Safety assessment and adverse drug reaction reporting of tea tree oil (Melaleuca aetheroleum).

Tea tree (Melaleuca alternifolia) essential oil is widely used as an antiseptic. It mainly consists of monoterpenes with terpinen-4-ol as the major constituent. The aim of this study was to review literature on safety data about tea tree oil and to assess its safety by investigating 159 cases of adverse reactions possibly caused by the oil, reported to the World Health Organization (WHO) from December 1987 until September 2021. To extract these data, VigiBase, the WHO global database of individual case safety reports maintained by the Uppsala Monitoring Centre (UMC), was used. All cases were categorized and analysed and 16 serious cases further assessed. It was concluded that tea tree oil should never be administered orally, as it can lead to central nervous system depression and pneumonitis. Applied topically, skin disorders may occur, especially when the oil had been exposed to light or air. This yields monoterpene oxidation products, being potent skin irritants. Tea tree oil stored under appropriate conditions and not exceeding the expiration date should be considered safe to use by non-vulnerable people for non-serious inflammatory skin conditions, although the occurrence of adverse reactions such as contact allergies is difficult to predict.

Red yeast rice (Monascus purpureus) supplements: Case series assessment of spontaneously reported cases to The Netherlands Pharmacovigilance Centre Lareb.

Serious concerns are expressed on the safe use of red yeast rice (RYR) supplements. The aim of the present study was to analyse cases received by Lareb on RYR-related adverse health events. These cases were analysed for the number of reports, number of adverse drug reactions (ADRs), causality, seriousness of the reaction, latency-period, age and sex of the patients, concomitant medication and type of reporter. A total of 94 individual reports were collected by Lareb, corresponding with 187 ADRs. The analysis showed most reported ADRs were labelled musculoskeletal and connective tissue disorders (n = 64), gastrointestinal disorders (n = 33) and general disorders and administration site conditions (n = 23). The use of RYR supplements should be considered as a significant safety concern. Exposure to monacolin K could lead to serious adverse effects. To fully assess the safety profile of RYR supplements, more research is necessary to compose a complete ADR profile of RYR supplements.

Qualitative Interviews with Stakeholders in Herbal Pharmacovigilance and Recommendations for Best Practices to be Applied Worldwide.

BACKGROUND AND OBJECTIVE: The use of herbal products globally is substantial, but varying definitions and regulatory frameworks have led to differences in their status as medicinal products and in approaches to monitoring their safety. This article explores the current landscape of herbal pharmacovigilance, drawing insights from interviews with global experts in the field, and offers recommendations for best practices to enhance the safety and benefit-to-harm balance of herbal products. METHODS: This study comprised semi-structured interviews with members of the International Society of Pharmacovigilance-Herbal and Traditional Medicines Special Interest Group and the Nutrivigilance Information Exchange Network, recruited using purposive sampling. Data were stored and coded using NVIVO® and analysed thematically using a qualitative inductive approach. RESULTS: Sixteen participants from 11 countries were interviewed, revealing diverse regulatory approaches and challenges in herbal pharmacovigilance. Key themes included legal status, awareness, identification and coding of herbal products, pre-/post-marketing product control, reporting of adverse drug reactions, causality assessment and signals of herbal products. This study yielded five general recommendations to further improve herbal pharmacovigilance worldwide. CONCLUSIONS: This study offers an overview of the global landscape of herbal pharmacovigilance, highlighting challenges in monitoring herbal products and presenting universal recommendations. These recommendations encompass increasing awareness, enhancing education and improving legislative frameworks. Given the growing use of herbal products, the implementation of strong pharmacovigilance practices is crucial to ensure consumer safety.

An Indonesian slimming drug with undeclared ingredients causing harm.

