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
The adverse event profile of XGEVA® has been evaluated in more than 5,600 patients with solid tumors1
Acute events

In a prespecified integrated analysis, fewer acute phase reaction events were reported in the XGEVA® arm2,3

In a prespecified integrated analysis, fewer acute phase reaction events were reported in the XGEVA® arm2,3

Pivotal Trial Safety: Acute Phase Reactions

Pivotal Trial Safety: Acute Phase Reactions

  • Acute phase reaction events are defined as those occurring within the first 3 days of treatment; the most common were pyrexia, fatigue, bone pain, arthralgia, and chills
  • Q4W=every 4 weeks.

Hypocalcemia

Calcium and vitamin D supplementation can reduce the risk of hypocalcemia

Calcium and vitamin D supplementation can reduce the risk of hypocalcemia

Hypocalcemia is a blood calcium level that is less than normal4

  • Normal blood calcium levels range from 8.5 mg/dL to 10.2 mg/dL. Normal value ranges may vary slightly among different laboratories5
  • In the XGEVA® phase 3 pivotal studies, daily supplementation with at least 500 mg of calcium and 400 IU of vitamin D was strongly recommended to prevent hypocalcemia6-8
  • In these studies, severe hypocalcemia occurred in 3.1% of patients treated with XGEVA® and 1.3% of patients treated with zoledronic acid1
Hypocalcemia in pivotal trials

Across 3 head-to-head phase 3 studies of more than 5,600 patients

The incidence of any grade of hypocalcemia* was 18% with XGEVA® and 9% with zoledronic acid1

Data from an integrated analysis of 3 head-to-head studies in patients who received ≥1 active dose of investigational product. Includes only treatment-emergent adverse events (AEs).1,9

The incidence of any grade of hypocalcemia* was 18% with XGEVA® and 9% with zoledronic acid1

Data from an integrated analysis of 3 head-to-head studies in patients who received ≥1 active dose of investigational product. Includes only treatment-emergent adverse events (AEs).1,9

Hypocalcemia in Pivotal Trials: Adverse Events of Hypocalcemia in Patients with vs without oral calcium and/or vitamin D supplementation

*Laboratory-derived and below the central laboratory lower limit of normal (8.3-8.5 mg/dL [2.075-2.125 mmol/L]) for calcium.1

Includes patients who received oral calcium and/or oral vitamin D supplement any time during the study, but excludes subjects who ONLY received the supplement after the first AE of hypocalcemia.9

Includes patients who never received oral calcium and/or oral vitamin D supplement or who ONLY received the supplement after the first AE of hypocalcemia.9

Hypocalcemia in Pivotal Trials: Adverse Events of Hypocalcemia in Patients with vs without oral calcium and/or vitamin D supplementation

Hypocalcemia in Pivotal Trials: Adverse Events of Hypocalcemia in Patients with vs without oral calcium and/or vitamin D supplementation

Advise patients

Advise patients

  • Help XGEVA® patients by emphasizing the importance of supplementing XGEVA® treatment with calcium and vitaminD daily as necessary1
  • Advise patients to contact a healthcare professional if they have symptoms of hypocalcemia, including paresthesia or muscle stiffness, twitching, spasms, or cramps1

Monitor calcium levels and supplement with calcium and vitamin D daily as necessary to treat or prevent hypocalcemia1



Monitor calcium levels and supplement with calcium and vitamin D daily as necessary to treat or prevent hypocalcemia1


Severe hypocalcemia

Incidence of severe hypocalcemia in patients with or without calcium and/or vitamin D supplementation10

Pivotal Trial Safety: Severe Hypocalcemia

Severe hypocalcemia

Incidence of severe hypocalcemia in patients with or without calcium and/or vitamin D supplementation10

Pivotal Trial Safety: Severe Hypocalcemia

Data from an integrated analysis of 3 head-to-head studies in patients who received ≥1 active dose of investigational product.

*Includes patients who received oral calcium and/or oral vitamin D supplement at any time during the study, but excludes subjects who ONLY received the supplement after the first lab showed CTC grade ≥2 hypocalcemia.10

Includes subjects who never received oral calcium and/or oral vitamin D supplement or who ONLY received the supplement after the first lab showed CTC grade ≥2 hypocalcemia.10

CTC=common terminology criteria.

Renal considerations

With XGEVA®, there is no need to adjust dosing for patients with impaired renal function1

XGEVA® is a fully human* monoclonal antibody and is not cleared by the kidneys1,11-15

With XGEVA®, there is no need to adjust dosing for patients with impaired renal function1

XGEVA® is a fully human* monoclonal antibody and is not cleared by the kidneys1,11-15

*Correlation with safety and efficacy is unknown.

Dose adjustments/withholdings in head-to-head phase 3 studies of XGEVA® vs zoledronic acid2

Patients with CrCl <30 mL/min were excluded from XGEVA® pivotal trials2

  • XGEVA® (n=2,862)
    • Per protocol, no dose adjustments or dose withholdings were required due to renal function
  • Zoledronic acid (n=2,861)
    • 18% of patients (n=502) required dose adjustments based on baseline CrCl
    • 10% of patients (n=277) required dose withholdings due to increased serum creatinine during therapy

Studies in patients with renal impairment

In clinical trials of 87 patients with varying degrees of renal dysfunction, including patients on dialysis, the degree of renal impairment had no effect on the pharmacokinetics and pharmacodynamics of denosumab

  • 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 (CrCl <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 intake.1

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. XGEVA® (denosumab) prescribing information, Amgen.
  2. 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.
  3. Data on file, Amgen.
  4. MedlinePlus. Low calcium level-infants. National Institutes of Health website. https://www.nlm.nih.gov/medlineplus/ency/article/007229.htm. Updated December 21, 2017. Accessed January 19, 2018.
  5. MedlinePlus. Calcium blood test. National Institutes of Health website. http://www.nlm.nih.gov/medlineplus/ency/article/003477.htm. Updated December 21, 2017. Accessed January 19, 2018.
  6. 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.
  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(9768):813-822.
  8. 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.
  9. Data on file, Amgen.
  10. Data on file, Amgen.
  11. 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(7):1059-1066.
  12. Keizer RJ, Huitema ADR, Schellens JHM, Beijnen JH. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49(8):493-507.
  13. Lewiecki EM. Denosumab: an investigational drug for the management of postmenopausal osteoporosis. Biologics. 2008;2(4):645-653.
  14. Mould DR, Green B. Pharmacokinetics and pharmacodynamics of monoclonal antibodies: concepts and lessons for drug development. BioDrugs. 2010;24(1):23-39.
  15. 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(12):793-807.

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