呼吸功能下降、死亡可能與肉毒桿菌有關


  February 8, 2008 — 在一篇正在進行的安全回顧中,美國食品藥物管理局(FDA)提出有關肉毒桿菌A(Botox、Botox Cosmetic;Allergan)和肉毒桿菌B(Myobloc;Solstice Neurosciences公司)的初步結果;這些藥物與全身性的不良反應有關,包括呼吸功能下降和死亡,類似肉毒桿菌中毒,肉毒桿菌在體內擴散到注射部位之外。
  
  在最嚴重的案例中,大部分是治療腦性麻痺肢痙攣的小孩,產生的後果包括住院和死亡;不過,以肉毒桿菌A和肉毒桿菌B治療其他疾病者出現呼吸功能下降和死亡,劑量範圍各異,包括了FDA核准的和 FDA未核准的劑量。
  
  有文獻指出使用肉毒桿菌毒素治療肢痙攣,並未獲得FDA核准,不論小孩或成人;對於12歲以下的小孩,不論何種適應症,此藥之安全性、效果和劑量都未建立。
  
  這篇聲明稿指出,發布此一訊息不代表FDA結論認為此一製劑與這安全問題有關,也不代表FDA建議醫療人員停止處方這些藥物;FDA正在斟酌,但是尚未對此有任何控管結論。
  
  FDA現在回顧藥廠臨床研究的安全資料、不良反應通報系統資料庫的上市後不良反應、以及使用肉毒桿菌毒素注射後出現肉毒桿菌中毒的小孩與成人案例;當有新的資訊時,此一聲明將做更新。
  
  針對此一回顧的結果,FDA對醫師列出以下有關肉毒桿菌毒素的建議:
  * 瞭解各種肉毒桿菌毒素製劑的強度測定(單位),以及各種單位劑量所出現的臨床表現,特別是不同的肉毒桿菌毒素製劑。
  * 仍應對肉毒桿菌毒素製劑使用者提出全身性作用警告,包括發音困難、吞嚥困難、虛弱、呼吸困難或者呼吸時痛苦;這些症狀被視為肉毒桿菌中毒,在治療後1天到數週發生。
  * 告知病患和照護者如何辨識注射肉毒桿菌毒素後的副作用症狀與徵兆;建議病患在出現意料之外的吞嚥或發音困難、呼吸困難或者肌肉虛弱等狀況時,立即尋求醫療處置。
  
  16歲以下的肉毒桿菌中毒案例,大部分是那些使用肉毒桿菌毒素製劑治療腦性麻痺肢痙攣的病患,這些不良反應包括發音困難、呼吸功能不佳、需插管餵食或者輔助呼吸、住院以及死亡;這些案例的劑量範圍,肉毒桿菌A是 6.25 -32 U/kg、肉毒桿菌B則是388 - 625 U/kg。
  
  成人肉毒桿菌中毒案例,包括頸部虛弱、發音困難、眼瞼下垂、下肢虛弱與麻木;有些嚴重成人案例需要住院,但是沒有需要插管或者呼吸輔助,也沒有死亡案例報告;這些案例的劑量範圍,肉毒桿菌A是100 - 700 U 、肉毒桿菌B則是10,000 -20,000 U。
  
  FDA核准的Botox適應症是眼臉痙攣、斜頸症和嚴重原發腋汗症;Botox Cosmetic則被核准暫時治療中度到嚴重臉部眉心紋;Myobloc用於成人斜頸症。
  
  目前這些產品的標籤所記載的不良反應主要是在注射部位附近,包括治療斜頸症之後出現發音困難、或者治療皺眉紋之後出現眼瞼下垂、或是治療眼臉痙攣之後出現斜視。
  
  目前的警告標語指出的嚴重不良反應,包括嚴重發音困難和呼吸困難,可能發生在神經肌肉異常病患局部注射一般劑量的肉毒桿菌毒素製劑之後 ;基於上述,FDA現在依照類似證據,認為腦性麻痺與小孩等,使用此類製劑會有致命的全身性毒性。
  
  聲明之結論為,此一初步聲明維持FDA持續對大眾公佈藥物安全回顧的立場;FDA將向大眾公佈結論、提出建議、並在完成資料回顧之後提出控管。
  
  嚴重的不良反應必須向FDA的MedWatch通報,可以打電話1-800-FDA-1088、也可以傳真1-800-FDA-0178、或者上網 http://www.fda.gov/medwatch/report/hcp.htm 、或者寫信到 5600 Fishers Lane, Rockville, MD 20853-9787。

Respiratory Compromise, Death<

By Laurie Barclay, MD
Medscape Medical News

February 8, 2008 — As a result of an ongoing safety review, the US Food and Drug Administration (FDA) has issued an early communication regarding botulinum toxin type A (Botox, Botox Cosmetic; Allergan), and botulinum toxin type B (Myobloc; Solstice Neurosciences, Inc). These drugs have been associated with systemic adverse reactions, including respiratory compromise and death resembling that seen with botulism, in which botulinum toxin spreads in the body beyond the injection site.

