When the antibiotic Raxar was approved on Nov. 6, 1997, FDA officials knew that it might cause irregular rhythm and stop a patient's heart. An agency medical officer, Dr. Andrea N. Meyerhoff, suspected that two of four patients who died after taking Raxar in clinical trials possibly suffered heart-rhythm disturbances caused by the drug.
Meyerhoff noted in her review that the drug manufacturer, Glaxo Wellcome Inc., said Raxar played no role in the deaths. But Meyerhoff wrote that the two cases posed an open question. Each patient who died had taken 600-milligram doses. Regarding one of those patients, a 68-year-old man who died a week after completing the clinical trial, Meyerhoff wrote: "This patient may have been at higher risk for [fatal] arrhythmia due to QT interval prolongation from grepafloxacin," the chemical name of Raxar. The second patient died five days after withdrawing from the clinical trial.
She added in her review, dated November 1997: "Again it is not clear that this event is unrelated to [Raxar]. Sudden death in a patient with no prior cardiac history is suggestive of an arrhythmia. . . . The label will need to have an adequate warning regarding the possibility of QT prolongation." Overall, she found a "significantly higher" rate of adverse events among patients who had taken 600 milligrams compared with lower doses. With Meyerhoff's assent, the FDA approved Raxar for treating bronchitis, pneumonia, urinary tract infections and gonorrhea. The drug's label stated that "prolongation of the QT interval has been observed in healthy volunteers receiving Raxar."
But the label did not disclose the fatalities described in Meyerhoff's review. It said that "there were no deaths or permanent disabilities" among those who took Raxar in 400-milligram doses. The statement was true, if incomplete: All four of the study patients who died took Raxar in 600-milligram doses. And Glaxo marketed the drug at doses of 200 milligrams, 400 milligrams and 600 milligrams. A total of 925 patients took the 600 milligrams dose in the clinical studies. On Oct. 27, 1999, Glaxo pulled Raxar off the market.
In a subsequent letter to doctors, Glaxo said that because of Raxar's effect on "QT interval prolongation" the drug was unacceptably risky. In a separate statement, the company said it "is no longer convinced that the benefits of Raxar outweigh the potential risk to patients, given the availability of alternative antibiotics." Records filed with the FDA show that Raxar was cited as a suspect in the voluntarily reported deaths of 13 patients. They ranged in age from 42 to 86; most of them were under 70.
"[Raxar] goes on the market, kills people and has to come off," said Dr. Raymond L. Woosley, the pharmacology department chairman at Georgetown University who served on an FDA advisory committee in the 1980s. "It had been proven, over and over, that this QT prolongation predicts terrible events." By the time of the withdrawal, Raxar had generated $23.5 million in U.S. sales. Securities analysts had predicted it could be a $1-billion drug.
With so many other antibiotics on the market, why did the FDA expose patients to the risk of Raxar? In a written response to questions, Woodcock indicated that the FDA sought to address the drug's cardiac risk through precautionary language in its labeling. Asked why that labeling did not acknowledge the deaths of patients who took doses of 600 milligrams, Woodcock wrote that none of the fatalities "was shown to be attributable to Raxar."
In an interview over the summer, Woodcock said the FDA's patience was gone for new drugs that prolong the QT interval. "We're encouraging people, if there's QT prolongation, don't develop it," she said. This would mark a turnabout. Just last December-less than two months after the withdrawal of Raxar-the FDA approved a new antibiotic, called Avelox, despite the drug's well-documented propensity in clinical studies to prolong the QT interval. Avelox was approved for treating sinus infections, bronchitis and pneumonia. On the 267th line of the Avelox label, doctors are warned in bold type that it "has been shown to prolong the QT interval."
So far, Avelox, made by Bayer Corp., has been prescribed for more than 300,000 patients in the U.S. The drug has been cited as a suspect in 18 deaths here and abroad. A Bayer spokesman, Robert Kloppenburg, said that the company does not believe any of the fatalities were "attributable" to Avelox and that most of the patients had serious preexisting conditions.
Avelox, he said, holds an advantage over many antibiotics because it need only be taken once daily for five days to be effective against bronchial infections. Securities analysts predicted in February that Avelox would generate sales topping $1 billion within three years. Woodcock said the FDA approved Avelox because "the extent of QT prolongation was too small to pose a significant risk in the face of the benefits." She noted that an agency advisory committee recommended approval and said that "a conservative approach was taken in the label."