A Bloomberg investigation has revealed that Glaxo, which went on to form pharmaceutical giant GSK, was aware of the possible carcinogenic content of its popular heartburn drug Zantac for over 40 years.
The once-popular heartburn drug Zantac (ranitidine) was developed in the 1970s by the then-small British pharmaceutical company Glaxo. It was marketed as better and safer than Tagamet (cimetidine) and it soon outsold it and became one of the company’s best-selling drugs.
NDMA belongs to a class of compounds known as nitrosamines, came to light in cancer research when it was found that nitrites could combine with amines in the stomach, giving rise to cancer-causing compounds. This led to calls for restrictions of sodium nitrites, found in various cured foods, but the food industry has resisted this.
This all came to an end in 2019, when Zantac was found to be contaminated by the chemical N-Nitrosodimethylamine (NDMA), a pale yellow liquid at room temperature. NDMA is a known carcinogen at high concentrations and a possible one at low concentrations. This contamination was not due to a manufacturing error, however: NDMA can form from other reactions and in this case came from within the drug itself. Around the world, Zantac was pulled from shelves, and in 2020 the drug was banned by the FDA. NDMA currently is only produced in small amounts to induce cancer in rats. Whether it is carcinogenic at very low levels is still a matter of debate, but Zantac products contained NDMA at levels which could increase over time.
According to Bloomberg, Glaxo was aware of this, as the possibility of ranitidine being converted in the stomach to nitrosamines being raised in 1980. Tests with human subjects taking ranitidine showed this. Even though NDMA is widely held to be a carcinogen in humans, it is difficult to prove that a particular chemical is responsible for mutations leading to cancers. Glaxo simply took the view that ranitidine did not cause cancer in rodent studies, and that any possible cancer risk was minimised by short exposure. In fact, users would take Zantac for extended periods, even years or decades.
The company was thus warned over 40 years by its own scientists as well as independent researchers, with thousands of pages of documentation seen by Bloomberg for the first time. One 1981 Lancet study showed that Zantac mixed with nitrite in the stomach (as from a meal) would produce nitrosamines. Glaxo scientists countered by saying that the nitrite levels in the study were far above those found in a human stomach, a defence which would become their standard response.
While Glaxo was preparing for FDA approvals in 1982, another study came to their attention. Concerned, Glaxo asked one of their scientists, Richard Tanner, to replicate it and he found that some samples contained 232 000ng of NDMA – the FDA approved limit for each drug was 96ng, though with lower nitrite levels, no NDMA was detected. The daily FDA exposure limit from all sources for NDMA is 190ng, which includes NDMA from all sources, including other medications (which may produce their own NDMA over time) as well as biological processes.
This report would remain secret for more than 40 years. More trouble came from the fact that NDMA could be formed from exposure to either heat or humidity. When it went through the FDA approval process, it did not mention the Tanner report and the notion of storage was glossed over: approved in 150mg doses for eight weeks, storage requirements were listed as a dry place at a temperature no higher than 86°F (30°C).
Zantac surged in popularity, turning the company into a multi-billion dollar enterprise, though the FDA took action over Glaxo’s claims. An over-the-counter 75mg version was launched in 1996. It was coloured pink due to issues of discolouration with white pills turning yellow or brown over time.
While discolouration issues were briefly investigated, it was only in 2019 when there were concerns over NDMA contamination, spurred by recalls of a blood pressure drug, valsartan. A private laboratory warned the FDA over NDMA discovery in Zantac and ranitidine generics, and after the FDA conducted its own tests, the company that was now GSK turned over its documentation.
Within a month, distribution of ranitidine was halted nearly worldwide, and the FDA took the drastic further stop of ordering its production halted. Shortly afterward, the FDA stated that the evidence for NDMA in ranitidine was inconclusive, and clarified that the NDMA concerns were from contamination being produced during its storage, not production in the stomach.
For GSK, the damages from the thousands of plaintiffs may range from US$5 to 17 billion, but damages are likely to be reduced and previous lawsuits of this type have struggled to prove that the relevant compound caused cancer. For Zantac, however, this will be less of an obstacle as NDMA is almost universally accepted as a carcinogen.
Source: Bloomberg
