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Pronunciation:

(FLOO may ze nil)

U.S. Brand Names:

Romazicon®

Generic Available:

Yes

Canadian Brand Names:

Anexate®; Romazicon®

Use:

Benzodiazepine antagonist; reverses sedative effects of benzodiazepines used in conscious sedation and general anesthesia; treatment of benzodiazepine overdose

Pregnancy Risk Factor:

Pregnancy Implications:

Teratogenic effects were not seen in animal studies. Embryocidal effects were seen at large doses. There are no adequate or well-controlled studies in pregnant women. Use only if clearly needed.

Lactation:

Excretion in breast milk unknown/use caution

Contraindications:

Hypersensitivity to flumazenil, benzodiazepines, or any component of the formulation; patients given benzodiazepines for control of potentially life-threatening conditions (eg, control of intracranial pressure or status epilepticus); patients who are showing signs of serious cyclic-antidepressant overdosage

Warnings/Precautions:

Benzodiazepine reversal may result in seizures in some patients. Patients who may develop seizures include patients on benzodiazepines for long-term sedation, tricyclic antidepressant overdose patients, concurrent major sedative-hypnotic drug withdrawal, recent therapy with repeated doses of parenteral benzodiazepines, myoclonic jerking or seizure activity prior to flumazenil administration. Flumazenil does not reverse respiratory depression/hypoventilation or cardiac depression. Resedation occurs more frequently in patients where a large single dose or cumulative dose of a benzodiazepine is administered along with a neuromuscular blocking agent and multiple anesthetic agents. Flumazenil should be used with caution in the intensive care unit because of increased risk of unrecognized benzodiazepine dependence in such settings. Should not be used to diagnose benzodiazepine-induced sedation. Reverse neuromuscular blockade before considering use. Flumazenil does not antagonize the CNS effects of other GABA agonists (such as ethanol, barbiturates, or general anesthetics); nor does it reverse narcotics. Use with caution in patients with a history of panic disorder; may provoke panic attacks. Use caution in drug and ethanol-dependent patients; these patients may also be dependent on benzodiazepines. Not recommended for treatment of benzodiazepine dependence. Use with caution in head injury patients. Use caution in patients with mixed drug overdoses; toxic effects of other drugs taken may emerge once benzodiazepine effects are reversed. Flumazenil does not consistently reverse amnesia; patient may not recall verbal instructions after procedure. Use caution in severe hepatic dysfunction and in patients relying on a benzodiazepine for seizure control. Safety and efficacy have not been established in children >1 year of age.

Adverse Reactions:

>10%: Gastrointestinal: Vomiting, nausea

1% to 10%:

Cardiovascular: Palpitations

Central nervous system: Headache, anxiety, nervousness, insomnia, abnormal crying, euphoria, depression, agitation, dizziness, emotional lability, ataxia, depersonalization, tears increased, dysphoria, paranoia, fatigue, vertigo

Endocrine & metabolic: Hot flashes

Gastrointestinal: Xerostomia

Local: Pain at injection site

Neuromuscular & skeletal: Tremor, weakness, paresthesia

Ocular: Abnormal vision, blurred vision

Respiratory: Dyspnea, hyperventilation

Miscellaneous: Diaphoresis

<1%: Abnormal hearing, altered blood pressure (increases and decreases), confusion, sensation of coldness, bradycardia, chest pain, generalized convulsions, hiccups, hypertension, junctional tachycardia, shivering, somnolence, tachycardia, thick tongue, ventricular tachycardia, withdrawal syndrome

Postmarketing and/or case reports: Fear, panic attacks

Overdosage/Toxicology:

Excessively high doses may cause anxiety, agitation, increased muscle tone, hyperesthesia and seizures.

Drug Interactions:

Nonbenzodiazepine hypnotics (zaleplon, zolpidem, zopiclone): Flumazenil reverses the effects of these hypnotics.

Stability:

Store at 15°C to 30°C (59°F to 86°F). For I.V. use only; compatible with D5W, lactated Ringer's, or normal saline; once drawn up in the syringe or mixed with solution use within 24 hours; discard any unused solution after 24 hours

Compatibility:

Stable in D5W, LR, NS

Compatibility when admixed: Compatible: Aminophylline, cimetidine, dobutamine, dopamine, famotidine, heparin, lidocaine, procainamide, ranitidine

Mechanism of Action:

Competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex. Flumazenil does not antagonize the CNS effect of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (ethanol, barbiturates, general anesthetics) and does not reverse the effects of opioids

Pharmacodynamics/Kinetics:

Onset of action: 1-3 minutes; 80% response within 3 minutes

Peak effect: 6-10 minutes

Duration: Resedation: ~1 hour; duration related to dose given and benzodiazepine plasma concentrations; reversal effects of flumazenil may wear off before effects of benzodiazepine

Distribution: Initial Vd: 0.5 L/kg; Vdss 0.77-1.6 L/kg

Protein binding: 40% to 50%

Metabolism: Hepatic; dependent upon hepatic blood flow

Half-life elimination: Adults: Alpha: 7-15 minutes; Terminal: 41-79 minutes

Excretion: Feces; urine (0.2% as unchanged drug)

Dosage:

Children and Adults: I.V.: See table.

