Osteonecrosis Cases Reported Among Patients on Bisphosphonates
Mar 8, 2005 - 6:54:00 AM
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It appears that osteonecrosis may be a class effect as exhibited by alendronate cases, in addition to zoledronic acid and pamidronate
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By Akanksha, Pharmacology Correspondent,
[RxPG] A review from FDAs Office of Drug Safety (ODS) states that osteonecrosis cases have been found for both injectable and oral bisphosphonates and may be a class effect.
ODS conducted a post-marketing safety review of the approved bisphosphonates Novartis Zometa (zoledronic acid) and Aredia (pamidronate), Mercks Fosamax (alendronate) and Procter & Gamble/Sanofi-Aventis Actonel (risedronate).
It appears that osteonecrosis may be a class effect as exhibited by alendronate cases, in addition to zoledronic acid and pamidronate, the ODS review states.
Changes to the product label for zoledronic acid have been made to include language about osteonecrosis, but more language is necessary to highlight this adverse event because it is associated with the therapeutic class of bisphosphonates, as evidence by our case analysis, the review dated Aug. 25, 2004 states.
A search of the Adverse Event Reports (AERS) database found 139 cases of osteonecrosis (bone death), 47 with pamidronate, 33 with zoledronic acid and 59 in patients receiving both drugs. Twelve cases were found in alendronate patients and one in risedronate patients.
The ODS review of new cases of osteonecrosis with bisphosphonates served as an update to a prior consult that was completed on Nov. 21, 2003 on the two intravenous drugs, zoledronic acid and pamidronate, which are indicated for treatment of hypercalcemia of malignancy, bone metastases and multiple myeloma. Alendronate and risedronate are indicated for osteoporosis.
Osteonecrosis of the jaw with zoledronic acid and pamidronate will be discussed at the March 4 meeting of FDAs Oncologic Drugs Advisory Committee, after its consideration of AstraZenecas Iressa confirmatory trial data.
FDA said that osteonecrosis with oral bisphosphonates will not be considered at the meeting.
Although there have been anecdotal reports of ONJ in association with oral bisphosphonates administered for osteoporosis, we wish to limit todays discussion to ONJ in association with zoledronic acid and pamidronate, an FDA memo to the committee states.
There have been fewer reports of ONJ associated with the oral bisphosphonates, and risk-benefit considerations are different for patients with malignant as opposed to benign disease, FDA added.
FDA explained that the purpose of bringing the ONJ issue with IV bisphosphonates to the committee is to highlight a drug safety issue in oncology and stimulate discussion of how post-marketing safety issues in oncology should be addressed.
Zoledronic acid and pamidronate labeling were updated in 2004 to include precautions about osteonecrosis of the jaw. The precaution states that a dental exam and preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors such as cancer, chemotherapy, corticosteroids, and poor oral hygiene.
Novartis convened two advisory boards of experts on the osteonecrosis issue. The boards produced a white paper, which Novartis distributed at the American Society of Clinical Oncology annual meeting in June 2004.
The company plans to publish the white paper recommendations for diagnosis, prevention and treatment of cancer patients with osteonecrosis of the jaw in peer-reviewed oncology and dental journals.
Novartis will also complete a retrospective review of cancer patients treated with IV bisphosphonates in the last 10 years being conducted by the M.D. Anderson Cancer Center.
In a preliminary review of the data collected up to Jan. 12, 2005 of the first 953 patients charts, 18 cases of ONJ were identified. The effort will ultimately include a review of over 4,000 patient charts.
The committees discussion could also have an impact on Novartis pending product Aclasta, a once-yearly IV infusion formulation of zoledronic acid for treatment of Pagets disease. The priority review user fee date for the indication is in March. Novartis anticipates a 2007 filing for Aclasta in treatment of osteoporosis.
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