SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Lormetazepam 0.5 mg tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 0.50 mg of lormetazepam

Excipients with known effect:

Each tablet contains 86.40 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablets.

Round white tablet.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Short-term treatment of insomnia.

Benzodiazepines are only indicated when the disorder is severe, disabling or subjecting the individual to extreme distress.

4.2    Posology and method of administration

Dosage and duration of therapy should be individualised. The lowest effective dose should be prescribed for the shortest time possible. Generally, it varies from a few days to two weeks with a maximum period, including gradual reduction, of four weeks.

Adults: 0.5mg to 1.5mg before retiring. Subsequently the initial dosage may be increased to 2 mg in individual cases if this proves necessary.

Elderly: The lower adult dose is preferable for elderly patients.

Paediatric population

Lormetazepam must not be used in children and adolescents under 18 years of age without a careful assessment of the need for the treatment.

The tablets should be taken with a small amount of liquid before going to bed.

4.3 Contraindications

Lormetazepam is contraindicated in patients with:

•    Hypersensitivity to benzodiazepines or to any of the excipients of Lormetazepam tablets

•    Myasthenia gravis

•    Severe respiratory insufficiency (for example, severe chronic obstructive pulmonary disease), sleep apnoea syndrome.

•    Acute intoxication with alcohol, hypnotics, analgesics or psychotropic drugs (neuroleptics, antidepressants, lithium).

•    Severe liver insufficiency.

Pregnancy and lactation (see also 4.6 “Fertility, pregnancy and lactation”)

4.4 Special warnings and precautions for use

Duration of treatment

The duration of treatment should be as short as possible (see also 4.2. “Posology and method of administration”). Generally it varies from a few days to two weeks with a maximum period of four weeks, including the time required for gradual withdrawal of the medication.

It may be useful to inform the patient when treatment is started that it will be of limited duration and to explain clearly how the dose will be gradually decreased.

Treatment must never be prolonged without re-assessment of the patient.

For further information on use in patients under 18 years of age, see section 4.2 “Posology and method of administration”.

Tolerance

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

Patients should be advised that since their tolerance for other CNS depressants will be diminished in the presence of lormetazepam, these substances should either be avoided or taken in reduced dosage.

Dependence

Use of lormetazepam and other benzodiazepines may lead to the development of physical and psychic dependence. 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, use in individuals with a history of alcoholism or drug abuse should be avoided. Abuse of benzodiazepines has been reported.

Dependence may lead to withdrawal symptoms, especially if treatment is discontinued abruptly. Therefore, the drug should always be discontinued gradually.

Symptoms reported following discontinuation of benzodiazepines include headaches, muscle pain, anxiety, tension, depression, insomnia, restlessness, confusion, irritability, sweating and the occurrence of "rebound" phenomena whereby the symptoms that led to treatment with benzodiazepines recur in an enhanced form. These symptoms may be difficult to distinguish from the original symptoms for which the drug was prescribed.

The following symptoms have been described in severe cases: Derealisation; depersonalisation; hyperacusis; tinnitus; numbness and tingling of the extremities; hypersensitivity to light, noise, and physical contact; involuntary movement; vomiting; hallucinations; convulsions. Convulsions may be more common in patients with pre-existing seizure disorders or who are taking other drugs that lower the convulsive threshold such as antidepressants.

Use of short-acting benzodiazepines in some indications may result in withdrawal symptoms appearing at therapeutic plasma levels, especially at high doses.

This is unlikely to happen with lormetazepam because its elimination half-life is about 10 hours (see section 5.2 “Pharmacokinetic properties”).

However, switching to lormetazepam after prolonged and/or high-dose use of significantly longer-acting benzodiazepines may result in the appearance of withdrawal symptoms.

Rebound insomnia and anxiety

A transient syndrome has been described whereby the symptoms that led to treatment recur in an enhanced form on withdrawal of treatment.

Since the risk of withdrawal/rebound phenomena is greater after abrupt termination of treatment, it is recommended that the dose be decreased gradually until its definitive withdrawal.

The patient should be made aware of the possibility of rebound phenomena, thereby minimising anxiety over such symptoms should they occur upon discontinuation of the medication (see also section 4.8 “Undesirable effects”).

Amnesia

Benzodiazepines may induce anterograde amnesia. This condition occurs most commonly in the first few hours after the product has been administered. Therefore, to reduce the associated risk, patients should ensure that they will be able to get 7-8 hours of uninterrupted sleep (see also section 4.8 “Undesirable effects”).

Psychiatric and paradoxical reactions

Benzodiazepines may cause reactions such as restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects. Should this occur, treatment should be discontinued.

These reactions are more common in children and the elderly, and in patients with organic brain syndrome.

