echinaforce forte cold & flu tablets thr 13668/0013 … forte cold & flu tablets...

MHRA PAR; ECHINAFORCE FORTE COLD & FLU TABLETS, THR 13668/0013 1

Echinaforce Forte Cold & Flu Tablets

THR 13668/0013

UKPAR

TABLE OF CONTENTS

Lay summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

2

Summary of product characteristics

Page 13

Product information leaflet

Page 17

Labelling Page 20


ECHINAFORCE FORTE COLD & FLU TABLETS

THR 13668/0013

LAY SUMMARY

The Medicines and Healthcare products Regulatory Agency (MHRA) granted Bioforce (UK) Ltd a Traditional Herbal Registration certificate for the traditional herbal medicinal product Echinaforce Forte Cold & Flu Tablets (Traditional Herbal Registration number: THR 13668/0013). This product is available without prescription and can be bought from pharmacies and other outlets. The active ingredients of Echinaforce Forte Cold & Flu Tablets come from the fresh herb and root of the plant, Echinacea purpurea. Echinacea purpurea herb and root are traditional herbal medicines used to relieve the symptoms of the common cold and influenza type infections. This registration is based exclusively upon the longstanding use of Echinacea purpurea as a traditional 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 13668/0013

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 remedy Echinaforce Forte Cold & Flu Tablets (Traditional Herbal Registration number: THR 13668/0013) to Bioforce (UK) Ltd on 11 June 2009. This product is on the general sales list (GSL). This application was submitted according to Article 16.c of Directive 2001/83 EC, as amended, as part of the Traditional Herbal Medicines Registration Scheme. Echinaforce Forte Cold & Flu Tablets is a traditional herbal medicinal product used to relieve the symptoms of the common cold and influenza type infections based on traditional use only. 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 report supporting the proposed product.


PHARMACEUTICAL ASSESSMENT

HERBAL SUBSTANCES There are two herbal substances used in Echinaforce Forte Cold & Flu Tablets: Echinacea purpurea herb and Echinacea purpurea radix (root).

(1) ECHINACEA PURPUREA HERB Latin name: Echinacea purpurea (L.) Moench.

Common name: Purple coneflower herb Other names: Echinacea purpurea herba recens

Family: Asteraceae / Compositae Parts of the plant used: Fresh, flowering, aerial parts

Physcial description The herbaceous perennial plant is around 60 cm to 150 cm high. The stem is green to red, upright and slightly branched. The leaves are alternate, ovate to ovate-lanceolate, irregularly serrate, rugose on both surfaces, dark green with prominent light green veins; the lamina is thick and shiny. The involucral bracts of the large capitulum are arranged in 2-3 rows. The solid receptacle is slightly convex. Each of the outer violet ligulate florets (4-6 cm) and of the inner violet-pink tubular florets is attached to a reddish acute and coriaceous bract, which overtops the tubular flowers. The calyx is reduced to a very short crown, one of the sepals is up to 1 mm long. The achenes are green to light brown.

(2) ECHINACEA PURPUREA RADIX Latin name: Echinacea purpurea (L.) Moench. Common name: Purple coneflower herb Other names: Echinacea purpurea radix

Family: Asteraceae / Compositae Parts of the plant used: Fresh underground parts

Physcial description The rhizome is 10 cm to 15 cm long, branched, red-brown to dark brown on the surface and carries many stem bases; the inside is fibrous and white. The numerous roots are spirally twisted, light to dark brown and show a fine cross structuring on the surface.

Manufacture of Herbal Substances The plant is grown in central Europe under organic conditions (according to EC Directive 2092/91)

and in accordance with Good Agricultural and Collection Practice (GACP) guidelines. The plant is cultivated as a perennial crop. Crop rotation is performed to minimise pests and diseases. No pesticides are applied. Weeds are manually or mechanically removed and fertilisation is done using compost. The above ground parts are mechanically harvested during flowering time between July and August (old crop) and September (first year crop). The plants are processed not later than one day after harvest. The roots are mechanically harvested between September and November in the second year of growth or later. They are washed with drinking water to remove the soil, dripped dry and then processed fresh.

Control of Herbal Substances


Appropriate specifications based on their respective Ph Eur monographs are applied to both Echinacea purpurea herb and Echinacea purpurea radix and are acceptable. The specifications are supported by the batch data provided.

Reference Standards or Materials Suitable certificates of analysis have been provided for the reference substances used.

Container Closure System Echinacea purpurea herb is stored in appropriate containers no more than 1 day after harvesting.

Echinacea purpurea radix is not stored.

Stability No stability data have been provided and none are needed due to the short time between harvest and processing.

HERBAL PREPARATIONS

There are two herbal preparations used in Echinaforce Forte Cold & Flu Tablets: Echinacea purpurea herb tincture and Echinacea purpurea radix tincture.

