RAXAR:Warning on Label Omits Deaths
http://www.latimes.com/news/nation/reports/fda/lat_raxar001220.htm
Heart problems were mentioned in fine print, but not key dosage
data.
Wednesday, December 20, 2000 |
When the antibiotic Raxar was
approved on Nov. 6, 1997, FDA officials knew that it too 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."