CMDh/223/2005 February 2014 Public Assessment Report Scientific discussion Original Schwedenbitter Riviera - Lösung zum Einnehmen Liquid extract of a mixture of Artemisia absinthium L., herba, Gentiana lutea L., radix, Angelica archangelica L., radix, Acorus calamus L., rhizoma, Potentilla erecta (L.) Raeusch., rhizoma, Commiphora molmol Engler gummi-resina, Taraxacum officinale Weber ex Wigg., radix, Marubium vulgare L., herba, Curcuma zedoaria (Christm.) Roscoe, rhizoma, Juglans regia L., folium, Valeriana officinalis L., radix, Cinnamomum verum J.S.Presl, cortex, Elettaria cardamomum, (L.) Maton, fructus AT/H/0584/001/MR Date: 03.04.2017 This module reflects the scientific discussion for the approval of Original Schwedenbitter Riviera - Lösung zum Einnehmen. The procedure was finalised on 22.03.2017. For information on changes after this date, please refer to the module ‘Update’. 1 I. INTRODUCTION Based on the review of the quality, safety and efficacy data, the Member States have granted a traditional use registration for herbal medicinal product application for Original Schwedenbitter Riviera - Lösung zum Einnehmen, from Riviera Pharma & Cosmetics GmbH. The product is a traditional herbal medicinal product for use in mild dyspepsia (such as feeling of abdominal fullness, flatulence) and loss of appetite. The product is a traditional herbal medicinal product for use in the specified indication exclusively based upon long-standing use. A comprehensive description of the indications and posology is given in the SmPC. The traditional use registration has been granted pursuant to Article 16a of Directive 2001/83/EC. The medicinal product was registered in Austria on 14.09.2009 according to art. 16a of Dir 2001/83 as amended. In Austria the product is in medicinal use since 1977. II. QUALITY ASPECTS II.1 Introduction Original Schwedenbitter Riviera - Lösung zum Einnehmen is an oral solution which is presented in a brown glass bottle. II.2 Drug Substance The active substance in Original Schwedenbitter Riviera - Lösung zum Einnehmen is an extract (as liquid extract) of a mixture of herbal substances from Artemisia absinthium L., herba (wormwood herb), Gentiana lutea L., radix (gentian root), Angelica archangelica L., radix (angelica root), Commiphora molmol Engler, gummi-resina (myrrh), Taraxacum officinale Weber ex Wigg., radix (dandelion root), Curcuma zedoaria (Christm.) Roscoe, rhizoma (zedoary rhizome), Juglans regia L., folium (walnut leaves), Acorus calamus L., rhizoma (calamus rhizome), Potentilla erecta (L.) Raeusch., rhizoma (tormentil), Marubium vulgare L., herba (white horehound), Valeriana officinalis L., radix (valerian root), Cinnamomum verum J.S. Presl, cortex (cinnamon), Elettaria cardamomum (L.) Maton, fructus (cardamom fruit). The specification of the herbal preparation comprises tests regarding identity and physical- chemical parameters only, as the liquid extract is processed continuously to the finished product. The analytical methods are well described and, if necessary, validated. As the liquid extract is processed continuously to the finished product no container closure system and no stability data for the herbal preparation are necessary. 2 II.3 Medicinal Product Original Schwedenbitter Riviera - Lösung zum Einnehmen contains the following excipients: - Ethanol - Nutmeg flavour - Sugar couleur - Purified water This medicinal product contains 38 vol % ethanol (alcohol), i.e. up to 1.5 g per dose (5 ml), equivalent to 37.5 ml beer or 15 ml wine per dose. The development of the product has been sufficiently made and deemed appropriate. The usage of all the excipients has been described. The release specification includes the check of all parameters relevant to this pharmaceutical form. Appropriate data concerning the control of the finished product support the compliance with the release specifications. The packaging of the medicinal product complies with the current legal requirements. Stability studies under ICH conditions have been performed and data presented support the shelf life claimed in the SmPC, with a shelf life of 36 months. The unopened medicinal product does not require any special storage conditions. The pharmaceutical quality of Original Schwedenbitter Riviera - Lösung zum Einnehmen has been adequately shown. II.4 Discussion on chemical, pharmaceutical and biological aspects Information on development, manufacture and control of active substance and medicinal product has been presented in a satisfactory manner. The results of tests carried out indicate satisfactory consistency and uniformity of important product quality characteristics. III. NON-CLINICAL ASPECTS III.1 Pharmacology According to the company and overview of the non-clinical testing strategy specific studies were not performed as the active ingredients have a well know effects according to the presented literature. This is endorsed. III.2 Pharmacokinetics According to the NCO, Original Sweden Bitters (OSB) is a complex drug and the active ingredients are herbs containing numerous substances that influence the organism pharmacokinetic. Thus, description of absorption, distribution, metabolism, plasma binding and excretion cannot be provided. The argumentation of the company regarding pharmacokinetics is acceptable. 