French drugmaker Sanofi recently announced a recall of over-the-counter Zantac, the widely used acid reflux medication, in the U.S. and Canada over concerns of possible contamination from a probable carcinogen. This action followed recalls by manufacturers and retailers of generic versions of the drug, called ranitidine. The recalls have prompted questions about whether the drugs’ levels of a chemical called N-nitrosodimethylamine (NDMA)—which has been linked to cancer in animals—pose a more serious health risk than initially reported.
Several blood pressure medications, including the angiotensin receptor II blockers valsartan, losartan and irbesartan, were recalled last year over NDMA contamination. The U.S. Food and Drug Administration first flagged the possible contamination of ranitidine products this September. At that time, the FDA said the NDMA levels found in preliminary tests “barely exceed amounts you might expect to find in common foods.” But the agency released a statement on Oct. 2 calling the levels “unacceptable.” Asked to elaborate, FDA spokesperson Jeremy Kahn says, “Although the FDA has detected NDMA in limited ranitidine samples at low levels, these levels still exceed what [the] FDA considers acceptable for these products.
In its petition, Valisure also claimed that the NDMA is likely formed as the result of an inherent instability of the ranitidine molecule. “We think the problem is much worse than contamination,” says Valisure CEO David Light. He alleges that the drug itself may break down to form NDMA.
Ranitidine has been widely used for decades. If it poses a risk to human health, how could that have gone unnoticed for so long? Light alleges that there were some limitations in early safety studies involving Zantac in the 1980s. Glaxo—a company that eventually merged into GlaxoSmithKline (GSK)—Zantac’s original manufacturer, published a study of ranitidine’s metabolites in urine in 1981, but Light says that study appears not to have looked for NDMA. Glaxo published another study in 1987 that tested the stomach contents of people taking ranitidine, concluding that there was “no significant increase” in the concentration of nitrosamines, a group of chemicals—many of them carcinogenic—that includes NDMA. But Light says the detection method used in that paper was designed for food products and does not directly measure nitrosamines. In addition, the study discarded all stomach samples that contained ranitidine because they could have “falsely high” concentrations of nitrosamines, so any NDMA produced by the breakdown of ranitidine would not have been detected.
In a statement to Scientific American, GSK says it had considered the potential formation of nitrosamines in the body—during ranitidine’s development, during its regulatory review and in subsequent studies. Scientists had hypothesized that any drugs that raised the stomach’s pH could increase the growth of bacteria that produce nitrites, which could interact with chemicals called amines to produce nitrosamines. Although several studies did find that taking ranitidine could increase the concentration of nitrites in the stomach—and at least one found a statistically significant increase in nitrosamines—that does not mean they cause cancer, GSK says. The company adds that ranitidine was not carcinogenic in studies of rodents whose diet and bacterial metabolism were similar to those of humans and claims that “extensive pharmacovigilance monitoring, regular safety reviews and substantive epidemiological studies have not linked ranitidine to raised cancer risks.”
Further, the issue of nitrosamine formation in the body “is fundamentally different to the current regulatory interest in the presence of NDMA in drug substance and drug product,” says GSK, which has issued a recall of its generic version of Zantac. “The reason for the current precautionary recall of ranitidineis due to an emerging finding that some sources of drug substance and therefore drug product may contain very small amounts of nitrosamine. While the manufacturers, suppliers and regulatory authorities clarify the root cause of this issue, we have stopped supply and recalled product from the market as a precautionary measure.”
Nevertheless, the recalls suggest a level of caution may be justified. The FDA says that consumers taking over-the-counter medications containing ranitidine could consider using other approved drugs and that patients who are taking prescription ranitidine and want to stop should consult their doctors about alternative options. The agency has asked ranitidine manufacturers to test their own products for NDMA and to send it samples of them. Kahn says the agency “continues to test ranitidine samples and will provide information as it becomes available.”