1WHO Drug Information Vol. 27, No. 1, 2013WHO Drug InformationAccess to Blood ProductsAccess to safe and effective blood products in low and middle income countries 3Current TopicsMechanism to combat substandard/ spurious/falsely-labelled/falsified/ counterfeit medical products 6Speeding up access to quality medicines in Africa 6PQM technical support for prequalification of medicines 8International Generic Drug Regulator’s Pilot Project 9Safety and Efficacy IssuesTolvaptan: risk of liver injury 10Roflumilast: risk of suicidal behaviour 10Sodium picosulfate/magnesium citrate: convulsions 11Risperidone and rhabdomyolysis 12Docetaxel: serious respiratory- related adverse reactions 13Zolpidem: impaired activity 14Combination treatment with telaprevir, peginterferon alfa and ribavirin: serious skin reactions 14Dabigatran etexilate mesylate: not for patients with mechanical prosthetic heart valves 15Sodium oxybate with alcohol or drugs: respiratory depression 15 Statins: risk of increased blood sugar levels and diabetes 15Immunomodulatory medicines: progressive multifocal leuko- encephalopathy 16Thyroxine and fractures 17Oral bowel cleansing products: serious electrolyte disturbances 18Combined contraceptives: venous and arterial thromboembolism 19Fibrin sealant spray: gas embolism 19Corticosteroids: musculoskeletal adverse events 20Regulatory Action and NewsHerbal medicines: strengthening assessment methodology and improved communication 22Advanced therapies: incentives and strengthened interaction 22Methodologies in pharmacovigilance and pharmacoepidemiology 23Nicotinic acid/laropiprant: suspension recommended 23Bevacizumab approved for meta- static colorectal cancer 24Mercury free healthcare 24Ocriplasmin: approved for vitreo- macular traction 25India: clinical trial conditions amended 25eSubmission Gateway release II and eSubmission web client 26Deferasirox approved for nontrans- fusion-dependent thalassaemia 26Pomalidomide approved for advanced multiple myeloma 27Nalmefene approved for reduction of alcohol consumption 27Mipomersen sodium and lomitapide approved for inherited cholesterol disorder 27Memantine: Imatinib mesilate: marketing authorization application withdrawal 28Imatinib mesilate: marketing authorizaation application withdrawal 29Contents... (continued)
2WHO Drug Information Vol. 27, No. 1, 2013Recent Publications, Informationand EventsWHO/WIPO/WTO: health innovation and access to medicines 29EPN study: availability and pricing of children’s medicines in Ghana 30IOM report on substandard and falsified medicines 30HIFA: Information for healthcare providers 31New pregnancy registry protocol 32Malaria: rapid diagnostic testing 33WHO Drug InformationDigital librarye-mail table of contentssubscriptionsavailable at:http://www.who.int/druginformationInternational course on dengue 33Paediatric ACTs for the treatment of uncomplicated malaria 33Consultation DocumentThe International Pharmacopoeia4. Reference Substances and Reference Spectra 35International NonproprietaryNamesRecommended List No. 69 41 Contents (continued)
3WHO Drug Information Vol. 27, No. 1, 2013not suitable for further manufacture.Generally accepted internationalstandards require, among other things,appropriate freezing and cold storageconditions, traceability of donors, testingto lower the residual viral risk, regulatorycontrols, quality systems and adherenceto good manufacturing practices (GMP).Improvement in quality standards, know-how and production processes in bloodestablishments should therefore directlycontribute to reducing the rate of trans-mission by transfusion of blood-borneinfectious diseases.Even while the need for plasma productsgrows, a substantial and increasingvolume of recovered plasma in LMIC iscurrently being wasted. This volume hasbeen estimated — based on the globalapproximations of whole blood donationsand the volume of recovered plasmacurrently used for direct transfusion or forfractionation — to be close to 9.3 millionlitres each year. This volume correspondsto more than 40% of world supply ofrecovered plasma.The volume of discarded plasma isexpected to increase substantially asthe volume of blood collected to meetprojected LMIC needs for red cells (theprimary determinant of the number ofwhole blood collections) increases andas blood component therapy becomesmore widely applied. This has been theexperience supported by decades ofclinical data from HIC.The challenge now is to support LMICinvestment in improving the quality ofthe blood they collect by improving theknowledge base, infrastructure, produc-tion standards and regulatory oversight inblood establishments and by emphasizingthe positive impact that such a moveAccess to Blood ProductsAccess to safe and effectiveblood products in low andmiddle income countriesBlood products include blood and bloodcomponents produced as single-donorproducts for direct transfusion, so-calledlabile blood components (i.e., red bloodcells, platelets and plasma), as well asnumerous plasma-derived medicinalproducts (e.g., albumin, polyvalent andspecific immunoglobulins, and bloodcoagulation factors) that are preparedin fractionation facilities from pools ofthousands of plasma units.In high-income countries (HIC), each unitof whole blood collected is separated intoseveral therapeutic blood components toboth deliver the most effective treatment(component therapy) and to make mostefficient use of a precious and limitedhuman resource. The plasma componentcan be used directly for transfusion, orsent for further manufacture into thera-peutic plasma protein concentrates.Access to safe and effective bloodproducts is a major challenge in low andmiddle income countries (LMIC) wherelocal blood establishments may havevery basic facilities and systems, wherequality and safety standards need to beestablished or strengthened, and whereblood supplies may be insufficient to meetmedical needs.World Health Assembly resolutionWHA63.12, in addressing the avail-ability, quality and safety of bloodproducts, points out that in many LMICa large percentage of human plasma,separated from whole blood is currentlydiscarded. This wastage occurs in largepart because the separated plasma is
4WHO Drug Information Vol. 27, No. 1, 2013will have on public health. The short-term investment in improving localproduction standards in blood establish-ments of countries currently discardinglarge volumes of plasma is a means toimprove access to essential plasma-derived medicinal products while at thesame time improving the quality andsafety of the other blood components, thesafety and health of the blood donor andthe long-term benefits to the public healthof national and worldwide populations.To examine and analyze the availabledata, the drivers of technology transferand local production in blood establish-ments, and the potential benefits andrisks that arise from such an initiative,WHO convened a stakeholders’ work-shop in Geneva on 14–15 June 2012.Participants included representativesfrom national regulatory authorities,blood collection organizations, patientorganizations, national bloodprogrammes, plasma fractionators,members of the WHO Blood RegulatorsNetwork, nongovernmental organizations,public health and funding agencies.The report of these deliberations will bepublished in April 2013 and posted atthe web site address: http://www.who.int/bloodproducts. The report examines thevolume of plasma separated from wholeblood that is currently wasted worldwideand identifies challenges and opportuni-ties and the key steps needed to improvethe current situation.The steps proposed should have multiplebenefits, at the national, regional andglobal levels. They include strengtheninglocal production capacity in bloodestablishments in countries currentlydiscarding plasma, through transfer oftechnology and know-how, buildingtechnical capacity and expertise ofnational regulatory authorities in thewhole-blood area, improving the healthof the blood donor and blood-productrecipient, and providing data on theepidemiology and demographics ofmarkers of blood-borne infections.Overall, it is imperative for governmentsin LMIC to address the large wastage ofblood and plasma estimated to occur,and it is clearly in their interest to do so.The process, methods, and timelinesfor improving blood collection systemswill vary in different countries. The gapsbetween HIC and LMIC are significant,but differ from region to region. Suitableregulatory oversight is often lacking, andin its absence progress will be falteringand at risk. Sustainability of aid providedto many countries, largely because of theAIDS pandemic, will only occur with theexertion of national will and locally appro-priate regulatory and legislative action.Another initiative intended to improvethe safety, availability, quality, andaccessibility of blood products is theproposal endorsed by the WHO BloodRegulators Network to add whole bloodand red blood cells to the WHO ModelList of Essential Medicines (EML). Thisproposal was also endorsed by the 63rdWHO Expert Committee on BiologicalStandardization and the 15th Interna-tional Conference of Drug RegulatoryAuthorities. Whole blood and red cellsmeet the generally accepted definitionof medicines; they are among the mostwidely prescribed therapies (an estimated90 million units annually worldwide), andare credited with saving millions of liveseach year.Blood is a national resource, derived fromvoluntary public donations and processedinto medicines to advance that samepublic’s health. Blood is a uniquebiological in that the “raw material” isthe blood donor and the health of thatdonor is linked directly to the health ofthe recipient. The EML designatesmedicines as essential based on theirefficacy and safety, availability, ease ofuse in different settings, comparativecost-effectiveness, and public healthBlood Products and Components
