WHOPAR GUIDANCE for APPLICANTS v 2.

4

Guidance note to Applicants on the compilation of the WHO Public Assessment Report (WHOPAR)

1.

Purpose of Guidance

To provide background information on the WHO Public Assessment Report (WHOPAR) and to provide detailed guidance to Applicants on the documentation required for the WHOPAR as part of the submission of a product dossier to WHO for assessment under the WHO Prequalification Programme1. Note: This guidance should be seen in addition to the existing submission requirements as published on the website of the Prequalification Programme. It addresses only those requirements related to documentation necessary in support of a WHOPAR. WHO Public Assessment Report

2.

The purpose of the WHOPAR is to promote the most possible transparency on the procedure following the assessment of a finished pharmaceutical product (FPP) for possible inclusion in the “List of prequalified products and manufacturers”. In addition, the WHOPAR aims at providing relevant information on the product’s quality, efficacy and safety. Also, the inspection status will be reflected in the WHOPAR. Publication of WHOPARs is based on Resolution WHA57.142 of 22 May 2004 in which the Director General of WHO requests under point 3.(4): ”to ensure that the prequalification review process and the results of inspection and assessment reports of the listed products, aside from proprietary and confidential information, are publicly available”. WHOPARs are published on the WHO Prequalification website3. The structure and format of the WHOPAR are adapted from the European Public Assessment Report (EPAR)4 as published by the European Medicines Evaluation Agency (EMEA)5 to best serve the requirements of the WHO prequalification procedure. The development of a WHOPAR will follow the steps set forth below: 2.1 Step 1. Step 2. Step 3. Step 4. Procedure The applicant submits documents required for the WHOPAR as part of the initial submission to WHO; WHO compiles the draft WHOPAR when the assessment is completed; WHO sends6 the draft WHOPAR to the applicant for comments; The applicant reviews and comments (annotates) the relevant parts of the draft WHOPAR, especially to ensure that the WHOPAR does not contain proprietary or confidential information; The applicant returns the amended draft WHOPAR to WHO7; WHO reviews proposed text (steps 3 to 6 may be repeated in case any item needs further clarification) and finalizes the WHOPAR;

Step 5. Step 6.

1 2

http://www.who.int/prequal www.who.int/gb/ebwha/pdf_files/WHA57/A57_R14-en.pdf 3 http://www.who.int/prequal/WHOPAR/pq_whopar.htm 4 http://www.emea.europa.eu/htms/human/epar/a.htm
5 6

http://www.emea.europa.eu/ Documents are exchanged in electronic format between WHO and Applicant, preferably by email. 7 Documents are exchanged in electronic format between Applicant and WHO, preferably by email.

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Step 7.

Step 8.

If the product, as produced at the specified manufacturing site(s), has been found to meet the recommended standards, WHO accepts the product for inclusion in the ‘List of prequalified products and manufacturers’8 and publishes the WHOPAR; the applicant is informed accordingly. Within within three months after acceptance/publication of the WHOPARs. Please note that the format should be in line with the recommendations as set out in the “Guideline of the readability of the labelling and the package leaflet of medicinal products for human use” (HTTP://EC.EUROPA.EU/ENTERPRISE/PHARMACEUTICALS/EUDRALEX/VOL2/C/2009_01_12_READABILITY_GUIDELINE_FINAL.PDF), which is also referred to in the current WHOPAR guidance.

3.

WHOPAR structure

The WHOPAR consists of 8 Parts: 1. Abstract 2. All Accepted Presentations 3. Package Leaflet in English 4. Summary of Product Characteristics in English 5. Labelling in English 6. Discussion 7. Steps taken for Prequalification 8. Steps taken following Prequalification The characteristics of the above mentioned WHOPAR parts are described in Appendix 1. The applicant contributes relevant information for the respective parts, depending on the type of product as detailed in section 4 of this guidance.

4.

Requirements for submission

Required documentation as described in Appendix 2, is to be submitted as part of the initial submission. Failure to include any of the required documentation may result in rejection of the application. The “Procedure for Assessing the Acceptability, in principle, of Pharmaceutical Products for Purchase by United Nations Agencies”9 under paragraph 2.2 “Submission of dossiers” identifies two types of submissions: for innovator products and for multisource (generic) products. 4.1 Innovator products Detailed requirements for submission are provided on the website of the Prequalification Programme10. With respect to the submission of documents in support of a WHOPAR one of two approaches will apply depending on the availability of publicly accessible information in English about the evaluation and the evaluation process of the product e.g. in a public assessment report as made available by a Drug Regulatory Authority in the ICH regions or associated countries11. 1. A public assessment report as referred to is available: The WHOPAR will essentially refer to the public assessment report as published by the relevant Drug Regulatory Authority.

8 9

http://www.who.int/prequal/ choose: HIV/AIDS - List of prequalified products and manufacturers http://www.who.int/prequal/info_general/documents/TRS943/TRS943.pdf#page=97 10 http://www.who.int/prequal 11 At the time of issue of this guidance public assessment reports are available from the EMEA (see footnote 5 and 6) and FDA at Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

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The applicant should provide: • the Package Leaflet (Part 3), Summary of Product Characteristics (Part 4) and Labelling (Part 5) in accordance with the guidance provided in Appendix 3. An authorized English translation has to be provided, whenever the original texts were issued in another language. • For each part of the WHOPAR referring to the public assessment report (parts 3, 4, 5 and 6) the relevant links. • Information on international licensing status, stating countries and licensing numbers. 2. No public assessment report as referred to above is available12: The applicant should provide: • Package Leaflet (Part 3), Summary of Product Characteristics (Part 4) and Labelling (Part 5) as English language version in accordance with the guidance provided in Appendix 3. • Summary of Product Safety and Efficacy of the FPP as contribution to the Discussion (Part 6) (see Appendix 4). • Information on international licensing status, stating countries and licensing numbers. 4.2 Multisource or generic products Detailed requirements for the submission are provided on the website of the Prequalification Programme13. With respect to the submission of documents in support of a WHOPAR one of two approaches will apply depending on the availability of an innovator or comparator / reference product: 1. A comparator / reference product acceptable to WHO is available: The applicant should provide: • Package Leaflet (Part 3), Summary of Product Characteristics (Part 4) and Labelling (Part 5) in accordance with the guidance provided in Appendix 3. The text should reflect the information as available for the innovator/comparator product. Especially the indication and safety profile should be the same as approved for the comparator / reference product(s) acceptable to WHO. • Information on international licensing status, stating countries and licensing numbers. A Summary on Product Safety and Efficacy is not considered necessary, as relevant information on product safety and efficacy is generally available for this type of products. 2. An innovator or an acceptable comparator / reference product is not available e.g. new combinations of existing products like fixed dose combinations or traditionally used multisource products such as the artemisinines. The applicant should provide: • Package Leaflet (Part 3), Summary of Product Characteristics (Part 4) and Labelling (Part 5) in accordance with the guidance provided in Appendix 3. • Comprehensive summary of Product Safety and Efficacy of the Finished Pharmaceutical Product as contribution to the Discussion (Part 6) (see Appendix 4); • Bibliographic submission containing all relevant scientific literature, in case of FDCs including evidence on the safety and efficacy when combining the individual agents, original clinical research (if carried out) and other documentation in support of the information provided in the Package Leaflet, Summary of Product Characteristics and Summary on Safety and Efficacy in the Discussion (see Appendix 2). • Information on international licensing status, stating countries and licensing numbers.
12

A confidential Assessment Report may be available from a National Drug Regulatory Authority in the ICH regions and associated countries; if available, the Applicant (Manufacturer) may enclose this report with the submission or assessors will request a copy of this report from the relevant Drug Regulatory Authority to assist in the evaluation for Prequalification.
http://www.who.int/prequal

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5.

Additional Information

Additional information on this procedure may be obtained by email from Dr M. Stahl at stahlm@who.int to whom also comments may be submitted.

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WHOPAR GUIDANCE for APPLICANTS (MANUFACTURERS) v 2.1 – Appendix 1

Guidance note to Applicants (Manufacturers) on the compilation of the WHO Public Assessment Report

Appendix 1 Characteristics of WHOPAR Parts.

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Appendix 1 Part 1 2 3 Title

Characteristics of WHOPAR Parts. Responsibility for Submission Applicant Applicant Purpose to provide : Overview of key information Tabulated product summary Practical, easily understandable information for the user of the FPP such that, if necessary, he is able to directly act on it All practical and essential medical (back ground) information on FPP for health care providers All text for packaging Outcome of quality and bioequivalence evaluation and, if required, the overview of current product safety and efficacy

Abstract All Accepted Presentations All Package Leaflets in English

Drafting WHO, Applicant WHO Applicant

Acceptance WHO WHO WHO

4

All Summaries of Product Characteristics in English All Labelling in English Discussion

Applicant

Applicant

WHO

5 6

7

Steps taken for Prequalification

Applicant WHO, based on • assessor reports on Quality and Bioequivalence and • Summary of Product Safety and Efficacy WHO

Applicant

WHO WHO

Applicant1 WHO Chronological description of main steps undertaken for assessment of the product and by whom Chronological description of main steps undertaken following assessment of the product and by whom

8

Steps taken following Prequalification

WHO

WHO

1

As appropriate, see ‘Requirements for Submission’ and Appendix 2

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WHOPAR GUIDANCE for APPLICANTS (MANUFACTURERS) v 2.0 – Appendix 2

Guidance note to Applicants (Manufacturers) on the compilation of the WHO Public Assessment Report

Appendix 2 Documentation to submit together with the initial submission.

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Appendix 2

Documentation to submit together with the initial submission.

