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Nitrazepam 5mg Tablets

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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Nitrazepam 5mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 5mg of Nitrazepam.

For excipients, see 6.1.

3 PHARMACEUTICAL FORM

Tablets

White, flat bevelled edged scored tablets, engraved with logo on one side and with a breakline and A287 on the other side.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Nitrazepam Tablets are indicated for the short-term treatment of insomnia only when it is severe, disabling or subjecting the individual to extreme distress.

4.2 Posology and method of administration

Adults: 5mg before retiring. This dose may, if necessary be increased to 10mg. Elderly and debilitated patients: the elderly or patients with impaired renal and/or hepatic function will be particularly susceptible to the adverse effects of Nitrazepam 5mg tablets. Doses should not exceed half those normally recommended.

If organic brain changes are present, the dosage of Nitrazepam 5mg tablets should not exceed 5mg.

In patients with chronic pulmonary insufficiency and in patients with chronic renal or hepatic disease, dosage may need to be reduced.

Children: This product is not recommended for paediatric use.

Dosage should be adjusted on an individual basis. 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. 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.

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

Treatment should always be tapered off gradually

The product should be taken just before going to bed.

In addition, for long acting benzodiazepines, it must be stated that the patient 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.

Nitrazepam Tablets are for oral administration

4.3 Contraindications

Known sensitivity to benzodiazepines or any of the excipients. Hypersensitivity reactions with the benzodiazepines including rash, angioedema and hypertension have been reported on rare occasions in susceptible patients.

Use of this drug is also contraindicated in patients with acute pulmonary insufficiency, respiratory depression, chronic psychosis, myasthenia gravis, sleep apnoea syndrome, severe hepatic insufficiency, phobic or obsessional states and use in children

4.4 Special warnings and precautions for use

Nitrazepam 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.

Nitrazepam should not be used for the treatment of psychotic illness.

In patients with chronic pulmonary insufficiency, and in patients with chronic renal or hepatic disease, dosage may need to be reduced. Benzodiazepines are contraindicated in patients with severe hepatic insufficiency.

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

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

Use of benzodiazepines may lead to the development of physical and psychological dependence upon these products. The risk of dependence 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, headaches, muscle weakness, nervousness, extreme anxiety, tension, restlessness, confusion, mood changes, rebound insomnia, irritability, sweating, and diarrhoea have been reported following abrupt cessation of treatment in patients receiving even normal therapeutic doses for short periods of time.

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.

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 and psychotic manifestations and convulsions. Abuse of the benzodiazepines has been reported.

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

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 the elderly.

Benzodiazepines may induce anterograde amnesia. The condition usually occurs 1 to 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.

Due to myorelaxant effect there is a risk of falls and consequently of hip fractures particularly for elderly patients when they get up at night.

4.5 Interaction with other medicinal products and other forms of interaction

Alcohol interacts with nitrazepam resulting in an enhanced sedative effect. This affects the ability to drive or use machinery.

Aluminium hydroxide mixture appears to promote early absorption of nitrazepam. Plasma concentrations of nitrazepam are increased by concomitant administration of cimetidine.

Nitrazepam may interact with antiepileptics and 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.

Enhanced central depressive effect may occur when benzodiazepines are given concomitantly with neuroleptics, tranquillisers, antipsychotics, narcotic analgesics, antidepressants, hypnotics, anaesthetics and sedative antihistamines. In the case of narcotic analgesics, enhancement of euphoria may also occur, leading to an increase in psychic dependence. The elderly require special supervision.

Known inhibitors of hepatic enzymes, particularly cytochrome P450 have been shown to reduce the clearance of benzodiazepines and may potentiate their action and known inducers of hepatic enzymes e.g.Rifampicin may increase clearance of benzodiazepines.

4.6 Fertility, Pregnancy and lactation

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 discontinuation of the product if she intends to become or suspects she is pregnant.

If, for compelling medical reasons, the product is administrated during the late phase of pregnancy, or during labour at high doses, effects on the neonate, such as irregularities in foetal heart rate, hypothermia, hypotonia, poor sucking 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 of developing withdrawal symptoms in the postnatal period.

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

4.7 Effects on ability to drive and use machines

Nitrazepam enhances the effects of CNS depressants and can adversely affect the patient’s ability to drive vehicles or operate machinery. Sedation, amnesia, impaired concentration and impaired muscle function may adversely affect the ability to drive or use machinery. If insufficient sleep occurs, the likelihood of impaired alertness may be increased (see also interactions). These effects are potentiated by alcohol, which 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:

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 administration of nitrazepam is associated with mild and infrequent side-effects most common being drowsiness during the day, numbed emotions, reduced alertness, confusion, fatigue, headache, dizziness, muscle weakness, blurred vision, lightheadedness and ataxia. Elderly and debilitated patients are especially susceptible to these reactions.