5WHO Drug Information Vol. 27, No. 1, 2013need as judged by disease prevalence.The EML is important because in manycountries it forms the basis of nationaldrug policies. Governments and healthministries often refer to the EML whenmaking decisions regarding resourceallocation and health spending.Adding blood to the EML should encour-age investment in building local systemsto provide safe and effective blood whichis accessible to more patients. Althoughthe cost of upgrading standards, infra-structure and regulatory oversightrequires an initial investment, the resultis safer available blood, reduction in therisk of another epidemic of blood-bornedisease transmission, and long-termsocietal benefit. Most HIC alreadydistinguish blood components as aproduct in terms of preparation,storage and handling, from the processof transfusion which has traditionallybeen considered medical practice, andmany already regulate blood componentsas medicines.There is no conflict between the conceptsof blood as a medicine and blood dona-tion as an altruistic act. The opposite istrue. Addition of whole blood and redblood cells to the EML should benefitthe development of voluntary non-remunerated donation by protecting thehealth of the blood donor and by raisingthe standards for safe collection, accuratescreening and testing, and follow-up ofdonors who require care. Countries thatalready regulate blood as a medicineoversee and protect the appropriate careof the donor. Nor is there evidence thatregarding blood as a medicine will pro-mote commercialism of human tissue byintroducing the sale of blood or paymentof donors. In virtually all countries thathave regulated blood as a medicine fordecades, blood components derive fromvoluntary, unremunerated donors. Listingblood on a WHO-sponsored documentshould further emphasize the importanceof voluntary non-remunerated blooddonation and the not-for-profit status ofblood collecting organizations: policiesthat WHO has endorsed for many years.In all cases, the purpose of the EML isto reduce the burden of disease. Theapplication to add blood to the EML willencourage governments to invest ininfrastructure and the governance ofblood systems, support safe bloodcollection and regulated blood prepara-tion, storage and shipment, and improvepublic health.At the 15th International Conference ofDrug Regulatory Authorities, regulatorsfrom more than 100 countries endorsedthe recommendations that:• Member States should take steps toassure the quality, safety and avail-ability of blood for transfusion, includingoversight through regulation; and• Member States are encouraged toestablish lists of essential medicinesand to include whole blood and bloodcomponents for transfusion on theirlists.These recommendations underline theobjectives of Resolution WHA63.12adopted in 2010 which supports accessto quality, safe blood products at theglobal level.Blood Products and Components
6WHO Drug Information Vol. 27, No. 1, 2013Current TopicsMechanism to combatsubstandard/spurious/falsely-labelled/falsified/counterfeitmedical productsThe Member State Mechanism onSubstandard/spurious/falsely-labelled/falsified/counterfeit (SSFFC) MedicalProducts was established in May 2011 bythe World Health Assembly at its sixty-fifth session. The goal of the SSFFCMechanism is to promote internationalcollaboration on strategies to address thefalsification of medicines from the stand-point of public health, excluding tradeand intellectual property considerations.The first meeting of the Member StateMechanism on SSFFC Medical Products,was organized by the World HealthOrganization (WHO) and the ArgentineMinistry of Health. On 21 November2012, representatives from sixty-fiveWHO Member States met in BuenosAires, Argentina, and agreed to pro-mote strengthening of action to combatSSFFC medical products. The meetingended with a call to all countries to jointlyaddress this global public health problemthat affects millions of people worldwide.The 200 representatives at the meetingagreed on a workplan that highlights theimportance of cooperation between dif-ferent national authorities and the sharingof best practices and experiences. Theyagreed to establish a global committeecomprising two delegates from eachWHO Region to support implementationof a workplan which provides for thereinforcement of national regulatorybodies through capacity-building andnetworking.The meeting also stressed the needto develop educational initiativestargeted at consumers, health profes-sionals and industry to prevent SSFFCmedical products. It called for thedevelopment of methodologies andinstruments to obtain more accurateinformation on the nature and magnitudeof the problem. Participants advocatedthe establishment of guidelines on howto respond to the detection of SSFFCmedicines and on securing the distri-bution chain to avoid the infiltration ofSSFFC medical products.The manufacture, distribution and saleof SSFFC medical products is a problemthat endangers the health of the popula-tion within all regions and Member States,and impacts on the credibility of healthservices. Globalization, free trade andInternet technology have all affectedthe way in which patients obtain theirmedicines and have made it more com-plex for national regulatory authorities toeffectively control the distribution systemsin their countries.Through the Mechanism, WHO will alsoenable strengthening of national andregional capacity by developingstrategies to prevent SSFFC medicalproducts reaching patients.Reference: SSFFC Mechanism and activitiesrelated to SSFFC medical products at http://www.who.int/medicinesSpeeding up access to qualitymedicines in AfricaTen African countries have joined a WHOinitiative that aims to speed up access tomedicines and develop local expertise inmedicines regulation.
7WHO Drug Information Vol. 27, No. 1, 2013The Accelerated Registration PilotProject is a new collaborative activitybetween medicines regulators in devel-oping countries and international expertsworking with WHO’s Prequalification ofMedicines Programme. WHO’s list ofprequalified products is a vital tool forUnited Nations agencies and otherorganizations involved in bulk purchasingof medicines.The list includes medicinesthat have been evaluated for quality,safety and efficacy based on informationfrom manufacturers and inspection ofmanufacturing and clinical sites.The Accelerated Registration PilotProject encourages national regulatoryauthorities to fast track the registrationof medicines that have already beenassessed and approved by WHO’sprequalification procedure. In manycountries, the same medicines are alsorequired to go through a national processof quality assurance before their use isauthorized. This is a lengthy, expensiveprocedure that can discourage or delaypharmaceutical companies from applyingto import their products.The Global Fund to Fight AIDS, Tuber-culosis and Malaria encourages use ofthe accelerated registration initiative andurges national authorities to use prequali-fication conclusions to avoid duplicatingwork and spending time and money on aprocedure that has already been carriedout. Some national medicines regulatoryauthorities may have limited resourcesand this project will help them to benefitfrom the international expertise and rigo-rous standards of WHO’s Prequalificationof Medicines Programme.Within the project, when a manufacturerapplies to register a prequalified pro-duct in a participating country, it agreesto share the complete prequalificationassessment and inspection file with anominated person from the nationalregulatory authority via a secure internetsite.The national authority may use theCurrent Topicsprequalification reports to make anindependent decision on whether toregister the medicine in that country.This provides an opportunity to takeadvantage of WHO prequalificationwithout losing national autonomy.The initiative establishes strong linesof communication on assessment andinspection outcomes with