Nitrazepam Tablets 5mg
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Nitrazepam Tablets 5mg
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 5mg Nitrazepam BP
3 PHARMACEUTICAL FORM
Uncoated Tablets
Creamy white tablets with bevel edge, embossed ‘N/5’ on one face and ‘PV’ on the other.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Insomnia: Nitrazepam is only indicated for the short term treatment of insomnia only when it is severe, disabling or subjecting the individual to extreme distress and where daytime sedation is acceptable.
4.2 Posology and method of administration
Posology
Adults: 5mg before retiring. This dose may, if necessary, be increased to 10mg.
Children: Not recommended for use in children under 12 years of age.
Elderly and debilitated patients: 2.5-5mg before retiring.
Doses should not exceed half those normally recommended.
The lowest dose which can control symptoms should be used. It should not be Continued beyond 4 weeks
Treatment should be as short as possible. Generally the duration of treatment
varies from a few days to weeks with a maximum, including tapering off process of four weeks. 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 status. Treatment should be started with the lowest recommended dose. Patients who have received benzodiazepines for a long time may require an extended withdrawal period. Long-term chronic use is not recommended.
The maximum dose should not be exceeded.
Dose recommendation for patients with impaired liver and/or renal function must be given. Patient should be checked regularly at the start of the treatment in order to decrease if necessary, the dose or frequency of administration to prevent overdose due to accumulation.
Method of Administration For oral administration.
4.3 Contraindications
Patients with known sensitivity to benzodiazepines any other ingredients in the tablets, acute pulmonary insufficiency, respiratory depression/anxiety (ventilatory failure may be exacerbated), chronic psychosis.
Not for use in phobic or obsessional states. Should not be used alone to treat depression, or anxiety associated with depression. Should not be used for the treatment of 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), and acute porphyria.
4.4 Special warnings and precautions for use
An underlying cause should be sought before deciding upon the use of benzodiazepines for symptomatic relief.
In patients with chronic pulmonary insufficiency, and in patient with chronic renal or hepatic disease, dosage may need to be reduced. Excessive or prolonged use of benzodiazepines may occasionally result in the development of some psychological dependence, with withdrawal symptoms on sudden discontinuation of the drug. This is particularly so in patient with a history of alcoholism or drug abuse, or in patient with marked personality disorder. 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.
Regular monitoring of such patients is essential; routine repeat prescriptions should be avoided and treatment should be withdrawn gradually.
Symptoms such as depression, nervousness , 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. In rare instances, withdrawal following excessive doses may produce confusional states, psychotic manifestations and convulsions. Abnormal psychological reactions to benzodiazepines have been reported.
Rare behavioural effects include paradoxical outbursts excitement, confusion and the uncovering of depression with suicidal tendencies. Other psychiatric and paradoxical reactions includes restlessness, agitation, irritability, delusion, rages, nightmares, hallucination, psychoses, inappropriate behaviour and other adverse behavioural effects are known to occur when using benzodiazepines . Should this occur, use of the medicinal product should be discontinued, they are more likely to occur in children and elderly.
In cases of loss or bereavement psychological adjustment may be inhibited by benzodiazipines. Dis-inhibiting effects may be manifested in various ways, suicide may be precipitated in patients who are depressed and aggressive behaviour towards self and others. Extreme caution should therefore be used in prescribing benzodiazipines in patients with personality disorder. Withdrawal from benzodiazepines may be associated with psychological symptoms of withdrawal including depression.
Withdrawal symptoms occur with benzodiazepines following normal therapeutic dose give for a short time. An underlying cause for insomnia should be sought before deciding upon the use of nitrazepam for symptomatic relief. It is important to warn against changing to a benzodiazepine with a short duration of action, as withdrawal symptoms may develop.
Some loss of efficacy to the hypnotic effects of benzodiazepines may develop after repeated use for a few weeks. Physical dependence may consist of headaches, muscle pain, extreme anxiety tension, restlessness, confusion and irritability. In severe cases the following symptoms may occur: derealisation, depersonalisation, hyperacusis, numbness and tingling of the extremities, hypersensitivity to the light, noise and physical contact, hallucinations or epileptic seizures.
