Around 70,000 people are claiming their cancer was caused by the heartburn remedy Zantac, which contained high levels of NDMA, a powerful carcinogen
A powerful cancer-causing compound has been discovered in 10 prescription drugs. More than 70,000 people who believe they developed cancer while taking one of the drugs—the heartburn remedy Zantac—have filed lawsuits in US courts.
The compounds are nitrosamines, identified in the 1970s as the most potent carcinogens yet discovered. They have been found in batches of some of the world’s most prescribed drugs, including the antihypertensives Avapro (irbesartan) and Cozaar (losartan), the antidiabetic medication Glucophage (metformin), and the stop-smoking aid Chantix (varenicline).
Nitrosamines were detected in batches of the antihypertensive Diovan (valsartan) in 2018, and a year later, the same online pharmacy discovered high levels of NDMA (N-Nitrosodimethylamine), a form of nitrosamine, in every batch of Zantac (ranitidine) it tested. It alerted the US’s drug regulator, the Food and Drug Administration (FDA), which banned the drug in 2020.
Even before the ban was imposed, around 12 countries had already pulled Zantac from stores, and GSK had stopped manufacturing it.
It was quite a fall for a drug that in the 1980s had been the world’s best-seller, achieving more than $1 billion in sales every year. The ban was extended to any drug that had ranitidine as its active ingredient, and there have also been 250 voluntary nitrosamine-related recalls since then.
Ranitidine is linked to least 10 cancers, and people who have lodged lawsuits have reported developing cancers of the bladder, esophagus, liver, pancreas and stomach. Many of the cases include army veterans who developed cancer after taking Zantac, which was routinely handed out to US armed forces.
Pharmaceutical analysts at Morgan Stanley, the investment bank, say that drug manufacturers could face judgments that total up to $45 million—if the drugs can be proven to be the cause of the cancers.
Thus far, things aren’t looking good for the plaintiffs. Last December, the district court for Southern Florida dismissed thousands of claims because “there is no widespread acceptance in the scientific community of an observable statistically significant association between ranitidine and cancer.” A GSK spokesperson said the company was pleased that “unreliable and litigation-driven science did not enter the federal courtroom.”
Other bellwether cases are being heard in courts across America this year, and these will help claimants and their lawyers assess the likelihood of a successful outcome and the settlement figure, if any. One plaintiff settled his claim before trial after accepting a payout of $500,000.
Lawyers are appealing the Florida judgment because NDMA is a recognized carcinogen and the amounts discovered in the Zantac samples were far above safe levels. The FDA revealed that the ranitidine tablets they tested contained four times the safe limit of NDMA.
Although nitrosamines are found in drinking water and processed meats, just one person per 100,000 develops cancer after eating or drinking them at safe levels over a long time—but levels found in recalled batches of Zantac were so high that they could cause cancer in one in every 3,000 users. Under a milligram of it causes cells in mice to mutate, and 2 g kills a person in a couple of days.
There’s also the possibility that other pharmaceuticals contain nitrosamines that haven’t been detected. It’s suspected the contaminants are getting into the drugs during the manufacturing process—which suggests any drug being made in plants with low quality controls could become contaminated.
But in the case of Zantac, its active ingredient ranitidine breaks down into NDMA while it’s on the pharmacy shelf or exposed to heat, and it can transform into the carcinogen when it reaches the stomach. This instability was detected when Glaxo—as it was then known, but today trades as GSK—was developing the compound in the 1970s.
According to papers it has submitted to the courts as part of the discovery process, “Glaxo had been warned by its own scientists and independent researchers about the potential dangers,” say researchers with Bloomberg Businessweek, who had access to the court papers. “Over the years, the company also backed flawed research designed to minimize concerns and chose not to routinely transport and store the medication in ways that could have eased the problem.
“Glaxo sold a drug that might harm people, tried to discount evidence of that and never gave anyone the slightest warning.”1
The profit motive may have had a part to play. Glaxo had its sights fixed on Tagamet, Smith Kline & French’s heartburn remedy, which was the world’s best-selling drug at the time. Its researchers quickly developed ranitidine, and the FDA was just as speedy in approving it in 1983. In 1986, Tagamet became the first drug in history to achieve billion-dollar sales—yet just a year later, it was overtaken by Zantac. The drug generated half of Glaxo’s revenues for years and was its most profitable product. It dominated the heartburn and ulcer remedies market with a 53 percent share.
