Background: Ranitidine is a widely used histamine H₂-receptor antagonist (H₂RA) indicated for the management of gastroesophageal reflux disease (GERD), peptic ulcer disease, and other acid-related gastrointestinal disorders. In 2019, the detection of N-nitrosodimethylamine (NDMA), a probable human carcinogen classified by the International Agency for Research on Cancer (IARC Group 2A), in certain ranitidine formulations raised significant concerns regarding drug quality and patient safety. Subsequent investigations demonstrated that NDMA concentrations may increase during manufacturing, storage, and exposure to elevated temperatures, resulting in global regulatory actions, including the withdrawal or suspension of ranitidine products in several countries.

Objective: This review summarizes the current scientific evidence on NDMA contamination in ranitidine, including its mechanisms of formation, toxicological effects, analytical detection, regulatory responses, and the available evidence regarding cancer risk.

Methods: A comprehensive literature search was conducted using PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar, together with official reports from the FDA, EMA, WHO, and IARC. Peer-reviewed articles and regulatory documents published between 2018 and 2026 were critically evaluated according to predefined eligibility criteria.

Results: Available evidence indicates that NDMA formation in ranitidine is influenced by molecular instability, manufacturing conditions, storage duration, and elevated temperatures. Experimental studies consistently demonstrate the genotoxic potential of NDMA through DNA alkylation, oxidative stress, and mutagenic mechanisms. However, epidemiological studies have reported inconsistent findings, and current evidence does not establish a definitive causal association between therapeutic ranitidine use and current evidence is insufficient to confirm that therapeutic ranitidine exposure contributes to cancer development.

Conclusion: NDMA Contamination Represents a Significant Pharmaceutical Quality Concern Requiring Stringent Impurity Monitoring and Regulatory Oversight. Further multicentre epidemiological studies, standardized analytical methods, and improved pharmacovigilance are essential to clarify the long-term health implications to better understand the long-term health consequences associated with NDMA exposure while supporting the development of safer and higher-quality pharmaceutical therapies.

KEYWORDS: Ranitidine, N-nitrosodimethylamine (NDMA), Histamine H₂-receptor Antagonist, Cancer Risk, Nitrosamine Impurities, Drug Safety, Pharmacovigilance, Toxicology, Regulatory Affairs.