Prolia (Page 3 of 9)

5.9 Musculoskeletal Pain

In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking Prolia [see Adverse Reactions (6.2)]. The time to onset of symptoms varied from one day to several months after starting Prolia. Consider discontinuing use if severe symptoms develop [see Patient Counseling Information (17)].

5.10 Suppression of Bone Turnover

In clinical trials in women with postmenopausal osteoporosis, treatment with Prolia 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 Prolia are unknown. The long-term consequences of the degree of suppression of bone remodeling observed with Prolia may contribute to adverse outcomes such as osteonecrosis of the jaw, atypical fractures, and delayed fracture healing. Monitor patients for these consequences.

6 ADVERSE REACTIONS

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

The most common adverse reactions reported with Prolia in patients with postmenopausal osteoporosis are back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis.

The most common adverse reactions reported with Prolia in men with osteoporosis are back pain, arthralgia, and nasopharyngitis.

The most common adverse reactions reported with Prolia in patients with glucocorticoid-induced osteoporosis are back pain, hypertension, bronchitis, and headache.

The most common (per patient incidence ≥ 10%) adverse reactions reported with Prolia 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 Prolia in patients with postmenopausal osteoporosis are back pain and constipation.

To report Adverse Reactions with Prolia® , please call Amgen Medical Information at 1-800-772-6436, email medinfo@amgen.com, or report the event at FDA 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 Prolia 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 Prolia 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 Prolia group. The incidence of nonfatal serious adverse events was 24.2% in the placebo group and 25.0% in the Prolia group. The percentage of patients who withdrew from the study due to adverse events was 2.1% and 2.4% for the placebo and Prolia groups, respectively.

Adverse reactions reported in ≥ 2% of postmenopausal women with osteoporosis and more frequently in the Prolia-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 Prolia(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)

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 Prolia group. The nadir in serum calcium level occurs at approximately day 10 after Prolia 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 Prolia dosing was -5.5% in subjects with creatinine clearance < 30 mL/min vs. -3.1% 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 Prolia 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 Prolia treatment groups. However, the incidence of nonfatal serious infections was 3.3% in the placebo and 4.0% in the Prolia groups. Hospitalizations due to serious infections in the abdomen (0.7% placebo vs. 0.9% Prolia), urinary tract (0.5% placebo vs. 0.7% Prolia), and ear (0.0% placebo vs. 0.1% Prolia) were reported. Endocarditis was reported in no placebo patients and 3 patients receiving Prolia.

Skin infections, including erysipelas and cellulitis, leading to hospitalization were reported more frequently in patients treated with Prolia (< 0.1% placebo vs. 0.4% Prolia).

The incidence of opportunistic infections was similar to that reported with placebo.

Dermatologic Adverse Reactions

A significantly higher number of patients treated with Prolia 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 Prolia groups (p < 0.0001). Most of these events were not specific to the injection site [see Warnings and Precautions (5.8)].

Osteonecrosis of the Jaw

ONJ has been reported in the osteoporosis clinical trial program in patients treated with Prolia [see Warnings and Precautions (5.4)].

Atypical Subtrochanteric and Diaphyseal Femoral Fractures

In the osteoporosis clinical trial program, atypical femoral fractures were reported in patients treated with Prolia. The duration of Prolia exposure to time of atypical femoral fracture diagnosis was as early as 2½ years [see Warnings and Precautions (5.5)].

Multiple Vertebral Fractures (MVF) Following Discontinuation of Prolia Treatment

In the osteoporosis clinical trial program, multiple vertebral fractures were reported in patients after discontinuation of Prolia. In the phase 3 trial in women with postmenopausal osteoporosis, 6% of women who discontinued Prolia and remained in the study developed new vertebral fractures, and 3% of women who discontinued Prolia 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 Prolia. Prior vertebral fracture was a predictor of multiple vertebral fractures after discontinuation [see Warnings and Precautions (5.6)].

Pancreatitis

Pancreatitis was reported in 4 patients (0.1%) in the placebo and 8 patients (0.2%) in the Prolia groups. Of these reports, 1 patient in the placebo group and all 8 patients in the Prolia group had serious events, including one death in the Prolia group. Several patients had a prior history of pancreatitis. The time from product administration to event occurrence was variable.

New Malignancies

The overall incidence of new malignancies was 4.3% in the placebo and 4.8% in the Prolia groups. New malignancies related to the breast (0.7% placebo vs. 0.9% Prolia), reproductive system (0.2% placebo vs. 0.5% Prolia), and gastrointestinal system (0.6% placebo vs. 0.9% Prolia) were reported. A causal relationship to drug exposure has not been established.

Treatment to Increase Bone Mass in Men with Osteoporosis

The safety of Prolia 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 Prolia 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 Prolia group. The incidence of nonfatal serious adverse events was 7.5% in the placebo group and 8.3% in the Prolia group. The percentage of patients who withdrew from the study due to adverse events was 0% and 2.5% for the placebo and Prolia groups, respectively.

Adverse reactions reported in ≥ 5% of men with osteoporosis and more frequently with Prolia than in the placebo-treated patients were: back pain (6.7% placebo vs. 8.3% Prolia), arthralgia (5.8% placebo vs. 6.7% Prolia), and nasopharyngitis (5.8% placebo vs. 6.7% Prolia).

Serious Infections

Serious infection was reported in 1 patient (0.8%) in the placebo group and no patients in the Prolia group.

Dermatologic Adverse Reactions

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 Prolia group.

Osteonecrosis of the Jaw

No cases of ONJ were reported.

Pancreatitis

Pancreatitis was reported in 1 patient (0.8%) in the placebo group and 1 patient (0.8%) in the Prolia group.

New Malignancies

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 Prolia group.

Treatment of Glucocorticoid-Induced Osteoporosis

The safety of Prolia 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 Prolia 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 Prolia group. The incidence of serious adverse events was 17% in the active-control group and 16% in the Prolia 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 Prolia groups, respectively.

Adverse reactions reported in ≥ 2% of patients with glucocorticoid-induced osteoporosis and more frequently with Prolia 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 Prolia than in Active-Control-treated Patients
Preferred Term Prolia(N = 394)n (%) Oral Daily Bisphosphonate (Active-Control)(N = 384)n (%)
*
Events of worsening of underlying polymyalgia rheumatica.
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)

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 Prolia. The duration of Prolia exposure to time of atypical femoral fracture diagnosis was at 8.0 months [see Warnings and Precautions (5.5)].

Serious Infections

S erious infection was reported in 15 patients (3.9%) in the active-control group and 17 patients (4.3%) in the Prolia group.

Dermatologic Adverse Reactions

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 Prolia 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 Prolia 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 Prolia 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 Prolia group. The percentage of patients who withdrew from the study due to adverse events was 6.1% and 7.0% for the placebo and Prolia groups, respectively.

The safety of Prolia 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 Prolia 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 Prolia group. The percentage of patients who withdrew from the study due to adverse events was 4.2% and 0.8% for the placebo and Prolia groups, respectively.

Adverse reactions reported in ≥ 10% of Prolia-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% Prolia) and back pain (10.5% placebo vs. 11.5% Prolia). Pain in extremity (7.7% placebo vs. 9.9% Prolia) and musculoskeletal pain (3.8% placebo vs. 6.0% Prolia) have also been reported in clinical trials. Additionally, in Prolia-treated men with nonmetastatic prostate cancer receiving ADT, a greater incidence of cataracts was observed (1.2% placebo vs. 4.7% Prolia). Hypocalcemia (serum calcium < 8.4 mg/dL) was reported only in Prolia-treated patients (2.4% vs. 0.0%) at the month 1 visit.

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