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Working document QAS14582

April 2014

Document for comment

983089

983090

FIP-WHO TECHNICAL GUIDELINES983091

POINTS TO CONSIDER IN THE983092

PROVISION BY HEALTH-CARE PROFESSIONALS OF983093

CHILDREN-SPECIFIC PREPARATIONS THAT ARE NOT983094

AVAILABLE AS AUTHORIZED PRODUCTS983095

(APRIL 2014)983096

983097

DRAFT FOR COMMENT983089983088

983089983089

983089983090

copy World Health Organization 2014 983089983091

All rights reserved983089983092

This draft is intended for a restricted audience only ie the individuals and organizations having received this draft The983089983093

draft may not be reviewed abstracted quoted reproduced transmitted distributed translated or adapted in part or in whole983089983094

in any form or by any means outside these individuals and organizations (including the organizations concerned staff and983089983095

member organizations) without the permission of the World Health Organization The draft should not be displayed on any983089983096

website983089983097

Please send any request for permission to983090983088

Dr Sabine Kopp Group Lead Medicines Quality Assurance Technologies Standards and Norms Department of Essential983090983089

Medicines and Health Products World Health Organization CH-1211 Geneva 27 Switzerland Fax (41-22) 791 4730983090983090

email koppswhoint983090983091

The designations employed and the presentation of the material in this draft do not imply the expression of any opinion983090983092

whatsoever on the part of the World Health Organization concerning the legal status of any country territory city or area or983090983093

of its authorities or concerning the delimitation of its frontiers or boundaries Dotted lines on maps represent approximate983090983094border lines for which there may not yet be full agreement983090983095

The mention of specific companies or of certain manufacturersrsquo products does not imply that they are endorsed or983090983096

recommended by the World Health Organization in preference to others of a similar nature that are not mentioned Errors983090983097

and omissions excepted the names of proprietary products are distinguished by initial capital letters983091983088

All reasonable precautions have been taken by the World Health Organization to verify the information contained in this983091983089

draft However the printed material is being distributed without warranty of any kind either expressed or implied The983091983090

responsibility for the interpretation and use of the material lies with the reader In no event shall the World Health983091983091

Organization be liable for damages arising from its use983091983092

This draft does not necessarily represent the decisions or the stated policy of the World Health Organization983091983093

983091983094

Should you have any comments on the attached text please send these to

Dr Sabine Kopp Group Lead Medicines Quality Assurance Technologies Standards and Norms World

Health Organization 1211 Geneva 27 Switzerland email koppswhoint fax (+41 22) 791 4730

(koppswhoint) and to Ms Marie Gaspard (gaspardmwhoint) by 1 May 2014

Working documents are sent out electronically and they will also be placed on the Medicines website

for comment If you do not already receive directly our draft guidelines please let us have your email

address (to bonnywwhoint) and we will add it to our electronic mailing list




page 2

SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS14582983091983095



PROVISION BY HEALTH-CARE PROFESSIONALS OF CHILDREN-SPECIFIC983092983088

PREPARATIONS THAT ARE NOT AVAILABLE AS AUTHORIZED PRODUCTS983092983089

First draft prepared by Professor A Nunn UK

commissioned by Dr S Hill Medicines Access and

Rational Use Department of Essential Medicines and

Pharmaceutical Policies World Health Organization

March 2011

Discussion at informal consultation on paediatrics and

generics guidelines development

4-6 May 2011

Revision prepared incorporating amendments by WHO

committee

August 2011

Revision sent out for comments August 2011

Consolidation of comments received September 2011

Discussion at forty-sixth meeting of the WHO Expert

Committee on Specifications for PharmaceuticalPreparations

10-14 October 2011

Revision prepared and sent out for comments August 2012


Discussion at forty-seventh meeting of the WHO Expert


October 2012

Review of comments received and recommendations of

WHO Expert Committee on Specifications for

Pharmaceutical Preparations and in-depth discussion

between the Secretaries of the FIP Expert Group and


Pharmaceutical Preparations

February 2013

Preparation of new working document for circulation March 2013

Circulation of new working document for comments March 2013

Discussion during Expert Committee on the Selection

and Use of Essential Medicines

8 April 2013

Compilation of feedback received June 2013

Any further action by WHO and FIP July-September 2013




page 3

983092983090

983092983091

Presentation to the forty-eighth meeting of the WHO

Expert Committee on Specifications for Pharmaceutical

Preparations

14-18 October 2013

New document received by WHO from FIP March 2014





Preparations

13-17 October 2014

Any further action as necessary hellip




page 4




PREPARATIONS THAT ARE NOT AVAILABLE AS AUTHORIZED PRODUCTS

983092983095

983092983096

The present draft is based on working document QAS13525 discussed at the October 2013983092983097

meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations983093983088

The working document text has been reorganized and brought into balance with the contents983093983089

of the WHO document Development of paediatric medicines points to consider in983093983090

formulation Parts of the original draft (QAS11399) have been reintroduced eg Appendix983093983091

4 on potential problems in compounding Comments received on the working document are983093983092

largely taken into account At the October 2013 meeting experts expressed concern on good983093983093

manufacturing practices (GMP) aspects of compounded medicines for stock A new section983093983094

on GMP aspects is therefore proposed As the document is intended for a wide audience of983093983095

practitioners it is advisable to include a glossary983093983096

983093983097

1 Introduction and scope helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip983094983088

11 Background helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip983094983089

12 Purpose helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip983094983090

13 Target audience and health-care settings helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip983094983091

2 Glossaryhelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip983094983092

3 Alternatives to compounding helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip983094983093

31 Sourcing of a commercially available or manufactured product if available hellip983094983094

32 Dose rounding helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip983094983095

33 Therapeutic alternatives helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip983094983096

34 Manipulation of dosage forms helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip983094983097

341 Tablet splitting helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip983095983088

342 Tabletcapsule dispersion for oral administration helliphelliphelliphelliphelliphelliphelliphelliphellip983095983089

343 Crushing tabletsopening capsules and mixing powder with food983095983090

and drink helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip983095983091

344 Giving the injectable form by the oral route helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip983095983092

345 Splitting suppositories helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip983095983093

346 Other possibilities helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip983095983094

4 Compounding helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 983095983095




page 5

41 Good manufacturing practices aspects helliphelliphellipsecthelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip983095983096

983095983097

42 Potential problems helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip983096983088

43 Basic considerations helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip983096983089

5 Information availability and access helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 983096983090

51 Standards of practice and guidelines helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip983096983091

52 Formularies and compendia helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip983096983092

53 Source and supply helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip983096983093

54 Networks and information services helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip983096983094

6 References helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip 983096983095

Annex 1 Examples of therapeutic alternatives helliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphelliphellip983096983096

Annex 2 Compounded preparations ndash consideration of potential problems helliphelliphelliphelliphellip983096983097

983097983088

983097983089

1 INTRODUCTION AND SCOPE983097983090

983097983091

11

Background983097983092

983097983093

Paediatric patients should have access to authorized age-appropriate preparations of983097983094

medicines that can be administered safely and effectively Nothing in this document should983097983095

detract from this objective However it is recognized that such preparations are not always983097983096

available and a safe and effective alternative must be sought983097983097

983089983088983088

In the context of paediatric pharmacy practice and for the purpose of this document983089983088983089

compounding is the technique applied by pharmacists to produce medicines from active983089983088983090

pharmaceutical ingredients (APIs) or using authorized medicines when no commercially983089983088983091

available authorized age-appropriate or adequate dosage form exists Unless stated explicitly983089983088983092

in this document the compounded medicine is assumed to be dispensed immediately after983089983088983093

preparation and not kept in stock Compounding does not apply to reconstitution of983089983088983094

authorized medicines prior to dispensing983089983088983095

983089983088983096

Compared to the use of authorized medicines there are significant risks associated with983089983088983097

compounding quality safety and efficacy can rarely all be assured and there have been983089983089983088




page 6

many errors reported in the preparation of such medicines In some situations compounding983089983089983089

of a medicine for a child may be the only option which may be supported by industry-983089983089983090

verified compounding There may be alternatives to compounding which also should be983089983089983091

considered for example use of a therapeutic alternative or manipulation of authorized dosage983089983089983092

forms983089983089983093

983089983089983094

This points-to-consider document is supported by a literature review of the evidence available983089983089983095

Report for WHO on findings of a review of existing guidanceadvisory documents on how983089983089983096

medicines should be administered to children including general instructions on983089983089983097

extemporaneous preparations and manipulation of adult dosage forms (working document983089983090983088

QAS11400 ndash available on demand)983089983090983089

983089983090983090

The document is to consider as a time-limited document that addresses current needs for983089983090983091

advice in the search for an alternative to an authorized age-appropriate dosage form983089983090983092

Wherever possible the guidance is informed by the relevant evidence However the evidence983089983090983093

base is weak or non-existent in most situations Consequently the guidance is predominantly983089983090983094

informed by best practice based on sound scientific and therapeutic principles and expert983089983090983095

consensus Whilst the guidance is a working practical document it is important to invite983089983090983096

comment and input from interested practitioners so that the guidance can be developed983089983090983097

further in response to feedback983089983091983088

983089983091983089

12 Purpose983089983091983090

983089983091983091

The purpose of the document is to983089983091983092

983089983091983093

bull provide evidence-based or best practice advice about alternatives to compounding of983089983091983094

medicines for paediatric patients983089983091983095

bull

describe and educate practitioners in the potential problems of compounding and how983089983091983096

to avoid them983089983091983097

bull provide brief advice on compounding983089983092983088

bull provide a bibliography of relevant literature supporting evidence and existing983089983092983089

guidance983089983092983090

983089983092983091




page 7

The document will not reproduce areas where existing guidance and standards exist (eg983089983092983092

GMP standards for facilities and documentation) Where appropriate reference is made to the983089983092983093

relevant resources and publications983089983092983094

983089983092983095

13 Target audience and health-care settings983089983092983096

983089983092983097

The document is intended for a wide audience of health-care stakeholders including983089983093983088

983089983093983089

bull all practitioners involved in health care of the paediatric population but mainly983089983093983090

pharmacists physicians paediatricians and nursing staff983089983093983091

bull national drug regulatory authorities and professional bodies eg national paediatric983089983093983092

organizations national pharmacy associations983089983093983093

bull general hospitals and health clinics983089983093983094

bull specialized paediatric hospitals and primary care clinics983089983093983095

bull pharmaceutical industry given its role in providing information983089983093983096

983089983093983097

Pharmaceutical manufacturers can often provide useful information on validated983089983094983088

compounded formulae and other information relating to the manipulations and specific983089983094983089

characteristics of formulations983089983094983090

983089983094983091

The document may be particularly useful in resource-poor situations where access to age-983089983094983092

appropriate dosage forms is limited and where it may be difficult to obtain relevant983089983094983093

information andor achieve the highest standards of quality assurance when dispensing983089983094983094

compounded preparations983089983094983095

983089983094983096

2 GLOSSARY983089983094983097

983089983095983088

active pharmaceutical ingredient (API)983089983095983089

Any substance or mixture of substances intended to be used in the manufacture of a983089983095983090

pharmaceutical dosage form and that when so used becomes an active ingredient of that983089983095983091

pharmaceutical dosage form Such substances are intended to furnish pharmacological983089983095983092




page 8

activity or other direct effect in the diagnosis cure mitigation treatment or prevention of983089983095983093

disease or to affect the structure and function of the body983089983095983094

983089983095983095

authorized dosage form 983089983095983096

A pharmaceutical dosage form that has been authorized by the competent authority to be983089983095983097

marketed for the treatment of specific indications983089983096983088

983089983096983089

child-resistant container983089983096983090

A form of packaging difficult for young children to open but not unduly difficult for adults to983089983096983091

open properly983089983096983092

983089983096983093

compounding983089983096983094

The technique applied by pharmacists to produce non-authorized medicines from active983089983096983095

pharmaceutical ingredients or using authorized medicines983089983096983096

983089983096983097

dispensing pharmacy983089983097983088

The pharmacy receiving the prescription for a patient and providing the pharmaceutical983089983097983089

preparation to the patient For compounded medicines the dispensing pharmacy is not983089983097983090

necessarily the preparing pharmacy983089983097983091

983089983097983092

dose rounding983089983097983093

983089983097983094

983089983097983095

excipient 983089983097983096

Any ingredient other than the active pharmaceutical ingredient which has been evaluated for983089983097983097

safety and included in a pharmaceutical dosage form to (i) aid the processing of the dosage983090983088983088

form during its manufacture (ii) protect support or enhance stability bioavailability or983090983088983089

patient acceptability (iii) assist in product identification or (iv) enhance any other attribute983090983088983090

of the overall safety and effectiveness of the dosage form during storage or use983090983088983091

983090983088983092

good manufacturing practices (GMP)983090983088983093

A philosophy of practice and processes to assure the quality and safety of manufactured983090983088983094

pharmaceutical products specified in for example WHO guidelines983090983088983095




page 9

983090983088983096

labelling information983090983088983097

Information to the user provided on the package label or in the patient information leaflet983090983089983088

983090983089983089

manipulation of a dosage form983090983089983090

Operation performed by the pharmacist or parentcaregiver to facilitate the administration of983090983089983091

a dosage form It can be simple eg breaking a tablet or complex for example using tablets983090983089983092

as a source for an active pharmaceutical ingredient to prepare a suspension983090983089983093

983090983089983094

pharmaceutical dosage form983090983089983095

The physical form in which a medicine is presented the name of a dosage forms combines its983090983089983096

physical form and the intended route of administration eg a tablet (to be swallowed) oral983090983089983097

suspension (liquid suspension of solid particles intended for oral intake and swallowing)983090983090983088

983090983090983089

route of administration983090983090983090

The way in which a medicine is given to a patient eg oral administration (administration via983090983090983091

the oral route) rectal administration (administration to the rectum)983090983090983092

983090983090983093

SmPC983090983090983094

Summary of product characteristics approved by the competent authority983090983090983095

