FDA Continues Investigation and Recalls for Generic Sartan Drugs

By Lillian Torres -

March 6, 2019

The US Food and Drug Administration (FDA) is updating the agency’s ongoing investigation surrounding the recent voluntary recalls of multiple generic “sartan”-containing products, angiotensin II receptor blockers (ARBs), used to treat high blood pressure and heart failure. 

Most recently, Hetero Labs, headquartered in Hyderabad, India, has announced a recall of 87 lots of losartan potassium tablets (25 mg, 50 mg and 100 mg). The recalled losartan potassium tablets, made by Hetero Labs and distributed by Camber Pharmaceuticals, based in Piscataway, New Jersey, contain the impurity, N-nitroso-N-methyl-4-aminobutyric acid (NMBA). Hetero identified NMBA in lots of losartan potassium during recent testing. The impurity is a known animal and potential human carcinogen. This is the first ARB recall resulting from the presence of NMBA, which is the third type of nitrosamine impurity detected in ARB medicines. 

“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 [N-nitrosodimethylamine] exposure but less than the risk from NDEA [N‑nitrosodiethylamine] exposure,” said FDA Commissioner Scott Gottlieb, in a March 1, 2019 statement. “That said, any presence of such impurities in drug products is not acceptable. Over the past few months, the FDA has conducted a major investigation and has worked with drug companies to address the presence of impurities in these products.”

Recent testing of these recalled lots of losartan potassium tablets showed NMBA levels higher than the FDA’s interim acceptable intake limits. The FDA’s evaluation suggests that the nitrosamines found in ARBs may be generated when specific chemicals and reaction conditions are present in the manufacturing process of the drug’s active pharmaceutical ingredient, and may also result from the reuse of materials, such as solvents. 

Gottlieb said that FDA scientists have developed novel and sophisticated testing methods specifically designed to detect and measure N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) impurities in ARB medicines. “Because of the potential for discovering other nitrosamine impurities, we are conducting an extensive organic chemistry analysis to develop novel testing methods to detect additional nitrosamine impurities, including NMBA,” he said.

 “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. We are making important strides at understanding how these impurities form, and we are continuing to examine if nitrosamine impurities may also arise during the manufacture of other ARB drug products,” said Gottlieb in the FDA statement.

NMBA has not been found in previously recalled ARB products; however, the FDA is continuing its investigation. Previously, two other nitrosamine impurities, NDMA and NDEA, were found in drug products containing the active pharmaceutical ingredients valsartan, losartan and irbesartan, and those products containing nitrosamines above the interim acceptable limits were recalled.

Recent FDA analyses of NDMA and NDEA in recalled valsartan found that overall, the risk to individual patients is very low although this doesn’t diminish the significance of this issue or the FDA’s concerns. The agency continues to evaluate the risks nitrosamines pose to patients. The FDA and drug manufacturers continue to test all ARBs for nitrosamine impurities. “If NDEA, NDMA, NMBA, or other nitrosamine impurities are found in products at levels above the interim acceptable intake limits, the FDA will work with companies to swiftly remove affected products from the market,” said Gottlieb in his statement.

The FDA said it will continue to update the list of products included in the recall as more information becomes available from ongoing testing.

Source: US Food and Drug Administration