Postmarketing Nutrivigilance Safety Profile: A Line of Dietary Food Supplements Containing Red Yeast Rice for Dyslipidemia.

Abstract

Introduction: In 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).

Methods: We 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.

Results: The 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.

Conclusions: This 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.

Full text

Clinical research
Cardiology
Corresponding author:
Prof. Maciej Banach
MD, PhD, FNLA, FAHA,
FESC, FASA
Department
of Hypertension
Medical University of Lodz
281/289 Rzgowska St
93-338 Lodz, Poland
Phone: +48 42271 11 24
E-mail: maciej.banach@
iczmp.edu.pl
1
Polish Mother’s Memorial Hospital Research Institute (PMMHRI), Lodz, Poland
2
Department of Hypertension, Medical University of Lodz (MUL), Lodz, Poland
3
Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland
4
First Department of Internal Medicine, Diabetes Center, Division of Endocrinology
and Metabolism, Medical School, Aristotle University of Thessaloniki,
AHEPA Hospital, Thessaloniki, Greece
5
Institute of Cardiology and Regenerative Medicine, Faculty of Medicine, University
of Latvia, Riga, Latvia
6
Pauls Stradins Clinical University Hospital, Riga, Latvia
7
Department of Health Promotion Sciences Maternal and Infantile Care, Internal
Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
8
2nd Department of Cardiology of the East Slovak Institute of Cardiovascular Disease
and Faculty of Medicine PJ Safarik University, Kosice, Slovak Republic
9
School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University,
Liverpool, UK
10
Liverpool Centre for Cardiovascular Science, Liverpool, UK
11
Department of Internal Medicine, University Hospital Center Zagreb, Zagreb, Croatia
12
IRCCS Azienda Ospedaliero-Universitaria Di Bologna, Bologna, Italy
13
Alma Mater Studiorum University of Bologna, Bologna, Italy
Submitted: 14 February 2021
Accepted: 26 February 2021
Arch Med Sci
DOI: https://doi.org/10.5114/aoms/133716
Copyright © 2021 Termedia & Banach
Postmarketing nutrivigilance safety profile: aline
of dietary food supplements containing red yeast rice
for dyslipidemia
Maciej Banach1,2,3, Niki Katsiki4, Gustavs Latkovskis5,6, Manfredi Rizzo7, Daniel Pella8,
Peter E. Penson9,10, Zeljko Reiner11, Arrigo FG Cicero12,13
Abstract
Introduction: In the absence of a European standardized postmarketing
food supplement surveillance system (nutrivigilance), some member states
and companies have developed their own approaches to monitoring poten-
tial 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 methods: We report the data from awidely used product mar-
keted under the trademark Armolipid/Armolipid Plus. Postmarketing infor-
mation 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.
Results: The 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 as-
sessed by the manufacturer as serious and potentially related to exposure
to the above-mentioned RYR-based nutraceutical.