983090983090983096

3 ALTERNATIVES TO COMPOUNDING983090983090983097

983090983091983088

Before deciding to compound consider possible alternatives that will give the greatest983090983091983089

assurance of clinical effectiveness and safety983090983091983090

983090983091983091

In some situations for example if the stability and method of preparation of an oral liquid are983090983091983092

well documented eg if compounding has been industry-verified and all facilities and983090983091983093

ingredients are available it may be less compelling to seek an alternative On the other hand983090983091983094

if there are no stability data and for example the API forms a caking suspension in the only983090983091983095

available excipients (eg a syrup) an alternative must be considered to ensure safe and983090983091983096

effective treatment983090983091983097

983090983092983088




page 10

In any case the decision on how to prepare andor provide a non-authorized preparation983090983092983089

should be based on an assessment of risks and benefits of the dosing strategy On a case-by-983090983092983090

case basis potential benefits from use should be weighed against all possible risks arising983090983092983091

from preparation and administration of such medicines Even in cases where the compounded983090983092983092

preparation can be considered a validated formulation the impact of compounding on983090983092983093

bioavailability may not be known983090983092983094

983090983092983095

Main alternatives to compounding are983090983092983096

983090983092983097

31 Sourcing of a commercially-available or manufactured product1 if available983090983093983088

983090983093983089

The logistics of supply and access are obvious factors that might work against this but983090983093983090

practitioners should liaise with suppliers importers and regulatory authorities to access these983090983093983091

products if possible983090983093983092

983090983093983093

Importation of products may be expensive and reputable suppliers should be used to avoid983090983093983094

spuriousfalsely-labelledfalsifiedcounterfeit (SFFC) medicines Quality assurance systems983090983093983095

should be in place for example to ensure that recall systems are available and information983090983093983096

provided in the local language983090983093983097

983090983094983088

Large-scale use of compounded oral liquids for children should not be justified on the983090983094983089

grounds that they are cheaper than commercial products Other options including local983090983094983090

manufacture using GMP standards should be investigated983090983094983091

983090983094983092

32 Dose rounding983090983094983093

983090983094983094

If the dose prescribed does not correspond to a dosage form which is commercially available983090983094983095

consider whether the dose can be suitably amended whilst maintaining safety and efficacy983090983094983096

The therapeutic index of the medicine and patient characteristics are to be considered before983090983094983097

making a decision983090983095983088

983090983095983089

1 This includes products prepared to GMP standards for example at an accredited hospital manufacturing unit




page 11

Some drug doses are calculated accurately on the basis of body weight yet the therapeutic983090983095983090

index is such that one dose can be used for a broad weight or age band Consult the WHO983090983095983091

Model Formulary for Children Available from983090983095983092

httpappswhointmedicinedocsenmabstractJs17151e 983090983095983093

983090983095983094

33 Therapeutic alternatives983090983095983095

983090983095983096

If a medicine is prescribed in a formulation which is not available eg in an age-appropriate983090983095983097

form consider the possibility of using a medicine with a similar therapeutic action which is983090983096983088

available in a more suitable form Examples are presented in Appendix 1983090983096983089

983090983096983090

34 Manipulation of dosage forms983090983096983091

983090983096983092

In situations where the prescribed dose is less than what is commercially available if there983090983096983093

are swallowing difficulties or the stability of a compounded oral liquid cannot be assured983090983096983094

consider the possibilities for manipulation of a dosage form as outlined below983090983096983095

983090983096983096

The practitioner should have in mind that manipulation such as tablet splitting tabletcapsule983090983096983097

dispersion or tablet crushing and mixing with food or drink may increase the potential for983090983097983088

inaccurate dosing and it may affect the stability and bioavailability of the dosage form in983090983097983089

particular when mixed with food or drink Excipients that are safe for adults may not983090983097983090

necessarily be so for children983090983097983091

983090983097983092

When medicines are mixed with food or drink an unpleasant taste of the mix may cause983090983097983093

aversion by the child Mixing with breast milk could potentially be used in very young983090983097983094

children (lt 6 months) but may cause aversion in breastfed children the mother should983090983097983095

therefore observe milk intake and signs for breast-milk refusal983090983097983096

983090983097983097

341 Tablet splitting983091983088983088

Many tablets are designed to allow splitting either by breaking if scored or by using a983091983088983089

purposely designed tablet cutter If the child is able to take solid dose forms safely (age will983091983088983090

vary but usually from age 6ndash8 and above) a tablet fraction can be given otherwise it can be983091983088983091

dispersed or mixed with food or juice as below983091983088983092




page 12

983091983088983093

There is evidence that splitting of marketed tablet formulations may result in segments that983091983088983094

are far from meeting pharmacopoeia requirements for dose uniformity Unless the tablet is983091983088983095

provided with a score line to facilitate breaking and swallowing the full dose it is important983091983088983096

that regulatory authorities and manufacturers assure that such tablet formulations that may be983091983088983097

splitted also meet the relevant uniformity requirements for the tablet segments and that983091983089983088

information about possible splitting occurs in the summary of product characteristics (SmPC)983091983089983089

983091983089983090

In the lack of appropriate information and especially when the API is potent or has a narrow983091983089983091

therapeutic index compounding may be preferable when an accurate dose cannot be assured983091983089983092

Thus consider on a case-by-case basis whether splitting of tablets might lead to toxicity or983091983089983093

reduced effect983091983089983094

983091983089983095

Not all tablets can be split In general those with a sustained release or enteric coating cannot983091983089983096

be split but it may be possible to split those with a sustained-release matrix Formularies or983091983089983097

manufacturerrsquos information and the SmPC should be consulted983091983090983088

983091983090983089

Consideration should be given to splitting tablets with an appropriate commercial tablet983091983090983090

splitter in the pharmacy If possible tablets with score lines and uniform distribution of the983091983090983091

active drug should be sourced and information sought on the stability of segments If carers983091983090983092

are cutting segments they should be given a commercial tablet splitter with adequate983091983090983093

instruction on the method of preparing and storing tablet segments983091983090983094

983091983090983095

342 Tabletcapsule dispersion for oral administration983091983090983096

It may be possible to disperse tablets or the contents of capsules in water or other liquid If983091983090983097

the tablet disperses the tablet or a fraction of the tablet can be dispersed in a small volume983091983091983088

appropriate for the concerned child and the whole dose given when a suspension is formed983091983091983089

mixed with a flavored vehicle if required Assure that the whole dose is administered by983091983091983090

flushing the container Consider the impact of dispersion and the risk for interactions with the983091983091983091

contents of the flavoured vehicle on bioavailability983091983091983092

983091983091983093

Conventional tablets do not disperse readily but some form a suspension within a short time983091983091983094

Soluble tablets and dispersible tablets disintegrate and dissolve or disperse within a short time983091983091983095




page 13

in water at room temperature When the API is known to be soluble dissolving or dispersing983091983091983096

the tablet in a known volume of water can allow a fractional dose to be appropriately983091983091983097

measured with a syringe as in the case of captopril As extraction of soluble API from the983091983092983088

tablet excipients may be incomplete the suspension should be shaken or stirred prior to983091983092983089

measuring the dose and not filtered unless it has been established that the API is not removed983091983092983090

In the case of a poorly soluble API the measurement of a fractional dose by taking an aliquot983091983092983091

from a suspension formed in this way is generally not recommended due to probable rapid983091983092983092

sedimentation of insoluble API and resultant dosage inaccuracy983091983092983093

983091983092983094

The remainder of a tablet or capsule dispersion shall not be stored and reused because of983091983092983095

stability reasons (microbiological chemical physicochemical)983091983092983096

983091983092983097

Tablet dispersion may not always be practical for infants when the doses required are the983091983093983088

equivalent of small tablet fractions that are unable to be reliably prepared eg a fifth of a983091983093983089

tablet or if the tablet is not scored983091983093983090

983091983093983091

When dispersion is intended for tube feeding parameters such as particle size viscosity983091983093983092

dosing volume and compatibility of the oral preparation with the tube material should be983091983093983093

considered Dispersions may be too viscous or contain large particles that can make the983091983093983094

administration by feeding tube not feasible Adsorption of API to the tube material results in983091983093983095

inappropriate dosing this concern is most relevant for lipophilic and potent APIs983091983093983096

983091983093983097

WHO is promoting the use of flexible solid oral dosage forms such as dispersible tablets (see 983091983094983088

Development of paediatric medicines points to consider in formulation WHO Technical983091983094983089

Report Series No 970 Annex 5) The use of custom-made dispersible tablets for paediatric983091983094983090

dosing should be used wherever possible but there is a need to ensure that carers understand983091983094983091

how they are to be administered983091983094983092

983091983094983093

343 Crushing tabletsopening capsules and mixing powder with food or drink983091983094983094

The practice of crushing tablets or opening capsules and adding the powder to a palatable983091983094983095

drink or sprinkling onto solid food are common alternatives However there may be little983091983094983096

evidence to support the efficacy and safety since stability and bioavailability may be altered983091983094983097

In case of potent APIs consider the risks associated with handling of powdered material for983091983095983088




page 14

parentscarers Modified-release tablets and capsules cannot be crushed or opened without983091983095983089

affecting bioavailability andor stability and this should therefore not be done983091983095983090

983091983095983091

In general the possibility to crush tablets should be based on bioavailability studies983091983095983092

Information should be sought from manufacturers (eg the SmPC and website) and983091983095983093

formularies whenever possible The process is acceptable only if bioavailability is not983091983095983094

affected by food or drink and when the product is used immediately983091983095983095

983091983095983096

It is difficult to ensure that a complete dose has been taken and the practice of nurses and983091983095983097

carers handling powdered medicines may present health concerns Tablet dispersion may be a983091983096983088

simpler more reliable and potentially safer method983091983096983089

983091983096983090

Aliquots should usually not be taken from liquid-filled capsules since it is difficult to remove983091983096983091

and measure the total contents983091983096983092

983091983096983093

344 Giving the injectable form by the oral route983091983096983094

Oral administration is possible although an expensive option for some injections If the983091983096983095

injectable form of the API is the same as the oral form (for example labetalol hydrochloride983091983096983096

ondansetron hydrochloride) it can be assumed that the API will be absorbed enterally from983091983096983097

the injectable formulation However as the API is in solution more rapid absorption and983091983097983088

higher peak levels may occur compared to the slower absorption from a solid oral dose form983091983097983089

When evaluating whether an injection is suitable for oral use specialist advice eg983091983097983090

consultation with a medicines information centre should be sought because there are983091983097983091

important factors which must be considered eg first-pass effect oral bioavailability gastric983091983097983092

acidity (eg effect on stability) pH effects (eg precipitation of soluble salts of weak acids)983091983097983093

and palatability983091983097983094

983091983097983095

Injections may contain excipients that are undesirable in some patients eg propylene glycol983091983097983096

and ethanol The pH of some injections may mean that they should not be given orally or be983091983097983097

diluted before administration to avoid irritation eg furosemide injection (pH 9)983092983088983088

pantoprazole injection (pH 9ndash105) phenytoin sodium injection (pH 10ndash12)983092983088983089

983092983088983090

983092983088983091




page 15

345 Splitting suppositories983092983088983092

There is little information on the accuracy with which suppositories can be split Splitting is983092983088983093

usually associated with major problems with regard to accurate dosing The majority of983092983088983094

commercially available suppositories are formulated as suspensions which means that983092983088983095

sedimentation of the solid API particles may occur during solidification of the suppository983092983088983096

therefore if suppositories need to be split this should be done lengthwise983092983088983097

983092983089983088

Suppositories have been melted and recast into smaller moulds This option is associated with983092983089983089

a risk of recrystallization and for affecting the distribution of the API resulting in over- or983092983089983090

under-dosing It is therefore generally discouraged983092983089983091

983092983089983092

Therapeutic index and the consequences of over- or under-dosing should be taken into983092983089983093

account when determining whether it is safe to split suppositories If possible this should be983092983089983094

done in the pharmacy and segments should be weighed to ensure the desired weight983092983089983095

983092983089983096

346 Other possibilities983092983089983097

In any case where a change of the route of administration as intended for an authorized983092983090983088

medicine is considered advice should be sought from formularies and the literature and even983092983090983089

specialist advice In general use of an altered route of administration results in a different983092983090983090

pharmacokinetic profile introducing a high risk of dosing errors and may compromise safety983092983090983091

and efficacy983092983090983092

983092983090983093

4 COMPOUNDING983092983090983094

983092983090983095

41 Good manufacturing practices aspects 983092983090983096

983092983090983097

The dispensing pharmacy receives the prescription for a patient and provides the983092983091983088

compounded preparation to the patient Preparation may take place in another pharmacy or983092983091983089

hospital manufacturing unit983092983091983090

983092983091983091

When a non-authorized medicine is prepared for stock the preparing pharmacy or hospital983092983091983092

unit should meet GMP requirements to personnel premises and equipment quality assurance983092983091983093

system documentation and product dossier Further an authorization by the competent983092983091983094




page 16

authority to carry out operations should be considered Reference in this aspect is made to the983092983091983095

PICS Guide to Good Practices for the preparation of Medicinal Products in Healthcare983092983091983096

Establishments (wwwpicschemeorg) and to other guidelines including WHO guidelines on983092983091983097

GMP and corresponding national guidelines983092983092983088

983092983092983089

In case of compounding as a single event and the preparation is dispensed immediately to the983092983092983090

patient requirements may be less strict Nevertheless there are quality assurance983092983092983091

requirements to take into account983092983092983092

983092983092983093

bull the preparing pharmacy should have appropriate premises and equipment983092983092983094

bull the pharmacist and staff must have sufficient training and background for983092983092983095

compounding983092983092983096

bull access to relevant literature (pharmacopoeias handbooks scientific journals etc) and983092983092983097

the Internet983092983093983088

bull general instructions for every type of preparation should be available983092983093983089

bull a record on each preparation should be retained showing the key processing and983092983093983090

packaging steps including the name of the person responsible for each step983092983093983091

983092983093983092

42 Potential problems983092983093983093

983092983093983094

Formulation of a compounded medicine is associated with a number of potential problems983092983093983095

that may impact on the safety and effectiveness of the formulation Awareness of the relative983092983093983096

complexity of the formulation and the things that can go wrong will help to avoid such983092983093983097

problems Guidance on compounding can be found in for example Marc Jackson and983092983094983088

Andrew Lowey Handbook of Extemporaneous Preparation Pharmaceutical Press 2010983092983094983089

