A carcinogenic impurity has been found in ranitidine drugs

In early October, the State Register of Medicines (GRLS) revealed the suspension of a number of ranitidine drugs intended to treat peptic ulcer disease.  The reason for the mass suspension was the conclusion of FSBI «Scientific Centre for Expert Evaluation of Medicinal Products» of the Ministry of Health of the Russian Federation which was based on information on the presence of carcinogenic N - nitrosodimethylamine (NDMA) in the ranitidine drugs.

For the first time, the presence of an NDMA impurity in ranitidine preparations became known from the U.S. FDA. In September 2019, information on the detection of the substance in the aforementioned drugs was published on the official website of the institution, as well as a call for voluntary recall of drugs, including of the original Zantac drug from Sanofi. A year later, in September 2020, the use of ranitidine was suspended in Europe as well.

N-nitrosodimethylamine is a known environmental contaminant found in water, foods (such as dairy products, vegetables), and several industrial processes. Many animal studies have demonstrated the carcinogenic effects of NDMA.  In addition, the mechanism of the development of tumor diseases caused by NDMA is known. Presumably, in humans NDMA consumption is positively associated with either gastric or colorectal cancer.

Ranitidine and certain other dimethylamine drugs can form NDMA because of product degradation over time and with exposure to a common drinking water disinfectant, researchers have found. Another in vitro study conducted in 2021 found that large amounts of NDMA were created in acidic conditions that simulated the human stomach when ranitidine was introduced in conjunction with sodium nitrite, which is present in some foods and may be created with the metabolism of dietary nitrates, common in cured foods. However, the results of clinical studies conducted by Jeffrey Florian and co-authors showed no increase in urinary NDMA secretion when taking ranitidine and foods containing dietary nitrates compared to taking a placebo combined with the same diet.

In addition, it is worth noting that available safety data do not show that ranitidine increases the risk of cancer, and any possible risk is likely to be very low. However, NDMA has been found in several ranitidine medicines above levels considered acceptable and this fact certainly requires additional thorough safety study.

Since the detectiom of NDMA in ranitidine drugs, studies have been conducted by scientists in various countries devoted to the study of the development of tumor diseases among patients taking ranitidine. For example, scientists from South Korea have found that the risk of tumour disease in patients taking ranitidine is no higher than in patients taking famotidine.

Although there is currently no evidence of the association of ranitidine with the development of tumour diseases, we should hardly expect to see the return of drugs based on it to global market soon. In addition, at the end of October, it was reported that ranitidine is planned to be removed from the list of life-saving and essential drugs (ZNVLP) in Russia. Its place may be taken by an analogue — famotidine.

1. Yoon HJ, Kim JH, Seo GH, Park H. Risk of Cancer Following the Use of N-Nitrosodimethylamine (NDMA) Contaminated Ranitidine Products: A Nationwide Cohort Study in South Korea. J Clin Med. 2021;10(1):153. Published 2021 Jan 5. doi:10.3390/jcm10010153
2. Florian, Jeffry & Matta, Murali & DePalma, Ryan & Gershuny, Victoria & Patel, Vikram & Hsiao, Cheng-Hui & Zusterzeel, Robbert & Rouse, Rodney & Prentice, Kristin & Nalepinski, Colleen & Kim, Insook & Yi, Sojeong & Zhao, Liang & Yoon, Miyoung & Selaya, Susan & Keire, David & Korvick, Joyce & Strauss, David. (2021). Effect of Oral Ranitidine on Urinary Excretion of N -Nitrosodimethylamine (NDMA): A Randomized Clinical Trial. JAMA. 326. 10.1001/jama.2021.9199.