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WHO Drug Information Vol 21, No. 1, 2007

WHO Drug Information

Contents

World Health Organization

Quality AssuranceInternational Conference on

Harmonization (ICH) 3New developments in quality 3

Safety and Efficacy IssuesRotavirus vaccine and intussusception 8Zolpidem and bizarre sleep related effects 8Rituximab: life-threatening brain infection 9Methadone for pain: cardiac and respiratory

changes 9Levofloxacin: dysglycemia and liver

disorder 10Domperidone: heart rate and rhythm

disorders 11Complications with use of bone cement 12Infant deaths associated with cough and

cold medications 13Ranibizumab and stroke 14Increased risk of fractures: antiepileptic

medicines 14Vasomist® and nephrogenic systemic

fibrosis 15

Access to medicinesThe challenges of ensuring pain

medication 16Import and safe distribution of oral

morphine for pain relief in Uganda 18

Topics of Current InterestDevelopments in biological quality, safety

and efficacy 21Transparency in Medicines Management 24WHO Programme on Good Governance

for Medicines 24

Rational Use of MedicinesUse of concordance to improve patient

adherence 27Influencing health professionals for better

health outcomes 27

ATC/DDD ClassificationATC/DDD Classification (Temporary) 33ATC/DDD Classification (Final) 36

International PharmacopoeiaDraft proposal: oseltamivir phosphate 38Draft proposal: lumefantrine 43Dissolution tests 47

Recent Publications,Information and EventsInternational Pharmacopoeia: fourth

edition 51Draft report: Specifications for

Pharmaceutical Preparations 51User guide for micro, small and medium

sized enterprises 52

Recommended InternationalNonproprietary Names: List 57 53

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WHO Drug Information Vol 21, No. 1, 2007World Health Organization

Announcement

The 13th International Conferenceof Drug Regulatory Authorities (ICDRA)will be hosted by the Swiss Medicines

Agency SWISSMEDIC in collaboration withthe World Health Organization.

The ICDRA will take placein Berne, Switzerland

from 16 to 19 September 2008.

Updated information will be provided regularly at:http://www.icdra.ch

or

http://www.who.int/medicines/icdra/en/index/html

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Quality Assurance

International Conference on Harmonization (ICH)

New developments in qualityThe ICH Steering Committee (SC) and itsExpert Working Groups (EWGs) met inChicago, Illinois from 21 to 26 October2006. WHO has observer status in ICHand participated in the discussions of theSC and various EWGs with the objectiveof providing input and disseminatinginformation beyond the ICH regions.

ICH quality strategy discussionThe objective of the quality strategymeeting in Chicago was to identify thoseareas in pharmaceutical quality whichneed to be addressed at ICH level.General issues, which can have implica-tions on the non-ICH Member States ofWHO, are listed below:

• Agreement by regulators and industryon future quality vision as regardsevolution of dossier assessment, (GMP)inspection and laboratory controls.

• ICH guidelines are globalizing regula-tory expectations.

• Further discussion is needed in order toreach common understanding of con-cepts behind the definitions:

Design spaceQuality by design (QbD)Regulatory flexibility

• Small and medium-size companies willnot necessarily follow the QbD ap-proach.

• Common training of assessors, inspec-tors and industry is needed to facilitatethe implementation of the Q8, Q9 andQ10 guidelines.

• No new regulatory requirements beyondthe current ones are intended by thetripartite adoption of Q8, Q9 and Q10guidelines but their impact on dossierassessment, post-approval changesand inspections should be assessed.

• Further discussion will take place at thenext EWG meeting in Brussels in May2007 where the following issues will

The harmonization of regulatory requirements between Europe, Japan and the USAbegan to materialize as a result of discussions held in conjunction with the Interna-tional Conference of Drug Regulatory Authorities (ICDRA) of the World Health Or-ganization (WHO) in Paris, in 1989 (1). The International Conference on Harmoniza-tion of Technical Requirements for Registration of Pharmaceuticals for Human Use(ICH) was soon born at a meeting in Brussels in April 1990. Representatives of theregulatory authorities and industry associations of Europe, Japan and the USA metto plan an International Conference but the meeting also discussed the wider impli-cations and terms of reference of ICH. The ICH Steering Committee — which wasestablished at that meeting — has since met at least twice a year, with the locationrotating between the three regions (1).

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have to be clarified: development/manufacture guideline for APIs andimplementation of Q8, Q9 and Q10when it is finalized.

The existing portfolio of ICH guidelineswas also reviewed. Progress of EWGs issummarized under the title of the corre-sponding guidelines.

Q4B – Regulatory Acceptance ofAnalytical Procedures and/or Accept-ance Criteria (RAAPAC)1

This document describes a procedure tofacilitate acceptance by regulatory au-thorities of pharmacopoeial analyticalprocedures and/or acceptance criteria(APAC)2 for use in the three ICH regions.

The Q4B process focuses on the follow-ing 11 General Test Chapters:

Dissolution Disintegration Uniformity of Content → Harmonized to

Uniformity of Uniformity of Mass → Dosage Units Extractable Volume Particulate Matter Sterility Microbiological Quality Bacterial Endotoxins Residue on Ignition Colour and Clarity

The harmonization of pharmacopoeialgeneral chapters is important to WHOnormative work in the area of pharmaceu-ticals because each of the generalmonographs affects a large number offinished pharmaceutical products (FPPs),which belong to the same dosage form.

Particularly important are the mono-graphs on the Dissolution and the Uni-formity of Dosage Units. Both tests areextensively used not only for qualitycontrol (QC) purposes but also for manu-facturing process validation. In addition,the Dissolution test is an essential tool forchange detection and evaluation duringthe pharmaceutical development stageand the stability studies as well as for theassessment of post-approval variations tothe marketing authorization (MA).

The output of this EWG depends on theinput received from the PharmacopoeialDiscussion Group (PDG), which startedbefore ICH and has proceeded in parallel.The work of ICH Q4B seems to bemoving from pharmacopoeia to harmo-nized general ICH monographs.

Q8 – Pharmaceutical Development3

The ICH guidelines Q1 to Q6 are techni-cal; the Q7 and Q9–Q10 guidelines aresystem-oriented, while the Q8 guideline isboth technical and conceptual in charac-ter. The core guideline — recommendedfor adoption to the three regulatoryparties to ICH — “describes the sug-gested contents for the 3.2.P.2 (Pharma-ceutical Development) section of aregulatory submission in the ICH M4Common Technical Document (CTD)format” and it also “provides an opportu-nity to present the knowledge gainedthrough the application of scientificapproaches and quality risk manage-ment.” “The guideline also indicates areaswhere the demonstration of greaterunderstanding of pharmaceutical andmanufacturing sciences can create abasis for flexible regulatory approaches.”These three functions together could be

1. http://www.ich.org/LOB/media/MEDIA3092. pdf

2. The term analytical procedures and/or acceptance criteria (APAC) refers to pharmacopoeialmonographs, general test chapters, analytical methods, and/or associated acceptance criteria.

3. http://www.ich.org/LOB/media/MEDIA1707.pdf

Quality Assurance

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briefly described as the road from formu-lation development, through baseline inprocess control (IPC) and QC, to productand process know-how management.

The pharmaceutical development reporthas been a regulatory requirement inapplications for MA in the EuropeanUnion. However, the 2nd and the 3rd

functions imply that if industry demon-strates product and process knowledgebeyond QC specifications, stabilitystudies and the three validation batches,then drug regulatory authorities do notrequire even notification after certainpost-approval variations to the MA. As anillustration of the point, a definition isquoted from the Q8 core guideline:

“Design Space: The multidimensionalcombination and interaction of inputvariables (e.g., material attributes) andprocess parameters that have beendemonstrated to provide assurance ofquality. Working within the design spaceis not considered as a change. Movementout of the design space is considered tobe a change and would normally initiate aregulatory post approval change process.Design space is proposed by the appli-cant and is subject to regulatory assess-ment and approval.”

The definition suggests that if criticalproduct attributes or process variablesare brought under control within thedesign space, then they become non-critical. Another interpretation opines thatcritical attributes or variables remainalways critical only the product andprocess quality risk is reduced (possiblyto a large extent) even if such parametersare monitored in line/on line to supportreal time batch release.

In the QbD methodology, the choicemanufacturing process and details ofeach unit operation are evaluated todemonstrate a high level of processunderstanding and control.

The following points illustrate subjects ofdiscussion at the EWG meeting onQ8(R1) Pharmaceutical Development inChicago:

• There are overlapping areas betweenthe baseline (conventional, traditional,and basic) and enhanced [expanded,intensive, quality-by-design (QbD)]experimentation methods of pharma-ceutical development.

• Flexibility — regulatory including inspec-tion, operational — (effect) is created bythe design space and should be basedon science (cause).

• Pharmaceutical development is dis-cussed as a life cycle concept of theFPP (API is excluded as of today)against the everyday interpretation ofpre-formulation, formulation and scale-up activities.

The Q8(R1) Pharmaceutical Develop-ment guideline is expected to be pub-lished after the next ICH Steering Com-mittee meeting to be held in Brussels,Belgium, from 7 to 10 May 2007.

Q9 - Quality Risk Management4

“This guideline provides principles andexamples of tools for quality risk manage-ment that can be applied to differentaspects of pharmaceutical quality. Theseaspects include development, manufac-turing, distribution, and the inspection andsubmission/review processes throughoutthe lifecycle of drug substances, drug(medicinal) products, biological andbiotechnological products (including theuse of raw materials, solvents, excipients,packaging and labelling materials in drug(medicinal) products, biological andbiotechnological products).”

The ICH-Q9 guideline outlines a modelfor quality risk management, as follows:

4. http://www.ich.org/LOB/media/MEDIA1957.pdf

Quality Assurance

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WHO Drug Information Vol 21, No. 1, 2007Quality Assurance

The Steering Committee encouragedimplementation of the guideline, which isalso quoted as a tool box because aBriefing Pack5 is offered as a supplemen-tary explanation of the ICH Q9 both forregulators and industry.

Q10 – Pharmaceutical Quality Systems(PQS)The objective of this draft guideline is toestablish a new tripartite guideline de-scribing a model for an effective qualitymanagement system for the pharmaceuti-cal industry, referred to as the pharma-ceutical quality system, that:

• ensures the realization of a quality drugproduct.

• establishes and maintains a state ofcontrol.

• facilitates continual improvement overthe product life cycle.

This guideline will complement existinggood manufacturing practices (GMP) witheffective pharmaceutical quality systemelements, providing the opportunity forcapable processes, resulting in drugsubstances and drug products thatconsistently meet their intended qualityattributes. Q10 thereby serves as abridge between different regional regula-tions, helping industry and regulators toachieve harmonization of pharmaceuticalquality systems. This guideline is ex-pected to focus on the pharmaceuticalquality systems and complements andfacilitates the implementation of ICH Q8“Pharmaceutical Development” and ICHQ9 “Quality Risk Management”.

Pharmaceutical Quality System, Version8.0, 26 October 2006 was completed inChicago as a revised draft for the step 2guideline which is expected to be final-ized during the forthcoming meeting ofthe Steering Committee in Brussels, May2007.

5. http://www.ich.org/cache/compo/276-254-1.html

Model for quality risk management

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SummaryThis article has described progressachieved by ICH EWGs in Chicago,Illinois from 21 to 26 October 2006. ICHQ strategy discussion will be finalized inBrussels in May 2007 in order to work outa harmonized quality strategy and a workplan. The annexes of the Q4 guidelinelead to internationally harmonized generalpharmacopoeia monographs. Science-and risk-based concepts are described in

the Q8, Q9 and Q10 guidelines. Theimplementation of these guidelines isintended to be voluntary; however, ifimplemented industry hopes to getregulatory flexibility in post-approvalvariations of the MA and during GMPinspections.

Reference

1. ICH website at http://www.ich.org

Quality Assurance

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Safety and Efficacy Issues

Rotavirus vaccineand intussusceptionUnited States of America — The Foodand Drug Administration (FDA) hasnotified health care providers about 28post-marketing reports of intussusceptionfollowing administration of rotavirus liveoral pentavalent vaccine (RotaTeq®),indicated for the prevention of rotavirusgastroenteritis. Intussusception is aserious and potentially life-threateningcondition that occurs when the intestinegets blocked or twisted. One portion ofthe intestine telescopes into a nearbyportion, causing intestinal obstruction (1).

Since its licensure on 3 February 2006until 31 January 2007, 28 cases ofintussusception have been reported inthe US in infants who received RotaTeq®.Cases occurred after dose 1, dose 2 anddose 3. Approximately half of the casesoccurred 1 to 21 days after vaccination,with a range of 0 to 73 days. Sixteen ofthe 28 infants with intussusceptionrequired hospitalization and surgery ontheir intestine. The remaining 12 infantshad reduction of the intussusception bycontrast or air enema. No deaths due tointussusception were reported.

The number of intussusception casesreported to date after RotaTeq® adminis-tration does not exceed the numberexpected based on background rates of18–43 per 100 000 per year for anunvaccinated population of children 6 to35 weeks. The FDA notification wasissued to encourage reporting of anyadditional cases of intussusception thatmay have occurred or that occur in thefuture after administration of RotaTeq® toremind health care providers of Intussus-ception as a potential complication (2).

The WHO Global Advisory Committee onVaccine Safety has previously concludedthat clinical trial data and preliminary datafrom adverse event reports in the post-marketing phase, from the US andelsewhere, did not show an increased riskfor intussusception following RotaTeq®;the committee further concluded that therecent information from the US does notchange its previous conclusions thatfurther monitoring is warranted (2).

