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Drug Details

Anexate 500 micrograms/5ml Solution for Injection or Infusion

• Drug Class Description
  Imidazobenzodiazepine
• Generic Name
  Flumazenil
• Presentation
  Solution for Injection or infusion. A clear, almost colourless, sterile aqueous solution.
• Description
  Each 5ml ampoule contains 500 micrograms of flumazenil (100 micrograms per ml). Excipient: Sodium 3.7 mg/ml
• Indications
  

  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.

  For the reversal of conscious sedation induced with benzodiazepines in children > 1 year of age.

   

• Adult Dosage
  

  Flumazenil must be administered intravenously by an anaesthetist or a doctor with experience in anaesthesiology. flumazenil may be administered either undiluted or diluted.

  It can be administered together with other reanimation measures.

  Anaesthesiology:

  The initial dose is 200 micrograms administered intravenously in 15 seconds. If the desired degree of consciousness is not obtained within 60 seconds, a second dose of 100 micrograms can be administered . This may be repeated at 60-second intervals where necessary, up to a maximum total dose of 1 mg. The usual dose is 300–600 micrograms.

  Intensive care:

  The recommended initial dose of flumazenil is 300 micrograms intravenously. If the desired level of consciousness is not obtained within 60 seconds, a repeat dose of 100 micrograms may be administered. If necessary, this may be repeated at 60 second intervals up to a total dose of 2 mg. If drowsiness recurs, a second bolus injection of flumazenil may be administered. An intravenous infusion of 100–400 micrograms per hour has also been shown to be useful. The dosage and rate of infusion should be individually adjusted to achieve the desired level of sedation.

  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.

  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.

   

• Child Dosage
  

  Children above 1 year of age:

  For the reversal of conscious sedation induced with benzodiazepines in children > 1 year of age, the recommended initial dose is 10 micrograms/kg (up to 200 micrograms) administered intravenously over 15 seconds. If the desired level of consciousness is not obtained after waiting an additional 45 seconds, further injection of 10 micrograms/kg may be administered (up to 200 micrograms) and repeated at 60 second intervals where necessary (a maximum of 4 times) to a maximum total dose of 50 micrograms/kg or 1 mg, whichever is lower. The dose should be individualised based on the patient's response. No data are available on the safety and efficacy of repeated administration of flumazenil to children for re-sedation.

• Elderly Dosage
  

  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.

• Contra Indications
  

  Flumazenil is contra-indicated in patients:

  • with hypersensitivity to the active substance, benzodiazepines or any of the excipients.

  • who have been administered benzodiazepines for the treatment of a potentially life-threatening condition (e.g. increased 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

• Special Precautions
  

  Until sufficient data are available, flumazenil should only be administered to children if the risks to the patient (especially in the case of accidental overdose) have been weighed up against the benefits of the treatment.

  Elimination may be delayed in patients with hepatic impairment

  The antagonistic effect of flumazenil is specific to benzodiazepines; an effect is therefore not to be expected if the 'non-awakening' is caused by other substances. If flumazenil is administered for anesthsiology at the end of the operation, the effect of the peripheral muscle relaxants must first have disappeared. Because flumazenil generally has a shorter duration of action than the benzodiazepines and therefore sedation can re-occur, the clinical state of the patient must be monitored, preferably in the intensive care unit, until the effect of flumazenil is eliminated.

  In high-risk patients, the benefits of a benzodiazepine-induced sedation should be weighed up against the risks of a rapid return to consciousness. In patients (e.g with cardiac problems), maintenance of a certain degree of sedation during the early post-operative period may be preferable to complete consciousness.

  Rapid injection of flumazenil should be avoided. In patients with high dose and/or long-term exposure to benzodiazepines ending at any time within the weeks preceding flumazenil administration, rapid injection of doses equal to or higher than 1 mg has led to withdrawal symptoms, including palpitations, agitation, anxiety, emotional lability as well as mild confusion and sensory distortions.

  In patients who are anxious during the pre-operative phase or in patients who are known to suffer from chronic or transient anxiety, the dosage of flumazenil should be adjusted carefully.