983092983094983090

Consideration must be given to the properties of the API (eg aqueous solubility pH effect983092983094983091

on solubility particle size when poorly soluble) and stability of both API and the983092983094983092

compounded formulation ie chemical physical and microbiological instability983092983094983093

983092983094983094

Further consideration must be given to the selection of excipients and excipients present in983092983094983095

manipulated dose forms It is important to consider any possible adverse effects of the983092983094983096

ldquoinactiverdquo components of the preparation The use of preservatives ethanol and sugars must983092983094983097




page 17

be carefully considered Some guidance and literature references on the formulation can be983092983095983088

found in Development of paediatric medicines points to consider in formulation (WHO983092983095983089

Technical Report Series No 970 Annex 5) 983092983095983090

983092983095983091

Annex 2 presents examples of potential problems in compounding983092983095983092

983092983095983093

43 Basic considerations983092983095983094

983092983095983095

bull Quality of API and excipients983092983095983096

It is important to ensure that the API and excipients meet pharmacopoeia standards983092983095983097

with regard to both identity and purity The choice of excipients should be restricted983092983096983088

to those that have been used in authorized medicines intended for the same route of983092983096983089

administration983092983096983090

983092983096983091

bull Consider use of an authorized dosage form as a starting point983092983096983092

It may be safer and more effective to crush tablets or use the contents of hard capsules983092983096983093

with an appropriate suspending vehicle rather than preparing from API and excipients983092983096983094

There are many formulations available with validated shelf-life but sourcing of983092983096983095

suspending agents may be difficult andor expensive983092983096983096

983092983096983097

There might be instances where the pharmacist crushes a number of tablets or opens a983092983097983088

number of capsules dilutes the powder with a suitable excipient and doses the powder983092983097983089

in ready-to-use single dose sachets Before doing so consider the stability of the983092983097983090

preparation including in-use stability against humidity and exposure to air983092983097983091

983092983097983092

bull Consult literature and guidelines if available983092983097983093

If possible always use a validated formulation (ie based on literature stability983092983097983094

studies and guidelines) Consult product information and the latest national and983092983097983095

international guidelines andor a specialist information centre if possible983092983097983096

983092983097983097

bull Employ the principles of GMP 983093983088983088

This involves the processes put in place to give the highest level of assurance possible983093983088983089

that the product will be safe and effective It is accepted that few units will be able to983093983088983090




page 18

conform to the requirements of GMP However as stated in Section 31 the983093983088983091

principles of quality assurance are possible and essential under any conditions983093983088983092

983093983088983093

bull Medication error potential983093983088983094

There have been many examples of medication error when preparing compounded983093983088983095

medicines and some have resulted in death or serious harm to patients The potential983093983088983096

for medication error must be recognized and steps taken to minimize the risk This983093983088983097

will include as a minimum the use of a worksheet listing the formulation ingredients983093983089983088

and the identity of ingredients quantities calculations and measurements should be983093983089983089

double-checked by trained personnel and signatures provided The pharmacist983093983089983090

responsible should check the final product and label against the signed worksheet983093983089983091

ingredients and prescription983093983089983092

983093983089983093

bull Caution in extrapolating from other formulations 983093983089983094

Caution is required if extrapolating the formulation from a published study or983093983089983095

formulary Formulations made from APIs may be more stable than formulations made983093983089983096

from solid dose forms and vice versa Tablet and capsule excipients can increase or983093983089983097

decrease the stability of the API in an oral liquid preparation The salt form of the983093983090983088

drug used in a published study could be different to the form locally available and this983093983090983089

may affect the drugrsquos solubility and stability Consult pharmacopoeias and seek983093983090983090

specialist advice if possible983093983090983091

983093983090983092

Similarly the results of a published study using a drug mixed with a commercial983093983090983093

suspending base (eg Ora-Plusreg) cannot generally be extrapolated to a situation983093983090983094

where the same drug is mixed with a simple base of syrup or glycerol983093983090983095

983093983090983096

Formulations for compounded medicines based on APIs and crushed tablets are not983093983090983097

interchangeable983093983091983088

983093983091983089

bull Dose uniformity may be a problem ndash explain importance of shaking prior to use983093983091983090

If the API is poorly soluble in water it will generally be more chemically stable in an983093983091983091

aqueous suspension but uniformity of dosing the suspension may be a problem A983093983091983092

suspending agent will be required Always check that the finished preparation983093983091983093




page 19

resuspends under in-use conditions and explain the importance of resuspension by983093983091983094

shaking to patientscarers983093983091983095

983093983091983096

If the API is soluble it will generally be less stable in a liquid preparation As the983093983091983097

API is soluble the inclusion of a suspending agent is less important in a preparation983093983092983088

based on crushed tablets983093983092983089

983093983092983090

As excipients and other formulation components can affect solubility all compounded983093983092983091

liquid formulations should be shaken prior to administration The entire API may not983093983092983092

be in solution even if it is highly soluble The only exception would be if the983093983092983093

preparation is made from pure API and it can be assured that the entire API is in983093983092983094

solution983093983092983095

983093983092983096

bull Exceptionally when no published formulation is available 983093983092983097

The pharmacist must assess the risks for different options and use knowledge and983093983093983088

experience to formulate a product983093983093983089

983093983093983090

o Obtain physicochemical properties of the API if available983093983093983091

API solubility and the pH stability profile are useful when considering the983093983093983092

approach to formulation or dose administration If possible obtain basic983093983093983093

physicochemical information about the API especially the aqueous solubility983093983093983094

of the API at the expected pH of the final preparation This allows a983093983093983095

judgement on whether an API solution or suspension is formed983093983093983096

983093983093983097

o Test the physical characteristics prior to patient use 983093983094983088

Tabletcapsule formulations vary worldwide especially with respect to983093983094983089

excipients content The differences can influence the effectiveness and983093983094983090

acceptability of the preparation Basic performance tests should be done983093983094983091

before patient use particularly on formulations prepared for the first time983093983094983092

This includes ease of resuspension and pouring degree of caking on storage983093983094983093

observation of physical behaviour and characteristics983093983094983094

983093983094983095




page 20

o Consider risk of microbial growth 983093983094983096

All compounded liquid formulations are highly susceptible to microbial983093983094983097

growth An antimicrobial preservative must be included unless the final983093983095983088

product will be used completely within 2ndash3 days and stored under983093983095983089

refrigeration Oral liquids that are not adequately preserved will support rapid983093983095983090

growth of bacteria and fungi especially at warm to hot temperatures and can983093983095983091

pose hazards to patients especially if immunosuppressed983093983095983092

983093983095983093

Preparation of compounded liquids should be carried out under conditions to983093983095983094

minimize the introduction of microbial contamination983093983095983095

983093983095983096

bull Use appropriate final containers983093983095983097

Final containers and closures should be clean and free from dust and other residues It983093983096983088

is recommended to use new containers Containers that are reused should be983093983096983089

thoroughly washed rinsed with sterile or freshly boiled water and dried Light-983093983096983090

protective (eg dark plastic or amber glass) containers should generally be used983093983096983091

Consider the use of a light protective wrapping such as foil if a light-protective983093983096983092

container is not available983093983096983093

983093983096983094

Selection of the final container should consider potential drug adsorption to plastic983093983096983095

containers983093983096983096

983093983096983097

bull Dosing device983093983097983088

In view of the dosing needs of liquid preparations the feasibility of appropriate dosing983093983097983089

should be confirmed as not all dosing devices may allow delivering the required983093983097983090

volume As most compounded liquids should be shaken prior to administration this983093983097983091

may introduce entrapped air in the liquid which may cause problems with accurate983093983097983092

measurement of small volumes983093983097983093

983093983097983094

bull Consider in-use storage983093983097983095

In-use storage conditions may vary considerably from those in a published study or983093983097983096

formulary recommendation Always consider if it will be possible to store and use the983093983097983097

preparation under the optimal conditions described in the study which usually are983094983088983088




page 21

refrigeration protection from light and with minimal possibility of in-use983094983088983089

contamination If these conditions are not possible locally it can be assumed that the983094983088983090

preparation will be less stable and more susceptible to microbial growth Reduce the983094983088983091

shelf-life (eg from one month to one week) according to professional judgement If983094983088983092

possible consult expert advice983094983088983093

983094983088983094

bull Expiry date983094983088983095

Chemical stability and potential for microbial growth under patient-use conditions are983094983088983096

seldom tested in published studies983094983088983097

983094983089983088

It is recommended that each compounded preparation be given an expiry date983094983089983089

assigned in a conservative way taking into account API-specific and general stability983094983089983090

documentation and literature when available This will encourage regular fresh983094983089983091

preparations and help to assure effectiveness and safety It also allows the practitioner983094983089983092

to regularly review the patientrsquos use of the preparation983094983089983093

983094983089983094

The following items should be considered when determining such expiry date nature983094983089983095

of the API and its degradation mechanisms dosage form and its components983094983089983096

potential for microbial proliferation in the preparation container in which the983094983089983097

preparation is packaged expected storage conditions and the intended duration of983094983090983088

therapy983094983090983089

983094983090983090

When an authorized medicine is used as the source of the API stability information983094983090983091

could be obtained from the manufacturer Otherwise applicable information on983094983090983092

stability compatibility and degradation of ingredients and use has to be sought in the983094983090983093

literature983094983090983094

983094983090983095

bull Give clear instruction to caregiverspatients983094983090983096

This may include instructions on storage resuspension changes in taste smell983094983090983097

appearance adverse effects and other pharmaceutical advices983094983091983088

983094983091983089

It is common practise that parentscarers add powdered dosage form to a liquid983094983091983090

(water juice etc) or sprinkle it onto food to improve palatability and mask983094983091983091




page 22

unpleasant taste This should be done only when bioavailability is not affected and983094983091983092

intake of the full dose can be ensured Provide parentscarers with appropriate983094983091983093

information983094983091983094

983094983091983095

If an oral syringe or other measuring device is used it is important to check the983094983091983096

technique to ensure the correct dose is administered Advise the use of clean983094983091983097

measuring devices and ways to avoid contaminating the preparation when preparing983094983092983088

the dose983094983092983089

983094983092983090

bull Label information983094983092983091

In addition to dosage instructions include at least the following information983094983092983092

983094983092983093

- if applicable the name of the pharmaceutical preparation983094983092983094

- the route of administration983094983092983095

- the name(s) of the API(s) and excipients of known pharmacological action983094983092983096

eg antimicrobial agents antioxydants983094983092983097

- if liquid concentration(s) of the API(s) eg in mgml and the amount or983094983093983088

volume of the preparation in the container983094983093983089

- if solid amount(s) of the API(s) in each dose and the number of doses in the983094983093983090

container983094983093983091

- reference or batch number (or date of preparation)983094983093983092

- expiry date (ldquodo not use afterrdquo)983094983093983093

- any special storage conditions and handling precautions that may be983094983093983094

necessary eg ldquoto be shaken before userdquo983094983093983095

- the pharmacy name and contact information983094983093983096

- name of the patient983094983093983097

983094983094983088

bull

Document concerns and share information983094983094983089

Practitioners are encouraged to maintain dialogue with regulatory bodies and983094983094983090

international agencies and networks about problems and concerns associated with the983094983094983091

preparation and availability of age-appropriate medicines for children The sharing of983094983094983092

solutions to problems is also important 983094983094983093

983094983094983094




page 23

5 INFORMATION AVAILABILITY AND ACCESS983094983094983095

983094983094983096

A number of networks websites and other resources are available which provide information983094983094983097

on standards of practice formulas for compounded preparations manufacturers suppliers of983094983095983088

oral liquid formulations and networks and responsive information services These should be983094983095983089

consulted by practitioners and regulators to provide the safest and most effective treatment983094983095983090

options for children who require an age- appropriate formulation983094983095983091

983094983095983092

51 Standards of practice and guidelines983094983095983093

983094983095983094

Some national regional and international guidelines for extemporaneous formulations and983094983095983095

medicines administration to children have been published Consulting these documents may983094983095983096

assist in forming local policies of practice and educational activities for practitioners983094983095983097

983094983096983088

52 Formularies and compendia983094983096983089

983094983096983090

These may be helpful in providing formulation advice and general advice on dosage983094983096983091

manipulations The information in these formularies may be difficult to transfer to a local983094983096983092

situation where the base ingredients (eg commercial suspending bases antimicrobial983094983096983093

preservatives pure drug powder) are not readily available983094983096983094

983094983096983095

The eMixt database (wwwpharminfotechconz) is being developed to provide983094983096983096

comprehensive information for all settings and environments983094983096983097

983094983097983088

Mark Jackson and Andrew Lowey Handbook of Extemporaneous Preparations983094983097983089

Pharmaceutical Press 2010 contains formulations and associated stability summaries for oral983094983097983090

liquid preparations983094983097983091

983094983097983092

53 Source and supply983094983097983093

983094983097983094

A database of sources and prices of medicines for children has been compiled by Unicef This983094983097983095

will be available electronically by mid-2011983094983097983096

(httpwwwuniceforgsupplyindex_47129html) 983094983097983097




page 24

983095983088983088

The database can be searched to find worldwide suppliers of oral liquids and other age-983095983088983089

appropriate formulations for paediatric use983095983088983090

983095983088983091

54 Networks and information services983095983088983092

983095983088983093

- Local national and international medicines information centres may respond to983095983088983094

questions about formulation such as the WHO Paediatric medicines Regulatory983095983088983095

Network (PmRN) Partnerships and twinning arrangements between hospitals in983095983088983096

poorly-resourced countries and developed countries can be explored and are often983095983088983097

beneficial 983095983089983088

983095983089983089

Questions can also be posted via the eMIxt website wwwpharminfotechconz983095983089983090

983095983089983091

- Sharing of information and advice on paediatric formulations should be explored983095983089983092

whenever possible983095983089983093

983095983089983094

- International discussion lists can be useful for posting questions on formulations and983095983089983095

the archives can be searched for previous questions and answers Examples include983095983089983096

eDrug and INDICES accessed via httpwwwessentialdrugsorg 983095983089983097

983095983090983088

6 REFERENCES 983095983090983089

983095983090983090

1 Pharmaceutical development for multisource (generic) pharmaceutical products In WHO983095983090983091

Expert Committee on Specifications for Pharmaceutical Preparations Forty-sixth report 983095983090983092