medicinesregulatory authorities in developingcountries and could serve as a modelfor collaboration among the authoritiesthemselves, particularly in countries withsimilar health needs.In countries which lack experts inmedicines regulation, particularly in theassessment of quality and efficacy ofmedicines, the pilot project is an oppor-tunity to build capacity and learn frombest practices. It also provides a forumfor information sharing and exchangewith WHO’s prequalification experts whoare drawn from well-resourced regulatoryauthorities around the world.A major focus is on getting productsregistered and maintaining a two-wayflow of information once the product isin use. WHO will inform the nationalauthority of any withdrawals, suspensionsor delisting of prequalified medicines andthey, in turn, will keep WHO informedof any national deregistration or issuesabout the medicine’s safety or efficacy.The accelerated registration projecthas the potential to improve medicinesregistration globally. Besides makingtreatment available to patients morerapidly, it also has a positive effect ontraining and capacity building in thepartner countries, and gives them theultimate responsibility for their own sys-tems.Reference: WHO Prequalification of Medi-cines Programme is available at http://www.who.int/prequal and http://www.who.int/fea-tures/2013/accelerated_registration/en/index.html
8WHO Drug Information Vol. 27, No. 1, 2013PQM technical support forprequalification of medicinesThe Programme for Promoting the Qualityof Medicines (PQM) is funded by the USAgency for International Development(USAID) and implemented by the USPharmacopeial Convention (USP). Its aimis to increase the availability of affordable,high-quality medicines to treat patientsworldwide suffering from multidrug-resistant tuberculosis by providingtechnical assistance at no cost to manu-facturers. The initiative has yielded its firstantituberculosis medicine, cycloserine,250 mg capsule, which has now achievedprequalification status from the WorldHealth Organization (WHO).The WHO Prequalification of MedicinesProgramme (PQP) evaluates and assuresthe quality of medicines bought by inter-national aid programmes. This improvestreatment results in developing countriesand beyond. Given the policy of manyorganizations and agencies that onlymedicines prequalified by WHO orapproved by a stringent regulatoryauthority are suitable for procurement,the increase in demand for prequalifiedproducts has stretched WHO’s resources.To address this resource gap, the PQMprogramme — which also works tocombat substandard and counterfeitmedicines in developing countries andincrease the supply of quality-assuredmedicines — offers technical assistanceby providing support to interestedmanufacturers to achieve prequalification.PQM may provide assistance duringpreparation of product dossiers forsubmission to PQP by guiding manu-facturers toward compliance with WHOgood manufacturing practices or byaddressing WHO comments on manu-facturer submissions. Assistance isparticularly focused on «second-line»antituberculosis medicines used formultidrug-resistant tuberculosis. Thisform of tuberculosis is more difficult andlengthy to manage — often requiring upto two years of treatment. Poor-qualitymedicines can lead to drug resistanceand undermine desired treatment out-comes.By expediting the process of prequalifi-cation with WHO, PQM is able to expandthe pool of viable manufacturers and,in turn, increase the supply of quality-assured medicines. Ultimately, thesemedicines can help prevent unnecessarypatient deaths, particularly amongvulnerable populations including manywomen and children.In its efforts to improve access to quality-assured medicines, the PQM technicalassistance programme also supports theGlobal Drug Facility (GDF) — a pooledprocurement system for antituberculosismedicines operated by WHO. PQM,in collaboration with GDF, USAID andWHO, identify promising manufacturerswho may then receive PQM technicalassistance.PQM offers technical assistance fortwelve types of medications to treatmultidrug-resistant tuberculosis. PQMis currently working with approximatelytwenty manufacturers of finished productsor active pharmaceutical ingredients fromaround the world to prepare products forprequalification. Some of these manu-facturers produce multiple second-linetuberculosis medicines.Through a series of workshops held inconjunction with WHO and GDF, PQMhas been reaching out to manufacturersin regions of the world with a high burdenof tuberculosis or where manufacturersare working to improve their manufactu-ring practices.Reference: PQM Press Release, 7 February2013 at http://www.usp.org/around-world/pqm-uspusaid/increasing-supply-qa-medicines.Information on US Pharmacopeial Convention(USP) is available at http://www.usp.org.Current Topics
9WHO Drug Information Vol. 27, No. 1, 2013International Generic DrugRegulator’s Pilot ProjectThe International Generic Drug Regula-tor’s Pilot Project (IGDRP) was createdto promote regulatory collaboration andconvergence in generic drug regulatoryprogrammes in order to addresschallenges posed by increasinglyheavy workloads, globalization, and thegrowing complexity of scientific issues.Following on from its previous meeting inWashington, D.C. in April 2012, IGDRPrepresentatives from the medicinesregulatory authorities of Australia, Brazil,Canada, China, Chinese Taipei, Japan,Republic of Korea, Mexico, Singapore,Switzerland and the United States ofAmerica, as well as the World HealthOrganization and the European Direc-torate for the Quality of Medicines andHealthcare, met in Nanchang, China from3–4 December 2012.Representatives discussed worksharingpossibilities in the areas of activesubstance master files (ASMFs)/drugmaster files (DMFs), exchange ofconfidential information, inspection ofsites conducting bioequivalence andbioanalytical studies, conditionsassociated with granting biowavers,and pharmaceutical quality issues.Potential efforts to assist WHO inimplementing proposed changes tothe WHO Prequalification of MedicinesProgramme as it moves toward a newoperating model were also canvassed,as were the operational possibilities ofa number of secure platforms for thesharing of confidential informationbetween agencies. The next meeting ofthe IGDRP is tentatively scheduled forApril or May 2013 in Australia.Reference: Prequalification of MedicinesProgramme at http://www.who.int/prequalCurrent Topics
10WHO Drug Information Vol. 27, No. 1, 2013Safety and Efficacy IssuesTolvaptan: risk of liver injuryUnited States of America — Health-care professionals have been notified ofsignificant liver injury associated with theuse of tolvaptan (Samsca®).In a double-blind, placebo-controlledtrial in about 1400 patients with auto-somal dominant polycystic kidney disease(ADPKD) and its open-label extensiontrial, three patients developed significantincreases in serum alanine amino-transferase with concomitant, clinicallysignificant increases in serum total biliru-bin. In the trials, the maximum daily doseadministered (90 mg in the morning and30 mg in the afternoon) was higher thanthe maximum 60 mg daily dose approvedfor the treatment of hyponatraemia.Tolvaptan is a selective vasopressinV2-receptor antagonist indicated for thetreatment of clinically significant hyper-volaemic and euvolaemic hyponatraemia.Samsca® is not approved for the treat-ment of ADPKD.Most of the liver enzyme abnormalitieswere observed during the first 18 monthsof therapy. Following discontinuation oftreatment, all three patients improved.An external panel of experts assessedthese cases as being either probably orhighly likely to be caused by tolvaptan.These findings indicate that tolvaptanhas the potential to cause irreversibleand potentially fatal liver injury. Thesedata are not adequate to exclude thepossibility that patients receivingtolvaptan for its indicated use of clinicallysignificant hypervolaemic and euvolae-mic hyponatraemia are at a potentialincreased risk for irreversible and potenti-ally fatal liver injury.Healthcare providers should performliver tests promptly in patients whoreport symptoms that may indicate liverinjury, including fatigue, anorexia, rightupper abdominal discomfort, dark urineor jaundice. If hepatic injury is suspected,tolvaptan should be promptly discon-tinued, appropriate treatment shouldbe instituted, and investigations shouldbe performed to determine probablecause. Tolvaptan should not be re-initiated in patients unless the cause forthe observed liver injury is definitivelyestablished to be unrelated to treatmentwith tolvaptan.Reference: FDA Safety Communication, 25January 2013 at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsfo-rHumanMedicalProducts/ucm336669.htmRoflumilast: risk of suicidalbehaviourUnited Kingdom — Roflumilast(Daxas®) is a phosphodiesterase-type-4(PDE4) inhibitor used for maintenancetreatment of severe chronic obstructivepulmonary disease (COPD) associatedwith chronic bronchitis. It is indicated foradult patients with a history of frequentexacerbations as an add-on to broncho-dilator treatment. The recommendeddose is one 500 microgram tablet daily.From clinical trial data, roflumilast isknown to be associated with an increasedrisk of psychiatric disorders such asinsomnia, anxiety, nervousness anddepression. Rare instances of suicidalideation and behaviour, includingcompleted suicide, have also beenobserved. A recent review of post-marketing data (unpublished) has foundthat cases of suicidal behaviour have also
