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."
REDUX: Unheeded Warnings on Lethal Diet Pill
Heart damage causes billions of dollars in potential legal liability.
Before coming to the FDA as a medical officer in 1989, Dr. Leo Lutwak had specialized in the fields of obesity and osteoporosis as a Cornell University professor, as a drug company consultant and as a practicing physician. He said he hired on at the FDA because he relished the scientific challenge of new drugs and the call of public service.
In 1995, Lutwak was the lead FDA medical officer reviewing the diet drug Redux, which in one pill approximated half of the now-infamous slimming cocktail known as fen-phen.
Both Lutwak and his boss, Dr. Solomon Sobel, told The Times that they resisted the approval of Redux.
"I, as the primary reviewer, felt that the drug had low effectiveness and very high risk for neurotoxicity and pulmonary hypertension," a disorder that damages the respiratory system, Lutwak said.
"I was insisting on a black box," he added, referring to the bold border at the top of a prescription label that alerts doctors and patients to severe life-threatening risk. "But the management accepted the company's arguments against the black box. And I don't know why."
Sobel, director of the FDA's endocrine and metabolic drugs division throughout the 1990s and who remains at the agency, was concerned that Redux did not work. He said he refused to sign the agency's formal letter of approval.
"Well let me tell you," Sobel said. "I was supposed to sign off on that letter. . . . I told [an FDA administrator, Dr. James] Bilstad that I would not sign on it. If he wanted to approve it, he should sign on it. And the record shows, he's the one who signed on it."
How Redux came to be approved in April 1996 remains a curiosity.
After an FDA advisory committee voted, 5 to 3, that evidence of Redux's safety was "not sufficient to warrant approval," Bilstad took the unusual step of scheduling a second meeting, just two months later. At that meeting, in November 1995, the committee voted, 6 to 5, to recommend approval.
Lutwak said he was "shocked" by the scheduling of the second meeting.
Much was riding on Redux. Analysts at one securities firm, Rodman & Renshaw, estimated the drug would gross $1.8 billion within four years.
But Redux was withdrawn on Sept. 15, 1997, after heart valve damage was detected in patients put on the drug. Civil lawsuits that are now pending also allege that Redux caused the potentially fatal respiratory disorder that had worried Lutwak.
American Home Products Corp., which marketed Redux and Pondimin, a diet pill that was used widely in formulations of fen-phen, agreed last fall to pay or set aside $4.75 billion to settle lawsuits related to the drugs' potential to cause heart valve damage. The company more recently has set aside up to an additional $4.75 billion to pay other patients who have suffered from the respiratory condition or heart valve damage.
"We are aggressively settling as many cases as we can," said Douglas Petkus, a spokesman for Wyeth-Ayerst Laboratories Inc., a subsidiary of American Home.
In its one year on the market, Redux generated sales of $255.3 million. The FDA received reports before and after the withdrawal that cited Redux as a suspect in 123 deaths.
Bilstad, who left the FDA in January, declined to be interviewed this fall when reached at his home.
In a written statement, Woodcock acknowledged that "the possibility of including a black box warning" on Redux's label was discussed with Wyeth-Ayerst. But, she said, FDA officials decided "it was not warranted." She said that the drug's potential respiratory risk was noted within the labeling in bold type. Before Redux went on the market, Woodcock said, "there was no hint" that it would cause heart valve damage.
Lutwak, now 72, said he regrets the approval of Redux--and the agency's failure to insist on a black box warning.
"It might have saved lives," he said.