Flumazenil

INDICATIONS AND USAGE Adult Patients: Flumazenil injection is indicated for the complete or partial reversal of the sedative effects of benzodiazepines in cases where general anesthesia has been induced and/or maintained with benzodiazepines, where sedation has been produced with benzodiazepines for diagnostic and therapeutic procedures, and for the management of benzodiazepine overdose. Pediatric Patients (aged 1 to 17): Flumazenil injection is indicated for the reversal of conscious sedation induced with benzodiazepines (see PRECAUTIONS: Pediatric Use ).

DOSAGE AND ADMINISTRATION Flumazenil injection, USP is recommended for intravenous use only. It is compatible with 5% dextrose in water, lactated Ringer’s and normal saline solutions. If flumazenil injection is drawn into a syringe or mixed with any of these solutions, it should be discarded after 24 hours. For optimum sterility, flumazenil injection should remain in the vial until just before use. As with all parenteral drug products, flumazenil injection 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 should be administered through a freely running intravenous infusion into a large vein. Reversal of Conscious Sedation: Adult Patients For the reversal of the sedative effects of benzodiazepines administered for conscious sedation, the recommended initial dose of flumazenil 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 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 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 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 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 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 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) …

CONTRAINDICATIONS Flumazenil injection is contraindicated: • in patients with a known hypersensitivity to flumazenil or benzodiazepines. • in patients who have been given a benzodiazepine for control of a potentially life-threatening condition (e.g., control of intracranial pressure or status epilepticus). • in patients who are showing signs of serious cyclic antidepressant overdose (see WARNINGS ).

ADVERSE REACTIONS Serious Adverse Reactions: 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) (see WARNINGS ). 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). 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 Postmarketing Experience: The following events have been reported during post-approval 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.

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 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.

DESCRIPTION Flumazenil Injection, USP is a benzodiazepine receptor antagonist. Chemically, flumazenil is ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a](1,4) benzodiazepine-3-carboxylate. Flumazenil has an imidazobenzodiazepine structure a calculated molecular weight of 303.3 and the following structural formula: Flumazenil is a white to off-white crystalline compound with an octanol:buffer partition coefficient of 14 to 1 at pH 7.4. It is insoluble in water but slightly soluble in acidic aqueous solutions. Flumazenil is available as a sterile parenteral dosage form for intravenous administration. Each mL contains 0.1 mg of Flumazenil compounded with 1.8 mg of Methylparaben , 0.2 mg of Propylparaben , 0.9% mg Sodium Chloride , 0.01% Edetate Disodium Dihydrate , and 0.1 mg Glacial Acetic Acid ; the pH is adjusted to 3.4 to 4.6 with Hydrochloric Acid and/or, if necessary, Sodium Hydroxide and Water for Injection q.s. to 1 mL. structure

OVERDOSAGE There is limited experience of acute overdose with flumazenil. There is no specific antidote for overdose with flumazenil. Treatment of an overdose with flumazenil should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. Intravenous bolus administration of doses ranging from 2.5 to 100 mg (exceeding those recommended) of flumazenil, when administered to healthy normal volunteers in the absence of a benzodiazepine agonist, produced no serious adverse reactions, severe signs or symptoms, or clinically significant laboratory test abnormalities. In clinical studies, most adverse reactions to flumazenil were an extension of the pharmacologic effects of the drug in reversing benzodiazepine effects. Reversal with an excessively high dose of flumazenil may produce anxiety, agitation, increased muscle tone, hyperesthesia and possibly convulsions. Convulsions have been treated with barbiturates, benzodiazepines and phenytoin, generally with prompt resolution of the seizures (see WARNINGS ).

HOW SUPPLIED Flumazenil Injection, USP, for Intravenous use is supplied in: For Intravenous Multiple-Dose Use: AIN00213 NDC 36000-148-10 , 0.1 mg/mL, 5 mL vial; Pack of 10 Vials For Intravenous Multiple-Dose Use: AIN00212 NDC 36000-149-10 , 0.1 mg/mL, 10 mL vial; Pack of 10 Vials Sterile, Nonpyrogenic. The container closure is not made with natural rubber latex. Storage Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] PROTECT FROM LIGHT. DO NOT FREEZE. Manufactured for: Baxter Healthcare Corporation Deerfield, IL 60015 USA Manufactured by: Baxter Pharmaceuticals India Private Ltd Ahmedabad 382213, India 1400006464 2018/08/09