11WHO Drug Information Vol. 27, No. 1, 2013been reported in patients with and withouta history of depression, usually in the firstweeks of treatment.If patients have existing psychiatricsymptoms, or if concomitant treatmentis intended with other medicines likelyto cause psychiatric symptoms, roflumi-last treatment should only be started orcontinued after careful assessment ofthe benefits and risks.Reference: Drug Safety Update, Volume 6,Number 6: S2, January 2013 at http://www.mhra.gov.uk/Safetyinformation/DrugSa-fetyUpdate/CON228753Sodium picosulfate/magnesiumcitrate: convulsionsCanada — Pico-Salax® containssodium picosulfate and magnesiumcitrate (also referred to as citric acid andmagnesium oxide) and is available as anonprescription oral purgative indicatedfor the clearance of the bowel prior tox-ray examination, endoscopy or surgery(1). In addition to Pico-Salax®, there arefour other marketed medications con-taining sodium picosulfate/magnesiumcitrate in Canada: Picodan®, Purg-Odan®, Picoflo® and Oral Purgative®.Pico-Salax® acts as an osmotic laxative,stimulates peristalsis and has a powerfulwashing out effect within 3 to 6 hours orless of administration (1). The diarrhoeaproduced by the medication can lead todehydration and loss of electrolytes,particularly sodium which may result inhyponatraemia and convulsions (1–3).Elderly and debilitated individuals areparticularly at risk. Pico-Salax® mayalso decrease the absorption of oralmedications due to an increase ingastrointestinal transit rate, and may beassociated with convulsions in patientstaking anticonvulsants (1).As of 30 June 2012, Health Canadahas received 11 reports of convulsionssuspected of being associated withPico-Salax®. Several articles in theliterature reported incidents of seizuresand hyponatraemia or emphasized therisk of electrolyte disturbances whenusing sodium picosulfate/magnesiumcitrate (4–7). It is important to replaceelectrolytes as well as fluids whenrehydrating (8). Both the risk of hypo-natraemia and decreased drug absorptionare well described in the prescribing andconsumer information for Pico-Salax®(1).Extracted from the Canadian Adverse Reac-tion Newsletter, Volume 23, Number 1,January 2013 at http://www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/carn-bcei_v23n1-engReferences1. Pico-Salax® (Magnesium oxide, citric acidand sodium picosulfate). North York (ON):Ferring Pharmaceuticals; 2012.2. Hoy SM, Scott LJ, Wagstaff AJ. Sodiumpicosulfate/magnesium citrate: A reviewof its use as a colorectal cleanser. Drugs2009;69(1):123–36.3. Sanders G, Mercer SJ, Saeb-Parsey K, etal. Randomized clinical trial of intravenousfluid replacement during bowel preparation forsurgery. Br J Surg 2001;88(10):1363–5.4. Frizelle FA, Colls BM. Hyponatremiaand seizures after bowel preparation:report of three cases. Dis Colon Rectum2005;48(2):393–6.5. Dillon CE, Laher MS. The rapid develop-ment of hyponatraemia and seizures in anelderly patient following sodium picosulfate/magnesium citrate (Picolax). Age Ageing2009;38(4):487.6. Parente F, Marino B, Crosta C. Bowelpreparation before colonoscopy in the era ofmass screening for colo-rectal cancer: Apractical approach. Dig Liver Dis 2009;41(2):87–95.7. Sarre R. Bowel preparation. AustralianPrescr 2005;28(1):16–7.Safety and Efficacy Issues
12WHO Drug Information Vol. 27, No. 1, 2013As of 30 June 2012, Health Canada hasreceived five reports of rhabdomyolysisindependent of NMS suspected of beingassociated with risperidone. All but onepatient had recovered at the time ofreporting. No deaths were reported.Reports of significant and transientelevation of CPK in stable patientswithout the presence of NMS involvingrisperidone and other antipsychoticshave been described in the literature (3,10, 11). However, the exact pathophy-siological mechanism that mediates thisassociation remains unclear. There areindividual vulnerability factors involvedin the development of rhabdomyolysisin the presence of antipsychotics (12). Ithas also been proposed, based on animalstudies, that the accumulation of sero-tonin in skeletal muscle can play a role inthe development of muscle injury (11).Health professionals should be awareof the risk of rhabdomyolysis without thepresence of NMS suspected of beingassociated with the use of risperidone.Extracted from the Canadian Adverse Reac-tion Newsletter, Volume 23, Number 1,January 2013 at http://www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/carn-bcei_v23n1-engReferences1. Risperdal® (risperidone) [product mono-graph]. Toronto (ON): Janssen Inc.; 2011.2. Vanholder R, Sever MS, Erek E, etal. Rhabdomyolysis. J Am Soc Nephrol2000;11(8):1553–61.3. Yasui N, Kondo T, Otani K, et al. Rhab-domyolysis without neuroleptic malignantsyndrome induced by additional treatment ofrisperidone. Hum Psychopharmacol Clin Exp1998;13(8):575–7.4. Clozaril® (clozapine) [product monograph].Dorval (QC): Novartis PharmaceuticalsCanada Inc.; 2012.5. Zyprexa® (olanzapine) [product mono-graph]. Toronto (ON): Eli Lilly Canada Inc.;2012.8. McQuaid KR. Chapter 15. GastrointestinalDisorders. In: Papadakis MA, McPhee SJ,Rabow MW, editors. Current Medical Diagno-sis & Treatment 2013. 52nd ed. New York:McGraw-Hill.Risperidone and rhabdomyolysisCanada — Risperidone is an atypicalantipsychotic agent indicated for the treat-ment or management of schizophrenia,inappropriate behaviour associated withsevere dementia and manic episodesassociated with Bipolar I disorder (1).All atypical antipsychotics marketed inCanada can trigger neuroleptic malignantsyndrome (NMS), and rhabdomyolysiscan be part of this syndrome.Rhabdomyolysis refers to the dis-integration of striated muscle and theconsequent release of muscular cellcontents such as myoglobin into extra-cellular fluid and circulation. Myoglobinis normally bound to plasma globulins, ofwhich a small amount may be excretedin the urine. When a massive amount ofmyoglobin is released, and the bindingcapacity of plasma proteins is surpassed,myoglobin is filtered by the glomeruli andeventually reaches the tubules, where itcan cause obstruction and may lead torenal failure (2). Clinical signs and symp-toms of rhabdomyolysis include musclepain, weakness, and dark red-colouredurine. Typically, serum creatine phospho-kinase (CPK) levels are also markedlyelevated and can be used to assess thepresence and intensity of muscle damage(2–3).Other atypical antipsychotics includingclozapine, olanzapine, quetiapine, aripi-prazole and one paliperidone product arecurrently labelled for the risk of rhabdo-myolysis independent of NMS, as well aspart of NMS, in their respective Canadianproduct monographs (4–8). Risperidoneand ziprasidone are not labelled for therisk of rhabdomyolysis independent ofNMS (1, 9).Safety and Efficacy Issues
13WHO Drug Information Vol. 27, No. 1, 20136. Seroquel® (quetiapine) [product mono-graph]. Mississauga (ON): AstraZenecaCanada Inc.; 2012.7. Abilify® (aripiprazole) [product monograph].Montreal (QC): Bristol-Myers Squibb Canada;2012.8. Invega® (paliperidone) [product mono-graph]. Toronto (ON): Janssen Inc.; 2012.9. Zeldox® (ziprasidone) [product mono-graph]. Kirkland (QC): Pfizer Canada Inc.;2011.10. Holtmann M, Meyer AE, Pitzer M, et al.Risperidone-induced marked elevation ofserum creatine kinase in adolescence: A casereport. Pharmacopsych 2003;36(6):317–8.11. Meltzer HY, Cola PA, Parsa M. Markedelevations of serum creatine kinase activityassociated with antipsychotic drug treatment.Neuropsychopharmacol 1996;15(4):395–405.12. Jermain DM, Crismon ML. Psychotropicdrug-related rhabdomyolysis. Ann Pharmaco-ther 1992;26(7–8):948–54.Docetaxel: serious respiratory-related adverse reactionsCanada — Docetaxel (Taxotere®) is aninjectable chemotherapy drug that wasfirst marketed on 31 December 1995. Itis currently indicated for the treatment ofcancer: breast, non-small cell lung, ova-rian and prostate, as well as squamouscell carcinoma of the head and neck (1).Currently, there is one generic productmarketed in Canada.Docetaxel belongs to a group of anti-neoplastic medicines known as taxaneswhich act by disrupting the microtubularnetwork essential for cell division (1).Specifically, it promotes the assembly andstabilization of microtubules and leadsto the production of microtubule bundleswithout normal function, resulting in theinhibition of