Although first detected in summer 2018, angiotensin II receptor blockers (ARBs) contaminated with nitrosamines have been on the market in the United States for 4 years, according to the Food and Drug Administration.
“FDA scientists estimate that, if 8,000 people took the highest daily valsartan dose (320 mg) that contained NDMA [N-Nitrosodimethylamine] for 4 years (the time we think the affected products had been on the U.S. market), there may be one additional case of cancer beyond the average cancer rate among those 8,000 Americans,” the agency said in a Jan. 25from Commissioner Scott Gottlieb, MD, and Janet Woodcock, MD, director of the Center for Drug Evaluation and Research.
“The vast majority of patients exposed to NDMA through ARBs received much smaller amounts of the impurity than this worst-case scenario. Since not all ARBs are affected, it’s very likely that a patient taking an ARB for 4 years would not have always received one of the affected products. We’re still seeking to similarly quantify the risk from NDEA [N-Nitrosodiethylamine] and plan to communicate our findings as soon as possible,” they said.
“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,” Dr. Gottlieb and Dr. Woodcock said in the statement. Through ongoing and “exhaustive” efforts, they pledged the agency will resolve the problem and ensure it never happens again.
Meanwhile, the ongoing recalls have led to a shortage of valsartan, and other ARBs may soon follow suit. The agency hoped the one case of cancer per 8,000 patients analysis would help providers “balance the risk of patients ingesting low levels of the impurities ... for a short period of time” during shortages until a suitable replacement or alternative is found.
The problem surfaced last year when FDA was alerted to nitrosamine contamination in valsartan manufactured in China and marketed in the U.S. by generic pharmaceutical companies. Contamination has since been detected in generic irbesartan and losartan.
The impurities are generated “when specific chemicals and reaction conditions are present in the manufacturing process ... and may also result from the reuse of materials, such as solvents,” something “neither regulators nor industry fully understood” before. The agency has developed and shared new tests to detect nitrosamines. “Manufacturers using processes at risk for these impurities are expected to test for them to ensure that active ingredients and finished products are free of detectable levels,” it said.
Meanwhile, the recalls keep coming, the latest for losartan and hydrochlorothiazide combination tablets from Torrent Pharmaceuticals. The recalls are listed on FDA’s.