ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS:. Serious Adverse Reactions. Deaths have occurred in patients who received flumazenil in 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) (see WARNINGS).Two of the 446 patients who received flumazenil in controlled clinical trials for the management of benzodiazepine overdose had cardiac dysrhythmias (1 ventricular tachycardia, junctional tachycardia).. 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 Whole: fatigue (asthenia, malaise), headache, injection site pain and injection site reaction (thrombophlebitis, skin abnormality, rash)Cardiovascular System: cutaneous vasodilation (sweating, flushing, hot flushes)Digestive System: nausea and vomiting (11%)Nervous System: agitation (anxiety, nervousness, dry mouth, tremor, palpitations, insomnia, dyspnea, hyperventilation), dizziness (vertigo, ataxia) (10%) and emotional lability (crying abnormal, depersonalization, euphoria, increased tears, depression, dysphoria, paranoia)Special Senses: abnormal vision (visual field defect, diplopia) and 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) and 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 Whole: rigors, shiveringCardiovascular System: arrhythmia (atrial, nodal, ventricular extrasystoles), bradycardia, tachycardia, hypertension and chest painDigestive System: hiccupNervous 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 surgical procedure.. Additional Adverse Reactions Reported During Postmarketing Experience. The following events have been reported during postapproval use of flumazenil.Nervous System: Fear, panic attacks in patients with history of panic disorders.Withdrawal symptoms may occur following rapid injection of flumazenil in patients with long-term exposure to benzodiazepines.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY:. Flumazenil, an imidazobenzodiazepine derivative, antagonizes the actions of benzodiazepines on the central nervous system. Flumazenil competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex. Flumazenil is weak partial agonist in some animal models of activity, but has little or no agonist activity in man.Flumazenil does not antagonize the central nervous system effects of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (including ethanol, barbiturates, or general anesthetics) and does not reverse the effects of opioids.In animals pretreated with high doses of benzodiazepines over several weeks, flumazenil elicited symptoms of benzodiazepine withdrawal, including seizures. similar effect was seen in adult human subjects.. Pharmacodynamics. Intravenous flumazenil has been shown to antagonize sedation, impairment of recall, psychomotor impairment and ventilatory depression produced by benzodiazepines in healthy human volunteers.The duration and degree of reversal of benzodiazepine effects are related to the dose and plasma concentrations of flumazenil as shown in the following data from study in normal volunteers. Generally, doses of approximately 0.1 mg to 0.2 mg (corresponding to peak plasma levels of to ng/mL) produce partial antagonism, whereas higher doses of 0.4 to 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 to minutes after the injection is completed. Eighty percent response will be reached within minutes, with the peak effect occurring at 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.. graph. Pharmacokinetics. After IV administration, plasma concentrations of flumazenil follow two-exponential decay model. The pharmacokinetics of flumazenil are dose-proportional up to 100 mg.DistributionFlumazenil is extensively distributed in the extravascular space with an initial distribution half-life of to 11 minutes and 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 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.MetabolismFlumazenil 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.EliminationElimination 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 L/hr/kg.Pharmacokinetic parameters following 5-minute infusion of total of mg of flumazenil mean (coefficient of variation, range): Cmax (ng/mL) 24 (38%, 11 to 43) AUC (ngohr/mL) 15 (22%, 10 to 22) Vss (L/kg) (24%, 0.8 to 1.6) Cl (L/hr/kg) (20%, 0.7 to 1.4) Half-life (min) 54 (21%, 41 to 79) Food EffectsIngestion of food during an intravenous infusion of the drug results in 50% increase in clearance, most likely due to the increased hepatic blood flow that accompanies meal.. Special Populations. The ElderlyThe pharmacokinetics of flumazenil are not significantly altered in the elderly.GenderThe pharmacokinetics of flumazenil are not different in male and female subjects.Renal Failure (creatinine clearance <10 mL/min) and HemodialysisThe pharmacokinetics of flumazenil are not significantly affected.Patients With Liver DysfunctionFor 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 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 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 to 17 years who had undergone minor surgical procedures. The average doses administered were 0.53 mg (0.044 mg/kg) in patients aged to years, 0.63 mg (0.020 mg/kg) in patients aged to 12 years, and 0.8 mg (0.014 mg/kg) in patients aged 13 to 17 years. Compared to adults, the half-life was somewhat shorter and more variable in these patients, averaging 40 minutes and generally ranging from 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.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION:. Flumazenil Injection, USP is recommended for intravenous use only. It is compatible with 5% dextrose in water, lactated Ringers and normal saline solutions. If Flumazenil Injection, USP is drawn into syringe or mixed with any of these solutions, it should be discarded after 24 hours. For optimum sterility, Flumazenil Injection, USP should remain in the vial until just before use. As with all parenteral drug products, Flumazenil Injection, USP should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.To minimize the likelihood of pain at the injection site, Flumazenil Injection, USP should be administered through freely running intravenous infusion into large vein.. Reversal of Conscious Sedation. Adult PatientsFor the reversal of the sedative effects of benzodiazepines administered for conscious sedation, the recommended initial dose of Flumazenil Injection, USP 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, further dose of 0.2 mg (2 mL) can be injected and repeated at 60-second intervals where necessary (up to maximum of additional times) to maximum total dose of mg (10 mL). The dosage should be individualized based on the patients response, with most patients responding to doses of 0.6 mg to 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 