The GCC Guidance for Presenting the SPC, PIL and Labeling ...

Executive Board of the Health Ministers’ Council for GCC StatesThe GCC Guidance forPresenting the SPC, PILand LabelingInformationVersion 1.1Date issued 17/05/2011Date of implementation 17/08/2011Page 1 of 52

Document ControlVersion Date Author(s) Comments1.0 30/01/2010Product Evaluation and Standards Published for commentsSetting Department1.1 17/05/2011Product Evaluation and Standards Final versionSetting DepartmentPage 2 of 52

ContentsI. Introduction 4II. Labeling 51. Particulars to appear on the 52. Minimum particulars to appear on blisters or strips 83. Minimum particulars to appear on small immediate packaging units 9III. Patient Information Leaflet (PIL) 111. What {product name} is and what it is used for 132. Before you {product name} 133. How to {product name} 15. ٤ Possible side effects 16. ٥ How to store {product name} 166. Further information 17IV. Summary of Product Characteristics (SPC) 191. Name of the medicinal product 192. Qualitative and quantitative composition 193. Pharmaceutical form 194. Clinical particulars 205. Pharmacological properties 236. Pharmaceutical particulars 267. Marketing authorisation holder 288. Marketing authorisation number(s) 289. Date of first Authorisation/ renewal of the authorisation 2810. Date of revision of the text 2811. 2912. 29Appendix 5: Additional information that are required to be translated into Arabic language 37Appendix 6: Readability of the label and patient information leaflet (PIL) 42References 52Page 3 of 52

I. IntroductionThese guidelines are adapted from the EMEA Notice to applicants and regulatory guidelinesmedicinal products for human use, EudraLex - Volume 2.This document is indented to guide applicants on how to present the required information by theGulf Cooperation Council (GCC) States for:• Summary of Product Characteristics (SPC);• Patient Information Leaflet (PIL); and• Labeling.The SPC is the basis of information for health professionals on how to use the medicinal productsafely and effectively. The Patient Information Leaflet (PIL) shall be drawn up in accordancewith the SPC.This guideline provides advice on the principles of presenting information. Applicants shouldmaintain the integrity of each section of the document by only including information in eachsection, which is relevant to the section heading. However, some issues may need to beaddressed in more than one section and in such situations the individual statements may crossreferto other sections when these contain relevant additional information.When submitting a new application for registration, renewal or variation, the informationpresented by the applicant regarding the SPC, PIL and labeling must follow this guidance.Additionally, it should be noted that pharmaceutical products with different strengths must havedifferent packaging color codes that differentiate between different strengths. Furthermore, theapplicant must provide Arabic translation of the information on the outer package including:name of the medicinal product along with storage conditions for all medicines except those usedsolely in hospitals.Following the GCC's approval of the SPC, PIL and labeling contents, such contents cannot bechanged except with the approval of the GCC (refer to guidelines for variation requirements).Page 4 of 52

II. LabelingThe data should be presented according to the template below, irrespectively of their sequenceon the actual labeling and their position and possible repetition on the individual sides/flaps ofthe packaging (e.g. top flap, front, back etc.).A separate text for outer and inner packaging labeling should be completed per strength and perpharmaceutical form.Bracketing convention:{text}:Information to be filled in.:Text to be selected or deleted as appropriate.1. Particulars to appear on the a. Name of the medicinal product{(Invented) name strength pharmaceutical form}{Active substance(s)}• Note: The invented (trade) name in Arabic language should be added.b. Statement of active substance(s)Expressed qualitatively and quantitatively per dosage unit or according to the form ofadministration for a given volume or weight. Where the active substance is present asa salt, this should be clearly indicated.c. List of excipientsExpress qualitatively those excipients known to have a recognised action or effect.However, if the medicinal product is a parenteral, a topical or an eye preparation or ifused for inhalation, all excipients must be stated.Page 5 of 52

d. Pharmaceutical form and contentsContents by weight, by volume or by number of doses or number of units ofadministration of the medicinal product (e.g. 28 tablets, 100 mL, ...)e. Method and route(s) of administrationMethod of administration: directions for proper use of the medicinal product, e.g. “Donot swallow”, “Do not chew”, “Shake well before use”. In all cases, and especially iffull details cannot be included on the outer packaging itself, a reference to the patientinformation leaflet must be made:Read the patient information leaflet before use.f. Special warning that the medicinal product must be stored out of the reach and sight ofchildrenKeep out of the reach and sight of children.g. Other special warning(s), if necessaryh. Manufacturing and Expiry datesDates should be expressed with the month given as 2 digits or 3 characters and the yearas 4 digits. e.g.: 02/2010, Feb 2010.Where applicable, the shelf life after reconstitution, dilution or after first opening thecontainer should be included.i. Special storage conditions[For recommended labeling statements see Appendix 1]• Note: Storage conditions in Arabic language should be added.Page 6 of 52

j. Special precautions for disposal of unused medicinal products or waste materials derivedfrom such medicinal products, if appropriate[E.g. radiopharmaceuticals, cytostatics.][A reference to any appropriate collection system in place should be included on theouter packaging.]k. Name and address of the marketing authorisation holder{Name and Address}l. Marketing authorisation number(s)m. Batch number {number}n. General classification for supplyo. PricePage 7 of 52

2. Minimum particulars to appear on blisters or stripsa. Name of the medicinal product{(Invented) name strength pharmaceutical form}{Active substance(s)}b. Name of the marketing authorisation holder{Name}c. Manufacturing and Expiry datesDates should be expressed with the month given as 2 digits or 3 characters and the year as 4digits. e.g.: 02/2010, Feb 2010.d. Batch number {number}e. Other[Space permitting, any other information necessary for the correct use and administrationof the product can be included here, e.g. calendar days.]Page 8 of 52

