Nevertheless, the warning signs continued to build up. A 1980 report titled “Glaxo, Ranitidine – Cause for Concern,” found that ranitidine could potentially form a potentially dangerous, and cancerous, compound in the stomach.
Glaxo, which was seeking FDA approval for Zantac, prepared for “defensive action” to protect itself from the report’s findings. The Bloomberg Businessweek story noted that Glaxo’s board never tested ranitidine to see if it might form a nitrosamine compound.
In a 1981 trial in Britain, 11 healthy men who were administered a daily two-dose regimen of ranitidine for four weeks developed more nitrite in their digestive system – meaning that conditions were favourable for the formation of nitrosamines.
These results were deemed inconclusive by Glaxo scientists, who said that “Ranitidine is recommended only for short-term use” – even though most Zantac users took the drug “for months, sometimes years, even decades,” according to Bloomberg Businessweek.
Another 1981 study, published in The Lancet by Italian scientist Silvio De Flora, found that when ranitidine was mixed with nitrite, it led to “toxic and mutagenic effects.” De Flora later suggested that the consumption of Zantac occur long before or after a meal.
However, says Bloomberg Businessweek, “instructions for taking Zantac to prevent heartburn would recommend using it close to mealtime.”
De Flora, who told Bloomberg Businessweek that “Pharmaceutical companies do not like this kind of study,” said he was quickly approached by Glaxo executives, who then published a follow-up letter in The Lancet attempting to downplay De Flora’s findings.
A 1982 study, which infamously became known as the “Tanner study,” also found danger. Specifically, this study, conducted by scientist Richard Tanner of rival drugmaker Smith, Kline & French, found that ranitidine when combined with different concentrations of nitrite, formed a cancerous poison that was soon named NDMA.
According to Bloomberg Businessweek, “back in 1982, court documents show, Glaxo kept the study secret. The associate director of clinical research in the US was never told about the Tanner report. The senior medical adviser for gastrointestinal research was unaware of it. So was the FDA.”
At the same time, reports Bloomberg Businessweek, “Glaxo also knew of another potentially serious problem with ranitidine. It wasn’t always stable. The drug was sensitive to heat and humidity, and when exposed to too much of either could degrade … That creates conditions for NDMA to form in the drug itself.”
However, later in 1982, Glaxo officials did not reveal this knowledge to a panel of FDA officials and independent researchers. “The Glaxo scientists disputed the idea that ranitidine could form a nitrosamine under any normal human conditions,” according to Bloomberg Businessweek.
By May 1983, the FDA had approved Zantac in a rapid process — and by 1989, it “was worth $2 billion. It accounted for half of Glaxo’s sales and 53% of the market for prescription ulcer remedies.”
However, problems persisted. In the early 1990s, it was found that the pills were not stable and were changing color while in storage. According to Bloomberg Businessweek, “Discoloration is often a sign that tablets are degrading. In some cases, degradation can cause dangerous impurities to form.”
However, Glaxo’s solution was to change the color of the pills. At this time, the company was seeking FDA approval for a less potent over-the-counter version of Zantac. This approval came in the spring of 1996.
Nevertheless, issues with discoloration persisted into the last decade. In 2010, Zantac was “tested for impurities that were known to cause … yellow discoloration.” Although, according to Bloomberg Businessweek, “NDMA used in labs is yellow,” no tests were conducted for this particular substance.
Similarly, when a manufacturing site in China identified problems with “discolored and degraded Zantac tablets” in 2015, GSK sought to downplay the issue, while no testing for NDMA was conducted. Instead, “inappropriate storage” was blamed.
During this period, GSK was fined by regulators in the US and China, but not over Zantac specifically. In 2012, GSK pled guilty and was fined $3 billion “for marketing drugs for inappropriate uses, disregarding safety data and cheating Medicaid,” according to the Bloomberg Businessweek report.