Maciej Banach, Niki Katsiki, Gustavs Latkovskis, Manfredi Rizzo, Daniel Pella, Peter E. Penson, Zeljko Reiner, Arrigo FG Cicero
2 Arch Med Sci
Conclusions: This 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.
Key words: adverse event, dyslipidaemia, nutrivigilance, red yeast rice, supplement.
Introduction
Elevated serum low-density lipoprotein choles-
terol (LDL-C) is an established risk factor for ath-
erosclerotic cardiovascular (CV) disease [1–3]. For
the general population and those at increased CV
risk, decreasing the LDL-C by dietary adjustment
represents the primary method of CV risk reduc-
tion and therefore deserves special emphasis in
the evaluation of lifestyle changes [2]. Dietary ad-
justments, however, achieve areduction of LDL-C
which is insufficient to reach the recommended
LDL-C levels in most cases [4].
To this end, the European Society of Cardiolo-
gy (ESC)/European Atherosclerosis Society (EAS)
guidelines 2019 recommend lifestyle interven-
tions, which include not only dietary adjustments
but also the use of functional foods [2]. Anutra-
ceutical ingredient, red yeast rice (RYR), has the
higher-level (grade A) recommendation because
of its clinically relevant impact on improving li-
poprotein profiles [2]. The relevance of RYR was
discussed in the ESC/EAS guidelines in 2011, to-
gether with arecommendation supporting its use.
This guidance was reconfirmed in the 2019 up-
date [2, 5]. Its important role in the lipid-lower-
ing management was also confirmed in the first
nutraceuticals guidelines of the International Lipid
Expert Panel (ILEP) [6, 7].
For individuals who fall into the low-to-mod-
erate CV risk category, changes in lifestyle may
be indicated, whereas statin therapy may not [8].
The guidelines also state that RYR may be consid-
ered for subjects with elevated cholesterol levels
for whom statin therapy is not yet indicated [2].
The ESC/EAS guidelines note that clinically rele-
vant cholesterol decreases were reported with RYR
amounts containing monacolin K doses of 2.5 mg/
day to 10 mg/day [2].
Several RYR-based supplements are available
on the market, some contain only RYR, whereas
other products contain additional ingredients [8]
such as policosanol [9], berberine [9–11], co-en-
zyme Q10 (CoQ10) [12–14].
In the European Food Safety Authority’s (EFSA’s)
assessment of RYR use (2018), decisions were
based on selected studies which evaluated sup-
plementation with mono-ingredient products [15].
The EFSA observed that most reported AEs were
musculoskeletal in nature, followed by fatigue,
pain, and gastrointestinal (GI) symptoms [15].
Hepatic AEs were also observed to occur in asig-
nificant number of patients receiving RYR supple-
mentation, according to the EFSA [15]. The EFSA
considered the lactone form of monacolin K to be
identical to lovastatin and states that RYR food
supplement intake could result in an exposure
to monacolin K levels comparable with thera-
peutic doses of lovastatin [15]. However, taking
into account the selectivity of the data sources
used in the report, lack of complete data on the
quality production, and lack of rechallenge in the
included studies, it was difficult to confirm the
causality of the reported AEs with the RYR sup-
plementation [16].
A 2017 analysis of 28 brands of RYR supple-
ments available in the United States and the Eu-
ropean Union showed that 7% provided labeling
advising against the concurrent use of statins and
that monacolin K content was not included on
any of the product labels [17]. In 2 of the analyzed
products, monacolin K was undetectable, and
across the brands that did contain monacolin K,
the dose per 1200 mg of RYR ranged from 0.09
mg to 5.48 mg [17]. Moreover, the lack of harmo-
nization among nutrivigilance processes and pro-
cedures for food supplement products at the EU
level further complicates the EU regulatory land-
scape of food supplements. As aconsequence, the
reporting requirements of supplement associated
AEs, if they exist, may differ from one EU member
state to another.
On the contrary, at least 3 controlled trials have
shown that RYR is well tolerated [18–20]. In anoth-
er study, no AEs were reported following 10 weeks,
during which 50 patients with dyslipidemia were
randomized to a combination food supplement
containing monacolin K (3 mg) or placebo [21].
In a2012 study, 64 hyperlipidemic patients were
randomized to a combination food supplement
containing monacolin K (3 mg) or placebo for
18 weeks, after which no hepatic or renal chang-
es and no serious AEs (SAEs) were reported [22].
In studies that involved a 6- to 48-week course
of Armolipid enhanced RYR supplement, 2.2% of
the 1600 treated subjects reported only nonseri-
ous AEs, and no life-threatening events were re-
ported. The rates of subjects reporting AEs were
not different from placebo [9]. Finally, in arecent
meta-analysis that included more than 8500 sub-
jects, RYR supplementation was not associated