In the most serious cases, reported mostly in children treated for limb spasticity associated with cerebral palsy, outcomes included hospitalization and death. However, respiratory compromise and death were reported after the use of botulinum toxin types A and B for treatment of a variety of conditions, using a wide range of botulinum toxin doses, for both FDA-approved and FDA-unapproved uses.

Despite the literature describing use of botulinum toxin to treat limb spasticity, use of botulinum toxin for treatment of limb spasticity is not an FDA-approved use, either in children or adults. The safety, efficacy, and dose of botulinum toxin have not been established for this indication or for any indication in children younger than 12 years.

"Posting this information does not mean that FDA has concluded there is a causal relationship between the drug products and the emerging safety issue," the early communication states. "Nor does it mean that FDA is advising healthcare professionals to discontinue prescribing these products. FDA is considering, but has not reached a conclusion about whether this information warrants any regulatory action."

The FDA is now reviewing safety data from clinical studies provided by the drug manufacturers, postmarketing adverse event reports from its Adverse Event Reporting System database, and the medical literature concerning children and adults diagnosed with botulism after a local injection with a marketed botulinum toxin product. Their communication will be updated as new information becomes available.

Pending the results from this review, the FDA makes the following recommendations for clinicians who administer medicinal botulinum toxin:

  • Realize that potency determinations (units) vary among the botulinum toxin products and that clinical doses expressed in units are not comparable from one botulinum product to the next.
  • Remain vigilant for systemic effects that may follow administration of botulinum toxins, including dysphagia, dysphonia, weakness, dyspnea, or respiratory distress. These symptoms, which are suggestive of botulism, have been reported from 1 day to several weeks after treatment.
  • Inform patients and caregivers regarding how to recognize the signs and symptoms of systemic effects after being injected with a botulinum toxin. Advise patients to seek immediate medical attention for worsening or unexpected difficulty swallowing or talking, trouble breathing, or muscle weakness.

Botulism cases in children younger than 16 years, most of whom received botulinum toxin for treatment of limb muscle spasticity associated with cerebral palsy, were associated with adverse events including dysphagia, respiratory insufficiency requiring use of gastric feeding tubes and ventilatory support, hospitalization, and death. Doses in these cases ranged from 6.25 to 32 U/kg for botulinum toxin type A and from 388 to 625 U/kg for botulinum toxin type B.

Adverse events associated with adult botulism cases included neck weakness, dysphagia, ptosis, and lower extremity weakness and numbness. Some serious cases in adults required hospitalization, but none required intubation or ventilatory support, and there were no reported deaths. Doses in these cases ranged from 100 to 700 U for botulinum toxin type A and from 10,000 to 20,000 U for botulinum toxin type B.

FDA-approved indications for Botox are blepharospasm, cervical dystonia, and severe primary axillary hyperhydrosis; Botox Cosmetic is approved for temporary treatment of moderate to severe facial frown lines; and Myobloc is cervical dystonia in adults.

Current labeling for these products describes adverse reactions near the injection site, including dysphagia after injections for cervical dystonia or ptosis after injections for glabellar frown lines or for strabismus and blepharospasm.

Current warnings note that important systemic adverse effects, including severe dysphagia and difficulty breathing, may occur in patients with neuromuscular disorders after local injection of usual doses of botulinum toxin. As described above, the FDA now has evidence of similar, potentially life-threatening systemic toxicity in patients with other underlying conditions, such as those with cerebral palsy, and in children.

"This early communication is in keeping with FDA's commitment to inform the public about its ongoing safety reviews of drugs," the statement concludes. "FDA will communicate to the public its conclusions, resulting recommendations, and any regulatory actions after the review of the data are completed."

Serious adverse events should be reported to FDA's MedWatch by telephone at 1-800-FDA-1088, by fax to 1-800-FDA-0178, online at http://www.fda.gov/medwatch/report/hcp.htm, or by mail to 5600 Fishers Lane, Rockville, MD 20853-9787.

    
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