Flumazenil
Romazicon
- Flumazenil is structurally related to benzodiazepines but acts as an antagonist to reverse the sedative effects of these agents.
- It acts at the GABAA receptor complex to competitively inhibit the activity of benzodiazepine at the receptor sites.
- Flumazenil is administered intravenously to counteract the effects of benzodiazepines including sedation, memory loss, psychomotor impairment, and respiratory depression. It is more effective in reversing sedation and amnesia than respiratory depression.
- Flumazenil’s action is highly specific, therefore it cannot be used to reverse the effects of opioids or other sedative agents that do not have an affinity for the benzodiazepine receptors.
Flumazenil Dosing for Endoscopic Sedation Adult - Initial dose: 0.2 mg administered intravenously over 15 seconds*
- Additional doses: If desired consciousness is not reached within 45 seconds, up to 4 additional doses 0.2 mg can be administered at 60 second intervals
- Onset of action: 1-2 minutes
- Peak effect: 3 minutes
- Duration of effect: 10-15 minutes
- Repeat treatment: If resedation occurs, repeated doses can be administered at 20 minute intervals. No more than 1 mg (given as 0.2 mg/min) should be administered at any one time. No more than 3 mg should be given in any one hour.
Pediatric (children aged 1 - 17 years) - Initial dose: 0.1 mg/kg administered intravenously over 15 seconds*
- Additional doses: If desired consciousness is not reached within 45 seconds, up to 4 additional doses 0.01 mg/kg (up to 0.2 mg) can be administered at 60 second intervals up to a maximum dose
- Maximum dose: 0.05 mg/kg or 1 mg, whichever is lower.
*It is recommended that flumazenil be administered as a series of small injections rather a single bolus to allow for the reversal of sedation to the desired endpoint and minimize the risk of adverse effects. |
Top of Page
- Most patients tolerate higher than the minimally-effective dose of flumazenil, however higher doses may complicate the management of patients physically dependent on benzodiazepines.
- When used in the presence of benzodiazepines, excessive doses of flumazenil may cause anxiety, agitation, increased muscle tone, and the possibility of benzodiazepine-induced seizure activity.
- Administering flumazenil at a titration rate of 0.2 mg/minute over 5 to 10 minutes to wake the patient may help reduce symptoms.
- Head Injury: 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.
- Use in Psychiatric Patients: Flumazenil has been reported to provoke panic attacks in patients with a history of panic disorder.
- Use in Respiratory Disease: The primary treatment of patients with serious lung disease who experience serious respiratory depression due to benzodiazepines should be appropriate ventilatory support rather than the administration of flumazenil. Flumazenil is capable of partially reversing benzodiazepine-induced alterations in ventilatory drive in healthy volunteers, but has not been shown to be clinically effective.
- Use in Cardiovascular Disease: 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/minute 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.
- Use in Liver 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. 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.
- Use in Drug- and Alcohol-Dependent Patients:
- 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. 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 (5 to 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.
- Drug Interactions:
- 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.
- 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 non-benzodiazepine 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.
- Use in Ambulatory Patients:
- 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 greater than 10 mg of midazolam) have been used.
- 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.
- Carcinogenesis, Mutagenesis, Impairment of Fertility:
- No studies in animals to evaluate the carcinogenic potential of flumazenil have been conducted.
- No evidence for mutagenicity was noted in the Ames test using five different tester strains.
- A reproduction study in male and female rats did not show any impairment of fertility at oral dosages of 125 mg/kg/day. From the available data on the area under the curve (AUC) in animals and man the dose represented 120x the human exposure from a maximum recommended intravenous dose of 5 mg.
- Use in pregnancy: Pregnancy Category C. There are no adequate and well-controlled studies of the use of flumazenil in pregnant women. Flumazenil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- Use in Pediatric Patients:
- The safety and effectiveness of flumazenil have been established in pediatric patients 1 year of age and older. Use of flumazenil in this age group is supported by evidence from adequate and well-controlled studies of flumazenil in adults with additional data from uncontrolled pediatric studies including one open-label trial.
