Benzodiazepine antagonists.

Flumazenil

Each 5ml ampoule contains 500 micrograms of flumazenil (100 micrograms per ml).

Solution for Injection or infusion. A clear, almost colourless, sterile aqueous solution.

Anexate is indicated for the complete or partial reversal of the central sedative effects of benzodiazepines. It may therefore be used in anaesthesia and intensive care in the following situations: Termination of general anaesthesia induced and/or maintained with benzodiazepines. Reversal of benzodiazepine sedation in short diagnostic and therapeutic procedures. For the specific reversal of the central effects of benzodiazepines, to allow return to spontaneous respiration and consciousness, in patients in intensive care.

Anexate is for slow intravenous injection or infusion. It should only be administered under the supervision of an experienced physician.

Anexate may be used concurrently with other resuscitative procedures.

Adults

The recommended initial dose is 200 micrograms administered intravenously over 15 seconds. If the desired level of consciousness is not obtained within 60 seconds a further dose of 100 micrograms can be injected and repeated at 60-second intervals where necessary, up to a maximum total dose of 1mg or in intensive care situations, 2mg. The usual dose required is 300 - 600 micrograms.

If drowsiness recurs, an intravenous infusion of 100 - 400 micrograms per hour may be employed. The rate of infusion should be individually adjusted to achieve the desired level of arousal.

The individually titrated, slow injections or infusions of Anexate should not produce withdrawal symptoms, even in patients exposed to high doses of benzodiazepines and/or for long periods of time. If, however, unexpected signs of overstimulation occur, an individually titrated dose of diazepam (Valium) or midazolam (Hypnovel) should be given by slow intravenous injection.

If a significant improvement in consciousness or respiratory function is not obtained after repeated doses of Anexate, a non-benzodiazepine aetiology must be assumed.

Use in renal and hepatic insufficiency

No dosage adjustments are necessary in patients with renal impairment. However, since flumazenil is primarily metabolised in the liver, careful titration of dosage is recommended in patients with impaired hepatic function.

There are insufficient data to make dosage recommendations for Anexate in children. It should, therefore, be administered only if the potential benefits to the patient outweigh the possible risks.

No specific data are available on the use of Anexate in the elderly, but it should be remembered that this population is more sensitive to the effects of benzodiazepines and should be treated with due caution.

Anexate is contra-indicated in patients with known hypersensitivity to flumazenil, benzodiazepines or any of the excipients.

Anexate is contra-indicated in patients who have been given a benzodiazepine for control of a potentially life-threatening condition (e.g. control of intracranial pressure or status epilepticus).

In mixed intoxications with benzodiazepines and tricyclic and/or tetracyclic antidepressants, the toxicity of the antidepressants can be masked by protective benzodiazepine effects. In the presence of autonomic (anticholinergic), neurological (motor abnormalities) or cardiovascular symptoms of severe intoxication with tricyclics/tetracyclics, Anexate should not be used to reverse benzodiazepine effects.

In view of the short duration of action of Anexate and the possible need for repeat doses, the patient should remain under close observation until all possible central benzodiazepine effects have subsided.

The use of Anexate is not recommended in epileptic patients who have been receiving benzodiazepine treatment for a prolonged period. Although Anexate exerts a slight intrinsic anticonvulsant effect, its abrupt suppression of the protective effect of a benzodiazepine agonist can give rise to convulsions in epileptic patients.

Anexate should be used with caution in patients with head injury as it may be capable of precipitating convulsions or altering cerebral blood flow in patients receiving benzodiazepines.

Benzodiazepines have a dependence potential when used chronically. Symptoms such as depression, nervousness, rebound insomnia, irritability, sweating and diarrhoea may arise following abrupt cessation of benzodiazepines in patients treated with high doses and/or for prolonged periods of time. Rapid injection of Anexate in such patients may trigger these withdrawal symptoms, even in patients who stopped taking the benzodiazepine in the weeks preceding Anexate administration (depending on the half-life of the benzodiazepine used) and should therefore be avoided. There is also a possibility of mild and transient withdrawal reactions occurring even after a short period of administration of benzodiazepines.

When Anexate is used with neuromuscular blocking agents, it should not be injected until the effects of neuromuscular blockade have been fully reversed.

In high-risk patients, the advantages of counteracting the central nervous system depression associated with benzodiazepines should be weighed against the drawbacks of rapid awakening.

The dosage of Anexate should be adjusted individually to the needs of patients suffering from pre-operative anxiety or having a history of chronic or episodic anxiety. In anxious patients, particularly those with coronary heart disease, it is preferable to maintain a degree of sedation throughout the early post-operative period rather than bring about complete arousal.

The pain felt by patients in the post-operative period must be taken into account. Following a major intervention, it is preferable to maintain a moderate degree of sedation.

Anexate is not recommended either as a treatment for benzodiazepine dependence or for the management of protracted benzodiazepine abstinence syndromes.

Anexate blocks the central effects of benzodiazepines by competitive interaction at the receptor level; the effects of non-benzodiazepines acting via the benzodiazepine receptor, such as zopiclone, are also blocked by Anexate. However, Anexate is ineffective when unconsciousness is due to other substances.

Interaction with other central nervous system depressants has not been observed. However, particular caution is necessary when using Anexate in cases of intentional overdosage since the toxic effects of other psychotropic drugs (especially tricyclic antidepressants) taken concurrently may increase with the subsidence of the benzodiazepine effect.

The pharmacokinetics of benzodiazepines are unaltered in the presence of Anexate and vice versa.

Anexate is generally well tolerated. In post-operative use, nausea and/or vomiting are occasionally observed, particularly if opiates have also been employed. Flushing has also been noted. If patients are awakened too rapidly, they may become agitated, anxious or fearful.

Very rarely, seizures have been reported, particularly in patients known to suffer from epilepsy or severe hepatic impairment, particularly after long-term treatment with benzodiazepines or in cases of mixed drug overdose.

In cases of mixed-drug overdose, particularly with cyclic antidepressants, toxic effects (such as convulsions and cardiac dysrhythmias) may emerge with the reversal of benzodiazepine effects by Anexate.

Transient increases in blood pressure and heart rate may occur on awakening in intensive care patients.

Any side-effects associated with Anexate usually subside rapidly without the need for special treatment.

Excessive and/or rapidly injected doses of Anexate may induce benzodiazepine withdrawal symptoms such as anxiety attacks, tachycardia, dizziness and sweating in patients on long-term and/or high dose benzodiazepine treatment ending at any time within the weeks preceding Anexate administration (depending on the half-life of the benzodiazepine used). Such symptoms may be treated by slow intravenous injection of diazepam or midazolam. There is also a possibility of mild and transient withdrawal reactions occurring even after a short period of administration of benzodiazepines.

Anexate has been reported to provoke panic attacks in patients with a history of panic disorders.

Hypersensitivity reactions (including anaphylaxis) have occurred very rarely.

Roche Products Limited

(POM)

30 June 2009