BILDYOS is a RANK ligand (RANKL) inhibitor indicated for/to:

• Postmenopausal Women with Osteoporosis at High Risk for Fracture: BILDYOS is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy. In postmenopausal women with osteoporosis, BILDYOS reduces the incidence of vertebral, nonvertebral, and hip fractures.

• Increase Bone Mass in Men with Osteoporosis: BILDYOS is indicated for treatment to increase bone mass in men with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy.

• Glucocorticoid-Induced Osteoporosis: BILDYOS is indicated for the treatment of glucocorticoid-induced osteoporosis in men and women at high risk of fracture who are either initiating or continuing systemic glucocorticoids in a daily dosage equivalent to 7.5 mg or greater of prednisone and expected to remain on glucocorticoids for at least 6 months. High risk of fracture is defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis therapy.

• Bone Loss in Men Receiving Androgen Deprivation Therapy for Prostate Cancer: BILDYOS is indicated as a treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy (ADT) for nonmetastatic prostate cancer. In these patients, denosumab products also reduced the incidence of vertebral fractures.

• Bone Loss in Women Receiving Adjuvant Aromatase Inhibitor Therapy for Breast Cancer: BILDYOS is indicated as a treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer.

SELECTED SAFETY INFORMATION

SEVERE HYPOCALCEMIA IN PATIENTS WITH ADVANCED KIDNEY DISEASE
Patients with advanced chronic kidney disease (eGFR <30mL/min/1.73m2), including dialysis dependent patients, are at greater risk of severe hypocalcemia following denosumab products administration. Severe hypocalcemia resulting in hospitalization, life-threatening events, and fatal cases have been reported.

The presence of chronic kidney disease-mineral bone disorder (CKD-MBD) markedly increases the risk of hypocalcemia in these patients.

Prior to initiating BILDYOS in patients with advanced chronic kidney disease, evaluate for the presence of CKD-MBD. Treatment with BILDYOS in these patients should be supervised by a health care provider with expertise in the diagnosis and management of CKD-MBD.

CONTRAINDICATIONS

BILDYOS is contraindicated in patients with hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating BILDYOS. BILDYOS is contraindicated in women who are pregnant and may cause fetal harm when administered to a pregnant woman. In women of reproductive potential, pregnancy testing should be performed prior to initiating treatment with BILDYOS. BILDYOS is contraindicated in patients with a history of systemic hypersensitivity to any component of the product. Reactions have included anaphylaxis, facial swelling, and urticaria.

WARNINGS AND PRECAUTIONS

Severe Hypocalcemia and Mineral Metabolism Changes
 Denosumab products can cause severe hypocalcemia and fatal cases have been reported. Pre-existing hypocalcemia must be corrected prior to initiating therapy with BILDYOS. Adequately supplement all patients with calcium and vitamin D.

In patients without advanced chronic kidney disease who are predisposed to hypocalcemia and disturbances of mineral metabolism (eg, treatment with other calcium lowering drugs), assess serum calcium and mineral levels (phosphorus and magnesium) 10 to 14 days after BILYDOS injection.

Drug Products with Same Active Ingredient
 The active ingredient in BILDYOS is denosumab. Patients receiving BILDYOS should not receive other denosumab products concomitantly.

Hypersensitivity
 Clinically significant hypersensitivity, including anaphylaxis, has been reported with denosumab products. Symptoms have included hypotension, dyspnea, throat tightness, facial and upper airway edema, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue further use of BILDYOS.

Osteonecrosis of the Jaw (ONJ)
 ONJ, which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing. ONJ has been reported in patients receiving denosumab products. A routine oral exam should be performed by the prescriber prior to initiation of BILDYOS. A dental examination with appropriate preventive dentistry is recommended prior to treatment in patients with risk factors for ONJ such as invasive dental procedures (eg, tooth extraction, dental implants, oral surgery), diagnosis of cancer, concomitant therapies (eg, chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders (eg, periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). Good oral hygiene practices should be maintained during treatment with BILDYOS. Concomitant administration of drugs associated with ONJ may increase the risk of developing ONJ. The risk of ONJ may increase with duration of exposure to denosumab products.

