ECHINAFLU effervescent tablets THR 18397/0004 UKPAR · ECHINAFLU effervescent tablets THR 18397/0004 LAY SUMMARY The Medicines and Healthcare products Regulatory Agency (MHRA) granted

ECHINAFLU effervescent tablets

THR 18397/0004

UKPAR

TABLE OF CONTENTS

Lay summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

Page 12

Summary of product characteristics

Page 13

Product information leaflet

Page 17

Labelling Page 19

MHRA PAR; ECHINAFLU EFFERVESCENT TABLETS, THR 18397/0004 1


THR 18397/0004

LAY SUMMARY

The Medicines and Healthcare products Regulatory Agency (MHRA) granted Swiss Caps GmbH a Traditional Herbal Registration Certificate for the traditional herbal medicinal product ECHINAFLU effervescent tablets (Traditional Herbal Registration number: 18397/0004). This product is available without prescription and can be bought from pharmacies and other outlets. ECHINAFLU effervescent tablets are used to relieve the symptoms of the common cold and influenza type infections, based on traditional use only. The tablets’ active ingredient is dry pressed juice from fresh, flowering Purple Coneflower herb, also known as Echinacea purpurea (L.). This registration is based exclusively upon evidence of traditional use of Echinacea purpureaas as a herbal medicine and not upon data generated from clinical trials. There is no requirement under the Traditional Herbal Registration scheme to prove scientifically that the product works. No new or unexpected safety concerns arose from this application and it was, therefore, decided that a Traditional Herbal Registration Certificate could be granted.



THR 18397/0004

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction

Page 4

Pharmaceutical assessment

Page 5

Preclinical assessment

Page 9

Clinical assessment

Page 10

Overall conclusions and risk assessment Page 11


INTRODUCTION

The MHRA granted a Traditional Herbal Registration Certificate for the traditional herbal medicinal product ECHINAFLU effervescent tablets to Swiss Caps GmbH on 16 June 2008. This product is on the general sales list (GSL). The application was submitted under Article 16.c of Directive 2001/83 EC, as amended, as part of the Traditional Herbal Medicines Registration Scheme. This product consists of tablets containing 176 mg of dried pressed juice from fresh flowering Echinacea purpurea (L.) Moench herb. The product is used for relief from the symptoms of the common cold and influenza type infections. This THR is based exclusively on evidence of traditional use of Echinacea purpurea. The recommended dose is one or two effervescent tablets daily. This product is not intended for children below 12 years of age. The data supplied by the applicant demonstrate 30 years of traditional use of Echinacea purpurea in the European Community. A satisfactory review of the available safety data on Echinacea purpurea has also been provided, together with an expert safety report supporting the proposed product.


PHARMACEUTICAL ASSESSMENT

HERBAL SUBSTANCE Latin name: Echinacea purpurea (L.) Moench Common name: Purple coneflower herb Other names: Echinacea purpurea herba recens Family: Asteraceae / Compositae Parts of plant used: Fresh, above ground plant parts harvested at flowering time Manufacture All plants are cultivated in line with the regulations for organic cultivation certified according to 2092/91/EEC. This legislation covers organic production of agricultural products, restricting the use of certain pesticides and fertilisers amongst other things. The above ground parts are mechanically harvested during flowering time from July to October. Contamination from the soil is minimised by cutting the herb a sufficient distance from the ground. The plants are not stored but processed directly after harvesting. The whole fresh plant is tested for identity and adulteration derived from other Echinacea species in the run-up to harvest and manufacture. The fresh plants are inspected pre-harvesting for adulteration and, in case of doubt, samples are taken and analysed. The certification provided shows that the supplier has continually complied with Organic Production processes. Confirmation has also been provided that the herbal substance is grown under organic conditions. This is considered acceptable and sufficient to cover Guideline on Good Agricultural and Collection Practice (GACP) EMEA/HMPC/246816/2005.

Control of Herbal Substance A specification in the style of a monograph has been provided as well as a sampling plan

for fresh plants. Satisfactory certificates of analysis for the herbal substance have been provided.

Container Closure System No details are given as the herbal drug is not stored.

Stability No details are given as the herbal drug is not stored.

HERBAL PREPARATION General information Dry pressed juice: Isolated non-existing dry pressed juice from fresh, flowering purple coneflower herb (20-28:1)


Dry pressed juice 88%: Herbal preparation from the dry pressed juice, maltodextrin, citric acid and precipitated silicon dioxide. No extracting solvents are used. General Properties: Fine brown powder and typical odour

Manufacture

A satisfactory description of the manufacturing process of the herbal preparation and flow diagram has been provided. Juice is extracted from the harvested plants and dried and packed. The process is satisfactory.

