Nitrazepam 5 Mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Nitrazepam 5 mg Tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 5.0 mg of Nitrazepam Ph.Eur.
3. PHARMACEUTICAL FORM
A white, flat, bevel edged tablets. Engraved, Berk 1N4 or 1N4 with a breakline on reverse.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
For short term (2-4 weeks only) use:
• Insomnia - but only if severe, disabling or subjecting the individual to extreme distress
• An underlying cause should always be sought (and addressed) before deciding to use benzodiazepines for insomnia
Not for use:
• Long term (i.e. longer than 4 weeks)
• In children under the age of 12 years
• If daytime sedation is not acceptable
4.2 Posology and method of administration
For oral administration.
Recommended Doses and Dosage Schedules
The lowest effective dose should be used. Treatment should not be continued beyond 4 weeks including the tapering off process, and should, where possible, be intermittent. Long term chronic use is not recommended. Treatment with benzodiazepines should always be withdrawn gradually. Patients who have been receiving treatment for a long time may require longer periods during which the doses are reduced.
In certain cases extension beyond the maximum treatment period may be necessary, but it should not take place without re-evaluation of the situation.
In addition, for long-acting benzodiazepines, such as nitrazepam, the patient should be checked regularly at the start of treatment in order to decrease if necessary, the dosage or the frequency of administration to prevent overdosage due to accumulation.
When treatment is started the patient should be informed that:
• Treatment will be of limited duration
• The dosage will be progressively decreased
• There is the possibility of rebound insomnia
Adults:
Usually 5 mg before retiring. This may be increased to 10 mg when necessary or to 20 mg in hospitalised patients.
Special populations
Elderly and/or debilitated patients
The elderly or debilitated patients will be particularly susceptible to the adverse effects of nitrazepam. Doses should not exceed half those normally recommended.
Children (until 12 years)
Nitrazepam is not for paediatric use
Patients with chronic pulmonary insufficiency
• Dose may need to be reduced
• Contraindicated in acute pulmonary insufficiency (see section 4.3)
Patients with impaired hepatic and/or renal function
• Dosage should not exceed half the adult dose and steps should be taken to ensure there is no accumulation of plasma nitrazepam
• Contraindicated in severe hepatic insufficiency (see section 4.3)
If organic brain changes are present, the dosage of nitrazepam should not exceed 5 mg in these patients.
4.3 Contraindications
• Known hypersensitivity to benzodiazepines or to any of the excipients.
• Acute pulmonary insufficiency and respiratory depression (ventilatory failure may be exacerbated).
• Phobic or obsessional states; chronic psychosis.
• Myasthenia gravis (condition may be exacerbated).
• Sleep apnoea syndrome (condition may be exacerbated).
• Severe hepatic insufficiency (elimination half-life of nitrazepam may be prolonged).
• Children under 12 years of age.
• Acute porphyria.
• Planning a pregnancy (see section 4.6)
• Pregnancy (unless there are compelling reasons - see section 4.6)
4.4 Special warnings and precautions for use
An underlying cause for insomnia 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 may occur following normal therapeutic doses given for short periods of time.
Withdrawal from benzodiazepines may be associated with physiological and psychological dependence. Once physical dependence has developed, abrupt termination of treatment will be accompanied by symptoms of withdrawal including headaches, nervousness, depression, muscle weakness, irritability, confusion, muscle pain, extreme anxiety, rebound insomnia, tension, restlessness, mood changes, diarrhoea and sweating.
The risk of dependence increases with the dose and duration of treatment, and in patients with a history of alcoholism and drug abuse.
Nitrazepam is a long-acting benzodiazepine. Caution should be used when changing to a short-acting benzodiazepine, as withdrawal symptoms may develop. In severe cases the following symptoms may occur: depersonalisation, derealisation, numbness and tingling of the extremities, hyperacusis, hypersensitivity to light, noise, and physical contact, hallucinations or epileptic seizures. In rare cases, withdrawal following excessive dosages may produce psychotic manifestations, confusional states and convulsions. Abuse of benzodiazepines has been reported.
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 exactly how the dosage will be progressively decreased. In addition, it is important that the patient should be aware of the chance of rebound phenomena (see section 4.8) thereby minimising anxiety over such symptoms should they occur while the medicinal product is being discontinued.
Amnesia
Benzodiazepines may induce anterograde amnesia. This condition usually occurs 1-2 hours after ingesting the product and may last up to several hours. To reduce the risk, patients should ensure that they are able to have an undisturbed sleep of 7 to 8 hours (see section 4.8).
Recall may be impaired, if the patient is woken during the period of maximum drug activity.
Alcohol
Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse, as these patients are predisposed to habituation and dependence. Regular monitoring in such patients is essential.
