Denosumab-BMWO
Injection · Subcutaneous
Uses
Denosumab-bmwo is a RANK ligand (RANKL) inhibitor indicated for treatment: of postmenopausal women with osteoporosis at high risk for fracture ( 1.1 ) to increase bone mass in men with osteoporosis at high risk for fracture ( 1.2 ) of glucocorticoid-induced osteoporosis in men and women at high risk for fracture ( 1.3 ) to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer ( 1.4 ) to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer ( 1.5 ) 1.1 Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture Denosumab-bmwo 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, denosumab reduces the incidence of vertebral, nonvertebral, and hip fractures [see Clinical Studies (14.1) ] . 1.2 Treatment to Increase Bone Mass in Men with Osteoporosis Denosumab-bmwo 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 [see Clinical Studies (14.2) ] . 1.3 Treatment of Glucocorticoid-Induced Osteoporosis Denosumab-bmwo 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 [see Clinical Studies (14.3) ] . 1.4 Treatment of Bone Loss in Men Receiving Androgen Deprivation Therapy for Prostate Cancer Denosumab-bmwo 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 also reduced the incidence of vertebral fractures [see Clinical Studies (14.4) ] . 1.5 Treatment of Bone Loss in Women Receiving Adjuvant Aromatase Inhibitor Therapy for Breast Cancer Denosumab-bmwo is indicated as a treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer [see Clinical Studies (14.5) ] .
Dosage and administration
Pregnancy must be ruled out prior to administration of Denosumab-bmwo. ( 2.1 ) Before initiating Denosumab-bmwo in patients with advanced chronic kidney disease, including dialysis patients, evaluate for the presence of chronic kidney disease mineral and bone disorder with intact parathyroid hormone, serum calcium, 25(OH) vitamin D, and 1,25(OH) 2 vitamin D. ( 2.2 , 5.1 , 8.6 ) Denosumab-bmwo should be administered by a healthcare provider. ( 2.3 ) Administer 60 mg every 6 months as a subcutaneous injection in the upper arm, upper thigh, or abdomen. ( 2.3 ) Instruct patients to take calcium 1000 mg daily and at least 400 IU vitamin D daily. ( 2.3 ) 2.1 Pregnancy Testing Prior to Initiation of Denosumab-bmwo Pregnancy must be ruled out prior to administration of Denosumab-bmwo. Perform pregnancy testing in all females of reproductive potential prior to administration of Denosumab-bmwo. Based on findings in animals, denosumab products can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1 , 8.3 )] . 2.2 Laboratory Testing in Patients with Advanced Chronic Kidney Disease Prior to Initiation of Denosumab-bmwo In patients with advanced chronic kidney disease [i.e., estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m 2 ], including dialysis-dependent patients, evaluate for the presence of chronic kidney disease mineral and bone disorder (CKD-MBD) with intact parathyroid hormone (iPTH), serum calcium, 25(OH) vitamin D, and 1,25 (OH) 2 vitamin D prior to decisions regarding Denosumab-bmwo treatment. Consider also assessing bone turnover status (serum markers of bone turnover or bone biopsy) to evaluate the underlying bone disease that may be present [see Warnings and Precautions (5.1) ] . 2.3 Recommended Dosage Denosumab-bmwo should be administered by a healthcare provider. The recommended dose of Denosumab-bmwo is 60 mg administered as a single subcutaneous injection once every 6 months. Administer Denosumab-bmwo via subcutaneous injection in the upper arm, the upper thigh, or the abdomen. All patients should receive calcium 1000 mg daily and at least 400 IU vitamin D daily [see Warnings and Precautions (5.1) ] . If a dose of Denosumab-bmwo is missed, administer the injection as soon as the patient is available. Thereafter, schedule injections every 6 months from the date of the last injection. 2.4 Preparation and Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Denosumab-bmwo is a clear, colorless to pale yellow solution. Do not use if the solution is discolored or cloudy or if the solution contains particles or foreign particulate matter. Prior to administration, Denosumab-bmwo may be removed from the refrigerator and brought to room temperature up to 25°C (77°F) by standing in the original carton. This generally takes 15 to 30 minutes. Do not warm Denosumab-bmwo in any other way [see How Supplied/Storage and Handling (16) ] . Instructions for Administration of Prefilled Syringe with Safety Guard IMPORTANT: To reduce the risk of accidental needle stick injury, each prefilled syringe has a safety guard that is automatically activated to cover the needle after you have given the