UK Public Assessment Report · This is a summary of the public assessment report (PAR) for Seven Seas JointCare Comfrelieve Cream and Nature’s Best Comfrey Cream (PL 01932/0056)

UK Public Assessment Report

Seven Seas JointCare Comfrelieve Cream Nature’s Best Comfrey Cream

PL 01932/0056

Seven Seas Limited Trading As Merck Consumer Healthcare Limited

Seven Seas JointCare Comfrelieve Cream

PL 01932/0056

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LAY SUMMARY Seven Seas JointCare Comfrelieve Cream

Nature’s Best Comfrey Cream (Comfrey root extract)

This is a summary of the public assessment report (PAR) for Seven Seas JointCare Comfrelieve Cream and Nature’s Best Comfrey Cream (PL 01932/0056). Throughout this report the product will be referred to by the originally authorised product name, Seven Seas JointCare Comfrelieve Cream, for ease of reading. It explains how Seven Seas JointCare Comfrelieve Cream was assessed and its authorisation recommended, as well as its conditions of use. It is not intended to provide practical advice on how to use Seven Seas JointCare Comfrelieve Cream. For practical information about using Seven Seas JointCare Comfrelieve Cream, patients should read the package leaflet or contact their doctor or pharmacist. What is Seven Seas JointCare Comfrelieve Cream and what is it used for? Seven Seas JointCare Comfrelieve Cream is a medicine with a ‘well-established use’. This means that the medicinal use of the active substance of Seven Seas JointCare Comfrelieve Cream has been well-established in the European Union (EU) for at least ten years, with recognised efficacy and an acceptable level of safety. Seven Seas JointCare Comfrelieve Cream is used for the topical (put on the skin) treatment of joint pains, sprains, inflammation and strains associated with restricted movement. How does Seven Seas JointCare Comfrelieve Cream work? Seven Seas JointCare Comfrelieve Cream contains the active substance Comfrey Root Liquid Extract. This active substance has anti-inflammatory (reduces inflammation and swelling) and analgesic (pain relieving) properties. How is Seven Seas JointCare Comfrelieve Cream used? Seven Seas JointCare Comfrelieve Cream should be applied to the skin of the part of the body to be treated, as a 2 to 6 cm length thread, which is then massaged into the skin carefully. The amount of cream can be adjusted depending on the size of the joint to be treated and how bad the symptoms are. This should be repeated 4 times a day for up to 8 days. Please read Section 3 of the package leaflet for detailed information on dosing recommendations, the route of administration, and the duration of treatment. Seven Seas JointCare Comfrelieve Cream can be obtained without a prescription. What benefits of Seven Seas JointCare Comfrelieve Cream have been shown in studies? As the Comfrey root extract is a well-known substance, and its use in the topical treatment of joint pains, sprains, inflammation and strains associated with restricted movement is well-established, the applicant presented data from the scientific literature. The literature provided confirmed the efficacy and safety of Comfrey root extract in the topical treatment of joint pains, sprains, inflammation and strains associated with restricted movement.


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What are the possible side effects of Seven Seas JointCare Comfrelieve Cream? Like all medicines, this medicine can cause side effects, although not everybody gets them. For information about side effects that may occur when using Seven Seas JointCare Comfrelieve Cream, please refer to the package leaflet or the Summary of Product Characteristics (SmPC) available on the Medicines and Healthcare products Regulatory Agency website. Why is Seven Seas JointCare Comfrelieve Cream approved? It was considered that the benefits of Seven Seas JointCare Comfrelieve Cream outweigh the risks, and the grant of this marketing authorisation was recommended. What measures are being taken to ensure the safe and effective use of Seven Seas JointCare Comfrelieve Cream? Known side effects are continuously monitored. Furthermore, new safety signals reported by patients and healthcare professionals will be monitored and reviewed continuously as well. Other information about Seven Seas JointCare Comfrelieve Cream The marketing authorisation for Seven Seas JointCare Comfrelieve Cream was granted in the UK on 31 May 2007.

The full PAR for Seven Seas JointCare Comfrelieve Cream follows this summary. For more information about treatment with Seven Seas JointCare Comfrelieve Cream, read the package leaflet or contact your doctor or pharmacist. This summary was last updated in April 2015.


