Recall of three brands of losartan products found to contain N-Nitroso-N-Methyl-4-Aminobutyric Acid (NMBA)

On 28 March 2019, HSA recalled three brands of losartan products, Hyperten, Losagen and Losartas as they were detected to contain trace amounts of a nitrosamine impurity, N-nitroso-N-methyl-4-aminobutyric acid (NMBA) that exceeded internationally acceptable limits.

List of recalled losartan products

Not all losartan medicines are affected by the recall. Seven brands* of single-ingredient losartan products and five brands* of combination losartan products are not affected by NMBA contamination based on HSA’s testing and available information to-date.

*Cozaar 50mg & 100mg, Losartan Hexal 50mg & 100mg, A-Losartan 50mg & 100mg, Rosart 50mg & 100mg, Myotan 50mg, Sartocad 50mg & 100mg and Lozarsin 50mg, Hyzaar Tablet, Hyzaar Forte, Hyzaar Plus 100/12.5, Cozaar XQ 5mg/50mg & 5mg/100mg, Losartan + HCT Mevon 50/12.5mg & 100/25mg, Rosart HCT 50mg/12.5mg & 100mg/25mg and Losarb Plus 100mg/25mg.

Background

Since June 2018, there have been several overseas recalls of angiotensin II receptor blocker (ARB) medicines due to the presence of two nitrosamine impurities, N- Nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA). Following the initial discovery of these impurities, HSA has been testing the registered ARBs that were available in Singapore. To date, no ARB medicines have been found to contain unacceptable levels of these 2 nitrosamine impurities.

Recently, several losartan products were recalled overseas due to the presence of a new nitrosamine impurity, NMBA, in the losartan active ingredient manufactured by Hetero Labs Limited, India. In March 2019, HSA developed the test methodology and proceeded to conduct testing of all losartan products in the Singapore market for the presence of the new impurity.  Hyperten, Losagen and Losartas brands of losartan medicines were found to contain NMBA at levels above the internationally acceptable levels. The tests were part of HSA’s ongoing investigations into the potential contamination of ARB medicines by nitrosamine impurities. All the other brands of losartan medicines and ARBs (namely candesartan, irbesartan, valsartan, telmisartan, olmesartan, fimasartan) have been tested and were not found to contain NMBA.

Nitrosamine impurities

Nitrosamine impurities, including NDMA, NDEA and NMBA, are potential human carcinogens based on the carcinogenic effects observed in animal studies. These compounds may also be found in very small quantities in certain food (e.g. pickled vegetables, salted fish and processed meat products) and tobacco products. The potential risk of cancer is associated with the long-term exposure to unacceptable levels of the impurities.

Preliminary evaluation suggests these impurities could be generated when specific chemicals and reaction conditions are present during the manufacturing of the ARB active ingredients, particularly during chemical synthesis of the tetrazole ring structure in ARB medicines. The tetrazole ring structure is a common structure in ARBs, except for telmisartan and eprosartan.

HSA’s benefit-risk assessment

The presence of carcinogenic impurities is generally unacceptable in medicines. In circumstances where these impurities are unavoidable, stringent limits are set based on international harmonised guidelines. The internationally acceptable daily intake level is determined based on a cancer risk of 1 in 100,000 for exposure over a lifetime (i.e. over 70 years). HSA had previously convened an Expert Panel comprising specialists in the fields of toxicology, pharmacology, oncology and cardiology to advise on the regulatory approach for products detected with these impurities. The panel had reviewed and recommended that products found to contain nitrosamine impurities that exceeded the acceptable limits should be recalled from the market.

The levels of NMBA detected in the three affected brands of losartan products were in trace amounts which exceeded the acceptable limit of 96 ng/day. HSA has advised patients not to stop taking their affected medicines unless replacement medicines have been provided as the health risks of stopping the medicines is higher than the potential risk of cancer. 

The contamination of ARB medicines with nitrosamine impurities is a new and evolving issue. HSA is closely monitoring the situation and working with the companies and international regulatory authorities to identify the root causes of the contamination and the corresponding measures to address the issue.

System-wide co-ordinated effort to ensure continued access of medicines

HSA completed the testing of all the losartan products marketed in Singapore prior to instituting the product recall so that healthcare professionals would know which alternative products they could consider switching their patients to.

The public healthcare family worked closely together to proactively reach out to affected patients and ensured that there were sufficient supplies of replacement medications for these patients. Moving forward, to assure the continued safety of the medicines supplied in Singapore, HSA has required companies supplying ARBs to test their products and ensure that they do not contain unacceptable levels of nitrosamine impurities.