New Zealand - English - Medsafe (Medicines Safety Authority)
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NEW ZEALAND DATA SHEET
DBL™ Flumazenil Injection
QUALITATIVE AND QUANTITATIVE COMPOSITION
administration). and also the following ingredients: disodium edetate, acetic acid, sodium
chloride, sodium hydroxide in water for injections adjusted to pH 4.0. DBL
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.
DBL™ Flumazenil Injection is a colourless to almost colourless clear liquid, adjusted to pH
Solution for injection
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
Flumazenil Injection should be administered intravenously by an anaesthetist or
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
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
Children > 1 year of age (see section 4.4)
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.
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
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
4.4 Special warnings and precautions for use
benzodiazepine withdrawal at high doses (also see section 5.1 and section 4.8).
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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
an appropriate period based on the dose
and duration of effect of the
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
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
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.
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
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
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
benzodiazepine effect by flumazenil.
4.6 Fertility, pregnancy and lactation
No data available.
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
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
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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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.
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
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 has been reported to provoke panic attacks in patients with a history of panic
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicine is important. It
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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).
5.1 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
adenosine receptor agonists and other agents were not affected by flumazenil, but those of
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
5.2 Pharmacokinetic properties
The pharmacokinetics of flumazenil is dose-proportional within and above the therapeutic
range (up to 100 mg).
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
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The carboxylic acid was identified in free and conjugated form as the main metabolite in
benzodiazepine agonist or antagonist.
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
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.
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
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.
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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
6.1 List of excipients
Water for injections.
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
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Pfizer New Zealand Limited
P O Box 3998
Auckland, New Zealand
Toll Free Number: 0800 736 363
DATE OF FIRST APPROVAL
15 March 2007
10. DATE OF REVISION OF THE TEXT
22 January 2019
Summary table of changes
Summary of new information
Reformatting according to new Medsafe datasheet guidance