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FLUMAZENIL 0.1MG/ML SOLUTION FOR INJECTION

Active substance(s): FLUMAZENIL

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Flumazenil 0.1mg/ml
Solution for Injection
Read all of this leaflet carefully before you start taking
this medicine.
• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or
pharmacist.
• This medicine has been prescribed for you. Do not pass
it on to others. It may harm them, even if their symptoms
are the same as yours.
• If any of the side effects gets serious, or if you notice any
side effects not listed in this leaflet, please tell your doctor
or pharmacist.
• The name of your medicine is Flumazenil solution for
injection, which will be referred to as ‘Flumazenil’ or
‘Flumazenil 0.1mg/ml Solution for Injection’ throughout
this leaflet.
In this leaflet:
1 What Flumazenil 0.1mg/ml Solution
for Injection is and what it is used for
2 Before you use
3 How you use
4 Possible side effects
5 How to store
6 Further information

1 What Flumazenil 0.1mg/ml Solution for Injection is
and what it is used for

Flumazenil 0.1mg/ml Solution for Injection contains the active ingredient
flumazenil. Flumazenil belongs to a group of medicines known as
benzodiazepine antagonists.
Flumazenil is used to reverse the effects of a group of medicines known
as benzodiazepines, which are used to cause deep sleep. By reversing the
effects of benzodiazepines, it allows the patient to become conscious so
that they can breathe unaided.
Flumazenil can be used to partly or completely reverse the effects of
benzodiazepine sedation and general anaesthesia after medical tests and
operations in the hospital. It is used on intensive care patients to bring
about unaided breathing. It is also used to diagnose and treat patients
who have been given, or taken too much, benzodiazepines.
Flumazenil is also used in children (more than 1 year old) to wake them
up after they have been given a ‘benzodiazepine’ medicine to make them
sleepy during a medical procedure.

2 Before you use
Do not use Flumazenil 0.1mg/ml Solution for Injection if you:

• are allergic (hypersensitive) to flumazenil or any of the other ingredients
of Flumazenil 0.1mg/ml Solution for Injection (see list of ingredients
in Section 6). An allergic reaction may include rash, itching, difficulty
breathing or swelling of the face, lips, throat or tongue.
• are receiving benzodiazepines to control a life-threatening condition,
such as intracranial pressure (pressure on the brain) or status
epilepticus (continuous fits).
• have taken or been given too much benzodiazepines and certain
antidepressants.
• have side effects caused by too much of certain antidepressants.
Continued top of next column

Information for the healthcare professional only
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Flumazenil 0.1 mg/ml solution for injection.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml contains 0.1 mg flumazenil.
1 ampoule with 5 ml contains 0.5 mg flumazenil.
1 ampoule with 10 ml contains 1 mg flumazenil.
Excipient: each ml of solution contains 3.8 mg sodium.
For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM
Solution for injection.
Clear colourless solution.

