EMA/CMDh: Update of Appendix 1 for Nitrosamines

The nitrosamine Q&A document "Questions and answers for marketing authorization holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products" of the EMA/CMDh contains three appendices (Appendix 1-3) in its current version of January 2024. These documents are published on the EMA website and can be viewed under "Questions and answers".

Appendix 1 "Acceptable intakes established for N-nitrosamines" was prepared by the "Non-clincal Working Party (NcWP)" and the information provided there for the acceptable intakes (AIs) is based on the "Carcinogenic Potency Categorization Approach (CPCA)". In May 2024, new substances were added to Appendix 1, which consists of a tabular list of substances, and some existing entries in the list were updated. Sixteen substances were added and are marked in red and clearly recognizable in the list of acceptable intakes (AIs). These include:

  • 2-(4-nitrosopiperazin-1-yl)ethanol
  • 3-((ethyl(nitroso)amino)methyl) benzenesulfonate
  • 4-nitroso-methyl piperazine-1-carboxylate
  • N-(2-hydroxy-2-phenylethyl)-N-(4-nitrophenethyl)nitrous amide
  • N-(4-aminophenethyl)-N-(2-hydroxy-2-phenylethyl)nitrous amide
  • N-nitroso-articaine
  • N-nitroso-desmethyl-edoxaban
  • N-nitroso-fenfluramine
  • N-nitroso-furosemide
  • N-nitroso-N-desmethyl-dextromethorphan
  • N-nitroso-posaconazole Impurity 1
  • Rivaroxaban Nitroso Impurity 1
  • Rivaroxaban Nitroso Impurity 2
  • Rivaroxaban Nitroso Impurity 5
  • N-nitroso-trientine Impurity 1
  • N-nitroso-vibegron

The entries for the substances "N-nitroso-folic acid" and "N-nitroso-lisinopril" have been updated.

Annexes 2 and 3 as well as Appendix 1 and the Q&A document for nitrosamines can be viewed on the EMA website.

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