Bilprevda

Description for Bilprevda for Injection

Denosumab-nxxp is a human IgG2 monoclonal antibody with affinity and specificity for human RANKL (receptor activator of nuclear factor kappa-B ligand). Denosumab-nxxp has an approximate molecular weight of 147 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells.

Bildyos (denosumab-nxxp) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution for subcutaneous use.

Each 1 mL single-dose prefilled syringe of Bildyos and each 1 mL single-dose vial contain 60 mg denosumab- nxxp (60 mg/mL solution), glacial acetic acid (1.02 mg), polysorbate 20 (0.1 mg), sorbitol (47.0 mg), Water for Injection (USP), and sodium hydroxide to a pH of 5.2.

ADVERSE REACTIONS

The following adverse reactions are discussed below and elsewhere in the labeling:

• Hypersensitivity [see Warnings and Precautions (2)]
• Hypocalcemia [see Warnings and Precautions (3) and Use in Specific Populations (8.6)]
• Osteonecrosis of the Jaw [see Warnings and Precautions (4)]
• Atypical Subtrochanteric and Diaphyseal Femoral Fracture [see Warnings and Precautions (5)]
• Hypercalcemia following treatment discontinuation in patients with giant cell tumor of bone and in patients with growing skeletons [see Warnings and Precautions (6) and Use in Specific Populations (8.4)]
• Multiple vertebral fractures (MVF) following treatment discontinuation [see Warnings and Precautions (7)]

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)

Body System	Denosumab n = 2841 %	Zoledronic Acid n = 2836 %
GASTROINTESTINAL
Nausea	31	32
Diarrhea	20	19
GENERAL
Fatigue/Asthenia	45	46
INVESTIGATIONS
Hypocalcemiab	18	9
Hypophosphatemiab	32	20
NEUROLOGICAL
Headache	13	14
RESPIRATORY
Dyspnea	21	18
Cough	15	15
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]

Severe Mineral/Electrolyte Abnormalities

• Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 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 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. Calcium and vitamin D supplementation was recommended but not required.

The median duration of exposure to denosumab was 16 months (range: 1-50) and median duration on-study was 17 months (range: 0-49). Of patients who received denosumab, 46% were female, 83% were White, 13% Asian, 3% Black or African American, and 4% Hispanic/Latino. The median age of the patients randomized to denosumab was 63 years (range: 29-91) and all patients who received denosumab received concomitant anti- myeloma chemotherapy.

The adverse reaction profile of denosumab in patients with multiple myeloma, Study 20090482, was similar to that observed in Studies 20050136, 20050244, and 20050103. The most common adverse reactions (incidence ≥ 10%) were diarrhea (34%), nausea (32%), anemia (22%), back pain (21%), thrombocytopenia (19%), peripheral

edema (17%), hypocalcemia (16%), upper respiratory tract infection (15%), rash (14%), and headache (11%). The most common serious adverse reaction (incidence ≥ 5%) was pneumonia (8%). The most common adverse reaction resulting in discontinuation of denosumab (≥ 1%) was osteonecrosis of the jaw.

Hypocalcemia and Hypophosphatemia

Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) and severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than 0.6 mmol/L) occurred in 2% and 21% patients treated with denosumab, respectively.

Osteonecrosis of the Jaw (ONJ)

In the primary treatment phase of Study 20090482, ONJ was confirmed in 4.1% of patients in the denosumab group (median exposure of 16 months; range: 1-50) and 2.8% of patients in the zoledronic acid group (median 15 months, range: 1-45 months). At the completion of the double-blind treatment phase of Study 20090482, the patient-year adjusted incidence (number of events per 100 patient years) of confirmed ONJ in the denosumab group (median exposure of 19.4 months; range: 1-52) was 2% during the first year of treatment, 5% in the second year, and 4.5% per year thereafter. The median time to ONJ was 18.7 months (range: 1-44) [see Warnings and Precautions (5.4)].

