Review of common medicines used to treat hypertension – valsartan – due to detection of impurity, N-nitrosodimethylamine (NDMA), a probable human carcinogen! (Part IV)
- 19 сентября 2018
- active substance, API, cancer, carcinogen, CEP, EDQM, EMA, headspace GC/MS, human, hypertension, impurity, inspection, investigation, manufacturer, manufacturing, manufacturing site, medicinal product, medicines, method, N-nitrosodimethylamine, NDEA, NDMA, nitrosamine, N‑nitrosodiethylamine, OMCL, patient, process, recall, review, risk, sartans, test, valsartan, Zhejiang Huahai Pharmaceuticals, Zhejiang Tianyu Pharmaceutical Co. Ltd.,
The European Medicines Agency (EMA) has updated its calculation of the risk from valsartan medicines containing N‑nitrosodimethylamine (NDMA), taking into account results from latest tests on the active substance from Zhejiang Huahai.
In line with EMA’s previous assessment, the life-time risk of cancer is considered low and is estimated to be in the order of 1 in 5,000 for an adult patient who had taken an affected valsartan medicine at the highest dose (320 mg) every day from July 2012 to July 2018.
Patients who have taken treatments with lower doses or for shorter lengths of time will be at a lower risk. The risk will also be lower for patients who have taken valsartan produced by Zhejiang Tianyu, which had smaller amounts of NDMA than valsartan produced by Zhejiang Huahai.
In addition to NDMA, EMA is assessing the impact of a related substance, N‑nitrosodiethylamine (NDEA), which has been detected in valsartan made by Zhejiang Huahai using its previous manufacturing process before changes were introduced in 2012. Both NDEA and NDMA belong to the class of nitrosamines and are classified as probable human carcinogens (substances that could cause cancer).
Data on levels of NDEA are currently very limited, and EMA will provide further information on whether its presence impacts the risk assessment once more information becomes available.
Although the review covers all valsartan medicines, the immediate focus has been on medicines containing the active substance manufactured by Zhejiang Huahai and Zhejiang Tianyu where unacceptable levels of NDMA have been confirmed. EU authorities have now carried out inspections of the manufacturing sites of both companies in China and will consider the findings.
Medicines containing valsartan from Zhejiang Huahai and Zhejiang Tianyu are no longer being distributed in the EU or have been recalled. Both companies are not currently authorised to produce valsartan for medicines in the EU.
EMA continues to work closely with national authorities, international partners and EDQM to gather the necessary information which would allow the Agency to have a better understanding of why impurities were present in the active substance in the first place.
Based on the final outcome of the review, authorities in the EU will take necessary measures to ensure that similar problems do not occur in future.
The EDQM continues investigating and defining actions to address the presence of all kinds of nitrosamines, including NDMA and NDEA in valsartan and other sartans which may be affected.
OMCLs release validated method for testing sartans
One method – established by the Irish OMCL in the Public Analyst’s Laboratory in Galway (PALG) on behalf of the Network – is now publicly available and can be accessed here. The PALG method is based on Headspace-GC-MS (single quad) and applicable to the determination of NDMA in Active Pharmaceutical Ingredients (API) and corresponding powdered tablets of the sartan group.
We have already informed on our website about the ongoing review of valsartan medicines due to the detection of impurity N - nitrosodimethylamine (NDMA) as well as suspensions of CEPs by EDQM in Part I, Part II and Part III entries.
Source: EMA, EDQM