Applicants contribute relevant documentation on Parts 3, 4 and 5 of the WHOPAR and, if required, a Summary of Product Safety and Efficacy to be included in Part 6. Submissions for a multisource product for which no comparator / reference product exists, should include a bibliographic submission. Documentation to submit for an: Innovator product, for which a public assessment report has been issued by a Drug Regulatory Authority from the ICH regions or associated countries which is available: • Package Leaflet in English (Part 3), • Summary of Product Characteristics in English (Part 4), • Labelling in English (Part 5), • Summary of Product Safety and Efficacy as contribution to the Discussion (Part 6) may be voluntarily submitted; submission and subsequent publication of this summary ensures availability of product information for all Finished Pharmaceutical Products (FPPs) that are accepted for Prequalification on the WHO Prequalification web site. Innovator product, for which no public assessment report is available: • Package Leaflet in English (Part 3) • Summary of Product Characteristics in English (Part 4) • Labelling in English (Part 5) • Summary of Product Safety and Efficacy (contribution to Part 6) Multisource (generic) product, for which an innovator or comparator / reference product is available: • Package Leaflet in English (Part 3) • Summary of Product Characteristics in English (Part 4) • Labelling in English (Part 5) Multisource product, for which an innovator or comparator / reference product is not available: • Package Leaflet in English (Part 3) • Summary of Product Characteristics in English (Part 4) • Labelling in English (Part 5) • Summary of Product Safety and Efficacy (contribution to Part 6) • Bibliographic submission containing all literature, original clinical research (if carried out) and other documentation in support of the information provided in the Package Leaflet, Summary of Product Characteristics and Summary of Product Safety and Efficacy in the Discussion. Format and contents of documentation • • • Further guidance on contents and format of the Package Leaflet (Part 3), Summary of Product Characteristics (Part 4) and Labelling (Part 5) is provided in Appendix 3. The format and contents of the Summary of Product Safety and Efficacy as contribution to the Discussion (Part 6) is provided in Appendix 4. Bibliographic submission For multisource products for which an innovator or comparator / reference product is not available e.g. products containing a new combination of active ingredients like FDC’s or are traditionally used multisource products such as the artemisinines, full information on safety and efficacy as defined in guidelines of the European Union (Commission and EMEA), Japanese Ministry of Health, Labour and Welfare (MHLW) and the US Food and Drug Administration (FDA) must be submitted in a bibliographic submission. A bibliographic submission should contain all relevant scientific literature, in the case of
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FDC’s including evidence on the safety and efficacy of the equivalent combination of single API products, original clinical research (if carried out) and other documentation in support of the information provided in the Package Leaflet, Summary of Product Characteristics and Summary of Product Safety and Efficacy in the Discussion. The format for presentation of information and data should follow the manual ‘Marketing Authorization of Pharmaceutical Products with special Reference to Multisource (Generic) Products: a Manual for a Drug Regulatory Authority’1. Further useful guidance is provided in the draft WHO “Guidelines for Registration of Fixed Dose Combination Medicinal Products”2 of September 2004 e.g. attachment 2, “Principles for determining whether data from scientific literature are acceptable”. Information, especially with respect to submissions according to the format of the Common Technical Document (CTD) can be found at the website of the International Conference on Harmonization (ICH)3 as well as on those of the ICH Regulatory Bodies: EU (Commission4 and EMEA5), Japan (MHLW6) and USA (FDA7).

1
2

http://www.who.int/prequal/info_general/documents/WHO_DMP_RGS_98_5_R.pdf http://www.who.int/prequal/info_applicants/Guidelines/info_for_applicants_guidelines_fdcs.htm 3 http://www.ich.org/ 4 http://europa.eu.int/comm/enterprise/pharmaceuticals/index_en.htm 5 http://www.emea.eu.int/ 6 http://www.mhlw.go.jp/english/ 7 http://www.fda.gov/ November 2006 WHO Prequalification of Medicines Programme 3

WHOPAR GUIDANCE for APPLICANTS (MANUFACTURERS) v 2.0 – Appendix 3

Guidance note to Applicants (Manufacturers) on the compilation of the WHO Public Assessment Report

Appendix 3 Guidance on Package Leaflet, Summary of Product Characteristics and Labelling.

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Appendix 3

Guidance on Package Leaflet, Summary of Product Characteristics and Labelling.

Guidance documents on the Package Leaflet, Summary of Product Characteristics and Labelling are listed below and attached for immediate reference. The documents are essentially as published by the EMEA. Since these documents are subject to regular updates interested parties are advised to consult the EMEA Quality Review of Documents (QRD) web pages as appropriate1, 2 . Guidance documents to consult include: Templates: 1. Summary of Product Characteristics (template) Package Leaflet (template) Labelling (template) These are Word versions, which are directly usable as a template to start developing the documents. 2. Annotated Summary of Product Characteristics Annotated Package Leaflet template Annotated Labelling template 3. Appendix I Statements for use in Section 4.6 “Pregnancy and lactation” of Summary of Product Characteristics 4. Appendix II MedDRA terminology to be used in Section 4.8 “Undesirable effects” of the Summary of Product Characteristics 5. Appendix III New standards for required storage statements 6. Appendix IV Terms for Batch number and Expiry date QRD support documents: 1. Convention to be followed for EMEA - QRD templates 2. Compilation of QRD decisions on the use of terms 3. Compilation of QRD decisions on stylistic matters in product information. 4. Tables of non-standard abbreviations

1 2

www.emea.eu.int/htms/human/qrd/qrdintro.htm www.emea.eu.int/htms/human/qrd/qrdplt/24530905en.pdf WHO Prequalification of Medicines Programme 2

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SUMMARY OF PRODUCT CHARACTERISTICS

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1.

NAME OF THE MEDICINAL PRODUCT

{(Invented) name strength pharmaceutical form}

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

<Excipient(s):> For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

<The scoreline is only to facilitate breaking for ease of swallowing and not to divide into equal doses.> <The tablet can be divided into equal halves.>

4. 4.1

CLINICAL PARTICULARS Therapeutic indications

<This medicinal product is for diagnostic use only.> 4.2 Posology and method of administration

<{(Invented) name} is not recommended for use in children <above> <below> {age Y} due to <a lack of> <insufficient> data on <safety> <and> <or> <efficacy> <(see section <5.1> <5.2>).> <The experience in children is limited.> <There is no experience in children> <(see section <4.4> <5.2>).> <There is no relevant indication for use of {(Invented) name} in children.> <{(Invented) name} is contraindicated in children (see section 4.3).> 4.3 Contraindications

<Hypersensitivity to the active substance(s) or to any of the excipients <or {name of the residue(s)}>.> 4.4 4.5 Special warnings and precautions for use Interaction with other medicinal products and other forms of interaction

<No interaction studies have been performed.> <Interaction studies have only been performed in adults.> 4.6 Pregnancy and lactation [For Pregnancy and lactation statements see Appendix I.] 4.7 Effects on ability to drive and use machines

<{Invented name} has <no <or negligible> influence> <minor or moderate influence> <major influence> on the ability to drive and use machines.> <No studies on the effects on the ability to drive and use machines have been performed.> <Not relevant.> 4.8 Undesirable effects
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[MedDRA frequency convention and system organ class database, see Appendix II] Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 4.9 Overdose

<No case of overdose has been reported.>

5. 5.1

PHARMACOLOGICAL PROPERTIES Pharmacodynamic properties

Pharmacotherapeutic group: {group}, ATC code: {code} <This medicinal product has been authorised under a so-called “conditional approval” scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency (EMEA) will review new information on the product every year and this SPC will be updated as necessary.> <This medicinal product has been authorised under “Exceptional Circumstances”. This means that <due to the rarity of the disease> <for scientific reasons> <for ethical reasons> it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency (EMEA) will review any new information which may become available every year and this SPC will be updated as necessary.> 5.2 5.3 Pharmacokinetic properties Preclinical safety data

<Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.> <Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.> <Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:>

6. 6.1 6.2

PHARMACEUTICAL PARTICULARS List of excipients Incompatibilities

<Not applicable.> <In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.> <This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.> 6.3 Shelf life

<...> <6 months> <...> <1 year> <18 months> <2 years> <30 months> <3 years> <...> 6.4 Special precautions for storage [For storage conditions statements see Appendix III]
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<For storage conditions of the <reconstituted> <diluted> medicinal product, see section 6.3.> 6.5 Nature and contents of container

<Not all pack sizes may be marketed.> 6.6 Special precautions for disposal

<No special requirements.> <Any unused product or waste material should be disposed of in accordance with local requirements.>

7.

<MARKETING AUTHORISATION> <PREQUALIFICATION> HOLDER

{Name and address} <{tel}> <{fax}> <{e-mail}>

8.

<MARKETING> <PREQUALIFICATION> AUTHORISATION NUMBER(S)

9.

DATE OF FIRST <PREQUALIFICATION> <AUTHORISATION> / RENEWAL OF THE <PREQUALIFICATION> <AUTHORISATION>

<{DD/MM/YYYY}> <{DD month YYYY}>

10.

DATE OF REVISION OF THE TEXT

{MM/YYYY}

<Detailed information on this medicinal product is available on the website of the WHO Prequalification program http://www.who.int/prequal>

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PACKAGE LEAFLET

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PACKAGE LEAFLET: INFORMATION FOR THE USER {(Invented) name strength pharmaceutical form} {Active substance(s)} <Read all of this leaflet carefully before you start <taking> <using> this medicine. Keep this leaflet. You may need to read it again. If you have any further questions, ask your <doctor, health care provider> <or> <pharmacist>. <This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.> If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your <doctor, health care provider> <or> <pharmacist>.> In this leaflet: 1. What {product name}is and what it is used for 2. Before you <take> <use> {product name} 3. How to <take> <use> {product name} 4. Possible side effects 5. How to store {product name} 6. Further information

1.

WHAT {PRODUCT NAME} IS AND WHAT IT IS USED FOR

2.

BEFORE YOU <TAKE> <USE> {PRODUCT NAME}

Do not <take> <use> {product name} <if you are allergic (hypersensitive) to {active substance(s)} or any of the other ingredients of {product name}.> <if ...> Take special care with {product name} <if you ...> <when ...> <Before treatment with {product name},…> <Taking> <Using> other medicines <Please tell your <doctor, health care provider> <or> <pharmacist> if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.> <Taking> <Using> {product name} with food and drink Pregnancy and breast-feeding <Ask your <doctor, health care provider> <or> <pharmacist> for advice before taking any medicine.> Driving and using machines <Do not drive <because...>.> <Do not use any tools or machines.> Important information about some of the ingredients of {product name}

3.

HOW TO <TAKE> <USE> {PRODUCT NAME}

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<Always <take> <use> {product name} exactly as your doctor or health care provider has told you. You should check with your <doctor, health care provider> <or> <pharmacist> if you are not sure.> <The usual dose is...> If you <take> <use> more {product name} than you should If you forget to <take> <use> {product name} <Do not take a double dose to make up for a forgotten <tablet> <dose> <…>.> If you stop <taking> <using> {product name} <If you have any further questions on the use of this product, ask your <doctor, health care provider> <or> <pharmacist>.>

4.

POSSIBLE SIDE EFFECTS

Like all medicines, {product name} can cause side effects, although not everybody gets them. If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your <doctor, health care provider> <or> <pharmacist>.

5. HOW TO STORE {PRODUCT NAME} [For storage conditions statements see Appendix III] Keep out of the reach and sight of children. <Do not store above ºC>, <Store in the original <container><carton>> Do not use {product name} after the expiry date which is stated on the <label> <carton> <bottle> <...> <after {abbreviation used for expiry date}.> <The expiry date refers to the last day of that month.> <Do not use {product name} if you notice {description of the visible signs of deterioration}.> <Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.>

6.