References

1. CBER, 13 February 2007 on MedWatch,http://www.fda.gov/medwatch andhttp://www.fda.gov/cber/safety/phnrota021307.htm

2. World Health Organization Statement. http://www.who.int/vaccine_safety/topics/rotavirus/rotateq_statement/en/index.html

Zolpidem and bizarre sleeprelated effectsAustralia — Zolpidem (Stilnox®) wasmarketed in Australia in late 2000 for theshort term treatment of insomnia. It isstructurally unrelated to the benzo-diazepines, but has a similar pharmaco-logical action. In 2002, the AustralianAdverse Reactions Advisory Committee(ADRAC) reviewed the first year of useand it was noted about 75% of the reportsreceived described one or more neuro-logical or psychiatric reactions, especiallyvisual hallucinations, confusion, depres-sion and amnesia (1). This pattern, whichis not shared by other hypnotics, hascontinued with hallucinations (104 re-ports) and amnesia (62) now the mostfrequently reported effects. Reactionsassociated with sleeping or falling asleephave been described in half of all reportssubmitted. Of particular interest have

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WHO Drug Information Vol 21, No. 1, 2007 Safety and Efficacy Issues

been 16 reports of sleep walking, whichdescribe inappropriate or strange auto-matic behaviour “while asleep”, includingbinge eating and house painting.

There have been isolated reports in theliterature describing sleep walking,including an article in the popular maga-zine Time which mentioned the impend-ing publication of a case series describinga few dozen people who, after takingzolpidem, developed uncontrollable urgesto eat while asleep and did not rememberthe feeding binges when they awoke (2).A case series describing 5 patients takingzolpidem who experienced uncontrolledeating while asleep has previously beenpublished (3).

There are two reports to ADRAC thatdescribe this situation. In one report, apatient put on 23 kg in weight over 7months while taking zolpidem. It was onlywhen she was discovered eating in frontof an open refrigerator while asleep thatthe problem was resolved. In anotherreport, a patient who had experiencedsignificant weight gain was found by arelative taking food from the refrigeratorand kitchen cupboards while asleep.Other reports to ADRAC describe apatient who woke with a paintbrush in herhand after painting the front door whileasleep, a patient who walked around thehouse like a “mad man” while asleep, andtwo further reports which suggest thepossibility of driving while asleep.

ADRAC recommends prescribers shouldbe alert to the fact that zolpidem may beassociated with distressing neurologicalor psychiatric reactions, including thoseassociated with sleeping or falling asleep,and should warn their patients about thepossibility of these untoward effects,particularly if they are going to takezolpidem for the first time.

Extracted from Australian Adverse DrugReactions Bulletin, Volume 26, Number 1,February 2007.

References

1. ADRAC. Seeing things with Zolpidem. AustAdv Drug React Bull 2002; 21: 3.

2. Gorman C. Sleeping-pill puzzler. Time2006, May 19.

2. Morgenthaler TI, Silber MH. Amnesticsleep-related eating disorder association withzolpidem. Sleep Medicine 2002; 3: 323-327.

Rituximab: life-threateningbrain infectionUnited States of America — The Foodand Drug Administration (FDA) hasreceived reports of death in two patientstreated with rituximab (Rituxan®) forsystemic lupus erythematosus (SLE).Both patients developed progressivemultifocal leukoencephalopathy (PML).PML is usually fatal and there are noknown effective treatments.

The signs of PML include confusion,dizziness or loss of balance, difficultytalking or walking, and vision problems.Recognition of these warning signs ofPML may be obscured by the fact thatthey are also associated with the underly-ing diseases for which rituximab may beprescribed.

Rituximab is a powerful medication usedto suppress the immune system. It worksby blocking the effect of specific immunecells in the blood for up to six to ninemonths. Rituximab is approved for useonly in patients with non-Hodgkin lym-phoma and for rheumatoid arthritis whenother treatments have failed.

Reference: MedWatch, 18 December 2006.http://www.fda.gov/medwatch.

Methadone for pain: cardiacand respiratory changesUnited States of America — The Foodand Drug Administration (FDA) hasreceived reports of death and life-threat-ening side effects in patients taking

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WHO Drug Information Vol 21, No. 1, 2007Safety and Efficacy Issues

methadone (Dolophine®). These haveoccurred in patients newly starting metha-done for pain control and patientsswitched to methadone after beingtreated for pain with other strong narcoticpain relievers. Methadone can causeslow or shallow breathing and dangerouschanges in heart beat that may not be feltby the patient.

Prescribing methadone is complex.Methadone should only be prescribed forpatients with moderate to severe painwhen their pain is not improved with othernon-narcotic pain relievers. Pain relieffrom a dose of methadone lasts about 4to 8 hours. However methadone stays inthe body much longer—from 8 to 59hours after it is taken. Methadone maybuild up in the body to a toxic level if it istaken too often, if the amount is too high,or if taken with certain other medicines orsupplements.

Reference: MedWatch, 27 November 2006.http://www.fda.gov/medwatch.

Levofloxacin: dysglycemiaand liver disorderCanada — Levofloxacin, marketed inCanada since 1997, is a broad-spectrumfluoroquinolone antibiotic that is indicatedfor the treatment of certain respiratorytract, skin and urinary tract bacterialinfections in adults (1). Dysglycemia (2–4)and liver disorders (5, 6) in associationwith levofloxacin have been reported inthe literature.

From 1997–2006, Health Canada re-ceived 22 domestic reports of dysgly-cemia suspected of being associated withlevofloxacin. Adverse reactions (ARs)included 1 report of diabetes mellitus, 2reports of hyperglycemia alone, 16 ofhypoglycemia alone and 3 of hyper-glycemia and hypoglycemia combined.

It is postulated that one of the mecha-nisms behind the development of

hypoglycemia with levofloxacin mayinvolve the inhibition of pancreatic a-cellpotassium channels. This inhibitionresults in the release of insulin, which inturn could result in hypoglycemia (7).Disturbances of blood glucose levels arelabelled in the product monograph (1).

With regards to liver disorders, between1997 and 2006, Health Canada received44 domestic reports of liver and biliarydisorders suspected of being associatedwith levofloxacin. Of these 44 cases,there were 5 cases of hepatic failure, 9 ofhepatitis and 1 of hepatorenal syndrome.Five of these 15 cases of liver disorderswere fatal. The remaining 29 reportsincluded ARs of increased liver enzymelevels, cholestatic hepatitis and jaundice.

The mechanisms leading to the develop-ment of liver disorders with levofloxacinare not well defined. Although drug-induced liver diseases can mimic allforms of acute and chronic hepatobiliarydiseases, a particular drug generally hasa characteristic clinical and pathologicalsignature and latency period when liverinjury occurs. Most drug-induced liverdisorders are similar to acute hepatitis,cholestasis, or mixed presentation (8).

Extracted from Canadian Adverse ReactionNewsletter, Volume 17(1), January 2007.

References

1. Levaquin (levofloxacin) [product mono-graph]. Toronto: Janssen-Ortho Inc.; 2006.

2. Park-Wyllie LY, Juurlink DN, Kopp A, et al.Outpatient gatifloxacin therapy and dys-glycemia in older adults. N Engl J Med2006;354(13):1352-61.

3. Friedrich LV, Dougherty R. Fatal hyp-oglycemia associated with levofloxacin.Pharmacotherapy 2004;24(12):1807-12.

4. Garon N, Cloutier I. Une hypoglycémieassociée à la lévofloxacine (Levaquin).Québec Pharmacie 2001;48(1):71-4.

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5. Papastavros T, Dolovich LR, Holbrook A, etal. Adverse events associated with pyrazina-mide and levofloxacin in the treatment oflatent multidrug-resistant tuberculosis. CMAJ2002;167(2):131-6.

6. Schwalm JD, Lee CH. Acute hepatitisassociated with oral levofloxacin therapy inhemodialysis. CMAJ 2003;168(7):847-8.

7. Saraya A, Yokokura M, Gonoi T, et al.Effects of fluoroquinolones on insulin secretionand â-cell ATP-sensitive K+ channels. Eur JPharmacol 2004;497(1): 111-7.

8. Kaplowitz N. Drug-induced liver injury. ClinInfect Dis 2004;38(Suppl 2):S44-8.

Domperidone: heart rateand rhythm disordersDomperidone is a peripheral dopamineantagonist structurally related to thebutyrophenones with antiemetic andgastroprokinetic properties (1). InCanada, domperidone (Motilium®) wasmarketed in 1985 but has not beenavailable since 2002. However, manygeneric brands are currently available.

Domperidone is indicated for the sympto-matic management of upper gastro-intestinal motility disorders associatedwith chronic and subacute gastritis anddiabetic gastroparesis. It may also beused to prevent gastrointestinal symp-toms associated with the use ofdopamine agonist antiparkinsonianagents (1). In addition, the off-labelclinical use of antidopaminergic drugs toinduce and maintain adequate lactation inbreast-feeding women has been sug-gested (2, 3).

Health Canada has received 9 domesticreports of heart rate and rhythm disorderssuspected of being associated with theuse of domperidone. Domperidone hasbeen reported in the medical literature toinduce QTc prolongation and Torsade dePointes (4, 5). Some non-drug-relatedfactors that may be associated with QTprolongation include female sex, ad-

vanced age, bradycardia, cardiac diseaseand electrolyte disturbance (6).

The main metabolic pathway of domperi-done is via cytochrome P450 3A4(CYP3A4). Studies of interactions haveshown marked CYP3A4 inhibition byketoconazole, which results in an in-creased plasma concentration of dom-peridone and a slightly prolonged QTinterval (7). Other examples of CYP3A4inhibitors include macrolide antibiotics,HIV protease inhibitors, selective serot-onin reuptake inhibitors (SSRIs) andgrapefruit juice (1, 6, 8). The combineduse of multiple drugs that prolong the QTcinterval can also increase the risk forTorsade de Pointes (9).

Attention should be paid to any druginteractions and clinical risk factors thatcould result in an exaggerated prolonga-tion of the QT interval. Health Canadacontinues to monitor ARs suspected ofbeing associated with the use ofdomperidone and is working with themanufacturers of generic domperidone toupdate their product monographs.

Extracted from Canadian Adverse ReactionNewsletter, Volume 17(1), January 2007.

References

1. Motilium (domperidone maleate tablets)[product monograph]. Toronto: Janssen-OrthoInc.; 2001.

2. Petraglia F, De Leo V, Sardelli S, et al.Domperidone in defective and insufficientlactation. Eur J Obstet Gynecol Reprod Biol1985;19(5):281-7.

3. Da Silva OP, Knoppert DC. Domperidone forlactating women. CMAJ 2004;171(7):725-6.

4. Straus SM, Sturkenboom MC, BleuminkGS, et al. Non-cardiac QTc-prolonging drugsand the risk of sudden cardiac death. EurHeart J 2005;26(19):2007-12.

5. Roden DM. Drug-induced prolongation ofthe QT interval. N Engl J Med 2004;350(10):1013-22.

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6. Adverse Drug Reactions Advisory Commit-tee (ADRAC). Medicines and QT prolongation.Aust Adv Drug Reactions Bull 2005;24(6):22.

7. Motilium (dompéridone). In: Le DictionnaireVidal. 82nd ed. Paris: Vidal; 2006.

8. Medicines Control Council. Interactionbetween ketoconazole and domperidone andthe risk of QT prolongation - important safetyinformation. S Afr Med J 2006;96(7):596.

9. Pham CP, de Feiter PW, van der Kuy PH, etal. Long QTc interval and torsade de pointescaused by fluconazole. Ann Pharmacother2006;40(7-8):1456-61.

Complications with useof bone cementCanada — Reports have been receivedrelating to serious complications, includ-ing death, associated with the use ofbone cement in vertebroplasty andkyphoplasty procedures.

Vertebroplasty and kyphoplasty arerelatively new procedures that are beingincreasingly used in the treatment ofpatients with vertebral compressionfractures. Advocates of both proceduresclaim to offer advantages over the con-servative therapy in immediate pain reliefand mechanical stabilization of thevertebral body. Vertebroplasty is per-formed by percutaneously injecting bonecement into the vertebral bodies underfluoroscopic and/or computed tomogra-phy guidance. Kyphoplasty includes anattempt to expand the vertebra with aninflatable balloon prior to the injection ofbone cement. Currently, only certainpolymethylmethacrylate (PMMA) bonecements are licensed by Health Canadafor use in these procedures.

Serious complications associated with theuse of the bone cements in these proce-dures have been reported. They include:

• Death due to sudden blood pressuredrop that may be related to the releaseof the PMMA monomer into the vascularsystem;

• Bone cement extravasation into thespinal canal leading to neurologicdeficit, with compression of the spinalcord and/or nerve roots;

• New fractures, usually of adjacent non-augmented vertebrae;

• Pulmonary embolism of the PMMA.

These adverse events can result inneurologic complications ranging fromminor motor and sensory loss to paraple-gia. Further intervention (surgical correc-tion, rehabilitation therapy) is required inmany cases. Deaths due to sudden bloodpressure drop, PMMA embolism andother factors related to pre-existingcardiovascular disease, have beenreported internationally. More of theseserious complications at this time appearto be related to the balloon kyphoplasty,possibly related to greater disruption ofthe vertebral body in attempting to regainvertebral body height.

In order to minimize the risk, HealthCanada recommends the following:

• A period of conservative therapy shouldbe considered in all patients havingacute osteoporotic vertebral bodyfractures.

• Only qualified physicians who arethoroughly trained in performingvertebroplasty and kyphoplasty shouldperform these procedures.

• Use only bone cements indicated forvertebroplasty and kyphoplasty proce-dures, and carefully review and followthe Instructions for Use.

• Monitor the procedures with high qualityimaging systems to allow recognition ofPMMA leakage.

• Closely monitor patients’ blood pressureduring and immediately after the proce-dures; multiple-level treatment mayincrease the risk of sudden drop inblood pressure related to the release of

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PMMA monomer into the circulation. Nomore than 3 vertebral level treatmentshould be done in a single visit.

Careful diagnosis and special precautionsshould be taken when the procedures areperformed in treating patients with spinaltumours that have eroded the posteriorvertebral body wall.

Traumatic burst fractures with disruptionof the posterior vertebral body should bea relative contraindication to vertebro-plasty or kyphoplasty.

References

1. Guglielmi G, Andreula C, Muto M, Gilula LA.Percutaneous vertebroplasty: indications,contraindications, technique, and complica-tions. Acta Radiol 2005 May;46(3):256-68.

