kaloba syrup thr 05332/0006 ukpar - gov.uk · the active ingredient of kaloba syrup comes from the...

MHRA PAR; KALOBA SYRUP, THR 05332/0006 1

Kaloba Syrup

THR 05332/0006

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 18

Labelling Page 22


KALOBA SYRUP

THR 05332/0006

LAY SUMMARY

The Medicines and Healthcare products Regulatory Agency (MHRA) granted Dr. Willmar Schwabe GmbH & Co. KG, Germany a Traditional Herbal Registration certificate for the traditional herbal medicinal product Kaloba Syrup (Traditional Herbal Registration number: THR 05332/0006). This product is available without prescription and can be bought from pharmacies and other outlets. The active ingredient of Kaloba Syrup comes from the roots of the Pelargonium plant (Pelargonium sidoides DC). Kaloba Syrup is a traditional herbal medicinal product used to relieve the symptoms of upper respiratory tract infections including the common cold, such as sore throat, cough and blocked or runny nose. This registration is based exclusively upon the use of Pelargonium sidoides 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.


KALOBA SYRUP

THR 05332/0006

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 Kaloba Syrup (THR 05332/0006) to Dr. Willmar Schwabe GmbH & Co. KG on 11 June 2010. 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. Kaloba is an orange to light brown, viscous syrup containing liquid extract from the roots of the Pelargonium plant (Pelargonium sidoides DC). The product is used to relieve the symptoms of upper respiratory tract infections including the common cold, such as sore throat, cough and blocked or runny nose. This THR is based exclusively on evidence of traditional use of Pelargonium root. The recommended dose is 7.5 ml of the syrup three times per day for people over 12 years and 5 ml three times per day for children aged between 6-12 years. The data supplied by the applicant demonstrate at least 30 years of traditional use of Pelargonium sidoides including at least 15 years in the European Community. A satisfactory review of the available safety data on Pelargonium sidoides has also been provided, together with an expert report supporting the proposed product.


PHARMACEUTICAL ASSESSMENT

HERBAL SUBSTANCE: PELARAGOMIUM SIDOIDES

Scientific name of the plant: Pelargonium sidoides DC Synonyms of the herbal substance: Geranium sideaefolium Thumb. Family: Geraniaceae Parts of the plant used: Roots (dried) of Pelargonium

Manufacture

Plants grown in the wild are harvested from September through to April. Cultivated plants are collected after about 3 years of growth. The roots are washed, cut and dried. The harvested plant material is transported and then stored in sacks in warehouses under dry conditions and at room temperature.

The herbal substance is produced in accordance with Good Agricultural and Collection Practice (GACP) (EMEA/HMPC/246816/2005).

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.

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

Container Closure System A suitable container is used to store the herbal substance, which is kept under dry conditions at room temperature.

Stability

No stability data are provided. 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:

Herbal preparation: Dried liquid extract of the dried roots of Pelargonium sidoides

Scientific name of the plant: Pelargonium sidoides Parts of the plant used: Dried roots

Ratio of the herbal substance to the herbal preparation (native): 1:8-10 Extraction solvent: Ethanol 11 % w/w

Manufacture


A satisfactory description of the manufacturing process of the herbal preparation has been provided. The in-process controls are satisfactorily detailed. There are no critical steps identified as the manufacture of the herbal preparation is considered a standard procedure. 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.

Reference Standards or Materials

Suitable details have been provided for the reference standards used.

Container Closure System Since the herbal preparation is processed immediately, no container closure system is necessary.

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

HERBAL PRODUCT

Description and Composition of the Herbal Product The herbal product is described as being an orange to light brown, viscous syrup. The excipients used in the product are maltodextrin, xylitol, glycerol (85%), citric acid (anhydrous), potassium sorbate, xanthan gum and purified water. 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. Certificates of Analysis of the excipients are provided. Manufacture A description and flow-chart of the manufacturing method has been provided. The manufacturing method is a standard 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 packed in class III hydrolytic amber glass bottles (Ph. Eur.), with an LDPE pourer as dosage aid, screw cap (PP) with seal (PEHD/PELD) and a measuring cup (PP). These containers come in pack sizes of 100 ml or 200 ml syrup. The suitability of the finished product stored in the package is confirmed through the stability studies. Specifications and certificates are provided from the manufacturers for all components. Confirmation is provided that all components of the container closure system comply with Directive 2008/39/EC relating to plastic materials and articles intended to come into contact with foodstuffs.

