Flumazenil

FLUMAZENIL- flumazenil injection, solution
A-S Medication Solutions

Rx ONLY

DESCRIPTION

Flumazenil Injection, USP is a benzodiazepine receptor antagonist. Chemically, flumazenil is ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a](1,4) benzodiazepine-3-carboxylate. Flumazenil has an imidazobenzodiazepine structure, a calculated molecular weight of 303.3, and the following structural formula:

Structural Formula

Flumazenil is a white to off-white crystalline compound with an octanol: buffer partition coefficient of 14 to 1 at pH 7.4. It is insoluble in water but slightly soluble in acidic aqueous solutions. Flumazenil injection is available as a sterile parenteral dosage form for intravenous administration. Each mL contains 0.1 mg of flumazenil compounded with 1.8 mg of methylparaben, 0.2 mg of propylparaben, 0.9% sodium chloride, 0.01% edetate disodium, and 0.01% acetic acid; the pH is adjusted to approximately 4 with hydrochloric acid and/or, if necessary, sodium hydroxide.

CLINICAL PHARMACOLOGY

Flumazenil, an imidazobenzodiazepine derivative, antagonizes the actions of benzodiazepines on the central nervous system. Flumazenil competitively inhibits the activity at the benzodiazepine recognition 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.

Flumazenil 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.

In animals pretreated with high doses of benzodiazepines over several weeks, flumazenil elicited symptoms of benzodiazepine withdrawal, including seizures. A similar effect was seen in adult human subjects.

Pharmacodynamics

Intravenous flumazenil has been shown to antagonize sedation, impairment of recall, psychomotor impairment and ventilatory depression produced by benzodiazepines in healthy human volunteers.

The duration and degree of reversal of sedative benzodiazepine effects are related to the dose and plasma concentrations of flumazenil as shown in the following data from a study in normal volunteers.

Chart 1
(click image for full-size original)

Chart 1

Generally, doses of approximately 0.1 mg to 0.2 mg (corresponding to peak plasma levels of 3 to 6 ng/mL) produce partial antagonism, whereas higher doses of 0.4 to 1 mg (peak plasma levels of 12 to 28 ng/mL) usually produce complete antagonism in patients who have received the usual sedating doses of benzodiazepines. The onset of reversal is usually evident within 1 to 2 minutes after the injection is completed. Eighty percent response will be reached within 3 minutes, with the peak effect occurring at 6 to 10 minutes. The duration and degree of reversal are related to the plasma concentration of the sedating benzodiazepine as well as the dose of flumazenil given.

In healthy volunteers, flumazenil did not alter intraocular pressure when given alone and reversed the decrease in intraocular pressure seen after administration of midazolam.

Pharmacokinetics

After IV administration, plasma concentrations of flumazenil follow a two-exponential decay model. The pharmacokinetics of flumazenil are dose-proportional up to 100 mg.

Distribution

Flumazenil is extensively distributed in the extravascular space with an initial distribution half-life of 4 to 11 minutes and a terminal half-life of 40 to 80 minutes. Peak concentrations of flumazenil are proportional to dose, with an apparent initial volume of distribution of 0.5L/kg. The volume of distribution at steady-state is 0.9 to 1.1 L/kg. Flumazenil is a weak lipophilic base. Protein binding is approximately 50% and the drug shows no preferential partitioning into red blood cells. Albumin accounts for two thirds of plasma protein binding.

Metabolism

Flumazenil is completely (99%) metabolized. Very little unchanged flumazenil (< 1%) is found in the urine. The major metabolites of flumazenil identified in urine are the de-ethylated free acid and its glucuronide conjugate. In preclinical studies there was no evidence of pharmacologic activity exhibited by the de-ethylated free acid.

Elimination

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. Clearance of flumazenil occurs primarily by hepatic metabolism and is dependent on hepatic blood flow. In pharmacokinetic studies of normal volunteers, total clearance ranged from 0.8 to 1.0 L/hr/kg.

Pharmacokinetic parameters following a 5-minute infusion of a total of 1 mg of flumazenil mean (coefficient of variation, range):

Cmax (ng/mL) 24 (38%, 11 -43)
AUC (ngยท hr/mL) 15 (22%, 10-22)
Vss (L/kg) 1 (24%, 0.8-1.6)
Cl (L/hr/kg) 1 (20%, 0.7-1.4)
Half-life (min) 54 (21%, 41-79)

Food Effects

Ingestion of food during an intravenous infusion of the drug results in a 50%increase in clearance, most likely due to the increased hepatic blood flow that accompanies a meal.

Special Populations

The Elderly:

The pharmacokinetics of flumazenil are not significantly altered in the elderly.

Gender:

The pharmacokinetics of flumazenil are not different in male and female subjects.

Renal Failure (creatinine clearance < 10 mL/min) and Hemodialysis:

The pharmacokinetics of flumazenil are not significantly affected.

Patients With Liver Dysfunction:

For patients with moderate liver dysfunction, their mean total clearance is decreased to 40% to 60% and in patients with severe liver dysfunction, it is decreased to 25% of normal value, compared with age-matched healthy subjects. This results in a prolongation of the half-life to 1.3 hours in patients with moderate hepatic impairment and 2.4 hours in severely impaired patients. Caution should be exercised with initial and/or repeated dosing to patients with liver disease.

Drug-Drug Interaction:

The pharmacokinetic profile of flumazenil is unaltered in the presence of benzodiazepine agonists and the kinetic profiles of those benzodiazepines studied (i.e., diazepam, flunitrazepam, lormetazepam, and midazolam) are unaltered by flumazenil. During the 4-hour steady-state and post infusion of ethanol, there were no pharmacokinetic interactions on ethanol mean plasma levels as compared to placebo when flumazenil doses were given intravenously (at 2.5 hours and 6 hours) nor were interactions of ethanol on the flumazenil elimination half-life found.

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