Medicines and Healthcare products Regulatory Agency (MHRA) announces that 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.
In May 2019, MHRA 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.
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.
Healthcare professionals are advised:
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
- 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
Please refer to the following website in MHRA for details:
http://www.gov.uk/drug-safety-update/lemtrada-alemtuzumab-updated-restrictions-and-strengthened-monitoring-requirements-following-review-of-serious-cardiovascular-and-immune-mediated-reactions
In Hong Kong, Lemtrada Concentrate For Solution For Infusion 12mg/1.2ml (HK-64543) is a registered pharmaceutical product containing alemtuzumab. The product is registered by Sanofi-Aventis Hong Kong Limited, and is a prescription-only medicine. So far, the Department of Health (DH) has received 3 cases of adverse drug reaction related to alemtuzumab, but these cases are not related to autoimmune hepatitis, haemophagocytic lymphohistiocytosis, acquired haemophilia A or serious cardiovascular reactions.
Related news was previously issued by various overseas drug regulatory authorities, and was posted on the Drug Office website since 30 Nov 2018, with the latest update posted on 16 Nov 2019. Letters to inform local healthcare professionals were issued by the DH on 30 Nov 2018 and 15 Apr 2019.
In Sep 2019, the Registration Committee of the Pharmacy and Poisons Board discussed the matter, and decided that the sales pack or package insert of the product should include safety information about immune-mediated conditions and problems with the heart and blood vessels. The DH will remain vigilant on safety update of the product issued by other overseas drug regulatory authorities.
Ends/Thursday, Feb 13, 2020
Issued at HKT 17:00
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