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Benzodiazepine Overdose Benzodiazepines are sedative-hypnotic drugs that cause central nervous system and respiratory depression. Intoxications with benzodiazepines are generally well-tolerated but can cause prolonged coma. Overall the complication rate with benzodiazepine overdose is low1. Most patients requiring intubation after benzodiazepine overdose have ingested multiple sedating substances. However, some patients with large benzodiazepine ingestions may benefit from flumazenil administration to avoid intubation. In 2019, there were 58,430 total benzodiazepine exposures reported to US poison centers. Of those involving only benzodiazepines, 731 (1.25 %) patients experienced a major outcome and 11 (0.01 %) died.2 Flumazenil Flumazenil is a benzodiazepine receptor antagonist FDA approved in 1992 for reversal of benzodiazepine overdose and postoperative sedation from benzodiazepine anesthetics. Flumazenil is a 1,4-benzodiazepine derivative that has a high affinity for the benzodiazepine binding site on the GABA receptor. It is a competitive antagonist at these receptors and reverses the effects of benzodiazepines. Reversal effects are typically seen within 1-2 minutes with a peak effect at 6-10 minutes3. Wakefulness may be transient and re-sedation can be observed due to its short clinical effect, however, this may be mitigated with the use of a continuous infusion. Safety Considerations The package insert of flumazenil contains a black box warning stating that the drug is associated with the occurrence of seizures, and states that providers should individualize the dosage and be prepared to manage seizures. Patients who may be at risk for seizures are those who have also ingested a proconvulsant medication (i.e. tricyclic antidepressants, bupropion, etc.), those with benzodiazepine dependence, and those who have a benzodiazepine prescribed for seizure disorder. Retrospective reviews conducted through the California Poison Control System from 1998 – 2008 looking at both pediatric and adult patients evaluated the safety of flumazenil use in benzodiazepine ingestions4,5. Of the observed adult patients, 13 patients (1.4%) experienced seizures and 32% of patients were also exposed to a proconvulsant. In their review of pediatric patients, only 1 patient was reported to have a seizure, and the medical toxicologist consulted on the case determined that the seizure was unrelated to the administration of flumazenil. Although poison centers have an abundant database of toxicologic cases, reporting to poison centers is voluntary and does not capture all cases of overdoses and toxicity. In a review of 43 cases of flumazenil-related seizures reported to FDA, 42% occurred in patients who had also ingested tricyclic antidepressants6. An urban ED at a tertiary level I trauma center conducted a retrospective observational review of patients from 2007 to 2013 who were administered flumazenil for known or suspected benzodiazepine overdose7. A total of 49 patients were included in their study, and about 30% reported a co-ingestion of a proconvulsant medication. Patients were treated with doses of flumazenil ranging from 0.1-0.4 mg. No patients experienced seizures. In a retrospective review of ICU patients, 35 patients presenting with coma treated with flumazenil were sorted into low and high-risk groups8. The low-risk group were uncomplicated benzodiazepine exposures while the high-risk group included those with long-term benzodiazepine use, seizures, and antidepressant ingestion. In the high-risk group, 16% of patients had a seizure following flumazenil administration. Dosing & Goals of Therapy Guidance for the use of flumazenil can be taken from the literature. This includes avoiding administration of the drug in patients with co-ingestion of a proconvulsant medication, such as tricyclic antidepressants, cocaine, methylxanthines, isoniazid, propoxyphene, monoamine oxidase inhibitors, and bupropion or in patients with signs of a concurrent stimulant toxicity including hyperreflexia, mydriasis, and tachycardia. Adults: 0.2 mg IV over 15 seconds, may be repeated every 1 to 2 minutes until the patient is arousable and protecting their airway. Children: 0.01 mg/kg (maximum 0.2 mg), may be repeated if no response in 2-3 minutes, total dose not to exceed 1 mg or 0.05 mg/kg. If seizures were to occur following the administration of flumazenil, understand that benzodiazepines will not work to abort seizures. Be prepared to utilize other agents such as phenobarbital. Patients may require intubation and sedation with propofol. Conclusion Common teaching is to avoid flumazenil in benzodiazepine ingestions because the risks significantly outweigh the benefits. However, in the literature, there have been minimal reports of seizures, and risk factors have been identified, primarily co-ingestion of a proconvulsant medication. Flumazenil should be considered in pediatric ingestions with respiratory insufficiency and acute adult overdose with respiratory insufficiency if no other proconvulsant medications are co-ingested. References: Authors: Katie Dwyer, PharmD, PGY2 Emergency Medicine Pharmacy Resident, University of Utah & Michael Moss, MD, Medical Director, Utah Poison Control Center AdultPediatric Dosage Forms & Strengthsinjectable