FARMACIA, 2019, Vol.

67, 3
https://doi.org/10.31925/farmacia.2019.3.24 ORIGINAL ARTICLE

NUTRIVIGILANCE: A NEW ACTIVITY IN THE FIELD OF DIETARY

SUPPLEMENTS

CLAUDIU MORGOVAN 1,2#, STELIANA GHIBU 3*, ANCA MARIA JUNCAN 2#, LUCA LIVIU
RUS 2#, ANCA BUTUCĂ 2, LOREDANA VONICA 2, ANDREI MUNTEAN 2, LIANA MOŞ 4,
FELICIA GLIGOR 2, NELI-KINGA OLAH 1
1
“Vasile Goldiş” Western University, Faculty of Pharmacy, 86 Liviu Rebreanu Street, Arad, Romania
2
“Lucian Blaga” University, Faculty of Medicine, Preclinical Department, 2A Lucian Blaga Street, Sibiu, Romania
3
“Iuliu Haţieganu” University of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacology, Physiology
and Pathophysiology, 8 Victor Babeş Street, Cluj-Napoca, Romania
4
“Vasile Goldiş” Western University, Faculty of Medicine, 86 Liviu Rebreanu Street, Arad, Romania

*corresponding author: stelianaghibu@yahoo.com

#
Authors with equal contributions
Manuscript received: October 2018

Abstract
Dietary supplements (DS) used to improve the quality of life, can produce adverse events, either as a result of inappropriate
consumption, or as the intrinsic properties of active compounds, either as drug-dietary supplement interactions or due to
contaminations or adulterations. The European legislation, including the Romanian legislation doesn’t refer to all types of
DS, and even more it doesn’t contain any regulations regarding detecting, monitoring or reporting adverse events. In the last
years, some countries (USA, France, Czech Republic) started the nutrivigilance, a scientific support in order to identify the
possible adverse effects of DS and to enhance consumer safety, necessary for detection, understanding and prevention of
adverse events related to the use of DS, a major public health risk, which can lead to an inappropriate practice and may
eventually be harmful to patients’ lives. This study highlights the necessity to introduce the nutrivigilance as a habitual
practice and activity of all authorities and actors from the Romanian dietary supplements’ market, due the increase of dietary
supplements consumption and their risks for the people’s health.

Rezumat
Utilizate cu scopul de a creşte calitatea vieţii, suplimentele alimentare pot cauza reacţii adverse, fie ca urmare a consumului
inadecvat sau din cauza proprietăţilor intrinseci ale compuşilor activi conţinuţi, fie datorită interacţiunilor medicament – supliment
alimentar, sau chiar a contaminării sau falsificării lor. Legislaţia europeană, inclusiv cea românească, nu reglementează toate
categoriile de suplimente, şi cu atât mai mult nu conţine aspecte privind detectarea, monitorizarea şi raportarea reacțiilor
adverse cauzate de acestea. In ultimii ani, câteva state (SUA, Franţa, Cehia etc.) au introdus nutrivigilenţa, o nouă ştiinţă şi
activitate necesară pentru detectarea, evaluarea, înţelegerea şi prevenirea efectelor adverse produse de suplimentele
alimentare. Lucrarea de faţă doreşte să evidenţieze necesitatea introducerii nutrivigilenţei ca o practică şi activitate
permanentă a tuturor autorităţilor şi actorilor implicaţi în piaţa suplimentelor alimentare din România, ca urmare a tendinţei
de creştere accelerată a consumului acestora, dar şi a riscurilor pe care aceste produse le pot avea pentru sănătatea populaţiei.

