The discovery of the contamination of ranitidine medicine with N-nitrosodimethylamine (NDMA) was made by Valisure, an online pharmacy, that had also uncovered a previously unknown fourth carcinogen in valsartan-based medicines.
After testing ranitidine, also known by its brand name, Zantac, the pharmacy found “extremely high levels of NDMA, a probable human carcinogen, in every lot tested, across multiple manufacturers and dosage forms,” Valisure stated in a Citizen Petition to the US Food and Drug Administration (FDA).
The pharmacy suggested that the reason behind this is the ‘inherent instability’ of the ranitidine molecule, which is formed of both a nitrite and a dimethylamine group, known to combine to form NDMA.
Valisure noted that between its own testing and that performed by Stanford University, “the evidence presented shows this instability and the resulting NDMA occurs in the conditions representative of those in the human body and builds a compelling case for ranitidine being a likely human carcinogen.”
However, in its own public statement, the FDA contested the severity of the findings, stating, “Although NDMA may cause harm in large amounts, the levels [it] is finding in ranitidine from preliminary tests barely exceed amounts you might expect to find in common foods.”
The European Medicines Agency (EMA) also announced that it had started a review of ranitidine medicines.
The medicine itself is widely used to treat gastrointestinal conditions, such as acid indigestion, heartburn, and gastroesophageal reflux disease.
Despite being off-patent, sales of the branded drug, Zantac, still reached $128.9m (€117m) during 2018, according to Statista.
Case against pharma companies
The same day as the FDA and the EMA issued their public statements, a lawsuit was filed in the US District Court for the Northern District of California against the manufacturers of Zantac.
Sanofi and Boehringer Ingelheim are the two companies that stand accused of “knowingly manufacturing and selling over-the-counter Zantac containing a concealed carcinogen to millions of people in the US,” the lawsuit filed by Hagens Berman states.
The class action complaint suggests the dangers of the medicine have been known for over 40 years and that Sanofi (current US rights owner since 2017) and Boehringer (previous US rights owner, from 2007 to 2017) “knew or had reason to know that Zantac exposes users to unsafe levels of the carcinogen NDMA.”
Sartan saga continues
The case is an extension of the ongoing probe into how ‘sartan’ medications came to be contaminated by dimethylformamide (DMF), N-nitrosodiethylamine (NDEA), N-Nitroso N-Methyl 4-amino butyric acid (NMBA) and NDMA.
Previously, the FDA has posted its findings suggesting that the contamination had arisen from the reuse of solvents and through specific chemical and reaction conditions during the manufacturing process.
The findings saw both the FDA and EMA instigating widespread recall of sartan products, which led the FDA to prioritize the review of such medicine to mitigate the ensuing shortages.