Denosumab

INDICATIONS AND USAGE Denosumab-bmwo is a RANK ligand (RANKL) inhibitor indicated for treatment: of postmenopausal women with osteoporosis at high risk for fracture ( 1.1 ) to increase bone mass in men with osteoporosis at high risk for fracture ( 1.2 ) of glucocorticoid-induced osteoporosis in men and women at high risk for fracture ( 1.3 ) to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer ( 1.4 ) to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer ( 1.5 ) 1.1 Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture Denosumab-bmwo is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, denosumab reduces the incidence of vertebral, nonvertebral, and hip fractures [see Clinical Studies (14.1) ] . 1.2 Treatment to Increase Bone Mass in Men with Osteoporosis Denosumab-bmwo is indicated for treatment to increase bone mass in men with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy [see Clinical Studies (14.2) ] . 1.3 Treatment of Glucocorticoid-Induced Osteoporosis Denosumab-bmwo is indicated for the treatment of glucocorticoid-induced osteoporosis in men and women at high risk of fracture who are either initiating or continuing systemic glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and expected to remain on glucocorticoids for at least 6 months. High risk of fracture is defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy [see Clinical Studies (14.3) ] . 1.4 Treatment of Bone Loss in Men Receiving Androgen Deprivation Therapy for Prostate Cancer Denosumab-bmwo is indicated as a treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy (ADT) for nonmetastatic prostate cancer. In these patients denosumab also reduced the incidence of vertebral fractures [see Clinical Studies (14.4) ] . 1.5 Treatment of Bone Loss in Women Receiving Adjuvant Aromatase Inhibitor Therapy for Breast Cancer Denosumab-bmwo is indicated as a treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer [see Clinical Studies (14.5) ] .

DOSAGE AND ADMINISTRATION Pregnancy must be ruled out prior to administration of Bosaya. ( 2.1 ) Before initiating Bosaya in patients with advanced chronic kidney disease, including dialysis patients, evaluate for the presence of chronic kidney disease mineral and bone disorder with intact parathyroid hormone, serum calcium, 25(OH) vitamin D, and 1,25(OH) 2 vitamin D. ( 2.2 , 5.1 , 8.6 ) Bosaya should be administered by a healthcare provider. ( 2.3 ) Administer 60 mg every 6 months as a subcutaneous injection in the upper arm, upper thigh, or abdomen. ( 2.3 ) Instruct patients to take calcium 1000 mg daily and at least 400 IU vitamin D daily. ( 2.3 ) 2.1 Pregnancy Testing Prior to Initiation of Bosaya Pregnancy must be ruled out prior to administration of Bosaya. Perform pregnancy testing in all females of reproductive potential prior to administration of Bosaya. Based on findings in animals, denosumab products can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1 , 8.3) ] . 2.2 Laboratory Testing in Patients with Advanced Chronic Kidney Disease Prior to Initiation of Bosaya In patients with advanced chronic kidney disease [i.e., estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m 2 ], including dialysis-dependent patients, evaluate for the presence of chronic kidney disease mineral and bone disorder (CKD-MBD) with intact parathyroid hormone (iPTH), serum calcium, 25(OH) vitamin D, and 1,25 (OH)2 vitamin D prior to decisions regarding Bosaya treatment. Consider also assessing bone turnover status (serum markers of bone turnover or bone biopsy) to evaluate the underlying bone disease that may be present [see Warnings and Precautions (5.1) ] . 2.3 Recommended Dosage Bosaya should be administered by a healthcare provider. The recommended dose of Bosaya is 60 mg administered as a single subcutaneous injection once every 6 months. Administer Bosaya via subcutaneous injection in the upper arm, the upper thigh, or the abdomen. All patients should receive calcium 1000 mg daily and at least 400 IU vitamin D daily [see Warnings and Precautions (5.1) ] . If a dose of Bosaya is missed, administer the injection as soon as the patient is available. Thereafter, schedule injections every 6 months from the date of the last injection. 