Consumer medicine information

Flumazenil APOTEX Solution for injection

Flumazenil

BRAND INFORMATION

Brand name

Flumazenil APOTEX Solution for injection

Active ingredient

Flumazenil

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Flumazenil APOTEX Solution for injection.

What is in this leaflet

This leaflet answers some common questions about flumazenil. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the last page. More recent information on this medicine may be available.

Ask your doctor or pharmacist:

  • if there is anything you do not understand in this leaflet,
  • if you are worried about taking your medicine, or
  • to obtain the most up-to-date information.

You can also download the most up-to-date leaflet from www.apotex.com.au.

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

Pharmaceutical companies cannot give you medical advice or an individual diagnosis.

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

What this medicine is used for

The name of your medicine is Flumazenil APOTEX solution for injection. It contains the active ingredient flumazenil.

It is used to reverse benzodiazepine overdose, both suspected and known.

It is given to arouse people after surgery or benzodiazepine overdose.

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

There is no evidence that this medicine is addictive.

This medicine is available only with a doctor's prescription.

Before you are given this medicine

When you must not be given it

Do not use this medicine if:

  • You are taking a benzodiazepine for control of a potentially life-threatening condition
  • You are hypersensitive to, or have had an allergic reaction to, flumazenil or any of the ingredients listed at the end of this leaflet.
    Symptoms of an allergic reaction may include: cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin; fainting; or hay fever-like symptoms.
    If you think you are having an allergic reaction, do not take any more of the medicine and contact your doctor immediately or go to the Accident and Emergency Department at the nearest hospital.
  • The expiry date (EXP) printed on the pack has passed.
  • The packaging is torn, shows signs of tampering or it does not look quite right.

Before you are given it

Your doctor must know about all the following before you are given this medicine.

You must tell your doctor if:

  1. You have allergies to:
  • any other medicines
  • any other substances, such as foods, preservatives or dyes.
  1. You have or have had any medical conditions, especially the following:
  • you suffer from epilepsy
  • you have severe liver disease
  • you suffer from panic disorder
  • you have been taking high doses of benzodiazepines and/or you have been taking benzodiazepines for a long time.
  1. You are currently pregnant or you plan to become pregnant, or are breastfeeding.
  2. You are taking or are planning to take any other medicines. This includes vitamins and supplements that are available from your pharmacy, supermarket or health food shop.

Some medicines may interact with ketamine. These include:

  • benzodiazepines e.g. diazepam, bromazepam, temazepam etc.
  • sedating agents, e.g. zopiclone
  • anticonvulsants
  • antidepressants

If you are taking any of these you may need a different dose or you may need to take different medicines.

Other medicines not listed above may also interact with flumazenil.

How this medicine is given

How much of this medicine is given

Your doctor will decide what dose you will receive. This depends on your condition and other factors, such as your age and other medicines that are being given.

Usually only a single dose of this medicine is required.

How it is given

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

If you receive too much (overdose)

As flumazenil is given to you in a hospital under the supervision of your doctor, it is very unlikely that you will receive an overdose. You will be closely monitored while in the hospital so that any unwanted side effects can be treated. However if you experience severe side effects tell your doctor immediately.

Symptoms of an overdose may include the side effects listed below in the 'Possible side effects' section but are usually of a more severe nature.

While you are using this medicine

Things to be careful of

Be careful when driving or operating machinery until you know how this medicine affects you.

This medicine may cause drowsiness or dizziness in some people. This can be due to the possibility of resedation within the first 24 hours after administration.

If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

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.

Possible side effects

Tell your doctor as soon as possible if you do not feel well after you have been given flumazenil or if you have any questions or concerns.

This medicine helps most people who experience an overdose with benzodiazepine medicines but it may have unwanted side effects in a few people.

Do not be alarmed by the following lists of side effects. You may not experience any of them. All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Tell your doctor if you notice any of the following:

  • nausea with or without vomiting
  • dizziness, lightheadedness
  • feeling anxious or fearful
  • rapid or irregular heart beat
  • depression, tearfulness with or without agitation

These may be related to the reversal of anaesthetic.

Allergic reactions

If you think you are having an allergic reaction to flumazenil, do not take any more of this medicine and tell your doctor immediately or go to the Accident and Emergency Department at your nearest hospital.

Symptoms of an allergic reaction may include some or all of the following:

  • cough, shortness of breath, wheezing or difficulty breathing
  • swelling of the face, lips, tongue, throat or other parts of the body
  • rash, itching or hives on the skin
  • fainting
  • hay fever-like symptoms.