Pediatric Dosage:

Flumazenil

Pediatric Dosage (further studies needed)
Pediatric dosage for reversal of conscious sedation and general anesthesia:

Initial dose	0.01 mg/kg over 15 seconds (maximum: 0.2 mg)
Repeat doses (maximum: 4 doses)	0.005-0.01 mg/kg (maximum: 0.2 mg) repeated at 1-minute intervals
Maximum total cumulative dose	1 mg or 0.05 mg/kg (whichever is lower)
Adult Dosage
Adult dosage for reversal of conscious sedation and general anesthesia:

Initial dose	0.2 mg intravenously over 15 seconds
Repeat doses	If desired level of consciousness is not obtained, 0.2 mg may be repeated at 1-minute intervals.
Maximum total cumulative dose	1 mg (usual dose: 0.6-1 mg) In the event of resedation: Repeat doses may be given at 20-minute intervals with maximum of 1 mg/dose and 3 mg/hour.

Adult dosage for suspected benzodiazepine overdose:

Initial dose	0.2 mg intravenously over 30 seconds; if the desired level of consciousness is not obtained, 0.3 mg can be given over 30 seconds
Repeat doses	0.5 mg over 30 seconds repeated at 1-minute intervals
Maximum total cumulative dose	3 mg (usual dose 1-3 mg) Patients with a partial response at 3 mg may require additional titration up to a total dose of 5 mg. If a patient has not responded 5 minutes after cumulative dose of 5 mg, the major cause of sedation is not likely due to benzodiazepines. In the event of resedation: May repeat doses at 20-minute intervals with maximum of 1 mg/dose and 3 mg/hour.

Resedation: Repeated doses may be given at 20-minute intervals as needed; repeat treatment doses of 1 mg (at a rate of 0.5 mg/minute) should be given at any time and no more than 3 mg should be given in any hour. After intoxication with high doses of benzodiazepines, the duration of a single dose of flumazenil is not expected to exceed 1 hour; if desired, the period of wakefulness may be prolonged with repeated low intravenous doses of flumazenil, or by an infusion of 0.1-0.4 mg/hour. Most patients with benzodiazepine overdose will respond to a cumulative dose of 1-3 mg and doses >3 mg do not reliably produce additional effects. Rarely, patients with a partial response at 3 mg may require additional titration up to a total dose of 5 mg. If a patient has not responded 5 minutes after receiving a cumulative dose of 5 mg, the major cause of sedation is not likely to be due to benzodiazepines.

Elderly: No differences in safety or efficacy have been reported. However, increased sensitivity may occur in some elderly patients.

Dosing in renal impairment: Not significantly affected by renal failure (Clcr<10 mL/minute) or hemodialysis beginning 1 hour after drug administration

Dosing in hepatic impairment: Initial dose of flumazenil used for initial reversal of benzodiazepine effects is not changed; however, subsequent doses in liver disease patients should be reduced in size or frequency

Administration:

I.V.: Administer in freely-running I.V. into large vein. Inject over 15 seconds for conscious sedation and general anesthesia and over 30 seconds for overdose.

Monitoring Parameters:

Monitor patients for return of sedation or respiratory depression

Patient Education:

Flumazenil does not consistently reverse amnesia. Do not engage in activities requiring alertness for 18-24 hours after discharge. Avoid alcohol or OTC medications for 24 hours after receiving this medication, unless approved by prescriber. Resedation may occur in patients on long-acting benzodiazepines (such as diazepam). Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.

Nursing Implications:

Parenteral: For I.V. use only; administer via freely running I.V. infusion into larger vein to decrease chance of pain, phlebitis

Anesthesia and Critical Care Concerns/Other Considerations:

Flumazenil does not antagonize the CNS effects of other GABA agonists (such as ethanol, barbiturates, or general anesthetics), nor does it reverse narcotics.

Dental Health: Effects on Dental Treatment:

Key adverse event(s) related to dental treatment: Xerostomia (normal salivary flow resumes upon discontinuation).

