SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

[product name] 2 mg/10 ml solution for injection/infusion

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ampoule of 10 ml contains 2 mg Lormetazepam. For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection/infusion. Clear, colourless solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Adults: [product name] is indicated ◦ for the symptomatic treatment of acute attacks of tension, excitation and anxiety during surgical intervention and during intervention for diagnostic purposes and also in intensive care. ◦ for induction of anaesthesia.

Paediatric population: In children from 2 years and adolescents [product name] is only indicated for administration prior to diagnostic or surgical interventions (anaesthesia, intensive care).

4.2 Posology and method of administration

Dosage and duration of therapy must be individualised with respect to the patient’s individual ability to respond and the nature and severeness of illness. In general, the lowest effective dose should be administered for the shortest time possible.

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Posology

The following posology is recommended: a) Premedication before intervention under general anaesthesia

On the previous days, on the previous evening and/or on the day of intervention:

Recommended Dosage of Equivalent Dosage of [product name] Lormetazepam

0.4 – 1.0 mg Lormetazepam 2 – 5 ml

b) Sedation before surgical intervention under general anaesthesia

Recommended Dosage of Equivalent Dosage of [product name] Lormetazepam

0.4 – 2.0 mg Lormetazepam, equivalent 2 - 10 ml to 0.006 – 0.03 mg/kg body weight

c) Sedation (induction of sleep) during intervention for diagnostic purposes

Recommended Dosage of Equivalent Dosage of [product name] Lormetazepam

1.0 – 2.0 mg Lormetazepam, 5 - 10 ml equivalent to 0.015 – 0.03 mg/kg body weight

d) Symptomatic treatment of acute attacks of tension, excitation and anxiety and basic sedation before intervention under local anaesthesia

Prior to anaesthesia:

Recommended Dosage of Equivalent Dosage of [product name] Lormetazepam

0.4 – 1.0 mg Lormetazepam, 2 - 5 ml equivalent to 0.006 – 0.015 mg/kg body weight

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And additionally during the intervention depending on the intended depth of sedation:

Recommended Dosage of Equivalent Dosage of [product name] Lormetazepam

up to a total dose of 2.0 mg up to 10 ml Lormetazepam

e) Symptomatic treatment of acute attacks of tension, excitation and anxiety during interventions for diagnostic purposes

Recommended Dosage of Equivalent Dosage of [product name] Lormetazepam

0.6 – 1.0 mg Lormetazepam, 3 - 5 ml equivalent to 0.009 – 0.015 mg/kg body weight

f) Basic sedation during intensive care

Up to a depth of sedation of RASS 0 / − 1, if required, up to RASS-3.

Recommended Dosage of Equivalent Dosage of [product name] Lormetazepam

0.2 – 0.4 mg Lormetazepam 1 – 2 ml

Special populations Elderly patients: Administer and dose carefully - especially if cardiac and respiratory performance is inadequate (cardiorespiratory insufficiency). Often, excretion is delayed in elderly patients, whereas the effects of benzodiazepines may be enhanced.

Patients in a poor general condition Patients in a poor general condition, especially those with organic brain changes, circulatory or respiratory insufficiency:

Recommended Dosage of Equivalent Dosage of [product name] Lormetazepam

0.2 – 1.0 mg Lormetazepam, 1 - 5 ml equivalent to 0.003 – 0.015 mg/kg body weight

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Paediatric population (see also section 4.1) Children from 2 to 10 years of age:

Recommended Dosage of Equivalent Dosage of [product name] Lormetazepam

0.1 – 0.8 mg Lormetazepam, equivalent 0.5 - 4 ml to 0.0015 – 0.012 mg/ kg body weight

Taking the respective age group into account, slowly administer into large calibre veins (not faster than 5 ml injection solution/min). Observe the recommended dosage and continuously pay close attention to respiration, blood pressure and heart rate.

The daily dose in children should not exceed 3.5 mg (see also below “Maintenance of the effect”). Children and adolescents from 10 to 18 years follow the posology of the adults. The dosage recommendations for children under 10 years are based on very limited clinical experience in this age group.

Maintenance of the effect:

Repeated administration of [product name] is possible. In general however, daily doses should not exceed 5 mg Lormetazepam in adults, 4 mg in risk patients and 3.5 mg in children and adolescents.