Keywords: nutrivigilance, dietary supplements, adverse events, legislation and regulations

Introduction epilepsy, respiratory or digestive disease etc. [20, 34,

36, 62] determined people to use more and more
Nowadays, the modern human being has new standards
natural products as adjuvant therapy, or for prevention
regarding their personal life, like having good
or correction of some biological imbalances. In some
health status or increasing their quality of life. The
cases, the DS can partially replace the high amount of
daily stress, food habits, sedentary lifestyle and the
prescribed drugs (non-steroidal anti-inflammatory
pollution are the main factors which can lead to a
drugs, antihypertensive drugs, statins, oral antidiabetics,
suboptimal state of health. This can be attenuated or
gastrointestinal agents etc.) [1, 5, 6, 22, 59], for limiting
reduced by the use of dietary supplements (DS) [10, 60].
the risks of drugs adverse reactions. Today, when
The demand for these products shows an increasing
the pharmaceutical market registers a lot of tensions,
trend all over the world. The DS market makes a fast
the development of the health products trade (drugs,
development, so, drugs manufacturers identified a
DS, cosmetics, medical devices etc.) is a good
good opportunity for their business, in this segment.
opportunity to improve the economic efficacy of
The increasing prevalence of different pathologies
the pharmacies. Thus, this business determines an
such as cardiovascular diseases, cancers, diabetes,
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increase in the turnover, in the net profit and also in products’ authorization procedure by a notification
the cash flow obtained by pharmacies [35]. [15, 16, 47]. It should be mentioned that even if DS
are foodstuffs, the specific legislation regarding the
Materials and Methods food labelling or advertising [46] doesn’t refer entirely
to DS. The EU authorities launched a process
In this study there were analysed the main
evaluation of all possible foodstuffs components, in
regulations about DS from European Union (EU) and
order to establish which kind of health-related claims
Romania: a) Directive 2002/46 EC; b) Regulation
can be approved to be written on the products’
(EU) no. 432/2012; c) Law 491/2003 republished in
labels. The result of this process was the issue of a
2011; d) Joint Order no. 244/401/2005 of Ministry
new EU Regulation (432/2012) that established the
of Agriculture, Forests and Rural Development and
wording of the health claims for all vitamins and
Ministry of Health; e) Joint Order no. 1228/2005/
minerals and respectively for a few other usual nutrients
63/244/2006 of the Ministry of Agriculture, President
[48]. At the same time, this process has shown how
of the National Sanitary Veterinary and Food Safety
difficult it is to evaluate the botanicals, from the
Authority and Ministry of Health; f) Order no. 1069/
same point of view as the vitamins and minerals.
2007 of the Ministry of Health; g) Order no. 1946/
However, we are still missing a unitary legislation
2014 of Ministry of Agricultures and Rural Development
or requirements for botanical-origin DS.
[15, 30, 40-43, 48]. This research has been carried out
At the moment, in Romania, the specific legislation of
employing the comparative method and interpretation
DS includes many normative acts (Table I). Thus,
method [9, 10] of the regulations from this field.
the legislative aspects referring to DS from medicinal
plants and hive products was regulated through the
Results and Discussion
republished Law no. 491/2003 [30] and through the
Regulations regarding the dietary-supplement activity Joint Order of Ministry of Agriculture, Forests and
The first regulation regarding DS was introduced in Rural Development and Ministry of Health no. 244/
1994, in the US. In this regard, the “Dietary 401 from 2005 [40]. The Joint Order no. 1228/2005/
Supplement Health and Education Act of 1994” 63/244/2006 contains regulations regarding the DS
stipulates that DS are foodstuffs, not drugs [57]. of animal, plant origin and/or their mixtures with
Following this regulation, the EU authorities have vitamins, minerals or other nutritive substances. In
tried to implement some rules for the DS field. this Order, there are established: 1) the DS categories;
Despite all EU Commission’s and the professionals’ 2) the authorization procedure; 3) the labelling and
efforts from over the last 25 years, the field of dietary advertising rules adopted from the foods legislation