Patients should be warned of the possibility of drowsiness occurring, particularly in the first few days of therapy, and advised to avoid alcohol.
Renal or hepatic impairment
Nitrazepam should be used with caution in patients with impairment of renal or hepatic functions, as the elimination half-life of nitrazepam may be prolonged. In such cases the dosage may need to be reduced (please see section 4.2) and it is advisable to review treatment regularly and to discontinue use as soon as possible.
Chronic pulmonary insufficiency
Nitrazepam should be used with caution in patients with chronic pulmonary insufficiency, especially those who are elderly or debilitated. In such cases the dosage may need to be reduced (please see section 4.2) and it is advisable to review treatment regularly and to discontinue use as soon as possible.
Bereavement
In cases of loss or bereavement, psychological adjustment may be inhibited by benzodiazepines.
Hypoalbuminaemia
Hypoalbuminaemia (may predispose patient to higher incidence of sedative side effects).
Depression or anxiety associated with depression
Nitrazepam should not be used alone to treat depression or anxiety associated with depression, suicide may be precipitated in such cases.
Chronic Psychosis
Benzodiazepines should not be used for the treatment of chronic psychosis. Personality Disorders
On rare occasions abnormal psychological reactions to benzodiazepines have been reported. Rare behavioural effects include paradoxical aggressive outbursts, confusion, excitement, restlessness, irritability, agitation, rages, delusion, nightmares, hallucinations or psychoses. Abnormal behaviour and suicide in patients who are depressed, and aggressive behaviour towards self and others may be precipitated. Extreme caution should therefore be used in prescribing benzodiazepines in 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 elderly patients (see section 4.8).
Risk of falls
Due to the myorelaxant effect, there is a risk of falls and consequently of hips fractures particularly for elderly patients when they get up at night.
This product contains lactose, therefore it should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
4.5 Interaction with other medicinal products and other forms of interaction
Not recommended
• Alcohol: Nitrazepam should not be used together with alcohol (enhanced sedative effects; this affects the ability to drive or operate machinery - see section 4.7)
• Sodium oxybate: Avoid concomitant use (enhanced effects of sodium oxybate)
Take into account
• Centrally acting drugs: Enhancement of the central depressive effect may occur if nitrazepam is combined with drugs such as neuroleptics, antipsychotics, tranquilisers, antidepressants, hypnotics, analgesics, anaesthetics, barbiturates and sedative antihistamines. The elderly may require special supervision.
• Anti- epileptic drugs: Plasma phenytoin concentrations can be altered (increased/decreased) by nitrazepam. When used concurrently, side effects and toxicity may be more evident, particularly with hydantoins (e.g. phenytoin) and/or barbiturates. This requires extra care in adjusting dosage in the initial stages of treatment.
• Narcotic analgesics: Enhancement of the euphoria may lead to increased psychological dependence.
• Other drugs enhancing the sedative effect of nitrazepam: cisapride, lofexidine, nabilone, disulfram and the muscle-relaxants baclofen and tizanidine.
• Compounds that affect hepatic enzymes (particularly cytochrome P450):
• Inhibitors (e.g. cimetidine; oestrogen-containing oral contraceptives; isoniazide) reduce clearance and may potentiate the action of benzodiazepines)
• Inducers (e.g. rifampicin) may increase clearance of benzodiazepines.
• Antihypertensives, vasodilators & diuretics: Enhanced hypotensive effect with ACE-inhibitors, alpha-blockers, angiotensin-II receptor antagonists, calcium channel blockers, adrenergic neurone blockers, beta-blockers, moxonidine, nitrates, hydralazine, minoxidil, sodium nitroprusside and diuretics.
• Enhanced sedative effect with alpha-blockers or moxonidine.
• Dopaminergics: possible antagonism of the effect of levodopa by nitrazepam.
• Aluminium hydroxide mixtures: my enhance absorption of nitrazepam.
• Ritonavir: may inhibit nitrazepam metabolism.
• Probenecid: may increase nitrazepam effects (possible excess sedation).
• Theophylline: concurrent use may reduce the sedative effects of nitrazepam.
• Caffeine: concurrent use may reduce the sedative effects of nitrazepam.
4.6. 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 in 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.
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, irregularities in the foetal heart rate, 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 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
• Patients should be advised that sedation, amnesia, impaired concentration, dizziness, blurred vision and impaired muscle function may occur and that, if affected, they should not to drive or use machines, or take part in other activities where this would put themselves or others at risk. Patients should be warned against driving or operating machinery.
• If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased.