solution0.2 mg IV over 15 sec IF after 45 sec no response, administer 0.2 mg again over 1 min; may repeat at 1 min intervals; not to exceed 4 doses (1 mg) IF resedation occurs, may repeat doses at 20-min intervals; not to exceed 1 mg/dose or 3 mg/hr Benzodiazepine Overdose0.2 mg IV over 15-30 sec IF no response after 30 sec, administer 0.3 mg over 30 sec 1 min later; IF no response, repeat dose of 0.5 mg IV over 30 sec at 1-min intervals to max cumulative dose of 3 mg/hr In the event of resedation, may repeat dose at 20-min intervals if needed; not to exceed 1 mg (administered as 0.5 mg/min) administered at any one time and no more than 3 mg/hr Rarely patient may require titration up to total dose 5 mg; IF no response after 5 min, sedation unlikely to be secondary to benzodiazepines Dosing ConsiderationsSlow infusion of lowest dose required to decrease adverse effects Dosing ModificationsRenal impairment: Not studied Hepatic impairment: Initial dose adjustment not necessary; reduce dose or frequency of subsequent doses Dosage Forms & Strengthsinjectable solutionInitial dose: 0.01 mg/kg IV x1 dose over 15 sec May repeat after 45 sec and then every minute; not to exceed 4 doses for a maximum 0.05 mg/kg or 1 mg, whichever is lower
 No Interactions Found Interactions Found ContraindicatedSerious - Use AlternativeSignificant - Monitor CloselyMinorAll Interactions Sort By: SeverityName Contraindicated (0)Serious - Use Alternative (0)Monitor Closely (1)
Minor (0)
Nausea and vomiting (11%) 1-10%Dizziness (10%) Abnormal/blurred vision (3-9%) Agitation (3-9%) Dyspnea (3-9%) Hyperventilation (3-9%) Pain at injection site (3-9%) Xerostomia (3-9%) Diaphoresis (1-3%) Emotional lability (1-3%) Fatigue (1-3%) Headache (1-3%) Paresthesia (1-3%) Tremor (1-3%) Weakness (1-3%) <1%<> Delirium Abnormal hearing Junctional tachycardia Thick tongue Tinnitus Coldness sensation Generalized seizure
Hypersensitivity to flumazenil or benzodiazepines Possible concomitant: Cyclic antidepressant overdose Chronic benzodiazepine user; patients receiving a benzodiazepine for life-threatening condition (eg, intracranial pressure control, status epilepticus) CautionsHead trauma History of seizures Chronic alcoholism Not for reversal of respiratory depression (need to establish an airway, assist ventilation, and continue to observe patient)-monitor for return of respiratory depression/sedation May not reverse amnesia May cause CNS depression and impair ability to perform hazardous tasks Resedation occurs frequently in patients who have received a large single dose or cumulative dose of a benzodiazepine administered along with a neuromuscular blocker and multiple anesthetic agents Agitation produced in some patients Patients rarely seize with 0.2 mg dose If seizure after flumazenil, recommend valium 20-30 mg, then immediately to barbiturates Use caution in patients with head injury Use caution in patients with hepatic dysfunction Use caution in patients with panic disorder Unmasking of seizures, precipitation of benzodiazepine withdrawal Not for diagnosis of benzodiazepine-induced sedation
Pregnancy category: C Lactation: Excretion in milk unknown; use with caution Pregnancy CategoriesA: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk. B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.
Competitive benzodiazepine receptor antagonist; inhibits activity at the benzodiazepine receptor site on the GABA/benzodiazepine receptor complex; does not reverse the effect of opioids AbsorptionOnset of action: 1-2 min; 80% response within 3 min Peak effect: 6-10 min DistributionProtein bound: 40-50% Vd: 0.5 L/kg EliminationHalf-life: 53 min Excretion: Feces, urine First order elimination
Over 15-30 sec To minimize pain, administer through a freely running IV infusion line into a large vein Avoid extravasation
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NO MONOGRAPH AVAILABLE AT THIS TIME USES: Consult your pharmacist. HOW TO USE: Consult your pharmacist. SIDE EFFECTS: Consult your pharmacist.In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345. PRECAUTIONS: Consult your pharmacist. DRUG INTERACTIONS: Consult your pharmacist.Keep a list of all your medications with you, and share the list with your doctor and pharmacist. OVERDOSE: If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center. NOTES: No monograph available at this time. MISSED DOSE: Consult your pharmacist. STORAGE: Consult your pharmacist.Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product. Information last revised July 2016. Copyright(c) 2022 First Databank, Inc. IMPORTANT: HOW TO USE THIS INFORMATION: This is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate for you. This information is not individual medical advice and does not substitute for the advice of your health care professional. Always ask your health care professional for complete information about this product and your specific health needs. FormularyPatient Discounts Adding plans allows you to compare formulary status to other drugs in the same class. To view formulary information first create a list of plans. Your list will be saved and can be edited at any time. Adding plans allows you to:
Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature. |
When should you administer flumazenil?
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