Method of administration

Generally, slowly administer (approx. 5 ml injection solution/min) into large calibre veins. Thereby, pay close attention to respiration, blood pressure and heart rate.

[product name] may be administered without dilution and it may be administered together with the named solutions for infusion (see below).

 Instructions on administration as injection without dilution: [product name] is administered without dilution. [product name] has to be administered exclusively intravenously. It is not suitable for intramuscular injection. Intraarterial application should be avoided. In case of an unintended intraarterial injection of [product name], flush the concerning artery with 50 ml physiologic saline solution by the indwelling needle. Afterwards pull out the needle and bandage up the puncture by a pressure bandage.

For further information please refer to section 6.6.

 Instructions on administration after addition to solutions for infusion: [product name] may be added to 5 % glucose solution, 0.9 % physiologic sodium chloride solution or to Ringer’s solution, respectively. The application of further medicines or infusions into an ongoing infusion of Lormetazepam should be carried out by a three-way connection or an ypsiloid connection immediately next to the infusion tube.

For further information please refer to section 6.6.

Duration of administration: The designated starting dose of [product name] should be administered within 2 minutes, to obtain the desired

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effect. The choice of the maintenance dose depends on the required degree of effect and on the compliance of the patient. Without a compelling reason, [product name] should not be used longer than about a week. Thereby, the duration of administration and treatment depends on the medical necessities and is decided by the responsible attending doctor.

4.3 Contraindications

◦ Hypersensitivity to the active substance, other benzodiazepines or to any of the excipients listed in section 6.1 ◦ Known history of dependence upon alcohol and other medicines or drugs ◦ Acute intoxication with alcohol, hypnotics, analgesics, or psychotropic drugs (neuroleptics, antidepressants, lithium) ◦ Myasthenia gravis ◦ Sleep-apnoea syndrome ◦ Severe respiratory insufficiency ◦ Severe hepatic insufficiency

4.4 Special warnings and precautions for use

[product name] may only be administered under special precautions in patients with ◦ spinal and cerebellar ataxia, ◦ renal insufficiency.

Tolerance Some loss of efficacy to the hypnotic effects of Lormetazepam may develop after repeated use for a few weeks.

Dependence Lormetazepam such as other benzodiazepines has a primary dependency potential that may lead to the development of physical and psychic dependence. There is a risk of dependence, even in the case of daily application for only a few weeks. This applies not only to abuse with particularly high doses, but also to the therapeutic dose range.

Abrupt termination of treatment after longer previous daily administration of Lormetazepam may be accompanied by withdrawal symptoms such as headaches, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability, sleep disturbances and enhanced dreaming. In severe cases derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures may occur. The following symptoms may occur: Tremor and sweating and may be enhanced up to threatening physical (convulsive attacks) and psychological reactions, such as symptomatic psychosis (such as withdrawal delirium).

Amnesia Benzodiazepines may induce anterograde amnesia. The condition occurs (most often a few hours) after administration of the product. The patient may then not recall his activities. In order to reduce this dose dependent risk of anterograde amnesia it should be ensured that sufficient uninterrupted sleep of 7 – 8 hours is possible for the patients (see also section 4.8).

Psychiatric reactions Pre-existing depression may be unmasked and may emerge during benzodiazepine treatment. Suicide may be precipitated in such patients. In patients whose anxiety state is superimposed on depression, treatment with benzodiazepines, even if these are not primarily used for anxiolysis, can lead to such severe manifestation of the depressive symptoms after reduction of anxiety that suicidal tendencies become evident. Corresponding

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precautions must therefore be taken. Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines.

Paradoxical reactions The possibility of paradoxical reactions such as increased aggressiveness, acute states of excitation, anxiety, suicidal intentions, muscle spasms, disturbed sleep, such as dyskoimesis and dysphylaxia have to be considered. In case of such reactions, administration of [product name] should be ended. Psychiatric and paradoxical reactions are more likely to occur in children and the elderly.

Repeated administration If in exceptional cases, repeated administration of [product name] should be necessary, the benefit of the treatment must be outweighed against the risks of development of physical and psychological dependence.

In principle, injections and especially infusions, should be given into large calibre veins. Generally, care should be taken to avoid injections and infusions into small calibre veins to minimize the risk of vein irritations which rises with decrease of vein diameter. In individual cases, allergic skin reactions (exanthema) and other allergic reactions may occur. Respiratory depression may occur in patients with airway obstruction and with brain damage. Generally, patients should be attended 6 - 12 hours after administration of [product name].

