Flumazenil Kabi

/ Neopharm (Israel) 1996 Ltd.

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 1.0 mg. The usual dose required lies between 0.3 and 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 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 total dose of 2 mg or until the patient awakes.
If drowsiness recurs, a second bolus injection may be administered.
An intravenous infusion of 0.1 – 0.4 mg/h has also been shown to be useful. The dosage and 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 resedation 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.
Paediatric population
Children above 1 year of age
For the reversal of conscious sedation induced by 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.

Benzodiazepine antagonist for reversal of benzodiazepine anesthesia, as well as for patients with Benzodiazepine intoxication.
In a hospital setting:
In anaesthesiology to neutralise the sedative effects of benzodiazepines on the central nervous system in adults and children older than 1 year:
* Reversal of sedative effect during general anaesthesia induced and maintained by benzodiazepines
* Reversal of conscious sedation induced by benzodiazepines in short operations with a diagnostic or therapeutic objective.
In intensive care to neutralise the sedative effects of benzodiazepines on the central nervous system and treat a coma of unknown etiology, in adults and children (including newborns) if the semiology is compatible with the hypothesis of a benzodiazepine or related substance-induced coma:
* Diagnosis and/or treatment of intentional or accidental benzodiazepine overdose
* Etiological diagnosis of an unexplained coma in order to differentiate what is caused by a benzodiazepine from another cause (pharmacological or neurological).
* specific cancellation of the effects on the central nervous system by excessive benzodiazepine doses (re-establishment of spontaneous ventilation to avoid intubation or interrupt ventilatory assistance).
In an emergency situation or medical transport, in adults and children older than 6 years:
* Reversal of benzodiazepine-induced conscious sedation in case of respiratory depression or apnoea.

* Hypersensitivity to the active substance or to 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 effect.

* 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 reverse
* 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 high dose and/or chronic treatment with benzodiazepines at any time within the weeks preceding flumazenil administration, rapid injection of doses equal 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.
* Postoperative pain must be taken into account. 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 carefully 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.
* 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.
* 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.
* 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.
* 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.
* 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.

Very common: Nausea (during postoperative use)
Common: allergic reactions, anxiety, emotional lability, insomnia, somnolence, vertigo, headache, agitation, tremor, dry mouth, hyperventilation, speech disorder, paresthesia, diplopia, strabismus, lacrimation increased, palpitations, flushing, hypotension, orthostatic hypotension, transient increased blood pressure (on awakening), vomiting (during postoperative use), hiccup, sweating, fatigue, injection site pain.
See prescribing information for full details

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.

Pregnancy: The possible risk to humans caused by flumazenil during pregnancy has not been determined. Therefore, flumazenil should only be used during pregnancy if the possible benefit to the patient outweighs the potential risks for the foetus.
Lactation: It is not known whether flumazenil is excreted in human milk. For this reason, breastfeeding should be interrupted for 24 hours when flumazenil is used during lactation. Emergency use of flumazenil during pregnancy and lactation is not contra-indicated.

There is very limited experience of acute overdose in humans with Flumazenil. However, even when administered intravenously at doses of 100 mg, no symptoms of overdose attributable to flumazenil have been observed.
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.
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.

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.