relaxherb coated tablets thr 23056/0008 ukpar - gov.uk · mhra par; relaxherb coated tablets, thr...

MHRA PAR; RELAXHERB COATED TABLETS, THR 23056/0008 1

RelaxHerb coated Tablets

THR 23056/0008

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 21


RELAXHERB COATED TABLETS

THR 23056/0008

LAY SUMMARY

The Medicines and Healthcare products Regulatory Agency (MHRA) granted Schwabe Pharma (UK) Ltd a Traditional Herbal Registration Certificate for the traditional herbal medicinal product RelaxHerb coated Tablets (Traditional Herbal Registration number: 23056/0008). This product is available without prescription and can be bought from pharmacies and other outlets. RelaxHerb coated Tablets are used for the temporary relief of symptoms associated with stress such as mild anxiety based on traditional use only. The tablets’ active ingredient is dry extract from aerial parts of the passion flower, also known as Passiflora incarnata L. This registration is based exclusively upon evidence of traditional use of passion flower 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 23056/0008

SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

Introduction

Page 4

Pharmaceutical assessment

Page 5

Preclinical assessment

Page 8

Clinical assessment

Page 9

Overall conclusions and risk assessment Page 11


INTRODUCTION

The MHRA granted a Traditional Herbal Registration Certificate for the traditional herbal medicinal product RelaxHerb coated Tablets to Schwabe Pharma (UK) Ltd on 27 February 2009. 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 coated tablets containing 425 mg of dry extract from aerial parts of the passion flower (Passiflora incarnata L.) The product is used to treat symptoms associated with stress, such as mild anxiety. This THR is based exclusively on evidence of traditional use of passion flower. The recommended dose is one tablet daily if required The data supplied by the applicant demonstrate 30 years of traditional use of passion flower in the European Community. A satisfactory review of the available safety data on passion flower has also been provided, together with an expert safety report supporting the proposed product.


PHARMACEUTICAL ASSESSMENT

HERBAL SUBSTANCE: PASSION FLOWER

Scientific name of the plant: Passiflora incarnata L. Family: Passifloraceae Synonyms of the herbal substance: Passion flower Parts of the plant used: Dried aerial parts of Passiflora incarnata L. Manufacture The herbal drug "Passion flower" originates from southwest Europe and the USA. The aerial parts of Passiflora incarnata, which may contain flowers and / or fruits, are harvested from June to August during flowering. Harvesting is either mechanical or manual. The fragmented or cut herbal drug is dried either naturally or artificially. The dried herbal drug passion flower is stored protected from light, heat and moisture. Cultivated herb is treated with herbicide and fungicide but not insecticides. Assurance is provided that the herbal drug is not treated with fumigants such as ethylene oxide or irradiation. The supplier of the passion flower has provided confirmation that the herbal substance is cultivated under GACP controlled conditions Control of Herbal Substance

An appropriate specification based on the Ph Eur monograph is applied and is acceptable. The specification is supported by the batch data provided.

Container Closure System Satisfactory details of the container closure system are provided and confirmation has been given that all components of the container closure system comply with Directive 2002/72/EC relating to plastic materials and articles intended to come into contact with foodstuffs.

Stability A confirmation is given that the herbal substance is tested prior to making the herbal preparation. A shelf-life for the herbal drug based on real time stability data is not necessary because it is a precursor of the active substance, the herbal preparation.

HERBAL PREPARATION: PASSION FLOWER DRY EXTRACT

General information Herbal preparation: Passion Flower dry extract Scientific name of the plant: Passiflora incarnata L. Parts of the plant used: Fragmented or cut, dried aerial parts of Passiflora incarnata,

it may contain flowers and / or fruits Ratio of the herbal substance to the herbal preparation (native): 5 – 7 : 1 Extraction solvent: Ethanol 50 % m/m

Manufacture Manufacture of the extract is a standard procedure. A satisfactory description of the manufacturing

process of the herbal substance and flow diagram has been provided.


The in-process controls (IPC) and specifications are satisfactorily detailed. There are no critical steps identified as the manufacture of the herbal preparation is considered a standard procedure. The dry extract is stored in tightly closed containers, protected from light, heat and moisture. Certificates of analysis for all materials used in the manufacture of the herbal preparation have been provided. 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

The extract is stored in a suitable container. Specifications have been provided by the supplier together with the declaration of compliance with Directive 2002/72/EC. Stability Stability studies have been carried out on batches of the herbal preparation under ICH long term and accelerated conditions in the containers proposed for marketing. The proposed retest period for the dry extract is 36 months when stored below 25°C protected from heat, light and moisture.