Pre-existing depression may be unmasked during benzodiazepine treatment. Suicide may be precipitated in these patients (see also section 4.8 “Undesirable effects”).

Specific patient groups

-    Paediatric patients

In case of insomnia, Lormetazepam must not be administered in patients under 18 years of age without performing a careful assessment of the need for the treatment. Treatment duration must be as short as possible (see section 4.2 “Posology and method of administration”).

-    Elderly patients

Benzodiazepines may be associated with an increased risk of falling due to adverse reactions including ataxia, muscle weakness, dizziness, drowsiness and fatigue; it is therefore recommended that elderly patients are treated with caution.

Elderly patients should be given a reduced dose (see section 4.2 “Posology and method of administration”).

-    Patients with spinal ataxia or cerebellar ataxia

Lormetazepam must be administered with caution in patients with spinal ataxia or cerebellar ataxia (see section 4.8 Undesirable effects).

-    Patients with chronic respiratory failure

It is also recommended that lower doses be used in patients with chronic respiratory failure owing to the associated risk of respiratory depression (see sections 4.2 “Posology and method of administration” and 4.3 “Contraindications”).

- Patients with liver failure

Increased systemic exposure has been observed in patients with liver failure. Therefore, a dose reduction must be considered (see section 4.2 Posology and method of administration).

There are few pharmacokinetic data on single-dose administration of Lormetazepam in patients with mild or moderate liver failure. The reduced plasma clearance in these patients leads to a mean 2-fold increase in plasma concentration and systemic exposure (AUC). However, there are no pharmacokinetic data from clinical trials regarding administration of repeated doses of Lormetazepam in this type of patient.

It is recommended that patients with serious liver failure be treated with caution, since benzodiazepines may cause encephalopathy.

- Patients with severe renal insufficiency

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

Lormetazepam and other benzodiazepines are not recommended as a first-line treatment for psychotic disease.

Lormetazepam and other benzodiazepines should not be used alone for the treatment of anxiety associated with depression (risk of suicide) or for the treatment of sleep disorders associated with depression.

• Other warnings

This medicinal product contains lactose. Patients with hereditary galactose intolerance, Lapp lactase deficiency (deficiency observed in certain populations of Lapland) or glucose-galactose malabsorption should not take this medicinal product.

Some patients taking benzodiazepines have developed a blood dyscrasia, and some have had elevations in liver enzymes. Periodic haematologic and liver-function assessments are recommended where repeated courses of treatment are considered clinically necessary

Although hypotension has occurred only rarely, benzodiazepines should be administered with caution to patients in whom a drop in blood pressure might lead to cardiovascular or cerebrovascular complications. This is particularly important in elderly patients.

Abuse of benzodiazepines has been reported.

Caution should be used in the treatment of patients with narrow-angle glaucoma.

4.5 Interaction with other medicinal products and other forms of interaction

When alcohol and other CNS depressants are administered, the effect of benzodiazepines is potentiated.

Simultaneous alcohol consumption is not recommended. Particular caution must be exercised with medicines that depress respiratory function such as opioids (analgesics, cough suppressants, replacement therapies), above all in elderly patients.

Lormetazepam must be administered with caution in combination with other CNS depressants. The CNS depressant effect may be potentiated in concomitant administration of antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, some antidepressants, opioids, anti epileptics, anaesthetics and sedative H1-antihistamines.

In the case of narcotic analgesics, an increased feeling of euphoria may also occur. This may increase psychic dependence.

Interactions between benzodiazepines and other classes of medicines such as beta blockers, cardiac glycosides, methylxanthines, oral contraceptives and several antibiotics (e.g. rifampicin) have been reported. Patients treated concomitantly with beta blockers, cardiac glycosides, methylxanthines, oral contraceptives and antibiotics must be treated with caution, especially at the start of treatment with lormetazepam.

Administration of theophylline or aminophylline may reduce the sedative effects of benzodiazepines, including lormetazepam.

Concomitant administration of clozapine should cause enhanced sedative effects, increased salivation and ataxia.

4.6 Fertility, pregnancy and lactation

As a general guideline, lormetazepam should not be used during pregnancy, labour or lactation.

Women who may become pregnant

If the product is prescribed to a woman of childbearing potential, she should be advised to contact her doctor in order to discontinue treatment if she intends to become pregnant or suspects that she is pregnant.

Pregnancy

If, for strict medical reasons, the product is administered during the late phase of pregnancy, or during labour at high doses, effects on the neonate, such as hypothermia, hypotonia and moderate respiratory depression, can be expected.

Infants born to mothers who took benzodiazepines chronically during the latter stages of pregnancy may have developed physical dependence and may be at some risk of developing a withdrawal syndrome in the postnatal period.

