The use of flumazenil has been associated with the occurrence of seizures. These are most frequent in patients who have been on benzodiazepines for long-term sedation or in overdose cases where patients are showing signs of serious cyclic antidepressant overdose. Practitioners should individualize the dosage of flumazenil and be prepared to manage seizures.
Benzodiazepine reversal, procedural sedation or general anesthesia:
IV: Initial: 0.2 mg over 2 minutes; if the desired level of consciousness is not obtained after 1 minute, 0.2 mg may be repeated at 1-minute intervals up to 4 times; usual cumulative dosage range: 0.6 to 1 mg; maximum cumulative dose: 1 mg (Howland 2019; manufacturer's labeling).
Resedation: IV: In the event of resedation, repeat 0.2 to 1 mg doses (administered at 0.1 mg/minute) may be administered at 20-minute intervals as needed; maximum cumulative resedation dose: 3 mg in 1 hour (Howland 2019; manufacturer's labeling).
Benzodiazepine overdose, treatment: Note: Routine use of flumazenil is controversial, as most benzodiazepine-poisoned patients can be treated successfully with supportive measures alone, and use of flumazenil is associated with a risk of adverse effects (eg, withdrawal seizures, arrhythmias), especially in patients who have co-ingested a proconvulsant or proarrhythmic agent, patients that are physiologically dependent on benzodiazepines, or patients with an underlying seizure disorder (Höjer 1988; Howland 2019; Penninga 2016; Schult 2021). Consider consultation with poison control center or medical toxicologist; refer to institutional protocols.
IV: Initial: 0.2 mg over 2 minutes; if the desired level of consciousness is not obtained 30 seconds after the dose, 0.3 mg can be administered over 3 minutes; if the desired level of consciousness is still not obtained, 0.5 mg can be administered over 5 minutes and repeated at 1-minute intervals; usual cumulative dosage range: 1 to 3 mg; usual cumulative maximum dose: 3 mg (Howland 2019; manufacturer's labeling).
Note: Patients with a partial response to a cumulative dose of 3 mg may rarely require additional titration up to a total dose of 5 mg (although doses >3 mg do not reliably produce additional effects). If a patient has not responded 5 minutes after a cumulative dose of 5 mg, benzodiazepines are likely not the major cause of sedation; sedation may be due to exposure to additional CNS depressants (eg, opioids).
Resedation: IV: In the event of resedation, repeat 0.5 to 1 mg doses (administered at 0.1 mg/minute) may be administered at 20-minute intervals as needed; maximum cumulative resedation dose: 3 mg in 1 hour (Howland 2019; manufacturer's labeling).
Note: After an overdose with high doses of benzodiazepines, the duration of a single dose of flumazenil is not expected to exceed 1 hour; if clinically necessary, the period of wakefulness may be prolonged with repeated low IV doses of flumazenil, or by an infusion of 0.1 to 1 mg/hour (off label) (Höjer 1991; Maxa 2003; Weinbroum 1996).
Nonbenzodiazepine hypnotic overdose or gabapentin overdose, treatment (off-label use): Note: May consider during the treatment of patients who are experiencing toxicity secondary to a nonbenzodiazepine hypnotic agent (eg, eszopiclone, zaleplon, zolpidem, zopiclone) or gabapentin (Butler 2003; Cienki 2005; Höjer 2002; Lheureux 1990; Patat 1994). Limited data available; dose based on use in benzodiazepine overdose.
IV: Initial: 0.2 mg over 2 minutes; if the desired level of consciousness is not obtained 30 seconds after the dose, 0.3 mg can be administered over 3 minutes; if the desired level of consciousness is still not obtained, 0.5 mg can be administered over 5 minutes and repeated at 1-minute intervals; usual cumulative dosage range: 1 to 3 mg; usual maximum cumulative dose: 3 mg (Howland 2019; manufacturer's labeling).
Note: Based on use in benzodiazepine overdose, patients with a partial response to a cumulative dose of 3 mg may rarely require additional titration up to a total dose of 5 mg (although doses >3 mg do not reliably produce additional effects). If a patient has not responded 5 minutes after a cumulative dose of 5 mg, the major cause of sedation may be due to exposure to additional CNS depressants (eg, opioids).
Resedation: IV: In the event of resedation, repeat 0.5 to 1 mg doses (administered at 0.1 mg/minute) may be administered at 20-minute intervals if needed; maximum cumulative resedation dose: 3 mg in 1 hour (Howland 2019; manufacturer's labeling).
Note: Due to the short duration of sedation of nonbenzodiazepine hypnotics, a continuous infusion is probably unnecessary in patients intoxicated with these agents (Gunja 2013).
No dosage adjustment provided in manufacturer's labeling; however, pharmacokinetics are not significantly affected by renal failure (CrCl <10 mL/minute) or hemodialysis.
Initial reversal: No dosage adjustment necessary. Repeat doses: Reduce dose or frequency.
