Nitrazepam 5mg Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Nitrazepam 5 mg Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains Nitrazepam 5 mg
Also contains 378.2 mg of lactose per tablet. For a full list of excipients. see section 6.1.
3. PHARMACEUTICAL FORM
Tablet
White, flat, bevelled tablets. Engraved MP37 on one side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Adults:
Short term treatment of insomnia only when it is severe, disabling, or subjecting the individual to extreme distress, where daytime sedation is acceptable
An underlying cause for insomnia should be sought before deciding on the use of benzodiazepines for symptomatic relief.
Benzodiazepines are not recommended for the primary treatment of psychotic illness. Children:
Not recommended.
4.2 Posology and method of administration
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 section 4.4), thereby minimizing anxiety over such symptoms should they occur while the medicinal product is being discontinued. Nitrazepam therapy should not be stopped abruptly, but the dose tapered off.
Posology
Dosage should be adjusted on an individual basis according to the patient’s response and the severity of the insomnia. Treatment should, if possible, be on an intermittent basis. The lowest dose which can control symptoms should be used. 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 2 weeks with a maximum of 4 weeks; including the tapering off process.
In certain cases, extension beyond the maximum treatment period may be necessary; if so, it should not take place without reevaluation of the patient's status. Long term chronic use is not recommended.
Patients who have taken benzodiazepines for a long time may require a longer period during which the doses are reduced. Specialist help may be appropriate.
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.
Adults:
The recommended dose is 5 mg before retiring to bed. This, however, may be increased to 10 mg if necessary.
Elderly or debilitated patients:
The elderly or patients with impaired renal and/or hepatic function will be particularly susceptible to the adverse effects of nitrazepam. Doses should not exceed half the normal adult dose in the elderly. If organic brain changes are present, the dosage of nitrazepam should not exceed 5 mg in these patients.
Other population :
In patients with chronic pulmonary insufficiency and in patients with chronic renal or hepatic disease, dosage may need to be reduced. (See Warnings and Adverse Effects)
Paediatric Population:
Nitrazepam 5 mg tablets are not recommended for use in children.
Method of administration Oral ~
4.3 Contraindications
Nitrazepam is contraindicatated in patients with:
• Known sensitivity to benzodiazepines, nitrazepam or to any of the excipients contained in Nitrazepam 5 mg tablets (see list in section 6.1). Hypersensitivity reactions with the benzodiazepines including rash, angioedema and hypertension have been reported on rare occasions in susceptible patients;
• Acute pulmonary insufficiency;
• Respiratory depression;
• Chronic psychosis;
• Phobic or obsessional states;
• Marked neuromuscular respiratory weakness including unstable myasthenia gravis;
• Sleep apnoea syndrome;
• Severe hepatic insufficiency.
Nitrazepam is not for use alone to treat depression (or anxiety associated with depression).
4.4 Special warnings and precautions for use
Tolerance
Some loss of efficacy to the hypnotic effects of short-acting benzodiazepines may develop after repeated use for a few weeks.
Dependance
The use of benzodiazepines may lead to development of physical and psychological dependency upon these agents. The risk of dependence is greater the higher the dose and the longer the duration of treatment and in patients with a history of alcoholism or drug abuse, or in patients with marked personality disorders. In such cases, benzodiazepines should be used with extreme caution, the patient should be regularly monitored, routine repeat prescriptions avoided and treatment should be withdrawn gradually.
Rebound phenomenon: 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 sleep disturbances, restlessness, depression, headaches, muscle weakness, nervousness, extreme anxiety, tension, confusion, mood changes, irritability, sweating, panic attacks, dysphoria and diarrhoea, which have been reported following abrupt withdrawal of treatment even in patients who received even normal therapeutic doses for short 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 cases, withdrawal following excessive doses may cause convulsions, confusional states and psychotic disorders. Abuse of the benzodiazepines has been reported.
Duration of Treatment
Duration of treatment should be as short as possible. It should not exceed four weeks including the tapering off process, and should not be extended beyond this without reevaluation of the situation.
Amnesia
If the patient is awoken during the period of maximum drug activity, recall may be impaired.
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.
Psychiatric and Paradoxical Reactions
Extreme caution should be used in prescribing benzodiazepines to patients with personality disorders.
