Medical Editor: John P. Cunha, DO, FACOEP
What Is Prolia?
Prolia (denosumab) is a monoclonal antibody used to treat bone loss (osteoporosis) in women who are at high risk for bone fracture after menopause.
What Are Side Effects of Prolia?
Prolia may cause serious side effects including:
- new or unusual pain in your thigh, hip or groin,
- severe pain in joints, muscles, or bones,
- dry skin,
- peeling skin,
- redness,
- itching,
- blisters,
- oozing or crusting,
- numbness or tingly feeling around your mouth, fingers or toes,
- muscle tightness or contractions,
- overactive reflexes
- ,
- fever,
- chills,
- night sweats,
- swelling,
- pain,
- tenderness,
- warmth,
- pain or burning when you urinate,
- increased or urgent need to urinate,
- severe stomach pain,
- cough, and
- shortness of breath
Get medical help right away, if you have any of the symptoms listed above.
Common side effects of Prolia include:
- low calcium levels (especially if you have kidney problems),
- weakness,
- constipation,
- back pain,
- muscle pain,
- pain in your arms and legs,
- anemia,
- diarrhea, or
- skin problems (eczema, blisters, dry skin, peeling, redness, itching, small bumps).
You may also be more likely to get a serious infection, such as a skin, ear, stomach/gut, or bladder infection while taking Prolia. Tell your doctor if you develop signs of infection, such as:
- fever/chills, night sweats,
- red/swollen/tender/warm skin (with or without pus),
- severe stomach or abdominal pain,
- ear pain or drainage, trouble hearing,
- frequent/painful/burning urination, or
- pink/bloody urine.
- severe itching, burning, rask, blistering, peeling, or dryness of the skin,
- cough,
- shortness of breath,
- pinpoint purple or red spots under your skin,
- flu symptoms, or
- weight loss.
Tell your doctor if your experience serious side effects of Prolia including jaw pain, new or unusual thigh/hip/groin pain, or bone/joint/muscle pain.
Seek medical care or call 911 at once if you have the following serious side effects:
- Serious eye symptoms such as sudden vision loss, blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights;
- Serious heart symptoms such as fast, irregular, or pounding heartbeats; fluttering in your chest; shortness of breath; and sudden dizziness, lightheadedness, or passing out;
- Severe headache, confusion, slurred speech, arm or leg weakness, trouble walking, loss of coordination, feeling unsteady, very stiff muscles, high fever, profuse sweating, or tremors.
This document does not contain all possible side effects and others may occur. Check with your physician for additional information about side effects.
Dosage for Prolia
Prolia should be administered by a doctor. The recommended dose of Prolia is 60 mg administered as a single subcutaneous (under the skin) injection once every 6 months.
What Drugs, Substances, or Supplements Interact with Prolia?
The effects of some drugs can change if you take other drugs or herbal products at the same time. This can increase your risk for serious side effects or may cause your medications not to work correctly. Tell your doctor about all the products you use (including prescription drugs, nonprescription drugs, and herbal products) before starting treatment with this product.
Prolia During Pregnancy and Breastfeeding
Prolia is usually used in women after menopause. It is unlikely to be used during pregnancy or breastfeeding. It is not recommended for use during pregnancy. It may harm a fetus. It is unknown if this medication passes into breast milk. Consult your doctor before breastfeeding.
Additional Information
Our Prolia (denosumab) Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
QUESTION
What joints are most often affected by osteoarthritis? See AnswerGet emergency medical help if you have signs of an allergic reaction: hives, itching, rash; difficult breathing, feeling light-headed; swelling of your face, lips, tongue, or throat.
Call your doctor at once if you have:
- new or unusual pain in your thigh, hip, or groin;
- severe pain in your joints, muscles, or bones;
- skin problems such as dryness, peeling, redness, itching, blisters, bumps, oozing, or crusting; or
- low calcium level--muscle spasms or contractions, numbness or tingly feeling (around your mouth, or in your fingers and toes).
Serious infections may occur during treatment with Prolia. Call your doctor right away if you have signs of infection such as:
- fever, chills, night sweats;
- swelling, pain, tenderness, warmth, or redness anywhere on your body;
- pain or burning when you urinate;
- increased or urgent need to urinate;
- severe stomach pain; or
- cough, wheezing, feeling short of breath.
Common side effects may include:
- bladder infection (painful or difficult urination);
- lung infection (cough, shortness of breath);
- headache;
- back pain, muscle pain, joint pain;
- increased blood pressure;
- cold symptoms such as stuffy nose, sneezing, sore throat;
- high cholesterol; or
- pain in your arms or legs.
This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
SLIDESHOW
Slideshow: Exercises for Knee Osteoarthritis and Joint Pain See SlideshowSIDE EFFECTS
The following serious adverse reactions are discussed below and also elsewhere in the labeling:
- Hypocalcemia [see WARNINGS AND PRECAUTIONS]
- Serious Infections [see WARNINGS AND PRECAUTIONS]
- Dermatologic Adverse Reactions [see WARNINGS AND PRECAUTIONS]
- Osteonecrosis of the Jaw [see WARNINGS AND PRECAUTIONS]
- Atypical Subtrochanteric and Diaphyseal Femoral Fractures [see WARNINGS AND PRECAUTIONS]
- Multiple Vertebral Fractures (MVF) Following Discontinuation of Prolia Treatment [see WARNINGS AND PRECAUTIONS]
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 [email protected], or report the event at FDA MedWatch.
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].
Osteonecrosis Of The Jaw
ONJ has been reported in the osteoporosis clinical trial program in patients treated with Prolia [see WARNINGS AND PRECAUTIONS].
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].
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].
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 (%) |
| 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. | ||
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].
Serious Infections
Serious 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.
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.
The following adverse reactions have been identified during post approval use of Prolia:
- Drug-related hypersensitivity reactions: anaphylaxis, rash, urticaria, facial swelling, and erythema
- Hypocalcemia: severe symptomatic hypocalcemia
- Musculoskeletal pain, including severe cases
- Parathyroid Hormone (PTH): Marked elevation in serum PTH in patients with severe renal impairment (creatinine clearance < 30 mL/min) or receiving dialysis
- Multiple vertebral fractures following discontinuation of Prolia
- Cutaneous and mucosal lichenoid drug eruptions (e.g. lichen planus-like reactions)
- Alopecia
- Vasculitis (e.g., ANCA positive vasculitis, leukocytoclastic vasculitis)
- Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome
Immunogenicity
Denosumab is a human monoclonal antibody. As with all therapeutic proteins, there is potential for immunogenicity. Using an electrochemiluminescent bridging immunoassay, less than 1% (55 out of 8113) of patients treated with Prolia 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.
The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of a positive antibody (including neutralizing antibody) test result may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies to denosumab with the incidence of antibodies to other products may be misleading.
DRUG INTERACTIONS
No Information provided
Read the entire FDA prescribing information for Prolia (Denosumab Injection)
© Prolia Patient Information is supplied by Cerner Multum, Inc. and Prolia Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.
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