Summary of Product Characteristics (SmPC) - Lormetazepam 1 mg tablets
1 NAME OF THE MEDICINAL PRODUCT
Lormetazepam 1 mg tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 1mg of lormetazepam.
Excipient with known effect
Each tablet contains 86.40 mg lactose monohydrate.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Tablets.
White, round tablets scored in one side. The tablets can be divided into equal doses.
4 CLINICAL PARTICULARS
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
Posology
Prior to starting treatment with lormetazepam tablet, a discussion should be held with patients to put in place a strategy for ending treatment with lormetazepam tablet in order to minimise the risk of dependence, addiction and drug withdrawal syndrome (see section 4.4).
Treatment should be given for the shortest possible duration.
Dosage and duration of therapy should be individualised. 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.
Respiratory insufficiency:
For patients with mild to moderate chronic respiratory insufficiency, a dose reduction should be considered.
Hepatic impairment:
For patients with 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Treatment in all patients should be withdrawn gradually to minimise possible withdrawal symptoms (see Special Warnings and Precautions for Use).
Paediatric population
Lormetazepam has not been evaluated for the treatment of children.
Dosage:
Adults: 0.5 mg to 1.5 mg 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.
Method of administration
The tablets should be taken with a small amount of liquid before going to bed.
4.3 Contraindications
- Hypersensitivity to benzodiazepines including Lormetazepam Tablets or their components.
- Severe respiratory insufficiency.
- Sleep apnoea syndrome.
- Myasthenia gravis.
- Severe hepatic failure.
4.4 Special warnings and precautions for use
CNS depressants
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.
Alcohol
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).
Psychiatric disorders
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.
Pre-existing depression may emerge during benzodiazepine use.
Suicide/suicidal thoughts
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.
Dependence and withdrawal
The use of benzodiazepines may lead to physical and psychological dependence. The risk of dependence on lormetazepam is low when used at the recommended dose and duration, but increased with higher doses and longer term use. The risk of dependence is further increased in patients with a history of alcoholism or drug abuse or in patients with significant personality disorders. Therefore, use in individuals with a history of alcoholism or drug abuse should be avoided.
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 tablet should be reviewed regularly, with frequent assessments of patients being undertaken during the course of their treatment.
Dependence may lead to withdrawal symptoms, especially if treatment is discontinued abruptly (see 4.8 Undesirable effects). Therefore, the drug should always be discontinued gradually.
It may be useful to inform the patient that treatment will be of limited duration and that it will be discontinued gradually. The patient should also be made aware of the possibility of "rebound" phenomena to minimise anxiety should they occur.
Drug withdrawal syndrome
Prior to starting treatment with lormetazepam tablet, 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 tablet 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.
Abuse of benzodiazepines has been reported.
Tolerance
Some loss of efficacy to the hypnotic effects of short-acting benzodiazepines may develop after repeated use for a few weeks.
Narrow-angle glaucoma
Caution should be used in the treatment of patients with acute narrow-angle glaucoma.
Insomnia
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.
Renal and hepatic impairment
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.
Haematological effects
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.
Amnesia
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
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).
Hypotension
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).
Excipients
This medicinal product contains 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
Other CNS depressants
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.
Muscle relaxants
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).
Alcohol
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.
Narcotic analgesics
An enhancement of the euphoria induced by narcotic analgesics may occur with benzodiazepine use, leading to an increase in psychological dependence.
Compounds that affect hepatic enzymes
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.
Theophylline / Aminophylline
Administration of theophylline or aminophylline may reduce the sedative effects of benzodiazepines, including lormetazepam.
Antihypertensives
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 Fertility, pregnancy and lactation
Fertility
Fertility in male and female rats was not adversely affected by oral lormetazepam.
Pregnancy
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.
Breast-feeding
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.
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
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:
- The medicine has been prescribed to treat a medical or dental problem and
- You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and
- 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.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Nervous System. Psycholeptics. Hypnotics and Sedatives. Benzodiazepine derivates.
ATC code: N05CD06
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.
Lormetazepam is a benzodiazepine with anxiolytic, muscle relaxant, sedative and hypnotic properties. Clinical studies have shown minimal effects on REM sleep and on psychomotor performance on the day after treatment with lormetazepam.
5.2 Pharmacokinetic properties
Absorption
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.
Distribution
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.
Biotransformation
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.
Elimination
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.
Linearity/non-linearity
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 (t1/2 = 20 hours) in comparison to young subjects (t1/2 = 12 hours).
Pharmacokinetic/pharmacodynamic relationship(s)
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
There are no non-clinical data of relevance to the prescriber other than those mentioned elsewhere in this SmPC.
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
5 years
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 blisters packed into cartons containing 30 tablets.
6.6 Special precautions for disposal
No special requirements.
7. MARKETING AUTHORISATION HOLDER
Crescent Pharma Limited
Key House, Sarum Hill,
Basingstoke, RG21 8SR,
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL20416/0665
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
29/09/2022
10 DATE OF REVISION OF THE TEXT
08/01/2026