This information is intended for use by health professionals

1. Name of the medicinal product

Dalmane 15 mg Capsules

2. Qualitative and quantitative composition

Capsules with opaque grey cap and opaque yellow body with printed in red on both cap and body, containing 16.4 mg flurazepam monohydrochloride (equivalent to 15 mg flurazepam).

Each capsule contains 114.6 mg lactose.

For the full list of excipients, see section 6.1

3. Pharmaceutical form

Dalmane capsules 15 mg

4. Clinical particulars
4.1 Therapeutic indications

Short-term treatment of insomnia when it is severe, disabling or subjecting the individual to extreme distress. Dalmane is helpful in overcoming difficulties in getting to sleep and also in the problem of frequent nocturnal awakenings. Its properties make it particularly indicated where the total duration of sleep is less than adequate.

An underlying cause for insomnia should be sought before deciding upon the use of benzodiazepines for symptomatic relief.

Benzodiazepines are not recommended for the primary treatment of psychotic illness.

4.2 Posology and method of administration

Posology:

Adults - The dosage of Dalmane should be determined on an individual basis taking into account the severity of the insomnia and the patient's response to treatment. Dosage is important in determining the duration of effect and the occurrence of residual effects.

The usual dose is 15 or 30mg. 15 mg is optimal for most patients and this will ensure a full night's sleep with minimal residual effects on wakening. Patients with severe insomnia may require 30 mg (but no more than 60 mg), but residual effects on awakening, associated with an anxiolytic effect, are more frequent at this dose.

Elderly or debilitated patients - The elderly will be particularly susceptible to the adverse effects of Dalmane. The initial dose should not exceed 15 mg. If organic brain changes are present, the dosage of Dalmane should not exceed 15 mg.

Patients with hepatic and renal impairment – The initial dose is 15 mg and in general should not be exceeded.

Patients with chronic pulmonary insufficiency - In patients with chronic pulmonary insufficiency the dosage may need to be reduced.

Paediatric population - Dalmane is contra-indicated for use in children.

Duration of treatment - Treatment should, if possible, be on an intermittent basis.

Treatment should be as short as possible and should be started with the lowest recommended dose. The maximum dose should not be exceeded. Generally the duration of treatment varies from a few days to two weeks with a maximum of four weeks, including the tapering off process.

In certain cases, extension beyond the maximum treatment period may be necessary; if so, it should not take place without re-evaluation of the patient's status. Long-term chronic use is not recommended.

Flurazepam is a long-acting benzodiazepine so the patient must be regularly checked to reduce the dosage or frequency of administration if necessary to prevent overdose due to accumulation.

Patients who have taken benzodiazepines for a prolonged time may require a longer period during which doses are reduced. Specialist help may be appropriate. Little is known regarding the efficacy or safety of benzodiazepines in long-term use.

Method of administration:

Dalmane capsules are for oral administration.

The product should be taken just before going to bed.

To be swallowed with water without chewing.

4.3 Contraindications

Dalmane is contraindicated in:

-Patients with known hypersensitivity to flurazepam, other benzodiazepines or to any of the excipients listed in section 6.1

• myasthenia gravis;

• severe pulmonary insufficiency;

• respiratory depression;

• phobic or obsessional states;

• chronic psychosis; -

• sleep apnoea syndrome;

• severe hepatic insufficiency;

• spinal and cerebellar ataxia; and

• use in children.

4.4 Special warnings and precautions for use

Dalmane should not be used alone to treat depression or anxiety associated with depression, since suicide may be precipitated in such patients.

Benzodiazepines should be used in extreme caution in patients with a history of alcohol or drug abuse.

Benzodiazepines are not recommended for the primary treatment of psychotic illness.

In cases of loss or bereavement, psychological adjustment may be inhibited by benzodiazepines.

Dalmane is not indicated in patients with spinal and cerebellar ataxia.

Elderly patients should be given a reduced dose (see section 4.2 Posology). Due to the myorelaxant effect there is a risk of falls and consequently fractures in the elderly.

A lower dose is also recommended for patient with chronic respiratory insufficiency due to the risk of respiratory depression. Benzodiazepines are not indicated to treat patients with severe hepatic insufficiency as they may precipitate encephalopathy and reduced doses should be given to patients with renal or hepatic disease.

Dalmane should not be given in acute intoxication with alcohol, sedative agents, hypnotic agents, analgesics or psychotropic agents (neuroleptic agents, antidepressants, lithium).

Dalmane is not indicated for children. If necessary for compelling reasons, benzodiazepines should be prescribed for children and adolescents after careful appraisal of the risk-benefit ratio only.

