For the use of a Registered Medical Practitioner or a Hospital or a Institution only.
FLUMAZENIL INJECTION USP (Flumazenil) is 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. The molecular formula is C15H14FN3O3 and molecular weight is 303.29.
STRUCTURAL FORMULA :
Its structural formula is :
FLUMAZENIL INJECTION USP is a sterile, nonpyrogenic, clear and colourless solution filled in ampoule of suitable size.
Each ml contains :
Flumazenil USP 0.1 mg
Methyl Paraben USP 0.18 % w/v
Propyl Paraben USP 0.02 % w/v
Sodium Chloride USP 0.9 % w/v
Water for Injection USP q.s.
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 a 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 anaesthetics) and does not reverse the effects of opioids.
After IV administration, plasma concentrations of flumazenil follow a two-exponential decay model. The pharmacokinetics of flumazenil are dose-proportional up to 100 mg.
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 showsno preferential partitioning into red blood cells. Albumin accounts for two thirds of plasma protein binding.
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.
The Elderly :
The pharmacokinetics of flumazenil are not significantly altered in the elderly.
The pharmacokinetics of flumazenil are not different in male and female subjects. Renal Failure (creatinine clearance <10 ml/min) and Haemodialysis: 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.
Adult Patients :
FLUMAZENIL INJECTION USP is indicated for the complete or partial reversal of the sedative effects of benzodiazepines in cases where general anaesthesia 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.
Paediatric Patients (aged 1 to 17) :
FLUMAZENIL INJECTION USP is indicated for the reversal of conscious sedation induced with benzodiazepines. FLUMAZENIL INJECTION USP is indicated for the complete or partial reversal of the central sedative effects of benzodiazepines. It may therefore be used in anaesthesia and intensive care in the following situations :
• termination of general anaesthesia induced and/or maintained with benzodiazepines;
• reversal of benzodiazepine sedation in short diagnostic and therapeutic procedures;
• for the diagnosis and/or management of deliberate or accidental benzodiazepine overdosage.
FOR I.V. USE ONLY.
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 a 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 ampoule 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 a freely running intravenous infusion into a large vein.
INSTRUCTIONS FOR USE OF AMPOULE :
The ampoule used in this product is equipped with O.P.C (One Point Cut) opening system. No ampoule file is needed to open the ampoule. The neck of the ampoule is prescored at the point of constriction. A coloured dot on the ampoule head helps to orientate the ampoule. Take the ampoule and face the coloured dot. Let the solution at the head of the ampoule to flow down by shaking or a gentle stroke. The ampoule opens easily by placing the thumb on the coloured dot and gently pressing downwards as shown.
Adult Patients :
For 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, 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 patients response, with most patients responding to doses of 0.6 mg to 1 mg. 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 USP 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 .
Paediatric Patients :
For the reversal of the sedative effects of benzodiazepines administered for conscious sedation in paediatric 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 patients response.It is recommended that FLUMAZENIL INJECTION USP 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 .The safety and efficacy of FLUMAZENIL INJECTION USP in the reversal of conscious sedation in paediatric patients below the age of 1 year have not been established.
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 INJECTION USP 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 INJECTION USP 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 INJECTION USP 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.
Patients who have received FLUMAZENIL INJECTION USP 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 INJECTION USP has not been established in patients as an effective treatment for hypoventilation due to benzodiazepine administration. In healthy male volunteers, FLUMAZENIL INJECTION USP 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 INJECTION USP (1 mg or less) may wear off before the effects of many benzodiazepines. The effects of FLUMAZENIL INJECTION USP 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.
Return of Sedation :
FLUMAZENIL INJECTION USP may be expected to improve the alertness of patients recovering from a procedure involving sedation or anaesthesia with benzodiazepines, but should not be substituted for an adequate period of postprocedure monitoring. The availability of FLUMAZENIL INJECTION USP does not reduce the risks associated with the use of large doses of benzodiazepines for sedation. 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 INJECTION USP. Resedation is least likely in cases where FLUMAZENIL INJECTION USP is administered to reverse a low dose of a short-acting benzodiazepine (<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 anaesthetic 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 1 mg of FLUMAZENIL INJECTION USP 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 a pharmacologic study in normal volunteers.