mitosis in cells.Several antineoplastic drugs, includingdocetaxel, have been known to inducepulmonary toxicity, which may result in avariety of pathological syndromes rangingfrom unspecified dyspnea to pulmonarypneumonitis that may lead to permanentpulmonary fibrosis and possible death(2–3). This type of drug-associated lunginjury typically occurs as a result ofcellular dysfunction which can triggerapoptosis or by impairing the cell andtissue repair sequence (4).As of 31 July 2012, Health Canada hasreceived 31 reports of respiratory-relatedadverse reactions suspected of beingassociated with docetaxel involvingpneumonitis, interstitial lung disease(ILD), lung infiltration or respiratoryfailure. Among these cases, 23 patientsrequired hospitalization. A fatal outcomewas reported in nine cases.Several cases of serious respiratory-related adverse reactions in patientsusing docetaxel, either alone or in com-bination with other antineoplastic agents,have been reported in the literature.Reported adverse reactions includepneumonitis or interstitial pneumonitis,pulmonary infiltrates, acute respiratorydistress syndrome, respiratory failure,ILD, interstitial infiltrates and pneumo-cystis pneumonia. Some of these casesresulted in fatal outcomes (5).Extracted from the Canadian Adverse Reac-tion Newsletter, Volume 23, Number 1,January 2013 at http://www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/carn-bcei_v23n1-engReferences1. Taxotere® (docetaxel) [product mono-graph]. Laval (QC): sanofi-aventis CanadaInc.; 2012.2. Briasoulis E, Pavlidis N. Noncardiogenicpulmonary edema: An unusual and seriouscomplication of anticancer therapy. Oncologist2001;6(2):153–61.3. Danson S, Blackhall F, Hulse P, et al.Interstitial lung disease in lung cancer: Sepa-rating disease progression from treatmenteffects. Drug Saf 2005;28(2):103-13.Safety and Efficacy Issues
14WHO Drug Information Vol. 27, No. 1, 2013than for men. The FDA has prepared alist of questions and answers as anoverview of this safety issue.Reference: FDA Safety Communication, 10January 2013 at http://www.fda.gov/Drugs/DrugSafety/ucm334033.htmCombination treatment withtelaprevir, peginterferon alfa andribavirin: serious skin reactionsUnited States of America —The Foodand Drug Administration (FDA) hasreceived reports of serious skin reactions,some fatal, in patients taking the hepatitisC drug telaprevir (Incivek®) in combina-tion with the drugs peginterferon alfaand ribavirin (Incivek® combinationtreatment). Significantly, some patientsdied when they continued to receiveIncivek® combination treatment afterdeveloping a worsening, or progressiverash and systemic symptoms. As aresult, FDA has added a boxed warningto the drug label stating that Incivek®combination treatment must be imme-diately stopped in patients experiencinga rash with systemic symptoms or aprogressive severe rash. Considerationshould also be given to stopping anyother medications that may be associatedwith serious skin reactions. Typicalsystemic symptoms and signs mayinclude fever, nausea, diarrhoea, mouthsores or ulcers, facial edema, red orinflamed eyes, swelling or hepatitis.All patients with serious skin reactionsshould also receive urgent medical care.Incivek® is a hepatic C virus NS3/4Aprotease inhibitor indicated in com-bination with peginterferon alfa andribavirin for the treatment of genotype 1chronic hepatitis C in adult patients withcompensated liver disease, includingpatients who have cirrhosis, aretreatment-naïve, or who have beenpreviously received interferon-basedtreatment. Incivek® must always be usedin combination with peginterferon alfa andribavirin.4. Charpidou AG, Gkiozos I, Tsimpoukis S, etal. Therapy-induced toxicity of the lungs: Anoverview. Anticancer Res 2009;29(2):631–9.5. Read WL, Mortimer JE, Picus J. Severeinterstitial pneumonitis associated withdocetaxel administration. Cancer 2002;94(3):847–53.Zolpidem: impaired activityUnited States of America —The Foodand Drug Administration (FDA) hasnotified the public of new informationabout zolpidem, prescribed for insomnia.New data show that blood levels in somepatients may be high enough the morningafter use to impair activities that requirealertness, including driving. Zolpidem-containing products and generics includeAmbien®, Ambien CR®, Edluar®, andZolpimist®.Healthcare professionals are urgedto caution all patients using zolpidemproducts about the risks. Data showthe risk for next-morning impairmentis highest for patients taking theextended-release forms of these drugs(Ambien CR® and generics). Womenappear to be more susceptible to this riskbecause they eliminate zolpidem fromtheir bodies more slowly than men.The recommended dose of zolpidem forwomen should now be lowered from10 mg to 5 mg for immediate-releaseproducts and from 12.5 mg to 6.25 mgfor extended-release products (AmbienCR®). The FDA has also informed themanufacturers that, for men, the labelingshould recommend that healthcareprofessionals consider prescribing thelower doses ― 5 mg for immediate-release products and 6.25 mg forextended-release products.The recommended dose for Intermezzo®,a lower dose zolpidem product approvedfor middle-of-the-night awakening, is notchanging. At the time of approvalin November 2011, the label alreadyrecommended a lower dosage for womenSafety and Efficacy Issues
15WHO Drug Information Vol. 27, No. 1, 2013of natural biological tissue, known as abioprosthetic valves, has not been eva-luated and cannot be recommended.References1. Van de Werf, F, Brueckman M, ConnollySJ, et al. A comparison of dabigatran etexilatewith warfarin in patients with mechanical heartvalves: the randomized, phase II study toevaluate the safety and pharmacokinetics oforal dabigatran etexilate in patients after heartvalve replacement (RE-ALIGN). Am Heart J2012; 163:931–937.2. FDA Safety Communication, 19 December2012 at http://www.fda.gov/Drugs/DrugSafety/ucm332912.htmSodium oxybate with alcohol ordrugs: respiratory depressionUnited States of America — TheFood and Drug Administration (FDA) isreminding healthcare professionals andpatients that the combined use of sodiumoxybate (Xyrem®) with alcohol or centralnervous system (CNS) depressant drugscan markedly impair consciousness andmay lead to respiratory depression.The use of alcohol with Xyrem® is anew contraindication added to the label,which already contraindicates its usewith insomnia drugs. Use with otherCNS depressant drugs such as opioidanalgesics, benzodiazepines, sedatingantidepressants or antipsychotics,general anesthetics, and musclerelaxants should be avoided.Sodium oxybate is approved to reducecataplexy and treat daytime sleepiness inpatients with narcolepsy. Sodium oxybateis also known as gamma-hydroxybutyrate(GHB). GHB is a known drug of abuseassociated with central nervous system(CNS) adverse events, including death.Even at recommended doses, Xyrem®can cause confusion, depression, andother neuropsychiatric events.Reference: FDA Safety Communication, 17December 2012 at http://www.fda.gov/Drugs/DrugSafety/ucm332029.htmSerious skin reactions, including drugrash with eosinophilia and systemicsymptoms (or DRESS) and Stevens-Johnson Syndrome (SJS) have beenpreviously reported in patients takingIncivek® combination treatment. Ifserious skin reactions occur, all threecomponents of Incivek® combinationtreatment must be immediately dis-continued.Reference: FDA Safety Communication, 19December 2012 at http://www.fda.gov/Drugs/DrugSafety/ucm332731.htmDabigatran etexilate mesylate:not for patients with mechanicalprosthetic heart valvesUnited States of America — Healthcareprofessionals have been notified thatthe anticoagulant dabigatran etexilatemesylate (Pradaxa®) should not be usedto prevent major thromboembolic eventsin patients with mechanical heart valves,also known as mechanical prostheticheart valves. The RE-ALIGN clinical trialconducted in Europe (1) was recentlystopped because Pradaxa® users weremore likely to experience strokes, heartattacks, and blood clots forming on themechanical heart valves than were usersof the anticoagulant warfarin. There wasalso more bleeding after valve surgeryin Pradaxa® users than in the warfarinusers.Dabigatran is approved to reduce therisk of stroke and systemic embolism inpatients with non-valvular atrialfibrillation. It is not approved for patientswith atrial fibrillation caused by heartvalve problems. The FDA is requiring acontraindication of dabigatran for patientswith mechanical heart valves. Healthcareprofessionals should promptly transitionany patient with a mechanical heart valvewho is taking dabigatran to another medi-cation.The use of dabigatran in patients withanother type of valve replacement madeSafety and Efficacy Issues