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

Tolerance:

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

Dependency:

Use of benzodiazepines may lead to the development of physical and psychological dependence. The dependence potential of the benzodiazepines is low, particularly when limited to short-term use, but this increases when high doses are used, especially when given over long periods. This is particularly so in patients with a history of alcoholism or drug abuse or in patients with marked personality disorders. Regular monitoring in such patients is essential, routine repeat prescriptions should be avoided and treatment should be withdrawn gradually. Symptoms such as depression, nervousness, extreme anxiety, tension, restlessness, confusion, mood changes, rebound insomnia, irritability, sweating, diarrhoea, headaches and muscle pain have been reported following abrupt cessation of treatment in patients receiving even normal therapeutic doses for short periods of time.

In severe cases the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact and hallucinations or epileptic seizures. In rare instances, withdrawal following excessive dosages may produce confusional states, psychotic manifestations and convulsions. Abuse of the benzodiazepines has been reported.

Rebound Insomnia and Anxiety:

This is a transient syndrome whereby the symptoms that led to treatment with a benzodiazepine recur in an enhanced form, may occur on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety or sleep disturbances and restlessness. Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage is decreased gradually.

Psychiatric and paradoxical reactions:

Abnormal psychological reactions to benzodiazepines have been reported. Rare behavioural effects include paradoxical aggressive outbursts, excitement, confusion, restlessness, agitation, irritability, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and the uncovering of depression with suicidal tendencies. Extreme caution should therefore be used in prescribing benzodiazepines to patients with personality disorders. If any of these reactions occur, use of the drug should be discontinued. These reactions may be quite severe and are more likely to occur in children and the elderly.

Amnesia:

Benzodiazepines may induce anterograde amnesia. The condition usually occurs 1-2 hours after ingesting the product and may last up to several hours. Therefore, to reduce the risk, patients should ensure that they will be able to have an uninterrupted sleep of 7 to 8 hours.

If the patient is awoken during the period of maximum drug activity, recall may be impaired.

Duration of treatment:

The duration of treatment should be as short as possible (see section 4.2 Posology) depending on the indication, but should not exceed 4 weeks, including tapering off process. Extension beyond these periods should not take place without re-evaluation of the situation.

It may be useful to inform the patient when treatment is started that it will be of limited duration and to explain precisely how the dosage will be progressively decreased.

Moreover it is important that the patient should be aware of the possibility of rebound phenomena, thereby minimising anxiety over such symptoms should they occur while the medicinal product is being discontinued.

When benzodiazepines with a long duration of action are being used it is important to warn against changing to a benzodiazepine with a short duration of action, as withdrawal symptoms may develop.

4.5 Interaction with other medicinal products and other forms of interaction

The benzodiazepines, including flurazepam, produce additive CNS depressant effects when co-administered with other CNS drugs such as barbiturates, antipsychotics, sedative/hypnotics, anxiolytics, antidepressants, narcotic analgesics, sedative antihistamines, anticonvulsants, anaesthetics, antihypertensives and beta (receptor) blockers.

Administration of theophylline or aminophylline may reduce the sedative effects of benzodiazepines. In case of narcotic analgesics enhancement of the euphoria may also occur leading to an increase in psychological dependence.

The elderly require special supervision.

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

When Dalmane is used in conjunction with anti-epileptic drugs, side-effects and toxicity may be more evident, particularly with hydantoins or barbiturates or combinations including them. This requires extra care in adjusting dosage in the initial stages of treatment.

Concomitant intake with muscle relaxants may increase the relaxant effect of flurazepam.

Known inhibitors of hepatic enzymes, eg cimetidine, omeprazole and disulfuram, have been shown to reduce the clearance of benzodiazepines and may potentiate their action and known inducers of hepatic enzymes, eg rifampicin, may increase the clearance of benzodiazepines.

Concomitant intake with alcohol should be avoided. The sedative effect of Dalmane may be modified and enhanced in an unpredictable way if the product is used in combination with alcohol. This adversely affects the ability to drive or use machines.

4.6 Fertility, pregnancy and lactation

Pregnancy

There is no evidence as to drug safety in human pregnancy, nor is there evidence from animal work that it is free from hazard. Do not use during pregnancy, especially during the first and last trimesters, unless there are compelling reasons.

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

Administration of benzodiazepines in the last trimester of pregnancy or during labour has been reported to produce irregularities in the foetal heart rate, and hypotonia, poor sucking and hypothermia and moderate respiratory depression in the neonate.

Moreover, 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 withdrawal symptoms in the postnatal period.

