Flumazenil Injection - Consumer Medicine Information
|Manufacture:||Fresenius Kabi USA, LLC|
|Condition:||Benzodiazepine Overdose, Reversal of Sedation|
|Form:||Liquid solution, Intravenous (IV)|
|Ingredients:||Flumazenil, water, methylparaben, propylparaben, sodium chloride, edetate disodium, acetic acid, hydrochloric acid, sodium hydroxide|
About This Medication
What the Medication is Used For
Flumazenil Injection, USP is indicated for the complete or partial reversal of the central sedative effects of benzodiazepines. It may therefore be used in anesthesia and intensive care in the following situations:
- termination of general anesthesia induced and/or maintained with benzodiazepines;
- reversal of benzodiazepine sedation in short diagnostic and therapeutic procedures;
- for the diagnosis and/or management of deliberate or accidental benzodiazepine overdosage.
What it Does
Flumazenil is a benzodiazepine-specific antagonist which blocks the central effects of agents that act via the benzodiazepine receptor, by competitive inhibition.
The hypnotic-sedative effects of benzodiazepines are rapidly reversed by flumazenil. However, the residual effects may reappear gradually within a few hours, depending on the dose of flumazenil, the time elapsed since the benzodiazepine agonist was given, and the dose and elimination half-life of the previously administered benzodiazepine.
When it Should not be Used
- in patients with known hypersensitivity to flumazenil or to benzodiazepines;
- in epileptic patients who have been receiving benzodiazepine treatment for a prolonged period. The abrupt suppression of the protective effect of benzodiazepines may induce convulsions in epileptic patients;
- in patients who are showing signs of serious cyclic antidepressant overdose;
- in patients who have been given a benzodiazepine for a potentially life-threatening condition (e.g., intracranial pressure).
What the Medicinal Ingredient Is
What the Important Nonmedicinal Ingredients Are
For a full listing of nonmedicinal ingredients, see Part I of the Product Monograph.
What Dosage Forms it Comes In
Flumazenil Injection, USP is a sterile liquid for intravenous injection and contains 0.1 mg flumazenil per mL of solution. Flumazenil Injection, USP is available in multiple-dose glass vials:
C402405: 5 mL fill in a 6.5 mL vial; packaged in trays of 10 vials
C402410: 10 mL fill in a 10 mL vial; packaged individually
Warnings and Precautions
In view of the short duration of action of flumazenil and the possible need for repeat doses, the patient should remain closely monitored until all possible central benzodiazepine effects have subsided.
Flumazenil should be administered only when the continued observation of patients for recurrence of sedation can be assured.
The immediate availability of oxygen, resuscitative equipment and skilled personnel for the maintenance of airway, ventilation and cardiac function should be ensured before the administration of any benzodiazepine or flumazenil.
When used in anesthesiology at the end of surgery, flumazenil should not be given until the effects of neuromuscular blockade have been completely antagonized and careful monitoring of the respiratory depressant effect of opiate analgesics has been assured. After the benzodiazepine has been antagonized with flumazenil, any residual respiratory depressant effect of other agents, such as opiates, should be appropriately treated.
The ability of flumazenil to reverse benzodiazepine- induced respiratory depression is equivocal; in some studies, residual effects of benzodiazepines on respiration were still present despite reversal of sedation.
In patients treated for long periods of time and/or with high doses of benzodiazepines, flumazenil may trigger withdrawal symptoms (e.g., convulsions, agitation, anxiety, emotional lability as well as mild confusion and sensory distortions); rapid intravenous injections should therefore be avoided. Seizures have been reported in patients known to suffer from epilepsy, or severe hepatic impairment, particularly after long-term treatment with benzodiazepines or in cases of mixed-drug overdose. Flumazenil should be used with caution in the Intensive Care Unit because of the increased risk of unrecognized benzodiazepine dependence in such settings.
The dosage of flumazenil should be adjusted carefully in patients suffering from preoperative anxiety or having a history of chronic or episodic anxiety.
Patients who have received flumazenil to reverse the effects of benzodiazepine sedation should be instructed, if possible in writing, not to drive, operate machinery or engage in any other physically or mentally demanding activity for 24 hours or until the effects of the benzodiazepine have subsided, since the effect of the benzodiazepine may return. Patients should also be warned not to take alcohol, or drugs not prescribed by their physician, until the effects of the benzodiazepines have subsided.
Caution is advised when administering flumazenil to patients with myocardial infarction or cardiac arrhythmias.
In patients with liver insufficiency, the elimination of flumazenil can be delayed. Seizures have been reported in patients known to suffer from severe hepatic impairment, particularly after long-term treatment with benzodiazepines or in cases of mixed-drug overdose.
In patients with increased intracranial pressure, flumazenil may further increase intracranial pressure and decrease cerebral perfusion pressure, or precipitate convulsions.