16WHO Drug Information Vol. 27, No. 1, 2013Statins: risk of increased bloodsugar levels and diabetesCanada — Health Canada hasannounced a labelling update for allstatins regarding the risk of increasedblood sugar levels and a small increasedrisk of diabetes among patients alreadyat risk for the disease.Based on the review of all available data,Health Canada concluded that the riskof diabetes appears to be mainly inpatients with pre-existing risk factors fordiabetes, such as high levels of glucoseor triglycerides, obesity or high bloodpressure. Health Canada continuesto believe the overall cardiovascularbenefits of statin drugs in reducing bloodcholesterol outweigh their risks.A new warning about increased bloodsugar levels and the risk of diabetes,including information on how to identifyhigh-risk patients, has been added to thedrug labels for the six statins currentlymarketed in Canada: atorvastatin, lovas-tatin, rosuvastatin, simvastatin, pravasta-tin and fluvastatin.Reference: Health Canada Safety Alert, 24January 2013 at http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2013/16949a-eng.phpImmunomodulatory medicines:progressive multifocal leuko-encephalopathyAustralia — Immunomodulatory medi-cines have been associated with thedevelopment of progressive multifocalleukoencephalopathy. Awareness of riskfactors and early recognition of symptomsis important as early diagnosis is likely toimprove the prognosis (1).Progressive multifocal leukoencephalo-pathy (PML) is a rare, but often fatal,demyelinating disease of the centralnervous system. PML lesions are typic-ally asymmetrical demyelinated plaqueareas with irregular borders, surroundedby macrophages and irregular astrocyteswith large, multiple nuclei (2). Patientswith PML can have a variety of symptomsincluding muscle weakness, sensorydeficit, cognitive dysfunction, languageimpairment and/or coordination and gaitdifficulties (3).PML is caused by a human polyomavi-rus, the JC virus. Approximately 50% ofthe world’s population are infected withthe virus by the time they reach age 20,although most remain asymptomatic(4). After initial virus infection, the virusremains quiescent in the kidneys, bonemarrow and lymphoid tissue (3).In immunocompromised individualsthe quiescent virus can reactivate, enterthe bloodstream and then gain entryto the central nervous system where itinfects oligodendrocytes and astrocytes.Infection of these cells leads to cell death,and the resulting demyelination producesthe neurological signs and symptoms ofPML (5). Viruses isolated from the brainsof individuals with PML have a genomicrearrangement in the regulatory regionthat is not found in the strains responsiblefor initial infection (4,5).Cell-mediated immunity disorders arethe major immunological disorders thatpredispose individuals to the develop-ment of PML (4). Cases have beenreported in patients with HIV, lympho-proliferative disorders, malignancies,patients on immunosuppressive therapyafter solid organ transplantation and inrheumatic diseases such as systemiclupus erythematosus (6,7).Immunosuppressive medications thathave been associated with PML includecyclophosphamide, corticosteroids,mycophenolate mofetil and monoclonalantibodies including natalizumab,rituximab and alemtuzumab (8).The early signs of PML are often relatedto cognitive dysfunction, manifestingSafety and Efficacy Issues
17WHO Drug Information Vol. 27, No. 1, 2013as mental slowness, disorientation andbehavioural changes (2). Motor andsensory disturbance, characterized bylack of coordination, gait disturbance,ataxia, hemiparesis or visual deficits mayalso be found at the time of presentation(2). Seizures, language difficulties andheadaches can occur but are lesscommon. These signs and symptomsprogress over the course of a few weeksand death can occur weeks to monthsafter diagnosis.Australian and New Zealand reports ofPML associated with immunomodula-tory medicines (to 30 November 2012)Rituximab* 13Natalizumab 13Alemtuzumab 1Cyclophosphamide* 1Prednisolone* 1Mycophenolate mofetil# 1Tacrolimus# 1Dexamethasone# 1* Co-suspect medicines in same report.# Co-suspect medicines in same report.Improved chance of survival is associatedwith early diagnosis, younger age at diag-nosis and if the disease is limited to onelobe of the brain (1). Current treatment ofPML is limited and is generally supportivein nature. A treatment strategy for PMLin HIV-negative patients is to restore thehost adaptive immune response by stop-ping or decreasing immunosuppression(3).Recovery of the immune system can trig-ger immune reconstitution inflammatorysyndrome (IRIS). In HIV-negative patientswith PML-IRIS, the current treatment iscorticosteroids to reduce the inflammatoryresponse (3).References1.Vermersch P, Kappos L, Gold R, Foley JF,Olsson T, Cadavid D, et al. Clinical outcomesof natalizumab-associated progressivemultifocal leukoencephalopathy. Neurology2011;76:1697–704.2. Major EO. Progressive multifocal leuko-encephalopathy in patients on immuno-modulatory therapies. Annu Rev Med2010;61:35–47.3. Tan CS, Koralnik IJ. Progressive multifocalleukoencephalopathy and other disorderscaused by JC virus: clinical features andpathogenesis. Lancet Neurol 2010;9:425–37.4. Berger JR, Khalili K. The pathogenesis ofprogressive multifocal leukoencephalopathy.Discov Med 2011;12:495–503.5. Tyler KL. Progressive multifocal leuko-encephalopathy: can we reduce risk inpatients receiving biological immunomodula-tory therapies? Ann Neurol 2010;68:271–4.6. Molloy ES, Calabrese LH. Progressivemultifocal leukoencephalopathy: a nationalestimate of frequency in systemic lupuserythematosus and other rheumatic diseases.Arthritis Rheum 2009;60:3761–5.7. Holman RC, Torok TJ, Belay ED, JanssenRS, Schonberger LB. Progressive multifocalleukoencephalopathy in the United States,1979-1994: increased mortality associa-ted with HIV infection. Neuroepidemiology1998;17:303–9.8. Piccinni C, Sacripanti C, Poluzzi E, MotolaD, Magro L, Moretti U, et al. Stronger asso-ciation of drug-induced progressive multifocalleukoencephalopathy (PML) with biologicalimmunomodulating agents. Eur J ClinPharmacol 2010;66:199–206.Thyroxine and fracturesAustralia — Health professionals areadvised that the product information forthyroxine (Eutroxsig® and Oroxine®)has recently been updated to include aprecaution about the increased risk ofosteoporotic fracture associated withexcessive thyroxine doses. Control ofhypothyroidism should be monitoredregularly, especially in the elderly, and thethyroxine dose adjusted accordingly.Chronic hyperthyroidism promotes boneturnover, characterized by increases inbone resorption and in urinary excretionof calcium and phosphorus. IncreasedSafety and Efficacy Issues
18WHO Drug Information Vol. 27, No. 1, 2013Extracted from the Medicines Safety Update,Volume 4, Number 1, February 2013 at http://www.tga.gov.au/safetyReferences1.Turner MR, Camacho X, Fischer HD,Austin PC, Anderson GM, Rochon PA, et al.Levothyroxine dose and risk of fracture inolder adults: nested case-control study. BMJ2011;342:d2238.2.Flynn RW, Bonellie SR, Jung RT, MacDo-nald TM, Morris AD, Leese GP. Serum thyroid-stimulating hormone concentration and morbi-dity from cardiovascular disease and fracturesin patients on long-term thyroxine therapy.J Clin Endocrinol Metab 2010;95:186–193.Oral bowel cleansing products:serious electrolyte disturbancesAustralia — The use of oral bowelcleansing products is part of the prepara-tion for a number of medical, diagnosticand surgical procedures. These productscreate a cathartic effect by osmoticaction, resulting in a transfer of fluid andelectrolytes to the gut lumen. Markeddehydration, electrolyte abnormalities andassociated complications may occur asa result in otherwise well patients. TheTherapeutic Goods Administration (TGA)has previously alerted prescribers to therisk of severe electrolyte disturbances inassociation with the use of sodiumpicosulfate-containing products (1).Since January 2002, the TGA has re-ceived a total of 51 adverse event reportsfor these products of which 18 were re-ports of serious electrolyte disturbances.While it is known that the elderly, the frailand those with cardiac failure or renalimpairment are potentially at higher riskof an adverse event, health professionalsare reminded that serious adverse eventscan occur in patients under the age of 60years who are otherwise fit and healthy,and that this should be considered whenprescribing/dispensing these products.All patients should be reminded of theimportance of hydration and electrolytebone resorption may result in osteo-porosis and an increased risk of fracture.A similar risk appears to exist for hypo-thyroid patients receiving higher-than-needed doses of thyroxine. The elderlymay be at particularly increased risk,since thyroxine replacement needsdecrease with age, and age is anadditional risk factor for osteoporosis (1).Fracture risk with thyroxinereplacement therapyTwo recent large studies have examinedthe risk of fracture in patients on long-term thyroxine replacement. A nestedcase-control study in 213 511 Canadianthyroxine users aged over 70 followedpatients for a mean of 3.8 years (1) andan observational cohort study in 17 684Scottish thyroxine users aged 18 andover, was conducted with a medianfollow-up of 4.5 years (2). Althoughneither study measured both thyroxineand TSH levels, each found an associa-tion between either high or excessive (asmeasured by TSH suppression) thyroxinedose and fracture. As well as increasingthe risk of osteoporosis, excess thyroxinemay also increase the risk of fallssecondary to arrhythmia or muscleweakness, particularly in the elderly (1).The Product Information for thyroxine(Oroxine®, Eutroxsig®) has recently beenupdated with a new precaution aboutthe effects of thyroxine on bone mineraldensity. It is recommended that patientsreceiving thyroxine are given the mini-mum dose necessary to achieve thedesired clinical and biochemicalresponse. Prescribers should keep inmind that replacement thyroxine needsdecrease in the elderly and serum TSHshould be monitored regularly andthyroxine doses adjusted accordingly. Therisk of fracture may be greater in patientswith other risk factors for osteoporosis,including postmenopausal women, thosewith a family history or past history offracture or osteoporosis, smokers, andpatients with vitamin D deficiency.Safety and Efficacy Issues
