Ezetrol (ezetimibe) and the Risks of Drug-Induced Liver Injury and Severe Cutaneous Adverse Reactions

Issue

Ezetrol (ezetimibe) may cause serious adverse reactions, including drug-induced liver injury (DILI) and severe cutaneous adverse reactions (SCARs) such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilic and systemic symptoms (DRESS). Audience Healthcare professionals including general practitioners, family physicians, cardiologists, dermatologists, pediatricians, emergency physicians, gastroenterologists, internists, endocrinologists, nurse practitioners, and pharmacists. Key messages Ezetrol (ezetimibe) may cause drug-induced liver injury (DILI) and severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilic and systemic symptoms (DRESS). Healthcare professionals are advised to: Consider performing liver function tests at the initiation of Ezetrol, whether administered as monotherapy or in combination with a statin or fenofibrate, and subsequently as required. Instruct patients to immediately contact a healthcare professional if they experience symptoms of liver injury. Liver function should be evaluated if liver injury is suspected. Instruct patients to stop taking Ezetrol and to seek immediate medical help if they experience symptoms of SCARs. The Canadian Product Monograph (CPM) for Ezetrol has been updated to include warnings about these serious adverse reactions. Health Canada will work with the manufacturers of generic versions of ezetimibe to update their respective CPMs. Background Ezetrol is indicated, as an adjunct to diet and lifestyle changes when the response to these and other non-pharmacological measures alone has been inadequate, for the treatment of primary hypercholesterolemia (administered alone, with an HMG-CoA reductase inhibitor (statin) or in combination with fenofibrate, depending on the clinical objective), homozygous familial hypercholesterolemia (administered with a statin) and homozygous sitosterolemia (phytosterolemia). Ezetrol is authorized for use in adults and children 10 years of age and older. Treatment with Ezetrol in children less than 10 years of age is not recommended. The Market Authorization Holder conducted a review of international safety data and the scientific literature and identified 42 post-marketing cases of DILI in patients taking Ezetrol, including a Canadian case of liver injury associated with ezetimibe monotherapy. There was sufficient evidence to suggest a causal association between ezetimibe monotherapy and DILI. Therefore, the current recommendation to consider performing liver function tests at the initiation of, or during treatment with, Ezetrol in combination with a statin or fenofibrate has been expanded to include Ezetrol monotherapy. The review also identified rare cases of SCARs in patients taking Ezetrol. There was sufficient evidence to suggest at least a reasonable possibility of a causal association with some cases of SJS, TEN, and DRESS. Information for consumers Ezetrol is used along with a change in diet and lifestyle to lower the level of cholesterol and other fats (such as triglycerides) in the blood of children (10 years of age and older) and adults. In these children and adults, diet and other lifestyle changes alone were not effective in lowering their cholesterol. The use of Ezetrol in children less than 10 years of age is not recommended. Ezetrol may be used alone or with other cholesterol lowering medicines called statins or fenofibrate. Ezetrol can cause serious side effects including drug-induced liver injury, and serious skin reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilic and systemic symptoms. Patients taking Ezetrol alone or with a statin or fenofibrate may need to have blood tests done before and during treatment to check and monitor the health of their liver. Patients should contact their healthcare professional immediately if they experience symptoms of liver injury such as, severe abdominal pain (especially if felt on the upper right side below the ribs), dark urine, general itchiness, severe nausea or vomiting, pale stools, or yellowing of the skin or eyes. Patients should stop taking Ezetrol and seek immediate medical help if they experience symptoms of serious skin reactions, including severe peeling and swelling of the skin, blistering of the skin, mouth, eyes, or genitals, and fever; skin rash with pink-red blotches, particularly on the palms of the hands or soles of the feet, which may blister; accompanying flu-like symptoms such as fever, chills, or aching muscles. Patients/parents/caregivers should discuss any questions or concerns about this information with their healthcare professional. Information for healthcare professionals Healthcare professionals are advised to: Consult the safety information in the Ezetrol CPM. Consider the benefits and risks for patients prior to initiating or continuing treatment with Ezetrol. Consider performing liver function tests at the initiation of Ezetrol, whether administered as monotherapy or in combination with a statin or fenofibrate and subsequently as required. Instruct patients to immediately contact a healthcare professional if they experience symptoms of liver injury. Liver function should be evaluated if liver injury is suspected. Instruct patients to stop taking Ezetrol and to seek immediate medical help if they experience symptoms of SCARs. Action taken by Health Canada Health Canada, in collaboration with Organon Canada Inc., updated the CPM for Ezetrol. Health Canada will work with manufacturers of generic versions of ezetimibe to update their respective CPMs. Health Canada is communicating this important safety information to healthcare professionals and Canadians via the Recalls and Safety Alerts Database on the Healthy Canadians Web Site. This communication will be further distributed through the MedEffect™ e-Notice email notification system. Report health or safety concerns Managing marketed health product-related side effects depends on health care professionals and consumers reporting them. Any case of DILI or SCARs including SJS, TEN, and DRESS, or other serious or unexpected side effects, in patients receiving Ezetrol should be reported to Organon Canada Inc., to the respective generic ezetimibe manufacturer, or Health Canada. Organon Canada Inc. 16766 route Transcanadienne Kirkland, QC Canada H9H 4M7 Email: medinfocanada@organon.com Telephone: 1-844-820-5468 Fax: 1-844-820-5470 You can report any suspected adverse reactions associated with the use of health products to Health Canada by: Calling toll-free at 1-866-234-2345; or Visiting MedEffect Canada's Web page on Adverse Reaction Reporting for information on how to report online, by mail or by fax. For other health product inquiries related to this communication, contact Health Canada at: Marketed Health Products Directorate Email: mhpd-dpsc@hc-sc.gc.ca Telephone: 1-613-954-6522 Fax: 1-613-952-7738 Original signed by Rui Mesquita, MD, PhD. Director, Medical Affairs Organon Canada Inc.

What you should do

• See Key Messages below