NITRAZEPAM TABLETS BP 5mg

Each tablet contains 5mg Nitrazepam PhEur.

White uncoated tablets.

White, circular, flat bevelled-edge uncoated tablets impressed “C” and the identifying letters “NA” on either side of a central division line on one face.

1) Indicated for the short-term treatment of insomnia only when it is severe, disabling, or subjecting the individual to extreme stress and where daytime sedation is acceptable.

Posology

The lowest effective dose should be employed, and treatment should, if possible, be intermittent. Dosage regimes should not extend beyond 4 weeks and treatment should gradually be withdrawn. Patients who have received benzodiazepines for a long time may require an extended withdrawal period. Long-term chronic use is not recommended.

Adults: 5mg before retiring. This dose may be increased, if necessary, up to 10mg.

Elderly and debilitated patients: 2.5-5mg before retiring.

Children: Not recommended for children under 12 years of age.

Method of Administration

For oral administration.

• Known hypersensitivity to benzodiazepines and any other ingredients in the tablets

• Phobic or obsessional states; chronic psychosis

• Acute pulmonary insufficiency; respiratory depression (ventilatory failure may be exacerbated)

• Myasthenia gravis (condition may be exacerbated)

• Sleep apnoea (condition may be exacerbated)

• Severe hepatic insufficiency (elimination half-life of nitrazepam may be prolonged)

• Acute porphyria

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

• Tolerance –Tolerance to their effects develops within 3-14 days of continuous use and hence treatment regimes should be kept to a minimum and repeat prescriptions avoided. Limits of tolerance in patients with organic cerebral changes (particularly resulting from arteriosclerosis) or cardiorespiratory insufficiency may be very wide; care must be taken in adapting the dosage with such patients.

• Dependence and Withdrawal –Withdrawal symptoms occur with benzodiazepines following normal therapeutic doses given for short periods of time.

Use of nitrazepam may lead to the development of physical and psychological dependence. The risk of dependence increases with the dose and duration of treatment, and in patients with a history of alcoholism and drug abuse.

Once physical dependence has developed, abrupt termination of treatment will be accompanied by withdrawal symptoms (see Section 4.8 Undesirable Effects).

• Rebound insomnia: a transient syndrome whereby the symptoms that led to treatment with nitrazepam may recur in an enhanced form 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 depending on the indication, but should not exceed 4 weeks including tapering off process. Treatment should not continue beyond 4 weeks without re-evaluation of the patient's condition. Where long-term therapy is essential, it is recommended that the patient's requirements be reviewed on a regular basis.

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 is being discontinued. Care is needed when switching from long acting benzodiazepines, such as nitrazepam, to a benzodiazepine with a short duration of action due to the risk of withdrawal symptoms developing.

• Amnesia: nitrazepam 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 uninterrupted sleep of 7-8 hours. (See section 4.8)

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

• Care should be taken in patients with chronic renal or hepatic disease (elimination half-life of nitrazepam may be prolonged).

• Hypoalbuminaemia (may predispose patient to higher incidence of sedative side effects).

• Care should be exercised in prescribing nitrazepam for patients with a history of alcoholism or drug abuse as these patients are predisposed to habituation and dependence. Regular monitoring in such patients is essential. Alcohol should be avoided during treatment with nitrazepam (additive CNS depression).

• Depression or anxiety associated with depression. Benzodiazepines should not be used alone in the treatment of depression or anxiety associated with depression as suicide may be precipitated in such patients.

• Extreme caution should be used in prescribing nitrazepam to patients with personality disorders.

The following drug interactions with nitrazepam should be considered:

• Enhancement of other CNS depressant drugs such as antipsychotics, narcotic analgesics (enhancement of euphoria may also occur, leading to an increase in psychological dependence), antidepressants, hypnotics, anaesthetics, sedative antihistamines, lofexidine, nabilone.

• Alcohol (concomitant intake with alcohol is not recommended. The sedative effects may be enhanced when nitrazepam is used in combination with alcohol. This affects the ability to drive or use machines.)

• Antiepileptic drugs (plasma phenytoin concentrations increased or decreased by nitrazepam. Side effects may be more evident with hydantoins or barbiturates).

• Dopaminergics (concurrent use with benzodiazepines may decrease the therapeutic effects of levodopa).

• Caffeine and theophylline (concurrent use may result in reduced sedative and anxiolytic effects of nitrazepam).

• Cimetidine, oestrogen-containing contraceptives, disulfiram (these medicines may inhibit hepatic metabolism of nitrazepam).

• Antibacterials (Rifampicin may increase the metabolism of nitrazepam. Isoniazid may inhibit the metabolism of benzodiazepines).

