Source: FDA, National Drug Code (US) Revision Year: 2024
Jubbonti is contraindicated in:
Denosumab products can cause severe hypocalcemia and fatal cases have been reported. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Jubbonti. 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 Jubbonti 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 [i.e., eGFR < 30 mL/min/1.73 m²] 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 Jubbonti 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 Jubbonti 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 Jubbonti in these patients should be supervised by a healthcare provider who is experienced in diagnosis and management of CKD-MBD.
The active ingredient in Jubbonti is denosumab-bbdz. Patients receiving Jubbonti should not receive other denosumab products concomitantly.
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 Jubbonti [see Contraindications (4), Adverse Reactions (6.2)].
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 Jubbonti treatment. A dental examination with appropriate preventive dentistry is recommended prior to treatment with Jubbonti 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 Jubbonti. 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 Jubbonti should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of Jubbonti therapy should be considered based on individual benefit-risk assessment.
Atypical low energy or low trauma fractures of the shaft have been reported in patients receiving 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. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with antiresorptive agents.
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 Jubbonti 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 Jubbonti therapy should be considered, pending a benefit-risk assessment, on an individual basis.
Following discontinuation of denosumab treatment, fracture risk increases, including the risk of multiple vertebral fractures. Treatment with denosumab results in significant suppression of bone turnover and cessation of denosumab treatment results in increased bone turnover above pretreatment values 9 months after the last dose of denosumab. Bone turnover then returns to pretreatment values 24 months after the last dose of denosumab. In addition, bone mineral density (BMD) returns to pretreatment values within 18 months after the last injection [see Clinical Pharmacology (12.2), Clinical Studies (14.1)].
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 discontinuation. Evaluate an individual’s benefit-risk before initiating treatment with Jubbonti.
If Jubbonti treatment is discontinued, patients should be transitioned to an alternative antiresorptive therapy [see Adverse Reactions (6.1)].
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 [see Adverse Reactions (6.1)]. Serious skin infections, as well as infections of the abdomen, urinary tract, and ear, were more frequent in patients treated with denosumab. Endocarditis was also reported more frequently in denosumabtreated patients. The incidence of opportunistic infections was similar between placebo and denosumab groups, and the overall incidence of infections was 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 Jubbonti. In patients who develop serious infections while on Jubbonti, prescribers should assess the need for continued Jubbonti therapy.
In a large 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 in the denosumab group compared to the placebo group. Most of these events were not specific to the injection site [see Adverse Reactions (6.1)]. Consider discontinuing Jubbonti if severe symptoms develop.
In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking denosumab products [see Adverse Reactions (6.2)]. The time to onset of symptoms varied from one day to several months after starting denosumab products. Consider discontinuing use if severe symptoms develop [see Patient Counseling Information (17)].
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 [see Clinical Pharmacology (12.2), Clinical Studies (14.1)]. The significance of these findings and the effect of long-term treatment with denosumab products are unknown. The long-term consequences of the degree of suppression of bone remodeling observed with denosumab may contribute to adverse outcomes such as osteonecrosis of the jaw, atypical fractures, and delayed fracture healing. Monitor patients for these consequences.
Jubbonti is not approved for use in pediatric patients. Hypercalcemia has been reported in pediatric patients with osteogenesis imperfecta treated with denosumab products. Some cases required hospitalization [see Pediatric Use (8.4)].
The following serious adverse reactions are discussed below and also elsewhere in the labeling:
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.
To report Adverse Reactions with Jubbonti, please call Sandoz Inc. at 1-800-525-8747, or report the event at FDA MedWatch.
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.
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.
