1. Introduction or pharmacovigilance), (iii) hypersensitivity, allergic and idiosyncratic reactions (detectable by pharmacovigilance), (iv) mid-term and long-term toxic effects including liver, renal, cardiac and neurotoxicity also genotoxicity and teratogenicity (detectable by in vitro and in viv...
1.Introduction
Pharmacovigilance is defined as ‘the study of the safety of marketed drugs or pharmacovigilance), (iii) hypersensitivity, allergic and idiosyncratic reactions
under the practical conditions of clinical usage in large communities’ (Mann and (detectable by pharmacovigilance), (iv) mid-term and long-term toxic effects
Andrews, 2002). The objective is to extend safety monitoring and detect drug including liver, renal, cardiac and neurotoxicity also genotoxicity and
adverse events that have previously been unrecognised despite evaluation in teratogenicity (detectable by in vitro and in vivo toxicological studies or by
clinical trials. Although these methods were developed for monitoring pharmacovigilance). As many herbal products on the market have not been
pharmaceutical medicines they are also used for additional evaluation of the thoroughly testedfortheirpharmacologyandtoxicology,pharmacovigilance has
safetyofothermedicinalproductsincludingherbals,blood products,vaccinesand paramountimportanceindetectingunwantedreactions.
evenmedicaldevices. In addition there is an ongoing problem with unexpected toxicity of herbal
As the use of herbal medicines has increased, so too have the reports of products due to quality issues, including use of poor quality herbal material,
suspected toxicity and adverse events. Such unwanted reactions can be due to (i) incorrect or misidentified herbs, incorrect processing methods, supply of
side effects (usually detectable by pharmacodynamics and often predictable); (ii) adulterated or contaminated herbs or products (Shaw, 2010a). These quality
reactionsoccurringasaresultofoverdose,overduration,tolerance, dependence- issues can be addressed to some degree by improved regulation requiring GMP
addiction (detectableeitherbypharmacodynamics standards for manufacturing. However medicinal herbs/products come from
many countries with differing manufacturing standards and enforcement of
regulationssopoorqualityproductsarelikely toremainaproblem.
The safety of herbal medicines has become an issue for the regulatory
Correspondingauthor.
authorities,asseriouseffectshavebeenreported, including hepatotoxicity,renal
∗
failure and allergic reactions (Perharic et al., 1995; Nortier and Vanherweghem,
2007). The World Health Organisation, recognising the growing importance of the
useofherbal
, / treator preventdiseaseorcontainapharmacologicallyactivesubstance. Thiscanbe
a complex area with the same herb being supplied as a herbal medicine but also as an
medicines worldwide developed guidelines for the monitoring of herbal safety ingredient in a dietary supplement. There are regulatory implications. In Europe,
withintheexistingpharmacovigilanceframework (WHO,2004). herbal medicines are registered under two directives, either ‘well-established use’
or ‘traditional herbal medicinal products’ both of which have significant
2. Challengesofherbalpharmacovigilance requirements for quality (GMP) and safety (amongst others). Food supplements do
nothavethesamelegalrequirements for qualitycontrol.
Herbal medicines in Europe come from all traditions including Chinese, Indian, The definition of a herbal product as a food or medicine may therefore have
north and south American and African systems as well as that of European systems. considerableimpactforpharmacovigilance.
This diversity adds to the challenges of herbal pharmacovigilance including basic
questions such as defining the most appropriate herb naming system (botanical, 2.2.Nomenclatureandwhatwasused
common, pharmaceuticalnameorherbaldrug name)andvalidationof the botanical
identity of the herbal ingredients. These are not normally an issue with monitoring Adverse reaction reports, whether submitted to regulatory authorities or
synthetic medicines. Some of these questions, such as naming issues or published in the medical literature, are meaningless if the medicinal herb(s) or
adulterations, do not fit easily into the existing systems of pharmacovigilance or the ingredientsina product cannotbe identified. Namesformedicinalherbsinclude
electronicdata systemsthatweredevelopedforpharmaceuticals (DynPage, UMC). the Latin scientific name, the common or vernacular name, the pharmaceutical
However, although some modifications may be needed, developing separate name or pharmacopoeal name or the specific herbal drug names (as used in
systems for herbals is not the answer as this is likely to add complications and cause Traditional Chinese Medicine (TCM)). Herbal prescriptions, product packaging
confusion if different forms or systems are used with the risk of reducing reporting or labels may have one or more of these ( occasionally no label) depending on
ratesfurther(Menniti-Ippolitoetal.,2008).Asagoodexampleof harmonisation,the source and regulatory status of the product. These have to be interpreted with
Uppsala Monitoring Centre (UMC) takes ADR reports from over 100 countries careaseventhescientificnames mayhavesynonyms.
around the world and in 2010 their database contained over 4 million reports, of
The common or vernacular name is the least precise and the same name may
whichapprox 21,000 includedherbalornaturalproducts(UMC, 2011).These areall
be used for plants from different genera or species and so should be avoided if
incorporated in a single database with review of suspected signals carried out by
possible. In Europe and US however, the common name is frequently the term of
expertsinrelevantfields.
reference, although the EU guidelines require the Latin scientific name on the
labelling. If the product is of pharmacopoeial quality then the identity of the
2.1.Specificchallenges species and plant part will be defined in the European Pharmacopoeia (PhEur).
