ST LOUIS (MD Consult) - On February 5, 2010, the US Food and Drug Administration (FDA) issued an alert about updated information concerning the risk of progressive multifocal leukoencephalopathy (PML) occurring in patients who receive the immunosuppressant drug Tysabri (natalizumab). The product label will now state that the risk of PML increases with the number of Tysabri infusions given. This new safety information was added after the FDA received reports of 31 confirmed cases of PML (as of January 21, 2010) in patients who had received Tysabri infusions.
In February 2005, the marketing of Tysabri was suspended by the manufacturer after 3 patients in clinical trials (2 patients in multiple sclerosis [MS] trials and 1 patient in a Crohn's disease [CD] trial) experienced PML. In June 2006, the FDA approved an application for the remarketing of Tysabri as monotherapy for the treatment of patients with relapsing forms of MS.
Approximately 66,000 persons worldwide have received at least 1 dose of Tysabri since marketing resumption (through December 31, 2009), and no reported cases of PML occurred in patients treated for <12 months. In patients treated with 24 to 36 infusions of Tysabri, the overall worldwide rate and the rate in the United States of PML development is similar to the rate seen during clinical trials (1 case per 1,000 patients treated). Outside of the United States, the rate is approximately 2 cases per 1,000 patients. The reasons for this difference are unknown. Limited clinical experience exists beyond 36 Tysabri infusions either in clinical trials or in the postmarketing setting.
Tysabri is generally recommended for patients with MS who have demonstrated an inadequate response to, or are unable to tolerate, an alternate MS therapy. Tysabri is also approved for inducing and maintaining a clinical response and remission in patients with moderately to severely active CD who have shown an inadequate response to, or are unable to tolerate, conventional CD therapies.
Progressive multifocal leukoencephalopathy is a rare infection of the brain caused by the JC virus, which is a common virus often acquired during childhood. Most adults have been infected with JC virus, but do not experience PML. The virus appears to remain inactive unless certain circumstances, such as an immunosuppressive state, foster viral reactivation. Once reactivated, the virus may infect the brain and cause PML.
The symptoms of PML may begin gradually, usually worsen rapidly, and vary depending on which part of the brain is infected. These symptoms may include difficulty with walking and other movements, decline in mental function, and problems with vision and speech. Rarely, headaches and seizures occur. Symptoms of PML may be similar to those associated with multiple sclerosis.
Tysabri should be withheld at the first sign or symptom suggestive of PML. A diagnosis of PML is made on the basis of results from magnetic resonance imaging of the brain, and is confirmed by the discovery of JC virus in cerebrospinal fluid.
An additional update to the Warnings and Precautions section of Tysabri's drug label has been added to inform healthcare professionals about the occurrence of Immune Reconstitution Inflammatory Syndrome in patients in whom PML developed and who subsequently discontinued Tysabri. Immune Reconstitution Inflammatory Syndrome is a rare condition characterized by a severe inflammatory response that can occur during or after immune system recovery, causing an unexpected decline in a patient's condition.
At this time, despite all of these concerns, the FDA believes that the clinical benefits of Tysabri continue to outweigh the potential risks.
圣路易斯(MD Consult)——2010年2月5日，美国食品药品管理局(FDA)发布了一条有关接受免疫抑制剂Tysabri(那他珠单抗)治疗的患者中进行性多灶性白质脑病(PML)发病风险的最新警示。该药品的说明书将标明， PML发病风险会随着Tysabri 输液的给药剂数而增加。FDA在收到31例接受Tysabri输液治疗的患者确诊为PML的报告(即2010年1月21日)后补充了这条新的安全性信息。
2005年2月，Tysabri的生产厂家因临床试验中出现3例PML患者 [多发性硬化症(MS)试验中有2例，克罗恩病(CD)试验中有1例]而暂停了该药的上市销售。2006年6月，FDA批准Tysabri重新上市，作为复发性MS患者的单药治疗药物。
自Tysabri重新上市后(直至2009年12月31日)，全球范围内约有66,000例患者接受了至少1剂Tysabri治疗，在疗程>12个月的患者中无PML病例报告。在接受24~36剂Tysabri输液治疗的患者中，全球的PML总发病率和美国的PML发病率均与临床试验结果相近(1例PML/1,000例接受治疗的患者)。美国以外其他国家的发病率约为2/1,000例患者。差异原因尚不清楚。在临床试验中及上市后应用36剂以上Tysabri输液进行治疗的临床经验均很有限。
Tysabri通常被推荐用于治疗那些已证实MS替代疗法疗效不充分或对其无法耐受的MS患者。对于患有中度和重度活动期CD、经证实CD常规疗法的疗效不充分或对其无法耐受的患者，FDA亦批准将Tysabri作为其诱导治疗及临床有效期和缓解期的维持治疗。
进行性多灶性白质脑病系乳头多瘤空泡病毒(JC病毒)所导致的一种罕见的脑部感染，该病毒是一种常见病毒，常感染于儿童期。大多数成人均感染有JC病毒，只是未发生PML。此病毒可能一直处于休眠状态，只在免疫功能低下等某些特定情况下方可激活。一旦激活，病毒即可感染脑部并导致PML。
PML的症状出现缓慢，通常恶化迅速，并因受累的脑区而异。这些症状包括行走及其他运动困难、智力下降以及视力和言语障碍等。极少数情况下还可出现头痛和癫痫。PML的症状与多发性硬化症相近。
出现PML的首发征象时应停用Tysabri。PML的诊断依据为脑部磁共振成像结果，脑脊液中发现JC病毒是该病的确诊依据。
Tysabri的药品说明书在警告和注意事项部分亦做了更新，以告知医护人员那些发生PML及随后停用Tysabri的患者可出现免疫重建炎症综合征。免疫重建炎症综合征是一种罕见疾病，特征表现为重度炎症反应，发生于免疫系统恢复过程中或之后，可导致患者病情突然恶化。
目前，尽管存在上述各种顾虑，FDA仍认为，Tysabri的临床收益将继续超过其潜在风险。