  However, after major surgery, the post operative pain should be considered and it may be preferable to keep the patient lightly sedated.

  For patients who have been treated chronically with high doses of benzodiazepines, the advantages of the use of flumazenil should be carefully weighed up against the risk of withdrawal symptoms; if, despite careful dosing, withdrawal symptoms occur, treatment with low doses of benzodiazepines, titrated intravenously according to the patient's response, may be considered if necessary.

  Use of the antagonist is not recommended in patients with epilepsy who have been treated with benzodiazepines for a prolonged period. Although flumazenil exerts a slight intrinsic anticonvulsant effect, the abrupt suppression of the protective effect of a benzodiazepine agonist can induce convulsions in epileptic patients.

  In patients with severe brain injury (and/or instable intracranial pressure) who are being treated with flumazenil – to antagonise the effects of benzodiazepines – increased intracranial pressure may develop

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

  Particular caution is necessary when using flumazenil in cases of mixed-drug overdose. In particular in the case of an intoxication with benzodiazepines and cyclic antidepressants, certain toxic effects such as convulsions and cardiac arrhythmias, which are caused by these antidepressants but which emerge less readily on concomitant administration with benzodiazepines, are exacerbated on administration of flumazenil.

  Patients who have received flumazenil for the reversal of Benzodiazepine effects should be monitored for resedation, respiratory depression or other residual benzodiazepine effects for an appropriate period based on the dose and duration of effect of the benzodiazepine employed

  Flumazenil is not recommended for the treatment for benzodiazepine dependence or for the treatment of protracted benzodiazepine abstinence syndromes.

  This medicine contains 3.7 mg sodium per ml (18.5 mg per 5 ml vial). Dosages over 600 micrograms contain more than 1 mmol sodium (23 mg). To be taken into consideration by patients on a controlled sodium diet.

• Interactions
  

  Flumazenil antagonises the central effects of benzodiazepines by competitive interaction at the receptor. The effects of non-benzodiazepine agonists that act via the benzodiazepine receptor, such as zopiclone, triazolpyridazine and others, are also blocked by flumazenil. Interactions with other centrallyacting substances have not been observed. The pharmacokinetics of benzodiazepines are not influenced by the antagonist flumazenil.

  On administering flumazenil concomitantly with the benzodiazepines midazolam, flunitrazepam and lormetazepam, the pharmacokinetic parameters of flumazenil were unaffected.

  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.

  There is no pharmacokinetic interaction between ethanol and flumazenil.

• Adverse Drug Reactions
  

  Psychiatric disorders

  Uncommon: anxiety, fear: following rapid injection, generally did not require treatment.

  Unknown: Withdrawal symptoms (e.g., agitation, anxiety, emotional lability, confusion, sensory distortions, tachycardia, dizziness, sweating), following rapid injection of doses of 1 mg or more in patients with high-dose and/or long-term exposure to benzodiazepines ending at any time within the weeks preceding flumazenil administration; panic attacks (in patients with a history of panic reactions); abnormal crying, agitation, aggressive reactions (the side effect profile in children is generally similar to that in adults. When Flumazenil has been used for the reversal of conscious sedation, abnormal crying, agitation and aggressive reactions have been reported).

  Nervous system disorders

  Unknown: Seizures: particularly in patients known to suffer from epilepsy or severe hepatic impairment, mainly after long-term treatment with benzodiazepines or in cases of mixed-drug overdose.

  Cardiac disorders

  Uncommon: Palpitations: following rapid injection, generally did not require treatment.

  Unknown: Transient increases in heart rate (on awakening).

  Vascular disorders

  Unknown: Transient increased blood pressure (on awakening).

  Gastrointestinal disorders

  Common: Nausea: vomiting: during post-operative use, particularly if opiates have also been used.

  Skin and subcutaneous tissue disorders

  Unknown: Flushing,

  General disorders and administration site conditions

  Rare: Hypersensitivity reactions (including analphylaxis)

  Unknown: Chills: following rapid injection, generally did not require treatment.