Rebound insomnia and anxiety: 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 disturbance and restlessness. Since the risk of withdrawal phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage is decreased gradually.
Duration of treatment: The duration of the treatment be as short as possible depending on the indication, but should not exceed 4 weeks including tapering off process. Extension beyond these periods should not take place 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 will be of limited duration and to explain precisely how to dosage will be progressively decreased. Moreover it is important that the patient should be aware of the possibility of rebound phenomena, therapy minimising anxiety over such symptoms should may occur while the medicinal product 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 patient should ensure that they will be able to have an uninterrupted sleep of 7-8 hours. (See section 4.8)
Specific patient group: 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 reduced dose. Benzodiazepines are not indicated to treat patients with severe hepatic insufficiency or chronic renal as they may precipitate encephalopathy (elimination half-life of nitrazepam may be prolonged).
Benzodiazepines should not be used alone to treat depression or anxiety associated with depression (suicide may be precipitated in such patients).
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).
Care should be excercised in patients with epilepsy since there have been reports of rare paradoxical exacerbation of seizures in these patients (See section 4.5).
Extreme caution should be used in prescribing nitrazepam to patients with personality disorders
Contains 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
If nitrazepam is combined with centrally acting drugs such as neuroleptic, tranquillisers, antidepressant , hypnotics, narcotic analgesics (enhancement of euphoria may also occur, leading to an increase in psychological dependence), sedative, antihistamine, anaesthetics, lofexidine, nabilone and alcohol, the sedative effects are likely to be intensified.
When nitrazepam is used in conjunction with anti- epileptic drugs, 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.
Compound which inhibits 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.
• 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).
Not recommended: Concomitants intake with alcohol. The sedative effects may be enhanced when the product is used in combination with alcohol. This affects the ability to drive or use machine.
4.6 Fertility, pregnancy and lactation
An increased risk of congenital malformations in humans has been associated with its use, particularly in the first and second trimesters. If the product is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding stopping if she intends to become or suspects she may be pregnant.
Do not use during pregnancy, if the product is prescribed to a woman of child bearing potential, she should be warned to contact her physician regarding discontinuance of the product if she intends to become or suspect 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, effect 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 benzodiazepine 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 benzodiazepine are found in the breast milk, benzodiazepine should not be given to breast feeding mothers.
4.7 Effects on ability to drive and use machines
Nitrazepam may modify the patients' performance at skilled tasks, driving, operating machinery etc. To a varying degree depending upon dosage and individual susceptibility. Patients should be advised that alcohol may intensify impairment, and should therefore be avoided during treatment. If the patient awakens for short intervals during the period of drug activity the ability to recall these events may be impaired.
4.8 Undesirable effects
The following undesirable effects have been divided into the following categories: Very common: >1/10, Common: >1/100 to <1/10, Uncommon: >1/1,000 to<1/100 Rare: >1/10,000 to <1/1,000, Very rare: <1/10,000, not known (cannot be estimated from the available data)
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Blood and the lymphatic system disorders Rare |
Blood dyscrasias |
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Immune system disorders Very rare |
Hypersensitivity reactions (anaphylaxia and angiooedema) |
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Psychiatric disorders Uncommon |
Confusion, sleeping disorders, including insomnia. |
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Rare |
Psychiatric and paradoxical reactions Muscular cramps, libido fluctuations |
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Not known |
Dependence and abuse of benzodiazepines, amnesia, depression, withdrawal symptoms |
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Nervous system disorders Common |
Dizziness, sedation, unsteadiness, ataxia, (they are dose related and may persist into the following day, even after a single dose, usually disappear with repeated administration) drowsiness |
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Uncommon |
Disturbances in attention, tremor |
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Rare |
Dystonia, headache, fatigue, numbed emotion |
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Not known |
Dysarthria |
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Eye disorders Rare |
Visual disturbances |
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Not known |
Double vision |
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Ear and labyrinth disorders Rare |
Vertigo |
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Vascular disorders Rare |
Hypotension |
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Respiratory, thoracic and mediastinal disorders Rare |
Respiratory depression |
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Gastrointestinal disorders Rare |
Nausea, gastrointestinal upsets |
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Hepato-biliary disorders Rare |
Jaundice |
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Skin and subcutaneous tissue disorders Rare |
Rash and other allergic skin reactions in the form of urticaria, pruritus, dermatitis, erythema multiforme, Stevens-Johnson syndrome |
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Renal and urinary disorders Rare |
Urinary retention |
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Musculoskeletal, connective tissue and bone disorders Uncommon |
Muscular weakness |
Common adverse effect includes
The elderly are particularly sensitive to the effect of central depressant drugs and may experience confusion, especially if organic brain changes are present, the dosage of nitrazepam should not exceed one-half that normally recommended for other adults.