For patients requiring invasive dental procedures, clinical judgment of the treating physician and/or oral surgeon should guide the management plan of each patient based on individual benefit-risk assessment.

Patients who are suspected of having or who develop ONJ while on BILDYOS should receive care by a dentist or an oral surgeon. Extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of BILDYOS should be considered based on individual benefit-risk assessment.

Atypical Subtrochanteric and Diaphyseal Femoral Fractures
 Atypical low-energy, or low trauma fractures of the shaft have been reported in patients receiving denosumab products. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with antiresorptive agents.

During BILDYOS 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. Interruption of BILDYOS therapy should be considered, pending a benefit-risk assessment, on an individual basis.

Multiple Vertebral Fractures (MVF) Following Discontinuation of Treatment
 Following discontinuation of denosumab treatment, fracture risk increases, including the risk of multiple vertebral fractures. New vertebral fractures occurred as early as 7 months (on average 19 months) after the last dose of denosumab. Prior vertebral fracture was a predictor of multiple vertebral fractures after denosumab product discontinuation. Evaluate an individual’s benefit-risk before initiating treatment. If BILDYOS treatment is discontinued, patients should be transitioned to an alternative antiresorptive therapy.

Serious Infections
 In a clinical trial of over 7800 women with postmenopausal osteoporosis, serious infections leading to hospitalization were reported more frequently in the denosumab group than in the placebo group. Serious skin infections, as well as infections of the abdomen, urinary tract, and ear, were more frequent in patients treated with denosumab products. Endocarditis was also reported more frequently in denosumab-treated patients. The incidence of opportunistic infections and the overall incidence of infections were similar between the treatment groups. Advise patients to seek prompt medical attention if they develop signs or symptoms of severe infection, including cellulitis.

Patients on concomitant immunosuppressant agents or with impaired immune systems may be at increased risk for serious infections. Consider the benefit-risk profile in such patients before treating with BILDYOS. In patients who develop serious infections while on BILDYOS, prescribers should assess the need for continued BILDYOS therapy.

Dermatologic Adverse Reactions
 In a clinical trial of over 7800 women with postmenopausal osteoporosis, epidermal and dermal adverse events such as dermatitis, eczema, and rashes occurred at a significantly higher rate with denosumab treatment compared to placebo. Most of these events were not specific to the injection site. Consider discontinuing BILDYOS if severe symptoms develop.

Musculoskeletal Pain
 In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients during denosumab treatment. Onset of symptoms varied from one day to several months after starting denosumab products. Consider discontinuing use if severe symptoms develop.

Suppression of Bone Turnover
 In clinical trials in women with postmenopausal osteoporosis, treatment with denosumab resulted in significant suppression of bone remodeling as evidenced by markers of bone turnover and bone histomorphometry. The significance of these findings and the effect of long-term treatment with denosumab products are unknown. Monitor patients for consequences, including ONJ, atypical fractures, and delayed fracture healing.

Hypercalcemia in Pediatric Patients with Osteogenesis Imperfecta
 BILDYOS is not approved for use in pediatric patients. Hypercalcemia has been reported in pediatric patients with osteogenesis imperfecta treated with denosumab products.

ADVERSE REACTIONS

The most common adverse reactions (>5% and more common than placebo) reported with denosumab products in women with postmenopausal osteoporosis are back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis.

The most common adverse reactions (>5% and more common than placebo) reported with denosumab products in men with osteoporosis are back pain, arthralgia, and nasopharyngitis. Pancreatitis has been reported with denosumab products.

The most common adverse reactions (>3% and more common than active-control group) reported with denosumab products in patients with glucocorticoid-induced osteoporosis are back pain, hypertension, bronchitis, and headache.

The most common (per patient incidence ≥10%) adverse  reactions reported with denosumab products in patients with bone loss  receiving androgen deprivation therapy for prostate cancer or adjuvant  aromatase inhibitor therapy for breast cancer are arthralgia and back pain.  Pain in extremity and musculoskeletal pain have also been reported in clinical  trials.

