main topic Wien Med Wochenschr DOI 10.1007/s10354-015-0370-9
Drug safety aspects of herbal medicinal products T. Wegener · B. Deitelhoff · A. Silber-Mankowsky
Received: 11 March 2015 / Accepted: 23 June 2015 © Springer-Verlag Wien 2015
Summary There are numerous statements in the literature suggesting that the safety of herbal products or herbal medicinal products is inadequately considered. Despite the presence of risk, the potential is commonly underestimated as herbals are considered to be natural substances. It is necessary to consider the different categories of herbal products in the market. On one hand there are authorised herbal medicinal products (HMPs) which have adhered to the requirements to present data on quality, efficacy and safety. On the other hand there are products falling outside the use of marketing authorisations as for remedies. In the European Union (EU), HMPs are subject to an ambitious and comprehensive risk management system as for chemically defined drugs, which react effectively to risk concerns with scientific methods, as has been shown in the past. The established methods of pharmacovigilance and risk management favour the authorisation of herbal preparations for medicinal purposes as proprietary medicinal drugs. Keywords Herbal medicinal products · Drug safety · Pharmacovigilance · Adverse reactions · Risk management
Arzneimittelsicherheit bei Phytopharmaka Zusammenfassung Regelmäßig findet sich in der Literatur die Aussage, dass die Anwendungssicherheit pflanzlicher Produkte und pflanzlicher Arzneimittel nicht angemessen berücksichtigt werde. Häufig läge ein Risikopotenzial vor, werde jedoch wegen der „Natürlichkeit“ der Pflanzen eher vernachlässigt. Daher sind die unterschiedlichen Produktkategorien pflanzlicher Produkte auf dem Markt zu berücksichtigen: Einerseits als zugelassene Arzneimittel mit der Erfordernis, Daten zur Qualität, Wirksamkeit und Sicherheit vorzulegen, andererseits als Produkte ohne Anforderungen wie für die Arzneimittel. In der EU unterliegen pflanzliche Arzneimittel wie auch Arzneimittel mit chemisch-definierten Wirkstoffen einem anspruchsvollen und umfassenden Risikomanagementsystem, das auf bekannt gewordene Sicherheitsbedenken adäquat reagiert, wie viele Beispiele zeigen können. Die etablierten Verfahren der Pharmakovigilanz und das damit einhergehende Risikomanagement befürwortet die Zulassung pflanzlicher Zubereitungen für medizinische Anwendungen als Arzneimittel. Schlüsselwörter Pflanzliche Arzneimittel · Arzneimittelsicherheit · Pharmakovigilanz · Nebenwirkungen · Risikomanagement
Dr. T. Wegener () · B. Deitelhoff Consulting HMP, Brückstraße 11, 69469 Weinheim, Germany E-mail: [email protected] A. Silber-Mankowsky · Dr. T. Wegener Bremer Pharmacovigilance Service GmbH, Krefelder Straße 34, 28327 Bremen, Germany
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Introduction The use of herbal preparations for medicinal purposes has gained increasing interest worldwide [1–4]. While some patients ask for herbal preparations as an alternative or complement (co-use, administration) to chemically defined substances, other patients use them as they are easy to access, especially in developing countries [3, 5–7]. Herbal medicines are repeatedly stated to be natu-
Drug safety aspects of herbal medicinal products
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main topic Fig. 1 Absolute numbers of papers in Medline on herbal drug safety, retrieved with search terms for ‘herbal medicine’ and ‘adverse reactions or events’ including medical subject heading (MeSH) terms published in the calendar years since 1990
Hits
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ral and therefore safe when compared to chemical medicines [1, 8–15]. It is common knowledge that only a minor percentage of adverse drug reactions (ADR) to medicinal products is reported to companies or authorities with estimated less than 10 % for prescription (chemical) medicines [4, 9]. However, for ‘natural’ medicines this percentage is considered to be even lower. This is assumed to be a result of the perception that herbal medicinal products (HMP) and botanicals are of low risk as they are ‘natural’. This may lead to consumers and patients disregarding any association between their use and any adverse reaction (AR) [10]. Furthermore, consumers and patients are reluctant to inform their healthcare professionals and physicians about their use of such products resulting in lack of awareness of usage [4, 6, 9]. However, there is an increasing awareness of the safety issues for herbal medicines, which can be derived from the absolute number of publications on herbal safety found in the worldwide literature, as retrieved from Medline (Fig. 1). The different product categories and regulations of herbals have an impact on drug safety. If medicinal products are prescribed as single, individual preparations, prescribed by a herbal practitioner or a physician, are self-made or made by a pharmacist for example, and not as a proprietary product, all responsibility lies solely on the recommending person. For example, this is true for the use of traditional Chinese medicine (TCM) as individual prescription [11]. Another product category being dietary supplements brought to the market without health claims, as in the USA for those products the manufacturer probably carries the responsibility for their quality, but there is only limited responsibility for safe use and no responsibility at all for medicinal effects; despite the increasing awareness of safety issues by government and the dietary supplements industry [16]. In the European Union, manufactured herbal products with medicinal claims are considered to be HMPs. All responsibility belongs to the manufacturers and competent authority in charge before, during and after the authorisation process; and all requirements for quality, safety and efficacy are in principle not below those for established pharmaceutical drugs. These requirements are regulated both by
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national drug laws and a harmonised legislation framework which has been established in the European Union (EU) for herbal medicinal products [17, 18].
Regulation of herbal medicinal products in the EU with regard to drug safety The European Union regulates herbal medicinal products with directives 2001/83/EC and 2004/24/EC. Products can only be marketed following a licensing procedure by the regulatory drug authorities. The licensing procedure for HMPs results in sufficient clinical information for proper indications (well-established use, traditional use), as finally reflected in the summary of product characteristics (SPC) and/or patient leaflet [17, 18]. It is suggested that the numerous papers alleging ‘unrecognized’ safety for herbals [2, 8, 12, 17–19, 20] should be viewed in the context of type and regulation of the products. Holders of marketing authorisations, as well as competent authorities, are proactively responsible for ongoing pharmacovigilance (the science relating to the collection, detection, assessment, monitoring and prevention of AR with pharmaceutical products) of those medicinal products they place on the market [17]. In the EU, the quality requirements for conducting the pharmacovigilance tasks are guided by good pharmacovigilance practice (GVP); several GVP documents guide the performance of pharmacovigilance by marketing authorisation holders, the national authorities and the central European Medicines Agency (EMA). A medicinal product is authorised on the basis that in the specified indication at the time of authorisation the risk–benefit balance is judged to be positive for the target population. However, many of the risks associated with the use of a medicinal product will only be discovered and characterised after authorisation. This is also true for herbal medicinal products, for such information continues to increase during marketing. Continuous pharmacovigilance activities are thus required to be established
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in order to improve the safety profile of medicinal products including HMPs.
Operation of pharmacovigilance activities for registered HMPs in the EU Some major changes and decisions in the marketing of HMPs might show that this system of regulation is working effectively.
