Drug information of Flumazenil

Flumazenil

Drug group:

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.

Mechanism of effect

Systemic: Flumazenil selectively antagonizes or attenuates the effects of benzodiazepines in the CNS by competitively inhibiting their actions at the benzodiazepine binding site of the gamma aminobutric acid (GABA)-benzodiazepine receptor complex.

 flumazenil does not antagonize the effects of CNS-active substances that act via other receptors.Also, flumazenil does not alter the pharmacokinetics of benzodiazepines. The extent to which flumazenil reverses the effects of a benzodiazepine depends on the dose and plasma concentration of both medications and on the effect being assessed. Flumazenil reverses some components of benzodiazepin-induced hypoventilation, leading to at least partial improvement in respiratory function.

one study showed that midazolam's effect on respiration results primarily (but not exclusively) from a reduction in tidal volume, and that flumazenil completely reverses this effect. However, several studies have shown that flumazenil may not affect other measures of respiratory function, especially measures that are independent of patient effort or wakefulness. Also, amnesia is antagonized less consistently than psychomotor deficits, which may be reversed less completely than sedation. 

Pharmacodynamic

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.

Pharmacokinetics

Absorption

Onset of action: 1-2 min; 80% response within 3 min

Peak effect: 6-10 min

Distribution

Protein bound: 40-50%

Vd: 0.9 to 1.1 L/kg

Mtabolism

Hepatic. Flumazenil is completely (99%) metabolized. The major metabolites of flumazenil identified in urine are the de-ethylated free acid and its glucuronide conjugate.

Elimination

Half-life: 53 min

Clearance: 1 L/hr/kg [healthy volunteers receiving a 5-minute infusion of a total of 1 mg]

Excretion: 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.

First order elimination

Drug indications

Alcohol withdrawal syndrome

Dosage

Ampule

0/5 mg/5 ml

Adults:

  • Drug overdose, Benzodiazepine, known or suspected: initial, 0.2mg IV over 30s; if desired level of consciousness not obtained after an additional 30s, give dose of 0.3mg IV over 30s; further doses of 0.5mg IV over 30s may be given at 1-min intervals if needed to MAX total dose of 3mg; patients with only partial response to 3mg may require additional slow titration to a total dose of 5mg; if no response 5 min after receiving total dose of 5 mg, overdose is unlikely to be benzodiazepine and further treatment with flumazenil will not help
  • Drug overdose, Benzodiazepine, known or suspected: occurrence of resedation, may give repeated doses at 20-min intervals; MAX single dose 1mg (0.5 mg/min) and MAX total dose 3 mg/h.
  • Reversal of benzodiazepine activity: 0.2mg IV over 15seconds; if desired level of consciousness is not obtained after waiting 45seconds, a second dose of 0.2mg IV may be given and repeated at 60-second intervals as needed (up to a maximum of 4 additional times) to a maximum total dose of 1mg; most patients respond to doses of 0.6 to 1mg; in the event of resedation, repeated doses may be given at 20-minute intervals if needed; for repeat treatment, no more than 1mg (given as 0.5 mg/min) should be given at any one time and no more than 3 mg should be given in any one hour 

Pediatrics:

  • safety and efficacy in the reversal of conscious sedation in pediatric patients below the age of 1 year have not been established
Reversal of benzodiazepine activity: children 1 year or older, 0.01 mg/kg (up to 0.2 mg) IV over 15 seconds; if adequate sedation reversal does not occur after an additional 45 seconds, further injections of 0.01 mg/kg (up to 0.2 mg) may be repeated at 1-minute intervals, as needed up to 4 times; maximum total dose 0.05 mg/kg or 1 mg, whichever is lower

Drug contraindications

hypersensitivity to this drug

Side effects

Seizures , Blurred vision , vertigo

Alerts

  • The use of flumazenil has been associated with the occurrence of seizures. Seizures are mostfrequentin patients who have been on benzodiazepines for long-term sedation or in overdose cases where patients are showing signs of serious tricyclic antidepressant overdose. Individualize the dosage of flumazenil and be prepared to manage seizures.
The use of flumazenil is not recommended in epileptic patients who have been receiving benzodiazepine treatment for a prolonged period. Although flumazenil exerts a slight intrinsicanticonvulsant effect, its abrupt suppression of the protective effect of a benzodiazepine agonist can give rise to convulsions in epileptic patients.

Points of recommendation

  • Advise patient not to undertake any activities requiring complete mental alertness. Do not operate hazardous machinery or a motor vehicle until at least 24 h after discharge and until it has been determined that no residual sedative effects of benzodiazepines remain.
  • Drug does not consistently reverse benzodiazepine-induced amnesia. Counsel patient, preferably in writing, that memory and judgment may be impaired. This information may also be given to a responsible family member.
Avoid alcohol or non-prescription drugs for 24 h after administration of flumazenil or if the effects of benzodiazepines persist.

Pregnancy level

C


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