INDICATIONS
XGEVA® is indicated for the prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors.
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
Proven superior for the prevention of bone complications* vs zoledronic acid (ZA) in patients with bone metastases from solid tumors1

*Bone complications, also known as skeletal-related events (SREs), are defined as radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.2

Evaluated in 3 identically designed head-to-head studies vs ZA

STUDY DESIGN AND SCHEMA1,2

Study Design and Schema

Study Design and Schema

Study design and schema of 3 international, phase 3, double-blind, double-dummy, active-controlled studies comparing XGEVA® with 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 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.2-5

Select exclusion criteria: patients with creatinine clearance < 30 mL/min; patients receiving current or prior IV bisphosphonate therapy (patients receiving oral bisphosphonates for the treatment of osteoporosis were not excluded).1,2

Daily supplementation of calcium ≥500 mg and vitamin D ≥400 IU was recommended.3-5

Endpoints

Click here for information about a separate study of only multiple myeloma patients ▶

*Bone complications, also known as skeletal-related events (SREs), are defined as radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.2

Q4W=every 4 weeks.

  • Primary endpoint1,2
  • Time to first on-study bone complication* (noninferiority)
  • Secondary endpoints1,2
  • 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.

Click here for information about a separate study of only multiple myeloma patients ▶

*Bone complications, also known as skeletal-related events (SREs), are defined as radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.2

Q4W=every 4 weeks.

Baseline characteristics in a prespecified integrated analysis of 3 pivotal studies2

Baseline characteristics in a pre-specified integrated analysis of 3 pivotal studies

Baseline characteristics in a pre-specified integrated analysis of 3 pivotal studies

*Patients with creatinine clearance <30 mL/min were excluded from XGEVA® pivotal trials.2

Bone complications, also known as skeletal-related events (SREs), are defined as radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.2

ECOG=Eastern Cooperative Oncology Group.

Trials included patients with many tumor types

Trials included patients with many tumor types

Based on randomization; total may not equal 100% due to rounding.1

Based on randomization; total may not equal 100% due to rounding.1


Three head-to-head trials included more than 5,600 patients across more than 50 solid tumor types1,2


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 cancer, 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 Giant Cell Tumor of Bone (GCTB) and in Patients with Growing Skeletons

Clinically significant hypercalcemia requiring hospitalization and complicated by acute renal injury has been reported in XGEVA®-treated patients with GCTB and in patients with growing skeletons within one year of treatment discontinuation. Monitor patients for signs and symptoms of hypercalcemia after treatment discontinuation and treat appropriately.

Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation

Multiple vertebral fractures (MVF) have been reported following discontinuation of treatment with denosumab. Patients at higher risk for MVF include those with risk factors for or a history of osteoporosis or prior fractures. When XGEVA® treatment is discontinued, evaluate the individual patient’s risk for vertebral fractures.

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 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.

For multiple myeloma patients receiving XGEVA®, the most common adverse reactions were diarrhea, nausea, anemia, back pain, thrombocytopenia, peripheral edema, hypocalcemia, upper respiratory tract infection, rash, and headache. The most common serious adverse reaction was pneumonia. The most common adverse reaction resulting in discontinuation of XGEVA® was osteonecrosis of the jaw.

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.

Indications

XGEVA® is indicated for the prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors.

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.

Please see 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. 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(16):3082-3092.
  2. XGEVA® (denosumab) prescribing information, Amgen.
  3. 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(9768):813-822.
  4. 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(35):5132-5139.
  5. 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(9):1125-1132.
  6. Data on file, Amgen.

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