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OMNIFLOX ADVERSE EVENTS PROFILE "OUT OF PROPORTION" WITH OTHER MARKETED QUINOLONES; "SERIOUS" ADVERSE EVENTS OCCURRED 28 TIMES OUT OF 100,000 SCRIPTS

Executive Summary

Abbott's Omniflox (temafloxacin) appears to be associated with a rate of adverse events that is "out of proportion" with other marketed fluoroquinolones, FDA Medical Officer Michael Blum, MD, told the agency's Anti-Infective Drugs Advisory Committee July 10. Blum said FDA has compared reporting for Omniflox with quinolones including Merck's Noroxin (noroxacin), Miles' Cipro (ciprofloxacin) and Ortho's Floxin (ofloxacin). "We believe that temafloxacin caused a multisystem illness in a frequency which was well out of proportion to that seen with other drugs in this class," Blum told the committee. "This syndrome consisted of hemolysis, renal failure, disseminated intravascular coagulation (DIC), thrombocytopenia and/or liver dysfunction." Abbott withdrew the antibiotic worldwide June 5 ("The Pink Sheet" June 8, T&G-1). FDA Division of Epidemiology and Surveillance Acting Director Joyce Johnson presented a controled comparison of the adverse events reported in the first 120 days of marketing for Omniflox with those for the other quinolones. The timeframe was chosen because "we only had 120 days experience" with Omniflox, Johnson said. The comparison was based on IMS drug data. Johnson found a reporting rate of 108 per 100,000 prescriptions for Omniflox, compared with 25 for Floxin, 20 for Noroxin and 13 for Cipro. Reports characterized as "serious" occurred 28 times in 100,000 scripts for Omniflox, six FDA for Cipro, four for Noroxin and three for Floxin. The Omniflox withdrawal was based on more than 50 adverse event reports. Blum also presented ADRs submitted since the withdrawal of Omniflox. Blum said that there were 46 manufacturer reports and 12 reports delivered directly to FDA "between June 6 and July 6." Of these, 15 manufacturer reports and six FDA reports "fit the spectrum" of adverse events found before Omniflox was withdrawn. The events in the most recent reports include "hemolysis or hemolytic anemia or suggestions of it" accompanied by "a variety of the other manifestations," such as renal failure, DIC and hypotension, the FDAer said. Included in these reports were five deaths "that fit the spectrum." These additional reports led Blum to conclude: "The data does lend credence to the fact that there is some type of repetitive multisystem illness going on here." Blum, who was in charge of reviewing the Omniflox adverse event reports, said that a number of variables have been ruled out as factors in the events, including contamination at Abbott's manufacturing facilities, association of the reactions with particular indications, interaction of temafloxacin with other drugs and dosage regimen. The committee was unable to determine the mechanism of action of the Omniflox adverse events based on the currently available data. Invited expert Ernest Beutler, MD, Scripps Research Institute, said: "Without the necessary data, we could say anything." He added, however that "there is a window of opportunity here for us to get serum from the patients" who had reactions to Omniflox. He said that if the reactions were "immune modulated," the antibodies created could "disappear rapidly" from patients' blood. CDER Deputy Director for Scientific and Medical Affairs Bruce Burlington, MD, said the agency has been "trying to contact the doctors involved" with the adverse reactions, but those efforts "have not been very fruitful." Blum suggested that temafloxacin's "difluorinated phenyl group" side chain, which is not found in the structure of the other quinolones, could be a factor in Omniflox' side effect profile. He said some of the same side effects are found with fluconazole (Pfizer's Diflucan) and Merck's Dolabid (diflunisal), both of which have the same difluorinated phenyl group. He added that "this is pure speculation." Committee Chairman Thomas Beam, MD, Buffalo V-A Medical Center, said that the committee "should offer some guidance to companies with quinolones in development" on how to detect the reactions found with Omniflox. Committee member Russell Steele, MD, Louisiana State University, suggested that "there might be an animal model" that would detect rare reactions "once we know the mechanism of action." The committee agreed with his suggestion that "particular attention" could be paid to those quinolones in development that "have that side chain."

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