When online pharmacy Valisure discovered high levels of a likely carcinogen in Zantac and its generic copycats in 2019, global recalls ensued. Contamination was one fear, but the bigger issue, as Valisure saw it, was the instability of the ranitidine molecule itself.
Now, the company has rolled out data supporting its suspicions that the once-popular heartburn med is inherently unsafe.
Valisure’s latest study, published in the Journal of the American Medical Association (JAMA) Network Open, suggests Sanofi’s Zantac and other ranitidine drugs can cause the suspected cancer agent N-Nitrosodimethylamine (NDMA) to form under a range of conditions, including in the human body.
In a separate study posted on the preprint server MedRxiv, the company noted a “significant association” between the H2-blocker’s use and increased breast, thyroid, bladder and prostate cancer diagnoses.
The NDMA scare began back in 2018 with recalls of “sartan”-based blood pressure drugs, extended through Zantac recalls and then to the popular Type 2 diabetes med metformin. Unlike the sartan meds and metformin—which were likely contaminated during the manufacturing process, experts say—ranitidine itself is the culprit, Valisure says.
The pharmacy's studies support “decades of research that ranitidine is fundamentally unstable, can form NDMA in a variety of conditions including in the human body and could be carcinogenic and toxic to humans,” David Light, founder and CEO of the company, said in a release.
For the JAMA Network study, Valisure used liquid chromatography-high resolution mass spectrometry (LC-HRMS) to detect the suspected cancer agent in simulated gastric fluid. The company varied pH, as well as nitrite and ranitidine concentrations, to assess possible NDMA formation under different conditions in the stomach.
At the two-hour mark, researchers linked one 150-mg tablet of cool mint Zantac—mixed with a low-end concentration of sodium nitrite—to formation of 947 ng of NDMA. When the nitrite concentration was increased, the cool mint tablet yielded a maximum of 320,000 ng of the likely carcinogen. That's 320 micrograms—massively outstripping the 0.096-microgram NDMA concentration deemed safe for daily human consumption, a Valisure spokesperson confirmed via email.
“Valisure detected NDMA in every brand and every dosage form of ranitidine that we tested whether over the counter or prescription and regardless of manufacturer,” Kaury Kucera, Ph.D., chief scientific officer at the company, added. “This appears to be a fundamentally different problem than NDMA contamination found in drugs like valsartan and metformin because it occurs in every brand of ranitidine and is inherent to the molecule itself.”
For its MedRxiv study, Valisure looked at 10,347 cancer patients. A cross-sectional analysis showed ranitidine use, versus other common heartburn drugs, was correlated with a higher risk of breast cancer. The researchers found similar links between ranitidine and thyroid, bladder and prostate cancer risk.
Valisure’s research is something of a post-mortem after 2019’s recall spree. Sanofi in late 2019 pulled all over-the-counter Zantac products from U.S. shelves, while Valisure's spokesperson said she was "not aware of any manufacturers still selling or distributing ranitidine products."
Sanofi wasn't immediately available to comment.
Valisure isn’t the only one to sound the alarm on ranitidine. A 2008 study from the Fred Hutchinson Cancer Research Center assessed the link between breast cancer risk and three major H2 blockers—cimetidine, famotidine, and ranitidine. After looking at more than 3,000 subjects, the researchers cleared famotidine and cimetidine, but they found ranitidine was “significantly associated” with a common form of breast cancer.
Valisure, meanwhile, brought NDMA to the forefront of drug safety conversations in 2018 when it detected the likely carcinogen in the blood pressure drug valsartan, which in turn led to its own spate of recalls.
In 2020, the plot thickened when Valisure identified NDMA in certain batches of the popular diabetes drug metformin. More than a half-dozen manufacturers, from Lupin to Sun Pharma to the U.S.’s Nostrum Laboratories, had to pull their metformin products, and the recall parade has already bled over into 2021.
Product pulls for metformin and “sartan” blood pressure drugs have been tied to contamination specifically, and Valisure noted that, so far, epidemiological studies have failed to link valsartan use to any human cancers.