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:
| SYSTEM ORGAN CLASS Preferred Term | Denosumab (N = 3886) n (%) | Placebo (N = 3876) n (%) |
|---|---|---|
| BLOOD AND LYMPHATIC SYSTEM DISORDERS | ||
| Anemia | 129 (3.3) | 107 (2.8) |
| CARDIAC DISORDERS | ||
| Angina pectoris | 101 (2.6) | 87 (2.2) |
| Atrial fibrillation | 79 (2.0) | 77 (2.0) |
| EAR AND LABYRINTH DISORDERS | ||
| Vertigo | 195 (5.0) | 187 (4.8) |
| GASTROINTESTINAL DISORDERS | ||
| Abdominal pain upper | 129 (3.3) | 111 (2.9) |
| Flatulence | 84 (2.2) | 53 (1.4) |
| Gastroesophageal reflux disease | 80 (2.1) | 66 (1.7) |
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS | ||
| Edema peripheral | 189 (4.9) | 155 (4.0) |
| Asthenia | 90 (2.3) | 73 (1.9) |
| INFECTIONS AND INFESTATIONS | ||
| Cystitis | 228 (5.9) | 225 (5.8) |
| Upper respiratory tract infection | 190 (4.9) | 167 (4.3) |
| Pneumonia | 152 (3.9) | 150 (3.9) |
| Pharyngitis | 91 (2.3) | 78 (2.0) |
| Herpes zoster | 79 (2.0) | 72 (1.9) |
| METABOLISM AND NUTRITION DISORDERS | ||
| Hypercholesterolemia | 280 (7.2) | 236 (6.1) |
| MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS | ||
| 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) |
| Bone pain | 142 (3.7) | 117 (3.0) |
| Myalgia | 114 (2.9) | 94 (2.4) |
| Spinal osteoarthritis | 82 (2.1) | 64 (1.7) |
| NERVOUS SYSTEM DISORDERS | ||
| Sciatica | 178 (4.6) | 149 (3.8) |
| PSYCHIATRIC DISORDERS | ||
| Insomnia | 126 (3.2) | 122 (3.1) |
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS | ||
| Rash | 96 (2.5) | 79 (2.0) |
| Pruritus | 87 (2.2) | 82 (2.1) |
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 occurs 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. These included no subjects in the normal renal function group, 10% of subjects in the creatinine clearance 50 to 80 mL/min group, 29% of subjects in the creatinine clearance < 30 mL/min group, and 29% of subjects in the hemodialysis group. These subjects did not receive calcium and vitamin D supplementation. In a study of 4550 postmenopausal women with osteoporosis, the mean change from baseline in serum calcium level 10 days after denosumab dosing was -5.5% in subjects with creatinine clearance < 30 mL/min vs. -3.1% in subjects with creatinine clearance ≥ 30 mL/min.
Receptor activator of nuclear factor kappa-B ligand (RANKL) is expressed on activated T and B lymphocytes and in lymph nodes. Therefore, a RANKL inhibitor such as denosumab products may increase the risk of infection.
In the clinical study of 7808 postmenopausal women with osteoporosis, the incidence of infections resulting in death was 0.2% in both placebo and denosumab treatment groups. However, the incidence of nonfatal serious infections was 3.3% in the placebo and 4.0% in the denosumab groups. Hospitalizations due to serious infections in the abdomen (0.7% placebo vs. 0.9% denosumab), urinary tract (0.5% placebo vs. 0.7% denosumab), and ear (0.0% placebo vs. 0.1% denosumab) were reported. Endocarditis was reported in no placebo patients and 3 patients receiving denosumab.
Skin infections, including erysipelas and cellulitis, leading to hospitalization were reported more frequently in patients treated with denosumab (< 0.1% placebo vs. 0.4% denosumab).
The incidence of opportunistic infections was similar to that reported with placebo.
A significantly higher number of patients treated with denosumab developed epidermal and dermal adverse events (such as dermatitis, eczema, and rashes), with these events reported in 8.2% of the placebo and 10.8% of the denosumab groups (p < 0.0001). Most of these events were not specific to the injection site [see Warnings and Precautions (5.8)].
ONJ has been reported in the osteoporosis clinical trial program in patients treated with denosumab [see Warnings and Precautions (5.4)].
In the osteoporosis clinical trial program, atypical femoral fractures were reported in patients treated with denosumab. The duration of denosumab exposure to time of atypical femoral fracture diagnosis was as early as 2½ years [see Warnings and Precautions (5.5)].
In the osteoporosis clinical trial program, multiple vertebral fractures were reported in patients after discontinuation of denosumab. In the phase 3 trial in women with postmenopausal osteoporosis, 6% of women who discontinued denosumab and remained in the study developed new vertebral fractures, and 3% of women who discontinued denosumab and remained in the study developed multiple new vertebral fractures. The mean time to onset of multiple vertebral fractures was 17 months (range: 7-43 months) after the last injection of denosumab. Prior vertebral fracture was a predictor of multiple vertebral fractures after discontinuation [see Warnings and Precautions (5.6)].
Pancreatitis was reported in 4 patients (0.1%) in the placebo and 8 patients (0.2%) in the denosumab groups. Of these reports, 1 patient in the placebo group and all 8 patients in the denosumab group had serious events, including one death in the denosumab group. Several patients had a prior history of pancreatitis. The time from product administration to event occurrence was variable.
