azenil 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 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. this is because 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. warning box

lumazenil is well tolerated at the recommended doses in individuals who have no tolerance to (or dependence on) benzodiazepines. the recommended doses and titration rates in anesthesia and conscious sedation (0.2 mg to 1 mg given at 0.2 mg/min) are well tolerated in patients receiving the drug for reversal of a single benzodiazepine exposure in most clinical settings (see adverse reactions ). the major risk will be resedation because the duration of effect of a long-acting (or large dose of a short-acting) benzodiazepine may exceed that of flumazenil injection. resedation may be treated by giving a repeat dose at no less than 20-minute intervals. for repeat treatment, no more than 1 mg (at 0.2 mg/min doses) should be given at any one time and no more than 3 mg should be given in any one hour. benzodiazepine overdose in adult patients the risk of confusion, agitation, emotional lability, and perceptual distortion with the doses recommended in patients with benzodiazepine overdose (3 mg to 5 mg administered as 0.5 mg/min) may be greater than that expected with lower doses and slower administration. the recommended doses represent a compromise between a desirable slow awakening and the need for prompt response and a persistent effect in the overdose situation. if circumstances permit, the physician may elect to use the 0.2 mg/minute titration rate to slowly awaken the patient over 5 to 10 minutes, which may help to reduce signs and symptoms on emergence. flumazenil has no effect in cases where benzodiazepines are not responsible for sedation. once doses of 3 mg to 5 mg have been reached without clinical response, additional flumazenil is likely to have no effect. patients tolerant to benzodiazepines flumazenil may cause benzodiazepine withdrawal symptoms in individuals who have been taking benzodiazepines long enough to have some degree of tolerance. patients who had been taking benzodiazepines prior to entry into the flumazenil trials, who were given flumazenil in doses over 1 mg, experienced withdrawal-like events 2 to 5 times more frequently than patients who received less than 1 mg. in patients who may have tolerance to benzodiazepines, as indicated by clinical history or by the need for larger than usual doses of benzodiazepines, slower titration rates of 0.1 mg/min and lower total doses may help reduce the frequency of emergent confusion and agitation. in such cases, special care must be taken to monitor the patients for resedation because of the lower doses of flumazenil used. patients physically dependent on benzodiazepines flumazenil is known to precipitate withdrawal seizures in patients who are physically dependent on benzodiazepines, even if such dependence was established in a relatively few days of high-dose sedation in intensive care unit (icu) environments. the risk of either seizures or resedation in such cases is high and patients have experienced seizures before regaining consciousness. flumazenil should be used in such settings with extreme caution, since the use of flumazenil in this situation has not been studied and no information as to dose and rate of titration is available. flumazenil should be used in such patients only if the potential benefits of using the drug outweigh the risks of precipitated seizures. physicians are directed to the scientific literature for the most current information in this area.

ly over 15 seconds. if the desired level of consciousness is not obtained after waiting an additional 45 seconds, a second dose of 0.2 mg (2 ml) can be injected and repeated at 60-second intervals where necessary (up to a maximum of 4 additional times) to a maximum total dose of 1 mg (10 ml). the dosage should be individualized based on the patient’s response, with most patients responding to doses of 0.6 mg to 1 mg (see individualization of dosage ). in the event of resedation, repeated doses may be administered at 20-minute intervals as needed. for repeat treatment, no more than 1 mg (given as 0.2 mg/min) should be administered at any one time, and no more than 3 mg should be given in any one hour. it is recommended that flumazenil injection be administered as the series of small injections described (not as a single bolus injection) to allow the practitioner to control the reversal of sedation to the approximate endpoint desired and to minimize the possibility of adverse effects (see individualization of dosage ). pediatric patients for the reversal of the sedative effects of