Nitrosamines, which are known carcinogens, have recently been found in pharmaceutical drugs, including Zantac, Januvia, and generic valsartan. Experts believe they come from chemical reactions and form in medicines during their manufacture. A recent Morgan Stanley report says nitrosamine lawsuits against Zantac’s makers, including GSK and Sanofi, could reach $45 billion alone. But other big companies like Merck and Pfizer have also found nitrosamines in their drugs, and the Zantac trials could draw attention to them.
“What’s alarming is the number of drugs where this is occurring,” says Michael Carome, director of the health research group at the consumer advocacy group Public Citizen. “If there is a large settlement against the makers of Zantac, it is likely to trigger lawsuits against other drugs contaminated with carcinogens.”
A trial against Zantac’s makers is scheduled to begin in California in February, and others will follow later in 2023. But as tainted drugs continue to be discovered, the true impact of nitrosamine contamination could take much longer to be seen. Merck & Co was the latest to add to the list, confirming on August 9 that nitrosamines had been found in blockbuster diabetes drug Januvia. The US Food and Drug Administration has allowed Merck to continue selling the drug for now, saying the potential shortages outweigh the risk. Many other drugs have been withdrawn from the market.
Nitrosamine contamination in everyday drugs was not revealed until 2018, when tests at Swiss drugmaker Novartis AG on an active ingredient used in generics of one of its blockbuster blood pressure drugs revealed a chemical called NDMA, a nitrosamine that it was once used in rocket fuel and is classified by the World Health Organization as a possible carcinogen. Similar pills, known collectively as angiotensin II receptor blockers, or ARBs, were found to be contaminated with comparable chemicals and a series of recalls were announced.
The FDA allows drugs to contain 96 nanograms of NDMA based on the agency’s calculations that this level would approach a 1 in 100,000 cancer risk for people who ingest the nitrosamine over a lifetime. Some of the earlier recalled blood pressure pills contained as much as 20,000 nanograms of NDMA. Neither the agency nor the pharmaceutical industry has released nitrosamine levels associated with more recent infections.
Over the next two years, nitrosamines were found in the diabetes treatment metformin as well as Zantac. After the FDA ordered all drug manufacturers to test their products for potential carcinogens in 2020, more drugs began to appear: Pfizer Inc.Stop smoking drug Chantix, blood pressure pills and muscle relaxants from the Sandoz generic unit of Pfizer and Novartis, and more recently Merck’s diabetes drugs. One difference with the most recent recalls is that the companies are finding nitrosamines that have never been detected before, meaning there is no clear understanding of their toxicity.
Drug companies have filed more than 250 nitrosamine-related recall reports with the FDA since 2018 — not including drugs that contain nitrosamines below levels considered dangerous or those that the FDA has allowed to remain on the market to ensure special offer.
“The issue with nitrosamines is real, and I would expect we might see more recalls,” says Ed Gump, vice president for small molecules at the US Pharmacopeia, an organization that works with industry to help control impurities.
The recent spate of infections is not the FDA’s first brush with nitrosamines. The chemicals appeared in cosmetics in the late 1970s, a few years before Zantac won regulatory approval. Researchers in Massachusetts flagged possible contamination, which led the FDA to test 252 products in the US. they found a form of nitrosamine in 110 of them. Guidance has been issued to help companies avoid processes that can lead to the formation of chemicals, but cosmetics are much less tightly regulated than drugs and do not require FDA approval to be sold to consumers.
The challenges that pharmacists now face are more complicated and complex because it is not always clear how nitrosamines are developed into drugs. Contamination is unique to each drug: In the generic blood pressure drug valsartan, for example, regulators determined the cause was chemical reactions during manufacturing or the use of contaminated ingredients recycled from drugs that had undergone chemical reactions that formed nitrosamine. Other cases, like Zantac, may depend on how a tablet is stored or what inactive ingredients are used. Major companies have teams of up to 50 people looking at how contamination occurs, and the FDA has a task force at the Center for Drug Evaluation and Research dedicated to the topic.
In the meantime, uncertainty about how many drugs contain nitrosamines—and how much is safe to consume—makes calculating the risk difficult. That’s especially true among people who may be taking multiple medications that contain the chemicals, compounding impurity levels, says George Gray, a professor of environmental and occupational health at George Washington University who specializes in health-related risk analysis. People are also exposed to nitrosamines in other ways, mainly through foods such as processed or cured meats, such as bacon. “It’s really hard to say how big the risk of these drugs might be,” Gray says, “especially given the benefit they might provide to people.”
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