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ROCHE’s MAZICON WILL BE AVAILABLE IN PHARMACIES BY EARLY FEBRUARY; BENZODIAZEPINE ANTAGONIST IS APPROVED 11 DAYS AFTER "NDA DAY" AND ONE YEAR AFTER FILING

Executive Summary

Hoffmann-La Roche's Mazicon will be shipped to pharmacies by early February following approval of the first injectable benzodiazepine antagonist by FDA on Dec. 20, the company said. Mazicon (flumazenil) was approved 11 days after FDA held an "NDA Day" to review the application. FDA review of the NDA took just over one year. Roche filed the NDA on Dec. 10, 1990. Mazicon 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," approved labeling states. Flumazenil is specific to benzodiazepines and does not antagonize the central nervous system effects of alcohol, barbiturates, general anesthetics or opioids, labeling notes. The drug begins to reverse the effects of benzodiazepines within one to two minutes and achieves an 80% response within three minutes, labeling states. Roche estimates that there are 31 mil. procedures performed with benzodiazepines each year and about 200,000 intentional benzodiazepine overdoses annually. While flumenazil will be used to counteract sedation induced by benzodiazepines, such as Roche's Valium and Versed, it may not provide an answer to some of the more serious risks of benzodiazepine use, including cardio-respiratory events and death. Labeling states that patients should be monitored for resedation and respiratory depression since flumazenil "has not been established as an effective treatment for hypoventilation due to benzodiazepine administration." The precautions section of labeling notes that flumazenil should not be substituted for an adequate period of post-procedure monitoring and that "the availability of Mazicon does not reduce the risks associated with the use of large doses of benzodiazepines for sedation." In studies of 970 patients under conscious sedation induced by diazepam or midazolam (Roche's Valium and Versed), flumazenil at doses of .4 mg to 1 mg was effective in reversing sedation in 78% of patients. In general anesthesia trials of 644 patients receiving flumazenil following sedation with midazolam, 81% became alert or slightly drowsy. However, flumazenil was not as effective in the reversal of sedation in patients who received multiple anesthetic agents in addition to benzodiazepines, labeling states. Resedation occurred in 10-15% of the patients who had responded to flumazenil after general anesthesia. In overdose trials, flumazenil demonstrated improvement in consciousnes in 80% of the 148 patients studied. The dose required to reverse the effects of overdose in these patients -- 1 mg to 3 mg -- was higher than that for other patients. Labeling notes that "the risk of confusion, agitation, emotional liability and perceptual distortion with the doses recommended in patients with benzodiazepine overdose (3 mg to 5 mg administered as .5 mg/min.) may be greater than that expected with lower doses and slower administration." The physician may choose to use a .2 mg/min. titration to awaken the patients over 5-10 minutes, labeling states. Flumazenil labeling contains a boxed warning about the risk of seizures in patients receiving the drug. Six seizures occurred in 446 patients receiving flumazenil in controlled clinical trials. "These are most frequent in patients who have been on benzodiazepines for long-term sedation or in overdose cases where patients are showing signs of serious cyclic antidepressant overdose," labeling notes. Other adverse reactions include dizziness, agitation, and abnormal and blurred vision. In the flumazenil approval letter, FDA notes that Roche has committed to three Phase IV studies. The company will conduct separate studies to evaluate flumazenil dosing in adult and pediatric overdose cases. In addition, Roche will study the use of flumazenil in reversing the effects of long-term benzodiazepine use in the intensive care unit. Labeling cautions against flumazenil use in the ICU for unrecognized benzodiazepine dependence because of the risk that the drug may produce convulsions in such patients.

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