Especially in cases of high dosages of Lormetazepam or after repeated treatment reversible disorders may occur, such as retarded or indistinct speaking (articulation disorders), movement disorders, unstable way of walking, visual disturbances/impaired vision (double vision) and nystagmus. The risk of occurrence of undesirable effects is higher in elderly patients. Elderly patients should be warned of the risk of falls due to the myorelaxant effect of Lormetazepam.

Patients with hepatic insufficiency There are limited pharmacokinetic data concerning single dosing of Lormetazepam in patients with mild to moderate hepatic insufficiency. The reduced plasma clearance in these patients leads to an average 2-fold increase of maximum concentration and systemic exposure (AUC) following p.o. administration of 0.03 mg/kg and AUC was increased by about 50 % after i.v. administration of 0.015 mg/kg. However, no pharmacokinetic data from clinical trials are available regarding repeated dosing of Lormetazepam in this patient population. It is recommended to treat patients with hepatic insufficiency with caution, as benzodiazepines may precipitate encephalopathy.

Risk from concomitant use of opioids: Concomitant use of [product name] 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 [product name] with opioids should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe [product name] 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).

Paediatric population [product name] must not be given to children and adolescents, unless administration prior to diagnostic or surgical interventions (anaesthesia, intensive care) is planned.

4.5 Interaction with other medicinal products and other forms of interaction

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Mutual enhancement of the effects may occur in cases of concomitant use with other CNS depressants such as neuroleptics, tranquilizers, antidepressant agents, hypnotics, analgesics, anaesthetics and antihistamines. The concomitant use of sedative medicines such as benzodiazepines or related drugs such as [product name] 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 effects may also be changed and enhanced, in an unpredictable way, when the product is used in combination with alcohol. The effects of muscle relaxants may be enhanced. The nature and extent of interactions cannot be predicted with certainty in patients receiving permanent treatment with other drugs that influence circulatory and respiratory functions (e.g. beta- receptor blockers, cardioactive glycosides, methylxanthines). These also include oral contraceptives and a number of antibiotics. Therefore, before parenteral administration, the attending doctor should clarify whether the patient is on corresponding permanent treatment. In such cases, special caution is required on treatment with Lormetazepam.

4.6 Fertility, pregnancy and lactation

Pregnancy During pregnancy, [product name] should only be given in exceptional cases and for compelling medical reasons, since no experience in the administration of Lormetazepam to pregnant women has been documented. Prior to administration of [product name] to a woman of childbearing potential, she should be asked by the physician in charge if she is or suspects to be pregnant. If benzodiazepines are used repeatedly during pregnancy the child may develop physical dependence, with withdrawal symptoms in the postnatal phase. If, for compelling medical reasons, [product name] is administered during the late phase of pregnancy, or during labour and delivery, effects on the neonate, such as respiratory depression, hypothermia, reduced muscular tension and sucking difficulties (floppy infant syndrome) can be expected due to the pharmacological action of the compound. The risk of malformations after therapeutic doses of benzodiazepines during early pregnancy in humans appears to be low, although a number of epidemiological studies have indicated an increased risk of cleft palate. Cases of congenital abnormalities and mental retardation have been reported in children after prenatal exposure, after overdoses and intoxications with benzodiazepines.

Breastfeeding Lormetazepam passes into human breast milk. Therefore, [product name] should not be given to nursing mothers. If there are compelling reasons for giving repeated or high dosages of [product name] (e.g. in conditions of anxiety that cannot be controlled by any other means), the child must be weaned, or breast- feeding must be interrupted.

Fertility Experiments for Lormetazepam are not available.

4.7 Effects on ability to drive and use machines

[product name] has a major influence on the ability to drive and use machines, as it causes impaired capacity of reaction even in therapeutic use. This applies to an increased extent in association with alcohol.

Therefore, patients should not drive or operate machinery or carry out other dangerous activities on the day of their treatment. The decision in each individual case has to be made by the physician in charge and will depend on the individually applied dose and the individual state of reaction of the patient.

In case that Lormetazepam is used for the preparation of a diagnostic intervention, on an outpatient basis, the patient should be discharged only accompanied and should be advised not to take an active part in road traffic.

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4.8 Undesirable effects

Adverse reactions are listed by frequency: 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); not known (cannot be estimated from the available data).