This paper reports the presence of undeclared drugs in the herbal slimming supplement Sulami®. The four cases of the adverse drug reactions related to Sulami® were reported to the Dutch Pharmacovigilance Centre (Lareb) or the Dutch Poisons Information Centre (DPIC). The analysis of all four collected samples revealed adulteration with sibutramine and canrenone. Both drugs can cause serious adverse drug reactions. From a legal point of view, it is clear that Sulami® does not meet the legal requirement for safety. As defined in the European General Food Law Regulation, food business operators are responsible for food safety. This also applies to online store owners who sell herbal preparations. Thus, it is clear that it is forbidden to sell Sulami® on the European and Dutch market. Collaboration between involved national authorities makes it possible to identify risky products. This allows the nationally responsible regulators to take targeted action. They can call on users to report sell points what makes it possible to arrest the sellers and confiscate the dangerous products. Beyond the national, also, the European enforcement organizations should take legal measures where possible, to protect public health. The Heads of Food Safety Agencies Working Group on Food Supplements "an Initiative on European level" is a good example of efforts to improve consumer safety.

Analysis of Safety Concerns on Herbal Products with Assumed Phytoestrogenic Activity.

Phytoestrogens (PEs) are plant-based compounds that can interact with estrogen receptors and are mainly used to treat menopausal complaints. However, the safety of products with assumed phytoestrogenic activity is not fully understood. This study aimed to identify plant species with assumed phytoestrogenic activity, review existing literature on their use and safety, and critically evaluate adverse reaction (AR) reports of single-herb, multi-herb, and mixed-multiple products, as submitted to the Netherlands Pharmacovigilance Centre Lareb and to VigiBase of the World Health Organization (WHO). In the Lareb database, the most commonly reported plant species to cause ARs (total of 67 reports) were Actaea racemosa L. (black cohosh) (47.8%), Humulus lupulus L. (hops) (32.8%), and Glycine max (L.) Merr. (soybean) (22.4%). In the VigiBase database (total of 21,944 reports), the top three consisted of Glycine max (L.) Merr. (71.4%), Actaea racemosa L. (11.6%), and Vitex agnus-castus L. (chaste tree) (6.4%). In the scoping review (total of 73 articles), Actaea racemosa L. (30.1%), Glycine max (L.) Merr. (28.8%), and Trifolium pratense L. (13.7%) were the most frequently mentioned plant species. ARs were most frequently reported in the system organ classes "gastrointestinal disorders", "skin and subcutaneous tissue disorders", "reproductive system and breast disorders", and "general disorders and administration site conditions". Furthermore, from the scoping review, it appeared that the use of products with assumed phytoestrogenic activity was associated with postmenopausal bleeding. It was concluded that, while the potential benefits of products with assumed phytoestrogenic activity have been extensively pursued, the potential occurrence of ARs after using these products is less well understood. This study highlights the need for further investigation and careful monitoring of these products to better understand their effects and ensure the safety and well-being of individuals using them.

Governance of nutrivigilance in the Netherlands: Reporting adverse events of non-registered products.

The Dutch Pharmacovigilance Centre Lareb receives an increasing number of reports on products that fall within the grey area of non-registered health-enhancing products, including supplements. Currently, there is no structural vigilance approach to handling these spontaneous reports of suspected adverse events. This explorative study identified whether and how a vigilance framework in the Netherlands can be organised to contribute to consumer protection from adverse reactions to health-enhancing food products. Conducted interviews showed that involved organisations form a complex network, without official governance structures. Organisations lack a legal basis to handling reports, whilst representatives do feel the need to take reports seriously. Interviewees identified various opportunities to improve vigilance, including raising consumer awareness. Following our study, first steps were taken towards improving safety by officially designating Lareb to study adverse events. Further advances to food supplement safety were announced by the Dutch Ministry but have not yet been implemented. With highly differing approaches to governing vigilance in- and outside the EU, it remains necessary to further analyse how nutrivigilance can be organised best to stimulate consumer protection from unsafe substances.

[Dangerous herbal preparations being sold by web shops]. / Gevaarlijke kruidenpreparaten te koop via de webshops.