Particular caution is necessary when using flumazenil in cases of multiple-drug overdosage, since the toxic effects (cardiac arrhythmias and/or convulsions) of other psychotropic drugs, especially cyclic antidepressants, may increase as the effects of benzodiazepines subside.
Interactions With This Medication
Flumazenil blocks the central effects of benzodiazepines by competitive interaction at the receptor level; the effects of non-benzodiazepines which act via the benzodiazepine receptor, such as zopiclone, triazolopyridazines and others, are also blocked. However, flumazenil does not reverse the effects of drugs that do not act via this route.
The pharmacokinetics of flumazenil are unaltered in the presence of benzodiazepines, and similarly, flumazenil does not affect the kinetics of benzodiazepines.
There is no pharmacokinetic interaction between ethanol and flumazenil.
Proper use of This Medication
Flumazenil should be administered intravenously by a physician with experience in anesthesiology.
The dose of flumazenil should always be individually titrated to the desired response to avoid abrupt awakening. Particular care is needed with patients who are physically dependent on benzodiazepines, patients who have ingested multiple drugs, and patients who are prone to anxiety.
Flumazenil may be diluted in a glass bottle to a final concentration of 0.05 mg/mL with 0.9% Sodium Chloride Injection, 0.45% Sodium Chloride and 2.5 % Dextrose Injection, 5% Dextrose Injection, or Lactated Ringer’s Injection.
Reversal of General Anesthesia/Sedation
The recommended initial dose is 0.2 mg administered intravenously over 15 seconds. If the desired level of consciousness is not obtained within 60 seconds, a further dose of 0.1 mg can be injected and repeated at 60-second intervals, up to a maximum total dose of 1 mg.
Known or Suspected Benzodiazepine Overdose
For the reversal of excessive sedative effects of benzodiazepines in overdose cases, titrate flumazenil as described below, until the patient clearly responds or until the maximum recommended dose has been reached.
The recommended initial dose is 0.3 mg administered intravenously over 30 seconds, followed by a series of 0.3 mg injections, each administered over a 30-second period, at 60-second intervals. The maximum recommended dose is 2.0 mg.
If drowsiness recurs, an intravenous infusion of 0.1-0.4 mg/hr may be useful. The rate of the infusion should be individually adjusted to the desired level of arousal.
Side Effects and What to do About Them
Flumazenil is generally well tolerated. In postoperative use, nausea and/or vomiting are observed, particularly if opiates have also been employed. Flushing has also been noted. If patients are awakened too rapidly, they may become agitated, anxious or fearful. Transient increases in blood pressure and heart rate may also occur.
Excessively and/or rapidly injected doses of flumazenil may induce benzodiazepine withdrawal symptoms such as anxiety attacks, tachycardia, dizziness, and sweating in patients on long-term benzodiazepine treatment.
Although clinical experience with flumazenil is limited, seizures and/or cardiac arrhythmias have been observed in patients who are physically dependent on benzodiazepines, and in multiple-drug overdose, particularly in the presence of tricyclic antidepressants.
Flumazenil has been reported to provoke panic attacks in patients with a history of panic disorders.
Serious Side Effects, how Often They Happen and What to do About Them
|Symptom/effect||Talk with your doctor or pharmacist||Stop taking drug and call your doctor or pharmacist|
|Only if severe||In all cases|
|increased blood pressure||✓|
|increased heart rate||✓|
|abnormal heart rate||✓|
This is not a complete list of side effects. For any unexpected effects while taking Flumazenil Injection, USP, contact your doctor or pharmacist.
How to Store It
Flumazenil Injection, USP should be stored between 15 ºC and 30 ºC.
Multidose vial. Discard unused portion 28 days after initial puncture.
Infusion solutions containing flumazenil should be used within 24 hours, and unused portions discarded.
Reporting Side Effects
You can help improve the safe use of health products for Canadians by reporting serious and unexpected side effects to Health Canada. Your report may help to identify new side effects and change the product safety information.
3 ways to report:
- Online at MedEffect (http://hc-sc.gc.ca/dhpmps/medeff/index-eng.php);
- By calling 1-866-234-2345 (toll-free);
- By completing a Consumer Side Effect Reporting Form and sending it by:
- Fax to 1-866-678-6789 (toll-free), or
- Mail to: Canada Vigilance Program
Health Canada, Postal Locator 0701E
Postage paid labels and the Consumer Side Effect Reporting Form are available at MadEffet (http://hc-sc.gc.ca/dhpmps/medeff/index-eng.php).
NOTE: Contact your health professional if you need information about how to manage your side effects. The Canada Vigilance Program does not provide medical advice.
This document plus the full Product Monograph, prepared for health professionals, can be obtained by contacting the sponsor, Fresenius Kabi Canada Ltd., at 1-877-821-7724.