FURTHER INFORMATION

What {product name} contains The active substance(s) is (are)… The other ingredient(s) is (are)...

What {product name} looks like and contents of the pack <Prequalification><Marketing Authorisation> Holder and Manufacturer {Name and address} <{tel}> <{fax}> <{e-mail}>

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For any information about this medicinal product, please contact the local representative of the <Prequalification><Marketing Authorisation> Holder: {Country} {Name} <{Address} B-0000 {City}> tel: + {telephone number} <{e-mail}> {Country} {Name} <{Address} B-0000 {City}> tel: + {telephone number} <{e-mail}>

<as appropriate, add additional local representatives to the above table> This leaflet was last approved in {MM/YYYY}. <Detailed information on this medicine is available on the WHO Prequalification web site: http://www.who.int/prequal/>

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LABELLING

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PARTICULARS TO APPEAR ON THE <OUTER PACKAGING> <AND> <THE IMMEDIATE PACKAGING> {NATURE/TYPE}

1.

NAME OF THE MEDICINAL PRODUCT

{(Invented) name strength pharmaceutical form} {Active substance(s)}

2.

STATEMENT OF ACTIVE SUBSTANCE(S)

3.

LIST OF EXCIPIENTS

4.

PHARMACEUTICAL FORM AND CONTENTS

5.

METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.

6.

SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children.

7.

OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE [For terms on Batch number and Expiry date see Appendix IV]

9. SPECIAL STORAGE CONDITIONS [For storage conditions statements see Appendix III]

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

11. NAME AND ADDRESS OF THE <PREQUALIFICATION> <MARKETING AUTHORISATION> HOLDER {Name and Address} <{tel}>
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<{fax}> <{e-mail}>

12.

<PREQUALIFICATION> <MARKETING AUTHORISATION> NUMBER(S)

EU/0/00/000/000

13. BATCH NUMBER [For terms on Batch number and Expiry date see Appendix IV]

14.

GENERAL CLASSIFICATION FOR SUPPLY

<Medicinal product subject to medical prescription.> <Medicinal product not subject to medical prescription.>

15.

INSTRUCTIONS ON USE

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS {NATURE/TYPE}

1.

NAME OF THE MEDICINAL PRODUCT

{(Invented) name strength pharmaceutical form} {Active substance(s)}

2.

NAME OF THE <PREQUALIFICATION> <MARKETING AUTHORISATION> HOLDER

{Name} 3. EXPIRY DATE [For terms on Batch number and Expiry date see Appendix IV]

4. BATCH NUMBER [For terms on Batch number and Expiry date see Appendix IV]

5.

OTHER

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS {NATURE/TYPE}

1.

NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

{(Invented) name strength pharmaceutical form} {Active substance(s)} {Route of administration}

2.

METHOD OF ADMINISTRATION

3. EXPIRY DATE [For terms on Batch number and Expiry date see Appendix IV]

4. BATCH NUMBER [For terms on Batch number and Expiry date see Appendix IV]

5.

CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6.

OTHER

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SUMMARY OF PRODUCT CHARACTERISTICS [NOTE: the following are those items of information required by Article 11 of Directive 2001/83/EC, as amended, and current practice in the centralised procedure. This guidance should be read in conjunction with the relevant guidelines that can be found on the EMEA website (See also “Convention” for format and layout): http://www.emea.eu.int/htms/human/qrd/qrdplt/qrdconvention.pdf, in particular the “Guideline on Summary of Product Characteristics” as published on the Website of the European Commission in the Notice to Applicants, Volume 2C: http://pharmacos.eudra.org/F2/eudralex/vol-2/home.htm During the evaluation process, applicants may present SPCs for different strengths in one document, clearly indicating with grey-shaded titles the strength or presentation to which alternative text elements refer. However, a separate SPC per strength and per pharmaceutical form, containing all pack-sizes related to the strength and pharmaceutical form concerned will have to be provided by the applicant as follows: - English language version: immediately after adoption of the opinion. - All other language versions: at the latest 22 days after adoption of the opinion (i.e. at the latest after incorporation of Member States comments). See also: The new Product Information linguistic review process for new applications in the Centralised Procedure - http://www.emea.eu.int/pdfs/human/regaffair/554202en.pdf Standard statements are given in the template, which must be used whenever they are applicable. If the applicant needs to deviate from these statements to accommodate product-specific requirements, alternative or additional statements will be considered on a case-by-case basis. Bracketing convention: {text}:Information to be filled in <text>:Text to be selected or deleted as appropriate]

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1.

NAME OF THE MEDICINAL PRODUCT

{(Invented) name strength pharmaceutical form} [no ® ™ symbols attached here and throughout the text; “tablets” and “capsules” in the plural.]

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

[Name of the active substance(s) in the language of the text.] [Qualitative and quantitative composition in terms of the active substances and constituents of the excipient, knowledge of which is essential for proper administration of the medicinal product. The usual common name or chemical description shall be used. See also the “Guideline on excipients” as published on the Website of the European Commission in the Notice to Applicants, Volume 3B http://pharmacos.eudra.org/F2/eudralex/vol-3/home.htm.] <Excipient(s):> For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

[The pharmaceutical form should be stated according to the full “Standard Terms” published by the Council of Europe, in the singular. Where the Council of Europe short standard term is used on small immediate packaging materials, the short term should be added in brackets.] [Include here a description of the visual appearance of the product pharmaceutical form as marketed, including information on pH and osmolarity as required. Information on appearance of reconstituted parenteral solution should appear under section 6.6.] <The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.> <The tablet can be divided into equal halves.>

4. 4.1

CLINICAL PARTICULARS Therapeutic indications

[Specify, if appropriate <This medicinal product is for diagnostic use only.> If applicable, results of clinical trials to appear under section 5.1.] 4.2 Posology and method of administration

[In case of restricted medical prescription start this section by specifying the conditions. Method of administration: directions for proper use by healthcare professionals or by the patient. Further practical details for the patient can be included in the package leaflet, e.g. in the case of inhalers, subcutaneous self-injection. Instructions for preparation are to be placed under section 6.6 or 12, and cross-referenced here.] <{(Invented) name} is not recommended for use in children <above> <below> {age Y} due to <a lack of> <insufficient> data on <safety> <and> <or> <efficacy> <(see section <5.1> <5.2>)>.> <The experience in children is limited.> <There is no experience in children> <(see section <4.4> <5.2>)>.> <There is no relevant indication for use of {(Invented) name} in children.> <{(Invented) name} is contraindicated in children (see section 4.3).>
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4.3

Contraindications

<Hypersensitivity to the active substance(s) or to any of the excipients <or {name of the residue(s)}>.> 4.4 4.5 Special warnings and precautions for use Interaction with other medicinal products and other forms of interaction

<No interaction studies have been performed.> <Interaction studies have only been performed in adults.> 4.6 Pregnancy and lactation [For Pregnancy and lactation statements see Appendix I.] [Results from reproduction toxicology to be included under section 5.3 and cross-referenced here, if necessary.] 4.7 Effects on ability to drive and use machines

<{Invented name} has <<no> or negligible> influence> <minor or moderate influence> <major influence> on the ability to drive and use machines.> [describe effects where applicable] <No studies on the effects on the ability to drive and use machines have been performed.> <Not relevant.> 4.8 Undesirable effects [MedDRA frequency convention and system organ class database, see Appendix II.] Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 4.9 Overdose

[Describe the symptoms, emergency procedures, and antidotes (if available) in case of overdose.] <No case of overdose has been reported.>

5. 5.1

PHARMACOLOGICAL PROPERTIES Pharmacodynamic properties

Pharmacotherapeutic group: {group [lowest available level]}, ATC code: {code} [For products approved under “conditional approval”, include the following statement:] <This medicinal product has been authorised under a so-called “conditional approval” scheme. This means that further evidence on this medicinal product is awaited. The European Medicines Agency (EMEA) will review new information on the product every year and this SPC will be updated as necessary.> [For products approved under “exceptional circumstances”, include the following statement:] <This medicinal product has been authorised under “Exceptional Circumstances”. This means that due to <the rarity of the disease> <for scientific reasons> <for ethical reasons> it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency (EMEA) will review any new information which may become available every year and this SPC will be updated as necessary.>

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5.2 5.3

Pharmacokinetic properties Preclinical safety data

<Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.> <Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.> <Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to clinical exposure levels and with possible relevance to clinical use were as follows:>

6. 6.1

PHARMACEUTICAL PARTICULARS List of excipients

[Each to be listed on a separate line according to the different parts of the product.] [Name of the excipient(s) in the language of the text.] 6.2 Incompatibilities

<Not applicable.> [if appropriate, e.g. for solid oral pharmaceutical forms.] <In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.> [e.g. for parenterals.] <This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.> 6.3 Shelf life

[Information on the finished product shelf life and on the in-use stability after 1st opening and/or reconstitution/dilution should appear here. Only one overall shelf life for the finished product is to be given even if different components of the product may have a different shelf life (e.g. powder & solvent).] <...> <6 months> <...> <1 year> <18 months> <2 years> <30 months> <3 years> <...> 6.4 Special precautions for storage [For Storage condition statements see Appendix III.] [General storage conditions of the finished product should appear here, together with a cross-reference to section 6.3 where appropriate: <For storage conditions of the <reconstituted> <diluted> medicinal product, see section 6.3>] 6.5 Nature and contents of container

[All pack sizes must be listed. If applicable, add:] <Not all pack sizes may be marketed.> 6.6 Special precautions for disposal

[Include practical instructions for preparation and handling of the product including disposal of the medicinal product, and waste materials derived from the used medicinal product.] <No special requirements.> <Any unused product or waste material should be disposed of in accordance with local requirements.>

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7.

MARKETING AUTHORISATION HOLDER

[Country name in the language of the text. Telephone, fax numbers or-e-mail addresses may be included (no websites, no e-mails linking to websites).] {Name and address} <{tel}> <{fax}> <{e-mail}>

8.

MARKETING AUTHORISATION NUMBER(S)

[Item to be completed by the Marketing Authorisation Holder once the Marketing Authorisation has been granted.] 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

<{DD/MM/YYYY}> <{DD month YYYY}> [Item to be completed by the Marketing Authorisation Holder once the Marketing Authorisation has been granted or renewed. The date should correspond to the initial authorisation of the medicinal product concerned. It should not reflect individual strength/presentation approvals introduced via subsequent variations and/or extensions. Both the date of first authorisation and, if the authorisation has been renewed, the date of the (last) renewal should be stated in the format given in the following example: Date of first authorisation: 3 April 1985. Date of last renewal: 3 April 2000.]