Postmarketing nutrivigilance safety profile: aline of dietary food supplements containing red yeast rice for dyslipidemia
Arch Med Sci 3
with an increased risk for muscular or non-mus-
cular AEs (which have been observed with statin
use); the authors additionally observed significant
reduction of SAEs [23].
Based on the abovementioned inconsistent
data on RYR safety, the aim of our study was to
evaluate the safety of aline of RYR food supple-
ments (Meda Pharma; aViatris Company, Monza,
Italy), available since October 2004, in the post-
marketing real-life setting via the company’s nu-
trivigilance and safety data collection methods.
Material and methods
As an example of a proactive approach, by
companies in Europe, to report post-marketing in-
formation about safety, we report the data from
awidely used product, marketed since 1st October
2004, under the trademark Armolipid and Armo-
lipid Plus, manufactured by Meda Pharma, aVia-
tris Company (Monza, Italy). Evaluated products
were well characterized from aquality perspective
(including citrinin content), have customer-friend-
ly labeling, and have comparable formulations
(RYR content), allowing the analysis and compar-
ison of postmarketing data while avoiding biases
stemming from different contents in the formula-
tions. One tablet of the standard RYR supplement
contains RYR (200 mg, the equivalent of mona-
colin K, 3 mg), folic acid (0.2 mg), CoQ10 (2 mg),
and astaxanthin (0.5 mg), and in some countries,
policosanol (10 mg). One tablet of the enhanced
RYR supplement contains Berberis aristata extract
(588 mg, equivalent to berberine chloride 500 mg),
RYR (200 mg, the equivalent of monacolin K,
3 mg), policosanol (10 mg), folic acid (0.2 mg),
CoQ10 (2.0 mg), and astaxanthin (0.5 mg) [24].
Anutrivigilance process was used to monitor
the reporting rate and nature of AEs suspected to
be associated with the RYR. An AE was defined as
“any untoward medical occurrence” in aconsum-
er while using afood supplement, even when an
apparent causal relationship does not necessarily
exist. The causal relationship might already have
been suspected by the reporter or by the com-
plaining consumer; nevertheless, acausality as-
sessment was performed for all the case reports
later in the company’s nutrivigilance process. The
AEs described on the food supplement label avail-
able to the consumer were considered to be “ex-
pected” or “labeled”. Serious AEs were defined
as: death; alife-threatening event; an event that
required or prolonged hospitalization; or one that
resulted in asignificantly or persistently incapac-
itated or disabled state, abirth defect, or acon-
genital abnormality. Severe events, based on the
definition of the European Medicines Agency
(EMA) [25], were not considered synonymous
with SAEs.
Since product launch in 2004 an internal nutriv-
igilance database was developed, with increasing
global pharmacovigilance-like systems and pro-
cedures. The database was validated and imple-
mented to record case reports from worldwide
sources. Spontaneous reports originating from
healthcare professionals (HCPs), consumers or
health authorities were verified as original source
reports (i.e., not duplicates), and AEs were coded
according to the standard Medical Dictionary for
Regulatory Activities. Collected reports included
those, in which acorrelation between an AE and
afood supplement was suspected by the reporter
and was later evaluated for causal association (af-
ter entry into the database). Additional collected
information included reports of deficient efficacy,
misuse (e.g., divergence from label instructions),
and contraindicated use during pregnancy or
breastfeeding. The World Health Organization-Up-
psala Monitoring Centre system was selected to
guide the evaluation of causality via parameters
including time to onset, clinical plausibility, de-
challenge, and rechallenge [24]. Cumulative data
reported over a16-year period (from 1st October
2004 through December 31, 2019) were carefully
evaluated and correlated with extrapolated con-
sumer exposure to the RYR food supplement line.
Results
An estimated total of 2,287,449 consumers
from 16 countries (Italy, Spain, Ireland, Germany,
Greece, Belgium, Luxemburg, Malta, Hungary, Po-
land, Russia, Belarus, Ukraine, Thailand, Singapore
and Taiwan) took the recommended 1 tablet per
day of the Armolipid RYR-based nutraceutical con-
tinuously for 1 year. This number was calculated
from an estimated annual exposure based on the
834,918,819 tablets manufactured in the Europe-
an Union from the time of initial marketing in Oc-
tober 2004 through December 31, 2019, and the
recommended dose of 1 tablet per day. The data-
base accumulated 542 spontaneous case reports,
estimated to equate to 542 consumers, with 855
suspected AEs. Consumers who reported ≥ 1 AEs
with respect to use of the RYR were 0.0237% of
the 1-year exposed consumers.
The percentage of any-cause AEs in associa-
tion with RYR was 0.0374% of the 1-year exposed
consumers (Table I). The majority of reported AEs
were nonserious, with atotal of 829 in 855 sus-
pected AEs, which was 97% of all the AEs and
comprised a0.0362% prevalence in the exposed
consumers. Atotal of 26 initial SAEs were record-
ed, received in 21 case reports with ≥ 1 SAEs.
The 21 cases related to 21 different consumers,
comprising 0.0009% of the exposed consumers.
Based on the 26 SAEs, aSAE prevalence equal to
0.0011% of exposed consumers was estimated.

