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. 1 ) Male osteoporosis: Most common adverse reactions (> 5% and more common than placebo) were: back pain, arthralgia, and nasopharyngitis.
1 ) Glucocorticoid-induced osteoporosis: Most common adverse reactions (> 3% and more common than active-control group) were: back pain, hypertension, bronchitis, and headache. 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. 1 ) To report SUSPECTED ADVERSE REACTIONS, contact CELLTRION USA, Inc. gov/medwatch . 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.
8% (n = 70) in the denosumab group. 0% in the denosumab group. 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. 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.
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. 5% in subjects with creatinine clearance < 30 mL/min vs. 1% in subjects with creatinine clearance ≥ 30 mL/min. Serious Infections 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. 2% in both placebo and denosumab treatment groups. 0% in the denosumab groups. 7% placebo vs. 5% placebo vs. 0% placebo vs. 1% denosumab) were reported.
Endocarditis was reported in no placebo patients and 3 patients receiving denosumab. 1% placebo vs. 4% denosumab). The incidence of opportunistic infections was similar to that reported with placebo. 0001). 8) ] . 4) ] . Atypical Subtrochanteric and Diaphyseal Femoral Fractures In the osteoporosis clinical trial program, atypical femoral fractures were reported in patients treated with denosumab.
5) ] . Multiple Vertebral Fractures (MVF) Following Treatment Discontinuation 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. 6) ] . 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. 8% in the denosumab groups. 7% placebo vs. 2% placebo vs. 6% placebo vs. 9% denosumab) were reported. A causal relationship to drug exposure has not been established.
Treatment to Increase Bone Mass in Men with Osteoporosis 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. 8% (n = 1) in the denosumab group. 3% in the denosumab group. 5% for the placebo and denosumab groups, respectively. 7% placebo vs.
8% placebo vs. 8% placebo vs. 7% denosumab). 8%) in the placebo group and no patients in the denosumab group. 2%) in the denosumab group. Osteonecrosis of the Jaw No cases of ONJ were reported. 8%) in the denosumab group. 3%) patients (3 prostate cancers, 1 basal cell carcinoma) in the denosumab group.
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. 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.
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. 8) Polymyalgia rheumatica Events of worsening of underlying polymyalgia rheumatica. 3) Osteonecrosis of the Jaw No cases of ONJ were reported. Atypical Subtrochanteric and Diaphyseal Femoral Fractures Atypical femoral fractures were reported in 1 patient treated with denosumab.
5) ] . 3%) in the denosumab group. 8%) in the denosumab group. Treatment of Bone Loss in Patients Receiving Androgen Deprivation Therapy for Prostate Cancer or Adjuvant Aromatase Inhibitor Therapy for Breast Cancer 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.
6% in the denosumab group. 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.
7% in the denosumab group. 8% for the placebo and denosumab groups, respectively. 0% placebo vs. 5% placebo vs. 5% denosumab). 7% placebo vs. 8% placebo vs. 0% denosumab) have also been reported in clinical trials. 2% placebo vs. 7% denosumab).
4% vs. 0%) at the month 1 visit. 2 Postmarketing Experience 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.
g. ANCA positive vasculitis, leukocytoclastic vasculitis) Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome