This information is intended for use by health professionals

1. Name of the medicinal product

Temazepam 10 mg Tablets

2. Qualitative and quantitative composition

Each tablet contains 10 mg of Temazepam.

Excipient: Each Tablet contains 72.30 mg of lactose monohydrate.

For a full list of excipients, see section 6.1.

3. Pharmaceutical form

Tablets.

White to pale yellow, round, flat beveled-edged scored tablets with 7 mm diameter, marked 'T/10' on the scored side, and 'G' on the other.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4. Clinical particulars
4.1 Therapeutic indications

Short-term management of insomnia. Benzodiazepines are only indicated when the disorder is severe, disabling or subjecting the individual to extreme distress.

For premedication prior to minor surgery or other related procedures.

4.2 Posology and method of administration

Posology

Adults including older people

Treatment should be started with the lowest recommended dose. The maximum dose should not be exceeded.

Insomnia

Dosage should be checked regularly at the start of treatment in order to decrease, if necessary, the dose or frequency of administration to prevent overdose due to accumulation. Treatment should be as short as possible. Generally the duration of treatment varies from a few days to two weeks with a maximum, including tapering-off, of four weeks. The tapering-off process should be tailored to the individual. 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.

The product should be taken on retiring or up to 30 minutes before going to bed.

Adults: 10-20 mg. In exceptional circumstances the dose may be increased to 30-40 mg.

Older people: 10 mg. In exceptional circumstances the dose may be increased to 20 mg.

Premedication

Adults:

The usual dose is 20-40 mg, 30 to 60 minutes before procedure.

Elderly:

Elderly patients are likely to respond to smaller doses, possibly half the normal adult dose or less.

Patients should be accompanied home when temazepam has been used as a premedicant prior to surgery or other procedures on a day attendance basis.

Paediatric population

The safety and efficacy of temazepam in children and adolescents less than 18 years of age has not been established and as such is not recommended for use.

Patients with hepatic impairment

Patients with impaired liver function should have a reduced dose.

Method of administration

For oral use.

4.3 Contraindications

Hypersensitivity to the active substance, other benzodiazepines or to any of the excipients listed in section 6.1

Myasthenia gravis

Severe respiratory insufficiency

Sleep apnoea syndrome

Severe hepatic insufficiency

Use in children and adolescents.

4.4 Special warnings and precautions for use

Psychiatric and paradoxical reactions

Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur with using benzodiazepines. They are more likely to occur in older people. Should this occur, use of the drug should be discontinued.

Tolerance

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

Amnesia

Benzodiazepines may induce anterograde amnesia at therapeutic dosages, with the risk increasing at high dosages. The condition occurs most often several hours after ingesting the product, and therefore patients should ensure that they will be able to have an uninterrupted sleep of 7 - 8 hours. Amnesia effects may be associated with inappropriate behaviour.

Dependence

Use of benzodiazepines (even at therapeutic doses) may lead to the development of physical and psychic dependence upon these products. 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 or in patients with significant personality disorders.

Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms. These may consist of headaches, muscle pain, extreme anxiety, tension, depression, restlessness, insomnia, confusion and irritability and sweating. 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, vomiting, hallucinations or epileptic seizures.

Rebound insomnia and anxiety

A transient syndrome whereby the symptoms that led to treatment with a benzodiazepine recur in an enhanced form, may occur on withdrawal of hypnotic treatment. It may be accompanied by other reactions including mood changes, anxiety, sleep disturbances and restlessness. These symptoms may be difficult to distinguish from the original symptoms for which the drug was prescribed.

Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment it is recommended that the dosage is decreased gradually.

Duration of treatment and withdrawal

The duration of treatment should be as short as possible (see section 4.2), depending on the indication, but should not exceed 4 weeks for insomnia including the tapering off process. Extension beyond this period 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.

There are indications that, in the case of benzodiazepines with a short duration of action, withdrawal phenomena can become manifest within the dosage interval, especially when the dosage is high. 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.

Older people

Older people should be given a reduced dose (see section 4.2). Due to the myorelaxant effect of benzodiazepines there is risk of falls and consequently of hip fractures, particularly for older patients when they get up at night.

Respiratory insufficiency

A lower dose is recommended for patients with chronic respiratory insufficiency due to the risk of respiratory depression.

