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1. Nitrazepam Mixture 2.5mg/5ml Oral Suspension Bp
2. Nitrazepam Mixture 2.5mg/5ml Oral Suspension Bp

SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Nitrazepam Mixture 2.5mg/5ml Oral suspension BP

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5 ml spoonful contains 2.5 mg Nitrazepam .

3 PHARMACEUTICAL FORM

Oral suspension.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For the short term treatment of insomnia where daytime sedation is acceptable.

Benzodiazepines should be used to treat insomnia only when it is severe, disabling, or subjecting the individual to extreme distress.

4.2    Posology and method of administration

Nitrazepam is a long acting benzodiazepine, and the lowest dose which can control the symptoms should be used. If possible, treatment should be intermittent. The maximum dose should not be exceeded.

Adults: 5 mg (two 5 ml spoonfuls) before retiring to bed. This dose may, if necessary, be increased to 10 mg (four 5 ml spoonfuls).

Elderly and patients with impaired liver and/or renal function:

2.5 mg (one 5 ml spoonful) before retiring to bed. This dose may, if necessary, be increased to 5 mg (two 5 ml spoonfuls)

Children: Not recommended.

Generally the duration of treatment varies from a few days to two weeks with a maximum, including the tapering off process, of four weeks.

Patients who have taken benzodiazepines chronically may require a longer tapering off period. 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.

4.3 Contraindications

Chronic psychosis Myasthenia gravis Severe hepatic insufficiency Severe respiratory insufficiency Sleep apnoea syndrome Acute porphyria

Hypersensitivity to benzodiazepines and other ingredients

4.4 Special warnings and precautions for use

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

Dependence: Use of benzodiazepines 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.

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, restlessness, confusion and irritability. In severe cases the following symptoms may occur: derealization, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, 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 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.

Duration of treatment: The duration of treatment should be as short as possible (see Posology) depending on the indication, but should not exceed 4 weeks including any dose-tapering period for insomnia. 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 Nitrazepam mixture oral suspension is being discontinued.

If a change is made to a benzodiazepine with a short duration of action, the patient should be warned that withdrawal symptoms may develop.

Amnesia: Benzodiazepines may induce anterograde amnesia. The condition occurs most often several hours after ingesting the product and therefore to reduce the risk patients should ensure that they will be able to have an uninterrupted sleep of 7-8 hours (see also Undesirable Effects).

Psychiatric and paradoxical reactions: Reactions like restlessness, agitation, confusion, 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 in children and the elderly. Should they occur, use of the medicinal product should be discontinued.

Specific patient groups: Benzodiazepines should not be given to children without careful assessment of the need to do so; the duration of treatment must be kept to a minimum. Elderly should be given a reduced dose (see Posology). A lower dose is also recommended for patients with chronic respiratory insufficiency due to the risk of respiratory depression (cross refer to section 4.3 - contraindicated in severe respiratory insufficiency). Benzodiazepines are not indicated to treat patients with severe hepatic insufficiency as they may precipitate encephalopathy.

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

Benzodiazepines should not be used alone to treat depression or anxiety associated with depression (suicide may be precipitated in such patients).

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

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, anti-epileptic products, anaesthetics and sedative antihistamines.

In the case of narcotic analgesics enhancement of the euphoria may also occur leading to an increase in psychic dependence.

In the case of anti-epileptics, the following

Barbiturates

Carbamazepine

Hydantoins

are inducers of hepatic metabolism and may enhance the metabolism of benzodiazepines.

Phenytoin concentration may be increased or decreased.

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

Cimetidine inhibits the metabolism of nitrazepam.

Benzodiazepines possibly antagonise the effects of levodopa.

Rifampicin, by enzyme induction, reduces the half-life of nitrazepam and increases the clearance.

Probenecid may increase the sedative effects, possibly excessively.

4.6 Fertility, Pregnancy and lactation

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.

If, for compelling 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, due to the pharmacological action of the compound.