3. Minimum particulars to appear on small immediate packaging unitsSmall immediate packaging units are defined as containers sized up to and including 10 ml.On a case-by-case basis the minimum particulars could also be considered for othercontainers where it is not be feasible to include all the information. Such exceptional caseshave to be justified, discussed and agreed upon with the GCC.a. Name of the medicinal product and route(s) of administration{(Invented) name strength pharmaceutical form}{Active substance(s)}{Route of administration}b. Method of administrationMethod of administration: directions for proper use of the medicinal product, e.g. “Do notswallow”, “Do not chew”, “Shake well before use”. If full details cannot be included onthe immediate packaging itself, a reference to the patient information leaflet should bemade, e.g. “Read the patient information leaflet before use”.c. Manufacturing and Expiry datesDates should be expressed with the month given as 2 digits or 3 characters and the yearas 4 digits. e.g.: 02/2010, Feb 2010.Where applicable, the shelf life after reconstitution, dilution or after first opening thecontainer should be included.d. Batch number {number}e. Contents by weight, by volume or by unitPage 9 of 52

FAMILIARISATIONSITTING COMFORTABLYFront seatsHead restraint heightiOther functions available...Table position for the frontpassenger seat (SW).Storing driving positions (driver'selectric seat).Heated seats.Front armrestSteering wheel adjustmentLumbar1. Unlocking the control.2. Adjustment for height and reach.3. Locking the control.!As a safety precaution, theseoperations must only be carriedout when stationary.For your comfort, the height andlongitudinal position of the front armrestcan be adjusted.It also has a storage compartment.12 65 77 106APp-308BB_01_2010_anglais_cag_pd12 12 04/11/2010 16:27:17

III. Patient Information Leaflet (PIL)A separate patient information leaflet should be provided per strength and per pharmaceuticalform. However, applicants may present patient information leaflets for different strengths in onedocument during the evaluation process, clearly indicating the strength or presentation to whichalternative text elements refer. Where applicants consider to also market a combined packageleaflet, a detailed justification for such a combined patient information leaflet should be providedin the application at submission.The following items must appear in the patient information leaflet as required by this guidance.In exceptional cases, alternative headings may be acceptable, especially for those headingscontaining or where a different wording would be more appropriate for the productconcerned e.g. to better reflect the user of the product. This should not in any case impact on thecontent required for the section concerned. Applicants should justify the use of alternativeheadings (e.g. by reference to user testing results). For certain medicinal products not all itemsmay be relevant, in this case the corresponding heading should not be included.It is important that the PIL can easily be tracked for updates and review. Each PIL should begiven a reference number along with the date the leaflet was issued and a suitable review date.Each PIL should be reviewed every 5 years or when necessary.Bracketing convention:{text}: Information to be filled in.: Text to be selected or deleted as appropriate.Page 11 of 52

Patient Information Leaflet (PIL){(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 bestated here in bold. This should be followed by the active substance(s) (as stated on thelabel section 1), which may be written on the line below.In this leaflet:1. What {product name}is and what it is used for2. Before you {product name}3. How to {product name}4. Possible side effects5. How to store {product name}6. Further informationPage 12 of 52

1. What {product name} is and what it is used for− Pharmacotherapeutic group:The pharmacotherapeutic group or type of activity should be stated here using patientunderstandable language.− Therapeutic indications:The therapeutic indications should be stated here, using patient understandablelanguage. If appropriate, specify that:2. Before you {product name}a. Do not {product name}− − b. Take special care with {product name}− − − c. other medicines, herbal or dietary supplements− Describe the effects of other products on {product name} and vice versa.Page 13 of 52

d. {product name} with food and drink− Interactions not related to medicinal products should be mentioned here. 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.e. Pregnancy and breast-feeding− Where the information is significantly different, pregnancy and breast-feedinginformation can be presented under separate headings.− Include conclusion summary of the information given in the SPC, in addition to thefollowing optional statement:f. Driving and using machines− − g. Important information about some of the ingredients of {product name}− If appropriate, details of those excipients knowledge of which is important for the safeand effective use of the medicinal product, including relevant warnings for residuesfrom the manufacturing process.Page 14 of 52

3. How to {product name} − You may include the following sub-headings within the headings given below if needed toincrease readability:• Instructions for proper use• Dosage• Method and/or route(s) of administration• Frequency of administration• Duration of treatmenta. If you more {product name} than you should• Describe how to recognise if someone has taken an overdose and what to do.b. If you forget to {product name}• Make clear to patients what they should do after irregular use of a product; e.g.c. If you stop {product name}• Indicate any effects of interrupting or ending the treatment early, if applicable.• Indicate withdrawal effects when the treatment ends, when necessary.• As appropriate, close this section with:Page 15 of 52

4. Possible side effects− Describe the side effects and whenever possible, an estimate of frequency should be provided,expressed in standard category of frequency (see Appendix 2).− Begin this section with: "Like all medicines, {product name} can cause side effects, althoughnot everybody gets them".− Describe, if necessary, the actions to be taken. If the patient needs to seek help urgently, theuse of the term is recommended; for less urgent conditions, can be used.− Close this section with: "If any of the side effects gets serious, or if you notice any side effectsnot listed in this leaflet, please tell your ".5. How to store {product name}− Keep out of the reach and sight of children.− , − Do not use {product name} after the expiry date which is stated on the − − Page 16 of 52

d. This leaflet was last approved in {MM/YYYY}; version number { }e. To report any side effect(s):• Saudi Arabia:− National Pharmacovigilance Center (NPC)o Fax: +966-1-210-7398o E-mail: npc.drug@sfda.gov.sao Website: www.sfda.gov.sa/npc• Other GCC States:− Please contact the relevant competent authority.f. Council of Arab Health MinistersThe following statements issued by the Council of Arab Health Ministers should beprinted in the PIL.This is a Medicament− Medicament is a product which affects your health and its consumption contrary toinstructions is dangerous for you.− Follow strictly the doctor’s prescription, the method of use and the instructions of thepharmacist who sold the medicament.− The doctor and the pharmacist are the experts in medicines, their benefits and risks.− Do not by yourself interrupt the period of treatment prescribed for you.− Do not repeat the same prescription without consulting your doctor.− Keep all medicaments out of reach of children.Council of Arab Health MinistersUnion of Arab PharmacistsPage 18 of 52