Tabulated list of adverse reactions

Adverse reactions associated with lormetazepam are tabulated below.

System organ class Frequency: not known Immune system disorders Angioedema Psychiatric disorders Depressive mood, suicidal ideation/attempt, hallucination, dependence, delusions, withdrawal symptoms (rebound insomnia), agitation, aggressiveness, irritability, restlessness, anxiety, nightmares, inappropriate behaviour, emotional disorder, acute psychoses Nervous system disorders Headache, dizziness, drowsiness, sedation, amnesia, reduced alertness, concentration disorders and prolonged reaction times, confusion, clouding of consciousness, ataxia, muscle weakness, dysarthria/slurred speech, visual disturbances, dysgeusia, bradyphrenia Cardiac disorders Tachycardia Respiratory, thoracic and mediastinal disorders Respiratory depression Gastrointestinal disorders Vomiting, nausea, upper abdominal pain, constipation, xerostomia Skin and subcutaneous tissue disorders Pruritus, urticaria, rash Renal and urinary disorders Micturition disorders General disorders and administration site conditions Thrombosis, thrombophlebitis, extravasation symptoms, asthenia, hyperhidrosis, fatigue Injury, poisoning and procedural complications Fall

Description of selected adverse reactions (frequency not known):

Psychiatric disorders So-called paradoxical reactions may occur, such as increased aggressiveness, acute state of agitation, anxiety, suicidality, muscle spasms, sleep disorders. If these occur, the treatment should be discontinued. Sudden withdrawal after prolonged daily administration of lormetazepam may lead to sleep disorders and increased dreaming. Anxiety, tension as well as arousal and inner restlessness can get intensified. Symptoms may include tremor and sweating and may be enhanced up to physical (convulsive attacks) and psychological reactions, such as symptomatic psychosis (e.g. withdrawal delirium).

Nervous system Benzodiazepines can cause anterograde amnesia. See also Section 4.4. Reversible disorders, such as slow or slurred speech (articulation disorders), unsteady movement and unstable way of walking, visual disorders like diplopia and nystagmus, may occur especially at high doses and repeated administration.

Vascular disorders

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Injections in a too small calibre vein or rapid i.v. injection may cause irritation to the venous wall, swelling, vascular changes, thrombosis or thrombophlebitis.

Respiratory, thoracic and mediastinal disorders Respiratory depression may occur in patients with airway obstruction and brain damage.

Skin and subcutaneous tissue disorders In isolated cases, skin reactions (exanthem) and other allergic reactions may occur.

Elderly patients The risk of occurrence of side effects is higher in elderly patients and due to the muscle-relaxing effect, caution is advised (risk of falling).

Reporting of suspected adverse reactions Reporting of 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 reaction via the national reporting system [to be added nationally].

4.9 Overdose

As with other benzodiazepines, overdose of Lormetazepam should not present a threat to life unless combined with other CNS depressants (including alcohol).

Overdose of benzodiazepines is usually - in relation to the applied dose - manifested by degrees of central nervous system depression that may range from somnolence, mental confusion, lethargy, visual disorders and dystonia up to ataxia, unconsciousness, central respiratory and circulatory depression and coma. Other symptoms may include: depression of consciousness, paradoxical reactions, agitation and hallucinations.

Treatment of overdose is mainly symptomatic:

Patients with milder symptoms of intoxication should be allowed to sleep them off under observation of respiratory and circulatory functions. In severe cases further measures should be taken, such as gastric lavage, stabilisation of cardiovascular functions and close observation in intensive care.

If necessary, the specific benzodiazepine antagonist, flumazenil, may be useful in hospitalised patients for the management of benzodiazepine overdose. Flumazenil product information should be consulted prior to use.

Due to pronounced plasma protein binding and the high volume of distribution, forced diuresis or haemodialysis is only of limited benefit in cases of intoxication with Lormetazepam solely.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Hypnotics and sedatives, Benzodiazepine derivatives ATC-Code: N05CD06

Pharmacodynamic effects Lormetazepam is a psychotropic substance belonging to the class of 1,4-benzodiazepines with sedative and hypnotic properties. It also exerts tension relieving, excitation suppressing and anxiolytic effects. In addition, Lormetazepam has central muscle relaxant and anticonvulsive properties.

