Federal regulators say they've identified the source of the cancer-causing impurities that have tainted millions of bottles of commonly used generic blood pressure and heart failure medications recalled by drugmakers over the last seven months.
The carcinogens are a chemical byproduct of the process used to synthesize the active ingredient in the drugs, which include valsartan, losartan and irbesartan. People who take those drugs may have been exposed to trace amounts of impurities for at least four years, after a switch in how companies manufactured the active ingredient, according to the Food and Drug Administration.
An FDA statement Friday disclosed that the contaminants, called N-Nitrosodimethylamine and N-Nitrosodiethylamine, are created when "specific chemicals and reaction conditions are present... and may also result from the reuse of materials, such as solvents." The agency said those byproducts would not have been detected in routine inspections because the process depends on scientists knowing which chemical intruders are likely to be accidentally created during the process, knowledge that they said regulators and companies lacked until recently.
But David Light, chief executive of Valisure, an online pharmacy that chemically validates drugs before shipping them to consumers, said it's possible that companies weren't cleaning up the active ingredients as a cost-saving measure. It wouldn't have been unexpected, he said, that the synthesis process would create contaminants.
"In chemistry, it's pretty easy to throw some chemicals together and get a reaction," Light said. "What's hard to do is to clean it up and only get the product you want ... The manufacturers know, or should have known, about the contamination. Common precision tools exist to analyze these contaminants, and there are standard procedures for getting rid of them."
It remains unclear how many patients may have been exposed to the carcinogens, but agency leaders have previously estimated that 1 million to 2 million people may have taken the medicines with the impurities.
"We are making important strides at understanding how these impurities occurred, mitigating the risk to patients and learning what steps need to be taken to prevent this from occurring again in the future," Commissioner Scott Gottlieb and Center for Drug Evaluation and Research director Janet Woodcock said in a statement. "While the total exposure to these impurities for most patients was small, we are deeply concerned that patients were exposed to this impurity in the first place and that the presence of nitrosamines went undetected for a period of time."
The agency has downplayed the public health risks of the contamination, pointing out that the carcinogens are also found in smoked and grilled meats. FDA said if 8,000 people took the highest dose of one drug, valsartan, for four years, there could be one additional case of cancer. But the official limit considered "safe" for human consumption is much lower - and would cause less than one additional case of cancer in 100,000 people over a lifetime.
The unfolding investigation shines a light on the dark corners of a complex, international drug supply chain - and in particular the difficulties that can crop up when safety issues arise for generic drugs, which may be made by multiple drug manufacturers and repackagers that may use active ingredients from one factory or a small handful of them.
The problems were first detected in drugs that traced back to active ingredient maker Zhejiang Huahai Pharmaceutical Co. in China, but were also found in drugs made from active ingredients made by Hetero Labs in India. Drug companies that sell the generic medications include Mylan Pharmaceuticals, Teva Pharmaceuticals, Sandoz, Prinston Pharmaceuticals, ScieGen and Torrent Pharmaceuticals. Some of those companies also sell the drugs under different labels. For example, Prinston recalled batches of drugs that were labeled Solco Healthcare, and Teva recalled batches labeled as made by Actavis and Major Pharmaceuticals.
Valsartan has been in shortage since August, and the agency warned in its statement that "other types of products may fall into shortage soon," without offering any specifics. The agency is urging patients to continue taking their medications until a pharmacist or doctor provides another option because they need to balance the risks of out-of-control blood pressure against that of a tiny elevated risk of cancer.
An FDA spokeswoman said the investigation continues and it is impossible to predict how many more recalls there might be. She said that drug manufacturers will continue to test their products and recall pills that contain impurities over an interim limit the FDA established to make sure patients can continue to have access to the medications in the short term.
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