Control of Herbal Preparation A satisfactory specification with appropriate tests and limits has been provided for the

herbal preparation

Satisfactory analytical procedures are used to control the quality of the herbal preparation. Analytical procedures have been validated, as appropriate.

Certificates of analysis have been provided for production batches of the herbal preparation, demonstrating satisfactory compliance with the proposed specification.

The proposed specification has been justified satisfactorily.

Container Closure System Specifications have been provided by the supplier of the container closure system together with the declaration of compliance with Directive 2002/72/EC relating to plastic materials and articles intended to come into contact with foodstuffs.

Stability Batches were packed in the container closure system and stored in ICH conditions. The

data support the proposed retest period of 18 months

HERBAL PRODUCT

Description and Composition of the Herbal Product The round, flat, ivory-coloured effervescent tablets are 25mm in diameter. As well as the herbal preparation, they consist of ascorbic acid, sodium hydrogen carbonate, saccharin sodium, sodium cyclamate, citric acid anhydrous and citric flavour Permaseal 84260-51. The choice of excipients is based on experience and compatibility of the chosen excipients with the drug substance is confirmed by stability testing. Interaction of the herbal product with the container is not expected based on the results of stability testing.

Control of Excipients Most of the excipients comply with the Ph. Eur., with the exception of citric flavour Permaseal 84260-51. Where the Ph. Eur is used, confirmation is provided that the most current version is applied. Satisfactory information about the non-pharmacopoeial flavouring agent citric flavour Permaseal 84260-51 has been provided. The individual components of this flavouring all comply with the Ph. Eur.


Representative certificates of analysis have been provided from the suppliers of all the excipients. Confirmation has been provided that excipients of human and animal origin are not used in the manufacture of the tablets.

Manufacture A flow diagram summarising the manufacturing process and in-process controls has been

provided. The production of the humid granulate material, the drying process, the tabletting and the packaging process are standard procedures ensuring a consistent quality of the drug product.

A number of in-process control tests are performed during the manufacturing process to ensure the quality of the product. All are considered adequate.

Control of Herbal Product

The finished product specifications at release and end of shelf life are detailed and the tests and limits used were found to be satisfactory for a product of this nature.

Satisfactory details have been provided on all analytical procedures and these analytical procedures are valid. Certificates of Analysis have been presented for batches of the drug product demonstrating little inter-batch variation.

Reference Standards or Materials Certificates of Analysis for all the markers, including the reference substance, have been provided by the finished product manufacturer.

Container Closure System

The product is presented in polypropylene tubes with polyethylene closures filled with the drying agent silica gel. One tube contains 20 effervescent tablets. Suitable specifications have been provided by the packaging suppliers. The components of the primary packaging system comply with Directive 2002/72 relating to contact with foodstuffs.

Stability Stability studies were conducted under ICH conditions on product batches.

Based on the results, a proposed shelf life of 3 years, if the tube is unopened, and 7 months, after first opening the container, with the storage condition “Store in the original packaging.” is justified. PRODUCT LITERATURE The product literature (Summary of Product Characteristics, Patient Information Leaflet and labelling) for this product are pharmaceutically satisfactory.


A package leaflet has been submitted to the MHRA along with results of consultations with target patient groups ("user testing"), in accordance with Article 59 of Council Directive 2001/83/EC. The results indicate that the package leaflet is well-structured and organised, easy to understand and written in a comprehensive manner. The test shows that the patients/users are able to act upon the information that it contains.

ASSESSOR’S OVERALL CONCLUSIONS ON QUALITY This product is satisfactory and a Traditional Herbal Registration can be granted.


