Pharmacy Recall: Multiple Losartan-containing drugs

Multiple lots of Losartan-containing drugs are being voluntarily recalled because of the potential for a nitrosamine impurity, N-Nitroso-N-methyl-4-aminobutyric acid (NMBA).
 
NMBA is potentially a human carcinogen, which means that long-term exposure could increase the potential risk of cancer, said Health Canada. 

Teva Canada is voluntarily recalling two lots of combination Losartan/hydrochlorothiazide (HCTZ) tablets after testing of one lot identified levels of NMBA above what is considered reasonably safe if the drug were taken over a lifetime. 

In response to this finding, Apotex Inc., Pharmascience Inc., and Pro Doc Limitée are voluntarily recalling multiple lots of Losartan-containing products as a precaution. 

Losartan is an angiotensin receptor blocker (ARB) drug, also known as a "sartan," which are a class of drugs used to treat patients with high blood pressure to help prevent heart attacks and stroke. They are also used in patients who have had heart failure or a recent heart attack. 

There have been multiple recalls of products containing another sartan, valsartan, in Canada and internationally since Jul. 2018 because of nitrosamine impurities, said Health Canada. As with previous recalls involving nitrosamine impurities, there is no immediate risk to patients taking these medications since the potential risk of cancer is with long-term exposure to the impurities. 

Health Canada said patients should not stop taking their medication unless advised to do so by their healthcare provider. 

Affected Products:

The following products contain Losartan manufactured by Hetero Labs Ltd. Unit 1, in India. 

Investigation

Health Canada said their team continues to work with companies and international regulatory partners, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency, to assess the issue of nitrosamine impurities in certain sartan drugs, its root causes and mitigation measures. 

So far, studies suggest that the nitrosamines may be generated when specific chemicals and reaction conditions are present in the manufacturing process of the drug's API. They may also result from the reuse of materials, such as solvents or starting materials, that are contaminated with the impurities, said Health Canada.

An API is the active ingredient in a drug that produces an effect on the body, used in the manufacturing of finished 'dosage form' drugs such as pills, capsules or tablets.

Health Canada said that in Dec. 2018, all companies that market sartans in Canada were asked to test products already on the market and those to be released in Canada for N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA). In addition, these companies were asked to consider using manufacturing practices that avoid the generation and presence of all nitrosamine impurities.

Health Canada said they have tested more than 50 samples of sartan drugs and will continue to post results of any new samples it tests on its website.

Health Canada continues to hold companies responsible for the safety and effectiveness of drugs sold in Canada and said they expect manufacturers to take any necessary actions to prevent the generation of nitrosamine impurities. Health Canada said they will take further steps as required to confirm that appropriate and timely action is taken to protect the health and safety of Canadians.

Manufacturers of recalled sartan APIs

A U.S FDA inspection of Hetero Labs Ltd. Unit 1, in India, found the manufacturer to be non-compliant with requirements for Good Manufacturing Practices (GMPs). Health Canada said that a non-compliant rating means Canadian companies can no longer import drug that contain APIs from this site unless they are medically necessary.

Health Canada has also identified the Chuannan sit of Zhejiang Huahai Pharmaceuticals (ZHP) in China, to be non-compliant with GMP standards. This site was found to manufacture valsartan, which was found to contain nitrosamine impurities. All drugs containing valsaran manufactured by ZHP have been recalled in Canada. 

GMPs are internationally accepted standards that help ensure that drugs are consistently manufactured, tested, stored and distributed in a way that meets Canada's high safety and quality standards. Health Canada said that a non-compliant rating does not necessarily indicate a product safety concern, but that their department has identified issues with a company's manfacturing process and procedures. 

Health Canada said they routinely inspect facilities or assess inspection results from trusted international regulatory partners, to make sure manufactureres meet these standards and maintains a database with inspection results. Health Canada continues to collaborate with international regulators on inspections of foreign manufacturers of sartans and will take action and update Canadians as needed. 

Alternatives

Health Canada said there are alternative products currently available on the Canadian market. Health Canada continues to monitor the supply situation. Patients with questions or concerns about any drug they are taking, including on what to do if that drug is not readily available, are encouraged to speak with their healthcare professional.

More information, including a complete list of recalled products related to this issue and Health Canada's lab test results and test method can be found here.