benzodiazepines administered for conscious sedation in pediatric patients greater than 1 year of age, the recommended initial dose is 0.01 mg/kg (up to 0.2 mg) administered intravenously over 15 seconds. if the desired level of consciousness is not obtained after waiting an additional 45 seconds, further injections of 0.01 mg/kg (up to 0.2 mg) can be administered and repeated at 60-second intervals where necessary (up to a maximum of 4 additional times) to a maximum total dose of 0.05 mg/kg or 1 mg, whichever is lower. the dose should be individualized based on the patient’s response. the mean total dose administered in the pediatric clinical trial of flumazenil was 0.65 mg (range: 0.08 mg to 1.00 mg). approximately one-half of patients required the maximum of five injections. resedation occurred in 7 of 60 pediatric patients who were fully alert 10 minutes after the start of flumazenil injection administration (see precautions : pediatric use). the safety and efficacy of repeated flumazenil administration in pediatric patients experiencing resedation have not been established. it is recommended that flumazenil injection be administered as the series of small injections described (not as a single bolus injection) to allow the practitioner to control the reversal of sedation to the approximate endpoint desired and to minimize the possibility of adverse effects (see individualization of dosage ). the safety and efficacy of flumazenil injection in the reversal of conscious sedation in pediatric patients below the age of 1 year have not been established. reversal of general anesthesia in adult patients for the reversal of the sedative effects of benzodiazepines administered for general anesthesia, the recommended initial dose of flumazenil injection is 0.2 mg (2 ml) administered intravenously over 15 seconds. if the desired level of consciousness is not obtained after waiting an additional 45 seconds, a further dose of 0.2 mg (2 ml) can be injected and repeated at 60-second intervals where necessary (up to a maximum of 4 additional times) to a maximum total dose of 1 mg (10 ml). the dosage should be individualized based on the patient’s response, with most patients responding to doses of 0.6 mg to 1 mg (see indivualization of dosage ). in the event of resedation, repeated doses may be administered at 20-minute intervals as needed. for repeat treatment, no more than 1 mg (given as 0.2 mg/min) should be administered at any one time, and no more than 3 mg should be given in any one hour. it is recommended that flumazenil injection be administered as the series of small injections described (not as a single bolus injection) to allow the practitioner to control the reversal of sedation to the approximate endpoint desired and to minimize the possibility of adverse effects (see indiviualization of dosage ). management of suspected benzodiazepine overdose in adult patients for initial management of a known or suspected benzodiazepine overdose, the recommended initial dose of flumazenil injection is 0.2 mg (2 ml) administered intravenously over 30 seconds. if the desired level of consciousness is not obtained after waiting 30 seconds, a further dose of 0.3 mg (3 ml) can be administered over another 30 seconds. further doses of 0.5 mg (5 ml) can be administered over 30 seconds at 1-minute intervals up to a cumulative dose of 3 mg. do not rush the administration of flumazenil injection. patients should have a secure airway and intravenous access before administration of the drug and be awakened gradually (see precautions ). most patients with a benzodiazepine overdose will respond to a cumulative dose of 1 mg to 3 mg of flumazenil injection, and doses beyond 3 mg do not reliably produce additional effects. on rare occasions, patients with a partial response at 3 mg may require additional titration up to a total dose of 5 mg (administered slowly in the same manner). if a patient has not responded 5 minutes after receiving a cumulative dose of 5 mg of flumazenil injection, the major cause of sedation is likely not to be due to benzodiazepines, and additional flumazenil injection is likely to have no effect. in the event of resedation, repeated doses may be given at 20-minute intervals if needed. for repeat treatment, no more than 1 mg (given as 0.5 mg/min) should be given at any one time and no more than 3 mg should be given in any one hour. safety and handling flumazenil injection is supplied in sealed dosage forms and poses no known risk to the healthcare provider. routine care should be taken to avoid aerosol generation when preparing syringes for injection, and spilled medication should be rinsed from the skin with cool water.