injection. Do not pull back on the plunger rod at any time. Step 1: Remove the Needle Cap Dispose of the needle cap right away in the nearest sharps disposal container. DO NOT re-cap the prefilled syringe. Image Image Step 2: Administer Subcutaneous Injection Choose an appropriate injection site. The recommended injection sites for Denosumab-bmwo include: the outer area of the upper arms OR the upper legs (thighs) OR around the stomach area (abdomen). Inject all of the liquid by using your thumb to push the plunger rod all the way down. If the plunger rod is not fully pressed, the safety guard will not extend to cover the needle when it is removed. Image Image Step 3: Remove the prefilled syringe from the injection site After the prefilled syringe is empty, slowly remove the needle by lifting your thumb from the plunger rod until the needle is completely covered by the safety guard. Do not rub the injection site. Immediately dispose of the prefilled syringe in the nearest sharps disposal container. Image
Dosage forms and strengths
Injection: 60 mg/mL of clear, colorless to pale yellow solution in a single-dose prefilled syringe. Injection: 60 mg/mL solution in a single-dose prefilled syringe ( 3 )
Contraindications
Denosumab-bmwo is contraindicated in: Patients with hypocalcemia: Pre-existing hypocalcemia must be corrected prior to initiating therapy with Denosumab-bmwo [see Warnings and Precautions (5.1) ] . Pregnant women: Denosumab products 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 Denosumab-bmwo [see Use in Specific Populations (8.1) ] . Patients with hypersensitivity to denosumab products: Denosumab-bmwo is contraindicated in patients with a history of systemic hypersensitivity to any component of the product. Reactions have included anaphylaxis, facial swelling, and urticaria [see Warnings and Precautions (5.3) , Adverse Reactions (6.2) ] . Hypocalcemia ( 4 , 5.1 ) Pregnancy ( 4 , 8.1 ) Known hypersensitivity to denosumab products ( 4 , 5.3 )
Warnings and precautions
Hypocalcemia: Pre-existing hypocalcemia must be corrected before initiating Denosumab-bmwo. May worsen, especially in patients with renal impairment. Adequately supplement all patients with calcium and vitamin D. Concomitant use of calcimimetic drugs may also worsen hypocalcemia risk. Evaluate for presence of chronic kidney disease mineral-bone disorder. Monitor serum calcium. ( 5.1 ) Same Active Ingredient: Patients receiving Denosumab-bmwo should not receive other denosumab products concomitantly. ( 5.2 ) Hypersensitivity including anaphylactic reactions may occur. Discontinue permanently if a clinically significant reaction occurs. ( 5.3 ) Osteonecrosis of the jaw: Has been reported with denosumab products. Monitor for symptoms. ( 5.4 ) Atypical femoral fractures: Have been reported. Evaluate patients with thigh or groin pain to rule out a femoral fracture. ( 5.5 ) Multiple vertebral fractures have been reported following treatment discontinuation. Patients should be transitioned to another antiresorptive agent if Denosumab-bmwo is discontinued. ( 5.6 ) Serious infections including skin infections: May occur, including those leading to hospitalization. Advise patients to seek prompt medical attention if they develop signs or symptoms of infection, including cellulitis. ( 5.7 ) Dermatologic reactions: Dermatitis, rashes, and eczema have been reported. Consider discontinuing Denosumab-bmwo if severe symptoms develop. ( 5.8 ) Severe bone, joint, muscle pain may occur. Discontinue use if severe symptoms develop. ( 5.9 ) Suppression of bone turnover: Significant suppression has been demonstrated. Monitor for consequences of bone over-suppression. ( 5.10 ) 5.1 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 Denosumab-bmwo. Adequately supplement all patients with calcium and vitamin D [see Dosage and Administration (2.1) , Contraindications (4) , and Adverse Reactions (6.1) ] . In patients without advanced chronic kidney disease who are predisposed to hypocalcemia and disturbances of mineral metabolism (e.g. history of hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, excision of small intestine, treatment with other calcium-lowering drugs), assess serum calcium and mineral levels (phosphorus and magnesium) 10 to 14 days after Denosumab-bmwo injection. In some postmarketing cases, hypocalcemia persisted for weeks or months and required frequent monitoring and intravenous and/or oral calcium replacement, with or without vitamin D. Patients with Advanced Chronic Kidney Disease Patients with advanced chronic kidney disease [i.e., eGFR <30 mL/min/1.73 m 2 ] including dialysis-dependent patients are at greater risk for severe hypocalcemia