DESCRIPTION

Flumazenil is a medication that blocks benzodiazepine receptors.

FORMS AND USES

Flumazenil is used to diagnose benzodiazepine overdose or to reverse benzodiazepine-induced conscious sedation. Flumazenil (Romazicon, Anexate) is available in 5- and 10-ml vials with concentration solution of 0.1 mg/ml.

MECHANISM OF ACTION

• Flumazenil is a specific benzodiazepine receptor antagonist that inhibits the CNS effects of benzodiazepine drugs by competing for the benzodiazepine receptor.
• It is structurally related to the short-acting benzodiazepine midazolam (Versed).
• The elimination half-life is short (approximately 1 hour), and the duration of action varies from 15 to 140 minutes.
• The pharmacokinetics of flumazenil do not change with age, gender, or renal insufficiency.
• Clearance of flumazenil is greatly reduced in patients with mild to moderate liver disease, prolonging its effect.

DRUG AND DISEASE INTERACTIONS

Reversal of benzodiazepine effect should be undertaken cautiously in patients who have also ingested drugs that lower the seizure threshold (tricyclic antidepressants, cocaine, haloperidol). Abrupt termination of benzodiazepine effect may precipitate seizures.

PREGNANCY AND LACTATION

• US FDA Pregnancy Category C. The drug exerts animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women.
• Flumazenil should be used in pregnancy as it is in other adult patients.

Section Outline:

• DESCRIPTION
• FORMS AND USES
• MECHANISM OF ACTION
• DRUG AND DISEASE INTERACTIONS
• PREGNANCY AND LACTATION

DIAGNOSIS OF BENZODIAZEPINE OVERDOSE

If a marked improvement of CNS depression follows administration of flumazenil to a patient with depressed mentation, the diagnosis of benzodiazepine intoxication is likely. This may allow some tests or procedures to be avoided (endotracheal intubation, head CT, lumbar puncture).

REVERSAL OF CONSCIOUS SEDATION

Flumazenil is used to treat patients who develop undesired respiratory or CNS depression during benzodiazepine administration for therapeutic procedures such as fracture reduction.

Section Outline:

• DIAGNOSIS OF BENZODIAZEPINE OVERDOSE
• REVERSAL OF CONSCIOUS SEDATION

CONTRAINDICATIONS

• Tricyclic antidepressant overdose (especially if QRS duration is greater than 100 msec), due to the possibility of ventricular dysrhythmia
• Chronic benzodiazepine treatment for seizure control, due to the likelihood of inducing withdrawal
• Known hypersensitivity reaction to benzodiazepines
• Patients who are potentially dependent upon benzodiazepines due to chronic use or high-dose administration in the intensive care unit (this may develop after only 2-3 days of treatment)
• Mixed overdose with agents known to cause seizures
  • Substances may include cocaine, lithium, methylxanthines, isoniazid, propoxyphene, monoamine oxidase inhibitors, bupropion, and cyclosporine.
  • Flumazenil treatment may eliminate benzodiazepine suppression of seizures and thus "unmask" seizures induced by the coingestant.
• Known seizure disorder
• Head injury patients receiving benzodiazepines (because antidote may alter blood flow and induce seizures)

ADVERSE EFFECTS

• Anxiety, vertigo, nausea, vomiting (which may lead to aspiration in obtunded patients), tremor, discomfort, dyspnea, and headache may occur.
• Hypotension and ventricular dysrhythmia have occurred in seriously ill patients, usually with preexisting severe acidosis or tricyclic antidepressant overdose.
• Seizures and the precipitation of an acute withdrawal reaction may occur in chronic benzodiazepine users. Because of the potential for complications of withdrawal (including seizures), it is suggested that small doses be used initially, with additional incremental doses given as needed.

Section Outline:

• CONTRAINDICATIONS
• ADVERSE EFFECTS

DIAGNOSIS OF BENZODIAZEPINE OVERDOSE

• Flumazenil should be administered as a series of small injections, not as a bolus.
• Adult. Initial dose of 0.2 mg (2.0 ml) is administered intravenously over 30 seconds. If there is no response, an additional 0.3 mg is administered. Repeated dosing with 0.5 mg can be used, administered every 1 to 2 minutes, up to a total of 3 mg (10 mg has been used in exceptional cases).
• The pediatric dose of 0.01 mg/kg (0.1 ml/kg) is administered intravenously, titrated to effect with a maximum dose of 1 mg.
• If there is no effect within 5 minutes, the cause of altered mental status is unlikely to be benzodiazepine and another cause should be sought.
• Patients should be monitored for recurrent sedation, respiratory depression, and signs of withdrawal. Recurrent sedation may occur within 30 minutes, but does not occur in all patients.
• Flumazenil should be administered in a setting, such as an emergency department or intensive care unit, where seizures can be promptly and effectively managed.
• Patients who have ingested longer acting benzodiazepines may require multiple doses or continuous infusion (0.1-0.2 mg/h). This should be attempted only if it offers a substantial benefit (e.g., if it avoids endotracheal intubation).

REVERSAL OF CONSCIOUS SEDATION

• Adult dose is 0.2 mg (2.0 ml), administered intravenously over 15 seconds. If there is no response, the dose should be repeated every 1 minute, up to a total dose of 1 mg.
• Pediatric dose is 0.01 mg/kg, administered intravenously with a maximum dose of 1 mg.
• The patient should be monitored for recurrent sedation or respiratory depression.

Section Outline:

• DIAGNOSIS OF BENZODIAZEPINE OVERDOSE
• REVERSAL OF CONSCIOUS SEDATION

• Flumazenil is not recommended for patients with agitation, tachycardia, tachypnea, or other signs of adrenergic stimulation because they are unlikely to have benzodiazepine toxicity as a major component of their condition. Thus, reversal may place the patient at risk of adverse effects without likely benefit.
• Patients should not be discharged soon after reversal because recurrent sedation has occasionally occurred 2 to 3 hours after flumazenil administration.

Poisoning by psychotropic agents: benzodiazepine-based tranquilizers.

RECOMMENDED READING

Geller E, Crome P, Schaller MD, et al. Risks and benefits of therapy with flumazenil (Anexate) in mixed drug intoxications. Eur Neurol 1991;31:241.

Hojer J, Baehrendtz S, Matell G, Gustafsson LL. Diagnostic utility of flumazenil in coma with suspected poisoning: a double blind, random-ised controlled study, BMJ 1990;301:1308.

Spivey WH, Roberts JR, Derlet RW. A clinical trial of escalating doses of flumazenil for reversal of suspected benzodiazepine overdose in the emergency department. Ann Emerg Med 1993;22:1813.

Authors: Jeffrey S. Peterson and Charles B. Cairns

Reviewer: Katherine M. Hurlbut