Investigating the possibility of N-Nitrosodimethylamine (NDMA) in famotidine containing products

Famotidine is a member of H₂ histamine receptor blockers that extensively is used for the treatment of stomach acid-related disorders. However, in the last few years, the presence of unacceptable levels of carcinogenic impurities has become one of the serious challenges. The genotoxic and carcinogenic potential of N-nitrosamines has become such a severe crisis that in September 2020, the FDA issued a letter to the pharmaceutical industry to control nitrosamines in pharmaceutical products. According to this evidence, due to the increased famotidine administration, it seems necessary to investigate the possibility of the presence of N-Nitrosodimethyl-amine ("NDMA"), a possible human carcinogen, in famotidine-containing dosage forms. So, the effect of parameters that may be effective on the production of NDMA was investigated using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Among these factors, we practiced the effect of sodium nitrite, pH, temperature, and the impact of different excipients. Also, the storage conditions of famotidine tablets purchased from local pharmacies were analyzed at two temperatures after 2 months storage period. According to the FDA, the presence of carcinogenic N-nitrosamine impurities should not exceed the permissible consumption limit of 96 ng per day. Examining the samples in different pH conditions and even before applying the temperature conditions shows that the famotidine powder often has high amounts of NDMA. Adding sodium nitrite in increasing concentrations did not show a significant effect on the formation of NDMA. It is concluded that, having an acceptable amount of NDMA at the time of manufacture does not guarantee that it remains within the limits during the defined shelf life period. According to findings, the amount of NDMA was in excess in all famotidine tablets irrespective of the brand, manufacturing lot, and dosage. The NDMA formation may be due to inherent instability or good reactive and storage conditions.