Metamizole is a very old product. Based on some experience I trust that - at least for Europe - many API suppliers hold CEP prior to nitrosamine Guideline. So no discussion on nitrosamines and especially on NDSRIs. I am pretty curious about any API supply issues may be faced now…
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I’m also quite curious about how this situation will unfold, especially considering the limited number of MTZ suppliers, no more than two. From experience, I believe the major challenge will lie in the final product rather than the API itself.
Pharma. companies in Brazil were expected to complete their nitrosamine risk assessment portfolios by June 2025, as per ANVISA’s guidelines. MTZ is a significant product in the Brazilian market, and with dengue cases on the rise, I assume ANVISA does not foresee a supply shortage. That makes any developments around MTZ particularly interesting.
What intrigues me is the apparent lack of awareness or new information regarding MTZ’s nitrosamine impurity. The MTZ impurity C is accepted at relatively high levels in the final product. If companies are justifying this based on older in vivo studies (as mentioned by @Igor ), and agencies are accepting these justifications without scrutiny, it could set a concerning precedent.
The studies being referenced are not particularly robust. One is essentially a summary from an annual meeting with no raw data, and the other builds on that to present teratogenicity findings—if I’m recalling correctly. There are also a few Ames tests involving NMAA, but the results vary and don’t fully meet regulatory expectations. One article even mentions a recent Ames test conducted by a private company, but the results haven’t been disclosed.
This limited availability of data and reliance on older studies does raise some important questions about the robustness of current risk assessments and how safety is being evaluated.
It’s certainly a topic worth following closely, and I’m interested to see how the conversation and regulatory perspectives evolve over time 
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At least for EU, the available in Vivo studies are not adequate to support or justify non mutagenicity, cause are not in line with current OECD principles.
I agree with you on mixed results of AMES test.
Also limited data on robust read across
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Hi, besides old animal studies (Berscheid et al., 1978; Sakai et al., 1980, 1981, 1982) there is more recent paper from Ziebarth (ArchPharm 1994, DOI: 10.1002/ardp.19943270607) a study on human volunteers!!!
Within this study, they treated 10 healthy volunteers with single oral dose of 500 mg metamizole + 500 mg potassium nitrate (KNO₃) to study endogenous nitrosation of N-methylaminoantipyrine (metabolite of MTZ) to NMAA.
- All subjects excreted measurable NMAA.
- ~300–400 µg NMAA recovered in urine within 24 h.
- This is ~3,000–4,000 × higher than the EMA AI of 100 ng/day
- No acute adverse effects were reported.
- No evidence of genotoxic response or clinical abnormalities was noted in this short-term study.
Based on this study it is evident, that endogenous formation of NMAA in all MTZ treated patients occurs with nitrite/nitrate rich diet. So EMA enforces the 25 ppb limit for exogenous NMAA in the finished product as a quality defect, while endogenous post-administration formation at levels thousands of times higher is unregulated ?!?
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I totally agree with you and I have the same thoughts.
What’s more the precursor molecule for the said NDSRI is the major metabolite of Metamizol itself. So NMAA endogenous formation is expected following at least oral administration…
Perhaps the study doesn’t fully comply with the guidelines?!
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Hi, even the study were not robust it proves that endogenous formation of NMAA is there, and given over 100 years of clinical use of MTZ (first registration 1922) we have long term evidence of NMAA safety after all no?
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Hi Igor.
think that common sense is not always sufficient when it comes to the nitrosamines case. Take NDMA, for example… Also, **we are all aware that nitrosamines can be present at high levels in food or formed endogenously. However, this knowledge alone is not enough to justify higher acceptable limits to the Authorities.
Given the current regulatory landscape, I believe the only viable path to support higher acceptable intakes is through the development of robust scientific assessments, incorporating all available data and knowledge.
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Hi,
I am following this communication closely and I think we all agree that this is too strict limit for this impurity, take into consideration that endogenous post-administration formation is evident. Is the only way to prove the non mutagenicity of this impurity to conduct a OECD 488 TGR study?
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