Flumazenil is intended as an adjunct to, not as a substitute for, proper management of airway, assisted breathing, circulatory access and support, internal decontamination by lavage and charcoal, and adequate clinical evaluation.
Necessary measures should be instituted to secure airway, ventilation and intravenous access prior to administering flumazenil. Upon arousal, patients may attempt to withdraw endotracheal tubes and/or intravenous lines as the result of confusion and agitation following awakening.
Flumazenil 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. It should be used only by practitioners prepared to manage such complications should they occur.
Flumazenil should not be used until the effects of neuromuscular blockade have been fully reversed.
Flumazenil has been reported to provoke panic attacks in patients with a history of panic disorder.
To minimize the likelihood of pain or inflammation at the injection site, flumazenil should be administered through a freely flowing intravenous infusion into a large vein. Local irritation may occur following extravasation into perivascular tissues.
The primary treatment of patients with serious lung disease who experience serious respiratory depression due to benzodiazepines should be appropriate ventilatory support (see PRECAUTIONS) rather than the administration of flumazenil injection. Flumazenil is capable of partially reversing benzodiazepine-induced alterations in ventilatory drive in healthy volunteers, but has not been shown to be clinically effective.
Flumazenil did not increase the work of the heart when used to reverse benzodiazepines in cardiac patients when given at a rate of 0. 1 mg/min in total doses of less than 0.5 mg in studies reported in the clinical literature. Flumazenil alone had no significant effects on cardiovascular parameters when administered to patients with stable ischemic heart disease.
The clearance of flumazenil is reduced to 40% to 60% of normal in patients with mild to moderate hepatic disease and to 25% of normal in patients with severe hepatic dysfunction (see CLINICAL PHARMACOLOGY: Pharmacokinetics). While the dose of flumazenil used for initial reversal of benzodiazepine effects is not affected, repeat doses of the drug in liver disease should be reduced in size or frequency.
Flumazenil should be used with caution in patients with alcoholism and other drug dependencies due to the increased frequency of benzodiazepine tolerance and dependence observed in these patient populations.
Flumazenil is not recommended either as a treatment for benzodiazepine dependence or for the management of protracted benzodiazepine abstinence syndromes, as such use has not been studied.
The administration of flumazenil can precipitate benzodiazepine withdrawal in animals and man. This has been seen in healthy volunteers treated with therapeutic doses of oral lorazepam for up to 2 weeks who exhibited effects such as hot flushes, agitation and tremor when treated with cumulative doses of up to 3 mg doses of flumazenil.
Similar adverse experiences suggestive of flumazenil precipitation of benzodiazepine withdrawal have occurred in some adult patients in clinical trials. Such patients had a short-lived syndrome characterized by dizziness, mild confusion, emotional lability, agitation (with signs and symptoms of anxiety), and mild sensory distortions. This response was dose-related, most common at doses above 1 mg, rarely required treatment other than reassurance and was usually short lived. When required, these patients (5to 10 cases) were successfully treated with usual doses of a barbiturate, a benzodiazepine, or other sedative drug.
Practitioners should assume that flumazenil administration may trigger dose-dependent withdrawal syndromes in patients with established physical dependence on benzodiazepines and may complicate the management of withdrawal syndromes for alcohol, barbiturates and cross-tolerant sedatives.
Interaction with central nervous system depressants other than benzodiazepines has not been specifically studied; however, no deleterious interactions were seen when flumazenil was administered after narcotics, inhalational anesthetics, muscle relaxants and muscle relaxant antagonists administered in conjunction with sedation or anesthesia.
Particular caution is necessary when using flumazenil in cases of mixed drug overdosage since the toxic effects (such as convulsions and cardiac dysrhythmias) of other drugs taken in overdose (especially cyclic antidepressants) may emerge with the reversal of the benzodiazepine effect by flumazenil (see WARNINGS).
The use of flumazenil is not recommended in epileptic patients who have been receiving benzodiazepine treatment for a prolonged period. Although flumazenil 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.
Flumazenil blocks the central effects of benzodiazepines by competitive interaction at the receptor level. The effects of nonbenzodiazepine agonists at benzodiazepine receptors, such as zopiclone, triazolopyridazines and others, are also blocked by flumazenil.
The pharmacokinetics of benzodiazepines are unaltered in the presence of flumazenil and vice versa.
There is no pharmacokinetic interaction between ethanol and flumazenil.
The effects of flumazenil may wear off before a long-acting benzodiazepine is completely cleared from the body. In general, if a patient shows no signs of sedation within 2 hours after a 1-mg dose of flumazenil, serious resedation at a later time is unlikely. An adequate period of observation must be provided for any patient in whom either long-acting benzodiazepines (such as diazepam) or large doses of short-acting benzodiazepines (such as >10 mg of midazolam) have been used (see INDIVIDUALIZATION OF DOSAGE).
Because of the increased risk of adverse reactions in patients who have been taking benzodiazepines on a regular basis, it is particularly important that physicians query patients or their guardians carefully about benzodiazepine, alcohol and sedative use as part of the history prior to any procedure in which the use of flumazenil is planned (see PRECAUTIONS: Use in Drug- and Alcohol-Dependent Patients).
Flumazenil does not consistently reverse amnesia. Patients cannot be expected to remember information told to them in the postprocedure period and instructions given to patients should be reinforced in writing or given to a responsible family member. Physicians are advised to discuss with patients or their guardians, both before surgery and at discharge, that although the patient may feel alert at the time of discharge, the effects of the benzodiazepine (e.g., sedation) may recur. As a result, the patient should be instructed, preferably in writing, that their memory and judgment may be impaired and specifically advised:
- Not to engage in any activities requiring complete alertness, and not to operate hazardous machinery or a motor vehicle during the first 24 hours after discharge, and it is certain no residual sedative effects of the benzodiazepine remain.
- Not to take any alcohol or non-prescription drugs during the first 24 hours after flumazenil administration or if the effects of the benzodiazepine persist.
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