Giant Cell Tumor of Bone

The safety of denosumab was evaluated in two single-arm trials (Study 20062004 and Study 20040215) [see Clinical Trials (14.3)] in which a total of 548 adult or skeletally mature adolescent patients with giant cell tumor of bone received at least 1 dose of denosumab. Patients received 120 mg denosumab subcutaneously every 4 weeks with additional 120 mg doses on Days 8 and 15 of the first month of therapy. Patients receiving concurrent bisphosphonate therapy were excluded from enrollment in both studies. 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 were excluded from enrollment in Study 20040215. During the trial, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required.

Of the 548 patients who received denosumab, 467 patients were treated with denosumab for ≥ 1 year, 323 patients for ≥ 2 years, and 255 patients for ≥ 3 years. The median number of doses received was 33 (range: 4- 138 doses) and the median number of months on-study was 60 (range: 0-140 months). Fifty-seven percent of the enrolled patients were women and 82% were White. The median age was 33 years (range: 13-83 years); a total of 19 patients were skeletally mature adolescents (12 to < 17 years of age).

The common adverse reaction profile of denosumab in patients with giant cell tumor of bone was generally similar to that reported in Studies 20050136, 20050244, and 20050103. The most common adverse reactions in patients (incidence ≥ 10%) were arthralgia, back pain, pain in extremity, fatigue, headache, nausea, nasopharyngitis, musculoskeletal pain, toothache, vomiting, hypophosphatemia, constipation, diarrhea, and cough. The most frequent serious adverse reactions were osteonecrosis of the jaw (3.6%), bone giant cell tumor (1.5%), anemia (1.1%), pneumonia (0.9%), and back pain (0.9%). The most frequent adverse reactions resulting in discontinuation of denosumab was osteonecrosis of the jaw (incidence of 3.6%). The adverse reaction profile appeared similar in skeletally mature adolescents and adults.

Hypocalcemia and Hypophosphatemia

• Moderate to severe hypocalcemia (corrected serum calcium less than 8 mg/dL or less than 2 mmol/L) occurred in 5% of patients treated with denosumab.
• Severe hypophosphatemia (serum phosphorus less than 2 to 1 mg/dL or less than 6 to 0.3 mmol/L) occurred in 20% of patients treated with denosumab.

Osteonecrosis of the Jaw (ONJ)

In the pooled analysis of Study 20062004 and Study 20040215, ONJ was confirmed in 7% of patients who received denosumab (median number of doses received: 33; range: 4-138 doses).

Study 20140114 (NCT03301857) was a 5-year long term follow-up study for patients (n = 85) who completed Study 20062004. In Study 20062004 and Study 20140114 combined, ONJ was confirmed in 7% of patients who received denosumab (median time on trial 62.2 months; range: 0 – 173). The combined patient-year adjusted incidence (number of events per 100 patient years) of confirmed ONJ was 0.2% during the first year of treatment, 1.5% in the second year, 1.8% in the third year, 2.1% in the fourth year, 1.4% in the fifth year, and 1.5% thereafter [see Warnings and Precautions (5.4)].

Atypical Subtrochanteric and Diaphyseal Fracture

In the pooled analysis of Study 20062004 and Study 20040215, atypical femoral fracture was observed in 0.9% of patients who received denosumab (median number of doses received: 33; range: 4-138 doses).

In Study 20062004 and Study 20140114, the combined incidence of confirmed atypical femoral fracture was 1.3% of patients who received denosumab [see Warnings and Precautions (5.5)].

Hypercalcemia Following Treatment Discontinuation

In the pooled safety population, 0.7% of patients experienced serious adverse events of hypercalcemia > 30 days following treatment discontinuation that was recurrent in some patients [see Warnings and Precautions (5.6)].

Hypercalcemia of Malignancy

Denosumab was evaluated in an open-label, single-arm trial (Study 20070315) in which 33 patients with hypercalcemia of malignancy (with or without bone metastases) refractory to treatment with intravenous bisphosphonate therapy were enrolled [see Clinical Trials (14.4)].

The adverse reaction profile of denosumab in patients with hypercalcemia of malignancy was similar to that reported in Studies 20050136, 20050244, 20050103, 20062004, and 20040215. Adverse reactions occurring in greater than 20% of patients were nausea (30%), dyspnea (27%), decreased appetite (24%), headache (24%),

peripheral edema (24%), vomiting (24%), anemia (21%), constipation (21%), and diarrhea (21%). The following adverse reactions of Grade 3 or greater severity related to study therapy were reported on-study: fatigue (3%) and infection (6%). Grade 3 laboratory abnormalities included hypomagnesemia (3%), hypokalemia (3%), and hypophosphatemia (76%) of patients. No deaths on-study were related to denosumab therapy.