hycardia). adverse events in clinical studies the following adverse reactions were considered to be related to flumazenil administration (both alone and for the reversal of benzodiazepine effects) and were reported in studies involving 1875 individuals who received flumazenil in controlled trials. adverse events most frequently associated with flumazenil alone were limited to dizziness, injection site pain, increased sweating, headache, and abnormal or blurred vision (3% to 9%). body as a whole: fatigue (asthenia, malaise), headache, injection site pain*, injection site reaction (thrombophlebitis, skin abnormality, rash) cardiovascular system: cutaneous vasodilation (sweating, flushing, hot flushes) digestive system: nausea, vomiting (11%) nervous system: agitation (anxiety, nervousness, dry mouth, tremor, palpitations, insomnia, dyspnea, hyperventilation)*, dizziness (vertigo, ataxia) (10%), emotional lability (crying abnormal, depersonalization, euphoria, increased tears, depression, dysphoria, paranoia) special senses: abnormal vision (visual field defect, diplopia), paresthesia (sensation abnormal, hypoesthesia) all adverse reactions occurred in 1% to 3% of cases unless otherwise marked. * indicates reaction in 3% to 9% of cases. observed percentage reported if greater than 9%. the following adverse events were observed infrequently (less than 1%) in the clinical studies, but were judged as probably related to flumazenil administration and/or reversal of benzodiazepine effects: nervous system: confusion (difficulty concentrating, delirium), convulsions (see warnings ), somnolence (stupor) special senses: abnormal hearing (transient hearing impairment, hyperacusis, tinnitus) the following adverse events occurred with frequencies less than 1% in the clinical trials. their relationship to flumazenil administration is unknown, but they are included as alerting information for the physician. body as a whole: rigors, shivering cardiovascular system: arrhythmia (atrial, nodal, ventricular extrasystoles), bradycardia, tachycardia, hypertension, chest pain digestive system: hiccup nervous system: speech disorder (dysphonia, thick tongue) not included in this list is operative site pain that occurred with the same frequency in patients receiving placebo as in patients receiving flumazenil for reversal of sedation following a surgical procedure. additional adverse reactions reported during post-marketing experience the following events have been reported during postapproval use of flumazenil. nervous system: fear, panic attacks in patients with a history of panic disorders. withdrawal symptoms may occur following rapid injection of flumazenil in patients with long-term exposure to benzodiazepines. to report suspected adverse reactions, contact west-ward pharmaceutical corp. at 1-877-233-2001 or the fda at 1-800-fda-1088 or www.fda.gov/medwatch.

ession produced by benzodiazepines in healthy human volunteers. the duration and degree of reversal of sedative benzodiazepine effects are related to the dose and plasma concentrations of flumazenil as shown in the following data from a study in normal volunteers. chart 1 generally, doses of approximately 0.1 mg to 0.2 mg (corresponding to peak plasma levels of 3 to 6 ng/ml) produce partial antagonism, whereas higher doses of 0.4 to 1 mg (peak plasma levels of 12 to 28 ng/ml) usually produce complete antagonism in patients who have received the usual sedating doses of benzodiazepines. the onset of reversal is usually evident within 1 to 2 minutes after the injection is completed. eighty percent response will be reached within 3 minutes, with the peak effect occurring at 6 to 10 minutes. the duration and degree of reversal are related to the plasma concentration of the sedating benzodiazepine as well as the dose of flumazenil given. in healthy volunteers, flumazenil did not alter intraocular pressure when given alone and reversed the decrease in intraocular pressure seen after administration of midazolam. pharmacokinetics after iv administration, plasma concentrations of flumazenil follow a two-exponential decay model. the pharmacokinetics of flumazenil are dose-proportional up to 100 mg. distribution flumazenil is extensively distributed in the extravascular space with an initial distribution half-life of 4 to 11 minutes and a terminal half-life of 40 to 80 minutes. peak concentrations of flumazenil are proportional to dose, with an apparent initial volume of distribution of 0.5 l/kg. the volume of distribution at steady-state is 0.9 to 1.1 l/kg. flumazenil is a weak lipophilic base. protein binding is approximately 50% and the drug shows no preferential partitioning into red blood cells. albumin accounts for two thirds of plasma protein binding. metabolism flumazenil is completely (99%) metabolized. very little unchanged flumazenil (< 1%) is found in the urine. the major metabolites of flumazenil identified in urine are the de-ethylated free acid and its glucuronide conjugate. in preclinical studies there was no evidence of pharmacologic activity exhibited by the de-ethylated free acid. elimination elimination of radiolabeled drug is essentially complete within 72 hours, with 90% to 95% of the radioactivity appearing in urine and 5% to 10% in the feces. clearance of flumazenil occurs primarily by hepatic metabolism and is dependent on hepatic blood flow. in pharmacokinetic studies of normal volunteers, total clearance ranged from 0.8 to 1.0 l/hr/kg. pharmacokinetic parameters following a 5-minute infusion