Cimicifuga Cimicifuga racemosa (black cohosh) rhizoma has been used worldwide for the treatment of menopausal complaints for several decades (e.g. more than 50 years in Germany). Consequently, an incalculably high number of daily dosages has been sold worldwide over the years, and the scientific interest reflects the importance of Cimicifuga preparations [21]. Liver toxicity of unknown frequency has been associated for years with the use of Cimicifuga-containing HMPs [21, 22]. From 2004, there was a discussion on this topic in the European Committee on Herbal Medicinal Products (HMPC) which finally adopted a public statement in 2007, providing recommendations to health care professionals and patients [23]. Various assessments revealed that the majority of cases had been poorly documented, and only a few showed a connection between liver damage or autoimmune hepatitis and an intake of Cimicifuga. No dose dependence or correlation to pathophysiological mechanisms are known to date [23]. Between 2007 and today further cases have been reported; nearly all were poorly documented and not assessable. As stated by the HMPC, the potential risks of HMPs containing C. racemosa can be sufficiently minimised by adequate labelling under ‘duration of use’, ‘contraindications’, ‘special warnings and precautions for use’. In parallel, a German graduated plan regarding pharmacovigilance measures for C. racemosa came into effect in June 2009 [23].
Hypercium For decades, Hypericum perforatum (St John’s Wort) herb has been used for the treatment of depression. Its efficacy has been shown in numerous clinical trials. Starting with some suspected ADR related to drug interactions, it is now well known that Hypericum can change or modify the efficacy of other medications by increasing the expression of cytochrome enzymes and P-glycoprotein [24, 25]. In EU member states, the potential risks to patients were judged to be significant. In the late 1990s, companies started to systematically explore the mechanisms for metabolizing enzyme induction and inhibition, resulting in the undeterminedly high number of clinical and experimental studies available today.
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The product information for registered HMPs has been amended to reflect these identified interactions and products have been voluntarily labelled with appropriate warnings [24]; and the HMPC monograph has been updated [26].
Ginkgo Preparations made from Ginkgo biloba (maidenhair tree) folium are among the most widely used HMPs worldwide for the treatment of cognitive deficits. Since the mid1990s there have been a number of case reports of spontaneous bleeding after taking ginkgo preparations, with most of them lacking substantial background information. These have included cases of postoperative bleeding, intracranial bleeding and bleeding in the liver and gastrointestinal tract. In many of these cases, ginkgo was used concomitantly with other antiplatelet or anticoagulant drugs [27]. An evaluation of case reports for evidence of a causal association between ginkgo use and bleeding, using different causality assessment elements, is difficult and results remain with open questions. For most of the case reports a possible causal association between ginkgo and bleeding events was suggested, but could neither be established nor definitively excluded. Based on meta-analysis of haemostasis outcomes in clinical studies, comparison of mean difference or baseline change between treatment and placebo groups did not indicate a higher bleeding risk associated with G. biloba extracts [27]. This finding ultimately contributes to an informed evaluation of G. biloba use, including patient self-medication [28, 29].
Kava Traditional preparations made from the rhizomes of Piper methysticum (kava) have been used for many centuries primarily among South Pacific islanders for ceremonial reasons. For their anxiolytic and sedative properties HMPs made with ethanolic or acetonic extracts had been registered on the European market [30, 31]. However, since the late 1990s, the intake of kava has been associated with hepatotoxicity. Systematic analyses of clinical cases, including required liver transplants, liver dysfunction and even fatal outcomes, revealed that only a small proportion might be classified as having a possible relationship (without a full assessment due to insufficient data or other potential causes of liver damage). A few cases were assessed as having a certain relationship with kava as the patient improved on withdrawal, but worsened with reintroduction. Many cases could not be evaluated due to lack of sufficient information [30–32]. In a critical review of clinical cases, it was concluded that the major risk factors in the use of kava products are overdose, prolonged treatment and co-medication with synthetic drugs which might cause hepatotoxicity [32].
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However, sales of kava extracts have been prohibited by the authorities in European countries since 2002 following these cases of (serious) hepatotoxicity [30, 31].
Chelidonium Chelidonium majus (greater celandine) rhizoma is used for gastrointestinal complaints. Since the late 1990s, the use of Chelidonium has been linked in a number of case reports to suspected liver injury. According to the HMPC, the WHO database contains more than 50 case reports of the liver-biliary system being affected after intake of medicinal products containing greater celandine [33]. Detailed systematic analyses revealed that the causality was highly probable and probable in only a few cases. In most other cases the causality was only possible or excluded [34]. It was concluded that greater celandine’s hepatotoxicity represents an idiosyncratic reaction of the metabolic type, as immunologic or obligatory hepatotoxic features are lacking. On account of a dose-relationship for the cases concerned, HMPs administered at a daily intake of more than 2.5 mg alkaloids have been withdrawn. As there is no evidence of a clinical use in doses up to and including 2.5 mg of alkaloids, monotherapy products underwent a graduated plan regarding pharmacovigilance measures and had to be withdrawn from the European market [33]. In conclusion, the examples given above clearly show that the system of pharmacovigilance in the EU ensures continued safety monitoring with respect to HMPs. The type, frequency and accumulation of the adverse events (AE) were clearly identified as a signal, and appropriate measures were taken by both marketing authorisation holders and competent authorities.
Quality of (published) case reports on suspected AE of HMPs Looking at the listing of case reports, for example on the hepatotoxicity of Cimicifuga and the distinct evaluation of HMPC in 2006, the majority of the case reports are not of sufficient quality to be finally evaluated as having substantiated evidence of a possible (or even certain) ADR. This is also true for AR reported with other HMPs, as shown in the examples above. In respect to clinical efficacy, a broad scientific consensus exists: Data must be reported and provided to consider an observed reaction or effect as ‘evident’. These requirements conclude with the term ‘evidencebased medicine’. Since the proposal and introduction of this term by Sacket et al. [35] in 1996 there has been an unmanageable discussion in the literature, with fixed guidelines and proposals by regulatory bodies (see e.g. clinical efficacy and safety guidelines at the EMA website) to define exactly the acceptance of observed actions and effects in a product’s indication.
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Table 1 Key elements to consider in reports of adverse events. [36] Patient Demographics
Age group, sex
Current health status
Disease or symptoms being treated with, duration of illness, severity of disease/symptoms, previous therapy
Medical history
Medical history relevant to AE; moreover, alcohol, tobacco, and substance abuse
Physical examination
Abnormal physical or laboratory findings, baseline laboratory findings with normal ranges
Patient disposition
Status of patient
Adverse event
Description of adverse event and its severity, onset (date) or temporal relationship, duration and outcome
Drug Identification
Generic/brand name with strength, product formulation
Herbals
Brand name, latin binomial name of drug(s), used plant part, type of preparation as e.g. extract characteristics on quality
Dosage
Approximate or exact dosage, duration of therapy
Administration
Route of administration
Drug-reaction interface
Therapy duration before appearance of AE
Concomitant therapies
Description of concomitant therapies, including prescription, non-prescription, herbal or complementary medicines including start and stop time/doses of concomitant therapies
Discussion
Presence or absence of evidence supporting a causal link
In the area of clinical safety and tolerability, these requirements of evidence do not clearly exist. It is understandable that there must be a safety guarantee for medicinal products. Manufacturers, as well as regulators, are obliged to guarantee sufficient safety in relation to efficacy and to provide precise information on their product’s safety profile, covering certain or possible ADRs, interactions, intolerability, etc. Therefore, it is understandable that even cases of possible AR to a HMP, not yet defined as ‘certain’, might be of relevance to be communicated to both patients and physicians, especially when they are of potential serious risk to health. Risk management measures might be in some cases be disproportionate and in others careless. The evaluation of relevance will be difficult in some cases and may not be made by substantiated clinical evidence.