Geneva World Health Organization WHO Technical Report Series No 970 Annex 4983095983090983093

2012 (httpwwwwhointmedicinesareasquality_safetyquality_assuranceen ) 983095983090983094

983095983090983095

2 Development of paediatric medicines points to consider in pharmaceutical983095983090983096

development In WHO Expert Committee on Specifications for Pharmaceutical983095983090983097

Preparations Forty-sixth report Geneva World Health Organization WHO Technical983095983091983088

Report Series No 970 Annex 5 2012983095983091983089

(httpwwwwhointmedicinesareasquality_safetyquality_assuranceen )983095983091983090




page 25

983095983091983091

3 WHO good manufacturing practices main principles for pharmaceutical products 983095983091983092

In WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-983095983091983093

eighth report Geneva World Health Organization WHO Technical Report Series No983095983091983094

986 Annex 2 2014 (in print)983095983091983095

983095983091983096

4 Good manufacturing practices for pharmaceutical products In Quality assurance of983095983091983097

pharmaceuticals WHO guidelines related guidance and GXP training materials983095983092983088

CD-ROM 2013983095983092983089

983095983092983090

5 The International Pharmacopoeia Fourth Edition including First Second and Third983095983092983091

Supplements (httpwhointmedicinespublicationspharmacopoeiaenindexhtml)983095983092983092

Available online and CD-ROM version (2013)983095983092983093

983095983092983094

6 Report for WHO on findings of a review of existing guidanceadvisory documents on983095983092983095

how medicines should be administered to children including general instructions on983095983092983096

extemporaneous preparations and manipulation of adult dosage forms (working983095983092983097

document QAS11400)983095983093983088

983095983093983089

7

The WHO Model Formulary for Children (2010)983095983093983090

(httpwwwwhointselection_medicineslistWMFc_2010pdf )983095983093983091

983095983093983092

8 Report of the Informal Expert Meeting on Dosage Forms of Medicines for Children983095983093983093

Geneva World Health Organization December 2008983095983093983094

[httpwwwwhointselection_medicinescommitteesexpert17applicationpaediatric 983095983093983095

Dosage_form_re-port DEC2008pdf 983095983093983096

983095983093983097

9 Handbook of Extemporaneous Preparation A guide to pharmaceutical compounding983095983094983088

Part A Standards In Handbook of Extemporaneous Preparation pages 1ndash65 Mark983095983094983089

Jackson and Andrew Lowey Pharmaceutical Press 2010983095983094983090

983095983094983091

10 Pharmaceutical Inspection Co-operation Scheme (httpwwwpicschemeorg )983095983094983092

In particular the following documents which can be downloaded free of charge PE983095983094983093




page 26

009-9 (Part I) PICS GMP guide (Part I Basic requirements for medicinal products)983095983094983094

PE 010-3 Guide to good practices for the preparation of medicinal products in983095983094983095

healthcare establishments983095983094983096

983095983094983097

11 Kastango ES Trissel LA Bradshaw BD An Ounce of Prevention Controlling Hazards983095983095983088

in Extemporaneous Compounding Practices International Journal of Pharmacy983095983095983089

Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

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983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097

Examples of therapeutic alternatives to extemporaneous formulations983095983096983088

983095983096983089

Required Possible alternative Notes

Enalapril liquid Captopril liquid

Dispersed captopril tablets

Available commercially in

some countries

Captopril tablets can be

easily dispersed prior to

giving the dose

Naproxen oral liquid Ibuprofen liquid if available NSAID may not be clinically

justified

Paracetamol (acetaminophen)

may be a suitable and safer

alternative

Felodipine oral liquid Dispersed amlodipine tablets Salts of amlodipine are very

soluble and fractional doses

can be prepared

Tinidazole oral liquid Metronidazole oral liquid Very few reasons why

tinidazole should be

preferred over metronidazole

983095983096983090

In some cases the therapeutic alternative may not be available as an oral liquid but as a more983095983096983091

easily manipulated form (see felodipine example above)983095983096983092

983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

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page 28

ANNEX 2983095983097983091

983095983097983092

Compounded preparations ndash consideration of potential problems983095983097983093

983095983097983094

The most frequently used method is to grind the required number of tablets to a fine983095983097983095

powder in a mortar and form a slurry by adding a small volume of water At this stage983095983097983096

there is the potential for the operator to be exposed to hazardous powdered drug and983095983097983097

microbial contamination of the product if clean equipment is not used983096983088983088

983096983088983089

Excipients such as antimicrobial preservatives suspending agents and flavouring agents983096983088983090

are added to make the final product A frequently used base is a mixture of glycerol or983096983088983091

syrup a suspending agent such as methylcellulose and para-hydroxybenzoates (parabens)983096983088983092

as a preservative Other agents sometimes added include alternative solvents such as983096983088983093

ethanol particularly when the drug is poorly soluble in water and buffer systems to983096983088983094

provide the optimum pH for drug stability or activity of the antimicrobial preservative983096983088983095

Whilst ostensibly simple such formulations can be complex comprising a mixture of the983096983088983096

base and a suspension or solution (usually a combination of both) of tablet excipients and983096983088983097

active drug If the drug is water soluble there is a temptation to filter out the insoluble983096983089983088

tablet excipients to leave a clear solution but filtration can remove significant amounts of983096983089983089

drug if extraction from tablets is incomplete Insoluble tablet excipients are in suspension983096983089983090

and may compromise product appearance whereas soluble excipients may alter drug983096983089983091

stability for example by changing the pH of the preparation Added ingredients or983096983089983092

excipients may not be appropriate for babies and infants eg ethanol propylene glycol983096983089983093

Whilst there may be advantages in using pure drug powder instead of tablets it may not be983096983089983094

easily obtainable983096983089983095

983096983089983096

The expiry date of a compounded oral liquid is assigned empirically or based on983096983089983097

published information on a particular formulation A conservative approach must be983096983090983088

adopted when assigning an expiry date because of lack of information on API stability or983096983090983089

limitations in either the design or the conclusions of a published report Also it may be983096983090983090

impractical to entirely reproduce the conditions of a study which was performed in983096983090983091

another institution or country under the controlled conditions of an experiment rather than983096983090983092

clinical use Most studies base their expiry date recommendation on chemical stability but983096983090983093




page 29

do not address possible physical or microbiological spoilage which may be significant983096983090983094

during actual use of the product For these reasons extemporaneously prepared oral983096983090983095

liquids should only be used for a maximum of one month from the date of preparation to983096983090983096

minimize any unrecognized product deterioration Longer expiry dates may be applied if983096983090983097

more extensive testing is performed983096983091983088

983096983091983089

Finally when deciding on a formulation it is important to consider any possible adverse983096983091983090

effects of the inactive components of the preparation Sucrose (in syrup) can promote983096983091983091

the formation of dental caries ethanol can cause hypoglycaemia and para-983096983091983092

hydroxybenzoates can cause hypersensitivity reactions and exacerbate the symptoms of983096983091983093

asthma It has also been suggested that benzoates and para-hydroxybenzoates can983096983091983094

aggravate neonatal hyperbilirubinaemia by displacing bilirubin which is bound to plasma983096983091983095

proteins but this effect has not been demonstrated in vivo and the amounts present in oral983096983091983096

formulations are unlikely to pose any risk Limits for the inclusion of ethanol in983096983091983097

paediatric formulations have been proposed by the American Academy of Pediatrics but983096983092983088

there is little supporting evidence for the recommendation983096983092983089

983096983092983090

Deterioration of an oral liquid may be due to chemical physical or microbiological983096983092983091

instability which can lead to a subtherapeutic dose of drug exposure to toxic degradation983096983092983092

products or ingestion of unacceptable numbers of microorganisms It is important for983096983092983093

pharmacists clinicians and nursing staff to be aware of potential problems caused by983096983092983094

instability to ensure that drug therapy is effective and safe983096983092983095

983096983092983096

Chemical instability 983096983092983097

983096983093983088

APIs in compounded liquids may be susceptible to chemical reactions leading to983096983093983089

degradation The most common reactions are hydrolysis oxidation and reduction Usually983096983093983090

the reaction rate or type is influenced by pH for example azathioprine is rapidly983096983093983091

hydrolysed to 6-mercaptopurine at alkaline pH but is relatively stable in acidic or neutral983096983093983092

conditions Other factors which may increase the rate of reaction include the presence of983096983093983093

trace metals which catalyse the oxidation of captopril methyldopa or exposure to light983096983093983094

which catalyses the oxidative degradation of 6-mercaptopurine The rate of chemical983096983093983095

degradation usually increases with temperature a factor which is the basis for accelerated983096983093983096




page 30

stability trials of pharmaceutical formulations Preparations made from tablets contain983096983093983097

excipients such as binders and disintegrating agents in addition to the API These983096983094983088

excipients may reduce chemical stability by changing the pH to a value at which more983096983094983089

rapid degradation occurs This probably explains why amiloride solution prepared from983096983094983090

pure API is more stable than an oral liquid prepared from tablets983096983094983091

983096983094983092

The API in the preparation may be totally or partially in solution or predominantly in the983096983094983093

solid state as a suspension APIs in solution are more susceptible to chemical degradation983096983094983094

than APIs in the solid state (ie suspensions) thus suspensions of acetazolamide and983096983094983095

chlorothiazide are more stable than solutions However it cannot be assumed in all cases983096983094983096

that a compounded suspension is more stable than a solution In a suspension an983096983094983097

equilibrium exists between the API in the solid state and an API in solution and even983096983095983088

though the amount of drug dissolved may be minimal the conditions could be optimal for983096983095983089

degradation Furosemide is a notable example which undergoes hydrolysis in acidic983096983095983090

conditions where the solid state is predominant but is much more stable at alkaline pH983096983095983091

where it is totally in solution983096983095983092

983096983095983093

Microbiological instability 983096983095983094

983096983095983095

Microbial growth in an oral liquid may cause foul odour and turbidity and adversely983096983095983096

effect palatability and appearance High titres of microorganisms may be hazardous to983096983095983097

health especially in very young or immunocompromised patients By-products of983096983096983088

microbial metabolism may cause a change in the pH of the preparation and reduce the983096983096983089

chemical stability or solubility of the drug Microbial contamination during preparation983096983096983090

must be minimized by using clean equipment sterile water (Water for Irrigation (BP))983096983096983091

and avoiding contaminated raw materials and containers If sodium benzoate or benzoic983096983096983092

acid are used as antimicrobial preservatives the final pH must be less than 5 so that the983096983096983093

active unionized form is predominant Consequently the API must also be stable at this983096983096983094

pH983096983096983095

983096983096983096

Effective preservative systems require rigorous evaluation which is seldom performed on983096983096983097

compounded formulations Many factors can reduce the effectiveness of the preservative983096983097983088

including use of contaminated materials chemical degradation binding of preservative to983096983097983089




page 31

suspending agents or tablet excipients incorrect storage or unhygienic use of the final983096983097983090

product983096983097983091

983096983097983092

Physical instability 983096983097983093

983096983097983094

Compounded oral suspensions may be susceptible to sedimentation of insoluble API983096983097983095

causing caking Difficulty in resuspending the API or rapid sedimentation following983096983097983096

shaking can lead to erratic dosage measurement as demonstrated with chlorothiazide983096983097983097

suspension and this inherent problem with compounded formulations is of considerable983097983088983088

concern Some spironolactone suspensions have been reported to be excessively thick and983097983088983089

almost unpourable Refrigeration whilst usually desirable to maximize chemical stability983097983088983090

and reduce microbial growth can also increase the viscosity of a suspension making983097983088983091

resuspension more difficult or cause the precipitation of API or preservatives It is983097983088983092

important to consider the effect on pH of all components of the formulation and the983097983088983093

possible impact on stability Syrup for example is relatively acidic and if used in983097983088983094

phenobarbitone sodium oral solution it will cause the precipitation of unionized983097983088983095

