FDA专家组无法确信阿片复方制剂的安全性

马里兰州银泉市——美国食品药品管理局（FDA）专家组不建议批准吗啡和羟考酮复方速释口服胶囊。

4月22日，FDA麻醉与镇痛药品专家组以14:0的投票结果，反对批准吗啡与羟考酮复方制剂用于中至重度疼痛治疗，原因是没有证据表明该复方制剂的安全性优于类似剂量的吗啡和羟考酮单药治疗。制造商QRxPharma公司申请这两种阿片类药物不同剂量的复方制剂用于门诊和住院患者中至重度急性疼痛的治疗。一旦获批，这将是首个含有两种阿片类药物的复方制剂，将以商品名Moxduo上市销售。

自2011年该公司首次提交申请以来，FDA已两次拒绝批准该药上市，原因包括未能提供足够证据表明Moxduo治疗可使患者获益。此外，尽管表明该复方制剂在缓解术后疼痛方面与同等有效剂量的吗啡和羟考酮单药治疗效果相当，但按照复方制剂审批规定，还应提供复方制剂优于现有单药治疗方案的证据。

为回应FDA此前的决定，QRxPharma公司对一项呼吸安全性研究进行了事后分析，试图表明该复方制剂比等效剂量的两种药物单药治疗在呼吸抑制方面具有安全性优势。不过，专家组在另一次投票表决时一致认为，该公司未能提供Moxduo比单一成分更为安全的证据。

该研究评价了拇囊炎切除术成人患者需氧饱和度下降率。受试者被分为3组，每6小时分别服用Moxduo（12 mg 吗啡/8 mg 羟考酮，127例）、24 mg吗啡（124例）或6 mg羟考酮（24例）。结果显示，Moxduo组氧饱和度<95%的患者比例最高，不过，与吗啡组或羟考酮组相比，Moxduo组氧饱和度严重下降（≤80%、≤75%和≤70%）的患者比例较低。

FDA医学官员Pamela Horn博士称，FDA评审员认为Moxduo上述优势结果可能纯属偶然。她指出，上述结果的临床意义并不明确，因为氧饱和度下降程度与有临床意义事件或临床干预并不相关。此外，在与阿片类药物相关的常见不良事件方面，Moxduo未使患者额外受益，包括恶心和呕吐。FDA还指出，该研究样本量较小， Moxduo组患者接受吸氧治疗的比例也不明确，而这些都可能导致结果偏倚。

专家组成员、华盛顿大学麻醉与疼痛医学部教授Gregory W. Terman博士指出，该研究没有针对临床上相关的患者进行评价，阿片类药物通常并不用于该研究所纳入的术后患者。他认为，与阿片类药物相关的呼吸抑制是一个难题，开发确实能够降低呼吸抑制风险的阿片类药物非常实用，继续寻找这一问题的解决方案非常重要。

专家组认为，设计更为合理的研究将有助于确认该复方制剂是否具有临床优势。一位专家组成员还强调，将所有口服阿片类药物制成抗破碎性制剂以防止注射和吸入非常重要。

FDA通常会遵循其专家组的建议，专家组成员中已经排除了潜在利益冲突者，但偶尔也会有一名成员被豁免，不过此次会议没有豁免者参加。预计FDA将于5月25日作出是否批准的决定。

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SILVER SPRING, MD. – An immediate-release combination of morphine and oxycodone in an oral capsule formulation should not be approved, a Food and Drug Administration advisory panel has recommended.

At a meeting on April 22, the FDA’s Anesthetic and Analgesic Drug Products Advisory Committee voted 14-0 that the morphine-oxycodone combination should not be approved for the management of moderate to severe pain, because there is no evidence that the combined product is safer than morphine and oxycodone when used individually at comparable doses. The manufacturer, QRxPharma, had proposed that different dose combinations of the two opioids be approved for the management of moderate to severe acute pain in outpatient and inpatient settings. If approved, this would be the first combination product that contains two opioids, and it would be marketed as Moxduo.

Since the company first filed for approval in 2011, the FDA has rejected approval twice for reasons that included the failure of the company to provided adequate evidence that there is a patient population that could benefit from treatment with Moxduo. Additionally, although the combination was shown to be as effective in alleviating postoperative pain as equally potent doses of morphine and oxycodone given separately, more evidence for a benefit over existing therapeutic options is needed for products combining drugs that are available separately, based on regulations for combination drug products.

In response to the FDA’s earlier decision, QRxPharma had conducted a post hoc analysis of a respiratory safety study in an attempt to show the combination had a safety advantage in terms of respiratory depression over equivalent doses of the separate components. In another vote, the panel unanimously agreed that the company had not provided evidence that Moxduo was safer than the individual components.

The study evaluated oxygen desaturation rates among adults after a bunionectomy who were divided into three treatment groups. Study participants received either Moxduo (12 mg of morphine/8 mg of oxycodone) every 6 hours (127 patients); 24 mg of morphine every 6 hours (124 patients); or 6 mg of oxycodone every 6 hours (24 patients).

The highest proportion of patients who dropped below 95% oxygen saturation was in the Moxduo group. The proportion of those who had more serious levels of oxygen desaturation (at or below 80%, at or below 75%, at or below 70%) was lower among those on Moxduo, compared with those on either morphine or oxycodone, however.

Dr. Pamela Horn, an FDA medical officer, said that the FDA review concluded that the analyses favoring Moxduo could be a chance finding. She noted that the clinical relevance of these findings was not clear, since the depth of desaturation was not correlated with clinically notable events or clinical interventions. In addition, Moxduo was not associated with a benefit regarding common opioid-related adverse events, including nausea and vomiting. The FDA also noted that the study was small and that it was unclear how many patients receiving Moxduo were started on oxygen therapy, which could have skewed the results.

Panelist Dr. Gregory W. Terman, professor in the department of anesthesiology and pain medicine at the University of Washington, Seattle, said the study did not evaluate what he considered clinically relevant patients, noting that opiates are not typically administered on a schedule postoperatively, as was the case in the study. Respiratory depression associated with opiate treatment is a huge problem, and it would be useful to have an opiate that could reliably reduce the risk of respiratory depression, he said, noting that it is important to continue to look for solutions to this problem.

The panel agreed that more appropriately designed studies would be helpful in determining whether the combination provided any clinically relevant advantages. One panelist stressed the importance of making all oral opiate products crush-resistant to deter injection and snorting.

The FDA usually follows the recommendations of its advisory panels. Panel members have been cleared of potential conflicts. Occasionally, a panelist is given a waiver but not at this meeting. A decision on approval is expected by May 25.