CHICAGO – Several different generic formulations of clopidogrel sold in India and Europe contain significant levels of methyl chloride, a known toxin and mutagen.
In contrast, tested samples of brand-name clopidogrel, Plavix, proved clean from methyl chloride, Dr. Indermohan Thethi reported at the annual Scientific Sessions of the American Heart Association. The tested generic formulations contained methyl chloride levels that ranged from about 10 parts per million to more than 400 ppm depending on the specific formulation, the amount of time it was stored prior to testing, and storage conditions. European Union guidelines set 20 ppm as the threshold of toxicologic concern, noted Dr. Thethi, a researcher in the hemostasis and thrombosis research labs at Loyola University in Maywood, Ill.
“I think this is a major concern. Generics need to be looked at very closely because they often come onto the market without much surveillance,” Dr. Thethi said in an interview. The implications of the study apply not only to clopidogrel but to other generic formulations as well, he added. “The number of generic formulations on the market is astounding. We need more stringent measures, and input from industry to look into the possibility of other compounds that might lead to long-term toxicity. We want drugs to be generic, but we also want to have the data and know that these drugs can go wrong.”
Methyl chloride can cause hepatic, renal, and nervous system damage, he said. It also produces a positive result in an Ames test, indicating it also has mutagenic activity and carcinogenic potential.
Dr. Thethi and his associates at Loyola began their study when they realized that one, generic formulation of clopidogrel was marketed as the salt clopidogrel hydrochloride. Hydrochloride has the potential to interact with either methanol or with a methyl ester such as clopidogrel to produce methyl chloride. As a result, the Loyola researchers decided to measure methyl chloride levels in generic clopidogrel formulations purchased in India. During their research, they contacted scientists at Sanofi-Aventis, the company that markets brand-name clopidogrel (Plavix), and learned that Sanofi researchers had begun investigating methyl chloride levels in generic clopidogrel formulations sold in Europe. The two groups began collaborating and reported results from both studies together at the meeting.
Three different clopidogrel formulations sold by three European companies, Consilient, Sandoz, and Mylan, are in the form clopidogrel hydrochloride. Using headspace gas chromatography, the researchers found methyl chloride levels in their clopidogrel samples of about 40 ppm when the drugs were first obtained. While stored under “normal” conditions, at 25° C, methyl chloride contamination levels rose over time. After 3 months, levels reached as high as 100 ppm. When stored in “extreme” conditions, at a temperature of 40° C, the concentration rose above 400 ppm after 6 months.
The researchers also measured levels in eight different generic clopidogrel formulations sold in India, with the names Clavix, Clopigrel, Clopilet, Clopitab, Clopivas, Ceruvin, Deplatt, and Plagril. The panel of formulations tested included several that contained a salt other than clopidogrel hydrochloride. At the time of purchase, methyl chloride concentrations in the eight formulations ranged from about 10 ppm to about 110 ppm. These formulations did not undergo additional testing following storage.
In addition to examining more formulations, future studies should also measure levels of methyl bromide, a compound even more genotoxic than methyl chloride, Dr. Thethi said. Some generic formulations sold in India contain clopidogrel methylbromide salts, he said.
According to Dr. Paul A. Gurbel, Dr. Thethi’s report raised concerns for him. The findings highlight two unknowns about generic clopidogrel formulations. First, is their safety because of contaminants. The second question is their pharmacodynamic equivalency to brand-name clopidogrel, said Dr. Gurbel, director of the Center for Thrombosis Research at Sinai Hospital in Baltimore.
Many U.S. patients who are prescribed clopidogrel get their drug as a generic from India, Canada, or elsewhere. Patients who want to cut their costs for medications, sometimes go on the Internet and find places to buy generic clopidogrel.
“I know of at least one patient in my practice who buys his clopidogrel as a generic from India, and I plan to show him this new report. I tell my patients to never use generic clopidogrel and always use the standard drug because we don’t know if the generics are pharmacokinetically and pharmacodynamically equivalent,” he said. “You don’t want to guess about the efficacy of a drug like clopidogrel. It’s the No. 1, most-important drug for having pharmacodynamic equivalency because if it’s wrong, the consequences for the patient can be catastrophic. An antithrombotic agent is the most important drug we prescribe to patients who have a stent in their heart.”