Echinaforce Sore Throat Spray THR 13668/0026 UKPAR PAR; ECHINAFORCE SORE THROAT SPRAY, THR...

MHRA PAR; ECHINAFORCE SORE THROAT SPRAY, THR 13668/0026 1

Echinaforce Sore Throat Spray

THR 13668/0026

UKPAR

TABLE OF CONTENTS

Lay summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

4

Summary of Product Characteristics

Page 15

Product Information Leaflet

Page 21

Labelling Page 24


ECHINAFORCE SORE THROAT SPRAY

THR 13668/0026

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 Sore Throat Spray (Traditional Herbal Registration number: THR 13668/0026). This product is available without prescription and can be bought from pharmacies and other outlets. The active ingredients in Echinaforce Sore Throat Spray come from the fresh herbs and roots of the Echinacea (Echinacea purpurea (L.) Moench) plant and from the fresh leaves of the Sage (Salvia officinalis L.) plant. Echinacea herb and root and Sage leaf are traditional herbal medicines used to relieve sore throats associated with coughs, colds and flu. This registration is based exclusively upon the longstanding use of Echinacea herb and root and Sage leaf as traditional herbal medicines 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 13668/0026

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS Introduction

Page 4

Pharmaceutical assessment

Page 5

Non-clinical assessment

Page 10

Clinical assessment

Page 11

Overall conclusions and risk assessment Page 13


INTRODUCTION

The MHRA granted a Traditional Herbal Registration Certificate for the traditional herbal medicinal product Echinaforce Sore Throat Spray (THR 13668/0026) to Bioforce (UK) Ltd on 17 November 2011. 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 Sore Throat Spray is a traditional herbal medicinal product used to relieve sore throats associated with coughs, colds and flu, based on traditional use only. The data supplied by the applicant demonstrate 30 years of traditional use of Echinacea herb and root and Sage leaf in the European Community. A satisfactory review of the available safety data on Echinacea and Sage has also been provided, together with an expert report supporting the proposed product.


PHARMACEUTICAL ASSESSMENT

HERBAL SUBSTANCES There are three herbal substances used in Echinaforce Sore Throat Spray: Echinacea purpurea herb, Echinacea purpurea root and Salvia officinalis leaf.

(1) ECHINACEA PURPUREA HERB

Latin name of plant: Echinacea purpurea (L.) Moench. Common name of plant: Purple coneflower herb Other names of plant: Echinacea purpurea herba recens

Plant family: Asteraceae, Compositae Parts of the plant used: Fresh, flowering, aerial parts

Physical 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 ROOT Latin name of plant: Echinacea purpurea (L.) Moench. Common name of plant: Purple coneflower herb Other names of plant: Echinacea purpurea herba recens

Plant family: Asteraceae, Compositae Parts of the plant used: Fresh underground parts

Physical 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. (3) SALVIA OFFICINALIS LEAF Latin name of plant: Salvia officinalis L. English name of plant: Sage Plant family: Lamiaceae Parts of the plant used: Fresh aerial parts

Physical Description The lamina of whole sage leaf is about 2 cm to 10 cm long and 1 cm to 2 cm wide, oblongovate and elliptical. The margin is finely crenate to smooth. The apex is


rounded or subacute and the base is shrunken at the petiole and rounded or cordate. The upper surface is greenish-grey and finely granular; the lower surface is white and pubescent and shows a dense network of raised veinlets. Manufacture of Herbal Substances

The plants are grown in central Europe under organic conditions (according to EC Directive 2092/91) and in accordance with Good Agricultural and Collection Practice (GACP) guidelines.

Echinacea 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. Sage is harvested mechanically between May and September, depending on the stage of development. The fresh plants are cut and immediately transferred into containers. The plants are processed within one day of harvesting.

Control of Herbal Substances

Appropriate specifications based on their respective Ph Eur monographs are applied to Echinacea herb, Echinacea root and Sage leaf. The specifications are supported by the batch data provided and are acceptable.

Reference Standards or Materials Suitable Certificates of Analysis have been provided for the reference substances used.

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

harvesting. Echinacea root and Sage leaf are 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 three herbal preparations used in Echinaforce Sore Throat Spray: Echinacea purpurea herb tincture, Echinacea purpurea root tincture and Salvia officinalis leaf tincture.