Benzodiazepines may inhibit psychological adjustment in cases of loss or bereavement.
Nitrazepam should not be used alone to treat depression or anxiety associated with depression, since suicide may be precipitated in such patients. Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse. Benzodiazepines are not recommended for the primary treatment of psychotic illness.
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.
Specific Patient Groups
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, as they may precipitate encephalopathy.
Nitrazepam should be given with caution in patients with muscle weakness,
(including myasthenia gravis), and/or acute porphyria. 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.
Nitrazepam is not recommended for the primary treatment of psychotic illness.
Nitrazepam should not be used alone to treat depression or anxiety associated with depression because suicide may be precipitated in such patients.
Nitrazepam should be used with extreme caution in patients with a history of alcohol or drug abuse.
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
Enhanced central depressive effect may occur when benzodiazepines are given concomitantly with antipsychotics (neuroleptics), tranquillisers, narcotic analgesics, antidepressants, hypnotics, analgesics and anaesthetics, anti-epileptics and sedative antihistamines. In particular, avoid concomitant use of benzodiazepines with sodium oxybate. The elderly require special supervision. In the case of narcotic analgesics, enhancement of euphoria may also occur, leading to an increase in psychic dependence.
Concomitant intake with alcohol should be avoided. The sedative effect may be enhanced when the product is used in combination with alcohol. This adversely affects the ability to drive or use machines.
Disulfiram inhibits the metabolism of nitrazepam resulting in increased sedative
effects. Other drugs which enhance the sedative effects of nitrazepam are: lofexidine, nabilone, the muscle-relaxants baclofen and tizanidine, and possibly moxonidine.
Known inhibitors of hepatic enzymes (e.g. cimetidine), particularly cytochrome P450 have been shown to inhibit the metabolism of many benzodiazepines and potentiate their action. Grapefruit juice is known to inhibit enzyme CYP3A4, and has been reported to be able to increase the bioavailability of benzodiazepines, as such it should not be taken with nitrazepam.
Conversely, known inducers of hepatic enzymes, e.g rifampicin, may increase clearance of nitrazepam.
Fluvoxamine and ritonavir lead to increased plasma concentration of some benzodiazepines.
Isoniazid inhibits diazepam metabolism, and that of other benzodiazepines.
When nitrazepam is used in conjunction with anti-epileptics, side effects and toxicity may be more evident, particularly when barbiturate and hydantoins or combinations including them are taken. This requires extra care in adjusting dosage in the initial stages of treatment.
The effects of benzodiazepines are possibly reduced by theophylline.
The hypotensive effects of many anti-hypertensives, ACE-inhibitors, adrenergic neurone blockers, alpha-blockers, angiotensin-II receptor antagonists, beta-blockers, calcium-channel blockers, diuretics, nitrates and sodium nitroprusside are enhanced when given concurrently with anxiolytic and hypnotic medicines.
There is also an increased risk of hypotension, bradycardia, and respiratory depression when parenteral benzodiazepines are given with intramuscular olanzapine.
Benzodiazepines possibly antagonise the effects of levadopa.
4.6 Fertility, pregnancy and lactation
Pregnancy
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.
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, 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 irregularities in the foetal heart rate, hypothermia, hypotonia, poor suckling 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.
Breast-feeding
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 can impair cognitive function and can affect a patient’s ability to drive or operate machinery safely. Alcohol may intensify such effects and should be
avoided during treatment.
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
If insufficient sleep duration occurs, the likelihood of impaired alertness may be increased.
4.8 Undesirable effects
Dose-related adverse effects which occur commonly with nitrazepam and which may persist into the following day, even after a single dose include sedation, drowsiness and lightheadedness during the day, numbed emotions, reduced alertness, fatigue, headache, dizziness, muscle weakness, double vision, unsteadiness and ataxia (especially in the elderly). These phenomena occur predominantly at the start of therapy, and usually disappear with repeated administration.
The elderly are particularly sensitive to the effects of central nervous system depressant drugs and experience confusion, especially if organic brain changes are present.
Less common adverse effects include; vertigo, hypotension, salivation changes, gastro-intestinal disturbances, skin rashes, visual disturbances, dysarthria, tremor, changes in libido, incontinence and urinary retention. Isolated cases of blood dyscrasias and jaundice have been reported.
