"March 7, 2013 -- An FDA panel voted to stop recommending calcitonin salmon for the treatment of osteoporosis in women who are at least five years past menopause.
The committee voted 12-9 against continued marketing of the drug, citing"...
Prolia Side Effects Center
Medical Editor: John P. Cunha, DO, FACOEP
Prolia (denosumab) is used to treat bone loss (osteoporosis) in women who are at high risk for bone fracture after menopause. It belongs to a class of drugs called monoclonal antibodies. Common side effects include low calcium levels, especially if you have kidney problems. You may also be more likely to get a serious infection, such as a skin, ear, stomach/gut, or bladder infection. Tell your doctor if you develop signs of infection, such as: fever/chills, red/swollen/tender/warm skin (with or without pus), severe abdominal pain, ear pain, frequent/painful/burning urination, pink/bloody urine.
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. 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 is usually used in women after menopause. It is unlikely to be used during pregnancy or breast-feeding. 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 breast-feeding.
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.
What is Patient Information in Detail?
Easy-to-read and understand detailed drug information and pill images for the patient or caregiver from Cerner Multum.
Prolia in Detail - Patient Information: Side Effects
Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.
Serious infections may occur during treatment with Prolia. Call your doctor right away if you have signs of infection such as:
- severe itching, burning, rash, blistering, peeling, or dryness of the skin;
- swelling, pain, tenderness, warmth, or redness anywhere on your body;
- pain or burning when you urinate, blood in your urine;
- severe stomach pain;
- ear pain or drainage, trouble hearing;
- fever, chills, night sweats;
- cough, feeling short of breath;
- pinpoint purple or red spots under your skin; or
- flu symptoms, weight loss.
Call your doctor at once if you have a serious side effect such as:
- numbness or tingly feeling around your mouth or in your fingers or toes, fast or slow heart rate, muscle cramps or contraction, overactive reflexes; or
- severe pain in your upper stomach spreading to your back, nausea and vomiting, fast heart rate.
Less serious side effects may include:
- back pain, muscle pain; 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.
Read the entire detailed patient monograph for Prolia (Denosumab Injection) »
What is Patient Information Overview?
A concise overview of the drug for the patient or caregiver from First DataBank.
Prolia Overview - Patient Information: Side Effects
Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.
Denosumab may cause low calcium levels, especially if you have kidney problems. Take calcium and vitamin D as directed by your doctor. (See also How to Use section.) Your doctor will order calcium blood tests before your first injection and during treatment. Tell your doctor immediately if you have any symptoms of low calcium such as: muscle spasms/cramps, mental/mood changes (such as irritability or confusion), numbness/tingling (especially around lips/mouth or in fingers/toes), seizures.
Denusomab can affect your immune system. You may be more likely to get a serious infection, such as a skin, ear, stomach/gut, or bladder infection. Tell your doctor immediately if you develop any signs of infection, such as: fever/chills, red/swollen/tender/warm skin (with or without pus), severe abdominal pain, ear pain, frequent/painful/burning urination, pink/bloody urine.
Tell your doctor immediately if this unlikely but serious side effect occurs: jaw pain.
A very serious allergic reaction to this drug is rare. However, get medical help right away if you notice any symptoms of a serious allergic reaction, including: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.
Denosumab can cause skin problems such as dryness, peeling, redness, itching, small bumps/patches, or blisters. However, you may not be able to tell it apart from a rare rash that could be a sign of a severe allergic reaction. Therefore, get medical help right away if you develop any rash or if any of these symptoms persist or worsen.
This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.
In the US -
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.
Read the entire patient information overview for Prolia (Denosumab Injection)»
What is Prescribing information?
The FDA package insert formatted in easy-to-find categories for health professionals and clinicians.
Prolia FDA Prescribing Information: Side 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]
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 are back pain and constipation.
The Prolia Postmarketing Active Safety Surveillance Program is available to collect information from prescribers on specific adverse events. Please see www.proliasafety.com or call 1-800-772-6436 for more information about this program.
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 = 3876)
|BLOOD AND LYMPHATIC SYSTEM DISORDERS|
|Anemia||129 (3.3)||107 (2.8)|
|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)|
|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)|
|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 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 patients 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.
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 group and 4.0% in the Prolia group. 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).
There was no imbalance in the reporting of opportunistic infections.
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].
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.
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 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%) at the month 1 visit.
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: rash, urticaria, facial swelling and erythema
- Hypocalcemia: severe symptomatic hypocalcemia
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.
Read the entire FDA prescribing information for Prolia (Denosumab Injection) »
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