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 (5.3)].

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)].

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.

7 DRUG INTERACTIONS
No drug-drug interaction studies have been conducted with Prolia.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C
There are no adequate and well-controlled studies of Prolia in pregnant women. In genetically engineered mice in which RANK ligand (RANKL) was turned off by gene removal (a “knockout mouse”), absence of RANKL (the target of denosumab) caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice also showed altered maturation of the maternal mammary gland, leading to impaired lactation postpartum [see Use in Specific Populations (8.3)].

Prolia is approved only for use in postmenopausal women. Prolia should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Women who become pregnant during Prolia treatment are encouraged to enrol