Exposure to Valsartan Products Containing Nitrosamine Impurities in the United States, Canada, and Denmark

Background: Following the mass recall of valsartan products with nitrosamine impurities in July 2018, the number of patients exposed to these products, the duration of exposure, and the potential for cancer remains unknown. Therefore, we assessed the extent and duration of use of valsartan products with a nitrosamine impurity in the United States, Canada, and Denmark.

Methods: We conducted a retrospective cohort study using administrative healthcare data from the US FDA Sentinel System, four Canadian provinces that contribute to the Canadian Network for Observational Drug Effect Studies (CNODES), and the Danish National Prescription Registry. Patients, 18 years and older between May 2012 and December 2020 with a valsartan dispensing were identified in each database. Patients were followed from the date of valsartan dispensing until discontinuation. We defined four valsartan exposure categories based on nitrosamine impurity status; recalled generic products with confirmed NDMA/NDEA levels (recalled-tested); recalled generic products that were not tested (recalled); non-recalled generic and non-recalled branded products. In Denmark, the recalled-tested category was not included due to absence of testing data. The proportion and duration of use of valsartan episodes stratified by nitrosamine-impurity status was calculated.

Results: We identified 3.3 and 2.8 million (United States) and 51.3 and 229 thousand (Canada) recalled-tested and recalled valsartan exposures. In Denmark, where valsartan exposure was generally low, there were 10 747 recalled exposures. Immediately after the recall notices were issued, there was increased rates of switching to a non-valsartan ARB. The mean duration of use of the recalled-tested products was 167 (±223.1) and 146 (±255.8) days in the United States and Canada respectively. For the recalled products, mean cumulative duration of use was 178 (±249.6), 269 (±397.3) and 166 (±251.0) days in the United States, Canada, and Denmark, respectively.

Conclusion: In this cohort study, despite widespread use of recalled generic valsartan between 2012 and 2018, the duration of use was relatively short and probably did not pose an elevated risk of nitrosamine-induced cancer. However, since products with nitrosamine impurity could have been on the market over a 6-year period, patients exposed to these products for longer durations could have a potentially different risk of cancer.