BOMYNTRA

1 INDICATIONS AND USAGE Bomyntra 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. ( 1.1 ) 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. ( 1.3 ) 1.1 Multiple Myeloma and Bone Metastasis from Solid Tumors Bomyntra is indicated for the prevention of skeletal-related events in patients with multiple myeloma and in patients with bone metastases from solid tumors. 1.2 Giant Cell Tumor of Bone Bomyntra 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 [see Clinical Trials ( 14.2 )]. 1.3 Hypercalcemia of Malignancy Bomyntra is indicated for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.

2 DOSAGE AND ADMINISTRATION Bomyntra should be administered by a healthcare provider. ( 2.1 ) Bomyntra is intended for subcutaneous route only and should not be administered intravenously, intramuscularly, or intradermally. ( 2.1 ) 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. ( 2.2 ) 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. ( 2.3 ) Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia. ( 2.2 , 2.3 ) 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. ( 2.4 ) 2.1 Important Administration Instructions Bomyntra should be administered by a healthcare provider. Bomyntra is intended for subcutaneous route only and should not be administered intravenously, intramuscularly, or intradermally. 2.2 Multiple Myeloma and Bone Metastasis from Solid Tumors The recommended dose of Bomyntra 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 [see Warnings and Precautions ( 5.3 )] . 2.3 Giant Cell Tumor of Bone The recommended dose of Bomyntra 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 [see Warnings and Precautions ( 5.3 )] . 2.4 Hypercalcemia of Malignancy The recommended dose of Bomyntra 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. 2.5 Preparation and Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Bomyntra is a clear, colorless to pale yellow solution that is free from visible particles. Do not use if the solution is discolored or cloudy or if the solution contains particles or foreign particulate matter. Prior to administration, Bomyntra 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 Bomyntra in any other way [see How Supplied/Storage and Handling ( 16 )] . Instructions for Bomyntra Vial 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. Instructions for Administration of Bomyntra Prefilled Syringe with Needle Safety Guard IMPORTANT: In order to minimize accidental needlesticks, the Bomyntra single-dose prefilled syringe has an automatic clear needle safety guard. Bomyntra prefilled syringe (Before & After use) . See figure below. Step 1: Remove Needle Cap (see Figure A ) Do not hold the prefilled syringe by the plunger rod. Do not twist or bend the needle cap. Figure A Step 2: Administer Subcutaneous Injection Choose an injection site. The recommended injection sites for Bomyntra include (see Figure B ): upper thigh abdomen upper arm Do not administer into muscle or blood vessel. Pinch the skin and insert the needle at a 45 to 90-degree angle. Push the plunger with a slow and constant pressure until you cannot press further and have injected all the liquid subcutaneously (see Figure C ). You may hear or feel a “click”. Figure B Figure C Step 3. Release Plunger Keeping the prefilled syringe at the injection site, slowly release the plunger and lift syringe off the skin. The …

3 DOSAGE FORMS AND STRENGTHS Injection: 120 mg/1.7 mL (70 mg/mL) clear, colorless to pale yellow solution in a single-dose vial. Injection: 120 mg/1.7 mL (70 mg/mL) clear, colorless to pale yellow solution in a single-dose prefilled syringe. Injection: 120 mg/1.7 mL (70 mg/mL) solution in a single-dose vial and in a single-dose prefilled syringe ( 3 )

4 CONTRAINDICATIONS Hypocalcemia ( 4.1 ) Known clinically significant hypersensitivity to denosumab products ( 4.2 ) 4.1 Hypocalcemia Pre-existing hypocalcemia must be corrected prior to initiating therapy with Bomyntra [see Warnings and Precautions ( 5.3 )] . 4.2 Hypersensitivity Bomyntra is contraindicated in patients with known clinically significant hypersensitivity to denosumab products [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.2 )] .