supplements is not yet entirely covered by a unitary which shouldn’t overlap with regulations of drugs
legislation to this day. In this regard, the Directive [10, 41]. The legislation regarding DS with minerals
2002/46/EC, approximates the laws of the Member and/or vitamins was adopted in Romania by the
States relating to DS. According to this Directive, Health Minister’s Order no. 1069 from 2007. The
the dietary supplements mean foodstuffs used to Romanian legislation also specifies that a DS is a
supplement the normal diet. Moreover, DS “are product which supplements the normal diet, taken
concentrated sources of nutrients or other substances orally by a healthy person which needs an increase
with a nutritional or physiological effect, alone or in nutrients exogenous intake [42].
in combination, marketed in dose forms”, meaning In the last few years it was introduced the term of
capsules, pastilles, tablets, pills and other similar “novel food” to cover the possibility of introducing
forms, sachets with powder, ampoules with liquids, new food ingredients that are not recognized at this
drops in dispensing bottles, and other similar forms moment as foodstuffs. The new EU and Romanian
of liquids and powders designed to be taken in regulations in this field has the aim to request from
measured small-unit quantities [15]. The DS contain the manufacturers more proofs regarding the safety
a wide range of nutrients or other ingredients: vitamins, and efficacy of these kind of food ingredients before
minerals, amino acids, enzymes, essential fatty acids, they are introduced in usual foods or are marketed
prebiotics, probiotics, botanicals and botanical extracts, as they are [26].
as: Q10 coenzyme, lycopene, inositol, glucosamine, The Romanian DS legislation respects two essential
spirulina etc. [15, 18]. principles: 1) the consumer has not been misled or
These products started to gain market share in the exposed to aggressive trade techniques; 2) any
EU over the last twenty years, after the recognition of affirmation must be clear, exact and justified, and
their nutritional role [18]. At the moment, there is a must allow the consumer to choose the desired and
unitary EU legislation regarding the DS with vitamins appropriate product [10, 37, 40-43]. The DS label is
and minerals. This establishes: 1) the vitamins and not mandatory to contain information referring to
minerals that can be used as DS and their maximal the prevention, treatment or cure of any pathology
quantities; 2) the wording of health-related claims [42, 43].
that can be written on the packages respectively; 3) the
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Table I
Romanian legal background for dietary supplements
Regulatory approach Year Description
− rules for manufacturing of medicinal plants and hive products
2003
− medicinal plants or hive products must be notified at the Institute for
Law no. 491 [30] (republished
Food Bio-Resources Bucharest or at Regional Centre of Public Health
in 2011)
from Cluj-Napoca, Iaşi or Timişoara
Joint Order of Ministry of − list of botanicals that can be used in DS
Agriculture, Forests and Rural − list of herbs and plants prohibited to use in DS
2005
Development and Ministry of − list of cultivated and wild mushrooms that can be used in DS
Health no. 401/244 [40]
− trade in DS which contain animal or herbal products (extracts) or in
Joint Order no. 1228/63/244 of
combination with vitamins and minerals
the Ministry of Agriculture,
− dosage forms of DS and authorization, packing, labelling and advertising
President of the National
2005 rules
Sanitary Veterinary and Food
− the animal or herbal DS must be notified at the Institute for Food Bio-
Safety Authority and Ministry
of Health [41] Resources Bucharest or at the Regional Centre of Public Health from
Cluj-Napoca, Iaşi or Timişoara
− notification of DS consisting exclusively of nutrients (such as vitamins
and minerals), such nutrients being synthetically obtained.
Order of Ministry of Health
2007 − rules regarding DS authorization, packing, labelling and advertising
no. 1069 [42]
− DS (exclusively vitamins or minerals) must be notified at the Ministry of
Health
− the notification procedure of DS which contain animal or herbal
Order of Ministry of
products (extracts), or in combination with vitamins and minerals
Agricultures and Rural 2014
(including external products, hive products, cosmetics etc.)
Development no. 1946 [43]
− the content of the safety report on DS
Government Decision no. 590 − the procedural steps of the consultation process for establishing the status
2018
[26] of novel food

