N-Nitrosodimethylamine-Contaminated Valsartan and the Risk of Cancer

Gomm, Willy; Röthlein, Christoph; Schüssel, Katrin; Brückner, Gabriela; Schröder, H.; Hess, Steffen; Frötschl, Roland; Broich, Karl; Haenisch, Britta

doi:10.3238/arztebl.m2021.0129

Cited by 7 publications

(12 citation statements)

References 16 publications

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“…Although evidence to support major risk concerns for patients’ health is missing or at least very low, [ 1,27 ] it has become apparent that the analytical focus of drug analysis was too narrow in the past. Not all nitrosamines are inevitably mutagenic or carcinogenic (e.g., N ‐nitrosodiphenylamine), as Elder et al [ 28 ] have shown in their review, but without the knowledge of NA formation, it is already evident that this public health problem will persist.…”

Section: Discussionmentioning

confidence: 99%

Risk assessment for nitrosated pharmaceuticals: A future perspective in drug development

Schmidtsdorff

Neumann

Schmidt³

et al. 2022

Archiv der Pharmazie

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Since June 2018, thousands of drug products from around the world had to be recalled due to the unexpected presence of nitrosamines (NAs). Starting with the pharmaceutical group of sartans, antidiabetic drugs, antihistamines, and antibiotics also became the subject of investigation. The occurrence of NAs has shown that pharmaceutical companies and regulatory agencies did not focus on these substances in the past during drug development. In this study, we incorporated a nitrosation assay procedure into highresolution supercritical fluid chromatography (SFC)-mass spectrometry screening to test the potential of direct nitrosation of active pharmaceutical ingredients (APIs). The forced degradation study was performed with a four-fold molar excess of sodium nitrite, relative to the drug substance, at pH 3-4 for 4 h at 37°C. Chromatographic separation was performed on a porous graphitic carbon column by SFC. The mass analysis then focused on direct N-nitrosation or N-nitroso compounds (NOCs) formed after dealkylation. Substances (n = 67) from various pharmaceutical classes were evaluated and 49.3% of them formed NOCs, of which 21.2% have not yet been reported in the literature. In addition, for two APIs, which are known to form an unidentified NOC, the structure could be identified. A few substances also showed multiple NOCs and even N,N'-dinitroso-species.As NAs are carcinogens, they have to be eliminated or at least limited to prevent cancer in patients, who rely on these drugs. This study contributes a procedure that can be implemented in preapproval drug development and postapproval risk assessment to prevent unexpected findings in the future.

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Section: Discussionmentioning

confidence: 99%

Risk assessment for nitrosated pharmaceuticals: A future perspective in drug development

Schmidtsdorff

Neumann

Schmidt³

et al. 2022

Archiv der Pharmazie

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“…Pottegård et al ( 2018 ) conducted a cohort study to investigate the association between the use of contaminated Valsartan products with NDMA and risk of cancer and found no increased risk for overall cancer (HR: 1.09, 95% CI: 0.85–1.41) and cancer subtypes. Gomm et al ( 2021 ), in a large cohort study found no association between exposure to NDMA‐contaminated Valsartan and the overall risk of cancer (HR: 1.01; 95% CI: 0.99–1.03). However, a statistically significant association between exposure to NDMA‐contaminated Valsartan and hepatic cancer (HR 1.16; 95% CI: 1.03; 1.31) was observed.…”

Section: Assessmentmentioning

confidence: 98%

“…The Panel is aware of epidemiological studies that investigated the association between cancer and NDMA contaminated drugs such as Ranitidine (Adami et al, 2021 ; Cardwell et al, 2021 ; Kim et al., 2021 ; Yoon et al, 2021 ) and Valsartan (Pottegård et al, 2018 ; Gomm et al, 2021 ). The detailed description of these studies is provided in Appendix F.3 .…”

Section: Assessmentmentioning

confidence: 99%

“…Limitations of the study were the short follow-up time, small sample size and lack of control for important confounding factors. Gomm et al (2021) conducted a cohort study (N = 780,871) to study the relation between NDMAcontaminated Valsartan and the risk of cancer. Participants were individuals who had filled a prescription for Valsartan between 2012 and 2017 and data were obtained from a large German statutory health insurance provider.…”

Section: F22mentioning

confidence: 99%

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Risk assessment of N‐nitrosamines in food

