EMA Q&A Appendix 1 is updated Sept 4, 2024

New NDSRIs

Name Source CPCA AI(ng/day) Note
N-nitroso-2,4-thiazole amine Nirmatrelvir/ Ritanovir 1 18 CPCA-derived AI as substance tested positive in in vivo mutagenicity study
N-nitroso-acebutolol Acebutolol 4 1500
N-nitroso-buspirone Impurity 1 Buspirone 3 400
N-nitroso-desmethyl-dimetindene Dimetindene 1 18
N-nitroso-desmethyl-rivastigmine Rivastigmine 2 100
N-nitroso-iminodibenzyl Melipramin 78000 Limit derived using structure-activity-relationship (SAR)/read-across approach using the TD50 of NDPh as point of departure.
N-nitroso-maprotiline Maprotiline 1 18
N-nitroso-propafenon Propafenon 2 100
N-nitroso-valsartan cyano-desvalerylmethylester Valsartan 2 100
N-nitroso-vanzacaftor Vanzacaftor 4 1500
N-nitroso vildagliptin amide impurity Vildagliptin 5 1500

Updated NDSRIs

Name Source CPCA AI(ng/day) Note
N-nitroso-ciprofloxacin Ciprofloxacin NMI Substance tested negative in in vivo mutagenicity study. Can be controlled according to ICH Q3B.
N-nitroso-diclofenac Diclofenac 78000 Limit derived using structure-activity-relationship (SAR)/read-across approach using the TD50 of NDPh as point of departure.
N-nitroso-nortriptyline Amitriptyline, Nortryptyline 1 18 CPCA derived AI as substance tested positive in in vivo mutagenicity study
N-nitroso-sertraline Sertraline 2 100 CPCA-derived AI as substance tested positive in in vivo mutagenicity study

N-nitroso-ciprofloxacin: 1500 => NMI
N-nitroso-diclofenac: 1500 => 78000
N-nitroso-nortriptyline: 8 => 18
N-nitroso-sertraline: 1500 => 100

The AI of some Category 5 compounds may be changed to 78000.

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