IV. Summary of Product Characteristics (SPC)During the evaluation process, applicants may present SPCs for different strengths in onedocument, clearly indicating with grey-shaded titles the strength or presentation to whichalternative text elements refer. However, a separate SPC per strength and per pharmaceuticalform, containing all pack-sizes related to the strength and pharmaceutical form concerned willhave to be provided by the applicant.Bracketing convention:{text}: Information to be filled in.: Text to be selected or deleted as appropriate.1. Name of the medicinal productThe name should be followed by both the strength and the pharmaceutical form.{(Invented) name strength pharmaceutical form}2. Qualitative and quantitative composition− Full details of the qualitative and quantitative composition in terms of the activesubstance(s) and excipients.− A standard statement should be included at the end of the section, i.e. ‘For a full list ofexcipients, see section 6.1.3. Pharmaceutical form− Full description of the pharmaceutical form should be provided.− It is recommended that a visual description of the appearance of the product (color,markings, etc.) is given, including information on pH and osmolarity as required e.g.:‘Tablet White, circular flat bevelled-edge tablets marked ‘100’ on one side’.Page 19 of 52

− In case of tablets designed with a score line, information should be given whether or notreproducible dividing of the tablets has been shown. e.g.:.4. Clinical particulars4.1 Therapeutic indications− The indication(s) should be stated clearly and concisely and should define the targetdisease or condition distinguishing between treatment (symptomatic, curative ormodifying the evolution or progression of the disease), prevention (primary orsecondary) and diagnostic indication. When appropriate it should define the targetpopulation especially when restrictions to the patient populations apply.− When the product is indicated in a specific age group such as children/adolescents, theindication should state the age limit e.g. ‘X is indicated in from the age of X ‘.4.2 Posology and method of administration− In case of restricted medical prescription start this section by specifying the conditions.− The route of administration and concise relevant instruction for correct administrationand use should be given here.− Instructions for preparation are to be placed under section 6.6 or 12, and crossreferencedhere.− Dose recommendations (e.g. mg, mg/kg, mg/m 2 ) should be specified per dose interval foreach category where appropriate (specify age/weight/body surface area of subsets of thepopulation as appropriate). Frequency of dosing should be expressed using time units(e.g. once or twice daily or every 6 hour) and, to avoid confusion, abbreviations e.g. ODor BID should not be used.Page 20 of 52

− Dosage adjustments or other posology related information on special populations shouldbe presented here, in well-defined sub-sections ordered by importance, e.g. regarding:elderly population; paediatric population; renal impairment; hepatic impairment,patients with a particular genotype; other relevant special population (e.g. patients withother concomitant disease or overweight patients).4.3 Contraindications− Situations where the medicinal product must not be given for safety reasons, i.e.contraindications, are the subject of this section.4.4 Special warnings and precautions for use− The order of warnings and precautions should be determined by the importance of thesafety information provided.4.5 Interaction with other medicinal products and other forms of interaction− This section should provide information on the potential for clinically relevantinteractions based on the pharmacodynamic properties and in vivo pharmacokineticstudies of the medicinal product, with a particular emphasis on the interactions, whichresult in a recommendation regarding the use of this medicinal product.− If no interaction studies have been performed, this should be clearly stated.4.6 Fertility, Pregnancy and lactation− Efforts should be made by the Marketing Authorization Applicant or Holder to providethe reasons for the recommendations for use in pregnant or lactating women and inwomen of childbearing potential. This information is important for the healthcareprofessionals informing the patient.Page 21 of 52

− In the overall assessment, all available knowledge should be taken into account,including clinical studies and post-marketing surveillance, pharmacological activity,results from non-clinical studies, and knowledge about compounds within the same class.− Efforts should be made to update the recommendations for use during pregnancy andlactation on the basis of increasing human experience in exposed pregnancies whicheventually supersede the animal data.− The following should be mentioned:o Women of childbearing potential / Contraception in males and females.o Pregnancyo Breastfeedingo Fertility− [For Pregnancy and lactation statements see Appendices 3 & 4 ]4.7 Effects on ability to drive and use machines− On the basis of the pharmacodynamic profile, reported Adverse Reactions and/or specificstudies on a relevant target population addressing the performance related to driving orusing machines, specify whether the medicinal product has:a. no or negligible influence;b. minor or moderate influence, orc. major influence on these abilities.Effects of the disease itself on these abilities should not be discussed.Page 22 of 52

4.8 Undesirable effects− This section should include all adverse reactions from clinical trials, post-authorizationsafety studies and spontaneous reporting.− Within each frequency grouping, undesirable effects are presented in order of decreasingseriousness.4.9 Overdose− Describe acute symptoms and signs and potential sequelae of different dose levels of themedicinal product based on all available information including accidental intake,mistakes and suicide attempts by patients.− Taking into account all relevant evidence, describe management of overdose in man, e.g.in relation to monitoring or use of specific agonists/antagonists, antidotes or methods toincrease elimination of the medicinal product such as dialysis.5. Pharmacological properties5.1 Pharmacodynamic propertiesDescribe the following:− Pharmacotherapeutic group: {group}, ATC code: {code}. If an ATC code is not yetavailable, this should be mentioned as ‘not yet assigned’.− Mechanism of action (if known).− Pharmacodynamic effects.− Clinical efficacy and safety.5.2 Pharmacokinetic properties− Pharmacokinetic properties of the active substance(s) relevant for the advised dose,strength and the pharmaceutical formulation marketed should be given in this section. IfPage 23 of 52