Postmarketing Experience

The following adverse reactions have been identified during post approval use of denosumab products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Hypocalcemia: Severe symptomatic hypocalcemia, including fatal cases [see Contraindications (1) and Warnings and Precautions (5.3)].
• Hypercalcemia: Severe symptomatic hypercalcemia following treatment discontinuation can occur [see Adverse Reactions (6) and Warnings and Precautions (6)].
• Hypersensitivity, including anaphylactic reactions [see Contraindications (2) and Warnings and Precautions (5.2)].
• Musculoskeletal pain, including severe musculoskeletal Positive re-challenge has been reported.
• Lichenoid drug eruptions (e.g., lichen planus-like reactions).
• Alopecia.

Drug Interactions for Bilprevda for Injection

No information provided

Warnings for Bilprevda for Injection

Included as part of the PRECAUTIONS section.

Precautions for Bilprevda for Injection

Drug Products with Same Active Ingredient

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

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)].

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.

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.

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)].

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)].

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 Bilprevda. Advise pregnant women and females of reproductive potential that exposure to Bilprevda 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 Bilprevda [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)].

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity

The carcinogenic potential of denosumab products has not been evaluated in long-term animal studies.

Mutagenicity

The genotoxic potential of denosumab products has not been evaluated.

Impairment of Fertility

Denosumab had no effect on female fertility or male reproductive organs in monkeys at doses that were 13- to 50-fold higher than the recommended human dose of 60 mg subcutaneously administered once every 6 months, based on body weight (mg/kg).

Animal Toxicology and/or Pharmacology

Denosumab products are inhibitors of osteoclastic bone resorption via inhibition of RANKL.

In ovariectomized monkeys, once-monthly treatment with denosumab suppressed bone turnover and increased BMD and strength of cancellous and cortical bone at doses 50-fold higher than the recommended human dose of 60 mg administered once every 6 months, based on body weight (mg/kg). Bone tissue was normal with no evidence of mineralization defects, accumulation of osteoid, or woven bone.

Because the biological activity of denosumab in animals is specific to nonhuman primates, evaluation of genetically engineered (“knockout”) mice or use of other biological inhibitors of the RANK/RANKL pathway, namely OPG-Fc, provided additional information on the pharmacodynamic properties of denosumab products. RANK/RANKL knockout mice exhibited absence of lymph node formation, as well as an absence of lactation due to inhibition of mammary gland maturation (lobulo-alveolar gland development during pregnancy).

Neonatal RANK/RANKL knockout mice exhibited reduced bone growth and lack of tooth eruption. A corroborative study in 2-week-old rats given the RANKL inhibitor OPG-Fc also showed reduced bone growth, altered growth plates, and impaired tooth eruption. These changes were partially reversible in this model when dosing with the RANKL inhibitors was discontinued.

Patient Information for Bilprevda for Injection

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Hypocalcemia

Advise the patient to adequately supplement with calcium and vitamin D and instruct them on the importance of maintaining serum calcium levels while receiving Bildyos [see Warnings and Precautions (5.1), Use in Specific Populations (8.6)]. Advise patients to seek prompt medical attention if they develop signs or symptoms of hypocalcemia.

Severe Hypocalcemia in Patients with Advanced Chronic Kidney Disease

Advise 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. Advise these patients to have their serum calcium measured weekly for the first month after Bildyos administration and monthly thereafter [see Dosage and Administration (2.2), Warnings and Precautions (5.1), Use in Specific Populations (8.6)].

Drug Products with Same Active Ingredient

Advise patients that if they receive Bildyos, they should not receive other denosumab products concomitantly [see Warnings and Precautions (5.2)].

Hypersensitivity

Advise patients to seek prompt medical attention if signs or symptoms of hypersensitivity reactions occur. Advise patients who have had signs or symptoms of systemic hypersensitivity reactions that they should not receive denosumab products [see Warnings and Precautions (5.3), Contraindications (4)].