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 for developing withdrawal symptoms in the postnatal period.

Since benzodiazepines are found in the breast milk, benzodiazepines should not be given to breast feeding mothers.

4.7 Effects on ability to drive and use machines

Sedation, amnesia, impaired concentration and impaired muscular 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 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

The following occur predominantly at the start of therapy and usually disappear with repeated administration:

ataxia or double vision, confusion, dizziness, drowsiness, fatigue, headache, muscle weakness, numbed emotions, reduced alertness.

Undesirable effects may persist into the following day due to the long half-life.

Other side effects like gastrointestinal disturbances, changes in libido, skin reactions, have been reported occasionally.

Blood dyscrasias, jaundice, hypotension and urinary retention have been reported rarely.

Amnesia: Anterograde amnesia may occur using therapeutic dosages, the risk increasing at higher dosages. Amnestic effect may be associated with inappropriate behaviour. (See Special Warnings and Special Precautions for Use).

Depression: Pre-existing depression may be unmasked during benzodiazepine use.

Psychiatric and Paradoxical Reactions: Psychiatric and paradoxical reactions are known to occur. (See Special Warnings and Special Precautions for Use).

Dependence: Use (even at therapeutic doses) may lead to the development of physical dependence: discontinuation of the therapy may result in withdrawal or rebound phenomena. (See Special Warnings and Special Precautions for Use). Psychic dependence may occur.

Abuse:

Abuse of benzodiazepines has 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 at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus. Coma, hypotension and respiratory depression occasionally occur but are seldom serious if these drugs are taken alone. Coma usually lasts only a few hours but in elderly people it may be more protracted and cyclical. Benzodiazepine respiratory depressant effects are more serious in patients with severe chronic respiratory disease.

Benzodiazepines potentiate the effects of other central nervous system depressants, including alcohol.

Management

Consider activated charcoal in adults or children who have taken more than 1mg/kg within 1 hour, provided they are not too drowsy. Gastric lavage is unnecessary if these drugs have been taken alone. Patients who are asymptomatic at four hours are unlikely to develop symptoms. Institute supportive measures as indicated by the patient’s clinical state.

If CNS depression is severe consider the use of flumazenil (Anexate) a benzodiazepine antagonist. This should rarely be required. It has a short halflife (about an hour) and should NOT BE USED IN MIXED OVERDOSE OR AS A “DIAGNOSTIC” TEST. It is contraindicated in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Nitrazepam is a long acting benzodiazepine with anxiolytic, sedative and hypnotic characteristics.

5.2 Pharmacokinetic properties

Nitrazepam mixture Oral suspension is well absorbed from the GI tract with peak blood levels of nitrazepam being achieved within 2-3 hours of administration.

Half-life is approximately 30 hours and plasma steady state levels are achieved after 5 days.

Nitrazepam is metabolised in the liver with the excretion mainly in the urine in the form of metabolites and up to about 20% of an oral dose being found in faeces.

Nitrazepam undergoes biotransformation to a number of metabolites, none of which possess significant clinical activity. About 5% is excreted unchanged in the urine together with less than 10% each of the 7-amino- and 7-acetylamino-metabolites in the first 48 hours. The percentage ratio between the CSF (cerebrospinal fluid) and the plasma concentration increases from 8% at 2 hours to 16% at 36 hours after administration. Nitrazepam is eliminated very slowly from the CSF with a half-life approximately 2 times longer than that of plasma (about 27 hours in plasma and 68 hours in CSF) corresponding partially to the unbound fraction of plasma protein.

5.3 Preclinical safety data

Preclinical studies provide only limited evidence of safety. Nitrazepam has no significant systemic toxicity potential at the doses in clinical use with the exception of use in pregnancy and lactation for which evidence of safety is lacking.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Sucrose, microcrystalline cellulose, carboxymethyl cellulose sodium, mixed esters of p-hydroxybenzoic acid, cherry flavour and water

6.2 Incompatibilities

None known.

Shelf life

1 year

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