Maciej Banach, Niki Katsiki, Gustavs Latkovskis, Manfredi Rizzo, Daniel Pella, Peter E. Penson, Zeljko Reiner, Arrigo FG Cicero
4 Arch Med Sci
Upon further evaluation, only 6 of the 26 SAEs
qualified as serious reactions (fulfilling the estab-
lished definition) and reactions, in which the food
supplement could not be excluded as the cause.
This resulted in aSAE frequency of 0.0003% of ex-
posed consumers.
GI AEs were the most commonly reported
(293/855), constituting 34.3% of the AEs and
0.0128% of the RYR-based nutraceutical-exposed
consumers. GI-related events included in the
21 case reports of SAEs included reports of diarrhea,
vomiting, nausea with vomiting, lipedema, and
1 of intestinal obstruction that was later suspected
to be constipation, as it did not require hospital-
ization and resolved with laxative treatment. The
seriousness of the vomiting/nausea reports were
assessed as questionable, as was the causality of
the lipedema. None of the GI events reported as
serious were confirmed as serious or as resulting
only from exposure to this nutraceutical.
Reports of musculoskeletal disorder AEs fol-
lowed those with GI features in frequency, com-
prising 148 of the 855, or 17.3% of the AEs, and
0.0064% of the RYR-exposed consumers. Of the
musculoskeletal AEs, 2 were serious in nature
but were associated with noncompliance with
the recommendations on the supplement’s label.
Rhabdomyolysis was reported in 2 consumers
(1 involved hospitalization), but in both cases the
product’s label warnings were not followed. In the
first of these 2 cases, an elderly woman who was
taking sertraline and rosuvastatin started the en-
hanced RYR supplement without seeking medical
advice. She developed rhabdomyolysis but re-
covered after discontinuing the RYR supplement
and rosuvastatin. The enhanced RYR supplement
label advises against its concomitant use with
other hypolipidemic products. The second case
involved an unknown-gendered consumer who
developed rhabdomyolysis and required hospital-
ization after having started taking the enhanced
RYR supplement without prior medical consulta-
tion. This subject had ahistory of rhabdomyoly-
sis in response to simvastatin, and the enhanced
RYR supplement label advises consumers to con-
sult aphysician to decrease the risk for musculo-
skeletal AEs. Therefore, no case of rhabdomyoly-
sis without concomitant or prior statin exposure
was detected.
Hepatic AEs, including reports of transaminase
alterations, occurred in 26 of the 855 reported AEs,
constituting 3.0% of the AEs and afrequency of
0.0011% in the RYR-exposed consumers. Hepatic
SAEs occurred in 7 patients who were diagnosed
Table I. Armolipid line Red Yeast Rice–Exposed Consumers and Adverse Events
Parameter Number Frequency in exposed
consumers (%)
AEs, total 855 0.0374
Consumers reporting ≥ 1 AEs 542 0.0237
Nonserious AEs 829 0.0362
AEs reported as serious by reporter 26 0.0011
Consumers reporting an SAE 21 0.0009
Consumers reporting SAEs confirmed as serious and unable to exclude
causal relationship
60.0003
GI AEs, total 293 0.0128
GI SAEs (as reported) 50.0002
GI SAEs confirmed as serious and unable to exclude causal relationship 00.0000
Musculoskeletal AEs, total 148 0.0064
Musculoskeletal SAEs (as reported) 20.0001
Musculoskeletal SAEs confirmed as serious and unable to exclude causal
relationship
10.0000
Hepatic AEs (including transaminase alteration), total 26 0.0011
Hepatic SAEs (as reported) 90.0004
Hepatic SAEs confirmed as serious and unable to exclude causal
relationship
30.0001
Other SOC AEs, total 388 0.0170
Other SOC SAEs 50.0002
Other SOC SAEs confirmed as serious and unable to exclude causal
relationship
20.0001
Consumers exposed 2 287 449
AE – adverse event, GI – gastrointestinal, SADR – serious adverse reaction, SOC – system organ class.

