June 21, 2021 -- In 2016, researchers had some very bad news for anyone taking antacids. They found that healthy men and women who took a normal dose of the heartburn medicine ranitidine, often known by the brand name Zantac, had extremely high levels of a chemical known as NDMA, a probable cancer-causing substance.
NDMA levels in their urine increased by 400-fold after taking a dose of the antacid, the researchers found. Their research and that of others set off a cascade of events that eventually led to the FDA requesting the recall of Zantac and its many generic versions in April 2020.
Now, however, the co-authors of that paper have asked the journal, Carcinogenesis, to retract that paper, and the journal has. In the retraction notice, the journal editors said that ''the authors have informed the journal that their NDMA measurements are not reliable." The problem has to do with the method they used to measure the NDMA levels. They found levels of NDMA as high as 47,600 nanograms -- much higher than the 96 ng the FDA says is an acceptable daily level of NDMA from a drug.
Could this new wrinkle mean a return of ranitidine, a best-selling drug since the FDA approved it as Zantac in 1983? Sales of Zantac (not including several generic versions of ranitidine) topped $136 million in 2019, according to Statista. The drug works by reducing acid production in the stomach. Besides heartburn, it was used to treat ulcers and throat and stomach problems.
And what effect might this have on the lawsuits of thousands of people who say the medication gave them cancer or that they wouldn't have used it had they known about the potential risk?
Medical experts interviewed by WebMD concur that the drug won't return to market. (Zantac 360, now on the market, has famotidine as its active ingredient, the same as in Pepcid.)
Attorneys involved in the litigation agree and say the lawsuit efforts will proceed on schedule. One attorney predicts a payout that will surpass the nearly $11 billion settlement he helped win for cancer-causing claims against the weed killer Roundup.
Experts: Why Ranitidine Won't Return
The 2016 study, despite the measuring methods used that are now not recommended, was just one of many pointing to the potential NDMA-cancer link.
"Other studies have shown this [link] using other methods," says Ivan Oransky, MD, co-founder of Retraction Watch, which publicized the retraction of the study on June 15. "This wasn't the only line of evidence that the FDA and others were citing when they made that decision to recall.”
"The ranitidine molecule itself is fundamentally unstable," says David Light, CEO of Valisure, an online pharmacy and testing laboratory that first brought the problem of NDMA in ranitidine to the attention of the FDA in June 2019 before filing a petition in September seeking the drug’s recall.
"It will absolutely have no effect on the recall of ranitidine," agrees Ron Najafi, PhD, CEO of Emery Pharma, a research laboratory that tested the medication using another measurement method approved by the FDA and then filed its own petition seeking a recall Jan. 2, 2020. Najafi is also working as a consultant for plaintiffs claiming ranitidine caused their cancers.
When asked if the FDA might take another look at ranitidine, FDA spokesperson Jeremy Kahn pointed out the two approved testing methods now used for NDMA, different from the one used in the 2016 paper. He didn't answer directly about ranitidine, but says in an email: "The FDA is continuing its ongoing review, surveillance, compliance and pharmaceutical quality efforts, and will continue to work with drug manufacturers to ensure safe, effective and high-quality drugs for the American public."
Measuring NDMA in Drugs: Old Vs. Newer Methods
NDMA, or n-nitrosodimethylamine, is a nitrosamine. It’s common in low levels in water and foods such as grilled meats, but it has also recently been found in commonly used medications such as some blood pressure drugs.
The test method used by the Stanford and Syracuse professors, who have not yet responded to a request for comment, is known as gas chromatography mass spectrometry or GC/MS. "Gas chromatography has to heat the sample in order for you to be able to analyze anything," Najafi of Emery Pharma says. "That heating messes up the sample."
According to the Stanford and Syracuse professors, however, the GC/MS measurement method was standard for analyzing NDMA in drugs as recently as January 2019.
In September and October 2019, however, the FDA published two other testing methods involving liquid, not gas chromatography, that don't involve heating the sample, which they recommend to detect NDMA in ranitidine.
