Glaxo Wellcome is withdrawing the quinolone antibiotic Raxar (grepafloxacin) from the worldwide markets after receiving a total of seven reports of cardiovascular event-related fatalities associated with use of the drug.

Review of the adverse event data could not rule out Raxar as a contributing factor to the seven fatal events, Glaxo said. The oral fluoroquinolone has also been associated with two confirmed cases of torsade de pointes and one suspected case.

Five of the fatal cardiovascular events occurred in Germany, with the two remaining fatalities having taken place in France and the U.S.

Two of the torsade de pointes cases were in the U.S. and one was reported in Germany. Raxar is being withdrawn from all 36 countries in which it is marketed.

"While the reported incidence of such cardiovascular events is infrequent, the company is no longer convinced that the benefits of Raxar outweigh the potential risks to patients, given the availability of alternative antibiotics," Glaxo said.

Raxar was first launched in Germany in August 1997 and was launched in the U.S. in December of that year. The company reported that 2.7 mil. patient treatments have been prescribed for the drug.

Raxar, however, was never a significant contributor to the Glaxo portfolio. Glaxo licensed the drug from Otsuka and brought it to market at about the same time that Pfizer launched its quinolone antibiotic Trovan.

Glaxo supported the product with over 1,500 reps in the U.S. at launch. However, U.S. sales in 1998 were only $6.6 mil. and had fallen off to $1.6 mil. in the first half of 1999. Worldwide sales were $17 mil. in 1998 and $8 mil. in the first half of 1999.

Antibiotics are an important franchise for Glaxo, representing 10% of the company's revenues in the first half of 1999 (approximately $700 mil.). Glaxo devotes about 4% of its R&D budget to microbial diseases.

In the U.S. and Europe, Raxar carried indications for acute exacerbations of chronic bronchitis, community-acquired pneumonia, uncomplicated gonorrhea and nongonococcal urethritis and cervicitis.

U.S. and European labeling carried warnings regarding evidence of QT interval prolongation.

Because of the risk potential for cardiac arrhythmias, U.S. and EU Raxar labeling recommended against concomitant administration with class I and class III antiarrhythmic agents.

Labeling for Rhone-Poulenc Rorer's Zagam (sparfloxacin) similarly carries a contraindication in patients receiving QT interval prolonging antiarrhythmics. While the loss of Raxar should not have a significant commercial impact on Glaxo, it could have a larger ripple effect on the quinolone class.

The issue of QT interval prolongation was a factor in the Oct. 21 advisory committee review of Bayer's Avelox (moxifloxacin), with the committee deciding that the small mean change in QT intervals associated with the drug should not preclude approval (¹ Also see "FDA/PhRMA Task Force To Assess QT Risk By Preclinical Markers" - Pink Sheet, 1 November, 1999.)

During the review, Center for Drug Evaluation & Research Associate Director for Medical Policy Robert Temple, MD, pointed out that QT prolongation is a relatively common finding in clinical trials, but is not always an indicator of a risk of torsade de pointes.

The withdrawal of Raxar also has greater significance in the context of other safety problems to emerge in the quinolone class. In the second quarter, Trovan, which had a much more successful commercial uptake than Raxar, was suspended in the EU and sharply restricted in the U.S. following reports of liver toxicity.

Earlier in the decade, Abbott's Omniflox (temafloxacin) was withdrawn in 1992 because of serious multisystem adverse reactions. Searle's Maxaquin (lomefloxacin) was the subject of a "dear prescriber" letter in 1993 regarding phototoxicity and possible photocarcinogenicity. Maxaquin is now marketed by Unimed.

Also in 1993, FDA's Anti-Infective Drugs Advisory Committee examined the issue of central nervous system-related spontaneous adverse event reports with the fluoroquinolone class, a phenomenon anecdotally connected to Ortho's Floxin in lay media reports.

Glaxo Withdraws Raxar Following Seven Fatal Cardiovascular AEs

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