of a total of 1 mg of flumazenil mean (coefficient of variation, range): food effects ingestion of food during an intravenous infusion of the drug results in a 50% increase in clearance, most likely due to the increased hepatic blood flow that accompanies a meal. special populations the elderly: the pharmacokinetics of flumazenil are not significantly altered in the elderly. gender: the pharmacokinetics of flumazenil are not different in male and female subjects. renal failure (creatinine clearance < 10 ml/min) and hemodialysis: the pharmacokinetics of flumazenil are not significantly affected. patients with liver dysfunction: for patients with moderate liver dysfunction, their mean total clearance is decreased to 40% to 60% and in patients with severe liver dysfunction, it is decreased to 25% of normal value, compared with age-matched healthy subjects. this results in a prolongation of the half-life to 1.3 hours in patients with moderate hepatic impairment and 2.4 hours in severely impaired patients. caution should be exercised with initial and/or repeated dosing to patients with liver disease. drug-drug interaction: the pharmacokinetic profile of flumazenil is unaltered in the presence of benzodiazepine agonists and the kinetic profiles of those benzodiazepines studied (i.e., diazepam, flunitrazepam, lormetazepam, and midazolam) are unaltered by flumazenil. during the 4-hour steady-state and post infusion of ethanol, there were no pharmacokinetic interactions on ethanol mean plasma levels as compared to placebo when flumazenil doses were given intravenously (at 2.5 hours and 6 hours) nor were interactions of ethanol on the flumazenil elimination half-life found. pharmacokinetics in pediatric patients: the pharmacokinetics of flumazenil have been evaluated in 29 pediatric patients ranging in age from 1 to 17 years who had undergone minor surgical procedures. the average doses administered were 0.53 mg (0.044 mg/kg) in patients aged 1 to 5years, 0.63 mg (0.020 mg/kg) in patients aged 6 to 12 years, and 0.8 mg (0.014 mg/kg) in patients aged 13 to 17 years. compared to adults, the elimination half-life in pediatric patients was more variable, averaging 40 minutes (range: 20 to 75 minutes). clearance and volume of distribution, normalized for body weight, were in the same range as those seen in adults, although more variability was seen in the pediatric patients. chart tabel

maximum total dose of 1 mg. seventy-eight percent of patients receiving flumazenil responded by becoming completely alert. of those patients, approximately half responded to doses of 0.4 mg to 0.6 mg, while the other half responded to doses of 0.8 mg to 1 mg. adverse effects were infrequent in patients who received 1 mg of flumazenil or less, although injection site pain, agitation, and anxiety did occur. reversal of sedation was not associated with any increase in the frequency of inadequate analgesia or increase in narcotic demand in these studies. while most patients remained alert throughout the 3-hour postprocedure observation period, resedation was observed to occur in 3% to 9% of the patients, and was most common in patients who had received high doses of benzodiazepines (see precautions ). general anesthesia in adults flumazenil was studied in four trials in 644 patients who received midazolam as an induction and/or maintenance agent in both balanced and inhalational anesthesia. midazolam was generally administered in doses ranging from 5 mg to 80 mg, alone and/or in conjunction with muscle relaxants, nitrous oxide, regional or local anesthetics, narcotics and/or inhalational anesthetics. flumazenil was given as an initial dose of 0.2 mg iv, with additional 0.2 mg doses as needed to reach a complete response, up to a maximum total dose of 1 mg. these doses were effective in reversing sedation and restoring psychomotor function, but did not completely restore memory as tested by picture recall. flumazenil was not as effective in the reversal of sedation in patients who had received multiple anesthetic agents in addition to benzodiazepines. eighty-one percent of patients sedated with midazolam responded to flumazenil by becoming completely alert or just slightly drowsy. of those patients, 36% responded to doses of 0.4 mg to 0.6 mg, while 64% responded to doses of 0.8 mg to 1 mg. resedation in patients who responded to flumazenil occurred in 10% to 15% of patients studied and was more common with larger doses of midazolam (> 20 mg), long procedures (>60 minutes) and use of neuromuscular blocking agents (see precautions ). management of suspected benzodiazepine overdose in adults flumazenil was studied in two trials in 497 patients who were presumed to have taken an overdose of a benzodiazepine, either alone or in combination with a variety of other agents. in these trials, 299 patients were proven to have taken a benzodiazepine as part of the overdose, and 80% of the 148 who received flumazenil responded by an improvement in level of consciousness. of the patients who responded to flumazenil, 75% responded to a total dose of 1 mg to 3 mg. reversal of sedation was associated with an increased frequency of symptoms of cns excitation. of the patients treated with flumazenil, 1% to 3% were treated for agitation or anxiety. serious side effects were uncommon, but six seizures were observed in 446 patients treated with flumazenil in these studies. four of these 6 patients had ingested a large dose of cyclic antidepressants, which increased the risk of seizures (see warnings ).