phenobarbitone983097983088983096

983097983088983097

983097983089983088




page 2

SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS14582983091983095




PREPARATIONS THAT ARE NOT AVAILABLE AS AUTHORIZED PRODUCTS983092983089

First draft prepared by Professor A Nunn UK

commissioned by Dr S Hill Medicines Access and

Rational Use Department of Essential Medicines and

Pharmaceutical Policies World Health Organization

March 2011

Discussion at informal consultation on paediatrics and

generics guidelines development

4-6 May 2011

Revision prepared incorporating amendments by WHO

committee

August 2011

Revision sent out for comments August 2011


Discussion at forty-sixth meeting of the WHO Expert


10-14 October 2011

Revision prepared and sent out for comments August 2012


Discussion at forty-seventh meeting of the WHO Expert


October 2012

Review of comments received and recommendations of


Pharmaceutical Preparations and in-depth discussion

between the Secretaries of the FIP Expert Group and


Pharmaceutical Preparations

February 2013

Preparation of new working document for circulation March 2013


Discussion during Expert Committee on the Selection

and Use of Essential Medicines

8 April 2013


Any further action by WHO and FIP July-September 2013




page 3

983092983090

983092983091



Preparations

14-18 October 2013






Preparations

13-17 October 2014





page 4





983092983095

983092983096











983093983097






















page 5


983095983097











983097983088

983097983089


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11


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page 6





forms983089983089983093

983089983089983094






983089983090983090









983089983091983089

12 Purpose983089983091983090

983089983091983091


983089983091983093



bull


to avoid them983089983091983097



guidance983089983092983090

983089983092983091




page 7




983089983092983095


983089983092983097


983089983093983089








983089983093983097




983089983094983091





983089983094983096

2 GLOSSARY983089983094983097

983089983095983088








page 8



983089983095983095




983089983096983089



open properly983089983096983092

983089983096983093

compounding983089983096983094



983089983096983097





983089983097983092

dose rounding983089983097983093

983089983097983094

983089983097983095

excipient 983089983097983096






983090983088983092







page 9

983090983088983096



983090983089983089





983090983089983094





983090983090983089




983090983090983093

SmPC983090983090983094


983090983090983096


983090983091983088



983090983091983091







983090983092983088




page 10







983090983092983095


983090983092983097


983090983093983089




983090983093983093





983090983094983088




983090983094983092

32 Dose rounding983090983094983093

983090983094983094





983090983095983089





page 11





983090983095983094


983090983095983096




983090983096983090


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983090983096983096






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983090983097983097









page 12

983091983088983093







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983091983089983095




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page 13









983091983092983094



983091983092983097




983091983093983091






983091983093983097






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page 14



983091983095983091





983091983095983096




983091983096983090



983091983096983093












983091983097983095





983092983088983090

983092983088983091




page 15







983092983089983088




983092983089983092




983092983089983096






and efficacy983092983090983092

983092983090983093

4 COMPOUNDING983092983090983094

983092983090983095


983092983090983097




983092983091983091







page 16





983092983092983089




983092983092983093



compounding983092983092983096


the Internet983092983093983088




983092983093983092


983092983093983094






983092983094983090




983092983094983094







page 17




983092983095983091


983092983095983093


983092983095983095






983092983096983091






983092983096983097





983092983097983092





983092983097983097







page 18



983093983088983093










983093983089983093









983093983090983092




983093983090983096



983093983091983089








page 19



983093983091983096




983093983092983090





solution983093983092983095

983093983092983096




983093983093983090







983093983093983097








983093983094983095




page 20








983093983095983093



983093983095983096








983093983096983094


containers983093983096983096

983093983096983097







983093983097983094








page 21






983094983088983094




983094983089983088






983094983089983094





therapy983094983090983089

983094983090983090




literature983094983090983094

983094983090983095




983094983091983089






page 22



information983094983091983094

983094983091983095




the dose983094983092983089

983094983092983090



983094983092983093








container983094983093983091







983094983094983088

bull






983094983094983094




page 23


983094983094983096






983094983095983092


983094983095983094




983094983096983088


983094983096983090





983094983096983095



983094983097983088




983094983097983092


983094983097983094







page 24

983095983088983088



983095983088983091


983095983088983093





beneficial 983095983089983088

983095983089983089


983095983089983091



983095983089983094




983095983090983088

6 REFERENCES 983095983090983089

983095983090983090





983095983090983095









page 25

983095983091983091




986 Annex 2 2014 (in print)983095983091983095

983095983091983096



CD-ROM 2013983095983092983089

983095983092983090




983095983092983094




document QAS11400)983095983093983088

983095983093983089

7



983095983093983092





983095983093983097




983095983094983091






page 26




983095983094983097



Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

983095983095983093

983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

983095983097983092


983095983097983094





983096983088983089

















983096983089983096











page 29






983096983091983089











983096983092983090






983096983092983096


983096983093983088












page 30






983096983094983092











983096983095983093


983096983095983095










pH983096983096983095

983096983096983096







page 31


product983096983097983091

983096983097983092


983096983097983094













983097983088983097

983097983089983088




page 3

983092983090

983092983091



Preparations

14-18 October 2013






Preparations

13-17 October 2014





page 4





983092983095

983092983096











983093983097






















page 5


983095983097











983097983088

983097983089


983097983091

11


983097983093





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page 6





forms983089983089983093

983089983089983094






983089983090983090









983089983091983089

12 Purpose983089983091983090

983089983091983091


983089983091983093



bull


to avoid them983089983091983097



guidance983089983092983090

983089983092983091




page 7




983089983092983095


983089983092983097


983089983093983089








983089983093983097




983089983094983091





983089983094983096

2 GLOSSARY983089983094983097

983089983095983088








page 8



983089983095983095




983089983096983089



open properly983089983096983092

983089983096983093

compounding983089983096983094



983089983096983097





983089983097983092

dose rounding983089983097983093

983089983097983094

983089983097983095

excipient 983089983097983096






983090983088983092







page 9

983090983088983096



983090983089983089





983090983089983094





983090983090983089




983090983090983093

SmPC983090983090983094


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page 10







983090983092983095


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32 Dose rounding983090983094983093

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page 11





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page 15







983092983089983088




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and efficacy983092983090983092

983092983090983093

4 COMPOUNDING983092983090983094

983092983090983095


983092983090983097




983092983091983091







page 16





983092983092983089




983092983092983093



compounding983092983092983096


the Internet983092983093983088




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solution983093983092983095

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containers983093983096983096

