INDICATIONS AND LIMITATION OF USE
XGEVA® is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.
Limitation of use: XGEVA® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.
XGEVA® is indicated for 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 indicated for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.
Close Indication
Denosumab is an NCCN category 1–recommended treatment option for patients whose breast or prostate cancer has metastasized to bone11,2,2

XGEVA® was evaluated in 3 identically designed head-to-head studies vs ZA

XGEVA® prevented bone complications* for a median of 27.7 months

In a prespecified integrated analysis of 3 pivotal trials (N = 5,723), XGEVA® was proven to delay the median time to first bone complication by 8.2 months longer than zoledronic acid (ZA).33,4,4

XGEVA® is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.33

MEDIAN TIME TO FIRST BONE COMPLICATION44

*Bone complications, also known as skeletal-related events (SREs), are defined as radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.   1010

Hazard ratio (HR) is defined as the increase or decrease in likelihood of an event of interest (in this case, a bone complication) for one group relative to a comparator group.

P value for superiority.

NCCN = National Comprehensive Cancer Network; Q4W = every 4 weeks.

MEDIAN TIME TO FIRST BONE COMPLICATION44

XGEVA® was evaluated in 3 identically designed head-to-head studies vs ZA

STUDY DESIGN AND SCHEMA33,4,4

Study design and schema of 3 international, phase 3, double-blind, double-dummy, active-controlled studies comparing XGEVA® with zoledronic acid (ZA) for the prevention of bone complications in patients with bone metastases from solid tumors or multiple myeloma. Per protocol, based on the ZA label, the intravenous (IV) product was dose-adjusted for baseline creatinine clearance ≤ 60 mL/min. No dose adjustments were made, and no doses were withheld, for increased serum creatinine for the subcutaneous (SC) product.3,3,5-75-7

Select exclusion criteria: patients with creatinine clearance < 30 mL/min; patients receiving current or prior IV bisphosphonate therapy (patients receiving oral bisphosphonate for the treatment of osteoporosis were not excluded).33,4,4

Daily supplementation of calcium ≥ 500 mg and vitamin D ≥ 400 IU was recommended.5-75-7

Study design and schema of 3 international, phase 3, double-blind, double-dummy, active-controlled studies comparing XGEVA® with zoledronic acid (ZA) for the prevention of bone complications in patients with bone metastases from solid tumors or multiple myeloma. Per protocol, based on the ZA label, the intravenous (IV) product was dose-adjusted for baseline creatinine clearance ≤ 60 mL/min. No dose adjustments were made, and no doses were withheld, for increased serum creatinine for the subcutaneous (SC) product.3,3,5-75-7

Select exclusion criteria: patients with creatinine clearance < 30 mL/min; patients receiving current or prior IV bisphosphonate therapy (patients receiving oral bisphosphonate for the treatment of osteoporosis were not excluded).33,4,4

Daily supplementation of calcium ≥ 500 mg and vitamin D ≥ 400 IU was recommended.5-75-7

  • Primary endpoint33,4,4
  • Time to first on-study bone complication* (noninferiority)
  • Secondary endpoints33,4,4
  • Time to first on-study bone complication (superiority)
  • Time to first and subsequent bone complication (superiority using multiple-event analysis)

If the primary endpoint of noninferiority was met, the superiority test for secondary endpoints was conducted.
Safety and tolerability were also assessed.33

*Bone complications, also known as skeletal-related events (SREs), are defined as radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.   1010

Hazard ratio (HR) is defined as the increase or decrease in likelihood of an event of interest (in this case, a bone complication) for one group relative to a comparator group.

P value for superiority.

NCCN = National Comprehensive Cancer Network; Q4W = every 4 weeks.

XGEVA® is the only bone-targeting agent that blocks the function of RANK Ligand (RANKL)33

XGEVA® targets and inhibits RANKL to prevent bone complications*—a unique mechanism of action among bone-targeting agents.33

In patients with bone metastases, increased RANKL production creates a vicious cycle of bone destruction88

XGEVA® is the only bone-targeting agent that blocks the function of RANKL33

 

*Bone complications, also known as skeletal-related events (SREs), are defined as radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.   1010

Hazard ratio (HR) is defined as the increase or decrease in likelihood of an event of interest (in this case, a bone complication) for one group relative to a comparator group.

P value for superiority.

NCCN = National Comprehensive Cancer Network; Q4W = every 4 weeks.

Important Safety Information

Hypocalcemia

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, especially in the first weeks of initiating therapy, 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.

An increased risk of hypocalcemia has been observed in clinical trials of patients with increasing renal dysfunction, most commonly with severe dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake.

Hypersensitivity

XGEVA® is contraindicated in patients with known clinically significant hypersensitivity to XGEVA®, including anaphylaxis that has been reported with use of XGEVA®. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. 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) has been reported in patients receiving XGEVA®, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure.

Patients with a history of tooth extraction, poor oral hygiene, or use of a dental appliance are at a greater risk to develop ONJ. Other risk factors for the development of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroids, diabetes, and gingival infections.

Perform an oral examination and appropriate preventive dentistry prior to the initiation of XGEVA® and periodically during XGEVA® therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with XGEVA®. Consider temporarily interrupting XGEVA® therapy if an invasive dental procedure must be performed.

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.

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. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During XGEVA® treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patients 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.

Hypercalcemia Following Treatment Discontinuation in Patients with Growing Skeletons

Clinically significant hypercalcemia has been reported in XGEVA® treated patients with growing skeletons, weeks to months following treatment discontinuation. Monitor patients for signs and symptoms of hypercalcemia and treat appropriately.

Embryo-Fetal Toxicity

XGEVA® can cause fetal harm when administered to a pregnant woman. Based on findings in animals, XGEVA® is expected to result in adverse reproductive effects.

Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after the last dose of XGEVA®. Apprise the patient of the potential hazard to a fetus if XGEVA® is used during pregnancy or if the patient becomes pregnant while patients are exposed to XGEVA®.

Adverse Reactions

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 resulting in discontinuation were osteonecrosis and hypocalcemia.

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.

Please see accompanying Full Prescribing Information.

 

Important Safety Information

Hypocalcemia
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, especially in the first weeks of initiating therapy, 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.

References

  • 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer, Version 1.2015. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#prostate. Published October 24, 2014. Accessed November 10, 2015.
  • 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer, Version 3.2015. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#breast. Published July 16, 2015. Accessed November 10, 2015.
  • 3. XGEVA® (denosumab) prescribing information, Amgen.
  • 4. Lipton A, Fizazi K, Stopeck AT, et al. Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials. Eur J Cancer. 2012;48:3082-3092.
  • 5. Stopeck AT, Lipton A, Body J-J, et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010;28:5132-5139.
  • 6. Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol. 2011;29:1125-1132.
  • 7. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377:813-822.
  • 8. Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350:1655-1664.
  • 9. Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002;2:584-593.
  • 10. Gralow JR, Biermann JS, Farooki A, et al. NCCN Task Force report: bone health in cancer care. J Natl Compr Canc Netw. 2013;11(suppl 3):s1-s50.

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