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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Lormetazepam Tablets 1mg.

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 1 mg of Lormetazepam.

Excipient(s): Contains 98.8 mg Lactose (anhydrous)

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablet.

White, round, flat bevel edged tablet, approximately 7 mm in diameter, marked LT breakline 1 on one side with “G” on the reverse

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Lormetazepam Tablets are indicated for the short term (up to 4 weeks) treatment of insomnia, when it is severe, disabling or subjecting the individual to extreme distress.

As with all benzodiazepines, doctors should be aware that long-term use may lead to dependency and withdrawal symptoms in certain patients.

4.2    Posology and method of administration

For oral administration.

In all cases the lowest effective dose necessary to control symptoms should be used (up to four weeks). Treatment should, if possible, be intermittent. Lormetazepam should not be used for long term chronic treatment.

For more information concerning patients under 18 years of age, see section 4.2 ‘Posology and method of administration’.

Tolerance

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

Dependence

Use of Lormetazepam and other benzodiazepines may lead to the development of physical and psychic dependence upon these products. Abuse of benzodiazepines has been reported. The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a history of alcohol or drug abuse. Therefore, Lormetazepam should be used with extreme caution in patients with a history of alcohol or drug abuse.

Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal reactions. These may consist of extreme anxiety, tension, restlessness, confusion, irritability, headaches and muscle pain. In severe cases the following symptoms may occur: derealization, depersonalization, hallucinations, paresthesia of the limbs, sensory disturbance to light, noise and physical contact, hyperacusis and epileptic seizures.

There are indications that, in the case of benzodiazepines with a short duration of action, withdrawal phenomena can become manifest within the dosage interval, especially when the dosage is high. This is unlikely to happen with Lormetazepam because its elimination half-life is about 10 hours.

However, switching to Lormetazepam after long and/or high-dose use of a benzodiazepine with a significantly longer duration of action may result in the development of withdrawal symptoms.

Rebound insomnia, a transient syndrome whereby the insomnia that led to treatment with a benzodiazepine recurs in enhanced form, may occur on withdrawal of treatment.

Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage is gradually decreased. The patient should be made aware of the possibility of rebound phenomena thereby minimizing anxiety over such symptoms, should they occur while Lormetazepam is being discontinued.

Amnesia

Lormetazepam may induce anterograde amnesia. The condition occurs most often in the first few hours after ingesting the product. In order to reduce the risk of anterograde amnesia patients should ensure that sufficient uninterrupted sleep of 7 - 8 hours is possible.

Psychiatric and paradoxical reactions

Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate, abnormal behavior and other adverse behavior disorders are known to occur when using benzodiazepines. Should this occur, use of the product should be discontinued.

These reactions are more likely to occur in children and the elderly, as well as in patients with organic brain syndrome.

Lormetazepam is not recommended for the primary treatment of psychotic illness. It should not be used alone for the treatment of sleep disorder associated with depression.

Pre-existing depression may be unmasked during benzodiazepine use, including Lormetazepam Suicide may be precipitated in such patients. Lormetazepam should be used with caution in these patients with depression.

Specific patient groups Pediatric patients

For insomnia, Lormetazepam should not be given to patients under 18 years of age without careful assessment of the need to do so; the duration of treatment must be kept to a minimum (see section 4.2 ‘Posology and method of administration’).

Elderly

Benzodiazepines, including Lormetazepam may be associated with an increased risk of falling due to adverse effects including ataxia, muscle weakness, dizziness, somnolence/sleepiness, fatigue, and therefore it is recommended to treat particularly elderly patients with caution.

Elderly should be given a reduced dose (see section 4.2 ‘Posology and method of administration - Short term treatment of insomnia).

Patients with spinal and cerebellar ataxia

Lormetazepam should be administered with caution to patients with spinal and cerebellar ataxia.

Patients with chronic respiratory insufficiency

A lower dose is also recommended for patients with chronic respiratory insufficiency due to the risk of respiratory depression (see also section 4.3 ‘Contraindications’).

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). 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 severe hepatic insufficiency with caution, as benzodiazepines may precipitate encephalopathy.

Patients with severe renal insufficiency

Lormetazepam should be administered with caution to patients with severe renal insufficiency.

