Preliminary Renewal Assessment Report (PRAR) Hansaplast med Lokale Schmerz-Therapie

Bundesinstitut für Arzneimittel
und Medizinprodukte
Preliminary Renewal Assessment Report
(PRAR)
Hansaplast med Lokale Schmerz-Therapie
ABC Wärme-Pflaster Capsicum
DE/H/0254/001/R/002
Applicant: Beiersdorf AG
Renewal Procedure Start Date
09.05.2012
Circulation of the preliminary assessment report 19.06.2012
Comments due from CMSs
03.07.2012
Proposed new common Renewal Date
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The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health.
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TABLE OF CONTENTS
I.
RECOMMENDATION
4
II.
EXECUTIVE SUMMARY
4
II.1
II.2
II.3
INTRODUCTION
ABOUT THE PRODUCT
GENERAL COMMENTS ON THE SUBMITTED DOSSIER
4
4
5
III.
SCIENTIFIC DISCUSSION
5
III.1
III.2
III.3
III.4
III.4.1
III.4.2
III.5
VI.
V
V.1.
V.2.
QUALITY
NONCLINICAL
CLINICAL EFFICACY AND SAFETY
PRODUCT INFORMATION
CLINICAL AND NON-CLINICAL COMMENTS ON THE PRODUCT INFORMATION
PHARMACEUTIC AL COMMENTS ON THE PRODUCT INFORMATION
POST-APPROVAL COMMITMENTS TO BE FULFILLED BY THE MAH
OVERALL CONCLUSION AND BENEFIT-RISK ASSESSMENT
LIST OF QUESTIONS AS PROPOSED BY RMS
POTENTIAL SERIOUS RISKS TO PUBLIC HEALTH
OTHER CONCERNS
5
6
6
8
8
8
9
9
9
9
9
IV.
<ANNEX (IF APPLICABLE)
11
V.
PROPOSED CHANGES TO THE <SPC>, <PL>, <LABELLING> ANNOTATED WITH
THE RMS’S COMMENTS AFTER EACH SECTION>
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COVER PAGE
Invented name of the medicinal product
INN (or common name) of the active
substance(s):
Pharmaco-therapeutic group
(ATC Code):
Pharmaceutical form(s) and strength(s):
Reference Number for the MR-Procedure:
Member States concerned:
In the Reference Member State:
Marketing authorisation holder (name and
address):
Names and addresses of manufacturers
responsible for batch release in the EEA:
Date of first authorisation:
Marketing Authorisation number(s):
Date of Assessment Report:
Name, telephone and telefax number of
contact point in the Member State for
discussion on issues raised by the
Assessment Report ( where applicable )
Hansaplast med Lokale Schmerz-Therapie
ABC Wärme-Pflaster Capsicum
Soft extract of cayenne pepper (4-7:1)
corresponding to 11 mg capsaicin. Extract
solvent is ethanol 80% (v/v)
M02AB
Medicated plaster
DE/H/0254/001/R/002
AT, DK, FR, LU, NO, SE
Germany
Beiersdorf AG
Unnastraße 48
20253 Hamburg
Beiersdorf AG
Unnastraße 48
20245 Hamburg
25.05.2000
44827.00.00
Name
Tel:
Fax:
Marion Schmitz-Drews
+49 (0)228 99 307-5667
+49 (0)228 99 307-5396
Email: [email protected]
Names of the assessors
Nonclinical:
Name(s)
Tel:
Jacqueline Wiesner
+49 (0)228 99 307-5980
Clinical :
Name(s)
Tel:
Dr. Godehard Krollmann
+49 (0)228 99 307-5628
Pharmacovigilance
Name(s)
Jens Rotthauwe
Tel:
+49 (0)228 99 307-3242
Quality:
Name(s)
Tel:
Michael Pfeiffer
+49 (0)228 99 307-5624
Pharmaceutical Comments
Name(s)
Tel:
+49 (0)228 99 307-
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I. RECOMMENDATION
Based on the review of the data submitted for this renewal application, the RMS recommends the
renewal of the Marketing Authorisation for Hansaplast med Lokale Schmerz-Therapie ABC
Wärme-Pflaster Capsicum,
provided that the MAH commits to fulfil the commitments as detailed in this assessment report
(see section III.5) and satisfactory responses are given to the preliminary list of questions (section
V).
II. EXECUTIVE SUMMARY
II.1 Introduction
Capsicum pain plaster 11 mg was first authorised in Germany on 25 May 2000 and in Europe on
25 May 2000. Capsicum pain plaster 11 mg has been marketed in Austria, Denmark, France,
Germany, Luxemburg Norway and Sweden during the reporting period. It is approved in a total of
7 countries and available in a total of 7 countries worldwide. Approximately 8.390.000 packaging
units containing 1 or 2 plasters have been distributed within the reporting period. There are no
pending variations at this time.