The overall incidence of new malignancies was 4.3% in the placebo and 4.8% in the denosumab groups. New malignancies related to the breast (0.7% placebo vs. 0.9% denosumab), reproductive system (0.2% placebo vs. 0.5% denosumab), and gastrointestinal system (0.6% placebo vs. 0.9% denosumab) were reported. A causal relationship to drug exposure has not been established.
The safety of denosumab in the treatment of men with osteoporosis was assessed in a 1-year randomized, double-blind, placebo-controlled study. A total of 120 men were exposed to placebo and 120 men were exposed to denosumab administered subcutaneously once every 6 months as a single 60 mg dose. All men were instructed to take at least 1000 mg of calcium and 800 IU of vitamin D supplementation per day.
The incidence of all-cause mortality was 0.8% (n = 1) in the placebo group and 0.8% (n = 1) in the denosumab group. The incidence of nonfatal serious adverse events was 7.5% in the placebo group and 8.3% in the denosumab group. The percentage of patients who withdrew from the study due to adverse events was 0% and 2.5% for the placebo and denosumab groups, respectively.
Adverse reactions reported in ≥ 5% of men with osteoporosis and more frequently with denosumab than in the placebo-treated patients were: back pain (6.7% placebo vs. 8.3% denosumab), arthralgia (5.8% placebo vs. 6.7% denosumab), and nasopharyngitis (5.8% placebo vs. 6.7% denosumab).
Serious infection was reported in 1 patient (0.8%) in the placebo group and no patients in the denosumab group.
Epidermal and dermal adverse events (such as dermatitis, eczema, and rashes) were reported in 4 patients (3.3%) in the placebo group and 5 patients (4.2%) in the denosumab group
No cases of ONJ were reported.
Pancreatitis was reported in 1 patient (0.8%) in the placebo group and 1 patient (0.8%) in the denosumab group.
New malignancies were reported in no patients in the placebo group and 4 (3.3%) patients (3 prostate cancers, 1 basal cell carcinoma) in the denosumab group.
The safety of denosumab in the treatment of glucocorticoid-induced osteoporosis was assessed in the 1-year, primary analysis of a 2-year randomized, multicenter, double-blind, parallel-group, active-controlled study of 795 patients (30% men and 70% women) aged 20 to 94 (mean age of 63 years) treated with greater than or equal to 7.5 mg/day oral prednisone (or equivalent). A total of 384 patients were exposed to 5 mg oral daily bisphosphonate (active-control) and 394 patients were exposed to denosumab administered once every 6 months as a 60 mg subcutaneous dose. All patients were instructed to take at least 1000 mg of calcium and 800 IU of vitamin D supplementation per day.
The incidence of all-cause mortality was 0.5% (n = 2) in the active-control group and 1.5% (n = 6) in the denosumab group. The incidence of serious adverse events was 17% in the active-control group and 16% in the denosumab group. The percentage of patients who withdrew from the study due to adverse events was 3.6% and 3.8% for the active-control and denosumab groups, respectively.
Adverse reactions reported in ≥ 2% of patients with glucocorticoid-induced osteoporosis and more frequently with denosumab than in the active-control-treated patients are shown in the table below.
Table 2. Adverse Reactions Occurring in ≥ 2% of Patients with Glucocorticoid-induced Osteoporosis and More Frequently with Denosumab than in Active-Control-treated Patients:
| Preferred Term | Denosumab (N = 394) n (%) | Oral Daily Bisphosphonate (Active-Control) (N = 384) n (%) |
|---|---|---|
| Back pain | 18 (4.6) | 17 (4.4) |
| Hypertension | 15 (3.8) | 13 (3.4) |
| Bronchitis | 15 (3.8) | 11 (2.9) |
| Headache | 14 (3.6) | 7 (1.8) |
| Dyspepsia | 12 (3.0) | 10 (2.6) |
| Urinary tract infection | 12 (3.0) | 8 (2.1) |
| Abdominal pain upper | 12 (3.0) | 7 (1.8) |
| Upper respiratory tract infection | 11 (2.8) | 10 (2.6) |
| Constipation | 11 (2.8) | 6 (1.6) |
| Vomiting | 10 (2.5) | 6 (1.6) |
| Dizziness | 9 (2.3) | 8 (2.1) |
| Fall | 8 (2.0) | 7 (1.8) |
| Polymyalgia rheumatica* | 8 (2.0) | 1 (0.3) |
* Events of worsening of underlying polymyalgia rheumatica.
