Carcinogenic Effects of Nitrosodimethylamine (NDMA) Contamination in Ranitidine: Defining the Relationship With Renal Malignancies

Abstract

Purpose: Ranitidine, a medication used to treat gastric ulcers and reflux, was once the highest selling drug in the world with over $1 billion in annual sales. However, in 2020, ranitidine, known more commonly by the brand name Zantac, virtually vanished from the market after multiple regulatory bodies including the US Food and Drug Administration recommended withdrawal. Their concern was based on detection of nitrosodimethylamine (NDMA), a known animal carcinogen, in ranitidine samples. NDMA has been shown to induce multiple tumor types, including renal tumors. The effects of human exposure, however, are not completely understood. This review aims to clarify what is known about NDMA contamination in ranitidine, the carcinogenic mechanisms of NDMA, and possible associations between ranitidine consumption and renal cancers. Materials and Methods: A comprehensive literature review was performed regarding ranitidine and NDMA, carcinogenesis, and associations with malignancy. Data were considered from environmental, preclinical, and clinical studies from various disciplines. Publications from governmental bodies, including the Food and Drug Administration and International Agency for Research on Cancer, were reviewed and included for analysis. Results: Multiple preclinical studies have demonstrated the carcinogenic effects of NDMA in animals with high rates of renal tumor development. NDMA has been detected in industrial, dietary, and pharmacologic sources. Regarding NDMA levels in ranitidine, evidence points to associations with storage conditions at elevated temperatures and/or prolonged duration as well as endogenous production facilitated by physiologic gastric conditions. Once metabolized, NDMA by-products form DNA adducts with established roles in carcinogenesis. Human data on ranitidine consumption and cancer development are derived from large population studies limited by their observational nature and inconsistent measure of NDMA exposure. To date, NDMA associations with renal malignancies—although evident in animal studies—is not clearly delineated in humans. Conclusions: Detection of NDMA in ranitidine has prompted governmental regulatory bodies to recommend withdrawal of ranitidine from US markets. Classification of NDMA as a “probable human carcinogen” is based on decades of animal studies with a notable rate of renal malignancies. Human observational studies do not clearly demonstrate an association with renal malignancies, but the available data have significant limitations and any conclusions drawn from these observational studies, whether supporting or challenging associations between ranitidine use and renal cancer, should be interpreted with caution.