SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Flumazenil 100 micrograms/ml solution for injection or infusion

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of solution for injection or infusion contains 100 micrograms of flumazenil.

1 vial with 5 ml contains 500 micrograms flumazenil.

Excipient(s) with known effect:

This medicinal product contains 3.6 mg sodium per ml (18 mg sodium per 5 ml vial).

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Solution for Injection or Infusion.

Clear, Colourless solution free from visible particles.

The pH of the solution is 3.4-4.8.

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.

-    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.

4.2 Posology and method of administration

Flumazenil should be administered intravenously by an anaesthetist or experienced physician. Flumazenil may be administered as injection or as infusion. (For instructions on dilution of the product before administration, see section 6.6).

Flumazenil may be used concomitantly with other resuscitative measures.

This medicinal product is for single use only. It should be inspected visually prior to use and should only be used if the solution is clear and practically free from particles.

Adults:

Anaesthesia

The recommended starting dose is 200 micrograms administered intravenously over 15 seconds. If the required level of consciousness is not obtained within 60 seconds, a further dose of 100 micrograms can be injected and repeated at 60-second intervals, up to a maximum dose of 1.0 mg. The usual dose required lies between 300 and 600 micrograms, but may deviate depending on the patient’s characteristics and the benzodiazepine used.

Intensive care

The recommended starting dose is 200 micrograms administered intravenously over 15 seconds. If the required level of consciousness is not obtained within 60 seconds, a further dose of 100 micrograms can be injected and repeated at 60-second intervals, up to a total dose of 2 mg.

If drowsiness recurs, an intravenous infusion of 100-400 micrograms per hour may be useful.

The rate of infusion should be adjusted individually to achieve the desired level of consciousness.

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 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.

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.

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

No dosage adjustments are necessary in patients with renal impairment. However, in patients with impaired hepatic function, the elimination of flumazenil may be delayed (see section 5.2) and therefore careful titration of dosage is recommended.

4.3 Contraindications

-    Hypersensitivity to flumazenil, benzodiazepines or any of the excipients.

-    Patients receiving benzodiazepines for control of a potentially life-threatening condition (e.g. control of 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, Flumazenil should not be used to reverse benzodiazepine effects.

4.4 Special warnings and precautions for use

Elimination may be delayed in patients with hepatic impairment.

The patient should be monitored for an adequate period of time (ECG, pulse, oximetry, patient alertness and other vital signs such as heart rate, respiratory rate and blood pressure).

Flumazenil specifically reverses benzodiazepines. Therefore if the patient does not wake up, another aetiology should be considered.

When used in anaesthesiology 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 patients at increased risk the advantages of sedation by means of benzodiazepines should be weighed against the drawbacks 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 high doses (more than 1 mg) flumazenil should be avoided in patients who receive chronic treatment with benzodiazepines as this may cause withdrawal symptoms.

In patients suffering from pre-operative anxiety or having a history of chronic or episodic anxiety the dosage of flumazenil should be adjusted carefully.

Postoperative pain must be taken into account.

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 an individually titrated dose of 5 mg diazepam or 5 mg midazolam should be given by slow intravenous injection.

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.

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 anti-epileptic effects, the abrupt antagonising effect can cause convulsions in patients with epilepsy.

In patients with serious brain damage (and/or instable intracranial pressure) receiving flumazenil - to reverse the effects of benzodiazepines - an increased intracranial pressure may develop.

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 this population.

Paediatric population

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.

Until sufficient data are available flumazenil should not be used in children of 1 year or younger unless the risks for the patient (especially in case of accidental overdose) have been weighed against the advantages of the therapy.

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.

This medicine contains 3.6 mg sodium per ml (18 mg per 5 ml vial). Dosages over 0.6 mg contain more than 1 mmol sodium (23 mg). 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 reverses the central effects of benzodiazepines by competitive interaction at the receptor level: the effects of non-benzodiazepine agonists acting via the benzodiazepine receptor, such as zopiclone, triazolpyridazine and others, are also antagonised by flumazenil. However, flumazenil does not block the effect of medicinal products 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 intentional 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 hasbeen observed in combination with the benzodiazepines midazolam, flunitrazepam and lormetazepam. Flumazenil does not affect the pharmacokinetics of these benzodiazepines.

4.6 Fertility, Pregnancy and lactation

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). Therefore, flumazenil should only be used during pregnancy if the possible benefit to the patient outweighs the potential risks for the foetus.