HERBAL PRODUCT Description and Composition of the Herbal Product

The formulation is straightforward and combines the active ingredient with well known pharmaceutical excipients, namely, maltodextrin, colloidal anhydrous silica, powdered cellulose, croscarmellose sodium, magnesium stearate, stearic acid, talc, sucrose, calcium carbonate E170, acacia, tragacanth, titanium dioxide E171, liquid glucose, spray dried, iron oxide hydrate E172 (yellow iron oxide), hypromellose and Capol 600 T.S. (containing white beeswax, carnauba wax, and shellac) The choice of excipients is based on experience and compatibility of the chosen excipients with the drug substance is confirmed by stability testing. All excipients used comply with their respective European Pharmacopoeial monograph, with the exception of Iron (III) oxide hydrate E 172, in the absence of a European Pharmacopoeial monograph for this colourant this is satisfactory. The colouring agent titanium dioxide E171 complies with Directive 95/45/EC. The Applicant has confirmed that all the relevant excipients comply with the monographs in the current Ph Eur. Certificates of analysis (CoA) of the excipients have been provided by the suppliers. The applicant has confirmed that the magnesium stearate and stearic acid are of vegetable origin. Appropriate certification has been provided from the suppliers. Iron (III) oxide hydrate E 172 (= yellow iron oxide): The colouring agent complies with the directive 95/45/EC relating to colouring agents allowed for use in medicinal products. It complies also with the directive 2001/50/EC, because there is no change according to iron oxide described.


Manufacture A description and flow-chart of the manufacturing method has been provided. The manufacturing method is a standard procedure for direct tabletting, coating and blistering. 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 packs of 21, 30, 60 and 90 coated tablets which are packed in PVC/ PVDC aluminium blisters that are inserted into a carton. 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 in the container type

proposed for marketing. Based on the results, a proposed shelf life of 4 years with the storage condition “Do not store above 30°C” 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 passion flower. NONCLINCIAL OVERVIEW The applicant has submitted a literature review with this application. An Expert Report on Safety was provided, which included reviews of some non-clinical data. The overview submitted in support of this application is satisfactory. Due to a shortage of published data on passion flower, it is not possible to assess if the safety package for the phytochemical constituents of passion flower 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. 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 passion flower is acceptable. An adequate literature review of passion flower 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

BACKROUND INFORMATION Passiflora products are widely available in the UK as herbal remedies exempt from licensing, under Section 12(2) of the Medicines Act 1968. Passion flower has been considered by the Committee on Herbal Medicinal Products (HMPC) and a Community Monograph has been adopted. The Community Monograph gives a traditional use only for passion flower as follows:

Traditional herbal medicinal product for relief of mild symptoms of mental stress and to aid sleep. LEGAL STATUS General Sales List (GSL) status is requested for the product. Passion flower is currently on the GSL order. PROPOSED INDICATION The applicant has proposed the following: ‘A traditional herbal medicinal product used for the temporary relief of symptoms associated with stress such as mild anxiety based on traditional use only’ This is satisfactory. PROPOSED POSOLOGY The applicant has proposed the following: ‘For oral short term use only. The patient should consult a healthcare practitioner if symptoms worsen or do not improve after 4 weeks. For adults and the elderly, take 1 tablet daily if required. Tablets should be swallowed whole with a little liquid. The tablets should not be chewed. This product is not indicated for use in patients less than 18 years old.’ This is satisfactory. EFFICACY No clinical efficacy data is required for registration of Traditional Herbal Medicinal Products (THMP). 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 of the evidence for the use of passion flower (Passiflora incarnata L.) within the EU for a period exceeding 30 years. Assessor’s comment: The information provided is considered to satisfactorily demonstrate that passion flower has been in use for at least 30 years (of which at least 15 have been in an EU member state), and that its use covers the indications sought. 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. A safety review has been provided and an Expert Report written by a pharmacist with expertise in herbal medicines. Assessor’s comment: The safety review is acceptable and includes most major studies. Adverse events associated with this product appear to be generally mild. PRODUCT LITERATURE The product literature (Summary of Product Characteristics, Patient Information Leaflet and labelling) for this product are medically 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. 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. An acceptable review of the available safety data on passion flower 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 passion flower 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 23056/0008