Postmarketing nutrivigilance safety profile: aline of dietary food supplements containing red yeast rice for dyslipidemia
Arch Med Sci 5
with serious hepatitis. Causality for one of these
cases, wherein the subject had an unremarkable
medical history and had also been taking ateno-
lol, levothyroxine, and potassium canrenoate, was
considered probable by the reporter. In another
case, the causality was considered by the report-
ing physician to be more likely associated with the
amoxicillin/clavulanic acid antibiotic (with liver in-
jury as aknown adverse drug reaction) also taken
by the consumer. In the other SAE reports, vari-
ous patterns of presentation (i.e., hepatocellular,
cholestatic) were mentioned and the symptoms
resolved spontaneously or after treatments of glu-
tathione, cortisone, or ursodeoxycholic acid. The
latency range in these reports varied widely, from
1 month to 2 years following RYR supplement in-
take, and the range of causality included probable
(in 1 case), possible (in 2 cases), and unlikely (in
2 cases).
The frequency of AEs was calculated, start-
ing from 1st October 2004 through December
31, 2017, then up to December 31, 2019, as
was done for the data previously discussed. Up
to 2017, consumers of the RYR supplement to-
talled 1,613,053, and 300 case reports were re-
ceived mentioning 501 AEs, of which 26 were
reported as SAEs by 21 consumers. These data
were also shared with the EFSA and with the
European Commission Directorate-General for
Health and Food Safety as comments to the sci-
entific opinion drafted and published by the EFSA
on August 31, 2018. Until the end of 2018, ex-
posed consumers increased to 1,912,475 and
case reports increased to 442, for a total of
705 AEs reported. Still, 26 AEs were reported as
serious by 21 consumers. Through the end of
2019, exposed consumers totalled 2,287,449,
with 542 case reports mentioning 855 AEs. Again,
26 AEs were reported as serious by 21 consum-
ers. Despite the increase in case reports, the num-
ber of reports mentioning SAEs has remained
unchanged over the past 3 years. Expanding
the evaluation up to the past 5 years (Figure 1)
showed increases in the number of consumers
exposed and in reported AEs. This could be due to
increased awareness among HCPs and consumers
about the importance of reporting suspected AEs,
and possibly as aconsequence of the EFSA’s pub-
lished opinion. Nocebo, or more correctly drucebo
effect, cannot be also ruled out as areason of ob-
served AEs [26, 27]. Some factors that also may
influence whether an event is reported include
length of time since marketing, market share of
the suspect product, publicity of the product, and
regulatory actions. Also, the mentioned nutriv-
igilance system showed improved effectiveness
over time, with Company’s employees trained to
systematically forward any case report to the cen-
tral office of nutrivigilance.
Discussion
Postmarketing nutrivigilance data showed
a high tolerability of the RYR. The percentage
of any-cause AE reported when taking RYR was
0.0374% of the 1-year-exposed consumers. The
majority of reported AEs were nonserious, with
atotal of 829 of 855, which was 97% of all AEs
and 0.0362% of the exposed consumers. Of the
21 case reports (which comprised 0.0009% of the
accumulated exposed consumers) with ≥ 1 SAEs,
6 qualified as confirmed serious in the nature of
the AE and wherein the RYR could not be excluded
as the cause, an SAE frequency of 0.0003% of the
exposed consumers. The incidence of AEs reported
with the RYR supplement product line were rare to
very rare, whereas they are rare to common with
lovastatin [8].
Up to 2015 Up to 2016 Up to 2017 Up to 2018 Up to 2019
Consumer exposed (millions) AE, total (per millions exposure)
Non serious AE (per million exposure) AE reported as serious by reporter (per million exposure)
AE confirmed as serious as AND whose causality with product cannot be excluded (per million exposure)
Figure 1. Adverse events on millions of exposed consumers
2.5
2.0
1.5
1.0
0.5
0
400
350
300
250
200
150
100
50
0
Consumer exposed (millions)
AE/million consumers exposed

