Continuing Education Activity

Flumazenil is a benzodiazepine antagonist. The primary FDA-approved clinical uses for flumazenil include reversal agents for benzodiazepine overdose and postoperative sedation from benzodiazepine anesthetics. Flumazenil injection is indicated for a complete or partial reversal of the sedative effects of benzodiazepines in conscious sedation and general anesthesia in adult and pediatric populations. This activity outlines the indications, mechanism of action, dosing, significant adverse effects, contraindications, monitoring, and toxicity of flumazenil so that providers can direct patient therapy to optimal outcomes in benzodiazepine reversal.

Objectives:

• Identify the mechanism of action of flumazenil.
• Outline the indications for using flumazenil.
• Summarize the adverse events associated with flumazenil administration.
• Review interprofessional team strategies for improving care coordination and communication to advance flumazenil therapy and improve outcomes.

Indications

Flumazenil is a benzodiazepine antagonist.[1][2] 

FDA-approved Indications

• 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 a complete or partial reversal of the sedative effects of benzodiazepines in conscious sedation and general anesthesia in the adult and pediatric populations. In addition, Flumazenil speeds the recovery from sedation following minor surgical procedures and shortened the post-operation monitoring period for minor surgery, resulting in earlier patient discharge.
• Flumazenil is also indicated for the 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 benzodiazepine intoxication than patients with multiple drug overdoses.[3]

Non-FDA Approved Indications

• Alcohol withdrawal syndrome[4]

• Drug action reversal, baclofen[5]

• Stupor, Idiopathic, recurring[6]

• Toxicity of drug, Cannabis[7]

• Hepatic encephalopathy[8]

As Flumazenil has not received approval from the FDA, the advantages and disadvantages of using this drug in non-FDA-approved conditions are based on the patient's condition and the physician's judgment.

Mechanism of Action

Flumazenil is a benzodiazepine antagonist. It 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 occurs within the first 3 minutes.The peak effect is 6 to 10 minutes after administration.The duration ranges from 19 minutes to 50 minutes, depending on the dose and benzodiazepine plasma concentrations.

Intravenous flumazenil has been shown to antagonize sedation, impairment of recall, psychomotor impairment produced by benzodiazepines.[9]

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. The administration is done by freely running IV infusion into a large vein or a series of small injections.[10]

Dosing: Adult

FDA Dosage for management of benzodiazepine overdose

• The clinician should give the initial dosage of 0.2 mg IV for 30 seconds 
• If the desired level of consciousness is not obtained after 30 seconds, the clinician can give an additional dose of 0.3 mg IV over 30 seconds
• May repeat doses of 0.5 mg IV over 30 seconds at 1-minute intervals to a 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 there is no response after administration of 5 mg, the primary 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

• The 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. A maximum of four additional doses may be given if required.
• The maximum total cumulative dose of 1 mg
• In the 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

• The initial dose of 0.01 mg/kg given over 15 seconds (up to a 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.
• The 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 necessary for patients with hepatic insufficiency.[11]

Adverse Effects

 Serious Adverse Events

• Sedation
• Neurologic effects
• Seizure
• Cardiovascular finding: arrhythmias[12]

Common Adverse Events

Cardiovascular

• Bradycardia
• Tachycardia
• Hypertension
• Chest pain

Neurologic

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

Gastrointestinal

• Nausea
• Vomiting

Immunologic

• Injection site reaction

Ophthalmic

• Defects of the visual field and diplopia
• Blurred vision

Otic

• Hearing loss

Psychiatric

• Anxiety
• Panic attack
• Psychotic disorder
• Agitation

Dermatologic

• Diaphoresis
• Injection site pain 

US Black Box Warning 

• Seizures: Benzodiazepine reversal has correlations with seizures. Seizures may happen more frequently in patients who have been on benzodiazepines for long-term sedation or in patients showing signs of severe tricyclic antidepressant overdose. The required dosage of Flumazenil should be measured and prepared by the practitioners to manage seizures. Flumazenil use requires caution in patients relying on a benzodiazepine for seizure control.[13]

Contraindications

Contraindications include:

• Hypersensitivity to flumazenil or benzodiazepines.

• Benzodiazepine use for life-threatening diseases such as control of intracranial pressure or status epilepticus.

• Caution if psychiatric disorder- provoke panic attacks in patients with a history of panic disorder.

• Convulsions may occur in patients with a chronic dependency on benzodiazepines.

• Flumazenil may precipitate convulsions or altered cerebral blood flow in patients with a head injury.

• Increased risk of seizures in epileptic patients on benzodiazepine treatment for a prolonged period.[14]

• Caution in patients with drug dependency or alcoholism due to increased frequency of benzodiazepine tolerance and dependence.[15]

• Do not use as primary treatment in patients with severe lung disease with respiratory depression secondary to benzodiazepines.

• Signs of tricyclic antidepressants overdose[16]

• Mixed overdose[17][15]

Monitoring

Patients should have monitoring for respiratory depression, benzodiazepine withdrawal, and other residual effects of benzodiazepines for at least 2 hours.[18]

Seizures may occur secondary to flumazenil administration. Seizures induced by flumazenil may require larger doses of benzodiazepine.[15]

Monitor the patient for the possible return of sedation, mostly in those who are tolerant of benzodiazepines or in the case of long-acting benzodiazepine overdose. Re-sedation may be treated in adults by administering flumazenil again until the therapeutic effect is achieved.[19]

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 benzodiazepines users experience withdrawal with abrupt discontinuation of the drug.[20][21]

Consult criteria:

• Contact a medical toxicologist or local poison 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 pro-convulsant drug.[22]

Enhancing Healthcare Team Outcomes

Today, with the epidemic of drug overdoses, nurses, pharmacists, and physicians need to be aware of flumazenil. This competitive antagonist of benzodiazepines can rapidly reverse benzodiazepine overdose. Despite the initial hype about the drug, many experts believe that its risks may outweigh its benefits. The problem with flumazenil is that its effects are not consistent or predictable. Not everyone with benzodiazepine overdose will respond to it. The drug may precipitate seizures and withdrawal in patients who have been using benzodiazepines for a medical disorder. Additionally, 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 naive benzodiazepine 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.[23][24] [Level 5]

Outcomes

In general, patients who overdose on benzodiazepines alone rarely have significant mortality. The problem arises when the individual has co-ingested alcohol or other illicit drugs. In most isolated cases of benzodiazepine overdose, supportive management may prove useful. 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][25] 

Normally flumazenil overdose is handled by emergency department physicians. Emergency department physicians should rapidly stabilize the patient. Hospital pharmacists should ensure proper dosing of flumazenil. Critical care physician consultation is required in severe poisoning with respiratory depression. In addition, medical toxicologist consultation is often required for multiple-drug ingestions. As depicted above, clinicians(MDs, DOs, NPs, PAs) should collaborate to improve patient outcomes. An interprofessional team approach would help achieve maximum efficacy and minimize potential risks associated with flumazenil therapy. [Level 5]