Three days after propranolol was recalled, Pfizer Canada recalled all lots of Accuretic(quinapril hydrochloride and hydrochlorothiazide), which is also used for blood pressure medication, due to N-nitrosamine contamination.
Inactive ingredients used in the formulation is as follows;
candelilla wax, crospovidone, hydroxypropyl cellulose, hypromellose, iron oxide red, iron oxide yellow, lactose, magnesium carbonate, magnesium stearate, polyethylene glycol, povidone, and titanium dioxide
The API with the secondary amine might react with nitrite in excipients.
Hi, @Sarada.jena. Thank you for adding the information. Yes, you are right. Both quinapril and hydrochlorothiazide have the structure of secondary amine. The total daily intake of these N-nitrosamines should be taken into account.
Thanks for the info. At first for this nitrosamine, there is only one sp3 carbon adjacent to the nitroso group. I have seen strategies around putting this kind of nitrosamines out of the Cohort of concern, but now into ICH M7 (when there is no sp3 carbon). Of course this should be checked in detail.
The Quinapril recalls continue, the Australian FDA announced the recall of several lots of Quinapril following the confirmation of N-nitroso-quinapril impurity being present at levels higher than the acceptable level.
FDA posted yesterday (21-Dec-22) a voluntary recall by Lupin of Quinapril due presence of N-nitroso-Quinapril above the acceptable daily intake.
Does anybody know what limit manufacturers or regulators are working against?
Please note that the EMA allowed a temporary AI (t-AI) of 178 ng/day
(total nitrosamines) for max 12 months (Q21), but this is valid for EU countries only; other authorities (e.g.FDA) may have a different approach.
Adding to @paliog comment, “It is expected that the t-AI would be used for a period of less than 12 months, as an exposure over this period of time is not expected to increase the theoretical overall lifetime risk above 1:100,000.”
I tried to apply the read-across approach with known nitrosamines, but I cannot find a good model with carcinogenicity data (i.e. TD50).
Considering only the core of N-nitroso Quinapril, i.e. the first two position around the N-nitroso group, a possible model may be the Nitrosoiminodiacetic acid:
This substance is present in the Lhasa database and is negative in rat carcinogenicity studies:
It has been tested in 11 Ames tests, one positive and 10 negative:
Moreover, the considerations already made in my post on N-nitroso Ramipril could be applied also to N-nitroso Quinapril and other ACE-inhibitors.
Summarizing, it is possible that N-Nitroso Quinapril may be not mutagen (or a very weak mutagen); but to demonstrate this you should perform a full Ames test with a negative result (and then further in vitro test).
In the meantime, I’m afraid you will have to apply the default limit (18 ng/day) or ask to the authorities to apply the EMA temporary limit (178 ng/day). The adoption of the t-AI is not automatic and is evaluated by the relevant authorities at the time of notification. Use of
the t-AI beyond 12 months will require additional consultation with competent authorities.