Maciej Banach, Niki Katsiki, Gustavs Latkovskis, Manfredi Rizzo, Daniel Pella, Peter E. Penson, Zeljko Reiner, Arrigo FG Cicero
6 Arch Med Sci
The unchanged number of SAEs over the past
3 years demonstrates that the RYR line is well tol-
erated, with afavorable safety profile when used
in line with the product’s labeling. The Armolipid
RYR line’s consumer package leaflets include rec-
ommendations regarding dosage, contraindicated
conditions (including the concurrent use of drugs
for dyslipidemia), and HCP consultation to avoid
potential musculoskeletal disorder risk.
Based on the best practices of some European
member states (e.g. in Italy, France, and Belgium),
the Armolipid RYR has astandardized minimum
global label warning that can be further extend-
ed based on local authorities’ requirements: “Do
not exceed the recommended daily dose. Keep out
of the reach of young children. Do not use during
pregnancy, lactation or in combination with hypo-
lipidemic drugs. It is advised to consult aphysi-
cian for the product use. Food supplements must
not be considered as substitutes of avaried, bal-
anced diet and a healthy lifestyle. Gastrointesti-
nal disorders and muscular pain may occur taking
(the Armolipid RYR), mainly in subjects intolerant
to statins. Adoctor should be consulted if muscu-
lar pain occurs”.
This evaluation about nutrivigilance had some
limitations and strengths. One of the limitations
was the inclusion of an RYR product line with
adosage of 3 mg of monacolin K; no other dos-
ages have been monitored, as they do not re-
port regular nutrivigilance data. These methods
of reporting cannot be obviously compared with
the pharmacovigilance methods, which are im-
plemented for drugs. However, since no vigilance
measures/reporting are required from Companies
under the current regulations for food supple-
ments/nutraceuticals, we consider this kind of
voluntary reporting a good practice, to be widely
recommended for monitoring of potential adverse
events.
Asurveillance assessment reported acollection
of suspected AEs from the Italian Surveillance
System of Natural Health Products regarding the
potential signs of liver injuries and myopathies
[16]. This assessment can only be considered
qualitatively. In addition, the authors acknowl-
edged the data analyzed had anumber of limita-
tions, primarily the unavailability of sales data for
RYR food supplements because of their regulatory
status (i.e., not reimbursed) [16]. Consequently,
such data were not captured in the standard ad-
ministrative databases to contextualize the num-
ber of reported AEs with participant exposure.
All supplements that were assessed, except one,
contained other natural components than RYR.
According to the surveillance authors, the case
reports contained limited documentation, lacking
information on underlying diseases and suspect-
ed concomitant medications. Of importance, such
information reported spontaneously from these
databases cannot be used to determine incidence
rates of AEs [16].
The present results are therefore relevant in
demonstrating the importance of anutrivigilance
system applied to food supplements when evalu-
ating the safety of products, once product quality
and labeling are established and do not introduce
bias. Scientific societies recommend HCPs select
products from manufacturers that follow high-lev-
el, industry-quality standards [10]. In addition,
HCPs are encouraged to report AEs to companies
[8]. Companies with standardized products and
nutrivigilance systems in place can capture and
analyze AE trends for their own products and con-
firm the products’ labeling or evaluate the need
for additional warnings to increase consumer
awareness.
In conclusion, the implementation of nutrivig-
ilance methods, together with high-quality stan-
dards, including control of contaminants, improve
consumer safety. Moreover, correct labeling with
clearly stated precautions is important for the
availability of comprehensive information to con-
sumers. Anutrivigilance system, capturing infor-
mation spontaneously reported from the markets,
also allows manufacturer to confirm the safety of
products. Based on the evaluation of the cumula-
tive safety data from the manufacturer’s nutrivig-
ilance database, the Armolipid family of RYR sup-
plements has demonstrated that it remains safe,
and an effective support for LDL control, as expert
guidelines recommend, when it is used according
to the instructions on the product label. Compli-
ance with label and/or package leaflet warnings,
as well as with healthcare provider (HCP) recom-
mendations, is essential to AE risk reduction, and
the overall efficacy and safety of food supplement
consumption.
Acknowledgments
We would like to kindly thank to the Meda
Pharma SpA, a Viatris Company (Monza, Italy)
for data sharing and providing some help in their
analysis and interpretation.
Conflict of interest
Dr Banach has received research grant(s)/sup-
port from Amgen, Mylan, Sanofi and Valeant, and
has served as a speaker and consultant for Am-
gen, Daichii Sankyo, Esperion, Freia Pharmaceu-
ticals, Herbapol, Kogen, KRKA, Mylan, Novartis,
Novo Nordisk, Polpharma, Polfarmex, Regeneron,
Sanofi-Aventis, Servier, Zentiva; Dr Katsiki has
given talks, attended conferences and participat-
ed in trials sponsored by Astra Zeneca, Bausch

