Pseudoephedrine Sulfate

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

AFT Pharmaceuticals has identified a major error with the formulation of over 1,300 cold and flu products used around the world. Many over the counter cold and flu products combine phenylephrine and paracetamol. The company’s groundbreaking research has revealed that when combined with paracetamol the level of phenylephrine is effectively twice what it should be. AFT Pharmaceutical’s findings have been published today in the New England Journal of Medicine. The Journal is considered to be the most prestigious medical journal in the world. “Frankly this is a pretty big finding, with huge implications for this category of product, and it’s reflected in the fact that the New England Journal of Medicine has published what we have found,” said Dr Hartley Atkinson, Managing Director of AFT Pharmaceuticals. “This is a very significant finding given the volume of over the counter cold and flu products that are consumed each year,” said Dr Atkinson. “The standard dose of phenylephrine in these products is 10mg. That’s all the drug regulatory authorities have allowed. But unbeknown to everyone including the regulators, when you add phenylephrine to paracetamol, the concentration of phenylephrine spikes to roughly 20mg because of the way the human body processes both drugs together. Basically this research tells us that people have inadvertently been taking the equivalent of double the recommended levels of phenylephrine.” The use of phenylephrine together with paracetamol has increased significantly in recent years. Previously paracetamol was typically combined with pseudoephedrine. But in many countries pseudoephedrine-based products are now only available on prescription because of pseudoephedrine’s use in making the illegal drug methamphetamine. “This is what makes these findings so important,” says Dr Atkinson. “Phenylephrine has been the ready replacement for pseudoephedrine in cold and flu remedies globally. But the international pharmaceutical companies and drug regulators haven’t known about the interaction between these two drugs. Until now.” The side effects of an increased amount of phenylephrine may include nervousness, feelings of being unwell, and possibly increased blood pressure. People susceptible to cardiovascular effects may require extra care. But Dr Atkinson said that addressing the consequences of AFT Pharmaceutical’s findings are now in the hands of others. “We immediately informed Medsafe (NZ) and the Therapeutic Goods Administration (Australia) of our findings. It is now up to the regulators to use the information as they see fit. We have also met with the United States Food and Drug Administration in January this year to fully inform them of our findings.” AFT Pharmaceutical’s discovery was the result of its standard analgesics research programme. The company has now reformulated its cold and flu medication and invented a new formulation that delivers the intended 10mg of phenylephrine to consumers when given in combination with paracetamol. This new product is ready to be filed within the next month for regulatory evaluation in New Zealand and Australia. These unexpected findings have thrown the international spotlight on AFT Pharmaceuticals. Dr Atkinson says the business has come a long way since it started in a room off his home garage in the late 1990s. “We’ve put a lot of time and effort into researching new products. It’s what drives us as a company and it’s paying off.” He says that this discovery, together with several other innovative new products in the pipeline, means that the future of AFT Pharmaceuticals is extremely bright. Technical information Article: Hartley C. Atkinson, Ioana Stanescu, and Brian J. Anderson, “Increased Phenylephrine Plasma Levels with Administration of Acetaminophen”, New England Journal of Medicine 370;12 (2014) 1171-1172. Studies: Three randomised, open-label, cross-studies in healthy volunteers, were undertaken as part of the development of a new fixed dose combination containing paracetamol, ibuprofen and phenylephrine. Results: The results for part of this research program are published in the New England Journal of Medicine and demonstrated an unexpected pharmacokinetic interaction between paracetamol and/ or ibuprofen and phenylephrine. There was a four-fold increase in Cmax and a two-fold increase in the area under the curve for phenylephrine 10mg administered in combination with paracetamol 1000mg and ibuprofen 300mg (see figure below). Ibuprofen was subsequently shown to be non- contributory. Halving the amount of phenylephrine combined with paracetamol to 5mg total produced a plasma time-concentration similar to that of 10mg phenylephrine administered alone. Explanation: The results can be explained on the basis that normally phenylephrine is extensively inactivated by being metabolised when it passes through the stomach and intestinal wall. However paracetamol competes for the same process and since the amount of paracetamol is considerably higher (1000mg) than phenylephrine (10mg), the paracetamol swamps the process, thus allowing twice the amount of phenylephrine to cross into the blood stream.