4 CLINICAL PARTICULARS
4.1 Therapeutic indications

Flumazenil is indicated for the complete or partial reversal of the
central sedative effects of benzodiazepines. It may therefore be used in
anaesthesia and in the intensive care in the following situations:
In anaesthesia
• Termination of hypnosedative effects in general anaesthesia induced
and/or maintained with benzodiazepines in hospitalized patients.
• Reversal of benzodiazepine sedation in short-term diagnostic and
therapeutic procedures in ambulatory patients and hospitalized
patients.
In intensive care situations
• For the specific reversal of the central effects of benzodiazepines, in
order to restore spontaneous respiration.
• For diagnosis and treatment of intoxications or overdose with only or
mainly benzodiazepines.
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 anaesthesist
or doctor with experience in anesthesiology. Flumazenil may be
administered either undiluted or diluted.
For dilution, see section 6.6.
It can be administered together with other reanimation measures.
Adults
Anaesthesia
The initial dose is 0.2 mg administered i.v. in 15 seconds. If the desired
degree of consciousness is not obtained within 60 seconds, a second
dose of 0.1 mg can be administered. This may be repeated at 60-second
intervals where necessary, up to a total dose of 1.0 mg. The usual dose is
0.3-0.6 mg, but may deviate depending on the patient’s characteristics and
the benzodiazepine used.
Intensive Care
The recommended initial dose of flumazenil is 0.3 mg i.v. If the desired
level of consciousness is not obtained within 60 seconds, a repeat dose
of 0.1 mg 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 i.v. infusion of 0.1 - 0.4 mg per hour has also been shown
to be useful. The dosage and the rate of infusion should be individually
adjusted to the desired level of sedation.
If no clear effect on awareness and respiration is obtained after repeated
dosing, it should be considered that the intoxication is not due to
benzodiazepines.
Infusion should be discontinued every 6 hours to verify whether
resedation occurs.
In the intensive care unit, in patients treated for a long period of time
with high doses of benzodiazepines, the individually titrated injections
of Flumazenil, slowly administered, should not produce withdrawal
symptoms (see section 4.4).
Elderly
In the absence of data on the use of flumazenil in elderly patients, it should
be noted that this population is generally more sensitive to the effects of
medicinal products and should be treated with due caution.
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 a 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.
Because of the potential for resedation and respiratory depression children
previously sedated with midazolam should be monitored at least 2 hours
after flumazenil administration. In case of other sedating benzodiazepines,
the monitoring time must be adjusted according to their expected
duration.
Children under the age of 1 year
There are insufficient data on the use of flumazenil in children under 1
year. Therefore flumazenil should only be administered in children under 1
year if the potential benefits to the patient outweigh the possible risk.
Patients with renal or hepatic impairment
In patients with impaired hepatic function, the elimination of flumazenil
may be delayed (see section 5.2) and therefore reduced dosage for the
repeated doses (not for the initial dose) is recommended. No dosage
adjustments are required in patients with renal impairment.

4.3 Contraindications

Flumazenil is contraindicated in patients:
• with hypersensitivity to the active substance or any of the excipients
• who have been administered benzodiazepines for the treatment
of a potentially life-threatening condition (e.g. increased intracranial
pressure or status epilepticus).

Continued top of next column

Take special care with Flumazenil 0.1mg/ml Solution for
Injection

• if sedation was brought on by other medicines than benzodiazepines.
Flumazenil will usually not have an effect because it is meant to reverse
the effects of benzodiazepines only.
• in children below the age of 1 year. Flumazenil should only be given
to children below the age of 1 year if considered absolutely necessary
(e.g. in case of accidental intake of benzodiazepine tablets).
• if you have a severe head injury. Flumazenil can cause increased
pressure on the brain.
• if you are anxious about the operation or suffer from general anxiety.
Flumazenil should be given with care.
• if you are treated with flumazenil because you took too much of several
medicines at once. Flumazenil may worsen some of the side effects that
can occur.
• if you suffer from epilepsy and you have received benzodiazepines for
longer periods. Flumazenil can cause convulsions.
• if you have a history of alcohol or drug abuse
• if you are on a controlled sodium diet
• if you have received benzodiazepines for long periods. Flumazenil
can cause withdrawal symptoms, especially when administered rapidly.
If, despite careful dosing, withdrawal symptoms occur, your doctor may
consider treatment with low doses of benzodiazepines.
• if you suffer from liver disease. Your doctor may need to adjust the dose
of flumazenil.
• if you receive this medicine for the reversal of benzodiazepine effects.
Your doctor will frequently monitor you.
• if you have a history of panic disorder. Panic attacks have been
reported after the use of flumazenil in patients with a history of panic
disorder.
If any of the above apply to you, or if you are not sure,contact your doctor
or nurse before you have Flumazenil 0.1mg/ml Solution for Injection.
Flumazenil is not recommended for the treatment of benzodiazepine
dependence or for the treatment of benzodiazepine withdrawal
symptoms.
In some cases it may be preferable to keep you lightly sedated, e.g. just
after an operation of if you have post-operative pain.

