Information Update - Multiple Losartan-containing drugs voluntarily recalled because of potential for nitrosamine impurity

OTTAWA, March 9, 2019 /CNW/ - Health Canada is advising Canadians that multiple lots of Losartan-containing drugs are being voluntarily recalled by Teva Canada, Apotex Inc., Pharmascience Inc., and Pro Doc Limitée 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.

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

The Losartan active pharmaceutical ingredient (API) in all of the recalled products is manufactured by Hetero Labs Ltd. Unit 1, in India. These recalls represent all lots of drugs distributed in Canada that contain Losartan API manufactured at Hetero Labs Ltd. Unit 1.

Losartan is an angiotensin receptor blocker (ARB) drug, also known as a "sartan." Sartans 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 July 2018 because of nitrosamine impurities (see links below for more information).

As with previous recalls involving nitrosamine impurities, Health Canada is advising that there is no immediate risk to patients taking these medications, since the potential risk of cancer is with long-term exposure to the impurities. Patients should not stop taking their medication unless advised to do so by their healthcare provider.

There are alternative products currently available on the Canadian market. Health Canada continues to monitor the supply situation. Health Canada encourages Canadians to visit drugshortagescanada.ca for information on drug shortages and discontinuances. Patients with questions or concerns about any drug they are taking, including on what to do if that drug is not readily available, should speak to their healthcare professional.

Canadians with questions about the recalls can contact:

• Apotex Inc. via Stericyle Inc. by calling toll-free at 1-877-492-4795;
• Pharmascience Inc. by calling toll-free at 1-800-340-9735;
• Pro Doc Limitée by calling toll-free at 1-800-361-8559, or by email at [e-mail]; or
• Teva Canada by calling toll-free at 1-800-268-4129, or by email at [e-mail].

Health Canada encourages consumers to report any health product-related side effects or complaints to the Department.

Affected products
The following products containing Losartan manufactured by Hetero Labs Ltd. Unit 1 are being recalled. Health Canada maintains a complete list of sartan drugs that have been recalled because of nitrosamine impurities on its website.

Product name/Active Pharmaceutical Ingredient (API)	DIN	Strength	Lot	Expiry
APO-LOSARTAN	02379058	25 mg	NL1453	08/2019
APO-LOSARTAN	02379058	25 mg	NL1452	08/2019
APO-LOSARTAN	02353504	50 mg	NK1254	08/2019
APO-LOSARTAN	02353504	50 mg	NK1253	08/2019
APO-LOSARTAN	02353512	100 mg	NL1461	08/2019
APO-LOSARTAN	02353512	100 mg	NG2092	04/2019
APO-LOSARTAN	02353512	100 mg	NH5932	06/2019
APO-LOSARTAN	02353512	100 mg	NH5933	06/2019
APO-LOSARTAN	02353512	100 mg	NL1460	08/2019
APO-LOSARTAN	02353512	100 mg	NH5934	06/2019
APO-LOSARTAN/HCTZ	02371235	50/12.5 mg	NL1441	08/2019
APO-LOSARTAN/HCTZ	02371235	50/12.5 mg	NZ8848	05/2020
APO-LOSARTAN/HCTZ	02371235	50/12.5 mg	NL1445	08/2019
APO-LOSARTAN/HCTZ	02371235	50/12.5 mg	NZ8849	05/2020
APO-LOSARTAN/HCTZ	02371235	50/12.5 mg	NZ8860	05/2020
APO-LOSARTAN/HCTZ	02371243	100/12.5 mg	NG2087	04/2019
APO-LOSARTAN/HCTZ	02371243	100/12.5 mg	NL1421	10/2019
APO-LOSARTAN/HCTZ	02371243	100/12.5 mg	NG2086	04/2019
APO-LOSARTAN/HCTZ	02371243	100/12.5 mg	NL1422	10/2019
APO-LOSARTAN/HCTZ	02371251	100/25 mg	NL1429	08/2019
APO-LOSARTAN/HCTZ	02371251	100/25 mg	NZ8846	05/2020
APO-LOSARTAN/HCTZ	02371251	100/25 mg	NZ8847	05/2020
APO-LOSARTAN/HCTZ	02371251	100/25 mg	NZ8845	05/2020
LOSARTAN (PRO DOC LIMITEE)	02394367	25 mg	498292	03/2019
LOSARTAN (PRO DOC LIMITEE)	02394367	25 mg	605344	02/2020
LOSARTAN (PRO DOC LIMITEE)	02394375	50 mg	498779	03/2019
LOSARTAN (PRO DOC LIMITEE)	02394375	50 mg	600046	06/2019
LOSARTAN (PRO DOC LIMITEE)	02394375	50 mg	603903	11/2019
LOSARTAN (PRO DOC LIMITEE)	02394375	50 mg	498284	03/2019
LOSARTAN (PRO DOC LIMITEE)	02394375	50 mg	603895	11/2019
LOSARTAN (PRO DOC LIMITEE)	02394383	100 mg	499008	03/2019
LOSARTAN (PRO DOC LIMITEE)	02394383	100 mg	605299	01/2020
LOSARTAN (PRO DOC LIMITEE)	02394383	100 mg	605297	01/2020
PMS-LOSARTAN	02309750	25 mg	498294	03/2019
PMS-LOSARTAN	02309750	25 mg	605342	02/2020
PMS-LOSARTAN	02309750	25 mg	611944	01/2021
PMS-LOSARTAN	02309769	50 mg	498285	03/2019
PMS-LOSARTAN	02309769	50 mg	600047	06/2019
PMS-LOSARTAN	02309769	50 mg	600091	06/2019
PMS-LOSARTAN	02309769	50 mg	603894	11/2019
PMS-LOSARTAN	02309769	50 mg	612025	01/2021
PMS-LOSARTAN	02309769	50 mg	612031	01/2021
PMS-LOSARTAN	02309769	50 mg	612679	01/2021
PMS-LOSARTAN	02309769	50 mg	616743	08/2021
PMS-LOSARTAN	02309777	100 mg	498864	03/2019
PMS-LOSARTAN	02309777	100 mg	602668	09/2019
PMS-LOSARTAN	02309777	100 mg	603816	09/2019
PMS-LOSARTAN	02309777	100 mg	605298	01/2020
PMS-LOSARTAN	02309777	100 mg	605300	01/2020
PMS-LOSARTAN	02309777	100 mg	613935	03/2021
PMS-LOSARTAN	02309777	100 mg	613936	03/2021
TEVA-LOSARTAN/HCTZ	02358263	50/12.5 mg	35349397A	09/2019
TEVA-LOSARTAN/HCTZ	02358263	50/12.5 mg	35344801A	09/2020

