ANEXATE 500MICROGRAMS/5ML SOLUTION FOR INJECTION OR INFUSION

Active substance: FLUMAZENIL

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Anexate® 500 micrograms/5ml Solution for Injection or Infusion

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 5ml ampoule contains 500 micrograms of flumazenil (100 micrograms per ml).
Excipient: Sodium 3.7 mg/ml
For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM
Solution for Injection or infusion.
A clear, almost colourless, sterile aqueous solution.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Anexate is indicated for the complete or partial reversal of the central sedative effects of
benzodiazepines. It may therefore be used in anaesthesia and intensive care in the
following situations:
Termination of general anaesthesia induced and/or maintained with benzodiazepines.
Reversal of benzodiazepine sedation in short diagnostic and therapeutic procedures.
For the specific reversal of the central effects of benzodiazepines, to allow return to
spontaneous respiration and consciousness, in patients in intensive care.
For the reversal of conscious sedation induced with benzodiazepines in children > 1 year
of age.

4.2

Posology and method of administration
Flumazenil must be administered intravenously by an anaesthetist or a doctor with
experience in anaesthesiology. flumazenil may be administered either undiluted or
diluted.
For dilution, see section 6.6.
It can be administered together with other reanimation measures.
Anaesthesiology:
The initial dose is 200 micrograms administered intravenously in 15 seconds. If the
desired degree of consciousness is not obtained within 60 seconds, a second dose of 100
micrograms can be administered. This may be repeated at 60-second intervals where
necessary, up to a maximum total dose of 1 mg. The usual dose is 300–600 micrograms.
Intensive care:
The recommended initial dose of flumazenil is 300 micrograms intravenously. If the
desired level of consciousness is not obtained within 60 seconds, a repeat dose of 100
micrograms may be administered. If necessary, this may be repeated at 60 second
intervals up to a total dose of 2 mg. If drowsiness recurs, a second bolus injection of
flumazenil may be administered. An intravenous infusion of 100–400 micrograms per
hour has also been shown to be useful. The dosage and rate of infusion should be
individually adjusted to achieve the desired level of sedation.
Children above 1 year of age:
For the reversal of conscious sedation induced with benzodiazepines in children > 1 year
of age, the recommended initial dose is 10 micrograms/kg (up to 200 micrograms)
administered intravenously over 15 seconds. If the desired level of consciousness is not
obtained after waiting an additional 45 seconds, further injection of 10 micrograms/kg
may be administered (up to 200 micrograms) and repeated at 60 second intervals where
necessary (a maximum of 4 times) to a maximum total dose of 50 micrograms/kg or 1
mg, whichever is lower. The dose should be individualised based on the patient’s
response. No data are available on the safety and efficacy of repeated administration of
flumazenil to children for re-sedation.
Elderly
No specific data are available on the use of Anexate in the elderly, but it should be
remembered that this population is more sensitive to the effects of benzodiazepines and
should be treated with due caution.
Use in renal and hepatic insufficiency
No dosage adjustments are necessary in patients with renal impairment. However, since
flumazenil is primarily metabolised in the liver, careful titration of dosage is
recommended in patients with impaired hepatic function.
The individually titrated, slow injections or infusions of Anexate should not produce
withdrawal symptoms, even in patients exposed to high doses of benzodiazepines and/or
for long periods of time. If, however, unexpected signs of overstimulation occur, an

individually titrated dose of diazepam (Valium) or midazolam (Hypnovel) should be
given by slow intravenous injection.
If a significant improvement in consciousness or respiratory function is not obtained after
repeated doses of Anexate, a non-benzodiazepine aetiology must be assumed.

4.3

Contraindications
Flumazenil is contra-indicated in patients:



with hypersensitivity to the active substance, benzodiazepines or any of the
excipients.
who have been administered benzodiazepines for the treatment of a potentially lifethreatening condition (e.g. increased intracranial pressure or status epilepticus).

In mixed intoxications with benzodiazepines and tricyclic and/or tetracyclic
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, Anexate should not be used to reverse benzodiazepine effects.

4.4

Special warnings and precautions for use
Until sufficient data are available, flumazenil should only be administered to children if
the risks to the patient (especially in the case of accidental overdose) have been weighed
up against the benefits of the treatment.
Elimination may be delayed in patients with hepatic impairment.
The antagonistic effect of flumazenil is specific to benzodiazepines; an effect is therefore
not to be expected if the ‘non-awakening’ is caused by other substances. If flumazenil is
administered for anaesthesiology at the end of the operation, the effect of the peripheral
muscle relaxants must first have disappeared. Because flumazenil generally has a shorter
duration of action than the benzodiazepines and therefore sedation can re-occur, the
clinical state of the patient must be monitored, preferably in the intensive care unit, until
the effect of flumazenil is eliminated.
In high-risk patients, the benefits of a benzodiazepine-induced sedation should be
weighed up against the risks of a rapid return to consciousness. In patients (e.g. with
cardiac problems), maintenance of a certain degree of sedation during the early postoperative period may be preferable to complete consciousness.
Rapid injection of flumazenil should be avoided. In patients with high dose and/or longterm exposure to benzodiazepines ending at any time within the weeks preceding
flumazenil administration, rapid injection of doses equal to or higher than 1 mg has led to
withdrawal symptoms, including palpitations, agitation, anxiety, emotional lability as
well as mild confusion and sensory distortions.