NON-CLINICAL ASSESSMENT NONCLINICAL ASPECTS The Expert Safety Report submitted by the applicant lists relevant references to published work studying the toxicology of Echinacea purpurea. NONCLINCIAL OVERVIEW The applicant has submitted a good literature review with this application. An Expert Report on Safety was provided, which included reviews of some non-clinical data. The Expert Safety Report was written by a suitably qualified expert and is dated 3 June 2005. The overview submitted in support of this application is satisfactory. Due to a shortage of published data on Echinacea purpurea, it is not possible to assess if the safety package for the phytochemical constituents of Echinacea purpurea is acceptable to the standards of today’s GLP and safety testing requirements. However, the information supplied demonstrating traditional use is acceptable and thus the lack of provision of a complete standard safety package is acceptable and in compliance with guideline EMEA/HMPC/32116/05. Data in the literature for genotoxic and carcinogenic potential of the product is deficient as basic genotoxicity tests have not been conducted. The company have provided their assurance that they will address this lack of data before renewal of their licence. SUMMARY OF PRODUCT CHARACTERISTICS (SPC) The SPC for this product is satisfactory from a preclinical point of view. ENVIRONMENTAL RISK ASSESSMENT

An environmental risk assessment is not required for herbal medicinal products according to guidance CPMP/SWP/4447/00.

CONCLUSION The information supplied demonstrating traditional use of Echinacea purpurea is acceptable. An adequate literature review of Echinacea purpurea has been carried out by the applicant and no new non-clinical data was submitted for assessment with this application. Granting of a THR is acceptable.


CLINICAL ASSESSMENT

EVIDENCE OF TRADITIONAL USE Article 16 c 1 (c) requires the Applicant to provide bibliographic or expert evidence to show that the medicinal product in question, or a corresponding product, has been in medicinal use throughout a period of at least 30 years, including at least 15 years within the Community. The Applicant has provided a bibliographic review which shows ample evidence for the use of Echinacea purpurea herb within the EU for a period exceeding 30 years. PROPOSED INDICATION The applicant has proposed the following: “A traditional herbal medicinal product used to relieve the symptoms of the common cold and influenza type infections based on traditional use only.” This is satisfactory. SAFETY REVIEW Article 16 c 1 (D) requires the Applicant to provide bibliographic of safety data together with an expert report. A safety review has been provided and an Expert Report written by a medically qualified doctor. These are satisfactory. PRODUCT LITERATURE The product literature (Summary of Product Characteristics, Patient Information Leaflet and labelling) for this product are medically satisfactory. DISCUSSION This is an application for registration under the Traditional Herbal Medicinal Products Directive. The data supplied by the Applicant are sufficient to demonstrate 30 years of traditional use within the Community for corresponding products. A satisfactory review of the available safety data on Echinacea has been provided together with an Expert Report supporting the proposed product. RECOMMENDATIONS A Traditional Registration may be granted.


OVERALL CONCLUSION AND RISK ASSESSMENT

QUALITY The quality data submitted with this application are satisfactory. PRECLINICAL No new preclinical data were submitted and none are required for an application of this type. EFFICACY AND SAFETY No clinical efficacy data are required for registration of Traditional Herbal Medicinal Products (THMP). The Applicant has provided a bibliographic review which shows ample evidence for the use of Echinacea purpurea within the EU for a period exceeding 30 years. A satisfactory review of the safety data has been provided. The SPC, PIL and labelling are satisfactory. RISK ASSESSMENT The quality of the product is acceptable and no new preclinical or clinical safety concerns have been identified.



THR 18397/0004

STEPS TAKEN FOR ASSESSMENT

1 The MHRA received the Traditional Herbal Registration application 10 April 2006

2 Following standard checks and communication with the applicant the MHRA considered the application valid on 10 April 2006

3 Following assessment of the application the MHRA requested further information relating to the quality dossier on 10 April 2006, and the clinical dossier on 24 July 2006. The applicant responded to the MHRA’s requests, providing further information on the quality dossier on 10 April 2006 and the clinical dossier on 5 December 2007.

4 Following assessment of the response the MHRA requested further information relating to the quality dossier on 10 April 2006 and 15 May 2008. The applicant responded to the MHRA’s requests, providing further information on the quality dossier on 28 May 2008

5 A THR was granted on 16 June 2008


SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

ECHINAFLU effervescent tablets 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One effervescent tablet contains 176 mg of dried pressed juice from fresh flowering Echinacea purpurea (L.) Moench herb (20-28:1). This product contains 17.05 mmol (or 392 mg) sodium per tablet. For full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM Effervescent tablet Round, flat, ivory-coloured effervescent tablets

4 CLINICAL PARTICULARS 4.1 Therapeutic indications

A traditional herbal medicinal product used to relieve the symptoms of the common cold and influenza type infections based on traditional use only.

4.2 Posology and method of administration For oral administration Adults, elderly and children over 12 years: the recommended dosage is 1 or 2 effervescent tablets daily, dissolved in a glass of water (about 200 ml). The dissolved tablets should be drunk immediately. The effervescent tablet formulation is not intended for children below 12 years. Start at first signs of common cold. Do not use the product for more than 10 days. If symptoms worsen during the use of the product or persist for more than 10 days, a physician or a qualified healthcare practitioner should be consulted.