(For additional information see "Flumazenil: Pediatric drug information")
Benzodiazepine reversal when used in conscious sedation or general anesthesia: Infants, Children, and Adolescents: IV: Initial dose: 0.01 mg/kg (maximum dose: 0.2 mg) given over 15 seconds; may repeat 0.01 mg/kg (maximum dose: 0.2 mg) after 45 seconds, and then every minute to a maximum total cumulative dose of 0.05 mg/kg or 1 mg, whichever is lower; usual total dose: 0.08 to 1 mg (mean: 0.65 mg)
Suspected benzodiazepine overdose: Limited data available: Infants, Children, and Adolescents: Initial dose: 0.01 mg/kg (maximum dose: 0.2 mg) with repeat doses of 0.01 mg/kg (maximum dose: 0.2 mg) given every minute to a maximum total cumulative dose of 1 mg; as an alternative to repeat bolus doses, follow up continuous infusions of 0.005-0.01 mg/kg/hour have been used (Clark 1995; Richard 1991; Roald 1989; Sugarman 1994)
There are no dosage adjustments provided in the manufacturer’s labeling; adult pharmacokinetic data suggests drug not significantly affected by renal failure (CrCl <10 mL/minute) or hemodialysis.
Initial reversal dose: Use normal dose; repeat doses should be decreased in size or frequency
Refer to adult dosing. No differences in safety or efficacy have been reported; however, increased sensitivity may occur in some elderly patients.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous:
Generic: 0.5 mg/5 mL (5 mL); 1 mg/10 mL (10 mL)
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Solution, Intravenous:
Generic: 0.1 mg/mL (5 mL)
IV: Administer in freely running IV into large vein to minimize pain at the injection site. To decrease frequency of emergent confusion and agitation, administer at a rate of 0.1 mg/minute, especially with larger doses. May also administer at a rate of 0.2 mg/minute or as fast as 0.2 mg over 15 seconds; however, there may be an increase in adverse effects (An 2016; Howland 2019; manufacturer's labeling).
Parenteral: For IV use only; administer by rapid IV injection over 15-30 seconds via a freely running IV infusion into larger vein (to decrease chance of pain, phlebitis). Children: Do not exceed 0.2 mg/minute. In adults for repeat doses, the following is suggested: Do not exceed 0.2 mg/minute for reversal of general anesthesia and do not exceed 0.5 mg/minute for reversal of benzodiazepine overdose.
Benzodiazepine reversal, procedural sedation or general anesthesia: Complete or partial reversal of the sedative effects of benzodiazepines used in procedural sedation and general anesthesia.
Benzodiazepine overdose, treatment: Treatment of benzodiazepine overdose.
Nonbenzodiazepine hypnotic overdose or gabapentin overdose, treatment
Flumazenil may be confused with influenza virus vaccine
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%: Gastrointestinal: Vomiting (11%)
1% to 10%:
Cardiovascular: Palpitation (3% to 9%), flushing (1% to 3%), thrombophlebitis (1% to 3%), vasodilation (1% to 3%)
Central nervous system: Ataxia (10%), dizziness (10%), vertigo (10%), agitation (3% to 9%), anxiety (3% to 9%), insomnia (3% to 9%), nervousness (3% to 9%), depersonalization (1% to 3%), depression (1% to 3%), dysphoria (1% to 3%), emotional lability (1% to 3%; including crying), euphoria (1% to 3%), fatigue (1% to 3%), headache (1% to 3%), hypoesthesia (1% to 3%), malaise (1% to 3%), paranoia (1% to 3%), paresthesia (1% to 3%)
Dermatologic: Dermatological disease (skin abnormality: 1% to 3%), diaphoresis (1% to 3%), skin rash (1% to 3%)
Endocrine & metabolic: Hot flash (1% to 3%)
Gastrointestinal: Xerostomia (3% to 9%), nausea (1% to 3%)
Local: Pain at injection site (3% to 9%), injection site reaction (1% to 3%)
Neuromuscular & skeletal: Weakness (1% to 3%), tremor
Ophthalmic: Blurred vision (3% to 9%), lacrimation (1% to 3%), visual disturbance (1% to 3%)
Respiratory: Dyspnea (3% to 9%), hyperventilation (3% to 9%)
<1%, postmarketing, and/or case reports: Atrial tachycardia (paroxysmal), auditory disturbance, bradycardia, cardiac arrhythmia, chest pain, confusion, decreased blood pressure, delirium, drowsiness, fear, hiccups, hyperacusis, hypertension, increased blood pressure, lack of concentration, panic attack, reversible hearing loss, rigors, seizure (including generalized), sensation of cold, shivering, stupor, tachycardia, tinnitus, tongue edema, ventricular tachycardia, voice disorder, withdrawal syndrome
Hypersensitivity to flumazenil, benzodiazepines, or any component of the formulation; patients administered benzodiazepines for control of potentially life-threatening conditions (eg, control of intracranial pressure or status epilepticus); patients who may have ingested or are showing signs of cyclic-antidepressant overdosage.
