New York Times: Some cold medicines may have higher than expected levels of a decongestant

Some widely used over-the-counter cold and flu medicines may be exposing patients to unexpectedly high amounts of one ingredient, revealing a lapse in regulations and perhaps raising safety concerns, a company that develops such drugs reported on Wednesday.

The company, AFT Pharmaceuticals of New Zealand, said that when the nasal decongestant phenylephrine, or PE, was combined with the pain reliever acetaminophen, levels of PE in the blood were two to four times as high as when the same dose of PE was taken alone.

“Effectively, accidentally you are getting a higher dose here,” said Hartley C. Atkinson, chief executive for AFT.

He and colleagues reported their finding in a brief correspondence published on Wednesday online in The New England Journal of Medicine website. The letter said the combination increased exposure to PE “beyond levels that were previously deemed to be safe and effective.”

Drugs that combine PE and acetaminophen, which is the active ingredient in Tylenol, are common and include certain versions of Robitussin, Theraflu, Mucinex, DayQuil, Tylenol Cold and Flu and other brands. AFT sells a combination product in some markets outside of the United States.

The potential adverse side effects from a high dose of PE could include higher blood pressure, elevated heart rate and nervousness.

The Food and Drug Administration said it was aware of the finding but suggested it was not a safety concern. It said in a statement that PE was generally recognized as safe, including in combination with acetaminophen.

The Consumer Healthcare Products Association, which is based in Washington and represents over-the-counter drug manufacturers, also dismissed any concerns, saying PE had been used safely for decades.

Ron Eccles, director of the common cold center at Cardiff University in Britain, who was not involved in the study, said that while he did not think there were serious risks, “Regulatory authorities need to address this issue quickly to reassure the public that these freely available medicines are safe.”

Still, the F.D.A. declined several years ago to increase the permitted dose of PE to 25 milligrams from 10 milligrams. Dr. Atkinson of ATF said that 10 milligrams of PE taken in combination with acetaminophen leads to blood levels similar to what would come from taking 25 milligrams of PE by itself.

The Consumer Healthcare Products Association, in a 2007 document arguing against the dose increase, said that studies had found that the 25- milligram dose was more frequently associated with increased pulse rate and nervousness than the lower dose.

An F.D.A. review concluded, however, that past studies “suggest only negligible effects” at either dose.

The use of PE as a nasal decongestant increased markedly several years ago after access to another decongestant, pseudoephedrine, was restricted because it was being used to make methamphetamines.

Some experts said the finding of the unexpected interaction of acetaminophen and PE showed that over-the-counter drugs need to be tested more thoroughly before being allowed on the market.

“There’s a major public policy issue with respect to how over-the- counter products are regulated,” said Dr. Joshua Sharfstein, secretary of health and mental hygiene in Maryland and a former principal deputy commissioner of the F.D.A. Dr. Sharfstein was involved in 2007 in an effort to prohibit the use of certain cold medicines by infants and young children.
Dr. Atkinson said his company discovered this effect in the course of developing a combination of PE, acetaminophen and ibuprofen. It found that levels of PE in the blood of people who took this combination were much higher than expected. Further testing showed that the effect was because of the acetaminophen, not the ibuprofen.

He said it appeared that acetaminophen interfered with the breakdown of PE, allowing higher levels to build up in the blood.

Still, the data for blood levels of PE shown in The New England Journal of Medicine website was for the triple combination.

In its statement, the F.D.A. suggested the finding was irrelevant because the triple combination was not permitted to be sold in the United States.

AFT is developing a combination product with half the usual dose of PE. It would benefit commercially if it could establish that the existing dose used in rival products raises safety issues. There is also controversy over whether PE is even effective.

Leslie Hendeles, a professor of pharmacy and pediatrics at the University of Florida, said PE had only a minor effect at the dose used. Rather than raising safety concerns, he said, the finding that

the effective dose of PE is increased in the combination medicines “would actually render what is an ineffective compound effective.”

Source: New York Times, Andrew Pollack, 19 March 2014