(1) ECHINACEA PURPUREA HERB TINCTURE Clear, olive liquid, with an aromatic herbaceous odour and an aromatic, bitter and anesthetizing taste. The drug: extraction solvent ratio (DER) is 1:12 and the extraction solvent is ethanol 57.3% (m/m).


(2) ECHINACEA PURPUREA ROOT TINCTURE Clear, golden yellow liquid, with an aromatic sweet odour and an aromatic, bitter, anesthetizing taste. The drug: extraction solvent ratio (DER) is 1:11 and the extraction solvent is ethanol 57.3% (m/m). (3) SALVIA OFFICINALIS LEAF TINCTURE Clear liquid with a green to brown colour, characteristic odour and bitter taste. The drug: extraction solvent ratio (DER) is 1:17 and the extraction solvent is ethanol 60.0% (m/m).

Manufacture of Herbal Preparations A satisfactory description of the manufacturing processes for the herbal preparations has been provided. The in-process controls are satisfactorily detailed. The manufacturing methods used to make the herbal preparations are 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 have 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 preparation, demonstrating satisfactory compliance with the proposed specifications.

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

Container Closure System

The herbal preparations are stored in appropriate containers.

Stability Stability studies have been carried out under ICH conditions. The results support the proposed retest period of the herbal preparations. HERBAL PRODUCT: ECHINAFORCE SORE THROAT SPRAY

Description and Composition of the Herbal Product The product is a brown to yellow-green, clear, oromucosal spray with an aromatic odour of peppermint and a fresh, slightly bitter taste of alcohol. 1 ml of spray contains 863.3 mg Echinacea herb tincture, 45.5 mg Echinacea root tincture and 430.0 mg Sage leaf tincture. The spray also contains the excipients sucrose laurate, soy lecithin, ethanol, peppermint oil and sorbitol liquid (non crystallising). The choice of


excipients is based on experience and compatibility of the chosen excipients with the herbal substances, which is confirmed by stability testing. All excipients used comply with their respective Ph Eur monographs, apart from sucrose laurate and soy lecithin, which are controlled by appropriate in-house specifications. All excipients are from non-animal and non-human sources, and, therefore, pose no TSE risk.

Manufacture of the Herbal Product A description and flow-chart of the manufacturing method has been provided. The manufacturing method is a standard uncomplicated procedure. 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 stored in 30 ml, brown, hydrolytic glass Type III (Ph Eur) flasks with an air pump and adapter. The flasks are inserted into a cardboard outer carton with a patient information leaflet. Suitable specifications have been provided by the packaging suppliers and it has been confirmed that all primary packaging materials comply with Directive 2008/39/EC.

Stability Finished product stability studies have been conducted in accordance with current guidelines. Based on the results, a product shelf-life of 30 months for product in an unopened container and 2 months after first opening the container is appropriate.

Summary of Product Characteristics, labelling 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.


CONCLUSION There are no objections to granting of a Traditional Herbal Registration from a quality point of view.


NON-CLINICAL ASSESSMENT

NON-CLINCIAL 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 suitably qualified professional. The overview submitted in support of this application is satisfactory. Due to a shortage of published data on Echinacea and Sage, it is not possible to assess if the safety package for the phytochemical constituents of these active ingredients 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. The Echinacea and Sage extracts contained in Echinaforce Sore Throat Spray have been shown to be non-mutagenic in Salmonella typhimurium reverse mutation assay up to a dose of 5000 μg/plate. SUMMARY OF PRODUCT CHARACTERISTICS (SmPC) The SmPC for this product is satisfactory from a non-clinical 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 There are no objections to granting of a Traditional Herbal Registration from a non-clinical point of view.


CLINICAL ASSESSMENT

PROPOSED INDICATION The applicant has proposed the following: “A traditional herbal medicinal product used to relieve sore throats associated with coughs, colds and flu, based on traditional use only.” The proposed indication is acceptable. POSOLOGY AND METHOD OF ADMINISTRATION The applicant has proposed the following: “For oromucosal administration

Adults and the elderly: 2 sprays six to ten times daily to the back of the throat.

The use in children and adolescents under 18 years of age is not recommended (see section 4.3 ‘Contraindications’).

Method of administration: Remove the cap from the bottle and fit the nozzle onto the cap. Replace the cap gently but firmly onto the bottle.