following denosumab products administration. Severe hypocalcemia resulting in hospitalization, life-threatening events and fatal cases have been reported. The presence of underlying chronic kidney disease-mineral bone disorder (CKD-MBD, renal osteodystrophy) markedly increases the risk of hypocalcemia. Concomitant use of calcimimetic drugs may also worsen hypocalcemia risk. To minimize the risk of hypocalcemia in patients with advanced chronic kidney disease, evaluate for the presence of chronic kidney disease mineral and bone disorder with intact parathyroid hormone (iPTH), serum calcium, 25(OH) vitamin D, and 1,25(OH) 2 vitamin D prior to decisions regarding Denosumab-bmwo treatment. Consider also assessing bone turnover status (serum markers of bone turnover or bone biopsy) to evaluate the underlying bone disease that may be present. Monitor serum calcium weekly for the first month after Denosumab-bmwo administration and monthly thereafter. Instruct all 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. Treatment with Denosumab-bmwo in these patients should be supervised by a healthcare provider who is experienced in diagnosis and management of CKD-MBD. 5.2 Drug Products with Same Active Ingredient Patients receiving Denosumab-bmwo should not receive other denosumab products concomitantly. 5.3 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 Denosumab-bmwo [see Contraindications (4) , Adverse Reactions (6.2) ] . 5.4 Osteonecrosis of the Jaw Osteonecrosis of the jaw (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 [see Adverse Reactions (6.1) ] . A routine oral exam should be performed by the prescriber prior to initiation of Denosumab-bmwo treatment. A dental examination with appropriate preventive dentistry is recommended prior to treatment with Denosumab-bmwo in patients with risk factors for ONJ such as invasive dental procedures (e.g. tooth extraction, dental implants, oral surgery), diagnosis of cancer, concomitant therapies (e.g. chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and comorbid disorders (e.g. periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures). Good oral hygiene practices should be maintained during treatment with Denosumab-bmwo. 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.
Side effects
The following serious adverse reactions are discussed below and also elsewhere in the labeling: Severe Hypocalcemia and Mineral Metabolism Changes [see Warnings and Precautions (5.1) ] Hypersensitivity [see Warnings and Precautions (5.3) ] Osteonecrosis of the Jaw [see Warnings and Precautions (5.4) ] Atypical Subtrochanteric and Diaphyseal Femoral Fractures [see Warnings and Precautions (5.5) ] Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation [see Warnings and Precautions (5.6) ] Serious Infections [see Warnings and Precautions (5.7) ] Dermatologic Adverse Reactions [see Warnings and Precautions (5.8) ] The most common adverse reactions reported with denosumab products in patients with postmenopausal osteoporosis are back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis. The most common adverse reactions reported with denosumab products in men with osteoporosis are back pain, arthralgia, and nasopharyngitis. The most common adverse reactions 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. Postmenopausal osteoporosis: Most common adverse reactions (> 5% and more common than placebo) were: back pain, pain in extremity, hypercholesterolemia, musculoskeletal pain, and cystitis. Pancreatitis has been reported in clinical trials. ( 6.1 ) Male osteoporosis: Most common adverse reactions (> 5% and more common than placebo) were: back pain, arthralgia, and nasopharyngitis. ( 6.1 ) Glucocorticoid-induced osteoporosis: Most common adverse reactions (> 3% and more common than active-control group) were: back pain, hypertension, bronchitis, and headache. ( 6.1 ) Bone loss due to hormone ablation for cancer: Most common adverse reactions (≥ 10% and more common than placebo) were: arthralgia and back pain. Pain in extremity and musculoskeletal pain have also been reported in clinical trials. