4.1. Therapeutic indications

Lormetazepam is indicated for the short term treatment of insomnia when it is disabling or subjecting the individual to extreme distress.

4.2. Posology and method of administration

Dosage and duration of therapy should be individualised. Prior to starting treatment with lormetazepam, a discussion should be held with patients to put in place a strategy for ending treatment with lormetazepam in order to minimise the risk of dependence, addiction and drug withdrawal syndrome (see section 4.4).

The lowest effective dose should be prescribed for the shortest time possible. Generally, the duration of treatment varies from a few days to 2 weeks, with a maximum of 4 weeks including the tapering off process. Extension of the treatment period should not take place without re-evaluation of the need for continued therapy.

For patients with mild to moderate chronic respiratory insufficiency or hepatic insufficiency a dose reduction should be considered.

Since insomnia is often transient and intermittent, the prolonged administration of lormetazepam is generally unnecessary and is not recommended.

Treatment in all patients should be withdrawn gradually to minimise possible withdrawal symptoms (see Special Warnings and Precautions for Use).

Dosage:

Adults: 0.5mg to 1.5mg before retiring.

Subsequently the initial dosage may be increased in individual cases if this proves necessary

Elderly: The lower adult dose is preferable for elderly patients

Children: Lormetazepam has not been evaluated for the treatment of children

4.3. Contraindications

Severe respiratory insufficiency.

Sleep apnoea syndrome.

Hypersensitivity to benzodiazepines including Lormetazepam Tablets or their components.

Myasthenia gravis.

Severe hepatic failure.

4.4. Special warnings and precautions for use

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. Lormetazepam may enhance the sedative effects of alcohol. Since this affects the ability to drive or use machinery, alcohol should be avoided while taking lormetazepam.

Due to the potential adverse reactions including ataxia, muscle weakness, dizziness, drowsiness and fatigue (see Section 4.8), Benzodiazepines may be associated with an increased risk of falling especially in elderly patients. As a result, caution should be exercised particularly when getting up at night. The elderly should receive a reduced dose (see section 4.2).

Lormetazepam is not intended for the primary treatment of psychotic illness or depressive disorders, and should not be used alone to treat depressed patients with associated insomnia. The use of benzodiazepines may have a disinhibiting effect and may release suicidal tendencies in depressed patients. Therefore, large quantities of lormetazepam should not be prescribed to these patients.

Pre-existing depression may emerge during benzodiazepine use.

Abuse of benzodiazepines has been reported.

Some loss of efficacy to the hypnotic effects of short-acting benzodiazepines may develop after repeated use for a few weeks.

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

Insomnia may be a symptom of several other disorders. The possibility should be considered that the complaint may be related to an underlying physical or psychiatric disorder for which there is a more specific treatment.

Patients with impaired renal or hepatic function should be monitored frequently and have their dosage adjusted carefully according to patient response. Lower doses may be sufficient in these patients. The same precautions apply to elderly or debilitated patients and patients with chronic respiratory insufficiency.

As with all CNS-depressants, the use of benzodiazepines may precipitate encephalopathy in patients with severe hepatic insufficiency. Therefore, use in these patients is contraindicated.

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

Transient anterograde amnesia or memory impairment has been reported in association with the use of benzodiazepines. This condition, which may be associated with inappropriate behaviour, usually occurs several hours after ingestion. Therefore, patients should ensure that they will be able to have a period of uninterrupted sleep which is sufficient to allow dissipation of drug effect (e.g., 7-8 hours).

Paradoxical reactions have been occasionally reported during benzodiazepines use. Such reactions are more likely to occur in children and the elderly. Should these occur, use of the drug should be discontinued (see 4.8 Undesirable Effects).

Contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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.

Risk from concomitant use of opioids:

Concomitant use of lormetazepam 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 lormetazepam with opioids should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe lormetazepam 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).

Drug dependence, tolerance and potential for abuse

Drug addiction comprises behavioural, cognitive and physiological phenomena that may include a strong desire to take the drug, difficulties in controlling drug use and possible tolerance or physical dependence. Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, which manifests as withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug. Addiction and dependence are related but distinct presentations and in discussing these themes, terminology that apportion blame to the individual should be avoided.