Stability Finished product stability studies have been conducted in accordance with current guidelines. Based on the results, a product shelf-life of 3 years 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

NONCLINICAL ASPECTS The Expert Safety Report submitted by the applicant lists relevant references to published work studying the toxicology of Pelargonium sidoides. 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 pharmacologist with suitable expertise in Herbal medicines. The overview submitted in support of this application is satisfactory. It is not possible to assess if the published nonclinical data on Pelargonium sidoides are 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 applicant has provided an undertaking that an Ames test of the product will be carried out before the next licence renewal. 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 demonstrates the traditional use of Pelargonium sidoides. An adequate literature review of Pelargonium sidoides 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

PROPOSED INDICATION The applicant has proposed the following: “Traditional herbal medicinal product used to relieve the symptoms of upper respiratory tract infections including the common cold, such as sore throat, cough and blocked or runny nose, 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. A literature review has been submitted, along with a comprehensive summary. The information provided is considered to satisfy the requirement to demonstrate 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, addressed for this aspect. 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, along with an Expert Report written by a suitably qualified clinician. The review is comprehensive and summarises all safety data (including that from the most recently published literature), both from the literature and based on post marketing surveillance. PRODUCT LITERATURE 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 demonstrate use for at least 30 years, of which at least 15 years have been in an EU Member State, required for registration under the Traditional Herbal Medicines Product Directive. A satisfactory review of the available safety data relating to Pelargonium sidoides has been provided together with an expert report supporting the registration of the 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 preclinical study reports 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 Pelaragomium sidoides 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.


KALOBA SYRUP

THR 05332/0006

STEPS TAKEN FOR ASSESSMENT

1 The MHRA received the Traditional Herbal Registration application on 31 July 2009

2 Following standard checks and communication with the applicant the MHRA considered the application valid on 11 August 2009

3 Following assessment of the application the MHRA requested further information relating to the quality dossier on 17 February 2010 and the clinical dossier on 18 February 2010

4 The applicant responded to the MHRA’s requests, providing further information on the quality dossier on 27 April 2010 and the clinical dossier on 13 and 25 May 2010

5 A THR was granted on 11 June 2010


SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT

Kaloba syrup 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Active substance: 100 g (= 93.985 ml) syrup contain 0.2506 g dried liquid extract from the roots of Pelargonium sidoides DC (1 : 8 - 10) (EPs® 7630). The extraction agent is 11% ethanol (w/w). For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Syrup Kaloba is an orange to light brown, viscous syrup.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications Traditional herbal medicinal product used to relieve the symptoms of upper respiratory tract infections including the common cold, such as sore throat, cough and blocked or runny nose, based on traditional use only.

4.2 Posology and method of administration For oral use Shake the bottle well before use Adults, the elderly and adolescents over 12 years of age: Take 7.5 ml of the syrup three times per day. Children aged between 6-12 years: Take 5 ml of the syrup three times per day. Syrup is to be taken in the morning, midday and evening. The use in children under 6 years of age is not recommended (see section 4.4 “Special warnings and precautions for use”.) Duration of use After relief of symptoms, continuation of treatment is recommended for a further 2 – 3 days in order to prevent a relapse. However, treatment duration should not exceed 2 weeks.


If the symptoms persist during the use of the medicinal product, a doctor or a qualified health care practitioner should be consulted.