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact CELLTRION USA, Inc. at 1-800-560-9414 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in clinical practice. Treatment of Postmenopausal Women with Osteoporosis The safety of denosumab in the treatment of postmenopausal osteoporosis was assessed in a 3-year, randomized, double-blind, placebo-controlled, multinational study of 7808 postmenopausal women aged 60 to 91 years. A total of 3876 women were exposed to placebo and 3886 women were exposed to denosumab administered subcutaneously once every 6 months as a single 60 mg dose. All women were instructed to take at least 1000 mg of calcium and 400 IU of vitamin D supplementation per day. The incidence of all-cause mortality was 2.3% (n = 90) in the placebo group and 1.8% (n = 70) in the denosumab group. The incidence of nonfatal serious adverse events was 24.2% in the placebo group and 25.0% in the denosumab group. The percentage of patients who withdrew from the study due to adverse events was 2.1% and 2.4% for the placebo and denosumab groups, respectively. The most common adverse reactions reported with denosumab in patients with postmenopausal osteoporosis are back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis. Adverse reactions reported in ≥ 2% of postmenopausal women with osteoporosis and more frequently in the denosumab-treated women than in the placebo-treated women are shown in the table below. Table 1. Adverse Reactions Occurring in ≥ 2% of Patients with Osteoporosis and More Frequently than in Placebo-treated Patients Preferred Term Denosumab (N = 3886) n (%) Placebo (N = 3876) n (%) Back pain 1347 (34.7) 1340 (34.6) Pain in extremity 453 (11.7) 430 (11.1) Musculoskeletal pain 297 (7.6) 291 (7.5) Hypercholesterolemia 280 (7.2) 236 (6.1) Cystitis 228 (5.9) 225 (5.8) Vertigo 195 (5.0) 187 (4.8) Upper respiratory tract infection 190 (4.9) 167 (4.3) Edema peripheral 189 (4.9) 155 (4.0) Sciatica 178 (4.6) 149 (3.8) Bone pain 142 (3.7) 117 (3.0) Abdominal pain upper 129 (3.3) 111 (2.9) Anemia 129 (3.3) 107 (2.8) Insomnia 126 (3.2) 122 (3.1) Myalgia 114 (2.9) 94 (2.4) Angina pectoris 101 (2.6) 87 (2.2) Rash 96 (2.5) 79 (2.0) Pharyngitis 91 (2.3) 78 (2.0) Asthenia 90 (2.3) 73 (1.9) Pruritus 87 (2.2) 82 (2.1) Flatulence 84 (2.2) 53 (1.4) Spinal osteoarthritis 82 (2.1) 64 (1.7) Gastroesophageal reflux disease 80 (2.1) 66 (1.7) Herpes zoster 79 (2.0) 72 (1.9) Hypocalcemia Decreases in serum calcium levels to less than 8.5 mg/dL at any visit were reported in 0.4% women in the placebo group and 1.7% women in the denosumab group. The nadir in serum calcium level occurred at approximately day 10 after denosumab dosing in subjects with normal renal function. In clinical studies, subjects with impaired renal function were more likely to have greater reductions in serum calcium levels compared to subjects with normal renal function. In a study of 55 subjects with varying degrees of renal function, serum calcium levels < 7.5 mg/dL or symptomatic hypocalcemia were observed in 5 subjects.
Use in specific populations
Pregnant women and females of reproductive potential: Denosumab products may cause fetal harm when administered to pregnant women. Advise females of reproductive potential to use effective contraception during therapy, and for at least 5 months after the last dose of Denosumab-bmwo. ( 8.1 , 8 3 ) Pediatric patients: Denosumab-bmwo is not approved for use in pediatric patients. ( 8.4 ) Renal impairment: No dose adjustment is necessary in patients with renal impairment. Patients with advanced chronic kidney disease (eGFR < 30 mL/min/1.73 m 2 ), including dialysis-dependent patients, are at greater risk of severe hypocalcemia. The presence of underlying chronic kidney disease-mineral bone disorder markedly increases the risk of hypocalcemia. ( 5.1 , 8.6 ) 8.1 Pregnancy Risk Summary Denosumab-bmwo is contraindicated for use in pregnant women because it may cause harm to a fetus. 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 50-fold higher than the recommended human dose 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 ] . 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 50-fold higher than the recommended human dose 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 1 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 (8.2) , Nonclinical Toxicology (13.2) ] . The no effect dose for denosumab product-induced teratogenicity is unknown. However, a C max of 22.9 ng/mL was identified in cynomolgus monkeys as a level in which no biologic effects (NOEL) of denosumab were observed (no inhibition of RANKL) [see Clinical Pharmacology (12.3) ] . 8.2 Lactation Risk Summary There is no information regarding the presence of denosumab products in human milk, the effects on the breastfed infant, 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) , Nonclinical Toxicology (13.2) ] . 