- The use of flumazenil to reverse the effects of benzodiazepines used for moderate (conscious) sedation was evaluated in one uncontrolled clinical trial involving 107 pediatric patients between the ages of 1 and 17 years. At the doses used, flumazenil's safety was established in this population. Patients received up to 5 injections of 0.01 mg/kg flumazenil up to a maximum total dose of 1.0 mg at a rate not exceeding 0.2 mg/minute. Of 60 patients who were fully alert at 10 minutes, 7 experienced resedation. Resedation occurred between 19 and 50 minutes after the start of flumazenil administration. None of the patients experienced a return to the baseline level of sedation. All 7 patients were between the ages of 1 and 5 years. The types and frequency of adverse events noted in these pediatric patients were similar to those previously documented in clinical trials with flumazenil to reverse conscious sedation in adults. No patient experienced a serious adverse event attributable to flumazenil.
- The safety and efficacy of flumazenil in the reversal of moderate (conscious) sedation in pediatric patients below the age of 1 year have not been established.
- The risks identified in the adult population with flumazenil use also apply to pediatric patients.
- Use in Geriatric Patients:
- Of the total number of subjects in clinical studies of flumazenil, 248 were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.
- Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
- The pharmacokinetics of flumazenil have been studied in the elderly and are not significantly different from younger patients. Several studies of flumazenil in subjects over the age of 65 and one study in subjects over the age of 80 suggest that while the doses of benzodiazepine used to induce sedation should be reduced, ordinary doses of flumazenil may be used for reversal.
- Nursing Mothers: Caution should be exercised when deciding to administer flumazenil to a nursing woman because it is not known whether flumazenil is excreted in human milk.
- Teratogenic Effects: Flumazenil has been studied for teratogenicity in rats and rabbits following oral treatments of up to 150 mg/kg/day. The treatments during the major organogenesis were on days 6 to 15 of gestation in the rat and days 6 to 18 of gestation in the rabbit. No teratogenic effects were observed in rats or rabbits at 150 mg/kg; the dose, based on the available data on the area under the plasma concentration-time curve (AUC) represented 120x to 600x the human exposure from a maximum recommended intravenous dose of 5 mg in humans. In rabbits, embryocidal effects (as evidenced by increased preimplantation and postimplantation losses) were observed at 50 mg/kg or 200x the human exposure from a maximum recommended intravenous dose of 5 mg. The no-effect dose of 15 mg/kg in rabbits represents 60x the human exposure.
- Nonteratogenic Effects: An animal reproduction study was conducted in rats at oral dosages of 5, 25, and 125 mg/kg/day of flumazenil. Based on the available data from AUC, the effect level (125 mg/kg) represents 120x the human exposure from 5 mg, the maximum recommended intravenous dose in humans. The no-effect level represents 24x the human exposure from an intravenous dose of 5 mg.
Top of Page
- The availability of flumazenil does not reduce the risks associated with the use of large doses of benzodiazepines for sedation. Flumazenil may be expected to improve the alertness of patients recovering from a procedure involving sedation or anesthesia with benzodiazepines, but should not be substituted for an adequate period of postprocedure monitoring. Patients should be monitored for resedation, respiratory depression or other persistent or recurrent agonist effects for an adequate period of time after administration of flumazenil.
- Resedation is least likely in cases where flumazenil is administered to reverse a low dose of a short-acting benzodiazepine (less than 10 mg midazolam). It is most likely in cases where a large single or cumulative dose of a benzodiazepine has been given in the course of a long procedure along with neuromuscular blocking agents and multiple anesthetic agents.
- Deaths have occurred in patients who received flumazenil in a variety of clinical settings. The majority of deaths occurred in patients with serious underlying disease or in patients who had ingested large amounts of non-benzodiazepine drugs (usually cyclic antidepressants), as part of an overdose.
- Serious adverse events have occurred in all clinical settings, and convulsions are the most common serious adverse events reported. Flumazenil administration has been associated with the onset of convulsions in patients with severe hepatic impairment and in patients who are relying on benzodiazepine effects to control seizures, are physically dependent on benzodiazepines, or who have ingested large doses of other drugs (mixed-drug overdose)
- Two of the 446 patients who received flumazenil in controlled clinical trials for the management of a benzodiazepine overdose had cardiac dysrhythmias (1 ventricular tachycardia, 1 junctional tachycardia).
- 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.