Taking other medicines

Please tell your doctor or pharmacist if you are taking, or have recently
taken, any other medicines, including medicines obtained without a
prescription. This is especially important for the following medicines as
they may interact with your Flumazenil 0.1mg/ml Solution for Injection:
• medicines working in the same way as benzodiazepines e.g. zopiclone
(a type of sleeping pill) and triazolopyridazine. Flumazenil may decrease
the effects of these medicines.
• antidepressants or other treatments for mental illness (such as
amitriptyline, imipramine or dosulepin)
It may still be all right for you to be given Flumazenil and your doctor will
be able to decide what is suitable for you.

Pregnancy and breast-feeding

There are insufficient data on use of Flumazenil in human pregnancy for
an assessment of possible harmful effects. To date, there is no evidence of
harmful effects in animal studies. Tell your doctor if you are pregnant or if
you want to become pregnant.
It is not known whether Flumazenil passes into breast milk. In emergency
situations, Flumazenil can be administered to a patient who is
breastfeeding.
Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

You should not drive or use machines for at least 24 hours after your
treatment.
Continued over page

• In mixed intoxications with benzodiazepines and tricyclic and/or
tetracyclic anitdepressants, 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

Use in children for other indications than reversal of conscious sedation is
not recommended as no controlled studies are available. The same applies
for children below the age of 1 year.
• Until sufficient data are available, flumazenil should only be
administered to children below the age of 1 year 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 rapid return to consciousness.
In patients (e.g. with cardiac problems), maintenance of a certain degree
of sedation during the early post-operative period may be preferable to
complete consciousness.
• Rapid injection of flumazenil should be avoided. In patients with high
dose and/or long-term 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 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 anti convulsant 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.
• 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 of benzodiazepine
dependence or for the treatment of protracted benzodiazepine
abstinence syndromes.
• Panic attacks have been reported after the use of Flumazenil in patients
with a history of panic disorder.
• Due to the increased frequency of benzodiazepines tolerance and
dependence in patients with alcoholism and other drug dependencies,
Flumazenil should be used with caution in its population.
• This medicinal product contains approximately 3.8 mg sodium per ml of
flumazenil solution for injection. This should 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 receptor. The effects of non-benzodiazepine
agonists that act via the benzodiazepine receptor, such as zopiclon,
triazolopyridazine and others, are also blocked by flumazenil. However,
flumazenil does not block the effect of medicines that do not operate
via this route. Interaction with other centrally acting substances has
not been observed. The pharmacokinetics of benzodiazepines are not
influenced by the antagonist flumazenil. Particular caution is necessary
when using flumazenil in cases of accidental overdose since the toxic
effects of other psychotropic medicinal products (especially tricyclic
antidepressants) taken concurrently may increase with the subsidence of
the benzodiazepine effect.
On administering flumazenil concomitantly with the benzodiazepines
midazolam, flunitrazepam and lormetazepam, the pharmacokinetic
parameters of flumazenil were unaffected.
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.

Continued over page

Important information about some of the ingredients of
Flumazenil 0.1mg/ml Solution for Injection

This medicinal product contains 3.8mg sodium per ml of Flumazenil
0.1mg/ml Solution for Injection . This should be taken into consideration
by patients on a controlled sodium diet.

