Flumazenil


Article Author:
Nazila Sharbaf Shoar


Article Editor:
Abdolreza Saadabadi


Editors In Chief:
Zina Clark
Barbara Simmons


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
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Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
12/24/2018 12:23:32 PM

Indications

Flumazenil is a benzodiazepine antagonist. [1][2]The primary FDA-approved clinical uses for flumazenil are:

Treatment of benzodiazepine overdose

  • Adult, Category B, Class IIa  
  • Pediatric, Category C, Class IIb 

Reversal of postoperative sedation from benzodiazepine anesthetics

  • Adult, Category B, Class IIa
  • Pediatric, Category B, Class IIa

Flumazenil injection is indicated for complete or partial reversal of the sedative effects of benzodiazepines in conscious sedation and general anesthesia in adult and pediatric populations. Flumazenil speeds the recovery from sedation following minor surgical procedures and shortened the post-operation monitoring period for minor surgery, and earlier discharge may be possible. Flumazenil is also indicated for management and treatment of benzodiazepine overdose in adults. It is useful in reversing coma due to benzodiazepine overdose. Flumazenil is more effective in reversing sedation or coma in patients with benzodiazepine intoxication rather than in patients with multiple drug overdoses.[3]

Non-FDA Approved:

  1. Alcohol withdrawal syndrome
  2. Drug action reversal, Baclofen
  3. Hepatic encephalopathy
  4. Stupor, Idiopathic, recurring
  5. Toxicity of drug, Cannabis

Flumazenil has not been approved by FDA for the above uses. Advantages and disadvantages of using this drug in the non-FDA approved conditions are based on the patient's condition and physicians judgment.

Mechanism of Action

Flumazenil is a benzodiazepine antagonist. Competitively inhibits the activity of benzodiazepine and non-benzodiazepine substances that interact with benzodiazepine receptors site on the GABA/benzodiazepine receptor complex. It can also reverse the binding of benzodiazepines to benzodiazepine receptors.

The onset of action is about 1 to 2 minutes; 80% response is seen within the first 3 minutes.

Peak effect is 6 to 10 minutes after administration.

Duration range is from 19 minutes to 50 minutes as it depends on the dose was given and benzodiazepine plasma concentrations.

Administration

Flumazenil is for intravenous (IV) infusion. The solution is stable for 24 hours if drawn into a syringe or mixed with solutions such as D5W, LR, or NS. Administer is done through a freely running IV infusion into a large vein or as a series of small injections.[4]

Dosing: Adult

FDA Dosage for management of benzodiazepine overdose

  • Initial dosage of 0.2 mg IV should be given ver 30 seconds 
  • If the desired level of consciousness is not obtained after 30 seconds, additional dose of 0.3 mg IV over 30 seconds can be given
  • May repeat doses of 0.5 mg IV over 30 seconds at 1-minute intervals to maximum total cumulative dose of 3 mg
  • Patients with partial response to 3 mg may require additional slow titration up to a total dose of 5 mg. if no response was noted after administration of 5 mg the major cause of sedation is not benzodiazepine-related and further treatment with flumazenil will be ineffective.
  • In reoccurrence sedations repeat doses may be given at 20-minute intervals, not to exceed 1 mg (0.5 mg/minute) per dose or 3 mg/hour

FDA Dosage for Benzodiazepine reversal when used in conscious sedation or general anesthesia

  • Initial dosage of 0.2 mg IV over 15 seconds 
  • If the desired level of consciousness is not obtained after 45 seconds, 0.2 mg IV may be repeated at 1-minute intervals as needed. Maximum four additional doses may be given if required.
  • Maximum total cumulative dose of 1 mg
  • In reoccurrence of sedation, repeat doses may be given at 20-minute intervals, not to exceed 0.2 mg/min per dose or 3 mg/hour total.

