Flumazenil Other names: Flumazepil

Flumazenil, an imidazobenzodiazepine, is a benzodiazepine antagonist which, by competitive interaction, blocks the effects of substances acting via the benzodiazepine-receptor. Neutralisation of paradoxal reactions of benzodiazepines has been reported.

According to experiments in animals, the effects of substances, which are not acting via the benzodiazepine-receptor (like barbiturates, GABA-mimetics and adenosine-receptor agonists), are not blocked by flumazenil. Non-benzodiazepine-agonists, like cyclopyrrolones (zopiclone) and triazolopyridazines, are blocked by flumazenil. The hypnosedative effects of benzodiazepines are blocked rapidly (within 1-2 minutes) after intravenous administration. Depending on the difference in elimination time between agonist and antagonist, the effect can recur after several hours. Flumazenil has possibly a slight agonistic, anticonvulsive effect. Flumazenil caused withdrawal, including convulsions in animals receiving long-term flumazenil treatment.

Distribution

Flumazenil is a lipophilic weak base. Flumazenil is bound for approximately 50% to plasma proteins, from which two thirds are bound to albumin. Flumazenil is extensively divided over extra vascular space. During the distribution phase plasma concentration of flumazenil decreases with a half life of 4-15 minutes. The distribution volume under steady-state conditions (V_ss) is 0.9-1.1 L/kg.

Biotransformation

Flumazenil is mainly eliminated through hepatic metabolism. The carboxylic acid metabolite was shown in plasma (in free form) and in urine (in free and conjugated form) to be the most important metabolite.

In pharmacological tests this metabolite has proved to be inactive as benzodiazepine agonist or antagonist.

Elimination

Almost no unchanged flumazenil is excreted in the urine. This indicates a complete metabolic degradation of the active substance in the body. Radiolabelled medicinal product is completely eliminated within 72 hours, with 90 to 95% of the radioactivity appearing in the urine and 5 to 10% in the faeces. Elimination is rapid, as is shown by the short half life of 40 to 80 minutes. The total plasma clearance of flumazenil is 0.8 to 1.0 L/hour/kg and can almost completely be attributed to hepatic metabolism.

The pharmacokinetics of flumazenil is dose-proportional within the therapeutic dose-range and up to 100 mg.

The intake of food during the intravenous infusion of flumazenil results in an increase of 50% of the clearance probably due to postprandial increase in liver perfusion.

Pharmacokinetics in special patient groups

Elderly

The pharmacokinetics of flumazenil in elderly is not different from that in young adults.

Patients with impaired hepatic function

In patients with a moderately to severely impaired liver function the half life of flumazenil is increased (increase of 70-210%) and the total clearance is lower (between 57 and 74%) compared to normal healthy volunteers.

Patients with impaired renal function

Pharmacokinetics of flumazenil is not different in patients with impaired renal function or patients undergoing haemodialysis compared to normal healthy volunteers.

Paediatric population

In children above one year of age, the half life elimination is shorter and the variability is higher than in adults, approximately of 40 min with a range of 20 to 75 min. Clearance and volume of distribution, by kg of body weight are the same as in adults.

Late prenatal as well as per- and postnatal exposure to flumazenil induced both behavioural alterations and an increase of hippocampal benzodiazepine receptor density in the rat offspring. The effect of these findings is not considered relevant if the product is used for a very short time as instructed.