FLUMAZENIL Solution for injection or infusion Ref.[9518] Active ingredients: Flumazenil

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 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 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 1000 micrograms 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 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.

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 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 resedation, 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.

• Each 5 mL ampoule of the product contains less than 1 mmol sodium (23 mg), that is to say essentially ‘sodium-free’.
• Each 10 mL ampoule of the product contains 37 mg sodium, equivalent to 2% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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 antagonised 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 foetus.

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:

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)

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 1000 micrograms 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, paraesthesia

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: 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: Injection site pain

Uncommon: Shivering

Rare: Severe hypersensitivity reactions (including anaphylaxis)

*: following rapid injection, generally did not require treatment

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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