• Antivirals (Ritonavir may inhibit benzodiazepine hepatic metabolism).

• Antihypertensives (enhanced hypotensive effects. Enhances sedative effect with alpha blockers or moxonidine)

• Baclofen and tizanidine (enhanced sedative effect).

• Probenecid (may increase effects and possibility of excessive sedation).

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.

Sedation, amnesia 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).

• Drowsiness, sedation, unsteadiness and ataxia are common, dose-related and may persist into the following day, even after a single dose.

• The elderly and patients with impaired hepatic and/or renal function are particularly prone to adverse effects.

• The occurrence of ataxia is evidence of excessive dosage.

• Abnormal psychological reactions to benzodiazepines have been reported. Behavioural adverse effects include paradoxical aggressive outbursts, excitement, confusion and the uncovering of depression with suicidal tendencies.

• Other effects include drowsiness during the day, amnesia, dependence, abuse of benzodiazepines, double vision, dysarthria.

• Other adverse effects are rare and include allergic reaction (skin rash or itching), headache, vertigo, hypotension, gastrointestinal upsets, dystonic effects, visual disturbances, libido fluctuations, urinary retention, blood dyscrasias and jaundice.

• Withdrawal effects on abrupt cessation of treatment –Depression, nervousness, rebound insomnia, irritability, sweating and diarrhoea have been reported following abrupt cessation of treatment. In rare cases, withdrawal following excessive dosages may produce confusional states, psychotic manifestations and convulsions.

As with all benzodiazepines, withdrawal may be associated with physiological and psychological symptoms including depression.

The symptoms of nitrazepam overdose are mainly an intensification of the therapeutic effects (ataxia, drowsiness, dysarthria, sedation, muscle weakness, profound sleep) or paradoxical excitation. In most cases only observation of vital functions is required.

Extreme overdosage may lead to coma, areflexia, cardiosrespiratory depression and apnoea, requiring appropriate countermeasures (ventilation, cardiovascular support).

Treatment is symptomatic, but gastric lavage may be useful if performed soon after ingestion. Activated charcoal should be used to reduce absorption. Benzodiazepines are not significantly removed from the body by dialysis.

Anexate (flumazenil) is a specific IV antidote for use in emergency situations. There is a possibility of convulsions when flumazenil is used in benzodiazepine-dependent patients. Patients requiring such intervention should be monitored closely in hospital.

Occasionally a respirator may be required but generally few problems are encountered, although behavioural changes are likely in children.

If excitation occurs, barbiturates should not be used.

Effects of overdose are more severe when taken with centrally-acting drugs, especially alcohol, and in the absence of supportive measures, may prove fatal.

Nitrazepam is a benzodiazepine sedative and hypnotic.

Nitrazepam is fairly readily absorbed from the GI tract, although there is some individual variation. It is extensively bound to plasma proteins. It is metabolised in the liver, mainly by nitroreduction and acetylation (which is reported to be subject to genetic polymorphism). It is excreted in the urine in the form of metabolites with only small amounts of a dose appearing unchanged. Up to about 20% of an oral dose is found in the faeces. It crosses the placental barrier and traces are found in breast milk.

There are no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Also contains lactose, magnesium stearate, maize starch, stearic acid.

None known.

Shelf-life

Three years from the date of manufacture.

Shelf-life after dilution/reconstitution

Not applicable.

Shelf-life after first opening

Not applicable.

Store below 25°C in a dry place.

Protect from light.

The product containers are rigid injection moulded polypropylene or injection blow-moulded polyethylene tablet containers with polyfoam wad and snap-on polyethylene lids; in case any supply difficulties should arise the alternative is amber glass bottles with screw caps and polyfoam wad or cotton wool.

The product may also be supplied in blister packs in cartons:

a) Carton: Printed carton manufactured from white folding box board.

b) Blister pack: (i) 250µm white rigid PVC. (ii) Surface printed 20µm hard temper aluminium foil with 5-7g/M² PVC and PVdC compatible heat seal lacquer on the reverse side.

Pack sizes: 28's, 30's, 56's, 60's, 84's, 90's, 100's, 112's, 168's, 180's, 250's, 500's, 1000's.

Product may also be supplied in bulk packs, for reassembly purposes only, in polybags contained in tins, skillets or polybuckets filled with suitable cushioning material. Bulk packs are included for temporary storage of the finished product before final packaging into the proposed marketing containers.

Maximum size of bulk packs: 25,000.

Not applicable.

Name or style and permanent address of registered place of business of the holder of the Marketing Authorisation:

Actavis UK Limited (Trading style: Actavis)

Whiddon Valley

BARNSTAPLE

N Devon EX32 8NS

PL 0142/0086

September 1977

September 1997

May 2007