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 in the largest international trial ever conducted in multiple myeloma
XGEVA® effectively prevented bone complications1,2*

*XGEVA® was noninferior to zoledronic acid (ZA) in delaying time to first on-study bone complication.1

XGEVA® protects patients with multiple myeloma who may be vulnerable to bone complications via a subcutaneous option1,2

Primary Endpoint: Time to First On-Study Bone Complication (Noninferiority Analysis) Primary Endpoint: Time to First On-Study Bone Complication (Noninferiority Analysis)
  • Median time to first on-study bone complication in the XGEVA® arm was 22.8 months vs 24 months in the ZA arm1
  • Secondary endpoints of time to first bone complication (superiority) and time to first and subsequent bone complications (superiority) were not met1
Primary Endpoint: Time to First On-Study Bone Complication (Noninferiority Analysis) Primary Endpoint: Time to First On-Study Bone Complication (Noninferiority Analysis)
  • Median time to first on-study bone complication in the XGEVA® arm was 22.8 months vs 24 months in the ZA arm1
  • Secondary endpoints of time to first bone complication (superiority) and time to first and subsequent bone complications (superiority) were not met1

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

Removal of multiple myeloma Limitation of Use (LOU)

History and removal of multiple myeloma Limition of Use (LOU) for Solid Tumor Indication and Multiple Myeloma Indication History and removal of multiple myeloma Limition of Use (LOU) for Solid Tumor Indication and Multiple Myeloma Indication

Overall survival (OS) was similar between XGEVA® and ZA1

Overall survival (OS) was similar between XGEVA® and ZA1

  • Assessment of OS supported the removal of the LOU in patients with multiple myeloma
Overall survival (OS) was similar between XGEVA® and zoledronic acid (ZA) Overall survival (OS) was similar between XGEVA® and zoledronic acid (ZA)
  • Assessment of OS supported the removal of the multiple myeloma Limitation of Use
Overall survival (OS) was similar between XGEVA® and zoledronic acid (ZA) Overall survival (OS) was similar between XGEVA® and zoledronic acid (ZA)

Progression-free survival (PFS) was also assessed2,3

  • These data further support the removal of the LOU in patients with multiple myeloma for the prevention of bone complications§

Progression-free survival (PFS) was also assessed2,3

  • These data further support the removal of the LOU in patients with multiple myeloma for the prevention of bone complications§
Progression-free survival (PFS) Progression-free survival (PFS)
EXPLORATORY ENDPOINT

(not powered for statistical significance or adjusted for multiplicity)

  • Median progression-free survival was 46.1 months for XGEVA® compared with 35.4 months for ZA2
  • All patients received standard of care treatment for multiple myeloma, which was stratified between arms4
  • XGEVA® is indicated for the prevention of bone complications in patients with multiple myeloma. The study was not designed to establish an antitumor therapeutic effect1
Progression-free survival (PFS) Progression-free survival (PFS)
EXPLORATORY ENDPOINT

(not powered for statistical significance or adjusted for multiplicity)

  • Median progression-free survival was 46.1 months for XGEVA® compared with 35.4 months for ZA2
  • All patients received standard of care treatment for multiple myeloma, which was stratified between arms4
  • XGEVA® is indicated for the prevention of bone complications in patients with multiple myeloma. The study was not designed to establish an antitumor therapeutic effect1

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 a comparator group.

§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

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. Raje N, Terpos E, Willenbacher W, et al. An international, randomised, double-blind study of denosumab compared to zoledronic acid in bone disease treatment of newly diagnosed multiple myeloma. Lancet Oncol. In press.
  3. Data on file, Amgen.
  4. Data on file, Amgen.

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