N-nitroso-Duloxetine recall back in the news!

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NDSRI are back in the news radar… This time Nitroso-Duloxetine

Source: ABC News (Thousands of bottles of popular antidepressant recalled: 3 things to know - ABC News)

Thousands of bottles of popular antidepressant recalled: 3 things to know

Over 7,100 bottles of duloxetine are part of the recall, according to the FDA.
Thousands of bottles of a popular antidepressant medication are being recalled due to the presence of what the National Library of Medicine describes as a toxic chemical, according to a notice from the U.S. Food and Drug Administration.

The recall involves the medication duloxetine, which is sold under the brand name Cymbalta, according to the FDA’s notice of the voluntary recall, which began Oct. 10.

More details

Duloxetine is part of a class of drugs known as SNRIs, or selective serotonin/norepinephrine reuptake inhibitors, that are used to treat anxiety, depression and other mood disorders, according to the FDA.

Here are three things for consumers to know about the recall.

1. How do I know if my medication is impacted by the recall?

The recall involves 7,101 bottles of duloxetine delayed-release capsules distributed nationwide within the United States, according to the FDA.
The recalled capsules are 20mg in strength, and sold in 500-count bottles.

The lot number for the recalled capsules is 220128, with an expiration date of December 2024, according to the FDA notice. The recalled capsules are manufactured by Towa Pharmaceutical Europe.

In an emailed statement, Towa Pharmaceutical Europe referred ABC News to the FDA’s website on nitrosamine impurities in medications. N-nitroso duloxetine is a type of nitrosamine.

“With respect to nitrosamine impurities in drugs, FDA continues to say that ‘patients taking prescription medications with potential nitrosamine impurities should not stop taking their medications. Patients should talk to their health care professionals about concerns and other treatment options,’” Towa Pharmaceutical Europe said in a statement. “FDA has also said it is ‘working to determine the source of these impurities and will keep the public informed.’”

2. What is the potentially toxic chemical that sparked the recall?

The recalled duloxetine capsules were found to contain a higher level of N-nitroso-duloxetine than is permitted, according to the recall notice.

N-nitroso duloxetine is a chemical compound that can be toxic if swallowed in elevated concentrations and is suspected of potentially causing cancer, according to the U.S. National Library of Medicine.

The FDA designated the voluntary recall of duloxetine bottles as a Class II recall. The agency defines that as “a situation in which use of, or exposure to, a violative product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote.”

I am including a summary of the community’s discussion on limits, analytical methods, mitigation, and standards in the post below. Click for more.

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Analytical Methods:

Standards:

https://store.usp.org/product/1A04000

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Limits:

AMES Testing:

Recalls:

https://www.tga.gov.au/news/safety-alerts/safety-advisory-duloxetine

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From: https://pubs.acs.org/doi/10.1021/acsomega.4c00136

Critical Sample Extraction of NDXT:

Various sample preparation techniques were tried, such as liquid–liquid extraction using hexane and solid-phase extraction of Oasis HLB to remove the excipients and other impurities. Liquid–liquid extraction using hexane was not suitable because NDXT could not be extracted, and solid-phase extraction was also not suitable because of the low recovery rate of NDXT. Extraction in duloxetine drug products was also employed using methanol, acetonitrile, water, and mixtures of them. For the extraction with acetonitrile, there was concern about the stability of NDXT in the sample solution. On the other hand, the solution extraction with methanol was adopted because NDXT was extracted more quickly in methanol than in acetonitrile and there were no problems with stability in the sample solution.

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This is a tragedy. While N-nitroso duloxetine can be justified at a very conservative AI of 100 ng/day based on NNK as a surrogate, FDA has currently increase the limit temporarily to 600 ng/day. All of these are super conservative as we see in Jolly’s publication (Estimation of acceptable daily intake values based on modeling and in vivo mutagenicity of NDSRIs of fluoxetine, duloxetine and atomoxetine - PubMed) that the in vivo studies show these to be " the potency of the mutation response was ≥4400 ng/day for all compounds-an order of magnitude higher than published regulatory limits for these NDSRIs." Duloxetine has suicide ideation as a side effect and I worry how many people we are sending to the brink by withdrawing this drug.