10.

DATE OF REVISION OF THE TEXT

[Item to be completed by the Marketing Authorisation Holder at time of printing once a change to the SPC has been approved e.g. the latest Commission Decision, implementation date of the Urgent Safety Restriction or date of EMEA letter/notification.] {MM/YYYY}

[It is recommended that the following reference to the WHO PQ Website is included:] <Detailed information on this product is available on the website of the WHO Prequalification program http://www.who.int/prequal

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Version 7

LABELLING AND PACKAGE LEAFLET [The lay-out of the labelling and package leaflet presented in this template is intended for the word document (Commission Decision Annex) only. Guidance on how to best present the actual printed labelling and package leaflet (e.g. font size, use of colours, lay-out, etc.) is available in the “the Guideline on the Readability of the Label and Package Leaflet of Medicinal Products for Human Use” as published on the Website of the European Commission in the Notice To Applicants, Volume 2C http://pharmacos.eudra.org/F2/eudralex/vol-2/home.htm] [N.B.: boxed headings in Annex IIIA are provided to help applicants when completing the template; they should remain in the opinion/decision. However, they are not to appear in the final printed packaging materials (mock-ups/specimens). A separate text for outer and inner packaging labelling should be completed per strength and per pharmaceutical form. Different pack-sizes of the same strength can be presented in one document. Upon adoption by CHMP of a combined labelling text, the text does not need to be separated after adoption of the opinion. A separate package leaflet should be provided per strength and per pharmaceutical form. During the evaluation process however, applicants may present package leaflets for different strengths in one document, clearly indicating the strength or presentation to which alternative text elements refer. Where applicants consider to also market a combined package leaflet, a detailed justification for such a combined package leaflet will have to be included after the PL text and included in the application at submission or at the latest at Day 121. The justification should take into account the QRD guidance as published in the “Compilation of QRD decisions on stylistic matters”. Upon CHMP agreement (on a case-by-case basis) with a combined package leaflet text, the text does not need to be separated after adoption. However, in all other cases, a separate package leaflet per strength and per pharmaceutical form, containing all pack-sizes related to the strength and pharmaceutical form concerned will have to be provided by the applicant as follows: - English language version: immediately after adoption of the opinion. - All other language versions: at the latest 22 days after adoption of the opinion (i.e. at the latest after incorporation of Member States comments). Text which will not appear in the final printed material is to be presented as shaded text.]

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PACKAGE LEAFLET [NOTE: the following items must appear in the package leaflet as required by Title V of Directive 2001/83/EC, as amended. In exceptional cases, alternative headings may be acceptable, especially for those headings containing <take><use> or where a different wording would be more appropriate for the product concerned e.g. to better reflect the user of the product. This should not in any case impact on the content required for the section concerned. Applicants should justify the use of alternative headings (e.g. by reference to user testing results). For certain medicinal products not all items may be relevant, in this case the corresponding heading should not be included. The leaflet must be readable for the patient; please refer to the “Guideline on the Readability of the Label and Package Leaflet of Medicinal Products for Human Use” as published on the Website of the European Commission in the Notice To Applicants, Volume 2C: http://pharmacos.eudra.org/F2/eudralex/vol-2/home.htm Throughout the text “X” stands for the (invented) name of the medicinal product. Standard statements are given in the template which must be used whenever they are applicable. If the applicant needs to deviate from these statements to accommodate product-specific requirements, alternative or additional statements will be considered on a case-by-case basis. Guidance notes in orange cross-refer to the section/information of the SPC which is to be reflected in that particular section of the package leaflet. Applicants shall ensure that, on request from patients' organisations, the package leaflet is made available in formats appropriate for the blind and partially sighted.]

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PACKAGE LEAFLET: INFORMATION FOR THE USER [Heading to be printed] {(Invented) name strength pharmaceutical form} {Active substance(s)} [The (invented) name of the medicinal product (referred to as X throughout this document) followed by the strength and pharmaceutical form (i.e. as it appears in the SPC) should be stated here in bold. This should be followed by the active substance(s) (as stated on the label section 1), which may be written on the line below.] [For medicinal products available only on prescription:] <Read all of this leaflet carefully before you start <taking> <using> this medicine. Keep this leaflet. You may need to read it again. If you have any further questions, ask your <doctor> <or> <pharmacist>. <This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their symptoms are the same as yours.> If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your <doctor> <or> <pharmacist>.> In this leaflet: 1. 2. 3. 4. 5. 6. What X is and what it is used for Before you <take> <use> X How to <take> <use> X Possible side effects How to store X Further information

1.

WHAT X IS AND WHAT IT IS USED FOR

[Pharmacotherapeutic group.] [The pharmacotherapeutic group or type of activity should be stated here using patient understandable language.] [Therapeutic indications.] [The therapeutic indications should be stated here, using patient understandable language. If appropriate, specify that:] <This medicine is for diagnostic use only.>

2. BEFORE YOU <TAKE> <USE> X [Additional sub-headings within the headings given below may be included if needed to increase readability.] [List of information necessary before taking the medicinal product.] [The whole section 2 must take into account the particular condition of certain categories of users, e.g. children and the elderly (specify the age range; for children see CHMP Note for Guidance on Clinical Investigation of Medicinal Products in Children (CPMP/EWP/462/95)); special patient populations, e.g. patients with renal or hepatic impairment.] [Contraindications.] Do not <take> <use> X <if you are allergic (hypersensitive) to {active substance(s)} or any of the other ingredients of X.> [include reference to residues, if applicable.] <if...> July 2005 Prequalification of Medicines Programme

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[Give information on absolute contraindications here in accordance with the SPC; this should be in patient understandable language and should be strictly limited to contraindications, including contraindications due to interactions with other medicinal products. Other precautions and special warnings should be made in the next section. Care must be taken to ensure that complex details are not omitted. It is not acceptable to state only the common or major contraindications. Belief that a patient cannot understand a contraindication is not a reason for omitting it.] [Appropriate precautions for use; special warnings.] Take special care with X <if you ...> <when ...> < Before treatment with X, …> [Information in patient understandable language, special warnings and appropriate precautions for use should be provided here.] [Interaction with other medicinal products.] <Taking> <Using> other medicines [Describe the effects of other products on the product in question and vice versa. Reference should be made to the intensification/weakening and the extension/shortening of effects.] <Please tell your <doctor> <or> <pharmacist> if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.> [Interactions with herbal or alternative therapies should be addressed where necessary.] [Interactions with food and drink.] <Taking> <Using> X with food and drink [Interactions not related to medicinal products should be mentioned here. For example, patients should not consume milk in combination with tetracyclines and no alcohol should be consumed during treatment with benzodiazepines. Where relevant, guidance should always be included to clarify if the medicine must be taken with food, during/before meals, or clearly state if food/meals have no influence, etc.] [Use by pregnant or breast-feeding women.] Pregnancy and breast-feeding [Where the information is significantly different, pregnancy and breast-feeding information can be presented under separate headings.] [Include conclusion summary of the information given in the SPC, in addition to the following optional statement:] <Ask your <doctor> <or> <pharmacist> for advice before taking any medicine.> [Information on teratogenicity in patient understandable language, should be included in the leaflet when the product is contra-indicated during pregnancy.] [Effects on the ability to drive or to use machines.] Driving and using machines <Do not drive <because...>.> <Do not use any tools or machines.> [Excipients warnings.] Important information about some of the ingredients of X [If appropriate, details of those excipients knowledge of which is important for the safe and effective use of the medicinal product and included in the guideline on “Excipients in the Label and Package Leaflet of
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Medicinal Products for Human Use” (The rules governing medicinal products in the European Union, Volume 3B), including relevant warnings for residues from the manufacturing process.]

3. HOW TO <TAKE> <USE> X [Additional sub-headings within the headings given below may be included if needed to increase readability.] [Instructions for proper use.] [The following 4 items can be combined as one paragraph.]
[Dosage.]

<Always <take> <use> X exactly as your doctor has told you. You should check with your <doctor> <or> <pharmacist> if you are not sure.> <The usual dose is...> [Method and/or route(s) of administration.] [Method of administration: directions for a proper use of the medicinal product; e.g. “Do not swallow”, “Do not chew”, “Shake well before use”. Route(s) of administration according to “Standard Terms” published by the Council of Europe and an additional patient-friendly explanation may be given if necessary. When applicable, there should be descriptions (if useful with illustrations) of opening techniques for childresistant containers and other containers to be opened in an unusual way. Where relevant, guidance should always be included to clarify if the medicine must be taken with food, during/before meals, or clearly state if food/meals have no influence, etc.] [Frequency of administration.] [Specify if necessary the appropriate time(s) at which the medicinal product may or must be administered.] [Duration of treatment.] [If appropriate, especially for products available without prescription, precise statements should be included on: • the usual duration of the therapy; • the maximum duration of the therapy; • the intervals with no treatment; • the cases in which the duration of treatment should be limited.] [Symptoms in case of overdose and actions to be taken.] If you <take> <use> more X than you should [Describe how to recognise if someone has taken an overdose and what to do.] [Actions to be taken when one or more doses have been missed.] If you forget to <take> <use> X [Make clear to patients what they should do after irregular use of a product; e.g.:] <Do not take a double dose to make up for a forgotten <tablet> <dose> <…>.> [Indication of the risk of withdrawal effects.] If you stop <taking> <using> X [Indicate any effects of interrupting or ending the treatment early, if applicable. A statement on the potential consequences of stopping the treatment before finishing the course of treatment and the need for a prior discussion with the treating physician or pharmacist should be included as appropriate in patient understandable language. Indicate withdrawal effects when the treatment ends, when necessary.] [As appropriate, close this section with:] <If you have any further questions on the use of this product, ask your <doctor> <or> <pharmacist>>.

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4.

POSSIBLE SIDE EFFECTS

[Description of side effects (frequency according to MedDRA).] [Begin this section with:] Like all medicines, X can cause side effects, although not everybody gets them. [Describe, if necessary, the actions to be taken. If the patient needs to seek help urgently, the use of the term <immediately> is recommended; for less urgent conditions, <as soon as possible> can be used.] [Close this section with:] If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your <doctor> <or> <pharmacist>.

5.

HOW TO STORE X

Keep out of the reach and sight of children. [Expiry date.] [Where a specific abbreviation for Expiry date is used on the labelling, the full term should be mentioned here as well as the abbreviation.] Do not use X after the expiry date which is stated on the <label> <carton> <bottle> <...> <after {abbreviation used for expiry date}.> <The expiry date refers to the last day of that month.> [Storage conditions.] [For Storage condition statements see Appendix III.] [Where applicable, shelf life after reconstitution, dilution or after first opening the container.] [Please refer to “Note for Guidance on Maximum Shelf Life for Sterile Products for Human Use after First Opening or Following Reconstitution” (CPMP/QWP/159/96/corr).] [Where appropriate, warning against certain visible signs of deterioration.] <Do not use X if you notice {description of the visible signs of deterioration}.> <Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.>

6.

