Cardiac QT prolongation associated with Bayer's fluoroquinolone Avelox (moxifloxacin) should be evaluated in high risk patients, FDA's Anti-Infective Drugs Advisory Committee concluded Oct. 21.

"The higher risk subsets, which are very hard to study...are the ones we worry about, and that is the small subset in whom we have no data," committee consultant Jeremy Ruskin, MD, Massachusetts General Hospital, said. The committee concurred with Ruskin, who is chief of the Cardiac Arrhythmia Service at MGH.

"It would be helpful to look at the QT effects in the subset with congestive heart failure in particular," Ruskin said. "This may have some importance in treating some of the pneumonias. Clearly with the exacerbation of chronic bronchitis there will be a subset with CHF," he noted.

The committee met to consider Bayer's Avelox NDA (21-085) for the treatment of acute bacterial exacerbations of chronic bronchitis, acute sinusitis, community-acquired pneumonia, and uncomplicated skin and skin structure infections.

The committee agreed that moxifloxacin is safe for marketing approval by a vote of 7-3, provided that labeling include warnings of QT prolongation.

FDA specifically asked the committee to assess the relative risk associated with the QT interval prolongation observed in the studies.

Patients with a congenital history of QT prolongation and patients taking a class Ia or class III antiarrhythmic were excluded from the Avelox clinical studies once a risk was discovered. About two-thirds of patients enrolled fit these criteria, the company said.

Bayer evaluated the safety of moxifloxacin in 4,008 patients enrolled in controlled trials and treated with orally administered Avelox 400 mg once daily, and 3,689 patients treated with another antimicrobial agent.

The mean QTc prolongation among moxifloxacin patients was 6 msec with a total of 38 outliers vs. a 1 msec mean prolongation and 28 outliers in a comparator group that included clarithromycin, cephalexin, cefuroxime axetil, amoxicillin, and doxycycline-metronidazole. Outliers were considered to be patients who had prolongation of the QT interval as defined by the European Committee for Proprietary Medicinal Products ( > 450 msec for men, > 470 msec for women).

There was one cardiovascular event among the 38 outliers in the moxifloxacin group compared to four among the 28 outliers in the comparator group, leading Bayer to conclude that there was "no increased risk" of cardiovascular adverse events in moxifloxacin-treated patients who had a prolonged QT interval.

The committee proposed that labeling caution: "This drug is a weak Ikr blocker with a mild to moderate effect on the QT interval. In the patient populations studied in clinical trials, no adverse effect on cardiovascular morbidity or total mortality was observed. However, there are no data on safety in patients with pre-existing QT prolongation, or those currently taking other agents which prolong the QT interval, and therefore the drug should be avoided in those subsets."

Committee member Robert Danner, MD, National Institutes of Health, was not convinced by the risk/benefit ratio for Avelox, however, even with the provision that labeling would carry a warning.

Danner noted that "this is exactly the kind of place that you get into trouble....[A drug] is carefully studied in a trial, people are carefully excluded who have prolonged QT intervals [and] it is used for a very short interval of time."

"I think that there are enough things that haven't been answered, and I'm not sure I see what this drug adds to drugs we already have, that is so unique that we need this drug and we need it now," Danner commented.

On the subject of determining the risk of a prolonged QT interval, FDA Associate Director for Medical Policy Robert Temple, MD, told the committee "it is fairly clear that there is a dose response relationship in most cases between QT prolongation and dose (or concentration) and that there is some relationship at least on QT and how much trouble you get into."

"The problem here is that while QT effects are frequent and easily detected," torsade de pointes, a condition sometimes associated with QT prolongation, "is rare and not easy to detect in an NDA database. Temple suggested that "you can learn about whether drugs have the ability to cause torsade...in the post-marketing period."

FDA acknowledged that there are approved antibiotics also associated with QT prolongation. FDA said that they will be reviewed and relabeled as resources permit.

FDA Division of Drug Risk Evaluation I Medical Officer Allen Brinker, MD, presented postmarketing data on the relative risk of ventricular arrhythmias and cardiac arrest for eight currently marketed antibiotics. Seven of the eight drugs had cardiac event reports in the range of 3-30 per 10,000 prescriptions. FDA logged 145 cardiac events per 10,000 prescriptions associated with sparfloxacin (Rhone-Poulenc Rorer's Zagam).

Committee consultant Ruskin told the committee that it is very difficult to assess the risks being considered. "Nobody can tell you what the incidence is," he said, "except that it will be low. It would appear that [moxifloxacin] looks better than sparfloxacin and probably not quite as good as most of the comparators."

The committee voted unanimously that moxifloxacin is effective in the treatment of CAP, acute sinusitis, uncomplicated skin/skin structure infections and acute exacerbations of chronic bronchitis.

For acute sinusitis, 90% of patients treated with 400 mg once-daily moxifloxacin over 10 days were cured vs. 89% of patients treated with cefuroxime 250 mg twice daily for 10 days. In AECB, 91% of moxifloxacin patients were cured after 10 days and 89% were cured in five days compared to 89% cured after 10 days of treatment with clarithromycin 500 mg b.i.d.

After 10 days of treatment, 95% of patients with CAP were cured in both the moxifloxacin and clarithromycin groups. Uncomplicated skin and skin structure infections were cured in 89% of patients randomized to moxifloxacin 400 mg for seven days vs. 90% of patients treated with cephalexin with or without metronidazole for 5-14 days.

The committee recommended against Avelox for penicillin-intermediate or penicillin-resistant CAP or sinusitis, citing an inadequate body of data. It also recommended the sponsor conduct additional studies.

Avelox was 75% (6/8) effective in treating penicillin-resistant CAP and 88.2% (15/17) effective in treating penicillin-intermediate CAP. Moxifloxacin was 100% (6/6) effective in treating penicillin-resistant sinusitis and 89% (8/9) effective in treating penicillin-intermediate sinusitis.

However, FDA concluded that the clinical efficacy rate of moxifloxacin was less than that of high-dose amoxicillin (1,000 mg t.i.d.) for the treatment of CAP due to penicillin-resistant Streptococcus pneumonia or patients with pneumococcal bacteremia.

Bayer Avelox Cardiac Safety Studies Recommended By FDA Committee

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