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page 21






983094983088983094




983094983089983088






983094983089983094





therapy983094983090983089

983094983090983090




literature983094983090983094

983094983090983095




983094983091983089






page 22



information983094983091983094

983094983091983095




the dose983094983092983089

983094983092983090



983094983092983093








container983094983093983091







983094983094983088

bull






983094983094983094




page 23


983094983094983096






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983094983095983094




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page 24

983095983088983088



983095983088983091


983095983088983093





beneficial 983095983089983088

983095983089983089


983095983089983091



983095983089983094




983095983090983088

6 REFERENCES 983095983090983089

983095983090983090





983095983090983095









page 25

983095983091983091




986 Annex 2 2014 (in print)983095983091983095

983095983091983096



CD-ROM 2013983095983092983089

983095983092983090




983095983092983094




document QAS11400)983095983093983088

983095983093983089

7



983095983093983092





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page 26




983095983094983097



Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

983095983095983093

983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

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983095983097983094





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page 29






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product983096983097983091

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983089983088983096






page 6





forms983089983089983093

983089983089983094






983089983090983090









983089983091983089

12 Purpose983089983091983090

983089983091983091


983089983091983093



bull


to avoid them983089983091983097



guidance983089983092983090

983089983092983091




page 7




983089983092983095


983089983092983097


983089983093983089








983089983093983097




983089983094983091





983089983094983096

2 GLOSSARY983089983094983097

983089983095983088








page 8



983089983095983095




983089983096983089



open properly983089983096983092

983089983096983093

compounding983089983096983094



983089983096983097





983089983097983092

dose rounding983089983097983093

983089983097983094

983089983097983095

excipient 983089983097983096






983090983088983092







page 9

983090983088983096



983090983089983089





983090983089983094





983090983090983089




983090983090983093

SmPC983090983090983094


983090983090983096


983090983091983088



983090983091983091







983090983092983088




page 10







983090983092983095


983090983092983097


983090983093983089




983090983093983093





983090983094983088




983090983094983092

32 Dose rounding983090983094983093

983090983094983094





983090983095983089





page 11





983090983095983094


983090983095983096




983090983096983090


983090983096983092




983090983096983096






983090983097983092





983090983097983097









page 12

983091983088983093







983091983089983090





983091983089983095




983091983090983089






983091983090983095








983091983091983093






page 13









983091983092983094



983091983092983097




983091983093983091






983091983093983097






983091983094983093









page 14



983091983095983091





983091983095983096




983091983096983090



983091983096983093












983091983097983095





983092983088983090

983092983088983091




page 15







983092983089983088




983092983089983092




983092983089983096






and efficacy983092983090983092

983092983090983093

4 COMPOUNDING983092983090983094

983092983090983095


983092983090983097




983092983091983091







page 16





983092983092983089




983092983092983093



compounding983092983092983096


the Internet983092983093983088




983092983093983092


983092983093983094






983092983094983090




983092983094983094







page 17




983092983095983091


983092983095983093


983092983095983095






983092983096983091






983092983096983097





983092983097983092





983092983097983097







page 18



983093983088983093










983093983089983093









983093983090983092




983093983090983096



983093983091983089








page 19



983093983091983096




983093983092983090





solution983093983092983095

983093983092983096




983093983093983090







983093983093983097








983093983094983095




page 20








983093983095983093



983093983095983096








983093983096983094


containers983093983096983096

983093983096983097







983093983097983094








page 21






983094983088983094




983094983089983088






983094983089983094





therapy983094983090983089

983094983090983090




literature983094983090983094

983094983090983095




983094983091983089






page 22



information983094983091983094

983094983091983095




the dose983094983092983089

983094983092983090



983094983092983093








container983094983093983091







983094983094983088

bull






983094983094983094




page 23


983094983094983096






983094983095983092


983094983095983094




983094983096983088


983094983096983090





983094983096983095



983094983097983088




983094983097983092


983094983097983094







page 24

983095983088983088



983095983088983091


983095983088983093





beneficial 983095983089983088

983095983089983089


983095983089983091



983095983089983094




983095983090983088

6 REFERENCES 983095983090983089

983095983090983090





983095983090983095









page 25

983095983091983091




986 Annex 2 2014 (in print)983095983091983095

983095983091983096



CD-ROM 2013983095983092983089

983095983092983090




983095983092983094




document QAS11400)983095983093983088

983095983093983089

7



983095983093983092





983095983093983097




983095983094983091






page 26




983095983094983097



Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

983095983095983093

983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

983095983097983092


983095983097983094





983096983088983089

















983096983089983096











page 29






983096983091983089











983096983092983090






983096983092983096


983096983093983088












page 30






983096983094983092











983096983095983093


983096983095983095










pH983096983096983095

983096983096983096







page 31


product983096983097983091

983096983097983092


983096983097983094













983097983088983097

983097983089983088




page 5


983095983097











983097983088

983097983089


983097983091

11


983097983093





983089983088983088








983089983088983096






page 6





forms983089983089983093

983089983089983094






983089983090983090









983089983091983089

12 Purpose983089983091983090

983089983091983091


983089983091983093



bull


to avoid them983089983091983097



guidance983089983092983090

983089983092983091




page 7




983089983092983095


983089983092983097


983089983093983089








983089983093983097




983089983094983091





983089983094983096

2 GLOSSARY983089983094983097

983089983095983088








page 8



983089983095983095




983089983096983089



open properly983089983096983092

983089983096983093

compounding983089983096983094



983089983096983097





983089983097983092

dose rounding983089983097983093

983089983097983094

983089983097983095

excipient 983089983097983096






983090983088983092







page 9

983090983088983096



983090983089983089





983090983089983094





983090983090983089




983090983090983093

SmPC983090983090983094


983090983090983096


983090983091983088



983090983091983091







983090983092983088




page 10







983090983092983095


983090983092983097


983090983093983089




983090983093983093





983090983094983088




983090983094983092

32 Dose rounding983090983094983093

983090983094983094





983090983095983089





page 11





983090983095983094


983090983095983096




983090983096983090


983090983096983092




983090983096983096






983090983097983092





983090983097983097









page 12

983091983088983093







983091983089983090





983091983089983095




983091983090983089






983091983090983095








983091983091983093






page 13









983091983092983094



983091983092983097




983091983093983091






983091983093983097






983091983094983093









page 14



983091983095983091





983091983095983096




983091983096983090



983091983096983093












983091983097983095





983092983088983090

983092983088983091




page 15







983092983089983088




983092983089983092




983092983089983096






and efficacy983092983090983092

983092983090983093

4 COMPOUNDING983092983090983094

983092983090983095


983092983090983097




983092983091983091







page 16





983092983092983089




983092983092983093



compounding983092983092983096


the Internet983092983093983088




983092983093983092


983092983093983094






983092983094983090




983092983094983094







page 17




983092983095983091


983092983095983093


983092983095983095






983092983096983091






983092983096983097





983092983097983092





983092983097983097







page 18



983093983088983093










983093983089983093









983093983090983092




983093983090983096



983093983091983089








page 19



983093983091983096




983093983092983090





solution983093983092983095

983093983092983096




983093983093983090







983093983093983097








983093983094983095




page 20








983093983095983093



983093983095983096








983093983096983094


containers983093983096983096

983093983096983097







983093983097983094








page 21






983094983088983094




983094983089983088






983094983089983094





therapy983094983090983089

983094983090983090




literature983094983090983094

983094983090983095




983094983091983089






page 22



information983094983091983094

983094983091983095




the dose983094983092983089

983094983092983090



983094983092983093








container983094983093983091







983094983094983088

bull






983094983094983094




page 23


983094983094983096






983094983095983092


983094983095983094




983094983096983088


983094983096983090





983094983096983095



983094983097983088




983094983097983092


983094983097983094







page 24

983095983088983088



983095983088983091


983095983088983093





beneficial 983095983089983088

983095983089983089


983095983089983091



983095983089983094




983095983090983088

6 REFERENCES 983095983090983089

983095983090983090





983095983090983095









page 25

983095983091983091




986 Annex 2 2014 (in print)983095983091983095

983095983091983096



CD-ROM 2013983095983092983089

983095983092983090




983095983092983094




document QAS11400)983095983093983088

983095983093983089

7



983095983093983092





983095983093983097




983095983094983091






page 26




983095983094983097



Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

983095983095983093

983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

983095983097983092


983095983097983094





983096983088983089

















983096983089983096











page 29






983096983091983089











983096983092983090






983096983092983096


983096983093983088












page 30






983096983094983092











983096983095983093


983096983095983095










pH983096983096983095

983096983096983096







page 31


product983096983097983091

983096983097983092


983096983097983094













983097983088983097

983097983089983088




page 6





forms983089983089983093

983089983089983094






983089983090983090









983089983091983089

12 Purpose983089983091983090

983089983091983091


983089983091983093



bull


to avoid them983089983091983097



guidance983089983092983090

983089983092983091




page 7




983089983092983095


983089983092983097


983089983093983089








983089983093983097




983089983094983091





983089983094983096

2 GLOSSARY983089983094983097

983089983095983088








page 8



983089983095983095




983089983096983089



open properly983089983096983092

983089983096983093

compounding983089983096983094



983089983096983097





983089983097983092

dose rounding983089983097983093

983089983097983094

983089983097983095

excipient 983089983097983096






983090983088983092







page 9

983090983088983096



983090983089983089





983090983089983094





983090983090983089




983090983090983093

SmPC983090983090983094


983090983090983096


983090983091983088



983090983091983091







983090983092983088




page 10







983090983092983095


983090983092983097


983090983093983089




983090983093983093





983090983094983088




983090983094983092

32 Dose rounding983090983094983093

983090983094983094





983090983095983089





page 11





983090983095983094


983090983095983096




983090983096983090


983090983096983092




983090983096983096






983090983097983092





983090983097983097









page 12

983091983088983093







983091983089983090





983091983089983095




983091983090983089






983091983090983095








983091983091983093






page 13









983091983092983094



983091983092983097




983091983093983091






983091983093983097






983091983094983093









page 14



983091983095983091





983091983095983096




983091983096983090



983091983096983093












983091983097983095





983092983088983090

983092983088983091




page 15







983092983089983088




983092983089983092




983092983089983096






and efficacy983092983090983092

983092983090983093

4 COMPOUNDING983092983090983094

983092983090983095


983092983090983097




983092983091983091







page 16





983092983092983089




983092983092983093



compounding983092983092983096


the Internet983092983093983088




983092983093983092


983092983093983094






983092983094983090




983092983094983094







page 17




983092983095983091


983092983095983093


983092983095983095






983092983096983091






983092983096983097





983092983097983092





983092983097983097







page 18



983093983088983093










983093983089983093









983093983090983092




983093983090983096



983093983091983089








page 19



983093983091983096




983093983092983090





solution983093983092983095

983093983092983096




983093983093983090







983093983093983097








983093983094983095




page 20








983093983095983093



983093983095983096








983093983096983094


containers983093983096983096

983093983096983097







983093983097983094








page 21






983094983088983094




983094983089983088






983094983089983094





therapy983094983090983089

983094983090983090




literature983094983090983094

983094983090983095




983094983091983089






page 22



information983094983091983094

983094983091983095




the dose983094983092983089

983094983092983090



983094983092983093








container983094983093983091







983094983094983088

bull






983094983094983094




page 23


983094983094983096






983094983095983092


983094983095983094




983094983096983088


983094983096983090





983094983096983095



983094983097983088




983094983097983092


983094983097983094







page 24

983095983088983088



983095983088983091


983095983088983093





beneficial 983095983089983088

983095983089983089


983095983089983091



983095983089983094




983095983090983088

6 REFERENCES 983095983090983089

983095983090983090





983095983090983095









page 25

983095983091983091




986 Annex 2 2014 (in print)983095983091983095

983095983091983096



CD-ROM 2013983095983092983089

983095983092983090




983095983092983094




document QAS11400)983095983093983088

983095983093983089

7



983095983093983092





983095983093983097




983095983094983091






page 26




983095983094983097



Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

983095983095983093

983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

983095983097983092


983095983097983094





983096983088983089

















983096983089983096











page 29






983096983091983089











983096983092983090






983096983092983096


983096983093983088












page 30






983096983094983092











983096983095983093


983096983095983095










pH983096983096983095

983096983096983096







page 31


product983096983097983091

983096983097983092


983096983097983094













983097983088983097

983097983089983088




page 7




983089983092983095


983089983092983097


983089983093983089








983089983093983097




983089983094983091





983089983094983096

2 GLOSSARY983089983094983097

983089983095983088








page 8



983089983095983095




983089983096983089



open properly983089983096983092

983089983096983093

compounding983089983096983094



983089983096983097





983089983097983092

dose rounding983089983097983093

983089983097983094

983089983097983095

excipient 983089983097983096






983090983088983092







page 9

983090983088983096



983090983089983089





983090983089983094





983090983090983089




983090983090983093

SmPC983090983090983094


983090983090983096


983090983091983088



983090983091983091







983090983092983088




page 10







983090983092983095


983090983092983097


983090983093983089




983090983093983093





983090983094983088




983090983094983092

32 Dose rounding983090983094983093

983090983094983094





983090983095983089





page 11





983090983095983094


983090983095983096




983090983096983090


983090983096983092




983090983096983096






983090983097983092





983090983097983097









page 12

983091983088983093







983091983089983090





983091983089983095




983091983090983089






983091983090983095








983091983091983093






page 13









983091983092983094



983091983092983097




983091983093983091






983091983093983097






983091983094983093









page 14



983091983095983091





983091983095983096




983091983096983090



983091983096983093












983091983097983095





983092983088983090

983092983088983091




page 15







983092983089983088




983092983089983092




983092983089983096






and efficacy983092983090983092

983092983090983093

4 COMPOUNDING983092983090983094

983092983090983095


983092983090983097




983092983091983091







page 16





983092983092983089




983092983092983093



compounding983092983092983096


the Internet983092983093983088




983092983093983092


983092983093983094






983092983094983090




983092983094983094







page 17




983092983095983091


983092983095983093


983092983095983095






983092983096983091






983092983096983097





983092983097983092





983092983097983097







page 18



983093983088983093










983093983089983093









983093983090983092




983093983090983096



983093983091983089








page 19



983093983091983096




983093983092983090





solution983093983092983095

983093983092983096




983093983093983090







983093983093983097








983093983094983095




page 20








983093983095983093



983093983095983096








983093983096983094


containers983093983096983096

983093983096983097







983093983097983094








page 21






983094983088983094




983094983089983088






983094983089983094





therapy983094983090983089

983094983090983090




literature983094983090983094

983094983090983095




983094983091983089






page 22



information983094983091983094

983094983091983095




the dose983094983092983089

983094983092983090



983094983092983093








container983094983093983091







983094983094983088

bull






983094983094983094




page 23


983094983094983096






983094983095983092


983094983095983094




983094983096983088


983094983096983090





983094983096983095



983094983097983088




983094983097983092


983094983097983094







page 24

983095983088983088



983095983088983091


983095983088983093





beneficial 983095983089983088

983095983089983089


983095983089983091



983095983089983094




983095983090983088

6 REFERENCES 983095983090983089

983095983090983090





983095983090983095









page 25

983095983091983091




986 Annex 2 2014 (in print)983095983091983095

983095983091983096



CD-ROM 2013983095983092983089

983095983092983090




983095983092983094




document QAS11400)983095983093983088

983095983093983089

7



983095983093983092





983095983093983097




983095983094983091






page 26




983095983094983097



Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

983095983095983093

983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

983095983097983092


983095983097983094





983096983088983089

















983096983089983096











page 29






983096983091983089











983096983092983090






983096983092983096


983096983093983088












page 30






983096983094983092











983096983095983093


983096983095983095










pH983096983096983095

983096983096983096







page 31


product983096983097983091

983096983097983092


983096983097983094













983097983088983097

983097983089983088




page 8



983089983095983095




983089983096983089



open properly983089983096983092

983089983096983093

compounding983089983096983094



983089983096983097





983089983097983092

dose rounding983089983097983093

983089983097983094

983089983097983095

excipient 983089983097983096






983090983088983092







page 9

983090983088983096



983090983089983089





983090983089983094





983090983090983089




983090983090983093

SmPC983090983090983094


983090983090983096


983090983091983088



983090983091983091







983090983092983088




page 10







983090983092983095


983090983092983097


983090983093983089




983090983093983093





983090983094983088




983090983094983092

32 Dose rounding983090983094983093

983090983094983094





983090983095983089





page 11





983090983095983094


983090983095983096




983090983096983090


983090983096983092




983090983096983096






983090983097983092





983090983097983097









page 12

983091983088983093







983091983089983090





983091983089983095




983091983090983089






983091983090983095








983091983091983093






page 13









983091983092983094



983091983092983097




983091983093983091






983091983093983097






983091983094983093









page 14



983091983095983091





983091983095983096




983091983096983090



983091983096983093












983091983097983095





983092983088983090

983092983088983091




page 15







983092983089983088




983092983089983092




983092983089983096






and efficacy983092983090983092

983092983090983093

4 COMPOUNDING983092983090983094

983092983090983095


983092983090983097




983092983091983091







page 16





983092983092983089




983092983092983093



compounding983092983092983096


the Internet983092983093983088




983092983093983092


983092983093983094






983092983094983090




983092983094983094







page 17




983092983095983091


983092983095983093


983092983095983095






983092983096983091






983092983096983097





983092983097983092





983092983097983097







page 18



983093983088983093










983093983089983093









983093983090983092




983093983090983096



983093983091983089








page 19



983093983091983096




983093983092983090





solution983093983092983095

983093983092983096




983093983093983090







983093983093983097








983093983094983095




page 20








983093983095983093



983093983095983096








983093983096983094


containers983093983096983096

983093983096983097







983093983097983094








page 21






983094983088983094




983094983089983088






983094983089983094





therapy983094983090983089

983094983090983090




literature983094983090983094

983094983090983095




983094983091983089






page 22



information983094983091983094

983094983091983095




the dose983094983092983089