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Dear Aloka,
respect for the end of your post ‘‘Duloxetine has suicide ideation as a side effect and I worry how many people we are sending to the brink by withdrawing this drug.’’…it is so true :cry:

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Indeed, in the light of LTL principles for a temporary limit, MW corrected readacross to NNK or the AI based on PhysChem readacross or QM modelling and uncertainties, 600 ng/day t-AI might not sound too conservative. However, this indeed mostly disregards the in vivo mutagenicity data in BigBlue rats for N-nitroso-duloxetine:

N-nitroso-duloxetine:
• 6.8 mg/kg/day/50000 50 kg1000000 ng/mg = 6800 ng/day (Jolly 2024, in vivo TGR, liver BMDL, with justification to derive AI based on a mutagenicity endpoint)
• 6.8 mg/kg/day/0.21 mg/kg/day x 145 ng/day = 4695 ng/day (relative to NDMA)
• 6.8 mg/kg/day/0.1 mg/kg/day x 26.5 ng/day = 1802 ng/day (relative to NDEA)
• Overall Jolly 2024 conclusion based on in vivo data: >5000 ng/day

Strangely, this data has not been publicly endorsed yet by regulators. The studies seem to have been properly designed, including tissue selection and 3 compounds of the class have been tested showing a coherent picture, while a broader WoE on the compounds was presented. Ames test data and in vitro mammalian cell mutation assay data from other sources also point to a likely alpha-hydroxylation mechanism.
One of the general topics here is the in vivo mutagenicity vs. in vivo carcinogenicity correlation (which is the basis for calculations 2 and 3). The fact that this correlation has been built for a set of small nitrosamines now strangely leads to challenges on if this correlation would be true for NDSRIs as well. In absence of carcinogenicity data on a lot of NDSRIs this cannot be easily shown.

For small nitrosamines non-mutagenic carcinogenicity or mutagenicity non-carcinogenicity might indeed be rarer than for NDSRIs, which often have increased structural complexity and thus more theoretic options for alternative mechanisms. Possibly the quality of the correlation is therefore a little bit lower if it would be built for NDSRIs, here and there an NDSRI might be off the curve. But one should question if this can be a relevant blind spot, as there are only two out of curve situations possible (while actually the exceptions would influence the quality of the correlation and not there being a correlation):

  • Either you overestimate the carcinogenicity relative to the mutagenicity of the NDSRI, meaning that AI setting based on a mutagenicity endpoint is sufficiently conservative (no impact in case of slightly lower quality of the correlation).
  • Either you underestimate the carcinogenicity relative to the mutagenicity of the NDSRI, but that would be an indication of an non-nitrosotypical carcinogenicity occurring at least as part of the mechanism, meaning that the lack of (full) correlation muta-carci has nothing to do with the CoC principle on nitrosamines. Based on typical cancer mechanisms and the structure of the NDSRIs, I don’t think it would be often plausible to have a theory that such unidentified alternative cancer mechanisms would likely not be compatible with application of a 1500 ng/day TTC, which is fairly low. (And there is also the fact that mammalian cell line experiments point indirectly to there being a nitroso-typical mechanism as well.)

So I don’t understand what prevents to apply the Powley 2024 idea that 1500 ng/day is precautious for NDSRIs with such lower potency from in vivo mutagenicity studies, as it seems unlikely the aimed LCR cannot be maintained that way (especially when there is also a LTL element due to temporary application while science advances). Cutting the 6800 ng/day in 10 to 600 ng/day seems a little bit too conservative (especially for temporary use), good if you can reach it, but if it is leading to recalls and possible shortages I don’t know if it is pragmatic enough. (Remediation might also not be too easy given that the 600 ng/day introduced in February 2024 was prolonged from ending October 2024 to ending December 2024, linked to a shortage justification).

For this class of the oxetines, in vitro experiments have given some suspicion on cytotoxicity effects of the NDSRIs that are probably being investigated further, but I still believe this rationale is possible.

I hope the 31 December 2024 end of the t-AI also coincides with regulatory advancements on AI setting from in vivo mutagenicity data and that it is not prolonged to give time for in vivo carcinogenicity studies (though the cytotoxicity observations are probably explored).

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I agree with you. If you are in the meeting on Nov 6-7, please raise the issue.

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I agree that at the least, they need to agree to 1500 ng/day and eventually agree to accept the results of the studies performed and published. Afterall, CPCA was based on what was published by good nitrosamine scientists in the past. Why are we not respecting the current literature?

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CPCA (hope to say one day the original CPCA) was using the best available science on structural features, but also not aiming to translate that in not overly conservative quantitative terms. I believe regulators and Industry are aligned on that. It’s the locking of the appropriate number that seems to remain hard in both cases.

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I want to share the case about N-nitroso-atomoxetine contamination in atomoxetine in Japan. The Japanese government responded to Lilly’s suggestion to set AI of 1500 ng/day or 4400 ng/day as follows;

  • Current guidance does not allow setting AI greater than 1500 ng/day for nitrosamines for which there are no carcinogenicity data if the Ames and TGR studies are positive.
  • It is inappropriate to treat the NOEL and BMDL in the TGR study of N-nitroso-atomoxetine as equivalent to the NOEL and BMDL in carcinogenicity studies.
  • Direct AI calculation from TGR study results is also not allowed by ICH M7(R2) (Q&A No.7.2)

It is a conservative approach. I expect other regulatory lead discussions.

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