Flumazenil

Flumazenil
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gloria Picoy [2]

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Overview

Flumazenil is a benzodiazepine receptor antagonist that is FDA approved for the treatment of reversal of conscious sedation induced with benzodiazepines. Common adverse reactions include diaphoresis, injection site pain, dizziness, headache, abnormal vision, blurred vision, agitation.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

• Initial: 0.2 mg IV over 15 seconds
• Second dose: 0.2 mg IV may be given and repeated at 60-second intervals as needed (up to a maximum of 4 additional times) to a maximum total dose of 1 mg, if desired level of consciousness is not obtained after waiting 45 seconds.
• Flumazenil injection is indicated for the complete or partial reversal of the sedative effects of benzodiazepines in cases where general anesthesia has been induced and/or maintained with benzodiazepines, where sedation has been produced with benzodiazepines for diagnostic and therapeutic procedures, and for the management of benzodiazepine overdose.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Flumazenil in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Flumazenil in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

• Flumazenil injection is indicated for the reversal of conscious sedation induced with benzodiazepines
• Dosage

• Patients below the age of 1 year have not been established
• Children 1 year or older, 0.01 mg/kg IV over 15 seconds; if adequate sedation reversal does not occur after an additional 45 seconds, further injections of the same dosage may be repeated at 1-minute intervals, as needed up to 4 times

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Flumazenil in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Flumazenil in pediatric patients.

Contraindications

• In patients with a known hypersensitivity to flumazenil or benzodiazepines.
• In patients who have been given a benzodiazepine for control of a potentially life-threatening condition (e.g., control of intracranial pressure or status epilepticus).
• In patients who are showing signs of serious cyclic antidepressant overdose

Warnings

Risk of Seizures

• The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk populations. Possible risk factors for seizures include: concurrent major sedative-hypnotic drug withdrawal, recent therapy with repeated doses of parenteral benzodiazepines, myoclonic jerking or seizure activity prior to flumazenil administration in overdose cases, or concurrent cyclic antidepressant poisoning.

• Flumazenil is not recommended in cases of serious cyclic antidepressant poisoning, as manifested by motor abnormalities (twitching, rigidity, focal seizure), dysrhythmia (wide QRS, ventricular dysrhythmia, heart block), anticholinergic signs (mydriasis, dry mucosa, hypoperistalsis), and cardiovascular collapse at presentation. In such cases flumazenil should be withheld and the patient should be allowed to remain sedated (with ventilatory and circulatory support as needed) until the signs of antidepressant toxicity have subsided. Treatment with flumazenil has no known benefit to the seriously ill mixed-overdose patient other than reversing sedation and should not be used in cases where seizures (from any cause) are likely.

• Most convulsions associated with flumazenil administration require treatment and have been successfully managed with benzodiazepines, phenytoin or barbiturates. Because of the presence of flumazenil, higher than usual doses of benzodiazepines may be required.

Hypoventilation

• Patients who have received flumazenil for the reversal of benzodiazepine effects (after conscious sedation or general anesthesia) should be monitored for resedation, respiratory depression, or other residual benzodiazepine effects for an appropriate period (up to 120 minutes) based on the dose and duration of effect of the benzodiazepine employed.

• This is because flumazenil has not been established in patients as an effective treatment for hypoventilation due to benzodiazepine administration. In healthy male volunteers, flumazenil is capable of reversing benzodiazepine-induced depression of the ventilatory responses to hypercapnia and hypoxia after a benzodiazepine alone. However, such depression may recur because the ventilatory effects of typical doses of flumazenil (1 mg or less) may wear off before the effects of many benzodiazepines. The effects of flumazenil on ventilatory response following sedation with a benzodiazepine in combination with an opioid are inconsistent and have not been adequately studied. The availability of flumazenil does not diminish the need for prompt detection of hypoventilation and the ability to effectively intervene by establishing an airway and assisting ventilation.

• Overdose cases should always be monitored for resedation until the patients are stable and resedation is unlikely.

Adverse Reactions

Clinical Trials Experience

Serious Adverse Reactions

• Deaths have occurred in patients who received flumazenil in a variety of clinical settings. The majority of deaths occurred in patients with serious underlying disease or in patients who had ingested large amounts of non-benzodiazepine drugs (usually cyclic antidepressants), as part of an overdose.

• Serious adverse events have occurred in all clinical settings, and convulsions are the most common serious adverse events reported. Flumazenil administration has been associated with the onset of convulsions in patients with severe hepatic impairment and in patients who are relying on benzodiazepine effects to control seizures, are physically dependent on benzodiazepines, or who have ingested large doses of other drugs (mixed-drug overdose).

• Two of the 446 patients who received flumazenil in controlled clinical trials for the management of a benzodiazepine overdose had cardiac dysrhythmias (1 ventricular tachycardia, 1 junctional tachycardia).