Before using the product for the first time activate the spray by pressing the pump 2-3 times. To use the spray, shake the bottle well, place the nozzle just inside the mouth and point it towards the back of the throat. Press the pump to spray.

Do not use the product for more than 7 days. If symptoms worsen during the use of the product or persist for more than 7 days, a doctor or qualified healthcare practitioner should be consulted (see section 4.4 ‘Special warnings and precautions for use’).” This is acceptable. EFFICACY No clinical efficacy data is required for registration of Traditional Herbal Medicinal Products. 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 and Sage extracts have been used in combination 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 review of safety data together with an expert report. The safety review is written by professionals with relevant expertise and is acceptable.

PRODUCT LITERATURE The SmPC, PIL and labelling for this product are medically satisfactory. CONCLUSION There are no objections to granting of a Traditional Herbal Registration from a clinical point of view.


OVERALL CONCLUSION AND RISK ASSESSMENT QUALITY The quality data submitted with this application are satisfactory. NON-CLINICAL The results of genotoxicity testing were provided and the results were satisfactory. No other new non-clinical data were submitted with this application and none are needed. EFFICACY AND SAFETY No clinical efficacy data are required for registration of Traditional Herbal Medicinal Products. The information reviewed during the clinical assessment support the traditional use of the herbal preparations and the recommended posology of this product. A satisfactory review of the safety data was provided. The SmPC, PILs and labelling are satisfactory. RISK ASSESSMENT The quality of the product is acceptable and no new non-clinical or clinical safety concerns have been identified. The benefit: risk balance is acceptable and a Traditional Herbal Registration may be granted.



THR 13668/0026

STEPS TAKEN FOR ASSESSMENT

1 The MHRA received the Traditional Herbal Registration application on 23 July 2010

2 Following standard checks and communication with the applicant the MHRA considered the application valid on 28 July 2010

3 Following assessment of the application the MHRA requested further information relating to the clinical dossier on 14 March 2011 and the quality dossier on 16 March 2011

4 The applicant responded to the MHRA’s request, providing further information on the clinical and quality dossiers on 23 August 2011

5 A THR was granted on 17 November 2011


SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Echinaforce Sore Throat Spray 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml contains: • 863.3 mg of tincture from fresh Echinacea purpurea (L.)

Moench herb (1:12-13). Extraction solvent: Ethanol 65% V/V. • 45.5 mg of tincture from fresh Echinacea purpurea (L.)

Moench root (1:11-12). Extraction solvent: Ethanol 65% V/V. • 430.0 mg of tincture from fresh Sage leaves (Salvia officinalis

L. folium) (1:17-18). Extraction solvent: Ethanol 68% V/V.

1 spray = 0.22 ml

Excipients: 1 ml contains a maximum of 407 mg sorbitol, 370 mg ethanol (alcohol), 20 mg of soy lecithin and 5 mg sucrose laurate.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Oromucosal spray, solution. Brown to yellow-green, clear liquid

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

A traditional herbal medicinal product used to relieve sore throats associated with coughs, colds and flu, based on traditional use only.

4.2 Posology and method of administration

For oromucosal administration

Adults and the elderly: 2 sprays six to ten times daily to the back of the throat.

The use in children and adolescents under 18 years of age is not recommended (see section 4.3 ‘Contraindications’).

Method of administration: Remove the cap from the bottle and fit the nozzle onto the cap. Replace the cap gently but firmly onto the bottle.


Before using the product for the first time activate the spray by pressing the pump 2-3 times. To use the spray, shake the bottle well, place the nozzle just inside the mouth and point it towards the back of the throat. Press the pump to spray.

Do not use the product for more than 7 days. If symptoms worsen during the use of the product or persist for more than 7 days, a doctor or qualified healthcare practitioner should be consulted (see section 4.4 ‘Special warnings and precautions for use’).

4.3 Contraindications

Hypersensitivity to the active substances, plants of the Asteraceae (Compositae) family or to any of the excipients. Patients with a history of significant allergy or difficulties swallowing or breathing. This product contains soy lecithin. If you are allergic to peanut or soya, do not take this product. Refer to Section 2, Qualitative and Quantitative Composition for soya content. 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).

Children and adolescents under 18 years.