2.4 Preparation and Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Bosaya is a clear to slightly opalescent, colorless to pale yellow solution. Do not use if the solution is discolored or cloudy or if the solution contains visible particles or foreign particulate matter. Prior to administration, Bosaya may be removed from the refrigerator and brought to room temperature up to 25°C (77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Bosaya in any other way [see How Supplied/Storage and Handling (16)] . Instructions for Administration of Bosaya Prefilled Syringe with Needle Safety Guard IMPORTANT: The prefilled syringe has a needle safety guard that will be activated to cover the needle after the injection is given. The needle guard will help prevent needlestick injuries to anyone who handles the prefilled syringe after the injection has been given. Do not attempt to activate the needle safety guard prior to injection. Step 1: Remove the Gray needle Cap Hold the prefilled syringe by the needle safety guard, carefully pull the gray needle cap straight out and away from body (Figure B). Do not twist or bend the gray needle cap. Do not hold the prefilled syringe by the plunger rod. Throw the gray needle cap into the disposal container. Step 2:Administer Subcutaneous Injection Choose an injection site. The recommended injection sites for Bosaya include (Figure C): Upper thigh. Abdomen. Upper arm. Insert needle and inject all the liquid subcutaneously Do not administer into muscle or blood vessel. Push the plunger with slow and constant pressure until you feel or hear a “snap.” Push all the way down through the snap. (Figure D). Step 3: Release the Plunger after Injection Release the plunger until the entire needle is covered and then remove the prefilled syringe from the injection site. or Gently remove the needle from the injection site and release the plunger until the entire needle is covered by the needle safety guard. After releasing the plunger, the prefilled syringe safety guard will safely cover the injection needle Figure E). Do not put the gray needle cap back on used prefilled syringes. Immediately dispose of the used prefilled syringe and other supplies into a sharps disposal container.

WARNINGS AND PRECAUTIONS Hypocalcemia: Pre-existing hypocalcemia must be corrected before initiating Stoboclo. May worsen, especially in patients with renal impairment. Adequately supplement all patients with calcium and vitamin D. Concomitant use of calcimimetic drugs may also worsen hypocalcemia risk. Evaluate for presence of chronic kidney disease mineral-bone disorder. Monitor serum calcium. ( 5.1 ) Same Active Ingredient: Patients receiving Stoboclo should not receive other denosumab products concomitantly. ( 5.2 ) Hypersensitivity including anaphylactic reactions may occur. Discontinue permanently if a clinically significant reaction occurs. ( 5.3 ) Osteonecrosis of the jaw: Has been reported with denosumab products. Monitor for symptoms. ( 5.4 ) Atypical femoral fractures: Have been reported. Evaluate patients with thigh or groin pain to rule out a femoral fracture. ( 5.5 ) Multiple vertebral fractures have been reported following treatment discontinuation. Patients should be transitioned to another antiresorptive agent if Stoboclo is discontinued. ( 5.6 ) Serious infections including skin infections: May occur, including those leading to hospitalization. Advise patients to seek prompt medical attention if they develop signs or symptoms of infection, including cellulitis. ( 5.7 ) Dermatologic reactions: Dermatitis, rashes, and eczema have been reported. Consider discontinuing Stoboclo if severe symptoms develop. ( 5.8 ) Severe bone, joint, muscle pain may occur. Discontinue use if severe symptoms develop. ( 5.9 ) Suppression of bone turnover: Significant suppression has been demonstrated. Monitor for consequences of bone over-suppression. ( 5.10 ) 5.1 Severe Hypocalcemia and Mineral Metabolism Changes Denosumab products can cause severe hypocalcemia and fatal cases have been reported. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Stoboclo. Adequately supplement all patients with calcium and vitamin D [see Dosage and Administration (2.1) , Contraindications (4) , and Adverse Reactions (6.1) ] . In patients without advanced chronic kidney disease who are predisposed to hypocalcemia and disturbances of mineral metabolism (e.g. history of hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine, treatment with other calcium-lowering drugs), assess serum calcium and mineral levels (phosphorus and magnesium) 10 to 14 days after Stoboclo injection. In some postmarketing cases, hypocalcemia persisted for weeks or months and required frequent monitoring and intravenous and/or oral calcium replacement, with or without vitamin D. Patients with Advanced Chronic Kidney Disease Patients with advanced chronic kidney disease [i.e., eGFR <30 mL/min/1.73 m 2 ] including dialysis-dependent patients are at greater risk for severe hypocalcemia following denosumab products administration. Severe hypocalcemia resulting in hospitalization, life-threatening events and fatal cases have been reported. The presence of underlying chronic kidney disease-mineral bone disorder (CKD-MBD, renal osteodystrophy) markedly increases the risk of hypocalcemia. Concomitant use of calcimimetic drugs may also worsen hypocalcemia risk. To minimize the risk of hypocalcemia in patients with advanced chronic kidney disease, evaluate for the presence of chronic kidney disease mineral and bone disorder with intact parathyroid hormone (iPTH), serum calcium, 25(OH) vitamin D, and 1,25(OH) 2 vitamin D prior to decisions regarding Stoboclo treatment. Consider also assessing bone turnover status (serum markers of bone turnover or bone biopsy) to evaluate the underlying bone disease that may be present. Monitor serum calcium weekly for the first month after Stoboclo administration and monthly thereafter. Instruct all patients with advanced chronic kidney disease, including those who are dialysis-dependent, about the symptoms of hypocalcemia and the importance of maintaining serum calcium levels with adequate calcium and activated vitamin D supplementation. Treatment with Stoboclo in these patients should be supervised by a healthcare provider who is experienced in diagnosis and management of CKD-MBD. 5.2 Drug Products with Same Active Ingredient Patients receiving Stoboclo should not receive other denosumab products concomitantly. 5.3 Hypersensitivity Clinically significant hypersensitivity including anaphylaxis has been reported with denosumab products. Symptoms have included hypotension, dyspnea, throat tightness, facial and upper airway edema, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy, and discontinue further use of Stoboclo [see Contraindications (4) , Adverse Reactions (6.2) ] . 5.4 Osteonecrosis of the Jaw Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing. ONJ has been reported in patients receiving denosumab products [see Adverse Reactions (6.1) ] . A routine oral exam should be performed by the prescriber prior to initiation of Stoboclo treatment. A dental examination with appropriate preventive dentistry is recommended prior to treatment with Stoboclo in patients with risk factors for ONJ such as invasive dental procedures (e.g. tooth extraction, dental implants, oral surgery), diagnosis of cancer, concomitant therapies (e.g. chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and comorbid disorders (e.g. periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). Good oral hygiene practices should be maintained during treatment with Stoboclo. Concomitant administration of drugs associated with ONJ may increase the risk of developing ONJ. The risk of ONJ may increase with duration of exposure to denosumab products. For patients requiring invasive dental procedures, clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit-risk assessment. Patients who are suspected of having or who develop ONJ while on Stoboclo should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of Stoboclo therapy should be considered based on individual benefit-risk assessment. 5.5 Atypical Subtrochanteric and Diaphyseal Femoral Fractures Atypical low energy or low trauma fractures of the shaft have been reported in patients receiving denosumab products [see Adverse Reactions (6.1) ] . 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. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with antiresorptive agents. 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 Stoboclo 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. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of Stoboclo therapy should be considered, pending a benefit-risk assessment, on an individual basis. 5.6 Multiple Vertebral Fractures (MVF) F