Adverse reactions by system organ

• Body as a Whole

• Fatigue (asthenia, malaise), headache, injection site pain*, injection site reaction (thrombophlebitis, skin abnormality, rash)

• Cardiovascular System

• Cutaneous vasodilation (sweating, flushing, hot flushes)

• Digestive System

• Nausea, vomiting

• Nervous System

• Agitation (anxiety, nervousness, dry mouth, tremor, palpitations, insomnia, dyspnea, hyperventilation)*, dizziness (vertigo, ataxia) (10%), emotional lability (crying abnormal, depersonalization, euphoria, increased tears, depression, dysphoria, paranoia)

• Special Senses

• Abnormal vision (visual field defect, diplopia), paresthesia (sensation abnormal, hypoesthesia)

The following adverse events were observed infrequently (less than 1%) in the clinical studies, but were judged as probably related to flumazenil administration and/or reversal of benzodiazepine effects:

• Nervous System

• Confusion (difficulty concentrating, delirium), convulsions (see WARNINGS), somnolence (stupor)

• Special Senses

• Abnormal hearing (transient hearing impairment, hyperacusis, tinnitus)

The following adverse events occurred with frequencies less than 1% in the clinical trials. Their relationship to flumazenil administration is unknown, but they are included as alerting information for the physician.

• Body as a Whole:

• Rigors, shivering

• Cardiovascular System:

• Arrhythmia (atrial, nodal, ventricular extrasystoles), bradycardia, tachycardia, hypertension, chest pain.

• Digestive System:

• Hiccup

Nervous System:

• Speech disorder (dysphonia, thick tongue)

Not included in this list is operative site pain that occurred with the same frequency in patients receiving placebo as in patients receiving flumazenil for reversal of sedation following a surgical procedure.

Postmarketing Experience

Nervous System

• Fear, panic attacks in patients with a history of panic disorders.
• Withdrawal symptoms may occur following rapid injection of flumazenil in patients with long-term exposure to benzodiazepines.

Drug Interactions

There is limited information regarding Flumazenil Drug Interactions in the drug label.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): There is no FDA guidance on usage of Flumazenil in women who are pregnant.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Flumazenil in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Flumazenil during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Flumazenil in women who are nursing.

Pediatric Use

There is no FDA guidance on the use of Flumazenil in pediatric settings.

Geriatic Use

There is no FDA guidance on the use of Flumazenil in geriatric settings.

Gender

There is no FDA guidance on the use of Flumazenil with respect to specific gender populations.

Race

There is no FDA guidance on the use of Flumazenil with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Flumazenil in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Flumazenil in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Flumazenil in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Flumazenil in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Flumazenil Administration in the drug label.

Monitoring

There is limited information regarding Flumazenil Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Flumazenil and IV administrations.

Overdosage

There is limited information regarding Flumazenil overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Flumazenil Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Flumazenil Mechanism of Action in the drug label.

Structure

There is limited information regarding Flumazenil Structure in the drug label.

Pharmacodynamics

There is limited information regarding Flumazenil Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Flumazenil Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Flumazenil Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Flumazenil Clinical Studies in the drug label.

How Supplied

There is limited information regarding Flumazenil How Supplied in the drug label.

Storage

There is limited information regarding Flumazenil Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Flumazenil Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Flumazenil interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Flumazenil Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Flumazenil Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

Flumazenil

Clinical data
Pregnancy category	AU: B3 C
Routes of administration	Intravenous
ATC code	V03AB25 (WHO)
Pharmacokinetic data
Metabolism	Hepatic
Elimination half-life	7-15 min (initial) 20-30 min (brain) 40-80 min (terminal)
Excretion	Urine 90-95% Feces 5-10%
Identifiers
IUPAC name ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo- 4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate
CAS Number	78755-81-4
PubChem CID	3373
DrugBank	APRD00974
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C15H14FN3O3
Molar mass	303.288 g/mol

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List of terms related to Flumazenil

Flumazenil (also known as flumazepil, code name Ro 15-1788, trade names Anexate, Lanexat, Mazicon, Romazicon) is a benzodiazepine antagonist, used as an antidote in the treatment of benzodiazepine overdose. It reverses the effects of benzodiazepines by competitive inhibition at the benzodiazepine binding site on the GABA_A receptor. It was introduced in 1987 by Hoffmann-La Roche under the trade name Anexate.

The onset of action is rapid and usually effects are seen within one to two minutes. The peak effect is seen at six to ten minutes. The recommended dose for adults is 200 μg every 1-2 minutes until the effect is seen, to a maximum of 3 mg per hour. It is available as a clear, colourless solution for intravenous injection, containing 500 μg in 5 mls.

All benzodiazepines (including midazolam) have longer half-lives than flumazenil. Therefore, repeat doses of flumazenil may be required to prevent recurrent symptoms of overdosage once the initial dose of flumazenil wears off. It is hepatically metabolised to inactive compounds which are excreted in the urine. Subjects who are physically dependent on benzodiazepines may suffer benzodiazepine withdrawal symptoms, including seizure, upon administration of flumazenil.

See also

• Ro15-4513

References

• Romazicon product information, Roche USA

External links

• Template:DailyMed