Concerns related to adverse effects:
• Amnesia: Does not consistently reverse amnesia; patient may not recall verbal instructions after procedure.
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving) for 24 hours after discharge.
• Resedation: Occurs more frequently in patients where a large single dose or cumulative dose of a benzodiazepine has been administered along with a neuromuscular-blocking agent and multiple anesthetic agents.
• Respiratory depression: Should not rely upon to reverse respiratory depression/hypoventilation. Flumazenil is not a substitute for evaluation of oxygenation. Establishing an airway and assisting ventilation, as necessary, is always the initial step in overdose management.
• Seizures: [US Boxed Warning]: Benzodiazepine reversal may result in seizures; seizures may occur more frequently in patients on benzodiazepines for long-term sedation or following tricyclic antidepressant overdose. Dose should be individualized and practitioners should be prepared to manage seizures. Seizures may also develop in patients with concurrent major sedative-hypnotic drug withdrawal, recent therapy with repeated doses of parenteral benzodiazepines, myoclonic jerking or seizure activity prior to flumazenil administration. Use with caution in patients relying on a benzodiazepine for seizure control.
Disease-related concerns:
• Head injury: Use with caution in patients with a head injury; may alter cerebral blood flow or precipitate convulsions in patients receiving benzodiazepines.
• Hepatic impairment: Use with caution in patients with hepatic dysfunction; repeated doses of the drug should be reduced in frequency or amount.
• Panic disorder: Use with caution in patients with a history of panic disorder; may provoke panic attacks.
Special populations:
• Drug/alcohol dependence: Use caution in drug and ethanol-dependent patients; these patients may also be dependent on benzodiazepines.
• Intensive care patients: Should be used with caution in the intensive care unit because of increased risk of unrecognized benzodiazepine dependence in such settings.
Other warnings/precautions:
• Appropriate use: Should not be used to diagnose benzodiazepine-induced sedation. Reverse neuromuscular blockade before considering use. Flumazenil does not antagonize the CNS effects of other GABA agonists (such as ethanol, barbiturates, or general anesthetics); nor does it reverse opioids. Not recommended for treatment of benzodiazepine dependence.
• Overdose use: Use with caution in patients with mixed drug overdoses; toxic effects of other drugs taken may emerge once benzodiazepine effects are reversed.
Pediatric patients (especially 1 to 5 years of age) may experience resedation; these patients may require repeat bolus doses or continuous infusion.
None known.
There are no known significant interactions.
Teratogenic effects were not seen in animal reproduction studies. Embryocidal effects were seen at large doses. Use during labor and delivery is not recommended. In general, medications used as antidotes should take into consideration the health and prognosis of the mother; antidotes should be administered to pregnant women if there is a clear indication for use and should not be withheld because of fears of teratogenicity (Bailey 2003).
It is not known if flumazenil is excreted in breast milk. The manufacturer recommends that caution be used if administering to breast-feeding women.
Avoid alcohol for the first 24 hours after administration or as long as the effects of benzodiazepines exist.
Monitor for return of sedation, respiratory depression, benzodiazepine withdrawal, seizures, and other residual effects of benzodiazepines for at least 2 hours and until the patient is stable and resedation is unlikely.
Competitively inhibits the activity at the benzodiazepine receptor site on the GABA/benzodiazepine receptor complex. Flumazenil does not antagonize the CNS effect of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (ethanol, barbiturates, general anesthetics) and does not reverse the effects of opioids
Note: Follows a 2 compartment open model; Clearance and Vd per kg are similar for children and adults, but children display more variability.
Onset of action: 1 to 2 minutes; 80% response within 3 minutes.
Peak effect: 6 to 10 minutes.
Duration: Resedation may occur after ~1 hour (range: 19-50 minutes); duration related to dose administered and benzodiazepine plasma concentrations; reversal effects of flumazenil may wear off before effects of benzodiazepine.
Distribution: Initial Vd: 0.5 L/kg; Vdss: 0.9-1.1 L/kg.
Protein binding: ~50% (~67% of which is bound to albumin).
Metabolism: Hepatic; dependent upon hepatic blood flow.
Half-life elimination:
Children: Terminal: 20 to 75 minutes (mean: 40 minutes).
Adults: Alpha: 4 to 11 minutes; Terminal: 40 to 80 minutes.
Moderate hepatic dysfunction: 1.3 hours.
Severe hepatic impairment: 2.4 hours.
Excretion: Feces; urine (<1% as unchanged drug).
Clearance: Dependent upon hepatic blood flow; Adults: 0.8 to 1 L/hour/kg.
Hepatic function impairment: Moderate: Mean total clearance decreased 40% to 60%. Severe: Mean total clearance decreased 75%.
Solution (Flumazenil Intravenous)
0.5 mg/5 mL (per mL): $1.56 - $1.78
1 mg/10 mL (per mL): $1.56 - $8.20
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