Common Cold Meds May Pose Health Threats. Interaction of two ingredients could cause serious side effects, researchers say. By Steven Reinberg.consumer.healthday.com. March 19, 2014. Over-the-counter sinus and pain remedies that combine two common ingredients — phenylephrine and acetaminophen — might cause serious side effects such as high blood pressure, dizziness and tremors, New Zealand researchers warn.These side effects occur because acetaminophen (the main ingredient in Tylenol) boosts the effects of phenylephrine, according to a report in the March 20 issue of the New England Journal of Medicine.

Products containing this drug combination include Tylenol Sinus, Sudafed PE Sinus, Benadryl Allergy Plus Sinus and Excedrin Sinus Headache.
"What we found was surprising because it hasn’t been studied or reported," said lead researcher Hartley Atkinson, managing director of AFT Pharmaceuticals, Ltd., in Auckland.
Phenylephrine, which replaced pseudoephedrine in many over-the-counter medications, relieves nasal congestion from colds, allergies and hay fever. Pseudoephedrine had become a source for creating the illegal drug methamphetamine, and the U.S. Food and Drug Administration asked manufacturers to voluntarily remove it from their products.
When phenylephrine is combined with acetaminophen, blood levels of phenylephrine rise to four times higher than when the same amount of phenylephrine is used alone, Atkinson said.
"Basically, if you give the combination, a lot more phenylephrine absorbs into your body than what you would be expecting," Atkinson said.
Side effects can also include insomnia, headache, heart palpitations, anxiety and urine retention.
Atkinson noted that labels on products containing phenylephrine warn of possible side effects for people with heart disease or prostate problems. These warnings, however, refer only to the dose of phenylephrine approved for that product.
People with these conditions need to know that in actuality the dose might be higher, he said.
Similar reactions might occur with drugs such as vitamin C that are metabolized in the body like phenylephrine, Atkinson said.
"In a lot of countries, there are drugs that contain acetaminophen, phenylephrine and vitamin C together, which could cause an even greater interaction," he said.
Atkinson stumbled upon this drug interaction while developing a new drug containing acetaminophen, ibuprofen (the main ingredient in Advil) and phenylephrine. Ibuprofen does not cause harmful side effects when combined with phenylephrine, he said.
This drug interaction is a problem regulatory agencies need to consider, Atkinson said.
Another expert agreed the findings are worrisome.
"This article sheds light on a previously unknown reaction of acetaminophen with phenylephrine, which essentially raises the possibility of an overdose with a single dose," said Dr. Houman Danesh, director of integrative pain management at the Icahn School of Medicine at Mount Sinai, in New York City.
"Taking medications which contain ibuprofen with phenylephrine may be safer with regards to phenylephrine toxicity," Danesh said. "However, ibuprofen has increased risks of stomach ulcers, kidney issues and hearts issues as well. So, once again, consult with your doctor."
The FDA is aware of the problem, but agency spokeswoman Andrea Fischer said it has limited ability to regulate.
"Both phenylephrine and pseudoephedrine are generally recognized as safe and effective and may be marketed without premarket approval by the FDA," Fischer said.
Likewise, it’s permissible to combine either nasal decongestant with acetaminophen, she said.
According to McNeil Consumer Healthcare, the Johnson & Johnson subsidiary that makes some of these dual-ingredient remedies, combination acetaminophen-phenylephrine drugs are safe.
"Based upon clinical studies, years of use and post-marketing surveillance, we believe over-the-counter doses of acetaminophen and phenylephrine, when taken together, are considered safe," said Jodie Wertheim, a McNeil spokeswoman.
"When used as directed, over-the-counter medicines containing acetaminophen and phenylephrine are both effective and well-tolerated," she added.
Not everyone is convinced, however.
"More caution needs to be relayed to consumers," said Victoria Richards, an associate professor of medical sciences at the Frank H. Netter M.D. School of Medicine at Quinnipiac University in North Haven, Conn.
"Consumers should look at the labels carefully and talk with the pharmacist or with their doctor to understand exactly what they’re taking," she said.
More information
Learn more about phenylephrine from the U.S. National Library of Medicine.
SOURCES: Hartley Atkinson, Ph.D., managing director, AFT Pharmaceuticals Ltd., Auckland, New Zealand; Victoria Richards, Ph.D., associate professor of medical sciences, Frank H. Netter M.D. School of Medicine, Quinnipiac University, North Haven, Conn.; Houman Danesh, M.D., director, Integrative Pain Management, Icahn School of Medicine at Mount Sinai, New York City; Andrea Fischer, spokeswoman, U.S. Food and Drug Administration; Jodie Wertheim, spokeswoman, McNeil Consumer Healthcare; March 20, 2014, New England Journal of Medicine
Last Updated: Mar 19, 2014


Reference: Increased Phenylephrine Plasma Levels with Administration of AcetaminophenN Engl J Med 2014; 370:1171-1172March 20, 2014DOI: 10.1056/NEJMc1313942

To the Editor:
Over-the-counter combinations containing acetaminophen and phenylephrine for the treatment of the common cold and influenza are widespread after the substitution of phenylephrine for pseudoephedrine. This substitution has been allowed in the United States and elsewhere without any additional safety or efficacy studies, since phenylephrine has been called “generally recognized as safe and effective” at oral doses of 10 mg on the assumption that the pharmacokinetic behavior of one drug is not altered by another, despite a lack of supporting data.1-3Three randomized, open-label, crossover studies in healthy volunteers were undertaken as part of the development of a new-fixed dose combination containing acetaminophen, ibuprofen, and phenylephrine. The results showed an unexpected pharmacokinetic interaction among the three drugs: the administration of phenylephrine (at a dose of 10 mg) in combination with acetaminophen (1000 mg) and ibuprofen (300 mg), as compared with the administration of 10 mg of phenylephrine alone, resulted in nearly a quadrupling in the maximal plasma concentration (3220 pg per milliliter vs. 874 pg per milliliter) and a doubling in the area under the curve (2220 pg per milliliter per hour vs. 1020 pg per milliliter per hour) (Figure 1FIGURE 1Pharmacokinetic Interaction for Phenylephrine, Acetaminophen, and Ibuprofen.). Ibuprofen was subsequently shown not to contribute to this increase. Halving the dose of phenylephrine that was combined with acetaminophen to 5 mg produced a plasma concentration–time curve similar to that for 10 mg of phenylephrine administered alone.These findings have implications from both regulatory and safety perspectives. First, it is clear that many approvals for the addition of phenylephrine to any number of analgesic agents were based on assumptions that were incorrect for acetaminophen. Second, the plasma exposure of phenylephrine combined with acetaminophen (measured as the area under the curve) is doubled, increasing exposure beyond levels that were previously deemed to be safe and effective and increasing the potential risk of adverse events.Since phenylephrine is metabolized by sulfation in the intestinal wall, it seems likely that acetaminophen interferes with this process and increases the level of phenylephrine with respect to bioavailability.4 If so, other drugs may also interact with phenylephrine, including ascorbic acid. Multiple variants of acetaminophen combined with phenylephrine are now available on worldwide markets. Is further investigation required?Hartley C. Atkinson, M.Pharm., Ph.D.Ioana Stanescu, Phil.Lic., M.Sc.AFT Pharmaceuticals, Takapuna, New ZealandBrian J. Anderson, Ph.D.University of Auckland, Auckland, New Zealand briana@adhb.govt.nz