Denosumab

Bilprevda 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 Bilprevda 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 Bilprevda 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 Bilprevda 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, colorless to slightly yellow solution in a single-dose vial. Injection: 120 mg/1.7 mL (70 mg/mL) solution in a single-dose vial. ( 3 )

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 Bilprevda [see Warnings and Precautions ( 5.3 )] .

4.2 Hypersensitivity Bilprevda is contraindicated in patients with known clinically significant hypersensitivity to denosumab products [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.2 )] .

Drug Products with Same Active Ingredient: Patients receiving Bilprevda should not receive other denosumab products concomitantly. ( 5.1 ) Hypersensitivity reactions including anaphylaxis may occur. Discontinue permanently if a clinically significant reaction occurs. ( 5.2 ) Hypocalcemia: Denosumab products can cause severe symptomatic hypocalcemia. Fatal cases have been reported with denosumab products use. Correct hypocalcemia prior to initiating Bilprevda. Monitor calcium levels during therapy, especially in the first weeks of initiating therapy, and adequately supplement all patients with calcium and vitamin D. ( 5.3 ) Osteonecrosis of the jaw (ONJ) has been reported in patients receiving denosumab products. Perform an oral examination prior to starting Bilprevda. Monitor for symptoms. Avoid invasive dental procedures during treatment with Bilprevda. ( 5.4 ) Atypical femoral fracture: Evaluate patients with thigh or groin pain to rule out a femoral fracture. ( 5.5 ) 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. ( 5.6 , 8.4 ) Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation: When Bilprevda treatment is discontinued, evaluate the individual patient's risk for vertebral fractures. ( 5.7 ) 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 Bilprevda should not receive other denosumab products concomitantly.

5.2 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 Bilprevda therapy permanently [see Contraindications ( 4.2 ) and Adverse Reactions ( 6.2 )] .

5.3 Hypocalcemia Denosumab products can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to Bilprevda treatment. Monitor calcium levels, throughout Bilprevda 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 [see Contraindications ( 4.1 ), Adverse Reactions ( 6.1 , 6.2 ), and Patient Counseling Information ( 17 )] . 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 [see Adverse Reactions ( 6.1 ), Use in Specific Populations ( 8.6 ), and Clinical Pharmacology ( 12.3 )] .

5.4 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 [see Adverse Reactions ( 6.1 )] . 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 Bilprevda and periodically during Bilprevda therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Bilprevda. Consider temporary discontinuation of Bilprevda 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 Bilprevda 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.

5.5 Atypical Subtrochanteric and Diaphyseal Femoral Fracture Atypical femoral fracture has been reported with 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. 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 Bilprevda 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 Bilprevda therapy should be considered, pending a risk/benefit assessment, on an individual basis.

5.6 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 [see Adverse Reactions ( 6 ) and Use in Specific Populations ( 8.4 )] .

5.7 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 Bilprevda treatment is discontinued, evaluate the individual patient's risk for vertebral fractures [see Patient Counseling Information ( 17 )] .

5.8 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. […]