3 How you use
Dosage
Flumazenil is given intravenously (into a vein) by an anaesthesist or
experienced doctor.
Adults
The dose depends on the situation and is between 0.2mg and 2mg.
The usual starting dose for adults is 0.2mg administered intravenously
over 15 seconds. If the required level of consciousness is not obtained
within 60 seconds, a further dose of 0.1mg can be injected and repeated
at 60-second intervals to a maximum of 1mg during anaesthesia and 2mg
in intensive care.
Treatment is stopped every 6 hours to see if sedation occurs again.
For children over 1 year
In children (above 1 year of age), the dose is 10 micrograms /kg (body
weight) to a maximum of 50 micrograms//kg. The dose in children may
never exceed 1mg.
The usual starting dose is 10 micrograms /kg (body weight) (up to 200
micrograms), given intravenously over 15 seconds. If, after a waiting for
45 seconds, the required level of consciousness is not obtained another
injection of 10 micrograms /kg (body weight) (up to 200 micrograms)
may be given and repeated at 60-second intervals (up to a maximum of
4 times) to a maximum dose of 50 micrograms /kg (body weight) or 1mg,
depending on which is the lowest dose.
Patients with a liver disorder may need a lower dose.

If you use more Flumazenil 0.1mg/ml Solution for Injection
than you should

Flumazenil 0.1mg/ml Solution for Injection will be given to you by a doctor
or nurse who is familiar with this type of treatment so you will not be given
an overdose.

Withdrawal effects due to being given Flumazenil 0.1mg/ml
Solution for Injection

If you have taken benzodiazepines for long periods, Flumazenil 0.1mg/
ml Solution for Injection can cause withdrawal symptoms (see withdrawal
symptoms in Section 4).
If you have any further questions on the use of this product, ask your
doctor or pharmacist.

4 Possible side effects

Like all medicines, Flumazenil 0.1mg/ml Solution for Injection can cause
side effects, although not everybody gets them.
Tell your doctor straight away if you experience allergic reactions • sudden wheezing, difficulty in breathing, swelling of the eyelids, face or
lips, rash or itching (especially affecting your whole body)
• palpitations (irregular heartbeats), tachycardia or bradycardia (fast or slow
heart rate), extrasystole (a premature contraction of the heart)
• seizures - in patients suffering from epilepsy or severe liver disease, mainly
after long-term treatment with benzodiazepines or other drugs that can
be abused.
The following side effects have been reported:
Common (affects 1 to 10 users in 100)
• vertigo (spinning sensation), headache, agitation, tremor
• diplopia (double vision), strabismus (squinting), lacrimation (weeping
eye)
• hypotension (low blood pressure), orthostatic hypotension (dizziness on
standing)
• nausea (feeling sick) (after operation), vomiting (after operation,
particularly if opiates have been used)
• sweating
• fatigue, injection site pain

Uncommon (affects 1 to 10 users in 1,000)
• anxiety, fear
• dyspnea (breathlessness), cough, nasal congestion
Not known side effects (frequency cannot be estimated from the
available data)
• withdrawal symptoms (agitation, anxiety, emotional lability, confusion,
sense-related distortion), panic attacks, abnormal crying, agitation,
aggressive reactions
• temporary increased blood pressure (on awakening)
• flushing
• chills
If any of the side effects gets serious, or if you notice any side effects
not listed in this leaflet, please tell your doctor or pharmacist.

5 How to store

Keep out of the reach and sight of children.
Do not use Flumazenil 0.1mg/ml Solution for Injection after the expiry
date which is stated on the carton after EXP. The expiry date refers to the
last day of that month.
Store in the original package. Do not refrigerate or freeze.
After opening, the product should be used immediately.
This medicinal product is for single use only and any unused solution
should be discarded. Please inspect the medicinal product visually.
It should only be used if the solution is clear and practically free form
particles.
Chemical and physical in-use stability has been demonstrated for 48 hours
at 25 ºC.
From a microbiological point of view, the product should be used
immediately. If not used immediately, in-use storage times and conditions
prior to use are the responsibility of the user and would normally not
be longer than 24 hours at 2 to 8 ºC, unless dilution has taken place in a
controlled and validated aseptic conditions.
Medicines should not be disposed of via wastewater or household waste.
Ask your pharmacist how to dispose of medicines no longer needed.
These measures will help to protect the environment.

6 Further information
What Flumazenil 0.1mg/ml Solution for Injection contains

The active substance is flumazenil. Each 5ml ampoule contains 0.5mg
flumazenil. Each 10ml ampoule contains 1mg flumazenil.
The other ingredients are: disodium edetate, glacial acetic acid, sodium
chloride, sodium hydroxide, hydrochloric acid and water for injections.

