The European Medicines Agency (EMA) is expanding its review of impurities in valsartan following the detection of very low levels of N-nitrosodiethylamine (NDEA) in another active substance, losartan, made by Hetero Labs in India.
As a result of the detection of this impurity by German authorities, the review will now include medicines containing four other ‘sartans’, namely candesartan, irbesartan, losartan and olmesartan.
Like valsartan, these active substances have a specific ring structure (tetrazole) whose synthesis could potentially lead to the formation of impurities such as NDEA. Other medicines of the class which do not have this ring are not included in the review.
Both NDEA and a related compound N-nitrosodimethylamine (NDMA) are classified as probable human carcinogens (substances that could cause cancer). How these impurities came to be present during the manufacture of sartans is yet to be fully established and is being evaluated in the ongoing review.
Based on the trace amounts of NDEA seen so far in one batch of losartan from Hetero Labs, there is no immediate risk to patients. Patients are therefore advised not to stop taking losartan or other sartan medicines without speaking to their doctor.
Further tests are required to determine the extent of the contamination and whether impurities are present in sartan medicines above levels that can be considered acceptable.
This review was started when unacceptable levels of NDMA were found in some valsartan medicines, which have now been recalled in the EU. Subsequently, NDEA was detected in some of the recalled valsartan products.
The extension of the review to other sartans is precautionary. EMA is working closely with national authorities, international partners and EDQM to gather data on these medicines as quickly as possible.
Please refer to the following website in EMA for details:
http://www.ema.europa.eu/../news_detail_003023.jsp&mid=WC0b01ac058004d5c1
In Hong Kong, there are 253 above-mentioned registered sartan-containing pharmaceutical products, including candesartan (19 products), irbesartan (64 products), losartan (70 products), olmesartan (17 products) and valsartan (83 products). All products are prescription-only medicines.
Regarding impurities in valsartan, a public announcement was issued on 6 Jul 2018, and letters to inform local healthcare professionals were issued by the Department of Health (DH) on 6 Jul 2018, 9 Jul 2018, 25 Jul 2018 and 3 Aug 2018. Related news for impurities in valsartan was also previously issued by various overseas drug regulatory authorities, and was posted on the Drug Office website since 6 Jul 2018, with the latest update posted on 14 Sep 2018.
In summary, there are four manufacturers, namely Zhejiang Huahai, Zhejiang Tianyu and Zhuhai Rundu in China and Hetero Labs Limited in India, reported to have detection of trace amounts of NDMA and/or NDEA in the valsartan Active Pharmaceutical Ingredient (API) by various overseas drug regulatory authorities.
The DH contacted the certificate holders of all registered valsartan products to follow up on the local impact regarding valsartan API produced by the above mentioned manufacturers.
For API produced by Zhejiang Huahai, there are 5 affected products (HK-61786, HK-61787, HK-61784, HK-61785 and HK-60794) marketed in Hong Kong. The DH instructed the certificate holders to recall all the products from the market as a precautionary measure on 6 Jul 2018, and the DH noted that all the recalls have been completed.
For API produced by Zhejiang Tianyu, amongst the registered pharmaceutical products containing valsartan, there is only one product namely Retoni Tablets 80mg (HK-65604) registered by Swiss Pharmaceutical Co Limited (Swiss Pharmaceutical) which has used API produced by Zhejiang Tianyu and is available in the local market. As confirmed with Swiss Pharmaceutical, the API was tested by the Taiwan Food and Drug Administration (TFDA) and the company has not received any notice from the TFDA for NDMA contamination. The DH collected samples of Retoni tablets for analysis and no NDMA was detected.
For API produced by Zhuhai Rundu and Hetero Labs Limited, the certificate holders confirmed that the valsartan products available in local market are not manufactured using API produced by Zhuhai Rundu or Hetero Labs Limited.
According to the EMA’s announcements on the detection of the second impurity of NDEA in the API produced by Zhejiang Huahai and Hetero Labs Limited, there should be no local impact as all valsartan products manufactured using API produced by Zhejiang Huahai have been recalled from the market and valsartan products available in local market are not manufactured using API produced by Hetero Labs Limited.
In light of the above EMA’s announcement on the detection of NDEA in losartan, the DH will contact the certificate holders of all registered candesartan, irbesartan, losartan and olmesartan products to follow up on the local impact regarding NDEA impurities.
So far, the DH has received 13 adverse reactions related to candesartan, irbesartan, losartan, olmesartan and valsartan products. None of them are concluded to be related to the presence of NDMA and/or NDEA.The DH will keep vigilant on any further updates on the matter issued by overseas regulatory authorities.
Patients who are taking the above products should not stop taking the medicines, but should seek advice from their healthcare professionals as soon as possible for proper arrangement.
Ends/Saturday, Sep 22, 2018
Issued at HKT 12:00
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