Consumer medicine information

DBL Flumazenil Injection

Flumazenil

BRAND INFORMATION

Brand name

DBL Flumazenil Injection

Active ingredient

Flumazenil

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using DBL Flumazenil Injection.

What is in this leaflet

This leaflet answers some common questions about DBL™ Flumazenil Injection (flumazenil). It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you being given flumazenil against the benefits they expect it will have for you.

If you have any concerns about being given this medicine, ask your doctor or pharmacist.

Keep this leaflet. You may need to read it again.

What DBL Flumazenil Injection is used for

DBL Flumazenil Injection is used to reverse benzodiazepine overdose, both suspected and known.

It is given to arouse people after surgery involving benzodiazepine when required.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

It is available only with a doctor’s prescription.

Before you are given DBL Flumazenil Injection

When you must not be given it

You must not be given DBL Flumazenil Injection if you have an allergy to:

  • any medicine containing flumazenil
  • any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue or other parts of the body; rash, itching or hives on the skin.

You must not be given this medicine if you are taking a benzodiazepine for control of a potentially life-threatening condition.

Before you are given it

Your doctor must know about all the following before you are given DBL Flumazenil Injection.

You must tell your doctor if:

  • you are allergic to any other substances such as foods, preservatives or dyes
  • you suffer from epilepsy
  • you have liver disease
  • you suffer from panic disorder
  • you have taken high doses of benzodiazepines and/or you have been taking benzodiazepines for a long time.

If you have not told your doctor about any of the above, tell him/her before you are given flumazenil.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and flumazenil may interfere with each other. These include:

  • benzodiazepines eg diazepam, bromazepam, temazepam etc
  • anticonvulsants
  • antidepressants.

How DBL Flumazenil Injection is given

How much is given

Your doctor will decide what dose you will receive. This depends on your condition and other factors, such as your weight.

How it is given

Flumazenil is given as an injection into a vein. It must only be given by an anaesthetist or experienced physician.

Usually only a single dose of DBL Flumazenil Injection is required.

If you receive too much (overdose)

As DBL Flumazenil Injection is given to you in a hospital under the supervision of your doctor, it is very unlikely that you will receive an overdose. However if you experience side effects tell your doctor immediately. Symptoms of an overdose may include the side effects listed below in the 'Side Effects' section but are usually of a more severe nature.

Ask your doctor if you have any concerns.

While you are being given DBL Flumazenil Injection

Things to be careful of

Do not drive or operate machinery until you know how DBL Flumazenil Injection affects you. DBL Flumazenil Injection may cause drowsiness or dizziness in some people and therefore may affect alertness. This is due to the possibility of resedation within the first 24 hours after administration. Make sure you know how you react to DBL Flumazenil Injection before you drive a car or operate machinery or do anything else that could be dangerous if you are drowsy, dizzy or not alert.

Be careful if you are elderly, unwell or taking other medicines. Some people may experience side effects such as drowsiness, confusion, dizziness and unsteadiness in the first 24 hours after administration which may increase the risk of a fall.

There is also a possibility of other benzodiazepine effects such as difficulty in breathing, within the first 24 hours after administration.

Side effects

Tell your doctor or nurse as soon as possible if you do not feel well after being treated with DBL Flumazenil Injection.

This medicine helps most people who experience an overdose with benzodiazepine medicines but it may have unwanted side effects in a few people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of these side effects.

Ask your doctor to answer any questions you may have.

Tell your doctor or nurse if you notice any of the following and they worry you:

  • nausea with or without vomiting
  • dizziness, light-headedness
  • feeling anxious or fearful
  • rapid or irregular heartbeat
  • depression, tearfulness with or without agitation
  • wheezing with chest tightness, shortness of breath, cough, itchy rash and/or swelling of the lips, tongue eyes or face which are signs of an allergic reaction.

These may be related to the reversal of anaesthetic.

After using DBL Flumazenil Injection

Storage

DBL Flumazenil Injection will be stored in the pharmacy or on the ward. The injection is kept in a cool dry place, where the temperature stays below 25°C.

Product description

What it looks like

DBL Flumazenil Injection is a clear solution in a glass ampoule.

It is supplied as 0.5 mg/5 mL ampoule (5 pack).

