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Executive Summary

DUPONT's CARDENE I.V. AS SECOND-LINE THERAPY FOR HYPERTENSION was recommended for approval by FDA's Cardio-Renal Drugs Advisory Committee at its June 15 meeting. The panel voted six-to-one in favor of recommending approval for the new parenteral formulation of nicardipine in treatment of hypertension. Dupont Critical Care had sought an indication for treating patients with acute hypertension. Dupont sublicenses Cardene I.V. from Syntex, which in turn licenses rights to Cardene from Yamanouchi. Syntex markets Cardene oral. While the committee concluded that Cardene I.V. is effective in lowering blood pressure, one panel member could not vote for approvability because of concern that the correct dosing regimen for the antihypertensive has not been determined. Committee Pharmacokinetics Reviewer Craig Brater, MD, Indiana University School of Medicine, said: "If conditional [approvability] means once somebody figures out how to dose it, then I can say, 'yes.' If it doesn't then I have to say, 'no.'" Committee Medical Reviewer Milton Packer, MD, Mount Sinai Medical Center, suggested that the firm conduct postmarketing studies to find appropriate dosing. * The indication for Cardene I.V. was also recommended as a replacement indication for all marketed I.V. antihypertensives. The panel unanimously responded in the affirmative to the question: "Should labeling of intravenous preparations for hypertension carry with it a sentence...'this is second-line therapy and it's to be used only when'" oral therapy is neither feasible nor desirable. The committee also recommended in a five-to-two vote that for all I.V. antihypertensives the term "severe hypertension" should be replaced with term "hypertension" in the indication section of labeling. In one of the two studies submitted in support of the Dupont NDA, 73 patients with severe hypertension (diastolic blood pressure of 120 mmHg) were treated with nicardipine. The dose was titrated from 5 mg/hr to 15 mg/hr over 15 minutes per dose. Responses defined as a 15 mmHg decrease in diastolic blood pressure were observed in 23% of patients at the 5 mg dose, 49% of patients at 7.5 mg, and 95% of patients at 15 mg. "Almost 100% of patients or over 90% respond...but it took about two-and-a-half hours," said Dupont consultant Michael Weber, MD, University of California at Irvine. The offset of action or a 10 mmHg rise in blood pressure took place 30 to 40 minutes post infusion. The second study looked at hypertension in post-operative patients with baseline diastolic blood pressures of 95 mmHg. The patients received 10 mg/hr for 5 minutes, 12.5 mg/hr for 5 minutes, or 15 mg/hr for 15 minutes with a response considered to be a drop in diastolic blood pressure of 15%. Responses were observed in 27% of patients at 10 mg, 58% of patients at 12.5 mg, and 94% of patients at 15 mg dose. Responses occurred within 30 minutes, Weber said. The adverse reactions observed in both studies included hypotension in 6% of patients receiving nicardipine, headache in 15% and tachycardia in 2.6%. Six percent of patients discontinued therapy due to adverse events. The committee determined that Cardene I.V. cannot be indicated for treating hypertensive emergencies since Dupont did not study it in that population. FDA Division of Cardio-Renal Drugs Director Raymond Lipicky, MD, noted that "to use a drug in hypertensive emergency one would need to have some kind of special information or special efficacy risk/benefit assessment, or something." Explaining why the firm didn't study this population, Weber said: "The problem is we don't see enough of them in anyplace, anymore...I really don't know how we could set up a study." For use in hypertensive emergencies, Packer said, "the question with nicardipine is, is it fast enough?" He noted that a drug for this use should have rapid control of blood pressure "within an hour, maybe even in minutes." The onset of action for Cardene I.V. can range from 10 minutes to up to four to six hours, Packer pointed out. Regarding label warnings for Cardene I.V., Packer suggested that "there should be specific instruction or description that says that the onset and offset of this drug is variable, but may be long. That it might take...from 10 minutes to two hours to achieve a therapeutic response...and that it may take several hours for a hypotensive reaction to disappear." There should also be warnings about tachycardia, he said.

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