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Prolia (Denosumab) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

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 adverse reactions reported with Prolia are back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis.

The most common adverse reactions leading to discontinuation of Prolia are breast cancer, 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 (%)
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 were reported in 0.4% women in the placebo group and 1.7% women in the Prolia group at the month 1 visit. 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 CrCL 50 to 80 mL/min group, 29% of subjects in the CrCL <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 4,550 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 CrCL ≥ 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 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.

Dermatologic 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 placebo and 10.8% of Prolia group (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

Pancreatitis was reported in 4 patients (0.1%) in the placebo and 8 patients (0.2%) in the Prolia groups. Of these reports, one subject in the placebo group and all 8 subjects 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 breast (0.7% placebo vs. 0.9% Prolia), reproductive (0.2% placebo vs. 0.5% Prolia) and gastrointestinal systems (0.6% placebo vs. 0.9% Prolia) were reported. A causal relationship to drug exposure has not been established.

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.



REPORTS OF SUSPECTED PROLIA SIDE EFFECTS / ADVERSE REACTIONS

Below is a sample of reports where side effects / adverse reactions may be related to Prolia. The information is not vetted and should not be considered as verified clinical evidence.

Possible Prolia side effects / adverse reactions in 88 year old female

Reported by a physician from Greece on 2011-10-03

Patient: 88 year old female weighing 49.0 kg (107.8 pounds)

Reactions: Bedridden, Dysstasia, Musculoskeletal Pain, Mobility Decreased

Suspect drug(s):
Prolia

Other drugs received by patient: Digoxin; Lasix; Valsartan; Sintrom; Alpha D3



Possible Prolia side effects / adverse reactions in 72 year old female

Reported by a health professional (non-physician/pharmacist) from Germany on 2011-10-03

Patient: 72 year old female weighing 80.0 kg (176.0 pounds)

Reactions: Bedridden, Pain in Extremity, Sciatica, Headache, Fatigue, Arthralgia, Diarrhoea, Asthenia, Influenza Like Illness

Suspect drug(s):
Prolia

Other drugs received by patient: Aspirin; Ramipril Beta; Metohexal /00376902/; Pantoprazol /01263202/



Possible Prolia side effects / adverse reactions in 90 year old female

Reported by a physician from United States on 2011-10-03

Patient: 90 year old female weighing 49.4 kg (108.8 pounds)

Reactions: Incorrect Route of Drug Administration, Hypersensitivity, Urticaria, Rash

Suspect drug(s):
Prolia

Other drugs received by patient: Citrical /00108001/; Vitamin D



See index of all Prolia side effect reports >>

Drug label data at the top of this Page last updated: 2010-06-08

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