After using this medicine

Storage

This medicine will be stored in the pharmacy or on the ward. It is kept in a cool dry place where the temperature stays below 30°C.

Disposal

Flumazenil is used for one dose in one patient only. Any remaining contents should be discarded.

Product description

What Flumazenil APOTEX solution for injection looks like

A clear and colourless sterile solution, free from visible particles.

Ingredients

Each ampoule contains 0.5 mg/5mL of flumazenil as the active ingredient.

It also contains the following inactive ingredients:

  • disodium edetate
  • glacial acetic acid
  • sodium chloride
  • sodium hydroxide
  • water for injections

This medicine is gluten-free, lactose-free, sucrose-free, tartrazine-free and free of other azo dyes.

Australian Registration Numbers

Flumazenil APOTEX 0.5 mg/5mL solution for injection ampoule (Type I clear glass): AUST R 236672.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113

APO and APOTEX are registered trade marks of Apotex Inc.

This leaflet was last updated in February 2016.

BRAND INFORMATION

Brand name

Flumazenil APOTEX Solution for injection

Active ingredient

Flumazenil

Schedule

S4

 

1 Name of Medicine

Flumazenil.

6.7 Physicochemical Properties

Chemical Name: Ethyl 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4] benzodiazepine-3-carboxylate. Molecular Formula: C15H14FN3O3. Molecular Weight: 303.3.

Chemical structure.


CAS number.

78755-81-4.

2 Qualitative and Quantitative Composition

Flumazenil is a white or almost white, crystalline powder which is very slightly soluble in water, freely soluble in methylene chloride and sparingly soluble in methanol.
Flumazenil solution for intravenous injection is a clear and colourless solution, free from visible particles containing flumazenil, as the active ingredient. In addition, each solution for injection ampoule contains the following inactive ingredients: disodium edetate, glacial acetic acid, sodium chloride, sodium hydroxide in water for injections adjusted to pH 4.0.

Flumazenil APOTEX 0.5 mg/5 mL solution for injection.

A clear and colourless sterile solution, free from visible particles (AUST R 236672).

3 Pharmaceutical Form

See Section 2 Qualitative and Quantitative Composition.

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 (1-2 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%) non-renally 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 90-95% of the radioactivity appearing in urine and 5-10% in the faeces. Elimination is rapid, as shown by a short elimination half-life of 40-80 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 57-74% and the elimination half-life prolonged up to 2-fold.
The pharmacokinetics of flumazenil are not significantly affected in the elderly, haemodialysis, 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.

4 Clinical Particulars

4.1 Therapeutic Indications

Flumazenil 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.

4.3 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

Identified precautions.

Flumazenil blocks the effects of benzodiazepines in animals and can precipitate benzodiazepine withdrawal at high doses (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 5.1 Pharmacodynamic Properties; 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 i.v. 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/over sedation 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.
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 1-17 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% 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)
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 foetus.
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 i.v. 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).

4.8 Adverse Effects (Undesirable Effects)

Flumazenil was systemically and locally well tolerated. Nausea and/or vomiting was 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 http://www.tga.gov.au/reporting-problems or contact Apotex Medical Information enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.2 Dose and Method of Administration

Flumazenil should be administered intravenously by an anaesthetist or experienced physician.
The use of flumazenil 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.
Flumazenil 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.
Flumazenil is for use in one patient only. Discard any remaining contents.

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

The recommended initial dose is 0.2 mg administered i.v. within 15 seconds. If the desired degree of consciousness is not obtained within 60 seconds following the first i.v. 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 0.3-0.6 mg.

Children > 1 year of age (see Section 4.4 Special Warnings and Precautions for Use, Paediatric 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 i.v. 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 i.v. infusion of 0.1 - 0.4 mg/h has been shown to be useful. The rate of the infusion should be individually adjusted up to the desired level of arousal.

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.

4.9 Overdose

Symptoms.

There is very limited experience of acute overdose in humans with flumazenil.
Even when given at a dosage of 100 mg i.v., no symptoms of overdosage were observed. For withdrawal symptoms attributable to the agonist (see Section 4.4 Special Warnings and Precautions for Use).

Treatment.

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).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine. See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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 30°C.

6.5 Nature and Contents of Container

5 mL ampoules (Type I clear glass). Available in a carton containing 5 ampoules.

6.6 Special Precautions for Disposal

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

Summary Table of Changes