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 Organon LLC, a subsidiary of Organon & Co., at 1-844-674-3200 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 of the following criteria: At least 1% greater incidence in denosumab-treated patients, or Between-group difference (either direction) of less than 1% and more than 5% greater incidence in patients treated with zoledronic acid compared to placebo (US Prescribing Information for zoledronic acid) b Laboratory-derived and below the central laboratory lower limit of normal [8.3 – 8.5 mg/dL (2.075 – 2.125 mmol/L) for calcium and 2.2 – 2.8 mg/dL (0.71 – 0.9 mmol/L) for phosphorus] Body System Denosumab n = 2841 % Zoledronic Acid n = 2836 % GASTROINTESTINAL Nausea 31 32 Diarrhea 20 19 GENERAL Fatigue/Asthenia 45 46 INVESTIGATIONS Hypocalcemia b 18 9 Hypophosphatemia b 32 20 NEUROLOGICAL Headache 13 14 RESPIRATORY Dyspnea 21 18 Cough 15 15 Severe Mineral/Electrolyte Abnormalities Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) occurred in 3.1% of patients treated with denosumab and 1.3% of patients treated with zoledronic acid. Of patients who experienced severe hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia and 16% experienced 3 or more episodes [see Warnings and Precautions ( 5.3 ) and Use in Specific Populations ( 8.6 )] . Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than 0.6 mmol/L) occurred in 15% of patients treated with denosumab and 7% of patients treated with zoledronic acid. Osteonecrosis of the Jaw (ONJ) In the primary treatment phases of Studies 20050136, 20050244, and 20050103, ONJ was confirmed in 1.8% of patients in the denosumab group (median exposure of 12.0 months; range: 0.1-41) and 1.3% of patients in the zoledronic acid group. The trials in patients with breast (Study 20050136) or prostate (Study 20050103) cancer included an open-label extension treatment phase where patients were offered denosumab 120 mg once every 4 weeks (median overall exposure of 14.9 months; range: 0.1-67.2). The patient-year adjusted incidence (number of events per 100 patient years) of confirmed ONJ was 1.1% during the first year of treatment, 3.7% in the second year, and 4.6% per year thereafter. The median time to ONJ was 20.6 months (range: 4-53) [see Warnings and Precautions ( 5.4 )] . In a placebo-controlled clinical trial with an extension treatment phase evaluating denosumab for the prevention of bone metastases in patients with non-metastatic prostate cancer (a patient population for which denosumab is not indicated), with longer treatment exposure of up to 7 years, the patient-year adjusted incidence (number of events per 100 patient years) of confirmed ONJ was 1.1% during the first year of treatment, 3% in the second year, and 7% per year thereafter. Atypical Subtrochanteric and Diaphyseal Fracture In the clinical trial program, atypical femoral fracture has been reported in patients treated with denosumab and the risk increased with longer duration of treatment. Events have occurred during treatment and after treatment was discontinued [see Warnings and Precautions ( 5.5 )] . Multiple Myeloma The safety of denosumab was evaluated in an international, randomized (1:1), double-blind, active-controlled trial of patients with newly diagnosed multiple myeloma with treatment through disease progression [see Clinical Trials ( 14.2 )] . In this trial, patients received 120 mg denosumab every 4 weeks as a subcutaneous injection (n = 850) or 4 mg (dose adjusted for renal function) of zoledronic acid intravenously (IV) every 4 weeks by IV infusion (n = 852). 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. […]

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 showed altered maturation of the maternal mammary gland, leading to impaired lactation [see Use in Specific Populations ( 8.1 ) and Nonclinical Toxicology ( 13.2 )] . Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for Bilprevda treatment and any potential adverse effects on the breastfed child from Bilprevda or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential Based on findings in animals and its mechanism of action, denosumab products can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations ( 8.1 )] . Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating Bilprevda treatment. Contraception Females Advise females of reproductive potential to use effective contraception during therapy, and for at least 5 months after the last dose of Bilprevda.

8.4 Pediatric Use The safety and efficacy of Bilprevda have not been established in pediatric patients except in skeletally mature adolescents (aged 12–16 years) with giant cell tumor of bone. Bilprevda is recommended only for treatment of skeletally mature adolescents (aged 12–16 years) with giant cell tumor of bone [see Indications and Usage ( 1.2 )] . Clinically significant hypercalcemia after treatment discontinuation has been reported in pediatric patients with growing skeletons who received denosumab products for giant cell tumor of bone or for unapproved indications [see Adverse Reactions ( 6.2 ) and Warnings and Precautions ( 5.6 )] . Denosumab was studied in an open-label trial that enrolled a subset of 19 adolescent patients (aged 12-16 years) with giant cell tumor of bone who had reached skeletal maturity, defined by at least 1 mature long bone (e.g., closed epiphyseal growth plate of the humerus), and had a body weight ≥ 45 kg [see Indications and Usage ( 1.2 ) and Clinical Trials ( 14.3 )] . A total of one of five (20%) evaluable adolescent patients had an objective response by retrospective independent assessment of radiographic response according to modified Response Evaluation Criteria in Solid Tumors (RECIST 1.1). The adverse reaction profile and efficacy results appeared to be similar in skeletally mature adolescents and adults [see Adverse Reactions ( 6.1 ) and Clinical Trials ( 14.3 )] . Animal Data Treatment with denosumab products may impair bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of denosumab therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth eruption. Adolescent primates treated with denosumab at doses 5 and 25 times (10 and 50 mg/kg dose) higher than the recommended human dose of 120 mg administered once every 4 weeks, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes. Some bone abnormalities recovered once exposure was ceased following birth; however, axillary and inguinal lymph nodes remained absent 6 months post-birth [see Use in Specific Populations ( 8.1 )] .

8.5 Geriatric Use Of the total number of patients in clinical studies that received denosumab (n = 2841) in Studies 20050136, 20050244, and 20050103, 1271 (44%) were ≥ 65 years old, while 473 patients (17%) were ≥ 75 years old. Of the 859 patients in Study 20090482 that received denosumab, 387 patients (45%) were ≥ 65 years old, while 141 patients (16%) were ≥ 75 years old. No overall differences in safety or efficacy were observed between older and younger patients. […]

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.