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TABLE OF CONTENTS

I Introduction Page 5 II Quality aspects Page 6 III Non-clinical aspects Page 7 IV Clinical aspects Page 8 V User consultation Page 9 VI Overall conclusion, benefit/risk assessment

and recommendation Page 9

Table of content of the PAR update

Page 16


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I Introduction Based on the review of the data on quality, safety and efficacy, the UK granted a marketing authorisation for the medicinal product Seven Seas JointCare Comfrelieve Cream (PL 01932/0056) to Seven Seas Limited (Trading as Merck Consumer Healthcare) on 31 May 2007. This medicinal product is available from pharmacies and other outlets without prescription (General Sales List (GSL) medicine). This application for Seven Seas JointCare Comfrelieve Cream was submitted as an abridged application in accordance with article 10a of Directive 2001/83/EEC. This is justified, since the constituents of the product are generally well-established for medicinal use, with similar products being marketed in numerous European countries, including the UK. This product contains liquid extract of Comfrey root, Symphytum officinale L., and is indicated for the symptomatic treatment of joint pain, sprains, inflammation and strains associated with restricted joint mobility.


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II Quality aspects II.1 Introduction This application is submitted according to Article 10a of Directive 2001/83/EC, as amended, claiming to be an application for a product containing an active substance of well-established use. Seven Seas JointCare Comfrelieve Cream is formulated as a beige coloured cream 100 g Seven Seas JointCare Comfrelieve Cream contains 35 g of liquid extract (1:2) from Comfrey root (Symphytum officinale). The excipients present in the cream are arachis oil (peanut), cetylstearyl alcohol, glycerol-1-stearate, sodium lauryl sulphate, lavender oil, pine needle oil, bergamot oil, other perfumes, purified water and Phenonip (phenoxyethanol, parabens: E214, E216, E218, butyl-4-hydroxybenzoate). Seven Seas JointCare Comfrelieve Cream is packaged in in aluminium tubes in sizes of 50, 100 and 150g. The screw cap is plastic. II.2 Drug Substance Comfrey root extract The active ingredient is a liquid extract from the root of the Comfrey plant (extraction solvent: ethanol 60 % (v/v)). Fresh Comfrey roots are used to prepare the extract. The plants are cultivated in Germany without any chemical treatments. Plants are also collected from the wild in the Balkans. The formulation contains 35 g of Comfrey root liquid extract per 100 g of cream. The concentration of the active ingredient has been selected based on the German Commission E monograph on Comfrey root. Herbal drug Fresh Comfrey root is tested for contaminants (heavy metals, aflatoxins and pesticides) before use. No chemical treatments, such as pesticides, fumigants or ethylene oxide, are allowed. Harvested roots are washed intensively with water before extraction. An appropriate specification based on the DAC monograph has been provided. Analytical methods have been appropriately validated and are satisfactory for ensuring compliance with the relevant specifications. The herbal drug preparation a liquid extract. The information provided on the production of the extract is satisfactory. Batch analysis data are provided and comply with the proposed specification. Stability studies have been carried out on batches of extract stored under ICH conditions. The results support a retest period of 12 months when stored under long term conditions.


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II.3 Medicinal Product Pharmaceutical development The excipients chosen for the formulation are mainly standard excipients of pharmacopoeial quality. The inclusion of each excipient has been justified. All excipients used comply with their respective European Pharmacopoeial monograph. In the absence of a European Pharmacopoeial monograph an appropriate specification is applied, this is acceptable. Satisfactory certificates of analysis have been provided for all excipients. No materials of animal origin are used to make this product. Manufacture of the product s The manufacturing process is relatively straightforward for this type of dosage form and a description and flow-chart of the manufacturing method has been provided. In-process controls are appropriate considering the nature of the product and the method of manufacture. Process validation has been carried out and the results are satisfactory. Finished Product Specifications 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. Stability of the products Finished product stability studies have been conducted in accordance with current guidelines. Based on the results, a shelf-life of 3 years when stored in an unopened container and 1 year upon first opening the container has been set, which is satisfactory. There are no special precautions for storage. II.4 Discussion on chemical, pharmaceutical and biological aspects A marketing authorisation may be granted for this product. III Non-clinical aspects The application was submitted as a bibliographic application for an active of well-established use, according to Article 10(a) of Directive 2001/83/EC, as amended. No new non-clinical data have been supplied with this application and none are required for an application of this type. A non-clinical expert report has been written by a suitably qualified person and is satisfactory.


