The Swiss drugmaker said the stoppage is necessary to conform with new regulatory limits on nitrosamine, but will not affect commercial supply.
The FDA has sought to reduce patient exposure to nitrosamine impurities over worries they might cause cancer in Ph-3 trials of breast cancer drug Kisqali.
Kisqali 's API is ribociclib. N-nitroso -ribociclib impurity 1 is included in Appendix 1 as Category 3.
ribociclib
Hi Yosuke,
is getting more and more weirdâŚas far as i know this drug is for patients for advanced cancer, so the corresponding nitrosamine should be controlled under the limits of ICHQ3, according to the ICHS9.
ââThe FDA has sought to reduce patient exposure to nitrosamine impurities over worries they might cause cancer in Ph-3 trials of breast cancer drug Kisqali.ââ !!! is this a joke? It is not reasonable to me to set limits to address any cancer risk <1/100000 to patients who are suffering from cancer.
Hi Christos,
I donât think that this is an error or a joke. Ribociclib is currently authorized as anti-cancer drug, but a new study suggest the efficacy of Ribiciclib to prevent the risk of recurrence AFTER surgical removal:
Adding Ribociclib to Hormonal Therapy Reduces Risk of Recurrence for People With Most Common Subtype of Breast Cancer
In this case, because the cancer has been removed, such terapy cannot be strictly considered âfor advanced cancer indications as defined in the scope of ICH S9â. I suppose that Novartis is doing a similar clinical trial.
In fact Novartis suspended the clinical trial only, not the marketed drug product.
Of course this is only a supposition, but I think that it is reasonable.
thanks a lot Giovanni.
This could make some sense but only if the indication for ââadvance cancerââ was ommited. As long as the indication for advance cancer is still present then it is still under the scope of ICHS9.
Furthermore, ââdivingââ into the article that Yosuke add, it seems that all of this could be due to competition (?)
ââNonetheless, the manufacturing scrutiny will be a âmarginalâ positive for Eli Lilly, provided Verzenio doesnât have the same impuritiesâŚââ
Verzenio (abemaciclib is an ethyl-piperazine derivative, meaning that the formation of nitrosamine is much more difficult than the one in Ribociclib.
Anyway, this is very interesting case
I am sorry for confusing you, @chrischar. I am also confused with this complicated news. And thank you for your insight, @paliog. It sounds reasonable. In addition that, NDSRI guidance is applied to clinical, as guidance mentioned. The information shared has uncertainty, so we should pay attention to further news.
Yosuke
Yosuke, you did not confuse me, FDA has done this 
thanks
Ribociclib is a triple disaster when it comes to nitrosamines. It is a significant source of NDMA (amide of the secondary amine, dimethylamine) and has two secondary amino groups. Though it is a drug for breast cancer and is expected to be taken for a long period of time unlike many other chemotherapy drugs. I feel NDMA is the true threat here. But it will be interesting to see where we go with this.
Dear ASrinivasan,
between the two secondary amino-groups of Ribociclib, the piperazine type amine is far more reactive than the amine between the aromatic rings, so any free nitrite would react with the first one and not with the second.
Regarding the NDMA, for its formation in the final product, it is necessary first the hydrolysis of Ribociclib. Apparently, this is not very easy as the double bond in the pyrrole ring next to the amide could be in resonance with the carbonyl group and deactivate the positive charge on carbon.
NDMA could be a threat, in case dimethylamine is used in the last step of synthesis of the API.
Thanks for flag this issue.
Are you at liberty to disclose if this is based on general chemistry insights (though nitrosation selectiveness and ease can be different in solution: Mechanochemistry for Healthcare: Revealing the Nitroso Derivatives Genesis in the Solid State - Basoccu - 2024 - ChemSusChem - Wiley Online Library) or based on experimental testing linked to ribociclib or a related model system? (And if so, if it was investigating nitrosation in solution or in the solid phase?)
(International limit lists so far do support the specific attention to the piperazine.)
dear ccdw,
this claim was based just on general organic chemistryâŚaromatic amines should be generally less reactive as the negative charge of the nitrogen is delocalized through the resonance with the aromatic group. In case two aromatic rings are on both sides this phenophenon is anticipated to be stronger and the nucleophilicity of the secondary amine to decreased.
Hope i explain this sufficient
Agree, with traces of nitrite, it is the piperazine that is more vulnerable. But for these kind of molecules are more vulnerable at the secondary amine group. So NDMA may trump the NDSRI.
Thanks for clarifying, I was hoping you had stoichiometric chemistry qNMR data on conversion and selectivity between the amines and C-nitration and N-nitrosation, because it is such an interesting molecule as ASrinivasan points out. (Note that for alkylanilines also basicity plays a role and nitrosation can be quite fast, cf. Ashworth 2020 https://dx.doi.org/10.1021/acs.oprd.0c00224).
See also examples in Mechanochemistry for Healthcare: Revealing the Nitroso Derivatives Genesis in the Solid State - Basoccu - 2024 - ChemSusChem - Wiley Online Library: the reactivity trend might be matrix and risk-factor dependent. This explains why nonetheless nitrosated diarylamines are in the limit lists (whereas some limit lists only included NDSRIs which have been detected >10%), though such detection is not evident for each matrix, diversification in risk and selectivity across matrices can exist.
thanks a lot Wybon for such a valuable information, it is much appreciated.
Hi everyone. I finally reached a rep from Novartis and had a long conversation with them about the ribociclib/nitrosamine impurity situation. She explained that they measured nitrosamine levels in ribociclib and that those levels surpassed the allowable levels for patients with early-stage cancer (including those enrolled in the NATALEE trial). That said, the FDA has a higher allowable level for those with conditions considered terminal, so Novartis did not pull ribociclib for those patients (or inform oncologists or patients) taking it for metastatic disease. Novartis alerted NATALEE trial Principal Investigators to stop all patients from taking ribociclib until the production issues were fixed. Because FDA hadnât yet approved ribociclib for early-stage disease (that was the goal of the NATALEE trial), Novartis did not feel obligated to inform patients taking ribociclib or oncologists prescribing for early-stage breast cancer even though the ribociclib data were presented in Summer 2023 and many women started taking it âoff-labelâ because the results showed a disease-free survival benefit. When I asked the Novartis rep about their obligation to inform patients taking ribociclib for early-stage disease/treating oncologists/dispensing pharmacists about the nitrosamine impurity issue, she said they âdonât want to appear to be promoting ribociclib for an off-label useâ. Novartis ribociclib production was not segregated between NATALEE trial and general clinical use, so plenty of women taking ribociclib for early-stage disease would have been exposed to excess nitrosamine. Novartis is capable of figuring out who took ribociclib for early-stage disease because the starting dose is 400mg vs. 600mg starting dose for those with metastatic disease. I also encouraged Novartis to, at the minimum, create an FAQ available online for oncologists, pharmacists, and patients but they declined to do so, again saying they donât want to appear as though they are âpromotingâ off-label use. Novartis gets reimbursed $13,000 per person/per monthly prescription by insurance companies for ribociclib, so certainly they have the resources to find these patients taking ribociclib off-label who were impacted by the nitrosamine exposure.