服用芬戈莫德的MS患者报告首例PML

据美国食品药品管理局(FDA)报告，在接受芬戈莫德治疗的多发性硬化症(MS)患者中出现了首例进行性多灶性白质脑病(PML)病例。

8月29日，FDA报告称，该患者在接受了近8个月的芬戈莫德治疗后被诊断为PML。PML是一种罕见的、但往往是致命性的机会性脱髓鞘感染。

芬戈莫德是一种鞘氨醇-1-磷酸（S1P）受体调节剂，于2010年被批准用于复发性MS治疗。

该患者没有接受已知可增加大脑感染风险的MS药物——那他珠单抗的治疗，但在接受芬戈莫德治疗之前，接受了1个月的干扰素β-1a和硫唑嘌呤治疗，在开始芬戈莫德治疗后，停止了上述药物治疗。但患者在接受芬戈莫德治疗前以及治疗期间，还接受了为期数月的“多个疗程”的静注皮质类固醇药物治疗。患者所用芬戈莫德为诺华制药销售的产品，商品名为Gilenya。

据FDA声明，基于临床症状和脑脊液JC病毒DNA检测结果，患者被确诊为PML，确诊后患者停止了芬戈莫德治疗。但声明没有说明患者的生存情况。该病例发生在欧洲。

PML是由JC病毒引起的一种疾病。JC病毒是一种常见病毒，通常不会引起疾病，但可导致免疫功能低下或正在服用免疫抑制剂的人群罹患PML。

那他珠单抗(Tysabri)于2004年获批上市后的数月内，接受该药物治疗的MS患者出现多例PML病例报告，随即于2005年撤市。该药物于2006年6月重返市场，但需要评估患者PML风险，包括一项严格的销售程序。

声明指出，FDA正在与诺华制药合作调查该病例情况，并将在评估完成后提出推荐意见。FDA建议，患者在咨询其医疗专业人员之前，不要停止芬戈莫德治疗。

在芬戈莫德说明书“注意事项和警告”项下，包括一项有关该药物可导致剂量依赖性外周淋巴细胞计数下降，因为淋巴细胞倍可逆性隔离在淋巴组织内，因此该药物“可能增加感染风险，有的是严重感染”的声明，但没有提及PML。该说明书还指出，芬戈莫德还未曾与抗肿瘤药物、免疫抑制剂或免疫调节剂合用于MS治疗，芬戈莫德与上述药物合用“有可能增加免疫抑制风险。”

针对与芬戈莫德治疗相关的严重风险 ，包括治疗开始时心动过缓和房室传导阻滞、感染、黄斑水肿、呼吸效应、肝脏效应以及胎儿风险，芬戈莫德在获批时附带了一项风险评估和减低策略(REMS)计划。

诺华称，全球约71,000例患者接受了芬戈莫德治疗。

点击此处下载安全通告，应将与芬戈莫德相关的严重不良事件致电800-332-1088，报告至FDA的MedWatch不良事件报告系统。

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By: ELIZABETH MECHCATIE, Internal Medicine News Digital Network

The first case of progressive multifocal leukoencephalopathy has occurred in a patient with multiple sclerosis treated with fingolimod, according to the Food and Drug Administration.

The patient was diagnosed with progressive multifocal leukoencephalopathy (PML), the rare, often fatal opportunistic demyelinating infection, after almost 8 months of treatment with fingolimod, the agency reported on Aug. 29.

Fingolimod is a sphingosine 1-phosphate receptor modulator that was approved in 2010 for treating relapsing forms of MS.

The patient had not been treated with natalizumab, the MS drug that is known to increase the risk of the brain infection, but did receive 1 month of treatment with interferon beta-1a and azathioprine prior to beginning treatment with fingolimod. Those drugs were stopped when treatment with fingolimod began. However, the patient was also treated with "multiple courses" of intravenous corticosteroids for several months before and during treatment with fingolimod, which is marketed by Novartis under the name Gilenya.

Treatment with fingolimod was stopped after the diagnosis of PML, made on the basis of clinical symptoms and detection of JC viral DNA in cerebrospinal fluid, according to the FDA statement, which does not say whether the patient survived. The case was reported in Europe.

PML is caused by the JC virus, a common virus that usually does not cause illness, but can cause PML in people who are immunocompromised or are taking medications with immunosuppressive effects.

After several PML cases were reported in patients with MS treated with natalizumab  months after it was approved for treating MS in 2004, it was taken off the market in 2005 and reintroduced in June 2006 with measures to address the risk of PML, including a restricted distribution program.

The FDA is working with Novartis to investigate this case and will make recommendations when the evaluation has been completed, the statement said. The FDA is advising patients not to stop treatment with fingolimod before discussing this with their health care professionals.

The precautions and warnings section of the fingolimod label includes a statement that the treatment causes a dose-dependent reduction in peripheral lymphocyte count, due to reversible sequestration of lymphocytes in lymphoid tissues, and the drug "may therefore increase the risk of infections, some serious in nature," but PML is not mentioned. The label also says that it has not been administered with antineoplastic, immunosuppressive, or immune modulating therapies used to treat MS and that use of fingolimod with any of these treatments "would be expected to increase the risk of immunosuppression."

Fingolimod was approved with a risk evaluation and mitigation strategy, addressing the serious risks associated with treatment, including bradyarrhythmia and atrioventricular block at the start of treatment, infections, macular edema, respiratory effects, hepatic effects, and fetal risk.

According to Novartis, about 71,000 patients worldwide have been treated with fingolimod.

The safety communication is available here. Serious adverse events associated with fingolimod should be reported to the FDA’s MedWatch program at 800-332-1088.