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IV Clinical aspects IV.1 Introduction Seven Seas JointCare Comfrelieve Cream is a herbal drug containing liquid extract of Comfrey root as the therapeutically active ingredient. Comfrey has been used for centuries for the treatment of a wide variety of diseases due to its anti-inflammatory, analgesic and astringent properties. Extracts of the root of the plant are nowadays used externally for blunt injuries, to promote the healing of wounds and for diseases of bones and joints. Seven Seas JointCare Comfrelieve Cream is indicated for the symptomatic treatment of joint pain, sprains, inflammation and strains associated with restricted joint mobility. If not otherwise prescribed, depending on the size of the joint to be treated and the severity of the symptoms, apply a thread of cream of 2 - 6 cm in length four times daily for 8 days. Treatment duration should not exceed 21 days. A satisfactory clinical expert report has been submitted in support of this application. IV.2 Pharmacokinetics The pharmacological properties of Comfrey root are mainly attributed to the compounds allantoin and rosmarinic acid. No pharmacokinetic investigations in humans are available. The only studies conducted are those described in the literature regarding rosmarinic acid. The applicant states that investigations of the pharmacokinetics of the Comfrey root extract provide no information about the absorption, metabolism and elimination of the actives. According to the “Comments on Part 4 of Annex to Council Directive 75/318/EE, Euro Direct No 114/98” pharmacokinetic data is not required unless there are ground for safety concerns. IV.3 Pharmacodynamics Seven Seas JointCare Comfrelieve Cream is a topical anti-inflammatory drug on a plant base. The root extract in this product has an anti-inflammatory and analgesic action and promotes granulation and tissue regeneration. Allantoin, mucopolysaccharides and tannins can be mentioned as the constituents responsible for efficacy. IV.4 Clinical efficacy This application was initially based on the bibliography of two clinical studies, a pilot study by Lucker and a pivotal study by Koll. The pivotal study by Koll looked at 140 patients with ankle sprains and compared an identical product versus placebo. The evidence of efficacy supported by the studies allowed the approval of this product in the treatment of acute unilateral ankle distortion. A further clinical study was conducted that showed evidence of efficacy when Seven Seas JointCare Comfrelieve Cream is applied in patients with painful gonarthrosis for 21 days. There were no safety concerns. IV.5 Clinical safety Please see efficacy above.


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IV.6 Risk Management Plan (RMP) This application was submitted, and approved, before implementation of the Pharmacovigilance legislation on 21 July 2012 and, therefore, preceded the mandatory requirement of an RMP for a new marketing authorisation. A suitable justification for not submitting a Risk Management Plan was provided and this was considered satisfactory. IV.7 Discussion on the clinical aspects The marketing authorisation application (MAA) form, SmPC, labelling and package leaflet are satisfactory. This is a national bibliographical application for Seven Seas JointCare Comfrelieve Cream, which has been authorised in Germany since 1966 and in Switzerland since 1999. This product is a herbal drug containing liquid extract of Comfrey root as the therapeutically active ingredient. Comfrey has been used for centuries for the treatment of a wide variety of diseases due to its anti-inflammatory, analgesic and astringent properties. A clinical expert report provides a discussion of the relevant published data in relation to this application. The efficacy and safety of Seven Seas JointCare Comfrelieve Cream are satisfactory for the grant of a product licence. V User consultation This application was submitted before 01 July 2005 and, therefore, preceded the UK requirement for user consultation with target patient groups on the package leaflet for a new marketing authorisation. VI Overall conclusion, benefit/risk assessment and recommendation Quality The important quality characteristics of Seven Seas JointCare Comfrelieve Cream are well defined and controlled. The specifications and batch analytical results indicate consistency from batch to batch. There are no outstanding quality issues that would have a negative impact on the benefit/risk balance. Non-clinical No new non-clinical data have been supplied with this application and none are required for an application of this type. A non-clinical expert report has been written by a suitably qualified person and is satisfactory. Clinical The efficacy of Comfrey root extract has been well documented in the past. No new or unexpected safety concerns arise from this application. The SmPC, package leaflet and labelling are satisfactory.


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Risk benefit assessment The quality of the product is acceptable and no new non-clinical or clinical safety concerns have been identified. The risk benefit ratio is considered to be positive. The Summary of Product Characteristics (SmPC), package leaflet and labelling are satisfactory and in-line with current guidelines. In accordance with Directive 2012/84/EU, the current approved UK versions of the SmPC and package leaflet for this product is available on the MHRA website. The labels approved at the grant of this marketing authorisation are listed below: 50 g tube:


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50 g carton:


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100 g tube:


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100g carton:


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150 g tube:


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150 g carton:


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Table of content of the PAR update

Steps taken after the initial procedure with an influence on the Public Assessment Report (Type II variations, PSURs, commitments)

Date submitted Application type Scope Outcome 16 December 2008 Type IB To add the product

name Seven Seas Comfrelieve Cream to the licence.