2. Pflugmacher R, Kandziora F, Schroeder RJ,Melcher I, Hass NP, Klostermann CK. Percu-taneous balloon kyphoplasty in the treatmentof pathological vertebral body fracture anddeformity in multiple myeloma: a one-yearfollow-up. Acta Radiol. 2006 May;47(4):369-76.

3. Galibert P, Deramond H, Rosat P, Le GarsD. Preliminary note on the treatment ofvertebral angioma by percutaneous acrylicvertebroplasty. Neurochirurgie 1987;33(2):166-8.

4. Yeom JS, Kim WJ, Choy WS, Lee CK,Chang BS, Kang JW. Leakage of cement inpercutaneous transpedicular vertebroplasty forpainful osteoporotic compression fracture. JBone J Surg Br 2003 Jan;85(1):83-9.

5. Peh WC, Gilula LA. PercutaneousVertebroplasty for severe osteoporotic verte-bral body compression fractures. Radiology2002 April;223(1):121-6.

6. Lin EP, Ekholm S, Hiwatashi A, WestessonPL. Vertebroplasty: Cement leakage into thedisc increases the risk of new fracture ofadjacent vertebral body. AJNR Am JNeuroradiol 2004 Feb;25(2):175-80.

7. Hulme PA, Krebs J, Ferguson SJ,Berlemann U. Vertebroplasty andKyphoplasty: a systematic review of 69 clinicalstudies. Spine 2006 Aug;31(17):1983-2001.

8. Medeffect Advisory, 9 February 2007. http://www.hc-sc.gc.ca

Infant deaths sssociated withcough and cold medicationsUnited States of America — Cough andcold medications that contain nasaldecongestants, antihistamines, coughsuppressants, and expectorants com-monly are used alone or in combination inattempts to temporarily relieve symptomsof upper respiratory tract infection inchildren aged <2 years. However, during2004—2005, an estimated 1519 childrenaged <2 years were treated in US emer-gency departments for adverse events,including overdoses, associated withcough and cold medications.

In response to reports of infant deathsafter such events, CDC and the NationalAssociation of Medical Examiners(NAME) investigated deaths in U.S.infants aged <12 months associated withcough and cold medications. Deaths wereidentified in three infants aged <6 monthsin 2005, for which cough and cold medi-cations were determined by medicalexaminers or coroners to be the underly-ing cause.

The three infants ranged in age from 1 to6 months; two were male. All three infantshad what appeared to be high levels ofpseudoephedrine (a nasal decongestant)in postmortem blood samples. One infant(patient 2) had received both a prescrip-tion and an over-the-counter cough andcold combination medication at the sametime; both medications contained pseu-doephedrine. The other two infants alsohad received pseudoephedrine-contain-ing medications (one prescription and oneover the counter). Two of the infants(patients 1 and 2) had been administeredprescription medications containingcarbinoxamine (an antihistamine), al-though neither had detectable postmor-tem blood levels of carbinoxamine. Twoof the infants (patients 2 and 3) had

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detectable blood levels of dextro-methorphan (a cough suppressant) andacetaminophen (an antipyretic andanalgesic).

References

1. Food and Drug Administration. Cold, cough,allergy, bronchodilator, and antiasthmatic drugproducts for over-the-counter human use. 21CFR Part 341 (2006).

2. Gunn VL, Taha SH, Liebelt EL, Serwint JR.Toxicity of over-the-counter cough and coldmedications. Pediatrics 2001;108:E52.

3. Marinetti L, Lehman L, Casto B, Harshbar-ger K, Kubiczek P, Davis J. Over-the-countercold medications—postmortem findings ininfants and the relationship to cause of death.J Anal Toxicol 2005;29:738—43.

4. Boland DM, Rein J, Lew EO, Hearn WL.Fatal cold medication intoxication in an infant.J Anal Toxicol 2003;27:523—6.

5. Schroeder K, Fahey T. Over-the-countermedications for acute cough in children andadults in ambulatory settings. CochraneDatabase Syst Rev 2004(4):CD001831.

6. Smith MB, Feldman W. Over-the-countercold medications. A critical review of clinicaltrials between 1950 and 1991. JAMA1993;269: 2258—63.

7. Use of codeine- and dextromethorphan-containing cough remedies in children.American Academy of Pediatrics. Committeeon Drugs. Pediatrics 1997;99:918—20.

8. Irwin RS, Baumann MH, Bolser DC, et al.Diagnosis and management of cough execu-tive summary: ACCP evidence-based clinicalpractice guidelines. Chest 2006 Jan;129(1Suppl):1S—23S.

9. Food and Drug Administration. Carbino-xamine products; enforcement action dates.Federal Register 2006;71:33462.

10. Hanzlick R. National Association of Medi-cal Examiners Pediatric Toxicology (PedTox)Registry Report 3. Case submission summaryand data for acetaminophen, benzene, carb-oxyhemoglobin, dextro-methorphan, ethanol,phenobarbital, and pseudoephedrine. Am JForensic Med Pathol 1995;16:270—7.

11. Morbidity and Mortality Weekly [email protected].

Ranibizumab and strokeUnited States of America — The manu-facturer of ranibizumab injection(Lucentis®) has advised healthcareprofessionals of new safety information.

In an ongoing study (SAILOR) ofranibizumab delivered intravitreally topatients with neovascular (wet) age-related macular degeneration (AMD), aplanned interim safety analysis of Cohort1 showed a higher incidence of strokes inthe 0.5 mg dose group compared with the0.3 mg dose group. Patients with ahistory of prior stroke appeared to be athigher risk for a subsequent stroke.

Reference: Communication dated 24January 2007 from Genentech, Inc. onhttp://www.accessdata.fda.gov/scripts/medwatch/

Increased risk of fractures:antiepileptic medicinesAustralia — Reduced bone mineraldensity and subsequent increased risk offractures is documented in patients takingenzyme-inducing antiepileptic medicinessuch as phenytoin, phenobarbitone, andprimidone long-term (1). The risk is higherin women and increases with duration ofexposure. Patients with epilepsy mayhave many reasons for increased fracturerisk, e.g. seizures, lack of exposure tosunlight and reduced mobility. Abnormali-ties of bone metabolism are seen withincreased frequency in people takingantiepileptic medications. Biochemicalabnormalities include: hypocalcemia,hypophosphatemia, reduced serum levelsof biologically active vitamin D metabo-lites, and hyperparathyroidism. Boneturnover is also accelerated (1).

Medicines which induce cytochrome-P450 enzymes are thought to increasethe metabolism of vitamin D

3, thus lead-

15


ing to vitamin D deficiency or insufficiencyand a reduction in bone mineral density. Arecent case control study noted a statisti-cally significant reduction in bone mineraldensity in women aged over 40 yearstaking enzyme-inducing antiepilepticmedicines for at least 2 years, but it wasa small study and could not distinguishbetween the effects of individualantiepileptic medicines (2).

ADRAC has received relatively fewreports of reduced bone mineral densityin association with antiepileptic medi-cines. This may reflect a low level ofawareness of this important adverseeffect and the delayed nature of theevents, often occurring years after com-mencement of medication.

Patients taking antiepileptic medicineslong-term should be advised to have safebut adequate sun exposure, performweight-bearing exercise and avoid otherrisk factors for reduced bone mineraldensity such as alcohol and smoking. Insome cases periodic monitoring of bonemineral density may be appropriate anduse of supplemental calcium and vitaminD should be considered.

Extracted from Australian Adverse DrugReactions Bulletin, Volume 26, Number 1,February 2007.

References

1. Pack AM, Morrell MJ. Epilepsy and bonehealth in adults. Epilepsy & Behaviour 2004;5(2); S24-S29.

Spontaneous monitoring systems are useful in detecting signals of relatively rare, serious and unexpected adversedrug reactions. A signal is defined as "reported information on a possible causal relationship between an adverse eventand a drug, the relationship being unknown or incompletely documented previously. Usually, more than a single reportis required to generate a signal, depending upon the seriousness of the event and the quality of the information". Allsignals must be validated before any regulatory decision can be made.

2. Petty, SJ et al. Effect of antiepilepticmedication on bone mineral measures.Neurology 2005; 65:1358-1365.

Vasovist® and nephrogenicsystemic fibrosisEuropean Union — The Pharmacovigi-lance Working Party (PhVWP) hasdiscussed the issue of nephrogenicsystemic fibrosis (NSF) associated withgadolinium-containing contrast agents formagnetic resonance imaging (MRI).

Nephrogenic systemic fibrosis is a rare,debilitating and sometimes fatal condition,that only occurs in patients with severerenal impairment.

The CHMP is not aware of reports of NSFwith Vasovist® which is centrally author-ized and currently marketed in 13 Euro-pean Union countries, but has requesteda warning to be added to the labelling onthe occurrence of NSF in patients withsevere renal impairment. Productsreviewed were gadodiamide (Omniscan):gadobenic acid (Multihance®), gadobutrol(Gadovist®), gadofosveset (Vasovist®),gadopentetic acid (Magnevist®), gado-teric acid (Artirem®, Dotirem®),gadteridol (Prohance®) and gadoxeticacid (Primovist®).

This subject will be discussed further atthe February 2007 CHMP meeting.

Reference: EMEA Public Statement,EMEA/49741/2007. 7 February 2007.http://www.emea.europa.eu

16


Access to Medicines

On page 18 of this issue of WHO DrugInformation, Dr Jack Jagwe describeshow action by Hospice Africa Uganda(HAU) has made a dramatic difference tothe lives of people in his country sufferingfrom pain.

WHO estimates that annually over 60million people are adversely affected bylack of access to effective pain medicinescontrolled within the United NationsSingle Convention on Narcotic Drugs(1961) and the United Nations Conven-tion on Psychotropic Substances (1971).These two treaties provide the legal basisfor the international prevention of drugabuse, together with the United NationsConvention against Illicit Traffic in Nar-cotic Drugs and Psychotropic Substances(1988) (1). For almost 50 years, the focushas been on prevention of abuse, but thishas led to overly strict rules or inappropri-ate implementation of the internationaldrug control treaties in many countries.As a result, the medical use of controlledsubstances has been hampered and insome cases prohibited. Severe under-treatment is reported in more than 150countries, both developing and industrial-ized, involving about 80% of the world’spopulation. A balance therefore needs tobe sought between medical need andregulatory requirements.

By not being able to use these sub-stances on a regular basis, physiciansbecame less and less experienced inprescribing pain medication. Pain patientscan live for very long periods when usingthe correct dosage of opioids and there isno proof of undue shortening of life.Conversely, freeing patients of pain

prolongs the quality, usefulness andextent of their lives. As proposed in theWHO Guideline on Cancer Pain Relief,(2) pain medication can be effectivelyevaluated and dosed as part of a PainLadder as follows.

Step 1: (mild pain) non-opioid analgesics(e.g. paracetamol, NSAIDS), to which ifnecessary an adjuvant can be added.When a non-opioid no longer adequatelycontrols the pain, an opioid analgesicshould be added.

Step 2: (mild to moderate pain) weakacting opioid analgesics (e.g. codeine), towhich non-opioid analgesics and adju-vants can be added if the pain is stillpersisting or increasing.

Step 3: (moderate to severe pain) strongacting opioids, to which non-opioidanalgesics and adjuvants can be added ifnecessary.

If the pain is increasing, the dosage of theopioid should be increased in steps untilthe patient is free of pain. The effectiveanalgesic dose of morphine will varyconsiderably and ranges from as little as5 mg to more than 1000 mg every fourhours. The effective dose varies becauseof individual variations in systemic bio-availability, so that the correct dose is thedose that works.

The WHO Model List of Essential Medi-cines includes opioids and analgesics (3)and supports their use within the frame-work of human rights and health, that is“the Right of everyone to enjoy thehighest attainable standards of physical

The challenges of ensuring pain medication

17


and mental health” (4). In 2005, WHOwas urged to develop the Access toControlled Medications Programme inconsultation with the International Narcot-ics Control Board (INCB). The Pro-gramme sets out to improve legitimatemedical access to all medications control-led under the drug conventions. Lack ofaccess to controlled medicines does notonly affect low-income countries, butmany middle- and high-income countriesas well. Countries willing to improveaccess can follow the advice provided inthe WHO publication Achieving Balancein National Opioids Control Policies,Guidelines for Assessment available onthe internet in 22 languages (5).

As proposed by the World Health Assem-bly, it is the responsibility of governmentsto make every effort to bring pain medica-tions within the reach of those who needthem. Every year 6 million people diefrom cancer without sufficient analgesiaand often without any treatment for theirpain. About half of all end stage AIDSpatients suffer from severe pain. Then,there are many people with acute severepain from injuries (e.g. car accidents,victims of war), myocardial infarction andchronic pain patients. Regulations forobtaining pain medicines have becomemore and more stringent amid concernsfor prevention of drug abuse whichoverride the legitimate medical needs ofpatients. However, evidence shows thatthe majority of narcotic and psychotropicsubstances reach drug abusers throughillicit trade rather than pharmacy chan-nels.

Additionally, misconceptions have spreadbased on the unjustified fear that opioidmedication may cause dependence ordeath in patients. The mere presence ofphysical dependence on opioids pre-scribed for pain control does not, of itself,constitute drug dependence syndrome or“addiction”. In fact, becoming dependentwhen using a controlled medicine, after

prescription for a legitimate medicalpurpose, is rare. If it does occur, it can betreated in the same way as any otherside-effect.

Ephedrine and ergometrine are essentialmedicines used in obstetrics and deliverythat can be life saving. Although they arenot abused as drugs, they can be used tosynthesize other drug substances — andfor that reason they are controlled underthe 1988 Convention. Unfortunately, it isreported that these medicines are oftennot available when most needed, thuscontributing to the 250 000 maternaldeaths annually.

Dr Jagwe modestly describes what hisorganization has achieved. However, theimportance of his work cannot be under-estimated, either for Ugandans directly, orfor the many other countries that may usethe work carried out in Uganda as amodel. The joint efforts of HospiceUganda Africa and the Ugandan Ministryof Health to provide regulations andorganize pain care and medication insuch a way that it reaches many hastaken a number of years of enduringeffort. The innovation of nurse training tocarry out the task of prescribing andadministration was an important achieve-ment in finding a solution to overcome theshortage of physicians. A similar innova-tion has been implemented in the state ofKerala, India, where the shortage ofpharmacy assistants was overcome bylaymen volunteering to dispense themorphine tablets to the patient at home.

