Public Assessment Report Scientific discussion Echinacea Friggs, effervescent tablet (Echinacea purpurea fresh herb, dried expressed juice (20-28:1)) Asp. no: 2008-0557 This module reflects the scientific discussion for the approval of Echinacea Friggs, effervescent tablets. The procedure was finalised 3 September 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 Template version: 2010-01-21
LAY SUMMARY The Medical Products Agency (Läkemedelsverket, MPA) has granted Friggs AB a marketing authorisation for the herbal medicinal product Echinacea Friggs, effervescent tablets. The MAH has later changed to Midsona Sverige AB, Sweden. The product is available without prescription and can be bought from pharmacies and other outlets. Echinacea Friggs has an extensive medicinal use in the EU for the short-term prevention and treatment of common cold. The active ingredient is dried 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 Echinacea Friggs 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 Echinacea Friggs could be granted a marketing authorisation as a herbal medicinal product. 2/8
I. INTRODUCTION Friggs AB has applied for a marketing authorisation for Echinacea Friggs, effervescent tablets. The applications were 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 dried expressed juice from fresh herb of Echinacea purpurea (L.) Moench (purple coneflower/röd solhatt). For approved indications, see the Summary of Product Characteristics (SmPC). Echinacea Friggs, was first authorised as a natural remedy in 2003 under the name Friggs Echinacea. 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 Echinacea Friggs is presented in the form of effervescent tablets containing 176 mg of dried expressed juice, which corresponds to approximately 4 g of fresh herb from Echinacea purpurea. The excipients are: anhydrous citric acid, sodium hydrogen carbonate, maltodextrin, saccharin sodium, sodium cyclamate, ascorbic acid, Permaseal lemon flavour no. 84260-51 (ascorbic acid, citral, lemon oil, maltodextrin, sucrose and modified food starch), precipitated silica and citric acid monohydrate. 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, dried expressed juice (20-28:1). The herbal substance is collected from cultivations in Germany. Relevant information on growing conditions and controls of the herbal substance has been provided. The herbal substance is cut, steam treated and pressed. Separation is performed by centrifugation followed by concentration and drying. For manufacturing reasons excipients are added to the dry preparation. The manufacturing process has been adequately described and satisfactory specifications have been provided for starting materials. 3/8
The specifications for both the herbal substance and the herbal preparation include 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 Echinacea Friggs, effervescent tablets are formulated using excipients described in the current Ph. Eur. except for precipitated silica which has a monograph in the German Pharmacopoeia and Permaseal lemon flavour which is controlled using an in-house specification. 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 and storage conditions 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 Echinacea Friggs (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 4/8
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. 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, mouse lymphoma assay and mouse micronucleus test). 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 Echinacea Friggs 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 Echinacea Friggs 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 Echinacea Friggs (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 Echinacea Friggs 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. 5/8
IV.2 Pharmacokinetics 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 Echinacea Friggs. IV.4 Clinical efficacy Echinacea Friggs 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. Studies on the herbal preparation contained in Echinacea Friggs (dried expressed juice, DER 20-28:1) are not listed in the assessment report but similar preparations are reviewed. 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 they 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 Echinacea Friggs 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 Echinacea Friggs. 6/8
IV.6 Discussion on the clinical aspects Echinacea Friggs 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 Sweden since 2003. 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. OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND RECOMMENDATION According to the Community monograph on Echinacea purpurea, fresh herb, the herbal preparation in Echinacea Friggs 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 Echinacea Friggs. The benefi/risk ratio is considered positive and Echinacea Friggs, effervescent tablets is recommended for approval. VI. APPROVAL Echinacea Friggs, effervescent tablets was approved in the national procedure on 2009-09-03. 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 Template version: 2010-01-21