Best practice for reporting of (suspected) AE with HMPs To improve scientific evaluation of suspected AEs, various working groups and authors engaged themselves with the problem of inadequate reporting of AR to herbal products. A ‘best practice’ to report data on AE of herbal drugs has been developed [36]. These suggestions cover all the basic information as for chemically defined drugs
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main topic Fig. 2 Distribution of published case reports with herbal products in the worldwide literature with either sufficient/ adequate or insufficient/inadequate information in a subset of 110 cases published in PubMED and EMBASE since 2010; each analysis was done on the provided reference itself
Overall sufficiency of documentation Presence of other risk factors Temporal relationship Drug-reaction interface Route of administration (Daily) dose not indicated/ insufficient
Suspected drug
indicated/ sufficient
Concomitant Drug Medical and other history Demographics 0.00
but with additional information regarding the herbal product used (Table 1).
Reporting of (suspected) AE with herbal products and HMPs in the literature At a first glance, the submission of sufficient information for a case report of a suspected AR in the literature should not cause any problems. However, in reality this obviously still causes difficulties [36–38], and is also true for chemical (conventional) drugs [39]. The quality of published case reports with herbal products has continued to improve over the years [37]. The following figure (Fig. 2) highlights the completeness of key elements in published case reports and their evaluation. The data were derived from a continuous weekly search (conducted from 2010 to 2014) of case reports on AEs published worldwide in Medline or EMBASE. The searches were constructed with search terms for herbal drugs (e.g. binomial plant name, common name) used in Western European herbal medicine combined with search terms for AR or AE. The searches involved database-specific medical subject heading (MeSH) terms, controlled vocabularies and qualifiers. The aim of the searches was to identify cases of suspected serious and nonserious AR to herbal drugs, irrespective of the product categories. The causal relationship between the reported AR and the suspected herbal drug or herbal drug preparation was assessed according to the algorithm of the WHO-UMC Causality Categories (certain, probable/likely, possible, unlikely, unassessable/unclassifiable; the category conditional/unclassified was not used). The database searches retrieved a total of 110 case
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reports, which have all undergone a detailed evaluation based on the paper itself. In the worldwide literature, a high rate of published case reports of AEs suspected to be due to the use of herbal products do not contain sufficient information for a detailed analysis (Fig. 2). Therefore, in many cases the overall sufficiency of documentation has to be stated as ‘insufficient’. With regard to the required evaluation of causality (Fig. 3), about 22 % of cases were ‘unassessable’, a ‘certain’ or ‘probable’ relationship was seen in 4 % and 22 % respectively, whereas 26 % of cases were deemed ‘possible’ with respect to a causative contribution of the suspected herbal products. An analysis of the involved product categories revealed that only 19 % involved HMPs (Fig. 4). There was a high rate (66 %) of cases published from non-EU countries, mainly referring to other product categories (Fig. 5). From the results above, it can be suggested that a high rate of published case reports of suspected AEs to herbal products provide insufficient information, thus hampering the assessment of all relevant aspects. What is conspicuous is the high frequency of reports for herbal products that are not authorized, leaving open questions regarding the aspect of quality. This stresses the assertions repeatedly found in the literature that herbals have an unrecognised toxicity, are dangerous, and of an unknown safety profile. One might differentiate between, on the one hand, the aim to submit a case report on a suspected ADR to a herbal (medicinal) product, even if not all the information is available (to the reporter and/or author), and, on the other hand, the aim to describe a case report of a suspected ADR to a herbal (medicinal) product in order to accuse herbal products of being unsafe, harmful and overestimated. Perhaps the latter reasons are behind the
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main topic Fig. 3 Rating of published cases in respect to the overall causality assessment for herbal products in a subset of 110 cases in the worldwide literature, published in PubMED and EMBASE since 2010
30.00
25.00
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15.00
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5.00
0.00
Certain
90 80 70 60 50 40 30 20 10 0
Herbal Medicinal Products
Herbal products
Fig. 4 Frequency of suspected adverse reactions to herbal medicinal in comparison to other herbal products in a subset of 110 cases in the world-wide literature, published in PubMED and EMBASE since 2010 70
Possible
Unlikely
Unassessable
intention of authors in case reports in which only incomplete data is listed. As so many reports concern non-authorised products, clearly the handling of herbal products as HMPs, which involves the mechanisms of pharmacovigilance including a sufficient risk management of suspected case reports, favours a more scientifically driven management of suspected cases. This might be construed from the given example with a thoroughly guided and traceably documented process of evaluation and decision making on Cimicifuga, involving companies and authorities, and providing information for the safe use of HMPs with specified Cimicifuga preparations as active substance. Another example of a quick regulatory reaction was the decision for the withdrawal of kava-containing HMPs from the market, which however is repeatedly considered to be ahead of time and unnecessary.
Conclusion
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Probable
EU-Cases
Non-EU-Cases
Fig. 5 Frequency of suspected adverse reactions originating from EU countries or non-EU countries in a subset of 110 cases in the world-wide literature, published in PubMED and EMBASE since 2010
It is not correct, as stated repeatedly in the literature, that the safety of herbal (medicinal) products is neglected. This might be true for some countries and for those products marketed as herbal products without authorisation and an established risk management program. The EU pharmacovigilance system for the appropriate control and management of HMPs is above suspicion. In cases of suspected (new) ADRs, companies as well as regulators react in a timely manner, as they are liable for the information provided with an SPC or package leaflet. Therefore, the authorisation of HMPs as proprietary medicinal drugs provides systematic evaluation of safety not below that for established pharmaceutical drugs. Conflict of interest The authors declare that they have no conflict of interest.
