Flumazenil

Anexate®

Antidote

Pediatric

Flumazenil

Anexate®

ALERT: The use of flumazenil as a reversal agent for intentional benzodiazepine overdose is not routinely recommended due to risk of refractory seizures.

Indications

Reversal of sedation due to benzodiazepines used in diagnostic or therapeutic procedures.
Management/diagnosis of a pure benzodiazepine overdose causing clinically significant CNS or respiratory depression meeting the following criteria: no history of seizure disorder, no chronic use of benzodiazepines, and no coingestion of a toxin that can cause seizures or cardiac dysrhythmias.
Management of clinically significant CNS depression caused by overdose of zolpidem, zaleplon, or zopiclone.

Dosage

Minimal pediatric information available. The following data is based on published case reports.

Initial dose: (IV or intranasal)
0.01 mg/kg (up to maximum of 0.2 mg) over 15 seconds. If adequate sedation reversal does not occur after an additional 45 seconds, further injections of 0.01 mg/kg ( up to maximum 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.
If resedation occurs:
Consider IV infusion of 0.1 mg -1 mg/hour. Titrate to effect.

Administration

IV Direct: Administer undiluted over 15- 30 seconds via freely running infusion into larger vein to reduce phlebitis and pain. Maximum rate in children: 0.2 mg/minute. Cardiac and Respiratory monitoring is required.
Infusion: For a final concentration of 0.04 mg/mL: Add 1 mg (10 mL of 0.1 mg/mL solution) to 15 mL of sodium chloride 0.9% or dextrose 5% in water. Cardiac and Respiratory monitoring is required.

Compatibility, Stability

Compatible with sodium chloride 0.9%, dextrose 5% in water or lactated ringer’s.
Stable for 24 hours at room temperature when diluted in sodium chloride 0.9%, dextrose 5% in water or lactated ringers.

Potential Hazards of Administration

Central benzodiazepine effects may recur due to short duration of action. Closely monitor patient. Repeat doses may be required.
Nausea, vomiting, flushing.
Hypertension and tachycardia (transient)
May cause agitation and anxiety.
May precipitate benzodiazepine withdrawal reactions (anxiety, tachycardia, diaphoresis, seizures) in patients on long-term benzodiazepine therapy.
Pain at injection site.

Miscellaneous

The use of flumazenil should be avoided in tricyclic antidepressant, chloral hydrate, carbamazepine and multiple drug overdose as it has been associated with life-threatening complications such as seizure and arrhythmia.
As flumazenil has a short duration of action (half-life is approximately 1 hour) patients should be monitored for recurrence of sedation for up to 3 - 4 hours after flumazenil injection.
Although flumazenil can reverse benzodiazepine-induced sedation it has variable effects on benzodiazepine-induced respiratory depression.

References…

Bailey, B., Blais, R., Gaudreault, P., Gosselin, S., & Laliberte, M. (2009). Antidotes en toxicologie d'urgence (3rd ed.). Quebec, Canada: Centre antipoison du Quebec.

Goldfrank, L. R., Nelson, L. S., Lewin, N. A., Howland, M. A., Hoffman, R. S., (2015). Goldfrank's toxicologic emergencies(Tenth ed.). New York: McGraw Hill.

Gunja, N. (2013). Review article: The clinical and forensic toxicology of Z-drugs. Journal of Medical Toxicology, 9, 155-162.

Kreshak, A. A., Tomaszewski, C. A., Clark, R. F., & Cantrell, F. L. (2012). Flumazenil administration in poisoned pediatric patients. Pediatric Emergency Care, 28, 448-450.

Micromedex, T. H. A. (2014). Micromedex health care systems. Retrieved from http://www.micromedexsolutions.com

Olson, K. R. (2007). Poisoning & drug overdose (Sixth ed.). New York: McGraw Hill.

Phelps SJ, C. C. (2013). Teddy bear, pediatric injectable drugs. Retrieved from http://www.pharmpress.com/product/MC_PED/pediatric-injectable-drugs

Shannon, M. W., Borron, S. W., & Burns, M. J. (2007). Haddad and Winchester's clinical management of poisoning and drug overdose (Fourth ed.). Philadelphia: Saunders Elsevier.

Thornton, S. L., Negus, E., & Carstairs, S. D. (2013). Pediatric zolpidem ingestion demonstrating zero-order kinetics treated with flumazenil. Pediatric Emergency Care, 29, 1204-1206.

Trissel, Lawrence, A,. (2013). Handbook on injectable drugs (17th ed.). Bethesda, Maryland: American Society of Health-System Pharmacists

Veiraiah, A., Dyas, J., Cooper, G., Routledge, P. A., & Thompson, J. P. (2012). Flumazenil use in benzodiazepine overdose in the UK: A restrospective survey of NPIS data. Emergency Medicine Journal, 29, 565-569.