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April 1, 2020 -- Six months after independent testing first raised the possibility that popular heartburn drug ranitidine (Zantac) might break down into the powerful carcinogen n-nitrosodimethylamine (NDMA), the FDA has asked for the removal of all ranitidine products from the market. If you’re taking it now, stop.

“The agency has determined that the impurity in some ranitidine products increases over time when stored at higher than room temperatures and may result in consumer exposure to unacceptable levels of this impurity,” the FDA said in the announcement.

The agency doesn’t have mandatory recall authority, which is why this is only a request, Janet Woodcock, MD, director of the FDA's Center for Drug Evaluation and Research, said in a media briefing. But given the safety issues, they anticipate full cooperation.

For those who rely on ranitidine to treat their heartburn, the agency suggests several alternatives. “To date, the FDA’s testing has not found NDMA in famotidine (Pepcid), cimetidine (Tagamet), esomeprazole (Nexium), lansoprazole (Prevacid) or omeprazole (Prilosec),” the announcement said.

Results Take Time

In September Valisure, an online pharmacy that tests every batch of medication before dispensing, alerted the FDA to the potential for dangerous levels of NDMA to develop in ranitidine. While the FDA investigated, voluntary recalls removed most over-the-counter ranitidine products from the market, but it was still available by prescription.

Initial FDA testing of the products found acceptable levels, but agency researchers also stored the drugs for months at various temperatures. Numbers grew fastest while stored under high heat, but even a period at moderate heat brought levels above what’s acceptable. And at room temperature, time was the key factor -- the levels accumulated as months went by. Those findings prompted the request for removal.

“We’re saying they aren’t defective but could become defective stored under stressful conditions for the product,” Woodcock said during the briefing. “I can’t recall anything exactly like this happening before.”

What Next?

David Light, CEO of Valisure, is glad ranitidine is being removed from the market, but he doesn’t believe the problem has been solved completely. “The FDA was originally focused on manufacturing, which I can understand,” he said. “But if ranitidine is unstable enough to fall apart during storage and transportation, it underscores the concern for what happens when you put it in the human body, where the stomach has thousands of enzymes whose whole job is to break things down.”

While Woodcock sought to reassure parents who have given their infants prescription ranitidine to treat reflux, saying the agency doesn’t believe there’s a significant risk, Light feels it’s too soon to tell. “Any exposure at developmental stages in life can be substantially worse than as an adult,” he said.

Valisure is working with Memorial Sloan Kettering Cancer Center on disease studies. They hope to identify specific cancers associated with ranitidine, as well as how much exposure is required.

Potential Changes to Drug Approvals

Woodcock acknowledged that the lack of testing past the point of manufacturing needs to be changed. Ranitidine made today would still meet all the required standards as it rolls off the production line, so without Valisure’s testing and publicity, the problem may not have been discovered.

The approvals process itself may change after this discovery. “This needs to be institutionalized and put into the ordinary testing of pharmaceuticals, so we don’t find out once they’re on the market that there’s a problem,” she said. Woodcock expects the FDA to be putting out guidance for the industry in the near future.

Light applauds this possibility, but he says he believes that won’t go far enough. The first studies about the NDMA in ranitidine came out in the early 1980s, and it’s taken until now for the drug to be pulled. “Academics were talking about this for decades and being ignored,” he says. “You can’t keep ignoring the scope of information that’s outside the pharmaceutical regulatory bubble.”

Show Sources

FDA: “FDA Requests Removal of All Ranitidine Products (Zantac) from the Market.”

Janet Woodcock, MD, director, FDA Center for Drug Evaluation and Research.

David Light, CEO, Valisure.

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