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Full Prescribing Information
Important Safety Information
XGEVA® Efficacy Data

XGEVA® was evaluated in 3 head-to-head studies1

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An XGEVA® (denosumab) dose is a subcutaneous injection once every 4 weeks

Convenient administration1

  • 120 mg dose (1.7 mL injection)1

  • Administered by a healthcare professional once every 4 weeks

  • Recommended 13 doses/year

1 XGEVA® injection given every 4 weeks. It is recommended to have 13 doses per year1 XGEVA® injection given every 4 weeks. It is recommended to have 13 doses per year

Dosing considerations

XGEVA® is a fully human* monoclonal antibody and is not cleared by the kidneys; no dose adjustments are required1-6

*Correlation with safety and efficacy is unknown.

Dose adjustments/withholdings in head-to-head phase 3 studies of XGEVA® vs zoledronic acid7†

Dose adjustments/withholdings in head-to-head phase 3 studies of XGEVA® vs zoledronic acid7†

  • Patients with creatinine clearance < 30 mL/min were excluded from XGEVA® pivotal trials1

    • XGEVA® (n = 2,862)7

      • No dose adjustments or dose withholdings were required due to renal function

    • Zoledronic acid (n = 2,861)7

      • 18% of patients (n = 502) required dose adjustments based on baseline creatinine clearance

      • 10% of patients (n = 277) required dose withholding due to increased serum creatinine during therapy

Studies in patients with renal impairment

Studies in patients with renal impairment

Two clinical trials were conducted in patients without cancer and with varying degrees of renal function1:

  • In one study, patients (N = 55) with varying degrees of renal function (ranging from normal through end-stage renal disease requiring dialysis) received a single 60 mg subcutaneous dose of denosumab

  • In a second study, patients (N = 32) with severe renal dysfunction (creatinine clearance less than 30 mL/minute and/or on dialysis) were given two 120 mg subcutaneous doses of denosumab

In both studies, greater risk of developing hypocalcemia was observed with increasing renal impairment and with inadequate/no calcium supplementation. In the second study, hypocalcemia was mild to moderate in severity in 96% of patients.1

In patients with renal impairment, monitor calcium levels and calcium and vitamin D intake1

Data from a prespecified integrated analysis of three international, phase 3, double-blind, double-dummy, active-controlled trials comparing XGEVA® with zoledronic acid for the prevention of bone complications in patients with bone metastases from solid tumors or multiple myeloma. Patients with creatinine clearance < 30 mL/min were excluded. Per protocol, based on the zoledronic acid label, the intravenous (IV) product was dose-adjusted for baseline creatinine clearance ≤ 60 mL/min. Subsequent dose withholdings and intervals were determined by serum creatinine. Administration of the IV product was withheld for patients who experienced increased serum creatinine during therapy of an increase of ≥ 0.5 mg/dL for patients with normal baseline creatinine (< 1.4 mg/dL) or an increase of ≥ 1.0 mg/dL for patients with abnormal baseline creatinine (≥ 1.4 mg/dL). Re-exposure to the IV product occurred only if serum creatinine returned to within 10% of the baseline value. The IV product was reinitiated at the same dose as that prior to treatment interruption. No dose adjustments were made and no doses were withheld for increased serum creatinine for the subcutaneous product. Daily supplementation of calcium ≥ 500 mg and vitamin D ≥ 400 IU was recommended.1,8-13

XGEVA® storage1

  • Must be refrigerated at 36°F to 46°F (2°C to 8°C)

  • Upon removal from refrigeration, must not be exposed to temperatures above 77°F (25°C) or direct light and must be used within 14 days

XGEVA® must be stored between 36°F to 46°F (2°C to 8°C)XGEVA® must be stored between 36°F to 46°F (2°C to 8°C)

XGEVA® was evaluated in 3 head-to-head studies1

View XGEVA® efficacy »

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. Bekker PJ, Holloway DL, Rasmussen AS, et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res. 2004;19:1059-1066.

  3. Lewiecki EM. Denosumab: an investigational drug for the management of postmenopausal osteoporosis. Biologics. 2008;2:645-653.

  4. Keizer RJ, Huitema ADR, Schellens JHM, Beijnen JH. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49:493-507.

  5. Mould DR, Green B. Pharmacokinetics and pharmacodynamics of monoclonal antibodies: concepts and lessons for drug development. BioDrugs. 2010;24:23-39.

  6. Sutjandra L, Rodriguez RD, Doshi S, et al. Population pharmacokinetic meta-analysis of denosumab in healthy subjects and postmenopausal women with osteopenia or osteoporosis. Clin Pharmacokinet. 2011;50:793-807.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. Data on file, Amgen.

  12. Data on file, Amgen.

  13. Data on file, Amgen.

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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