EMA’s human medicines committee (CHMP) has aligned recommendations for limiting nitrosamine impurities in sartan medicines with recent recommendations it issued for other classes of medicines.
The main change concerns the limits for nitrosamines, which previously applied to the active ingredients but will now apply instead to the finished products (e.g. tablets). These limits, based on internationally agreed standards (ICH M7(R1)), should ensure that the excess risk of cancer from nitrosamines in any sartan medicines is below 1 in 100,000 for a person taking the medicine for lifelong treatment.
In line with previous recommendations, companies should have appropriate control strategies to prevent or limit the presence of nitrosamine impurities as much as possible and, where necessary, improve their manufacturing processes. Companies should also evaluate the risk of nitrosamines being present in their medicines and carry out appropriate tests.
Nitrosamines are classified as probable human carcinogens (substances that could cause cancer). In the vast majority of sartan medicines, these impurities were either not found or were present at very low levels.
The CHMP concluded its review of sartan medicines in January 2019. The committee subsequently conducted a wider review, taking into account the experience from sartans and other medicines where nitrosamines were detected. The revised conditions companies need to fulfil for sartans brings them in line with those for other classes of medicines issued in June 2020.
The review of sartans concerned candesartan, irbesartan, losartan, olmesartan and valsartan, which belong to a class of medicines called sartans (also known as angiotensin-II-receptor antagonists).
These sartan medicines have a specific ring structure (tetrazole) whose synthesis could potentially lead to the formation of nitrosamine impurities. Other sartan medicines which do not have this ring, such as azilsartan, eprosartan and telmisartan, were not included in this review but are covered by the subsequent review of other medicines.
Sartans are used to treat patients with hypertension (high blood pressure) and those with certain heart or kidney diseases. They work by blocking the action of angiotensin II, a hormone that constricts blood vessels and causes blood pressure to rise.
Please refer to the following website in EMA for details:
http://www.ema.europa.eu/en/news/nitrosamines-ema-aligns-recommendations-sartans-those-other-medicines
Currently in Hong Kong, there are 257 registered pharmaceutical products containing valsartan (94 products), candesartan (21 products), irbesartan (63 products), losartan (60 products) and olmesartan (19 products). All products are prescription-only medicines.
Regarding impurities in sartan-containing products, a public announcement was first 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 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 21 Sep 2019.
Regarding the announcements issued by various overseas drug regulatory authorities on the detection of N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) in sartan-containing products, the following 5 valsartan products and 1 irbesartan product were affected and recalled from the Hong Kong market on 6 Jul 2018 and 20 Dec 2018 respectively: HK-61786, HK-61787, HK-61784, HK-61785, HK-60794 and HK-63378. The DH noted that these recalls were completed.
The DH had collected samples of sartan-containing products in the local market for analysis. No NDMA and NDEA were detected.
Regarding the announcements issued by various overseas drug regulatory authorities on the detection of N-Methylnitrosobutyric acid (NMBA) in losartan, the DH endorsed the recall of 4 losartan products (HK-61932, HK-61933, HK-62634 and HK-62635) from the local market as a precautionary measure due to the potential for NMBA in the products on 11 Mar 2019. The DH noted that the recall was completed.
So far, the DH has received 30 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 impurities such as NDMA, NDEA and/or NMBA. The DH will keep vigilant on any safety updates on detection of impurities in sartan-containing products issued by overseas regulatory authorities.
Patients who are taking sartan-containing products should not stop taking the medicines, but should seek advice from their healthcare professionals as soon as possible for proper arrangement.
Ends/ Saturday, Nov 14, 2020
Issued at HKT 12:00
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