And in 2014, “China fined GSK $500 million and deported a top executive for bribing doctors to prescribe its drugs.”
Issues with Zantac did not come to a head until September 2019, when the FDA received a document from Valisure, an independent laboratory, which, according to Bloomberg Businessweek, “had found extremely high levels of NDMA in Zantac and several generic versions of ranitidine.”
Valisure conducted these tests after NDMA had been found in batches of the blood pressure medication valsartan the previous year. Bloomberg Businessweek reports that Valisure “found NDMA in every version of ranitidine it tested and concluded the problem was inherent to the molecule itself.”
Although the FDA issued an alert, it also questioned Valisure’s testing methods and conducted its own tests. “Within a month,” says Bloomberg Businessweek, “at least two dozen countries pulled ranitidine from stores or halted its distribution.” GSK stopped distributing the drug, as did Sanofi.
Ultimately, in April 2020, ranitidine was banned by the FDA. The agency found that “NDMA levels increase in ranitidine even under normal storage conditions … And NDMA has been found to increase significantly in samples stored at higher temperatures, including temperatures the product may be exposed to during distribution and handling by consumers.”
However, says Bloomberg Businessweek, the FDA has not shared specifics in any published paper about what its tests detected. Instead, these findings were revealed “during a monthly lecture series called FDA Grand Rounds,” in October 2021: one tablet of ranitidine contained “almost four times the FDA’s limit in any drug” when initially tested.
Nevertheless, in June 2021, the FDA said there were “no consistent signals” that Zantac increases cancer risk and that such links that were found in outside research papers were not conclusive. Bloomberg Businessweek says this “is now a regular part of Glaxo’s public-relations and, presumably, legal defense.”
A statement provided by GSK to Fierce Pharma in response to the Bloomberg Businessweek article says it “presents an incomplete and biased presentation of the facts surrounding the Zantac (ranitidine) litigation.”
“Patient safety is the highest priority for GSK, and the company categorically refutes any allegation of having covered up data regarding the safety of ranitidine,” the statement adds. “The safety of ranitidine has been thoroughly evaluated over the past 40 years.”
The Bloomberg Businessweek report states that “More than 70,000 people who took Zantac or generic versions of it are suing the company in US state courts for selling a potentially contaminated and dangerous drug,” with the first of these trials set to begin later this month in the Superior Court of California, County of Alameda.
Other companies that sold Zantac, including Pfizer, Sanofi and generic manufacturers, are also facing lawsuits.
There have been some setbacks for plaintiffs, however. According to the Bloomberg Businessweek report, a December 2022 ruling, by the US District Court for the Southern District of Florida, “dismissed thousands of federal lawsuits that had been consolidated in her courtroom for pretrial proceedings.”
US District Judge Robin Rosenberg found there is “no widespread acceptance in the scientific community of an observable, statistically significant association between ranitidine and cancer.” Lawyers for the plaintiffs plan to appeal.
GSK is hanging its hat on this ruling, according to Bloomberg Businessweek. In a statement, Kathleen Quinn, a spokesperson for the company, said, “The court’s view is consistent with the position that GSK and other co-defendants have taken throughout this litigation.”
And in a statement following the Florida federal court ruling, GSK said it was glad that “unreliable and litigation-driven science did not enter the federal courtroom.”
Fierce Pharma reports that following this ruling, not just GSK but “Pfizer, GSK, Sanofi and Boehringer Ingelheim are now able to wash their hands of thousands of Zantac-related lawsuits,” as about 50,000 claims were taken “off the drugmakers’ plates.”
And according to Law360, on Feb. 7, the same Florida judge issued a new ruling which will not allow tens of thousands of Zantac lawsuits to be combined.
This ruling was made on the basis that the lawsuits in question had signed up for “court-created registry of claims in the multidistrict legislation” that was “abandoned” following the December 2022 decision.
