Flumazenil is indicated for the complete or partial reversal of the central sedative effects of
benzodiazepines. It may therefore be used in anesthesia and in the intensive care in the following
situations:
In anesthesia
- Termination of hypnosedative effects in general anesthesia 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.
- For the reversal of conscious sedation induced with benzodiazepines in children > 1 year of age.
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 (see
section 4.4).

Posology:
Adults
- Anaesthesia
The recommended starting dose is 0.2 mg administered intravenously over 15 seconds. If the
required level of consciousness is not obtained within 60 seconds, a further dose of 0.1 mg can be
injected and repeated at 60-second intervals, up to a maximum dose of 1 mg. The usual dose is 0.3
to 0.6 mg, but may deviate depending on the patient's characteristics and the benzodiazepine used.
- Intensive Care
The recommended starting dose is 0.3 mg administered intravenously. If the required level of
consciousness is not obtained within 60 seconds, a further dose of 0.1 mg can be injected and
repeated at 60-second intervals, up to a total dose of 2 mg or until the patient awakes.
If drowsiness recurs, a second bolus injection of flumazenil may be administered. An intravenous
infusion of 0.1 – 0.4 mg/hour may be useful.
The dosage and rate of infusion should be adjusted individually to achieve the desired level of
consciousness.
If a significant improvement in consciousness or respiratory function is not obtained after repeated
doses of flumazenil, a non-benzodiazepine etiology must be assumed.
Infusion should be discontinued every 6 hours to verify whether re-sedation occurs.
To avoid withdrawal symptoms in patients treated for a long period of time with high doses of
benzodiazepines in the intensive care unit, the dosage of flumazenil has to be titrated individually
and the injection has to be administered slowly (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.
Patients with renal or hepatic impairment
Since flumazenil is primarily metabolized in the liver, careful titration of dosage is recommended in
patients with impaired hepatic function. No dosage adjustments are required in patients with renal
impairment.
Pediatric population
Children above 1 year of age
For the reversal of conscious sedation induced with benzodiazepines in children above 1 year of age,
the recommended initial dose is 0.01 mg/kg (up to 0.2 mg) administered intravenously over 15
seconds. If the desired level of consciousness is not obtained after waiting an additional 45 seconds,
further injection of 0.01 mg/kg may be administered (up to 0.2 mg) and repeated at 60 second
intervals where necessary (a maximum of 4 times) to a maximum total dose of 0.05 mg/kg or 1 mg,
whichever is lower. The dose should be individualized based on the patient's response. No data are
available on the safety and efficacy of repeated administration of flumazenil to children for resedation.
Children under the age of 1 year
There are insufficient data on the use of flumazenil in children younger than 1 year.
Therefore, flumazenil should only be administered in children younger than 1 year if the potential 

benefits to the patient outweigh the possible risk.

Method of administration:
For intravenous use only.
Flumazenil must be administered intravenously by an anesthetist or a doctor with experience in
anesthesiology.
Flumazenil may be administered as an infusion – for instructions on dilution of the medicinal
product before administration, see section 6.6.
Flumazenil may be used concomitantly with other resuscitative measures.

Use in children for other indications than reversal of conscious sedation is not recommended as no
controlled studies are available. 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 patient should be monitored for an adequate period of time based on the dose and duration of
effect of the benzodiazepine employed (ECG, pulse, oximetry, patient alertness and other vital
signs such as heart rate, respiratory rate and blood pressure).
- 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.
- When used in anesthesiology at the end of surgery, flumazenil should not be given until the
effects of peripheral muscle relaxants have been fully reversed.
- As the action of flumazenil is usually shorter than that of benzodiazepines and sedation may
possibly recur the patient should remain closely monitored, preferably in the intensive care unit,
until the effect of flumazenil has presumably worn off.
- In high-risk patients, the benefits of benzodiazepine-induced sedation should be weighed against
the risks of rapid awakening. In patients (e.g. with cardiac problems) maintenance of a certain level
of sedation may be preferable to being fully awake.
- 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 suffering from pre-operative anxiety or having a history of chronic or episodic anxiety
the dosage of flumazenil should be adjusted carefully.
- After major surgery, postoperative pain must be taken into account and it may be preferable to
keep the patient lightly sedated.
- In patients treated for long periods with high doses of benzodiazepines, the advantages of the use
of flumazenil should be weighed against the risk of withdrawal symptoms. If withdrawal symptoms

occur despite careful dosing individually titrated low doses of benzodiazepines (diazepam or
midazolam) should be given by slow intravenous injection.
- Because of the potential for re-sedation 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.
- The use of the antagonist is not recommended in patients with epilepsy, who have been treated
with benzodiazepines for a prolonged period of time. Although flumazenil has some intrinsic antiepileptic
effects, the abrupt antagonizing effect can cause convulsions in patients with epilepsy.
- In patients with severe brain injury (and/or instable intracranial pressure) receiving flumazenil –
to reverse the effects of benzodiazepines – an 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 re-sedation, respiratory depression or other residual benzodiazepine effects for an
appropriate period based on the dose and duration of effect of the benzodiazepine employed.
Because patients with underlying hepatic impairment may experience delayed effects as described
above, an extended observation period may be required.
- Flumazenil is not recommended for the treatment of benzodiazepine-dependence or for the
treatment of long-term 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.
Sodium content
This medicinal product contains approximately 3.7 mg sodium per ml of flumazenil solution for
injection/infusion.