these are not available, results obtained with other administration routes, otherpharmaceutical forms or doses can be given as alternative.− Basic primary pharmacokinetic parameters, for instance bioavailability, clearance andhalf-life, should be given as mean values with a measure of variability.− Pharmacokinetics items, which could be included in this section when relevant, are givenbelow.a. General introduction, information about whether the medicinal product is a prodrugor whether there are active metabolites, chirality, solubility etc.b. General characteristics of the active substance(s) after administration of themedicinal product formulation to be marketed.• Absorption: complete or incomplete absorption; absolute and/or relativebioavailability; first pass effect; T max ; the influence of food; in case oflocally applied medicinal product the systemic bioavailability.• Distribution: plasma protein binding; volume of distribution; tissue and/orplasma concentrations; pronounced multi-compartment behavior.• Biotransformation: degree of metabolism; which metabolites; activity ofmetabolites; enzymes involved in metabolism; site of metabolism; resultsfrom in vitro interaction studies that indicate whether the new compoundcan induce/inhibit metabolic enzymes.• Elimination: elimination half-lives, the total clearance; inter and/or intrasubjectvariability in total clearance; excretion routes of the unchangedsubstance and the metabolites.• Linearity/non-linearity: linearity/non-linearity of the pharmacokinetics ofthe new compound with respect to dose and/or time; if thepharmacokinetics are nonlinear with respect to dose and/or time, theunderlying reason for the non-linearity should be presented.Page 24 of 52

− Additional relevant information should be included here.a. Characteristics in patients• Variations with respect to factors such as age, gender, smoking status,polymorphic metabolism and concomitant pathological situations such asrenal failure, hepatic insufficiency, including degree of impairment. If thisinfluence on the pharmacokinetics is considered to be clinically relevant,it should be described here in quantitative terms (cross-referral to 4.2when applicable).b. Pharmacokinetic/pharmacodynamic relationship(s)• Relationship between dose/concentration/pharmacokinetic parameter andeffect (either true endpoint, validated surrogate endpoint or a side effect).• Contribution (if any) of metabolite(s) to the effect.5.3 Preclinical safety data− The findings of the non-clinical testing should be described in brief and qualitativestatements as outlined in the following example statements:− Conclusions on the environmental risk assessment on the product should be includedwhere relevant, with reference to section 6.6.Page 25 of 52

6. Pharmaceutical particulars6.1 List of excipients− A list should be given of the excipients, expressed qualitatively only. All excipients, whichare present in the product, should be included, even those present in small amounts, suchas printing inks.− Each to be listed on a separate line according to the different parts of the product.6.2 Incompatibilities− Information on physical and chemical incompatibilities of the medicinal product withother products with which it is likely to be mixed or co-administered should be stated.− Statements concerning compatibility of the product with other medicinal products ordevices should not be included in this section but in section 6.6. Statements concerningpharmacological incompatibilities with food should be included in section 4.5.− If appropriate, the standard statement, ‘Not applicable’, should be included.− For certain pharmaceutical forms, e.g. parenterals, either of the following standardstatements should be included as appropriate:6.3 Shelf life− Information on the finished product shelf life and on the in-use stability after 1 st openingand/or reconstitution/dilution should appear here. Only one overall shelf life for thefinished product is to be given even if different components of the product may have adifferent shelf life (e.g. powder & solvent). Page 26 of 52

6.4 Special precautions for storage− General storage conditions of the finished product should appear here, together with across-reference to section 6.3 where appropriate:− [For recommended labeling statements see Appendix 1]6.5 Nature and contents of container− The material of construction of the immediate container should be stated (‘Type I glassvials’, ‘PVC/Aluminium blisters’, ‘HDPE bottles’); and any other component of theproduct should be listed, e.g. needles, swabs, measuring spoons, inhaler devices,desiccant. The container of any solvent provided with the medicinal product should alsobe described. Excessive detail, e.g., concerning the color of the stopper, the nature of theheat-seal lacquer, should usually not be included. Examples on the text in this section:‘ ml suspension in a pre-filled syringe (type I glass) with plunger stopper(chlorobutyl rubber) with or without needle in pack sizes of 5 or 10.’‘HDPE bottle with a child-resistant closure and a silica gel desiccant. Pack-sizes of 30,60 or 90 filmcoated tablets.’− All pack sizes must be listed. Pack sizes mentioned should include the number of units,number of doses (for e.g. multi-dose vaccines, inhalers, etc.), total weight or volume ofthe immediate container, as appropriate, and the number of containers present in anyouter carton. If applicable, add:Page 27 of 52

6.6 Special precautions for disposal − Include practical instructions for preparation and handling of the product, whereapplicable, including disposal of the medicinal product, and waste materials derivedfrom the used medicinal product.− If applicable, e.g. for cytotoxics, the following standard statement should be included,‘Any unused product or waste material should be disposed of in accordance with localrequirements.’− If there are no special use or handling instructions for the pharmacist or other healthcareprofessionals, the following standard statement should be included:7. Marketing authorisation holder{Name and address}8. Marketing authorisation number(s)9. Date of first Authorisation/ renewal of the authorisation 10. Date of revision of the text{MM/YYYY}Page 28 of 52

11. − For radiopharmaceuticals, full details of internal radiation dosimetry.12. − − For radiopharmaceuticals, additional detailed instructions for extemporaneouspreparation and quality control of such preparation and, where appropriate, maximumstorage time during which any intermediate preparation such as an eluate or the readyto-usepharmaceutical will conform to its specifications.Page 29 of 52