In this new ruling, Judge Rosenberg also provided some insights into the appeals that were filed against the December 2022 decision, stating that “claimants in the registry are still now required to file their cases individually in federal court in order for their claims to be considered timely,” according to Law360.
However, as reported by Bloomberg Businessweek, “GSK does still have to fight the tens of thousands of cases waiting in state courts, where judges aren’t bound by the federal court’s ruling,” adding that “GSK could face years of lawsuits in California, Delaware and other states, with the possibility of billions in damages.”
Law360 reported Jan. 26 that despite the December 2022 Florida ruling, “New York’s Litigation Coordinating Panel on Thursday consolidated more than 40” Zantac lawsuits. Attorneys from Napoli Shkolnik PLLC, one of the firms representing plaintiffs in the lawsuits, described this as “a welcome alternative” to the Florida multidistrict litigation.
In the forthcoming Alameda County court case, GSK “is expected to urge” the court “to limit what expert testimony jurors can hear,” reports Reuters.
The plaintiff in that case, James Goetz, says he developed bladder cancer from taking Zantac over a period of many years. According to Bloomberg Businessweek:
“Goetz was 60 in 2017 when he was diagnosed with bladder cancer. That in and of itself wasn’t too unusual; 60 is about the age this particular cancer is often diagnosed in men. Smokers get bladder cancer, but Goetz hadn’t smoked since he was 22. His job hadn’t exposed him to any potentially harmful chemicals. It was perplexing, but he had no reason to think his getting cancer was anything other than random.
“When Zantac was recalled, he kept four bottles he’d already purchased. They’re in the freezer in the office of one of his attorneys, Brent Wisner, as are leftover pills from Russell. Tests showed that one of Goetz’s pills is contaminated with 3,000ng of NDMA, Wisner says; one of Russell’s has more than twice as much. Wisner says he’s invited GSK to test the tablets, but the company hasn’t done so.”
Goetz’s cancer has returned in aggressive form, necessitating surgery and dialysis. His bladder and prostate were removed, along with 20 feet of his intestines. He later suffered sepsis, kidney stones and kidney failure. His lawsuits against Boehringer Ingelheim, Pfizer and Sanofi were settled in December 2022, but his GSK case continues.
Depositions taken during the discovery process, brought to the public eye by Bloomberg Businessweek, have been revealing. A former senior medical adviser to Glaxo, when asked during a June 2021 deposition whether Glaxo had ever tested for the presence of NDMA in Zantac, answered, “Not to my knowledge.”
In a May 2022 deposition, Andrew Whitehead, who had been director of second-generation research and development for the company, testified that “it would have been known in the ‘80s as part of the development” of Zantac that ranitidine would degrade in high temperature conditions.
And a May 2021 deposition, Fred Eshelman, formerly Glaxo’s associate director of clinical research when Zantac was developed, agreed with a lawyer for the plaintiffs that “it is completely unheard of in the industry to go that fast” — referring to the clinical development of ranitidine.
As the lawsuits against the former manufacturers of Zantac continue, increased scrutiny of medications for the potential presence of nitrosamines has followed.
USA Today reports that the FDA “has asked drugmakers to evaluate all products for any risk they might contain nitrosamines,” adding that “Companies that identify any such risk must conduct follow-up testing, report changes and take action” by Oct. 1.
“We continue to closely evaluate this type of impurity and will continue to investigate and monitor the marketplace and manufacturing efforts to help ensure the availability of safe, quality products for US consumers,” stated FDA spokesman Jeremy Kahn.
According to USA Today, in recent years, several drugs have been recalled due to the presence of nitrosamines, including diabetes medication metformin, anti-smoking medication Chantix, and blood pressure, heart and kidney medications losartan, quinapril (sold as Accupril) and valsartan.
- Michael Nevradakis, Ph.D., based in Athens, Greece, is a senior reporter for The Defender and part of the rotation of hosts for CHD.TV’s “Good Morning CHD.”