The common name may be misleading or confusing if used on crude plant
Unlike synthetic medicines, herbal medicines are typically chemically rich and material or unlicensed herbal medicines that are not PhEur compliant. To avoid
complex products and not isolated single compounds. A number of factors can ambiguity it is desirable that the genus, species and part of the plant are listed
influencethequalitativeand quantitativechemicalprofileincluding: somewhereontheproduct orpackagingofthecrudematerial.
Unfortunately a botanically correct label does not necessarily confirm that
•
Geographical origin – climate, soil, photoperiod. the product contains what is listed on the label. In cases of serious adverse
reactions where specific toxins are suspected then laboratory analysis of the
product/herbmaybeadvisableto verifythereports.
•
Genotype.
•
Parts of the plant – leaves, stems, root, root bark, etc. 2.2.1.Initiativestoaddressnomenclatureandqualityissues
There is currently no single reference list of medicinal plants which presents
• anauthoritative view ontheircurrent scientific nameand linking allsynonyms of
Harvesting time (year, season, time of day) and conditions.
those plants that are found in the literature. The only names that are
standardised are Latin scientific names (e.g. Bupleurum chinense DC.); their
• standardisation is achieved though the ‘International Code of Nomenclature of
Storage, processing, extraction.
algae, fungi,andplants’(ICNformerlyICBN).
A new initiative, theMedicinalPlantsNamesIndex( MPNI ) underway atthe
•
Combinations of herbs and/or processing of the combined herbs Royal Botanic Gardens Kew will address this issue
asmedicines. (http://www.kew.org/science-research-data/directory/
projects/MPNI.htm). Working with a wide range of stakeholders, one of this
Asstandardisation ofherbsrelativetotheactivecompoundsis rarelyperformed, project’s main aims is to develop an authoritative index to scientific plant names
this intrinsic variability results in products that may be quite different and not mapped to frequently used vernacular, trade and pharmacopoeia names in
necessarilybioequivalentevenwhen fromthesamesingleherbalingredients(Loew order to support the development of global, industry-wide medicinal data
D.Shaw etal./Journal ofEthnopharmacology 140 (2012) 513–518 515
and Kaszkin, 2002). Combining reports of adverse effects (or efficacy) requires standards. This is a 3-year project (funded by Wellcome Trust) and will be
careful evaluation of the differences or similarities of the chemistry or biological accessed freely over the internet with a range of other information services
activity; however, if looking for safety signals for further investigation then a beingdevelopedtailoredtodifferentneeds.
potentially useful approach might be to study groups of herbs containing similar The UMC has worked with the Royal Botanic Gardens Kew and Uppsala
compounds. University to develop appropriate standardisation and cross-referencing of
herbal names for their database to enable international reporting of herbal
2.1.1.Herbalmedicinesanddietarysupplements ADRs. Review of potential signals in the UMC database clearly shows the
The classification and regulation of herbal products may vary between different challenges and issues of herbal pharmacovigilance, from identifying what was
countries/jurisdictions. In the EU they are classified as herbal medicines (regulatory used (plant, plant part, extract, dose) to clinical information available from
implications) with requirements for safety and quality standards. Some herbs may different countries. The UMC has subsequently developed the WHO Herbal
be supplied as food supplements. In the US, herbal products are classified as dietary Dictionary an international reference source of herbal products designed to be
supplements or botanicals, not medicines. Quality will vary although GMP usedforcodingandanalysisofdrugsafetydata bothpreandpostmarketing.
requirements were issued by the FDA in 2007. Pharmacovigilance reporting is not There are a number of initiatives to address herbal identification and set
compulsoryformanufacturers. quality standards. In addition to individual country pharmacopoeias (e.g. British
There are subtleties in the legal differentiation between food supplement and Pharmacopoeia) the European Pharmacopoeia has an extensive programme of
herbal medicine. But broadly a medicinal product is defined as ‘any substance or herbal monographs under development including herbs from China and the
combination of substances presented as having properties for treating or Indian sub-continent. In addition the European Medicines Agency is also
preventing disease in human beings’. In contrast a food supplement cannot claim to
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