FDA alerts to a voluntary recall of varenicline - What do we know?

Nitrosamines in the News
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What do we know so far?

8-nitroso-7,8,9,10-tetrahydro-6H-6,10-methanoazepino[4,5-g]quinoxaline
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Hi Naiffer @Naiffer_Host ,
Thanks for sharing, Nitrosamines also made it to the Bloomberg news article dated 1st July 2021.
https://www.bloomberg.com/news/articles/2021-07-01/carcinogens-still-vex-drug-industry-years-after-recalls-began

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I’m extremely curious to see who is dealing with this new API. It would be a great case study for Q(SAR) assessment since we have been talking extensively about the chemistry of Impurity @MichaelBurns @kpcross

To my knowledge, there are about 22 active regulatory filings for this API just in FDA (per public information)

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@Naiffer_Host
Hi Naiffer,
Here’s the latest update from FDA on this recall
https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-nitrosamine-varenicline-chantix?utm_medium=email&utm_source=govdelivery

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https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/pfizer-issues-voluntary-nationwide-recall-twelve-lots-chantixr-varenicline-tablets-due-n-nitroso?utm_medium=email&utm_source=govdelivery

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I found the possible root cause of the nitrosamine impurity of this drug in Dr. Johnson’s slide uploaded by @DAB.

varenicline
varenicline1153×651 112 KB

The other synthetic process is safe, however this not. And it’s very interesting because this nitrosamine is converted from another nitrosamine!!

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Varenicline is a Pfizer drug. The nitrosamine limit was apparently set by FDA resulting from an analog comparison to NTHP. Some have proposed the NPIP or NHEX would be more appropriate analogs as they varenicline does not have any fused aromatic system or double bond in it as in NTHP.

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Just to help illustrate what @kpcross is sharing

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@conudel Can you help us by giving some context to this particular case?

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These are the 3 most relevant analogs with rat TD50 values available in the CPDB database. Read-across using relevant analogs is one method to do risk assessment of nitrosamines that is supported by regulatory agencies. However analogs should have similar reactivity of the nitrosamine functionality as the target. In this case NTHP would be subject to nucleophilic attack at the ring double bond, whereas the other two analogs and the target would not.

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Thank you for sharing information. It’s very interesting. I add the link of NTHP, NPIP, and NHEX in LCDB for comparison. NTHP looks farthest from N-nitrosovarenicline visually at the shape, but they selected it for read-across from the point of reactivity of alpha hydroxylation of nitrosamine. That’s a noteworthy point.

Which do you guys select for read-across? I will select the most conservative one, as it’s too difficult.

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And the Recalls continue…extended to 4 additional lots of Varenicline tablets

https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/pfizer-expands-voluntary-nationwide-recall-include-four-additional-lots-chantixr-varenicline-tablets?utm_medium=email&utm_source=govdelivery

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Wondering if any support is needed on this? anything the community can offer to assit or help?

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@Naiffer_Host
Hi Naiffer,
This appears to be an issue pertinent to drug product perhaps or maybe from the API. Being ex Pfizer I can vouch for the extensive screening that’s done on drug candidates for evaluating tox potential. The community can provide Insights if more details of the drug product or substance are made available. Till such time we can only wait for information from the Agency

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@Naiffer_Host , latest on this Recall , Recall extended to all lots of 0.5 mg n 1 mg tabs
https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-nitrosamine-varenicline-chantix?utm_medium=email&utm_source=govdelivery

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@DAB thanks for the update… at this week EMA’s Committee for Medicinal product for Human Use (CHMP) meeting during ‘Post-authorization procedure oral explanations’, Pfizer Europe has an oral explanation on the Presence of the Nitrosamine N-nitroso-varenicline in Champix.
Meeting Report attached
IDRAC_335699_17-Sep-2021_CHMP 13_16-Sep-2021 Meeting.pdf (926.5 KB)
Hopefully, we hear more about this. I was gladly surprised to see FDA reacting and publishing a reference method.

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This week EMA’s Committee for Medicinal product for Human Use (CHMP) published 13-16 September meeting highlights.
Related to Nitrosamines:

CHMP concludes assessment of presence of a nitrosamine impurity in Champix
The CHMP has concluded its analysis on the presence of impurity N-nitroso-varenicline inChampix at levels above those considered acceptable for EU medicines. Champix should conformto a limit of impurity calculated based on compound-specific ICH M7 principles for a lifetimeexposure. The company will now be asked to vary its licence to comply with the set requirements.As a precautionary measure the company that markets Champix had already recalled severalbatches in June 2021 and paused distribution. The previously circulated direct healthcareprofessional communication (DHPC) is being revised informing healthcare professionals thatfurther shortages are anticipated. The updated DHPC will be published in the coming days on thefollowing page. As part of the assessment, CHMP considered the criticality of Champix in thecontext of its current therapeutic use and the availability of alternative treatment options. TheCHMP concluded that higher impurity limits were not acceptable as the product was not criticaland its absence from the EU market would not create a concern in terms of public health. Patientsshould not stop taking Champix without first consulting their healthcare professional and talk tothem if they have any questions or concerns

Official release: Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 13-16 September 2021 | European Medicines Agency

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Thanks Naiffer @Naiffer_Host for this update.
Looking forward to more information from the Agency wrt the RC & its resolution

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Continue the developments of Champix …

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