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main topic References 1. Bent S. Herbal medicine in the United States: review of efficacy, safety, and regulation: grand rounds at University of California, San Francisco Medical Center. J Gen Intern Med. 2008;23(6):854–9. 2. Jordan SA, Cunningham DG, Marles RJ. Assessment of herbal medicinal products: challenges, and opportunities to increase the knowledge base for safety assessment. Toxicol Appl Pharmacol. 2010;243(2):198–216. 3. Mosihuzzaman M. Herbal medicine in healthcare–an overview. Nat Prod Commun. 2012;7(6):807–12. 4. Shaw D, Graeme L, Pierre D, et al. Pharmacovigilance of herbal medicine. J Ethnopharmacol. 2012;140:513–8. doi:10.1016/j.jep.2012.01.051. (Epub 2012 Feb 9. Review. PubMed PMID: 22342381). 5. Kartal M. Intellectual property protection in the natural product drug discovery, traditional herbal medicine and herbal medicinal products. Phytother Res. 2007;21(2):113–9. 6. Neergheen-Bhujun VS. Underestimating the toxicological challenges associated with the use of herbal medicinal products in developing countries. Biomed Res Int. 2013;2013:804086. doi:10.1155/2013/804086. (Epub 2013 Sep 19). 7. Pan S, Neeraj A, Srivastava KS, et al. A proposal for a quality system for herbal products. J Pharm Sci. 2013;102(12):4230– 41. doi:10.1002/jps.23732. (Epub 2013 Oct 4). 8. Posadzki P, Watson L, Ernst E. Contamination and adulteration of herbal medicinal products (HMPs): an overview of systematic reviews. Eur J Clin Pharmacol. 2013;69(3):295– 307. doi:10.1007/s00228-012-1353-z. (Epub 2012 Jul 29). 9. Walji R, Boon H, Barnes J, et al. Adverse event reporting for herbal medicines: a result of market forces. Healthc Policy. 2009;4(4):77–90. 10. Schnabel K, Binting S, Witt CM, et al. Use of complementary and alternative medicine by older adults— a cross-sectional survey. BMC Geriatr. 2014;14:38. doi:10.1186/1471-2318-14-38. 11. Qu L, Zou W, Zhou Z, et al. Non-European traditional herbal medicines in Europe: a community herbal monograph perspective. J Ethnopharmacol. 2014;156:107–14. 12. Ruparel P, Lockwood B. The quality of commercially available herbal products. Nat Prod Commun. 2011;6(5):733–44. 13. Vickers KA, Jolly KB, Greenfield SM. Herbal medicine: women’s views, knowledge and interaction with doctors: a qualitative study. BMC Complement Altern Med. 2006;6:40. 14. Samojlik I, Mijatovic´ V, Gavaric´ N, et al. Consumers’ attitude towards the use and safety of herbal medicines and herbal dietary supplements in Serbia. Int J Clin Pharm. 2013;35(5):835–40. doi:10.1007/s11096-013-9819-3. (Epub 2013 Jul 3). 15. Marignani M, Gallina S, Di Fonzo M, et al. Use and safety perception of herbal remedies in patients with liver/biliary tract disorders: an Italian study. J Clin Gastroenterol. 2010;44 (Suppl 1):S54–7. doi:10.1097/MCG.0b013e3181e658bb. 16. Ventola CL. Current issues regarding complementary and alternative medicine (CAM) in the United States: part 2: regulatory and safety concerns and proposed governmental policy changes with respect to dietary supplements. P T. 2010;35(9):514–22. 17. Directive. 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (as amended).
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18. Directive. 2004/24/EC of the European Parliament and of the Council of 31 March 2004 amending, as regards traditional herbal medicinal products, Directive 2001/83/EC on the Community code relating to medicinal products for human use (as amended). 19. Zhang J, Wider B, Shang H, et al. Quality of herbal medicines: challenges and solutions. Complement Ther Med. 2012;20(1–2):100–6. doi:10.1016/j.ctim.2011.09.004. (Epub 2011 Nov 1). 20. Ernst E, Pittler MH. Risks associated with herbal medicinal products. Wien Med Wochenschr. 2002;152(7–8):183–9. 21. Naser B, Schnitker J, Minkin MJ, et al. Suspected black cohosh hepatotoxicity: no evidence by meta-analysis of randomized controlled clinical trials for isopropanolic black cohosh extract. Menopause. 2011;18:366–75. 22. Teschke R, Schwarzenboeck A, Schmidt-Taenzer W, et al. Herb induced liver injury presumably caused by black cohosh: a survey of initially purported cases and herbal quality specifications. Ann Hepatol. 2011;10:249–59. 23. Committee on Herbal Medicinal Products (HMPC). Assessment of case reports connected to herbal medicinal products containing Cimicifugae racemosae rhizoma (black cohosh, root). EMEA/HMPC/269258/2006 Rev. 1. 8 May 2007. 24. Henderson L, Yue QY, Bergquist C, et al. St John’s wort (Hypericum perforatum): drug interactions and clinical outcomes. Br J Clin Pharmacol. 2002;54(4):349–56. 25. Unger M. Pharmacokinetic drug interactions by herbal drugs: critical evaluation and clinical relevance. Wien Med Wochenschr. 2010;160:571–7. 26. Committee on Herbal Medicinal Products (HMPC). Community monograph on Hypericum perforatum L., herba. EMA/HMPC/101304/2008. 12 November 2009. 27. Kellermann AJ, Kloft C. Is there a risk of bleeding associated with standardized Ginkgo biloba extract therapy? A systematic review and meta-analysis. Pharmacotherapy. 2011;31(5):490–502. 28. Committee on Herbal Medicinal Products (HMPC). Assessment report on Ginkgo biloba L., folium (draft). EMA/ HMPC/321095/2012. 28 January 2014. 29. Committee on Herbal Medicinal Products (HMPC). Community monograph on Ginkgo biloba L., folium (draft). EMA/HMPC/321097/2012. 28 January 2014. 30. Ketola RA, Viinamäki J, Rasanen I, et al. Fatal kavalactone intoxication by suicidal intravenous injection. Forensic Sci Int. 2015;249:e7–11. doi:10.1016/j.forsciint.2015.01.032. (pii: S0379-0738(15)00046 – 8). 31. Teschke R, Schwarzenboeck A, Hennermann K-H. Kava hepatotoxicity: a clinical survey and critical analysis of 26 suspected cases. Eur J Gastroenterol Hepatol. 2008;20:1182–93. 32. Teschke R, Fuchs J, Bahre R, et al. Kava hepatotoxicity: comparative study of two structured quantitative methods for causality assessment. J Clin Pharm Ther. 2010;35:545–63. 33. Committee on Herbal Medicinal Products (HMPC). Public statement on Chelidonium majus L., herba. EMA/ HMPC/743927/2010. 13 September 2011. 34. Teschke R, Glass X, Schulze J, et al. Suspected greater celandine hepatotoxicity: liver-specific causality evaluation of published case reports from Europe. Eur J Gastroenterol Hepatol. 2012;24:270–80. 35. Sackett DL, Rosenberg WM, Gray JA, et al. Evidence based medicine: what it is and what it isn’t. BMJ. 1996;312(7023):71–2.
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main topic 36. Kelly WN, Arellano FM, Barnes J, et al. International society for pharmacoepidemiology, international society of pharmacovigilance. guidelines for submitting adverse event reports for publication. Drug Saf. 2007;30(5):367–73. 37. Hung SK, Hillier S, Ernst E. Case reports of adverse effects of herbal medicinal products (HMPs): a quality assessment. Phytomedicine. 2011;18(5):335–43. 38. Gardiner P, Adams D, Filippelli AC, et al. A systematic review of the reporting of adverse events associated with medical herb use among children. Glob Adv Health Med. 2013;2(2):46–55.
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39. Impicciatore P, Mucci M. Completeness of published case reports on suspected adverse drug reactions: evaluation of 100 reports from a company safety database. Drug Saf. 2010;33(9):765–73.