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

No information available to require special precautions

Dosage Forms:

Injection, solution: 0.1 mg/mL (5 mL, 10 mL) [contains edetate sodium]

International Brand Names:

Anexate® (AT, AU, BE, BG, BR, CA, CH, CO, CR, CU, CY, CZ, DE, DK, EC, EG, ES, FI, FR, GB, GR, GT, HK, HN, HR, HU, ID, IE, IL, IS, IT, JO, JP, KR, KW, LB, LK, LT, LU, LV, MA, MX, MY, NL, NO, NZ, PA, PE, PH, PL, PT, RO, RU, SE, SG, SI, SK, SY, TH, T; Fadaflumaz® (AR); Flumage® (AR); Flumanovag® (AR); Flumazenil® (AR); Fluxifarm® (AR); Lanexat® (AR, BR, CL, CO, DK, FI, MX, SE); Romazicon® (CA)

References

Baktai G, Szekely E, Marialigeti T, et al, "Use of Midazolam (Dormicum) and Flumazenil (Anexate) in Paediatric Bronchology,"Curr Med Res Opin, 1992, 12(9):552-9.

Chern CH, Chern TL, Hu SC, et al, "Complete and Partial Response to Flumazenil in Patients With Suspected Benzodiazepine Overdose,"Am J Emerg Med, 1995, 13(3):372-5.

Clark RF, Sage TA, Tunget C, et al, "Delayed Onset Lorazepam Poisoning Successfully Reversed By Flumazenil in a Child: Case Report and Review of the Literature,"Pediatr Emerg Care, 1995, 11(1):32-4.

Geller E, Crome P, Schaller MD, et al, "Risks and Benefits of Therapy With Flumazenil (Anexate®) in Mixed Drug Intoxications,"Eur Neurol, 1991, 31(4):241-50.

Ghouri AF, Ramirez Ruiz MA, and White PF, "Effect of Flumazenil on Recovery After Midazolam and Propofol Sedation,"Anesthesiology, 1994, 81(2):330-9.

Haverkos GP, Di Salvo RP, and Imhoff TE, "Fatal Seizures After Flumazenil Administration in a Patient With Mixed Overdose,"Ann Pharmacother, 1994, 28(12):1347-9.

Hoffman RS and Goldfrank LR, "The Poisoned Patient With Altered Consciousness. Controversies in the Use of a 'Coma Cocktail',"JAMA, 1995, 274(7):562-9.

Hojer J, Baehrendtz S, Magnusson A, et al, "A Placebo-Controlled Trial of Flumazenil Given by Continuous Infusion in Severe Benzodiazepine Overdosage,"Acta Anaesthesiol Scand, 1991, 35(7):584-90.

Jones RD, Lawson AD, Andrew LJ, et al, "Antagonism of the Hypnotic Effect of Midazolam in Children: A Randomized, Double Blind Study of Placebo and Flumazenil Administered After Midazolam-Induced Anaesthesia,"Br J Anaesth, 1991, 66(6):660-6.

Massanari M, Novitsky J, and Reinstein LJ, "Paradoxical Reactions in Children Associated With Midazolam Use During Endoscopy,"Clin Pediatr, 1997, 36(12):681-4.

McDuffee AT and Tobias JD, "Seizure After Flumazenil Administration in a Pediatric Patient,"Pediatr Emerg Care, 1995, 11(3):186-7.

Mokhlesi B, Leikin JB, Murray P, et al, "Adult Toxicology in Critical Care: Part II: Specific Poisonings,"Chest, 2003, 123(3):897-922.

Reisner-Keller LA and Pham Z, "Oral Flumazenil in the Treatment of Epilepsy,"Ann Pharmacother, 1995, 29(5):530-1.

Richard P, Autret E, Bardol J, et al, "The Use of Flumazenil in a Neonate,"J Toxicol Clin Toxicol, 1991, 29(1):137-40.

Roald OK and Dahl V, "Flunitrazepam Intoxication in a Child Successfully Treated With the Benzodiazepine Antagonist Flumazenil,"Crit Care Med, 1989, 17(12):1355-6.

Shannon M, Albers G, Burkhart K, et al, "Safety and Efficacy of Flumazenil in the Reversal of Benzodiazepine-Induced Conscious Sedation. The Flumazenil Pediatric Study Group,"J Pediatr, 1997, 131(4):582-6.

Shivdat J, Shih RD, and Marcus SM, "Flumazenil Usage: A Two Year Poison Center Experience,"Clin Toxicol, 1995, 33(5):522.

Spivey WH, "Flumazenil and Seizures: Analysis of 43 Cases,"Clin Ther, 1992, 14(2):292-305.

Sugarman JM and Paul RI, "Flumazenil: A Review,"Pediatr Emerg Care, 1994, 10(1):37-43.

Trujillo MH, Guerrero J, Fragachan C, et al, "Pharmacologic Antidotes in Critical Care Medicine: A Practical Guide for Drug Administration,"Crit Care Med, 1998, 26(2):377-91.

Wiley J and Wiley C, "Benzodiazepine Ingestions in Children,"Clin Toxicol, 1995, 33(5):520.

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