LEMTRADA (alemtuzumab) - Risk of Autoimmune Hepatitis, Haemophagocytic Lymphohistiocytosis, and Associated Serious Cardiovascular Reactions

Starting date:
October 15, 2019
Posting date:
October 15, 2019
Type of communication:
Dear Healthcare Professional Letter
Subcategory:
Drugs
Source of recall:
Health Canada
Issue:
Product Safety, Important Safety Information, Product label update
Audience:
Hospitals, Healthcare Professionals
Identification number:
RA-71299

Last updated:

Audience

Healthcare professionals including neurologists, family physicians, emergency physicians, internists, cardiologists, multiple sclerosis nurses, and hospital pharmacists

Key messages

  • Life-threatening and fatal cases have been reported in patients with relapsing remitting multiple sclerosis (RRMS) receiving LEMTRADA (alemtuzumab). This includes reports of autoimmune hepatitis (AIH) and haemophagocytic lymphohistiocytosis (HLH), as well as temporally associated serious cardiovascular reactions.
  • Healthcare professionals are advised to:
    • Evaluate serum transaminases (ALT and AST) and total bilirubin levels before starting treatment and periodically for 48 months after the last LEMTRADA dose.
    • Interrupt or stop treatment with LEMTRADA and promptly measure serum transaminases and total bilirubin if patients develop clinical signs and symptoms of hepatic dysfunction, including unexplained liver enzyme elevations.
    • Immediately evaluate patients who show symptoms of pathologic immune activation and consider a diagnosis of HLH.
    • Monitor vital signs, including blood pressure, before and during LEMTRADA infusion. If there are clinically significant changes in vital functions, stop LEMTRADA infusion and consider appropriate interventions as guided by clinical status.
  • The LEMTRADA Canadian Product Monograph has been updated to include a revised indication for use and safety information.

  

Issue

New safety information from post-market use of LEMTRADA has been reported and includes fatal cases, cardiovascular adverse events that have occurred shortly after LEMTRADA infusions, and immune-mediated adverse reactions. The LEMTRADA Canadian Product Monograph has been updated to include a revised indication for use and safety information.

Products affected

LEMTRADA® (alemtuzumab) 12 mg/1.2 mL (10 mg/mL)

Background information

LEMTRADA (alemtuzumab) is indicated for the management of adult patients with relapsing remitting multiple sclerosis (RRMS), with highly active disease defined by clinical and imaging features, despite an adequate course of treatment with at least two other disease modifying treatments (DMTs), or where any other DMT is contraindicated or otherwise unsuitable.

Previously, LEMTRADA was indicated for the management of adult patients with relapsing remitting multiple sclerosis (RRMS), with highly active disease defined by clinical and imaging features, who have had an inadequate response to interferon beta or other disease-modifying therapies.

This revised indication was implemented in light of new safety information identified from post-market use with LEMTRADA, including life-threatening and fatal cases reported in patients with relapsing remitting multiple sclerosis (RRMS) receiving LEMTRADA (alemtuzumab). This includes reports of autoimmune hepatitis (AIH) and haemophagocytic lymphohistiocytosis (HLH), as well as temporally associated serious cardiovascular reactions.

Haemophagocytic lymphohistiocytosis (HLH)
HLH is a life-threatening syndrome of pathologic immune activation characterized by clinical signs and symptoms of extreme systemic inflammation, including fever, swollen lymph nodes, bruising or skin rash. It is associated with high mortality rates if not recognized early and treated. Symptoms have been reported to occur within a few months to four years after treatment starts.

Who is affected

Information for consumers

LEMTRADA is used to treat relapsing forms of multiple sclerosis in adult patients with highly active disease who have not responded well to at least two other multiple sclerosis therapies or if these other therapies cannot be taken due to clinical reasons.

New side effects of the immune system, heart and liver have been reported with LEMTRADA. These can be serious, life-threatening or even fatal.

Patients receiving LEMTRADA should immediately speak with their healthcare professional if they experience any of the following conditions and associated symptoms:

  • Liver inflammation: nausea, vomiting, abdominal pain, fatigue, loss of appetite, yellow skin or eyes, dark urine, and bleeding or bruising more easily than normal
  • An inflammatory condition known as hemophagocytic lymphohistiocytosis: fever, swollen glands, bruising and skin rash
  • Heart problems: trouble breathing and chest pain
  • Stroke or tears in the arteries of the head and neck: drooping of parts of the face, weakness on one side of the body, difficulty with speech, sudden severe headache, and neck pain
  • Bleeding in lungs: trouble breathing and coughing blood

Information for healthcare professionals

Immune-mediated reactions
Serious cases of immune-mediated reactions, including AIH and HLH, could occur in patients treated with LEMTRADA. Healthcare professionals are advised to:

  • Evaluate serum transaminases (ALT and AST) and total bilirubin levels before starting treatment and periodically for 48 months after the last LEMTRADA dose.
  • Interrupt or stop treatment with LEMTRADA and promptly measure ALT, AST and total bilirubin in patients who develop clinical signs of hepatic dysfunction, including unexplained liver enzyme elevations or symptoms of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine.
  • Immediately evaluate patients who develop disease manifestations of pathologic immune activation and consider a diagnosis of HLH.

Cardiovascular reactions
Serious cardiovascular reactions (e.g., myocardial infarction, stroke, cervicocephalic arterial dissection, and pulmonary alveolar hemorrhage) could occur during LEMTRADA administration. Healthcare professionals are advised to:

  • Monitor vital signs, including blood pressure, before and during LEMTRADA infusion. If clinically significant changes in vital functions are observed, discontinue the infusion, continue monitoring patient’s vital signs, including ECG, and consider appropriate interventions.
  • Inform patients about the signs and symptoms of these temporally associated serious cardiovascular reactions, and advise them to seek immediate medical attention if any of these symptoms occur following infusion.

Action taken by Health Canada

Health Canada worked with sanofi-aventis Canada Inc. to update the LEMTRADA Canadian Product Monograph to include a revised indication for use and updated safety information. 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 as well as social media channels including LinkedIn and Twitter.

Report health or safety concerns

Health Canada’s ability to monitor the safety of marketed health products depends on healthcare professionals and consumers reporting adverse reactions and medical device incidents.  Any case of serious or unexpected side effects in patients receiving LEMTRADA should be reported to sanofi-aventis Canada Inc. or Health Canada.

sanofi-aventis Canada Inc.,
2905 Place Louis-R.-Renaud,
Laval (Québec) Canada, H7V 0A3
Telephone number: 1-800-589-6215
Email: Canada.pharmacovigilance@sanofi.com

To correct your mailing address or fax number, contact sanofi-aventis Canada Inc.

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
E-mail: hc.mhpd-dpsc.sc@canada.ca
Telephone: 613-954-6522
Fax: 613-952-7738

Sincerely,

Original signed by

Amit Suri, MD
Head, Medical Affairs Canada, MS
sanofi-aventis Canada Inc.