II.2 About the product
Mode of action.
Capsaicin is the primary pungent principle in the fruit of capsicum plants. The precise mechanism
of action has not been fully elucidated.
Topically applied capsaicin triggers local irritation, which manifests symptomatically as erythema
and a burning, sometimes itchy, sensation. This is generally attributed to a neurogenic
inflammatory process and explained by the release of the neurotransmitter substance P. A
clinical trial carried out with Elastoplast Heat Plaster has shown that capsaicin can induce
erythema and initial sensation of heat, sometimes in combination with itching.
The second stage of the capsaicin action is associated with antinociceptive effects, the duration
of which ranges from hours to weeks. Substance P depletion of the neurone following repeated
application leads to a long-term desensitisation to burning and pain.
Pharmacological classification.
Pharmacotherapeutic group: Capsicum preparations and similar agents
ATC-Code: M02AB
Indication
Elastoplast Heat Plaster 11 mg medicated plaster is to be used externally for the relief of muscle
pain, e.g. lower back pain.
Recommendation for use (including a possible risk management strategy)
Posology.
A maximum of one plaster per day should be applied and left in place for at least 4 and up to 12
hours. There should be an interval of at least 12 hours before a new plaster is applied on the
same application area.
New plasters should be applied until the pain subsides, if necessary, up to 3 weeks in duration.
Elastoplast Heat Plaster are not recommended for use in children below 12 years of age due to a
lack of clinical data on safety and efficacy.
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Method: The covering paper is peeled off and the plaster applied to dry, unbroken skin directly
over the painful area, with the adhesive side to the skin.
To remove the plaster, one corner is raised, and the plaster is carefully pulled off.
Any remnants remaining on the skin after detachment of the plaster can be removed with
vegetable oil, a moisturising cream or cold water.
Hands should be washed with soap and water after touching handling the plaster.
II.3 General comments on the submitted dossier
The documents submitted should be listed especially:
MRP Renaval Application form including 7 Annexes,
GMP certification for Baiersdorf AG (5 years old),
Declaration of the qualified persons from the MAH regarding GMP compliance for
manufacturer of the active substance, (app. 3 years old),
Chronological list of the approved Variations,
Module 1.4.1 (quality + CV, signed),
Module 1.4.3 (clinical + CV, signet),
SmPC, Labelling and Package leaflet,
Module 2.3 (quality),
Module 2.5 (clinical)
Summary bridging report, dated 13 October 2009
PSUR for Capsicum pain plaster 11 mg.
the
RMS comment:
The GMP certificate/compliance statements should be replaced by corresponding documents,
which are not older than 3 years.
III. SCIENTIFIC DISCUSSION
III.1
Quality
In the last seven years the following quality variations were approved:
- DE/H/0254/001/IA/005
- DE/H/0254/001/IB/007
- DE/H/0254/001/IB/008
- DE/H/0254/001/IB/009
- Change in the name of a manufacturer of the finished product,
- Change in the HPLC Method,
- Residual solvents,
- Change of a part from the caoutchouc.
The active substance of Capsicum pain plaster 11 mg is a soft extract of cayenne pepper (4-7:1)
corresponding to 11 mg capsaicin, according to the monograph “Standardized soft extract of
cayenne pepper of the German Pharmaceutical Codex, a supplementary Pharmacopoeia to the
European and German Pharmacopoeia / Deutscher Arzneimittel-Codex (DAC). The soft extract is
obtained from Capsicum annuum L; and contains NLT 2.0% and NMT 2.4% of total
capsaicinosides. It is manufactured at Finzelberg GmbH & Co. KG (Germany). Capsicum pain
plaster 11 mg consists of a flesh-coloured elastic flannel backing and a rubber based pressure
sensitive adhesive mass. It contains the API as an integral part of the formulation. The adhesive
mass is covered by two overlapping pieces of siliconised paper liners . The other excipients are:
2,2'-methylene-bis-(6-tert.-butyl-4-methylphenol); 2,2'-(propane-1,2-diyldiiminodimethyl)diphenol;
Orris root powder/rice flour mixture; Caoutchouc; Poly(butadiene-block-styrene) (76.5:23.5); Cis1,4-polyisoprene; Talcum; Beta-pinene; Poly(2-methylbut-2-ene-co-penta-1,3-diene); Glycerol
ester of hydrogenated colophony; Light liquid paraffin; Wool fat; Elastic flannel (plaster carrier)
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and Paper siliconised on one side (covering paper)”. Manufacturing, testing and batch release is
performed at Baiersdorf AG (Germany). 1 or 2 medicated plaster(s) is/are sealed in a sachet
consisting of a paper/polyethylene/aluminium/syrlin-composite. The approved shelf-live of
Capsicum pain plaster 11 mg is 3 years, if not stored above 25°C and 3 month after first opening.