In patients who are anxious during the pre-operative phase or in patients who are known
to suffer from chronic or transient anxiety, the dosage of flumazenil should be adjusted
carefully.
However, after major surgery, the post operative pain should be considered and it may be
preferable to keep the patient lightly sedated.
For patients who have been treated chronically with high doses of benzodiazepines, the
advantages of the use of flumazenil should be carefully weighed up against the risk of
withdrawal symptoms; if, despite careful dosing, withdrawal symptoms occur, treatment
with low doses of benzodiazepines, titrated intravenously according to the patient’s
response, may be considered if necessary.
Use of the antagonist is not recommended in patients with epilepsy who have been treated
with benzodiazepines for a prolonged period. Although flumazenil exerts a slight
intrinsic anticonvulsant effect, the abrupt suppression of the protective effect of a
benzodiazepine agonist can induce convulsions in epileptic patients.
In patients with severe brain injury (and/or instable intracranial pressure) who are being
treated with flumazenil – to antagonise the effects of benzodiazepines – increased
intracranial pressure may develop
When Anexate is used with neuromuscular blocking agents, it should not be injected until
the effects of neuromuscular blockade have been fully reversed.
Particular caution is necessary when using flumazenil in cases of mixed-drug overdose.
In particular in the case of an intoxication with benzodiazepines and cyclic
antidepressants, certain toxic effects such as convulsions and cardiac arrhythmias, which
are caused by these antidepressants but which emerge less readily on concomitant
administration with benzodiazepines, are exacerbated on administration of flumazenil.
Patients who have received flumazenil for the reversal of Benzodiazepine effects should
be monitored for resedation, respiratory depression or other residual benzodiazepine
effects for an appropriate period based on the dose and duration of effect of the
benzodiazepine employed.
Flumazenil is not recommended for the treatment for benzodiazepine dependence or for
the treatment of protracted benzodiazepine abstinence syndromes.
This medicine contains 3.7 mg sodium per ml (18.5 mg per 5 ml vial). Dosages over 600
micrograms contain more than 1 mmol sodium (23 mg). To be taken into consideration
by patients on a controlled sodium diet.

4.5

Interaction with other medicinal products and other forms of interaction
Flumazenil antagonises the central effects of benzodiazepines by competitive interaction
at the receptor. The effects of non-benzodiazepine agonists that act via the
benzodiazepine receptor, such as zopiclone, triazolpyridazine and others, are also blocked

by flumazenil. Interactions with other centrally acting substances have not been
observed. The pharmacokinetics of benzodiazepines are not influenced by the antagonist
flumazenil.
On administering flumazenil concomitantly with the benzodiazepines midazolam,
flunitrazepam and lormetazepam, the pharmacokinetic parameters of flumazenil were
unaffected.
However, particular caution is necessary when using Anexate in cases of intentional
overdosage since the toxic effects of other psychotropic drugs (especially tricyclic
antidepressants) taken concurrently may increase with the subsidence of the
benzodiazepine effect.
There is no pharmacokinetic interaction between ethanol and flumazenil.

4.6

Pregnancy and lactation
There are insufficient data on use in human pregnancy for an assessment of possible
harmful effects and efficacy in the foetus. Caution is therefore required. To date, there is
no evidence of harmful effects in animal studies. The efficacy in the foetus has not been
investigated in animal studies.
It is not known whether flumazenil passes into breast milk. In emergency situations,
however, the parenteral administration of flumazenil to a patient who is breastfeeding is
not contraindicated.

4.7

Effects on ability to drive and use machines
Although patients are awake and conscious after administration of flumazenil, they
should be advised not to operate dangerous machinery or drive a vehicle during the first
24 hours because the effect of the earlier administered benzodiazepine may recur.

Undesirable effects
The adverse events listed below have been reported. Adverse events usually subside
rapidly without the need for special treatment.
Frequency categories are defined using the following convention: very common ( 1/10);
common ( 1/100 to <1/10); uncommon ( 1/1,000 to <1/100); rare ( 1/10,000 to
<1/1,000); very rare (<1/10,000); unknown (cannot be estimated from the available data).