Dosing: Pediatric (Children 1 year and older and Adolescents)

FDA Dosage for Benzodiazepine reversal when used in conscious sedation or general anesthesia

  • Initial dose of 0.01 mg/kg given over 15 seconds (up to maximum dose of 0.2 mg)
  • If the desired level of consciousness is not obtained after 45 seconds, repeat 0.01 mg/kg (up to 0.2 mg) at 1-minute intervals as needed, up to four additional doses.
  • Maximum total cumulative dose of 1 mg or 0.05 mg/kg, whichever is lower
  • Mean total dose of 0.65 mg was administered during the clinical trial (range: 0.08 to 1 mg)

Hepatic dosing is required in patients with hepatic insufficiency.

Adverse Effects

Serious reaction:

  • Resedation
  • Neurologic Effects
  • Seizure
  • Cardiovascular finding: Arrhythmias

Common reactions:

Cardiovascular Findings

  • Bradycardia
  • Tachycardia
  • Hypertension
  • Chest pain

Neurologic Effects

  • Confusion
  • Dizziness
  • Headache
  • Impaired cognition
  • Opisthotonus
  • Shivering
  • Somnolence

Gastrointestinal Effects

  • Nausea
  • Vomiting

Immunologic Effects

  • Injection site reaction

Ophthalmic Effects

  • Defects of the visual field and diplopia
  • Blurred vision

Otic Effects

  • Hearing loss

Psychiatric Effects

  • Anxiety
  • Panic attack
  • Psychotic disorder
  • Agitation

Dermatologic Effects

  • Diaphoresis
  • Injection site pain 

US Black Box Warning: 

Seizures: Benzodiazepine reversal has been associated with seizures. Seizures may happen more frequently in patients who have been on benzodiazepines for long-term sedation or in patients who are showing signs of serious tricyclic antidepressant overdose.  Required dosage of flumazenil should be measured and prepared by the practitioners to manage seizures. flumazenil should be used with caution in patients relying on a benzodiazepine for seizure control.

Contraindications

Contraindications include:

  • Hypersensitivity to flumazenil or benzodiazepines 
  • Signs of Tricyclic antidepressants overdose
  • Benzodiazepine use for life-threatening diseases such as control of intracranial pressure or status epilepticus 
  • Mixed overdose
  • Caution if psychiatric disorder- provoke panic attacks in patients with history of panic disorder 
  • Convulsions may occur in patients with chronic dependency to benzodiazepines 
  • Convulsions or alter cerebral blood flow may precipitate in patients with head injury
  • Increased risk of convulsions in epileptic patients on benzodiazepine treatment for a prolonged period.
  • Caution in patients with drug dependency or alcoholism due to increased frequency of benzodiazepine tolerance and dependence
  • Do not use as primary treatment in patients with serious lung disease with respiratory depression secondary to benzodiazepines

Monitoring

Monitor the patient for the possible return of sedation mostly in those who are tolerant to benzodiazepines. Patients should be monitored for respiratory depression, benzodiazepine withdrawal, and other residual effects of benzodiazepines for at least 2 hours.

Toxicity

Flumazenil has been associated with precipitation of seizures in patients with benzodiazepine dependency with a history of seizures. Flumazenil overdose is extremely rare. There is no precise antidote for flumazenil toxicity. In mild to severe toxicity, symptomatic and supportive treatment should be considered. An overdose of flumazenil in a patient who is not a chronic benzodiazepines user is not expected to cause adverse effects however in chronic benzodiazepines user may precipitate withdrawal or seizures. Administration of benzodiazepines or barbiturates may be required for seizure control.[5][6]

Consult criteria:

Contact a medical toxicologist, or local poison center can be contacted for any patient with suspected severe adverse effects after receiving flumazenil such as seizures, dysrhythmias, and hypotension.

Enhancing Healthcare Team Outcomes

Today, with the epidemic of drug overdoses, nurses, pharmacists, and physicians all need to know about flumazenil. This competitive antagonist of benzodiazepines can rapidly reverse benzodiazepine overdose, but one also needs to know when to use it and what adverse effects to watch out for. Despite the initial hype about the drug, many experts believe that its risks may outweigh any benefit. The problem with flumazenil is that its effects are not consistent or predictable. Not everyone with benzodiazepine overdose will respond to it. In effect, the drug may precipitate seizures and withdrawal in patients who have been using benzodiazepines for a medical disorder. Plus, all healthcare workers need to know that this drug should not be used in patients with a history of seizures, head injury or those who have ingested a tricyclic antidepressant. The ideal circumstance for flumazenil is when a benzodiazepine naive individual has overdosed. The nurse and the pharmacist should educate the patient on the use of benzodiazepines, their potential to cause addiction and physical dependence. [7][8](Level V).