The most common adverse reactions leading to discontinuation of denosumab products in patients with postmenopausal osteoporosis are back pain and constipation.

Denosumab is a human monoclonal antibody. As with all therapeutic proteins, there is potential for immunogenicity.

Before prescribing BILDYOS, please read the Prescribing Information (https://www.organon.com/product/usa/pi_circulars/b/bildyos/bildyos_pi.pdf), including the Boxed Warning about severe hypocalcemia. The Medication Guide (https://www.organon.com/product/usa/pi_circulars/b/bildyos/bildyos_mg.pdf) also is available.

Please note, BILDYOS is part of the Risk Evaluation and Mitigation Strategy (REMS) program.

BILPREVDA is a RANK ligand (RANKL) inhibitor indicated for:

• 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.

• 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.

• Hypercalcemia of Malignancy: BILPREVDA is indicated for the treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.

SELECTED SAFETY INFORMATION

CONTRAINDICATIONS

Pre-existing hypocalcemia must be corrected prior to initiating therapy with BILPREVDA. BILPREVDA is contraindicated in patients with known clinically significant hypersensitivity to denosumab products.

WARNINGS AND PRECAUTIONS

Drug Products with Same Active Ingredient
 Patients receiving BILPREVDA should not receive other denosumab products concomitantly.

Hypocalcemia
 Denosumab products can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Pre-existing hypocalcemia must be corrected prior to initiating BILPREVDA. Monitor calcium levels throughout 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 health care 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.

Hypersensitivity
 BILPREVDA is contraindicated in patients with known clinically significant hypersensitivity to denosumab products, including anaphylaxis. 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.

Osteonecrosis of the Jaw (ONJ)
 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.

A history of tooth extraction, poor oral hygiene, or use of a dental appliance may be predisposing factors to developing ONJ. Other risk factors for the development of ONJ include immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroids, diabetes, and gingival infections.

Perform an oral examination and appropriate preventive dentistry prior to the initiation of BILPREVDA and periodically during therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with BILPREVDA. Consider temporarily interrupting therapy if an invasive dental procedure must be performed.

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.

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 (eg, 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. Patients 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 (GCTB) and in Patients with Growing Skeletons

Clinically significant hypercalcemia requiring hospitalization and complicated by acute renal injury has been reported in denosumab-treated patients with GCTB and in 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 patients’ calcium and vitamin D supplementation, and treat appropriately.

Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation
 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.

Embryo-Fetal Toxicity
 Based on data from animal studies and its mechanism of actions, denosumab products can cause fetal harm when administered to a pregnant woman.

Verify the pregnancy status of females of reproductive potential prior to the initiation of BILPREVDA. Advise females of reproductive potential to use effective contraception during therapy, and for at least 5 months after the last dose 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.

ADVERSE REACTIONS

The most common adverse reactions (incidence ≥25%) in patients with bone metastasis from solid tumors were fatigue/asthenia, hypophosphatemia, and nausea. The most common serious adverse reaction was dyspnea. The most common adverse reactions resulting in discontinuation were osteonecrosis and hypocalcemia.

The most common adverse reactions (incidence ≥10%) in patients with multiple myeloma were diarrhea, nausea, anemia, back pain, thrombocytopenia, peripheral edema, hypocalcemia, upper respiratory tract infection, rash, and headache. The most common serious adverse reaction was pneumonia. The most common adverse reaction resulting in discontinuation was osteonecrosis of the jaw.

The most common adverse reactions (incidence ≥10%) in patients with GCTB 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, bone giant cell tumor, anemia, pneumonia, and back pain. The most common adverse reaction resulting in discontinuation was osteonecrosis of the jaw.

The most common adverse reactions (incidence >20%) in patients with hypercalcemia of malignancy were nausea, dyspnea, decreased appetite, headache, peripheral edema, vomiting, anemia, constipation, and diarrhea.

Before prescribing BILPREVDA, please read the Prescribing Information (https://www.organon.com/product/usa/pi_circulars/b/bilprevda/bilprevda_pi.pdf).