http://www.medpagetoday.com/Hematolo...tology/dh/2509
Source News Article: ABC News, Boston Globe, San Francisco Chronicle, Washington Post
Off-Label Use of Hemophilia Drug May Be Risky
Review
ROCKVILLE, Md., Jan. 18 - Off-label use of the hemophilia drug factor VIIa (NovoSeven) had led to thromboembolic events in non-hemophiliacs, including 36 deaths, according to FDA researchers.
Physicians have increasingly been giving the drug to non-hemophiliacs to stop intracranial bleeding or to prevent excessive bleeding during surgery, among other indications, said Kathryn A. O'Connell, M.D., Ph.D., and colleagues at the FDA's Center for Biologics Evaluation and Research here in the Jan. 18 issue of the
Journal of the American Medical Association.
NovoSeven, a recombinant human coagulation factor, was approved by the FDA on March 25, 1999, for treating bleeding episodes in patients with hemophilia. The FDA researchers identified 431 adverse event reports associated with NovoSeven. Of these, the study focused on 168 reports describing 185 thromboembolic events.
Of the 168 reports, 59 came from clinical trials testing off-label uses of the drug, and the majority of so-called "spontaneous" reports (those not involving a clinical trial) were also associated with off-label uses (92 of 109).
Of 50 reported deaths, 36 were judged to be caused by the thromboembolic event. Of the 102 reports that included a causality assessment, 81 suggested a probable or possible link to the drug.
The median time from the last dose of NovoSeven to the first documented sign or symptom of an adverse event was about 24 hours, which further suggested a link to the drug, the authors said.
However, in 158 of the reports, the vast majority, there was no information on the patients' underlying medical conditions that may have contributed to an adverse event, they said.
"These findings are of uncertain clinical significance but suggest that rFVIIa [NovoSeven] might be more thrombogenic in patients without hemophilia and in patients with conditions predisposing to thrombosis, such as surgery, pregnancy, liver failure, congestive heart failure, or coronary artery disease," the authors said.
"The serious nature of the reported adverse events, their biological plausibility, and the inherent limitations of passive surveillance underscore the need for randomized controlled trials with appropriate control groups and robust end points to elucidate the safety and efficacy of rFVIIa for each indication," they concluded.
These 168 events included the following:
- 39 embolic/thrombotic cerebrovascular accidents (21.3%)
- 34 acute myocardial infarctions (18.6%)
- 26 arterial thromboembolic events (14.2%) involving the femoral, hepatic, pulmonary, renal, splenic, or iliac artery
- 32 reports of pulmonary emboli (17.5%)
- 42 venal thromboembolic events (22.9%) involving the jugular, mesenteric, portal, renal, or retinal vein.
- 10 reports of clogged devices, such as oxygen lines, dialysis shunts, and endotracheal rubes (5.5%)
- Two reports with no stated thromboembolism site
The estimated number of hospitalized patients treated with NovoSeven has increased from 349 patients in 2000 to more than 4,500 in 2004, said Dr. O'Connell and colleagues.
The researchers reviewed the FDA's Adverse Event Reporting System database from March 25, 1999 through December 31, 2004.
Although drug manufactures must report adverse events, especially those that occur during a clinical trial, reporting by doctors and patients is voluntary. Therefore, the system likely underestimates the true rate of adverse events for a particular drug, the authors said.
In an addendum to the
JAMA paper, the authors noted that the FDA in 2005 approved the use of NovoSeven for the added indications of surgical procedures in patients with hemophilia A or B and inhibitors and treatment of bleeding episodes in patients with factor VII deficiency.
They found that between Jan. 1, 2005, and Nov. 1, 2005, the FDA received another 168 adverse event reports for NovoSeven. Of these events, 52 described patients with 61 thromboembolic events. "The characteristics of these reports do not differ materially from the 1999-2004 reports described and do not change our conclusions," the authors wrote.
A spokesperson for Novo Nordisk, maker of NovoSeven, was not immediately available for comment.
Primary source: Journal of the American Medical Association
Source reference:
O'Connell KA et al. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa.
JAMA. 2006; 295(3):293-298.
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