Flumazenil

Pronunciation

Pronunciation: flew-MAZ-ah-nil
Class: Antidote

Trade Names

Romazicon
- Injection 0.1 mg/mL

Anexate (Canada)

Pharmacology

Antagonizes actions of benzodiazepines on CNS by blocking receptors.

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Pharmacokinetics

Absorption

Mean C max is 24 ng/mL (range, 11 to 43 ng/mL); mean AUC was 15 ng•h/mL (range, 10 to 22 ng•h/mL).

Distribution

Initial distribution t 1/ 2 is 7 to 15 min. VD initial is 0.5 L/kg; Vd ss is 0.l77 to 1.60 L/kg. Protein binding is about 50%.

Metabolism

Primarily hepatically metabolized and dependent on hepatic blood flow (highly extracted).

Elimination

Terminal t 1/ 2 is 41 to 79 min. Total Cl is 0.7 to 1.3 L/h/kg (increases by 50% during ingestion of food). Less than 1% is excreted unchanged in the urine; 90% to 95% is excreted in urine and 5% to 10% in feces.

Onset

1 to 2 min.

Peak

6 to 10 min.

Duration

Related to the plasma concentration of the benzodiazepine as well as the dose of flumazenil.

Special Populations

Hepatic Function Impairment
Moderate

Mean total Cl decreased 40% to 60%; t 1/ 2 increases to 1.3 h.

Severe

Mean total Cl decreased 75%; t 1/ 2 increases to 2.4 h.

Children
1 to 17 yr of age

The t 1/ 2 is shorter and more variable, ranging 20 to 75 min.

Indications and Usage

Complete or partial reversal of sedative effects of benzodiazepines where general anesthesia induced or maintained with benzodiazepines, where sedation produced with benzodiazepines for diagnostic or therapeutic procedures, and for the management of benzodiazepine overdose.

Contraindications

Hypersensitivity to flumazenil or benzodiazepines; in patients given benzodiazepines for control of a potentially life-threatening condition (eg, status epilepticus); in patients showing signs of serious cyclic antidepressant overdose.

Dosage and Administration

Reversal of Conscious Sedation or in General Anesthesia
Adults

IV 0.2 mg over 15 sec. If desired level of consciousness is not achieved in 45 sec, additional 0.2 mg doses can be administered at 60 sec intervals (max, 1 mg). In event of resedation, repeat doses (0.2 mg/min to max 1 mg) at 20 min intervals as needed (max, 3 mg/h).

Management of Suspected Benzodiazepine Overdose
Adults

IV 0.2 mg over 30 sec. If desired level of consciousness is not achieved in 30 sec, an additional dose of 0.3 mg over 30 sec can be administered. Further doses of 0.5 mg over 30 sec can be administered at 1 min intervals as needed (max, 3 mg).

Drug Interactions

Toxic effects of other drugs taken in toxic doses may emerge with reversal of benzodiazepine effect.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Cutaneous vasodilation (eg, sweating, flushing, hot flushes); palpitations.

CNS

Convulsions; headache; dizziness; agitation; emotional lability; fatigue; paresthesia; insomnia; dyspnea; hypoesthesia.

Dermatologic

Sweating.

EENT

Visual field defect; diplopia; blurred vision.

GI

Nausea; vomiting.

Respiratory

Hyperventilation.

Miscellaneous

Injection-site pain; injection-site reaction; dry mouth.

Precautions

Pregnancy

Category C .

Labor and delivery

Not recommended; effects on newborn are unknown.

Lactation

Undetermined.

Children

Safety and efficacy not determined.

Hepatic Function

Elimination of flumazenil is reduced in patients with liver disease.

Ambulatory

The effects of flumazenil may wear off before a long-acting benzodiazepine is completely cleared from the body.

Benzodiazepine tolerance

Flumazenil may cause benzodiazepine withdrawal symptoms in individuals who have been taking benzodiazepines long enough to have some degree of tolerance or physical dependence.

Drug/alcohol dependence

Use with caution in patients with alcoholism and other drug dependencies because of the increased frequency of benzodiazepine tolerance and dependence observed in these patient populations.

Head injury

Use with caution in patients with head injury because of risk of precipitating convulsions or altering cerebral blood flow in patients receiving benzodiazepines.

Intensive care unit

Use of flumazenil to diagnose benzodiazepine-induced sedation in the ICU is not recommended because of the risk of adverse reactions.

Neuromuscular blocking agents

Do not use flumazenil until effects of neuromuscular blocking agents have been fully reversed.

Overdose situations

Flumazenil is intended as an adjunct to, not a substitute for, proper management of overdose patients (eg, airway maintenance, decontamination).

Psychiatric

Flumazenil may provoke panic attacks in patients with a history of panic disorder.

Resedation/Hypoventilation

Flumazenil may not fully reverse postoperative airway problems or ventilatory insufficiency induced by benzodiazepines; its effects may wear off before the effects of many benzodiazepines.

Seizures

Reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk populations including the following: Concurrent major sedative-hypnotic drug withdrawal; recent therapy with repeated doses of parenteral benzodiazepines; myoclonic jerking or seizure activity prior to flumazenil in overdose cases; concurrent cyclic antidepressant poisoning.

Patient Information

  • Instruct patient that flumazenil does not reverse amnesia. Repeat patient instructions in post-procedure period.
  • Warn patient that despite feelings of alertness at time of discharge, effects of benzodiazepines may reoccur, affecting memory and judgment.
  • Instruct patient to avoid activities requiring complete alertness, such as operating hazardous machinery or driving, for at least 18 to 24 h after discharge.
  • Warn patients to avoid alcohol or over-the-counter drugs for at least 18 to 24 h after discharge.

Copyright © 2009 Wolters Kluwer Health.

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