FDA对双相患者使用抗癫痫药物规定添加构想自杀观念的警告

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FDA对双相患者使用抗癫痫药物规定添加构想自杀观念的警告
Stephen Barlas
2009年2月1日

FDA敦促所有抗癫痫药物的制造商在处方信息上增加可能构想自杀观念的新警告，同时为消费者提够新的经药房发布的用药指南。

另外，企业将不得不为每种药物都进行风险评估与降低计划（REMS），这是FDA为那些可能有非常危险副作用的药物而设置的。

十一种抗癫痫药物中的一些和FDA有关的，也用于治疗双相情感障碍。这些包括双丙戊酸钠（双丙戊酸钠），拉莫三嗪（拉莫三嗪）和卡马西平（痛痉宁）。双丙戊酸钠ER的处方信息长达28页；拉莫三嗪58页。没有一种药物当前包含构想自杀观念的警告。FDA命令企业必须把关于构想自杀观念的用语加入到医护人员标识的“警告”栏和用药指南里。

大量制药商的发言人指出他们会依从FDA的指导。这已经是从2008年3月开始的第五次FDA使用新的安全标识。这是当局通过国会在2007年度FDA修改案上授权此机构的。在去年夏天，此机构使用此项权利在抗精神类药物添加医护人员标识的警告信息。

作出规定构想自杀观念的警告放在医护人员标识的底部，包括在“警告”栏里。这是一种合适的要求比起警告需出现在框中或黑框中标识的开头要好多了。早在FDA修订案通过之前，这样的警告在SSRI抗抑郁剂药物上就明文规定了。

在2008年6月的FDA边缘及中央神经系统药物和心理药理学药物咨询委员会联合会议中，与会成员推荐新的标识用语和用药指南。

但是，至少一位有影响力的精神科医生对在服用抗癫痫药物的双相患者中实行新的警告产生疑议。David Kahn医学博士，哥伦比亚大学临床精神病学教授、纽约长老会医院哥伦比亚大学医学中心临床副主席质疑事情要做到这种程度——任何FDA引用的临床试验要包括双相障碍患者。他注意到构想自杀观念对于服用抗癫痫药物的双相患者来说是“非常不寻常的结果。”

Kahn说双相情感障碍患者如果不治疗，那么将“比因考虑的安全用药造成的结果有远远更高的自杀牵连”，他继续补充说：“事实上，如果出现少量患者变糟而不是更好，那么患者和医生注意这种可能性并监控它是合理的，但是不能因为有非常不寻常的结果而害怕治疗。”

Kahn同意许多精神科医生感到构想自杀观念的黑框警告，FDA敦促制药商添加到SSRI抗抑郁药物的标签，使医生和家庭都都不敢轻易使用抗抑郁药物。“来自我的同事John Mann的最新资料显示减少处方用药已经带来自杀增加的倾向。”他讲到。

回应FDA的公告，美国癫痫协会也产生同样的担忧。他们说：“医生已经表示担忧患者将自行停药造成发作风险。与抗癫痫药物有关的自杀的风险相比使患者不进行治疗的潜在风险要危险得多。”

Crystal Rice，FDA发言在给《精神病时代》一份声明指出：“在199例包括荟萃分析的试验中，28例有双相情感障碍。与安慰剂治疗相比，当患者接受癫痫、精神病和其他疾病治疗有很高比例的自杀行为和想法。自杀想法或行为的相关风险在癫痫(3.5)的临床试验上与其他精神疾病(1.9)治疗或其它缺陷(1.5)比要更高。但是癫痫和精神疾病的绝对风险的差异是相似的。”

FDA指定的新的“警告”用语确实涉及了当决定是否开出抗癫痫药物的处方，医生平衡风险和利益。但是，用语没有涉及到双相情感障碍的患者。这新的警告声明：“癫痫和许多其他用到抗癫痫药物的疾病，本身就有其发病率、死亡率和更高的自杀想法和行为。如果自杀想法和行为在治疗中出现，开药者需要考虑出现在每个患者身上的这些症状是否可能与被治疗的疾病有关。”

然而，涉及到精神疾病的必要的警告写到：“自杀想法或行为的相关风险在癫痫的临床试验中要高于精神疾病或其它疾病，但是绝对风险差异两者却很相似。”

FDA规定了抗癫痫药物要参与新的专业测试。这是国会2007年食品与药品管理修订案中赋予的。那项法案加强了机构改变标识的力度。在修订案中，FDA可以要求企业30天内提交新的标识，或者提供理由，为什么他们不认为改变标识是必要的。万一企业我行我素，法案提供了严格的时间解决这类争端并允许机构强制执行。
February 1, 2009
Psychiatric Times. Vol. 26 No. 2
Washignton Report
FDA Dictates Suicide Ideation Warning for Antiepileptics Used for BipolarDisorder
Stephen Barlas