Postmarketing nutrivigilance safety profile: aline of dietary food supplements containing red yeast rice for dyslipidemia
Arch Med Sci 7
Health, Boehringer Ingelheim, Elpen, Menarini,
Mylan, Novo Nordisk, Sanofi, Servier and Vianex;
Dr. Latkovskis reports grants, honoraria or non-fi-
nancial support from Abbott Laboratories, Amgen,
Astra-Zeneca, Bayer, Berlin-Chemie/Menarini,
Boehringer Ingelheim, GlaxoSmithKline, KRKA,
Mylan, Novartis, Novo Nordisk, Pfizer, Roche Diag-
nostics, Sanofi-Aventis, Servier, Siemens Health-
care, Zentiva; Dr Rizzo has given lectures, received
honoraria and research support, and participated
in conferences, advisory boards and clinical trials
sponsored by many pharmaceutical companies
including Amgen, AstraZeneca, Boehringer Ingel-
heim, Kowa, Eli Lilly, Meda, Merck Sharp & Dohme,
Mylan, Novo Nordisk, Novartis, Roche Diagnostics,
Sanofi and Servier; he is currently Medical Director,
Novo Nordisk BA LM; Dr Penson owns four shares
in AstraZeneca PLC and has received honoraria
and/or travel reimbursement for events sponsored
by AKCEA, Amgen, AMRYT, Link Medical, Napp and
Sanofi; Dr Reiner has received honoraria from Sa-
nofi and Novartis. Dr Cicero is ascientific consul-
tant for Meda-Mylan SpA, Sharper SpA and Mena-
rini IFR; Dr Pella has nothing to declare.
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