mg (given as 0.2 mg/min) should be administered at any one time, and no more than mg should be given in any one hour.It is recommended that Flumazenil Injection, USP be administered as the series of small injections described (not as 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 PatientsFor the reversal of the sedative effects of benzodiazepines administered for conscious sedation in pediatric patients greater than 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 maximum of additional times) to maximum total dose of 0.05 mg/kg or mg, whichever is lower. The dose should be individualized based on the patients response. The mean total dose administered in the pediatric clinical trial of flumazenil was 0.65 mg (range: 0.08 mg to mg). Approximately one-half of patients required the maximum of five injections.Resedation occurred in of 60 patients who were fully alert 10 minutes after the start of Flumazenil Injection, USP 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, USP be administered as the series of small injections described (not as 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, USP in the reversal of conscious sedation in pediatric patients below the age of 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, USP 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, further dose of 0.2 mg (2 mL) can be injected and repeated at 60-second intervals where necessary (up to maximum of additional times) to maximum total dose of mg (10 mL). The dosage should be individualized based on the patients response, with most patients responding to doses of 0.6 mg to 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 mg (given as 0.2 mg/min) should be administered at any one time, and no more than mg should be given in any one hour.It is recommended that Flumazenil Injection, USP be administered as the series of small injections described (not as 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).. Management of Suspected Benzodiazepine Overdose in Adult Patients. For initial management of known or suspected benzodiazepine overdose, the recommended initial dose of Flumazenil Injection, USP is 0.2 mg (2 mL) administered intravenously over 30 seconds. If the desired level of consciousness is not obtained after waiting 30 seconds, 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 cumulative dose of mg.Do not rush the administration of Flumazenil Injection, USP. Patients should have secure airway and intravenous access before administration of the drug and be awakened gradually (see PRECAUTIONS).Most patients with benzodiazepine overdose will respond to cumulative dose of mg to mg of Flumazenil Injection, USP, and doses beyond mg do not reliably produce additional effects. On rare occasions, patients with partial response at mg may require additional titration up to total dose of mg (administered slowly in the same manner).If patient has not responded minutes after receiving cumulative dose of mg of Flumazenil Injection, USP, the major cause of sedation is likely not to be due to benzodiazepines, and additional Flumazenil Injection, USP 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 mg (given as 0.5 mg/min) should be given at any one time and no more than mg should be given in any one hour.. Safety and Handling. Flumazenil Injection, USP 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.

PRECAUTIONS SECTION.

PRECAUTIONS:. Return of Sedation. Flumazenil may be expected to improve the alertness of patients recovering from procedure involving sedation or anesthesia with benzodiazepines, but should not be substituted for an adequate period of postprocedure monitoring. The availability of flumazenil does not reduce the risks associated with the use of large doses of benzodiazepines for sedation.Patients should be monitored for resedation, respiratory depression (see WARNINGS) 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 low dose of short-acting benzodiazepine (<10 mg midazolam). It is most likely in cases where large single or cumulative dose of benzodiazepine has been given in the course of long procedure along with neuromuscular blocking agents and multiple anesthetic agents.Profound resedation was observed in 1% to 3% of adult patients in the clinical studies. In clinical situations where resedation must be prevented in adult patients, physicians may wish to repeat the initial dose (up to mg of flumazenil given at 0.2 mg/min) at 30 minutes and possibly again at 60 minutes. This dosage schedule, although not studied in clinical trials, was effective in preventing resedation in pharmacologic study in normal volunteers.The use of flumazenil to reverse the effects of benzodiazepines used for conscious sedation has been evaluated in one open-label clinical trial involving 107 pediatric patients between the ages of and 17 years. This study suggested that pediatric patients who have become fully awake following treatment with flumazenil may experience recurrence of sedation, especially younger patients (ages to 5). Resedation was experienced in of 60 patients who were fully alert 10 minutes after the start of flumazenil administration. No patient experienced return to the baseline level of sedation. Mean time to resedation was 25 minutes (range: 19 to 50 minutes) (see PRECAUTIONS, Pediatric Use). The safety and effectiveness of repeated flumazenil administration in pediatric patients experiencing resedation have not been established.. Use in the ICU. Flumazenil should be used with caution in the ICU because of the increased risk of unrecognized benzodiazepine dependence in such settings. Flumazenil may produce convulsions in patients physically dependent on benzodiazepines (see Individualization of Dosage and WARNINGS).Administration of flumazenil to diagnose benzodiazepine-induced sedation in the ICU is not recommended due to the risk of adverse events as described above. In addition, the prognostic significance of patients failure to respond to flumazenil in cases confounded by metabolic disorder, traumatic injury, drugs other than benzodiazepines, or any other reasons not associated with benzodiazepine receptor occupancy is unknown.. Use in Overdosage. Flumazenil is intended as an adjunct to, not as 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.. 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 With Neuromuscular Blocking Agents. Flumazenil should not be used until the effects of neuromuscular blockade have been fully reversed.. Use in Psychiatric Patients. Flumazenil has been reported to provoke panic attacks in patients with history of panic disorder.. Pain on Injection. To minimize the likelihood of pain or inflammation at the injection site, flumazenil should be administered through freely flowing intravenous infusion into large vein. Local irritation may occur following extravasation into perivascular tissues.. 