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Drug safety aspects of herbal medicinal products T. Wegener · B. Deitelhoff · A. Silber-Mankowsky
Received: 11 March 2015 / Accepted: 23 June 2015 © Springer-Verlag Wien 2015
Summary There are numerous statements in the literature suggesting that the safety of herbal products or herbal medicinal products is inadequately considered. Despite the presence of risk, the potential is commonly underestimated as herbals are considered to be natural substances. It is necessary to consider the different categories of herbal products in the market. On one hand there are authorised herbal medicinal products (HMPs) which have adhered to the requirements to present data on quality, efficacy and safety. On the other hand there are products falling outside the use of marketing authorisations as for remedies. In the European Union (EU), HMPs are subject to an ambitious and comprehensive risk management system as for chemically defined drugs, which react effectively to risk concerns with scientific methods, as has been shown in the past. The established methods of pharmacovigilance and risk management favour the authorisation of herbal preparations for medicinal purposes as proprietary medicinal drugs. Keywords Herbal medicinal products · Drug safety · Pharmacovigilance · Adverse reactions · Risk management
Arzneimittelsicherheit bei Phytopharmaka Zusammenfassung Regelmäßig findet sich in der Literatur die Aussage, dass die Anwendungssicherheit pflanzlicher Produkte und pflanzlicher Arzneimittel nicht angemessen berücksichtigt werde. Häufig läge ein Risikopotenzial vor, werde jedoch wegen der „Natürlichkeit“ der Pflanzen eher vernachlässigt. Daher sind die unterschiedlichen Produktkategorien pflanzlicher Produkte auf dem Markt zu berücksichtigen: Einerseits als zugelassene Arzneimittel mit der Erfordernis, Daten zur Qualität, Wirksamkeit und Sicherheit vorzulegen, andererseits als Produkte ohne Anforderungen wie für die Arzneimittel. In der EU unterliegen pflanzliche Arzneimittel wie auch Arzneimittel mit chemisch-definierten Wirkstoffen einem anspruchsvollen und umfassenden Risikomanagementsystem, das auf bekannt gewordene Sicherheitsbedenken adäquat reagiert, wie viele Beispiele zeigen können. Die etablierten Verfahren der Pharmakovigilanz und das damit einhergehende Risikomanagement befürwortet die Zulassung pflanzlicher Zubereitungen für medizinische Anwendungen als Arzneimittel. Schlüsselwörter Pflanzliche Arzneimittel · Arzneimittelsicherheit · Pharmakovigilanz · Nebenwirkungen · Risikomanagement
Dr. T. Wegener () · B. Deitelhoff Consulting HMP, Brückstraße 11, 69469 Weinheim, Germany E-mail: [email protected] A. Silber-Mankowsky · Dr. T. Wegener Bremer Pharmacovigilance Service GmbH, Krefelder Straße 34, 28327 Bremen, Germany
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Introduction The use of herbal preparations for medicinal purposes has gained increasing interest worldwide [1–4]. While some patients ask for herbal preparations as an alternative or complement (co-use, administration) to chemically defined substances, other patients use them as they are easy to access, especially in developing countries [3, 5–7]. Herbal medicines are repeatedly stated to be natu-
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main topic Fig. 1 Absolute numbers of papers in Medline on herbal drug safety, retrieved with search terms for ‘herbal medicine’ and ‘adverse reactions or events’ including medical subject heading (MeSH) terms published in the calendar years since 1990
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ral and therefore safe when compared to chemical medicines [1, 8–15]. It is common knowledge that only a minor percentage of adverse drug reactions (ADR) to medicinal products is reported to companies or authorities with estimated less than 10 % for prescription (chemical) medicines [4, 9]. However, for ‘natural’ medicines this percentage is considered to be even lower. This is assumed to be a result of the perception that herbal medicinal products (HMP) and botanicals are of low risk as they are ‘natural’. This may lead to consumers and patients disregarding any association between their use and any adverse reaction (AR) [10]. Furthermore, consumers and patients are reluctant to inform their healthcare professionals and physicians about their use of such products resulting in lack of awareness of usage [4, 6, 9]. However, there is an increasing awareness of the safety issues for herbal medicines, which can be derived from the absolute number of publications on herbal safety found in the worldwide literature, as retrieved from Medline (Fig. 1). The different product categories and regulations of herbals have an impact on drug safety. If medicinal products are prescribed as single, individual preparations, prescribed by a herbal practitioner or a physician, are self-made or made by a pharmacist for example, and not as a proprietary product, all responsibility lies solely on the recommending person. For example, this is true for the use of traditional Chinese medicine (TCM) as individual prescription [11]. Another product category being dietary supplements brought to the market without health claims, as in the USA for those products the manufacturer probably carries the responsibility for their quality, but there is only limited responsibility for safe use and no responsibility at all for medicinal effects; despite the increasing awareness of safety issues by government and the dietary supplements industry [16]. In the European Union, manufactured herbal products with medicinal claims are considered to be HMPs. All responsibility belongs to the manufacturers and competent authority in charge before, during and after the authorisation process; and all requirements for quality, safety and efficacy are in principle not below those for established pharmaceutical drugs. These requirements are regulated both by
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national drug laws and a harmonised legislation framework which has been established in the European Union (EU) for herbal medicinal products [17, 18].
Regulation of herbal medicinal products in the EU with regard to drug safety The European Union regulates herbal medicinal products with directives 2001/83/EC and 2004/24/EC. Products can only be marketed following a licensing procedure by the regulatory drug authorities. The licensing procedure for HMPs results in sufficient clinical information for proper indications (well-established use, traditional use), as finally reflected in the summary of product characteristics (SPC) and/or patient leaflet [17, 18]. It is suggested that the numerous papers alleging ‘unrecognized’ safety for herbals [2, 8, 12, 17–19, 20] should be viewed in the context of type and regulation of the products. Holders of marketing authorisations, as well as competent authorities, are proactively responsible for ongoing pharmacovigilance (the science relating to the collection, detection, assessment, monitoring and prevention of AR with pharmaceutical products) of those medicinal products they place on the market [17]. In the EU, the quality requirements for conducting the pharmacovigilance tasks are guided by good pharmacovigilance practice (GVP); several GVP documents guide the performance of pharmacovigilance by marketing authorisation holders, the national authorities and the central European Medicines Agency (EMA). A medicinal product is authorised on the basis that in the specified indication at the time of authorisation the risk–benefit balance is judged to be positive for the target population. However, many of the risks associated with the use of a medicinal product will only be discovered and characterised after authorisation. This is also true for herbal medicinal products, for such information continues to increase during marketing. Continuous pharmacovigilance activities are thus required to be established
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in order to improve the safety profile of medicinal products including HMPs.
Operation of pharmacovigilance activities for registered HMPs in the EU Some major changes and decisions in the marketing of HMPs might show that this system of regulation is working effectively.
Cimicifuga Cimicifuga racemosa (black cohosh) rhizoma has been used worldwide for the treatment of menopausal complaints for several decades (e.g. more than 50 years in Germany). Consequently, an incalculably high number of daily dosages has been sold worldwide over the years, and the scientific interest reflects the importance of Cimicifuga preparations [21]. Liver toxicity of unknown frequency has been associated for years with the use of Cimicifuga-containing HMPs [21, 22]. From 2004, there was a discussion on this topic in the European Committee on Herbal Medicinal Products (HMPC) which finally adopted a public statement in 2007, providing recommendations to health care professionals and patients [23]. Various assessments revealed that the majority of cases had been poorly documented, and only a few showed a connection between liver damage or autoimmune hepatitis and an intake of Cimicifuga. No dose dependence or correlation to pathophysiological mechanisms are known to date [23]. Between 2007 and today further cases have been reported; nearly all were poorly documented and not assessable. As stated by the HMPC, the potential risks of HMPs containing C. racemosa can be sufficiently minimised by adequate labelling under ‘duration of use’, ‘contraindications’, ‘special warnings and precautions for use’. In parallel, a German graduated plan regarding pharmacovigilance measures for C. racemosa came into effect in June 2009 [23].
Hypercium For decades, Hypericum perforatum (St John’s Wort) herb has been used for the treatment of depression. Its efficacy has been shown in numerous clinical trials. Starting with some suspected ADR related to drug interactions, it is now well known that Hypericum can change or modify the efficacy of other medications by increasing the expression of cytochrome enzymes and P-glycoprotein [24, 25]. In EU member states, the potential risks to patients were judged to be significant. In the late 1990s, companies started to systematically explore the mechanisms for metabolizing enzyme induction and inhibition, resulting in the undeterminedly high number of clinical and experimental studies available today.
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The product information for registered HMPs has been amended to reflect these identified interactions and products have been voluntarily labelled with appropriate warnings [24]; and the HMPC monograph has been updated [26].
Ginkgo Preparations made from Ginkgo biloba (maidenhair tree) folium are among the most widely used HMPs worldwide for the treatment of cognitive deficits. Since the mid1990s there have been a number of case reports of spontaneous bleeding after taking ginkgo preparations, with most of them lacking substantial background information. These have included cases of postoperative bleeding, intracranial bleeding and bleeding in the liver and gastrointestinal tract. In many of these cases, ginkgo was used concomitantly with other antiplatelet or anticoagulant drugs [27]. An evaluation of case reports for evidence of a causal association between ginkgo use and bleeding, using different causality assessment elements, is difficult and results remain with open questions. For most of the case reports a possible causal association between ginkgo and bleeding events was suggested, but could neither be established nor definitively excluded. Based on meta-analysis of haemostasis outcomes in clinical studies, comparison of mean difference or baseline change between treatment and placebo groups did not indicate a higher bleeding risk associated with G. biloba extracts [27]. This finding ultimately contributes to an informed evaluation of G. biloba use, including patient self-medication [28, 29].
Kava Traditional preparations made from the rhizomes of Piper methysticum (kava) have been used for many centuries primarily among South Pacific islanders for ceremonial reasons. For their anxiolytic and sedative properties HMPs made with ethanolic or acetonic extracts had been registered on the European market [30, 31]. However, since the late 1990s, the intake of kava has been associated with hepatotoxicity. Systematic analyses of clinical cases, including required liver transplants, liver dysfunction and even fatal outcomes, revealed that only a small proportion might be classified as having a possible relationship (without a full assessment due to insufficient data or other potential causes of liver damage). A few cases were assessed as having a certain relationship with kava as the patient improved on withdrawal, but worsened with reintroduction. Many cases could not be evaluated due to lack of sufficient information [30–32]. In a critical review of clinical cases, it was concluded that the major risk factors in the use of kava products are overdose, prolonged treatment and co-medication with synthetic drugs which might cause hepatotoxicity [32].
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However, sales of kava extracts have been prohibited by the authorities in European countries since 2002 following these cases of (serious) hepatotoxicity [30, 31].
Chelidonium Chelidonium majus (greater celandine) rhizoma is used for gastrointestinal complaints. Since the late 1990s, the use of Chelidonium has been linked in a number of case reports to suspected liver injury. According to the HMPC, the WHO database contains more than 50 case reports of the liver-biliary system being affected after intake of medicinal products containing greater celandine [33]. Detailed systematic analyses revealed that the causality was highly probable and probable in only a few cases. In most other cases the causality was only possible or excluded [34]. It was concluded that greater celandine’s hepatotoxicity represents an idiosyncratic reaction of the metabolic type, as immunologic or obligatory hepatotoxic features are lacking. On account of a dose-relationship for the cases concerned, HMPs administered at a daily intake of more than 2.5 mg alkaloids have been withdrawn. As there is no evidence of a clinical use in doses up to and including 2.5 mg of alkaloids, monotherapy products underwent a graduated plan regarding pharmacovigilance measures and had to be withdrawn from the European market [33]. In conclusion, the examples given above clearly show that the system of pharmacovigilance in the EU ensures continued safety monitoring with respect to HMPs. The type, frequency and accumulation of the adverse events (AE) were clearly identified as a signal, and appropriate measures were taken by both marketing authorisation holders and competent authorities.
Quality of (published) case reports on suspected AE of HMPs Looking at the listing of case reports, for example on the hepatotoxicity of Cimicifuga and the distinct evaluation of HMPC in 2006, the majority of the case reports are not of sufficient quality to be finally evaluated as having substantiated evidence of a possible (or even certain) ADR. This is also true for AR reported with other HMPs, as shown in the examples above. In respect to clinical efficacy, a broad scientific consensus exists: Data must be reported and provided to consider an observed reaction or effect as ‘evident’. These requirements conclude with the term ‘evidencebased medicine’. Since the proposal and introduction of this term by Sacket et al. [35] in 1996 there has been an unmanageable discussion in the literature, with fixed guidelines and proposals by regulatory bodies (see e.g. clinical efficacy and safety guidelines at the EMA website) to define exactly the acceptance of observed actions and effects in a product’s indication.
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Table 1 Key elements to consider in reports of adverse events. [36] Patient Demographics
Age group, sex
Current health status
Disease or symptoms being treated with, duration of illness, severity of disease/symptoms, previous therapy
Medical history
Medical history relevant to AE; moreover, alcohol, tobacco, and substance abuse
Physical examination
Abnormal physical or laboratory findings, baseline laboratory findings with normal ranges
Patient disposition
Status of patient
Adverse event
Description of adverse event and its severity, onset (date) or temporal relationship, duration and outcome
Drug Identification
Generic/brand name with strength, product formulation
Herbals
Brand name, latin binomial name of drug(s), used plant part, type of preparation as e.g. extract characteristics on quality
Dosage
Approximate or exact dosage, duration of therapy
Administration
Route of administration
Drug-reaction interface
Therapy duration before appearance of AE
Concomitant therapies
Description of concomitant therapies, including prescription, non-prescription, herbal or complementary medicines including start and stop time/doses of concomitant therapies
Discussion
Presence or absence of evidence supporting a causal link
In the area of clinical safety and tolerability, these requirements of evidence do not clearly exist. It is understandable that there must be a safety guarantee for medicinal products. Manufacturers, as well as regulators, are obliged to guarantee sufficient safety in relation to efficacy and to provide precise information on their product’s safety profile, covering certain or possible ADRs, interactions, intolerability, etc. Therefore, it is understandable that even cases of possible AR to a HMP, not yet defined as ‘certain’, might be of relevance to be communicated to both patients and physicians, especially when they are of potential serious risk to health. Risk management measures might be in some cases be disproportionate and in others careless. The evaluation of relevance will be difficult in some cases and may not be made by substantiated clinical evidence.