References

1. United Nations Single Convention onNarcotic Drugs (1961), United NationsConvention on Psychotropic Substances(1971). United Nations Convention against theIllicit Traffic in Narcotic Drugs and Psycho-tropic Substances (1988). http:www.who.int/medicines

Access to Medicines

18


2. World Health Organization. Cancer PainRelief with a Guide to Opioid Availability. 2nd.ed. Geneva, 1996.

3. World Health Organization. Selection andUse of Essential Medicines. Model List ofEssential Medicines (Updated March 2005).Technical Report Series, (in press).

Dr Jack G. M. Jagwe, FRCP, FRCP (Edin) is Senior Advisor, National Policy, Drugs andAdvocacy, to Hospice Africa Uganda, Kampala. e-mail: [email protected].

Early beginningsof palliative careWith support from friends in the UnitedKingdom, Dr Anne Merriman introducedpalliative care to Uganda in 1993 basedon methods of dealing with severe painoriginally devised at St. Christopher’sHospice, London. Her vision was torelieve the suffering of people with seri-ous illnesses such as cancer. Relying onWHO Foundation measures to initiate apalliative care programme and withpolitical support from the Government, DrMerriman was able to advocate availabil-ity of oral morphine.

As a consequence, oral morphine wasregistered by the National Drug Authority(NDA) for the first time in 1993 andpowdered morphine sulphate was im-ported by the Government. The Pro-gramme embarked on education, trainingand offering a service to the people ofUganda. Initially, it addressed cases ofsevere pain arising from cancer. Later, itwas called upon to help patients withAIDS and cancer arising from HIV infec-tion through adaptation of measures usedfor cancer pain management. HospiceAfrica Uganda (HAU), in Kampala, is nowan outstanding health centre offeringclinical management for severe pain andtraining of health professionals in this newspecialty of palliative medicine.

Progress and organizationPalliative care is an interdisciplinaryspecialty addressing a patient with a life-limiting illness, such as cancer or HIV/AIDS. Such health conditions havethrown Uganda into a public healthturmoil. HAU follows a holistic approachto the problem of severe pain, andinterventions include supportive andhome care. HAU collaborates with doc-tors, nurses, pharmacists, policy makersand health institutions to reach out to asmany suffering Ugandans as possible toimprove the quality of their life. They alsonetwork with many nongovernmentalorganizations operating in Uganda sinceHIV/AIDS was first publicly declared ahealth problem by the Government in1986, and collabate with treatmentorganizations, income generating organi-zations, organizations dealing with legalissues and orphanages.

A clinical service is offered and covers aradius of 20 km from the centre of Kam-pala, reaching into the poor suburbs.HAU collaborates with the main NationalReferral and Teaching Mulago Hospitaland several other hospitals in the city.Although it runs an outpatient service forthose who can come to Makindye, manypatients receive regular visits at theirhomes.

Import and safe distribution of oral morphinefor pain relief in Uganda

4. World Health Organization. Constitution.Geneva, 1948.

5. World Health Organization. AchievingBalance in National Opioids Control Policies,Guidelines for Assessment. Pain and PolicyStudies Group. Geneva, 2000.

Access to Medicines

19


Since HAU started, it has trained healthprofessionals in the art and science ofpalliative care. It has given lectures atmedical schools situated in MakerereUniversity, Kampala and Mbarara Univer-sity of Science and Technology. In orderto meet the needs of teaching and re-search, HAU has opened a branchMbarara Mobile Hospice near the Univer-sity of Science and Technology in thewest and the Little Hospice Hoima in arural underserved district of Uganda toevaluate in what ways palliative careservices can be effectively extended torural areas.

Changing attitudes and behaviourWith the increasing number of trainedhealth professionals, palliative care isextending to more districts of Uganda.Major progress has been made not onlyin initiating palliative care but breaking themyths, fears and misconceptions aboutthe use of morphine for severe pain. TheWHO 3-step ladder of analgesia hasbeen fully utilized to underscore manage-ment of severe pain by health profession-als. HAU has incorporated the statements

made by WHO over the years into itscancer pain relief services. For example,WHO stated in 1986 that morphine is thedrug of choice for severe pain and thatfreedom from cancer pain is a right ofevery cancer patient, with access to paintherapy a measure of respect for thisright. WHO has advised that for themajority of patients with cancer, a realistictreatment regimen must include painrelief and palliative care.

HAU has also noted and used pro-nouncements from the internationalNarcotics Control Board which has statedthat in many countries consumption ofopioid analgesics remain extremely low incomparison to medical needs, and thatgovernments have yet to address thisimportant deficit. Presently, oral morphineis widely accepted in Uganda as the drugof choice for severe pain. HAU teachesthat the feared myth of addiction is veryrare when morphine is used for theindication of severe pain. But HAU alsocautions that addiction may occur whenmorphine is used for non-medical pur-poses.

Model for making simple affordable morphine solution: Peter in the pharmacy

Access to Medicines

20


Extending involvementand cooperationHAU has been invited to help othercountries wishing to introduce palliativecare in their countries. Advocacy hasbeen carried out in a number of sub-Saharan countries and palliative care istaking root in Ghana, Malawi, Nigeria,Republic of Tanzania, Sierra Leone andZambia.

HAU has participated in a regionalworkshop for the Eastern Africa Region toadvocate for use of opioid analgesics. Amember of HAU was invited to present apaper jointly with WHO and the Pain andPolicy Studies Group (PPSG) at the 12th

ICDRA held in Seoul, Korea in 2006 andat the UICC Cancer Congress in Wash-ington DC, USA, to discuss how, inworking with Government and nursingpersonnel at HAU it has proved possibleto take pain relief to the periphery inUganda.

The prospects for extending palliativecare programmes currently look good.HAU personnel have developed interna-tional collaboration on morphine use withsuch organizations as the Pain and PolicyStudy Group in Madison, Wisconsin,USA. Recently, a member of HAU partici-pated in an International Expert Collabo-ration workshop to help representativesfrom Colombia, Nigeria, Panama, Serbia,Sierra Leone, Uganda, and Vietnam todevelop action plans for the introductionof palliative care and to make opioidsavailable for use. HAU has also linked upwith other organizations wishing to helpsub-Saharan Africa to develop palliativecare programmes. These include NationalHospice and Palliative Care Organizationof USA (NHPCO), Foundation for Hos-pices in Subsaharan Africa (FHSSA),Medicines Policy and Standards Depart-ment at WHO, Open Society Institute(OSI), and USAID.

Defining achievementsThrough advocacy to political leaders,Ministry of Health officials, policy makers,health professionals and the public, theHAU programme has facilitated access tooral morphine for cancer and AIDSpatients, procured by the Government ofUganda and provided without cost to thepatient. The programme has been able toinfluence the Government to accept andincorporate palliative care into the HealthSector Support Programme as an essen-tial service offered in all governmentalhealth institutions.

Despite limited resources and manyobstacles, HAU has managed to trainnurses and clinical officers to the level ofspecialized palliative care professionalscertified by the Ministry of Health who areauthorized to prescribe morphine andother palliative care drugs. This is a majorachievement in sub-Saharan Africa!Planning and initiation of the above threeactivities should be considered theminimum recommended requirement forother countries in Africa to alleviate thesuffering of people afflicted with cancer,HIV/AIDS and other life-limiting diseases.

The epidemic of pain now affecting Africaand extending to other countries of theworld due to cancer and HIV/AIDS can beaddressed by simple management ofpalliative care and application of theWHO 3-step ladder of Analgesia. To-gether with the introduction of palliativecare, advocacy, education and sensitiza-tion can demystify the fear of addictionattributed to morphine. In this way, thequality of life of patients with devastatingillnesses can be improved.

“Change is a law of life: And those wholook only to the past or present are

certain to miss the future”.President J. F. Kennedy.

Access to Medicines

21


Topics of Current Interest

Developments in biologicalquality, safety and efficacyBiological medical products such asvaccines, blood products, biotherapeuticsand associated diagnostics save lives,reduce suffering and improve health, butonly if products and technologies are ofgood quality, safe, effective, available,affordable and properly used. In manycountries, not all of these conditions aremet. This may be due to:

• Lack of awareness of the potentialbenefits in medical outcomes andeconomic savings.

• Lack of political will and public invest-ment.

• Commercial and political pressure,including donor pressure.

• Fragmented financing and supplystrategies.

WHO is working to promote productionand use of biological medicines of as-sured quality in national health systems.The aim of the WHO Expert Committeeon Biological Standardization (ECBS) isto establish global norms and standardsthat help define products of assuredquality.

Highlights of the 2006 ECBS meeting

• A new written standard was establishedfor human papillomavirus vaccines.

This new vaccine has potential to preventmorbidity and mortality due to certaintypes of cervical cancer. The new WHOstandard paves the way for prequalifica-tion of the vaccine.

• A new written standard for meningo-coccal type A conjugate vaccine wasadopted.

Although group A isolates were at onetime a common cause of meningococcaldisease worldwide, they are now princi-pally responsible for recurrent epidemicsin the “meningitis belt” countries of sub-Saharan Africa. If a major epidemicoccurs, the availability of WHO guidancewill assist Member States in the evalua-tion and licensure of candidate vaccinesthat are currently under development.

• A new written standard that definesregulatory expectations for the evalua-tion of the stability of vaccines wasestablished.

This standard opens a new regulatorypathway for vaccine stability studies. Topromote and gain experience in theevaluation of vaccine stability, a series ofin-country workshops will be conducted.

A new project to develop strategies tomonitor the implementation of WHOnorms and standards in Member Stateswas endorsed by the ECBS. Networkingwith national regulatory authorities andWHO Regional Offices will be establishedto survey the implementation of WHOwritten and measurement standards incountries. Results from the survey willassist the committee in developing orrevising WHO standards.

Strategic initiatives for quality, safety andefficacy of blood products and quality ofrelated in vitro diagnostic devices duringthe next five to seven years were en-dorsed.

22


Biological substances: International standards andreference reagents

At its meeting in October 2006, the WHO Expert Committee on Biological Standardizationmade the following additions to the previous list. (These substances are held and distrib-uted by the International Laboratory for Biological Standards, National Institute for Biologi-cal Standards and Control, Potters Bar, Herts., EN6 3QG, England.)

Preparation Activity Status

Antigens and related substances

Pertussis vaccine (whole cell) 40 IU per ampoule Fourth International Standard

Poliovirus, Sabin, type 3 No assigned value WHO(SO+2)/III Neuro-virulence Reference Preparation

Smallpox vaccine 7.3 log10 chorioallantoic Secondmembrane pock forming units/ml International

after reconstitution in 0.25ml sterile water Standard

Antisera

Anti-measles (plasma) 3 IU per ampoule of Thirdneutralizing antibody International Standard

Anti-poliovirus 11, 32 and 3 IU per vial of Thirdserum types, 1,2 & 3 neutralizing antibody to polio- International

virus types 1, 2 and 3 respectively Standard

Blood products and related substances

Alpha-1-antitrypsin, 243 nmoles (12.4 mg) active First Internationalplasma alpha-1-antitrypsin per ampoule Standard

Blood coagulation Factor 0.93 IU/ampoule of FXIII First InternationalXIII, plasma, human antigen Standard

Protein C, plasma, 0.85 IU/ampoule of protein C Secondhuman functional activity; and 0.84 IU/ International

ampoule of protein C antigen Standard

Protein S, plasma, 0.83 IU/ampoule total protein S Secondhuman antigen; 0.81 IU/ampoule free protein International

protein S antigen; and 0.77 IU/ampoule Standardprotein S functional activity


23


A WHO project on “Animal-derived sera”was endorsed. Animal-derived seraare crucial in the treatment or preventionof a number of human and veterinarydiseases. These include snake bites andother venomous bites and stings, rabies,botulism, tetanus, gas gangrene, diphthe-ria, digoxin and other poisoning. Thediagnosis, treatment and prevention ofbioterrorism agents may also requirespecific animal-derived sera.

A total of 16 new or replacement globalreference preparations for the control ofvaccines, biotherapeutics, blood productsand associated in vitro diagnostic medicaldevices was established (see table).Among them, reference materials for the

control of whole cell pertussis, smallpoxand polio vaccines and for the validationof hepatitis B, Plasmodium falciparumand anti-HIV diagnostic tests. These arethe primary calibrants against whichregional or national measurement stand-ards are benchmarked.

A list of International Standards andReference Reagents for biological sub-stances was published in the WHOTechnical Report Series, No. 897, 2000(Annex 4) and an updated version isavailable on the Internet at http://www.who.int/biologicals.

Reference: Biologicals: http://www.who.int/biologicals/en/


Preparation Activity Status

Cytokines, growth factors and endocrinological substances

Thyroid-stimulating hormone, 9.5 IU/ampoule Firsthuman, recombinant, for bioassay International

Standard

Interleukin 17 10,000 U/ampoule Reference reagent

Interleukin 18 10,000 U/ampoule Reference reagent

Diagnostic reagents

Hepatitis B DNA, for 5x10 5 IU/vial Secondnucleic acid amplification Internationaltest assays Standard

Plasmodium falciparum, in 5x10 8IU/vial Firstwhole blood, for nucleic acid Internationalamplification test assays Standard

Anti-human immunodeficiency No assigned unitage First Internationalvirus tests Reference Panel

Anti-human platelet antigen No assigned activity; however a First3a, for minimum potency 1 in 8 dilution should define the Internationalestimations minimum potency specification Standard

for anti-HPA-3a detection

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WHO Programme on GoodGovernance for MedicinesIn response to the current situation, andguided by its Medicines Strategy (1),WHO has initiated the Good Governancefor Medicines Programme. Established inlate 2004, the Programme’s overall goalis to curb corruption in medicines pro-curement and regulation through applica-tion of transparent procedures and thepromotion of ethical practices by healthprofessionals and others involved in thehandling of pharmaceutical products.

