CHAPTER 3-32: FLUMAZENIL

INTRODUCTION

1. Pharmacology. Flumazenil (Romazicon) is an imidazobenzodiazepine derivative that competitively inhibits the activity of CNS benzodiazepine receptors and antagonizes the CNS effects of benzodiazepines. It has no demonstrable benzodiazepine agonist activity and no significant toxicity, even in high doses. It has no effect on other GABAergic drugs (eg, barbiturates), opioids, or alcohol intoxication. Flumazenil has poor oral bioavailability (16%) owing to high first-pass effect, and it is most effective when administered parenterally. After intravenous administration, the onset of benzodiazepine reversal occurs within 1–2 minutes, with 80% response reached within 3 minutes; reversal peaks at 6–10 minutes and lasts for 1–5 hours depending on the dose of flumazenil and the degree of preexisting benzodiazepine effect. Flumazenil is eliminated by hepatic metabolism and has a terminal half-life of approximately 1 hour (41-79 minutes). Hepatic dysfunction can significantly reduce normal flumazenil clearance.

2. Indications

   1. Rapid reversal of benzodiazepine overdose-induced coma and respiratory depression, both as a diagnostic aid and as a potential substitute for endotracheal intubation. Routine use of flumazenil in patients with coma of unknown etiology or with possible mixed drug overdose is not recommended, especially in high-risk patients (see Adverse Effects, below). Lowest-risk patients include those with a known iatrogenic exposure, toddlers with an ingestion, and patients with a paradoxical response (characterized by agitation or excitement and excessive movement or restlessness) to a therapeutic dose of a benzodiazepine when reversal of effect is desired.

   2. Postoperative or postprocedure reversal of benzodiazepine sedation.

   3. Flumazenil may also reverse CNS depression from certain nonbenzodiazepine sedatives and hypnotics (eg, zolpidem [Ambien], zaleplon [Sonata], and eszopiclone [Lunesta]).

   4. Flumazenil may have significant transient effect in patients with hepatic encephalopathy but no impact on recovery or survival.

3. Contraindications

   1. Known hypersensitivity to flumazenil or benzodiazepines.

   2. Suspected serious tricyclic antidepressant or other proconvulsant overdose.

   3. Benzodiazepine use for control of a potentially life-threatening condition (eg, status epilepticus or increased intracranial pressure).

4. Adverse effects

   1. Anxiety, agitation, headache, dizziness, nausea, vomiting, tremor, and transient facial flushing.

   2. Black box warning. Rapid reversal of benzodiazepine effect in high-tolerance patients, such as those with benzodiazepine addiction or chronic use, especially if they have a history of seizures, may result in an acute withdrawal state, including hyperexcitability, tachycardia, and seizures.

   3. Black box warning. Seizures may be unmasked in patients with a serious tricyclic antidepressant or other proconvulsant overdose due to loss of protective effect of benzodiazepines.

   4. Flumazenil has precipitated arrhythmias in a patient with mixed benzodiazepine and chloral hydrate overdose.

   5. Other risks include re-sedation and aspiration.

   6. Use in pregnancy. FDA Category C (indeterminate). This does not preclude its acute, short-term use for a seriously symptomatic patient (Introduction).

5. Drug or laboratory interactions. No known interactions. Flumazenil does not appear to alter the kinetics of benzodiazepines or other drugs.

6. Dosage and method of administration

   1. Benzodiazepine overdose. Titrate the dose until the desired response is achieved.

      1. Administer 0.2 mg IV over 30 seconds (pediatric dose is not established; start with 0.01 mg/kg and see dosing information below for pediatric reversal of ...