19WHO Drug Information Vol. 27, No. 1, 2013The risk of venous thromboembolismwith these medicines is low but wellknown and warnings are included in theproduct information to alert patients andprescribers to the risks. The PRAC willevaluate all available evidence on thebenefits and risks of these medicinesand give a recommendation on whethermarketing authorization should remainas at present, be varied, suspended orrevoked, in the interest of all patients inthe European Union.The PRAC has also formally starteda review of combined contraceptivescontaining chlormadinone, desogestrel,dienogest, drospirenone, etonogestrel,gestodene, nomegestrol, norelgestrominand norgestimate, often referred toas third and fourth generation contra-ceptives.Reference: EMA Press Release, EMA/82707/2013, 8 February 2013 at http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/02/news_de-tail_001711.jsp&mid=WC0b01ac058004d5c1Fibrin sealant spray: gas embolismEuropean Union — The European Medi-cines Agency’s Committee for MedicinalProducts for Human Use (CHMP) hasrecommended a number of new instruc-tions for healthcare professionals usingthe fibrin sealants Tisseel®, Tissucol®,Artiss® and Beriplast P® (and associatednames) to optimize the safe use of thesemedicines when applied as spray duringsurgery.This follows the CHMP advice on twoother fibrin sealants, Evicel® and Quixil®,adopted in November 2012.Fibrin sealants are used in a wide rangeof surgical procedures to help reducelocal bleeding. They can be applied bydripping or spraying the solution ontobleeding tissue, where they form a fibrinclot, stopping bleeding and therebyhelping the wound to heal.replacement while taking these productsand to seek medical attention if theyexperience any signs of severe dehydra-tion, such as excessive thirst, dizziness,confusion and decreased urine output ordark coloured urine.Extracted from the Medicines Safety Update,Volume 4, Number 1, February 2013 at http://www.tga.gov.au/safetyReference: Electrolyte disturbances withsodium picosulfate bowel cleansing products.Aust Adv Drug React Bull 2002;21:1.Combined contraceptives: venousand arterial thromboembolismEuropean Union — The EuropeanMedicines Agency’s PharmacovigilanceRisk Assessment Committee (PRAC) hasformally started a safety review of Diane35® (cyproterone acetate 2 mg, ethiny-lestradiol 35µg), associated names andits generics at its February 2013 meeting.The Europe-wide review has beeninitiated at the request of the Frenchmedicines regulatory agency (ANSM),following the announcement of its planto suspend the marketing authorizationsfor Diane 35® and its generics for acnetreatment in France over the next threemonths. This was the result of ananalysis of known data, including reportsof venous and arterial thromboembolismrecorded in the French national pharma-covigilance database in association withDiane 35® and its generics over a periodof more than 20 years.These medicines have been authorizedat the level of individual Member Statesfor many years. They are widely usedacross Europe. However, their authorizeduses differ between Member States. Inmany countries they are authorized as acontraceptive in women with hormone-related conditions such as acne, hirsutismand alopecia. In France, they are onlyauthorized for the treatment of acne, butANSM has noted widespread off-labeluse as a contraceptive.Safety and Efficacy Issues
20WHO Drug Information Vol. 27, No. 1, 2013Reference: EMA Press Release, EMA/CHMP/772180/2012, 14 December 2012at http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/newsCorticosteroids: musculoskeletaladverse eventsNew Zealand — Healthcare profession-als are reminded that corticosteroids areassociated with multiple musculoskeletaladverse reactions including avascularnecrosis of the bone, osteoporosis andtendinopathies (1).Avascular necrosis of the bone isan uncommon adverse reactionassociated with corticosteroids (1, 2).Higher doses of corticosteroids areassociated with a greater risk ofavascular necrosis even when used forshort periods (2). Importantly, avascularnecrosis has also been reported withtopical application of corticosteroids (3).Osteoporosis is a common adversereaction associated with long-termcorticosteroid treatment, where up to50% of patients are affected (1, 4).Bone loss is more rapid during theearly stages of therapy, is dose-dependent and primarily occurs intrabecular bone (1, 4, 5). Daily dosesof greater than 7.5 mg prednisolone (orequivalent) have been associated witha higher risk of fracture than daily dosesof less than 2.5 mg prednisolone (orequivalent) (5).Tendinopathies associated withcorticosteroid use are predominantlyreported in the Achilles and patellartendons (6). Tendon ruptures have alsobeen reported. Tendinopathies have beenassociated mainly with oral and intra-articular corticosteroid use (6).In New Zealand, 40 reports ofmusculoskeletal adverse eventsassociated with corticosteroids werereported to the Centre for AdverseThe review of fibrin sealants was initiatedfollowing reports of gas embolism withEvicel® and Quixil® in association withthe use of spray devices that use apressure regulator to administer thesemedicines. These events appear to berelated to the use of the spray device athigher-than-recommended pressuresand/or in closer-than-recommendedproximity to the tissue surface.The Committee recommended that :• The product information should be up-dated with clear and consistent advicefor healthcare professionals regardingrecommended pressure and distance touse during spraying application.• Marketing authorization holders forthese medicines should ensure thatthey are used with pressure regula-tors that do not exceed the maximumpressure required to deliver the fibrinsealant, and that they contain labelsstating the recommended pressure anddistance.• The product information should includea warning that the risk of gas embo-lism appears to be higher when fibrinsealants are sprayed using air, ascompared to CO2, and patients shouldbe closely monitored for signs of gasembolism.• Healthcare professionals in the Euro-pean Union (EU) will receive a letteroutlining the updated information on thesafe use of these medicines.However, for Beriplast P® (and asso-ciated names), the CHMP concludedthat there is no risk associated with thisproduct because it does not requirea gas-assisted spray device duringapplication, therefore there is no risk ofgas embolism with this product whenused in accordance with prescribing ad-vice and with the recommended device.Safety and Efficacy Issues