Ingredients

DBL Flumazenil Injection ampoules contain 0.1 mg/mL of flumazenil in aqueous solution as the active ingredient.

It also contains:

  • disodium edetate
  • acetic acid
  • sodium chloride
  • sodium hydroxide in water for injections adjusted to pH 4.0.

This medicine does not contain lactose, sucrose, gluten, tartrazine or any other azo dyes.

Supplier

Pfizer Australia Pty Ltd
Sydney NSW
Toll Free Number: 1800 675 229
www.pfizer.com.au

AUST R number(s):

  • AUST R 121098

™ = Trademark

This leaflet was prepared in September 2020.

Published by MIMS October 2020

BRAND INFORMATION

Brand name

DBL Flumazenil Injection

Active ingredient

Flumazenil

Schedule

S4

 

1 Name of Medicine

Flumazenil.

2 Qualitative and Quantitative Composition

Ampoules contain 0.1 mg/mL flumazenil in aqueous solution (for intravenous administration) and also the following ingredients: disodium edetate, acetic acid, sodium chloride, sodium hydroxide in water for injections adjusted to pH 4.0.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

DBL Flumazenil Injection is a colourless to almost colourless clear liquid, available as 0.5 mg/5 mL, solution for injection.

4 Clinical Particulars

4.1 Therapeutic Indications

DBL Flumazenil Injection is indicated for use in hospitalised patients for the reversal of acute benzodiazepine effects (overdose or therapeutic). Hospitalised patients are patients admitted to hospital, inpatient care and under continued professional observation while under the influence of flumazenil. Not to be used in outpatients or short stay patients. Not to be used as a diagnostic.

4.2 Dose and Method of Administration

Dosage.

Reversal of benzodiazepine effects at therapeutic doses (anaesthesia or sedation).

The recommended initial dose is 0.2 mg administered intravenously within 15 seconds. If the desired degree of consciousness is not obtained within 60 seconds following the first intravenous administration, a second dose of 0.1 mg can be injected and this may be repeated at 60 second intervals where necessary, up to a total dose of 1 mg. The usual dose is 0.3 to 0.6 mg.

Children > 1 year of age (see Section 4.4 Special Warnings and Precautions for Use).

The recommended initial dose is 0.01 mg/kg (or up to 0.2 mg, whichever is lower) administered intravenously over 15 seconds. If the desired level of consciousness is not obtained after waiting for 60 seconds, further injections of 0.01 mg/kg (or up to 0.2 mg, whichever is lower) can be administered and repeated at 60 second intervals where necessary to a maximum total dose of 0.05 mg/kg or 1 mg, whichever is lower. The dose should be individualised based on the patient's response. The patients should be observed for at least 2 hours after treatment with flumazenil. Repeated administration of flumazenil to children for re-sedation is not recommended as its safety and efficacy have not been studied.
When using flumazenil, consideration should be given to the potential impact of rapid reversal of sedation and anxiolysis, and the risk of precipitating withdrawal symptoms. The safety and efficacy of flumazenil for reversal of prolonged sedation, such as in an intensive care unit, has not been studied.

Hepatic impairment.

Since flumazenil is primarily metabolised in the liver, careful titration of dosage is recommended in patients with impaired hepatic function (see Section 4.4 Special Warnings and Precautions for Use).

Reversal of benzodiazepine effects at overdose, known or suspected.

The recommended initial intravenous dose is 0.3 mg. If the desired degree of consciousness is not obtained within 60 seconds, flumazenil may be injected repeatedly until the patient awakes or up to a total dose of 2 mg. If drowsiness recurs, an intravenous infusion of 0.1 to 0.4 mg/hour has been shown to be useful. The rate of the infusion should be individually adjusted up to the desired level of arousal.

Method of administration.

DBL Flumazenil Injection should be administered intravenously by an anaesthetist or experienced physician.
The use of DBL Flumazenil Injection should be balanced against the risk of precipitating withdrawal symptoms (see Section 4.4 Special Warnings and Precautions for Use). The desirability of retaining a degree of sedation in the early postoperative period should be considered.
DBL Flumazenil Injection may be diluted in glucose 5% in water or 0.9% NaCl for infusion and may also be used concurrently with other resuscitative procedures. In order to reduce microbial contamination hazards, infusion should be commenced as soon as practicable after preparation. Infusion should be completed within 24 hours of preparation and any residue discarded.
DBL Flumazenil Injection is for use in one patient only. Discard any remaining contents.