Outcomes

In general, patients who overdose on benzodiazepines alone rarely have significant mortality. The problem arises when the individual has coingested alcohol or other illicit drugs. In most isolated cases of benzodiazepine overdose, supportive management may prove effective. A few patients may develop rhabdomyolysis and aspiration pneumonia. Overall, the use of flumazenil to manage benzodiazepine overdose is diminishing as the drug may cause more harm than good. [1][9](Level V)


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Flumazenil - Questions

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Which of the following must be available for reversing a benzodiazepine used during induction of Drug Assisted Assisted Intubation (DAI)?



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Flumazenil is the treatment of choice for which of the following?



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What is the treatment for benzodiazepine overdose?



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Which of the following drugs is the appropriate antidote for benzodiazepine intoxication?



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A patient is given sedation with 3 mg midazolam and 50 mcg fentanyl. A few minutes later the patient's oxygen saturation drops to the 80's and is not arousable. Of the following, what should be administered first?



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What is the onset of action of flumazenil?



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A 17-year-old college student is admitted to the intensive care unit for a suspected overdose of lorazepam. What is the mechanism of the antidote used to counteract the effects of his overdose?



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A 17-year-old male presents to the emergency department after a friend found him unconscious. His respiratory rate is 5 breaths/min, blood pressure 80/70 mmHg, and heart rate 60 beats/min. Flumazenil is given, and the patient's vitals improve. One should monitor for what adverse effect of flumazenil?



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Flumazenil - References

References

Baandrup L,Ebdrup BH,Rasmussen JØ,Lindschou J,Gluud C,Glenthøj BY, Pharmacological interventions for benzodiazepine discontinuation in chronic benzodiazepine users. The Cochrane database of systematic reviews. 2018 Mar 15     [PubMed]
Zhu S,Noviello CM,Teng J,Walsh RM Jr,Kim JJ,Hibbs RE, Structure of a human synaptic GABA{sub}A{/sub} receptor. Nature. 2018 Jul     [PubMed]
Seelhammer TG,DeGraff EM,Behrens TJ,Robinson JC,Selleck KL,Schroeder DR,Sprung J,Weingarten TN, [The use of flumazenil for benzodiazepine associated respiratory depression in postanesthesia recovery: risks and outcomes]. Revista brasileira de anestesiologia. 2018 Jul - Aug     [PubMed]
Parthvi R,Mehra S, Flumazenil for Mixed Drug Overdose. American journal of therapeutics. 2017 Jul 6     [PubMed]
Wallace IR,Campbell EC,Trimble M, Use of a flumazenil infusion to treat chlordiazepoxide toxicity. Acute medicine. 2017     [PubMed]
Vukcević NP,Ercegović GV,Segrt Z,Djordjević S,Stosić JJ, Benzodiazepine poisoning in elderly. Vojnosanitetski pregled. 2016 Mar     [PubMed]
Tamburin S,Faccini M,Casari R,Federico A,Morbioli L,Franchini E,Bongiovanni LG,Lugoboni F, Low risk of seizures with slow flumazenil infusion and routine anticonvulsant prophylaxis for high-dose benzodiazepine dependence. Journal of psychopharmacology (Oxford, England). 2017 Oct     [PubMed]
Tae CH,Kang KJ,Min BH,Ahn JH,Kim S,Lee JH,Rhee PL,Kim JJ, Paradoxical reaction to midazolam in patients undergoing endoscopy under sedation: Incidence, risk factors and the effect of flumazenil. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2014 Aug     [PubMed]
Isbister GK,O'Regan L,Sibbritt D,Whyte IM, Alprazolam is relatively more toxic than other benzodiazepines in overdose. British journal of clinical pharmacology. 2004 Jul     [PubMed]

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