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SUBJECT: Risks associated with the use of XGEVA® (denosumab 120 mg) Severe symptomatic hypocalcemia, including fatal cases Hypersensitivity, including anaphylactic reactions August 27, 2013 Dear Health Care Professional, This letter is issued to notify healthcare providers about risks associated with  the use of Xgeva; severe symptomatic hypocalcemia, including fatal cases, and hypersensitivity, including anaphylactic reactions. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors and for the treatment of adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity. Xgeva is not indicated  for the prevention of skeletal-related events in patients with multiple myeloma. Severe symptomatic hypocalcemia, including fatal cases In the postmarketing setting, in patients with cancer receiving Xgeva for prevention of skeletal-related events, severe symptomatic hypocalcemia,  including fatal cases, has been reported. Signs and symptoms of these  cases include altered mental status, tetany, seizures and QTc prolongation, which were temporally associated with Xgeva use and decreased serum calcium levels.  The calculated reporting rate of severe symptomatic hypocalcemia suggests that the incidence in the postmarketing setting is similar to the rate observed in clinical trials. During clinical trials, severe hypocalcemia (corrected serum calcium < 7 mg/dL or < 1.75 mmol/L) occurred in 3.1% of patients receiving treatment with Xgeva and 1.4% of patients had hypocalcemia reported  as a serious adverse event. Action being taken by Amgen To communicate this important safety information, changes have been made  to the US prescribing information (USPI) as described below: The Contraindications section has been updated to reflect that pre-existing  hypocalcemia must be corrected prior to initiating therapy with Xgeva. The Warnings and Precautions section has been updated to reflect that  Xgeva can cause severe symptomatic hypocalcemia, and fatal cases have  been reported. The Adverse Reactions section has been updated to include “severe symptomatic  hypocalcemia, including fatal cases” as a postmarketing adverse drug reaction. Summary of Recommendations for Health Care Professional The risk of severe symptomatic hypocalcemia among patients receiving Xgeva can be minimized by the following: Correction of pre-existing hypocalcemia prior to Xgeva treatment. Administration of calcium and vitamin D as necessary to treat or prevent  hypocalcemia. Monitor calcium levels and administer calcium, magnesium,  and vitamin D as necessary. Monitor levels more frequently when Xgeva is  administered with other drugs that can also lower calcium levels. Advise  patients to contact a healthcare professional for symptoms of hypocalcemia. Identification of risk factors for hypocalcemia in patients receiving Xgeva.   Based on clinical trials using a lower dose of denosumab (single dose of  60 mg denosumab), patients without cancer and with severe renal impairment  (creatinine clearance less than 30 mL/min) or receiving dialysis were at greater  risk of severe hypocalcemia compared to patients with normal renal function. Hypersensitivity, including anaphylactic reactions In the postmarketing setting, two spontaneously reported cases of anaphylactic reactions were identified and were considered causally related to Xgeva. The calculated reporting rate of anaphylactic reaction is 5.4 per 100,000 patient-years, which classifies  anaphylactic reaction as a very rare event. Action being taken by Amgen To communicate this important safety information, changes have been made to the  US prescribing information (USPI) as described below: The Contraindications section has been updated to reflect that Xgeva is  contraindicated in patients with known clinically significant hypersensitivity to Xgeva. The Warnings and Precautions section and the Adverse Reactions section  have been updated to indicate that clinically significant hypersensitivity   including anaphylactic reactions has been reported with use of Xgeva. Summary of Recommendations for Health Care Professional Patients with clinically significant hypersensitivity to Xgeva should not receive Xgeva. Further Information These are not the only risks associated with the use of this product. Please see  the full prescribing information for more information about the risks associated with the use of this product. This information is also available at www.xgeva.com. Contact details for adverse event reporting or to request further information Any suspected adverse reactions should be reported to FDA’s MedWatch Adverse Event Reporting Program: by phone (1-800-FDA-1088), by facsimile (1-800-FDA-0178), online (www.fda.gov/medwatch), or by mail using the MedWatch Form FDA 3500 postage paid form,  to the FDA Medical Products Reporting Program, 5600 Fishers Lane,  Rockville, MD 20852-9787. Should you have any questions or require additional information regarding the use of Xgeva, please contact Amgen’s Medical Information Department at 1-800-77-AMGEN. Sincerely, Michael Severino, MD Senior Vice President, Global Development, and Chief Medical Officer Amgen Amgen, Inc. | PO Box 681308 | Indianapolis, IN 46268 74864-R1-V1

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