FURTHER INFORMATION

[Full statement of the active substance(s) and excipient(s).] What X contains [The active substance(s) (expressed qualitatively and quantitatively) and the other ingredients (expressed qualitatively) should be identified using their names as given in the SPC and in the language of the text, e.g.] The active substance(s) is (are)… [see guidance in section 2 of outer packaging.] The other ingredient(s) is (are)... [separate the excipients of the different parts of the medicinal product, e.g. tablet core/coating, capsule contents/shell; powder/solvent (e.g. water for injections).] [Pharmaceutical form, nature and contents of container in weight, volume or units of dosage.] What X looks like and contents of the pack [The pharmaceutical form should be stated according to the full “Standard Terms” published by the Council of Europe and an additional patient-friendly explanation may be given if necessary. Where the Council of Europe short standard term is used on small immediate packaging materials, the short term should be added in brackets. It is recommended to include a physical description e.g. shape, colour, texture, imprint.]

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[All pack sizes for this pharmaceutical form and strength should be detailed here; if appropriate indicate that not all pack sizes may be marketed. A cross-reference to other pharmaceutical forms and strengths may be included.] [Name and address of the marketing authorisation holder and of the manufacturing authorisation holder responsible for batch release, if different.] Marketing Authorisation Holder and Manufacturer {Name and address} <{tel}> <{fax}> <{e-mail}> [State the name and address of the Marketing Authorisation Holder and identify as such e.g. “Marketing Authorisation Holder: ABC Ltd, etc.” (Full address: name of the country to be stated in the language of the text. Telephone, fax numbers or e-mail addresses may be included (no websites, no e-mails linking to websites).] [State the name and address of the manufacturer responsible for batch release and identify as such e.g. “Manufacturer: DEF Ltd, etc.” (Full address: name of the country to be stated in the language of the text. Telephone or fax numbers, e-mail addresses or websites are not allowed).] [If MAH and manufacturer are the same, the general heading “Marketing Authorisation Holder and Manufacturer” can be used.] [In cases where more than 1 manufacturer responsible for batch release is designated, all should be listed here. However, the printed package leaflet of the medicinal product must clearly identify the manufacturer responsible for the release of the concerned batch or mention only the specific manufacturer responsible for the release of that batch.] [List of local representatives, where applicable. Listing of local representatives is not a requirement, but where used they must be stated for all Member States. However, a representative may be designated for more than one country and may also be the MAH where no other local representative is indicated. In cases where the same representative is designated for more than one country, the representative’s details may be listed only once below the names of the countries concerned. Where a local representative is located outside the country concerned and where an address is given, the country name must be included in the address of the local representative and must be given in the language(s) of the country for which the local representative is designated. ISO country codes* may be used to replace the full name of the country heading. ISO codes together with the respective names of EU/EEA countries can be found at the following web site: http://publications.eu.int/code/en/en-370101.htm. In order to save space in the printed package leaflet, local representatives may be presented sequentially rather than in a tabulated format. In case of multi-lingual leaflets, the list of local representatives can be printed only once at the end of the printed leaflet. The local representative may be indicated by name, telephone number and electronic e-mail address (optional) only. Postal address may be added space permitting. Website addresses or e-mails linking to websites are not allowed. If a representative is outside the relevant country, indicate the name of the country. For Belgium (Brussels) and Finland (Swedish speaking Finland) addresses may appear in two languages, respectively Dutch/French and Finnish/Swedish. For Greece and Cyprus, the address must appear in Greek. Telephone numbers: international dialling code followed by the area code and telephone number, e.g. EMEA Tel: + 44-(0)20 7418 8400.] *[except for the United Kingdom, for which UK is recommended (instead of the ISO code GB] For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder: July 2005 WHO Prequalification of Medicines Programme 7

Country {Nom/Naam/Name} <{Adresse/Adres/Anschrift } B-0000 {Localité/Stad/Stadt}> Tél/Tel: + {N° de téléphone/Telefoonnummer/ Telefonnummer} <{e-mail}>

Country {Nom} <{Adresse} L-0000 {Localité/Stadt}> Tél/Tel: + {N° de téléphone/Telefonnummer} <{e-mail}>

This leaflet was last approved in {MM/YYYY} [Date of granting of the Marketing Authorisation/approval of latest variation or transfer, e.g. the latest Commission Decision, implementation date of the Urgent Safety Restriction or date of EMEA letter/notification. Item to be completed by the Marketing Authorisation Holder at time of printing.] [It is recommended that the following reference to the EMEA Website is included:] <Detailed information on this medicine is available on the WHO Prequalification web site: http://www.who.int/prequal/ >

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Version 7

LABELLING AND PACKAGE LEAFLET [The lay-out of the labelling and package leaflet presented in this template is intended for the word document (Commission Decision Annex) only. Guidance on how to best present the actual printed labelling and package leaflet (e.g. font size, use of colours, lay-out, etc.) is available in the “the Guideline on the Readability of the Label and Package Leaflet of Medicinal Products for Human Use” as published on the Website of the European Commission in the Notice To Applicants, Volume 2C http://pharmacos.eudra.org/F2/eudralex/vol-2/home.htm] [N.B.: boxed headings in Annex IIIA are provided to help applicants when completing the template; they should remain in the opinion/decision. However, they are not to appear in the final printed packaging materials (mock-ups/specimens). A separate text for outer and inner packaging labelling should be completed per strength and per pharmaceutical form. Different pack-sizes of the same strength can be presented in one document. Upon adoption by CHMP of a combined labelling text, the text does not need to be separated after adoption of the opinion. A separate package leaflet should be provided per strength and per pharmaceutical form. During the evaluation process however, applicants may present package leaflets for different strengths in one document, clearly indicating the strength or presentation to which alternative text elements refer. Where applicants consider to also market a combined package leaflet, a detailed justification for such a combined package leaflet will have to be included after the PL text and included in the application at submission or at the latest at Day 121. The justification should take into account the QRD guidance as published in the “Compilation of QRD decisions on stylistic matters”. Upon CHMP agreement (on a case-by-case basis) with a combined package leaflet text, the text does not need to be separated after adoption. However, in all other cases, a separate package leaflet per strength and per pharmaceutical form, containing all pack-sizes related to the strength and pharmaceutical form concerned will have to be provided by the applicant as follows: - English language version: immediately after adoption of the opinion. - All other language versions: at the latest 22 days after adoption of the opinion (i.e. at the latest after incorporation of Member States comments). Text which will not appear in the final printed material is to be presented as shaded text.]

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LABELLING [NOTE: these are all mandatory items listed in Title V of Directive 2001/83/EC, as amended. The data should be presented according to the template below, irrespectively of their sequence on the actual labelling and their position and possible repetition on the individual sides/flaps of the packaging (e.g. top flap, front, back etc.). Blue-boxes and their contents should not be included. Where the same text for outer and inner packaging is used, this should be clearly indicated in the heading and in {nature/type}. Text which is identical for different presentations should be provided only once e.g. text of inner vial label where such vial is part of different pack-sizes. On the printed outer packaging material, an empty space should be provided for the prescribed dose; however, this should not appear in the Labelling text (Annex IIIA).]

[Boxed headings are provided to help applicants when completing the template; they should remain in the opinion/decision annexes. However, they are not to appear in the final printed packaging materials (mockups/specimens).]

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PARTICULARS TO APPEAR ON < THE OUTER PACKAGING> <AND> <THE IMMEDIATE PACKAGING> {NATURE/TYPE} 1. NAME OF THE MEDICINAL PRODUCT

{(Invented) name strength pharmaceutical form} [as it appears in the SPC under section 1.] {Active substance(s)} [The reference to the active substance should correspond to the strength expressed in the name. E.g. (invented) name 60 mg capsules toremifene (since 60 mg corresponds to toremifene, even if the active substance is actually present as toremifene citrate) (invented) name 60 mg tablets diltiazem hydrochloride (since 60 mg corresponds to the hydrochloride salt)] [For mock-ups and specimens, this information may be presented on different lines of text or in different font sizes if necessary, provided that the appearance of the name is as an integrated item. E.g. (invented) name Z mg/ml Solution for injection]

[The international non-proprietary name (INN) of the active substance(s) shall be included, or, in absence of INN name, the common names should be used. In addition, the different strengths of fixed-combination products should be presented separated by a “/”. The names of the active substances should be presented separated by a “/” and in the same order relating to the strength. E.g. (invented) name 150 mg/12.5 mg tablets irbesartan/hydrochlorothiazide]

2.

STATEMENT OF ACTIVE SUBSTANCE(S)

[Expressed qualitatively and quantitatively per dosage unit or according to the form of administration for a given volume or weight. Where the active substance is present as a salt, this should be clearly indicated. E.g. for the examples given above: “60 mg toremifene (as citrate)” or “toremifene citrate equivalent to 60 mg toremifene”;“60 mg diltiazem hydrochloride”.]

3.

LIST OF EXCIPIENTS

[Express qualitatively those excipients known to have a recognised action or effect and included in guideline on “Excipients in the Label and Package Leaflet of Medicinal Products for Human Use” (The rules governing medicinal products in the European Union, Volume 3B). However, if the medicinal product is a parenteral, a topical or an eye preparation or if used for inhalation, all excipients must be stated. Additional excipients information (e.g. warnings) should be presented under this section and not under section 7.]

4.

PHARMACEUTICAL FORM AND CONTENTS

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[Pharmaceutical form according to the full “Standard terms” published by the Council of Europe. Contents by weight, by volume or by number of doses or number of units of administration of the medicinal product (i.e. pack size, including a reference to any ancillary items included in the pack such as needles, swabs, etc.). In case of a combined labelling text covering different pack-sizes of the same strength, each pack-size should be listed on a separate line in grey shading: e.g. 28 tablets 56 tablets 100 tablets]

5.

METHOD AND ROUTE(S) OF ADMINISTRATION

[Method of administration: directions for proper use of the medicinal product, e.g. “Do not swallow”, “Do not chew”, “Shake well before use”. In all cases, and especially if full details cannot be included on the outer packaging itself, a reference to the package leaflet must be made:] Read the package leaflet before use. [Route of administration according to the “Standard terms” published by the Council of Europe.]

6.

SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF THE REACH AND SIGHT OF CHILDREN

Keep out of the reach and sight of children.

7.

OTHER SPECIAL WARNING(S), IF NECESSARY

8.

