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