U.S. rejects nighttime Tylenol, Excedrin study

WASHINGTON (Reuters) - Tylenol PM and other widely used acetaminophen pain drugs that include a sleep-aid failed to show significant benefit in a key study, U.S. health regulators have told drugmakers 15 years after the industry submitted the data.

Patients taking the drugs, most commonly sold as Johnson & Johnson’s Tylenol PM and Novartis AG’s Excedrin PM, did not fall asleep significantly faster than those who took only acetaminophen or the sedative, known as diphenhydramine citrate, the FDA said in a letter to the industry earlier this year.

“There is an insufficient basis to support the combination of acetaminophen and diphenhydramine as a nighttime sleep aid for relief of occasional sleeplessness when associated with minor aches and pains,” Dr. Charles Ganley, head of the FDA’s Office of Nonprescription Products, wrote in a February 16 letter to the Consumer Healthcare Products Association, or CHPA, which represents makers of nonprescription medicines.

The letter, obtained this week by Reuters, comes amid closer scrutiny of dozens of other Tylenol products for children recalled last Friday after FDA inspection turned up contaminated ingredients and unsanitary conditions.

While the agency’s letter does not raise any safety questions with acetaminophen nighttime drugs, it does call into question data backing up their effectiveness.

“The concern ... is that we need an additional study demonstrating that the combination product is more effective than acetaminophen alone and more effective than diphenhydramine alone,” FDA spokeswoman Shelly Burgess said.

In March, J&J’s McNeil Consumer Healthcare unit, which makes Tylenol PM, submitted additional data that it said showed the combination has “significantly more benefit for the relief of pain and sleeplessness than either ingredient alone.”


It is not immediately clear what impact the agency’s decision could have on the combination products, for which the industry initially sought FDA backing in 1995.

Such nonprescription products are not big money-makers but carry significant brand recognition and are widely used.

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While they have been sold on the U.S. market for years, winning the FDA’s formal backing offers companies stronger ground to market their products.

“We know then that the ingredients have been accepted as safe and effective, we know the final labeling, we know the final dosages ... there’s much more certainty,” said Barbara Kowchanowski, a vice president at CHPA.

The study submitted in 1995 failed to meet its main goal of showing that the combination of the pain and sleep ingredients could help people fall asleep faster, the FDA’s letter said.

An agency analysis found the combo pill offered some improvements over acetaminophen alone in terms of consumers’ quality of sleep or how often they woke up, but no significant benefit over the sleep aid alone.

Tylenol PM is the top-selling nighttime painkiller, ahead of Excedrin PM and Pfizer Inc’s Advil PM, which combines the same sleep aid with ibuprofen.

J&J’s version had sales of $94.5 million over the year ending mid-April, according to market research firm SymphonyIRI Group. Excedrin brought in $14.7 million in sales.

Advil PM saw $48.6 million over the same period, according to the Chicago-based group, which tracks most drugstores, supermarkets and mass market retailers. Advil PM won FDA backing in 2005.


Unlike prescription drugs, those sold over the counter can be marketed without a formal approval process as long as their main ingredients are on FDA’s approved list, or monograph. But if a nonprescription drug does not meet the list’s standards, it must win formal FDA approval before it can be sold.

Still, the FDA’s 15-year gap comes somewhat as a surprise even at an agency where actions can take years.

Even before the FDA’s decision, J&J finalized its study plan in 2006 with agency input and it completed the last of two studies with several hundred people last year, J&J spokeswoman Caroline Almeida told Reuters.

The results “demonstrate that both ingredients ... contribute to its claimed effects,” McNeil wrote in a March 31 letter to the agency.

“These data indicate that the combination of an analgesic and sleep-aid provides significantly more benefit for the relief of pain and sleeplessness than either ingredient alone,” McNeil wrote in a March 31 letter to the agency.

It was not immediately clear if other makers conducted similar studies. Novartis referred questions to the CHPA, which said it did not prompt the FDA for the February response and did not ask the agency about the delay.

FDA’s Burgess said the agency would “review the studies as soon as possible, dependent on other agency priorities.”

Ganley was not available for an interview, but Burgess cited the agency’s “significant workload in regulating over-the-counter drug products” and the need to prioritize based on available agency resources.

She added that the letter did not reflect any other initiatives at the FDA, including Friday’s recall or recent concerns over acetaminophen’s risk of liver toxicity.

While the FDA’s timing seems startling, Ganley’s answer was not, an industry source familiar with the letters said. Standards have changed since CHPA’s 1995 submission and two studies, not one, are now typical.

“This was simply a study that didn’t work. ... I don’t think it surprised anyone,” the source said.

Reporting by Susan Heavey; Additional reporting by Lewis Krauskopf in New York and Toni Clarke in Boston; Editing by Peter Cooney and Richard Chang