Schrenk¹,

Bignami²,

Bodin³

et al. 2023

EFS2

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EFSA was asked for a scientific opinion on the risks to public health related to the presence of Nnitrosamines (N-NAs) in food. The risk assessment was confined to those 10 carcinogenic N-NAs occurring in food (TCNAs), i.e. NDMA, NMEA, NDEA, NDPA, NDBA, NMA, NSAR, NMOR, NPIP and NPYR. N-NAs are genotoxic and induce liver tumours in rodents. The in vivo data available to derive potency factors are limited, and therefore, equal potency of TCNAs was assumed. The lower confidence limit of the benchmark dose at 10% (BMDL 10 ) was 10 μg/kg body weight (bw) per day, derived from the incidence of rat liver tumours (benign and malignant) induced by NDEA and used in a margin of exposure (MOE) approach. Analytical results on the occurrence of N-NAs were extracted from the EFSA occurrence database (n = 2,817) and the literature (n = 4,003). Occurrence data were available for five food categories across TCNAs. Dietary exposure was assessed for two scenarios, excluding (scenario 1) and including (scenario 2) cooked unprocessed meat and fish. TCNAs exposure ranged from 0 to 208.9 ng/kg bw per day across surveys, age groups and scenarios. 'Meat and meat products' is the main food category contributing to TCNA exposure. MOEs ranged from 3,337 to 48 at the P95 exposure excluding some infant surveys with P95 exposure equal to zero. Two major uncertainties were (i) the high number of left censored data and (ii) the lack of data on important food categories. The CONTAM Panel concluded that the MOE for TCNAs at the P95 exposure is highly likely (98-100% certain) to be less than 10,000 for all age groups, which raises a health concern.

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“…Another study found no association with NDMA contaminated valsartan batches and overall risk of cancer. However, slightly increased risk of hepatic cancer was noted 37 …”

Section: Introductionmentioning

confidence: 99%

Angiotensin II receptor blockers (ARBs) and manufacturing contamination: A retrospective National Register Study into suspected associated adverse drug reactions

Salim

Jones

2022

Brit J Clinical Pharma

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The aim of this study was to determine if any suspected adverse drug reactions (ADRs) observed with the use of angiotensin II receptor blockers (ARBs) could be linked to either (a) their unique respective physicochemical and pharmacological profiles and (b) the recently disclosed suspected carcinogenic manufacturing contaminants found in certain sartan drug class batches. Methods:The pharmacology profiles of ARBs were data-mined from the Chemical Database of bioactive molecules with drug-like properties, European Molecular Biology Laboratory (ChEMBL). Suspected ADR data (from 01/2016-10/2022, inclusive) and prescribing rates of ARBs over a 5-year prescribing window (from 09/2016 to 08/2021, inclusive) were obtained via analysis of the United Kingdom Medicines and Healthcare products Regulatory Authority (MHRA) Yellow Card drug analysis profile and Open prescribing databases, respectively. Results:The overall suspected ADRs and fatalities per 100 000 prescriptions identified across the ARBs studied were found to be different between the sartan drug class members (chi-squared test, P < .05). There is a greater relative rate of reports for valsartan across all investigated organ classes of ADRs, than other ARBs, despite valsartan's more limited pharmacological profile and similar physicochemical properties to other sartans. The disparity in ADR reporting rates with valsartan vs other ARBs could be due to the dissimilarity in formulation excipients, patient factors and publicity surrounding batch contaminations, amongst others. Cancer-related ADRs and fatalities per 100 000 prescriptions identified across the ARBs studied are not statistically significant (chi-squared test, P > .05) based on the datasets used over the 5-year period. Conclusion:No connection between ARB pharmacology and their suspected ADRs could be found. No conclusion between sartan batch contaminations and increased suspected cancer-related ADRs was found.

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N-Nitrosodimethylamine-Contaminated Valsartan and the Risk of Cancer

Cited by 7 publications

References 16 publications

Risk assessment for nitrosated pharmaceuticals: A future perspective in drug development

Risk assessment for nitrosated pharmaceuticals: A future perspective in drug development

Risk assessment of N‐nitrosamines in food

Angiotensin II receptor blockers (ARBs) and manufacturing contamination: A retrospective National Register Study into suspected associated adverse drug reactions

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