Flumazenil (Page 2 of 7)

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.

CLINICAL TRIALS

Flumazenil has been administered in adults to reverse the effects of benzodiazepines in conscious sedation, general anesthesia, and the management of suspected benzodiazepine overdose. Limited information from uncontrolled studies in pediatric patients is available regarding the use of flumazenil to reverse the effects of benzodiazepines in conscious sedation only.

Conscious Sedation in Adults

Flumazenil was studied in four trials in 970 patients who received an average of 30 mg diazepam or 10 mg midazolam for sedation (with or without a narcotic) in conjunction with both inpatient and outpatient diagnostic or surgical procedures. Flumazenil was effective in reversing the sedating and psychomotor effects of the benzodiazepine; however, amnesia was less completely and less consistently reversed. In these studies, flumazenil was administered as an initial dose of 0.4 mg IV (two doses of 0.2 mg) with additional 0.2 mg doses as needed to achieve complete awakening, up to a 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 5mg 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).

INDIVIDUALIZATION OF DOSAGE

General Principles

The serious adverse effects of flumazenil are related to the reversal of benzodiazepine effects. Using more than the minimally effective dose of flumazenil is tolerated by most patients but may complicate the management of patients who are physically dependent on benzodiazepines or patients who are depending on benzodiazepines for therapeutic effect (such as suppression of seizures in cyclic antidepressant overdose).

In high-risk patients, it is important to administer the smallest amount of flumazenil that is effective. The 1-minute wait between individual doses in the dose-titration recommended for general clinical populations may be too short for high-risk patients. This is because it takes 6 to 10 minutes for any single dose of flumazenil to reach full effects. Practitioners should slow the rate of administration of flumazenil administered to high-risk patients as recommended below.

Anesthesia and Conscious Sedation in Adult Patients

Flumazenil 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 5mg 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 5to 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 5mg 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 5times 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.

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