Breast-feeding

There is insufficient information on the excretion of flurazepam and/or metabolites into human milk. However, in common with other benzodiazepines, its passage into breast milk might be expected. The use of Dalmane in mothers who are breast-feeding is not recommended.

4.7 Effects on ability to drive and use machines

Patients should be advised that, like all medicaments of this type, Dalmane might modify patients' performance at skilled tasks (driving, operating machinery, etc) to a varying degree depending upon dosage, administration, and sleep pattern and individual susceptibility. Patients should further be advised that alcohol may intensify any impairment, and should therefore be avoided during treatment.

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

Common adverse effects include somnolence during the day, emotional poverty, reduced alertness, confusional state, fatigue, headache, dizziness, muscle weakness, ataxia and diplopia. These phenomena are dose-related and are likely to be uncommon with the recommended dosage; they occur predominantly at the start of therapy and usually disappear with repeated administration or after dose adjustment. The elderly are particularly sensitive to the effects of centrally depressant drugs.

Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: Very common (>1/10), Common (>1/100 to <1/10), Uncommon (>1/1,000 to <1/100), Rare (>1/10,000 to <1/1,000), Very rare (<1/10,000), Frequency not known (cannot be estimated from the available data).

Blood and lymphatic system disorders:

Frequency not known: blood disorders (e.g. thrombocytopenia, leukopenia, agranulocytosis, pancytopenia).

Immune system disorders:

Rare: Hypersensitivity (e.g. angioedema)

Psychiatric disorders:

Uncommon: Emotional poverty,

Frequency not known: Confusional state, hallucinations, dependence, withdrawal syndrome, rebound effect, depression, paradoxical drug reactions (e.g. anxiety, sleep disorders, insomnia, nightmares, restlessness, agitation, irritability, aggression, delusion, psychotic disorder, abnormal behaviour, emotional disturbances, suicide attempt, suicidal ideation).

Nervous system disorders:

Common: Somnolence, reduced alertness, ataxia, dizziness, headache, dysgeusia

Frequency not known: Extrapyrimidal disorder, anterograde amnesia

Eye disorders:

Rare: Visual impairment (e.g. diplopia)

Ear and labyrinth disorders:

Rare: Vertigo

Vascular disorders:

Rare: Hypotension

Respiratory, thoracic and mediastinal disorders:

Rare: Respiratory depression (particularly at night)

Gastrointestinal disorders:

Rare: Abdominal discomfort, nausea

Hepatobiliary disorders:

Very rare: Jaundice, hepatic enzyme increase

Skin and subcutaneous tissue disorders:

Rare: Skin reactions (e.g. rash)

Musculoskeletal and connective tissue disorders:

Common: Muscle weakness. Due to the myorelaxant effect there is a risk of falls and consequently fractures in the elderly.

Renal and urinary disorders:

Rare: Urinary retention

Reproductive system and breast disorders:

Rare: Libido disorder

General disorders and administration site conditions:

Uncommon: Fatigue

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

When taken alone in overdosage Dalmane presents few problems in management and should not present a threat to life unless combined with other CNS depressants (including alcohol).

Symptoms:

Depending on the dose ingested, intoxication with benzodiazepines is usually manifested by various degrees of central nervous system depression ranging from somnolence, mental confusion, dysarthria and lethargy, impaired vision and dystonia to ataxia, unconsciousness, central respiratory and/or circulatory depression and rarely coma and very rarely death.

Management:

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

Following overdose with oral benzodiazepines, 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.

General supportive and symptomatic measures are recommended.

Special attention should be paid to respiratory and cardiovascular functions in intensive care.

The value of dialysis has not been determined and is expected to be low for Dalmane.

Flumazenil is a specific IV antidote for use in emergency situations. Patients requiring such intervention should be monitored closely in hospital (see separate prescribing information).

The physician should be aware of a risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose.

If excitation occurs, barbiturates should not be used.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Hypnotics and Sedatives, Benzodiazepine derivatives,

ATC code: N05CD01

Flurazepam is a psychotropic substance from the class of 1,4-benzodiazepines. Onset of sedative effects occurs within 30 minutes. Due to accumulation of the active metabolite N1-desalkyl-flurazepam peak response is not observed before night 2-3 of treatment.

Flurazepam binds to specific benzodiazepine receptors located on GABA-ergic neurones and potentiates the inhibitory actions of GABA-ergic neurones in the nervous system.

After prolonged flurazepam treatment, development of tolerance has been observed. Chronic benzodiazepine use leads to compensating changes in the central nervous system. GABAA receptors may become less responsive to the continuing acute effects of benzodiazepines, either as a result of adaption in the GABAA receptor itself, intracellular mechanisms, or changes in the neurotransmitter systems. Probably multiple adaptive mechanisms simultaneously co-exist.