Breast-feeding

Since benzodiazepines are excreted in breast milk, benzodiazepines should not be given to breast-feeding mothers.

4.7    Effects on ability to drive and use machines

Lormetazepam induces sleep. It may alter the ability to react, impair concentration and cause amnesia, particularly at the start of treatment or after a dose increase. Likewise, drowsiness may persist the morning after administration of the medicinal product. It is not advisable to drive or use machinery which requires special attention or concentration, until it is verified that the ability to perform these activities is not affected.

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 the safety profile

At the start of treatment, the following may occur: daytime somnolence, emotional disturbance, fainting, confusion, fatigue, headache, dizziness, muscle weakness, ataxia and double vision. These reactions normally disappear with repeated administration.

The most common adverse reactions observed in patients treated with Lormetazepam are headache, sedation and anxiety.

The most serious adverse reactions observed in patients treated with Lormetazepam are angioedema, completed suicide and attempted suicide associated with masking of pre-existing depression.

Tabulated list of adverse reactions

The following table lists the adverse reactions observed with Lormetazepam, according to organ class. To describe a particular reaction and its synonyms and related disorders, the most appropriate MedDRA term has been used.

The adverse reactions observed in clinical trials (in 852 patients; dose administered: 0.5 mg to 3 mg of lormetazepam) are classified according to their frequencies.

The adverse reactions identified during post-marketing surveillance, whose frequency could not be estimated, are listed in the “not known” frequency column.

Within each frequency group, the adverse reactions are listed in order of decreasing seriousness.

Table 1: Adverse 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)	Unknown frequency (cannot be estimated from the available data)
Immune system disorders		Angioedema*
Psychiatric disorders		Anxiety Decreased libido	Completed suicide (masking of preexisting depression)* Attempted suicide (masking of preexisting depression)* Acute psychosis§ Hallucinations§ Dependence Depression (masking of preexisting depression)* Delirium § Withdrawal syndrome (rebound insomnia) § Agitation § Aggressiveness § Irritability § Jumpiness § Fits of rage § Nightmares § Inappropriate behaviour § Emotional disturbances

Nervous system disorders	Headache	Dizziness§ Sedation Somnolence§ Attention disorder Amnesia§ Vision disorder Speech disorder Dysgeusia Bradyphrenia	Confusion Decreased level of consciousness Ataxia§ Muscle weakness§
Cardiac disorders		Tachycardia
Gastrointestinal disorders		Vomiting Nausea Upper abdominal pain Constipation Dry mouth
Skin and subcutaneous tissue disorders		Pruritus	Urticaria Exanthem
Renal and urinary disorders		Micturition disorder
General disorders and administration site conditions		Asthenia Hyperhydrosis	Fatigue§
Traumatic injury, intoxication and complications of therapeutic procedures
*) Is life-threatening and/or cases of death		have been reported

§) See section “Special warnings and precautions for use”)

Description of selected adverse reactions

Dependence

Administration of Lormetazepam and other benzodiazepines may induce the development of physical and psychic dependence.

Once physical dependence has developed, abrupt termination of the treatment may be accompanied by withdrawal symptoms. Some of them may be marked anxiety, tension, jumpiness, confusion, irritability, headaches or muscle pain. In serious cases, the following symptoms have been reported: derealisation; depersonalisation; hallucinations; paraesthesia in the limbs; sensory intolerance to light, sounds and physical contact; hyperacusis and epileptic seizures.

For more information on the dependence/withdrawal phenomenon, see section “Special warnings and precautions for use”.

Psychiatric disorders

Rebound anxiety may occur when the medicine is stopped (see 4.4 “Special warnings and precautions for use”).

Psychiatric and paradoxical reactions: When Lormetazepam is used, reactions such as jumpiness, agitation, irritability, aggressiveness, delirium, fits of rage, nightmares, hallucinations, psychosis, inappropriate abnormal behaviour and other behavioural abnormalities may occur.

The use of benzodiazepines, including Lormetazepam, may mask pre-existing depression. Suicides may be triggered in these patients. Lormetazepam must be used with caution in patients with depression.

Nervous system disorders

Amnesia: Lormetazepam may induce anterograde amnesia.

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

As with other benzodiazepines, overdose with lormetazepam is not life-threatening unless combined with other CNS depressants (including alcohol).

In the clinical management of overdose with any medicinal product, it should be taken into account that the patient may have taken multiple products and that respiratory depression, rarely coma and very rarely death may occur. Special attention should be paid to respiratory and cardiovascular functions if the patient requires intensive care.

