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4.2 Posology and method of administration
Anexate is for slow intravenous injection or infusion. It should onlyFlumazenil must be administered intravenously by an anaesthetist or a doctor with under the supervision of an experienced physician in anaesthesiology. Anexateflumazenil may be administered either undiluted or diluted.
For dilution, see section 6.6.
It can be administered together with other reanimation measures.
Anexate may be used concurrently with other resuscitative procedures.
Adults
Anaesthesiology:
The recommended initial dose is 200 micrograms administered intravenously overin 15 seconds. If the desired level degree of consciousness is not obtained within 60 seconds, a secondfurther dose of 100 micrograms can be administered injected. This may be and repeated at 60-second intervals where necessary, up to a maximum total dose of 1 mg or in intensive care situations, 2mg. The usual dose required is 300–600 micrograms.
Intensive care:
The recommended initial dose of flumazenil is 300 micrograms intravenously. If the desired level of consciousness is not obtained within 60 seconds, a repeat dose of 100 micrograms 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 intravenous infusion of 100 - 400 micrograms per hour may be employed. An intravenous infusion of 100–400 micrograms per hour has also been shown to be useful. The dosage and rate of infusion should be individually adjusted to achieve the desired level of arousalsedation.
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.
The individually titrated, slow injections or infusions of Anexate should not produce withdrawal symptoms, even in patients exposed to high doses of benzodiazepines and/or for long periods of time. If, however, unexpected signs of overstimulation occur, an individually titrated dose of diazepam (Valium) or midazolam (Hypnovel) should be given by slow intravenous injection.
If a significant improvement in consciousness or respiratory function is not obtained after repeated doses of Anexate, a non-benzodiazepine aetiology must be assumed.
Elderly:
No specific data are available on the use of Anexate in the elderly, but it should be remembered that this population is more sensitive to the effects of benzodiazepines and should be treated with due caution.
Children
There are insufficient data to make dosage recommendations for Anexate in children. It should, therefore, be administered only if the potential benefits to the patient outweigh the possible risks.
Use in renal and hepatic insufficiency:
No dosage adjustments are necessary in patients with renal impairment. However, since flumazenil is primarily metabolised in the liver, careful titration of dosage is recommended in patients with impaired hepatic function.
The individually titrated, slow injections or infusions of Anexate should not produce withdrawal symptoms, even in patients exposed to high doses of benzodiazepines and/or for long periods of time. If, however, unexpected signs of overstimulation occur, an individually titrated dose of diazepam (Valium) or midazolam (Hypnovel) should be given by slow intravenous injection.
If a significant improvement in consciousness or respiratory function is not obtained after repeated doses of Anexate, a non-benzodiazepine aetiology must be assumed.
4.3 Contraindications
Anexate Flumazenil is contra-indicated in patients:
· with known hypersensitivity to the active substanceflumazenil, benzodiazepines or any of the excipients.
· Anexate is contra-indicated in patients who have been given aadministered benzodiazepines for controlthe treatment of a potentially life-threatening condition (e.g. control ofincreased 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, Anexate should not be used to reverse benzodiazepine effects.
4.4 Special warnings and precautions for use
Until sufficient data are available, flumazenil should only be administered to children 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 anesthsiology at the end of the operation, the effect of the peripheral muscle relaxants must first have disappeared. In view of theBecause flumazenil generally has a shorter duration of action of Anexate and the possible need for repeat doses,than the benzodiazepines and therefore sedation can re-occur, the clinical state of the patient should remain under close observation until all possible central benzodiazepine effects have subsidedmust be monitored, preferably in the intensive care unit, until the effect of flumazenil is eliminated.
The use of Anexate is not recommended in epileptic patients who have been receiving benzodiazepine treatment for a prolonged period. Although Anexate exerts a slight intrinsic anticonvulsant effect, its abrupt suppression of the protective effect of a benzodiazepine agonist can give rise to convulsions in epileptic patients.
Anexate should be used with caution in patients with head injury as it may be capable of precipitating convulsions or altering cerebral blood flow in patients receiving benzodiazepines.
In high-risk patients, the advantagesbenefits of a benzodiazepine-induced sedation of counteracting the central nervous system depression associated with benzodiazepines should be weighed up against the risks of a rapid return to consciousness drawbacks of rapid awakening. 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.
Benzodiazepines have a dependence potential when used chronically. Symptoms such as depression, nervousness, rebound insomnia, irritability, sweating and diarrhoea may arise following abrupt cessation of benzodiazepines in patients treated with high doses and/or for prolonged periods of time. Rapid injection of Anexate flumazenil should be avoided. iIn such patients may trigger these withdrawal symptoms, even in patients who stopped taking the benzodiazepine in the weeks preceding Anexate administration (depending on the half-life of the benzodiazepine used) and should therefore be avoided. There is also a possibility of mild and transient withdrawal reactions occurring even after a short period of administration of benzodiazepineswith 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.
The dosage of Anexate should be adjusted individually to the needs of patients suffering from pre-operative anxiety or having a history of chronic or episodic anxiety. In patients who are anxious patients, particularly those with coronary heart disease, it is preferable to maintain a degree of sedation throughout the early postduring the pre-operative periodphase or in patients who are known to suffer from chronic or transient anxiety, the dosage of flumazenil should be adjusted carefully rather than bring about complete arousal.
