Adverse Events to Food Supplements Containing Red Yeast Rice: Comparative Analysis of FAERS and CAERS Reporting Systems

IntroductionIn the absence of a European standardized postmarketing food supplement surveillance system (nutrivigilance), some member states and companies have developed their own approaches to monitoring potential adverse reactions to secure a high level of product safety. This paper describes the use of a nutrivigilance system in monitoring the incidence of spontaneously reported suspected adverse reactions associated with food supplements containing red yeast rice (RYR).Material and methodsWe report the data from a widely used product marketed under the trademark Armolipid/Armolipid Plus. Postmarketing information was collected in a voluntary nutrivigilance system established by the manufacturing company (Meda Pharma SpA, a Viatris Company, Monza, Italy). From 1st October 2004 to 31st December 2019, this system captured cases of suspected adverse reactions spontaneously reported by consumers, healthcare professionals, health authorities, regardless of causality.ResultsThe total number of case reports received mentioning the RYR food supplement product line was 542, in which 855 adverse events (AEs) were reported. The total reporting rate of AEs was estimated to be 0.037% of 2,287,449 exposed consumers. Of the 542 cases, 21 (0.0009% of exposed consumers) included suspected serious adverse events (SAEs). After careful investigation, 6 cases (0.0003% of consumers exposed) and 6 AEs were assessed by the manufacturer as serious and potentially related to exposure to the above-mentioned RYR-based nutraceutical.ConclusionsThis nutrivigilance-derived data analysis clearly demonstrates a low prevalence of suspected adverse events associated with the red yeast rice product line. Consumer safety of food supplements could be generally improved by raising awareness of the importance of following the indications and warnings detailed in a food supplement’s labeling.

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A quantitative UHPLC-MS/MS method for citrinin and ochratoxin A detection in food, feed and red yeast rice food supplements

World Mycotoxin Journal ◽

10.3920/wmj2015.1971 ◽

2016 ◽

Vol 9 (3) ◽

pp. 343-352 ◽

Cited By ~ 10

Author(s):

J.A.L. Kiebooms ◽

B. Huybrechts ◽

C. Thiry ◽

E.K. Tangni ◽

A. Callebaut

Keyword(s):

Risk Assessment ◽

Ochratoxin A ◽

High Performance ◽

Food Supplements ◽

Red Yeast Rice ◽

Red Yeast ◽

Relative Standard ◽

Future Data ◽

Food And Feed ◽

Feed Samples

Mycotoxins may cause deleterious effects (among others nephrogenic, hepatogenic, carcinogenic, teratogenic, neurogenic) in animals and humans, therefore they have been intensely studied and monitored over the years. For citrinin (CIT), a nephrotoxic mycotoxin, however, this has not yet been the case. According to the latest European Food Safety Authority report, a correct risk assessment of CIT was not possible due to the lack of occurrence data. Besides, traces of CIT or its metabolite, dehydrocitrinone are widely (in up to 90% of samples) present in human urine according to recent Belgian and German scientific reports, which might imply chronic exposure. Only recently, a European maximum limit has been set for CIT in cholesterol reducing food supplements including red yeast fermented rice (RYR). During production of RYR through fungal (among others Monascus purpureus) fermentation of rice other components, like CIT, as well as nephrotoxic ochratoxin A (OTA) may form. Consequently, the present work attempted develop to a robust and routinely applicable ultra-high performance liquid chromatographytandem mass spectrometry (UHPLC-MS/MS) method for the analysis of CIT and OTA in food, feed and in RYR food supplements. The method was successfully validated based on EU/657/2002 and EU/519/2014 in RYR food supplements and wheat flour, achieving respective limits of quantification (LOQ) for CIT of 0.4 μg/kg and 0.1 μg/kg and for OTA of 15 μg/kg and 0.4 μg/kg. The average between-day recoveries varied from 72 to 110% with relative standard deviations ≤16%. Single-day validation in rice, curry and apple matrices showed LOQs ranging from 0.3-1.0 μg/kg. Next, the occurrence of CIT/OTA was surveyed in 138 RYR, food and feed samples, proving the potential of this method for future data acquisition within a risk assessment framework specifically for CIT, while also gaining information about the (co-)occurrence of OTA in edible matrices.

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1443Safety of red yeast rice supplementation: a systematic review and meta-analysis of randomized controlled trials

European Heart Journal ◽

10.1093/eurheartj/ehz748.0078 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

F Fogacci ◽

M Banach ◽

D P Mikhailidis ◽

E Bruckert ◽

P P Toth ◽

...