Hepatic or renal impairment

Benzodiazepines are not indicated to treat patients with severe hepatic insufficiency as it may precipitate encephalopathy.

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.

Psychoses

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

Depression

Pre-existing depression may be unmasked during benzodiazepine use. Benzodiazepines should not be used alone to treat depression or anxiety associated with depression (suicide may be precipitated in such patients).

Drug and alcohol abuse

Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse. Abuse has been reported in polydrug abusers.

Other potential causes of 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 more specific treatment.

Lactose

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

4.5 Interaction with other medicinal products and other forms of interaction

Not recommended:

Concomitant intake with alcohol. The sedative effect may be enhanced when the product is used in combination with alcohol. This affects the ability to drive or use machines.

Take into account:

Combination with CNS depressants. Enhancement of the central depressive effect may occur in cases of concomitant use with antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressant agents, narcotic analgesics, antiepileptic drugs, anaesthetics and sedative antihistamines. In the case of narcotic analgesics enhancement of the euphoria may also occur leading to an increase in psychic dependence.

The sedative effect of temazepam may be enhanced when it is taken in combination with disulfiram.

Concomitant use of oral contraceptive steroids may enhance the elimination of temazepam and slightly decrease the drug effect.

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

4.6 Fertility, pregnancy and lactation

Pregnancy

Insufficient data are available on temazepam to assess its safety during pregnancy. Temazepam is not recommended for administration during pregnancy. Animal studies with benzodiazepines have shown minor effects on the foetus while a few studies have reported late behavioural disturbance in offspring exposed in utero.

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 pregnant or suspects that she is pregnant.

If, for compelling medical reasons, temazepam is administered during the late phase of pregnancy, or during labour, effects on the neonate, such as hypothermia, hypotonia and moderate respiratory depression, can be expected due to the pharmacological action of the product.

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.

Breastfeeding

Temazepam may pass into breast milk, consequently its use during breastfeeding is not recommended.

4.7 Effects on ability to drive and use machines

Not recommended:

Sedation, amnesia, impaired concentration and impaired muscle function may adversely affect the ability to drive or to use machines. If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased (see also section 4.5).

As with all patients on CNS depressant drugs, patients should be warned not to drive or operate machinery until it is known that they do not become drowsy or dizzy from temazepam. Drowsiness is most likely to occur after initiation of the use of benzodiazepines and gradually subsides. Driving skills are usually not affected in the morning after taking a 20mg dose of temazepam in the preceding evening.

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

Blood and lymphatic system disorders

Blood dyscrasias have been reported rarely.

Psychiatric disorders

Numbed emotions (this phenomenon occurs predominantly at the start of therapy and usually disappears with repeated administration).

Changes in libido have been reported occasionally.

Depression has been reported occasionally. Pre-existing depression may be unmasked during benzodiazepine use.

Anterograde amnesia may occur using therapeutic dosages, the risk increasing at higher dosages. Amnesic effects may be associated with inappropriate behaviour (see section 4.4).

Reactions like restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines. They may be quite severe and are more likely to occur in the elderly (see section 4.4).

Nervous system disorders

Drowsiness during the day, reduced alertness, confusion, impaired concentration, fatigue, headache, dizziness, , ataxia and sleep disturbance/restless sleep. These phenomena occur predominantly at the start of therapy and usually disappear with repeated administration.

Eye disorders

Double vision (this phenomenon occurs predominantly at the start of therapy and usually disappears with repeated administration).

Vascular disorders

Hypotension has been reported rarely.

Gastrointestinal disorders

Dryness of the mouth or gastro-intestinal disturbances have been reported occasionally.

Skin and subcutaneous tissue disorders

Skin reactions have been reported occasionally.

Musculoskeletal and connective tissue disorders

Muscle weakness (this phenomenon occurs predominantly at the start of therapy and usually disappears with repeated administration).

Investigations

Abnormal liver function tests have been reported rarely

Withdrawal reactions

Withdrawal of treatment may be accompanied by mood changes, anxiety, sleep disturbances or restlessness. The risk of withdrawal or rebound phenomena is greater after abrupt discontinuation of treatment. It is recommended that the dosage is decreased gradually.

