The FDA is adding more medications to the recall now that a third cancer-causing contaminant has been identified.
N-Nitroso-N-methyl-4-aminobutyric acid (NMBA) was detected resulting in the latest recall of losartan, an angiotensin receptor blocker commonly used to treat hypertension (high blood pressure). It is believed to have been created during the manufacturing process of the generic drug.
The FDA reports:
Hetero Labs Ltd. in 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 contain the impurity, N-Nitroso-N-methyl-4-aminobutyric acid (NMBA). 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.
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 API, and may also result from the reuse of materials, such as solvents.
“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. 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,” said FDA Commissioner Scott Gottlieb, M.D. “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. 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. 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. The FDA is committed to implementing measures to prevent the formation of these impurities during drug manufacturing processes in the future.”
NMBA, according to Toronto Research Chemicals, is a known carcinogen in a wide range of animal species.
Earlier this Fall, ScieGen Pharmaceuticals, Inc. recalled certain lots of irbesartan, a similar angiotensin receptor blocker used in blood pressure management.
The recalls initially began last summer when FDA recalled a number of lots of valsartan due to an “impurity”, N-nitrosodimethylamine (NDMA) that is known to cause cancer in animals. Weeks later they additionally found traces of N-nitrosodiethylamine (NDEA).
According to Reuters, earlier last summer, the MHRA, Medicines and Healthcare Products Regulatory Agency, located in the UK, said the appearance of the impurity, N-nitrosodimethylamine (NDMA), came after a change in the process for making valsartan at one facility owned by Zhejiang Huahai Pharmaceuticals, a company in Linhai, China.
In animals, NDMA is known to cause liver and lung cancer. In humans its carcinogenic risk is unknown, however the CDC states it may cause liver function impairment and cirrhosis.
With NDEA, data is limited, but due to its classification as a nitrosamine and its prevalence in tobacco smoke it is classified as a probable human carcinogen.
According to New Jersey Department of Health’s website, NDEA has been linked to liver, lung and gastrointestinal tract cancer in animals.
Losartan, valsartan and irbesartan are medications in the class of angiotensin receptor blockers (ARBs) used for high blood pressure and congestive heart failure.
Those taking either tablet for their blood pressure are urged to not abruptly stop their medication but rather check with their medical provider and pharmacy to see if their particular prescription is involved in the recall.
I suspect more recalls will follow as processes may be similar across multiple pharmaceutical facilities and NMBA, NDMA and NDEA are byproducts that may not be individually unique to just one “brand” of medication manufacturing.