Recalls of “sartan”-containing drugs continues with Torrent Pharmaceuticals, an Ahmedabad, India-based pharmaceutical company, expanding its voluntary recall of select lots of losartan potassium tablets, and Prinston Pharmaceutical, a Cranbury, New Jersey-based pharmaceutical company, initiating a voluntary recall of select lots of irbesartan products due to suspected impurities. Overall, the recall and investigation of drugs with “sartan” active pharmaceutical ingredients (APIs) began in July 2018 with valsartan and has since extended to multiple companies and other “sartan” APIs, including valsartan, losartan, irbesartan, candesartan, and olmesartan. These APIs are primarily used in anti-hypertensive and cardiovascular drugs.

In the latest recall, Torrent Pharmaceuticals is expanding its voluntary recall from 10 lots of losartan potassium tablets USP to include six lots of losartan potassium and hydrochlorothiazide tablets, USP, to the consumer level due in the US to the detection of trace amounts of an unexpected impurity found in the API manufactured by Hetero Labs, a Hyderabad, India-headquartered API producer and part of the pharmaceutical parent company Hetero Drugs.

The impurity detected in the API is N-nitrosodiethylamine (NDEA), which is a substance that occurs naturally in certain foods, drinking water, air pollution, and industrial processes, and has been classified as a probable human carcinogen as per the International Agency for Research on Cancer (IARC) classification. Torrent is only recalling lots of losartan containing products that contain NDEA above the acceptable daily intake levels released by the US Food and Drug Administration (FDA). To date (as of January 22, 2019), the company says it has not received any reports of adverse events related to this recall.

Losartan is used to treat hypertension, hypertensive patients with left ventricular hypertrophy and for the treatment of nephropathy in Type 2 diabetic patients.

Separately, Prinston Pharmaceutical Inc., dba Solco Healthcare LLC., has initiated a voluntary recall of one lot of irbesartan and seven lots of irbesartan hydrochlorothiazide (HCTZ) tablets to the consumer level in the US due to the detection of trace amount of an NDEA impurity found in the API manufactured by Zhejiang Huahai Pharmaceuticals (ZHP), a Linhai, China-based pharmaceutical company.

Prinston is only recalling lots of irbesartan-containing products that contain NDEA above the acceptable daily intake levels released by the FDA. To date (as of January 18, 2019), Prinston Pharmaceutical said it has not received any reports of adverse events related to this recall.

Irbesartan and irbesartan HCTZ are used to control high blood pressure and for the treatment of heart failure. Irbesartan in combination with amlodipine plus HCTZ is used to control high blood pressure.

This is the latest recall and investigation into products containing “sartan” APIs. Earlier this month (January 2019), Aurobindo Pharma USA, Inc., the US-based operations of Aurobindo Pharma, a Hyderabad, India-headquartered generics and API manufacturer, announced a voluntary recall of 80 lots of amlodipine valsartan tablets USP, valsartan HCTZ tablets USP, and valsartan tablets USP in the US to the consumer level due to the detection of trace amounts of NDEA.

In December 2018, Mylan Pharmaceuticals expanded its consumer-level voluntary US recall of valsartan-containing products to include all lots of valsartan-containing products within expiry. The company had earlier issued (November 2018) a voluntary recall to the consumer level of select lots of valsartan-containing products due to detected trace amounts of NDEA contained in valsartan. The valsartan API used in the recalled products was manufactured at one of Mylan’s plants in India. Teva Pharmaceutical Industries also announced a recall in November 2018 when it detected NDEA in the valsartan supply it received from Mylan’s plant in India.

In November 2018, Sandoz, the generics arm of Novartis, voluntarily recalled in the US one lot of losartan potassium hydrochlorothiazide tablets (USP 100 mg/25 mg) due to a trace amount of NDEA found in the API. The API was manufactured by ZHP, which was issued a FDA Warning Letter on December 11, 2018 that outlined several manufacturing violations at ZHP’s Chuannan, China facility, including those relating to impurity control, change control, and cross contamination from one manufacturing process line to another.

In July 2018, the FDA and the European Medicines Agency (EMA) began their initial investigations into the “sartans” after the EMA learned that ZHP had detected N-nitrosodimethylamine (NDMA) and NDEA, two probable human carcinogens, in several batches of its valsartan API. The FDA’s investigation began when a manufacturer of valsartan products detected NDMA in its API supplied from ZHP, which followed with other companies recalling valsartan products, including Teva. The EU’s detection of the two impurities led to an EU-wide review of all valsartan medicines marketed in the EU. The review was subsequently extended to other “sartan” medicines when very low levels of NDEA were found in losartan made by Hetero Labs. In October 2018, the EMA updated that it was evaluating the APIs, candesartan, irbesartan, losartan, and olmesartan, marketed in the EU in addition to its investigation into valsartan products. After low levels of NDEA were found in irbesartan, supplied to a US pharmaceutical company by Aurobindo Pharma, the FDA expanded its investigation to include both valsartan and irbesartan. An investigation of losartan followed in November.

Source: FDA (Torrent Pharmaceuticals) and FDA (Prinston Pharmaceutical)