CONTRAINDICATIONS Denosumab-bmwo is contraindicated in: Patients with hypocalcemia: Pre-existing hypocalcemia must be corrected prior to initiating therapy with Denosumab-bmwo [see Warnings and Precautions (5.1) ] . Pregnant women: Denosumab products may cause fetal harm when administered to a pregnant woman. In women of reproductive potential, pregnancy testing should be performed prior to initiating treatment with Denosumab-bmwo [see Use in Specific Populations (8.1) ] . Patients with hypersensitivity to denosumab products: Denosumab-bmwo is contraindicated in patients with a history of systemic hypersensitivity to any component of the product. Reactions have included anaphylaxis, facial swelling, and urticaria [see Warnings and Precautions (5.3) , Adverse Reactions (6.2) ] . Hypocalcemia ( 4 , 5.1 ) Pregnancy ( 4 , 8.1 ) Known hypersensitivity to denosumab products ( 4 , 5.3 )

ADVERSE REACTIONS The following serious adverse reactions are discussed below and also elsewhere in the labeling: Severe Hypocalcemia and Mineral Metabolism Changes [see Warnings and Precautions (5.1) ] Hypersensitivity [see Warnings and Precautions (5.3) ] Osteonecrosis of the Jaw [see Warnings and Precautions (5.4) ] Atypical Subtrochanteric and Diaphyseal Femoral Fractures [see Warnings and Precautions (5.5) ] Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation [see Warnings and Precautions (5.6) ] Serious Infections [see Warnings and Precautions (5.7) ] Dermatologic Adverse Reactions [see Warnings and Precautions (5.8) ] The most common adverse reactions reported with denosumab products in patients with postmenopausal osteoporosis are back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis. The most common adverse reactions reported with denosumab products in men with osteoporosis are back pain, arthralgia, and nasopharyngitis. The most common adverse reactions reported with denosumab products in patients with glucocorticoid-induced osteoporosis are back pain, hypertension, bronchitis, and headache. The most common (per patient incidence ≥ 10%) adverse reactions reported with denosumab products in patients with bone loss receiving androgen deprivation therapy for prostate cancer or adjuvant aromatase inhibitor therapy for breast cancer are arthralgia and back pain. Pain in extremity and musculoskeletal pain have also been reported in clinical trials. The most common adverse reactions leading to discontinuation of denosumab products in patients with postmenopausal osteoporosis are back pain and constipation. 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. ( 6.1 ) Male osteoporosis: Most common adverse reactions (> 5% and more common than placebo) were: back pain, arthralgia, and nasopharyngitis. ( 6.1 ) Glucocorticoid-induced osteoporosis: Most common adverse reactions (> 3% and more common than active-control group) were: back pain, hypertension, bronchitis, and headache. ( 6.1 ) 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. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact CELLTRION USA, Inc. at 1-800-560-9414 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. Treatment of Postmenopausal Women with Osteoporosis The safety of denosumab in the treatment of postmenopausal osteoporosis was assessed in a 3-year, randomized, double-blind, placebo-controlled, multinational study of 7808 postmenopausal women aged 60 to 91 years. A total of 3876 women were exposed to placebo and 3886 women were exposed to denosumab administered subcutaneously once every 6 months as a single 60 mg dose. All women were instructed to take at least 1000 mg of calcium and 400 IU of vitamin D supplementation per day. The incidence of all-cause mortality was 2.3% (n = 90) in the placebo group and 1.8% (n = 70) in the denosumab group. The incidence of nonfatal serious adverse events was 24.2% in the placebo group and 25.0% in the denosumab group. The percentage of patients who withdrew from the study due to adverse events was 2.1% and 2.4% for the placebo and denosumab groups, respectively. The most common adverse reactions reported with denosumab in patients with postmenopausal osteoporosis are back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis. Adverse reactions reported in ≥ 2% of postmenopausal women with osteoporosis and more frequently in the denosumab-treated women than in the placebo-treated women are shown in the table below. Table 1. Adverse Reactions Occurring in ≥ 2% of Patients with Osteoporosis and More Frequently than in Placebo-treated Patients Preferred Term Denosumab (N = 3886) n (%) Placebo (N = 3876) n (%) Back pain 1347 (34.7) 1340 (34.6) Pain in extremity 453 (11.7) 430 (11.1) Musculoskeletal pain 297 (7.6) 291 (7.5) Hypercholesterolemia 280 (7.2) 236 (6.1) Cystitis 228 (5.9) 225 (5.8) Vertigo 195 (5.0) 187 (4.8) Upper respiratory tract infection 190 (4.9) 167 (4.3) Edema peripheral 189 (4.9) 155 (4.0) Sciatica 178 (4.6) 149 (3.8) Bone pain 142 (3.7) 117 (3.0) Abdominal pain upper 129 (3.3) 111 (2.9) Anemia 129 (3.3) 107 (2.8) Insomnia 126 (3.2) 122 (3.1) Myalgia 114 (2.9) 94 (2.4) Angina pectoris 101 (2.6) 87 (2.2) Rash 96 (2.5) 79 (2.0) Pharyngitis 91 (2.3) 78 (2.0) Asthenia 90 (2.3) 73 (1.9) Pruritus 87 (2.2) 82 (2.1) Flatulence 84 (2.2) 53 (1.4) Spinal osteoarthritis 82 (2.1) 64 (1.7) Gastroesophageal reflux disease 80 (2.1) 66 (1.7) Herpes zoster 79 (2.0) 72 (1.9) Hypocalcemia Decreases in serum calcium levels to less than 8.5 mg/dL at any visit were reported in 0.4% women in the placebo group and 1.7% women in the denosumab group. The nadir in serum calcium level occurred at approximately day 10 after denosumab dosing in subjects with normal renal function. In clinical studies, subjects with impaired renal function were more likely to have greater reductions in serum calcium levels compared to subjects with normal renal function. In a study of 55 subjects with varying degrees of renal function, serum calcium levels < 7.5 mg/dL or symptomatic hypocalcemia were observed in 5 subjects. These included no subjects in the normal renal function group, 10% of subjects in the creatinine clearance 50 to 80 mL/min group, 29% of subjects in the creatinine clearance < 30 mL/min group, and 29% of subjects in the hemodialysis group. These subjects did not receive calcium and vitamin D supplementation. In a study of 4550 postmenopausal women with osteoporosis, the mean change from baseline in serum calcium level 10 days after denosumab dosing was -5.5% in subjects with creatinine clearance < 30 mL/min vs. -3.1% in subjects with creatinine clearance ≥ 30 mL/min. Serious Infections Receptor activator of nuclear factor kappa-B ligand (RANKL) is expressed on activated T and B lymphocytes and in lymph nodes. Therefore, a RANKL inhibitor such as denosumab products may increase the risk of infection. In the clinical study of 7808 postmenopausal women with osteoporosis, the incidence of infections resulting in death was 0.2% in both placebo and denosumab treatment groups. However, the incidence of nonfatal serious infections was 3.3% in the placebo and 4.0% in the denosumab groups. Hospitalizations due to serious infections in the abdomen (0.7% placebo vs. 0.9% denosumab), urinary tract (0.5% placebo vs. 0.7% denosumab), and ear (0.0% placebo vs. 0.1% denosumab) were reported. Endocarditis was reported in no placebo patients and 3 patients receiving denosumab. Skin infections, including erysipelas and cellulitis, leading to hospitalization were reported more frequently in patients treated with denosumab (< 0.1% placebo vs. 0.4% denosumab). The incidence of opportunistic infections was similar to that reported with placebo. Dermatologic Adverse Reactions A significantly higher number of patients treated with denosumab developed epidermal and dermal adverse events (such as dermatitis, eczema, and rashes), with these events reported in 8.2% of the placebo and 10.8% of the denosumab groups (p < 0.0001). Most of these events were not specific to the injection site [see Warnings and Precautions (5.8) ] . Osteonecrosis of the Jaw ONJ has been reported in the osteoporosis clinical trial program in patients treated with

Mechanism of Action Denosumab products bind to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption, thereby modulating calcium release from bone. Increased osteoclast activity, stimulated by RANKL, is a mediator of bone pathology in solid tumors with osseous metastases. Similarly, giant cell tumors of bone consist of stromal cells expressing RANKL and osteoclast-like giant cells expressing RANK receptor, and signaling through the RANK receptor contributes to osteolysis and tumor growth. Denosumab products prevent RANKL from activating its receptor, RANK, on the surface of osteoclasts, their precursors, and osteoclast-like giant cells.