New Labeling Required for OTC Pain Relievers and Fever Reducers… And More to Come?

May 1, 2009

By Carrie S. Martin

On April 29, 2009, FDA issued a final rule requiring new labeling for over-the-counter (“OTC”) pain relievers and fever reducers, also known as internal analgesic, antipyretic, and anti-rheumatic drug products (“IAAAs”).  The rule revises 21 C.F.R. Part 201 to require manufacturers to add specific warnings to their labeling about the safety risks associated with acetaminophen and non-steroidal anti-inflammatory drugs (“NSAIDs”), like aspirin, ibuprofen, naproxen, and ketoprofen.  In addition, the final rule requires that certain information, such as ingredient names, be prominently displayed on principal display panels (“PDPs”) of these products. 

FDA did not, however, issue final rules for several labeling issues discussed in its 2006 proposed rule.  As a result, OTC IAAA manufacturers can likely expect FDA to issue additional labeling changes at some point in the future. 

What products are covered under the new rule?

The final rule applies to all OTC pain relievers and fever reducers that contain acetaminophen or an NSAID, including combination products that contain one of these ingredients and other non-analgesic ingredients.

What new labeling is required?

There are four new major labeling requirements in FDA’s final rule:


• Manufacturers of products containing acetaminophen must add a warning about severe liver injury on the outside container or wrapper of the retail package (or the immediate container label if there is not outside container or wrapper) of their products.  New 21 C.F.R. §§ 201.66, 201.326(a)(1)(iii)-(v).

• Likewise, manufacturers of products containing an NSAID must add a warning about severe stomach bleeding on the outside container or wrapper of the retail package (or the immediate container label if there is not outside container or wrapper) of their products.  New 21 C.F.R. §§ 201.66, 201.326(a)(2)(iii)-(v).

• The new rules contain the specific language that must be included based on whether the product is indicated for adults, children under the age of 12, or both.  New 21 C.F.R. §§ 201.326(a)(1)(iii)-(v), (a)(2)(iii)-(v).

Statement of Identifies 

• The ingredient names (e.g., acetaminophen, aspirin, ibuprofen) of the IAAA products must be:  (a) highlighted (e.g., fluorescent, color contrast) or be in bold type; and (b) be in a prominent print size on the PDP.  This requirement applies to combination products as well.  New 21 C.F.R. §§ 201.326(a)(1)(i), (a)(2)(i).

• For NSAID products or combination products containing an NSAID, the term “(NSAID)” must be:  (a) highlighted or be in bold type; and (b) be in a prominent print size on the PDP as part of the established name of the drug or after the general pharmacological (principal intended) action of the NSAID ingredient.  New 21 C.F.R. §§ 201.326(a)(1)(i), (a)(2)(i).

Temporary Directional Statement 

• The PDP for IAAA products must include a directional statement—“See new warnings information”—for the next 12 months (i.e., until April 29, 2010).  The statement must also be highlighted or in bold type and be in a prominent print size.  New 21 C.F.R. § 201.326(b).

Alcohol Warnings 

• The new warnings about liver injury and stomach bleeding must also incorporate the warning on alcohol use while using the IAAA products instead of being a separate warning, as was previously required.   New 21 C.F.R. §§ 201.326(a)(1)(iii), (a)(2)(iii). 

What labeling requirements are precatory?

FDA’s new rule allows for voluntary highlighting of information under the “Active Ingredient” and “Purpose” headings in the Drug Facts section for all OTC IAAA drug products.  New 21 C.F.R. §§ 201.326(a)(1)(ii), (a)(2)(ii).

Who is required to implement the provisions of this rule?

Manufacturers of OTC pain relievers and fever reducers are required to comply with the new rule.  If an OTC drug product was approved via a new drug application (NDA), the NDA holder must submit the labeling changes as a supplement under 21 C.F.R. § 314.70(c).  The labeling, however, can be used without advance FDA approval.  New 21 C.F.R. § 201.326(c).

When does the rule go into effect?

All manufacturers must re-label their products to comply with the new rule within one year, i.e., April 29, 2010.

Why are these new labeling requirements being required?

FDA first proposed these labeling changes in a 2006 proposed rule based on the Agency’s review of data concerning the risk of liver damage and stomach bleeding with IAAA products.  FDA’s analysis found that unintentional overuse of acetaminophen was associated with a large number of emergency visits and hospital admissions and is responsible for approximately 100 deaths a year.  Post-marketing reports concerning NSAIDs showed that serious stomach bleeding can occur even when the products are used according to the directions and the warnings on the label.  Moreover, the proposed labeling changes corresponded to recommendations made by a 2002 FDA Advisory Committee meeting that addressed OTC IAAA products.

What is not covered by this final rule?

In the interest of time and the public safety, FDA decided not to address certain issues raised in the proposed rule in this final rule.  Some of these include the following:  (1) the safe daily dose for acetaminophen in healthy users; (2) the safe daily dose for acetaminophen users with chronic liver disease; (3) the safe daily dose for acetaminophen with alcohol use; (4) certain pediatric dosing; (5) various warnings that were proposed in 21 C.F.R. Part 343 but are not part of 21 CFR part 201; (6) acetaminophen-narcotic combinations; and (7) prescription labeling for OTC IAAA drug products.  FDA will, however, continue to evaluate the issues and address them in separate Federal Register notices.  The Agency did not, however, give a timeline as to when such notices might be issued.  In addition, on June 29 and 30, 2009, two FDA Advisory Committees will convene to discuss additional steps needed to warn about risks of acetaminophen overdoses.  As a result, industry should be on the look-out for additional labeling requirements involving OTC IAAA products to be coming down the pike.  This new rule, is likely only the beginning.

Categories: Drug Development