Alcohol

Lormetazepam oral drops, solution contains small amounts of ethanol (alcohol), less than 100 mg per ml (1 ml corresponds to 25 drops). This may be harmful for those suffering from alcoholism. To be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease, or epilepsy.

Excipients

This medicinal product contains lactose-anhydrous. 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

Benzodiazepines produce an additive effect when co-administered with alcohol or other CNS depressants.

Concomitant intake with alcohol is not recommended. Special care should be made with drugs depressing respiratory function such as opioids (analgesics, antitussives, substitutive treatments), notably in the elderly people.

Lormetazepam should be used with caution when combined with other CNS depressants. Enhancement of the central depressive effect may occur in case of concomitant use with anaesthetics, antipsychotics (neuroleptics), anxiolytics/sedatives, some antidepressant agents, opioids, anticonvulsants, sedative H1-antihistamines.

Interactions of benzodiazepines and other drug classes (beta-blocking agents, cardiac glycosides, methylxantines, oral contraceptives and several antibiotics) have been reported. Patients using beta-blocking agents, cardiac glycosides, methylxantines, oral contraceptives and antibiotics concomitantly should be treated with caution, especially at the beginning of the treatment with lormetazepam.

4.6 Fertility, pregnancy and lactation

As a precaution, Lormetazepam should not be used during pregnancy, delivery and lactation.

Women of childbearing potential

If Lormetazepam is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding discontinuation of Lormetazepam if she intends to become or suspects that she is pregnant.

Pregnancy

If, for compelling medical reasons, Lormetazepam is administered during the late phase of pregnancy, or during labor and delivery, effects on the neonate, such as hypothermia, hypotonia, moderate respiratory depression and sucking difficulties can be expected due to the pharmacological action of the compound.

Moreover, infants born to mothers who took Lormetazepam or other benzodiazepines chronically during the late phase of pregnancy may have developed physical dependence and may be at some risk of developing withdrawal symptoms in the postnatal period.

Lactation

Since small amounts of the drug may enter the breast-milk, Lormetazepam should not be administered to breastfeeding mothers.

4.7 Effects on ability to drive and use machines

Lormetazepam has major influence on the ability to drive and use machines, as it causes sedation, amnesia, impaired concentration and impaired muscular function. If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased.

This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:

•    The medicine is likely to affect your ability to drive

•    Do not drive until you know how the medicine affects you

•    It is an offence to drive while under the influence of this medicine

•    However, you would not be committing an offence (called ‘statutory’ defence’) if:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and o It was not affecting your ability to drive safely

4.8 Undesirable effects

Summary of safety profile

At the beginning of the treatment, somnolence during the day, emotional disorder, depressed consciousness, confusion, fatigue, headache, dizziness, muscular weakness,

ataxia or double vision may occur; these reactions usually disappear with repeated administration.

The most frequently observed adverse drug reactions (ADRs) in patients receiving Lormetazepam are headache, sedation, and anxiety.

The most serious adverse drug reactions (ADRs) in patients receiving Lormetazepam are angioedema, completed suicide or suicide attempt in association with unmasking of pre-existing depression.

Tabulated list of adverse reactions

The adverse drug reactions observed with Lormetazepam are represented in the table below. They are classified according to System Organ Class. The most appropriate MedDRA terminology is used to describe a certain reaction and its synonyms and related conditions.

Adverse drug reactions from clinical trials (in 852 patients; administered dose: 0.5 mg to 3 mg lormetazepam) are classified according to their frequencies.

The ADRs identified only during post marketing surveillance, and for which a frequency could not be estimated, are listed under “not known”.

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1: Adverse drug reactions reported in clinical trials or during post-marketing surveillance in patients treated with Lormetazepam

System Organ Class (MedDRA)	Very common (>1/10)	Common (>1/100 to <1/10)	Not known (cannot be estimated from the available data)
Immune system disorders		Angioedema *

System Organ Class (MedDRA)	Very common (>1/10)	Common (>1/100 to <1/10)	Not known (cannot be estimated from the available data)
Psychiatric disorders		Anxiety Libido decreased	Completed suicide (unmasking of pre-existing depression)* Suicide attempt (unmasking of pre-existing depression)* Acute psychosis§ Hallucination^ Dependence^ Depression (unmasking of preexisting depression/ Delusion§ Withdrawal syndrome (rebound insomnia) § Agitation§ Aggression§ Irritability§ Restlessness§ Anger § Nightmare§ Abnormal behavior§ Emotional disorder
Nervous system disorders	Headache	Dizziness§ Sedation Somnolence^ Disturbance in attention Amnesia§ Visual impairment Speech disorder Dysgeusia Bradyphrenia	Confusional state Depressed level of consciousness Ataxia§ Muscular weakness§
Cardiac disorders		Tachycardia