According to court papers, Glaxo ignored inconvenient naysayers about the possible hazards of ranitidine. In 1969, US government cancer researcher William Lijinsky had discovered that nitrosamines can form in the stomach, especially if nitrite chemicals from cured and grilled meats, beer and coffee—foods that are common causes of heartburn and acid reflux—were also present.
His early observations were ignored, although a report published two years before Zantac was granted approval found that ranitidine could form a cancer-causing compound in the stomach. Italian researcher Silvio De Flora discovered that ranitidine led to “toxic and mutagenic effects” if it was mixed with nitrite and gastric fluid.2
Another scientist, Richard Tanner, discovered that ranitidine formed a carcinogen—which became known as NDMA—when it was mixed with nitrite. He made this discovery a year before Zantac was approved, but he was an employee of Smith Kline & French, Glaxo’s bitter rivals in the heartburn remedy market, and so his findings were discounted as a display of commercial partiality.3
Even though Tanner’s study was published, Glaxo kept it from regulators. Its own researchers were also noticing that ranitidine was an unstable substance that changed when exposed to heat or humidity, and NDMA started to form. Again, this observation was kept from regulators.
After Zantac was approved, problems continued to pop up. It was getting harder to hide ranitidine’s instability from pharmacies, which began to report that the pills were changing color when they were on the shelf. Glaxo’s solution was to change the pill’s original color so that any discoloration was harder to detect.
Glaxo was keen to keep a lid on any alarms as it was going through the process of producing a milder version that could be sold over the counter (OTC) without a prescription. The FDA duly complied, and the drug was granted its OTC license in 1996.
Health agencies around the world have recognized that nitrosamines—and NDMA in particular—cause cancer, although the poison is in the dose and exposure. Although the amounts of NDMA in Zantac samples have been way above safe levels, the 70,000 who believe they got cancer because they wanted something to ease their indigestion will have to prove a direct causal link to Zantac to win the day. GSK has set aside $40 million to fight the cases—but not a cent to settle damages, which gives an indication of the way the wind is blowing.
It’s hard to avoid nitrosamines. Around 300 of the organic chemicals have been identified, and they can be found in vegetables, water and dairy products. They are also created when meats are grilled, cured or processed. Around 30 of them have been classified as carcinogenic, although the dose and exposure determine whether someone gets cancer from consuming them.
NDMA (N-nitrosodimethylamine), which has been found in Zantac, is a nitrosamine that was classified as a carcinogen in 1956 and was thought to raise the risk of liver cancer. In laboratory tests, it caused cancer in every type of animal that was given doses. It was also an ingredient in rocket fuel, although it is now actively used only in medical tests.
Ten pharmaceuticals have been banned or had batches recalled because of levels of nitrosamines. Since the problem was recognized in 2018, drug companies have recalled more than 250 batches of their drugs.
Zantac (ranitidine): Banned by the FDA in 2020 after amounts of the nitrosamine NDMA four times above safe levels were discovered in batches that were tested. Sanofi’s heartburn remedy, Zantac 360, has not been banned as its active ingredient is famotidine.
Avapro (irbesartan): Batches of the antihypertensive were recalled in 2021 because high levels of the nitrosamine N-nitrosoirbesartan were discovered. The supplier, Lupin Pharmaceuticals, announced it had stopped marketing the drug.
Cozaar (losartan): Batches of the antihypertensive were recalled in 2018. The source was traced back to a manufacturing plant.
Glucophage (metformin): The FDA detected high levels of NDMA in batches of the antidiabetic remedy in 2020, and batches made by several manufacturers were recalled.
Tazac (nizatidine): The ulcer remedy was plagued by recalls in 2020. Three lots were taken off the shelves across the US, and the oral version was also removed a few months later. All the batches contained NDMA.
Accupril (quinapril): Five batches of the antihypertensive were recalled in 2022 after levels of N-nitroso-quinapril were discovered.
Rifadin (rifampin): The FDA discovered nitrosamine impurities in several lots of the antibiotic in 2020.
Januvia (sitagliptin): Batches of the antidiabetic medication had traces of the nitrosamine NTTP (nitroso-STG-19) in tests carried out in 2022. Levels were above safe limits, but the FDA allowed Merck to continue supplying the drug. Merck has said it has upped quality controls at its manufacturing plants to ensure it meets FDA requirements.
Diovan (valsartan): The drug that started the nitrosamine saga in 2018 when high levels of NDMA were discovered in batches of the antihypertensive. The FDA has ordered dozens of recalls since then. The problem has been traced back to an active ingredient manufactured in China.
Chantix (varenicline): Shipments of the smoking cessation remedy were stopped in 2021 after levels of the nitrosamine N-nitroso-varenicline were discovered.