The stomach-acid-blocking drug Zantac was prescribed more than 15 million times a year with little worry about the safety of the medication, available for decades.
But it’s been harder to get the drug since September, when the Food and Drug Administration said testing showed versions of Zantac and its generic, ranitidine, contained a probable carcinogen. The French drugmaker Sanofi recalled Zantac from drugstores and retailers’ shelves. A half-dozen generic drugmakers pulled ranitidine from the market.
How did a drug routinely used by millions of heartburn sufferers and available with or without a prescription become a potential cancer risk? It’s a question the FDA, drug manufacturers and consumers want answered.
“Every patient who comes into my office now, it’s almost the first thing that comes out in conversation: ‘What about ranitidine? What should I do with the medication? Should I come off of it or not?’ ” said Jon Ernstoff, a gastroenterologist in Meriden, Connecticut.
In September, the FDA found unacceptable levels of the probable carcinogen, NDMA, or nitrosodimethylamine, in Zantac and generic medications. The regulatory agency wants manufacturers to test and recall the drugs if NDMA levels exceed its standards. The FDA extended the voluntary recall to a similar drug, nizatidine, sold under the brand name Axid, if testing shows NDMA exceeding daily limits.
The FDA said consumers might want to choose different medications. The agency tested samples of over-the-counter alternatives such as Pepcid, Tagamet, Nexium, Prevacid and Prilosec and found no NDMA.
The agency’s investigation of ranitidine seeks to uncover the root cause of NDMA found in the commonly used medication. Researchers at Memorial Sloan Kettering Cancer Center in New York are assessing whether people who used Zantac or its generics face a greater cancer risk.
The warning first came after Valisure, a Connecticut-based online pharmacy and laboratory, discovered NDMA in several forms of the drug and alerted the FDA. The private company said clues of the drug’s potential risk can be traced to medical studies published since the early 1980s.
NDMA is the same carcinogen that led to a widespread recall beginning in July 2018 of the blood-pressure-lowering drugs valsartan and losartan. The blood pressure recall stemmed from a new manufacturing process first used by a drug ingredient factory in China.
Zantac’s risk appears to be the unstable nature of the drug itself, said Valisure CEO David Light.
“This isn’t some new, bad manufacturing process overseas like what happened with valsartan and losartan,” Light said. “It is our view that this problem with ranitidine has been there since the 1980s.
“It’s a much more serious issue.”
‘Nobody found it’
The FDA tested about 1,500 samples of Zantac and generic versions of ranitidine and found “low levels” of the probable carcinogen. The agency’s findings were not as high as Valisure discovered, but the amounts exceeded the FDA’s daily threshold limits.
Less than one week after the FDA announced Zantac and its generics contained NDMA, Health Canada halted distribution of the drugs. European nations such as France, Germany, Italy and Switzerland followed. Taiwan warned it would fine pharmacies keeping ranitidine on shelves. Pakistan banned all distribution and manufacturing of the drug.
The FDA has taken a more measured approach. Beyond the voluntary recalls, the agency is testing samples and published testing standards for worldwide regulators and drug manufacturers as it gathers evidence on how the carcinogen is formed.
Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, told the House Committee on Energy and Commerce on Oct. 30 that the ranitidine carcinogen is a “different problem” from other manufacturing flaws such as drug ingredient contamination in the blood pressure medication recalls.
“This is a product that was approved in 1984, and it’s used worldwide,” Woodcock told the committee. “And nobody found it.”
The FDA asked pharmaceutical companies to examine whether ranitidine’s ingredients are exposed to nitrites during manufacturing.
“Our chemists believe that it is formed by the molecule ranitidine reacting with something, either during the manufacturing synthesis or during the finished dosage form or during storage,” Woodcock told the committee last week.
The FDA studied how the drug reacts with fluids in the stomach and intestines. During such stimulated tests, the FDA did not find evidence Zantac formed carcinogens. The FDA said it must test the drug in humans to evaluate whether it forms NDMA.
Valisure tested Zantac in stomach-like fluids with and without added nitrites, chemicals commonly found in foods and the body. When those chemicals were added, Valisure found NDMA levels for one tablet of Zantac reached more than 3,100 times the FDA’s daily threshold.
Light said testing the drug with added nitrites created “stomach relevant” conditions.
“Ingesting nitrite-containing foods like hot dogs can significantly increase stomach levels of nitrite,” Light said. “These foods are often eaten by individuals either before or after taking antacid products.”
Studies pointing to risk date to 1980s
In 2016, Stanford University researchers tested urine samples of 10 people who took a 150-milligram tablet of Zantac and found NDMA levels far greater than the FDA’s daily limits.
William Mitch is a Stanford University professor of civil and environmental engineering who studies wastewater converted to drinking water. He said his Zantac-urine study was a “chance finding from a peripheral field” after a study on potential NDMA contamination in drinking water.
He said it should be followed by a more robust study using the FDA’s testing methods.
“The challenge is there’s so much concern about cancer risk. Could you get approval from someone to eat a Zantac and collect the urine sample?” Mitch said, noting such a request would be odd and ethically challenging, given the drug has a known carcinogen and remains on the market.
Lior Braunstein, a Memorial Sloan Kettering oncologist and researcher, is studying ranitidine and cancer risk. He does not want to discuss the study until the findings are published in a peer-reviewed journal, according to Caitlin Hool, a hospital spokeswoman.
Light said studies conducted in the 1980s raised concern about potential safety risks. In a citizen petition to the FDA, Valisure said Zantac’s originator, Glaxo Research Group, conducted its own study in 1987 “after numerous studies raised concerns” about ranitidine.
The Glaxo study examined stomach contents of people who took the drug. It found people had no significant increase in nitrosamines such as NDMA within 24 hours of taking ranitidine.
Light said the study’s testing methods were less accurate and researchers discarded stomach samples that contained ranitidine. Without those samples, researchers would not find NDMA or nitrosamines that form as a result of taking the drug, Light said.
Light said the Stanford study and his lab’s own analysis shows the potential health risk for people who took the drug.
“The negative affect of exposure to this drug and its formation of NDMA is something that has created a huge public health problem,” he said, “and we’re going to be dealing with it going forward.”