An increase in intensity and incidence of CNS toxicity with age has been observed, especially at high doses. Therefore the initial dose of Dalmane in elderly should not exceed 15 mg (see section 4.2). The increased CNS toxicity in elderly seems to be the result of the combination of pharmacokinetic and pharmacodynamic factors.

Under the treatment with 15 and 30 mg flurazepam impairment of psychomotor and cognitive performance was observed in several investigations. Especially the driving ability is affected (see section 4.7). In elderly patients the effect is more pronounced.

5.2 Pharmacokinetic properties

The pharmacokinetic properties of Dalmane make it particularly indicated for patients whose total duration of sleep is less than adequate. The dosage of the drug is important in balancing the duration of effect with the occurrence of residual effects.

Absorption:

Flurazepam hydrochloride is rapidly and almost completely absorbed after oral administration. Maximum plasma concentrations were measured after 1 to 3 hours. The maximum plasma concentrations of the two pharmacologically active major metabolites N1-hydroxyethyl-flurazepam and N1-desalkyl flurazepam were observed after 1 to 4 hours and 0.5 to 96 hours, respectively. In most subjects, the N1-desalkyl-flurazepam concentration reached a plateau value after 1 to 24 hours. The maximum plasma concentration of N1-hydroxyethyl-flurazepam ranges between 6 and 28 ng/ml and of N1-desalkyl-flurazepam ranges between 5 and 40 ng/ml after a single oral dose.

Distribution:

Flurazepam undergoes considerable first-pass metabolism.

The plasma protein binding is high for flurazepam (83%) and N1-desalkyl-flurazepam (96.5%) and lower for N1-hydroxyethyl-flurazepam (65%).

Taking flurazepam hydrochloride over a period of 15 days the N1-desalkyl-flurazepam accumulated. The plasma concentrations were 7.5 times higher on the 15th day versus the 1st day.

The concentration of flurazepam and its metabolites is 2 times (for N1-hydroxyethyl-flurazepam), 7 times (for flurazepam) or 8 times (for N1-desalkyl-flurazepam) higher in cerebrospinal fluid compared to plasma.

In animal models, flurazepam was eliminated from serum in biphasic fashion, consistent with two-compartment model and volume of distribution was between 2.65 and 5.5 l/kg.

Flurazepam and/or active metabolites cross the placental barrier in rodents. Human data are not available.

No information concerning secretion of flurazepam and metabolites in the breast milk are available. However in common with other benzodiazepines, its passage into breast milk might be expected.

Biotransformation:

The plasma half-life for flurazepam and N1-hydroxyethyl-flurazepam was 3.1 hours and 2.3 to 3.4 hours, respectively. For N1-desalkyl-flurazepam, the corresponding values were 19 to 133 hours. In elderly subjects (66 - 85 years) still higher values for N1-desalkyl-flurazepam were obtained (71-289 hours). The metabolites are further conjugated to glucuronides and / or sulfates for renal excretion

Elimination:

Flurazepam monohydrochloride and its metabolites are eliminated primarily by renal excretion (about 80%). The major urinary metabolite, N1-hydroxyethyl-flurazepam as glucuronide/sulphate conjugate accounts for 20-55% of an orally administered dose.

5.3 Preclinical safety data

Mutagenic and tumourigenic potential:

There is insufficient data available to evaluate the genotoxic potential of flurazepam. The limited studies performed to date showed no evidence of genotoxicity

6. Pharmaceutical particulars
6.1 List of excipients

15 mg capsules contain the following excipients: lactose, talc purified, magnesium stearate, black iron oxide E172, titanium dioxide E171 and yellow iron oxide E172.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Amber glass bottles and plastic adept containers - 5 years.

PVDC blister packs - 3 years.

Polythene bags in tins and small HDPE bottles - 2 years.

White securitainers - 1 year.

6.4 Special precautions for storage

Dalmane capsules should be stored in a dry place with a recommended maximum storage temperature of 25°C.

6.5 Nature and contents of container

PVDC blister packs, amber glass bottles, polythene bags in tins, plastic adept containers, white securitainers and small HDPE bottles, containing 30 capsules.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Mylan Products Ltd,

Station Close,

Potters Bar,

Hertfordshire,

EN6 1TL,

United Kingdom

8. Marketing authorisation number(s)

PL 46302/0125

9. Date of first authorisation/renewal of the authorisation

03/05/1999

10. Date of revision of the text

May 2018