In accordance with the “CMD(h) Best Practice Guide on the Processing of Renewals in the
Mutual Recognition and Decentralised Procedure” (version May 2011) a quality expert statement
has been submitted for Capsicum pain plaster 11 mg (signed 14 December 2009; Dr. Sigrid Ott;
Qualified Person; Baiersdorf AG) confirming:
-
That the product is in compliance with Article 23 of Directive 2001/83/EC, as amended, which
obliges the MAH “…. to take account of technical and scientific progress and introduce any
changes…”.
The active substance and the finished product Capsicum pain plaster 11 mg comply with the
currently authorised specifications approved in the mutual recognition procedure.
-
The statement includes the currently authorised specifications for the drug substance and the
release specification of the drug product. The qualitative and quantitative composition of the drug
product is presented. An updated version of Module 3 was not presented.
RMS comment:
Acceptable so far, but the MAH should take into account that the general Ph.Eur.-monograph
“5.1.4 - Microbiological quality of non-sterile pharmaceutical preparations and substances for
pharmaceutical use” was revised meanwhile. The MAH should update the specifications
accordingly.
It is also noted the EDQM TSE-Certificate for wool fat is not longer valide and should be replaced
by a valide one.
III.2
Nonclinical
The MAH did not confirm that no new non-clinical data are available since the granting of the last
renewal to the present application.
RMS comment
Relevant non-clinical issues in the past 5 years should be summarised. Changes concerning
the points 4.6 (“Pregnancy and Lactation”) and 5.3 (“Preclinical safety data”) compared to the
final English SPX text agreed on during the last renewal should be highlighted and discussed.
III.3
Clinical efficacy and Safety
No clinical trials or post-marketing studies were conducted or planned since the last renewal
in 2005. According to the applicant there are no new major findings bearing on the
established overall safety profile of the product. There have been no safety-related marketing
authorisation withdrawals or suspensions and no restrictions to distribution and there were no
further safety-related measures of the Marketing Authorisation Holder.
There were no post approval commitments.
III.3.1 Clinical Efficacy
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See above.
Since no new efficacy data has been generated, the applicant concludes that clinical efficacy is
established and unchanged positive.
RMS comment:
This position is endorsed provided that the applicant updates the expert statement and no
relevant new clinical data / relevant published data emerge that could alter the benefit-riskevaluation. The clinical expert statement at present is considered insufficient (see the list of
“Other concerns” below).
III.3.2 Clinical Safety
III.3.2.1 Cumulative experience 1 May 2005 - 20 September 2009
Capsaicin pain plaster is currently authorised in seven countries in the EU and marketed in five.
During the reporting period there have been no actions taken for safety reasons and no safety
related changes were made to the reference safety information/SmPC.
Approximately 8.390.000 packaging units containing 1 or 2 plasters have been distributed.
There have been no company sponsored studies.
There is no risk management plan in place.
III.3.2.2 Report of Post Marketing Experience 1 May 2005 - 20 September 2009
In addition, the MAH submitted within the renewal dossier a PSUR covering the period 1 May
2005 - 20 September 2009.
60 individual case reports were received. There were 88 non-serious adverse reactions and 1
serious reaction.
The single serious reaction involved a 73 years old patient with pre-existing heart disease who
experienced increased pulse rate and increased blood pressure leading to hospital admission
following application of capsicum plaster for lumbago.
For a list of adverse reactions please see the following table:
WHO preferred term
Application site reaction
Allergy
Pain
Circulatory failure
Paraesthesia
Colitis
Bullous eruption
Pruritus
Rash
Rash erythematous
∑
No. of adverse events
8
2
5
1
18
1
8
2
1
15
61
RMS comment:
There is a discrepancy between the number of reports and reactions (60 reports, 88 ADR) given
in the text and the numbers presented in the summary tabulation (42 reports, 61 ADR).
Before marketing renewal can be granted the MAH is requested to present the correct number of
case reports and ADR. Additionally the MAH is requested to present a line listing of all reports
and a summary tabulation of all ADR by SOC, indicating seriousness and listedness.
The MAH should ensure the correct use of the terms adverse event (AE) and adverse drug
reaction (ADR).
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III.3.2.3
Conclusion on Safety
RMS:
For a final assessment the MAH is requested to present the correct number of case reports and
ADR as well as an updated line listing and summary tabulation.
III.4
Product Information
The MAH proposed no changes to the Product Information (PI) during this procedure.
The RMS requests further amendments to the PI as discussed below.
III.4.1 Clinical and Non-Clinical Comments on the Product Information
III.4.1.1
Summary of Product Characteristics>
1. The applicant should submit an updated version of the SPC using the actual SPCtemplate which can be downloaded from the EMA homepage.
