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FDA Approves Amgen's XGEVA® (Denosumab) For The Treatment Of Hypercalcemia Of Malignancy Refractory To Bisphosphonate Therapy
HCM is a serious complication in patients with advanced cancer, including those with hematologic malignancies, and indicates poor prognosis.1,2 The condition results from cancer-driven increases in bone resorption, and if untreated, can lead to renal failure, progressive mental impairment, coma and death.1-3
"Our continued study of XGEVA reinforces
The approval of XGEVA is based on positive results from an open-label, single-arm study, which enrolled patients with advanced cancer and persistent hypercalcemia after recent bisphosphonate treatment. The primary endpoint was the proportion of patients with a response, defined as albumin-corrected serum calcium (CSC) <11.5 mg/dL (2.9 mmol/L; Common Terminology for Adverse Events [CTCAE] grade <1) within 10 days after the first dose of XGEVA. Secondary endpoints included the proportion of patients who experienced a complete response (defined as CSC <10.8 mg/dL [2.7 mmol/L]) by day 10, time to response and response duration (defined as the number of days from the first occurrence of CSC <11.5 mg/dL). The study achieved its primary endpoint with a response rate at day 10 of 63.6 percent in the 33 patients evaluated. The overall complete response rate was 63.6 percent. The estimated median time to response (CSC <11.5 mg/dL) was nine days, and the median duration of response was 104 days.4,5
The most common adverse reactions in patients receiving XGEVA for hypercalcemia of malignancy were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation and diarrhea.5
For patients with HCM, XGEVA is administered as a subcutaneous injection (120 mg) every four weeks with additional doses of 120 mg on days eight and 15 of the first month of therapy.5
XGEVA binds to RANK Ligand (RANKL), a protein essential for the formation, function and survival of osteoclasts, the cells responsible for bone resorption, thereby modulating calcium release from bone. XGEVA prevents RANKL from activating its receptor, RANK, on the surface of osteoclasts, thereby decreasing bone destruction and calcium release.5
About Hypercalcemia of Malignancy
Hypercalcemia of malignancy (HCM) is a serious complication in patients with advanced cancer, including those with hematological malignancies.1 In 2012, the estimated prevalence of HCM in cancer patients in the U.S. was 2.7 percent.6 HCM is indicative of poor prognosis and occurs most often in patients with squamous cell cancer (e.g., lung cancer, head and neck cancer), breast cancer, kidney cancer, myeloma and lymphoma.1,2,7 HCM results from cancer-driven increases in bone resorption, and, if untreated, can lead to renal failure, progressive mental impairment, coma and death.1-3
XGEVA was approved by the
XGEVA Important Safety Information
Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA. XGEVA can cause severe symptomatic hypocalcemia, and fatal cases have been reported. 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.
XGEVA is contraindicated in patients with known clinically significant hypersensitivity to XGEVA, including anaphylaxis that has been reported with use of XGEVA. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue XGEVA therapy permanently.
Drug Products with Same Active Ingredient
Patients receiving XGEVA should not take Prolia® (denosumab).
Osteonecrosis of the Jaw
Osteonecrosis of the jaw (ONJ) can occur in patients receiving XGEVA. Patients who are suspected of having or who develop ONJ while on XGEVA should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. In clinical trials in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure.
Atypical Subtrochanteric and Diaphyseal Femoral Fracture
Atypical femoral fracture has been reported with XGEVA. These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.
Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. During XGEVA treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of XGEVA therapy should be considered, pending a risk/benefit assessment, on an individual basis.
XGEVA can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use highly effective contraception during therapy, and for at least five months after the last dose of XGEVA.
The most common adverse reactions in patients receiving XGEVA with bone metastasis from solid tumors were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea.
The most common adverse reactions in patients receiving XGEVA for giant cell tumor of bone were arthralgia, headache, nausea, back pain, fatigue, and pain in extremity. The most common serious adverse reactions were osteonecrosis of the jaw and osteomyelitis. The most common adverse reactions resulting in discontinuation of XGEVA were osteonecrosis of the jaw and tooth abscess or tooth infection.
The most common adverse reactions in patients receiving XGEVA for hypercalcemia of malignancy were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.
Denosumab is also marketed as Prolia® in other indications.
Please visit www.amgen.com for Full Prescribing Information.
This news release contains forward-looking statements that are based on the current expectations and beliefs of
No forward-looking statement can be guaranteed and actual results may differ materially from those we project. Discovery or identification of new product candidates or development of new indications for existing products cannot be guaranteed and movement from concept to product is uncertain; consequently, there can be no guarantee that any particular product candidate or development of a new indication for an existing product will be successful and become a commercial product. Further, preclinical results do not guarantee safe and effective performance of product candidates in humans. The complexity of the human body cannot be perfectly, or sometimes, even adequately modeled by computer or cell culture systems or animal models. The length of time that it takes for us and our partners to complete clinical trials and obtain regulatory approval for product marketing has in the past varied and we expect similar variability in the future. We develop product candidates internally and through licensing collaborations, partnerships and joint ventures. Product candidates that are derived from relationships may be subject to disputes between the parties or may prove to be not as effective or as safe as we may have believed at the time of entering into such relationship. Also, we or others could identify safety, side effects or manufacturing problems with our products after they are on the market. Our business may be impacted by government investigations, litigation and product liability claims. If we fail to meet the compliance obligations in the corporate integrity agreement between us and the U.S. government, we could become subject to significant sanctions. We depend on third parties for a significant portion of our manufacturing capacity for the supply of certain of our current and future products and limits on supply may constrain sales of certain of our current products and product candidate development.
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The scientific information discussed in this news release relating to new indications for our products is preliminary and investigative and is not part of the labeling approved by the
- Ralston SH. Cancer-associated hypercalcemia: morbidity and mortality. Annals of Int Med. 1990;112:499-504.
- Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med. 2005;352(4):373-379.
- Coleman RE. Clinical features of metastatic bone disease and risk of skeletal morbidity.
Clin Cancer Res. 2006;12(suppl 20):6243s-6249s.
- Hu MI. Denosumab for treatment of hypercalcemia of malignancy. J Clin Endocrinol Metab. 2014; 99(9):3144–3152
- XGEVA® (denosumab) prescribing information.
- Gastanaga V, Jain R, Pirolli M, et al. Prevalence of hypercalcemia of malignancy in
the United States: projection methods using oncology electronic health records (EHR). Eur J Cancer. 2013;49:S1–S1028, Abstract 1415, p. 25.
- Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol. 2001;19(2):558-567.
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