No GRASE For Ibuprofen, No Future In OTC Internal Analgesic Monograph
Executive Summary
Nonprescription products containing ibuprofen can now only be marketed in the US through NDAs. No companies took advantage of a proposed ibuprofen addition to the the internal analgesic, antipyretic and antirheumatic OTC monograph, issued in 2002.
US FDA has determined that ibuprofen does not meet the threshold for being permanently added to an OTC monograph and thus nonprescription products containing the analgesic ingredient must be approved through the agency's new drug application process.
Perhaps wary of FDA's safety concerns related to ibuprofen, no manufacturers used a proposal to add ibuprofen to the current analgesic, antipyretic and antirheumatic (IAAA) tentative final monograph as a vehicle to bring new products to market, even though it was issued in 2002. (The proposal was effective even though it was part of a "tentative" final monograph.)
A May 14 Federal Register notice withdraws that proposed addition to the tentative final monograph (TFM), saying specifically that ibuprofen will not be "generally recognized as safe and effective," the standard for adding monograph ingredients.
The ingredient is used in Johnson & Johnson's Motrin and Pfizer Inc.’s Advil lines and in private label OTCs. When FDA published the TFM in a proposed final rule a decade and a half ago, ibuprofen OTCs were marketed under approved NDAs or abbreviated NDAs. "This is still the case today – all ibuprofen drug products in the OTC marketplace are covered by NDAs or ANDAs. FDA is not aware of any ibuprofen drug products marketed under the TFM," the agency's Center for Drug Evaluation and Research stated in the notice.
CDER said safety issues caused it to question whether ibuprofen can be GRASE. Other elements of earlier proposed changes to the IAAA monograph – to include consistent pregnancy and allergy warnings for OTC IAAA products containing NSAIDs – remain in effect.
Ibuprofen Label Changes Since Monograph Proposal
The agency has asked multiple advisory committees to discuss the safety of ibuprofen and other nonsteroidal anti-inflammatory drugs (NSAIDs) in both Rx and OTC products since the agency 2002 proposal.
Based on the input from the panels and agency research, FDA already requires OTC ibuprofen products marketed under NDAs and ANDAs to bear warnings about gastrointestinal bleeding. The label warnings state the risk of bleeding is higher in persons who are 60 or older, have stomach ulcers or bleeding problems, take a blood thinning (anticoagulant) or steroid drug, take other Rx or nonprescription drugs, have three or more alcoholic drinks daily or who take more or for a longer time than directed. (Also see "FDA Expands Acetaminophen, NSAID Labeling Beyond Tentative Final Rule" - Pink Sheet, 4 May, 2009.)
Recommendations from advisory committees and additional FDA research also led the agency in 2016 to ask ibuprofen manufacturers to update product labels with warnings about increased risk of heart attack and stroke with the use of NSAIDs other than aspirin. (Also see "OTC NSAIDs Need Additional Label Warnings – FDA Advisory Panel" - Pink Sheet, 19 Feb, 2014.)
More recently, advisory committees discussing results of Pfizer's PRECISION trial comparing the cardiovascular risk of Rx anti-inflammatory celecoxib with naproxen and ibuprofen recommended against adding an aspirin-contraindication warning to OTC ibuprofen product labels. (Also see "OTC Naproxen Labeling: US FDA Advisory Panel Finds Imprecise Direction In PRECISION" - Pink Sheet, 26 Apr, 2018.)
From the editors of the Tan Sheet.