983094983092983090



983094983092983093








container983094983093983091







983094983094983088

bull






983094983094983094




page 23


983094983094983096






983094983095983092


983094983095983094




983094983096983088


983094983096983090





983094983096983095



983094983097983088




983094983097983092


983094983097983094







page 24

983095983088983088



983095983088983091


983095983088983093





beneficial 983095983089983088

983095983089983089


983095983089983091



983095983089983094




983095983090983088

6 REFERENCES 983095983090983089

983095983090983090





983095983090983095









page 25

983095983091983091




986 Annex 2 2014 (in print)983095983091983095

983095983091983096



CD-ROM 2013983095983092983089

983095983092983090




983095983092983094




document QAS11400)983095983093983088

983095983093983089

7



983095983093983092





983095983093983097




983095983094983091






page 26




983095983094983097



Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

983095983095983093

983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

983095983097983092


983095983097983094





983096983088983089

















983096983089983096











page 29






983096983091983089











983096983092983090






983096983092983096


983096983093983088












page 30






983096983094983092











983096983095983093


983096983095983095










pH983096983096983095

983096983096983096







page 31


product983096983097983091

983096983097983092


983096983097983094













983097983088983097

983097983089983088




page 9

983090983088983096



983090983089983089





983090983089983094





983090983090983089




983090983090983093

SmPC983090983090983094


983090983090983096


983090983091983088



983090983091983091







983090983092983088




page 10







983090983092983095


983090983092983097


983090983093983089




983090983093983093





983090983094983088




983090983094983092

32 Dose rounding983090983094983093

983090983094983094





983090983095983089





page 11





983090983095983094


983090983095983096




983090983096983090


983090983096983092




983090983096983096






983090983097983092





983090983097983097









page 12

983091983088983093







983091983089983090





983091983089983095




983091983090983089






983091983090983095








983091983091983093






page 13









983091983092983094



983091983092983097




983091983093983091






983091983093983097






983091983094983093









page 14



983091983095983091





983091983095983096




983091983096983090



983091983096983093












983091983097983095





983092983088983090

983092983088983091




page 15







983092983089983088




983092983089983092




983092983089983096






and efficacy983092983090983092

983092983090983093

4 COMPOUNDING983092983090983094

983092983090983095


983092983090983097




983092983091983091







page 16





983092983092983089




983092983092983093



compounding983092983092983096


the Internet983092983093983088




983092983093983092


983092983093983094






983092983094983090




983092983094983094







page 17




983092983095983091


983092983095983093


983092983095983095






983092983096983091






983092983096983097





983092983097983092





983092983097983097







page 18



983093983088983093










983093983089983093









983093983090983092




983093983090983096



983093983091983089








page 19



983093983091983096




983093983092983090





solution983093983092983095

983093983092983096




983093983093983090







983093983093983097








983093983094983095




page 20








983093983095983093



983093983095983096








983093983096983094


containers983093983096983096

983093983096983097







983093983097983094








page 21






983094983088983094




983094983089983088






983094983089983094





therapy983094983090983089

983094983090983090




literature983094983090983094

983094983090983095




983094983091983089






page 22



information983094983091983094

983094983091983095




the dose983094983092983089

983094983092983090



983094983092983093








container983094983093983091







983094983094983088

bull






983094983094983094




page 23


983094983094983096






983094983095983092


983094983095983094




983094983096983088


983094983096983090





983094983096983095



983094983097983088




983094983097983092


983094983097983094







page 24

983095983088983088



983095983088983091


983095983088983093





beneficial 983095983089983088

983095983089983089


983095983089983091



983095983089983094




983095983090983088

6 REFERENCES 983095983090983089

983095983090983090





983095983090983095









page 25

983095983091983091




986 Annex 2 2014 (in print)983095983091983095

983095983091983096



CD-ROM 2013983095983092983089

983095983092983090




983095983092983094




document QAS11400)983095983093983088

983095983093983089

7



983095983093983092





983095983093983097




983095983094983091






page 26




983095983094983097



Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

983095983095983093

983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

983095983097983092


983095983097983094





983096983088983089

















983096983089983096











page 29






983096983091983089











983096983092983090






983096983092983096


983096983093983088












page 30






983096983094983092











983096983095983093


983096983095983095










pH983096983096983095

983096983096983096







page 31


product983096983097983091

983096983097983092


983096983097983094













983097983088983097

983097983089983088




page 10







983090983092983095


983090983092983097


983090983093983089




983090983093983093





983090983094983088




983090983094983092

32 Dose rounding983090983094983093

983090983094983094





983090983095983089





page 11





983090983095983094


983090983095983096




983090983096983090


983090983096983092




983090983096983096






983090983097983092





983090983097983097









page 12

983091983088983093







983091983089983090





983091983089983095




983091983090983089






983091983090983095








983091983091983093






page 13









983091983092983094



983091983092983097




983091983093983091






983091983093983097






983091983094983093









page 14



983091983095983091





983091983095983096




983091983096983090



983091983096983093












983091983097983095





983092983088983090

983092983088983091




page 15







983092983089983088




983092983089983092




983092983089983096






and efficacy983092983090983092

983092983090983093

4 COMPOUNDING983092983090983094

983092983090983095


983092983090983097




983092983091983091







page 16





983092983092983089




983092983092983093



compounding983092983092983096


the Internet983092983093983088




983092983093983092


983092983093983094






983092983094983090




983092983094983094







page 17




983092983095983091


983092983095983093


983092983095983095






983092983096983091






983092983096983097





983092983097983092





983092983097983097







page 18



983093983088983093










983093983089983093









983093983090983092




983093983090983096



983093983091983089








page 19



983093983091983096




983093983092983090





solution983093983092983095

983093983092983096




983093983093983090







983093983093983097








983093983094983095




page 20








983093983095983093



983093983095983096








983093983096983094


containers983093983096983096

983093983096983097







983093983097983094








page 21






983094983088983094




983094983089983088






983094983089983094





therapy983094983090983089

983094983090983090




literature983094983090983094

983094983090983095




983094983091983089






page 22



information983094983091983094

983094983091983095




the dose983094983092983089

983094983092983090



983094983092983093








container983094983093983091







983094983094983088

bull






983094983094983094




page 23


983094983094983096






983094983095983092


983094983095983094




983094983096983088


983094983096983090





983094983096983095



983094983097983088




983094983097983092


983094983097983094







page 24

983095983088983088



983095983088983091


983095983088983093





beneficial 983095983089983088

983095983089983089


983095983089983091



983095983089983094




983095983090983088

6 REFERENCES 983095983090983089

983095983090983090





983095983090983095









page 25

983095983091983091




986 Annex 2 2014 (in print)983095983091983095

983095983091983096



CD-ROM 2013983095983092983089

983095983092983090




983095983092983094




document QAS11400)983095983093983088

983095983093983089

7



983095983093983092





983095983093983097




983095983094983091






page 26




983095983094983097



Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

983095983095983093

983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

983095983097983092


983095983097983094





983096983088983089

















983096983089983096











page 29






983096983091983089











983096983092983090






983096983092983096


983096983093983088












page 30






983096983094983092











983096983095983093


983096983095983095










pH983096983096983095

983096983096983096







page 31


product983096983097983091

983096983097983092


983096983097983094













983097983088983097

983097983089983088




page 11





983090983095983094


983090983095983096




983090983096983090


983090983096983092




983090983096983096






983090983097983092





983090983097983097









page 12

983091983088983093







983091983089983090





983091983089983095




983091983090983089






983091983090983095








983091983091983093






page 13









983091983092983094



983091983092983097




983091983093983091






983091983093983097






983091983094983093









page 14



983091983095983091





983091983095983096




983091983096983090



983091983096983093












983091983097983095





983092983088983090

983092983088983091




page 15







983092983089983088




983092983089983092




983092983089983096






and efficacy983092983090983092

983092983090983093

4 COMPOUNDING983092983090983094

983092983090983095


983092983090983097




983092983091983091







page 16





983092983092983089




983092983092983093



compounding983092983092983096


the Internet983092983093983088




983092983093983092


983092983093983094






983092983094983090




983092983094983094







page 17




983092983095983091


983092983095983093


983092983095983095






983092983096983091






983092983096983097





983092983097983092





983092983097983097







page 18



983093983088983093










983093983089983093









983093983090983092




983093983090983096



983093983091983089








page 19



983093983091983096




983093983092983090





solution983093983092983095

983093983092983096




983093983093983090







983093983093983097








983093983094983095




page 20








983093983095983093



983093983095983096








983093983096983094


containers983093983096983096

983093983096983097







983093983097983094








page 21






983094983088983094




983094983089983088






983094983089983094





therapy983094983090983089

983094983090983090




literature983094983090983094

983094983090983095




983094983091983089






page 22



information983094983091983094

983094983091983095




the dose983094983092983089

983094983092983090



983094983092983093








container983094983093983091







983094983094983088

bull






983094983094983094




page 23


983094983094983096






983094983095983092


983094983095983094




983094983096983088


983094983096983090





983094983096983095



983094983097983088




983094983097983092


983094983097983094







page 24

983095983088983088



983095983088983091


983095983088983093





beneficial 983095983089983088

983095983089983089


983095983089983091



983095983089983094




983095983090983088

6 REFERENCES 983095983090983089

983095983090983090





983095983090983095









page 25

983095983091983091




986 Annex 2 2014 (in print)983095983091983095

983095983091983096



CD-ROM 2013983095983092983089

983095983092983090




983095983092983094




document QAS11400)983095983093983088

983095983093983089

7



983095983093983092





983095983093983097




983095983094983091






page 26




983095983094983097



Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

983095983095983093

983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

983095983097983092


983095983097983094





983096983088983089

















983096983089983096











page 29






983096983091983089











983096983092983090






983096983092983096


983096983093983088












page 30






983096983094983092











983096983095983093


983096983095983095










pH983096983096983095

983096983096983096







page 31


product983096983097983091

983096983097983092


983096983097983094













983097983088983097

983097983089983088




page 12

983091983088983093







983091983089983090





983091983089983095




983091983090983089






983091983090983095








983091983091983093






page 13









983091983092983094



983091983092983097




983091983093983091






983091983093983097






983091983094983093









page 14



983091983095983091





983091983095983096




983091983096983090



983091983096983093












983091983097983095





983092983088983090

983092983088983091




page 15







983092983089983088




983092983089983092




983092983089983096






and efficacy983092983090983092

983092983090983093

4 COMPOUNDING983092983090983094

983092983090983095


983092983090983097




983092983091983091







page 16





983092983092983089




983092983092983093



compounding983092983092983096


the Internet983092983093983088




983092983093983092


983092983093983094






983092983094983090




983092983094983094







page 17




983092983095983091


983092983095983093


983092983095983095






983092983096983091






983092983096983097





983092983097983092





983092983097983097







page 18



983093983088983093










983093983089983093









983093983090983092




983093983090983096



983093983091983089








page 19



983093983091983096




983093983092983090





solution983093983092983095

983093983092983096




983093983093983090







983093983093983097








983093983094983095




page 20








983093983095983093



983093983095983096








983093983096983094


containers983093983096983096

983093983096983097







983093983097983094








page 21






983094983088983094




983094983089983088






983094983089983094





therapy983094983090983089

983094983090983090




literature983094983090983094

983094983090983095




983094983091983089






page 22



information983094983091983094

983094983091983095




the dose983094983092983089

983094983092983090



983094983092983093








container983094983093983091







983094983094983088

bull






983094983094983094




page 23


983094983094983096






983094983095983092


983094983095983094




983094983096983088


983094983096983090





983094983096983095



983094983097983088




983094983097983092


983094983097983094







page 24

983095983088983088



983095983088983091


983095983088983093





beneficial 983095983089983088

983095983089983089


983095983089983091



983095983089983094




983095983090983088

6 REFERENCES 983095983090983089

983095983090983090





983095983090983095









page 25

983095983091983091




986 Annex 2 2014 (in print)983095983091983095

983095983091983096



CD-ROM 2013983095983092983089

983095983092983090




983095983092983094




document QAS11400)983095983093983088

983095983093983089

7



983095983093983092





983095983093983097




983095983094983091






page 26




983095983094983097



Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

983095983095983093

983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

983095983097983092


983095983097983094





983096983088983089

















983096983089983096











page 29






983096983091983089











983096983092983090






983096983092983096


983096983093983088












page 30






983096983094983092











983096983095983093


983096983095983095










pH983096983096983095

983096983096983096







page 31


product983096983097983091

983096983097983092


983096983097983094













983097983088983097

983097983089983088




page 13









983091983092983094



983091983092983097




983091983093983091






983091983093983097






983091983094983093









page 14



983091983095983091





983091983095983096




983091983096983090



983091983096983093












983091983097983095





983092983088983090

983092983088983091




page 15







983092983089983088




983092983089983092




983092983089983096






and efficacy983092983090983092

983092983090983093

4 COMPOUNDING983092983090983094

983092983090983095


983092983090983097




983092983091983091







page 16





983092983092983089




983092983092983093



compounding983092983092983096


the Internet983092983093983088




983092983093983092


983092983093983094






983092983094983090




983092983094983094







page 17




983092983095983091


983092983095983093


983092983095983095






983092983096983091






983092983096983097





983092983097983092





983092983097983097







page 18



983093983088983093










983093983089983093









983093983090983092




983093983090983096



983093983091983089








page 19



983093983091983096




983093983092983090





solution983093983092983095

983093983092983096




983093983093983090







983093983093983097








983093983094983095




page 20








983093983095983093



983093983095983096








983093983096983094


containers983093983096983096

983093983096983097







983093983097983094








page 21






983094983088983094




983094983089983088






983094983089983094





therapy983094983090983089

983094983090983090




literature983094983090983094

983094983090983095




983094983091983089






page 22



information983094983091983094

983094983091983095




the dose983094983092983089

983094983092983090



983094983092983093








container983094983093983091







983094983094983088

bull






983094983094983094




page 23


983094983094983096






983094983095983092


983094983095983094




983094983096983088


983094983096983090





983094983096983095



983094983097983088




983094983097983092


983094983097983094







page 24

983095983088983088



983095983088983091


983095983088983093





beneficial 983095983089983088

983095983089983089


983095983089983091



983095983089983094




983095983090983088

6 REFERENCES 983095983090983089

983095983090983090





983095983090983095









page 25

983095983091983091




986 Annex 2 2014 (in print)983095983091983095

983095983091983096



CD-ROM 2013983095983092983089

983095983092983090




983095983092983094




document QAS11400)983095983093983088

983095983093983089

7



983095983093983092





983095983093983097




983095983094983091






page 26




983095983094983097



Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

983095983095983093

983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

983095983097983092


983095983097983094





983096983088983089

















983096983089983096











page 29






983096983091983089











983096983092983090






983096983092983096


983096983093983088












page 30






983096983094983092











983096983095983093


983096983095983095










pH983096983096983095

983096983096983096







page 31


product983096983097983091

983096983097983092


983096983097983094













983097983088983097

983097983089983088




page 14



983091983095983091





983091983095983096




983091983096983090



983091983096983093












983091983097983095





983092983088983090

983092983088983091




page 15







983092983089983088




983092983089983092




983092983089983096






and efficacy983092983090983092

983092983090983093

4 COMPOUNDING983092983090983094

983092983090983095


983092983090983097




983092983091983091







page 16





983092983092983089




983092983092983093



compounding983092983092983096


the Internet983092983093983088




983092983093983092


983092983093983094






983092983094983090




983092983094983094







page 17




983092983095983091


983092983095983093


983092983095983095






983092983096983091






983092983096983097





983092983097983092





983092983097983097







page 18



983093983088983093










983093983089983093









983093983090983092




983093983090983096



983093983091983089








page 19



983093983091983096




983093983092983090





solution983093983092983095

983093983092983096




983093983093983090







983093983093983097








983093983094983095




page 20








983093983095983093



983093983095983096








983093983096983094


containers983093983096983096

983093983096983097







983093983097983094








page 21






983094983088983094




983094983089983088






983094983089983094





therapy983094983090983089

983094983090983090




literature983094983090983094

983094983090983095




983094983091983089






page 22



information983094983091983094

983094983091983095




the dose983094983092983089

983094983092983090



983094983092983093








container983094983093983091







983094983094983088

bull






983094983094983094




page 23


983094983094983096






983094983095983092


983094983095983094




983094983096983088


983094983096983090





983094983096983095



983094983097983088




983094983097983092


983094983097983094







page 24

983095983088983088



983095983088983091


983095983088983093





beneficial 983095983089983088

983095983089983089


983095983089983091



983095983089983094




983095983090983088

6 REFERENCES 983095983090983089

983095983090983090





983095983090983095









page 25

983095983091983091




986 Annex 2 2014 (in print)983095983091983095

983095983091983096



CD-ROM 2013983095983092983089

983095983092983090




983095983092983094




document QAS11400)983095983093983088

983095983093983089

7



983095983093983092





983095983093983097




983095983094983091






page 26




983095983094983097



Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

983095983095983093

983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

983095983097983092


983095983097983094





983096983088983089

















983096983089983096











page 29






983096983091983089











983096983092983090






983096983092983096


983096983093983088












page 30






983096983094983092











983096983095983093


983096983095983095










pH983096983096983095

983096983096983096







page 31


product983096983097983091

983096983097983092


983096983097983094













983097983088983097

983097983089983088




page 15







983092983089983088




983092983089983092




983092983089983096






and efficacy983092983090983092

983092983090983093

4 COMPOUNDING983092983090983094

983092983090983095


983092983090983097




983092983091983091







page 16





983092983092983089




983092983092983093



compounding983092983092983096


the Internet983092983093983088




983092983093983092


983092983093983094






983092983094983090




983092983094983094







page 17




983092983095983091


983092983095983093


983092983095983095






983092983096983091






983092983096983097





983092983097983092





983092983097983097







page 18



983093983088983093










983093983089983093









983093983090983092




983093983090983096



983093983091983089








page 19



983093983091983096