Use (even at therapeutic doses) of benzodiazepines may lead to the development of physical and psychic dependence. Once physical dependence has occurred, abrupt termination of treatment will be accompanied by withdrawal symptoms or rebound phenomenon. These include headaches, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability. In severe cases symptoms may include derealisation, depersonalization, hyperacusis, numbness and tingling of extremities, hypersensitivity to light, noise and physical contact, hallucinations or epileptic seizures (see section 4.4).

Abuse has also been reported.

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: www.mhra.gov.uk/yellowcard

4.9 Overdose

As with other benzodiazepines, overdose should not present a threat to life unless combined with other CNS depressants (including alcohol).

However, in post-marketing experience, overdose with temazepam has occurred predominantly in combination with alcohol and/or other drugs. Therefore, in the management of overdose with any medicinal product, it should be borne in mind that multiple agents may 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.

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

3-OH benzodiazepines are, as a rule, not dialysable and their metabolites (glucuronides) only dialysable with difficulty. The value of dialysis has not been determined for temazepam.

Overdosage 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, symptoms may include ataxia, hypotonia, hypotension, respiratory depression, rarely coma and very rarely death.

Flumazenil may be useful as an antidote. Flumazenil product information should be consulted prior to temazepam use.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Benzodiazepine derivatives, ATC code: N05CD07

Temazepam is a benzodiazepine: it has anxiolytic, sedative and hypnotic characteristics as well as possible muscle relaxant and anticonvulsant characteristics.

5.2 Pharmacokinetic properties

Absorption

Pharmacokinetic studies have shown that temazepam is well absorbed (90 - 100%) and the first pass effect is slight (about 5%). The time to reach peak plasma levels is usually about 50 minutes when given orally. Maximum plasma levels observed after doses of 20 mg are 660 - 1100 ng/ml. With multiple dosing steady state is obtained by the third day and there is little or no accumulation of parent drug or metabolites.

Distribution

The volume of distribution is 1.3 to 1.5 l/kg body weight, for the unbound fraction 43 - 68 l/kg. Approximately 96% of unchanged drug is bound to plasma proteins.

Biotransformation

Temazepam is metabolised principally in the liver where most of the unchanged drug is directly conjugated to the glucuronide and excreted in the urine. Less than 5% of the drug is demethylated to oxazepam and eliminated as the glucuronide. The glucuronides of temazepam have no demonstrable CNS activity.

Elimination

Temazepam is rapidly eliminated, most studies showing an elimination half life in the range 7 - 11 hours (mean 8 hours). Following a single dose, 80% of the dose appears in the urine, mostly as the conjugates and 12% of the dose appears in the faeces. Less than 2% of the dose is excreted unchanged in the urine.

Elimination in reduced renal function

In established renal insufficiency the metabolic clearance of temazepam as well as the plasma levels of the non-protein bound temazepam remain within the normal range. The elimination half life for temazepam glucuronide is however increased by which this inactive metabolite accumulates. As stated under “Overdose” it is unlikely that temazepam may be significantly removed by dialysis.

5.3 Preclinical safety data

The acute LD50 dose for temazepam in mice has been determined as 85 mg/kg after intraperitoneal administration and 2600 mg/kg after oral administration. Repeated dose toxicity studies lasting up to six months did not reveal specific organ toxicity in mice, rats or dogs. A slight increase in the incidence of liver adenomas was found in female mice given 160 mg/kg temazepam in the diet for 18 months. Temazepam did not produce DNA strand breaks in the rat livers.

No animal data is available on teratogenic effects of temazepam.

6. Pharmaceutical particulars
6.1 List of excipients

Lactose monohydrate

Maize starch

Gelatin

Talc

Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Store below 25°C.

Bottles: Keep the container tightly closed and replace the cap immediately after use in order to protect from moisture.

Blisters: Store in the original package in order to protect from moisture.

6.5 Nature and contents of container

7, 10, 14, 28, 30, 56, 60, 84, 90, 100, 250, 500 tablets are presented in amber glass bottles with tamper-evident polyethylene lid or equivalent, polypropylene containers with polyethylene lid, or PVC/PVdC/Al blister packs. Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Marketing authorisation holder

Generics [UK] Ltd t/a Mylan

Station Close

Potters Bar

Hertfordshire EN6 1TL

United Kingdom

8. Marketing authorisation number(s)

PL 04569/0331

9. Date of first authorisation/renewal of the authorisation

25/07/2007

10. Date of revision of the text

03/2014