Flumazenil reverses the central effects of benzodiazepines by means of competitive interaction at
receptor level: the effects of non-benzodiazepine agonists acting via the benzodiazepine receptor,
such as zopiclone, triazolopyridazine and others, are also antagonized by flumazenil. However,
flumazenil does not block the effect of medicines that do not operate via this route. Interaction with
other central nervous system depressants has not been observed. 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.
No change in the pharmacokinetics of flumazenil has been observed in combination with the
benzodiazepines midazolam, flunitrazepam and lormetazepam. Flumazenil does not affect the
pharmacokinetics of these benzodiazepines.
There is no pharmacokinetic interaction between ethanol and flumazenil

Emergency use of flumazenil during pregnancy and lactation is not contraindicated.
Pregnancy
Flumazenil should only be used during pregnancy if the possible benefit to the patient outweighs the
potential risks for the fetus.
Breast-feeding
It is not known whether flumazenil is excreted in human milk. For this reason, breast-feeding should
be interrupted for 24 hours when flumazenil is used during lactation.
Fertility
Although studies in animals have not shown evidence of embryo toxicity or teratogenicity, the
possible risk to humans caused by flumazenil during pregnancy has not been determined (see
section 5.3).

Patients who have received flumazenil to reverse the effects of benzodiazepine sedation should be
warned not to drive, to operate machinery or to engage in other activities demanding physical or
mental exertion for at least 24 hours, since the effect of the benzodiazepine may return.

Any side-effects associated with Flumazenil usually subside rapidly without the need for special
treatment.
Frequency categories are defined using the following convention

The adverse events listed below have been reported.
Immune systems disorders
Common: Allergic reactions
Rare: Severe hypersensitivity reactions (including anaphylaxis)
Psychiatric disorders
Common: Anxiety*, emotional lability, insomnia, somnolence
Uncommon: Fear
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
Common: Vertigo, headache, agitation*, tremor, dry mouth, hyperventilation, speech
disorder, paresthesia
Uncommon: Convulsions (in patients suffering epilepsy or severe hepatic insufficiency, mainly
after long-term treatment with benzodiazepines or multiple medicinal products
abuse, see section 4.4).
Eye disorders
Common: Diplopia, strabismus, lacrimation increased
Ear and labyrinth disorders
Uncommon: Abnormal hearing
Cardiac disorders
Common: Palpitations*
Uncommon: Tachycardia or bradycardia, extrasystole
Vascular disorders
Common: Flushing, hypotension, orthostatic hypotension, transient increased blood pressure
(on awakening)
Respiratory, thoracic and mediastinal disorders
Uncommon: Dyspnea, cough, nasal congestion, chest pain
Gastrointestinal disorders
Very common: Nausea (during anesthesia)
Common: Vomiting (during anesthesia), hiccup
Skin and subcutaneous tissue disorders
Common: Sweating
General disorders and administration site conditions
Common: Injection site pain
Uncommon: Shivering
Rare: Severe hypersensitivity reactions (including anaphylaxis)
*: following rapid injection, generally did not require treatment

To report any side effect(s):
Saudi Arabia:
The National Pharmacovigilance and Drug Safety Centre (NPC)
Fax: +966-11-205-7662
Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
Toll free phone: 8002490000
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc
Other GCC States:
Please contact the relevant competent authority.

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 when administered intravenously at doses of 100 mg, no symptoms of overdose attributable to
flumazenil have been observed.

Pharmacotherapeutic group: All other therapeutic products, 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. Neutralization
of paradoxal reactions of benzodiazepines has been reported.
According to experiments in animals, the effects of substances, which are not acting via the
benzodiazepine-receptor (like barbiturates, GABA-mimetics and adenosine-receptor agonists), are
not blocked by flumazenil. Non-benzodiazepine-agonists, like cyclopyrrolones (zopiclone) and
triazolopyridazines, are blocked by flumazenil. The hypnosedative effects of benzodiazepines are
blocked rapidly (within 1-2 minutes) 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

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 extra
vascular space. During the distribution phase plasma concentration of flumazenil decreases with a
half-life of 4-15 minutes. The distribution volume under steady-state conditions (Vss) is 0.9-1.1
L/kg.
Biotransformation
Flumazenil is mainly eliminated through hepatic metabolism. The carboxylic 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.
Elimination
Almost no unchanged flumazenil is excreted in the urine. This indicates a complete metabolic
degradation of the active substance in the body. Radiolabeled 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 feces. 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 hemodialysis compared to normal healthy volunteers.
Pediatric population
In children above one year of age, 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 as in adults.

Late prenatal as well as per- and postnatal exposure to flumazenil induced both behavioral
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.

Disodium edetate 0.1mg
Acetic acid 0.11mg
Sodium chloride 9mg
NaOH/HCl for pH adjustment
Water for injection QS 1ml

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

Keep the vials in the outer carton in order to protect from light.
Do not freeze
Do not store above 30°C

Carton boxes with 5 vials (glass type 1) containing 5 ml solution for injection/infusion.

For single use only. If only part used, discard the remaining solution.
Do not use if bottle is leaking, solution cloudy, or contains particles.
When flumazenil is to be used in infusion, it must be diluted prior to infusion. Flumazenil should
only be diluted with 0.9% Sodium Chloride solution, 0.45%Sodium Chloride and 2.5% Dextrose
injection, 5% dextrose injection, or Lactate Ringer’s solution. Intravenous infusion solutions should
be discarded after 24 hours. Any unused product or waste material should be disposed of in
accordance with local requirements.