4.3 Contraindications

Flumazenil is contraindicated in patients with known hypersensitivity to the drug.
Flumazenil is contraindicated 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 mixed intoxications with benzodiazepines and cyclic antidepressants, the toxicity of the antidepressants can be masked by protective benzodiazepine effects. In the presence of autonomic (anticholinergic), neurological (motor abnormalities) or cardiovascular symptoms of severe intoxication with tricyclics/ tetracyclics, flumazenil should not be used to reverse benzodiazepine effects.

4.4 Special Warnings and Precautions for Use

Flumazenil blocks the effects of benzodiazepines in animals and can precipitate benzodiazepine withdrawal at high doses (see Section 5 Pharmacological Properties; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.8 Adverse Effects (Undesirable Effects)).
Flumazenil should be administered cautiously to patients with known or suspected benzodiazepine dependency or who have been treated with high doses of benzodiazepines for the weeks preceding the treatment. In such cases the reversal of benzodiazepine effects may precipitate withdrawal symptoms or convulsions. Titration of the dose may help to reduce this risk. In case of unexpected signs of withdrawal a slow intravenous injection of 5 mg diazepam or 5 mg midazolam should be given.
Flumazenil may remove the protective effect of benzodiazepines in multiple drug overdose. There have been several reports of tachyarrhythmia (the pathogenesis of which is unclear) following flumazenil administration in the presence of known arrhythmogenic drug overdose. Convulsions in epileptics previously treated with benzodiazepines may occur.
Consideration should be given to the possibility of resedation, respiratory depression or other residual benzodiazepine effects following the use of flumazenil. These patients should be monitored for an appropriate period based on the dose and duration of effect of the benzodiazepine employed.
The use of flumazenil in intensive care units for the interruption of long term/oversedation is not recommended because of a relative lack of clinical experience.
Flumazenil should not be used as a routine empirical means of assessing unconscious patients in settings where resuscitation equipment and expertise to deal with complications are not immediately to hand.
Patients with head injury (and/or unstable intracranial pressure) treated with flumazenil to reverse the effects of benzodiazepines may develop raised intracranial pressure. In addition, flumazenil may be capable of precipitating convulsions or altering cerebral blood flow in patients with head injury receiving benzodiazepines.
The use of flumazenil is not recommended in epileptic patients who have been receiving benzodiazepine treatment for a prolonged period. Although flumazenil exerts a slight intrinsic anticonvulsant effect, its abrupt suppression of the protective effect of a benzodiazepine agonist can give rise to convulsions in epileptic patients.
When flumazenil is used with neuromuscular blocking agents, it should not be injected until the effects of neuromuscular blockade have been fully reversed.
Rapid injection of flumazenil should be avoided in patients with high dose and/or long-term exposure to benzodiazepines ending at any time within weeks preceding flumazenil administration as it may produce withdrawal symptoms, including agitation, anxiety, emotional lability as well as mild confusion and sensory distortions.
Flumazenil is not recommended either as a treatment for benzodiazepine dependence or for the management of protracted benzodiazepine abstinence syndromes.
When used in anaesthesiology at the end of the operation, flumazenil should not be injected before the effect of peripheral muscle relaxants has disappeared.

Use in hepatic impairment.

As patients with underlying hepatic impairment may experience delayed benzodiazepine effects, an extended observation period may be required.

Use in the elderly.

No data available.

Paediatric use.