What Flumazenil 0.1mg/ml Solution for Injection looks like
and contents of the pack

Carton boxes with 1, 5, 6, 10 or 12 glass ampoules containing 5ml or 10ml
solution for injection.
Not all pack sizes may be marketed.
Marketing Authorisation Holder
Actavis Group PTC ehf
Reykjavíkurvegur 76-78,
220 Hafnarfjörður
Iceland
Manufacturer
Synthon Hispania SL
Castello 1, Poligono Las Salinas
08830 San Boi de Llobregat - Barcelona
Spain
This leaflet was last revised in October 2011

Continued top of next column
AAAC7774

Actavis, Barnstaple, EX32 8NS, UK

4.8 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), not known
(cannot be estimated from the available data).
Immune systems disorders
Common
Psychiatric disorders
Uncommon
Not known

Nervous system disorders
Common
Not known

Eye disorders
Common
Cardiac disorders
Uncommon
Vascular disorders
Common
Not known
Respiratory, thoracic and
mediastinal disorders
Uncommon
Gastrointestinal disorders
Common
Skin and subcutaneous tissue
disorders
Common
Not known
General disorders and
administration site conditions
Common
Not known

Allergic reactions.
Anxiety*, fear*
Withdrawal symptoms (e.g.,
agitation, anxiety, emotional lability,
confusion, sensory distortions),
following rapid injection of doses of
1 mg or more in patients with highdose 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).
Vertigo, headache, agitation*, tremor.
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 abuse).
Diplopia, strabismus, lacrimation
increased.
Palpitations*
tachycardia or bradycardia,
extrasystole.
Hypotension, orthostatic
hypotension,.
Transient increased blood pressure
(on awakening).
Dyspnea, cough, nasal congestion.
Nausea, vomiting: during postoperative use, particularly if opiates
have also been used.
Sweating
Flushing.
Fatigue, injection site pain.
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 flumazenil. 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

Pharmacotherapeutic group: Antidotes.
ATC code: V03A B25
Flumazenil, an imidazobenzodiazepine, is a benzodiazepine antagonist
which, by competitive interaction, blocks the effects of substances acting
via the benzodiazepine-receptor. Neutralisation of paradoxal reactions of
benzodiazepines has been reported.
According to experiments in animals, the effects of substances, which
are not acting via the benzodiazepinereceptor (like barbiturates, GABAmimetics and adenosinereceptor agonists), are not blocked by flumazenil.
Non-benzodiazepine-agonists, like cyclopyrrolones (zopiclon) and
triazolopyridazines, are blocked by flumazenil. The hypnosedative effects
of benzodiazepines are blocked rapidly (within 30-60 seconds) after
intravenous administration. Depending on the difference in elimination
time between agonist and antagonist, the effect can recur after several
hours. Flumazenil has possibly a slight agonistic, anticonvulsive effect.
Flumazenil caused withdrawal, including convulsions in animals receiving
long-term flumazenil treatment. Flumazenil is well tolerated, even in high
doses.

5.2 Pharmacokinetic properties

Elimination
Almost no unchanged flumazenil is excreted in the urine. This indicates
a complete metabolic degradation of the active substance in the body.
Radiolabelled medicinal product is completely eliminated within 72 hours,
with 90 to 95 % of the radioactivity appearing in the urine and 5 to 10 %
in the faeces. Elimination is rapid, as is shown by the short half life of 40 to
80 minutes. The total plasma clearance of flumazenil is 0.8 to 1.0 L/hour/kg
and can almost completely be attributed to hepatic metabolism.
The pharmacokinetics of flumazenil is dose-proportional within the
therapeutic dose-range and up to 100 mg.
The intake of food during the intravenous infusion of flumazenil results in
an increase of 50% of the clearance probably due to postprandial increase
in liver perfusion.
Pharmacokinetics in special patient groups
Elderly:
The pharmacokinetics of flumazenil in elderly is not different from that in
young adults.
Patients with impaired hepatic function:
In patients with a moderately to severely impaired liver function the
half life of flumazenil is increased (increase of 70 – 210 %) and the total
clearance is lower (between 57 and 74 %) compared to normal healthy
volunteers.
Patients with impaired renal function:
Pharmacokinetics of flumazenil is not different in patients with impaired
renal function or patients undergoing haemodialysis compared to normal
healthy volunteers.
Paediatric pop
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 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