According to Order no. 1946/2014 the notification In 2012, the worldwide market was valued at $82
file has to contain a Product Safety Report filled by a billion (US ~ 28%, Europe ~ 10%). It was estimated
qualified person in pharmacy, toxicology, medicine that the annual growth would be 5 - 6% [56]. In the
or other related field [43]. Even if DS are not drugs, US, there are more than 85,000 products with
the Romanian regulations allow the writing of short vitamins, minerals, botanicals, amino acids, probiotics
health claims on products, but there is no regulation etc. [8]. In 2013, in US, vitamins (32.2%) and
to force manufacturers to demonstrate the efficacy of botanicals (17.1%) were the best-selling DS [19].
DS, claimed on the labels or leaflets. As a result, due More than 36% American DS consumers were over
to the lax manner of notification on these products, 65 years old [56].
their efficacy and safety are exclusively the producers’ In 2015, the value of DS market in Europe was over
responsibility. There are some situations, when the 7.1 billion euros, and in 2020, it is projected to
inefficient, low-quality or unsafe (counterfeited or grow by around 9.5% (at 7.9 billion euros). Following
contaminated) products appeared on the market. the international trend, the DS Romanian market has
Also, in Romania, several instances in which DS been developing over the past years (72.2 million
advertising was misleading have been identified [10]. euros, in 2015). The Eastern European countries are
The evolution of dietary supplements market projected to be the top fastest-growing markets:
The request for DS has been registering a significant Romania (+41%), Turkey (+27%), Bosnia-Herzegovina
growth during the last years, which determined more (+23%), Russia (+21.5%) and Macedonia (+19%)
and more producers to enter in this segment. The [64]. Thus, the Romania represents the most attractive
results of different studies have shown a continuous market, with the greatest potential. Several factors
increasing of the number of healthcare products are contributing to this evolution. For example, the
such as drugs, DS, medical devices, cosmetics etc., people’s attitude towards adopting a healthy life-
on the pharmaceutical market [11, 18, 19, 28, 35]. style has improved due to the increase in the level of
The magazine articles, TV shows, advertising, online education and degree of information. Other causes
forums, blogs or websites, celebrities etc., all offer are the developing of distribution channels and the
information about DS. All these media increase the expansion of DS advertising [10, 56, 60]. The DS
credibility of DS, about their role in the preventive or can be procured from pharmacies, drugstores, super-
curative healthcare and also the DS consumption [56]. markets, specialized shops, the Internet, independent
sellers etc. In this context, the pharmacies role in the
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DS providing is reduced, although the pharmacists substances or b) the interactions between dietary
have the competences to offer appropriate information. supplements and drugs (Table II).
Thus, a study carried out in the US showed that in Other adverse events of DS can be determined by the
2012 only about 18% of DS were sold in pharmacies, adulteration to improving their activity (e.g.: improve
while the rest was sold by supermarkets or hyper- the sexual activity, reduce the articular or neck pain,
markets, specialized retailers, direct selling, Internet lose body weight, improve the athletic performances
or home-selling [56], possibly due to their easy etc.) with pharmacological active substances such as
affordability. steroids, antidepressants, neurostimulants (sibutramine,
Dietary supplements and adverse events a methamphetamine analogue), phenolphthalein,
As it was presented above, DS can be purchased sildenafil analogues etc. [8, 21, 32, 52]. On the other
from different unspecialized places including the hand, the involuntary or incorrect administration of
Internet which represents a comfortable source. some DS which contain prohibited substances (with
Unfortunately, the lack of correct medical information stimulant, doping effects etc.) may cause disqualification
or scientific support for these online-purchased products of the athletes from various competitions [32]. For
represents a major public health risk, which can lead example, three athletes were disqualified from the
to an inappropriate practice and may eventually be 2014 Winter Olympic Games because they used DS
harmful to patients’ lives. The main problems of DS contaminated with 1,3-dimethylamylamin - a sympatho-
intake are represented by several adverse events mimetic substance withdrawn from the market in 1983
(e.g.: hepatic, cardiac, renal, metabolic disorders, [8]. Although the DS are efficient and easily affordable,
neurotoxicity, teratogenicity etc.). An adverse event they can have negative consequences on health, as it
is defined as “any health-related event associated was mentioned above. Because of this, it is necessary
with the use of a dietary supplement that is adverse” to implement a system to prevent and monitore the
[51]. The adverse event can be determined by: a) the adverse events of DS.
intrinsic adverse effects of DS induced by the active
Table II