8.3 Females and Males of Reproductive Potential Based on findings in animals, 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 Denosumab-bmwo 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 Denosumab-bmwo. Males Denosumab was present at low concentrations (approximately 2% of serum exposure) in the seminal fluid of male subjects given denosumab. Following vaginal intercourse, the maximum amount of denosumab delivered to a female partner would result in exposures approximately 11000 times lower than the prescribed 60 mg subcutaneous dose, and at least 38 times lower than the NOEL in monkeys. Therefore, male condom use would not be necessary as it is unlikely that a female partner or fetus would be exposed to pharmacologically relevant concentrations of denosumab products via seminal fluid [see Clinical Pharmacology (12.3) ] . 8.4 Pediatric Use The safety and effectiveness of Denosumab-bmwo have not been established in pediatric patients. In one multicenter, open-label study with denosumab conducted in 153 pediatric patients with osteogenesis imperfecta, aged 2 to 17 years, evaluating fracture risk reduction, efficacy was not demonstrated. Hypercalcemia has been reported in pediatric patients with osteogenesis imperfecta treated with denosumab products.
Pregnancy
8.1 Pregnancy Risk Summary Denosumab-bmwo is contraindicated for use in pregnant women because it may cause harm to a fetus. 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 50-fold higher than the recommended human dose 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 ] . 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 50-fold higher than the recommended human dose 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 1 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 (8.2) , Nonclinical Toxicology (13.2) ] . The no effect dose for denosumab product-induced teratogenicity is unknown. However, a C max of 22.9 ng/mL was identified in cynomolgus monkeys as a level in which no biologic effects (NOEL) of denosumab were observed (no inhibition of RANKL) [see Clinical Pharmacology (12.3) ] .
Pediatric use
8.4 Pediatric Use The safety and effectiveness of Denosumab-bmwo have not been established in pediatric patients. In one multicenter, open-label study with denosumab conducted in 153 pediatric patients with osteogenesis imperfecta, aged 2 to 17 years, evaluating fracture risk reduction, efficacy was not demonstrated. Hypercalcemia has been reported in pediatric patients with osteogenesis imperfecta treated with denosumab products. Some cases required hospitalization and were complicated by acute renal injury [see Warnings and Precautions (5.11) ]. Clinical studies in pediatric patients with osteogenesis imperfecta were terminated early due to the occurrence of life-threatening events and hospitalizations due to hypercalcemia. Safety and effectiveness were not demonstrated for the treatment of glucocorticoid-induced osteoporosis in one multicenter, randomized, double-blind, placebo-controlled, parallel-group study conducted in 24 pediatric patients with glucocorticoid-induced osteoporosis, aged 5 to 17 years, evaluating change from baseline in lumbar spine BMD Z-score. Based on results from animal studies, denosumab may negatively affect long-bone growth and dentition in pediatric patients below the age of 4 years. Juvenile Animal Toxicity Data Treatment with denosumab products may impair long-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 10 and 50 times (10 and 50 mg/kg dose) higher than the recommended human dose of 60 mg administered every 6 months, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab [see Nonclinical Toxicology (13.2) ]. Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes, reduced hematopoiesis, tooth malalignment, and decreased neonatal growth. 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) ] .
Geriatric use
8.5 Geriatric Use Of the total number of patients in clinical studies of denosumab, 9943 patients (76%) were ≥ 65 years old, while 3576 (27%) were ≥ 75 years old. Of the patients in the osteoporosis study in men, 133 patients (55%) were ≥ 65 years old, while 39 patients (16%) were ≥ 75 years old. Of the patients in the glucocorticoid-induced osteoporosis study, 355 patients (47%) were ≥ 65 years old, while 132 patients (17%) were ≥ 75 years old. No overall differences in safety or efficacy were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Description
Denosumab-bmwo is a human IgG2 monoclonal antibody with affinity and specificity for human RANKL (receptor activator of nuclear factor kappa-B ligand). Denosumab-bmwo has an approximate molecular weight of 147 kDa and is produced in genetically engineered mammalian (Chinese hamster ovary) cells. Denosumab-bmwo injection is a sterile, preservative-free, clear, colorless to pale yellow solution for subcutaneous use. Each single-dose prefilled syringe contains 60 mg denosumab-bmwo, 0.26 mg acetic acid, 0.1 mg polysorbate 20, 1.05 mg sodium acetate, 47 mg sorbitol, and Water for Injection. The pH is 5.2.
