The FDA Asks Companies to Stop Selling Ranitidine

With its promise of taming the ravages of stomach acid, ranitidine—best known under the brand name Zantac—was counted among the agents of pharmaceutical salvation, the enduring and reliable drugs that treat intractable diseases and make daily life more tolerable. In 1987, Zantac became the most-prescribed drug in the world.

But last week ranitidine was essentially erased from the US market. The US Food and Drug Administration asked manufacturers to withdraw ranitidine products, both in prescription and over-the-counter forms, because of an “impurity” in the pharmaceutical compound. Over time or in the presence of heat, ranitidine can form unacceptable levels of a probable carcinogen known as N-nitrosodimethylamine, or NDMA, the agency determined.

“We didn’t observe unacceptable levels of NDMA in many of the samples that we tested. However, since we don’t know how or for how long the product might have been stored, we decided that it should not be available to consumers and patients unless its quality can be assured,” Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, wrote in the April 1 statement.

Pharmacy shelves already had been stripped of the product. Sanofi, maker of Zantac, had recalled its products last fall due to earlier FDA findings, as had generic manufacturers. National chains such as Walmart, Walgreen’s and CVS removed over-the-counter ranitidine. “We take this issue seriously and continue to work closely with the FDA to evaluate any potential safety risks associated with Zantac,” Sanofi spokesperson Nicolas Kressmann told WIRED in an email. “At Sanofi, we stand by the long-standing science that supports the safety of Zantac OTC (over-the-counter) products, which have been used by consumers for over two decades.”

“It is too early to say if and when we will be able to come back to the market as evaluations are ongoing,” Kressmann writes. But for the foreseeable future, the FDA’s withdrawal request ends decades of ranitidine use. More broadly, it highlights NDMA contamination in medicines—and troubling questions about drug quality in a global industry dominated by manufacturing in China and India. NDMA has been detected in other commonly-prescribed drugs: the blood pressure medicines valsartan, losartan and irbesartan and—in lower amounts—in metformin, a common diabetes drug.

NDMA is an organic chemical that was once used in the manufacture of rocket fuel and lubricants. It also is a byproduct of other chemical processes; for example, it’s found in rubber, dye, and pesticide production, tanneries, and foundries. It is even a byproduct of the chlorination of drinking water, where it can be detected in very small amounts. There is no federal standard for NDMA in drinking water, although some states have set their own limits.

Foods that contain nitrites or nitrates—including bacon, grilled or smoked meats, and even some fruits and vegetables—can fuel a chemical reaction in the stomach that creates NDMA. Based on studies that showed NDMA can cause liver, kidney, and lung cancer in animals, the US Environmental Protection Agency labels it a probable human carcinogen.

The problem of NDMA turning up in medicine first came to light in 2018 when Prinston Pharmaceuticals Inc. (which operates as Solco Healthcare), a New Jersey-based manufacturer of the high-blood pressure drug valsartan, notified the FDA about impurities in an active pharmaceutical ingredient the company had received from its parent company in China. Since 2011, the Chinese supplier of that ingredient had been using a new manufacturing process that yielded more of it at a lower cost—but the FDA found that the residue of a re-used solvent, combined with another chemical agent, led to the formation of NDMA. The FDA inspected the Chinese plant, cited quality problems, issued a warning letter and halted US imports from the company. The FDA case is still pending and an import alert remains in place, an FDA spokesman said.