Appendix 1: Recommended labeling statements• The statements that should be used if supported by the stability studies for finishedpharmaceutical products (FPPs) are listed in Table 1.Table 1: Recommended labeling statements for finished pharmaceutical products (FPPs)Testing condition under which the stability ofthe FPP has been demonstratedRecommended labeling statement30 °C/65% RH (long-term)40 °C/75% RH (accelerated)“Do not store above 30 °C” *5 °C ± 3 °C ”Store in a refrigerator (2 °C to 8 °C)”-20 °C ± 5 °C “Store in freezer”*“Protect from moisture” should be added as applicable.• Additional labeling statements that could be used in cases where the result of the stabilitytesting demonstrates limiting factors are listed in Table 2.Table 2: Additional labeling statements for use where the result of the stability testingdemonstrates limiting factorsLimiting factorsAdditional labeling statements, where relevantFPPs that cannot tolerate refrigerationFPPs that cannot tolerate freezingLight-sensitive FPPsFPPs that cannot tolerate excessive heat, e.g.suppositoriesHygroscopic FPPs"Do not refrigerate or freeze""Do not freeze""Protect from light"“Store and transport not above 30 °C”“Store in dry condition”Page 30 of 52

Appendix 2: Frequency of adverse drug reactions• The following standard categories of frequency are recommended:Adverse effectIncidenceVery common > 1/10Common > 1/100 and < 1/10Uncommon > 1/1000 and < 1/100Rare > 1/10,000 and < 1/1000Very rare < 1/10,000Page 31 of 52

Appendix 3: Pregnancy statements1.- {Generic name} causes/is suspected to cause serious birth defects when administeredduring pregnancy.- {Trade name} is contraindicated (only in case of a strict contraindication see section 4.3)in pregnancy.and if necessary- Women of childbearing potential have to use effective contraception during (and up to xweeks after) treatment.2.- {Generic name} has harmful pharmacological effects on pregnancy and/or thefoetus/newborn child.- {Trade name} should not be used during pregnancy unless clearly necessary (thesecircumstances should be specified).3.- There are no adequate data from the use of {Generic name} in pregnant women.- Studies in animals have shown reproductive toxicity (see section 5.3). The potential riskfor 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 (seesection 5.3). The potential risk for humans is unknown.- {Trade name} should not be used during pregnancy unless clearly necessary (thesecircumstances should be specified where possible).Page 32 of 52

4.- For {Generic name} no clinical data on exposed pregnancies are available.- Animal studies do not indicate direct or indirect harmful effects with respect topregnancy, embryonal/foetal development, parturition or postnatal development (seesection 5.3) Caution should be exercised when prescribing to pregnant women.5.- Data on a limited number (.........) of exposed pregnancies indicate no adverse effects of{Generic name} on pregnancy or on the health of the foetus/newborn child. To date, noother relevant epidemiological data are available. Animal studies have shownreproductive toxicity (see section 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 (seesection 5.3). The potential risk for humans is unknown.- Caution should be exercised when prescribing to pregnant women.6.- Data on a limited number (.........) of exposed pregnancies indicate no adverse effects of{Generic name} on pregnancy or on the health of the foetus/newborn child. To date, noother relevant epidemiological data are available. Animal studies do not indicate direct orindirect harmful effects with respect to pregnancy, embryonal/foetal development,parturition or postnatal development (see section 5.3).- Caution should be exercised when prescribing to pregnant women.7.- Data on a large number (.........) of exposed pregnancies indicate no adverse effects of{Generic name} on pregnancy or on the health of the foetus/newborn child. To date, noother relevant epidemiological data are available.- Caution should be exercised when prescribing to pregnant women.Page 33 of 52

8.- Well-conducted epidemiological studies indicate no adverse effects of {Generic name}on pregnancy or on the health of the foetus/newborn child.- {Trade name} can be used during pregnancy.9.- In case of interaction with oral contraceptives information should also be given in section4.5.- {Generic name} adversely interacts with oral contraceptives (OCs). Therefore, analternative, effective and safe method of contraception should be used during (and up to xweeks after) treatment.or- The concomitant medication [Generic name} adversely interacts with oral contraceptives(OCs).- Therefore an alternative, effective and safe method of contraception should be usedduring (and up to x weeks after) treatment.10.- In case of male-mediated effects on pregnancy outcome information should also be givenin section 4.4.- Both sexually active men and women should use effective methods of contraceptionduring (and up to x weeks after) treatment.Page 34 of 52

Appendix 4: Lactation statements1. {Active substance} is not excreted in breast milk. {Invented name} can be used duringlactation.2. {Active substance} is excreted in breast milk. However, at therapeutic doses of {Inventedname} no effects on the suckling child are anticipated. {Invented name} can be used duringbreast-feeding.3. {Active substance} is excreted in breast milk to such an extent that effects on the sucklingchild are likely if therapeutic doses of {Invented name} are administered to breast-feedingwomen.• Alternative recommendations (combinations of recommendations may be used):- {Invented name} should not be used during breast-feeding.- {Invented name} is contraindicated during breast-feeding (must also becontraindicated in 4.3).- Lactation should be discontinued during treatment with {Invented name}.- A decision must be made whether to discontinue breast-feeding or todiscontinue/abstain from {Invented name} therapy.• Additional recommendation (if applicable):- Due to the long retention time of {substance} in the body, breast-feeding must not beresumed until x (days, months) after {Invented name} therapy is completed.4. It is unknown whether {Active substance} is excreted in human breast milk. The excretion of{Active substance} in milk has not been studied in animals. A decision on whether tocontinue/discontinue breast-feeding or to continue/discontinue therapy with {Invented name}should be made taking into account the benefit of breast-feeding to the child and the benefitof {Invented name} therapy to the woman.Page 35 of 52

