Companies that make sartan blood pressure medicines (also known as angiotensin II receptor blockers) are being required to review their manufacturing processes so that they do not produce nitrosamine impurities.
Companies will have a transition period to make any necessary changes, during which strict temporary limits on levels of these impurities will apply. After this period, companies will have to demonstrate that their sartan products have no quantifiable levels of these impurities before they can be used in the EU.
These recommendations follow EMA’s review of N-nitrosodimethylamine (NDMA) and N nitrosodiethylamine (NDEA), which are classified as probable human carcinogens (substances that could cause cancer) and have been detected in some sartan medicines.
For the vast majority of sartan medicines, impurities were either not found or were present at very low levels.
The review estimated the highest possible cancer risk with these impurities. It concluded that if 100,000 patients took valsartan from Zhejiang Huahai (where the highest levels of impurities were found) every day for 6 years at the highest dose, there could be 22 extra cases of cancer due to NDMA over the lifetimes of those 100,000 patients. NDEA in these medicines could lead to 8 extra cases in 100,000 patients taking the medicine at the highest dose every day for 4 years.
Please refer to the following website in EMA for details:
http://www.ema.europa.eu/en/news/sartan-medicines-companies-review-manufacturing-processes-avoid-presence-nitrosamine-impurities
Currently in Hong Kong, there are 251 registered pharmaceutical products containing valsartan (83 products), candesartan (19 products), irbesartan (63 products), losartan (69 products) and olmesartan (17 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 the detection of impurities in sartan-containing products 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 25 January 2019.
In brief, 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 N-nitrosodimethylamine (NDMA) 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.
Regarding the announcements issued by various overseas drug regulatory authorities on the detection of the second impurity of N-nitrosodiethylamine (NDEA) in the valsartan API produced by Zhejiang Huahai, there should be no local impact as all valsartan products manufactured using API produced by Zhejiang Huahai have been recalled from the market.
Regarding the announcements issued by various overseas drug regulatory authorities on the detection of NDEA in the valsartan API produced by Mylan Laboratories Limited in India, the certificate holders confirmed that the valsartan products available in local market are not manufactured using API produced by this company.
Regarding the European Medicines Agency’s (EMA) announcement on the detection of NDEA in the losartan API produced by Hetero Labs Limited, the US Food and Drug Administration’s (FDA) announcement on NDEA in the losartan API produced by Zhejiang Huahai, and the announcements issued by EMA, FDA and TFDA on NDEA in the irbesartan API produced by Aurobindo Pharma in India, the DH has contacted the certificate holders of all registered candesartan, irbesartan, losartan and olmesartan products and will continue to follow up on the impact of NDEA impurities on the products available in the local market. On 20 Dec 2018, the DH endorsed Actavis Hong Kong Limited to recall one batch (batch number: 058818) of Irbesartan HCT Actavis Tablets 150/12.5mg (HK-63378) from the market as a precautionary measure because an impurity was detected in one of the raw materials of this batch of product, a public announcement was issued on 20 Dec 2018. The DH is closely monitoring the recall.
So far, the DH has received 16 cases of adverse drug reaction related to valsartan, candesartan, irbesartan, losartan and olmesartan. None of them is 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/ Saturaday, Feb 2, 2019
Issued at HKT 12:00
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