Best practice for reporting of (suspected) AE with HMPs To improve scientific evaluation of suspected AEs, various working groups and authors engaged themselves with the problem of inadequate reporting of AR to herbal products. A ‘best practice’ to report data on AE of herbal drugs has been developed [36]. These suggestions cover all the basic information as for chemically defined drugs
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main topic Fig. 2 Distribution of published case reports with herbal products in the worldwide literature with either sufficient/ adequate or insufficient/inadequate information in a subset of 110 cases published in PubMED and EMBASE since 2010; each analysis was done on the provided reference itself
Overall sufficiency of documentation Presence of other risk factors Temporal relationship Drug-reaction interface Route of administration (Daily) dose not indicated/ insufficient
Suspected drug
indicated/ sufficient
Concomitant Drug Medical and other history Demographics 0.00
but with additional information regarding the herbal product used (Table 1).
Reporting of (suspected) AE with herbal products and HMPs in the literature At a first glance, the submission of sufficient information for a case report of a suspected AR in the literature should not cause any problems. However, in reality this obviously still causes difficulties [36–38], and is also true for chemical (conventional) drugs [39]. The quality of published case reports with herbal products has continued to improve over the years [37]. The following figure (Fig. 2) highlights the completeness of key elements in published case reports and their evaluation. The data were derived from a continuous weekly search (conducted from 2010 to 2014) of case reports on AEs published worldwide in Medline or EMBASE. The searches were constructed with search terms for herbal drugs (e.g. binomial plant name, common name) used in Western European herbal medicine combined with search terms for AR or AE. The searches involved database-specific medical subject heading (MeSH) terms, controlled vocabularies and qualifiers. The aim of the searches was to identify cases of suspected serious and nonserious AR to herbal drugs, irrespective of the product categories. The causal relationship between the reported AR and the suspected herbal drug or herbal drug preparation was assessed according to the algorithm of the WHO-UMC Causality Categories (certain, probable/likely, possible, unlikely, unassessable/unclassifiable; the category conditional/unclassified was not used). The database searches retrieved a total of 110 case
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reports, which have all undergone a detailed evaluation based on the paper itself. In the worldwide literature, a high rate of published case reports of AEs suspected to be due to the use of herbal products do not contain sufficient information for a detailed analysis (Fig. 2). Therefore, in many cases the overall sufficiency of documentation has to be stated as ‘insufficient’. With regard to the required evaluation of causality (Fig. 3), about 22 % of cases were ‘unassessable’, a ‘certain’ or ‘probable’ relationship was seen in 4 % and 22 % respectively, whereas 26 % of cases were deemed ‘possible’ with respect to a causative contribution of the suspected herbal products. An analysis of the involved product categories revealed that only 19 % involved HMPs (Fig. 4). There was a high rate (66 %) of cases published from non-EU countries, mainly referring to other product categories (Fig. 5). From the results above, it can be suggested that a high rate of published case reports of suspected AEs to herbal products provide insufficient information, thus hampering the assessment of all relevant aspects. What is conspicuous is the high frequency of reports for herbal products that are not authorized, leaving open questions regarding the aspect of quality. This stresses the assertions repeatedly found in the literature that herbals have an unrecognised toxicity, are dangerous, and of an unknown safety profile. One might differentiate between, on the one hand, the aim to submit a case report on a suspected ADR to a herbal (medicinal) product, even if not all the information is available (to the reporter and/or author), and, on the other hand, the aim to describe a case report of a suspected ADR to a herbal (medicinal) product in order to accuse herbal products of being unsafe, harmful and overestimated. Perhaps the latter reasons are behind the
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main topic Fig. 3 Rating of published cases in respect to the overall causality assessment for herbal products in a subset of 110 cases in the worldwide literature, published in PubMED and EMBASE since 2010
30.00
25.00
20.00
15.00
10.00
5.00
0.00
Certain
90 80 70 60 50 40 30 20 10 0
Herbal Medicinal Products
Herbal products
Fig. 4 Frequency of suspected adverse reactions to herbal medicinal in comparison to other herbal products in a subset of 110 cases in the world-wide literature, published in PubMED and EMBASE since 2010 70
Possible
Unlikely
Unassessable
intention of authors in case reports in which only incomplete data is listed. As so many reports concern non-authorised products, clearly the handling of herbal products as HMPs, which involves the mechanisms of pharmacovigilance including a sufficient risk management of suspected case reports, favours a more scientifically driven management of suspected cases. This might be construed from the given example with a thoroughly guided and traceably documented process of evaluation and decision making on Cimicifuga, involving companies and authorities, and providing information for the safe use of HMPs with specified Cimicifuga preparations as active substance. Another example of a quick regulatory reaction was the decision for the withdrawal of kava-containing HMPs from the market, which however is repeatedly considered to be ahead of time and unnecessary.
Conclusion
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Probable
EU-Cases
Non-EU-Cases
Fig. 5 Frequency of suspected adverse reactions originating from EU countries or non-EU countries in a subset of 110 cases in the world-wide literature, published in PubMED and EMBASE since 2010
It is not correct, as stated repeatedly in the literature, that the safety of herbal (medicinal) products is neglected. This might be true for some countries and for those products marketed as herbal products without authorisation and an established risk management program. The EU pharmacovigilance system for the appropriate control and management of HMPs is above suspicion. In cases of suspected (new) ADRs, companies as well as regulators react in a timely manner, as they are liable for the information provided with an SPC or package leaflet. Therefore, the authorisation of HMPs as proprietary medicinal drugs provides systematic evaluation of safety not below that for established pharmaceutical drugs. Conflict of interest The authors declare that they have no conflict of interest.