Keyword(s):

Adverse Events ◽

Meta Analysis ◽

Lipid Lowering ◽

Forest Plot ◽

Tolerability Profile ◽

Red Yeast Rice ◽

Monacolin K ◽

Randomized Controlled ◽

Red Yeast ◽

Increased Risk

Abstract Background Recently, concerns regarding the safety of red yeast rice (RYR) have been raised after the publication of some case reports claiming toxicity. Purpose Since the previous meta-analyses on the effects of RYR were mainly focused on its efficacy to improve the lipid profile and other cardiovascular parameters, we carried out a meta-analysis on safety data derived from the available randomized controlled clinical trials (RCTs). Methods Primary outcomes were musculoskeletal disorders (MuD). Secondary outcomes were non-musculoskeletal adverse events (Non-MuD) and serious adverse events (SAE). Subgroups analyses were carried out considering the intervention (RYR alone or in association with other nutraceutical compounds), monacolin K administered daily dose (≤3, <3–5 and >5 mg/day), follow-up (>12 or ≤12 weeks), with statin therapy or statin-intolerance and type of control treatment (placebo or statin treatment). Results Data were pooled from 52 RCTs comprising 110 treatment arms, which included 8503 subjects, with 4421 in the RYR arm and 4287 in the control one. Monacolin K administration was not associated with increased risk of MuD (odds ratio [OR]=0.94, 95% confidence interval [CI] 0.53,1.65). (Figure below presents the forest plot comparing the RYR associated risk of MuD in the entire population). Moreover, we found a reduced risk of Non-MuD (OR=0.59, 95% CI 0.50, 0.69) and SAE (OR=0.54, 95% CI 0.46, 0.64) vs. control. Subgroups analyses confirmed the high tolerability profile of RYR. Furthermore, increasing daily doses of monacolin K were negatively associated with increasing risk of Non-MuD (slope: −0.10; 95% CI: −0.17, −0.03; two-tailed p<0.01). Forest plot on RYR link with MuD risk. Conclusions Based on our data, RYR use as lipid-lowering dietary supplement seems to be overall tolerable and safe in a large population of moderately hypercholesterolaemic subjects. Acknowledgement/Funding None

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Food supplements with red yeast rice: More regulations are needed

European Journal of Preventive Cardiology ◽

10.1177/2047487317716500 ◽

2017 ◽

Vol 24 (13) ◽

pp. 1429-1430 ◽

Cited By ~ 8

Author(s):

Guy G De Backer

Keyword(s):

Food Supplements ◽

Red Yeast Rice ◽

Red Yeast

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NMR evaluation of total statin content and HMG-CoA reductase inhibition in red yeast rice (Monascus spp.) food supplements

Chinese Medicine ◽

10.1186/1749-8546-7-8 ◽

2012 ◽

Vol 7 (1) ◽

pp. 8 ◽

Cited By ~ 23

Author(s):

Dirk W Lachenmeier ◽

Yulia B Monakhova ◽

Thomas Kuballa ◽

Sigrid Löbell-Behrends ◽

Sibylle Maixner ◽

...

Keyword(s):

Food Supplements ◽

Red Yeast Rice ◽

Hmg Coa Reductase ◽

Red Yeast ◽

Coa Reductase

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Citrinin Determination in Food and Food Supplements by LC-MS/MS: Development and Use of Reference Materials in an International Collaborative Study

Toxins ◽

10.3390/toxins13040245 ◽

2021 ◽

Vol 13 (4) ◽

pp. 245

Author(s):

Emmanuel K. Tangni ◽

François Van Hove ◽

Bart Huybrechts ◽

Julien Masquelier ◽

Karine Vandermeiren ◽

...

Keyword(s):

Reference Materials ◽

Ginkgo Biloba ◽

Raw Materials ◽

Collaborative Study ◽

Standard Operating Procedure ◽

Food Supplements ◽

Red Yeast Rice ◽

Proficiency Tests ◽

Red Yeast ◽

Food And Feed

The development of incurred reference materials containing citrinin (CIT) and their successful application in a method validation study (MVS) in order to harmonize CIT determination in food and food supplements are demonstrated. CIT-contaminated materials made of red yeast rice (RYR), wheat flour, and Ginkgo biloba leaves (GBL), as well as food supplements made of red yeast rice (FS-RYR) and Ginkgo biloba leaves (FS-GBL), were manufactured in-house via fungal cultivation on collected raw materials. The homogeneity and stability from randomly selected containers were verified according to the ISO 13528. CIT was found to be homogenously distributed and stable in all contaminated materials, with no significant degradation during the timescale of the MVS when storage was performed up to +4 °C. Next, an MVS was organized with eighteen international laboratories using the provided standard operating procedure and 12 test materials, including three RYRs (blank, <50 µg/kg, <2000 µg/kg), two wheat flours (blank, <50 µg/kg), two GBL powders (blank, <50 µg/kg), three FS-RYRs (blank, <50 µg/kg, <2000 µg/kg), and two FS-GBLs (blank, <50 µg/kg). The results of seven CIT-incurred materials showed acceptable within-laboratory precision (RSDr) varying from 6.4% to 14.6% and between-laboratory precision (RSDR) varying from 10.2% to 37.3%. Evidenced by HorRat values < 2.0, the results of the collaborative trial demonstrated that the applied analytical method could be standardized. Furthermore, the appropriateness of producing CIT reference materials is an important step towards food and feed quality control systems and the organization of proficiency tests.

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