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Denosumab
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- 3. • What isit ? • Mechanism of action ? • Uses ? • Side effects ? • Contra indications ? • Adverse drug reactions ? • Cost ? , availability ? • Current recommendations ?
- 4. What is it? • Monoclonal antibody ( IgG2 ) • Developed by AMGEN • On 2 June 2010, DENOSUMAB was approved by (FDA) for use in postmenopausal women with risk of osteoporosis under the trade name Prolia, and in November 2010, as Xgeva, for the prevention of skeleton-related events in patients with bone metastases from solid tumors.
- 5. • Denosumab isthe first RANKL inhibitor to be approved by the FDA. • On 13 June 2013, the US FDA approved Denosumab for treatment of adults and skeletally mature adolescents with Giant cell tumor of bone that is unresectable or where resection would result in significant morbidity.
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- 10. USES • Treatment ofpostmenopausal women with osteoporosis at high risk for fracture • Treatment to increase bone mass in men with osteoporosis at high risk for fracture • Treatment of glucocorticoid-induced osteoporosis in men and women at high risk for fracture
- 11. • Treatment toincrease bone mass in men at high risk for fracture receiving androgen deprivation therapy for non-metastatic prostate cancer • Treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer
- 12. DOSAGE AND ADMINISTRATION •Pregnancy must be ruled out prior to administration of Prolia • Prolia should be administered by a healthcare professional • Administer injection every 6 months as a subcutaneous injection in the upper arm, upper thigh, or abdomen • Instruct patients to take calcium 1000 mg daily and at least 400 IU vitamin D daily
- 13. DOSAGE AND STRENGTH •Single-use prefilled syringe containing 60 mg in a 1 mL solution
- 17. CONTRAINDICATIONS • Hypocalcemia • Pregnancy •Known hypersensitivity to Prolia
- 18. WARNING AND PRECAUTIOS •Same Active Ingredient: Patients receiving Prolia should not receive XGEVA • Hypersensitivity including anaphylaxis • Hypocalcemia: Must be corrected before initiating Prolia. May worsen, Especially in patients with renal impairment. • Adequately supplement Patients with calcium and vitamin D • Osteonecrosis of the jaw: Has been reported with Prolia.
- 19. • Atypical femoralfractures • Multiple vertebral fractures • Serious infections including skin infections • Dermatologic reactions: Dermatitis, rashes, and eczema have been reported. • Severe bone, joint, muscle pain may occur. • Suppression of bone turnover
- 20. ADVERSE DRUG REACTIONS •Postmenopausal osteoporosis: Most common adverse reactions (> 5% and more common than placebo) were: back pain, pain in extremity, hypercholesterolemia, musculoskeletal pain, and cystitis. Pancreatitis has been reported in clinical trials • Male osteoporosis: Most common adverse reactions (> 5% and more common than placebo) were: back pain, arthralgia, and nasopharyngitis • Glucocorticoid-induced osteoporosis: Most common adverse reactions (> 3% and more common than active-control group) were: back pain, hypertension, bronchitis, and headache • Bone loss due to hormone ablation for cancer: Most common adverse reactions (≥ 10% and more common than placebo) were: arthralgia and back pain. Pain in extremity and musculoskeletal pain have also been reported in clinical trials
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- 29. INDICATIONS AND USE •Prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors. • 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. • Treatment of hypercalcemia of malignancy
- 30. DOSAGE AND ADMINISTRATION •Multiple Myeloma and Bone Metastasis from Solid Tumors: Administer 120 mg every 4 weeks as a subcutaneous injection in the upper arm, upper thigh, or abdomen. • Giant Cell Tumor of Bone: Administer 120 mg every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. • Hypercalcemia of Malignancy: Administer 120 mg every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy.
- 31. DOSAGE FORMS ANDSTRENGTHS • Injection: 120 mg/1.7 mL (70 mg/mL) solution in a single-dose vial
- 32. WARNING SYMPTOMS ANDPRECAUTIONS • Hypersensitivity reactions including anaphylaxis may occur. • Hypocalcemia: Xgeva can cause severe symptomatic hypocalcemia, and fatal cases have been reported. • Correct hypocalcemia prior to initiating Xgeva. Monitor calcium levels during therapy, especially in the first weeks of initiating therapy, and adequately supplement all patients with calcium and vitamin D.
- 33. • Osteonecrosis ofthe jaw (ONJ) has been reported in patients receiving Xgeva • Atypical femoral fracture • Hypercalcemia Following Treatment Discontinuation in Patients with Giant Cell Tumor of Bone and in Patients with Growing Skeletons: Monitor patients for signs and symptoms of hypercalcemia, and manage as clinically appropriate.
- 34. • Multiple VertebralFractures (MVF) Following Treatment • Discontinuation: When Xgeva treatment is discontinued, evaluate the individual patient’s risk for vertebral fractures. • Embryo-Fetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to the fetus and to use effective contraception.
- 35. ADVERSE REACTIONS • BoneMetastasis from Solid Tumors: Most common adverse reactions (≥ 25%) were fatigue/asthenia, hypophosphatemia, and nausea. • Multiple Myeloma: Most common adverse reactions (≥ 10%) were diarrhea, nausea, anemia, back pain, thrombocytopenia, peripheral edema, hypocalcemia, upper respiratory tract infection, rash, and headache.
- 36. • Giant CellTumor of Bone: Most common adverse reactions (≥ 10%) were arthralgia, headache, nausea, back pain, fatigue, and pain in extremity. • Hypercalcemia of Malignancy: Most common adverse reactions (> 20%) were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.
- 37. DENOSUMAB IN GCT •GCT : locally aggressive benign neoplasm • Malignant transformation with out radiotherapy is uncommon and occurs in less than 1% of cases • Decrease in activity and control of symptoms • Malignant transformation is seen mostly following radiation therapy
- 38. • To enhancesurgeons ability to perform joint preserving intralesional surgery with an acceptable low risk of recurrence
- 40. • Sample :20 adults with recurrent / unresectable GCT • Dosage : SC Denosumab 120 mg every 4 wks (with additional doses on day 8 and day 15 ) • End point : 90 % or more elimination of giant cells from tumour • 100% subjects achieved end point . • 65 % increased portion of RANKL- positive stromal cells replaced by dense fibro-osseous tissue / new owen bone
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- 47. • MAY 2013 •DENOSUMAB started • 360 mg subcutaneous dose • Followed by 120 mg every month
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- 49. • Pain aroundknee joint diminished • Further resection ?? • Patient refused • Clinical improvement persisted until jan 14 • Presented with Rapidly growing painful palpable mass • Open biopsy : high grade sarcoma • A/K amputation
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- 65. RESULTS • 54 patientswith 30 primary and 25 recurrent tumours • 17 patients treated with out denosumab • 6 doses before surgery ( planned arbitrarily) • Clinical improvement in all (3 to 4 doses) • 3 doses prior in whom surgery was planned
- 66. • 14 recurrencesout of 37 curetted tumours(38%) • 11 of 25 patients in donesumab-treated curettage group had recurrences (44%) compared with 7 of 34 (21%) in the non denosumab-treated control group : not significant • No recurrence in the resection group • One malignant transformation in a pt with proximal humeral GCT. • Denosumab reduces risk of recurrence ???? • Further trials needed !!!!!!
- 71. SOURCES • Freedome trial •Freedome extension trial • Luis et.al case report • Mainsh et.al article on Denosumab in GCT • Xu et.al Denosumab in GCT review • AMGEN annual Denosumab update
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