Summary Safety Review - PROLIA (denosumab) - Risk of Malignancy (Cancer)
Review decision
A Summary Safety Review complements other safety related information to help Canadians make informed decisions about their use of health products. Each summary outlines what was assessed in Health Canada’s review, what was found and what action was taken by Health Canada, if any.
Issued: 2015-01-23
issue
A safety review was initiated to evaluate the current available information on the potential risk of cancer associated with PROLIA (denosumab). This review was prompted by a safety report of cases of death submitted to Health Canada from the manufacturer as part of regular regulatory requirements. In that report, Health Canada noted cases of cancer. Therefore, Health Canada requested that the manufacturer submit a summary report on all cases of cancer associated with the use of PROLIA for further evaluation.
Background
Approved use of PROLIA in Canada
PROLIA is used to treat osteoporosis (thinning and weakening of the bone) in women after menopause who have an increased risk of fractures. It is also used in some men with osteoporosis. PROLIA is also used to increase bone mass in men with prostate cancer and women with breast cancer who are receiving cancer treatment.
Cancer and Malignancy
Malignancy is a cancerous tumour which is able to grow and invade nearby tissues and spread to other parts of the body. Cancer cells that spread to other parts of the body are called metastases.
Objective
To assess the available evidence regarding the possible risk or chance of developing all types of cancer in patients taking PROLIA. Specifically, Health Canada assessed new cases of cancer after treatment with PROLIA was started. If the patient had cancer before, or if a previous cancer reoccurred, this was not considered to be caused by PROLIA. The evidence that was considered included Canadian patient reports, reports from the manufacturer, scientific literature reports and what is known about the use of this medicine both in Canada and internationally.
Key findings
Use of PROLIA in Canada1
- Health Canada estimates that the number of prescriptions for PROLIA has been increasing every year over the last 5 years. There were approximately 213,061 new and refill prescriptions from December 2010 through to January 2014.
Canadian reports of malignancies associated with PROLIA
- The reports provided by the manufacturer upon Health Canada’s request included 184 Canadian reports of malignancy in patients receiving PROLIA since August 6, 2010. In the majority of these reports, the patients either had other risk factors that could explain the cause of cancer or there was limited information to make an assessment of the reports. Therefore, there were very few cases where the evidence of cancer could be directly linked to the use of PROLIA.
Scientific reports
- The information from the currently available scientific and medical literature indicates that the rates of cancer in patients treated with PROLIA did not differ from patients who received a placebo (sugar pill).
- Also, there is no non-clinical (animal study) evidence to suggest a way in which PROLIA would cause cancer.
International data2
- At the time of this review, the World Health Organization (WHO) Global Individual Case Safety Reports Database System (VigiBase) contained 230 reports of malignancy in patients exposed to PROLIA between 2011 and 2014. A search of the Amgen Global Database provided 1,052 potential case reports of malignancy in people taking PROLIA from May 26, 2010 to January 31, 2014, regardless of the cause of cancer. The rate of malignancy overall is considered lower than the rate seen in the general population.
Conclusions and actions
Upon further analysis of both the Canadian and international case reports, only 16 cases of cancer out of a possible 1,140 were identified as potentially related to the use of PROLIA. The current PROLIA prescribing information contains statements explaining that the rates of cancer observed in clinical trials were similar in patients who received PROLIA compared to those who received the placebo.
Based on the information provided in this review, Health Canada concluded that there is not enough evidence at this time to suggest an association between the use of PROLIA and cancer.
Health Canada will continue its monitoring of adverse reaction information involving PROLIA, as it does for all health products, to assess and identify potential harms. Health Canada will keep Canadians informed and take action, as appropriate, if any new safety information is identified.
References
- Bone HG, Chapurlat R, Brandi ML, et al. The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension. J Clin Endocrinol Metab 2013;98:4483-92.
- Ferrari-Lacraz S, Ferrari S. Do RANKL inhibitors (denosumab) affect inflammation and immunity? Osteoporos Int 2011;2:435-46.
- González-Suárez E, Jacob AP, Jones J, et al. RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 2010;468:103-7.
- Zhou Z, Chen C, Zhang J, et al. Safety of denosumab in postmenopausal women with osteoporosis or low bone mineral density: a meta-analysis. Int J Clin Exp Pathol2014;7:2113-22.
Footnotes
- IMS utilization data provided by: IMS Health Canada Inc, An external party cannot refer to nor use IMS data, which have been generated by Health Canada, without a Third Party Agreement in place.
- World Health Organization (WHO) adverse reaction information provided by: The WHO Collaborating Centre for International Drug Monitoring. This information is not homogeneous with respect to the sources of the information or the likelihood that the health product caused the suspected adverse reaction. Also, this information does not represent the opinion of the WHO.
- This list of references is not intended to be exhaustive. References have been selected as suggestions for further reading and reflect the most current information at the time of the safety review.