6 ADVERSE REACTIONS The following adverse reactions are discussed below and elsewhere in the labeling: Hypersensitivity [see Warnings and Precautions ( 5.2 )] Hypocalcemia [see Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.6 )] Osteonecrosis of the Jaw [see Warnings and Precautions ( 5.4 )] Atypical Subtrochanteric and Diaphyseal Femoral Fracture [see Warnings and Precautions ( 5.5 )] Hypercalcemia following treatment discontinuation in patients with giant cell tumor of bone and in patients with growing skeletons [see Warnings and Precautions ( 5.6 ) and Use in Specific Populations ( 8.4 )] Multiple vertebral fractures (MVF) following treatment discontinuation [see Warnings and Precautions ( 5.7 )] Bone Metastasis from Solid Tumors: Most common adverse reactions (≥ 25%) were fatigue/asthenia, hypophosphatemia, and nausea. ( 6.1 ) Multiple Myeloma: Most common adverse reactions (≥ 10%) were diarrhea, nausea, anemia, back pain, thrombocytopenia, peripheral edema, hypocalcemia, upper respiratory tract infection, rash, and headache. ( 6.1 ) Giant Cell Tumor of Bone: Most common adverse reactions (≥ 10%) were arthralgia, headache, nausea, back pain, fatigue, and pain in extremity. ( 6.1 ) Hypercalcemia of Malignancy: Most common adverse reactions (> 20%) were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Bone Metastasis from Solid Tumors The safety of denosumab was evaluated in three randomized, double-blind, double-dummy trials [see Clinical Trials ( 14.1 )] in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of denosumab. In Studies 20050136, 20050244, and 20050103, patients were randomized to receive either 120 mg of denosumab every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater. Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required. The median duration of exposure to denosumab was 12 months (range: 0.1-41) and median duration on-study was 13 months (range: 0.1-41). Of patients who received denosumab, 46% were female. Eighty-five percent were White, 5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range: 18-93). Seventy-five percent of patients who received denosumab received concomitant chemotherapy. The most common adverse reactions in patients (incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1 ). The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation of denosumab were osteonecrosis and hypocalcemia. Table 1. Selected a Adverse Reactions of Any Severity (Studies 20050136, 20050244, and 20050103) a Adverse reactions reported in at least 10% of patients receiving denosumab in Studies 20050136, 20050244, and 20050103, and meeting one …

8 USE IN SPECIFIC POPULATIONS Pediatric patients: Recommended only for treatment of skeletally mature adolescents with giant cell tumor of bone. ( 8.4 ) Renal impairment: Patients with creatinine clearance less than 30 mL/min or receiving dialysis are at risk for hypocalcemia. Adequately supplement with calcium and vitamin D. ( 8.6 ) 8.1 Pregnancy Risk Summary Based on findings in animals and its mechanism of action, denosumab products can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology ( 12.1 )] . There are insufficient data with denosumab products use in pregnant women to inform any drug associated risks for adverse developmental outcomes. In utero denosumab exposure from cynomolgus monkeys dosed monthly with denosumab 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; and absent lymph nodes, abnormal bone growth, and decreased neonatal growth [see Data ] . Apprise pregnant women of the potential risk to the fetus. The background rate of major birth defects and miscarriage is unknown for the indicated population. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a “knockout mouse”). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy starting at gestational day 20 and at a pharmacologically active dose 25-fold higher than the recommended human dose of denosumab based on body weight, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia, and tooth malalignment; and decreased neonatal growth. At birth out to one month of age, infants had measurable blood levels of denosumab (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero ; however, development and lactation have not been fully evaluated. In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation [see Use in Specific Populations ( 8.3 ) and Nonclinical Toxicology ( 13.2 )] . 8.2 Lactation Risk Summary There is no information regarding the presence of denosumab products in human milk, the effects on the breastfed child, or the effects on milk production. Denosumab was detected in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio) and maternal mammary gland development was normal, with no impaired lactation. However, pregnant RANKL knockout mice sho …

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, 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.

11 DESCRIPTION Denosumab-bnht is a human IgG2 monoclonal antibody that binds to human RANKL. Denosumab-bnht has an approximate molecular weight of 147 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells. Bomyntra (denosumab-bnht) injection is a sterile, preservative-free, clear, colorless to pale yellow solution for subcutaneous use. Each ready-to-use, single-dose prefilled syringe (PFS) and single-dose vial of Bomyntra contains 120 mg denosumab-bnht (70 mg/mL solution), 0.39 mg glacial acetic acid , 0.17 mg polysorbate 20, 1.83 mg sodium acetate, 79.9 mg sorbitol, and Water for Injection (USP). The pH is 5.2.

10 OVERDOSAGE There is no experience with overdosage of denosumab products.

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Bomyntra injection is a clear, colorless to pale yellow solution supplied in a single-dose vial and in a single-dose prefilled syringe with a safety guard. 120 mg/1.7 mL (70 mg/mL) in a single-dose vial 1 vial per carton NDC 6521967001 120 mg/1.7 mL (70 mg/mL) in a single-dose prefilled syringe 1 syringe per carton NDC 6521967201 Storage and Handling Store Bomyntra in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Prior to administration, Bomyntra may be allowed to reach room temperature up to 25°C (77°F) in the original container. Once removed from the refrigerator, Bomyntra must not be exposed to temperatures above 77°F (25°C) or direct light and must be used within 14 days. Discard Bomyntra if not used within the 14 days. Do not use Bomyntra after the expiry date printed on the label. Protect Bomyntra from direct light and heat. Avoid vigorous shaking of Bomyntra.

How Supplied Bomyntra injection is a clear, colorless to pale yellow solution supplied in a single-dose vial and in a single-dose prefilled syringe with a safety guard. 120 mg/1.7 mL (70 mg/mL) in a single-dose vial 1 vial per carton NDC 6521967001 120 mg/1.7 mL (70 mg/mL) in a single-dose prefilled syringe 1 syringe per carton NDC 6521967201