For the Emery investigation, Najafi's team used a liquid chromatography as recommended by the FDA to evaluate NDMA in ranitidine. "You still see the NDMA," Najafi says. "The NDMA is not an impurity in Zantac. It is a side product of ranitidine. As time and temperature affect the product, NDMA is a breakdown product. Even at room temperature, if you keep it long enough, it keeps growing NDMA."
That finding was a major concern, Najafi says, because ranitidine was sold ''at every drugstore, every 7-11. People put in their [hot] cars." During the shipping process, the temperature of the medication was not controlled, he says.
In his research, Najafi found that a 150-milligram tablet of ranitidine, exposed to about 158 degrees, or the temperature a closed car could reach on a hot day, had 106 nanograms of NDMA by day five.
"It's all boiling down to the fact that it is a fundamentally unstable drug," Light, of Valisure, says. Despite the glitch with the measurement used in the retracted research, he says, “we still believe by far the most concerning element for public health for ranitidine is its potential to form NDMA in the human body."
Valisure, in its analysis using the gas chromatography method, found even higher levels than what the professors found in the 2016 study -- more than 3 million nanograms in some samples.
In 2020, researchers from GlaxoSmithKline, the original maker of Zantac before Sanofi took over its sales, published their findings in a chemistry journal, concluding that ''the presence of NDMA [in ranitidine] results from a slow degradation of the ranitidine molecule."
The Winding Road to Recall
Valisure first began looking closely at ranitidine after the infant daughter of a company co-founder was prescribed generic ranitidine syrup. As concern grew about the NDMA in ranitidine, Valisure filed the petition on Sept. 9, 2019, asking the FDA to recall the drug. Their request was followed by this chain of events:
- The FDA issued a safety announcement Sept. 13, 2019, stating that it had learned some ranitidine medicines contain NDMA. In this, it did not call for people to stop taking the drug, but it suggested those taking the prescription form should talk to their doctors if they wanted to discontinue it and those who wished to stop the OTC versions could consider other heartburn medicines.
- Many manufacturers began voluntary recalls.
- In November 2019, the FDA compared levels of NDMA in ranitidine to levels that people would expect when eating grilled or smoked meats.
- On April 1, 2020, the FDA requested removal of all ranitidine products from the market. It noted that the NDMA levels rise over time when the medication is stored at higher than room temperature.
The Ranitidine-Cancer Link
How strong is the ranitidine-cancer link in people? There's no consensus.
According to the FDA, "FDA does not expect nitrosamines to cause harm when ingested at low levels. Nitrosamine impurities may increase the risk of cancer if people are exposed to them at above acceptable levels and over long periods of time, but a person taking a drug that contains nitrosamines at, or below, the acceptable daily intake limits every day for 70 years is not expected to have an increased risk of cancer."
Researchers from Memorial Sloan Kettering Cancer Center and Valisure, however, compared the use of ranitidine and other acid blockers in more than 10,000 cancer patients, finding a link between ranitidine use and cancers of the breast, thyroid, bladder, and prostate. Their study was published as a preprint and is not yet peer reviewed.
In another study, researchers looked at more than 459,000 people from the U.K. Biobank and found more than 26,000 diagnosed with cancer. Of these, 1.9% reported ranitidine use, but the researchers found no link with its use and overall cancer risk. They did find those who used ranitidine regularly were 1.9 times more likely to have liver cancer.
The Route to Trial
"The future of the case is very much alive," says R. Brent Wisner, a vice president at Baum Hedlund Aristei & Goldman, Los Angeles, and lead liaison counsel for the California state court proceedings involving ranitidine. "The plan is to go to trial next year. We have all our experts lined up."
The claims are still supported, agrees Joe Waechter, an attorney for Morgan and Morgan, Orlando, which also represents clients with ranitidine claims. "The study was retracted because the methods used in the study to measure NDMA in ranitidine were determined to be unreliable, and not because a ranitidine/NDMA correlation was disproven."