3 III.3 Toxicology OSB manufactured by Riviera is a traditional herbal medicinal product. According to NCO all herbs have been used as constituents of herbal remedies for a very long time and have an established pharmacological and toxicological profile. Therefore, no specific studies except an AMES test to exclude mutagenicity of OSB were done. In the NCO the company argues that examinations on bioavailability, pharmacokinetics or the exact way of action are impossible in preparations of multiple herbs with the associated low quantity of every single herb and the complex nature of biological material. This argumentation is considered acceptable. To exclude any risks of mutagenicity an AMES with Salmonella typhimurium was performed according ISO 10993-3; OECD- Guideline 471. The test was performed both as Ames plate incorporation test and as Ames fluctuation assay in microtiter plate format. In both assays, “Original Schwedenbitter Riviera” showed no mutagenic potential. The amount of test substance comprises 0.312 µl (mg) per plate up to 5 µl (mg) per plate for the “plate incorporation assay”. The results show that no mutagenic potential of the “Original Schwedenbitter Riviera” could be detected. A literature search provided in NCO on the herbal constituents did not reveal new information. Thus, OSB manufactured by Riviera is considered to be safe provided for the necessary caution regarding the excipient ethanol. The risks associated with ethanol are well known. Use in alcoholics or in pregnancy and lactation is therefore contraindicated. III.4 Ecotoxicity/environmental risk assessment (ERA) According to the “Guideline on the environmental risk assessment of medicinal products for human use“ (EMEA/CHMP/SWP/4447/00) herbal medicinal products are exempted from environmental risk assessment due to the nature of their constituents. III.5 Discussion on the non-clinical aspects The non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and toxicology is adequate. IV. CLINICAL ASPECTS IV.1 Introduction Original Schwedenbitter Riviera is a bitter extract of herbal substances in 38 % v/v ethanol. The product is a traditional remedy for light gastrointestinal disturbances, therapeutic area: A03 or A09. The targeted indications are light stomach disturbances, loss of appetite, and light digestive disorders. 4 The name "Schwedenbitter (Swedish bitters)" indicates that the product was developed based on the long tradition of comparable products in Europe and thus is a traditional herbal medicinal product. IV.2 Pharmacokinetics Original Sweden Bitters (OSB) is a complex drug and the active ingredients are herbs containing numerous substances that influence the organism pharmacokinetic. Thus, description of absorption, distribution, metabolism, plasma binding and excretion cannot be provided. The argumentation of the company regarding pharmacokinetics is acceptable. According to Article 16 c (1) (a) (iii) of Directive 2001/83/EC, no studies on pharmacokinetics are required for a Traditional Herbal Registration. IV.3 Pharmacodynamics Reference is made to the assessment reports of the applicable European Union Herbal monographs and to other literature sources. The bitter taste is considered the main pharmacological effect. According to Article 16 c (1) (a) (iii) of Directive 2001/83/EC, no studies on pharmacodynamics are required for a Traditional Herbal Registration. IV.4 Clinical efficacy The preparation Original Sweden Bitters (OSB) by Riviera is a traditional herbal medicinal product that consists merely of well-known constituents with an established pharmacological profile. Specific efficacy studies were therefore not done. The approved indication for the traditional herbal medicinal product in the country of origin (Austria) is: Traditional herbal medicine used in slight gastrointestinal disturbances (such as sensation of fullness, flatulence) and loss of appetite. The European Union monographs, standard handbooks as well as Commission E monographs document the medicinal use of the single ingredients for the treatment of gastrointestinal disorders. The evidence on traditional use has been properly demonstrated. Changes in the composition were either due safety considerations or were triggered by national