STEPS TAKEN FOR ASSESSMENT

1 The MHRA received the Traditional Herbal Registration application on 27 March 2007

2 Following standard checks and communication with the applicant the MHRA considered the application valid on 30 July 2007

3 Following assessment of the application the MHRA requested further information relating to the clinical dossier on 26 September 2007 and the quality dossier on 27 September 2007. The applicant responded to the MHRA’s requests, providing further information on the dossiers on 19 December 2008

4 A THR was granted on 27 February 2009


SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT RelaxHerb coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1 coated tablet contains 425mg of extract (as dry extract aqueous ethanolic 50% v/v) from Passion flower (Passiflora incarnata L.)(equivalent to 2125 – 2975 mg of Passion flower). Each coated tablet contains 187 mg of sucrose and 5 mg of glucose. For full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Coated tablet. Light-yellow, round, biconvex, smooth glossy surface without ruptures.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

A traditional herbal medicinal product used for the temporary relief of symptoms associated with stress such as mild anxiety based on traditional use only

4.2 Posology and method of administration

For oral short term use only. The patient should consult a healthcare practitioner if symptoms worsen or do not improve after 4 weeks. For adults and the elderly, take 1 tablet daily if required. Tablets should be swallowed whole with a little liquid. The tablets should not be chewed. This product is not indicated for use in patients less than 18 years old.

4.3 Contraindications

Hypersensitivity to Passion flower or any of the other ingredients in this product. Pregnancy Lactation Patients under 18 years of age.

4.4 Special warnings and precautions for use

Do not exceed the stated dose. If the condition worsens, or if symptoms persist for more than four weeks, or if adverse effects not mentioned in the package leaflet occur, consult a healthcare practitioner. This product contains glucose. 1 coated tablet contains max. 5mg of glucose. This product contains sucrose. 1 coated tablet contains max. 187mg of sucrose or 0.29 carbohydrate units.


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

4.5 Interaction with other medicinal products and other forms of interaction

Although no clinical data about interactions with synthetic sedatives are available, concomitant use with synthetic sedatives (such as benzodiazepines) is not recommended.

4.6 Pregnancy and lactation

The safety of the product during pregnancy and lactation has not been established. Use during pregnancy and lactation is not recommended.

4.7 Effects on ability to drive and use machines

May cause drowsiness and impair the ability to drive and operate machines. If affected, do not drive or operate machines.

4.8 Undesirable effects

One case of hypersensitivity (vasculitis) and one case of nausea and tachycardia have been reported. The frequency is not known. If other adverse reactions not mentioned above occur, a doctor or a qualified healthcare practitioner should be consulted.

4.9 Overdose

No case of overdose has been reported. Symptomatic and supportive measures should be taken as appropriate.

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

Not required as per Article 16c(1)(a)(iii) of Directive 2001/83/EC as amended., unless necessary for the safe use of the product. Tests on reproductive toxicity, genotoxicity and carcinogenicity have not been performed.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Extract excipients: Maltodextrin Silica, colloidal anhydrous Tablet core: Maltodextrin

Silica, colloidal anhydrous Cellulose, powdered


Croscarmellose sodium Magnesium stearate Stearic acid

Talc Coating:

Sucrose Talc Calcium carbonate E170 Acacia

Tragacanth Titanium dioxide E171 Liquid glucose, spray dried

Iron oxide hydrate E172 (=yellow iron oxide) Hypromellose Capol 600 T.S. containing:

Beeswax, white Carnauba wax

Shellac 6.2 Incompatibilities

Not applicable 6.3 Shelf life

The shelf life is 4 years 6.4 Special precautions for storage

Do not store above 30°C. 6.5 Nature and contents of container

Original packages contain 21, 30, 60 and 90 coated tablets RelaxHerb coated tablets are packed in PVC/ PVDC- aluminium blisters and inserted into a carton.

6.6 Special precautions for disposal

No special requirements

7 MARKETING AUTHORISATION HOLDER

Schwabe Pharma (UK) Ltd Alexander House Mere Park Dedmere Road Marlow Buckinghamshire SL7 1PD

8 MARKETING AUTHORISATION NUMBER(S)

THR 23056/0008

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION


27/02/2009 10 DATE OF REVISION OF THE TEXT

27/02/2009


PATIENT INFORMATION LEAFLET


LABELLING

Foil:


Cartons

relaxherb coated tablets thr 23056/0008 ukpar - gov.uk · mhra par; relaxherb coated tablets, thr...

Documents