Denosumab-bbdz is a human IgG2 monoclonal antibody that binds to human RANKL. Denosumab-bbdz has an approximate molecular weight of 147 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells. Wyost (denosumab-bbdz) injection is a sterile, preservative-free, clear to slightly opalescent and colorless to slightly yellowish to slightly brownish solution for subcutaneous use. Each single-dose vial contains 1.7 mL solution of 120 mg denosumab-bbdz, glacial acetic acid (1.85 mg), polysorbate 20 (0.17 mg), sodium hydroxide (0.91 mg), sorbitol (78.9 mg), and Water for Injection (USP). Hydrochloric acid and sodium hydroxide may be added to adjust the pH to 5.2.

Wyost is a RANK ligand (RANKL) inhibitor indicated for: • 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. ( 1.2 , 14.3 ) • Treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy

Multiple Myeloma and Bone Metastasis from Solid Tumors Wyost is indicated for the prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors

Giant Cell Tumor of Bone Wyost is indicated for the 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

Hypercalcemia of Malignancy Wyost is indicated for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.

Injection: 120 mg/1.7 mL (70 mg/mL) clear to slightly opalescent and colorless to slightly yellowish to slightly brownish solution in a single-dose vial. • Injection: 120 mg/1.7 mL (70 mg/mL) solution in a single-dose vial.

• Wyost should be administered by a healthcare provider. • Wyost is intended for subcutaneous route only and should not be administered intravenously, intramuscularly, or intradermally. • 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. Administer subcutaneously in the upper arm, upper thigh, or abdomen. • Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia. • 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. Administer subcutaneously in the upper arm, upper thigh, or abdomen

Important Administration Instructions Wyost should be administered by a healthcare provider. Wyost is intended for subcutaneous route only and should not be administered intravenously, intramuscularly, or intradermally

Multiple Myeloma and Bone Metastasis from Solid Tumors The recommended dose of Wyost is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia

Giant Cell Tumor of Bone The recommended dose of Wyost is 120 mg administered 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. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia

Hypercalcemia of Malignancy The recommended dose of Wyost is 120 mg administered 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

Preparation and Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Wyost is a clear to slightly opalescent and colorless to slightly yellowish to slightly brownish 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, Wyost 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 Wyost in any other way . Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single entry.

• Drug Products with Same Active Ingredient: Patients receiving Wyost should not receive other denosumab products concomitantly. • Hypersensitivity reactions including anaphylaxis may occur. Discontinue permanently if a clinically significant reaction occurs. • Hypocalcemia: Denosumab products can cause severe symptomatic hypocalcemia. Fatal cases have been reported with denosumab products use. Correct hypocalcemia prior to initiating Wyost. Monitor calcium levels during therapy, especially in the first weeks of initiating therapy, and adequately supplement all patients with calcium and vitamin D. • Osteonecrosis of the jaw (ONJ) has been reported in patients receiving denosumab products. Perform an oral examination prior to starting Wyost. Monitor for symptoms. Avoid invasive dental procedures during treatment with Wyost. • Atypical femoral fracture: Evaluate patients with thigh or groin pain to rule out a 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. • Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation: When Wyost 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. ( 5.8 , 8.1 , 8.3 ) 5.1 Drug Products with Same Active Ingredient Patients receiving Wyost should not receive other denosumab products concomitantly

Hypersensitivity Clinically significant hypersensitivity including anaphylaxis has been reported with use of denosumab products. 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 Wyost therapy permanently

Hypocalcemia Denosumab products can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to Wyost treatment. Monitor calcium levels, throughout Wyost therapy, 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 provider 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/min and/or on dialysis), and with inadequate/no calcium supplementation. Monitor calcium levels and calcium and vitamin D intake

Osteonecrosis of the Jaw (ONJ) Osteonecrosis of the jaw (ONJ) has been reported in patients receiving denosumab products, 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 . Seventy-nine percent of patients with ONJ had a history of tooth extraction, poor oral hygiene, or use of a dental appliance as a predisposing factor. Other risk factors for the development of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroids, diabetes, and gingival infections. Similarly, for denosumab-treated patients with multiple myeloma that developed ONJ, 58% had a history of invasive dental procedures as a predisposing factor. Perform an oral examination and appropriate preventive dentistry prior to the initiation of Wyost and periodically during Wyost therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Wyost. Consider temporary discontinuation of Wyost therapy if an invasive dental procedure must be performed. There are no data available to suggest the optimal duration of treatment interruption. Patients who are suspected of having or who develop ONJ while on Wyost should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Clinical judgment of the treating healthcare provider should guide the management plan of each patient based on individual risk/benefit assessment

Atypical Subtrochanteric and Diaphyseal Femoral Fracture Atypical femoral fracture has been reported with denosumab products . 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 Wyost 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 Wyost 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 and in Patients with Growing Skeletons Clinically significant hypercalcemia requiring hospitalization and complicated by acute renal injury has been reported in denosumab product-treated patients with giant cell tumor of bone and patients with growing skeletons. Hypercalcemia has been reported within the first year after treatment discontinuation. After treatment is discontinued, monitor patients for signs and symptoms of hypercalcemia, assess serum calcium periodically, reevaluate the patient’s calcium and vitamin D supplementation requirements and manage patients as clinically appropriate

Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation Multiple vertebral fractures (MVF) have been reported following discontinuation of treatment with denosumab products. Patients at higher risk for MVF include those with risk factors for or a history of osteoporosis or prior fractures. When Wyost treatment is discontinued, evaluate the individual patient’s risk for vertebral fractures

Embryo-Fetal Toxicity Based on data from animal studies and its mechanism of action, denosumab products can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of denosumab to cynomolgus monkeys throughout pregnancy at a dose 25-fold higher than the recommended human dose of denosumab based on body weight resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent peripheral lymph nodes, abnormal bone growth and decreased neonatal growth. Verify the pregnancy status of females of reproductive potential prior to the initiation of Wyost. Advise pregnant women and females of reproductive potential that exposure to Wyost during pregnancy or within 5 months prior to conception can result in fetal harm. Advise females of reproductive potential to use effective contraception during therapy, and for at least 5 months after the last dose of Wyost .