Osteonecrosis of the Jaw

Advise patients to maintain good oral hygiene during treatment with Bildyos and to inform their dentist prior to dental procedures that they are receiving Bildyos. Patients should inform their physician or dentist if they experience persistent pain and/or slow healing of the mouth or jaw after dental surgery [see Warnings and Precautions (5.4)].

Atypical Subtrochanteric and Diaphyseal Femoral Fractures

Advise patients to report new or unusual thigh, hip, or groin pain [see Warnings and Precautions (5.5)].

Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation

Advise patients not to interrupt Bildyos therapy without talking to their physician [see Warnings and Precautions (5.6)].

Serious Infections

Advise patients to seek prompt medical attention if they develop signs or symptoms of infections, including cellulitis [see Warnings and Precautions (5.7)].

Dermatologic Adverse Reactions

Advise patients to seek prompt medical attention if they develop signs or symptoms of dermatological reactions (such as dermatitis, rashes, and eczema) [see Warnings and Precautions (5.8)].

Musculoskeletal Pain

Inform patients that severe bone, joint, and/or muscle pain have been reported in patients taking denosumab products. Patients should report severe symptoms if they develop [see Warnings and Precautions (5.9)].

Pregnancy/Nursing

Counsel females of reproductive potential to use effective contraceptive measure to prevent pregnancy during treatment and for at least 5 months after the last dose of Bildyos. Advise the patient to contact their physician immediately if pregnancy does occur during these times. Advise patients not to take Bildyos while pregnant or breastfeeding. If a patient wishes to start breastfeeding after treatment, advise her to discuss the appropriate timing with her physician [see Contraindications (4), Use in Specific Populations (8.1)].

Schedule of Administration

Advise patients that if a dose of Bildyos is missed, the injection should be administered as soon as convenient. Thereafter, schedule injections every 6 months from the date of the last injection. 

OVERDOSAGE

There is no experience with overdosage of denosumab products.

Contraindications for Bilprevda for Injection

Hypocalcemia

Pre-existing hypocalcemia must be corrected prior to initiating therapy with Bilprevda [see Warnings and Precautions (5.3)].

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)].

Clinical Pharmacology for Bilprevda for Injection

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.

Pharmacodynamics

In clinical studies, treatment with 60 mg of denosumab resulted in reduction in the bone resorption marker serum type 1 C-telopeptide (CTX) by approximately 85% by 3 days, with maximal reductions occurring by 1 month. CTX levels were below the limit of assay quantitation (0.049 ng/mL) in 39% to 68% of patients 1 to 3 months after dosing of denosumab. At the end of each dosing interval, CTX reductions were partially attenuated from a maximal reduction of ≥ 87% to ≥ 45% (range: 45% to 80%), as serum denosumab levels diminished, reflecting the reversibility of the effects of denosumab on bone remodeling. These effects were sustained with continued treatment. Upon reinitiation, the degree of inhibition of CTX by denosumab was similar to that observed in patients initiating denosumab treatment.

Consistent with the physiological coupling of bone formation and resorption in skeletal remodeling, subsequent reductions in bone formation markers (i.e., osteocalcin and procollagen type 1 N-terminal peptide [P1NP]) were observed starting 1 month after the first dose of denosumab. After discontinuation of denosumab therapy, markers of bone resorption increased to levels 40% to 60% above pretreatment values but returned to baseline levels within 12 months.

Pharmacokinetics

In a study conducted in healthy male and female volunteers (n = 73, age range: 18 to 64 years) following a single subcutaneously administered denosumab dose of 60 mg, the mean area-under-the-concentration-time curve up to 16 weeks (AUC_{0-16 weeks}) of denosumab was 316 mcg?day/mL (standard deviation [SD] = 101 mcg?day/mL). The mean maximum denosumab concentration (C_max) was 6.75 mcg/mL (SD = 1.89 mcg/mL). No accumulation or change in denosumab pharmacokinetics with time is observed with multiple dosing of 60 mg subcutaneously administered once every 6 months.

Absorption

Following subcutaneous administration, the median time to maximum denosumab concentration (T_max) was 10 days (range: 3 to 21 days).