The symptoms of mild lormetazepam intoxication are drowsiness, tiredness, ataxic symptoms and impaired vision. Oral intake of higher doses can cause from a deep sleep to unconsciousness, respiratory depression and hypotension.

Patients with milder symptoms of intoxication should be observed while sleeping.

Following overdose with lormetazepam or other benzodiazepines, vomiting should be induced (within one hour) if the patient is conscious or gastric lavage performed 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.

Overdose with benzodiazepines generally appears as varying degrees of central nervous system depression ranging from drowsiness to coma. In moderate cases, symptoms include drowsiness, confusion and lethargy. In more serious cases, symptoms may include ataxia, hypotonia, hypotension, respiratory depression, rarely coma and very rarely death.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Hypnotics and sedatives: Benzodiazepines, ATC code: N05C D06

Lormetazepam has a high affinity for specific binding sites in the central nervous system. These benzodiazepine receptors show a close functional relationship with the receptors of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). As a benzodiazepine receptor agonist, Lormetazepam reinforces the GABAergic inhibition of the activity of the distal neurons. This effect manifests pharmacologically in the form of an anxiolytic, anti-epileptic, muscle-relaxing and sedative-hypnotic effect.

Lormetazepam shortens the sleep latency period, reduces the frequency of nocturnal awakenings and prolongs sleep duration. The anxiolytic and muscle-relaxing effects may be useful during pre- and post-operative periods.

5.2 Pharmacokinetic properties

Lormetazepam is completely absorbed from the tablet. Absorption occurs with a halflife of 0.5 to 0.9 hours. Maximum plasma drug levels of 6 ng/ml are reached 1.5 hours after oral administration of one 1 mg lormetazepam tablet. Once the maximum plasma concentration (Cmax) has been reached, there is a two-phase decrease in the concentration characterised by half-lives of 2 to 2.5 hours for the first phase and around 10 hours for the second phase.

Lormetazepam is extensively bound to plasma albumin. Irrespective of the concentration, 8.6% of the total plasma level is present in free form. The metabolic clearance rate was 3.6 ml/min/kg. Lormetazepam is almost exclusively metabolised by glucuronidation. Lormetazepam glucuronide does not bind to the benzodiazepine receptors; it is the main and only metabolite found in plasma which is excreted almost exclusively in urine. Less than 6% of the dose administered is found as N-demethylated lormetazepam glucuronide exclusively in urine. The excretion rate was estimated for one phase in which a half-life of 13.6 hours was calculated. In urine, 86% of the dose administered was recovered. The renal clearance of lormetazepam glucuronide was approximately 0.65 ml/min/kg.

The pharmacokinetics of lormetazepam are dose linear, within the range of 1 to 3 mg. No gender-related pharmacokinetic differences were found for lormetazepam. Small differences were found in elderly volunteers in comparison to young volunteers studied. These differences were: a lower plasma clearance rate, longer half-life of the terminal disposition phase in plasma and higher steady-state plasma drug levels. Plasma elimination of lormetazepam glucuronide was significantly slower in the older population (ti_/2 = 20 hours) in comparison to young subjects (ti_/2 = 12 hours).

No drug-drug interactions are expected in protein binding. No interactions were expected or found with cimetidine in biotransformation phase I.

It has been calculated that at most, 0.35% of the daily dose of lormetazepam that a breast-feeding mother receives could reach the newborn.

5.3 Preclinical safety data

In studies on toxicity after repeated oral administration, there were no findings indicative of intolerance reactions related with the therapeutic use of lormetazepam.

In tumourigenicity studies, no tumourigenic effect of the product was observed.

“In vitro” and “in vivo” studies on genotoxic effects did not indicate a mutagenic potential for somatic or germ cells in humans.

Animal experiments to study the effects on fertility, embryonic development, delivery and lactation as well as on development and reproductive capacity of the offspring did not indicate the existence of undesirable effects; in particular, no teratogenic effects are to be expected in humans.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose monohydrate

Maize starch Povidone K-25 Croscarmellose sodium Magnesium stearate

6.2    Incompatibilities

Not applicable

6.3    Shelf life

24 months

6.4    Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5    Nature and contents of container

PVC/PVDC/Aluminium blister strips.

Lormetazepam 0.5 mg tablets come in packs of 30 tablets (normal pack).

6.6    Special precautions for disposal

No special requirements

7 MARKETING AUTHORISATION HOLDER

Winthrop Pharmaceuticals UK Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

United Kingdom

Trading as Zentiva, One Onslow Street, Guildford, Surrey, GU1 4YS, UK.

8    MARKETING AUTHORISATION NUMBER(S)

PL 17780/0608

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

11/01/2016

10    DATE OF REVISION OF THE TEXT

11/01/2016