三年前，FDA在联邦公告中发布通告，要求制药企业调整含对乙酰氨基酚的复方药品处方，每单位剂量所含对乙酰氨基酚不得超过325 mg。FDA为生产商留出三年时间调整，否则这些生产商的已获批申请将被撤销。昨天，在截止日期即将到来时，FDA在公布的一份声明中发出了最后通告，“计划近期对市场上仍存在于的处方中每单位剂量含对乙酰氨基酚超过325mg的复方药的采取注销行动”。
FDA 担心服用过多对乙酰氨基酚可能造成严重肝损伤。限制每单位剂量中对乙酰氨基酚剂量低于325毫克，但仍允许高至2倍单位剂量（650毫克）的使用。在FDA的OTC药品暂行最终专论（Tentative Final Monograph，TFM）中，规定的乙酰氨基酚的最大单剂量为1000 mg，最大剂量不应超过4000 mg。服用对乙酰氨基酚复方药的患者，由于处方中通常包括用于镇痛的阿片类药物，在不具备处方医师知识的情况下，可能会因为缺乏充分的疼痛控制而增大用药剂量（增大剂量单位或用药频率）。使用含对乙酰氨基酚剂量较低的325 mg复方药品（相比于500毫克，650毫克甚至770毫克），可有助于减少肝损伤。对患者在不知情的情况下服用不止一种含对乙酰氨基酚药品，或服用对乙酰氨基酚时饮酒的情况，也有益处。
FDA 在公告中建议医疗保健专业人员开始开具较低剂量药品处方，药剂师向处方医师建议使用低剂量产品。FDA并未计划开始召回已经在流通系统中的含高剂量对乙酰氨基酚的产品，但希望企业不再继续发运到昨天为止在其控制范围内的不符合新的剂量要求的药品。
需指出的是，这并不涵盖OTC对乙酰氨基酚药品，剂量超过325mg的此类产品（最常见的是500mg），仍可继续销售。FDA仍可能最终会重新考虑对OTC药品做出变更，或在发布涵盖此类药品的最终OTC专论前，修订暂行最终专论。这将涉及到解释与规则制定活动，所以如果接下来有更多变化，将会带来大量通告。我们确信FDA将同时监测来自含有对乙酰氨基酚的OTC药品与处方药的肝损伤报告，如果没有观察到不良反应减少，可能会有更严格的审查，以减少OTC药品中对乙酰氨基酚的用量。
那些既没有采取行动要求撤销申请，也没有遵守该联邦注册公告的企业，将可能收到FDA的信函。在FDA行动前尽快行动吧！
Lachman CONSULTANTS - Bob Pollock先生 2014-01-15
校译：识林-Kapok 2014-01-18
FDA Moves to Finalize Plans to Limit Acetaminophen in Prescription Combination Products
Written by Bob Pollock • January 15, 2014
Three years has come and gone since FDA published its Federal Register Notice (here) requiring drug companies to reformulate their acetaminophen (APAP)-containing combination drug products to contain no more than 325mg of APAP per dosage unit. FDA gave manufacturers three years to make the change or face withdraw of approval of their applicants. In an announcement posted at the very end of the day yesterday, FDA gave final notice that “[I]n the near future we intend to institute proceedings to withdraw approval of prescription combination drug products containing more than 325 mg of acetaminophen per dosage unit that remain on the market.”
FDA is concerned about the potential for severe liver damage from taking too much APAP. Limiting the strength of APAP to 325mg per dosage unit will still permit dosing of up to two dosage units (650mg). The maximum single dose cited for APAP in FDA’s OTC Tentative Final Monograph (TFM) is 1000mg with a total maximum dose not to exceed 4000mg. Patients taking APAP combinations, which typically include opioids for pain, may increase dosing (number of dose units or frequency of dosing) without prescriber knowledge due to lack of adequate pain control. Having APAP-containing combination products a with lower APAP dose of 325mg (as opposed to 500mg, 650mg or even 770mg) may help mitigate chances for liver damage. This may also help in a situation where the patient unknowingly took more than one APAP containing product or drinks alcohol when taking APAP.
The FDA notice (here) recommends that health care professionals begin writing prescriptions for the lower strength product and that pharmacists contact prescribers to suggest that the lower dose products be used. FDA does not plan to initiate recall of product containing a higher amount of APAP already in the distribution system, but expects that firms will have discontinued distribution of product under their control that does not comply with the new strength requirements as of yesterday.
It should be noted that this does not cover OTC APAP products which may continue to be marketed at strengths higher then 325mg (most notably 500mg). FDA may eventually reconsider changes to the OTC products or revise the TFM prior to issuing the final OTC Monograph covering this drug. This would involve Comment and Rulemaking activities, so there will be plenty of notice if more changes are coming down the road. We are certain that FDA will be monitoring reports of liver damage from both OTC and prescription products containing APAP and, if a reduction in adverse incidents is not observed, it is surmised that efforts to reduce the amount of APAP in OTC available products may come under greater scrutiny.
Firms that have not taken action to request withdrawal of applications not in compliance with the Federal Register Notice will likely be receiving a letter from FDA (here). Take action now before FDA does!
). Take action now before FDA does!