Adverse effects and drug interactions of some dietary supplement
Substance
Current use Adverse event Interactions with drugs
Medicinal plant
immunomodulatory, gastrointestinal complaints,
Aloe vera
antioxidant, arrhythmias, nephropathies, + antidiabetics → hypoglycaemia
[1, 7, 33]
antibacterial, laxative oedema
Aristolochic acids
joint pain, stomach ache,
Aristolochia sp. Nephropathy
malaria
[25, 52, 53]
Chelidonium majus dyspepsia, irritable bowel
Hepatitis + hormones, anti-inflammatories
[21, 54, 63] syndrome
enzyme inhibitor, acting on CYP3A4 and
antioxidant, P-glycoprotein
anti-tumoural, Interacts with calcium channel blockers,
Citrus sp.
anti-inflammatory, anti- Hyperacidity sedatives etc.
[7, 14, 38]
atherosclerotic, Inhibits the intestinal organic anion
natural preservative transporting polypeptides (OATPs) that
facilitate the drugs absorption
antioxidant, diuretic, dizziness, headache,
Cytisus sp. anxiolytic, antidiabetic, heartbeat changes, leg
[21, 63] antiparasitic weakness, sweating,
sleepiness, mydriasis
antioxidant, immunostimulant,
Echinacea purpurea + lorazepam, pantoprazole →
anti-inflamatory, anti- rash, headache, drowsiness
[1, 13, 24, 31] hallucinations
bacterial, antifungal, antiviral
gastrointestinal complaints, + amitriptyline, and acetaminophen–
Ginkgo biloba ischemic protective
allergic reactions, hydrocodone → seizure
[1, 3, 12, 24, 58] antioxidant
hypotension + warfarin use→ increased risk of bleeding
Green tea extract
+ warfarin, anti-hypertensives → reduces
Camellia sinensis body weight loss liver injury
drug effects
[4, 7, 38, 45, 54]
Hypericin + oral contraceptives, warfarin, omeprazole,
St. John’s wort diarrhoea, vomiting, amiodarone, carbamazepine, alprazolam →
antidepressant, anxiolytic
Hypericum drowsiness, agitation, rash, reduces the clinical efficiency of drugs
perforatum photosensitization + fluoxetine, paroxetine, sertraline,
[1, 3, 7, 12, 13, 29, 58] triptans → serotonin syndrome
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Substance
Current use Adverse event Interactions with drugs
Medicinal plant
Kava extract hepatitis, headache, nausea,
+ alprazolam → increases drug effect
Piper methysticum anxiolytic drowsiness, dyspnoea,
+ levodopa → decreases drug effect
[3, 7, 13, 24, 29] pruritus
Lamiaceae sp. With
Antioxidant, inhibits the organic anions transporters
high contents in
hepatoprotective, Hypertension SLC22A6 and SLC22A8, inhibiting
rosmarinic acid
antibacterial some drugs absorption
[21, 39]
Milk thistle
hepatoprotection headache, dizziness, + antiretrovirals, warfarin, diazepam →
Silybum marianum
protein synthesis pruritus, laxative effect decreases drug effect
[3, 21, 55]
Passiflora incarnate anxiolytic, dizziness, confusion + warfarin, antiepileptics → increases
[7, 21] antihypertensive drowsiness drug effect
Saw palmetto extract pruritus, tingling of
used in benign prostatic + hormone therapy → decreases drug
Seronoa repens extremities, nausea
hyperplasia effect
[7, 8, 13, 24] dizziness, vomiting
+ digitalis glycosides → increases
Senna digitalis toxicity
Cassia angustifolia laxative hepatitis + antiarrhythmic → arrhythmias
[21, 54] + indomethacin → decreases the
therapeutic effect of Senna
Usnic acid local irritation,
(a secondary lichen antimicrobial contact dermatitis, + rifampicin → increase drug effect
metabolite) [4, 54] liver injury
vomiting, nausea, agitation,
Valeriana officinalis + antiepileptics, barbiturates → increases
anxiolytic-sedative-hypnotic dizziness, drowsiness,
[7, 13, 29] drug effect
headache
metabolism of skeletal proteinuria, agitation,
Creatine [13] + glucose → increase total muscle mass
muscle vomiting
Lysine (partial 5HT4
receptor antagonist) anxiolytic diarrhoea, abdominal pain
[49]
prevention of cardio-
Omega-3 fatty acids vascular diseases,
gastrointestinal reactions, + anticoagulants → bleeding, bruising
(fish oil, linseed) reduces the production of
dysgeusia + antidepressant → increases drugs effect
[6, 12, 29] PGE2,
antidepressant
Melatonin regulates the circadian + antidepressants → decreases drug
nausea, headache, dizziness
[7, 23, 29] rhythm effect
Magnesium anxiolytic, involves in abdominal pain, + quinolones, tetracycline, nitrofurantoin
[7, 17] metabolic reactions diarrhoea → decreased antibiotic absorption.
relieves symptoms of
Zinc nausea, vomiting, metallic + quinolones, tetracycline → decreased
common colds,
[13, 29] taste, sideroblastic anaemia antibiotic absorption.
CNS functioning
constipating, bloating,
Vitamin D3 and Ca2+ + quinolones, tetracycline →
metallic taste, thirst,
calcium phosphate bone metabolism decreased antibiotic absorption
tiredness, weakness, loss of
[50]
appetite, muscle pain
Vitamin C nausea, pyrosis, diarrhoea, + co-trimoxazole → increases drug
antioxidant
[6, 49, 58] renal calculi absorption
general weakness, dizziness,
Vitamin A well-functioning of skin + isotretinoin, valproic acid → increase
headache, intracranial
[7, 49] antioxidant drug effect
pressure, nausea, vomiting
β-caroten
yellowish skin tinge, slight + simvastatin, niacin → decreases drugs
(provitamin A) inhibits proliferation of cells
diarrhoea effect
[49]
Vitamin E stimulation of fertility, gastric pain, vomiting and + oral anticoagulants, oestrogens →
(α-tocopherol) activation of immune diarrhoea, muscular weakness, bleedings
[7, 49, 58] system rashes, skin inflammations + antidiabetics → hypoglycaemia