System Organ Class (MedDRA)	Very common (>1/10)	Common (>1/100 to <1/10)	Not known (cannot be estimated from the available data)
Gastrointestinal disorders		Vomiting Nausea Abdominal pain upper Constipation Dry mouth
Skin and subcutaneous tissue disorders		Pruritus	Urticaria Rash
Renal and urinary disorders		Micturition disorder
General disorders and administration site conditions		Asthenia Hyperhidrosis	Fatigue§
Injury, poisoning, and procedural complications			Fall

* life-threatening and/or fatal cases have been reported § see section ‘Special warnings and precautions for use’

Description of selected adverse reactions Dependence

Use of Lormetazepam and other benzodiazepines may lead to the development of physical and psychic dependence upon these products.

Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal reactions. These may consist of extreme anxiety, tension, restlessness, confusion, irritability, headaches and muscle pain. In severe cases the following symptoms may occur: derealization, depersonalization, hallucinations, paresthesia of the limbs, sensory disturbance to light, noise and physical contact, hyperacusis and epileptic seizures.

For more information concerning dependence / withdrawal phenomena see section ‘Special warnings and special precautions for use’.

Psychiatric disorders

Rebound insomnia may occur on withdrawal of treatment.

Psychiatric and paradoxical reactions: Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate abnormal behavior and other adverse behavior disorders are known to occur when using Lormetazepam

Pre-existing depression may be unmasked during benzodiazepine use, including Lormetazepam. Suicide may be precipitated in such patients. Lormetazepam should be used with caution in these patients with depression.

Nervous system disorders

Amnesia: Lormetazepam may induce anterograde amnesia.

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). In the management of overdose with any medicinal product, it should be borne in mind that multiple agents may have been taken and that respiratory depression, rarely coma and very rarely death may occur. Special attention must be paid to respiratory and cardiovascular functions in intensive care.

Symptoms

The symptoms of mild lormetazepam intoxication are drowsiness, tiredness, ataxic symptoms, disturbed vision.

Oral intake of higher doses may result in deep sleep ranging to unconsciousness, respiratory depression, hypotension.

Therapy

Patients with milder symptoms of intoxication should be allowed to sleep them off under observation. On oral intake of larger amounts, vomiting should be induced within one hour if the patient is conscious, or gastric lavage undertaken with the airway protected if the patient is unconscious. If there is no advantage in emptying the stomach, activated charcoal should be given to reduce absorption.

Flumazenil may be useful as an antidote.

For further information concerning the safe use of flumazenil please refer to the SmPC for products containing flumazenil.

PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Lormetazepam is a benzodiazepine derivative with general properties similar to those of diazepam. It has been used as a hypnotic in the short-term management of insomnia in usual doses of 0.5 to 1.5mg at night.

5.2    Pharmacokinetic properties

Lormetazepam is rapidly absorbed from the gastro-intestinal tract and metabolised to the inactive glucuronide. The terminal half-life is reported to be about 12 hours.

5.3 Preclinical safety data

There are no preclinical safety data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose anhydrous

Dibasic calcium phosphate anhydrous

Crospovidone

Purified talc

Magnesium stearate

6.2    Incompatibilities

None known

6.3 Shelf life

36 months

6.4 Special precautions for storage

Store in a dry place below 25°C.

6.5 Nature and contents of container

Polypropylene containers with polyethylene caps (with optional use of polyethylene ullage filler) or HDPE containers with polyethylene snap closures in packs of 5, 7,10, 14, 15, 20, 21, 25, 28, 30, 50, 56, 60, 84, 90, 100, 112, 120, 168, 180, 250 and 500 tablets.

6.6 Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Generics [UK] Limited T/A Mylan Station Close Potters Bar Hertfordshire EN6 1TL

8. MARKETING AUTHORISATION NUMBER

PL 04569/0177

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date MA granted: 16^th February 1987 Last renewal date: 25^th September 1998

10 DATE OF REVISION OF THE TEXT

06/08/2014