Appendix 5: Additional information that are required to be translated intoArabic languageالمعلومات الواجب ترجمتها على الملصق الخارجي للمستحضر الصيدلاني باللغة العربية ‏(بالإضافةللمعلومات التي ذآرت سابقاَ‏ في الدليل الأساسي)‏•إسم المستحضر وترآيزهالشكل الصيدلاني للمستحضر وحجم العبوةظروف تخزين المستحضرالتسعيرة-‏ اسم الوآيل/مالك رخصة التسويقرقم التسجيل -.١.٢.٣.٤المعلومات الواجب ترجمتها على شريط المستحضر الصيدلاني باللغة العربية ‏(بالإضافة للمعلوماتالتي ذآرت سابقاَ‏ في الدليل الأساسي)‏•١. إسم المستحضر وترآيزهالمعلومات الواجب ترجمتها على ملصق العبوات الصغيرة ‏(أقل من ١٠ مل)‏ باللغة العربية‏(بالإضافة للمعلومات التي ذآرت سابقاَ‏ في الدليل الأساسي)‏•إسم المستحضر وترآيزهظروف تخزين المستحضرالتسعيرة-‏ اسم الوآيل/مالك رخصة التسويقرقم التسجيل -.١.٢.٣Page 37 of 52

بيانات النشرة الداخلية للمستحضر الصيدلاني(PIL)-معلومات لمستخدم الدواء النشرة الداخلية للمستحضر الصيدلاني :} الترآيز الشكل الصيدلاني للمستحضرالاسم - – {‏{المواد الفعالة}‏قم بقراءة هذه النشرة جيداً‏ قبل إستعمال أو تناول هذا الدواءإحتفظ بهذه النشرة،‏ لأنك قد تحتاج إليها لاحقاً.‏في حال آانت لديك أي أسئلة تتعلق بهذا المستحضر قم بإستشارة الطبيب أو الصيدلي.‏إن هذا الدواء قد تم صرفه خصيصاً‏ لك بناءاً‏ على وصفة طبية،‏ ولهذا يجب عليك عدم إعطائه لأيشخص حتى وإن آان هذا الشخص يعاني من نفس الأعراض التي سبق وأن عانيت منها.‏---قم بالإتصال بطبيبك المعالج أو الصيدلي في حال زيادةجانبي لم يتم ذآره في هذه النشرة.‏حدة الأعراض الجانبية أو الاصابة بعرض-تحتوي هذه النشرة على:‏ماهو.طريقة إستخدام > إسم المستحضر >.الأعراض الجانبية.‏ظروف تخزين > إسممعلومات إضافية.‏المستحضر >..٢.٣.٤.٥.٦Page 38 of 52

ماهوإسم المستحضر < على القيادة وإستخدام الآلاتمعلومات هامة حول بعض مكونات > إسم المستحضر إسم المستحضر ب-‏نسيان تناول جرعةإسم المستحضر إسم المستحضر إسم المستحضر

٦. معلومات إضافيةأ-‏ب-‏ج-‏د-‏ماهيمحتويات >ما هو الشكلإسم المستحضر اسم وعنوان مالك رخصة التسويق والمصنعتم الموافقة على هذه النشرة بتاريخإسم المستحضر < ووصفه وحجم عبوته} شهر / سنة ،{‏{رقم النسخة}‏٧. الإبلاغ عن الأعراض الجانبية:‏•المملكة العربية السعودية:‏− المرآز الوطني للتيقظ والسلامة الدوائيةفاآس:‏ 966-1-210-7398+البريد الالكتروني:‏الموقع الالكتروني:‏npc.drug@sfda.gov.sawww.sfda.gov.sa/npcooo•دول الخليج الأخرى:‏− الرجاء الاتصال بالمؤسسات والهيئات الوطنية في آل دولة.‏٨. وضع الإرشادات الصادرة من مجلس وزراء الصحة العرب آما يلي:‏إن هذا الدواءالدواء مستحضر يؤثر على صحتك واستهلاآه خلافاً‏ للتعليمات يعرضك للخطر.‏اتبع بدقة وصفة الطبيب وطريقة الاستعمال المنصوص عليها وتعليمات الصيدلي الذي صرفها لك.‏إن الطبيب والصيدلي هما الخبيران في الدواء وبنفعه وضرره.‏لا تقطع مدة العلاج المحددة لك من تلقاء نفسك.‏لا تكرر صرف الدواء بدون استشارة الطبيب.‏لا تترك الأدوية في متناول أيدي الأطفال.‏−−−−−−مجلس وزراء الصحة العربواتحاد الصيادلة العربPage 40 of 52

ملاحظة:‏يجب أن تكون النشرة الداخلية للمستحضر الصيدلاني:‏−−−مترجمة بطريقة احترافيه ‏(من حيث استخدام المصطلحات العلمية)،‏مدققة إملائياً‏ ولغوياً،‏مكتوبة بلغة سهلة ومفهومة للمريض.‏ولن يتم النظر في أي نشرة داخلية مقدمة للجنة الخليجية المرآزية ما لم تستوفي الشروط السابقة.‏Page 41 of 52

Appendix 6: Readability of the label and patient information leaflet (PIL)IntroductionThe main purpose of this document is to provide guidance on how to ensure that the informationon the labelling and patient information leaflet (PIL) is accessible to and can be understood bythose who receive it, so that they can use their medicine safely and appropriately.This document is written to assist applicants and marketing authorizations holders when drawingup the labeling and PIL and preparing the mock-ups or specimens of the sales presentations 1 .The document is intended to apply to all marketing authorization procedures and to all medicinalproducts.1 A mock-up is a copy of the flat artwork design in full colour, presented so that, following cutting and foldingwhere necessary, it provides a replica of both the outer and immediate packaging so that the three dimensionalpresentation of the labelling text is clear. This mock-up is generally referred to as a paper copy and not necessarilyin the material of the sales presentation. A specimen is a sample of the actual printed out outer and immediatepackaging materials and PIL (i.e. the sales presentation).Page 42 of 52

