use of Prazepam EG 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 Prazepam EG with opioids should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Prazepam EG 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).

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, total 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 CNS- depressant action (e.g. phenothiazines, 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.

Opioids The concomitant use of sedative medicines such as benzodiazepines or related drugs such as Prazepam EG 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).

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.

5/11 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 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 Fertility, 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. As the indications are rarely vitally urgent, it is preferable not to administer prazepam during the first trimester of pregnancy.

Children whose mothers have taken benzodiazepines during pregnancy may show malformations. When the product is administered for medical reasons during the last part of pregnancy or during labour, hypothermia, hypotonia 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.

Breastfeeding 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.

6/11 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 Very Common Uncommon Rare Very rare SOC common ≥ 1/100, <1/10 ≥1/1000, ≥1/10000, <1/10000 ≥ 1/10 <1/100 <1/1000 Psychiatric confusion, abnormal disorders dreams Nervous somnolence vertigo, dizziness, syncope system ataxia, headache, disorders tremor, speech disturbances Eye disorders blurred vision

Cardiac palpitations disorders Gastrointestina dry mouth, various l disorders gastro-intestinal complaints Skin and diaphoresis, rash pruritis anaphylactic subcutaneous shock tissue disorders Musculoskelet athralgy oedema of the al and feet connective tissue disorders Renal and several genital urinary and urinary disorders symptoms Reproductive menstruation, gynecomastia system and ovulation and breast sexual disorders disturbances General Fatigue, disorders and asthenia administration site conditions

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 and administration site conditions: 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 and children, e.g. increased

7/11 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. Frequency not known: Caution should be exercised especially in elderly patients (risk of falling), because of the muscle relaxant effect of benzodiazepines.

Hepatobiliary disorders: cholestasis and jaundice (rare).

Respiratory, thoracic and mediastinal disorders: respiratory depression in patients suffering from a non-specific chronic respiratory condition.

Blood and lymphatic system disorders: rarely, agranulocytosis.

Eye disorders: diplopia.

Amnesia 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.

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 the national reporting system listed in Appendix V*.

4.9 Overdose

Symptoms of benzodiazepine overdose include: fatigue which may be accompanied by ataxia, inability to coordinate movements and confusion.

8/11 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.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: anxiolytics, ATC code: N05BA11.

Mechanism 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; BNZ1 receptors are situated in the cerebellum and cerebral cortex, BNZ2 receptors are situated in the cerebral cortex and the spinal cord and BNZ3 receptors are situated in the peripheral tissues. Activation of the BNZ1 receptor is supposed to mediate sleep, while the BNZ2 receptor encourages muscle relaxation, anticonvulsant activity, motor coordination and memory.

Benzodiazepines are bound to BNZ1 and BNZ2 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.

9/11 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 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.

10/11 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, 50 and 60 tablets packed in blisters (Alu/PVC). Prazepam EG 20 mg tablets: 20, 50 and 60 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)

< to be completed nationally>

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

< to be completed nationally>

10. DATE OF APPROVAL/REVISION OF THE TEXT

Date of approval of the text: XX/2019 Date of revision of the text: 02/2019

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