Distribution

The mean volume of distribution for denosumab was 5.2 L (SD = 1.7 L).

Elimination

Serum denosumab concentrations declined over a period of 4 to 5 months with a mean half-life of 25.4 days (SD = 8.5 days; n = 46).

A population pharmacokinetic analysis was performed to evaluate the effects of demographic characteristics. This analysis showed no notable differences in pharmacokinetics with age (in postmenopausal women), race, or body weight (36 to 140 kg).

Seminal Fluid Pharmacokinetic Study

Serum and seminal fluid concentrations of denosumab were measured in 12 healthy male volunteers (age range: 43-65 years). After a single 60 mg subcutaneous administration of denosumab, the mean (±SD) C_max values in the serum and seminal fluid samples were 6170 (±2070) and 100 (±81.9) ng/mL, respectively, resulting in a maximum seminal fluid concentration of approximately 2% of serum levels. The median (range) T_max values in the serum and seminal fluid samples were 8.0 (7.9 to 21) and 21 (8.0 to 49) days, respectively. Among the subjects, the highest denosumab concentration in seminal fluid was 301 ng/mL at 22 days post-dose. On the first day of measurement (10 days post-dose), nine of eleven subjects had quantifiable concentrations in semen. On the last day of measurement (106 days post-dose), five subjects still had quantifiable concentrations of denosumab in seminal fluid, with a mean (±SD) seminal fluid concentration of 21.1 (±36.5) ng/mL across all subjects (n = 12).

Drug Interactions

In a study of 19 postmenopausal women with low BMD and rheumatoid arthritis treated with etanercept (50 mg subcutaneous injection once weekly), a single-dose of denosumab (60 mg subcutaneous injection) was administered 7 days after the previous dose of etanercept. No clinically significant changes in the pharmacokinetics of etanercept were observed.

Cytochrome P450 substrates

In a study of 17 postmenopausal women with osteoporosis, midazolam (2 mg oral) was administered 2 weeks after a single-dose of denosumab (60 mg subcutaneous injection), which approximates the T_max of denosumab. Denosumab did not affect the pharmacokinetics of midazolam, which is metabolized by cytochrome P450 3A4 (CYP3A4). This indicates that denosumab products should not alter the pharmacokinetics of drugs metabolized by CYP3A4 in postmenopausal women with osteoporosis.

Specific Populations

Gender: Mean serum denosumab concentration-time profiles observed in a study conducted in healthy men ≥ 50 years were similar to those observed in a study conducted in postmenopausal women using the same dose regimen.

Age: The pharmacokinetics of denosumab were not affected by age across all populations studied whose ages ranged from 28 to 87 years.

Race: The pharmacokinetics of denosumab were not affected by race.

Renal Impairment: In a study of 55 patients with varying degrees of renal function, including patients on dialysis, the degree of renal impairment had no effect on the pharmacokinetics of denosumab; thus, dose adjustment for renal impairment is not necessary.

Hepatic Impairment: No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of denosumab products.

Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of denosumab or of other denosumab products.

Using an electrochemiluminescent bridging immunoassay, less than 1% (55 out of 8113) of patients treated with denosumab for up to 5 years tested positive for binding antibodies (including pre-existing, transient, and developing antibodies). None of the patients tested positive for neutralizing antibodies, as was assessed using a chemiluminescent cell-based in vitro biological assay.

There was no identified clinically significant effect of anti-drug antibodies on pharmacokinetics, pharmacodynamics, safety, or effectiveness of denosumab.

MEDICATION GUIDE|
BILDYOS^® [bil' dee ose]
(denosumab-nxxp)
Injection, for subcutaneous use

What is the most important information I should know about Bildyos?

If you receive Bildyos, you should not receive other denosumab products at the same time.