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The nutrivigilance activity (10%). The targeted research fields were oncology,
In US, the herbal products are marked as dietary cardiology, and women’s reproductive health [24].
supplements or botanicals. The law covers aspects
regarding the reporting of adverse events to FDA Conclusions
MedWatch scheme, by consumers, manufacturers,
This study presents some aspects that encourage the
distributors, pharmacists etc. [51]. In EU, some herbal
development of nutrivigilance as a main activity in
products can be included on the drugs list, requiring
the dietary supplements field. Its main object is “to
safety and quality standards, and having the obligation
detect, assess, understand or prevent the adverse
to report adverse events. Unlike drugs, DS authorization
events of food, dietary supplements or medical foods”.
does not require any safety studies (preclinical,
In EU, including Romania, there are some regulations
clinical or toxicological). The European legislation
regarding dietary supplements which have been
(including the Romanian legislation) refers only to
changed and improved during the time. However,
their processing, preparing, authorising, trading,
these don’t refer to the detecting, monitoring or
advertising and labelling.
collecting the dietary supplements adverse reactions.
In 2012, Palet et al., proposed that the adverse events’
Taking into account of these aspects, the Romanian
reporting system must be strongly encouraged all
authorities should start the activity of nutrivigilance,
over the world [44]. This system represents the first
following the example other countries. Thus, a major
main step for developing a new domain, Nutrivigilance,
decrease in the risks related to dietary supplement
which is defined as “the science and activities
adverse-events can be achieved with a better
relating to the detection, assessment, understanding
involvement of the pharmacists.
and prevention of adverse events related to the use of
a food, dietary supplement, or medical food” [51].
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