Summary Safety Review - Mycophenolates (CELLCEPT and MYFORTIC) - Bronchiectasis (Damage to the Lung Airways) with or without Hypogammaglobulinemia (Low Levels of Immunoglobulins in the Blood)
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: 2015-02-04
issue
A safety review was conducted to evaluate the risk of damage to the lung airways (bronchiectasis) in patients taking certain drugs (mycophenolates) which are used to prevent transplant rejection. The review also evaluated the risk of hypogammaglobulinemia (decreased quantity of immunoglobulins G or IgG, in the blood), which may occur together with bronchiectasis in patients taking mycophenolates. The assessment was prompted by an observation of a growing number of international reports and literature reports of bronchiectasis in transplant recipients treated with products containing mycophenolates.
Background
Approved use of mycophenolates in Canada
In Canada, products containing mycophenolates are currently marketed as CELLCEPT (mycophenolate mofetil) and MYFORTIC (mycophenolic acid), as well as their generic products. These products are used to prevent organ rejection in adults receiving kidney, heart or liver transplants, in combination with other organ rejection drugs (cyclosporine and corticosteroids). Some of these products are also used in children aged 2 to 18 years under certain conditions.
Risks of bronchiectasis and hypogammaglobulinemia
Bronchiectasis is a chronic, progressive lung disease characterized by damage to the structure of bronchial tubes (airways). It is associated with respiratory symptoms that include cough, daily sputum or mucus production, and fatigue.
Hypogammaglobulinemia means low levels of immunoglobulins G (IgG) in the blood; IgG are antibodies that are important in fighting infections and their decrease is often associated with infections. In transplant patients, hypogammaglobulinemia may increase the chances of having respiratory infections. The respiratory infections may trigger bronchiectasis. However, both diseases do not always occur together.
Objective
To review the available evidence concerning the risk of developing bronchiectasis with or without hypogammaglobulinemia associated with products containing mycophenolates. This review considered information from Canadian adverse reaction reports, scientific literature, international safety data as well as what is known about the use of these products in Canada and internationally. The review evaluated the risk and suggested ways to minimize it.
Key findings
Use of mycophenolates in Canada1
From 2009 to 2013, there has been a steady annual increase in the total number of prescriptions for mycophenolates in Canada. Over those 5 years, annual prescriptions have increased by 32% (from 154,781 in 2009 to 228,077 in 2013).
Canadian reports of bronchiectasis with or without hypogammaglobulinemia associated with the use of mycophenolates
At the time of this review, Health Canada had not received any Canadian reports of bronchiectasis in transplant patients treated with mycophenolates.
Scientific reports
Evidence from published medical and scientific literature suggests that bronchiectasis might be related to the use of mycophenolates as noted by the following:
- Several studies noted that when patients did not take mycophenolates as part of their immunosuppressive therapy, they did not develop bronchiectasis.
- Patients who stopped taking mycophenolates had less lung complaints and less symptoms related to bronchiectasis.
- Some evidence also indicates that mycophenolates suppress immune system responses including the production of immunoglobulins, especially immunoglobulin G (IgG).
Based on their own reviews, the manufacturers for CELLCEPT and MYFORTIC could not rule out a cause and effect relationship between these drugs and bronchiectasis and/or hypogammaglobulinemia.
International data 2
At the time of the review, the World Health Organization (WHO) Global Individual Case Safety Reports Database System (VigiBase) had 38 reports of bronchiectasis and 36 reports of hypogammaglobulinemia in patients treated with mycophenolates. Twenty-three of 38 reports of bronchiectasis also reported hypogammaglobulinemia.
Conclusions and actions
The current evidence suggests that bronchiectasis with or without hypogammaglobulinemia may occur while taking products containing mycophenolates.
The prescribing information for CELLCEPT and MYFORTIC has been updated to include the possible risk of bronchiectasis and hypogammaglobulinemia. The prescribing information now also recommends that treating physicians further investigate patients with persistent lung symptoms and recurrent infections for the possibility of bronchiectasis and hypogammaglobulinemia, respectively. Manufacturers of generic versions of these drugs will also update their product information.
Health Canada will continue its ongoing monitoring of adverse reactions involving mycophenolates, in particular, the risk of bronchiectasis and/or hypogammaglobulinemia. Health Canada will keep Canadians informed and take action, as appropriate, if new safety information is identified.
References
- Boddana P, Webb LH, Unsworth J, et al. Hypogammaglobulinemia and bronchiectasis in mycophenolate mofetil-treated renal transplant recipients: an emerging clinical phenomenon? Clin Transplant 2011;25(3):417-9.
- Rook M, Postma DS, van der Jagt EJ, et al. Mycophenolate mofetil and bronchiectasis in kidney transplant patients: a possible relationship. Transplantation 2006;81(2):287-9.
- Pijnenburg MW, Cransberg K, Wolff E, et al. Bronchiectasis in children after renal or liver transplantation: a report of five cases. Pediatr Transplant 2004;8(1);71-4.
- Merkus PJ, Pijnenburg M, Cransberg K. Mycophenolate mofetil and bronchiectasis in pediatric transplant patients. Transplantation 2006;82(10):1386.
- Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 2000;47(2-3):85-118.
- Allison AC, Eugui EM. Mechanisms of action of mycophenolate mofetil in preventing acute and chronic allograft rejection. Transplantation 2005;80(2 Suppl):S181-90.
- Smith KG, Isbel NM, Catton MG, et al. Suppression of the humoral immune response by mycophenolate mofetil. Nephrol Dial Transplant 1998;13(1):160-4.
- Corales R, Chua J, Mawhorter S, et al. Significant post-transplant hypogammaglobulinemia in six heart transplant recipients: an emerging clinical phenomenon? Transpl Infect Dis 2000;2(3):133-9.
- Keven K, Sahin M, Kutlay S, et al. Immunoglobulin deficiency in kidney allograft recipients: comparative effects of mycophenolate mofetil and azathioprine. Transpl Infect Dis 2003;5(4):181-6.
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 pharmaceutical 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.