(1) Echinacea purpurea herb tincture 1:12 Clear, olive liquid, with an aromatic herbaceous odour and an aromatic, bitter, anesthetizing taste. (2) Echinacea purpurea radix tincture 1:11 Clear, olive liquid, with an aromatic herbaceous odour and an aromatic, bitter anesthetizing taste.

Manufacture Satisfactory descriptions of the manufacturing processes of the herbal preparations have been

provided. The in-process controls are satisfactorily detailed. There are no critical steps identified as the manufacture of the herbal preparations are considered to be standard procedures. Certificates of analysis for all materials used in the manufacture of the herbal preparations have been provided.

Control of Herbal Preparations Satisfactory specifications with appropriate tests and limits has been provided for the herbal

preparations.

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

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

The proposed specifications have been justified satisfactorily.

Reference Standards or Materials

Suitable details have been provided for the reference standards used.

Container Closure System


The herbal preparations are stored in an appropriate container. A declaration has been provided confirming that this container is suitable for storage of foodstuffs

Stability Stability studies have been carried under ICH conditions. The results support the proposed shelf life of the herbal preparations.

HERBAL PRODUCT: ECHINAFORCE FORTE COLD & FLU TABLETS Description and Composition of the Herbal Product The product is presented as round, homogeneous, biconvex, bevelled tablets. The tablets contain the excipients lactose monohydrate, pregelatinised starch , soya polysaccharide

and magnesium stearate. The choice of excipients is based on experience and compatibility of the chosen excipients with the active substance is confirmed by stability testing. All excipients used comply with their respective European Pharmacopoeial monograph, with the exception of soya polysaccharide, in the absence of a European Pharmacopoeial monograph for this excipient this is satisfactory. Certificates of analysis are provided from the finished product manufacturer for all excipients.

Lactose monohydrate is the only excipient of animal origin. A declaration is provided from the supplier confirming that the source of the raw material is from food grade cow’s milk, sourced from healthy animals as per the Note for Guidance on Transmissible Spongiform Encephalopathy (TSE). The rennet used to obtain the intermediate whey is sourced in accordance to EMEA/CPMP/571/02 of February 27th 2002. No other material of animal origin is used for the manufacture of lactose. The magnesium stearate used is of vegetable origin and a suitable statement from the supplier is provided confirming this. Manufacture A description and flow-chart of the manufacturing method has been provided. The manufacturing method is a standard uncomplicated procedure of direct tabletting. In-process controls are appropriate considering the nature of the product and the method of manufacture. Process validation has been carried out on product batches and the results are satisfactory.

Control of Herbal Product The finished product specification is satisfactory. Acceptance limits have been justified with respect to conventional pharmaceutical requirements and, where appropriate, safety. Test methods have been described and have been adequately validated, as appropriate. Batch data have been provided and comply with the release specification.

Reference Standards or Materials Suitable details have been provided for the reference standards used.

Container Closure System The finished product is packed in amber class III glass bottles with an aluminium pilfer proof closure fitted with a polyethylene liner. Pack sizes are 30, 40 or 120 tablets, although not all pack sizes may be marketed. The bottle is inserted into a cardboard outer carton with a patient information leaflet.


Specifications and certificates are provided from the manufacturers and confirmation that all components are safe for use in contact with foodstuffs and conform to Ph.Eur. standards is also provided.

Stability Finished product stability studies have been conducted in accordance with current guidelines. Based on the results, a product shelf-life of 3 years for product in an unopened container and 3 months after first opening the container is appropriate.

Assessor’s comments on the Summary of Product Characteristics, label and Patient Information Leaflet All product literature is 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 The grant of a Traditional Herbal Registration is acceptable.


NONCLINICAL ASSESSMENT

1 NONCLINICAL ASPECTS The Expert Safety Report submitted by the applicant lists relevant references to published work studying the toxicology of Echinacea purpurea. 2 NONCLINCIAL OVERVIEW The applicant has submitted a literature review with this application. An Expert Safety Report was provided, which included reviews of some non-clinical data. The Expert Safety Report was written by a medically qualified expert. The report is dated Novemver 2006. 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. Genotoxicity testing has been carried out on both of the extracts used in the product. The results of testing are satisfactory. 3 SUMMARY OF PRODUCT CHARACTERISTICS (SPC) The SPC for this product is satisfactory from a preclinical point of view. 4 ENVIRONMENTAL RISK ASSESSMENT

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

5 CONCLUSION The information supplied demonstrates the traditional use of Echinacea purpurea. An adequate literature review of Echinacea purpurea has been carried out by the applicant and genotoxicity testing results are satisfactory. Granting of a THR is acceptable.