Bildyos can cause serious side effects including:

• Increased risk of severe low calcium levels in your blood (hypocalcemia). Bildyos may lower the calcium levels in your blood. If you have low blood calcium before you start receiving Bildyos, it may get worse during Your low blood calcium must be treated before you receive Bildyos. Talk to your doctor before starting Bildyos. Your doctor may prescribe calcium and vitamin D to help prevent low calcium levels in your blood while you take Bildyos. Take calcium and vitamin D as your doctor tells you to. If you have advanced chronic kidney disease (may or may not be on kidney dialysis), Bildyos may increase your risk for severe low calcium levels in your blood, which could result in hospitalization, life-threatening events and death. A mineral and bone disorder associated with kidney disease called chronic kidney disease-mineral bone disorder (CKD-MBD) may increase your risk for severe low calcium levels in blood. Before you start Bildyos and during treatment, your doctor may need to do certain blood tests to check for CKD-MBD.
  Most people with low blood calcium levels do not have symptoms, but some people may have symptoms. Call your doctor right away if you have symptoms of low blood calcium such as:
• • spasms, twitches, or cramps in your muscles
  • numbness or tingling in your fingers, toes, or around your mouth
• Serious allergic reactions. Serious allergic reactions have happened in people who take denosumab products. Call your doctor or go to your nearest emergency room right away if you have any symptoms of a serious allergic reaction. Symptoms of a serious allergic reaction may include:

  low blood pressure (hypotension) trouble breathing throat tightness swelling of your face, lips, or tongue

  rash itching hives

• Severe jaw bone problems (osteonecrosis). Severe jaw bone problems may happen when you take Bildyos. Your doctor should examine your mouth before you start Bildyos. Your doctor may tell you to see your dentist before you start Bildyos. It is important for you to practice good mouth care during treatment with Bildyos. Ask your doctor or dentist about good mouth care if you have any questions.
• Unusual thigh bone Some people have developed unusual fractures in their thigh bone. Symptoms of a fracture include new or unusual pain in your hip, groin, or thigh.
• Increased risk of broken bones, including broken bones in the spine, after stopping, skipping or delaying Bildyos. Talk with your doctor before starting Bildyos treatment. After your treatment with Bildyos is stopped, or if you skip or delay taking a dose, your risk for breaking bones, including bones in your spine, is increased. Your risk for having more than 1 broken bone in your spine is increased if you have already had a broken bone in your spine. Do not stop, skip or delay taking Bildyos without first talking with your doctor. If your Bildyos treatment is stopped, talk to your doctor about other medicine that you can take.
• Serious infections. Serious infections in your skin, lower stomach area (abdomen), bladder, or ear may happen if you take Bildyos. Inflammation of the inner lining of the heart (endocarditis) due to an infection also may happen more often in people who take Bildyos. You may need to go to the hospital for treatment if you develop an infection.
  Bildyos is a medicine that may affect the ability of your body to fight infections. People who have a weakened immune system or take medicines that affect the immune system may have an increased risk for developing serious infections. Call your doctor right away if you have any of the following symptoms of infection:
  • fever or chills
  • skin that looks red or swollen and is hot or tender to touch
  • fever, shortness of breath, cough that will not go away
  • severe abdominal pain
  • frequent or urgent need to urinate or burning feeling when you urinate
• Skin Skin problems such as inflammation of your skin (dermatitis), rash, and eczema may happen if you take Bildyos. Call your doctor if you have any of the following symptoms of skin problems that do not go away or get worse:

  redness itching small bumps or patches (rash)

  your skin is dry or feels like leather blisters that ooze or become crusty skin peeling

• Bone, joint, or muscle Some people who take denosumab products develop severe bone, joint, or muscle pain.

Call your doctor right away if you have any of these side effects.

What is Bildyos?

Bildyos is a prescription medicine used to:

• Treat osteoporosis (thinning and weakening of bone) in women after menopause (“change of life”) who:
  • are at high risk for fracture (broken bone)
  • cannot use another osteoporosis medicine or other osteoporosis medicines did not work well
• Increase bone mass in men with osteoporosis who are at high risk for fracture.
• Treat osteoporosis in men and women who will be taking corticosteroid medicines (such as prednisone) for at least 6 months and are at high risk for fracture.
• Treat bone loss in men who are at high risk for fracture receiving certain treatments for prostate cancer that has not spread to other parts of the body.
• Treat bone loss in women who are at high risk for fracture receiving certain treatments for breast cancer that has not spread to other parts of the body.

It is not known if Bildyos is safe and effective in children. Bildyos is not approved for use in children.

