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Full Prescribing Information
Important Safety Information

XGEVA® (denosumab) prevented bone complications longer vs zoledronic acid — for patients with other solid tumors* or multiple myeloma metastatic to bone

Bone complications, also known as skeletal-related events (SREs), are defined as radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.1,2

Data from a prespecified integrated analysis of an international, phase 3, double-blind, double-dummy, active-controlled study comparing XGEVA® with zoledronic acid for the prevention of bone complications in patients with bone metastases from solid tumors or multiple myeloma.1

XGEVA® delayed first bone complication by:

4.2 months vs zoledronic acid in patients with other solid tumors* or multiple myeloma1,3

HR = 0.84 (95% CI: 0.71-0.98) P < 0.001, noninferiority;
P = 0.060, NS for superiority

6 months vs zoledronic acid in a subgroup analysis of patients with other solid tumors,* excluding multiple myeloma4

HR = 0.81 (95% CI: 0.68-0.96) P = 0.017

XGEVA® 120 mg Q4W (n = 886)

zoledronic acid 4 mg Q4W (n = 890)

HR = 0.84 (95% CI: 0.71-0.98) P < 0.001,
noninferiority; P = 0.060, NS for superiority

A subgroup analysis excluding multiple myeloma

XGEVA® 120 mg Q4W (n = 800)

zoledronic acid 4 mg Q4W (n = 797)

HR = 0.81 (95% CI: 0.68-0.96) P = 0.017

Median Time to First Bone Complication: XGEVA® - 20.5 months | Zoledronic Acid – 16.3 months | Difference – 4.2 months
ost-chart-sep
Median Time to First Bone Complication: XGEVA® - 21.4 months | Zoledronic Acid – 15.4 months | Difference – 6 months

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

*Excluding breast and prostate cancer.

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 that in a comparator group.

P value for superiority.

4.2 months vs zoledronic acid in patients with other solid tumors* or multiple myeloma1,3

HR = 0.84 (95% CI: 0.71-0.98) P < 0.001, noninferiority;
P = 0.060, NS for superiority

XGEVA® 120 mg Q4W (n = 886)

zoledronic acid 4 mg Q4W (n = 890)

HR = 0.84 (95% CI: 0.71-0.98) P < 0.001,
noninferiority; P = 0.060, NS for superiority

Median Time to First Bone Complication: XGEVA® - 20.5 months | Zoledronic Acid – 16.3 months | Difference – 4.2 months

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

*Excluding breast and prostate cancer.

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 that in a comparator group.

P value for superiority.

6 months vs zoledronic acid in a subgroup analysis of patients with other solid tumors,* excluding multiple myeloma4

HR = 0.81 (95% CI: 0.68-0.96) P = 0.017

A subgroup analysis excluding multiple myeloma

XGEVA® 120 mg Q4W (n = 800)

zoledronic acid 4 mg Q4W (n = 797)

HR = 0.81 (95% CI: 0.68-0.96) P = 0.017

Median Time to First Bone Complication: XGEVA® - 21.4 months | Zoledronic Acid – 15.4 months | Difference – 6 months

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

*Excluding breast and prostate cancer.

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 that in a comparator group.

P value for superiority.

  • In a pivotal phase 3 trial vs zoledronic acid, XGEVA® reduced the risk of first bone complication by 16% vs zoledronic acid in other solid tumors and multiple myeloma metastatic to bone (N = 1,776; P < 0.001, noninferiority; P = 0.060, NS for superiority)

View study design details
»

XGEVA® patients with other solid tumors* or multiple myeloma experienced fewer bone complications vs zoledronic acid3,4

XGEVA® 120 mg Q4W (n = 886)

zoledronic acid 4 mg Q4W (n = 890)

A subgroup analysis excluding multiple myeloma

XGEVA® 120 mg Q4W (n = 800)

zoledronic acid 4 mg Q4W (n = 797)

Total Number of Bone Complications on Study: XGEVA® - 392 | Zoledronic Acid - 436
ost-chart-sep
Total Number of Bone Complications on Study: XGEVA® - 328 | Zoledronic Acid - 374

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

*Excluding breast and prostate cancer.

XGEVA® 120 mg Q4W (n = 886)

zoledronic acid 4 mg Q4W (n = 890)

Total Number of Bone Complications on Study: XGEVA® - 392 | Zoledronic Acid - 436

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

*Excluding breast and prostate cancer.

A subgroup analysis excluding multiple myeloma

XGEVA® 120 mg Q4W (n = 800)

zoledronic acid 4 mg Q4W (n = 797)

Total Number of Bone Complications on Study: XGEVA® - 328 | Zoledronic Acid - 374

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

*Excluding breast and prostate cancer.

View study design details
»

Safety evaluated across three head-to-head phase 3 studies including more than 5,600 patients5

View the safety information »

Indication

XGEVA® (denosumab) is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

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

Important Safety Information

Hypocalcemia

  • Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA® (denosumab). 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.


  • 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® (denosumab) 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® (denosumab) should not take Prolia® (denosumab).


Osteonecrosis of the Jaw

  • Osteonecrosis of the jaw (ONJ) can occur in patients receiving XGEVA® (denosumab), 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.

  • 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®.

  • 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® (denosumab). 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. 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.


Embryo-Fetal Toxicity

  • XGEVA® (denosumab) 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® (denosumab) 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.


References

  1. XGEVA® (denosumab) prescribing information, Amgen.

  2. Brodowicz T, O’Byrne K, Manegold C. Bone matters in lung cancer. Ann Oncol. 2012;23:2215-2222.

  3. 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.

  4. Henry D, Vadhan-Raj S, Hirsh V, et al. Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: an analysis of data from patients with solid tumors. Support Care Cancer. 2014;22:679-687.

  5. 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.

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Indication

XGEVA® (denosumab) is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

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

Important Safety Information

Hypocalcemia

  • Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA® (denosumab). 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