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.
Amnesia: Anterograde amnesia may occur using therapeutic dosages, the risk increasing at higher dosages. Amnestic effect may be associated with inappropriate behaviour.
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 or benzodiazepine-like agents. They may be quite severe with this product. They are more likely to occur in children and elderly.
Dependence: Use (even at therapeutic doses) may lead to the development of physical dependence. Abuse of benzodiazepines has been reported.
Existing depression may be revealed during the use of benzodiazepines
(see also point 4.4).
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.
4.9 Overdose:
The symptoms of nitrazepam overdose are mainly an intensification of the therapeutic effects Overdose sign may includes drowsiness, ataxia ,and 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. 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.
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.
As with other benzodiazepines, overdose should not present a threat to life unless combined with other CNS depressants, including alcohol, and in the absence of supportive measures.
In the management of overdose with any medicinal product, it should be borne in mind that multiple agents may have been taken. In mild cases, symptoms includes drowsiness, mental confusion and lethargy, in more serious cases, symptoms may include ataxia, hyptonia, apnoea, hypotension, respiratory depression, rarely coma and very rarely death.
Particular attention should be paid to the maintenance of cardiovascular, respiratory and renal functions, and to the maintenance of electrolyte balance, dialysis is of little value. Hypotension should be managed with fluids and if persistent , a positive inotrope such as dobutamine. If excitation occurs, barbiturates should not be used.
5.1 Pharmacodynamic properties
Nitrazepam is a benzodiazepine sedative and hypnotic.
5.2 Pharmacokinetic properties
Nitrazepam is well absorbed with peak blood levels being achieved within two hours after administration. 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).
The half life of nitrazepam is on 24 hour. Steady state levels are achieved within 5 days. Nitrazepam undergoes biotransformation to a number of metabolites none of which possesses significant clinical activity. After oral administration about 50% to 70% of a dose is excreted in the urine in 120 hours and up to 20% is eliminated in the faeces.
Only a small amount (less than 4%) is excreted as unchanged nitrazepam. It crosses the placental barrier and traces are found in breast milk.
5.3 Preclinical safety data
N/A
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Pregelatinised Starch 010mg Colloidal Silicon Dioxide 004mg Stearic Acid 005mg
Magnesium Stearate 00lmg
6.2 Incompatibilities
None known
Shelf life
6.3
5 years
6.4 Special precautions for storage
Store in a cool dry place away from bright light.
6.5 Nature and contents of container
Plastic securitainer with polypropylene lids with double security closure containing nitrazepam tablets ( material of the container complies to EEC directives for plastic in contact with drugs and food stuff ) in the pack sizes of 28,56,500 and1000.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
none
7 MARKETING AUTHORISATION HOLDER
Pharmvit Limited 77 Bilton Road, Perivale Greenford, Middlesex,
UB6 7HQ
8 MARKETING AUTHORISATION NUMBER(S)
PL 04556/0001
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
28 May 1993 15 December 2009
10 DATE OF REVISION OF THE TEXT
30/07/2014