Do not take Bildyos if you:

• have been told by your doctor that your blood calcium level is too low.
• are pregnant or plan to become pregnant.
• are allergic to denosumab products or any of the ingredients in Bildyos. See the end of this Medication Guide for a complete list of ingredients in Bildyos.

Before taking Bildyos, tell your doctor about all of your medical conditions, including if you:

• are taking other denosumab products.
• have low blood calcium.
• cannot take daily calcium and vitamin D.
• had parathyroid or thyroid surgery (glands located in your neck).
• have been told you have trouble absorbing minerals in your stomach or intestines (malabsorption syndrome).
• have kidney problems or are on kidney dialysis.
• are taking medicine that can lower your blood calcium levels.
• plan to have dental surgery or teeth removed.
• are pregnant or plan to become pregnant. Bildyos may harm your unborn baby.

  Females who are able to become pregnant:

  • Your healthcare provider should do a pregnancy test before you start treatment with Bildyos.
  • You should use an effective method of birth control (contraception) during treatment with Bildyos and for at least 5 months after your last dose of Bildyos.
  • Tell your doctor right away if you become pregnant while taking Bildyos.
• are breastfeeding or plan to It is not known if Bildyos passes into your breast milk. You and your doctor should decide if you will take Bildyos or breastfeed. You should not do both.

Tell your doctor about all the medicines you take, including prescription and over-the- counter medicines, vitamins, and herbal supplements.

Know the medicines you take. Keep a list of medicines with you to show to your doctor or pharmacist when you get a new medicine.

How will I receive Bildyos?

• Bildyos is an injection that will be given to you by a healthcare provider. Bildyos is injected under your skin (subcutaneous).
• You will receive Bildyos 1 time every 6 months.
• You should take calcium and vitamin D as your doctor tells you to while you receive Bildyos.
• If you miss a dose of Bildyos, you should receive your injection as soon as you can.
• Take good care of your teeth and gums while you receive Bildyos. Brush and floss your teeth regularly.
• Tell your dentist that you are receiving Bildyos before you have dental work.

What are the possible side effects of Bildyos? Bildyos may cause serious side effects.

• See “What is the most important information I should know about Bildyos?”
• It is not known if the use of Bildyos over a long period of time may cause slow healing of broken bones.

The most common side effects of Bildyos in women who are being treated for osteoporosis after menopause are:

back pain pain in your arms and legs high cholesterol

muscle pain bladder infection

The most common side effects of Bildyos in men with osteoporosis are:

back pain joint pain

common cold (runny nose or sore throat)

The most common side effects of Bildyos in patients with glucocorticoid-induced osteoporosis are:

back pain high blood pressure

lung infection (bronchitis) headache

The most common side effects of Bildyos in patients receiving certain treatments for prostate or breast cancer are:

joint pain back pain

pain in your arms and legs muscle pain

Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of Bildyos.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Bildyos if I need to pick it up from a pharmacy?

• Keep Bildyos in a refrigerator at 36°F to 46°F (2°C to 8°C) in the original
• Do not freeze
• When you remove Bildyos from the refrigerator, Bildyos must be kept at room temperature [up to 77°F (25°C)] in the original carton and must be used within 30
• Do not keep Bildyos at temperatures above 77°F (25°C). Warm temperatures will affect how Bildyos works.
• Do not shake
• Keep Bildyos in the original carton to protect from

Keep Bildyos and all medicines out of the reach of children.

General information about the safe and effective use of Bildyos.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Bildyos for a condition for which it was not prescribed. Do not give Bildyos to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about Bildyos that is written for healthcare providers.

What are the ingredients in Bildyos? Active ingredient: denosumab-nxxp

Inactive ingredients: glacial acetic acid, polysorbate 20, sodium hydroxide, sorbitol, Water for Injection (USP).

Manufactured by:
Shanghai Henlius Biotech, Inc.
Room 901, 9th Floor, Building 1, No. 367 Shengrong Road, China (Shanghai) Pilot Free Trade Zone.
U.S. License No. XXXX

Manufactured for:
Organon LLC, a subsidiary of  
ORGANON & Co.,
Jersey City, NJ 07302, USA.
For more information, go to www. Bildyos.com or call Organon LLC. at 1-844-674-3200.

This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: 08/2025