CLINICAL ASSESSMENT

LEGAL STATUS Echinacea purpurea is currently on the General Sales List for internal use. 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.” The proposed indication is acceptable. EVIDENCE OF LONG-STANDING 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 information provided is adequate to demonstrate that Echinacea pururea herb and root have been in use for at least 30 years of which at least 15 years have been in an EU Member State. The requirements of the Directive are therefore satisfied. SAFETY REVIEW Article 16 c 1 (D) requires the Applicant to provide a bibliographic of safety data together with an expert report. A safety review has been provided along with an Expert Report written by suitabily qualified authors. The safety review is acceptable and includes all major studies. The SPC is in line with the HMPC Monograph on Echinacea purprea herb. This particular formulation is not indicated for children and thus no additional safety issues arise. ASSESSOR’S COMMENTS ON THE SUMMARY OF PRODUCT CHARACTERISTICS, LABEL AND PATIENT INFORMATION LEAFLET The product literature (Summary of Product Characteristics, Patient Information Leaflet and labelling) for this product are medically satisfactory. DISCUSSION The data supplied by the Applicant are sufficient to demonstrate 30 years of traditional use within the European Community as required for registration under the Traditional Herbal Medicines Product Directive. A comprehensive review of the available safety data relating to Echinacea purpurea herb and root has been provided. In view of the fact that Echinacea is on the GSL Order, there are a number of licensed products and the HMPC has almost finalised the Community Monograph on Echinacea purpurea herb no further information will be requested on the safety aspects. RECOMMENDATIONS A Traditional Registration may be granted.


OVERALL CONCLUSION AND RISK ASSESSMENT

QUALITY Bioforce (UK) Ltd has over 30 years of experience in manufacturing herbal medicinal products. The quality data submitted with this application are satisfactory. PRECLINICAL No 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. 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. The risk: benefit ratio is, therefore, acceptable.



THR 13668/0013

STEPS TAKEN FOR ASSESSMENT

1 The MHRA received the Traditional Herbal Registration application on 26 January 2007

2 Following standard checks and communication with the applicant the MHRA considered the application valid on 8 March 2007

3 Following assessment of the application the MHRA requested further information relating to the quality and clinical dossiers on 24 August 2007

4 The applicant responded to the MHRA’s requests, providing further information on the quality and clinical dossiers on 15 February 2008

5 Following assessment of the response the MHRA requested further information relating to the quality and clinical dossiers on 5 June 2008

6 The applicant responded to the MHRA’s requests, providing further information on the quality and clinical dossiers on 11 June 2009

7 A THR was granted on 11 June 2009


SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Echinaforce Forte Cold & Flu Tablets 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

One tablet contains 1,140 mg of extract (as dry extract) from fresh Echinacea purpurea (L.) Moench herb (1:12) and 60 mg of extract (as dry extract) from fresh Echinacea purpurea (L.) Moench root (1:11). Extraction solvent: Ethanol 65% v/v Excipients: One tablet contains 683.4 mg lactose monohydrate and 7.5 mg of soya polysaccharide. For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet. Greenish, round-shaped, bi-convex, bevelled tablet

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: 1 tablet two to three times daily This 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 doctor or 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), immunodeficiences (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). This product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this product. This product contains soya polysaccharide. If you are allergic to peanut or soya, do not take this product. Refer to Section 2, Qualitative and Quantitative Composition for lactose and soya content.

4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Do not exceed the stated dose. If the symptoms worsen or high fever occurs during the use of the product, or if symptoms persist for more than 10 days, a doctor or qualified healthcare practitioner should be consulted. There is a possible risk of anaphylactic reactions in atopic patients. Atopic patients should consult their doctor before using Echinacea. This formulation is not suitable for children under 12 years of age.

4.5 INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION

The product should not 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, Quinke 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 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 herb showed no toxicity in single-dose toxicity, repeated-dose toxicity and genotoxicity studies; tests on reproductive toxicity and carcinogenicity have not been performed. Tests on reproductive toxicity, genotoxicity and on carcinogenicity have not been performed with Echinacea purpurea root.

6 PHARMACEUTICAL PARTICULARS

6.1 LIST OF EXCIPIENTS

Lactose monohydrate Pregelatinised starch Soya polysaccharide Magnesium stearate

6.2 INCOMPATIBILITIES

Not known. 6.3 SHELF LIFE

Unopened: 3 years

After first opening the container: 3 months

6.4 SPECIAL PRECAUTIONS FOR STORAGE

This product does not require any special storage conditions. Keep out of reach and sight of children.

6.5 NATURE AND CONTENTS OF CONTAINER

Amber glass bottles (type III conforming to Ph.Eur. standards) with coated aluminium foil sealing and aluminium pilfer proof closure fitted with a polyethylene liner.

Pack sizes: 30 tablets 40 tablets


120 tablets

Not all pack sizes may be marketed. 6.6 SPECIAL PRECAUTIONS FOR DISPOSAL

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Bioforce (UK) Ltd, 2 Brewster Place, Irvine KA11 5DD, UK Telephone: 01294 277344 [email protected]

8 MARKETING AUTHORISATION NUMBER(S)

THR 13668/0013

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 11/06/2009 10 DATE OF REVISION OF THE TEXT

11/06/2009


PATIENT INFORMATION LEAFLET


LABELLING

Label (30 tablet pack):




Carton (30 tablet pack):

echinaforce forte cold & flu tablets thr 13668/0013 … forte cold & flu tablets...

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