4.4 Special warnings and precautions for use

Do not exceed the stated dose.

Do not use and consult your doctor if you have difficultly swallowing or breathing, if sore throat is severe and is accompanied by high fever, headache, nausea or vomiting.

Avoid contact with eyes.

If the symptoms worsen during the use of the product, or if symptoms persist for more than 7 days, a doctor or qualified healthcare practitioner should be consulted.

There is a possible risk of anaphylactic reactions in atopic patients. Atopic patients should not use this product.

This product contains 38 – 42 vol % ethanol (alcohol).


This corresponds to: • Up to 163 mg alcohol equivalent to 3.7 ml beer or 1.5 ml wine

(2 sprays)

Harmful for those suffering from alcoholism. To be taken into account in pregnant, or breast-feeding women, children and high-risk groups such as patients with liver disease or epilepsy.

This product contains soy lecithin and should not be used by patients who are allergic to peanut or soya.

This product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

This product contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine. Refer to Section 2, Qualitative and Quantitative Composition for sorbitol content.

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.

The intake of Sage leaf preparations might influence the effect of medicinal products acting via GABA receptor (e.g. barbiturates, benzodiazepines), even if not seen clinically. Therefore the concomitant use with such medicinal products is not recommended.

Contains alcohol and should be avoided in patients taking other medicines known to interact with alcohol (e.g. metronidazole).

4.6 Fertility, pregnancy and lactation

The safety of this product during pregnancy and lactation has not been established, therefore 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.

Safety during pregnancy and lactation has not been established for Salvia extracts.

Studies on the effects on fertility have not been performed.

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.


This product contains alcohol (see Section 4.4 for details of alcohol content).

4.8 Undesirable effects

Common (≥1/100 to <1/10) Rash on the buccal mucosa and a burning sensation of the throat have been reported in a clinical trial with this product. If this occurs the product should be stopped immediately.

Frequency not known 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).

If other adverse reactions not mentioned above occur, a doctor or qualified healthcare practitioner should be consulted.

4.9 Overdose

Overdose of this product may result in alcohol intoxication: the amount of alcohol in a full bottle (11 g in 30 ml; equivalent to a small glass of wine) may result in intoxication and should be treated accordingly.

For Sage leaves overdose has been reported with a sense of heat, tachycardia, vertigo and epileptic form convulsions (seizures) after intake corresponding to more than 15 g sage leaves (equivalent to between 38 and 66 doses).

No case of overdose has been reported for Echinacea.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties Not required as per Article 16c(1)(a)(iii) of Directive 2001/83/EC as amended. 5.2 Pharmacokinetic properties

Not required as per Article 16c(1)(a)(iii) of Directive 2001/83/EC as amended. 5.3 Preclinical safety data

Tests on reproductive toxicity, genotoxicity and carcinogenicity have not been performed with Echinaforce Sore Throat Spray.

Echinacea purpurea showed no toxicity in single dose toxicity (rodents) and repeated-dose toxicity (rodents).


The Echinaforce extract contained in Echinaforce Sore Throat Spray has been shown to be non-mutagenic in Salmonella typhimurium reverse mutation assay up to a dose of 5000 μg/plate. Tests on reproductive toxicity and carcinogenicity have not been performed.

The Sage extract contained in Echinaforce Sore Throat Spray has also been shown to be non-mutagenic in Salmonella typhimurium reverse mutation assay up to a dose of 5000 μg/plate. Tests on reproductive toxicity and carcinogenicity have not been performed.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sucrose laurate Soy lecithin Ethanol Peppermint oil Sorbitol, liquid (non crystallising)

6.2 Incompatibilities

Not known. 6.3 Shelf life

Unopened: 30 months

After first opening the container: 2 months

6.4 Special precautions for storage

This product does not require any special storage conditions. 6.5 Nature and contents of container

Brown glass flasks of hydrolytic glass Type III (Ph.Eur.) with air pump (snap-on-cap with spray pump; polyethylene / polyoxymethylene / stainless steel) and adapter (spray nozzle and actuator; polyethylene / polypropylene).

Pack size: 30 ml

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 13668/0026

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 17/11/2011 10 DATE OF REVISION OF THE TEXT

17/11/2011


PATIENT INFORMATION LEAFLET


LABELLING

Label:


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