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.
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XGEVA® is indicated for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy1

Meeting an unmet medical need for refractory hypercalcemia of malignancy (HCM)
HCM is a serious metabolic complication2

HCM is a serious metabolic complication in patients with advanced cancer.2

  • It may be indicative of poor prognosis and may lead to renal failure, coma, and death.3,4
  • Symptoms include nausea, vomiting, abdominal pain, dehydration, and confusion.5
  • It can be distressing for the patient, and it must be recognized and treated aggressively.6
  • The condition is caused primarily by cancer-induced bone resorption.7
  • Prevalence of HCM differs by tumor type; however, rates are higher in breast, lung, and myeloma.6,8
XGEVA® is approved for HCM refractory to bisphosphonate therapy1

In an open-label, single-arm trial of patients with HCM (N=33), by day 10, approximately 64% achieved CSC* ≤ 11.5 mg/dL.1

Efficacy in patients with HCM refractory to bisphosphonate therapy

Efficacy in patients with HCM refractory to bisphosphonate therapy

Data from an open-label, single-arm trial that enrolled 33 patients with HCM (with or without bone metastases) refractory to treatment with intravenous bisphosphonate therapy. In this trial, refractory HCM was defined as an albumin-corrected calcium of > 12.5 mg/dL (3.1 mmol/L) despite treatment with intravenous bisphosphonate therapy in 7 to 30 days prior to initiation of XGEVA® therapy.1

*CSC=corrected serum calcium.

†Primary endpoint.

HCM may occur through one of two dominant pathways—osteolytic or humoral3
Hypercalcemia of malignancy (HCM) Pathways: Osteolytic Mechanism of Disease
Hypercalcemia of malignancy (HCM) Pathways: Humoral Mechanism of Disease

Humoral HCM:

  • The second of two dominant HCM pathways. Parathyroid hormone–related protein (PTHrP) mediates this humoral arm and accounts for 80% of HCM in patients.3
  • Distant primary tumors release PTHrP into the circulatory system, which drives humoral-mediated HCM. Systemic circulation transports PTHrP to bone where it increases RANK Ligand production by osteoblasts and subsequent osteoclast activation.9
  • Osteoclast-driven calcium liberation from the bone matrix and inadequate renal calcium clearance due to PTHrP drive hypercalcemia.3,6
XGEVA® is the first and only RANK Ligand inhibitor in oncology1
Hypercalcemia of malignancy (HCM) Pathways: XGEVA® Mechanism of Action
  • XGEVA® is a fully human‡ monoclonal antibody.1
  • XGEVA® binds with high affinity and specificity to RANK Ligand.10
  • XGEVA® decreases bone resorption and inhibits calcium release.1

‡Correlation with safety and efficacy is unknown.

XGEVA® dosing and administration1

Administer 120 mg every 4 weeks with additional 120 mg doses on days 8 and 15 of the first month of therapy. Administer subcutaneously in the upper arm, upper thigh, or abdomen.1

  • XGEVA® is intended for subcutaneous route only and should not be administered intravenously, intramuscularly, or intradermally.1

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 morbidity1

  • First and only FDA-approved treatment for giant cell tumor of bone (GCTB)11
  • XGEVA® received FDA priority review status12
  • FDA orphan-drug designation received for this disease12

GCTB: A rare, locally aggressive benign tumor13

GCTB is a benign tumor that is aggressive at the site and often leads to destruction of bone and extension into the surrounding soft tissues.13-15 It is estimated that there are approximately 300 to 800 new cases of GCTB annually in the United States.16 GCTB represents approximately 5% of all primary bone tumors and 20% of benign primary bone tumors in the United States.17,18

XGEVA®: A mechanism of action (MOA) with a therapeutic effect on GCTB

Excess RANK Ligand (RANKL) has been implicated in giant cell tumor pathogenesis impacting tumor growth and bone destruction.19

XGEVA® specifically binds to RANKL, inhibiting the formation of osteoclast-like giant cells. This MOA of XGEVA® directly impacts the bone biology of GCTB—reducing tumor growth and bone destruction.1

  • RANKL is produced by bone cells in the skeleton and is a key mediator of bone resorption.9
  • Excess RANKL has been implicated in giant cell tumor pathogenesis—tumor growth and bone destruction.19
  • XGEVA® acts precisely to bind RANKL and inhibits osteoclast-like giant cell formation, function, and tumor growth.1
  • Pre-existing hypocalcemia must be corrected prior to initiating therapy with XGEVA®.1

XGEVA® dosing and administration1

Administer 120 mg every 4 weeks with additional 120 mg doses on days 8 and 15 of the first month of therapy. Administer subcutaneously in the upper arm, upper thigh, or abdomen.1

  • XGEVA® is intended for subcutaneous route only and should not be administered intravenously, intramuscularly, or intradermally.

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. Concomitant use of calcimimetics and other drugs that can lower calcium levels may worsen hypocalcemia risk and serum calcium should be closely monitored. 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. Concomitant use of calcimimetics and other drugs that can lower calcium levels may worsen hypocalcemia risk and serum calcium should be closely monitored. Advise patients to contact a healthcare professional for symptoms of hypocalcemia.

References

  1. XGEVA® (denosumab) prescribing information, Amgen.
  2. Major P, Lortholary A, Hon J, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol. 2001;19:558-567.
  3. Stewart AF. Hypercalcemia associated with cancer. N Engl J Med. 2005;352:373-379.
  4. Ralston SH, Gallacher SJ, Patel U, et al. Cancer-associated hypercalcemia: morbidity and mortality. Ann Intern Med. 1990;112:499-504.
  5. Grill V, Martin TJ. Hypercalcemia of malignancy. Rev Endocr Metab Disord. 2000;1:253-263.
  6. Mundy GR. Metastasis to bone: causes, consequences and therapeutic opportunities. Nat Rev Cancer. 2002;2(8):584-593.
  7. Hu MI, Glezerman IG, Leboulleux S, et al. Denosumab for treatment of hypercalcemia of malignancy. J Clin Endocrinol Metab. 2014;99:3144-3152.
  8. Gastanaga V, Jain R, Pirolli M, et al. Prevalence of hypercalcemia of malignancy in the United States. Poster presented at: American Society for Bone and Mineral Research Annual Meeting; October 4-7, 2013; Baltimore, MD.
  9. Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350(16):1655-1664.
  10. 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.
  11. FDA news release. FDA approves Xgeva to treat giant cell tumor of the bone. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm356528.htm. Accessed January 27, 2016.
  12. FDA supplemental approval. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2010/125320s007ltr.pdf. Accessed January 27, 2016.
  13. Turcotte RE. Giant cell tumor of bone. Orthop Clin North Am. 2006;37:35-51.
  14. Reid R, Banerjee SS, Sciot R. Giant cell tumour. In: Fletcher CDM, Unni KK, Mertens F, eds. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon, France: IARC Press; 2002:309-313.
  15. Mendenhall WM, Zlotecki RA, Scarborough MT, Gibbs CP, Mendenhall NP. Giant cell tumor of bone. Am J Clin Oncol. 2006;29:96-99.
  16. Data on file, Amgen.
  17. Thomas DM, Skubitz KM. Giant cell tumour of bone. Curr Opin Oncol. 2009;21:338-344.
  18. Garcia RA, Inwards CY, Unni KK. Benign bone tumors—recent developments. Semin Diagn Pathol. 2011;28:73-85.
  19. Kim Y, Nizami S, Goto H, Lee FY. Modern interpretation of giant cell tumor of bone: predominantly osteoclastogenic stromal tumor. Clin Orthop Surg. 2012;4:107-116.

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Please see Full Prescribing Information