An uncontrolled, single arm study has been conducted in children aged 1 to 17 years (n = 107) who were given weight based titration doses (see Section 4.2 Dose and Method of Administration) after undergoing various procedures (such as GI endoscopy and bronchoscopy) under midazolam. Agitation and aggressive reactions were seen in 3% and 2% of children, respectively. The pharmacokinetic data from a subset of 27 children showed high variability in pharmacokinetic parameters, although the mean clearance was similar to that in historical control data in adults.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Flumazenil blocks the central effects of benzodiazepines by competitive interaction at the receptor level; the effects of nonbenzodiazepine agonists at benzodiazepine receptors, such as zopiclone, triazolopyridazines and others are also blocked by flumazenil. Interactions with other CNS depressant substances have not been observed.
The pharmacokinetics of benzodiazepines are unaltered in the presence of the antagonist flumazenil.
Particular caution is necessary when using flumazenil in cases of mixed drug overdose since the toxic effects (such as convulsions and cardiac dysrhythmias) of other drugs taken in overdose (especially cyclic antidepressants) may emerge with the reversal of the benzodiazepine effect by flumazenil.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Flumazenil did not affect fertility in female and male rats at oral doses up to 125 mg/kg/day (> 300 times the clinical exposure at the maximum recommended i.v. dose of 2 mg, based on AUC).
(Category B3)
Category B3. This category specifies drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.
The safety of flumazenil in human pregnancy has not been established. Therefore, the benefits of drug therapy during pregnancy should be weighed against risks to the fetus.
No evidence of teratogenicity was observed in pregnant rats or rabbits given oral doses of flumazenil up to 150 mg/kg/day throughout the period of organogenesis. These doses represented > 300 to 1700 fold the clinical exposure at the maximum recommended intravenous dose of 2 mg, based on AUC. In rabbits, embryotoxicity (increased resorptions) was observed at oral doses ≥ 50 mg/kg/day (> 500 times the clinical exposure, based on AUC). The no-effect dose was 15 mg/kg/day (170 times the clinical exposure, based on AUC).
Because animal reproduction studies are not always predictive of human response, flumazenil should be used during pregnancy only if clearly needed.
 Caution should be exercised when deciding to administer flumazenil to a breastfeeding woman because it is not known whether flumazenil is excreted in human milk.
Oral administration of flumazenil to pregnant rats at 125 mg/kg/day from late gestation through weaning was associated with decreased pup survival, increased pup liver weight and retarded physical development (delayed incisor eruption and ear opening). This dose represented > 300-fold the clinical exposure at the maximum recommended dose of 2 mg, based on AUC. The no effect dose was 25 mg/kg/day (65 times the clinical exposure, based on available AUC data).

4.7 Effects on Ability to Drive and Use Machines

Patients should be warned against engaging in hazardous activities requiring complete mental alertness (such as operating dangerous machinery or driving a motor vehicle) during the first 24 hours after administration since sedation and drowsiness may occur.

4.8 Adverse Effects (Undesirable Effects)

Flumazenil was systemically and locally well tolerated. Nausea and/or vomiting were reported in clinical trials with flumazenil. This occurred more frequently when flumazenil was given as a single high dose to reverse anaesthesia and when opioids and other anaesthetic agents were used as a component of the anaesthesia. These reactions occurred rarely in volunteer studies or when benzodiazepines alone were used for sedation.
Hypersensitivity reactions, including anaphylaxis, have been observed.
Infrequently reported adverse events included dizziness, vertigo, anxiety, palpitation, fearfulness, depressed mood, and tearfulness with or without agitation. These may be related to reversal of the anaesthetic.
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.
In cases of mixed drug overdose, particularly with cyclic antidepressants, toxic effects (such as convulsions and cardiac dysrhythmias) may emerge with the reversal of benzodiazepine effects by flumazenil.
Withdrawal symptoms may occur following rapid injection of flumazenil in patients with long-term exposure to benzodiazepines ending at any time within the weeks preceding flumazenil administration.
Flumazenil has been reported to provoke panic attacks in patients with a history of panic disorders.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