EXPIRY DATE

[For terms on Batch number and Expiry date see Appendix IV.] [The expiry date printed on medicinal products stating only month and year should be taken to mean the last day of that month. Expiry dates should be expressed with the month given as 2 digits or at least 3 characters and the year as 4 digits. E.g.: February 2007, Feb 2007, 02-2007.] [Where applicable, shelf life after reconstitution, dilution or after first opening the container. Please refer to CHMP “Note for Guidance on Maximum Shelf Life for Sterile Products for Human Use after First Opening or Following Reconstitution” (CPMP/QWP/159/96/corr). If however the maximum in-use shelf life for the reconstituted product varies, depending on how, or with what, it is reconstituted, then there should be a statement on the label, such as: “read the leaflet for the shelf life of the reconstituted product”.]

9.

SPECIAL STORAGE CONDITIONS

[For Storage condition statements see Appendix III.]

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE

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[E.g. radiopharmaceuticals, cytostatics.] [A reference to any appropriate collection system in place should be included in the ‘Blue Box’ on the outer packaging.]

11.

NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

[Including town, postal code (if available) and country name of the MAH in the language of the text (Telephone, fax numbers or e-mail addresses may be included (no websites, no e-mails linking to websites). Local representatives of the MAH, if mentioned in the leaflet, may be included in the ‘Blue Box’ on the outer packaging.] {Name and address} <{tel}> <{fax}> <{e-mail}>

12.

MARKETING AUTHORISATION NUMBER(S)

[Item to be completed by the Marketing Authorisation Holder once the Marketing Authorisation has been granted.] [In case of a combined labelling text covering different pack-sizes of the same strength, the respective packsize should be included in grey shading after the corresponding EU Sub-Number and listed on a separate line. e.g. EU/0/00/000/001 28 tablets EU/0/00/000/002 56 tablets EU/0/00/000/003 100 tablets] EU/0/00/000/000

13.

BATCH NUMBER

[For terms on Batch number and Expiry date see Appendix IV.]

14.

GENERAL CLASSIFICATION FOR SUPPLY

<Medicinal product subject to medical prescription.> <Medicinal product not subject to medical prescription.>

15.

INSTRUCTIONS ON USE

[Only for medicinal products not subject to medical prescription only, include: - Indication(s). - Dosage recommendations, contraindication(s) and warnings, if full details cannot be printed a reference to the package leaflet should be made, e.g. “Read the package leaflet before use”. General warnings and overdose warnings are not routinely required, but for certain medicinal products such warnings may be added during the procedure at the request of the CHMP.] 16. INFORMATION IN BRAILLE

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[Information that will appear in Braille on the printed outer packaging material should be mentioned here in normal text format (See also the “Guidance concerning the Braille requirements for labelling and the package leaflet” published by the European Commission: http://pharmacos.eudra.org/F2/pharmacos/docs/Doc2005/04_05/Braille_text20050411.pdf)]

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MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS {NATURE/TYPE} 1. NAME OF THE MEDICINAL PRODUCT

{(Invented) name strength pharmaceutical form} {Active substance(s)} [Active substance – see guidance in section 1 of the outer packaging.] [Pharmaceutical form short terms according to the current version of the “Standard terms” published by the Council of Europe may be used in case of space limitation, if consistently used in all language versions.]

2.

NAME OF THE MARKETING AUTHORISATION HOLDER

{Name} [Full/short name of the Marketing Authorisation Holder.]

3.

EXPIRY DATE

[For terms on Batch number and Expiry date see Appendix IV.]

4.

BATCH NUMBER

[For terms on Batch number and Expiry date see Appendix IV.]

5.

OTHER

[Space permitting, any other information necessary for the correct use and administration of the product can be included here, e.g. calendar days.]

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS {NATURE/TYPE} [Small immediate packaging units are defined as containers sized up to and including 10 ml. On a case-bycase basis the minimum particulars could also be considered for other containers where it is not be feasible to include all the information. Such exceptional cases have to be justified, discussed and agreed with the Competent Authority/EMEA.] 1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

{(Invented) name strength pharmaceutical form} {Active substance(s)} {Route of administration} [Pharmaceutical form short terms according to the current version of the “Standard terms” published by the Council of Europe may be used in case of space limitation, if consistently used in all language versions.] [Where different labels apply to different constituents of the pharmaceutical form, the pharmaceutical form in the name on the specific label should only refer to the constituent concerned (e.g. separate label for powder vial and solvent ampoule).]

2.

METHOD OF ADMINISTRATION

[Method of administration: directions for proper use of the medicinal product, e.g. “Do not swallow”, “Do not chew”, “Shake well before use”. If full details cannot be included on the immediate packaging itself, a reference to the package leaflet should be made, e.g. “Read the package leaflet before use”.]

3.

EXPIRY DATE

[For terms on Batch number and Expiry date see Appendix IV.] [Where applicable, shelf life after reconstitution, dilution or after first opening the container. Please refer to “Note for Guidance on Maximum Shelf Life for Sterile Products for Human Use after First Opening or Following Reconstitution” (CPMP/QWP/159/96/corr).]

4.

BATCH NUMBER

[For terms on Batch number and Expiry date see Appendix IV.]

5.

CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

6.

OTHER

[Space permitting, any other information necessary for the correct use and administration of the product can be included here, e.g. storage conditions.]

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Version 11

TEMPLATE 1a APPENDIX I Statements for use in Section 4.6 “Pregnancy and lactation” of SPC (Annex I to the “Guideline on Summary of Product Characteristics”)

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EN
[1] <{Active substance} <causes> <is suspected to cause> serious birth defects when administered during pregnancy. {Trade name} is contraindicated (see 4.3) in pregnancy [only in case of a strict contraindication].> [and if necessary] <Women of childbearing potential have to use effective contraception during (and up to {number} weeks after) treatment.>> [2] <{Active substance} has harmful pharmacological effects on pregnancy and/or the foetus/new-born child.> <{Trade name} should not be used during pregnancy unless clearly necessary> [These circumstances should be specified] [3] <There are no adequate data from the use of {Active substance} in pregnant women.> <Studies in animals have shown reproductive toxicity (see 5.3). The potential risk for humans is unknown.> [or] <Animal studies are insufficient with respect to effects on pregnancy /and-or/ embryonal/foetal development/ and-or/ parturition/ and-or/ postnatal development (see 5.3). The potential risk for humans is unknown.> [Trade name] should not be used during pregnancy unless clearly necessary [these circumstances should be specified where possible].> [4] <For {Active substance} no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see 5.3). Caution should be exercised when prescribing to pregnant women.> [5] <Data on a limited number {number} of exposed pregnancies indicate no adverse effects of {Active substance} on pregnancy or on the health of the foetus/new-born child. To date, no other relevant epidemiological data are available. Animal studies have shown reproductive toxicity (see 5.3). The potential risk for humans is unknown.> [or] <Animal studies are insufficient with respect to effects on pregnancy/ and-or/ embryonal/foetal development/ and-or/ parturition/ and-or/ postnatal development (see 5.3). The potential risk for humans is unknown. Caution should be exercised when prescribing to pregnant women.> [6] <Data on a limited number {number} of exposed pregnancies indicate no adverse effects of {Active substance} on pregnancy or on the health of the foetus/new-born child. To date, no other relevant epidemiological data are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see 5.3). Caution should be exercised when prescribing to pregnant women.> [7] <Data on a large number {number} of exposed pregnancies indicate no adverse effects of {Active substance} on pregnancy or on the health of the foetus/new-born child. To date, no other relevant epidemiological data are available. Caution should be exercised when prescribing to pregnant women.

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[8] <Well-conducted epidemiological studies indicate no adverse effects of {active substance} on pregnancy or on the health of the foetus/new-born child. {Trade name} can be used during pregnancy.> [The subsequent two statements to be included as appropriate.] [9] [In case of interaction with oral contraceptives information should also be given in 4.5] <<{Active substance} adversely interacts with oral contraceptives. Therefore, an alternative, effective and safe method of contraception should be used during (and up to x weeks after) treatment.> [or] <The concomitant medication {active substance} adversely interacts with oral contraceptives. Therefore an alternative, effective and safe method of contraception should be used during (and up to {number} weeks after) treatment.>> [10] [In case of male-mediated effects on pregnancy outcome information should also be given in 4.4] <Both sexually active men and women should use effective methods of contraception during (and up to {number} weeks after) treatment.>

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[Version 05]

APPENDIX II

MedDRA terminology to be used in Section 4.8 “Undesirable effects” of SPC

The table below shows the equivalent terminology in the EU official languages plus Icelandic and Norwegian as well as in the 2 official languages of Bulgaria and Romania

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Ref 001 002 003 004 005 006 007 008 009 010 011 012 013 014 015 016 017 018 019 020 021 022 023 024 025 026 027 028 029 030 031

EN [MedDRA frequency convention] <Very common (>1/10)> <Common (>1/100, <1/10)> <Uncommon (>1/1,000, <1/100)> <Rare (>1/10,000, <1/1,000)> <Very rare (<1/10,000), <including isolated reports>> [MedDRA system organ class database] Infections and infestations Neoplasms benign, malignant and unspecified (including cysts and polyps) Blood and lymphatic system disorders Immune system disorders Endocrine disorders Metabolism and nutrition disorders Psychiatric disorders Nervous system disorders Eye disorders Ear and labyrinth disorders Cardiac disorders Vascular disorders Respiratory, thoracic and mediastinal disorders Gastrointestinal disorders Hepatobiliary disorders Skin and subcutaneous tissue disorders Musculoskeletal and connective tissue disorders Renal and urinary disorders Pregnancy, puerperium and perinatal conditions Reproductive system and breast disorders Congenital, familial and genetic disorders General disorders and administration site conditions Investigations Injury, poisoning and procedural complications Surgical and medical procedures Social circumstances

ENGLISH
SUMMARY OF PRODUCT CHARACTERISTICS 6.4 Special precautions for storage

<Do not store above <25°C> <30°C>> or <Store below <25°C> <30°C>> <Store in a refrigerator (2°C – 8°C)> <Store and transport refrigerated (2°C – 8°C)>* <Store in a freezer {temperature range}> <Store and transport frozen {temperature range}>** <Do not <refrigerate> <or> <freeze>> <Store in the original <package>> <Keep the {container}*** tightly closed> <Keep the {container}*** in the outer carton> <This medicinal product does not require any special storage conditions> <in order to protect from <light> <moisture>>

A. LABELLING 9. SPECIAL STORAGE CONDITIONS

<Do not store above <25°C> <30°C>> or <Store below <25°C> <30°C>> <Store in a refrigerator> <Store and transport refrigerated>* <Store in a freezer> <Store and transport frozen>** <Do not <refrigerate> <or> <freeze>> <Store in the original <package>> <Keep the {container}*** tightly closed> <Keep the {container}*** in the outer carton> <in order to protect from <light> <moisture>>

B. PACKAGE LEAFLET 5. STORING X

<Do not store above <25°C> <30°C>> or <Store below <25°C> <30°C>> <Store in a refrigerator (2°C – 8°C) <Store and transport refrigerated (2°C – 8°C)>* <Store in a freezer {temperature range}> <Store and transport frozen {temperature range}>** <Do not <refrigerate> <or> <freeze>> <Store in the original <package>> <Keep the {container}*** in the outer carton>

<Keep the {container}*** tightly closed> <This medicinal product does not require any special storage conditions> <in order to protect from <light> <moisture>>

* The stability data generated at 25°C/60%RH (acc) should be taken into account when deciding whether or not transport under refrigeration is necessary. The statement should only be used in exceptional cases. ** The statement should be used only when critical. *** The actual name of the container should be used (e.g. bottle, blister, etc.)