BACKGROUND: A large number of herbal preparations are offered on the internet. Some of these may contain substances not listed on the label. When these are illegal "regular" drugs, this can lead to serious side effects. CASE DESCRIPTION: In January 2021, The Netherlands Pharmacovigilance Centre Lareb received 4 reports of side effects after using the herbal preparation Montalin® from Indonesia. Laboratory analysis showed that effective amounts of paracetamol and meloxicam were also present in this herbal preparation. These have been added illegally and are not listed on the packaging. The five web shops that sold this product were ordered to immediately stop trading by order of the Dutch Food and Consumer Product Safety Authority (NVWA). CONCLUSION: Consumers should be careful when purchasing herbal preparations over the internet. It is not always clear what is in it. Certainly if a clear effect is experienced, it may be that (illegally) effective amounts of pharmacologically active substances have been added.

Analysis of Reports on Adverse Drug Reactions Related to Herbal Medicinal Products and Herbal Supplements in the Netherlands Received by the National Pharmacovigilance Centre Lareb.

INTRODUCTION: The inclusion of herbal medicinal products and herbal supplements in pharmacovigilance systems is important because a systematic approach of collecting and analyzing adverse drug reactions related to these products will help practitioners, patients, and regulators to gain more knowledge and prevent harm. OBJECTIVE: We aimed to categorize the adverse drug reaction reports on herbal medicinal products and herbal supplements submitted to the Pharmacovigilance Centre Lareb between 1991 and February 2021 on the basis of their regulatory status, herbs included, and adverse drug reactions involved. METHODS: We categorized products on the basis of their registration status and herbal ingredients. The products were then categorized according to the Herbal Anatomical Therapeutic Chemical Classification System. We used descriptive statistics in Microsoft Excel 2019. Pivot tables were used for the analysis and presentation of the data. RESULTS: Until February 2021, a total of 789 reports of herbal medicinal products and herbal supplements were received by Lareb. In these reports, a total of 823 herbal products were labeled as suspect. These products caused a total of 1727 adverse drug reactions. Of the 823 products, 229 were registered as a medicine, and 594 were on the market as a herbal supplement. Of the 823 herbal products, 522 reports concerned single-herb products, 256 reports concerned combination products, 27 reports concerned vitamin products containing herbal ingredients, and 18 reports concerned product issues. Approximately 15% of reports concerned serious adverse drug reactions, and adulterated products harbored a high risk of causing serious adverse drug reactions. CONCLUSIONS: Analysis of the herbal medicinal products and herbal supplements in the Dutch pharmacovigilance database revealed a variety of suspected herbal ingredients. The reports provide insight into the variety of herbal products used in the Netherlands and the adverse reactions associated with their use. Pharmacovigilance of herbal products is essential to ensure their safe use.

Analysis of Hepatobiliary Disorder Reports Associated With the Use of Herbal Medicines in the Global Suspected ADR Database Vigibase.

Introduction: Use of herbal medicines (HMs) is widespread across the world, with many people relying on HMs for their primary healthcare or using HMs in the context of a healthy life style. HMs originate from plant material and, as such, are often seen as "natural" and believed to be (relatively) safe by patients. Hepatobiliary disorders have been associated with numerous HMs. Aim: This paper aims to analyze reporting patterns for hepatobiliary disorders associated with HMs use from reports submitted to the WHO global database of individual case safety reports (ICSRs) VigiBase. Methods: A data extraction in VigiBase, the WHO international database of ICSR reports, was performed by the Uppsala Monitoring Centre on 2019-01-16. The dataset contained all ICSRs where an HM was identified with the UMC-assigned ATC code "V90: unspecified herbal and traditional medicine" and where the HM was classified as being either the suspected drug or an interacting drug, and containing at least one adverse reaction in the MedDRA® System Organ Class (SOC) Hepatobiliary Disorders (HBD). Descriptive analyses in Excel 2013® were used to determine general characteristics of the reports in the broad data set, including total number of reports, reporting country and patient characteristics. For single suspect herbal reports, reports categorized as "serious" according to CIOMS criteria (CIOMS), 2001) were extracted. Results: In total, 2,483 reports describing with at least one ADR in the SOC HBD were extracted from VigiBase. In total, 780 (31.4%) reports concern only one suspect HM. However, for 188 reports of these reports (24.1%), the single suspect herbal preparation contains more than one herbal ingredient. The 592 reports for single suspect herbal preparations described a total of 764 ADRs in the SOC HBD. Jaundice was the most reported ADR for these reports. Conclusion: Almost 2,500 reports for HMs and with at least one ADR coded to the MedDRA® SOC HBD were retrieved from VigiBase. Of the HBD SOC HM reports, around 25% concerned a single herbal species as the suspect "drug." Substantial issues with coding of the suspect herbal drugs were found. In-depth causality assessment of the cases is needed to draw conclusions on the strength of the relationships.

