The European Medicines Agency has restricted the use of alemtuzumab (Lemtrada) for multiple sclerosis while it completes its review of safety issues that have emerged in recent months. Use of the drug will be limited to RRMS patients with highly-active disease despite prior treatment with at least two disease-modifying therapies (DMTs) or for whom all other DMTs are contraindicated. Current patients on alemtuzumab can continue taking the drug in consultation with their neurologist.The EMA’s safety committee has also recommended an update to the product label that would include information on cases of autoimmune hepatitis, hemophagocytic lymphohistiocytosis, and cardiovascular complications.
Cardiovascular complications can include heart attack, stroke, cervicocephalic arterial dissection, and bleeding in the lungs, which have occurred in the 1-3 days following drug administration.
The advisory follows a safety alert issued by the U.S. Food and Drug Administration in November 2018. The alert warned of rare but serious cases of stroke and tears in the lining of arteries in the head and neck in MS patients shortly after receiving alemtuzumab.
The FDA stated that since approval of alemtuzumab in 2014 for MS, 13 cases of ischemic and hemorrhagic stroke or arterial dissection have been reported in the U.S. and Europe; 12 of these cases occurred within one day of starting alemtuzumab. These included seven cases with hemorrhagic stroke; one with both hemorrhagic stroke and dissection of both vertebral arteries; two with ischemic stroke; one with ischemic stroke and dissection of bilateral carotid and right vertebral arteries; two with dissection that involved the right carotid and left vertebral arteries; and two with unspecified type of stroke. There was one death.
The Health Canada MedEffects website lists one case of ischemic stroke with hemiplegia and facial paresis in a 50-year-old woman treated with alemtuzumab; the case was reported in 2015 (https://cvp-pcv.hc-sc.gc.ca/arq-rei/report-rapport.do?lang=en&id=000655958).
In published reports, there were two deaths in the phase II CAMMS223 trial that were possibly related to alemtuzumab: a 45-year-old female who died of an unspecified cardiovascular disorder two months after receiving the third annual cycle of drug; and a 39-year-old male who died of cerebral hemorrhage secondary to idiopathic thrombocytopenic purpura (ITP) seven months after the second annual cycle of alemtuzumab (FDA safety review, November 13, 2013). Thus far, there has been insufficient information about the 13 cases to identify patient risk factors.
A presentation at the 2019 American Academy of Neurology annual meeting will discuss five stroke cases with alemtuzumab (Azevedo et al. AAN 2019; abstract S26.005), with the suggestion that strokes were associated with rising systolic blood pressure during the week of drug infusions. The FDA noted that events occurred within the same time frame as the cytokine release syndrome, which has previously been associated with the high rate of infusion reactions during dosing. Symptoms of cytokine release were reported in the patient who later died of hemorrhagic stroke.
The U.S. product label for Lemtrada was updated in January 2019 to include a black-box warning about serious and life-threatening stroke. The Canadian product label was also updated in January 2019 but included no mention of stroke. Health Canada has not issued a safety advisory to clinicians about alemtuzumab in RRMS.