Limits of those Nitrosamines deleted from Table 1 in the guidance

[Sherry]

Hello, Does anyone know the limits of those nitrosamines removed from Table 1, e.g. N-nitroso-degarelix, N-nitroso-atomoxetine, N-nitroso-lorcaserin and N-nitroso-isoxsuprine? I know those removed from Table 2 have been added to Table 1, but where are those removed from Table 1? to ICH Q3A/B?

Thanks in advance!

[ccdw]

• N-nitroso-degarelix: still in Table 1 (but posted as deleted from Table 1 in revision table (September 2024))
• N-nitroso-atomoxetine: in Table 2 (deleted from Table 1 in December 2023)
• N-nitroso-lorcaserin : Deleted from Table 1 in October 2023, previously 1500 ng/day (API no longer marketed in US)
• N-nitroso-isoxsuprine: Deleted from Table 1 in October 2023, previously 1500 ng/day (stop distribution notification in 2021, FDA Notification Regarding Isoxsuprine Hydrochloride Drug Products | FDA)

See also:

Updated FDA list of published limits

On the N-nitroso-isoxsuprine and N-nitroso-lorcaserin deletion: Lorcaserin is no longer a marketed API in the US since 2020 I believe, for isoxsuprine there was a stop distribution from FDA in 2021. So from that perspective it could give a contradictory message to have the NDSRIs in the list. Cidoxepin NDSRI was not removed, I understand this API was developed in the ’60 but never marketed, but here you probably have to read the entry as an isomer of the doxepin NDSRI (cis instead of trans do…

It is considered the first publication of Table 1 was theoretic, publishing N-nitroso APIs and N-nitroso-demethylated APIs for a big list of known APIs, with soon later corrections for APIs which had no market relevance (anymore).

But for degarelix it is no clear what is going on, maybe removal due to ICH S9 category (advanced cancer treatment) or a redacting error.

[Sherry]

Thank you for the information @ccdw. Well to know it.