Summary Safety Review - NEUPOGEN (filgrastim) and NEULASTA (pegfilgrastim) - Capillary Leak Syndrome
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: 2014-07-29
issue
A safety review was initiated to evaluate the currently available information regarding the potential risk of capillary leak syndrome with NEUPOGEN (filgrastim) and NEULASTA (pegfilgrastim). The review was prompted from information shared by the European Medicines Agency (EMA). To follow up, Health Canada asked the manufacturer to provide their reports of capillary leak syndrome.
Background
Approved use of NEUPOGEN (filgrastim) and NEULASTA (pegfilgrastim) in Canada
NEUPOGEN and NEULASTA are used in Canada to treat neutropenia. Neutropenia is a condition where the body makes too few neutrophils, a type of white blood cell. Neutropenia can increase the chances of getting an infection and prevents the body from fighting it.
NEUPOGEN and NEULASTA have a similar effect.
NEUPOGEN has been marketed in Canada since 2002 and NEULASTA since 2004.
Capillary leak syndrome
Cases of capillary leak syndrome have been reported internationally as an adverse reaction in persons receiving NEUPOGEN and NEULASTA. Capillary leak syndrome is a rare disorder characterized by massive leakage of fluid from the small blood vessels, also called capillaries, into surrounding tissues and body cavities. The leakage is caused by a sudden, unexplained change in the walls of the capillaries. This leakage results in a sharp drop in blood pressure which can lead to destruction of body tissues and death.
Symptoms of capillary leak syndrome include swelling or puffiness, which may be associated with passing water less frequently, difficulty breathing, abdominal swelling, a feeling of fullness and a general feeling of tiredness. These symptoms generally develop rapidly. Episodes vary in severity and frequency and may be fatal.
Objective
To assess the association between the use of NEUPOGEN and NEULASTA and the occurrence of capillary leak syndrome. The evidence considered included Canadian adverse reaction reports, scientific and medical literature, as well as what is known about the use of this medicine in Canada and internationally. The review evaluated the risk and suggested ways to minimize it.
Key findings
Use of NEUPOGEN and NEULASTA in Canada1
NEUPOGEN and NEULASTA are products that are more commonly used in the hospital setting, but can also be dispensed from non-hospital based pharmacies. The number of NEUPOGEN and NEULASTA prescriptions filled in non-hospital based pharmacies in Canada has been increasing at approximately 13% annually since 2009. It was estimated that approximately 83,363 prescriptions were dispensed in 2013.
Canadian reports of capillary leak syndrome associated with NEUPOGEN and NEULASTA
As of January 2014, Health Canada did not receive any reports of capillary leak syndrome associated with NEUPOGEN and NEULASTA.
Scientific reports
It is not clear from the scientific and medical literature why capillary leak syndrome occurs after exposure to NEUPOGEN and NEULASTA. However, it has been suggested in the literature that these drugs could have a direct effect on capillary walls, or cause an inflammatory response which may lead to tissue damage. The syndrome does appear to be more common in persons with overwhelming infections, in persons who had a bone marrow transplant, and in persons who had received anti-cancer drugs.
International data
A search of the manufacturer's safety database retrieved 38 international cases of capillary leak syndrome following exposure to NEUPOGEN and 5 cases following exposure to NEULASTA. All the cases were reported to have also involved an anti-cancer therapy. Twenty-seven cases occurred after receiving the first dose of NEUPOGEN. Ten deaths were reported to have occurred following exposure to NEUPOGEN and 2 deaths occurred after exposure to NEULASTA. None of these cases were reported in Canada.
Conclusions and actions
Based on the information provided in this review, Health Canada concluded that there is sufficient evidence to support the association between the use of NEUPOGEN and NEULASTA and the occurrence of capillary leak syndrome.
The following actions have been undertaken by the manufacturer and Health Canada to minimize this risk:
- The Canadian product monographs for both NEUPOGEN and NEULASTA have been updated to include the adverse reaction of capillary leak syndrome in the sections Warnings & Precautions and Post Market Adverse Reactions.
- A Health Professional Communication and accompanying Public Communication were issued and posted on the Healthy Canadians website on April 10, 2014, to address the risk of capillary leak syndrome for both NEUPOGEN and NEULASTA.
Health Canada will keep Canadians informed and take action, as appropriate, if any new safety information is identified.
References
- Druey KM, Greipp PR. Narrative review: the systemic capillary leak syndrome. Ann Intern Med 2010;153(2):90-98.
- Kawabe S, Saeki T, Yamazaki H et al. Systemic capillary syndrome. Internal Med 2002;41:211-5.
- Nagao Y, Harada H, Yamanaka H, et al. Possible mediators for systemic capillary leak syndrome. Am J Med 2011;124(1):e7-9.
- Rechner I, Brito-Babapulle F, Fielden J. Systemic capillary leak syndrome after granulocyte colony-stimulating factor (G-CSF). Hematol J 2003;4:54-56.
- Shinohara K. Systemic capillary leak syndrome caused by granulocyte colony-stimulating factor. Intern Med 2011;50:2259.
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.
- 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.