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Duration of treatment: The duration of treatment should be as short as possible (see Posology) depending on the indication, but should not exceed 4 weeks including any dose-tapering period for insomnia . Extension beyond this period should not take

Psychiatric and paradoxical reactions: Reactions like restlessness, agitation, confusion, irritability, aggressiveness, delusion, rages, nightmares, hallucinations,

Specific patient groups: 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 a reduced dose (see Posology). A lower dose is also recommended for patients with chronic respiratory insufficiency due to the risk of respiratory depression (cross refer to section 4.3 - contraindicated in severe respiratory insufficiency).

4.5 Interaction with other medicinal products and other forms of interaction

In the case of anti-epileptics, the following Barbiturates Carbamazepine Hydantoins are inducers of hepatic metabolism and may enhance the metabolism of benzodiazepines. Phenytoin concentration may be increased or decreased. Compounds which inhibit 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. Cimetidine inhibits the metabolism of nitrazepam. Benzodiazepines possibly antagonise the effects of levodopa. Rifampicin, by enzyme induction, reduces the half-life of nitrazepam and increases the clearance. Probenecid may increase the sedative effects, possibly excessively.

4.8 Undesirable effects

The following occur predominantly at the start of therapy and usually disappear with repeated administration:

ataxia or double vision, confusion, dizziness, drowsiness, fatigue, headache, muscle weakness, numbed emotions, reduced alertness These phenomena occur predominantly at the start of therapy and usually disappear with repeated administration.

Undesirable effects may persist into the following day due to the long half-life.

Other side effects like gastrointestinal disturbances, changes in libido, skin reactions, have been reported occasionally.

Blood dyscrasias, jaundice, hypotension and urinary retention have been reported rarely.

Abuse: Abuse of benzodiazepines has been reported.

10 DATE OF REVISION OF THE TEXT

November 2006 November 2008 January 2009

4.5       Interaction with other medicinal products and other forms of interaction

Not recommended: Concomitant intake with alcohol.  The sedative effect may be enhanced when the product is used in combination with alcohol.  This affects the ability to drive or use machines.

Take into account: Combination with CNS depressants.

Enhancement of the central depressive effect may occur in cases of concomitant use with antipsychotics (neuroleptics), hypnotics, anxiolytics/sedatives, antidepressant agents, narcotic analgesics, anti-epileptic products, anaesthetics and sedative antihistamines.

In the case of narcotic analgesics enhancement of the euphoria may also occur leading to an increase in psychic dependence.    

In the case of anti-epileptics, the following

            Barbiturates
            Carbamazepine
            Hydantoins

are inducers of hepatic metabolism and may enhance the metabolism of benzodiazepines.

Phenytoin concentration may be increased or decreased.

Compounds which inhibit 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.

Cimetidine inhibits the metabolism of nitrazepam.

Benzodiazepines possibly antagonise the effects of levodopa.

Rifampicin, by enzyme induction, reduces the half-life of nitrazepam and increases the clearance.

Probenecid may increase the sedative effects, possibly excessively.

4.9       Overdose

As with other benzodiazepines, overdose 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.

Following overdose with oral benzodiazepines, 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.  Special attention should be paid to respiratory and cardiovascular functions in intensive care.

Overdose of benzodiazepines is usually manifested by degrees of central nervous system depression ranging from drowsiness to coma.   In mild cases, symptoms include drowsiness, mental confusion and lethargy; in more serious cases, symptoms may include ataxia, hypotonia, hypotension, respiratory depression, rarely coma and very rarely death.  Flumazenil may be useful as an antidote.

Benzodiazepines commonly cause drowsiness, ataxia, dysarthria and nystagmus.  Coma, hypotension and respiratory depression occasionally occur but are seldom serious if these drugs are taken alone.  Coma usually lasts only a few hours but in elderly people it may be more protracted and cyclical.  Benzodiazepine respiratory depressant effects are more serious in patients with severe chronic respiratory disease.

Benzodiazepines potentiate the effects of other central nervous system depressants, including alcohol.

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 (Anexate) 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.  It is contraindicated in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants).