Denosumab

12.1 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. Denosumab products prevent RANKL from activating its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone.

1 INDICATIONS AND USAGE Stoboclo 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 Stoboclo 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 Stoboclo 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 Stoboclo 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 fai

2 DOSAGE AND ADMINISTRATION Pregnancy must be ruled out prior to administration of Stoboclo. ( 2.1 ) Before initiating Stoboclo 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 ) Stoboclo 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 Stoboclo Pregnancy must be ruled out prior to administration of Stoboclo. Perform pregnancy testing in all females of reproductive potential prior to administration of Stoboclo. 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 Stoboclo 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 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 [see Warnings and Precautions (5.1) ] . 2.3 Recommended Dosage Stoboclo should be administered by a healthcare provider. The recommended dose of Stoboclo is 60 mg administered as a single subcutaneous injection once every 6 months. Administer Stoboclo 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 Stoboclo 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. Stoboclo is a clear, colorless to pale yellow solution. Do not use if the solution is discolored or cloudy or if the solution contains particles or foreign particulate matter. Prior to administration, Stoboclo may be removed from the refrigerator and brought to room temperature up to 25°C (77°F) by standing in the original carton. This generally takes 15 to 30 minutes. Do not warm Stoboclo in any other way [see How Supplied/Storage and Handling (16) ] . Instructions for Administration of Prefilled Syringe with Safety Guard IMPORTANT: To reduce the risk of accidental needle stick injury, each prefilled syringe has a safety guard that is automatically activated to cover the needle after you have given the injection. Do not pull back on the plunger rod at any time. Step 1: Remove the Needle Cap Dispose of the needle cap right away in the nearest sharps disposal container. DO NOT re-cap the prefilled syringe. Image Image Step 2: Administer Subcutaneous Injection Choose an appropriate injection site. The recommended injection sites for Stoboclo include: the outer area of the upper arms OR the upper legs (thighs) OR around the stomach area (abdomen). Inject all of the liquid by using your thumb to push the plunger rod all the way down. If the plunger rod is not fully pressed, the safety guard will not extend to cover the needle when it is removed. Image Image Step 3: Remove the prefilled syringe from the injection site After the prefilled syringe is empty, slowly remove the needle by lifting your thumb from the plunger rod until the needle is completely covered by the safety guard. Do not rub the injection site. Immediately dispose of the prefilled syringe in the nearest sharps disposal container. Image

6 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