4.3 Contraindications Hypersensitivity to the active substance or to plants of the Asteraceae (Compositae) family. Because of its immunostimulating activity, Echinacea must not be used in cases of progressive systemic disorders (tuberculosis, sarcoidosis), autoimmune diseases (e.g.: collagenoses, multiple sclerosis), immunodeficiencies (e.g.: HIV infection; AIDS), immunosuppression (e.g.: oncological cytostatic therapy; history of organ or bone marrow transplant), diseases of the white blood cell system (e.g.: agranulocytosis, leukemias) and allergic diathesis (e.g.: urticaria, atopic dermatitis, asthma). Children under 12 years of age.


4.4 Special warnings and precautions for use

Do not exceed the stated dose. If the condition worsens or high fever occurs during the use of the product or if symptoms persist for more than 10 days, consult a doctor or qualified healthcare practitioner. This formulation is not suitable for children under 12 years of age. There is a possible risk of anaphylactic reactions in atopic patients. Atopic patients should consult their doctor before using Echinacea. In patients for whom sodium intake is of medical concern (e.g. patients with congestive heart failure, renal failure, nephrotic syndrome), the sodium content of this product should be taken into account. Refer to Section 2, Qualitative and Quantitative Composition for sodium chloride content.

4.5 Interaction with other medicinal products and other forms of interaction Not to be used concomitantly with immunosuppressant medications such as ciclosporin and methotrexate.

4.6 Pregnancy and lactation In the absence of sufficient data the use in pregnancy and lactation is not recommended. Limited data (several hundreds of exposed pregnancies) indicate no adverse effects of Echinacea on pregnancy or on the health of the foetus/newborn child. Data concerning the immune system of the newborn child are not available. To date, no other relevant epidemiological data are available. The potential risk for humans is unknown.

4.7 Effects on ability to drive and use machines No studies on the effects on the ability to drive and use machines have been performed.

4.8 Undesirable effects Hypersensitivity reactions (rash, urticaria, Stevens-Johnson Syndrome, angioedema of the skin, Quincke edema, bronchospasm with obstruction, asthma and anaphylactic shock) may occur. Echinacea can trigger allergic reactions in atopic patients. Association with autoimmune diseases (encephalitis disseminata, erythema nodosum, immunothrombocytopenia, Evans Syndrome, Sjögren syndrome with renal tubular dysfunction) has been reported. Leucopenia may occur in long-term use (more than 8 weeks). The frequency is not known. If other adverse reactions not mentioned above occur, a doctor or a pharmacist should be consulted.

4.9 Overdose

No case of overdose has been reported.


5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

No relevant pharmacodynamic data are available. 5.2 Pharmacokinetic properties

No relevant pharmacokinetic data are available. 5.3 Preclinical safety data

Echinacea purpurea showed no toxicity in single-dose toxicity, repeated-dose toxicity and genotoxicity studies. Tests on reproductive toxicity and on carcinogenicity have not been performed.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Excipients of the herbal preparation: Maltodextrin Precipitated silicon dioxide Citric acid monohydrate Excipients of the tablet: Ascorbic acid Sodium hydrogen carbonate Saccharin sodium Sodium cyclamate Citric acid anhydrous Citric flavour Permaseal 84260-51.

6.2 Incompatibilities

None known. 6.3 Shelf life

Unopened 3 years. After first opening the container 7 months.

6.4 Special precautions for storage

Store in the original packaging. 6.5 Nature and contents of container

Effervescent tablets are packed in polypropylene tubes with polyethylene closures filled with the drying agent silica gel. One tube contains 20 effervescent tablets.

6.6 Special precautions for disposal

No special requirements.


7 MARKETING AUTHORISATION HOLDER

Swiss Caps GmbH Grassingerstraße 9 D-83043 Bad Aibling Germany

8 MARKETING AUTHORISATION NUMBER(S)

THR 18397/0004

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 16/06/2008 10 DATE OF REVISION OF THE TEXT

16/06/2008


PATIENT INFORMATION LEAFLET



LABELLING

Tube label:


Carton:



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ECHINAFLU effervescent tablets THR 18397/0004 UKPAR · ECHINAFLU effervescent tablets THR 18397/0004 LAY SUMMARY The Medicines and Healthcare products Regulatory Agency (MHRA) granted