Assessment is ongoing
Health Canada 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. Health Canada's evaluation so far suggests 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.

An API is the active ingredient in a drug that produces an effect on the body. APIs are used in the manufacture of finished "dosage form" drugs (such as pills, capsules or tablets). 

In December 2018, Health Canada requested all companies that market sartans in Canada to test products already on the market and those to be released in Canada for N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA). Health Canada also recommended that companies consider using manufacturing practices that avoid the generation and presence of all nitrosamine impurities. Health Canada has 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 expects manufacturers to take any necessary actions to prevent the generation of nitrosamine impurities. The Department 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

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

As previously communicated, Health Canada has also found the Chuannan site of Zhejiang Huahai Pharmaceuticals (ZHP) in China to be non-compliant with GMP requirements. This site manufactured valsartan that was found to contain nitrosamine impurities. All drugs containing valsartan 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. A non-compliant rating does not necessarily indicate a product safety concern. It means that the Department has identified issues with how the company is following good manufacturing processes and procedures. Health Canada routinely inspects facilities or assesses inspection results from trusted international regulatory partners to make sure they meet these standards and maintains a database with inspection results. Health Canada does not generally proactively communicate on these ratings, but is updating Canadians at this time as part of its commitment to communicating its activities related to nitrosamine impurities in sartans.

Health Canada continues to collaborate with international regulators on inspections of foreign manufacturers of sartans and will take action and update Canadians as needed.

Related links

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

Previous communications:

• Health Canada information update (2018-12-20): Health Canada releases test results of certain sartan drugs
• Health Canada information update (2018-11-29): Mylan-Valsartan voluntarily recalled as a precaution due to an impurity
• Health Canada information update (2018-10-02): Health Canada finds Zhejiang Huahai Pharmaceuticals site non-compliant with requirements for the manufacture of drug ingredients
• Health Canada information update (2018-09-13): Health Canada advises of a second impurity linked to recalled valsartan drugs
• Health Canada information update (2018-09-10): Health Canada updates Canadians on estimates of health risks for recalled valsartan drugs containing NDMA
• Health Canada information update (2018-08-18): Teva Canada expands recall of valsartan drugs to include additional lots, as a precaution
• Health Canada advisory (2018-07-09): Several drugs containing valsartan being recalled due to contamination with a potential carcinogen

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SOURCE Health Canada

For further information: Media Enquiries: Health Canada, [phone]; Public Enquiries: [phone], 1-866 225-0709