Mechanism of action
12.1 Mechanism of Action Denosumab products bind to RANKL, a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. 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.
How supplied
How Supplied Denosumab-bmwo injection is a clear, colorless to pale yellow solution supplied in a single-dose prefilled syringe with a safety guard. The prefilled syringe is not made with natural rubber latex. 60 mg/mL in a single-dose prefilled syringe 1 per carton NDC 72606-058-01 Storage and Handling Store Denosumab-bmwo refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Prior to administration, Denosumab-bmwo may be allowed to reach room temperature up to 25°C (77°F) in the original carton. Denosumab-bmwo may be stored at temperatures up to a maximum 25°C (77°F) for a single period of up to 63 days but not exceeding the original expiry date. If necessary, the product may be returned to the refrigerator once within 63 days and provided this does not exceed the original expiry date. It must be used after subsequent removal from refrigeration. Discard Denosumab-bmwo if not used or returned to refrigerator within the 63 days. Do not use Denosumab-bmwo after the expiry date printed on the label. Protect Denosumab-bmwo from direct light and heat. Avoid vigorous shaking of Denosumab-bmwo.
Storage
Storage and Handling Store Denosumab-bmwo refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Prior to administration, Denosumab-bmwo may be allowed to reach room temperature up to 25°C (77°F) in the original carton. Denosumab-bmwo may be stored at temperatures up to a maximum 25°C (77°F) for a single period of up to 63 days but not exceeding the original expiry date. If necessary, the product may be returned to the refrigerator once within 63 days and provided this does not exceed the original expiry date. It must be used after subsequent removal from refrigeration. Discard Denosumab-bmwo if not used or returned to refrigerator within the 63 days. Do not use Denosumab-bmwo after the expiry date printed on the label. Protect Denosumab-bmwo from direct light and heat. Avoid vigorous shaking of Denosumab-bmwo.
Patient information
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 Denosumab-bmwo [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 Denosumab-bmwo 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 Denosumab-bmwo, 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 Denosumab-bmwo and to inform their dentist prior to dental procedures that they are receiving Denosumab-bmwo. 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 Denosumab-bmwo 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 Denosumab-bmwo. Advise the patient to contact their physician immediately if pregnancy does occur during these times. Advise patients not to take Denosumab-bmwo 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 Denosumab-bmwo is missed, the injection should be administered as soon as convenient. Thereafter, schedule injections every 6 months from the date of the last injection.
Label text from the FDA structured product label by CELLTRION USA, Inc. (revised Feb 5, 2026). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Denosumab in 2 products
Denosumab-BMWO NDC products (2)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 72606-058 | Denosumab 60 mg/mL Injection | CELLTRION USA, Inc. | BLA |
| 72606-059 | Denosumab 120 mg/1.7mL Injection | CELLTRION USA, Inc. | BLA |
Frequently asked questions
What is Denosumab-BMWO used for?
Denosumab-bmwo is a RANK ligand (RANKL) inhibitor indicated for treatment: of postmenopausal women with osteoporosis at high risk for fracture ( 1.1 ) to increase bone mass in men with osteoporosis at high risk for fracture ( 1.2 ) of glucocorticoid-induced osteoporosis in men and women at high risk for fracture ( 1.3 ) to increase bone mass in men at high risk for fracture receiving androgen…
What are the side effects of Denosumab-BMWO?
The following serious adverse reactions are discussed below and also elsewhere in the labeling: Severe Hypocalcemia and Mineral Metabolism Changes [see Warnings and Precautions (5.1) ] Hypersensitivity [see Warnings and Precautions (5.3) ] Osteonecrosis of the Jaw [see Warnings and Precautions (5.4) ] Atypical Subtrochanteric and Diaphyseal Femoral Fractures [see Warnings and Precautions (5.5) ]… See the full label for the complete list.
Who makes Denosumab-BMWO?
Denosumab-BMWO is listed by 1 labeler in the FDA NDC directory, including CELLTRION USA, Inc..