Global health regulators sounded a coordinated alarm about the possibility that a stomach drug taken by millions of people could be tainted with the same cancer-causing agent that has sparked a worldwide recall of blood-pressure pills.
Drug-safety officials in the United States and Europe said Friday that they were looking into whether Sanofi heartburn medication Zantac and generic versions made by numerous manufacturers contain levels of the probable carcinogen NDMA that could pose a danger to patients.
Ranitidine, as the drug is known in generic form, is an antacid and antihistamine used to treat and prevent a range of gastrointestinal disorders. The chemical NDMA, or N-Nitrosodimethylamine, is a likely human carcinogen found in cooked or cured meats such as bacon, and is a common industrial byproduct.
The discovery further underscores the challenge pharmaceutical-industry regulators face in overseeing a vast global supply chain of drugs, drug ingredients and factory processes. Dozens of versions of the hypertension treatment valsartan have been recalled since last year out of concern they could be contaminated with NDMA.
Many of those drugs were made in China or India, raising questions about the quality of generic-drug manufacturing in far-flung factories around the globe. Poor quality controls and efforts to conceal manufacturing problems from the U.S. Food and Drug Administration have complicated oversight of overseas drug producers.
“Sanofi takes patient safety seriously, and we are committed to working with the FDA,” Ashleigh Koss, a spokeswoman for the company, said in an email. Zantac is made in Mexico and Sanofi sources its active ingredient from Spain, she said.
The review of ranitidine comes after Valisure, a New Haven, Conn.-based online pharmacy that tests all the medications it dispenses, alerted the FDA that it had detected high levels of NDMA in both generic and brand versions of Zantac sold at major pharmacies run by companies including Walgreens Boots Alliance Inc., CVS Health Corp. and Walmart Inc.
The FDA said Friday that it would review branded and generic versions of the medication. The European Medicines Agency said it “is evaluating the data to assess whether patients using ranitidine are at any risk from NDMA and will provide information about this as soon as it is available.”
The FDA detected NDMA in both prescription and over-the-counter versions of Zantac but hasn’t collected enough samples to give a range of carcinogen levels found, Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research, said in an interview. FDA and European regulators use different testing methods than Valisure, she said, but declined to give details.
Valisure filed a petition with the FDA on Friday asking the agency to recall Zantac and its generics that contain NDMA. The FDA said the NDMA levels in the drugs are low, while Valisure’s petition called them excessive.
“We don’t think this poses an immediate hazard to human health, so we’ll have an ongoing process to determine whether recalls are needed,” Woodcock said.
The FDA didn’t recommend people who take Zantac or its generics stop taking it, but the agency advised that other medications are available.
Once international regulators agree on methods to test the drugs for NDMA, the agency will ask manufacturers to test their versions of Zantac, Woodcock said. The agency will also seek samples from manufacturers to test itself and expects it will take a couple weeks to get more information, Woodcock said.
What’s the origin?
The FDA doesn’t know how NDMA got into the drugs, but its preliminary hypothesis is that it is different from the manufacturing process for the blood-pressure pills that are also tainted, agency spokesman Jeremy Kahn said in an email.
Valisure Chief Executive David Light said his company thinks NDMA is inherently present in Zantac. A Stanford University study was done in 2016 based on a similar understanding.
Stanford environmental researchers interested in how NDMA forms at low levels in wastewater measured levels of the carcinogen in the urine of 10 volunteers who took ranitidine. They found that NDMA levels rose 400-fold after volunteers took the drug, to 48 micrograms — nearly triple the 17 micrograms the FDA found in some recalled blood-pressure pills.
The scientists said in their research that the risks of ranitidine should be evaluated.
“We’re not in that field, so we basically left it at that,” William Mitch, one of the Stanford researchers, said in an interview. “We put it out as food for thought, hoping someone would pick it up.”
Researchers at the Memorial Sloan Kettering Cancer Center are also looking into whether NDMA levels in generic and brand-name Zantac may be linked to an increased risk of cancer based on the findings shared by Valisure, said Lior Braunstein, an oncologist at Sloan Kettering who is co-leading the research on Zantac.
Zantac and its generics are sold with and without a prescription in different strengths. Almost 25 million prescriptions for the drugs were written in 2018, according to Bloomberg Intelligence data.
Sanofi’s U.S.-traded shares slipped 0.2% to $43.71 on Friday. Earlier, in trading in Paris, the French company’s stock fell as much as 2.4% on the FDA statement but recouped most of that loss by day’s end.
The generic versions are made by multiple global manufacturers, including Teva Pharmaceutical Industries Ltd., whose U.S.-traded shares fell 2.9% on Friday. Shares of Mylan, which also makes a version of the drug, lost 2.5%.
“There’s no acceptable cancer risk for a drug like this,” Valisure CEO Light said.
Zantac isn’t just taken by adults. It is also given to infants suffering from reflux, in a syrup form that requires a prescription.
The FDA found NDMA levels as high as 17 micrograms in blood-pressure pills recalled starting in July 2018. Valisure detected NDMA levels as high as 3,000 micrograms in Zantac pills and its generics. In the wake of recalls of blood-pressure drugs, the FDA set an NDMA limit of less than one microgram for the pills and required all companies that make the hypertension treatments to test for the contaminant.