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.
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.
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
In healthy volunteers, flumazenil did not alter intraocular
pressure when given alone and reversed the decrease in intraocular pressure
seen after administration of midazolam.
After IV administration, plasma concentrations of
flumazenil follow a two-exponential decay model. The pharmacokinetics of
flumazenil are dose-proportional up to 100 mg.
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
0.5 L/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.
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 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):
||24 (38%, 11 -43)
|AUC (ng •hr/mL)
||15 (22%, 10-22)
||1 (24%, 0.8-1.6)
||1 (20%, 0.7-1.4)
||54 (21%, 41-79)
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.
The pharmacokinetics of flumazenil are not significantly
altered in the elderly.
The pharmacokinetics of flumazenil are not different in
male and female subjects.
Renal Failure (creatinine clearance < 10 mL/min) and
The pharmacokinetics of flumazenil are not significantly
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 agematched 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.
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.
Pharmacokinetics in Pediatric Patients
The pharmacokinetics of flumazenil have been evaluated in
29 pediatric patients ranging in age from 1 to 17 years who had undergone minor
surgical procedures. The average doses administered were 0.53 mg (0.044 mg/kg)
in patients aged 1 to 5years, 0.63 mg (0.020 mg/kg) in patients aged 6 to 12
years, and 0.8 mg (0.014 mg/kg) in patients aged 13 to 17 years. Compared to
adults, the elimination half-life in pediatric patients was more variable,
averaging 40 minutes (range: 20 to 75 minutes). Clearance and volume of
distribution, normalized for body weight, were in the same range as those seen
in adults, although more variability was seen in the pediatric patients.
Flumazenil has been administered in adults to reverse the
effects of benzodiazepines in conscious sedation, general anesthesia, and the
management of suspected benzodiazepine overdose. Limited information from
uncontrolled studies in pediatric patients is available regarding the use of
flumazenil to reverse the effects of benzodiazepines in conscious sedation
Conscious Sedation In Adults
Flumazenil was studied in four trials in 970 patients who
received an average of 30 mg diazepam or 10 mg midazolam for sedation (with or
without a narcotic) in conjunction with both inpatient and outpatient diagnostic
or surgical procedures. Flumazenil was effective in reversing the sedating and
psychomotor effects of the benzodiazepine; however, amnesia was less completely
and less consistently reversed. In these studies, flumazenil was administered
as an initial dose of 0.4 mg IV (two doses of 0.2 mg) with additional 0.2 mg
doses as needed to achieve complete awakening, up to a maximum total dose of 1
Seventy-eight percent of patients receiving flumazenil
responded by becoming completely alert. Of those patients, approximately half
responded to doses of 0.4 mg to 0.6 mg, while the other half responded to doses
of 0.8 mg to 1 mg. Adverse effects were infrequent in patients who received 1
mg of flumazenil or less, although injection site pain, agitation, and anxiety
did occur. Reversal of sedation was not associated with any increase in the
frequency of inadequate analgesia or increase in narcotic demand in these
studies. While most patients remained alert throughout the 3-hour postprocedure
observation period, resedation was observed to occur in 3% to 9% of the
patients, and was most common in patients who had received high doses of
benzodiazepines (see PRECAUTIONS).
General Anesthesia In Adults
Flumazenil was studied in four trials in 644 patients who
received midazolam as an induction and/or maintenance agent in both balanced
and inhalational anesthesia. Midazolam was generally administered in doses
ranging from 5 mg to 80 mg, alone and/or in conjunction with muscle relaxants,
nitrous oxide, regional or local anesthetics, narcotics and/or inhalational
anesthetics. Flumazenil was given as an initial dose of 0.2 mg IV, with
additional 0.2 mg doses as needed to reach a complete response, up to a maximum
total dose of 1 mg. These doses were effective in reversing sedation and
restoring psychomotor function, but did not completely restore memory as tested
by picture recall. Flumazenil was not as effective in the reversal of sedation
in patients who had received multiple anesthetic agents in addition to
Eighty-one percent of patients sedated with midazolam
responded to flumazenil by becoming completely alert or just slightly drowsy.
Of those patients, 36% responded to doses of 0.4 mg to 0.6 mg, while 64%
responded to doses of 0.8 mg to 1 mg.
Resedation in patients who responded to flumazenil
occurred in 10% to 15% of patients studied and was more common with larger
doses of midazolam ( > 20 mg), long procedures ( > 60 minutes) and use of neuromuscular
blocking agents (see PRECAUTIONS).