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main topic References 1. Bent S. Herbal medicine in the United States: review of efficacy, safety, and regulation: grand rounds at University of California, San Francisco Medical Center. J Gen Intern Med. 2008;23(6):854–9. 2. Jordan SA, Cunningham DG, Marles RJ. Assessment of herbal medicinal products: challenges, and opportunities to increase the knowledge base for safety assessment. Toxicol Appl Pharmacol. 2010;243(2):198–216. 3. Mosihuzzaman M. Herbal medicine in healthcare–an overview. Nat Prod Commun. 2012;7(6):807–12. 4. Shaw D, Graeme L, Pierre D, et al. Pharmacovigilance of herbal medicine. J Ethnopharmacol. 2012;140:513–8. doi:10.1016/j.jep.2012.01.051. (Epub 2012 Feb 9. Review. PubMed PMID: 22342381). 5. Kartal M. Intellectual property protection in the natural product drug discovery, traditional herbal medicine and herbal medicinal products. Phytother Res. 2007;21(2):113–9. 6. Neergheen-Bhujun VS. Underestimating the toxicological challenges associated with the use of herbal medicinal products in developing countries. Biomed Res Int. 2013;2013:804086. doi:10.1155/2013/804086. (Epub 2013 Sep 19). 7. Pan S, Neeraj A, Srivastava KS, et al. A proposal for a quality system for herbal products. J Pharm Sci. 2013;102(12):4230– 41. doi:10.1002/jps.23732. (Epub 2013 Oct 4). 8. Posadzki P, Watson L, Ernst E. Contamination and adulteration of herbal medicinal products (HMPs): an overview of systematic reviews. Eur J Clin Pharmacol. 2013;69(3):295– 307. doi:10.1007/s00228-012-1353-z. (Epub 2012 Jul 29). 9. Walji R, Boon H, Barnes J, et al. Adverse event reporting for herbal medicines: a result of market forces. Healthc Policy. 2009;4(4):77–90. 10. Schnabel K, Binting S, Witt CM, et al. Use of complementary and alternative medicine by older adults— a cross-sectional survey. BMC Geriatr. 2014;14:38. doi:10.1186/1471-2318-14-38. 11. Qu L, Zou W, Zhou Z, et al. Non-European traditional herbal medicines in Europe: a community herbal monograph perspective. J Ethnopharmacol. 2014;156:107–14. 12. Ruparel P, Lockwood B. The quality of commercially available herbal products. Nat Prod Commun. 2011;6(5):733–44. 13. Vickers KA, Jolly KB, Greenfield SM. Herbal medicine: women’s views, knowledge and interaction with doctors: a qualitative study. BMC Complement Altern Med. 2006;6:40. 14. Samojlik I, Mijatovic´ V, Gavaric´ N, et al. Consumers’ attitude towards the use and safety of herbal medicines and herbal dietary supplements in Serbia. Int J Clin Pharm. 2013;35(5):835–40. doi:10.1007/s11096-013-9819-3. (Epub 2013 Jul 3). 15. Marignani M, Gallina S, Di Fonzo M, et al. Use and safety perception of herbal remedies in patients with liver/biliary tract disorders: an Italian study. J Clin Gastroenterol. 2010;44 (Suppl 1):S54–7. doi:10.1097/MCG.0b013e3181e658bb. 16. Ventola CL. Current issues regarding complementary and alternative medicine (CAM) in the United States: part 2: regulatory and safety concerns and proposed governmental policy changes with respect to dietary supplements. P T. 2010;35(9):514–22. 17. Directive. 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (as amended).
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18. Directive. 2004/24/EC of the European Parliament and of the Council of 31 March 2004 amending, as regards traditional herbal medicinal products, Directive 2001/83/EC on the Community code relating to medicinal products for human use (as amended). 19. Zhang J, Wider B, Shang H, et al. Quality of herbal medicines: challenges and solutions. Complement Ther Med. 2012;20(1–2):100–6. doi:10.1016/j.ctim.2011.09.004. (Epub 2011 Nov 1). 20. Ernst E, Pittler MH. Risks associated with herbal medicinal products. Wien Med Wochenschr. 2002;152(7–8):183–9. 21. Naser B, Schnitker J, Minkin MJ, et al. Suspected black cohosh hepatotoxicity: no evidence by meta-analysis of randomized controlled clinical trials for isopropanolic black cohosh extract. Menopause. 2011;18:366–75. 22. Teschke R, Schwarzenboeck A, Schmidt-Taenzer W, et al. Herb induced liver injury presumably caused by black cohosh: a survey of initially purported cases and herbal quality specifications. Ann Hepatol. 2011;10:249–59. 23. Committee on Herbal Medicinal Products (HMPC). Assessment of case reports connected to herbal medicinal products containing Cimicifugae racemosae rhizoma (black cohosh, root). EMEA/HMPC/269258/2006 Rev. 1. 8 May 2007. 24. Henderson L, Yue QY, Bergquist C, et al. St John’s wort (Hypericum perforatum): drug interactions and clinical outcomes. Br J Clin Pharmacol. 2002;54(4):349–56. 25. Unger M. Pharmacokinetic drug interactions by herbal drugs: critical evaluation and clinical relevance. Wien Med Wochenschr. 2010;160:571–7. 26. Committee on Herbal Medicinal Products (HMPC). Community monograph on Hypericum perforatum L., herba. EMA/HMPC/101304/2008. 12 November 2009. 27. Kellermann AJ, Kloft C. Is there a risk of bleeding associated with standardized Ginkgo biloba extract therapy? A systematic review and meta-analysis. Pharmacotherapy. 2011;31(5):490–502. 28. Committee on Herbal Medicinal Products (HMPC). Assessment report on Ginkgo biloba L., folium (draft). EMA/ HMPC/321095/2012. 28 January 2014. 29. Committee on Herbal Medicinal Products (HMPC). Community monograph on Ginkgo biloba L., folium (draft). EMA/HMPC/321097/2012. 28 January 2014. 30. Ketola RA, Viinamäki J, Rasanen I, et al. Fatal kavalactone intoxication by suicidal intravenous injection. Forensic Sci Int. 2015;249:e7–11. doi:10.1016/j.forsciint.2015.01.032. (pii: S0379-0738(15)00046 – 8). 31. Teschke R, Schwarzenboeck A, Hennermann K-H. Kava hepatotoxicity: a clinical survey and critical analysis of 26 suspected cases. Eur J Gastroenterol Hepatol. 2008;20:1182–93. 32. Teschke R, Fuchs J, Bahre R, et al. Kava hepatotoxicity: comparative study of two structured quantitative methods for causality assessment. J Clin Pharm Ther. 2010;35:545–63. 33. Committee on Herbal Medicinal Products (HMPC). Public statement on Chelidonium majus L., herba. EMA/ HMPC/743927/2010. 13 September 2011. 34. Teschke R, Glass X, Schulze J, et al. Suspected greater celandine hepatotoxicity: liver-specific causality evaluation of published case reports from Europe. Eur J Gastroenterol Hepatol. 2012;24:270–80. 35. Sackett DL, Rosenberg WM, Gray JA, et al. Evidence based medicine: what it is and what it isn’t. BMJ. 1996;312(7023):71–2.
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main topic 36. Kelly WN, Arellano FM, Barnes J, et al. International society for pharmacoepidemiology, international society of pharmacovigilance. guidelines for submitting adverse event reports for publication. Drug Saf. 2007;30(5):367–73. 37. Hung SK, Hillier S, Ernst E. Case reports of adverse effects of herbal medicinal products (HMPs): a quality assessment. Phytomedicine. 2011;18(5):335–43. 38. Gardiner P, Adams D, Filippelli AC, et al. A systematic review of the reporting of adverse events associated with medical herb use among children. Glob Adv Health Med. 2013;2(2):46–55.
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39. Impicciatore P, Mucci M. Completeness of published case reports on suspected adverse drug reactions: evaluation of 100 reports from a company safety database. Drug Saf. 2010;33(9):765–73.
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