WHO recognizes that corruption is animmense, complex problem, and one thatis difficult to tackle. The World Bankidentifies it as the single greatest obstacleto economic and social development. TheWHO Programme is promoting action bymaking public health colleagues inministries of health and national medi-cines regulatory authorities more awareof the negative consequences of corruptpractices.

Good governance is particularly relevantto the pharmaceutical sector because ofthe impact on the health, future andwellbeing of populations. Corrupt prac-tices can impact the pharmaceuticalsector in at least three ways:

Health impactWastage of public resources reducesgovernment capacity to provide access to

good-quality essential medicines, whilethe risk of unsafe medical products on themarket increases due to counterfeitingand/or to bribery of officials.

Economic impactPharmaceutical expenditure in low-income countries may represent up to50% of total health care costs, whichmeans that corrupt pharmaceuticalpractices are extremely detrimental tonational health budgets and to house-holds paying out-of-pocket expenses formedicines, which will then be overpricedor ineffective.

Government image and trust impactInefficiency and lack of transparency re-duce the credibility of public institutions,and erode public and donor confidence ingovernment capacity to deliver policy.

In addition, the donor community isproviding sizeable grants or contributionsof in-kind medicines for global publichealth problems such as high childmortality, the spread of infectious dis-eases and neglected diseases (e.g. theGlobal Fund to Fight AIDS, Tuberculosisand Malaria, the Bill & Melinda GatesFoundation, PEPFAR). However, corrup-tion within the public sector risks under-mining these efforts by misappropriatingsome of this vital aid. Ultimately, success-ful allocation and use of such funds willdepend on good governance at nationallevel.

Transparency in Medicines Management

The value of the global pharmaceutical market is estimated to be over US$ 500 bil-lion, making the pharmaceutical sector highly vulnerable to corruption and unethicalpractices. Transparency International estimates that, on average, 10 to 25% of publicprocurement spending in the health sector is lost to corruption. It also reports that insome countries up to two thirds of medicines supplies at hospitals are lost throughcorruption and fraud. Resources that could otherwise be used to buy medicines orrecruit much needed health professionals are wasted as a result of corruption, whichreduces the availability of essential medicines and can cause prolonged illness andeven deaths.


25


Need for coordinated application of twobasic approaches for impact

Tackling corruption in the pharmaceuticalsector requires a long-term strategy.Experience to date shows that strategiesaddressing corruption require the coordi-nated application of two basic ap-proaches:

1. A discipline-based approach, consist-ing generally of a legislative reformwhereby laws against corruption areestablished, procedures promotingtransparency and accountability are put inplace, with appropriate punitive conse-quences for violations. This top-downapproach attempts to deter corruptionpractices through the fear of punishment.

2. A value-based approach, that attemptsto increase institutional integrity throughpromotion moral values and ethicalprinciples. This bottom-up approachseeks to motivate public servants to actethically.

Neither approach alone is sufficient tohave significant impact.

Progress in implementing the GoodGovernance for Medicines ProgrammeThe Good Governance for MedicinesProgramme is designed and implementedas a bottom-up approach. Tools andpolicies are pilot tested and refined inlight of country experience. The Pro-gramme operates currently in eight Asia-Pacific countries and one Latin American.It is implemented through a three-stepapproach.

Phase I: National assessment oftransparency and potentialvulnerability to corruptionIn order to address the problem of corrup-tion in the pharmaceutical sector, it isnecessary to assess the level of transpar-ency and potential vulnerability to corrup-tion of key functions in medicines regula-

tion and procurement. The nationalassessment is carried out after govern-ment clearance, by independent nationalinvestigators and using the standardizedWHO assessment instrument (2). Thenational investigators collect informationthrough a combination of desk researchand semi-structured interviews, and theassessment focuses on five key functionsof the pharmaceutical sector, namelyregistration of medicines, control ofmedicine promotion, inspection of estab-lishments, selection of essential medi-cines, and procurement of medicines.

Phase II: Development of nationalethical infrastructureAssessing the level of transparency andthe potential vulnerability to corruption isnot an end in itself. It is rather the begin-ning of a process aimed at bringing long-lasting changes to promote good govern-ance practices among health profession-als in the public pharmaceutical sector.Once a national assessment has beencarried out and problems identified, WHOsuggests developing, through a consulta-tion process, a national ethical infrastruc-ture responding to the needs of individualcountries. The WHO Ethical Infrastructurefor Good Governance in the PublicPharmaceutical Sector (3) can serve asreference in developing the nationalethical infrastructure.

Phase III: Socializing the nationalethical infrastructureIt is very important to avoid a nationalethical infrastructure remaining justanother policy document developed by afew key actors at central level and notwidely applied. Socialization is the proc-ess by which an ethical framework andcode of conduct can be learnt, internal-ized, applied and promoted by a group ofkey actors within the pharmaceuticalsector of ministries of health, until theprocess becomes fully integrated into theinstitutional culture (4).


26


Stakeholder group meetingAbout 40 participants representingcountries involved in the Good Govern-ance for Medicines Programme, theWorld Bank, Transparency International,donors (DFID, Australian government),and the Global Fund attended a 2-daymeeting, 30–31 October 2006.

Promoting transparency and tacklingcorruption in medicines regulation andprocurement is without doubt a priorityand an essential component of develop-ment efforts aimed at increasing accessto essential medicines. The discussionshelped to increase awareness of theimpact of corruption in the pharmaceuticalsector and to generate a clearer vision ofwhat actions are needed on the part ofdifferent stakeholders to promote goodgovernance. The recommendations ofthis meeting included (1) endorsement ofthe current strategic lines of action forWHO’s work on Good Governance forMedicines as described above, and (2)the establishment of an internationalgroup of experts to guide WHO’s work onthis important subject.

Looking aheadThe focus is now on consolidating on-going efforts in the countries which arealready part of the programme, and onadding new ones, specially in regionssuch as Africa, the Eastern Mediterra-

nean, Latin America and Europe. Selec-tion of countries and activities will bebased upon requests from governments,in collaboration with WHO RegionalOffices.

At the global level, lessons learnt incountries will continue to be used inrevising and adjusting the WHO tools andpolicy documents for this Programme.Efforts will also focus on maintaining themomentum created among partnersduring the October Stakeholder Meeting,as well as raising additional resources forthe expansion and further development ofthe Good Governance for MedicinesProgramme.

References

1. WHO Medicines Strategy 2004-2007:countries at the core.

2. Measuring transparency to improve goodgovernance in the public pharmaceuticalsector. Working document, January 2007, athttp:www.who.int/medicines

3. WHO ethical infrastructure for good govern-ance in the public pharmaceutical sector.Working document, November 2006.

4. WHO guidelines for socializing the ethicalinfrastructure. In preparation.

5. http://www.who.int/medicines/areas/policy/goodgovernance/home/en/index.html


27


Rational Use of Medicine

Influencing healthprofessionals forbetter health outcomesEffectiveness of drug therapy dependsto a great extent on patient adherence toprescribed medication. However, thereis abundant evidence [1] that patientadherence may sometimes average nomore than 50% in long-term treatment.Non-compliance is a multifactorial

problem and sub-compliance with the fullprescribed dose is a major concern [4].Enhancing adherence leads to improvedtherapy and better public health outcomes[5]. According to US estimates, [6,7] thecost of drug related morbidity and mortal-ity is often attributable to low adherenceand, in these circumstances, up to two-thirds of therapy failures are consideredas preventable [8].

* Kristin Krigsman, NEPI Foundation, Stockholm, Pia Bastholm Rahmner, Department of DrugManagement and Informatics, Stockholm County Council, Rickard Fuchs, Inger Nordström-Torpenberg, Sune Pettersson, and J. Lars G. Nilsson, NEPI Foundation, Stockholm. InfluencingHealth Professionals for Better Concordance and Adherence. Correspondence: to Professor J.Lars G. Nilsson, e-mail: [email protected]

Poor adherence to long-term therapies severely compromises the effectiveness oftreatment, making this a critical issue in public health both from the perspective ofimproved quality of life and health economics. Increasing the effectiveness of ad-herence can have an important impact on health outcomes, and interventions couldprovide significant positive return on investment through primary prevention of riskfactors and secondary prevention of adverse health (1).

However, studies have shown that patient adherence to long-term medication maybe as low as 50% and interventions aimed at improving adherence have not as yetbeen particularly successful. A three year national information project was carriedout in a primary health care setting in Sweden.* The aim was to create understand-ing among patients and health care providers of the need for adherence throughuse of concordance. Concordance is a fundamentally different approach to compli-ance or adherence: it focuses on the consultation process rather than on specificpatient behaviour, and it has an underlying ethos of a shared approach to decision-making (2) and agreement between a patient and healthcare professional aboutwhether, when and how medicines are to be taken (3).

By the end of the project, target groups had been acquainted with the project mes-sage and, in particular, doctors accepted that the rate of adherence in long-termtreatment was low. Although prescribers overall consider adherence as a responsi-bility of the patient, they also recognize that their actions can strongly influencebetter patient behaviour.

Use of concordance to improve patient adherence

28


A Cochrane review [5] indicates thatactivities to improve short-term adher-ence can be relatively successful,whereas methods to improve long-termadherence are not so effective. Sinceevidence for a solution is scant, it hasbeen proposed that activities to improveadherence need to continue for as longas medication is necessary [5].

However, several reports [2,3, 9–12] nowindicate that creation of concordancebetween patients and care givers is apromising alternative to such interven-tions. Concordance is presented as anew relationship between patients anddoctors, nurses and pharmacists, i.e., atherapeutic alliance that recognizes thehealth beliefs of both patients and profes-sionals, while at the same time aimed atavoiding misunderstandings and miscon-ceptions.

Interventions for improved adherencehave been generally patient rather thanprofessionally directed [5]. No reportshave been identified in the literatureconcerning interventions directed tohealth professionals based on the con-cept of concordance, although oneunpublished project has been conductedin the United Kingdom (3).

The projectThe project on Influencing health profes-sionals for better concordance andadherence was conducted to:

1. Raise awareness among doctors,nurses and pharmacists of the reasonsdriving low adherence in patients on long-term medication, and

2. Show how concordance can lead toimproved adherence.

An outline of the project was formulatedby a core group of three doctors, threenurses and three pharmacists and pub-lished in 2001 [13]. To facilitate thecreation of concordance the followingthree objectives were identified.

• See the patient as a partner — eachpatient should share responsibility andactively participate in the treatmentregimen.

• When prescribing or monitoring drugtreatment – identify the patient’s experi-ence and attitude to the disease and itstreatment, and ascertain that the patientunderstands how and why prescribedmedicines should be used.

• Consider each health profession (doc-tors, nurses and pharmacists) as apartnership – develop a mutual under-standing of each other’s functions, andcollaborate and use each other’scompetence to improve active patientparticipation in the treatment.

It is claimed that improved adherence canbe achieved when these three objectivesare applied at each patient encounter[2,3,9–12].

The study target group comprised almost30 000 individuals. Approximately 8000doctors in general practice and internalmedicine represented a group of highprescribers issuing 60–70% of all pre-scriptions to ambulatory patients inSweden. Additionally, almost 20 000district nurses and nurses working withoutpatients and in nursing homes and100 pharmacists specializing in providinginformation completed the group.

Communication is all importantA doctor, a nurse and a pharmacist (theABLA Group) were hired full time for thethree year project 2003–2005. Theproject also had a steering committeewith members from the national healthand pharmacy administrations and fromprofessional associations for doctors,nurses and pharmacists. The objectivewas to disseminate, clarify and discussthe “ABLA message”, i.e., that adherencein long-term medication is low but im-proved adherence can be achievedthrough concordance.


29


The ABLA Group used all availablechannels of communication to gainattention, including news media andhealth professional outlets. ABLA Groupmembers were interviewed several timeson TV and radio, and in newspapers andmagazines. A website was set up toprovide information (http://www.abla.se).Two films were also produced, a shortvideo (4 minutes) for patients and alonger educational video (20 minutes) forhealth care personnel. The short videowas shown extensively in customer areasof Swedish pharmacies.

Printed materials were also developed,including a pamphlet presenting scientificevidence to support action, and a text-book on concordance and adherenceintended for use in teaching and continu-ing education [14]. Numerous lectures,seminars and discussions with individualstook place and local, national and interna-tional conferences for health profession-als were organized. Meetings were heldwith the faculties of medicine, nursing andpharmacy to introduce concordance andadherence as part of the student curricu-lum.

In Sweden, regional government countycouncils are responsible for managinghealth care. Support for the project wasobtained from drug and therapeuticscommittees [15] in each of the 21 countycouncils, and local projects were set upearly to identify adherence problems.

First year progressAfter one year in operation, projectinformation dissemination was measuredbased on:

• number of participants in lectures andseminars organized by the ABLA Group;

• number of recipients of printed material;and

• estimated number of listeners to TV andradio interviews.

This gave an estimation of the extent towhich target audiences had heard of orotherwise been acquainted with the ABLAmessage

Within the study, patient refill adherencewas evaluated based on an analysis ofrepeat prescriptions [16]. Such data hadbeen unavailable before the project, sothe study was important in determining ifthe project had affected patient refilladherence. Randomly selected pharma-cies collected data on prescriptionsbetween March 2003 and October 2005.Satisfactory refill adherence was definedas dispensed refills covering 80–120% ofthe prescribed treatment time. A diver-gence from prescribed treatment timebelow 20% would indicate undersupplyand treatment gaps and above 20%,oversupply or drug stockpiling [16]. (SeeTable 1 on page 30).

Before the end of the project, a question-naire containing five statements regardingdrug use and adherence was distributedto 1000 general practitioners (GPs) at183 health centres within Stockholmcounty, which has a population of about1.9 million or 21% of the population ofSweden. (See Table 2 on page 30).

At the end of the first project year, themessage had reached at least 5600doctors (70% of the target group), 12 400nurses (62%) and more than 1000pharmacists (100%). It was concludedthat the ABLA message had successfullyreached almost all of the target groups.

