FDA Moves to Limit Maximum Dosage Strength of Acetaminophen in Prescription Combination Drug Products and Requires Labeling Changes

January 13, 2011

By Susan J. Matthees

FDA is announcing that it is taking steps to reduce the maximum dosage strength of acetaminophen in prescription combination products to 325 mg in a single dosage unit.  The Agency will also require safety labeling changes, including a boxed warning, for products that contain acetaminophen.  The changes will apply only to prescription drug combination products, not OTC products.  FDA has established a website to keep people informed about the changes. 

In a Federal Register notice, which is being published on January 14, 2011, FDA states that the changes were precipitated by the safety risks associated with acetaminophen.  Although FDA acknowledges that the recommended doses of acetaminophen do not, unlike other pain drugs, cause gastro-intestinal discomfort or bleeding, and that most people’s glutathione levels are sufficient to prevent liver damage, FDA states that the fact that some people are at increased risk for liver injury from acetaminophen is sufficient reason to warrant limiting the dosage strength of the drug.  FDA also notes that “there is a high incidence of cases of unintentional acetaminophen overdose” due to a variety of factors, including consumers taking more than their prescribed dose of pills unaware that they are taking too much acetaminophen and patients who are unaware that their prescription drugs contain acetaminophen because the ingredient is often identified as “APAP” or “ACET.” 

FDA will send sponsors of NDA and ANDA prescription acetaminophen products a letter notifying them of the required labeling changes.  FDA cites section 505(o) of the Federal Food, Drug, and Cosmetic Act (which was part of the 2007 Food and Drug Administration Amendments Act) as its authority to require safety-related labeling changes based on new safety information.  Pursuant to section 505(o), sponsors will have 30 days from the date of the letter to submit to FDA a new label or a statement detailing the reasons why the change is not warranted.  Sponsors will have until January 14, 2014, to request that FDA withdrawal approval of products containing more than 325 mg of acetaminophen.  FDA states that sponsors with approved products with more than one dosage strength, such as a dosage strength above 325 mg and below 325 mg, need only request withdrawal of approval for the higher dosage strength product and will not have to submit an application for approval of the lower strength product.  However, sponsors without a lower dosage strength will need to develop a new product strength and submit an application for approval.  FDA believes that these products will likely be approved through the ANDA process.  FDA also intimates that if companies do not voluntarily withdraw combination products that contain more than 325 mg of acetaminophen in a single dose that FDA will use the NDA withdrawal authority under section 505(e) to remove these products from the market.

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