FDA warns of valsartan shortage, provides risk estimates for carcinogenic impurity

People taking the widely prescribed blood-pressure medication valsartan may have been exposed to a probable human carcinogen for at least four years after a change in the manufacturing process introduced the impurity, according to an update from the FDA’s ongoing investigation into the contaminants that have been found in a series of angiotensin II receptor blockers (ARBs).

The FDA acknowledged that valsartan is currently experiencing a shortage, and said other ARB medicines “may fall into shortage soon.” Irbesartan and losartan have been found to contain N-nitrosodiethylamine (NDEA), while another carcinogenic culprit—N-nitrosodimethylamine (NDMA)—was detected in valsartan.

In its update, the FDA offered said the excess risks associated with NDMA are relatively low. The agency estimates if 8,000 people took the highest daily dose of valsartan (320 mg) for four years, there might be one additional case of cancer beyond the average cancer rate for that number of Americans.

“The vast majority of patients exposed to NDMA through ARBs received much smaller amounts of the impurity than this worst-case scenario,” wrote FDA Commissioner Scott Gottlieb, MD, and Janet Woodcock, MD, director of the Center for Drug Evaluation and Research, in the statement. “Since not all ARBs are affected, it’s very likely that a patient taking an ARB for four years would not have always received one of the affected products.

“We’re still seeking to similarly quantify the risk from NDEA and plan to communicate our findings as soon as possible.”

Valsartan impurities were first detected in the active pharmaceutical ingredients from Zhejiang Huahai Pharmaceutical Co., a Chinese company that manufactures generic valsartan-containing medicines. Several distributors use medicines from this facility and later issued voluntary recalls for valsartan products. The FDA’s list of valsartan lots which have been affected by recalls spanned 11 pages as of Jan. 28. There are also shorter lists for recalled lorsartan and irbesartan products.

At least three sellers of valsartan raised their prices amid the recalls—with one hiking its list price more than five-fold—according to the Wall Street Journal.

In their statement, Woodcock and Gottlieb said the FDA is working to establish testing protocols that will be more comprehensive and detect potential impurities earlier. Global regulators, including the FDA, didn’t detect the valsartan impurities for years and the FDA believes the affected valsartan products were on the U.S. market for four years before being recalled.

“While the total exposure to these impurities for most patients was small, we are deeply concerned that patients were exposed to this impurity in the first place and that the presence of nitrosamines went undetected for a period of time,” they said. “The potential for the development of genotoxic impurities during manufacturing processes is an area of intense focus. We’ll continue to improve our science and standards for detecting and preventing these risks.”

As it did during its previous recall announcements, the FDA recommended patients taking one of the affected drugs continue taking the medications until their physician or pharmacist provides an alternative or replacement—as the risks of stopping treatment likely outweigh the risk of exposure to the carcinogens.