Manufacturers argue several restrictions FDA is considering to reduce acetaminophen risks could cause more harm than good and carry "significant potential for serious unintended consequences."

In briefing materials prepared for an upcoming advisory committee meeting, industry stakeholders say potential actions such as standardizing liquid acetaminophen concentrations and removing the ingredient from combination products could increase the risk of dosing errors.

The Consumer Healthcare Products Association and McNeil Consumer Healthcare filed comments with FDA in advance of a June 29-30 advisory committee meeting to consider recommendations to reduce the risk of liver damage from acetaminophen (¹ Also see "Acetaminophen Proposals Could Hit Firms Hard Via Sales And Costs" - Pink Sheet, 1 June, 2009.).

At the meeting, a joint panel of nonprescription drug, safety and risk management and anesthetic drug experts will hear the manufacturer's and trade group's arguments, among others, as they consider specific risk-reduction options proposed by FDA.

McNeil and other firms represented by CHPA stand to lose significant revenue streams and/or incur costs related to reformulating if FDA pursues some of the options, which would take certain products off the OTC market.

One option panelists will consider is to standardize the concentration of liquid acetaminophen products to reduce the risk of a child taking a stronger concentration than appropriate or a caregiver confusing the doses of different concentrations.

CHPA says in the briefing materials that standardizing pediatric acetaminophen formulas could "lead to an increase in overdose events," if consumers use dose cups for less concentrated formulas to administer the new, mid-strength concentration.

Larger amounts of a single, mid-strength concentration also could be more difficult for "fussy or sick children" to swallow, notes McNeil, the maker of Tylenol .

The firm says changing the concentration is unlikely to significantly reduce overdoses given that so few incidents are associated with the concentrated drops.

If FDA allows only a single concentration, it would need to "re-educate" health care professionals who are accustomed to recommending dosing for the current available formulas, CHPA says. The agency also would need to educate parents and caregivers about proper dosing before changing concentrations.

A more effective way to reduce pediatric medication errors leading to overdose caused by consumer confusion is to include dosing instructions for children younger than 2 years on the product, McNeil explains.

Removing Combination Drugs Could Up Errors

CHPA and McNeil also strongly oppose FDA's proposal to remove acetaminophen from combination products to reduce the risk of consumers unknowingly taking multiple products with the ingredient and exceeding the recommended dose.

They argue combination products simplify dosing and reduce the risk of medication errors, because patients do not have to follow multiple, different dosing regimens as they would if they took two or more single-ingredient products simultaneously.

CHPA cites data in peer-reviewed journals that show combination products reduce the risk of noncompliant dosing by 24 percent to 26 percent compared to concurrent single-ingredient product use.

Combination products also ease the "pill burden" and are more affordable than taking multiple single-ingredient products, McNeil says.

The firm notes buying a separate pain reliever in addition to cough/cold medicines increases the total cost of symptom treatment by 31 percent.

CHPA says removing combination products will not significantly reduce overdoses because, "as cited in the FDA's briefing materials, serious liver injuries are rarely due to OTC combination products (less than 10 percent of all cases)."

Drug makers voluntarily strengthened labels in 2002-2003 to reduce the risk of unintentionally "doubling" acetaminophen doses by highlighting the ingredient in yellow or a contrasting color on the Drug Facts label and warning consumers not to use other medications with acetaminophen or to exceed the recommended dose, the trade group notes.

CHPA also says firms will strengthen warnings on acetaminophen labels about potential severe liver damage as required in an April 29 final monograph rule (² Also see "FDA Expands Acetaminophen, NSAID Labeling Beyond Tentative Final Rule" - Pink Sheet, 4 May, 2009.).

Pack And Dose Restrictions Could Backfire

The trade group and McNeil take issue with options to restrict pack sizes and lower the recommended adult single and daily doses.

FDA proposed both options to reduce the risk of unintentional overdose.

CHPA notes that the FDA working group did not recommend pack changes because data from U.K. studies offered a conflicting view on the impact of reduced count size, restricted sales and blister-packed acetaminophen products on liver injury.

Pack restrictions would limit access and make products with the ingredient more expensive for consumers because "larger sizes offer the best consumer value per dose," CHPA says.

Likewise, CHPA argues reducing the allowable single dose to 325 mg and the daily dose to 3,250 mg would limit consumers' choices to alleviate pain and fever, CHPA says.

"The efficiency of acetaminophen at the currently recommended strengths and at the currently recommended ... doses has been well-established" and "has a track record of safety with millions of people over decades of use," CHPA says.

Making the higher doses of acetaminophen available prescription-only also likely would increase consumer and health care system costs, McNeil adds.

Another downside to restricting packages and lowering doses is that if the changes affect only acetaminophen, consumers may switch to other OTC drugs, including NSAIDs, McNeil says.

Switching to NSAIDs may result in more people dying from NSAID-associated gastrointestinal bleeding and renal failure than those potentially spared from acetaminophen-linked liver damage, says McNeil.

Based on a study it commissioned, McNeil estimates that if 10 percent of acetaminophen users switched to NSAIDs, an additional 166 people would die annually from GI bleeding and an additional 114 people would die from acute renal failure. Conversely, if 10 percent of acetaminophen users switched to NSAIDs, there would be only 35 fewer acetaminophen poisonings annually.

However, the "dire consequences" predicted by the mathematical model are unlikely, said Paul Desjardins, senior VP for global clinical and medical affairs at Wyeth Consumer Healthcare, which makes the ibuprofen product Advil .

He explains that based on the "real-world case where there were package restrictions" in the U.K., there was also a "large increase in the number of patients who were consuming ibuprofen" between 1998 and 2000, but there "really were not additional mortalities related to GI bleeding or renal failure."

Education Is The Key

A more effective way to reduce liver damage caused by acetaminophen is through "enhanced and evidence-based education and labeling to encourage appropriate use of acetaminophen and to increase awareness of health risks associated with misuse and overdose," CHPA says.

Indeed, the trade group says it already is designing the elements of an evidence-based public health education initiative and is "committed to leading a national education effort, partnering with FDA, CDC and other stakeholders, to raise consumer awareness of the safe use of acetaminophen."

The two-pronged campaign aims to increase awareness and change perceptions about the risks of acetaminophen overdose, and modify consumer behavior so more people take the recommended dose, the trade group says in briefing materials.

CHPA plans to achieve its goals by developing and empirically testing messages geared to at-risk groups; distributing messages through traditional and online communication channels; identifying ways to educate people "at point of consumption"; and using "teachable moments" and "real-life experiences" to influence consumer behaviors.

CHPA adds it will "field a bi-annual quantitative survey" to assess and verify the campaign's success and it will present its results at regular meetings with FDA.

- Elizabeth Crawford (e.crawford@elsevier.com)

FDA Acetaminophen Options Have Unintended Consequences - Drug Makers

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