Indication

XGEVA® is indicated for the prevention of skeletal‐related events in patients with multiple myeloma and in patients with bone metastases from solid tumors.

MODEL SUMMARY1-7

Summary overview table for health economic Markov model of XGEVA® total value vs zoledronic acid. Summary overview table for health economic Markov model of XGEVA® total value vs zoledronic acid.

*It should be noted that all patients were not treated with XGEVA® for 15 years. The average survival in the model was 1.6 years.1

Based on a retrospective study of electronic medical records from the OSCER database to identify adult (age 18) solid tumor patients with first bone metastasis diagnosis between January 1, 2012, and December 31, 2014. A total of 14,881 patients with diagnoses of solid tumors and bone metastasis were identified.2

Based on Q3 2017 Centers for Medicare and Medicaid Services Average Selling Price (ASP). ASP values were estimated based on the ASP payment limit (ASP+6%) for each treatment per mg. ASP+6% was converted to ASP by dividing by 1.06. Per mg ASP rates were multiplied by the prescribed dose per administration. Cost per cycle was adjusted based on proportion of dose received by cancer type from pivotal registrational trial.1,4

§Based on a retrospective study of electronic medical records data from the OSCER database to identify adult (age 18) solid tumor patients with first bone metastasis diagnosis and 1 serum creatinine level recorded between January 1, 2009, and December 31, 2013. A total of 24,512 patients with diagnoses of solid tumors and bone metastasis were identified. Among these patients, 11,809 (48%) had at least 1 serum creatinine level reported. A total of 43% of patients with bone metastases due to solid tumors had renal impairment (eGFR <60 mL/min) over a 5-year study period. Within this population, the prevalence of renal impairment for estimated glomerular filtration rate (eGFR) <30 mL/min was utilized. eGFR <30 mL/min is considered severe renal impairment (stage IV-V chronic kidney disease). eGFR <15 mL/min was 1.4% and eGFR between 15-29 mL/min was 6.7%. It was assumed that 8% were defined as renal impairment and were assumed to be ineligible for treatment.6

SRE=skeletal-related event.

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.

Indication

XGEVA® is indicated for the prevention of skeletal‐related events in patients with multiple myeloma and in patients with bone metastases from solid tumors.

Please see Full Prescribing Information.

References

  1. Data on file, Amgen; [XGEVA® US Economic Model; 2017].
  2. Qian Y, Bhowmik D, Kachru N, Hernandez RK. Longitudinal patterns of bone-targeted agent use among patients with solid tumors and bone metastases in the United States. Support Care Cancer. 2017;25:1845-1851.
  3. XGEVA® (denosumab) prescribing information, Amgen.
  4. Centers for Medicare & Medicaid Services. 2017 ASP drug pricing files website. https://www.cms.gov/Medicare/Medicare-Fee-for-Service-Part-B-Drugs/McrPartBDrugAvgSalesPrice/2017ASPFiles.html. Accessed November 19, 2018.
  5. Zoledronic acid prescribing information, Novartis.
  6. Arellano J, Hernandez RK, Wade SW, et al. Prevalence of renal impairment and use of nephrotoxic agents among patients with bone metastases and solid tumors in the United States. Cancer Med. 2015;4:713-720.
  7. Neumann PJ, Cohen JT, Weinstein MC. Updating cost-effectiveness—the curious resilience of the $50,000-per-QALY threshold. N Engl J Med. 2014;371:796-797.
  8. Pavlakis N, Schmidt R, Stockler M. Bisphosphonates for breast cancer. Cochrane Database Syst Rev. 2005;20:CD003474.
  9. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94:1458-1468.
  10. Stopeck A, Rader M, Henry D, et al. Cost-effectiveness of denosumab vs zoledronic acid for prevention of skeletal-related events in patients with solid tumors and bone metastases in the United States. J Med Econ. 2012;15:712-723.
  11. Bureau of Labor Statistics Medical. CPI-all urban consumers (current series) website. https://data.bls.gov/timeseries/CUUR0000SAM?output_view=pct_12mths. Accessed November 19, 2018.
  12. Nash Smyth E, Conti I, Wooldridge JE, et al. Frequency of skeletal-related events and associated healthcare resource use and costs in US patients with multiple myeloma. J Med Econ. 2016;19:477-486.
  13. Jayasekera J, Onukwugha E, Bikov K, et al. The economic burden of skeletal-related events among elderly men with metastatic prostate cancer. Pharmacoeconomics. 2014;32:173-191.
  14. von Moos R, Body JJ, Egerdie B, et al. Pain and analgesic use associated with skeletal-related events in patients with advanced cancer and bone metastases. Support Care Cancer. 2016;24:1327-1337.
  15. Delea T, Langer C, McKiernan J, et al. The cost of treatment of skeletal-related events in patients with bone metastases from lung cancer. Oncology. 2004;67:390-396.
  16. Xie J, Namjoshi M, Wu EQ, et al. Economic evaluation of denosumab compared with zoledronic acid in hormone-refractory prostate cancer patients with bone metastases. J Manag Care Pharm. 2011;17:621-643.
  17. Bell MJ, Miller JD, Namjoshi M, et al. Comparative Budget Impact of Formulary Inclusion of Zoledronic Acid and Denosumab for Prevention of Skeletal-Related Events in Patients With Bone Metastases. Poster presented at: ISPOR 16th Annual International Meeting; May 21-25, 2011; Baltimore, Maryland.
  18. Gridelli C, Ferrara C, Guerriero C, et al. Informal caregiving burden in advanced non-small cell lung cancer: the HABIT study. J Thorac Oncol. 2007;2:475-480.
  19. Qian Y, Song X, Zhang K, et al. Short-term disability in solid tumor patients with bone metastases and skeletal-related events. J Med Econ. 2015;18:210-218.
  20. Matza LS, Chung K, Van Brunt K, et al. Health state utilities for skeletal-related events secondary to bone metastases. Eur J Health Econ. 2014;15:7-18.