No cases of ONJ were reported.
Atypical femoral fractures were reported in 1 patient treated with denosumab. The duration of denosumab exposure to time of atypical femoral fracture diagnosis was at 8.0 months [see Warnings and Precautions (5.5)].
Serious infection was reported in 15 patients (3.9%) in the active-control group and 17 patients (4.3%) in the denosumab group.
Epidermal and dermal adverse events (such as dermatitis, eczema, and rashes) were reported in 16 patients (4.2%) in the active-control group and 15 patients (3.8%) in the denosumab group.
The safety of denosumab in the treatment of bone loss in men with nonmetastatic prostate cancer receiving androgen deprivation therapy (ADT) was assessed in a 3-year, randomized, double-blind, placebo-controlled, multinational study of 1468 men aged 48 to 97 years. A total of 725 men were exposed to placebo and 731 men were exposed to denosumab administered once every 6 months as a single 60 mg subcutaneous dose. All men were instructed to take at least 1000 mg of calcium and 400 IU of vitamin D supplementation per day.
The incidence of serious adverse events was 30.6% in the placebo group and 34.6% in the denosumab group. The percentage of patients who withdrew from the study due to adverse events was 6.1% and 7.0% for the placebo and denosumab groups, respectively.
The safety of denosumab in the treatment of bone loss in women with nonmetastatic breast cancer receiving aromatase inhibitor (AI) therapy was assessed in a 2-year, randomized, double-blind, placebo-controlled, multinational study of 252 postmenopausal women aged 35 to 84 years. A total of 120 women were exposed to placebo and 129 women were exposed to denosumab administered once every 6 months as a single 60 mg subcutaneous 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 serious adverse events was 9.2% in the placebo group and 14.7% in the denosumab group. The percentage of patients who withdrew from the study due to adverse events was 4.2% and 0.8% for the placebo and denosumab groups, respectively.
Adverse reactions reported in ≥ 10% of denosumab-treated patients receiving ADT for prostate cancer or adjuvant AI therapy for breast cancer, and more frequently than in the placebo-treated patients were: arthralgia (13.0% placebo vs. 14.3% denosumab) and back pain (10.5% placebo vs. 11.5% denosumab). Pain in extremity (7.7% placebo vs. 9.9% denosumab) and musculoskeletal pain (3.8% placebo vs. 6.0% denosumab) have also been reported in clinical trials. Additionally, in denosumab-treated men with nonmetastatic prostate cancer receiving ADT, a greater incidence of cataracts was observed (1.2% placebo vs. 4.7% denosumab). Hypocalcemia (serum calcium < 8.4 mg/dL) was reported only in denosumab-treated patients (2.4% vs. 0.0%) at the month 1 visit.
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.
Denosumab products are a human monoclonal antibody. 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. No evidence of altered pharmacokinetic profile, toxicity profile, or clinical response was associated with binding antibody development.
Because postmarketing 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.
The following adverse reactions have been identified during post-approval use of denosumab products:
Jubbonti 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].
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 Cmax 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)].
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)].
Based on findings in animals, denosumab products can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].
Verify the pregnancy status of females of reproductive potential prior to initiating Jubbonti treatment.
Advise females of reproductive potential to use effective contraception during therapy, and for at least 5 months after the last dose of Jubbonti.
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)].
The safety and effectiveness of Jubbonti in pediatric patients have not been established. Jubbonti is not approved for use in pediatric patients.
In clinical trials, 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)]. Based on results from animal studies, denosumab may negatively affect long-bone growth and dentition in pediatric patients below the age of 4 years.
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 Animal Toxicology and/or Pharmacology (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)].
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.
No dose adjustment is necessary in patients with renal impairment.
Severe hypocalcemia resulting in hospitalization, life-threatening events and fatal cases have been reported postmarketing. In clinical studies, patients with advanced chronic kidney disease (i.e., eGFR < 30 mL/min/1.73 m²), including dialysis-dependent patients, were at greater risk of developing hypocalcemia. 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. Consider the benefits and risks to the patient when administering Jubbonti to patients with advanced chronic kidney disease. Monitor calcium and mineral levels (phosphorus and magnesium). Adequate intake of calcium and vitamin D is important in patients with advanced chronic kidney disease including dialysis-dependent patients [see Dosage and Administration (2.3), Warnings and Precautions (5.1), Adverse Reactions (6.1) and Clinical Pharmacology (12.3)].
No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of denosumab products.
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