A. Recommendations for the PILGeneral considerationsThe PIL is intended for the patient/user. If the PIL is well designed and clearly worded, thismaximizes the number of people who can use the information, including older children andadolescents, those with poor literacy skills and those with some degree of sight loss. Companiesare encouraged to seek advice from specialists in information design when devising their housestyle for the PIL to ensure that the design facilitates navigation and access to information.The following guidance sets out recommendations on various aspects related to the preparationof PILs . It is aimed at helping applicants/marketing authorization holders to fully comply withthe legal requirements and is based on experience where it has been shown that using thesetechniques optimizes the usability of the PIL.1. Type size and fontChoose a font which is easy to read. Stylized fonts which are difficult to read should not be used.It is important to choose a font in which similar letters/numbers, such as “i”, “l” and “1” can beeasily distinguished from each other.The type size should be as large as possible to aid readers. A type size of 9 points, as measured infont ‘Times New Roman’, not narrowed, with a space between lines of at least 3 mm, should beconsidered as a minimum.Consideration should be given to using different text sizes to enable key information to stand outand to facilitate navigation in the text (e.g., for headings).The widespread use of capitals should not be used. The brain recognizes words in writtendocuments by the word shape, so choose lower case text for large blocks of text. However,capitals may be useful for emphasis.Do not use italics and underlining as they make it more difficult for the reader to recognize theword-shape. Italics, however, may be considered when using Latin terms.Page 43 of 52

2. Design and layout of the informationThe use of “justified” text (that is text aligned to both left hand and right hand margins) should inprinciple not be used.Line spaces should be kept clear. The space between lines is an important factor influencing theclarity of the text. As a general rule the space between one line and the next should be at least 1.5times the space between words on a line, where practical.Contrast between the text and the background is important. Factors like paper weight, color ofthe paper, size and weight of the type, color of the type and the paper itself should be considered.Too little contrast between the text and the background adversely affects the accessibility of theinformation. Therefore, background images should in principle not be placed behind the textsince they may interfere with the clarity of the information making it harder to read.A column format for the text can help the reader navigate the information. The margin betweenthe columns should be large enough to adequately separate the text. If space is limited a verticalline to separate the text may be used. Related information should be kept together so the textflows easily from one column to the next. Consideration should be given to using a landscapelayout which can be helpful to patients. Where a multi-lingual PIL is proposed there should be aclear demarcation between the different languages used; all the information provided in eachlanguage should be assembled.3. HeadingsHeadings are important and can help patients navigate the text if used well. Therefore, bold typeface for the heading or a different color, may help make this information stand out. The spacingabove and below the headings should be consistently applied throughout the leaflet. Same levelheadings should appear consistently (numbering, bulleting, color, indentation, font and size) toaid the reader.The use of multiple levels of headings should be considered carefully, as more than two levelsmay make it difficult for readers to find their way around the leaflet. However, where complexinformation has to be communicated multiple levels of headings may be needed.Using lines to separate the different sections within the text can also be helpful as a navigationaltool.Page 44 of 52

4. Print colorAccessibility is not only determined by print size. Characters may be printed in one or severalcolors allowing them to be clearly distinguished from the background. A different type size orcolor is one way of making headings or other important information clearly recognizable.The relationship between the colors used is as important as the colors themselves. As a generalrule dark text should be printed on a light background. But there may be occasions when reversetype (light text on a dark background) could be considered to highlight for instance particularwarnings. In such circumstances the quality of the print will need careful consideration and mayrequire the use of a larger type size or bold text. Similar colors should not be used for the textand background as legibility is impaired.5. SyntaxSome people may have poor reading skills, and some may have poor health literacy. Aim to usesimple words of few syllables.Long sentences should not be used. It is better to use a couple of sentences rather than one longersentence, especially for new information.Long paragraphs can confuse readers, particularly where lists of side effects are included. Theuse of bullet points for such lists is considered more appropriate. Where possible, no more thanfive or six bullet points in a list are recommended.When setting out the side effects it is particularly important to consider the order in which theyare given so the patients/users may maximize the use of the information. In general, setting outthe side effects by frequency of occurrence, starting with the highest frequency, is recommendedto help communicate the level of risk to individuals. Frequency terms should be explained in away patients/users can understand – for example “very common” (more than 1 in 10 patients).However, where a serious side effect exists which would require the patient/user to take urgentaction this should be afforded greater prominence and appear at the start of the section. Settingside effects by organ/system/class is not recommended since patients/users are in general notfamiliar with these classifications.Page 45 of 52

6. StyleWhen writing, an active style should be used, instead of passive. For example:-'take 2 tablets' instead of '2 tablet should be taken','-'you must....' is better than 'it is necessary ...'When telling patients what action to take, reasons should be provided. Instructions should comefirst, followed by the reasoning, for example: ‘take care with X if you have asthma – it may bringon an attack’.“Your medicine, this medicine, etc.” should be used rather than repeating the name of theproduct, as long as the context makes clear what is being referred to.Abbreviations and acronyms should not usually be used unless these are appropriate. When firstused in the text, the meaning should be spelled out in full. Similarly scientific symbols (e.g. > or

8. Use of symbols and pictogramsThe images, pictograms and other graphics can be used to aid comprehension of the information,but these exclude any element of a promotional nature. Symbols and pictograms can be usefulprovided the meaning of the symbol is clear and the size of the graphic makes it easily legible.They should only be used to aid navigation, clarify or highlight certain aspects of the text andshould not replace the actual text. Evidence may be required to ensure that their meaning isgenerally understood and not misleading or confusing. If there is any doubt about the meaning ofa particular pictogram it will be considered inappropriate.Page 47 of 52