Amnesia
Benzodiazepines may induce antegrade amnesia which occurs most often several hours after ingesting the drug even at therapeutic dosages, with the risk increasing at higher dosages. Amnesic effects may be associated with inappropriate behaviour.
Depression
Pre-existing depression may be unmasked during benzodiazepine use.
Psychiatric and Paradoxical Reactions
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. Rare behavioural effects include excitement, confusion, paradoxical aggressive outbursts and unmasking of depression with suicidal tendencies. If these occur, nitrazepam should be discontinued.
Dependance
Withdrawal symptoms may occur with benzodiazepines following even normal therapeutic doses for short periods of time. Withdrawal from benzodiazepines may be associated with physiological and psychological symptoms, (see Section 4.4).
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 [www.mhra.gov.uk/yellowcard].
4.9 Overdose
When taken alone in overdosage nitrazepam presents few problems in management and should not present a threat to life unless combined with other CNS depressants (including alcohol).
In the management of overdose with any medicinal product, it should be borne in mind that multiple agents may have been taken.
Symptoms
Symptoms of nitrazepam overdosage are mainly an intensification of its therapeutic effects. In mild cases, symptoms include sedation, muscle weakness, dysarthria, lethargy, profound sleep, mental confusion or paradoxical excitation. In more severe cases, symptoms may include ataxia, hypotonia, hypotension, respiratory depression and rarely, coma and very rarely death. When combined with other CNS depressants, including alcohol, the effects of overdosage are likely to be more severe and may prove fatal.
Management
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 airways protected. If there is no advantage in emptying the stomach, activated charcoal should be administered to reduce absorption. Respiratory and cardiovascular functions should be carefully monitored in intensive care. The value of dialysis has not been determined.
If excitation occurs, barbiturates should not be used.
Flumazenil, a specific competitive inhibitor of the central effects of benzodiazepines, may be useful as an emergency antidote but expert advice is essential since adverse effects may occur (e.g. convulsions in patients with epilepsy dependent on benzodiazepines). Patients requiring such intervention should be monitored closely in hospital. Benzodiazepines are not significantly removed from the body by dialysis.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Hypnotics and Sedatives, Benzodiazepine derivatives
ATC Code: N05CD02
Nitrazepam is a benzodiazepine compound with sedative properties.
It acts in 30 to 60 minutes to produce sleep lasting 6 to 8 hours.
5.2 Pharmacokinetic properties
Absorption:
The drug is well absorbed from gastro-intestinal tract and maximum plasma concentration is reached in 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. Steady-state levels are achieved within 5 days.
Distribution:
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.
Biotransformation:
Nitrazepam undergoes biotransformation to a number of metabolites, none of which possess significant clinical activity.
Elimination:
About 5% of the metabolites are 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. Also excreted in the milk of lactating mothers.
The half-life is, on average, 24 hours.
Pharmacokinetic/ Pharmacodynamic relationship:
No clear correlation has been demonstrated between the blood levels of nitrazepam and its clinical effects.
5.3. Preclinical safety data
No relevant information additional to that contained elsewhere in the SPC.
6. PHARMACEUTICAL PARTICULARS
6.1. List of Excipients
Lactose Maize starch Starch, pregelatinised Ethylcellulose 100 cps Magnesium stearate
6.2.
Incompatibilities
Not applicable
6.3
6.4
6.5
Shelf life
Container: 36 months Blister pack: 36 months
Special precautions for storage
Containers: Do not store above 25°C. Store in the original container and keep the container tightly closed.
Blister Packs: Do not store above 25°C. Store in the original package to protect from light.
Nature and contents of container
Tablets containers: High density polyethylene with polythene closures and/or polypropylene containers with polypropylene or polythene lids and polyurethane or polythene inserts.
Blister packs: 250 micron PVC and 25 micron aluminium foil coated with heat resistant print primer on one side and heat-seal lacquer on the other.
Containers of 14, 15, 21, 28, 30, 50, 56, 60, 84, 100, 250, 500 & 1000 tablets.
Blister pack of 28 tablets.
7.
MARKETING AUTHORISATION HOLDER
Metwest Pharmaceuticals Limited 15 Runnelfield Harrow on the Hill Middlesex HA1 3NY
15/01/2009
10 DATE OF REVISION OF THE TEXT
13/08/2014