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
Don’t miss a critical opportunity to protect patients who may be vulnerable to bone complications11*

*Bone complications, also known as skeletal-related events (SREs), are defined as radiation to bone, pathologic fracture, surgery to bone, and spinal cord compression.11

Studies in metastatic breast and prostate cancer have shown that survival is approaching approximately 2 years2-72-7

More than half of patients suffer a bone complication before starting treatment with a bone-targeting agent88§
TIME TO BONE COMPLICATIONS

Bone complications can occur in less than 1 year from bone metastases diagnosis9,9,1010

Based on the data from the placebo arms of 3 intravenous (IV) bisphosphonate trials (breast: pamidronate vs placebo; prostate and lung/other solid tumors: zoledronic acid vs placebo) in patients with metastatic cancer involving bone.9-119-11

  • The definitions of bone complications for these 3 trials were:
  • Breast: pathologic fracture, surgery to bone, radiation to bone, spinal cord compression, and hypercalcemia of malignancy1010
  • Prostate: pathologic fracture, surgery to bone, radiation to bone, spinal cord compression, and change in antineoplastic therapy to treat bone pain99
  • Lung/other solid tumors: pathologic fracture, surgery to bone, radiation to bone, and spinal cord compression1111

     

BONE PAIN AND BONE COMPLICATIONS

Patients with bone metastases who feel no bone pain may still go on to develop bone complications1212

In a retrospective analysis of patients untreated with a bone-targeting agent, the same percentage of patients suffered 1 or more bone complications within 2 years, whether or not they had bone pain at baseline.1212

Data from the placebo arm (n = 208) of a retrospective analysis evaluating the efficacy of an intravenous (IV) bisphosphonate in the reduction of bone complications and bone pain in men with bone metastases from prostate cancer. In this trial, bone complications or skeletal-related events (SREs) were defined as pathologic fracture, surgery to bone, radiation to bone, spinal cord compression, and change in antineoplastic therapy to treat bone pain. One hundred ninety-one patients in the placebo arm had data capturing baseline pain.1212,13,13

SUBSEQUENT BONE COMPLICATIONS

Subsequent bone complications may commonly occur

  • Of elderly metastatic prostate cancer patients who have experienced an initial bone complication (n = 4,176), 63% experienced a subsequent bone complication (n = 2,619).1414
  • Among patients who experienced a subsequent bone complication, 35% (n = 1,442) experienced a bone complication of a different type.1414

An analysis from the SEER-Medicare linked database (which combines clinical information from population-based cancer registries with claims information from the Medicare program), including 8,997 elderly men diagnosed with metastatic prostate cancer between 2000 and 2009 and followed through December 31, 2010, or until they were lost to follow-up (median follow-up time: 18 months). Postdiagnosis bone complications were identified using claims that indicated spinal cord compression, pathologic fracture, surgery to bone, or radiation (potentially suggestive of bone palliative radiation).1414

BONE COMPLICATIONS

Patients with bone metastases from solid tumors are at risk for bone complications

Bone complications, also known as skeletal-related events (SREs), are defined as1515‚16‚16

  • Radiation to bone
    • Radiation to bone can require multiple treatments.17-1917-19
    • The most common reason for radiation is pain palliation; it is also used as prophylaxis for impending fracture or adjunct to surgery to reduce risk of bone complications.1818‚20‚20
    • A common schedule of radiation is 10 treatments over 2 weeks.17-1917-19
  • Pathologic fracture
    • Pathologic fractures can be painful for patients and often do not heal, resulting in bone destruction.2121
    • Pathologic fractures occur most commonly in the ribs, vertebrae, pelvis, and femur.2222‚23‚23
    • Fractures of weight-bearing bones often require surgical stabilization.2424
  • Surgery to bone
    • Surgery to bone may be required to treat pain, pathologic fracture, or other complications.2121‚24‚24
    • Postsurgical rehabilitation is often necessary.2525
  • Spinal cord compression
    • Spinal cord compression is considered an oncologic emergency.2626
    • The most common tumor types associated with spinal cord compression are2727‚28‚28:
      • Breast (20-30%)
      • Lung (15%)
      • Prostate (10-15%)

Based on data from the control arms of 3 trials in patients with metastatic breast cancer. Trial 1: the paclitaxel arm (n = 354) of a randomized controlled trial (vs paclitaxel plus bevacizumab) of 722 patients. Trial 2: the paclitaxel plus placebo arm (n = 288) of a randomized controlled trial (vs paclitaxel plus lapatinib) of 580 patients. Trial 3: the placebo, trastuzumab, and docetaxel arm (n = 406) of a randomized controlled trial (vs pertuzumab, trastuzumab, and docetaxel) of 808 patients.     2 2   ,4 ,4    ,5 ,5

Based on data from the control arms of 3 trials in patients with metastatic castration-resistant prostate cancer. Trial 1: the placebo arm (n = 171) of a randomized controlled trial (vs sipuleucel-T) of 512 patients. Trial 2: the docetaxel, prednisone, plus placebo arm (n = 526) of a randomized controlled trial (vs docetaxel, prednisome, plus bevacizumab) of 1,050 patients. Trial 3: the docetaxel and prednisone arm (n = 612) of a randomized controlled trial (vs aflibercept, docetaxel, and prednisone) of 1,224 patients.     3 3   ,6 ,6    ,7 ,7

§Data from ISM LifeLink (PharMetrics Plus) including medical and pharmacy claims for national commercially insured patients. Patients had evidence of a bone metastases diagnosis in 2011 or 2012, and were new to treatment with a bone-targeting agent (N = 1,843). The analysis determined whether bone-targeting agents were received prior to, after, or on the same day as an SRE, also known as a bone complication. In the analysis, 56% of patients suffered an SRE. SREs were defined as radiation (although specific anatomical site is unknown), pathologic fracture, surgery to bone, and spinal cord compression.     8 8

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

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