flumazenil
Romazicon

Available forms
Available by prescription only
Injection: 0.1 mg/ml in 5-ml and 10-ml multiple-dose vials

Indications and dosages
 Complete or partial reversal of sedative effects of benzodiazepines after anesthesia or short diagnostic procedures (conscious sedation). Adults: Initially, 0.2 mg I.V. over 15 seconds. If patient doesn’t reach desired level of consciousness after 45 seconds, repeat dose. Repeat at 1-minute intervals until a cumulative dose of 1 mg has been given (initial dose plus four additional doses). Most patients respond after 0.6 to 1 mg of drug. If resedation occurs, dose may be repeated after 20 minutes, but no more than 1 mg should be given at one time, and patient shouldn’t receive more than 3 mg/hour.
 Management of suspected benzodiazepine overdose. Adults: Initially, 0.2 mg I.V. over 30 seconds. If patient doesn’t reach desired level of consciousness after 30 seconds, administer 0.3 mg over 30 seconds. If patient still doesn’t respond adequately, give 0.5 mg over 30 seconds, then repeat 0.5-mg doses at 1-minute intervals until a cumulative dose of 3 mg has been given. Most patients with benzodiazepine overdose respond to cumulative doses between 1 and 3 mg; rarely, patients who respond partially after 3 mg may require additional doses. Don’t give more than 5 mg over 5 minutes initially; sedation that persists after this dose is unlikely to be caused by benzodiazepines. If resedation occurs, dose may be repeated after 20 minutes, but no more than 1 mg should be given at one time, and patient shouldn’t receive more than 3 mg/hour.

Pharmacodynamics
Antidote action: Flumazenil competitively inhibits the actions of benzodiazepines on the gamma-aminobutyric acid-benzodiazepine receptor complex.

Pharmacokinetics
Absorption: Administered I.V.
Distribution: After administration, drug is redistributed rapidly (initial distribution half-life is 7 to 15 minutes). It’s about 50% bound to plasma proteins.
Metabolism: Rapidly extracted from the blood and metabolized by the liver. Metabolites that have been identified are inactive. Ingestion of food during an I.V. infusion enhances extraction of drug from plasma, probably by increasing hepatic blood flow.
Excretion: About 90% to 95% is excreted in urine as metabolites; the remainder is excreted in feces. Plasma half-life is about 54 minutes.

Contraindications and precautions
Contraindicated in patients hypersensitive to drug or benzodiazepines, patients who show evidence of serious tricyclic antidepressant overdose, and patients who received a benzodiazepine to treat a potentially life-threatening condition such as status epilepticus or increased intracranial pressure.
  Use cautiously in alcohol-dependent or psychiatric patients, in those at high risk for seizures, and in those with head injuries, signs of seizures, or recent high intake of benzodiazepines, such as patients in the intensive care unit.

Interactions
Drug-drug. Antidepressants, drugs that can cause seizures or arrhythmias: May cause seizures or arrhythmias after flumazenil removes the effects of the benzodiazepine overdose. Don’t use flumazenil in mixed overdose, especially when seizures (from any cause) are likely to occur.
Drug-food. Any food: Ingestion of food during I.V. flumazenil infusion increases drug clearance by 50%. Be aware of this interaction.

Adverse reactions
CNS: dizziness, abnormal or blurred vision, headache,seizures, agitation, emotional lability, tremor, insomnia.
CV: arrhythmias, cutaneous vasodilation, palpitations.
GI: nausea, vomiting.
Respiratory: dyspnea, hyperventilation.
Skin: diaphoresis, pain at injection site.

Effects on lab test results
None reported.

Overdose and treatment
In clinical trials, large doses of flumazenil were administered I.V. to volunteers in the absence of a benzodiazepine agonist. No serious adverse reactions, clinical signs or symptoms, or altered laboratory tests were noted.
 In patients with benzodiazepine overdose, large doses of flumazenil may produce agitation or anxiety, hyperesthesia, increased muscle tone, or seizures. Seizures may be treated with barbiturates, phenytoin, or benzodiazepines.

Special considerations
• Because flumazenil has a duration of action shorter than that of benzodiazepines, monitor patient carefully and administer additional drug as needed. Duration and degree of effect depend on plasma levels of the sedating benzodiazepine and the dose of flumazenil.
• Monitor patient for resedation after reversal of benzodiazepine effect. Usually, serious resedation is unlikely in patient who fails to show signs of resedation 2 hours after a 1-mg dose of flumazenil.
• Flumazenil can be given by direct injection or diluted with a compatible solution.
Breast-feeding patients
• It isn’t known whether drug appears in breast milk. Use cautiously in breast-feeding women.
Pediatric patients
• Because no clinical data exist regarding risks, benefits, or dosage range in children, manufacturer doesn’t recommend its use in this age-group.

Patient education
• Because of risk of resedation, advise patient to avoid hazardous activities (such as driving a car), alcohol, CNS depressants, and OTC drugs within 24 hours of the procedure.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use