983093983092983090





solution983093983092983095

983093983092983096




983093983093983090







983093983093983097








983093983094983095




page 20








983093983095983093



983093983095983096








983093983096983094


containers983093983096983096

983093983096983097







983093983097983094








page 21






983094983088983094




983094983089983088






983094983089983094





therapy983094983090983089

983094983090983090




literature983094983090983094

983094983090983095




983094983091983089






page 22



information983094983091983094

983094983091983095




the dose983094983092983089

983094983092983090



983094983092983093








container983094983093983091







983094983094983088

bull






983094983094983094




page 23


983094983094983096






983094983095983092


983094983095983094




983094983096983088


983094983096983090





983094983096983095



983094983097983088




983094983097983092


983094983097983094







page 24

983095983088983088



983095983088983091


983095983088983093





beneficial 983095983089983088

983095983089983089


983095983089983091



983095983089983094




983095983090983088

6 REFERENCES 983095983090983089

983095983090983090





983095983090983095









page 25

983095983091983091




986 Annex 2 2014 (in print)983095983091983095

983095983091983096



CD-ROM 2013983095983092983089

983095983092983090




983095983092983094




document QAS11400)983095983093983088

983095983093983089

7



983095983093983092





983095983093983097




983095983094983091






page 26




983095983094983097



Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

983095983095983093

983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

983095983097983092


983095983097983094





983096983088983089

















983096983089983096











page 29






983096983091983089











983096983092983090






983096983092983096


983096983093983088












page 30






983096983094983092











983096983095983093


983096983095983095










pH983096983096983095

983096983096983096







page 31


product983096983097983091

983096983097983092


983096983097983094













983097983088983097

983097983089983088




page 16





983092983092983089




983092983092983093



compounding983092983092983096


the Internet983092983093983088




983092983093983092


983092983093983094






983092983094983090




983092983094983094







page 17




983092983095983091


983092983095983093


983092983095983095






983092983096983091






983092983096983097





983092983097983092





983092983097983097







page 18



983093983088983093










983093983089983093









983093983090983092




983093983090983096



983093983091983089








page 19



983093983091983096




983093983092983090





solution983093983092983095

983093983092983096




983093983093983090







983093983093983097








983093983094983095




page 20








983093983095983093



983093983095983096








983093983096983094


containers983093983096983096

983093983096983097







983093983097983094








page 21






983094983088983094




983094983089983088






983094983089983094





therapy983094983090983089

983094983090983090




literature983094983090983094

983094983090983095




983094983091983089






page 22



information983094983091983094

983094983091983095




the dose983094983092983089

983094983092983090



983094983092983093








container983094983093983091







983094983094983088

bull






983094983094983094




page 23


983094983094983096






983094983095983092


983094983095983094




983094983096983088


983094983096983090





983094983096983095



983094983097983088




983094983097983092


983094983097983094







page 24

983095983088983088



983095983088983091


983095983088983093





beneficial 983095983089983088

983095983089983089


983095983089983091



983095983089983094




983095983090983088

6 REFERENCES 983095983090983089

983095983090983090





983095983090983095









page 25

983095983091983091




986 Annex 2 2014 (in print)983095983091983095

983095983091983096



CD-ROM 2013983095983092983089

983095983092983090




983095983092983094




document QAS11400)983095983093983088

983095983093983089

7



983095983093983092





983095983093983097




983095983094983091






page 26




983095983094983097



Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

983095983095983093

983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

983095983097983092


983095983097983094





983096983088983089

















983096983089983096











page 29






983096983091983089











983096983092983090






983096983092983096


983096983093983088












page 30






983096983094983092











983096983095983093


983096983095983095










pH983096983096983095

983096983096983096







page 31


product983096983097983091

983096983097983092


983096983097983094













983097983088983097

983097983089983088




page 17




983092983095983091


983092983095983093


983092983095983095






983092983096983091






983092983096983097





983092983097983092





983092983097983097







page 18



983093983088983093










983093983089983093









983093983090983092




983093983090983096



983093983091983089








page 19



983093983091983096




983093983092983090





solution983093983092983095

983093983092983096




983093983093983090







983093983093983097








983093983094983095




page 20








983093983095983093



983093983095983096








983093983096983094


containers983093983096983096

983093983096983097







983093983097983094








page 21






983094983088983094




983094983089983088






983094983089983094





therapy983094983090983089

983094983090983090




literature983094983090983094

983094983090983095




983094983091983089






page 22



information983094983091983094

983094983091983095




the dose983094983092983089

983094983092983090



983094983092983093








container983094983093983091







983094983094983088

bull






983094983094983094




page 23


983094983094983096






983094983095983092


983094983095983094




983094983096983088


983094983096983090





983094983096983095



983094983097983088




983094983097983092


983094983097983094







page 24

983095983088983088



983095983088983091


983095983088983093





beneficial 983095983089983088

983095983089983089


983095983089983091



983095983089983094




983095983090983088

6 REFERENCES 983095983090983089

983095983090983090





983095983090983095









page 25

983095983091983091




986 Annex 2 2014 (in print)983095983091983095

983095983091983096



CD-ROM 2013983095983092983089

983095983092983090




983095983092983094




document QAS11400)983095983093983088

983095983093983089

7



983095983093983092





983095983093983097




983095983094983091






page 26




983095983094983097



Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

983095983095983093

983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

983095983097983092


983095983097983094





983096983088983089

















983096983089983096











page 29






983096983091983089











983096983092983090






983096983092983096


983096983093983088












page 30






983096983094983092











983096983095983093


983096983095983095










pH983096983096983095

983096983096983096







page 31


product983096983097983091

983096983097983092


983096983097983094













983097983088983097

983097983089983088




page 18



983093983088983093










983093983089983093









983093983090983092




983093983090983096



983093983091983089








page 19



983093983091983096




983093983092983090





solution983093983092983095

983093983092983096




983093983093983090







983093983093983097








983093983094983095




page 20








983093983095983093



983093983095983096








983093983096983094


containers983093983096983096

983093983096983097







983093983097983094








page 21






983094983088983094




983094983089983088






983094983089983094





therapy983094983090983089

983094983090983090




literature983094983090983094

983094983090983095




983094983091983089






page 22



information983094983091983094

983094983091983095




the dose983094983092983089

983094983092983090



983094983092983093








container983094983093983091







983094983094983088

bull






983094983094983094




page 23


983094983094983096






983094983095983092


983094983095983094




983094983096983088


983094983096983090





983094983096983095



983094983097983088




983094983097983092


983094983097983094







page 24

983095983088983088



983095983088983091


983095983088983093





beneficial 983095983089983088

983095983089983089


983095983089983091



983095983089983094




983095983090983088

6 REFERENCES 983095983090983089

983095983090983090





983095983090983095









page 25

983095983091983091




986 Annex 2 2014 (in print)983095983091983095

983095983091983096



CD-ROM 2013983095983092983089

983095983092983090




983095983092983094




document QAS11400)983095983093983088

983095983093983089

7



983095983093983092





983095983093983097




983095983094983091






page 26




983095983094983097



Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

983095983095983093

983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

983095983097983092


983095983097983094





983096983088983089

















983096983089983096











page 29






983096983091983089











983096983092983090






983096983092983096


983096983093983088












page 30






983096983094983092











983096983095983093


983096983095983095










pH983096983096983095

983096983096983096







page 31


product983096983097983091

983096983097983092


983096983097983094













983097983088983097

983097983089983088




page 19



983093983091983096




983093983092983090





solution983093983092983095

983093983092983096




983093983093983090







983093983093983097








983093983094983095




page 20








983093983095983093



983093983095983096








983093983096983094


containers983093983096983096

983093983096983097







983093983097983094








page 21






983094983088983094




983094983089983088






983094983089983094





therapy983094983090983089

983094983090983090




literature983094983090983094

983094983090983095




983094983091983089






page 22



information983094983091983094

983094983091983095




the dose983094983092983089

983094983092983090



983094983092983093








container983094983093983091







983094983094983088

bull






983094983094983094




page 23


983094983094983096






983094983095983092


983094983095983094




983094983096983088


983094983096983090





983094983096983095



983094983097983088




983094983097983092


983094983097983094







page 24

983095983088983088



983095983088983091


983095983088983093





beneficial 983095983089983088

983095983089983089


983095983089983091



983095983089983094




983095983090983088

6 REFERENCES 983095983090983089

983095983090983090





983095983090983095









page 25

983095983091983091




986 Annex 2 2014 (in print)983095983091983095

983095983091983096



CD-ROM 2013983095983092983089

983095983092983090




983095983092983094




document QAS11400)983095983093983088

983095983093983089

7



983095983093983092





983095983093983097




983095983094983091






page 26




983095983094983097



Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

983095983095983093

983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

983095983097983092


983095983097983094





983096983088983089

















983096983089983096











page 29






983096983091983089











983096983092983090






983096983092983096


983096983093983088












page 30






983096983094983092











983096983095983093


983096983095983095










pH983096983096983095

983096983096983096







page 31


product983096983097983091

983096983097983092


983096983097983094













983097983088983097

983097983089983088




page 20








983093983095983093



983093983095983096








983093983096983094


containers983093983096983096

983093983096983097







983093983097983094








page 21






983094983088983094




983094983089983088






983094983089983094





therapy983094983090983089

983094983090983090




literature983094983090983094

983094983090983095




983094983091983089






page 22



information983094983091983094

983094983091983095




the dose983094983092983089

983094983092983090



983094983092983093








container983094983093983091







983094983094983088

bull






983094983094983094




page 23


983094983094983096






983094983095983092


983094983095983094




983094983096983088


983094983096983090





983094983096983095



983094983097983088




983094983097983092


983094983097983094







page 24

983095983088983088



983095983088983091


983095983088983093





beneficial 983095983089983088

983095983089983089


983095983089983091



983095983089983094




983095983090983088

6 REFERENCES 983095983090983089

983095983090983090





983095983090983095









page 25

983095983091983091




986 Annex 2 2014 (in print)983095983091983095

983095983091983096



CD-ROM 2013983095983092983089

983095983092983090




983095983092983094




document QAS11400)983095983093983088

983095983093983089

7



983095983093983092





983095983093983097




983095983094983091






page 26




983095983094983097



Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

983095983095983093

983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

983095983097983092


983095983097983094





983096983088983089

















983096983089983096











page 29






983096983091983089











983096983092983090






983096983092983096


983096983093983088












page 30






983096983094983092











983096983095983093


983096983095983095










pH983096983096983095

983096983096983096







page 31


product983096983097983091

983096983097983092


983096983097983094













983097983088983097

983097983089983088




page 21






983094983088983094




983094983089983088






983094983089983094





therapy983094983090983089

983094983090983090




literature983094983090983094

983094983090983095




983094983091983089






page 22



information983094983091983094

983094983091983095




the dose983094983092983089

983094983092983090



983094983092983093








container983094983093983091







983094983094983088

bull






983094983094983094




page 23


983094983094983096






983094983095983092


983094983095983094




983094983096983088


983094983096983090





983094983096983095



983094983097983088




983094983097983092


983094983097983094







page 24

983095983088983088



983095983088983091


983095983088983093





beneficial 983095983089983088

983095983089983089


983095983089983091



983095983089983094




983095983090983088

6 REFERENCES 983095983090983089

983095983090983090





983095983090983095









page 25

983095983091983091




986 Annex 2 2014 (in print)983095983091983095

983095983091983096



CD-ROM 2013983095983092983089

983095983092983090




983095983092983094




document QAS11400)983095983093983088

983095983093983089

7



983095983093983092





983095983093983097




983095983094983091






page 26




983095983094983097



Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

983095983095983093

983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

983095983097983092


983095983097983094





983096983088983089

















983096983089983096











page 29






983096983091983089











983096983092983090






983096983092983096


983096983093983088












page 30






983096983094983092











983096983095983093


983096983095983095










pH983096983096983095

983096983096983096







page 31


product983096983097983091

983096983097983092


983096983097983094













983097983088983097

983097983089983088




page 22



information983094983091983094

983094983091983095




the dose983094983092983089

983094983092983090



983094983092983093








container983094983093983091







983094983094983088

bull






983094983094983094




page 23


983094983094983096






983094983095983092


983094983095983094




983094983096983088


983094983096983090





983094983096983095



983094983097983088




983094983097983092


983094983097983094







page 24

983095983088983088



983095983088983091


983095983088983093





beneficial 983095983089983088

983095983089983089


983095983089983091



983095983089983094




983095983090983088

6 REFERENCES 983095983090983089

983095983090983090





983095983090983095









page 25

983095983091983091




986 Annex 2 2014 (in print)983095983091983095

983095983091983096



CD-ROM 2013983095983092983089

983095983092983090




983095983092983094




document QAS11400)983095983093983088

983095983093983089

7



983095983093983092





983095983093983097




983095983094983091






page 26




983095983094983097



Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

983095983095983093

983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

983095983097983092


983095983097983094





983096983088983089

















983096983089983096











page 29






983096983091983089











983096983092983090






983096983092983096


983096983093983088












page 30






983096983094983092











983096983095983093


983096983095983095










pH983096983096983095

983096983096983096







page 31


product983096983097983091

983096983097983092


983096983097983094













983097983088983097

983097983089983088




page 23


983094983094983096






983094983095983092


983094983095983094




983094983096983088


983094983096983090





983094983096983095



983094983097983088




983094983097983092


983094983097983094







page 24

983095983088983088



983095983088983091


983095983088983093





beneficial 983095983089983088

983095983089983089


983095983089983091



983095983089983094




983095983090983088

6 REFERENCES 983095983090983089

983095983090983090





983095983090983095









page 25

983095983091983091




986 Annex 2 2014 (in print)983095983091983095

983095983091983096



CD-ROM 2013983095983092983089

983095983092983090




983095983092983094




document QAS11400)983095983093983088

983095983093983089

7



983095983093983092





983095983093983097




983095983094983091






page 26




983095983094983097



Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

983095983095983093

983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

983095983097983092


983095983097983094





983096983088983089

















983096983089983096











page 29






983096983091983089











983096983092983090






983096983092983096


983096983093983088












page 30






983096983094983092











983096983095983093


983096983095983095










pH983096983096983095

983096983096983096







page 31


product983096983097983091

983096983097983092


983096983097983094













983097983088983097

983097983089983088




page 24

983095983088983088



983095983088983091


983095983088983093





beneficial 983095983089983088

983095983089983089


983095983089983091



983095983089983094




983095983090983088

6 REFERENCES 983095983090983089

983095983090983090





983095983090983095









page 25

983095983091983091




986 Annex 2 2014 (in print)983095983091983095

983095983091983096



CD-ROM 2013983095983092983089

983095983092983090




983095983092983094




document QAS11400)983095983093983088

983095983093983089

7



983095983093983092





983095983093983097




983095983094983091






page 26




983095983094983097



Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

983095983095983093

983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

983095983097983092


983095983097983094





983096983088983089

















983096983089983096











page 29






983096983091983089











983096983092983090






983096983092983096


983096983093983088












page 30






983096983094983092











983096983095983093


983096983095983095










pH983096983096983095

983096983096983096







page 31


product983096983097983091

983096983097983092


983096983097983094













983097983088983097

983097983089983088




page 25

983095983091983091




986 Annex 2 2014 (in print)983095983091983095

983095983091983096



CD-ROM 2013983095983092983089

983095983092983090




983095983092983094




document QAS11400)983095983093983088

983095983093983089

7



983095983093983092





983095983093983097




983095983094983091






page 26




983095983094983097



Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

983095983095983093

983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

983095983097983092


983095983097983094





983096983088983089

















983096983089983096











page 29






983096983091983089











983096983092983090






983096983092983096


983096983093983088












page 30






983096983094983092











983096983095983093


983096983095983095










pH983096983096983095

983096983096983096







page 31


product983096983097983091

983096983097983092


983096983097983094













983097983088983097

983097983089983088




page 26




983095983094983097



Compounding 2003 7(5) 401-16983095983095983090

983095983095983091

983095983095983092

983095983095983093

983095983095983094

983095983095983095




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

983095983097983092


983095983097983094





983096983088983089

















983096983089983096











page 29






983096983091983089











983096983092983090






983096983092983096


983096983093983088












page 30






983096983094983092











983096983095983093


983096983095983095










pH983096983096983095

983096983096983096







page 31


product983096983097983091

983096983097983092


983096983097983094













983097983088983097

983097983089983088




page 27

ANNEX 1983095983095983096

983095983095983097


983095983096983089





some countries



giving the dose


justified



alternative



can be prepared




983095983096983090



983095983096983093

983095983096983094

983095983096983095

983095983096983096

983095983096983097

983095983097983088

983095983097983089

983095983097983090




page 28

ANNEX 2983095983097983091

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page 31


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page 28

ANNEX 2983095983097983091

983095983097983092


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983096983088983089

















983096983089983096











page 29






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page 30






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pH983096983096983095

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page 31


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983097983088983097

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page 29






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983096983092983090






983096983092983096


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page 30






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page 31


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983097983088983097

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page 30






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pH983096983096983095

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page 31


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983096983097983094













983097983088983097

983097983089983088




page 31


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983097983088983097

983097983089983088

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