Management Of Suspected Benzodiazepine Overdose In Adults
Flumazenil was studied in two trials in 497 patients who
were presumed to have taken an overdose of a benzodiazepine, either alone or in
combination with a variety of other agents. In these trials, 299 patients were
proven to have taken a benzodiazepine as part of the overdose, and 80% of the
148 who received flumazenil responded by an improvement in level of
consciousness. Of the patients who responded to flumazenil, 75% responded to a
total dose of 1 mg to 3 mg.
Reversal of sedation was associated with an increased
frequency of symptoms of CNS excitation. Of the patients treated with
flumazenil, 1% to 3% were treated for agitation or anxiety. Serious side
effects were uncommon, but six seizures were observed in 446 patients treated
with flumazenil in these studies. Four of these 6 patients had ingested a large
dose of cyclic antidepressants, which increased the risk of seizures (see WARNINGS).
Individualization Of Dosage
The serious adverse effects of flumazenil are related to
the reversal of benzodiazepine effects. Using more than the minimally effective
dose of flumazenil is tolerated by most patients but may complicate the management
of patients who are physically dependent on benzodiazepines or patients who are
depending on benzodiazepines for therapeutic effect (such as suppression of
seizures in cyclic antidepressant overdose).
In high-risk patients, it is important to administer the
smallest amount of flumazenil that is effective. The 1-minute wait between
individual doses in the dose-titration recommended for general clinical populations
may be too short for high-risk patients. This is because it takes 6 to 10
minutes for any single dose of flumazenil to reach full effects. Practitioners
should slow the rate of administration of flumazenil administered to high-risk
patients as recommended below.
Anesthesia and Conscious Sedation In Adult Patients
Flumazenil is well tolerated at the recommended doses in
individuals who have no tolerance to (or dependence on) benzodiazepines. The
recommended doses and titration rates in anesthesia and conscious sedation (0.2
mg to 1 mg given at 0.2 mg/min) are well tolerated in patients receiving the
drug for reversal of a single benzodiazepine exposure in most clinical settings
(see ADVERSE REACTIONS). The major risk will be resedation
because the duration of effect of a long-acting (or large dose of a
short-acting) benzodiazepine may exceed that of flumazenil injection.
Resedation may be treated by giving a repeat dose at no less than 20-minute
intervals. For repeat treatment, no more than 1 mg (at 0.2 mg/min doses) should
be given at any one time and no more than 3 mg should be given in any one hour.
Benzodiazepine Overdose In Adult Patients
The risk of confusion, agitation, emotional lability, and
perceptual distortion with the doses recommended in patients with
benzodiazepine overdose (3 mg to 5 mg administered as 0.5 mg/min) may be greater
than that expected with lower doses and slower administration. The recommended
doses represent a compromise between a desirable slow awakening and the need
for prompt response and a persistent effect in the overdose situation. If
circumstances permit, the physician may elect to use the 0.2 mg/minute
titration rate to slowly awaken the patient over 5 to 10 minutes, which may
help to reduce signs and symptoms on emergence.
Flumazenil has no effect in cases where benzodiazepines
are not responsible for sedation. Once doses of 3 mg to 5 mg have been reached
without clinical response, additional flumazenil is likely to have no effect.
Patients Tolerant To Benzodiazepines
Flumazenil may cause benzodiazepine withdrawal symptoms
in individuals who have been taking benzodiazepines long enough to have some
degree of tolerance. Patients who had been taking benzodiazepines prior to
entry into the flumazenil trials, who were given flumazenil in doses over 1 mg,
experienced withdrawal-like events 2 to 5 times more frequently than patients
who received less than 1 mg.
In patients who may have tolerance to benzodiazepines, as
indicated by clinical history or by the need for larger than usual doses of
benzodiazepines, slower titration rates of 0.1 mg/min and lower total doses may
help reduce the frequency of emergent confusion and agitation. In such cases,
special care must be taken to monitor the patients for resedation because of
the lower doses of flumazenil used.
Patients Physically Dependent On Benzodiazepines
Flumazenil is known to precipitate withdrawal seizures in
patients who are physically dependent on benzodiazepines, even if such
dependence was established in a relatively few days of high-dose sedation in
Intensive Care Unit (ICU) environments. The risk of either seizures or
resedation in such cases is high and patients have experienced seizures before
regaining consciousness. Flumazenil should be used in such settings with
extreme caution, since the use of flumazenil in this situation has not been
studied and no information as to dose and rate of titration is available.
Flumazenil should be used in such patients only if the potential benefits of
using the drug outweigh the risks of precipitated seizures. Physicians are
directed to the scientific literature for the most current information in this