B. Recommendations for the labelingGeneral considerationsLabeling covers both outer packaging and inner packaging. Although inner packaging mayinclude a lesser set of particulars, many of the principles outlined in relation to outer packagingwill apply equally to the labeling of blister packs or other small package units.Labeling ensures that the critical information necessary for the safe use of the medicine islegible, easily accessible and that users of medicines are assisted in assimilating this informationso that confusion and error are minimized.Those involved in the design of labeling should consider the following sections prior tosubmission to the competent authority. The recommendations given in relation to the PIL(section A) may be applicable to labeling and should be borne in mind in designing and layingout the required information on labels. The particulars appearing on the label of all medicinalproducts should be printed in characters of at least 7 points (or of a size where the lower case "x"is at least 1.4 mm in height), leaving a space between lines of at least 3 mm.In particular the information presented on small packs will need careful consideration so that thetext is presented in as large a type size as possible to reduce the likelihood of medication error.1. Name of the medicineThe full name of the medicinal product, with its strength and its pharmaceutical form, and, ifappropriate, whether it is intended for babies, children or adults, should appear on the outerpackaging and on the immediate packaging to aid accurate identification of the medicinalproduct.Where the medicinal product contains up to three active ingredients, the international nonproprietaryname (INN)/common name(s) of these active ingredient(s) should be stated after thefull name on the outer packaging and the immediate packaging, unless the INN/common name(s)is part of the name. The INN should be afforded due prominence for safety reasons.Page 48 of 52

2. Strength and total contentIn some cases the packaging may need to contain information on both the quantity per unitvolume and on the total quantity per total volume. The total quantity per total volume can beparticularly important for safety reasons for injectable products and other medicines available insolution or suspension.Different strengths of the same medicinal product should be expressed in the same manner: forexample 250 mg, 500 mg, 750 mg, 1000 mg and NOT 1 g. Trailing zeros should not appear (2.5mg and NOT 2.50 mg). The use of decimal points (or comma) should be avoided where thesecan be removed (i.e. 250 mg is acceptable whereas 0.25 g is not). For safety reasons it isimportant that micrograms is spelt out in full and not abbreviated. However, in certain instanceswhere this poses a practical problem which cannot be solved by using a smaller type size thenabbreviated forms may be used, if justified and if there are no safety concerns.3. Route of administrationThis should be as registered in the summary of product characteristics (SPC) only according tothe standard terms. Negative statements should not be used: for example “Not for intravenoususe”. In principle only standard abbreviations may be acceptable (i.v., i.m., s.c.).Other nonstandard routes of administration should be spelled out in full. Some routes ofadministration will be unfamiliar to patients and may need to be explained within the PIL. This isparticularly important when medicinal products are made available for self-medication.4. Design and layoutApplicants and marketing authorization holders should make best use of the space available toensure that the important information is clearly mentioned on prime spaces on the outer andimmediate packaging, presented in a sufficiently large type size. Company logos and pictogramsmay be presented, where space permits, on the outer packaging and on immediate packaging,provided they do not interfere with the legibility of the mandatory information.Use of a large type size will be appropriate, although other factors may also be important inmaking the information legible. Consideration should be given to the line-spacing and use ofwhite space to enhance the legibility of the information provided. For some small packs it maynot be possible to present all the critical information in the same field of view. The use of anyPage 49 of 52

innovative technique in packaging design to aid in the identification and selection of themedicinal product is encouraged. It is also encouraged where space is at a premium.Colors should be chosen to ensure a good contrast between the text and the background to assuremaximum legibility and accessibility of the information. Highly glossy, metallic or reflectivepackaging should be avoided, as this affects the legibility of the information. Different colors inthe name of the product are discouraged since they may negatively impact on the correctidentification of the product name. The use of different colors to distinguish different strengths isstrongly recommended.Similarity in packaging which contributes to medication error can be reduced by the judicioususe of color on the pack. The number of colors used on packs will need careful consideration astoo many colors could confuse. Where color is used on the outer pack it is recommended that itis carried onto primary packaging to aid identification of the medicine.Where a multi-lingual outer and/or immediate packaging is proposed there should be a cleardemarcation between different languages where space permits.5. Blister pack presentationsFor blister pack presentations it is important that the particulars remain available to the user up tothe point at which the last dose is removed. Often it will not be possible to apply all theinformation over each blister pocket, consequently where a random display of the information isproposed it should frequently appear across the pack. In all cases it will be acceptable to applythe batch number, manufacturing and expiry dates to the end of the blister strip. If technicallypossible, applying this information to both ends of each strip should be considered. Where a unitdoseblister presentation is proposed all the information required for blister packs must appear oneach unit dose presentation.In addition, blister foils should be printed to ensure maximum legibility of the information usinga sufficiently large font.Color for the text and the font style, should be chosen carefully as the legibility of the text on thefoil is already impaired due to the nature of the material. Where possible, non-reflective materialor colored foils should be considered to enhance the readability of the information presented andthe correct identification of the medicine.Page 50 of 52

Small containersWhere the labeling particulars cannot be applied in full to the labeling of small containers, theminimum particulars could be considered. Other factors may need to be taken into account suchas the amount of information which has to be included and the font size necessary to ensure thelegibility of the information.The criteria for small container status would normally apply to containers of nominal capacity of10 ml or less.Innovative pack design is encouraged where space is at a premium (e.g. the use of wraparound orconcertina labels). Paper labels are recommended to increase the legibility of the informationapplied to, for example, ampoules.Page 51 of 52

References• Guidance note to Applicants (Manufacturers) on the compilation of the WHO PublicAssessment Report version 1.0 - December 2004.• Notice to applicants and regulatory guidelines medicinal products for human use, EudraLex -Volume 2 - Pharmaceutical Legislation, European Commission.• Guideline on the readability of the label and package leaflet of medicinal products for humanuse, European Commission, 12 January 2009.Page 52 of 52