APPENDIX IV TERMS FOR BATCH NUMBER AND EXPIRY DATE TO BE USED ON OUTER AND/OR INNER LABELLING

FULL TERM

ABBREVIATION Batch

Batch number

Lot BN

Expiry date

EXP

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Compilation of QRD decisions on the use of terms
acceptable in PL approved preferred

Version 7 - December 2005

Term acetylsalicylic acid

not to be used

Comments According to the case, refer to ASA in package leaflets (e.g. for interactions) as follows: “acetylsalicylic acid <a substance present in many medicines used to relieve pain and lower fever> or <a substance present in many medicines used to prevent blood clotting>". Alternatively, as appropriate, use: " acetylsalicylic acid, a substance present in many medicines used to relieve pain and lower fever, as well as to prevent blood clotting "

Go to For the translations of the ASA statements in the EU official languages, plus Icelandic and Norwegian, please click

X

active ingredient active substance adolescents adverse effects adverse reactions adverse events

X X X X X age 12 years to 17 years (Note for guidance on clinical investigation of medicinal products in children, CPMP/EWP/462/97)

active substance

X aspirin breast-feeding children children, young clinical studies clinical trials dextrose X X X X X X X

adverse events, adverse reactions is to be used where there is a causal relationship with the use the adverse events, adverse medicinal product reactions is to be used where it occurs during the use of the medicinal product but adverse events, adverse its causal relationship is not yet established. Note that adverse events reactions without at least a suspected causal relationship should not be listed in the SPC. acetylsalicylic acid age 2 years to 11 years (Note for guidance on clinical investigation of medicinal products in children, CPMP/EWP/462/97) see Note for guidance on clinical investigation of medicinal products in children, CPMP/EWP/462/97. correct term, if chosen must be used consistently throughout text without alternating with "clinical trials". correct term, if chosen must be used consistently throughout text without alternating with "clinical studies". Not in Ph. Eur.

children, infants and toddlers (depending on age)

glucose

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Term dosage drug drug substance excipients expiration expiry expiry date formulation glucose health experts

not to be used

Comments to be used in package leaflets instead of "posology".

Go to posology active substance; medicinal product active substance; medicinal product other ingredients expiry, expiry date

X X X X X X X X X X

to be used in SPC. In PL: "other ingredients" is accepted.

medicinal product Ph. Eur. Reference to "health experts" generally means "best medical practice". It is advised to use the wording "It is recommended that..." HIV negative should not be hyphenised, as a hyphen at the end of a line can be mistaken for a negative sign. HIV positive

HIVHIV associated HIV infected HIV negative HIV positive HIV+ HIV-infected inactive ingredient inactive substance infants and toddlers intramuscular route intramuscular use intravenous intravenous route

X X X X X X X X X X X X X X "Standard Terms" published by the Council of Europe. age 28 days to 23 months (Note for guidance on clinical investigation of medicinal products in children, CPMP/EWP/462/97) the hyphen at the end of a line can be mistaken for a negative sign.

HIV infected/HIV positive HIV infected "excipients" in SPC, "other ingredients" in PL "excipients" in SPC, "other ingredients" in PL

intramuscular use

intravenous use

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Term intravenous use lactating mothers medication medicinal product medicine nursing mothers other ingredients overdose overdosage pack size posology presentation pre-term new-born infants rash Radio-active medicinal product Radiopharmaceuticals saline side effects sodium chloride solution subcutaneous use new-born infants

not to be used

Comments "Standard Terms" published by the Council of Europe.

Go to

X X X X X X X X X X X X X X X X X X X X X

nursing mothers medicinal product medicinal product to be used in package leaflet. In SPC use "excipients". excipients overdose to be used in SPC. In package use "dosage". ambiguous can mean "pack size" or "pharmaceutical form" pack size <36 weeks of gestation (Note for guidance on clinical investigation of medicinal products in children, CPMP/EWP/462/97) Is sometimes left in EN in translations. Preferred terms in all languages must be established. Radiopharmaceuticals

sodium chloride solution
for use in PL or labelling only. adverse reactions specify concentration, e.g. "sodium chloride 9 mg/ml (0.9%) solution for injection" "Standard Terms" published by the Council of Europe. age 0-27 days (Note for guidance on clinical investigation of medicinal products in children, CPMP/EWP/462/97)

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Version 7 - December 2005

Term

not to be used

Comments

Go to

acceptable in PL

approved

preferred

Keys Approved Preferred

not to be used

Definitions Terms used in legislation and templates, or originating from other official sources Terms which cannot be traced to a specific source, but which the group understands to constitute "good practice" and prefers to any other of the same meaning Terms considered to be correctly used in Package Leaflet (which requires "patient-friendly" terms). Such terms are accompanied by a "Go to" reference to the approved term Terms which the group deems unsuitable for use because misleading, unclear, obsolete or for other reasons. The "Go to" reference always leads to the approved term.

X X

Acceptable in PL X Not to be used X

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European Medicines Version 9 – December 2005

Compilation of QRD decisions on stylistic matters in product information
Issues Abbreviations and acronyms Abbreviations Antiretrovirals: reference and translations Conditional Connected problems Not always understood, particularly in package leaflet. Different languages have different approaches, so the acronyms are in the language of the translation or are derived from the English; e.g. ECT, COPD Subscript and Superscript are sometimes not used correctly in acronyms; e.g. Cmax, Cmax Different practices between Member States on whether it is acceptable to have the English full term followed by the English abbreviation (e.g. protease inhibitors (PIs) etc..) or whether the full term and/or the abbreviation should be translated The translation of “should” causes problems in Romance languages where its literal translations actually mean “it would be preferable” or “it is recommended”. QRD Suggestions Non-standard abbreviations and acronyms should be avoided and the term written out in full. In cases where this is not possible the acronym should be at least written out and introduced in brackets at its first occurrence. See also most frequently used non-standard abbreviations published on this Website. Acronyms must be written in their standard form; e.g. Cmax EL,FR,HU,LT,IS,RO,BG: full term and the abbreviation in national language BG,CS,DE,ES,ET,FI,IT,LV,MT,NL,NO,PL,PT, SL ,SK,SE: full term in national language. English abbreviation is acceptable Romance languages should make use of the form that best conveys the meaning equivalent to “must” where instructions to the patient or to the doctor are given. However, in order to offer a more precise indication on the mandatory nature of the advice it is advisable that the word “should” is avoided wherever possible in the English original itself. E.g. “Pregnant women should not breast-feed” could be phrased as “Pregnant women must not breast-feed” “X should be taken with food” could be phrased as “X is to be taken with food”. Once a particular style or house style has been selected it must be used consistently throughout the text. For general food the applicant should choose examples of food to take with a medicine based on their availability and cultural acceptability in all MS. Special meals should be described in a generic way. In the PL, if necessary, the following wording may be added: “Your doctor or pharmacist will advise you on what meal to take.” Foreign terms must be written in Italics; e.g. in vivo, in vitro, Helicobacter pylori. In Greek documents foreign terms appear in their original spelling, i.e. Roman characters. “He/she” should be used if no other neutral gender locution is possible. Patients can be referred to as “he” or as “she” when the medicinal product is exclusively for use by males or females.

Consistency Food and drink

Inconsistencies of style are often found in product information; e.g. punctuation, symbols, spacing, redaction style etc. Applicants sometimes choose examples of food to be taken with a medicinal product without considering whether such food is available in all Member-States (e.g.: apple sauce, cranberry juice). Foreign and particularly Latin terms appear frequently in product literature The patient or the physician is often referred to as “he”.

Foreign terms Gender

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Issues Health information

Connected problems Can general information on health or disease be included in the package leaflet in certain justified cases?

QRD Suggestions Council Directive 2001/83/EC art.62 states that “the package leaflet may include...” “ ...other information compatible with the SPC which is useful for health education, to the exclusion of any element of a promotional nature.” Information on the disease should normally be limited to a patient-friendly description of the sections “indications” and “pharmacotherapeutic group” of the SPC, under their respective headings. Any additional concise information on the disease (e.g. symptoms and signs of the disease, general precautions and appropriate treatment or other measures to take) could be included in section 1 or at the end of the package leaflet, for health education purposes. This information would usually relate to complex or chronic illnesses (e.g. diabetes, osteoporosis). Its inclusion has to be justified by the applicant, and will be assessed on a case-by-case basis. If references to patient organisations are included in the package leaflet, such organisations must be mentioned for all EU Member States (equal access to information for patients). Imperial measures, e.g. inches, can be included, where appropriate (e.g. if the product in question might be used by elderly patients), in brackets after the metric measures in the English text. These imperial measures must not appear in the translations in other languages. Combined printed PLs can only be acceptable if all the following 3 conditions are met: posology in the SPC/PL foresees 2 dosages (e.g. a high induction dose followed by lower maintenance dose); • PLs are completely identical, except for the few strength-specific details; • a combined PL does not cause confusion for the patient or user The applicant must submit their request for a combined PL in advance, together with a justification/rationale. A decision will be taken on a case-by-case basis. For decimals: EN: dot, e.g. 12.50 ml RO: coma, e.g. 12,50 ml All other languages: coma, e.g. 12,50 ml

Imperial measures

Package leaflet: combined printed package leaflets.

Surfaces or other measurements are sometimes expressed in imperial measures in the PL. Example: one sachet contains enough cream to cover an area of 20 cm2 (approx. 3 square inches). Are combined printed package leaflets acceptable? Are there any safety issues: i.e. are they clear for the patient?

Number separators

Different languages use different number separators (a coma or a dot) to distinguish between thousands and decimals. Style of number must correspond to language used.