It was observed that some GPs haddifficulty accepting that up to 50% of theirpatients did not adhere to long-termmedication regimens. Individual doctorsoften claimed that the low level of adher-ence did not apply to their patients.However, the level of disbelief was notformally measured. On the other hand,nurses and pharmacists did not appear todoubt the low adherence levels.


30


The ABLA Group held meetings with drugtherapeutics committees in Sweden.These were encouraged to start localprojects to assess and solve local adher-ence problems although, by the end ofthe ABLA Project, only a few of thecommittees had set this in motion.

Refill adherence of all types of drugsused in long-term treatments was meas-ured early and late in the project (Table1). In March 2003, 19 randomly selectedpharmacies located in different parts ofSweden collected 6634 copies of refillprescriptions and in November 2005, 15of the same pharmacies collected 5281copies. Refill adherence was determinedas described in Table 1 [16]. Levels of

satisfactory refill adherence, undersupplyand oversupply were very similar be-tween data sets. This was also the casefor adherence levels of individual druggroups.

A 42% response rate was recorded fromthe questionnaire distributed to 1000 GPsin Stockholm County (Table 2). In conclu-sion, GPs recognized that their behaviourdetermines patient adherence, but theyalso consider that adherence is theresponsibility of the patients.

DiscussionLiterature studies undertaken prior to theABLA Project identified non-adherence tolong-term medication as one of the most

.Statement in the survey % of GPs who agree

completely or partly

1. When I have prescribed a medicine it is the patient’s responsibility to use it in a correct way. 85

2. It is my behavior in relation to the patient that determines if the patient will use the medicine as prescribed. 91

3. Drugs are my most important tool in the treatment of patients. 36

4. It is easy to find out if my patients have been adherent. 15

5. I have the tools I need to follow up patient use of drugs. 19

Table 2. Survey on GP opinions: adherence and drug use

March 2003 October 2005

Men % Women % Men % Women %

Undersupply 26 25 25 28

Satisfactoryrefill adherence 56 56 56 55

Oversupply 18 19 20 17

Table 1. Refill adherence during the project


31


important drug therapy problems [13],and evidence for action has been re-viewed in a recent WHO report [1].Additionally, it is advocated [2,3,9–13]that shared decision-making in theconsultation process, i.e. concordance,improves adherence.

Because the ABLA Project was notprimarily designed or financed as aresearch project, some of the pursuedobjectives were difficult to measure. Also,during preparatory work, doctors, nursesand pharmacists often asked for adviceon how to create concordance, indicatingthat the concept was not always easy tograsp [9].

To make the concept more tangible, thethree stated objectives incorporate ideasof concordance as follows.

• See the patient as a partner — eachpatient should share responsibility andactively participate in the treatmentregimen.

Since it is the patient who ultimatelydecides whether or not to take theprescribed medication, the healthprovider has to take the patients’ opin-ion into consideration if the drugs are tobe properly used. If this objective isachieved at every patient encounter, apositive commitment and shared re-sponsibility for the treatment is created.The patient becomes an active partici-pant with shared responsibility for thetreatment regimen proposed during theconsultation.

• When prescribing or monitoring drugtreatment – identify the patient’s experi-ence and attitude to the disease and itstreatment, and ascertain that the patientunderstands how and why prescribedmedicines should be used.

If there is no two-way communicationduring consultation and/or if the patientsdo not know why the medicines have

been prescribed, there is no concord-ance and adherence will probably below. However, if this objective isachieved at every patient encounter,experience and knowledge of the careprovider is added to the experience andknowledge of the patient and concord-ance is possible.

• Consider each health profession (doc-tors, nurses and pharmacists) as apartnership – develop a mutual under-standing of each other’s functions, andcollaborate and use each other’scompetence to improve active patientparticipation in the treatment.

No professional group has all theanswers and solutions to problems thatpatients experience. It is often thepatient who is the messenger betweenmembers of the health professions withall the misunderstandings that this mayimply. A high degree of collaborationbetween professions is therefore ineveryone’s interest.

Estimations based on refill adherencefrom prescription records are claimed tobe the most reliable measure of adher-ence in large patient groups [17,18].Since no similar project had previouslybeen reported in the literature, a compari-son of the results could not be under-taken. Levels of refill adherence weresteady throughout the study duration,which may indicate that a 3-yeartimeframe is too short to accomplish achange in behaviour in health profession-als. However, measurement was impor-tant to illustrate the need for continuedefforts among health care workers.

ConclusionsIntroduction of the concept of concord-ance into Swedish primary health carewas slower than expected. At the end ofthe 3-year project, doctors recognizedthat adherence is low but still consideradherence as a responsibility of the


32


patient. None the less, they accepted thattheir behaviour was a major influence inshaping patient adherence.

References

1. World Health Organization. Adherence tolong-term therapies. Evidence for action.Geneva, 2003

2. Weiss M, Britten N. What is concordance?Pharm J 2003;271:493

3. Marinker M, Shaw J. Not to be taken asdirected. BMJ 2003;326:348–9

4. Col N, Fanale JE, Kronholm P. The role ofmedication noncompliance and adverse drugreactions in hospitalizations of the elderly.Arch Intern Med 150;1990:841–845

5. Haynes RB, Yao X, Degani A, Kriplani S,Garg A, McDonald HP. Interventions forenhancing medication adherence. TheCochrane Database of Systematic Reviews2005, Issue 4 Art.No.:CD000011.pub2.DOI:10.1002/14651858.CD000011.pub2.

6. Johnson JA, Bootman JL. Drug-relatedmorbidity and mortality. A cost-of-illnessmodel. Arch Intern Med 1995;155:1949–1956

7. Ernst FR, Grizzle AJ, Drug-related morbidityand mortality: Updating the cost-of-illnessmodel. J Am Pharm Assoc. 2001;41:192–199

8. Redman BK. The ethics of leadership inpharmacy. Am. J. Health-Syst. Pharm. 1995;2099–2104.

9. Bond C. Concordance-is it a synonym forcompliance or a paradigm shift? Pharm J.2003;271:496-7.

10. Coulter A. Paternalism or partnership?.BMJ 1999;319:719-20

11. Arnetz JE, Almin I, Bergström K, FranzenY, Nilsson H. Active patient involvement in theestablishment of physical therapy goals:Effects on treatment outcome and quality ofcare. Adv Physiotherap 2003,00:1–20

12. Michie S, Miles J, Weinman J. Patientcentredness in chronic illness: what is it anddoes it mater? Pat Educ Council2003;51:197–206

13. Less disease and better health by im-proved adherence. The role of the profes-sions. Report, Landstingsförbundet, Stock-holm 2001 (in Swedish)

14. Enligt ordination. Ihre T (ed). Studentlit-teratur, Lund, Sweden 2005. (in Swedish)

15. Sjöqvist F, Bergman U, Dahl M-L,Gustafsson LL, Hensjö L-O. Drug and thera-peutics committees: a Swedish experience.WHO Drug Inform. 2002;16;207–242

16. Andersson K, Melander A, Svensson C,Lind O, Nilsson JLG. Repeat prescriptions –refill adherence in relation to patient andprescriber characteristics, reimbursementlevel and type of medication. Eur J PublicHealth 2005;15:621–626

17. Steiner JF, Prochazka AV. The assess-ment of refill compliance using pharmacyrecords: methods, validity and applications.J Clin Epidemiol 1997; 50:105–116.

18. Jackevicius CA, Mamdani M, Tu JV.Adherence with statin therapy in elderlypatients with and without acute coronarysyndromes. JAMA 2002; 288(4): 462–467


33


ATC/DDD Classification

The following anatomical therapeutic chemical (ATC) classifications and defined dailydoses (DDDs) were agreed by the WHO International Working Group for Drug Sta-tistics Methodology 30–31 October 2006. Comments or objections to the decisionsshould be forwarded to the WHO Collaborating Centre for Drug Statistics Methodol-ogy at [email protected]. The new ATC codes and DDDs will be considered final and beincluded in the January 2008 issue of the ATC index. The inclusion of a substance inthe lists does not imply any recommendation of use in medicine or pharmacy. TheWHO Collaborating Centre for Drug Statistics Methodology can be contacted throughe-mail at: [email protected].

ATC/DDD Classification (temporary)

ATC level INN/Common name ATC code

New ATC level codes (other than 5th level):Agents for age related macular degeneration S01L1

Calcineurin inhibitors L04ADDipeptidyl peptidase 4 (DPP-4) inhibitors A10BHInterleukin receptor inhibitors L04ACMuscle relaxants C05AEOther antiobesity drugs A08AXOther estrogens G03CXTumor necrosis factor alpha (TNF-α) inhibitors L04AB

1 For the complete classification of S01L, see Summary of the main ATC alterations2 For the complete classification of J05AR, see Summary of the main ATC alterations

New ATC 5th level codes:Adapalene, combinations D10AD53Amifampridine N07XX05Certolizumab pegol L04AB05Dabigatran etexilate B01AE07Eculizumab L04AA25Fesoterodine G04BD11Fluticasone furoate R01AD12Glimepiride and pioglitazone A10BD06Hemoglobin glutamer (bovine) B05AA10Haemophilus influenzae B, combinations with meningo- coccus C, conjugated J07AG53Ixabepilone L01DC04Lapatinib L01XE07

34



New ATC 5th level codes (continued)Mecasermin rinfabate H01AC05Metformin and pioglitazone A10BD05Metformin and sitagliptin A10BD07Mifamurtide L03AX15Misoprostol G02AD06Nepafenac S01BC10Nilotinib L01XE08Oblimersen L01XX36Pegzerepoetin alfa B03XA03Ramelteon N05CM19Retapamulin D06AX13Rimonabant A08AX01Rotavirus, pentavalent, live, reassorted J07BH02Sitagliptin A10BH01Sitaxentan C02KX03Telavancin J01XA03Vapreotide H01CB04Vildagliptin A10BH02Xenon N01AX15

ATC code changes: (changes will not be implemented before January 2008)

Adalimumab L04AA17 L04AB04Afelimomab L04AA16 L04AB03Anakinra L04AA14 L04AC03Basiliximab L04AA09 L04AC02Ciclosporin L04AA01 L04AD01Daclizumab L04AA08 L04AC01Etanercept L04AA11 L04AB01Glyceryl trinitrate D03AX07 C05AE01Infliximab L04AA12 L04AB02Isosorbide dinitrate D03AX08 C05AE02Tacrolimus L04AA05 L04AD02Tetrabenazine N05AK01 N07XX06Tibolone G03DC05 G03CX01

ATC name changesAntihemorrhoidals for topical use Agents for treatment of hemorr-

hoids and anal fissures fortopical use C05A

Cytokines and immunomodulators Immunostimulants L03ADelapril and calcium channel blockers Delapril and manidipine C09BB12Enalapril and calcium channel blockers Enalapril and lercanidipine C09BB02

INN/Common name Previous ATC New ATC

Previous New ATC code


35


ATC name changes (continued)

Immunosuppressive agents Immunosuppressants L04Immunosuppressive agents Immunosuppressants L04AOmega-3-triglycerides Omega-3-triglycerides incl.

other esters and acids C10AX06Other antihemorrhoidals for topical use Other agents for treatment of

hemorrhoids and anal fissures for topical use C05AX

Other cytokines and immunomodulators Other immunostimulants L03AXOther immunosuppressive agents Other immunosuppressants L04AXRamipril and calcium channel blockers Ramipril and felodipine C09BB05Selective immunosuppressive agents Selective immuno-

suppressants L04AA


New DDDs:

INN/common name DDD Unit Adm.R ATC code

Abatacept 27 mg P L04AA24Alglucosidase alfa 0.1 g P A16AB07Carglumic acid 0.2 g O A16AA05Insulin (human) 15 mg Inhal A10AF01Lenalidomide 10 mg O L04AX04Parathyroid hormone 0.1 mg P H05AA03Ranolazine 1.5 g O C01EB18Rimonabant 20 mg O A08AX01Rotigotine 6 mg TD (patch) N04BC09Tigecycline 0.1 g P J01AA12Varenicline 2 mg O N07BA03


36


The following anatomical therapeutic chemical (ATC) classifications and defined dailydoses (DDDs) were agreed by the WHO International Working Group for Drug Sta-tistics Methodology in March 2006. They came into force on 1 October 2006 and willbe included in the January 2007 issue of the ATC index. The inclusion of a substancein the lists does not imply any recommendation of use in medicine or pharmacy. TheWHO Collaborating Centre for Drug Statistics Methodology can be contacted [email protected].

ATC/DDD Classification (final)


New ATC level codes (other than 5th level):Ocular vascular disorder agents S01LAngiotensin II antagonists and calcium channel blockers C09DBAntivirals for treatment of HIV infections, combinations J05ARInsulins and analogues, for inhalation A10AFAntineovascularisation agents S01LAPapillomavirus vaccines J07BM

New ATC 5th level codes:Abatacept L04AA24Aliskiren C09XA02Ambrisentan C02KX02Dasatinib L01XE06Deferasirox V03AC03Desvenlafaxine N06AX23Emtricitabine, tenofovir disoproxil and efavirenz J05AR06Fluocinolone acetonide S01BA15Gadofosveset V08CA11Garenoxacin J01MA19Insulin (human) A10AF01Medical air V03AN05Nelarabine L01BB07Nitrous oxide, combinations N01AX63Panitumumab L01XC08Papillomavirus (human types 6, 11, 16, 18) J07BM01Papillomavirus (human types 16, 18) J07BM02Ranibizumab S01LA04Sapropterin A16AX07Telbivudine J05AF11


37


New ATC 5th level codes (continued):Valsartan and amlodipine C09DB01Varenicline N07BA03Zidovudine, lamivudine and nevirapine J05AR05Zoster, live attenuated J07BK02

ATC code changes:Anecortave S01XA16 S01LA02Lamivudine and abacavir J05AF301) J05AR02Pegaptanib S01XA17 S01LA03Tenofovir disoproxil and emtricitabine J05AF301) J05AR03Verteporfin L01XD02 S01LA01Zidovudine and lamivudine J05AF301) J05AR01Zidovudine, lamivudine and abacavir J05AF301) J05AR04

1) J05AF30: ATC level name: Combinations

ATC name changesInsulins and analogues, fast-acting Insulins and analogues for

injection, fast-acting A10ABInsulins and analogues, intermediate- Insulins and analogues for acting injection, intermediate-acting A10ACInsulins and analogues, intermediate- Insulins and analogues for acting combined with fast-acting injection, intermediate-acting

combined with fast-acting A10ADInsulins and analogues, long-acting Insulins and analogues for

injection, long-acting A10AENew DDDs:

INN/common name DDD Unit Adm.R ATC code

Cefditoren 0.4 g O J01DD16Entecavir 0.5 mg O J05AF10Erdosteine 0.6 g O R05CB15Estradiol 7.5 mcg V1) G03CA03Hydroxybutyric acid 7.5 g O N07XX04Ibuprofen 30 mg P C01EB16Ivabradine 10 mg O C01EB17Natalizumab 10 mg P L04AA23Posaconazole 0.8 g O J02AC04Tipranavir 1 g O J05AE09

1) vaginal ring, refers to amount delivered per 24 hours


INN/Common name Previous ATC New ATC



38


International Pharmacopoeia

C16H28N2O4, H3PO4

Relative molecular mass. 410.4

Chemical name. (3R,4R,5S)-4-Acetylamino-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid, ethyl ester, phosphate (1:1)

Description. A white to off-white powder.