2. The target patient population (adult patients, adolescents ≥ 12 y.) should be specifically
stated in the SPC.
3. Relevant new subsections (e.g. subsections in 4.2 regarding special populations [children,
elderly, patients with kidney-/liver dysfunction] should be added when appropriate.
4. The safety information should be aligned with the safety information in the SPC of
procedure DE 552/…/R001.
III.4.1.2
Package Leaflet
Harmonised versions of the PL and labelling exist.
1. The applicant should submit an updated version of the PL using the actual PL-template
which can be downloaded from the EMA homepage.
2. The changes of the SPC as stated above should be implemented in the updated PLversion.
III.4.1.3
Assessment of User Testing
No user testing is foreseen by the applicant which is considered acceptable by the RMS.
III.4.2 Pharmaceutical Comments on the Product Information
III.4.2.1
Summary of Product Characteristics>
III.4.2.2
Package leaflet and user test>
III.4.2.3
Labelling>
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III.5 Post-approval commitments to be fulfilled by the MAH
The RMS proposes the following post-approval commitments:
Area1
Description
Pharmacovigilance
The next PSUR should be submitted after
3 years
Due date2
../../..
1Areas: Quality, Non-clinical, Clinical, Pharmacovigilance
2Due date for the follow-up measure or for the first interim report if a precise date cannot be committed to.
VI.
OVERALL CONCLUSION AND Benefit-risk assessment
RMS:
For a final assessment the MAH is requested to present the correct number of case reports and
ADR as well as an updated line listing and summary tabulation.
The RMS is of the opinion that the renewal can be granted provided that the MAH commits to
fulfil the above stated commitment and satisfactory responses are given to the preliminary list of
questions (Section V).
V
LIST OF QUESTIONS as proposed by RMS
V.1.
Potential serious risks to public health
None
V.2.
Other concerns
1.
The MAH should present updated GMP certificates and compliance statements, which
should not be older than 3 years (before the end of this procedure).
2.
The MAH should update the specifications according the revised general Ph.Eur.-monograph
“5.1.4 - Microbiological quality of non-sterile pharmaceutical preparations and substances for
pharmaceutical use”.
3.
The EDQM TSE-Certificate for wool fat is not longer valide and should be replaced by a
valide one.
4.
The submitted clinical expert statement is not considered adequate (see below). The clinical
expert statement should be updated (from 2009 to 2012). It has to include confirmatory
statements (a) that there are no new (pre-clinical or clinical) data which could change the
positive benefit/risk evaluation and b) that the product can be safely renewed for an unlimited
period (or if deemed necessary, proposes specific actions with justifications) and c) that the
authorities have been kept informed of any relevant new data.
5.
Changes concerning the points 4.6 (“Pregnancy and Lactation”) and 5.3 (“Preclinical safety
data”) compared to the final English SPX text agreed on during the last renewal should be
highlighted and discussed.
6.
In the clinical expert statement the applicant should discuss any changes from the last
renewal and relevant new publications (related to efficacy or safety) and he should
specifically address relevant patient sub-populations (e.g. adolescents, elderly, patients with
kidney or liver dysfunction) in the report (see Guideline on SPC, rev. 2). Consequences for
the safe use of the product / alterations in posology should be proposed and justified, if
necessary (Guideline on SPC).
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7.
There is a discrepancy between the number of reports and reactions (60 reports, 88 ADR)
given in the text and the numbers presented in the summary tabulation (42 reports, 61
ADR).The MAH is requested to present the correct number of case reports and ADR.
Additionally the MAH is requested to present a line listing of all reports and a summary
tabulation of all ADR by SOC, indicating seriousness and listedness. Medically unconfirmed
reports should be presented separately.
8.
The MAH should ensure the correct use of the terms adverse event (AE) and adverse drug
reaction (ADR).
9.
The applicant should submit an updated version of the SPC using the actual SPC-template
which can be downloaded from the EMA homepage.
10. The target patient population (adult patients) should be specifically stated in the SPC.
11. SPC section 4.2: Relevant new subsections (e.g. subsections in 4.2 regarding special
populations [children, elderly, patients with kidney-/liver dysfunction] should be added when
appropriate.
12. The safety information should be aligned with the safety information in the SPC of procedure
DE 552/…/R001.
13. PIL: The changes of the SPC as stated above should be implemented in the updated PLversion.
14. PIL: The applicant should submit an updated version of the PL using the actual PL-template
to be downloaded from the EMA homepage.
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IV. <ANNEX (IF APPLICABLE)
V. PROPOSED CHANGES TO THE <SPC>, <PL>, <LABELLING>
ANNOTATED WITH THE RMS’S COMMENTS AFTER EACH SECTION>
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