DBL™ Flumazenil

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Flumazenil 0.5 mg
Available from:
Pfizer New Zealand Limited
INN (International Name):
Flumazenil 0.5 mg
Dosage:
0.5 mg/5mL
Pharmaceutical form:
Solution for injection
Composition:
Active: Flumazenil 0.5 mg Excipient: Acetic acid Disodium edetate dihydrate Sodium chloride Sodium hydroxide Water for injection
Units in package:
Ampoule, glass, Type I clear one point cut 5 mL ampoule pack of 5, 25 mL
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Perrigo API Ltd
Therapeutic indications:
Latest Regulatory Activity
Product summary:
Package - Contents - Shelf Life: Ampoule, glass, Type I clear one point cut 5 mL ampoule pack of 5 - 25 mL - 24 months from date of manufacture stored at or below 25°C
Authorization number:
TT50-7678
Authorization date:
2006-05-26

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NEW ZEALAND DATA SHEET

1.

PRODUCT NAME

DBL™ Flumazenil Injection

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Ampoules

contain

mg/mL

flumazenil

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. DBL

Flumazenil

Injection is available as 0.5 mg/5 mL and 1 mg/10 mL ampoules.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

DBL™ Flumazenil Injection is a colourless to almost colourless clear liquid, adjusted to pH

4.0.

Solution for injection

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

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

Dose

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). The desirability of retaining a degree of sedation in

the early postoperative period should be considered.

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

commenced

soon

practicable after preparation. Infusion should be completed within 24 hours of preparation

and any residue discarded.

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Flumazenil Injection 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 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)

recommended

initial

dose

0.01

mg/kg

whichever

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.

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.

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.

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

effects

benzodiazepines

animals

precipitate

benzodiazepine withdrawal at high doses (also see section 5.1 and section 4.8).

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Flumazenil

should

administered

cautiously

patients

with

known

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/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,

abrupt

suppression

protective

effect

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

benzodiazepines

ending

time

within

weeks

preceding

flumazenil

administration

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.

Paediatric population

An uncontrolled, single arm study has been conducted in children aged 1 to 17 years

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(n = 107) who were given weight based titration doses (see section 4.2) after undergoing

various procedures (such as GI endoscopy and bronchoscopy) under midazolam. Agitation

aggressive

reactions

were

seen

children

respectively.

pharmacokinetic

data

from

subset

children

showed

high

variability

pharmacokinetic parameters, although the mean clearance was similar to that in historical

control data in adults.

4.5 Interaction with other medicines and other forms of interaction

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)

emerge

with

reversal

benzodiazepine effect by flumazenil.

4.6 Fertility, pregnancy and lactation

Fertility

No data available.

Pregnancy

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 foetus having been observed. Studies

animals

have

shown

evidence

increased

occurrence

foetal

damage,

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 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

>

1700

fold

clinical

exposure

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.

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Lactation

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 machinery

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 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.

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 of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It

allows

continued

monitoring

benefit/risk

balance

medicine.

Healthcare

professionals

asked

report

suspected

adverse

reactions

https://nzphvc.otago.ac.nz/reporting/.

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4.9 Overdose

Even when given at a dosage of 100 mg intravenously, no symptoms of overdosage were

observed. For withdrawal symptoms attributable to the agonist, see under section 4.4.

For advice on the management of overdose please contact the National Poisons Centre on

0800 POISON (0800 764766).

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

benzodiazepine

receptors,

such

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.

5.2 Pharmacokinetic properties

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.

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Biotransformation

The carboxylic acid was identified in free and conjugated form as the main metabolite in

human

urine.

pharmacological

tests,

this

main

metabolite

inactive

benzodiazepine agonist or antagonist.

Elimination

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

benzodiazepines

midazolam,

flunitrazepam

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

long-term

animal

studies

carcinogenic

potential

flumazenil

have

been

performed.

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Reproductive and developmental toxicity

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).

6.

PHARMACEUTICAL PARTICUALRS

6.1 List of excipients

Disodium edetate,

Acetic acid,

Sodium chloride,

Sodium hydroxide,

Water for injections.

6.2 Incompatibilities

No data available.

6.3 Shelf life

24 months from date of manufacture

6.4 Special precautions for storage

Store below 25ºC.

6.5 Nature and contents of container

Flumazenil Injection 0.5 mg/ 5 mL 5 x 5 mL ampoules

Flumazenil Injection 1 mg/ 10 mL 5 x 10 mL ampoules (not marketed)

6.6 Special precautions for disposal

Any unused medicine or waste material should be disposed of in accordance with local

requirements.

7.

MEDICINE SCHEDULE

Prescription Medicine

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8.

SPONSOR

Pfizer New Zealand Limited

P O Box 3998

Auckland, New Zealand

Toll Free Number: 0800 736 363

9.

DATE OF FIRST APPROVAL

15 March 2007

10. DATE OF REVISION OF THE TEXT

22 January 2019

Summary table of changes

Section changed

Summary of new information

Reformatting according to new Medsafe datasheet guidance

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