The – However, after major surgery, the post operative pain felt by patients in the post-operative period must be taken into account. Following a major intervention, it is preferable to maintain a moderate degree of sedationshould 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.
The - uUse of the antagonistAnexate is not recommended in epileptic patients with epilepsy who have been treated withreceiving benzodiazepines treatment for a prolonged period. Although Anexate flumazenil exerts a slight intrinsic anticonvulsant effect, itsthe abrupt suppression of the protective effect of a benzodiazepine agonist can inducegive rise to convulsions in epileptic patients.
Anexate should be used with caution - Iin patients with headsevere brain injury (and/or instable intracranial pressure) who are being treated with flumazenil – to antagonise the effects of benzodiazepines – increased intracranial pressure may develop as it may be capable of precipitating convulsions or altering cerebral blood flow in patients receiving benzodiazepines
When Anexate is used with neuromuscular blocking agents, it should not be injected until the effects of neuromuscular blockade have been fully reversed.
In high-risk patients, the advantages of counteracting the central nervous system depression associated with benzodiazepines should be weighed against the drawbacks of rapid awakening.
The dosage of Anexate should be adjusted individually to the needs of patients suffering from pre-operative anxiety or having a history of chronic or episodic anxiety. In anxious patients, particularly those with coronary heart disease, it is preferable to maintain a degree of sedation throughout the early post-operative period rather than bring about complete arousal.
The pain felt by patients in the post-operative period must be taken into account. Following a major intervention, it is preferable to maintain a moderate degree of sedation.
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
Anexate - Flumazenil is not recommended for the either as a treatment for benzodiazepine dependence or for the managementtreatment of protracted benzodiazepine abstinence syndromes.
This medicine contains 3.7 mg sodium per ml (18.5 mg per 5 ml vial). Dosages over 600 micrograms contain more than 1 mmol sodium (23 mg). To be taken into consideration by patients on a controlled sodium diet.
4.5 Interaction with other medicinal products and other forms of interaction
Anexate Flumazenilblocks antagonises the central effects of benzodiazepines by competitive interaction at the receptor level;. tThe effects of non-benzodiazepines agonists that acting via the benzodiazepine receptor, such as zopiclone, triazolpyridazine and others, are also blocked by Anexate flumazenil. However, Anexate is ineffective when unconsciousness is due to other substances
Interactions with other centrally nervous system depressants acting substances havehas not been observed. The pharmacokinetics of benzodiazepines are not influenced by the antagonist flumazenil.
However, particular caution is necessary when using Anexate in cases of intentional overdosage since the toxic effects of other psychotropic drugs (especially tricyclic antidepressants) taken concurrently may increase with the subsidence of the benzodiazepine effect.
The pharmacokinetics ofOn administering flumazenil concomitantly with the benzodiazepines midazolam, flunitrazepam and lormetazepam, the pharmacokinetic parameters of flumazenil were unaffectedare unaltered in the presence of Anexate and vice versa.
However, particular caution is necessary when using Anexate in cases of intentional overdosage since the toxic effects of other psychotropic drugs (especially tricyclic antidepressants) taken concurrently may increase with the subsidence of the benzodiazepine effect.
There is no pharmacokinetic interaction between ethanol and flumazenil.
4.6 Pregnancy and lactation
Like other benzodiazepine compounds, Anexate is expected to cross the placenta and to enter into breast milk, although the total quantities involved would be small. There has been little human usage but animal studies have shown no teratogenic potential. The established medical principle of only administering drugs in early pregnancy when considered absolutely necessary should therefore be observed.
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.
Emergency use of Anexate during lactation is not contra-indicated.
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 Ppatients who have received Anexate to reverse the effects of benzodiazepine sedation are awake and conscious after administration of flumazenil, they should be warned advised not to operate dangerous drive, to operate machinery or to engagedrive a vehicle during the first in any other physically or mentally demanding activity for at least 24 hours, since because the effect of the earlier administered benzodiazepine may returnrecur.
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); unknown (cannot be estimated from the available data).
Psychiatric disorders
Uncommon: anxiety, fear: following rapid injection, generally did not require treatment.
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
Unknown: 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 overdose (see section 4.4).
Cardiac disorders
Uncommon: Palpitations: following rapid injection, generally did not require treatment.
Unknown: Transient increases in heart rate (on awakening).
Vascular disorders
Unknown: Transient increased blood pressure (on awakening).
Gastrointestinal disorders
Common: Nausea: vomiting: during post-operative use, particularly if opiates have also been used.
Skin and subcutaneous tissue disorders
Unknown: Flushing,
General disorders and administration site conditions
Rare: Hypersensitivity reactions (including analphylaxis)
Unknown: 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 Anexate.
Even when given intravenously at dosages of 100 mg i.v., no symptoms of overdosage attributable to Anexate have beenwere observed.
There is no specific antidote for overdose with Anexate. Treatment should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.
Even when given intravenously at dosages of 100 mg i.v., no symptoms of overdosage attributable to Anexate have beenwere observed.
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