• Concurrent medication, particularly with CNS depressants, may increase these effects (see section 4.5)
• Patients should 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 side effects are dose related and include fatigue, drowsiness during the day, numbed emotions, reduced alertness, ataxia or light-headedness, unsteadiness, dizziness and muscle weakness. Confusion may occur in the elderly, especially if organic brain damage is present. These effects may persist into the following day, even after a single dose.
Other effects include amnesia, dependence, abuse of benzodiazepines, double vision, dysarthria.
Other adverse effects are rare and include vertigo, headache, gastro-intestinal upsets, hypotension, dystonic effects, visual disturbances, allergic reaction (skin rash or itching), urinary retention, and changes in libido. Isolated cases of jaundice and blood dyscrasias have also been reported.
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.
Abuse of benzodiazepines has been reported. Excessive or prolonged use of nitrazepam may result in development of physical and psychological dependence with withdrawal symptoms on discontinuance.
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.
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.
Reactions such as restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse effects are known to occur when using benzodiazepines. They may be quite severe with this product. They are more likely to occur in the elderly (see section 4.4).
Anterograde amnesia may occur at therapeutic dosages, the risk increasing at higher dosages. Amnesiac effects may be associated with inappropriate behaviour (see section 4.4).
As with all benzodiazepines, withdrawal may be associated with physiological and psychological symptoms including depression. Pre-existing depression may be unmasked during benzodiazepine therapy.
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
As with other benzodiazepines overdose would not be life-threatening unless it is combined with other CNS-depressants (including alcohol).
When treating overdosage with any drug it should be borne in mind that several substances may be taken.
Symptoms
Overdose with benzodiazepines is normally seen accompanied by different degrees of depression of the central nervous system, which may vary from lethargy to coma. In mild cases the symptoms include lethargy, mental confusion, drowsiness, dysarthria, and in more serious cases the symptoms include ataxia, hypotonia, hypotension, bradycardia, breathing difficulties, in rare cases coma and in very rare cases death. In children, behavioural changes are likely.
When taken in conjunction with centrally-acting drugs, especially alcohol, the effects of overdosage are likely to be more severe and may prove fatal in the absence of supportive measures.
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 (a benzodiazepine antagonist). This should rarely be required. It has a short half-life (about an hour) and should not be used in mixed overdose or as a “diagnostic” test. Flumazenil 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 hypnotic of the benzodiazepine group.
5.2 Pharmacokinetic properties
Nitrazepam is fairly readily absorbed from the gastro-intestinal tract. It is reported to act in 30 to 60 minutes to produce sleep lasting 6 - 8 hours. It has a biphasic half-life probably owing to tissue redistribution and 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.
One study has shown absorption of 5 mg nitrazepam was fairly rapid with a mean initial peak plasma concentration of 37.1 ng/ml (range 28.2 - 45.0 ng/ml) obtained after 81 minutes (range 30 - 240 minutes). In most patients there was a rapid decrease in plasma concentration until 4 hours after taking the dose followed by a slight increase to produce a second peak after 6 - 8 hours. The mean elimination half-life was 30 hr (range 18 - 36 hr). Another study found its P-phase half-life to be 27 hr in plasma and 68 hr in the CSF.
5.3. Pre-clinical Safety Data
Preclinical information has not been included because the safety profile of nitrazepam has been established after many years of clinical use. Please refer to section 4.
6. PHARMACEUTICAL PARTICULARS
6.1. List of Excipients
The tablet contains Maize Starch Ph.Eur., Lactose Monohydrate Ph.Eur., Pregelatinised Maize Starch BP, Microcrystalline Cellulose Ph.Eur., Magnesium Stearate Ph.Eur., and Sodium Starch Glycollate (type A) Ph.Eur.
6.2. Incompatibilities
None known.
6.3. Shelf Life
36 months - Tablets containers.
24 months - Blister packs and amber glass bottles.
6.4. Special Precautions for Storage
Store in a cool place. Protect from light.
6.5.
Nature and Contents of Container
HDPE or polypropylene containers with caps or child resistant closures in packs of 50 and 500 tablets.
Polyethylene containers with lids with polythene liners in packs of 12000 tablets.
Amber glass bottles with plastic screw caps in packs of 10 x 50 tablets.
250 pm PVC/40 gsm PVdC with 20 pm hard tempered aluminium foil strips in packs of 7, 10, 14, 21, 28, 30, 56, 60, 84, 90, 100, 110, 112, 120, 150, 160 and 168.
6.6. Instructions for Use, Handling and Disposal
Not applicable.
7 MARKETING AUTHORISATION HOLDER
TEVA UK Limited Brampton Road, Hampden Park,
Eastbourne, East Sussex, BN22 9AG
8 MARKETING AUTHORISATION NUMBER(S)
PL 00289/0191
9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION
22/07/96
10 DATE OF REVISION OF THE TEXT
07/07/2015