Lemtrada▼ (alemtuzumab): updated restrictions and strengthened monitoring requirements following review of serious cardiovascular and immune-mediated reactions

A review of the benefits and risks of alemtuzumab (including fatal reactions) in the treatment of multiple sclerosis has now concluded and recommended a revised indication, additional contraindications, and strengthened monitoring requirements before, during and after treatment. Patients offered alemtuzumab should be alerted to the early risks of cardiovascular events and thrombocytopenia around the time of infusion and to the delayed risk of immune-mediated reactions. Healthcare professionals should inform patients what to do if they develop any symptoms of these disorders.

Advice for healthcare professionals:

Restricted indication

  • alemtuzumab should only be used as single disease-modifying therapy in adults with either:
    • highly active relapsing-remitting multiple sclerosis despite a full and adequate course of treatment with at least one disease-modifying therapy or
    • rapidly evolving severe relapsing-remitting multiple sclerosis defined as 2 or more disabling relapses in 1 year, and with one or more gadolinium enhancing lesions on brain magnetic resonance imaging (MRI) or a significant increase in T2-lesion load compared to a recent MRI scan

New contraindications and revised monitoring requirements

  • alemtuzumab is contraindicated in patients with:
    • severe active infection until complete resolution
    • uncontrolled hypertension
    • a history of arterial dissection of the cervicocephalic arteries
    • a history of stroke
    • a history of angina or myocardial infarction
    • clotting abnormalities including treatment with antiplatelet or anticoagulant therapy
    • autoimmune diseases (apart from multiple sclerosis)
  • only administer alemtuzumab in a hospital with ready access to intensive care facilities
  • monitor patients closely before, during, and after alemtuzumab infusions for cardiovascular reactions and non-immune thrombocytopenia (see Revised monitoring requirements)

  • monitor patients for autoimmune disorders for at least 48 months after the last infusion – some autoimmune reactions have been reported after this routine monitoring period

Advice to give to patients

  • alert patients receiving alemtuzumab to the signs and symptoms of serious adverse reactions described within a few days of an infusion and to seek urgent medical attention if they develop the following:
    • chest pain, coughing up blood, or breathing difficulty
    • drooping of the face, severe headache, neck pain, weakness on one side, or difficulty speaking
    • skin or eyes turning yellow, or dark urine, abdomen pain, bleeding or bruising easily (signs of liver damage)
    • fever, swollen glands, bruising, or rash

Restricted indication and new contraindications for use

Lemtrada (alemtuzumab) is a monoclonal antibody authorised for the treatment of adults with relapsing-remitting multiple sclerosis. In May 2019, we informed of interim restrictions on the use of alemtuzumab (Lemtrada▼) for relapsing multiple sclerosis during an urgent European safety review of serious cardiovascular reactions occurring within a few days of infusion and of immune-mediated events.

The review concluded that serious cardiovascular reactions can rarely occur within 1 to 3 days of alemtuzumab infusions in people without any identifiable risk factors. Reactions included myocardial ischaemia, cerebral haemorrhage, arterial dissection of the cervicocephalic arteries, pulmonary alveolar haemorrhage, and non-immune thrombocytopenia.

The review also found unpredictable and potentially fatal immune-mediated reactions can occur within months and up to at least 4 years after treatment with alemtuzumab. Reactions included autoimmune hepatitis, haemophagocytic lymphohistiocytosis, and acquired haemophilia A. The review also identified serious cases of Epstein-Barr virus reactivation reported after treatment, including hepatitis. Some patients developed more than one autoimmune disorder following treatment.

Alemtuzumab should now only be used in adults with highly active relapsing-remitting multiple sclerosis if they have not responded to a full and adequate course of treatment with another disease-modifying treatment or if they have rapidly evolving severe relapsing-remitting multiple sclerosis. New contraindications and risk minimisation measures have also been introduced and a letter sent to prescribers and dispensers of alemtuzumab.

Frequencies of reactions reported

The frequency of thrombocytopenia (including both immune and acute non-immune cases) associated with alemtuzumab is common (affecting up to 1 in 10 patients). The frequency of myocardial infarction, pulmonary alveolar haemorrhage, and arterial dissection is not known because these reactions were only observed in the post-marketing setting. However, estimated post-marketing reporting indicates that the rate of events occurring within a week of treatment were 2 cases per 10,000 patients for myocardial infarction; 3.6 per 10,000 patients for stroke; 1.6 per 10,000 patients for arterial dissection; and 4.3 per 10,000 patients for pulmonary alveolar haemorrhage.

The frequency of acquired haemophilia A is uncommon (up to 1 in 100 patients) and the frequency of haemophagocytic lymphohistiocytosis is rare (up to 1 in 1000 patients). The frequency of autoimmune hepatitis is not known as this reaction was only observed in the post-marketing settings. The estimated post-marketing reporting rate was 10.7 cases of autoimmune hepatitis per 10,000 patients.

Revised monitoring requirements for alemtuzumab infusions

Alemtuzumab treatment should be started and monitored by a neurologist experienced in the treatment of multiple sclerosis in a hospital with immediate access to specialists and equipment required for the diagnosis and management of adverse reactions, including intensive care facilities.

Before starting alemtuzumab infusions:

  • check urinalysis including microscopy; full blood count (with differential white cell count); thyroid function test; serum creatinine and liver function tests;
  • take baseline electrocardiogram (ECG) and vital signs including blood pressure and heart rate

During alemtuzumab infusions:

  • monitor patients clinically and record their blood pressure and heart rate continuously or at least once every hour
  • discontinue the infusion if they develop a severe adverse reaction such as a serious cardiovascular or haemorrhagic event

After completing alemtuzumab infusions:

  • monitor patients for infusion reactions for at least 2 hours; consider hospital admission in any patient developing a serious adverse reaction and continue observing them until it has resolved
  • discuss the risk of delayed infusion-related reactions with patients and tell them to seek urgent medical care if they experience any possible symptoms or signs
  • check platelet counts immediately after finishing treatment on days 3 and 5 of the first infusion course and on day 3 of any subsequent course. Clinically significant thrombocytopenia should be monitored until it resolves and consider referring to a haematologist for advice on management.

Patients should be monitored for early signs of autoimmune disorders until at least 48 months after the last dose of alemtuzumab. Patients should be told that more than one autoimmune disorder could develop and that autoimmune conditions have been reported after this routine monitoring period.

Updated risk management programme

The Lemtrada patient alert card, prescriber checklist and guides for patients and healthcare professionals will be updated with detailed information on the risks of cardiovascular and immune-mediated reactions and the revised monitoring requirements.

Provide the patient guide and alert card to patients before prescribing alemtuzumab and discuss the risks of treatment with them.

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.

Article citation: Drug Safety Update volume 13, issue 7: February 2020: 2.

Published 12 February 2020