FDA Provides Update on Tainted ARB Investigation, With New Impurity Found

A third type of carcinogenic nitrosamine has been identified in the latest recall. The FDA is also developing new tests to identify contaminants.

FDA Provides Update on Tainted ARB Investigation, With New Impurity Found

Recalls continue to roll in as part of the US Food and Drug Administration’s investigation into angiotensin II receptor blockers (ARBs)—specifically valsartan, losartan, and irbesartan—contaminated with potential human carcinogens.

Last week, AurobindoPharma USA announced that it is expanding its recall to include 38 more lots of valsartan and amlodipine/valsartan tablets due to unacceptable levels of N-Nitrosodiethylamine (NDEA). Companies also issued new or expanded recalls of 87 lots of losartan potassium tablets, 114 lots of losartan potassium or losartan potassium/hydrochlorothiazide tablets, and one lot of losartan potassium/hydrochlorothiazide tablets.

Two of the latest losartan recalls involve a third type of nitrosamine—N-Nitroso-N-methyl-4-aminobutyric acid (NMBA)—found to be contaminating drugs in this class. Like the other two contaminants that have been found recently in ARBs, NDEA and N-Nitrosodimethylamine (NDMA), NMBA is considered a potential human carcinogen.

“We are deeply concerned about the presence of a third nitrosamine impurity in certain ARB medications, but it’s important to underscore that, based on the FDA’s initial evaluation, the increased risk of cancer to patients with NMBA exposure appears to be the same for NDMA exposure but less than the risk from NDEA exposure,” FDA Commissioner Scott Gottlieb, MD, said in a press release updating the progress of the agency’s investigation. “That said, any presence of such impurities in drug products is not acceptable.”

Story Continues to Evolve

Public health authorities around the world became aware of the presence of tainted ARBs last summer and recalls were initiated in July to pull valsartan products contaminated with NDMA. The list of affected valsartan products was then expanded in August.

In October, a manufacturer initiated a recall after finding irbesartan containing NDEA. And then in December, additional valsartan-containing medications were recalled due to trace amounts of NDEA.

The FDA has been investigating the issue and “has worked with drug companies to address the presence of impurities in these products,” Gottlieb said. “Our ongoing effort has determined that the impurities may be generated by specific chemical reactions in the manufacturing process of the drug’s active pharmaceutical ingredients.”

Gottlieb said FDA scientists have been working on new ways to test for the presence of NDMA, NDEA, and other nitrosamine impurities. “We’re continuing to share these testing methods with international regulators, industry, and the public to help manufacturers and other regulators evaluate these products for any potential nitrosamine impurity,” he added.

According to the FDA statement, the risk to patients stemming from these contaminants is very low, “although this doesn’t diminish the significance of this issue or the FDA’s concerns.”

An analysis published in September by Dutch researchers suggested that patients who took valsartan products potentially contaminated with NDMA did not have a higher risk of cancer over the short term.

Because of the identification of a third impurity, the FDA has updated its table of interim limits for nitrosamines in ARBs. It also tracks recalled products broken down by specific drug: valsartan, losartan, and irbesartan.

“The FDA reminds patients taking an ARB medication from a recalled lot to continue taking their medicine until their doctor or pharmacist provides a replacement or a different treatment option,” the agency said. “Any patient taking an ARB from a recalled lot who has not yet spoken to their pharmacist or doctor should do so promptly. Not all ARBs contain nitrosamine impurities.”

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