4.8

Psychiatric disorders
Uncommon: anxiety, fear: following rapid injection, generally did not require treatment.
Unknown: Withdrawal symptoms (e.g., agitation, anxiety, emotional lability, confusion,
sensory distortions, tachycardia, dizziness, sweating), following rapid injection of doses
of 1 mg or more in patients with high-dose and/or long-term exposure to benzodiazepines
ending at any time within the weeks preceding flumazenil administration (see section 4.4);
panic attacks (in patients with a history of panic reactions); abnormal crying, agitation,

aggressive reactions (the side effect profile in children is generally similar to that in
adults. When Flumazenil has been used for the reversal of conscious sedation, abnormal
crying, agitation and aggressive reactions have been reported).
Nervous system disorders
Unknown: Seizures: particularly in patients known to suffer from epilepsy or severe
hepatic impairment, mainly after long-term treatment with benzodiazepines or in cases of
mixed-drug overdose (see section 4.4).
Cardiac disorders
Uncommon: Palpitations: following rapid injection, generally did not require treatment.
Unknown: Transient increases in heart rate (on awakening).
Vascular disorders
Unknown: Transient increased blood pressure (on awakening).
Gastrointestinal disorders
Common: Nausea: vomiting: during post-operative use, particularly if opiates have also
been used.
Skin and subcutaneous tissue disorders
Unknown: Flushing,
General disorders and administration site conditions
Rare: Hypersensitivity reactions (including anaphylaxis).
Unknown: Chills: following rapid injection, generally did not require treatment.

4.9

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.
There is very limited experience of acute overdose in humans with flumazenil.
There is no specific antidote for overdose with Anexate. Treatment should consist of
general supportive measures including monitoring of vital signs and observation of the
clinical status of the patient.
Even at dosages of 100 mg i.v., no symptoms of overdosage were observed.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Anexate, an imidazobenzodiazepine, is a specific competitive inhibitor of
substances which act via the benzodiazepine receptors, specifically blocking their
central effects. The hypnotic-sedative effects of the agonist are rapidly reversed

by Anexate and may then reappear gradually within a few hours, depending on
the half-life and dose ratio of the agonist and antagonist.

5.2

Pharmacokinetic properties
The pharmacokinetics of flumazenil are dose-proportional within and above the
therapeutic range (up to 100mg).
Distribution
Flumazenil, a weak lipophilic base, is about 50% bound to plasma proteins. Albumin
accounts for two thirds of plasma protein binding. Flumazenil is extensively distributed
in the extravascular space. Plasma concentrations of flumazenil decrease with a half-life
of 4 - 11 minutes during the distribution phase. The volume of distribution at steady state
is 0.9 – 1.1 l/kg.
Metabolism
Flumazenil is extensively metabolised in the liver. The carboxylic acid metabolite is the
main metabolite in plasma (free form) and urine (free form and its glucuronide). This
main metabolite showed no benzodiazepine agonist or antagonist activity in
pharmacological tests.
Elimination
Flumazenil is almost completely (99%) eliminated by nonrenal routes. 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 0.8 – 1.0 l/hr/kg and can be attributed almost
entirely to hepatic clearance.
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.
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. The pharmacokinetics of
flumazenil are not significantly affected in the elderly, by gender, haemodialysis or renal
failure.
Paediatric population
In children above one year old, the half life elimination is shorter and the variability is
higher than in adults, approximately of 40 min with a range of 20 to 75 min. Clearance
and volume of distribution, by kg of body weight are the same than in adults.

5.3

Preclinical safety data

There are no preclinical data of relevance to the prescriber which are additional to
that already included in other sections of the SPC.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Disodium Edetate
Glacial Acetic Acid
Sodium Chloride
Sodium Hydroxide
Water for Injections

6.2

Incompatibilities
None stated.

6.3

Shelf life
Unopened: 5 years.
The product should be used immediately after opening.

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container
Clear glass 5ml ampoules. Cartons of 5 or 25.

6.6

Instructions for use/handling
Anexate ampoule solution may be diluted with Sodium Chloride Intravenous
Infusion BP or Dextrose 5% Intravenous Infusion BP. Chemical and physical
stability has been demonstrated for 24 hours at room temperature.
Anexate infusion should be administered within 3 hours of preparation.
No preparations other than those recommended should be added to the Anexate
ampoule or mixed with the Anexate infusion solution.
For single use only. Discard any unused contents.

7.

MARKETING AUTHORISATION HOLDER
Roche Products Limited
6 Falcon Way
Shire Park
Welwyn Garden City
AL7 1TW
United Kingdom

8.
MARKETING AUTHORISATION NUMBER
PL 00031/0228

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
19/04/2005

10

DATE OF REVISION OF THE TEXT
13/06/2011

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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