Lemtrada (alemtuzumab) and serious cardiovascular and immune-mediated adverse reactions: new restrictions to use and strengthened monitoring requirements

While an urgent EU safety review evaluates reports of serious cardiovascular events and immune-mediated reactions, including autoimmune hepatitis, the use of alemtuzumab (Lemtrada) has been restricted and strengthened requirements have been introduced to monitor vital signs and liver function before and during treatment. All patients on alemtuzumab for multiple sclerosis should be alerted to these risks and what to do if symptoms occur.

From:
Medicines and Healthcare products Regulatory Agency
Published
17 May 2019
Therapeutic area:
Cancer, Cardiovascular disease and lipidology, GI, hepatology and pancreatic disorders, Immunosuppression and transplantation, Neurology

Advice for healthcare professionals:

Restricted indication for new patients

  • alemtuzumab for multiple sclerosis should only be started in adults with either:
    • relapsing-remitting multiple sclerosis that is highly active despite an adequate course of treatment with at least 2 other disease-modifying therapies
    • highly active relapsing-remitting multiple sclerosis if all other disease-modifying therapies are contraindicated or otherwise unsuitable
  • patients already on alemtuzumab for multiple sclerosis may continue treatment if it is beneficial and they have discussed the additional monitoring requirements and new risks with their prescriber

New monitoring requirements and precautions for use

  • monitor vital signs, including blood pressure, before and periodically during alemtuzumab infusion – consider stopping the infusion and conducting additional monitoring, including electrocardiography (ECG), if any clinically significant changes in vital signs occur
  • monitor liver function tests before and during treatment with alemtuzumab for multiple sclerosis
  • consider discontinuing treatment in patients who develop hepatic injury or serious immune-mediated reactions
  • evaluate immediately any patients who develop early manifestations of pathologic immune activation, and consider a diagnosis of haemophagocytic lymphohistiocytosis (see below)

Advice to give to patients

  • alert patients to the symptoms of:
    • pulmonary haemorrhage, myocardial infarction, stroke, and arterial dissection within days of infusion – patients should seek urgent medical attention if they develop any symptoms of these disorders (see below), which may occur within a few days of treatment
    • hepatic injury – patients should seek urgent medical help if they develop any symptoms of liver injury including abdominal pain, jaundice, dark urine, and unexplained nausea or vomiting
    • haemophagocytic lymphohistiocytosis – patients should seek immediate medical attention if they develop unexplained fever, lymphadenopathy, bruising or rash, including if these symptoms occur several years after treatment
  • patients should speak to their doctor if they have any questions about alemtuzumab for multiple sclerosis

New urgent safety review following reports of serious cardiovascular and immune-mediated adverse reactions

An urgent EU-wide review of the safety of alemtuzumab for multiple sclerosis has begun following reports of immune-mediated reactions and serious cardiovascular events, particularly within 3 days of dosing. There have been some life-threatening and fatal cases.

While the review is ongoing, the use of alemtuzumab for multiple sclerosis has been restricted and new monitoring requirements introduced. We will update healthcare professionals once final recommendations are available.

Worldwide, more than 34,000 people with multiple sclerosis have been treated with Lemtrada in clinical trials and post-marketing in clinical practice. Since alemtuzumab (Lemtrada) was marketed in the UK in 2014, an estimated 9371 patient-courses have been administered (9474 patient-years).[footnote 1]

Cases of cardiovascular reactions

The underlying mechanism for these cardiovascular reactions has not been determined.

Pulmonary haemorrhage

5 patients developed pulmonary alveolar haemorrhage within a day of their last infusion of alemtuzumab. Reported symptoms or signs included cough, haemoptysis, hypoxia, and dyspnoea. These post-marketing cases did not have any confounding factors.

Myocardial infarction

10 post-marketing cases of myocardial infarction with increased troponin levels have been reported within 48 hours of last infusion. Of these cases, 5 did not have any risk factors, and for 2 cases it is difficult to establish the role of alemtuzumab due to other possible causes.

Arterial dissection

6 post-marketing cases of vertebral and/or carotid artery dissection have been reported, 4 of which occurred within 3 days of last infusion of alemtuzumab. No risk factors for arterial dissection were present in 3 patients.

Stroke

13 patients experienced stroke (haemorrhagic in 11 cases; ischaemic in 2) within a day of last infusion. A case series of 5 of these patients with no risk factors was published recently.[footnote 2] Some patients had significant increases in their blood pressure during treatment with alemtuzumab.

Cases of immune-mediated disorders

The immune-mediated reactions described below generally occurred around 6 months after alemtuzumab exposure so may represent secondary autoimmune mechanisms.

Autoimmune hepatitis

Several post-marketing cases of autoimmune hepatitis, including 2 fatalities have been reported following treatment with alemtuzumab. 2 of these cases have been published.[footnote 3][footnote 4]

Haemophagocytic lymphohistiocytosis

7 cases have been reported of secondary haemophagocytic lymphohistiocytosis within a few months to 4 years of starting treatment. These events occurred during post-marketing use of the medicine. A causal relationship could not be excluded in 6 cases and a description of 2 of these cases has been published.[footnote 5]

Secondary haemophagocytic lymphohistiocytosis is a life-threatening syndrome of uncontrolled immune activation. Clinical criteria for the diagnosis of secondary haemophagocytic lymphohistiocytosis have been established by the Histiocyte Society.6

About Lemtrada (alemtuzumab)

Lemtrada (alemtuzumab) 12 mg concentrate for solution for infusion was authorised in the EU in September 2013 for the treatment of adults with remitting relapsing multiple sclerosis and active disease defined by clinical or imaging features. Lemtrada is a monoclonal antibody that binds to CD52.

Report any suspected adverse drug reactions on a Yellow Card

Healthcare professionals and patients should continue to report any suspected adverse drug reactions to alemtuzumab to the Yellow Card Scheme.

Further information

Direct Healthcare Professional Communication. Alemtuzumab (Lemtrada): Restriction of use due to serious safety Concerns. April 2019.

EMA announcement. Use of multiple sclerosis medicine Lemtrada restricted while EMA review is ongoing. 12 April 2019

Article citation: Drug Safety Update volume 12, issue 10: May 2019: 1.

  1. Data derived from IQVIA IMS MIDAS, 01/2014-12/2018, and analysed by the MHRA, April 2019. The patient-courses estimate is based on the assumption that the average duration of a patient-course was 4 days. The patient-years estimate is based on the WHO Defined Daily Dose (DDD) of 0.13mg. ↩

  2. Azevedo CJ, et al. Intracerebral haemorrhage during alemtuzumab administration. Lancet Neurol 2019; 18: 329–31. ↩

  3. Canham LJW, et al. The first reported case of autoimmune hepatitis following alemtuzumab therapy for multiple sclerosis. ECTRIMS 2017; 199783. ↩

  4. El Sankari S, et al. Auto-immune hepatitis in a patient with multiple sclerosis treated with alemtuzumab. Acta Neurol Belg 2018; 118: 331–33. ↩

  5. Saarela M, et al. Hemophagocytic lymphohistiocytosis in 2 patients with multiple sclerosis treated with alemtuzumab. Neurology 2018; 90:849-51. ↩

Updates to this page

Published 17 May 2019
Contents