Public Assessment Report Scientific discussion Echinagard, oral drops, solution (Echinacea purpurea (L.) Moench, fresh herb, expressed juice (1.7-2.5:1)) Asp no: 2008-0658 This module reflects the scientific discussion for the approval of Echinagard, oral drops, solution. The procedure was finalised 2 December 2009. For information on changes after this date please refer to the module Update. Postadress/Postal address: P.O. Box 26, SE-751 03 Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Phone: +46 (0)18 17 46 00 Fax: +46 (0)18 54 85 66 Internet: www.mpa.se E-mail: registrator@mpa.se
LAY SUMMARY The Medical Products Agency (Läkemedelsverket, MPA) has granted Madaus GmbH, Germany, a marketing authorisation for the herbal medicinal product Echinagard, oral drops, solution. The product is available without prescription and can be bought from pharmacies and other outlets. Echinagard has an extensive medicinal use in the EU for the short-term prevention and treatment of common cold. The active ingredient is the expressed juice of Echinacea purpurea, fresh herb. The Committee on Herbal Medicinal Products (HMPC) of the European Medicines Agency (EMA) has concluded that the active substance in Echinagard has a well-established medicinal use with a recognised efficacy and acceptable level of safety. The chemical/pharmaceutical quality of the product is acceptable and no new or unexpected safety concerns have been identified during the assessment. It was therefore decided that Echinagard could be granted a marketing authorisation as a herbal medicinal product. 2/8
I. INTRODUCTION Madaus GmbH has applied for a marketing authorisation for Echinagard, oral drops, solution. The application was submitted under Article 10a Well-established use application of the Directive 2001/83 EC, as amended. The application is a national application for Sweden. The active substance is the expressed juice from fresh herb of Echinacea purpurea (L.) Moench (purple coneflower/röd solhatt). For approved indications, see the Summary of Product Characteristics (SmPC). Echinagard was first authorised as a natural remedy in 1995. With the new legislation regarding (traditional) herbal medicinal products the product was reclassified as a herbal medicinal product in 2009. II. II.1 QUALITY ASPECTS Introduction Echinagard is presented in the form of oral drops, solution, each ml containing 800 mg of the active substance Echinacea purpurea fresh herb, expressed juice (1.7-2.5:1) corresponding to 1.42.0 fresh herb from Echinacea purpurea (L.) Moench. The excipients are: ethanol and water. All manufacturers involved in the production operate in accordance with EU-GMP, or where relevant, GACP (Good Manufacturing Practice, respectively Good Agricultural and Collection Practice). II.2 Drug Substance Herbal substance: Echinacea purpurea (L.) Moench, fresh herb. Herbal preparation (active substance): Echinacea purpurea fresh herb, expressed juice (1.7-2.5:1). The fresh herbal substance does not have a monograph in the European Pharmacopoeia but is controlled using an in-house specification. The plants used are cultivated in Germany. Relevant information has been provided on growing conditions and controls of the herbal substance (such as residues of heavy metals and pesticides as well as microbiological quality). The herbal substance is ground and pressed. Ethanol is added and after sedimentation the expressed juice is filtered. The manufacturing process has been adequately described and satisfactory specifications have been provided for starting materials and solvents. 3/8
The active substance specification includes relevant tests and the limits for impurities have been justified. The analytical methods applied are suitably described and validated. Stability studies under ICH conditions have been conducted. II.3 Medicinal Product Echinagard, oral drops, solution, is formulated using excipients described in the current European Pharmacopoeia (Ph. Eur.). All raw materials used in the product are safe with view to possible TSE/BSE risk. The manufacturing process has been sufficiently described and critical steps identified. Results from the process validation studies confirm that the process is under control and ensure both batch to batch reproducibility and compliance with the product specification. The tests and limits in the specification are considered appropriate to control the quality of the finished product in relation to its intended purpose. Stability studies under ICH conditions have been performed and data presented support the shelf life claimed in the SPC. III. III.1 NON-CLINICAL ASPECTS Introduction The Committee on Herbal Medicinal Products (HMPC) of the European Medicines Agency (EMA) has issued a Community monograph on Echinacea purpurea (L.) Moench in 2008. In this monograph, it was concluded that the active substance in Echinagard (dried expressed juice from fresh herb of Echinacea purpurea) has a well-established medicinal use with a recognised efficacy and acceptable level of safety in the Community in accordance with Directive 2001/83/EC. The reader is referred to the Community monograph and the pertinent assessment report for details. III.2 Pharmacology The Committee on Herbal Medicinal Products has concluded that expressed juice of Echinacea purpurea has a well-established use for short-term prevention and treatment of common cold. Echinacea purpurea has shown to have an immunostimulating effect (stimulation of phagocytosis by macrophages and natural killer cells activity). According to the HMPC Assessment Report, several different candidate substances from Echinacea have been identified that may contribute to its immunomodulatory effects, including polysaccharides of various sizes, caffeic acid derivatives, alkamides and melanins. The most studied compounds are the polysaccharides, with supporting evidence coming from studies conducted both in vitro and in vivo. Research on the alkamides also indicates a major role for these compounds. Less evidence exists for the immunostimulatory actions of the caffeic acid derivatives. It is very likely that a combination of these and other unknown agents contribute to the overall therapeutic activity of Echinacea products. 4/8