Solubility. Freely soluble in water.

Category. Antiviral.

Storage. Oseltamivir phosphate should be kept in a well-closed container.

Draft proposal for The International Pharmacopoeia(December 2006)

Oseltamivir phosphate

39


REQUIREMENTS

Definition. Oseltamivir phosphate contains not less than 98.0% and not more than101.5% of C

16H

28N

2O

4, H

3PO

4, calculated with reference to the anhydrous substance.

Manufacture. The production method is validated to ensure that the substance is the(3R, 4R, 5S) enantiomer and that less than 100 ppm of the impurity ethyl (2R, 3R, 4R,5S)-2-azido-4-acetylamino-5-amino-3-(1-ethyl-propoxy)-cyclohexane-1-carboxylate ispresent, when determined by a suitable method such as liquid chromatographycombined with mass spectrometry (LC-MS). Where necessary, the production methodis also validated to demonstrate that tributyl phophine oxide is not detectable in thefinal product, when examined by a suitable method such as gas chromatography(GC).

Identity test

A. Carry out the examination as described under 1.7 Spectrophotometry in the infraredregion. The infrared absorption spectrum is concordant with the spectrum obtainedfrom oseltamivir phosphate RS or with the reference spectrum of oseltamivir phos-phate.

B. Determine the specific optical rotation (as described under method 1.4) using a10 mg/ml solution and calculate with reference to the anhydrous substance; [α]D

25˚C = - 30.7 to – 32.6˚.

[Note from the Secretariat: It is intended to include additional, alternative identificationtests, if possible. However, it is noted that oseltamivir does not exhibit a suitable UVspectrum. The possibility of a thin-layer chromatographic test is under investigation.]

Heavy metals. Use 1.0 g for the preparation of the test solution as described under2.2.3 Limit test for heavy metals, Procedure 1 and determine the heavy metal contentaccording to Method A; not more than 10 µg/g.

Sulfated ash (as described under method 2.3). Not more than 2.0 mg/g.

Water. Determine as described under 2.8 Determination of water by Karl FischerMethod, Method A. Use 1.0 g of the test substance. The water content is not morethan5 mg/g.

Related substances. Carry out the assay as described under 1.14.4 High perform-ance liquid chromatography, using the same conditions as under Assay, using solu-tions (1) (3) and (4).

Inject separately 15 µl each of solution (1), (3) and (4) and of the dissolution solvent inthe chromatographic system. Examine the blank chromatogram for any extraneouspeaks and disregard the corresponding peaks observed in the chromatogram obtainedwith solution (1).


40


Use the chromatogram obtained with solution (4) to identify the peaks due to impuri-ties A, B, C, D, E and F. The impurity peaks are eluted at the following relative reten-tion times with reference to oseltamivir phosphate (retention time about 19 minutes):impurity A about 0.16, impurity B about 0.17, impurity C about 0.51, impurity D about0.55, impurity E about 0.59, impurity F about 1.5. The test is not valid unless theresolution between the peaks due to impurities A and B and that between the peaksdue to impurities C, D and E is at least 1.0.

In the chromatogram obtained with solution (1) the area of any peak corresponding toimpurity B, when multiplied by a correction factor of 1.4, is not greater than 3 timesthe area of the peak in the chromatogram obtained with solution (3) (0.3%), the area ofany peak corresponding to impurity C , when multiplied by a correction factor of 2.7, isnot greater than the area of the peak in the chromatogram obtained with solution (3)(0.1%), the area of any other peak, apart from the principal peak, is not greater thanthe area of the peak in the chromatogram obtained with solution (3) (0.1%). The sumof the areas of all the peaks, apart from the principal peak, is not greater than 7 timesthe area of the peak obtained with solution (3) (0.7%). Disregard any peak with anarea less than 0.5 times the area of the principal peak obtained with solution (3)(0.05%).

Assay

[Note from the Secretariat: A potentiometric titration will be included as an alternativeassay to HPLC if a suitable method is available.]

Carry out the test as described under 1.14.4 High-performance liquid chromatography,using a stainless steel column (25 cm x 4.6 mm) packed with octylsilyl silica gel forchromatography (5 µm).

The mobile phase consists of a mixture of 620 ml of 0.05 M potassium dihydrogenphosphate (adjusted to pH 6 with potassium hydroxide (~110g/l TS), 245 ml methanolR and 135 ml acetonitrile R.

Operate with a flow rate of 1.2 ml per minute and the column oven temperature at50˚C. As a detector use an ultraviolet spectrophotometer set at a wavelength of about207 nm.

Prepare the following solutions in the dissolution solvent by mixing 620 ml of water R,245 ml of methanol R and 135 ml of acetonitrile R.

For solution (1) dissolve 50 mg of the test substance in the dissolution solvent anddilute to 50.0 ml with the same solvent. For solution (2) dissolve 50 mg of oseltamivirphosphate RS in the dissolution solvent and dilute to 50 ml with the same solvent. Forsolution (3) dilute 1.0 ml of solution (1) to 100 ml with dissolution solvent and thendilute 1.0 ml of this solution to 10 ml with the same solvent. For solution (4) dissolve5 mg of oseltamivir phosphate for system suitability RS (containing oseltamivir phos-phate and impurities A to F) in the dissolution solvent and dilute to 5 ml with the samesolvent.


41


[Note from the Secretariat: the means of identifying the impurity peaks is subject toconfirmation.]

Inject separately 15 µl each of solution (1), (2) and (4) and of the dissolution solvent inthe chromatographic system. Examine the blank chromatogram for any extraneouspeaks and disregard the corresponding peaks observed in the chromatogram ob-tained with solutions (1) and (2). The assay is not valid unless, in the chromatogramobtained with solution (4), the resolution between the peaks due to impurities A and Band that between the peaks due to impurities C, D and E is at least 1.0.

Measure the areas of the peak responses in the chromatograms obtained with solu-tions (1) and (2). Calculate the percentage of oseltamivir phosphate, C

16H

28N

2O

4,

H3PO4.

Impurities

A. Ro 0640951 (N5-acetyl carboxylic acid)

B. Ro 0640802 (Carboxylic acid)


42


C. Ro 0646661

D. Ro 0641634 (Methyl ester)

E. Ro 0647943 (Isobutylether derivative)

F. Ro 0640952 (N-5 acetyl derivative)


43


Draft proposal for The International Pharmacopoeia(October 2006)

LumefantrinumLumefantrine

C30

H32

Cl3NO

Relative molecular mass. 528.9

Chemical name. 2-Dibutylamino-1-[2, 7-dichloro-9-(4-chlorobenzylidene)-9H-fluoren-4-yl]-ethanol (racemate); CAS Reg. No. 82186-77-4

[Note from Secretariat: Name and structure to be checked.]

Other name. Benflumetol.

Description. A yellow crystalline powder.

Solubility. Practically insoluble in water; freely soluble in dimethylformamide R andethyl acetate R; soluble in dichloromethane R; slightly soluble in ethanol R and metha-nol R.

Category. Antimalarial.

Storage. Lumefantrine should be kept in a well-closed container.

Additional information. Lumefantrine melts at 128 –132 ˚C.

REQUIREMENTS

Definition. Lumefantrine contains not less than 98.5% and not more than 101.0% ofC

30H

32Cl

3NO, calculated with reference to the dried substance.

Identity test

Either tests A and B or tests C may be applied.


44


A. Carry out test A.1. or, where UV detection is not available, test A.2.

A.1. Carry out the test as described under 1.14.1 Thin-layer chromatography, usingsilica gel R6 as the coating substance and a mixture of 40 volumes of light petroleumR1, 10 volumes of ethyl acetate R and 5 volumes of glacial acetic acid R as themobile phase. Apply separately to the plate 10 µl of each of 2 solutions in ethylacetate R, containing (A) 5 mg of the test substance per ml and (B) 5 mg of lumefan-trine RS per ml. After removing the plate from the chromatographic chamber, allow itto dry exhaustively in air or in a current of cool air. Examine the chromatogram inultraviolet light (254 nm).

The principal spot obtained with solution A corresponds in position, appearance, andintensity to that obtained with solution B.

A.2. Carry out the test as described under 1.14.1 Thin-layer chromatography, usingsilica gel R5 as the coating substance and a mixture of 40 volumes of light petroleumR1, 10 volumes of ethyl acetate R and 5 volumes of glacial acetic acid R as themobile phase. Apply separately to the plate 10 µl of each of 2 solutions in ethylacetate R, containing (A) 5 mg of the test substance per ml and (B) 5 mg of lumefan-trine RS per ml. After removing the plate from the chromatographic chamber, allow itto dry exhaustively in air or in a current of cool air and expose to iodine vapours untilspots appear. Examine the chromatogram immediately in daylight.

The principal spot obtained with solution A corresponds in position, appearance, andintensity to that obtained with solution B.

B. Dissolve about 20 mg, accurately weighed, in 200 ml of methanol R by sonicationfor about 15 minutes. Allow the solution to cool to room temperature and dilute fivefoldwith methanol R. The absorption spectrum (as described under method 1.6) of thediluted solution when observed between 275 and 325 nm, exhibits a maximum atabout 302 nm; the specific absorbance (A1%

1cm) is between 314 and 348.

C. Carry out the examination as described under 1.7 Spectrophotometry in the infra-red region. The infrared absorption spectrum is concordant with the spectrum ob-tained from lumefantrine RS or with the reference spectrum of lumefantrine.

Heavy metals. Use 1.0 g for the preparation of the test solution as described under2.2.3 Limit test for heavy metals, Procedure 3 and determine the heavy metals con-tent according to Method A; not more than 20 µg/g.

Sulfated ash (as described under method 2.3). Not more than 2.0 mg/g.

Loss on Drying. Dry for 3 hours at 105 ˚C; it loses not more than 5.0 mg/g.

Related substances[Note from the Secretariat: The tentative method proposed below is still under investi-gation.]

Carry out the test as described under 1.14.4 High-performance liquid chromatography,using a stainless steel column (12.5 cm x 4.0 mm) packed with particles of silica gel,


45


the surface of which has been modified with chemically bonded octadecylsilyl groups(5 µm). (Nucleosil 100 is suitable).

Use the following conditions for gradient elution:

Mobile phase A: 200 volumes of ion pair reagent, 500 volumes of water R, 250volumes of acetonitrile R and 50 volumes of 1-propanol R.

Mobile phase B: 200 volumes of ion pair reagent, 100 volumes of water R, 650volumes of acetonitrile R and 50 volumes of 1-propanol R.

Mobile phase C: 100 volumes of purified water, 100 volumes of acetonitrile R and400 volumes of 1-propanol R.

Prepare the ion pair reagent by dissolving 5.65 g of sodium hexanesulfonate R and2.75 g of sodium dihydrogen phosphate R in about 900 ml of water R. Adjust the pH to2.3 using phosphoric acid (~105 g/l) TS, dilute to 1000 ml and filter through a 0.5 µmfilter.

Time Mobile phase A Mobile phase B Mobile phase C Comments(min) (% v/v) (% v/v) (% v/v)

0-14 25 75 0 Isocratic14-19 25 to 0 75 to 100 0 Linear gradient19-20 0 100 to 80 0 to 20 Linear gradient20-26 0 80 20 Isocratic26-27 0 80 to 30 20 to 70 Linear gradient27-50 0 30 70 Isocratic50-51 0 to 25 30 to 75 70 to 0 Linear gradient51-56 25 75 Isocratic re-

equilibration

Prepare the following solutions in acetonitrile R. For solution (1) use 0.3 mg of the testsubstance per ml. For solution (2) dilute a suitable volume of solution (1) to obtain aconcentration equivalent to 0.3 ìg of lumefantrine per ml. For solution (3) dissolve 3 mgof lumefantrine for system suitability RS (containing lumefantrine and impurities A, Band C) in 10 ml.

[Note from the Secretariat: The availability of lumefantrine spiked with impurities A, Band C is under investigation.]

Operate with a flow rate of 2.0 ml per minute. As a detector use an ultraviolet spectro-photometer set at a wavelength of about 265 nm.

Inject 20 µl of solution (3). The impurity peaks are eluted at the following relativeretention times with reference to lumefantrine (retention time about 10 minutes):impurity A about 0.9; impurity B about 4.3 and impurity C about 4.6. The test is notvalid unless the resolution factor between impurity A and lumefantrine is not less than0.5. If necessary adjust the amount of acetonitrile in mobile phase A, or adjust thegradient programme.


46


Inject alternatively 20 l each of solutions (1) and (2).