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.

Emergency use of flumazenil during pregnancy and lactation is not contraindicated.

4.7 Effects on ability to drive and use machines

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.

4.8 Undesirable effects

Undesirable effects have been summarised in the table below with MedDRA frequencies Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Very common:    (> 1/10)

Common:    (> 1/100 to < 1/10)

Uncommon:    (> 1/1000 to < 1/100)

Rare:    (> 1/10000 to < 1/1000)

Very rare	(< 1/10000),
Not known	cannot be estimated from the available data
Organ system
Frequency	Side effects

Immune systems disorders:

Common -	Allergic reaction
Psychiatric disorders
Common -	Anxiety*, emotional lability, insomnia, somnolence
Nervous systems 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).
Eye disorders
Common -	Diplopia, strabismus, lacrimation increased
Ear disorders:
Uncommon -	Abnormal hearing
Cardiac disorders:
Common -	Palpitations*
Uncommon -	Tachycardia or bradycardia, extrasystole (on awakening)
Vascular disorders:
Common -	Flushing, hypotension, orthostatic hypotension, transient increased blood pressure (on awakening)
Respiratory, thoracic and mediastinal disorders:
Uncommon -	dyspnoea, cough, nasal congestion, chest pain
Gastrointestinal disorders:
Very common -	Nausea (during anaesthesia)
Common -	Vomiting (during anaesthesia), hiccup
Skin and subcutaneous tissue disorders:
Common -	Sweating
General disorders and administration site conditions:
Common -	Fatigue, injection site pain
Uncommon -	Shivering

*• after rapid injection, not requiring treatment

In patients treated for long periods with benzodiazepines flumazenil can induce withdrawal symptoms. The symptoms are: tension, agitation, anxiety, confusion, hallucinations, tremor and convulsions.

In general the undesirable effect profile in children does not differ much from that in adults. When using flumazenil for the reversal of conscious sedation abnormal crying, agitation and aggressive reactions have been reported.

4.9 Overdose

There is very limited experience of acute overdose in humans with flumazenil.

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

In cases of mixed-drug overdose, particularly with cyclic antidepressants, toxic effects (such as convulsions and cardiac dysrrhythmias) may emerge with the reversal of benzodiazepine effects by 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antidotes ATC code: V03AB25

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 benzodiazepine-receptor (like barbiturates, GABA-mimetics and adenosine-receptor agonists), are not blocked by flumazenil. Nonbenzodiazepine-agonists, like cyclopyrrolones (zopiclon) 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.

5.2 Pharmacokinetic properties

Distribution

Flumazenil, 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 halflife of 4-15 minutes. The distribution volume under steady-state conditions (Vss) is 0.9 - 1.1 l/kg.

Metabolism

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. 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 population

In children above one year old, the half life elimination is shorter and the variability is higher than in adults, approximately 40 minutes with a range of 20 to 75 minutes. Clearance and volume of distribution, by kg of body weight are the same as in adults.

5.3 Preclinical safety data

Late prenatal as well as peri- and post-natal 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

•    Sodium Chloride

•    Disodium Edetate

•    Glacial Acetic acid

•    Hydrochloric acid (for pH-adjustment)

•    Sodium Hydroxide (for pH-adjustment)

•    Water for injections

6.2    Incompatibilities

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

6.3

After first opening the medicinal product should be used immediately. Shelf-life after dilution:

Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage time and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

For storage conditions after first opening or dilution, see section 6.3.

6.5 Nature and contents of container

Type I colourless tubular vials with grey bromobutyl omniflex rubber closure and white flip off aluminium seal.

Pack sizes 1 x 5 ml vial

5    x 5 ml vial

6    x 5 ml vial 10 x 5 ml vial 12 x 5 ml vial 25 x 5 ml vial

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

When flumazenil is to be used in infusion, it must be diluted prior to infusion. Flumazenil should only be diluted with Sodium chloride 0.9 % intravenous solution or Dextrose 5 % intravenous solution. Chemical and physical stability has been demonstrated for 24 hours at room temperature.

No preparations other than those recommended should be added to the vial or mixed with the infusion solution.

For single use only. Discard any unused contents.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

MARKETING AUTHORISATION HOLDER

Generics [UK] Limited t/a Mylan

Station Close

Potters Bar

Hertfordshire

EN6 1TL

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 04569/1556

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

14/03/2013

10    DATE OF REVISION OF THE TEXT

03/11/2014