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Lormetazepam has a high affinity for specific binding sites in the central nervous system. These benzodiazepine receptors display a close functional relationship to the receptors of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). As a benzodiazepine receptor agonist, Lormetazepam reinforces the GABA-ergic inhibition of the activity of distal neurons.

5.2 Pharmacokinetic properties

Absorption After intravenous administration, approximately 88% of the administered dose of Lormetazepam is bound to plasma proteins.

Biotransformation Biotransformation takes place in the liver by glucuronidation of the C3-hydroxyl group. Only a minor fraction is demethylated to form the active metabolite Lorazepam and inactivated immediately by glucuronidation. Since demethylation of Lormetazepam occurs slowly, the substance is not a prodrug of Lorazepam.

Elimination In the urine, more than 90 % of Lormetazepam is present as Lormetazepam-3-O-glucuronide and less than 10 % as Lorazepam-glucuronide. After an oral dose of 2 mg Lormetazepam less than 6 % was identified in the urine as Lorazepam-glucuronide. No free Lormetazepam was found.

The elimination half-life of Lormetazepam and its active metabolites is in average 9 hours (8 – 15 h).

The rate of inactivation and elimination of Lormetazepam is not affected by impaired hepatic function.

The pharmacokinetic properties of Lormetazepam remain largely unaffected in patients with renal impairment, because essentially only accumulation of the biologically inactive Lormetazepam-glucuronide occurs. As a rule, dose adjustment is not required.

Passage across the placenta and excretion into breast milk: Lormetazepam passes the placenta and is detectable in breast milk.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction.

Toxicological properties Acute toxicity of Lormetazepam is low (see section 4.9 Overdose).

Studies of chronic toxicity in the rat and dog gave no indication of substance-specific toxic effects.

Lormetazepam has been sufficiently studied with regard to mutagenic effects.

In tumorigenicity long-term studies no indication of a tumorigenic effect of Lormetazepam was observed in animals.

Benzodiazepines pass the placenta. Experiments for Lormetazepam are not available. Animal experiments of toxicity to reproduction of Lormetazepam gave no indication of teratogenic effects.

There are indications of behavioural disorders in the progeny of mother animals exposed to benzodiazepines.

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Environmental Risk Assessment (ERA) [product name] does not contain any component which results in an additional hazard to the environment during storage, distribution, use and disposal.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

◦ Macrogol-15-hydroxystearate ◦ Water for injections

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Unopened ampoules: 18 months Diluted in tested solutions for infusion: 24 hours

The compatibility of a mixture of [product name] with common solutions for infusion (5 % glucose, 0.9 % physiologic sodium chloride, Ringer’s solution) has been demonstrated for up to 24 hours at room temperature.

6.4 Special precautions for storage

Do not store above 25 °C. Do not freeze.

For storage conditions after mixture of the medicinal product with solutions for infusion, see section 6.3.

6.5 Nature and contents of container

Cardboard boxes containing: 5 glass ampoules of 10 ml 25 glass ampoules of 10 ml 50 glass ampoules of 10 ml 100 glass ampoules of 10 ml

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Do not use [product name], if the solution shows any turbidity or has been frozen.

Before opening the ampoule, wipe off the neck of the ampoule with medical alcohol (spray or alcohol pads). Discard the broken ampoules after administration of the medicinal product.

[product name] does not contain any antimicrobial preservatives. Therefore, immediately after opening and under aseptic conditions, the content of the ampoule has to be transferred into a sterile syringe for injection or into a sterile infusion set, in case of infusions.

Administration of [product name] has to be started immediately. The contents of each ampoule containing [product name], must only be administered as single administration for one patient.

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In case of infusion of [product name], use a burette, a drop counter, a syringe pump with infusion lines or a volumetric pump to control the infusion rate.

During infusion, strictly observe aseptic conditions for [product name] itself as well as for the infusion device. The contents of each ampoule or each syringe or each infusion system containing [product name], must only be administered as single administration for one patient.

After administration of injection or after termination of infusion or change of the infusion system, all remains of the solution have to be discarded.

Addition to solutions for infusion: [product name] may be added to 5 % glucose solution, 0.9 % physiologic sodium chloride solution or to Ringer’s solution, respectively.

The ampoules of [product name] are intended for single use. Any unused medicinal product or waste material should be disposed of in accordance with local 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 REVISION OF THE TEXT

[To be completed nationally]

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