- Adverse reactions most frequently associated with the use of flumazenil (both alone and for the reversal of benzodiazepine effects) include:
- Whole body: fatigue, headache, injection site pain, injection site reaction
- Cardiovascular system: sweating, flushing, hot flushes
- Digestive system: nausea, vomiting
- Nervous system: agitation, dizziness, emotional lability
- Special senses: abnormal vision, abnormal skin sensations
- Adverse reactions most frequently associated with flumazenil alone were limited to dizziness, pain at injection site, increased sweating, headache, and abnormal or blurred vision (3% to 9%).
Top of Page
BOX WARNING - THE USE OF FLUMAZENIL HAS BEEN ASSOCIATED WITH THE OCCURRENCE OF SEIZURES.
- THESE ARE MOST FREQUENT IN PATIENTS WHO HAVE BEEN ON BENZODIAZEPINES FOR LONG-TERM SEDATION OR IN OVERDOSE CASES WHERE PATIENTS ARE SHOWING SIGNS OF SERIOUS CYCLIC ANTIDEPRESSANT OVERDOSE.
- PRACTITIONERS SHOULD INDIVIDUALIZE THE DOSAGE OF FLUMAZENIL AND BE PREPARED TO MANAGE SEIZURES.
|
Risk of seizures
- The reversal of benzodiazepine effects may be associated with the onset of seizures in certain high-risk populations.
- Possible risk factors for seizures include: concurrent major sedative-hypnotic drug withdrawal, recent therapy with repeated doses of parenteral benzodiazepines, myoclonic jerking or seizure activity prior to flumazenil administration in overdose cases, or concurrent cyclic antidepressant poisoning.
- Flumazenil is not recommended in cases of serious cyclic antidepressant poisoning, as manifested by motor abnormalities (twitching, rigidity, focal seizure), dysrhythmia (wide QRS, ventricular dysrhythmia, heart block), anticholinergic signs (mydriasis, dry mucosa, hypoperistalsis), and cardiovascular collapse at presentation. In such cases flumazenil should be withheld and the patient should be allowed to remain sedated (with ventilatory and circulatory support as needed) until the signs of antidepressant toxicity have subsided.
- Treatment with flumazenil has no known benefit to the seriously ill mixed-overdose patient other than reversing sedation and should not be used in cases where seizures (from any cause) are likely.
- Most convulsions associated with flumazenil administration require treatment and have been successfully managed with benzodiazepines, phenytoin or barbiturates. Because of the presence of flumazenil, higher than usual doses of benzodiazepines may be required.
Hypoventilation
- Patients who have received flumazenil for the reversal of benzodiazepine effects (after moderate (conscious) sedation or general anesthesia) should be monitored for resedation, respiratory depression, or other residual benzodiazepine effects for an appropriate period (up to 120 minutes) based on the dose and duration of effect of the benzodiazepine employed.
- Flumazenil has not been established in patients as an effective treatment for hypoventilation due to benzodiazepine administration. In healthy male volunteers, flumazenil is capable of reversing benzodiazepine-induced depression of the ventilatory responses to hypercapnia and hypoxia after a benzodiazepine alone. However, such depression may recur because the ventilatory effects of typical doses of flumazenil (1 mg or less) may wear off before the effects of many benzodiazepines.
- The effects of flumazenil on ventilatory response following sedation with a benzodiazepine in combination with an opioid are inconsistent and have not been adequately studied.
- The availability of flumazenil does not diminish the need for prompt detection of hypoventilation and the ability to effectively intervene by establishing an airway and assisting ventilation.
- Overdose cases should always be monitored for resedation until the patients are stable and resedation is unlikely.
Top of Page
Contraindications for the use of flumazenil include:
- Patients who have a hypersensitivity to flumazenil or benzodiazepines
- Patients who have been given a benzodiazepine for control of a potentially life-threatening condition such as control of intracranial pressure or status epilepticus
- Patients who are showing signs of serious cyclic antidepressant overdose
SourcesCohen, LB et al.
AGA Institute Review of Endoscopic Sedation, Gastronenterology 2007;133:675-701.
Kost M. Moderate Sedation/Analgesia: Core Competencies for Practice, 2nd Ed. St. Louis, MO: Saunders, St. Louis; 2004:120.
Romazicon Injection (Roche). PDR Electronic Library [CD-ROM]. Vol. 2008:1.0. Thomson Healthcare. Montvale, NJ. 2007.
Wiener-Kronish J, Grooper. Conscious Sedation. Philadephia, PA: Hanley & Belfus, Inc; 2001.
Top of Page
Last Updated July 22, 2008