Introduction
Fumazenil is an imidazobenzodiazepine derivative and a potent benzodiazepine receptor antagonist that competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex, thereby reversing the effects of benzodiazepine on the central nervous system.
Uses
Flumazenil is a benzodiazepine antagonist that is used for the complete or partial reversal of the sedative effects caused by benzodiazepines in various clinical settings, such as induced general anesthesia for diagnostic and therapeutic procedures.
For the complete or partial reversal of the sedative effects of benzodiazepines in cases where general anesthesia has been induced and/or maintained with benzodiazepines, and where sedation has been produced with benzodiazepines for diagnostic and therapeutic procedures. Also for the management of benzodiazepine overdose as an adjunct for appropriate supportive and symptomatic measures.
Associated Conditions
Pharmacodynamics
Flumazenil antagonizes the CNS effects produced by benzodiazepines, but does not antagonize the central nervous system effects of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (including ethanol, barbiturates, or general anesthetics) and does not reverse the effects of opioids.
Mechanism of Action
Flumazenil, an imidazobenzodiazepine derivative, is a benzodiazepine antagonist. It competitively inhibits the benzodiazepine binding site on the GABA/benzodiazepine receptor complex. Flumazenil is a weak partial agonist in some animal models of activity, but has little or no agonist activity in man.
Volume of Distribution
- 0.9 to 1.1 L/kg
Protein Binding
Protein binding is approximately 50%, mostly (66%) to albumin. Protein binding is reduced in patients with hepatic cirrhosis.
Route of Elimination
Flumazenil is completely (99%) metabolized. Elimination of radiolabeled drug is essentially complete within 72 hours, with 90% to 95% of the radioactivity appearing in urine and 5% to 10% in the feces.
Half Life
Initial distribution half-life is 4 to 11 minutes and the terminal half-life is 40 to 80 minutes. Prolongation of the half-life to 1.3 hours in patients with moderate hepatic impairment and 2.4 hours in severely impaired patients. Compared to adults, the elimination half-life in pediatric patients was more variable, averaging 40 minutes (range: 20 to 75 minutes).
Clearance
- 1 L/hr/kg [healthy volunteers receiving a 5-minute infusion of a total of 1 mg]
Toxicity
In clinical studies, most adverse reactions to flumazenil were an extension of the pharmacologic effects of the drug in reversing benzodiazepine effects.
Food Interactions
- Take separate from meals. Eating during an intravenous infusion of flumazenil increases the elimination of flumazenil, potentially through elevated hepatic blood flow.
Dosage
In anaesthesia: The recommended initial dose of Flumazenil is 0.2 mg administered IV over 15 seconds. If the desired degree of consciousness is not obtained within 60 seconds, a second dose of 0.1 mg can be injected; this may be repeated at 60-second intervals where necessary, up to a total dose of 1 mg. The usual dose is 0.3-0.6 mg, but individual requirements may vary considerably, depending on the dose and duration of effect of the benzodiazepine administered and patient characteristics.
In intensive care and in the management of unconsciousness of unknown origin: The recommended initial dose of Flumazenil is 0.3 mg IV. If the desired level of consciousness is not obtained within 60 seconds, Flumazenil may be injected repeatedly until the patient awakes or up to a total dose of 2 mg. If drowsiness recurs, Flumazenil may be administered as one or more bolus IV doses as above, or as an IV infusion of 0.1-0.4 mg per hour. The rate of infusion should be individually adjusted to the desired level of arousal. If a significant improvement in consciousness or respiratory function is not obtained after repeated doses of Flumazenil, a non-benzodiazepine aetiology must be assumed. In the intensive care unit, in patients treated with high doses of benzodiazepines and/or for long periods of time, the individually titrated injections of Flumazenil, slowly administered, should not produce withdrawal syndromes. If unexpected symptoms occur, diazepam or midazolam could be carefully titrated intravenously according to patient response.
Children >1 year-of-age: For the reversal of conscious sedation induced with benzodiazepines in children above one year-of- age, the recommended initial dose is 0.01 mg/kg (up to 0.2 mg) administered IV over 15 seconds. If the desired level of consciousness is not obtained after waiting an additional 45 seconds, further injections of 0.01 mg/kg (up to 0.2 mg) can be administered and repeated at 60-second intervals where necessary (up to a maximum of four additional times) to a maximum total dose of 0.05 mg/kg or 1 mg, whichever is lower. The dose should be individualised based on patient response. No data are available on the safety and efficacy of repeated administration of Flumazenil to children for re-sedation.