For all patients, prolonged use of this product may lead to drug dependence and addiction but can occur with short-term use at recommended therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression).

Additional support and monitoring may be necessary when prescribing for patients at risk of drug misuse.

A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained on-line, and past and present medical and psychiatric conditions.

Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of symptom control as initially experienced. Patients may also supplement their treatment with additional medications to achieve the same effect. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.

Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else.

Patients should be closely monitored for signs of misuse, abuse, or addiction.

The clinical need for treatment with lormetazepam should be reviewed regularly, with frequent assessments of patients being undertaken during the course of their treatment.

Drug withdrawal syndrome

Prior to starting treatment with lormetazepam, a discussion should be held with patients to explain the risk of dependence, addiction, and drug withdrawal syndrome. A withdrawal strategy for ending treatment with lormetazepam should also be put in place with the patient before starting treatment (there may be exceptions to this in specific clinical situations such as symptom management in end of life palliative care).

Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take in excess of weeks or months. Patients should be informed of this when the medication is first prescribed.

The reduction schedule for a patient should be tailored to the individual and should be modified to allow intolerable withdrawal symptoms to improve before making the next reduction. If using a published withdrawal schedule, apply it flexibly to accommodate the person's preferences, changes to their circumstances and the response to dose reductions.

Suggest a slow stepwise rate of reduction proportionate to the existing dose, so that decrements become smaller as the dose is lowered, unless clinical risk is such that rapid withdrawal is needed.

If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level.

If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.

4.5. Interaction with other medicinal products and other forms of interaction

The benzodiazepines, including lormetazepam produce additive CNS depressant effects when co-administered with other medications which themselves produce CNS depression e.g., alcohol, barbiturates, antipsychotics, sedatives/hypnotics, anxiolytics, antidepressants, narcotic analgesics, sedative antihistamines, anticonvulsants, and anaesthetics.

When taken with muscle relaxants, the overall muscle-relaxing effect may be increased (accumulative) therefore caution is advised, especially in elderly patients and at higher doses (risk of falling, see Section 4.4).

Concomitant use of alcohol is not recommended. The sedative effects may be enhanced when lormetazepam is used in combination with alcohol. This will affect the ability to drive or use machines.

An enhancement of the euphoria induced by narcotic analgesics may occur with benzodiazepine use, leading to an increase in psychological dependence.

Compounds which inhibit certain hepatic enzymes (particularly cytochrome P450) may enhance the activity of benzodiazepines. To a lesser degree this also applies to benzodiazepines which are metabolised only by conjugation.

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

Enhanced hypotensive effects may occur when lormetazepam is given to patients treated with antihypertensive agents.

Opioids

The concomitant use of sedative medicines such as benzodiazepines or related drugs such as lormetazepam 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).

4.6. Pregnancy and lactation

Benzodiazepines should not be used during pregnancy, especially during the first and last trimesters. Benzodiazepines may cause foetal damage when administered to pregnant women.

If the drug is prescribed to a woman of childbearing potential, she should be warned to contact her physician about stopping the drug if she intends to become, or suspects that she is, pregnant.

There is a possibility that infants born to mothers who take benzodiazepines chronically during the later stages of pregnancy may develop physical dependence. Infants of mothers who ingested benzodiazepines for several weeks or more preceding delivery have been reported to have withdrawal symptoms during the postnatal period. Symptoms such as hypoactivity, hypotonia, hypothermia, respiratory depression, apnoea, feeding problems, and impaired metabolic response to cold stress have been reported in neonates born of mothers who have received benzodiazepines during the late phase of pregnancy or at delivery.

Lactation: Since limited data indicates that a small proportion of parent drug and its conjugate is excreted in breast milk, lormetazepam should not be given to breast-feeding women. Sedation and inability to suckle have occurred in neonates of lactating mothers taking benzodiazepines.