There is very limited experience of acute overdose in humans with flumazenil.
Even when given at a dosage of 100 mg intravenously, no symptoms of overdosage were observed. For withdrawal symptoms attributable to the agonist, see Section 4.4 Special Warnings and Precautions for Use.
There is no specific antidote for overdose with flumazenil. Treatment of an overdose with flumazenil should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Flumazenil, an imidazobenzodiazepine, is a benzodiazepine antagonist which specifically blocks the central effects of agents acting through the benzodiazepine receptor by competitive inhibition. In animal experiments the effects of compounds showing no affinity for the benzodiazepine receptor, e.g. barbiturates, ethanol, meprobamate, GABA mimetics, adenosine receptor agonists and other agents were not affected by flumazenil, but those of nonbenzodiazepine agonists of benzodiazepine receptors, such as cyclopyrrolones (e.g. zopiclone) and triazolopyridazines were blocked.
Flumazenil reverses the central sedative effects of benzodiazepines.
The hypnotic-sedative benzodiazepine effects are rapidly reversed by flumazenil after its intravenous injection (1 to 2 minutes) and may reappear gradually within the next few hours, depending on the half-life and dose ratio of the agonist and antagonist.
Flumazenil is well tolerated even in high doses.
Flumazenil may possess some weak intrinsic agonistic (e.g. anticonvulsant) activity.
In animals pre-treated with high doses of benzodiazepines over several weeks, flumazenil elicited signs of withdrawal, including seizure. A similar effect was seen in adult human subjects.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

The pharmacokinetics of flumazenil is dose-proportional within and above the therapeutic range (up to 100 mg).

Distribution.

Flumazenil, a weak lipophilic base, is about 50% bound to plasma proteins. Albumin accounts for two thirds of the plasma protein binding. Flumazenil is extensively distributed in the extravascular space. The distribution phase of flumazenil is approximately 4 minutes.
The mean volume of distribution at steady state (Vss = 0.95 L/kg) is close to that of structurally related benzodiazepines and indicates tissue binding and/or partitioning of the drug.

Metabolism.

The carboxylic acid was identified in free and conjugated form as the main metabolite in human urine. In pharmacological tests, this main metabolite was inactive as a benzodiazepine agonist or antagonist.

Excretion.

The average elimination half-life of flumazenil is 53 minutes.
Flumazenil is almost completely (99%) nonrenally eliminated. Practically no unchanged flumazenil is excreted in the urine, suggesting complete metabolic degradation of the drug. Elimination of radiolabelled drug is essentially complete within 72 hours, with 90 to 95% of the radioactivity appearing in urine and 5 to 10% in the faeces. Elimination is rapid, as shown by a short elimination half-life of 40 to 80 minutes. The total plasma clearance of flumazenil is on average 1 L/min and can be attributed almost entirely to hepatic clearance. The low renal clearance rate suggests an effective reabsorption of the drug after glomerular filtration.
Ingestion of food during an intravenous infusion of flumazenil results in a 50% increase in clearance, most likely due to the increased hepatic blood flow that accompanies a meal.
When administered together with the benzodiazepines midazolam, flunitrazepam or lormetazepam, the basic pharmacokinetic parameters of flumazenil were not affected.

Pharmacokinetics in special populations.

In patients with impaired liver function, the elimination half-life of flumazenil is longer and the total body clearance lower than in healthy subjects. In patients with moderate to severe hepatic impairment, clearance of flumazenil was found to be reduced by 57 to 74% and the elimination half-life prolonged up to 2 fold.
The pharmacokinetics of flumazenil is not significantly affected in the elderly, hemodialysis, or renal failure.

5.3 Preclinical Safety Data

Genotoxicity.

Flumazenil was not mutagenic in bacterial (Salmonella typhimurium or Saccharomyces cerevisiae) or mammalian (V79) cells in vitro nor clastogenic in human lymphocytes in vitro or rat micronuclei in vivo. Flumazenil caused a slight increase in unscheduled DNA synthesis in rat hepatocytes in vitro while no induction of DNA repair was observed in mouse germ cells in vivo.

Carcinogenicity.

No long-term animal studies on the carcinogenic potential of flumazenil have been performed.

6 Pharmaceutical Particulars

6.1 List of Excipients

Acetic acid, disodium edetate, sodium chloride, sodium hydroxide, water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Strength.

DBL Flumazenil Injection 0.5 mg/5 mL.

Pack.

5 x 5 mL ampoules (glass).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

The active ingredient of flumazenil belongs to the chemical group of 1,2- imidazo benzodiazepines and is ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo- 4H-imidazo [1,5-a] [1,4] benzodiazepine -3- carboxylate (flumazenil).

Chemical structure.


Molecular formula: C15H14FN3O3.
Molecular weight: 303.3.

CAS number.

78755-81-4.

7 Medicine Schedule (Poisons Standard)

Schedule 4.

Summary Table of Changes