Granted 17 December 2008

23 July 2009 Type IB To add the product name ‘Nature's Best Comfrey Cream’ to the licence.

Granted 18 November 2009

17 July 2012 Type II To update the SmPC in accordance with guideline on 'Excipients in the label and package leaflet of medicinal products for human use' (CPMP/463/00 Final) and the Company Core Data Sheet (CCDS).

Granted 23 February 2015


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Annex I

Reference: PL 01932/0056 - 0008 Product: Seven Seas JointCare Comfrelieve Cream Marketing Authorisation Holder: Seven Seas Limited Active Ingredients: Comfrey root liquid extract Reason: To add the product name ʻSeven Seas Confrelieve Cream’ to the licence. Supporting Evidence Section 1 of the SmPC has been updated. Amended labelling and a package leaflet were submitted to the Patient Information Quality Unit (PIQU) for assessment and therefore were not included in the submission documents for this Variation. Evaluation The proposed product name is acceptable. The SmPC has been updated accordingly. The current approved UK versions of the SmPC and package leaflet for this product are available on the Medicines and Healthcare products Regulatory Agency website. Decision - Granted Date - 17 December 2008


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Annex II

Reference: PL 01932/0056 - 0012 Product: Seven Seas JointCare Comfrelieve Cream Seven Seas Comfrelieve Cream Marketing Authorisation Holder: Seven Seas Limited Active Ingredients: Comfrey root liquid extract Reason: To add the product name Nature's Best Comfrey Cream to the licence. Supporting Evidence Section 1 of the SmPC has been updated and amended labelling and a package leaflet was submitted. Evaluation The proposed product name is acceptable and the product information has been updated accordingly. The current approved UK versions of the SmPC and package leaflet for this product are available on the Medicines and Healthcare products Regulatory Agency website. The approved labelling, following this update, is presented below. Decision - Granted Date - 18 November 2009


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Annex III

Reference: PL 01932/0056 - 0026 Product: Seven Seas JointCare Comfrelieve Cream; Nature’s Best

Comfrey Cream Marketing Authorisation Holder: Seven Seas Limited Active Ingredients: Comfrey root liquid extract Reason: To update sections 4.4, 4.6 and 4.8 of the SmPC in accordance with guideline on 'Excipients in the label and package leaflet of medicinal products for human use' (CPMP/463/00 Final) and the Company Core Data Sheet (CCDS). As a consequence the label and package leaflet have been updated. Additionally the product name ‘Seven Seas Comfrelieve Cream’ was removed from section 1 of the SmPC. Supporting Evidence Sections 1, 4.4, 4.6 and 4.8 of the SmPC have been updated and amended labelling and package leaflets were submitted. Evaluation The proposed product changes are acceptable and the product information has been updated accordingly. The current approved UK versions of the SmPC and package leaflet for this product are available on the Medicines and Healthcare products Regulatory Agency website. The approved labelling text following this update is presented below. Decision - Granted Date - 23 February 2015


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REGULATORY TEXT – CARTON

SEVEN SEAS JOINTCARE COMFRELIEVE CREAM, PL 01932/0056

Top of Carton

Seven Seas Jointcare

COMFRELIEVE ® CREAM

Front of Carton (design panel)

Seven Seas JointCare


100 g of cream contains 35 g of liquid extract (1:2) from Comfrey root (Symphytum officinale) (Extraction solvent: Ethanol 60% (v/v))

FOR CUTANEOUS USE

FOR THE SYMPTOMATIC TREATMENT OF JOINT PAINS, SPRAINS, INFLAMMATION, AND STRAINS ASSOCIATED WITH RESTRICTED JOINT MOBILITY

50 g

Side of carton (text panel)

Seven Seas Jointcare 50 g


Active ingredient: 100 g of cream contains: 35 g of liquid extract (1:2) from Comfrey root (Symphytum officinale) (Extraction solvent: Ethanol 60% (v/v)). Also contains arachis oil (peanut), cetostearyl alcohol, glycerol-1-stearate, sodium lauryl sulphate, lavender oil, pine needle oil, other perfumes, purified water, phenopip (phenoxyethanol, parabens: E214,E216, E218, butyl-4-hydroxybenzoate).