Vitamin B6 in Health Supplements and Neuropathy: Case Series Assessment of Spontaneously Reported Cases.

INTRODUCTION: In the literature, vitamin B6 has been linked to the development of polyneuropathy. Most often, these complaints were seen when taking high doses of vitamin B6 for a long time. Evidence as to whether a lower dosage range of vitamin B6 (< 50 mg/day) can also induce neuropathy is scarce. OBJECTIVE: We aim to comprehensively describe the cases of neuropathy associated with vitamin B6 received by the Netherlands Pharmacovigilance Centre Lareb and to assess the case series concerning the use of vitamin B6 and neuropathic complaints. METHODS: We describe the number and nature of the reported cases, including suspect product, dosage, duration of use, and vitamin B6 serum levels. In addition, we describe the causality for the individual cases (Naranjo Probability Scale) and for the entire case series (Bradford Hill criteria). RESULTS: In total, 90 reports on products containing vitamin B6 included at least one adverse drug reaction in the standardized Medical Dictionary for Regulatory Activities (MedDRA®) query (SMQ; broad) 'peripheral neuropathy'. The amount of vitamin B6 in the products varied between 1.4 and 100 mg per tablet. The serum vitamin B6 level was known in 36 cases (88-4338 nmol/l), and the mean serum vitamin B6 level was 907 nmol/l. However, no statistical correlation between dosage and vitamin B6 blood levels was found. DISCUSSION AND CONCLUSION: Causality assessment of the case series of 90 reports to Lareb shows it is plausible for the vitamin B6 supplements to have caused complaints such as neuropathies. This is especially the case with higher dosages and prolonged use, but dosages < 50 mg/day also cannot be excluded.

Post-Menopausal Vaginal Hemorrhage Related to the Use of a Hop-Containing Phytotherapeutic Product.

Two 54-year-old women developed abdominal cramps and vaginal hemorrhage as a result of endometrial hyperplasia during treatment with a hop-containing phytotherapeutic product (MenoCool®) for post-menopausal complaints. The women used the hop-containing phytotherapeutic product (418 mg of hop per tablet) twice daily (1 and 0.5 tablets by both patient A and B). Patient A developed abdominal cramps and vaginal hemorrhage after 2 months of use. After gynecological examination, she was diagnosed with endometrial hyperplasia. The patient was treated with a curettage. The hop-containing phytotherapeutic product was discontinued, and the patient recovered. Patient B developed abdominal pain/cramps and vaginal hemorrhage after 5 months of use. A cervix smear, internal examination, and ultrasound were performed. Due to the thickness of the endometrium, a pipelle endometrial biopsy was performed. Results showed no indication for cervix cancer. The use of MenoCool® was ceased; follow-up information received from the patient shortly thereafter indicated that she had almost entirely recovered from the abdominal pain/cramps and vaginal hemorrhage. Hop (Humulus lupulus) has phytoestrogenic properties that may be the cause of endometrial hyperplasia and subsequent vaginal hemorrhage. A Naranjo assessment score of 5 was obtained for both cases, indicating a probable relationship between the patient's endometrial proliferation and subsequent vaginal hemorrhage and their use of the suspect drug.