4.3 Contraindications - hypersensitivity to the active substance or to any of the excipients - increased tendency to bleeding - patients using coagulation-inhibiting drugs - severe hepatic and renal diseases due to lack of adequate data

4.4 Special warnings and precautions for use

In the patient information leaflet, the patient is advised to consult a doctor immediately if his or her condition does not improve within one week, in case of fever lasting for several days or in case of shortness of breath or blood in the sputum. On theoretical grounds Kaloba should not be used where there is a likelihood of increased tendency to bleeding or use of coagulation-inhibiting drugs. Kaloba should not be used in case of severe hepatic and renal diseases, due to lack of adequate data. The use of this product in children or adolescents under 6 years of age is not recommended because data are not sufficient and medical advice should be sought.

4.5 Interaction with other medicinal products and other forms of interaction Drug interactions have not been reported to date. However, due to the potential effect of Kaloba on coagulation parameters, this product may enhance the effect of coagulation-inhibiting drugs such as warfarin and should not be taken concomitantly with these drugs. (see section 4.3).

4.6 Pregnancy and lactation

Safety during pregnancy and lactation has not been established. In the absence of sufficient data use during pregnancy and lactation is not recommended.

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

The evaluation of adverse reactions is based on the following information on frequency:

Very common: more than 1 out of 10 treated persons

Common: less than 1 out of 10 but more than 1 out of 100 treated persons


Uncommon: less than 1 out of 100 but more than 1 out of 1000 treated persons

Rare: less than 1 out of 1000 but more than 1 out of 10 000 treated persons

Very rare: less than 1 out of 10 000 treated persons including cases with unknown frequency

Gastro-intestinal complaints such as stomach pain, heartburn, nausea or diarrhoea may occur uncommonly (≥ 1/1,000 to < 1/100) during treatment with Kaloba. In rare cases (≥ 1/10,000 to ≤ 1/1,000) mild bleeding from the gums or nose may occur. Furthermore, hypersensitivity reactions (e.g. exanthema, urticaria, pruritus of skin and mucous membranes) have been described in rare cases. Such reactions may occur after the first intake of the product. In very rare cases (≤ 1/10,000) serious hypersensitivity reaction with swelling of the face, dyspnoea and drop in blood pressure may occur. In single cases, signs indicating disturbances of liver function have been reported after the intake of Kaloba; the causal relationship between this effect and the use of the product has not been demonstrated. If other adverse reactions not mentioned above occur, a doctor or a qualified health care practitioner should be consulted.

4.9 Overdose

The effects of overdose are unknown. Although there are no data on cases of overdose, overdose is likely to increase side-effects. Thus, treatment should be symptomatic and as clinically indicated.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Not required as per article 16 c (1) (a) (iii) of Directive 2001/83/EC as amended.

5.2 Pharmacokinetic properties Not required as per article 16 c (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.


6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients Extract: Maltodextrin Syrup: Xylitol Glycerol 85% Citric acid anhydrous Potassium sorbate Xanthan gum Purified water

6.2 Incompatibilities Not applicable.

6.3 Shelf life

3 years. The shelf-life of the syrup after the container has been opened is 6 months. Note for the patient: Since Kaloba syrup is a natural product, slight variations in colour and taste may occur.

6.4 Special precautions for storage

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

Amber glass bottles, hydrolytic class III (Ph. Eur.), with pourer as dosage aid (LDPE), screw cap (PP) with seal (PEHD/PELD) and a measuring cup (PP), in pack sizes of 100 ml or 200 ml syrup. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Dr. Willmar Schwabe GmbH & Co. KG Willmar-Schwabe-Str. 4 D-76227 Karlsruhe Germany Distributed in the UK by: Schwabe Pharma (UK) Ltd Alexander House Mere Park Dedmere Road Marlow


Buckinghamshire SL7 1PD

8 MARKETING AUTHORISATION NUMBER(S)

THR 05332/0006

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION 11/06/2010 10 DATE OF REVISION OF THE TEXT

11/06/2010


PATIENT INFORMATION LEAFLET


LABELLING

100 ml pack Label:


Carton:


200 ml pack Label:


Carton:

kaloba syrup thr 05332/0006 ukpar - gov.uk · the active ingredient of kaloba syrup comes from the...

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