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RALEIGH, N.C. -- More than 40 serious cutaneous adverse events linked to the osteoporosis formulation of denosumab (Prolia) were discovered in a review of FDA records, investigators reported here.

The incidents included conditions such as angioedema, cellulitis, and pustular dermatitis. Nine patients required hospitalization during episodes of cutaneous events, said Beatrice Nardone, MD, of Northwestern University in Chicago.

Surprisingly, the reports of serious adverse events were limited to the denosumab formulation for osteoporosis (60 mg every 6 months), Nardone reported during the Society for Investigative Dermatology meeting. Only a handful of reports involved the Xgeva formulation that's used to treat cancer-induced bone disease (120 mg every 4 weeks).

"We have no explanation for finding serious adverse events with the 60-mg dose of the drug but not with the 120-mg dose," Nardone told 名媛直播. "That was very unexpected, because logically, one would think that the higher dose would carry a higher risk of adverse events. This observation should be studied further to see whether an explanation can be found."

In approving denosumab for osteoporosis, the FDA required that the prescribing information include cutaneous adverse events in the list of side effects reported by patients taking the drug. The requirement was based largely on findings from a phase III randomized clinical trial involving 7,800 postmenopausal women with osteoporosis.

Nardone said the cutaneous events were infrequent and minor.

More intriguing to her and colleagues at Northwestern's Research on Adverse Drug events and Reports (RADAR) program was the absence of any mention of cutaneous events in the prescribing information for the denosumab formulation used to treat cancer patients.

To characterize the frequency and nature of the cutaneous events, investigators reviewed records in the FDA Adverse Event Reporting System (AERS). Submitted by physicians, the reports include information about the type and severity of adverse events patients have reported while taking prescribed drugs. One report might mention multiple adverse events.

Nardone and colleagues searched the AERS database for cutaneous adverse events reported from June 2010 (when the FDA approved denosumab) through September 2011. The search yielded 173 reports and 383 adverse cutaneous events. All but three of the adverse events were related to use of the 60-mg dose.

After excluding those three reports and all others involving minor conditions, the investigators were left with 41 reports involving 46 serious adverse events, all related to the use of the 60-mg dose of denosumab.

The reports showed that nine patients required hospitalization, including six involving patients with treatment-related vasculitis.

Investigators used three methods to calculate the risk of serious adverse cutaneous events among patients taking denosumab versus patients taking other drugs: odds ratio, proportional reporting ratio (PRR), and empiric Bayesian geometric mean (EBGM).

By all three methods, patients taking denosumab 60 mg every 4 weeks had a two-to-three-fold greater risk of serious adverse cutaneous events:

• OR 2.81, P=0.001
• PRR 2.77, P=0.001
• EBGM 2.62, P=0.001

"These results identify important postmarketing dermatologic safety concerns and warrant enhanced monitoring for patients receiving treatment with denosumab," Nardone and colleagues concluded in a poster presentation.

"Although both products have a different targeted patient population, different dosage regimens, and different concurrent medications as confounding factors, the widely discrepant dermatologic cutaneous adverse event precautionary language in the two product package inserts for the same active agent should come under careful consideration for reconciliation, as may be partly reflected in the FDA-AERS database," they added.

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