The FDA is forcing manufacturers of all antiepileptic drugs to include new warnings of possible suicide ideation in the prescribing information and also to prepare a new Medication Guide to be distributed by pharmacies to consumers. In addition, the companies will have to produce a Risk Evaluation and Mitigation Strategy for each drug, which the FDA only requires for drugs with possible adverse effects it considers especially dangerous.
Some of the 11 antiepileptics of concern to the FDA are also used to treat bipolar disorder. These include divalproex (Depakote), lamotrigine (Lamictal), and carbamazepine (Tegretol). The prescribing information for Depakote ER is 28 pages long; for Lamictal, 58 pages. Neither drug currently carries a warning about suicide ideation. The FDA is dictating the language the companies must include on suicide ideation in the “Warnings” section of the professional labeling and in the Medication Guide.
Spokespersons for a number of manufacturers indicated they would comply with the FDA’s order. This is the fifth time since March 2008 that the FDA has used new safety labeling authority granted to the agency by the Congress in the FDA Amendments Act of 2007. This past summer, the agency used that authority to mandate a boxed warning on the professional labeling for antipsychotics.
Dictating the warning on suicide ideation in the depths of the professional label, within the “Warnings” section, is a milder requirement than requiring the warning to appear at the beginning of the labeling, in a box, or in a “black box.” Such a warning was mandated for SSRI antidepressants before passage of the FDA Amendments Act.
The new labeling language and Medication Guide were recommended at a joint meeting of the FDA’s Peripheral and Central Nervous System Drugs and Psychopharmacologic Drugs Advisory Committees in July 2008.
However, at least one prominent psychiatrist has raised questions about the application of the warning to patients who take antiepileptics for bipolardisorder. David Kahn, MD, clinical professor of psychiatry at Columbia University and vice chair for clinical affairs at Columbia University Medical Center of New York Presbyterian Hospital, questioned the extent to which any of the clinical trials the FDA cited included patients with bipolar disorder. He noted that suicide ideation for patients with bipolar disorder who were taking an antiepileptic agent was “a very unusual outcome.”
Kahn said bipolar disorder has “far higher rates of suicide attached to it if untreated, than is suggested to occur as a result of taking the specific drugs in question.” He added, “If there are, in fact, rare patients made worse rather than better, it is reasonable for both patients and doctors to be aware of this possibility and to monitor for it, but not to be afraid of the treatment since it is a very unusual outcome.”
Kahn agreed that many psychiatrists felt the black box warning on suicide ideation that the FDA forced manufacturers to add to the labels of SSRI antidepressants discouraged physicians and families from using antidepressants. “The more recent data from my colleague, John Mann, is that decreased prescribing has brought the trend of increased suicide,” he stated.
Reacting to the FDA announcement, the American Epilepsy Society raised the same concern. It said, “Doctors have voiced concern that patients will stop taking the drugs and risk seizures. The risk of suicide possibly associated with (epilepsy drugs) is extremely small compared to the potential danger of leaving patients untreated.”
Crystal Rice, an FDA spokeswoman, provided a statement to Psychiatric Times that read: “Of the 199 trials that were included in the meta-analysis, 28 trials had bipolar disorderas the trial indication. Patients who were treated for epilepsy, psychiatric disorders, and other conditions were all at increased risk for suicidal behavior and thoughts when compared to placebo. The relative risk for suicidal thoughts or behavior was higher in the clinical trials for epilepsy (3.5) compared to those for psychiatric (1.5) or other indications (1.9). The absolute risk differences, however, were similar for the epilepsy and psychiatric indications.”
The new “Warnings” language dictated by the FDA does indeed reference the need for physicians to balance risk and benefits when deciding whether to prescribe antiepileptics but the language does not make any reference to patients specifically with bipolar disorder. The new warning states: “Epilepsy and many other illnesses for which antiepileptic drugs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.”
However, the required warning does reference psychiatric conditions by noting: “The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.”
The FDA’s dictate on antiepileptics will test the new authority Congress gave it in the 2007 Food and Drug Administration Amendments Act. That law strengthened the agency’s hand with regard to requiring label changes. Under the Amendments Act, the FDA can require companies to submit new labeling within 30 days, or provide a reason why they do not believe such labeling changes are needed. In cases of nonadherence, the act provides strict timelines for resolving the issue and allows the agency to initiate an enforcement action.