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 (see PRECAUTIONS) 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 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.. 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 (see 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.. 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 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 weeks who exhibited effects such as hot flushes, agitation and tremor when treated with cumulative doses of up to 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 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 mg, rarely required treatment other than reassurance and was usually short-lived. When required (5 to 10 cases), these patients were successfully treated with usual doses of barbiturate, 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 (see WARNINGS).The use of flumazenil is not recommended in epileptic patients who have been receiving benzodiazepine treatment for prolonged period. Although flumazenil exerts slight intrinsic anticonvulsant effect, its abrupt suppression of the protective effect of 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 PatientsThe effects of flumazenil may wear off before long-acting benzodiazepine is completely cleared from the body. In general, if patient shows no signs of sedation within hours after 1 mg dose of flumazenil, serious resedation at 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 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).. Information for 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 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 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 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.. Not to engage in any activities requiring complete alertness, and not to operate hazardous machinery or 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.. Laboratory Tests. No specific laboratory tests are recommended to follow the patients response or to identify possible adverse reactions.. Drug/Laboratory Test Interactions. The possible interaction of flumazenil with commonly used laboratory tests has not been evaluated.. Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisNo studies in animals to evaluate the carcinogenic potential of flumazenil have been conducted.MutagenesisNo evidence for mutagenicity was noted in the Ames test using five different tester strains. Assays for mutagenic potential in S. cerevisiae D7 and in Chinese hamster cells were considered to be negative as were blastogenesis assays in vitro in peripheral human lymphocytes and in vivo in mouse micronucleus assay. Flumazenil caused slight increase in unscheduled DNA synthesis in rat hepatocyte culture at concentrations which were also cytotoxic; no increase in DNA repair was observed in male mouse germ cells in an in vivo DNA repair assay.Impairment of FertilityA 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 maximum recommended intravenous dose of mg.. Pregnancy. Pregnancy Category CThere 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.Teratogenic EffectsFlumazenil 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 to 15 of gestation in the rat and days 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 maximum recommended intravenous dose of 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 maximum recommended intravenous dose of mg. The no-effect dose of 15 mg/kg in rabbits represents 60x the human exposure.Nonteratogenic EffectsAn animal reproduction study was conducted in rats at oral dosages of 5, 25 and 125 mg/kg/day of flumazenil. Pup survival was decreased during the lactating period, pup liver weight at weaning was increased for the high-dose group (125 mg/kg/day) and incisor eruption and ear opening in the offspring were delayed; the delay in ear opening was associated with delay in the appearance of the auditory startle response. No treatment-related adverse effects were noted for the other dose groups. Based on the available data from AUC, the effect level (125 mg/kg) represents 120x the human exposure from mg, the maximum recommended intravenous dose in humans. The no-effect level represents 24x the human exposure from an intravenous dose of 5mg.. Labor and Delivery. The use of flumazenil to reverse the effects of benzodiazepines used during labor and delivery is not recommended because the effects of the drug in the newborn are unknown.. Nursing Mothers. Caution should be exercised when deciding to administer flumazenil to nursing woman because it is not known whether flumazenil is excreted in human milk.. Pediatric Use. The safety and effectiveness of flumazenil have been established in pediatric patients 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 conscious sedation was evaluated in one uncontrolled clinical trial involving 107 pediatric patients between the ages of and 17 years. At the doses used, flumazenils safety was established in this population. Patients received up to injections of 0.01 mg/kg flumazenil up to maximum total dose of mg at rate not exceeding 0.2 mg/min.Of 60 patients who were fully alert at 10 minutes, experienced resedation. Resedation occurred between 19 and 50 minutes after the start of flumazenil administration. None of the patients experienced return to the baseline level of sedation. All patients were between the ages of and 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 serious adverse event attributable to flumazenil.The safety and efficacy of flumazenil in the reversal of conscious sedation in pediatric patients below the age of year have not been established (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Pediatric Patients).The safety and efficacy of flumazenil have not been established in pediatric patients for reversal of the sedative effects of benzodiazepines used for induction of general anesthesia, for the management of overdose, or for the resuscitation of the newborn, as no well-controlled clinical studies have been performed to determine the risks, benefits and dosages to be used. However, published anecdotal reports discussing the use of flumazenil in pediatric patients for these indications have reported similar safety profiles and dosing guidelines to those described for the reversal of conscious sedation.The risks identified in the adult population with flumazenil use also apply to pediatric patients. Therefore, consult the CONTRAINDICATIONS WARNINGS PRECAUTIONS and ADVERSE REACTIONS sections when using flumazenil in pediatric patients.. Geriatric Use. 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.