For thousand: EN,BG: 1,000.00 DA, DE, EL, ES, IT, NL, PT, SL: 1.000,00 CS, FI, LV, PL, SK, SV: 1·000,00 or 1000,00 ET, HU,RO: 1000,00 BG,LT,FR: 1 000,00
(·= non-breaking space)

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Issues Trade name

Connected problems Excessive use of trade name and unnecessary repetition in SPC and package leaflet/insert. Format of the trade name and use throughout text. Is it admissible to register names with capital letters included within the trade name? If the registered trade name is written in uppercase, must it be written as such throughout the text of the product information and in the EPAR? What style can be used (maximum font size, bold, underlined, colour etc.)? Use of trademarks and brand names of medicinal products, materials or devices in product information. As no official translated pharmacopoeia is available in the national languages of some of the new EU Member States it is often unclear whether the Latin, English or the national language version of the INN can be used on the outer/inner packaging. The problem occurs in particular in cases of combined labelling material for more than one MS (e.g. the Baltic States) “0.9% w/v sodium chloride solution”, “9 mg/ml sodium chloride solution” or “sodium chloride 9 mg/ml (0.9%) solution” . Practices differ in the Member States. Can the strength in the name of medicinal product in the form of powders for reconstitution be expressed as the total quantity or as the concentration of the active substance

QRD Suggestions Avoid unnecessary repetition in all product information (SPC, label and package leaflet/insert). INN or pronouns should be used whenever possible in the SPC. In the package leaflet/insert the trade name or a pronoun should be used. The trade name of a medicinal product must appear in the format it is registered, e.g. in capitals. However, in the product information, it should be written in the same font and font size as surrounding text (i.e. Times New Roman, size 11) and must not be highlighted in any way. In such cases the applicant must provide proof of the style in which the trade name is registered. The common name or a generic description of the material, device or special meal should be used. When it is important for the correct use that only one specific device etc. (with a specific trademark) is used, then that specific trademark should be mentioned, together with a patient friendly general description in the PL, if necessary. For the purpose of allowing combined labelling material for some of the new Member States the English or Latin version of the INN will be acceptable. In such a case the national language version of the INN must be used throughout the SPC with the EN/Latin name in brackets after the description of the active substance in section 2. Equally, the national language version of the INN must be used throughout the PL with the EN/Latin name in brackets after the description of the active substance at the beginning of the PL. Reference in SPC, package leaflets: “sodium chloride 9 mg/ml (0.9%) solution for injection” Label for the vial of solvent: “sodium chloride 9 mg/ml <solution for> injection” - For single-dose presentations, either with or without solvent, the strength should be expressed as total quantity of the active substance. - For multi-dose presentations, the expression of strength should continue to be decided on a case by case basis until the QRD groups adopts a general rule.

Trade name

Trade marks/ brand names of materials/devices/sp ecial meals Translation of INNs in the new MS languages

Strength: sodium chloride solution Strength: expression of strength in the name of medicinal product in the form of powders for reconstitution prior to parenteral administration Units: general format

▪ Space between figure and unit is missing; e.g. 100ml ▪ Spaces occurring within numbers or between figures and mathematical symbols might break and lead to confusion.
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Preferred style is figure and unit or symbols separated by a non-breaking space; e.g. 100·ml; >·10; etc.
(·= non-breaking space)

Issues Units: degrees Units: SI base units

Connected problems Degrees are expressed in different styles; e.g. 10ºC, 10 ºC, 10º C International Standard base units have been introduced in the European Union with Council Directive 80/181/EEC of 20.12.79. (O.J. L 39 of 15.2.80). However this directive allows litre to be written either “l” or “L”. Microgram in name of the medicinal product and in text To be spelt out as “micrograms” in name of the product and in the text of package leaflet? Can it appear as µg in the text of the SPC? However in blisters or small immediate packs there might not be enough space for the full name.
(·= non-breaking space)

QRD Suggestions No space between the º symbol and the indicator of scale used; e.g. 10ºC, 10·ºC “Litre” must always be written as “l”, i.e. l, ml, dl, etc.

Units: microgram (µg)

Issue addressed in the European Commission’s Readability Guideline concerning the labelling and PL: “3.3 ... micrograms should always be spelled out in full rather than abbreviated, for safety reasons. However, in certain instances where this poses a practical problem which cannot be solved by using a smaller point size (< 7 points Didot) then abbreviated forms may be used, if they are justified and there are no safety concerns”. In the SPC, it is acceptable to use the abbreviated form (“µg”) throughout the text of the document. Except for the name of the medicinal product in section 1 of the SPC, where it should be spelled out in full to ensure consistency with the name on the label and the package leaflet. The accepted abbreviation is “µg”, although there may be some Member-States where this abbreviation is not used.

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Issues “Unit dose” pack sizes

Connected problems The term “unit dose” is intended to differentiate a perforated blister, which is presented to facilitate single tablet administration, from the standard tablet blister presentation.

QRD Suggestions
On the outer carton, the pack size must be stated in section 4 as e.g. “28 x 1 tablets”. In the SPC and Package leaflet the pack size must be stated as e.g. “28 x 1 tablets in <material*> perforated unit dose blisters”.
Please find below the term “perforated unit dose blisters” translated in all official languages plus Icelandic and Norwegian. BG : перфориран еднодозов блистер CS: perforovaný blistr jednodávkový DA: perforeret enkeltdosisblister DE: perforierter Blister zur Abgabe von Einzeldosen EN: perforated unit dose blisters ES: blister precortado unidosis ET: üheannuseline perforeeritud blisterpakend FI: yksittäispakattu läpipainopakkaus FR: plaquette thermoformée pour délivrance à l'unité EL: διάτρητο blister, µονάδων δόσης HU: adagonként perforált bliszter IT: blister divisibile per dose unitaria IS: rifgataðar stakskammtaþynnur LT: perforuoti vienadoziai blisteriai (for veterinary products) LT: perforuotos vienadozės lizdinės plokštelės (for human products) LV: perforēti blisteri ar vienu devu kontūrligzdā NL: geperforeerde eenheidsblisterverpakking NO: perforert endoseblister PL: blister perforowany podzielny na dawki pojedyncze PT: blisters destacáveis para dose unitária RO: blister perforat pentru eliberarea unei unităţi dozate SK: blister s perforáciou, umožňujúci oddelenie jednotlivej dávky SL: perforiranem pretisnem omotu za enkratni odmerek SV: perforerat endosblister *e.g. “Aluminium/PVC” 5/6

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APPENDIX IV TERMS FOR BATCH NUMBER AND EXPIRY DATE TO BE USED ON OUTER AND/OR INNER LABELLING

FULL TERM

ABBREVIATION Batch

Batch number

Lot BN

Expiry date

EXP

WHO Prequalification of Medicines Programme

European Medicines Agency

Version 7
FULL TERM angiotensin converting enzyme deoxyribonucleic acid monoamine oxidase inhibitors volume of distribution activated partial thromboplastin time half-life
EN ACE DNA MAOI Vd aPTT t½

TABLES OF NON-STANDARD ABBREVIATIONS
USE IN SUMMARY OF PRODUCT CHARACTERISTICS
BG ДНК МАОинхибитори aPTT CS DA DE DNS or DNA MAOHemmer X EL ΜΕΑ DNA IMAO ES ECA ET AKE FI FR IEC ADN αναστολείς ΜΑΟ X IMAO DNS HU

12/2005
IS

MAO-estäjä IMAO MAO-gátlók MAO-hemill

X

TCA

aPTI

AUC area under the curve Cmax maximum serum concentration Cmin minimum serum concentration time to maximum concentration tmax acquired immunodeficiency AIDS syndrome CMV cytomegalovirus human immunodeficiency virus HIV TNFα tumour necrosis factor alpha

ASC

СПИН * X

SIDA VIH X X EKG X PTKA UI RÜ (IU can be used) EKG

SIDA VIH FNTα EKG IRM ACPT UI NE

ALNÆMI

electrocardiogram magnetic resonance imaging percutaneous transluminal coronary angioplasty international unit polyvinylchloride high density polyethylene low density polyethylene

ECG MRI PTCA IU PVC HDPE LDPE

ЕКГ

EKG

EKG MRT

ΗΚΓ X X

ЯМР

hjartalínurit (ECG) segulómun (MRI) kransæðavík kun a.e.

IU or m.j.

I.E.

X X

PEHD PEBD

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FULL TERM angiotensin converting enzyme deoxyribonucleic acid monoamine oxidase inhibitors volume of distribution activated partial thromboplastin time half-life area under the curve maximum serum concentration minimum serum concentration time to maximum concentration acquired immunodeficiency syndrome cytomegalovirus human immunodeficiency virus tumour necrosis factor alpha electrocardiogram magnetic resonance imaging percutaneous transluminal coronary angioplasty international unit polyvinylchloride high density polyethylene low density polyethylene
same abbreviation as in English

IT

IMAO

LT AKF DNR MAO inhibitoriai Vd DATL t½ AUC Cmax Cmin tmax AIDS CMV ŽIV TNFα

LV AKE DNS MAO-inhibitori x

NL

NO

PL

PT IECA ADN IMAO

RO ECA ADN IMAO

SK

SL DNA zaviralci MAO X

SV

MAOMAO- IMAO remmers hemmere *

IMAO

MAOhämmare *

APTT t½, t0,5
ASC

SIDA VIH FNTα EKG EKG EKG

SIDA hiv

RMI

EKG BMR PTKA

NMR

X X

IRM

EKG NMR

EKG X X

EKG

UI

TV PVC DTPE MTPE X

SV PVH ABPE ZBPE

IE

IE

j.m. PCW

UI X X

UI PEID PEJD

i.e.

IE

no abbreviation available in this language, use full term.

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SMALL IMMEDIATE PACKAGING LABELLING ONLY FULL TERM Intravenous Subcutaneous Intramuscular FULL TERM Intravenous Subcutaneous Intramuscular
EN IV SC IM BG i.v. s.c. i.m. CS i.v. s.c. i.m. DA i.v. s.c. i.m. DE i.v. s.c. i.m. EL ES X ET i.v. s.c. i.m. FI FR HU iv. sc. im. IS i.v. s.c i.m. IT e.v. s.c. i.m. LT i.v. s.c. i.m. LV i.v. s.c. i.m.

EN IV SC IM

NO NL IV/I.V./i.v. iv / IV /iv SC/S.C./s. sc / SC c/sc IM/I.M./i. im / IM m./im X

PL iv. sc. im.

PT

RO i.v. s.c. i.m.

SK i.v. s.c. i.m.

SL i.v. s.c. i.m.

SV

same abbreviation as in English although not commonly used.

no abbreviation available in this language, use full term.

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