Use of N-nitrosodimethylamine (NDMA) contaminated valsartan products and risk of cancer: Danish nationwide cohort study

Abstract

ObjectiveTo perform an expedited assessment of cancer risk associated with exposure to N-nitrosodimethylamine (NDMA) through contaminated valsartan products.DesignNationwide cohort study.SettingDanish health registries on individual level prescription drug use, cancer occurrence, and hospital diagnoses.Participants5150 Danish patients with no history of cancer, aged 40 years or older, and using valsartan at 1 January 2012 or initiating use between 1 January 2012 and 30 June 2017. Participants were followed from one year after cohort entry (lag time period) until experiencing a cancer outcome, death, migration, or end of study period (30 June 2018). Each participant’s exposure to NDMA (ever exposure and predefined categories of cumulative valsartan exposure) was mapped out as a time varying variable while also applying a one year lag.Main outcome measuresAssociation between NDMA exposure and a primary composite endpoint comprising all cancers except non-melanoma skin cancer, estimated using Cox regression. In supplementary analyses, the risk of individual cancers was determined.ResultsThe final cohort comprised 5150 people followed for a median of 4.6 years. In total, 3625 cohort participants contributed 7344 person years classified as unexposed to NDMA, and 3450 participants contributed 11 920 person years classified as ever exposed to NDMA. With 104 cancer outcomes among NDMA unexposed participants and 198 among exposed participants, the adjusted hazard ratio for overall cancer was 1.09 (95% confidence interval 0.85 to 1.41), with no evidence of a dose-response relation (P=0.70). For single cancer outcomes, increases in risk were observed for colorectal cancer (hazard ratio 1.46, 95% confidence interval 0.79 to 2.73) and for uterine cancer (1.81, 0.55 to 5.90), although with wide confidence intervals that included the null.ConclusionsThe results do not imply a markedly increased short term overall risk of cancer in users of valsartan contaminated with NDMA. However, uncertainty persists about single cancer outcomes, and studies with longer follow-up are needed to assess long term cancer risk.

Understanding and Preventing (N-Nitrosodimethylamine) NDMA Contamination of Medications

“…7,8 The International Agency for Research on Cancer has classified NDMA as a probable carcinogen, with animal studies finding tumor formation predominantly in the gastrointestinal tract and liver but also in the lungs and kidneys. 8,9 NDMA, like other nitrosamine contaminants, activates ras oncogenes, and NDMA metabolism by CYP2E1 creates methyldiazonium, a known mutation inducer via methylation. [8][9][10] As such, NDMA is suspected to cause both localized and systemic carcinogenic effects.…”

“…8,9 NDMA, like other nitrosamine contaminants, activates ras oncogenes, and NDMA metabolism by CYP2E1 creates methyldiazonium, a known mutation inducer via methylation. [8][9][10] As such, NDMA is suspected to cause both localized and systemic carcinogenic effects. 9,10 Where Does NDMA Come From?…”

Metformin and nitrosamine impurities

“…13,14 Metformin, NDMA and FDA recall A Dutch study reported last year that exposure to NDMA-contaminated medicines was associated with a small increase in risk for overall cancer (HR, 1.09; 95% CI, 0.85-1.41). 15 The HR increased to 1.46 for colorectal cancer and 1.81 for uterine cancer, although confidence intervals were wide. FDA currently recognizes the danger of this compound and, as a result, has set strict daily acceptable intake limits on NDMA in pharmaceuticals of 96 nano grams.…”

Analysis of an Impurity, <i>N</i>-Nitrosodimethylamine, in Valsartan Drug Substances and Associated Products Using GC-MS

“…The contamination is in all likelihood related to a change in the manufacturing process in Zhejiang Huahai Pharmaceuticals in 2012. 9,10) Sodium azide and N,N-dimethylformamide (DMF) were used for the formation of the tetrazole ring in valsartan. Subsequently, excess sodium azide, remaining after the formation of the tetrazole ring, was quenched with sodium nitrite under acidic conditions, resulting in the formation of nitrous acid.…”