III.3 Pharmacokinetics Constituents responsible for the therapeutic effect of expressed juice from Echinacea purpurea are not entirely known, and thus pharmacokinetic studies are not possible/relevant. III.4 Toxicology Echinacea purpurea and in particular the expressed juice is toxicologically well examined. Different toxicological studies have been performed on expressed juice from fresh herb of Echinacea purpurea, i.e. single-dose toxicity and repeat-dose toxicity studies in rats and genotoxicity studies (Ames test with and without metabolic activation, mammalian cell tests e.g. mouse lymphoma assay and micronucleus test in mice). No signs of toxicological or mutagenic/genotoxic concerns have been detected in the experimental models tested. Tests on reproductive toxicity and on carcinogenicity have not been performed but because of the negative results of the experimental investigations for genotoxicity it is not necessary to carry out long-term carcinogenicity studies in mammals. III.5 Ecotoxicity/environmental risk assessment Echinagard is a herbal medicinal product. According to Guideline on the environmental risk assessment of medicinal products for human use (EMEA/CHMP/SW4447/00), herbal medicinal products are exempted from the obligation to present an environmental risk assessment due to the nature of their constituents. III.6 Discussion on the non-clinical aspects Expressed juice from fresh herb of Echinacea purpurea has been in medicinal use in the Community for a long period of time. The active substance in Echinagard is recognised to have a well-established medicinal use with an acceptable level of safety in the European Community. No serious concerns have been identified. IV. IV.1 CLINICAL ASPECTS Introduction The Committee on Herbal Medicinal Products (HMPC) of the European Medicines Agency (EMA) has issued a Community monograph on Echinacea purpurea (L.) Moench in 2008. In this monograph, it was concluded that the active substance in Echinagard (dried expressed juice from fresh herb of Echinacea purpurea) has a well-established medicinal use with a recognised efficacy and acceptable level of safety in the Community in accordance with Directive 2001/83/EC. According to the Community monograph, the active substance in Echinagard has a wellestablished medicinal use for short-term prevention and treatment of common cold. The reader is referred to the Community monograph and the pertinent assessment report for details. IV.2 Pharmacokinetics 5/8
There are no in-vivo studies concerning pharmacokinetics in humans. The lack of pharmacokinetic data is acceptable since constituents responsible for the therapeutic effect of expressed juice of Echinacea purpurea are not entirely known, and thus pharmacokinetic studies are neither possible nor relevant. IV.3 Pharmacodynamics An immunostimulating effect of Echinacea purpurea has been shown in human studies. The entire herbal preparation (dried expressed juice) is regarded as being the active constituent of Echinagard. IV.4 Clinical efficacy Echinagard fulfils the requirement for well-established use according to the Community monograph. In the assessment report pertaining to the Community monograph on Echinacea purpurea, fresh herb, an extensive review of clinical trials on many different herbal preparations of Echinacea purpurea was presented. Most of the clinical studies are related to the immunological effect and recurrent infections of the upper respiratory tract. Many clinical studies have been published, including meta-analyses and a Cochrane Review (Linde et al. 2006). Despite the fact, that some are not of optimal quality and did not all prove the efficacy of the drug, herbal drug preparations made of Echinacea purpurea can be considered effective in the treatment of respiratory tract infections. IV.5 Clinical safety In the assessment report pertaining to the Community monograph on Echinacea purpurea, herb, hypersensitivity to plants of the Asteraceae family is mentioned as well as severe immune reactions for atopic patients. Echinacea is contraindicated in cases of progressive systemic disorders and autoimmune diseases, immunodeficiencies, immunosuppression and diseases of the white blood cell system such as tuberculosis, leukoses, collagenoses, multiple sclerosis, AIDS or HIV-infections. Due to lack of safety data, the use of products containing expressed juice from fresh herb of Echinacea purpurea during pregnancy and lactation is not recommended. As no safety data on use in children are available, products containing expressed juice from fresh herb of Echinacea purpurea cannot be recommended for use in children aged 1 to 12 years. The use is contraindicated for children below the age of 1 year because their immune system is not fully developed. The use of Echinagard should be restricted to 10 days per treatment session. There are no new signals of safety concern in the submitted product specific documentation relating to Echinagard. IV.6 Discussion on the clinical aspects Echinagard, oral drops, solution is a herbal medicinal product available without prescription to be used for short-term prevention and treatment of common cold. It has been on the market in 6/8
Sweden since 1995. During this time there have been no sales restrictions, i.e. no prescription has been required and sale has been permitted also outside pharmacies. No new risks have been identified that would motivate a different sales status of the product. V. PRODUCT INFORMATION The product information (Summary of Product Characteristics, Package Leaflet and labelling) has been assessed and accepted by the Medical Products Agency. VI. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION According to the Community monograph on Echinacea purpurea, fresh herb, the herbal preparation in Echinagard has a well-established medicinal use with a recognised efficacy and acceptable level of safety for short-term prevention and treatment of common cold. The adverse reactions reported during an extensive use of Echinacea purpurea are no cause for safety concern. No new safety signals have been identified in the submitted product specific documentation relating to Echinagard. The benefit/risk ratio is considered positive and Echinagard, oral drops, solution is recommended for approval. VII. APPROVAL Echinagard, oral drops, solution was approved in the national procedure on 2009-12-02. 7/8
Public Assessment Report Update Scope Procedure number Product Information affected Date of start of the procedure Date of end of procedure Approval/ non approval Assessment report attached Y/N (version) Postadress/Postal address: P.O. Box 26, SE-751 03 Uppsala, SWEDEN Besöksadress/Visiting address: Dag Hammarskjölds väg 42, Uppsala Telefon/Phone: +46 (0)18 17 46 00 Fax: +46 (0)18 54 85 66 Internet: www.mpa.se E-mail: registrator@mpa.se