In the chromatogram obtained with solution (1) the area of any individual peak corre-sponding to impurity C is not greater than 3.0 times the area of the principal peakobtained with solution (2) (0.3%). The area of any other impurity peak is not greaterthan the area of the principal peak obtained with solution (2) (0.1%). The sum of theareas of all peaks, other than the principal peak, is not greater than 3.0 times the areaof the principal peak obtained with solution (2) (0.3%). Disregard any peak with anarea less than 0.5 times the area of the principal peak obtained with solution (2)(0.05%) and any peak resulting from the solvent.

AssayDissolve about 0.51 g, accurately weighed, in 50 ml of glacial acetic acid R1 by stirringfor about 15 minutes, and titrate with perchloric acid (0.1 mol/l) VS, determine the end-point potentiometrically as described under 2.6 Non aqueous titration, Method A. Eachml of perchloric acid (0.1 mol/l) VS is equivalent to 52.89 mg of C

30H

32Cl

3NO.

ImpuritiesThe following list of known and potential impurities that have been shown to be con-trolled by the tests in this monograph is given for information.

A. 529.0 C30

H32

Cl3NO

B. and C. 797.4 C44

H24

Cl6O

2


47


The International Pharmacopoeia

Dissolution tests

Work has been carried out on developing dissolution tests for addition to certain tabletmonographs of The International Pharmacopoeia in accordance with the approachand priorities agreed by the WHO Expert Committee on Specifications for Pharmaceu-tical Preparations.

It is proposed to add tests to the following monographs by means of the 1st Supple-ment to the 4th Edition of The International Pharmacopoeia. The format of these testsis modelled on that used in the test that has been added to the monograph for “Phe-noxymethylpenicillin potassium tablets” in the Fourth Edition. A test based on thisformat has also been included in the adopted monograph for “Isoniazid and Ethambu-tol hydrochloride tablets”, the final text for which can be found at: http://www.who.int/medicines/publications/pharmacopoeia/mon_tb/en/index.html).

The method text “5.5 Dissolution test for solid oral dosage forms” from the 4th editionof The International Pharmacopoeia is appended to this document as Annex 1 forconvenience.

Chloroquine phosphate tabletsDissolution. Carry out the test as described under 5.5 Dissolution test for solid oraldosage forms, using as the dissolution medium, 500 ml of dissolution buffer, pH 6.8,TS and rotating the paddle at 75 revolutions per minute. At 30 minutes withdraw asample of about 10 ml of the medium through an in-line filter. Measure the absorb-ance of the filtered sample, suitably diluted if necessary, at the maximum at 342 nm.At the same time measure the absorbance at the maximum at 342 nm of a suitablesolution of chloroquine diphosphate RS in dissolution buffer, pH 6.8, TS, using thesame buffer as a blank.

For each of the six tablets tested, calculate the total amount of chloroquine phos-phate, C

18H

26Cl N

3, 2H

3PO

4, in the medium. The average amount in solution is not less

than 85% of the amount declared on the label. If the amount obtained for one of thesix tablets is less than 80%, repeat the test using a further six tablets; the averageamount for all 12 tablets tested is not less than 85%.

Chloroquine sulfate tabletsDissolution. Carry out the test as described under 5.5 Dissolution test for solid oraldosage forms, using as the dissolution medium, 500 ml of dissolution buffer, pH 6.8,TS and rotating the paddle at 75 revolutions per minute. At 30 minutes withdraw asample of about 10 ml of the medium through an in-line filter. Measure the absorb-ance of the filtered sample, suitably diluted if necessary, at the maximum at 342 nm.At the same time measure the absorbance at the maximum at 342 nm of a suitablesolution of chloroquine sulfate RS in dissolution buffer, pH 6.8, TS, using the samebuffer as a blank.

For each of the six tablets tested, calculate the total amount of chloroquine sulfate,C

18H

26Cl N

3, H

2SO

4, in the medium. The average amount in solution is not less than


48


85% of the amount declared on the label. If the amount obtained for one of the sixtablets is less than 80%, repeat the test using a further six tablets; the averageamount for all 12 tablets tested is not less than 85%.

Ethambutol hydrochloride tabletsDissolution. Carry out the test as described under 5.5 Dissolution test for solid oraldosage forms, using as the dissolution medium, 500 ml of dissolution buffer, pH 6.8,TS and rotating the paddle at 75 revolutions per minute. At 30 minutes withdraw asample of about 10 ml of the medium through an in-line filter.

Either

Determine the content of ethambutol hydrochloride, C10

H24

N2O

2, 2HCl, as described

below under Assay.

Or

Measure the absorbance of the filtered sample, suitably diluted with copper-acetatebuffer, pH 5.0, TS (new reagent) in a ratio of 1:10 or 1:20, depending on the strengthof ethambutol dihydrochloride tablets tested, at the maximum at 270 nm. At the sametime measure the absorbance at the maximum at 270 nm of a suitable solution ofethambutol hydrochloride RS in copper-acetate buffer, pH 5.0, TS, using the samebuffer as a blank.

[Note from the Secretariat: Please comment on which of the two options for method ofanalysis is considered most suitable.]

For each of the six tablets tested, calculate the total amount of ethambutol hydrochlo-ride, C

10H

24N

2O

2, 2HCl, in the medium. The average amount in solution is not less

than 85% of the amount declared on the label. If the amount obtained for one of thesix tablets is less than 80%, repeat the test using a further six tablets; the averageamount for all 12 tablets tested is not less than 85%.

Doxycycline tabletsDissolution. Carry out the test as described under 5.5 Dissolution test for solid oraldosage forms, using as the dissolution medium, 500 ml of dissolution buffer, pH 6.8,TS and rotating the paddle at 75 revolutions per minute. At 30 minutes withdraw asample of about 10 ml of the medium through an in-line filter.

Either

Allow the filtered sample to cool to room temperature and dilute … ml to … ml withhydrochloric acid (0.01mol/l) VS [solution (3)]. Determine the content of doxycycline,C

22H

24N

2O

8 as described below under Assay using solution (3) in place of solution (1).

Or

Measure the absorbance of the filtered sample, suitably diluted if necessary, at themaximum at 274 nm. At the same time measure the absorbance at the maximum at274 nm of a suitable solution of doxycycline hyclate RS in dissolution buffer, pH 6.8,TS, using the same buffer as a blank.


49


[Note from the Secretariat: Please comment on which of the two options for method ofanalysis is considered most suitable. If the first option is used, the details of prepara-tion for solution (3) will be given.]

For each of the six tablets tested, calculate the total amount of doxycycline,C

22H

24N

2O

8 in the medium from the results obtained and from the declared content of

C22

H24

N2O

8 in doxycycline hyclate RS. The average amount in solution is not less than

85% of the amount declared on the label. If the amount obtained for one of the sixtablets is less than 80%, repeat the test using a further six tablets; the averageamount for all 12 tablets tested is not less than 85%.

Isoniazid tabletsDissolution. Carry out the test as described under 5.5 Dissolution test for solid oraldosage forms, using as the dissolution medium, 500 ml of dissolution buffer, pH 6.8,TS and rotating the paddle at 75 revolutions per minute. At 30 minutes withdraw asample of about 10 ml of the medium directly through an in-line filter. Measure theabsorbance of the filtered sample, suitably diluted if necessary, at the maximum at263 nm. At the same time measure the absorbance at the maximum at 263 nm of asuitable solution of isoniazid RS in dissolution buffer, pH 6.8, TS, using the samebuffer as blank.

For each of the six tablets tested, calculate the total amount of isoniazid, C6H

7N

3O in

the medium. The average amount in solution is not less than 85% of the amountdeclared on the label. If the amount obtained for one of the six tablets is less than80%, repeat the test using a further six tablets; the average amount for all 12 tabletstested is not less than 85%.

Metronidazole tabletsDissolution. Carry out the test as described under 5.5 Dissolution test for solid oraldosage forms, using as the dissolution medium, 500 ml of dissolution buffer, pH 6.8,TS and rotating the paddle at 75 revolutions per minute. At 30 minutes withdraw asample of about 10 ml of the medium directly through an in-line filter. Measure theabsorbance of the filtered sample, suitably diluted if necessary, at the maximum at319 nm. At the same time measure the absorbance at the maximum at 319 nm of asuitable solution of metronidazole RS in dissolution buffer, pH 6.8, TS, using the samebuffer as blank.

For each of the six tablets tested, calculate the total amount of metronidazole,C

6H

9N

3O

3 in the medium. The average amount in solution is not less than 85% of the

amount declared on the label. If the amount obtained for one of the six tablets is lessthan 80%, repeat the test using a further six tablets; the average amount for all 12tablets tested is not less than 85%.

Pyrazinamide tabletsDissolution. Carry out the test as described under 5.5 Dissolution test for solid oraldosage forms, using as the dissolution medium, 500 ml of dissolution buffer, pH 6.8,TS and rotating the paddle at 75 revolutions per minute. At 30 minutes withdraw asample of about 10 ml of the medium through an in-line filter. Determine the content ofpyrazinamide, C5H5N3O, as described below under Assay.


50


For each of the six tablets tested, calculate the total amount of pyrazinamide, C5H5N3O,in the medium from the results obtained. The average amount in solution is not lessthan 85% of the amount declared on the label. If the amount obtained for one of the sixtablets is less than 80%, repeat the test using a further six tablets; the average amountfor all 12 tablets tested is not less than 85%.

Note: Buffers

The composition of the following dissolution buffer will be amended to:

Dissolution buffer, pH 6.8, TS

Dissolve 6.9 g of sodium dihydrogen phosphate R and 0.9 g of sodium hydroxide R in800 ml of deionized water, adjust the pH to 6.8 with sodium hydroxide (~80g/l) TS anddilute to1000 ml with water.

A new reagent entry will be included for:

Copper-acetate buffer, pH 5.0, TS

Dissolve 55 mg Ammonium acetate R, 200 mg Copper(II)acetate R in 800 ml of waterR, adjust the pH to 5.00 with Glacial acetic acid R and dilute to1000 ml with water R.


51


Recent Publications,Information and EventsInternational Pharmacopoeia:fourth edition

This new edition consolidates the texts ofthe five separate volumes of the thirdedition. In preparing this consolidatededition, a review has been undertaken ofthe general notices with additions andamendments to clarify interpretation andfacilitate application of the requirementsby the user.

Certain aspects of the layout and formathave been revised. In this edition, all themonograph texts are brought together inone section and the method texts inanother. Each of these major sections aredivided into appropriate sub-sections andthe method texts are numbered for easeof cross-reference.

New monographs for the following antiret-roviral substances have been publishedin the Fourth edition: didanosine, indinavirsulfate, nelfinavir mesilate, nevirapine,ritonavir, saquinovir, and saquinovirmesilate. Revision of the current mono-graph for oral rehydration salts has beencarried out to conform to the modifiedformula published in the 13th Model Listof Essential Medicines and in the WHOModel Formulary 2004.

Method texts that have been updated toinclude, for example, the text on highperformance liquid chromatography[HPLC]. This has been revised to clarifycertain technical terms and to add adviceon adjustment of chromatographic condi-tions.

Available from WHO Press, CH-1211 Geneva27 • Switzerland. E-mail: [email protected] http://www.who.int/bookorders

Draft report: Specifications forPharmaceutical PreparationsThe advice and recommendations pro-vided by this Expert Committee onSpecifications for Pharmaceutical Prepa-rations are intended to serve national andregional authorities and, in particular,drug regulatory authorities, procurementagencies, and major international bodiesand organizations, such as the GlobalFund, and UNICEF. The internationalguidelines, specifications and nomencla-ture developed under the aegis of theExpert Committee serve all MemberStates, international organizations, UnitedNations agencies, regional andinterregional harmonization efforts, andunderpin important initiatives, includingthe prequalification of medicines, the RollBack Malaria Programme, and Stop TB.Making resources available for theseactivities is, therefore, very cost-effective.

1. The International Pharmacopoeia.Related substances tests: dosage formmonographs (Annex 1)

2. List of available International ChemicalReference Substances (Annex 2)

3. General guidelines for the establish-ment, maintenance and distribution ofchemical reference substances (Annex 3)

4. Procedure for assessing the accept-ability, in principle, of pharmaceuticalproducts for purchase by United Nationsagencies (Annex 4)

5. Procedure for assessing the accept-ability, in principle, of quality controllaboratories for use by United Nationsagencies (Annex 5)

52


6. Guidance on variations to a prequali-fied product dossier (Annex 6)

Available on http://www.who.int/medicines

User guide for micro, smalland medium sized enterprises

A user guide has been published by theEuropean Medicines Agency for micro,small and medium sized enterprises(SMEs) on the administrative and proce-dural aspects of the provisions laid downin Regulation (EC) No 726/2004, that areof particular relevance to SMEs operatingin the pharmaceutical sector. Its aim is tofacilitate understanding of the mainaspects of medicinal product legislation.The guide is structured to follow, as far aspossible, the chronological stages ofdeveloping a medicinal product. A con-cise overview of the scientific data re-quirements for obtaining a marketingauthorization in the European Union (EU)is provided. The regulatory proceduresthat are in place to optimize developmentand obtain an EU marketing authorizationare summarized.

This initial version of the guide focusesprimarily on the requirements for authoriz-ing innovative medicinal products for

human use. A chapter on veterinarymedicinal product development is underpreparation and will be incorporated intothe next version of the guide. The scopeof the guide may also be broadened at alater stage to include other aspects ofinterest for SMEs, such as generics,taking into account feedback receivedduring the consultation phase whichended in March 2007.

The guide is not intended to be an ex-haustive document but rather to raiseSME awareness of the various moredetailed sources of information available,with links throughout the text to additionalinformation.

Pursuant to the new regulation, SMEsnow have access to financial assistance(in the form of fee reductions and feedeferrals) and administrative assistancefrom the agency, details of which areoutlined in Section 2 of the guide. Tofacilitate contact with the agency, an‘SME Office’ has been launched that isdedicated to addressing the particularneeds of smaller companies.

EMEA. User guide for micro, small andmedium sized enterprises (SMEs). Doc. Ref.EMEA/206798/2006Draft, 31 January2007.http://www.emea.europa.eu

Recent Publications, Information and Events

who drug informationapps.who.int/iris/bitstream/10665/74108/1/21_1_2007.pdfincreased risk of...

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