Over-the-counter drug firms will make single-ingredient liquid acetaminophen pediatric products only in one standard concentration to help prevent dosing errors, their trade association said May 4.

The announcement comes with an FDA advisory panel on deck to consider questions on improving safety in children's use of acetaminophen, and the standardization follows a recommendation made by two previous panels.

In June, firms will start distributing single-ingredient liquid acetaminophen pediatric products only at 160 mg per 5 mL of medication, the Consumer Healthcare Products Association said.

Currently, firms also market liquid products for children 2 and under in a concentration of 80 mg/1 mL. With the change, 160 mg/5 mL will be the only concentration for single-ingredient acetaminophen products indicated for all children up to 12 years.

And Then There Was One

OTC firms will transition to 160 mg/5 mL as the only concentration for single-ingredient acetaminophen products indicated for all children up to 12 years.
Firms currently also market liquid acetaminophen for children 2 and under in a concentration of 80 mg/1 mL.
Currently available concentrated acetaminophen drops for infants at 100 mg per 1 mL will be discontinued.

The products include Children's Tylenol from Johnson & Johnson's McNeil Consumer Healthcare business and store brand products from Perrigo and other private labelers.

CHPA expects making the products available in one concentration will help curb adverse events linked to the most commonly used cough and cold drug ingredient.

"It's absolutely essential that parents and other caregivers have the information they need to appropriately administer OTC medicines," CHPA President Scott Melville said May 5 at the trade group's Regulatory & Scientific Conference in Bethesda, Md.

Single-ingredient liquid acetaminophen pediatric products with other concentrations of the ingredient will remain available in stores during the transition. By early 2012, only products in the single concentration will be available, CHPA says.

Manufacturers also will stop marketing concentrated acetaminophen drops for infants – 100 mg per 1 mL – and will ask retailers to remove those products from shelves during the transition, the trade group says.

Additionally, with the single-ingredient products for infants, firms will package syringes for more accurate dosing. Products indicated for 2- to 12-year-old children will continue to include dosing cups.

The syringes and cups will be marked in milliliters, or also with teaspoons depending on how the measurements are stated in a product's label directions, according to CHPA.

"It's essential that appropriate dosage be used," Melville commented. The syringes and cups are "age-appropriate and easier for parents to read and measure," he added.

At a joint meeting in June 2009 to discuss the safety of all OTC acetaminophen products, three FDA advisory committees voted to recommend firms market only one concentration of single-ingredient liquid products for children (Also see "Lower Acetaminophen Doses Recommended Despite Cost Impact, Lack Of Data" - Pink Sheet, 6 July, 2009.).

A Long Time In Coming

The industry move also comes nearly 10 years after an NDAC recommendation that FDA standardize the concentration of acetaminophen pediatric products.

The change could not come soon enough, says Richard Dart, a physician and director of Rocky Mountain Poison and Drug Center. The American Association of Poison Control Centers and other health care provider organizations long have advocated for the change, he said.

"It's a great thing," said Dart, who also serves as president of AAPCC. "We've had some really bad cases where parents got confused."

According to the AAPCC data, of the 207,165 cases of acetaminophen adverse events attributed only to dosing errors reported in 2010, 2.8% were for children age 5 and younger.

In 2009, the number of reports to poison control centers for all adverse events – attributable to dosing errors and all other causes – linked to single-ingredient acetaminophen products for children 5 years old and under was 28,982 and 1,969 for children 6 to 12, with 14 cases leading to hospitalization and no fatalities.

In an interview, Dart said some cases show parents and other caregivers were not aware the ingredient concentration differs among liquid acetaminophen products.

"They were giving doses that they thought were right. They just chose the wrong product, so that they were giving three times the dose that they should have. If you do that once it's not a big deal … but if you do it repeatedly, it's a definite overdose and a child can get liver failure or even die."

Voluntary Move Draws Praise

Allen Vaida, a member of the 2009 advisory panel on acetaminophen safety and an executive at the Institute for Safe Medication Practices, recalls that the question on a single concentration did not come from FDA, but was asked by the panel chair. The vote in favor was nearly unanimous, though the panel did not recommend which concentration should remain on the market, he said.

ISMP is "100 percent behind" having only a single concentration, Vaida, a pharmacist and the group's executive VP, said in an interview.

Dart commended the U.S. OTC industry for the across-the-board change. "It would have been dangerous for only one manufacturer to do it," Dart said.

Vaida also praised the voluntary change but added that a rulemaking still may be needed to prevent imports of liquid pediatric acetaminophen products in multiple concentrations.

"I don't think this should prohibit the FDA coming forward with a rulemaking," he said.

Directions, Units and Devices

While improvements in dosing devices also will help improve safe acetaminophen usage, a single concentration of the ingredient in children's products along with improvements in label instructions will make a bigger difference, Dart maintains.

On May 4, FDA published its liquid OTC dosing delivery final guidance, which encourages firms to include dosage devices with all such OTCs and to state the same measurements on a product's label and device.

"It's a step in the right direction," Dart said of the guidance. "My opinion is, that's not the major problem. The problem is the parent not taking the time to read the label at all."

Darren A. DeWalt, an assistant professor at the University of North Carolina School of Medicine, also sees a single concentration of acetaminophen as part of the solution to the problem of inaccurate dosing.

"This is a good thing. Still more to do, but a good step," DeWalt said.

He noted the importance of accurate dosing directions and devices in an editorial published with a study on the rate of OTC dosing errors in the Journal of the American Medical Association in November 2011 (Also see "Dosing Directions, Measuring Devices Vary For OTC Meds, JAMA Study Says" - Pink Sheet, 6 December, 2010.).

Vaida also characterized accurate dosing as an element of improving pediatric acetaminophen use, but he considers the liquid dosing guidance ineffective.

"With the variety of products out there, there should be one standard dosing device," he said.

In comments to FDA, ISMP recommended requiring all liquid OTCs dosing use milliliter measurements in addition to a uniform dosing device.

"This is one of many measures that can be taken to minimize the risk of medication errors in children." – FDA's CDER

At the 2009 meeting, the nonprescription drug, anesthetic drugs and drug safety and risk management advisory committees directed the agency to address the absence of acetaminophen dosing directions for children under 2.

NDAC On Deck

FDA has yet to release briefing materials for the May 17-18 joint advisory committee meeting, including the questions the agency will actually ask the panel members to vote on ("FDA Advisory Panel To Evaluate Acetaminophen Pediatric Dosing," "The Tan Sheet" March 14, 2011).

In a Federal Register notice announcing the meeting, FDA said the NDAC and the Pediatric Advisory Committee will:

• Review pertinent pharmacokinetic safety and efficacy data and discuss whether new dosing information for oral OTC drug products containing acetaminophen should be added to the label for children under 2 years of age.

• Consider adding a weight-based dosing regimen to the existing age-based dosing regimen for children 2 to 12 years of age.

• Discuss ways that administration by caregivers can be improved so medication errors can be minimized.

The panel is directed not to discuss dosing for children 12 years and older.

FDA commended industry's move, but pointed out that the concentration of pediatric acetaminophen "is not the focus" of the joint advisory committee meeting.

A Center for Drug Evaluation and Research official said the "main thrust" of the meeting is pediatric dosing of acetaminophen.

"FDA has long supported efforts by industry to minimize pediatric dosing errors, including the recent industry voluntary move to limit liquid pediatric acetaminophen products to a single concentration. This is one of many measures that can be taken to minimize the risk of medication errors in children," the official added in an email.

By Malcolm Spicer

OTC Industry Standardizes Pediatric Liquid Acetaminophen Concentration

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