The use of FLUMAZENIL INJECTION USP to reverse the effects of benzodiazepines used for conscious sedation has been evaluated in one open-label clinical trial involving 107 paediatric patients between the ages of 1 and 17 years. This study suggested that paediatric patients who have become fully awake following treatment with flumazenil may experience a recurrence of sedation, especially younger patients (ages 1 to 5). Resedation was experienced in 7 of 60 patients who were fully alert 10 minutes after the start of FLUMAZENIL INJECTION USP administration. No patient experienced a return to the baseline level of sedation. Mean time to resedation was 25 minutes (range : 19 to 50 minutes). The safety and effectiveness of repeated flumazenil administration in paediatric patients experiencing resedation have not been established.
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 foetus. The use of FLUMAZENIL INJECTION USP 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 :
It is not known whether flumazenil is excreted in human milk. For this reason, breast-feeding should be interrupted for 24 hours when flumazenil is used during lactation.
Paediatric Use :
The safety and effectiveness of FLUMAZENIL INJECTION USP have been established in paediatric patients 1 year of age and older. Use of FLUMAZENIL INJECTION USP in this age group is supported by evidence from adequate and well-controlled studies of FLUMAZENIL INJECTION USP in adults with additional data from uncontrolled paediatric studies including one open-label trial. The safety and efficacy of FLUMAZENIL INJECTION USP in the reversal of conscious sedation in paediatric patients below the age of 1 year have not been established . The safety and efficacy of FLUMAZENIL INJECTION USP have not been established in paediatric patients for reversal of the sedative effects of benzodiazepines used for induction of general anaesthesia, 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.
INTERACTIONS AND INCOMPATIBILITIES :
Interaction with central nervous system depressants other than benzodiazepines has not been specifically studied; however, no deleterious interactions were seen when FLUMAZENIL INJECTION USP was administered after narcotics, inhalational anaesthetics, muscle relaxants and muscle relaxant antagonists administered in conjunction with sedation or anaesthesia. Particular caution is necessary when using FLUMAZENIL INJECTION USP 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 INJECTION USP is not recommended in epileptic patients who have been receiving benzodiazepine treatment for a prolonged period. Although FLUMAZENIL INJECTION USP 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 INJECTION USP 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 INJECTION USP. The pharmacokinetics of benzodiazepines are unaltered in the presence of flumazenil and vice versa.There is no pharmacokinetic interaction between ethanol and flumazenil.
SIDE EFFECTS :
Flumazenil is generally well tolerated. In postoperative use, nausea and/or vomiting are observed, particularly if opiates have also been employed. Flushing has also been noted. If patients are awakened too rapidly, they may become agitated, anxious or fearful. Transient increases in blood pressure and heart rate may also occur Excessively and/or rapidly injected doses of flumazenil may induce benzodiazepine withdrawal symptoms such as anxiety attacks, tachycardia, dizziness, and sweating in patients on long-term benzodiazepine treatment. Although clinical experience with flumazenil is limited, seizures and/or cardiac arrhythmias have been observed in patients who are physically dependent on benzodiazepines, and in multiple-drug overdose, particularly in the presence of tricyclic antidepressants. Flumazenil has been reported to provoke panic attacks in patients with a history of panic disorders. The following table summarizes the adverse reactions which occurred with an incidence of >1 %. :
INFORMATION FOR PATIENTS :
FLUMAZENIL INJECTION USP does not consistently reverse amnaesia. 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 (eg, 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 :
1. 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.
2. 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.
There is limited experience of acute overdose with FLUMAZENIL INJECTION USP.
TREATMENT OF OVERDOSAGE :
There is no specific antidote for overdose with FLUMAZENIL INJECTION USP. Treatment of an overdose with FLUMAZENIL INJECTION USP 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 INJECTION USP, 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 INJECTION USP may produce anxiety, agitation, increased muscle tone, hyperaesthesia and possibly convulsions. Convulsions have been treated with barbiturates, benzodiazepines and phenytoin, generally with prompt resolution of the seizures.
PHARMACEUTICAL PRECAUTIONS :
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Store below 30°C (86°F), protected from light.
Do not refrigerate.
SHELF LIFE :
24 months from the date of manufacture.
FLUMAZENIL INJECTION USP is supplied as 0.500 mg Flumazenil USP in 5 ml aqueous solution.
Such 5 Ampoules of 5 ml are packed in a carton.
Disclaimer : For the use of a Registered Medical Practitioner or a Hospital or a Institution only. Also it is not intended to be used by healthcare professionals or patients for the purpose of prescribing or administering these products. Questions regarding the complete and current content of product labeling / specification / presentation should be directed to SGPharma.