Late prenatal as well as per- and postnatal exposure to flumazenil
induced both behavioural alterations and an increase of hippocampal
benzodiazepine receptor density in the rat offspring. The effect of these
findings is not considered relevant if the product is used for a very short
time as instructed.

6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients

Disodium edetate
Glacial acetic acid
Sodium chloride
Sodium hydroxide (10% m/V) for pH adjustment
Hydrochloric acid (10% m/V) for pH adjustment
Water for Injections.

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products
except for those mentioned in section 6.6.

6.3 Shelf life

3 years.
Shelf life after first opening:
After first opening the medicinal product should be used immediately.
Shelf life after dilution:
Chemical and physical in-use stability has been demonstrated for 48 hours
at 25 ºC.
From a microbiological point of view, the product should be used
immediately. If not used immediately, in-use storage times and conditions
prior to use are the responsibility of the user and would normally not
be longer than 24 hours at 2 to 8 ºC, unless dilution has taken place in a
controlled and validated aseptic conditions.

6.4 Special precautions for storage
Store in the original package.
Do not refrigerate or freeze.

6.5 Nature and contents of container

Carton boxes with 1, 5, 6, 10 or 12 ampoules (glass Type I) containing 5 ml
solution for injection.
Carton boxes with 1, 5, 6, 10 or 12 ampoules (glass Type I) containing 10 ml
solution for injection.
Not all pack sizes may be marketed.

6.6 Special precautions for disposal

This medicinal product is for single use only and any unused solution
should be discarded.
Please inspect the medicinal product visually. It should only be used if the
solution is clear and practically free form particles.
When Flumazenil is to be used in infusion, it must be diluted prior to
infusion. Flumazenil should only be diluted with sodium chloride 9 mg/
ml (0.9 %) solution, dextrose 50 mg/ml (5 %) solution or Lactated Ringer’s
solution. Compatibility between flumazenil and other solutions for
injection has not been established.
Intravenous infusion solutions or syringes filled with a flumazenil solution
should be discarded after 24 hours.
From a microbiological point of view the product should be used
immediately after diluting. If the diluted product is not used immediately,
the user/administrator is responsible for the terms of use employed and
storage conditions for administration.

7 MARKETING AUTHORISATION HOLDER
Actavis Group PTC ehf
Reykjavíkurvegur 76-78,
220 Hafnarfjörður
Iceland

Distribution
Flumazenil is a lipophilic weak base. Flumazenil is bound for approximately
50% to plasma proteins, from which two thirds are bound to albumin.
Flumazenil is extensively divided over extravascular space. During the
distribution phase plasma concentration of flumazenil decreases with
a half life of 4-11 minutes. The distribution volume under steady-state
conditions (Vss) is 0.9 – 1.1 L/kg.

8 MARKETING AUTHORISATION NUMBER(S)

Metabolism
Flumazenil is mainly eliminated through hepatic metabolism. The
carboxilic acid metabolite was shown in plasma (in free form) and in urine
(in free and conjugated form) to be the most important metabolite.
In pharmacological tests this metabolite has proved to be inactive as
benzodiazepine agonist or antagonist.

10 DATE OF REVISION OF THE TEXT

Continued top of next column
AAAC7774

PL 30306/0385

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
04/07/2011

October 2011

Actavis, Barnstaple, EX32 8NS, UK

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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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