FDA Proposes Liver, GI Risk Warnings For OTC Pain Relievers

FDA proposes adding warnings on labeling for OTC pain relievers to advise consumers of "potential health risks" associated with acetaminophen and NSAIDs such as aspirin, ibuprofen and naproxen.

The proposed rule, published in the Dec. 26 Federal Register, would require acetaminophen product labeling to include warnings about potential liver damage. Non-steroidal anti-inflammatory drugs would carry updated warnings on adverse gastrointestinal and renal side effects linked to improper use, under the proposal.

The rule would amend FDA's labeling regulations and the tentative final monograph on nonprescription internal analgesic, anti-pyretic and anti-rheumatic (IAAA) drug products.

"The new labeling would be required for all OTC drug products that contain only an IAAA ingredient, as well as products that contain an IAAA ingredient with other ingredients, such as cold symptom relievers," FDA said.

The proposed rule is based on the Nonprescription Drug Advisory Committee's discussions and recommendations from a 2002 meeting as well as on public comments and a review of scientific literature, according to the agency.

In the proposed rule, FDA outlines separate labeling changes for acetaminophen products and for NSAIDs.

Labeling for acetaminophen-containing products would be required to include new warnings highlighting the potential for liver toxicity.

The warnings will specifically address the increased risk of liver damage occurring "particularly when using acetaminophen in high doses, when taking more than one product with acetaminophen and when taken with moderate amounts of alcohol," FDA said.

The new warning incorporates alcohol warning language into the liver toxicity statement because it is "interrelated," saves space, and is more likely to be read and understood than separate warnings, according to the agency.

The liver warning would be the first listing under the "warnings" heading, except on products that contain both acetaminophen and aspirin, where it would follow warnings related to Reye's syndrome and allergies.

The proposed warning reads: "Liver Warning: This product contains acetaminophen. Severe liver damage may occur if you take

more than [insert maximum number of daily dosage units] in 24 hours

with other drugs containing acetaminophen

3 or more alcoholic drinks every day while using this product"

Other required statements would include "do not use with any other drug containing acetaminophen (prescription or nonprescription); ask a doctor or pharmacist before using with other drugs if you are not sure;" and "ask a doctor before use if you have liver disease."

FDA cites the prevalence of acetaminophen toxicity case reports in the databases involving people with pre-existing liver disease; the revised language is intended to drive consumers to involve their physicians in determining appropriate use of acetaminophen.

The American Liver Foundation (ALF) applauded the agency's proposed rule to amend labeling for acetaminophen products to accentuate liver risks associated with the analgesic.

"It is crucial for people to understand what drugs they are putting into their system," ALF Chairman James Boyer, M.D., stated Dec. 21.

"I regularly prescribe [acetaminophen] for my patients with liver disease. The crucial issue is to take the correct amount of the drug and no more. We feel the new information on the labels will help people understand the proper dosage of all of these products," Boyer added.

Acetaminophen products labeled for children under 12 would be required to carry similar warnings, specifying that severe liver damage could occur if the child takes "more than 5 doses in 24 hours" or with other drugs containing the ingredient.

To address adult use of pediatric products, FDA also proposes inclusion of a statement that the product does not contain directions or warnings for adult use.

The proposed rule includes variations on the warnings designed for products intended for both pediatric and adult use.

The agency plans to address the lack of standardization in pediatric dosage information, particularly for infants under age two, in a future Federal Register publication.

To prevent excessive dosing related to the use of multiple OTC products, FDA is proposing the name "acetaminophen" be "enhanced to allow consumers to better identify acetaminophen containing products among the many products currently available on the OTC market."

Manufacturers would be required to prominently identify acetaminophen as an ingredient on a product container's principal display panel (PDP) and, when applicable, a product's outer carton, in bold, contrasting or fluorescent type. The proposed rule also sets guidelines for the type size relative to other printed information on the package.

Meanwhile, NSAID product packaging would be required to include revised warnings about possible stomach bleeding. Specific warnings outlined in the proposed rule highlight an increased risk "in persons over age 60, in persons who have had prior ulcers or bleeding, in persons who take a blood thinner, when taking more than one product containing an NSAID, when taken with moderate amounts of alcohol and when taking for longer time than directed."

The agency previously proposed 65 as the threshold age for stomach-bleeding warning on NSAIDs labels. However, "a further review of the literature...indicates that the risk is higher" beginning at age 60, FDA said.

The agency tentatively concludes that children's NSAID products marketed under the OTC monograph should carry warnings regarding dehydration and fluid loss, which are already required for products approved under a new drug application. FDA requests comment "on the need for similar language for adults."

The agency also proposes NSAID-containing products prominently display the name of the ingredient and the term "NSAID" on the PDP, and spell out the acronym on the label. Products in compliance with a supplemental labeling request issued in 2005 would already be in compliance with this proposal (¹ (Also see "NSAID Labeling Revisions Revised By FDA; Compliance Date Extended" - Pink Sheet, 25 Jul, 2005.), p. 3 and ² (Also see "Wyeth Says NSAID Risk Label May Confuse Consumers" - Pink Sheet, 20 Jun, 2005.), p. 4).

FDA notes some manufacturers of OTC pain relievers already have voluntarily implemented the labeling changes.

Wyeth, manufacturer of Advil OTC ibuprofen products, says it began using the same warnings in 2005 and completed revising its labels by mid-2006.

In addition to labeling revisions, FDA plans to continue its ongoing campaign to increase consumer awareness of the potential adverse events related to the products.

FDA announced its public education campaign warning consumers about the link between acetaminophen and liver damage and possible GI and renal side effects associated with NSAIDs in January 2004 (³ (Also see "FDA Analgesic Safety Campaign Launches; Label Warnings Still In Progress" - Pink Sheet, 26 Jan, 2004.), p. 8).

The agency also will continue to monitor reports of adverse events associated with OTC pain relievers and will "examine available data to determine whether other measures may be needed in the future to try to decrease morbidity associated with OTC acetaminophen and NSAIDs."

The agency proposed the final version of the rule to take effect 12 months after publication in the Federal Register, "because of the importance of the proposed labeling to the safe use of OTC IAAA drug products."

Additionally, manufacturers voluntarily complying with the proposed labeling requirements before publication of the final rule will have 18 months after the rule is actually published to be in full compliance.

The agency estimates that manufacturers and marketers of affected products "would incur one-time compliance costs of $32 million in the first year to revise labeling to conform to the proposed rule." The total is based on an estimated average annualized cost to implement the changes of $677 per stock-keeping unit.

FDA's estimated compliance costs per firm range from $6,000, for firms with fewer than 20 employees, to $152,000 for firms with 500 to 749 employees.

The agency estimates savings from reduced hospital costs and deaths avoided will be "from $5.6 million to $16.8 million" each year.

The agency seeks comments on the proposed rule by June 19, 2007.

- Jessica Lake and Christopher Walker