Anterograde amnesia may occur at therapeutic doses, the risk increasing at higher doses. Amnesic effects may be associated with inappropriate behaviour.

Other minor side effects include hypotension, some degree of respiratory depression, nausea, constipation, changes in salivation, blurred vision with diplopia, dysarthria, skin rashes, urinary retention, incontinence, mental depression, tremor, headache, confusion, slurred speech, vertigo and change in libido. There have been isolated reports of blood disorders and jaundice.

Use (even at therapeutic doses) may lead to the development of physical and psychological dependence: discontinuation of the therapy may result in withdrawal or rebound phenomena, a transient syndrome whereby the symptoms that led to treatment with benzodiazepine or benzodiazepine-like agent recur in an enhanced form. It may be accompanied by other reactions including mood changes, anxiety and restlessness. Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage be decreased gradually.

Abuse of benzodiazepines has been reported.

Pre-existing depression may be unmasked during benzodiazepine use

4.9 Overdose

Overdosage with nitrazepam results in drowsiness, ataxia, dysarthria with CNS depression and coma in severe cases. Symptoms of nitrazepam overdosage are mainly an intensification of its therapeutic effects - sedation, muscle weakness, profound sleep or paradoxical excitation. In more severe cases, symptoms may include ataxia, hypotonia, hypotension, respiratory depression and rarely, coma and death. When combined with other CNS depressants, including alcohol, the effects of overdosage are likely to be more severe and may prove fatal.

Treatment of overdosage includes induction of emesis, within one hour, if the patient is conscious. If the patient is unconscious, gastric lavage should be undertaken with the airway protected. Activated charcoal should be administered to reduce absorption. Respiratory and cardiovascular functions should be carefully monitored in intensive care. If excitation occurs, barbiturates should not be used. Flumazenil, a specific competitive inhibitor of the central effects of benzodiazepines, may be useful as an antidote. Benzodiazepines are not significantly removed from the body by dialysis.

In recent severe overdosage with nitrazepam the stomach should be emptied by aspiration and lavage. Recovery usually follows symptomatic treatment.

5.1 Pharmacodynamic properties

Nitrazepam is a benzodiazepine hypnotic with actions similar to those of diazepam. It is reported to act in 30 to 60 minutes to produce sleep lasting for 6 to 8 hours. As a hypnotic, the usual dose for adults is 5 to 10 mg at night. The elderly and debilitated patients are generally given half of the usual adult dose.

5.2 Pharmacokinetic properties

The drug is well absorbed form the GI tract with peak blood levels being achieved within 2 hours of administration. Two hours after administration, the concentration of nitrazepam in the cerebrospinal fluid is about 8% and after 36 hours approximately 16% of the concentration in the plasma. The cerebrospinal fluid concentration thus corresponds to the non-protein-bound fraction of active ingredient in the plasma. The half-life is, on average, 24 hours. Steady-state levels are achieved within 5 days. 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. In younger persons the volume of distribution is 2L/kg, in elderly patients the volume of distribution is greater and the mean elimination half-life rises to 40 hours.

5.3 Preclinical safety data

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

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Maize starch Lactose monohydrate Pregelatinised maize starch Magnesium stearate

Sodium starch glycollate (Type A)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years for opaque plastic containers.

2 years for aluminium/opaque PVC blister packs.

6.4 Special precautions for storage

Plastic Containers: Store in the original package. Keep the container tightly closed.

Blister Packs: Keep the blister in the outer carton.

6.5 Nature and contents of container

Nitrazepam 5 mg Tablets are packed in the following containers and closures.

Opaque plastic containers (securitainers) for pack sizes of 28, 30, 42, 50, 56, 60, 84, 90, 100, 112, 250, 500 and 1000.

Opaque plastic containers composed of either high density polypropylene or high density polyethylene with a tamper-evident or child-resistant tamper-evident closure composed of high density polyethylene for all pack sizes (28, 30,42, 50, 56, 60, 84, 90, 100, 112, 250, 500 and 1000) with packaging inclusion of standard polyether foam or polyethylene or polypropylene-made filler.

Blister packs of aluminium/opaque PVC. It is subsequently packed in printed boxboard cartons in pack sizes of 28, 30, 42, 56, 60, 84, 90 and 112.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special instructions for use/handling.

7    MARKETING AUTHORISATION HOLDER

Ennogen Pharma Limited Unit G4,

Riverside Industrial Estate,

Riverside Way,

Dartford DA1 5BS UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 40147/0062

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

29/07/2012

10 DATE OF REVISION OF THE TEXT

18/11/2014