4.7. Effects on ability to drive and use machines

Sedation, amnesia, dizziness and impaired muscular function may adversely affect the ability to drive or use machines. If insufficient sleep occurs, the likelihood of impaired alertness may be increased (see also Interactions).

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

Adverse reactions, when they occur, are usually observed at the beginning of therapy and generally decrease in severity or disappear with continued use or upon decreasing the dose.

Most frequently reported adverse reactions associated with benzodiazepines include daytime drowsiness, dizziness, muscle weakness and ataxia.

Adverse reactions are listed by frequency: common (>1/100, <1/10); uncommon (>1/1,000, <1/100), rare (>1/10,000, <1/1,000); very rare (<1/10,000).

Blood and lymphatic system disorders

Very rare: Thrombocytopenia, leucopenia, agranulocytosis, pancytopenia

Immune system disorders

Very rare: Hypersensitivity including anaphylaxis/anaphylactoid reactions

Endocrine disorders

Very rare: Inappropriate antidiuretic hormone secretion, hyponatraemia

Psychiatric disorders

Rare: Confusion, depression and unmasking of depression, numbed emotions, disinhibition, euphoria, appetite changes, sleep disturbance, change in libido, decreased orgasm

Unknown: Drug dependence (see section 4.4), Suicidal ideation/attempt

Paradoxical reactions such as restlessness, agitation, irritability, aggressiveness, delusion, rage, insomnia, nightmares, hallucinations, psychoses, sexual arousal, and inappropriate behaviour have been occasionally reported during use.

Nervous system disorders

Very common: Daytime drowsiness, sedation

Common: Dizziness, ataxia

Rare: headache, reduced alertness, dysarthria/slurred speech, transient anterograde amnesia or memory impairment

Very rare: Tremor, extrapyramidal reactions, Coma (see 4.9 Overdose)

Eye disorders

Rare: Visual disturbances (diplopia, blurred vision)

Vascular disorders

Rare: Hypotension (see 4.4 Special warnings and precautions).

Respiratory thoracic and mediastinal disorders

Rare: Apnoea, worsening of sleep apnoea, worsening of obstructive pulmonary disease.

Respiratory depression (see 4.9 Overdose)

Gastrointestinal disorders

Rare: Nausea, constipation, salivation changes

Hepatobiliary disorders

Rare: Abnormal liver function test values (increases in bilirubin, transaminases, alkaline phosphatase), jaundice

Skin and subcutaneous tissue disorders

Rare: Rash, allergic dermatitis

Musculoskeletal disorders

Common: Muscle weakness

Reproductive system and breast disorders

Rare: Impotence

General disorders

Common: Asthenia, fatigue

Very rare: Hypothermia

Drug withdrawal symptoms (see 4.4 Special warnings and precautions)

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.

In severe cases the following symptoms may occur: derealisation; depersonalisation; hyperacusis; tinnitus; numbness and tingling of the extremities; hypersensitivity to light, noise, and physical contact; involuntary movements; hyperreflexia, tremor, nausea, vomiting; diarrhoea, abdominal cramps, loss of appetite, agitation, palpitations, tachycardia, panic attacks, vertigo, short-term memory loss, hallucinations/delirium; catatonia; hyperthermia, 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.

Injury, poisoning and procedural complications

Not known: Fall

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 or search for 'MHRA Yellow Card' in the Google Play or Apple App Store.

4.9. Overdose

In the management of overdose with any drug, it should be borne in mind that multiple agents may have been taken.

Overdose of benzodiazepines is usually manifested by degrees of central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, mental confusion, and lethargy. In more serious cases, and especially when other CNS-depressant drugs or alcohol are ingested, symptoms may include ataxia, hypotension, hypotonia, respiratory depression, coma, and very rarely, death.

If ingestion was recent, induced vomiting and/or gastric lavage should be undertaken followed by general supportive care, monitoring of vital signs and close observation of the patient. If there is no advantage in emptying the stomach, activated charcoal may be effective in reducing absorption. Special attention should be paid to respiratory and cardiovascular functions in intensive care. Hypotension, though unlikely, may be controlled with noradrenaline. Lormetazepam is poorly dialysable.

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

Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.