FDA警告：超快代谢型儿童使用常规量可待因可致死

圣路易斯(MD  Consult)——2012年8月15日，美国食品药品管理局(FDA)发出一项关于儿童在因阻塞性睡眠呼吸暂停综合征接受扁桃体切除术和(或)腺样体切除术后使用可待因镇痛的安全性通告。FDA指出，近期报告了3例儿童死亡和1例未致死但危及生命的呼吸抑制病例。有证据显示，这些儿童(年龄2~5岁)具有将可待因转化为危及生命或致死量吗啡的遗传学特质。这些儿童接受的都是常规剂量范围内的可待因治疗。

FDA在通告中指出，可待因被口服后可在肝脏通过细胞色素P450 2D6 (CYP2D6)酶转化为吗啡。一些人因DNA变异而使这种酶的活性增强，从而能够更快和更完全地将可待因转化为吗啡。这些人被称为超快代谢型，在服用可待因后更容易出现血液中吗啡浓度高于正常的情况。高浓度吗啡可导致呼吸困难甚至致命。对于超快代谢型患儿，在扁桃体切除术和(或)腺样体切除术术后使用可待因可能增加呼吸困难和死亡风险。估计一般每100人中可能有1~7人为超快代谢型，但在某些种族中(如埃塞俄比亚裔)，这一比例可能高达28/100。

FDA目前正在进行一项关于可待因的安全性审查，旨在确定是否存在其他因服用可待因导致意外药物过量或死亡的病例，以及这些不良事件是否发生于其他类型疼痛治疗过程中，如与其他类型操作相关的术后疼痛。

FDA建议，在处方含可待因药物时，应根据需要使用最低有效剂量和最短疗程。对于因阻塞性睡眠呼吸暂停综合征而接受扁桃体切除术和(或)腺样体切除术的儿童，处方其他镇痛药物可能更明智。

目前已有FDA认可的检测方法可测定患者的CYP2D6基因型。

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ST LOUIS (MD Consult) - On August 15, 2012, the US Food and Drug Administration (FDA) issued a safety announcement concerning use of the analgesic codeine in children who have undergone tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome. According to the FDA, 3 pediatric deaths and 1 non-fatal but life-threatening case of respiratory depression have been recently documented in the medical literature. These children (aged 2-5 years) showed evidence of an inherited ability to convert codeine into life-threatening or fatal amounts of morphine in the body. All of the children had received doses of codeine that were within the typical dose range.

The FDA announcement states that, after oral ingestion, codeine is converted to morphine in the liver by the enzyme cytochrome P450 2D6 (CYP2D6). Some persons have DNA variations that make this enzyme more active, causing codeine to be converted to morphine faster and more completely than in other persons. These persons, known as ultra-rapid metabolizers, are more likely to experience higher than normal amounts of morphine in their blood after taking codeine. High levels of morphine can result in breathing difficulty, which may be fatal. Taking codeine after tonsillectomy and/or adenoidectomy may increase the risk for breathing problems and death in children who are ultra-rapid metabolizers. The estimated number of ultra-rapid metabolizers is generally 1 to 7 per 100 persons, but may be as high as 28 per 100 persons in some ethnic groups (eg, persons of Ethiopian descent).

The FDA is currently conducting a safety review of codeine to determine if additional cases exist of inadvertent overdose or death in children taking codeine, and if these adverse events occurred during treatment for other kinds of pain, such as post-operative pain related to other types of procedures.

When prescribing codeine-containing drugs, the FDA advises that the lowest effective dose for the shortest period of time on an as-needed basis be used. It may be advisable to prescribe alternative analgesics for children undergoing tonsillectomy and/or adenoidectomy for obstructive sleep apnea syndrome.

FDA-cleared tests are available for determining a patient's CYP2D6 genotype.