Dosage / Administration
Flumazenil is a competitive benzodiazepine receptor antagonist with a well-established role as an antidote for benzodiazepine overdose and reversal of benzodiazepine procedural sedation or general anesthesia. Flumazenil is available as an injectable solution (5 or 10 mL ampoule): 0.1 mg/mL.

Administer in a large, freely running vein to minimize local pain at the injection site. Prepare for possible resedation 20-120 minutes after flumazenil administration.

Flumazenil is compatible with Lactated Ringer's solution, normal saline, and 5% dextrose in water.

Dosing for adults: Treatment of benzodiazepine overdose: 0.2 mg intravenous (IV) over 30 seconds; if the patient does not reach the desired level of consciousness, 0.3 mg can be administered over 30 seconds; if the patient still does not reach the desired level of consciousness, 0.5 mg can be given over 30 seconds and repeated at 1-minute intervals until cumulative dosage reaches 3 mg.

If the adult patient does not respond after reaching the maximum cumulative dosage, another major cause of sedation must be considered, such as mixed ingestion of another sedative agent.

Reversal of procedural sedation or general anesthesia with benzodiazepines: 0.2 mg IV over 30 seconds; if the patient does not reach the desired level of consciousness after 1 minute, 0.2 mg can be given up to 4 times until reaching the maximum cumulative dosage of 1 mg.

If the adult patient develops resedation, repeat 0.2 mg IV over 1 minute every 20 minutes until reaching the maximum cumulative resedation dosage of 3 mg in 1 hour.

• Kidney impairment, adult patient – No dosage adjustment necessary.
• Hepatic impairment, adult patient – No dosage adjustment necessary.

Dosing for children: Reversal of procedural sedation or general anesthesia with benzodiazepines: initial dose of 0.01 mg/kg (maximum of 0.2 mg) given over 15 seconds; if the patient does not reach the desired level of consciousness in 45 seconds, repeat 0.01 mg/kg and then every 1 minute until reaching the maximum cumulative dosage of 0.05 mg/kg or 1 mg total, whichever is lower.

Benzodiazepine overdose: initial dose 0.01 mg/kg (maximum of 0.2 mg); may repeat 0.01 mg/kg (maximum of 0.2 mg) every minute until reaching the maximum cumulative dosage of 1 mg.

Indications

• Onset of action: 1-2 minutes.
• Peak effect: 6-10 minutes.
• Pregnancy and lactation: Category C (per the US Food and Drug Administration [FDA]).

Pediatric population:

• Younger than 1 year – Safety and efficacy not established for this population.
• Older than 1 year – The risks identified in the adult population with flumazenil use also apply to pediatric patients.

Contraindications

• Patients with a known hypersensitivity to flumazenil or benzodiazepines.
• Patients who have been given a benzodiazepine for the treatment of a potentially life-threatening condition (ie, status epilepticus or increased intracranial pressure).
• Patients with signs of serious cyclic antidepressant overdose.
• Other contraindications to flumazenil use include:
  
  • History of seizures.
  • ECG demonstrating possible cyclic antidepressant use, such as QRS or QT interval prolongation, or terminal rightward 40-ms axis.
  • Ingestion of xenobiotic capable of triggering seizures or dysrhythmias.
  • Hypoxia and/or hypotension.
  • Head trauma.
  • Long-term use of benzodiazepines (see benzodiazepine use disorder).

Monitoring
No specific laboratory tests are recommended to follow the patient's response or to identify possible adverse reactions.

Adverse Effects

• Known adverse effects include seizures in benzodiazepine-dependent patients, dysrhythmias after coingestion of a benzodiazepine plus a prodysrhythmic xenobiotic, and resedation after 20-120 minutes of flumazenil administration.
• Hypoxia and hypotension should be addressed and corrected before flumazenil administration.
• Small titrated doses are recommended.
• Flumazenil should not be used in patients with a history of seizures or evidence of seizures.
• Flumazenil should not be used in patients with chronic benzodiazepine use.
• Flumazenil is not consistent in reversing respiratory depression caused by benzodiazepine administration, and it is not the initial intervention in those cases.

Adverse events (in clinical studies):

• The most frequently associated with flumazenil alone (3%-9%) were:
  • Dizziness, injection site pain, increased sweating, headache, and abnormal or blurred vision.
• Frequency of the following reactions is (1%-3%), unless marked otherwise.
  • Body as a whole – fatigue (asthenia, malaise), headache, injection site reaction (thrombophlebitis, skin abnormality, rash).
  • Cardiovascular – cutaneous vasodilation (sweating, flushing, hot flashes).
  • Digestive – nausea, vomiting (11%).
  • Nervous system – agitation (anxiety, nervousness, dry mouth, tremor, palpitations, insomnia, dyspnea, hyperventilation) (3%-9%), dizziness (vertigo, ataxia) (10%), emotional lability (crying abnormal, depersonalization, euphoria, increased tears, depression, dysphoria, paranoia).
• Frequency of the following reactions is less than 1%:
  • Body as a whole – rigors, shivering.
  • Cardiovascular – arrhythmia (atrial, nodal, ventricular extrasystoles), bradycardia, tachycardia, hypertension, chest pain.
  • Nervous system – confusion (difficulty concentrating, delirium), convulsions, somnolence (stupor), speech disorder (dysphonia, thick tongue).
  • Senses – abnormal hearing (transient hearing impairment, hyperacusis, tinnitus).
  • Digestive – hiccups.
• Reactions reported during postapproval use of flumazenil:
  • Nervous system – Fear, panic attacks in patients with a history of panic disorders.
  • Withdrawal symptoms may occur following rapid injection of flumazenil in patients with long-term exposure to benzodiazepines.

Toxicity
Flumazenil has some associations with the precipitation of seizures in patients with benzodiazepine dependency with a history of seizures. However, flumazenil overdose is extremely rare.

Clinical features:

• Anxiety
• Agitation
• Increased muscle tone
• Hyperesthesia
• Seizures

Management:

• There is no precise antidote for flumazenil toxicity.
• In mild-to-severe toxicity, symptomatic and supportive treatment should be a consideration.
• An overdose of flumazenil in a patient who is not a chronic benzodiazepine user would not be expected. Chronic benzodiazepine users experience withdrawal with abrupt discontinuation of the drug.

Consult criteria:

• Contact a medical toxicologist or local poison control center for any patient with suspected severe adverse effects after receiving flumazenil, such as seizures, dysrhythmias, and hypotension.
• It is important to note that seizures after flumazenil administration are significantly associated with exposure to a proconvulsant drug.

Mechanism of Action
The benzodiazepine receptor modulates the activity of GABA on the GABA_A receptors by increasing the frequency of chloride (Cl-) channel opening, leading to neuronal hyperpolarization. Agonists of such receptors, such as diazepam, will produce anxiolytic, anticonvulsant, amnestic, sedative-hypnotic, and muscle relaxant effects.

Flumazenil is a benzodiazepine analog that acts as a competitive antagonist at the α1 subtype of GABA_A receptors, resulting in the opposite effects described above. Also, by occupying the benzodiazepine receptor, flumazenil does not allow access to agonist molecules such as diazepam.

Metabolism: Flumazenil is almost completely (99%) metabolized. Very little unchanged flumazenil (< 1%) is found in the urine.

Elimination: About 90%-95% of the drug appears in the urine and 5%-10% in the feces. The clearance of flumazenil occurs primarily by hepatic metabolism and is dependent of hepatic blood flow.