PL 01932/0056

PL Holder and Manufacturer: Seven Seas Limited Trading as Merck Consumer Healthcare Limited, Hedon Road, Marfleet, Hull, HU9 5NJ Do not store above 30°C

Seven Seas, Seven Seas JointCare and Comfrelieve are registered Trade Marks licensed to Seven Seas Limited by Merck Consumer Healthcare Limited


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Back of carton (design panel)

Seven Seas JointCare


Comfrey root extract

FOR CUTANEOUS USE

FOR THE SYMPTOMATIC TREATMENT OF JOINT PAINS, SPRAINS, INFLAMMATION, AND STRAINS ASSOCIATED WITH RESTRICTED JOINT MOBILITY


Seven Seas Jointcare 50 g


Before use, always read the enclosed leaflet carefully.

Do not use in the case of hypersensitivity to any of the constituents, peanut, or soya.

Do not use if pregnant or breastfeeding.

Contains arachis oil (peanut oil), benzyl benzoate, parabens and cetostearyl alcohol, see leaflet for further information.

Adults, children aged 12 years and over and the elderly:

Directions: For application to the skin only. Depending on the size of the part of the body to be treated and the severity of the symptoms, apply a thread of cream of 2-6cm in length four times a day onto the affected area for eight days.

Do not apply to the eyes, mucous membranes or open wounds.

Application may only be made to intact skin. Not recommended in children under 12 years of age.

STORE OUT OF REACH AND SIGHT OF CHILDREN

50 g

Bottom of carton

Expiry date:

Lot no.:

For External Use Only


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REGULATORY TEXT – CARTON

NATURE’S BEST COMFREY CREAM, PL 01932/0056

Top of Carton

Comfrey Cream

COMFREY ROOT EXTRACT

Front of Carton (design panel)

Nature’s Best® Comfrey Cream

COMFREY ROOT EXTRACT (FOR CUTANEOUS USE)

For the symptomatic treatment of joint pains, sprains, inflammation, and strains associated with restricted joint mobility.



COMFREY ROOT EXTRACT 50 g

Active ingredient: 100 g of cream contains: 35 g of liquid extract (1:2) from Comfrey root (Symphytum officinale) (Extraction solvent: Ethanol 60% (v/v)).

Also contains arachis oil (peanut), cetostearyl alcohol, glycerol-1-stearate, sodium lauryl sulphate, lavender oil, pine needle oil, other perfumes, purified water, phenopip (phenoxyethanol, parabens: E214,E216, E218, butyl-4-hydroxybenzoate).

PL 01932/0056

PL Holder and Manufacturer: Merck Consumer Healthcare Limited, Hedon Road, Marfleet, Hull, HU9 5NJ

For further information contact Nature’s Best on 01892 552117.

Merck Consumer Healthcare Limited is a company of Merck KGaA.

Do not store above 30°C


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Back of carton (design panel)


COMFREY ROOT EXTRACT (FOR CUTANEOUS USE)

For the symptomatic treatment of joint pains, sprains, inflammation, and strains associated with restricted joint mobility.



COMFREY ROOT EXTRACT 50 g

Before use, always read the enclosed leaflet carefully.

Do not use in the case of hypersensitivity to any of the constituents, peanut, or soya.

Do not use if pregnant or breastfeeding.

Contains arachis oil (peanut oil), benzyl benzoate, parabens and cetostearyl alcohol, see leaflet for further information.

Adults, children aged 12 years and over and the elderly:

Directions: For application to the skin only. Depending on the size of the part of the body to be treated and the severity of the symptoms, apply a thread of cream of 2-6cm in length four times a day onto the affected area for eight days. Do not apply to the eyes, mucous membranes or open wounds. Application may only be made to intact skin. Not recommended in children under 12 years of age.

STORE OUT OF REACH AND SIGHT OF CHILDREN

Bottom of carton

Expiry date:

Lot no.:

Lamberts Healthcare Ltd., trading as Nature’s Best®.

Nature’s Best, Century Place, Tunbridge Wells TN2 3BE, England. Tel 01892 552117

For External Use Only

Documents

UK Public Assessment Report · This is a summary of the public assessment report (PAR) for Seven Seas JointCare Comfrelieve Cream and Nature’s Best Comfrey Cream (PL 01932/0056)