21WHO Drug Information Vol. 27, No. 1, 2013ment and dose is regularly reviewed.Use of more than one medicine with thepotential to cause adverse musculo-skeletal effects is likely to increase therisk of an adverse reaction, such asavascular necrosis, osteoporosis andtendon disorders.Extracted from Prescriber Update, Volume33, Number 4, December 2012 at http://www.medsafe.govt.References1. Martindale: The Complete Drug ReferenceOnline. London: Pharmaceutical Press. URL:www.medicinescomplete.com.2. Nixon JE. Early diagnosis and treatment ofsteroid induced avascular necrosis of bone.BMJ 1984;288: 741–4.3. McLean CJ, Lobo RF, Brazier DJ. Cata-racts, glaucoma, and femoral avascularnecrosis caused by topical corticosteroidointment. Lancet 1995;345: 330.4. Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis: pathogenesis andmanagement. Annals of Internal Medicine1990;112: 352–64.5. van Staa TP, Leufkens HG, Abenhaim L,et al. Oral corticosteroids and fracture risk:relationship to daily and cumulative doses.Rheumatology 2000;39: 1383–9.6. Blanco I, Krahenbuhl S, Schlienger RG.Corticosteroid associated tendinopathies:an analysis of the published literature andspontaneous pharmacovigilance data. DrugSafety 2005;28: 633–43.7. Medsafe. Quinolones — a tendency torupture. Prescriber Update 2012;33(3): 23–4.Spontaneous monitoring systems are useful in detecting signals of relatively rare, serious or unexpectedadverse drug reactions. A signal is defined as “reported information on a possible causal relationshipbetween an adverse event and a drug, the relationship being unknown or incompletely documented pre-viously. Usually, more than a single report is required to generate a signal, depending upon the seriousnessof the event and the quality of the information”. All signals must be vaidated before any regulatory decisioncan be made.Safety and Efficacy IssuesReaction Monitoring (CARM) betweenJanuary 2000 and June 2012. Themajority of the reports were associatedwith prednisone (30 reports).The remaining reports were associatedwith dexamethasone (nine reports),triamcinolone (two reports) and methyl-prednisolone (one report). In two cases,the patient was on more than onecorticosteroid. It is worth noting that inall but one case of tendon rupture thepatient was also taking a quinoloneantibiotic (7).The types of musculoskeletal adversereactions reported in these 40 reports areshown below. Avascular necrosis (55.6%)and osteonecrosis (13.3%) were themost commonly reported musculoskeletaladverse reactions. Of the reported casesof avascular necrosis, two-thirds reportedavascular necrosis of the femoral head.CARM reports of musculoskeletaladverse reactions associated withcorticosteroids for the periodJanuary 2000 to June 2012Avascular necrosis 55.6%Osteonecrosis 13.3%Tendon rupture 11.1%Myalgia 6.7%Arthritis 4.4%Septic arthritis 4.4%Osteoporosis 2.2%Fracture pathological 2.2%Healthcare professionals are encourag-ed to educate patients about possibleadverse reactions associated withcorticosteroid use and to ensure treat-
22WHO Drug Information Vol. 27, No. 1, 2013Regulatory Action and NewsHerbal medicines: strengtheningassessment methodology andimproved communicationEuropean Union — In 2012, theEuropean Medicines Agency’s Committeeon Herbal Medicinal Products (HMPC)adopted 15 Community herbal mono-graphs and released seven monographsfor public consultation. A total of 114 finalmonographs have been made availablesince the HMPC was established in 2004.The monographs published to date covera large number of therapeutic areas andthe work plan of the HMPC for 2013contains 30 draft or final monographs.A Community herbal monographcomprises the HMPC’s scientific opinionon a given herbal substance and pre-parations thereof, based on theevaluation of all available scientific dataand information on the historic use ofthese herbal ingredients in the EU vis-à-vis requirements of the legislation. Theinformation contained in such mono-graphs is used by Member States tosupport the evaluation of marketingapplications from companies.As part of the 2012–2015 work pro-gramme, the HMPC will look intostrengthening its assessment method-ology and aiming for continued highquality standards for its new or revisedassessments. The first monographshaving undergone systematic review/revision will be published in 2013.The Agency has also started working onmaking the main information containedin the monographs as well as the studiesand data used by the HMPC to issue itsrecommendations more accessible to thegeneral public.Patient and consumer organizationsinvolved in the Agency’s activities haveexpressed strong support for thisinitiative which will represent a valuablesource of information on the Europeanview on herbal medicines and add tothe vast amount of information releasedby the different national regulatory autho-rities on use of herbal medicines resultingfrom their scientific work within the EUnetwork of medicines agencies.Reference: EMA Press Release, 12February 2013 at http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/landing/news_and_events.jsp&mid=WC0b01ac0580022519Advanced therapies: incentivesand strengthened interactionEuropean Union — In 2013, TheEuropean Medicines Agency’s Committeefor Advanced Therapies (CAT) expectsto review three or four marketingauthorization applications (MAAs) foradvanced-therapy medicinal products(ATMPs). This compares to threeapplications received in 2012, whichled to the authorization for treatmentof lipoprotein lipase (LPL) deficiency,a very rare inherited disorder.While the number of MAAs for advancedtherapies is still limited, an analysisof ATMPs under clinical evaluationpublished in 2012 in the journalMolecular Therapy shows that theresearch and development pipeline islarge. This is confirmed by the amount ofscientific advice provided to companiesby the CAT and the number of ATMPswhich have been classified.Among the ATMPs under development,three quarters are cell-based medicinal
23WHO Drug Information Vol. 27, No. 1, 2013 Regulatory Action and NewsThe first of these two databases, theDrug Consumption Database, is acomprehensive and structured sourceof information on drug consumption inEurope. It is the result of reviewing,compiling and updating knowledge aboutEuropean sources of data on drugutilization in out- and in-patient healthcaresettings. Information is currently availablefor 17 EU countries (Belgium, Bulgaria,Czech Republic, Denmark, Finland,France, Germany, Hungary, Italy, Latvia,Netherlands, Norway, Poland, Portugal,Spain, Sweden, and United Kingdom) upto October 2012. Work is in progress toexpand data.The second database, the PROTECTADR database, is a listing of all ADRscontained in section 4.8 of the summaryof product characteristics (SmPC) ofmedicinal products centrally authorizedin the EU. It is based on the MedicalDictionary for Regulatory Activities(MedDRA) terminology. The goal of thisdatabase is to improve the efficiencyof the detection process of ADRs byallowing quick identification and filteringor flagging of listed and unlisted ADR.This database is updated every sixmonths and currently contains informationup to 30 June 2012.Reference: EMA Press Release, 12 February2013 at http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/landing/news_and_eventsNicotinic acid/laropiprant:suspension recommendedEuropean Union — The EuropeanMedicines Agency’s Committeefor Medicinal Products for HumanUse (CHMP) has confirmed therecommendation to suspend themarketing authorization for nicotinic acid/laropiprant (Tredaptive®, Pelzont® andTrevaclyn®) used to treat adults withdyslipidaemia. The CHMP decisionfollows the recent recommendation byproducts while one quarter representsgene therapies. Products are beingdeveloped for cancer, cardiovasculardiseases and haematology-relatedconditions.In December 2012, the Committeepublished a reflection paper clarifyingthe legal basis of the classification ofmedicines as advanced therapies andprovides information on how thesemedicines are classified as gene-therapy,somatic-cell-therapy, tissue-engineeredor combined medicines. Some border-line cases and areas where scientificknowledge is limited or evolving rapidlyare alsodiscussed.In 2012, 17 applications were sub-mitted for a scientific recommendationon advanced-therapy classification. TheCAT classified 14 of these as ATMPs,compared with the 12 submitted and12 adopted in 2011. A similar number isexpected in 2013.As part of its work programme 2010–2015, CAT will continue to hold meetingson specific topics with interested partiessuch as scientific associations or tradeorganizations.Reference: EMA Press Release, 13 February2013 at http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/landing/news_and_eventsMethodologies in pharmacovigil-ance and pharmacoepidemiologyEuropean Union — The PROTECTproject, a public-private partnership forinnovative methodologies in pharmaco-vigilance and pharmacoepidemiology,coordinated by the European MedicinesAgency (EMA), has reached a crucialstage with the delivery of two databaseswhich will offer access to important dataresources for pharmacovigilance activitiesand pharmacoepidemiological studies.
24WHO Drug Information Vol. 27, No. 1, 2013Regulatory Action and Newsthe Pharmacovigilance Risk AssessmentCommittee (PRAC) to suspend thesemedicines.Doctors should no longer prescribeTredaptive®, Pelzont® or Trevaclyn® andshould review patient treatment options.A review of nicotinic acid/laropiprantwas initiated in December 2012 afternew data from a large, long-term studycalled HPS2-THRIVE became available.The results of the study, which are stillpreliminary, indicated that taking nicotinicacid/laropiprant together with a statinhas no significant additional benefit inreducing the risk of major vascularevents such as heart attack and stroke,compared with statin-alone therapy. Inaddition, a higher frequency of non-fatal but serious side effects was seenin patients taking these medicines.Reference: EMA Press Release, 18 January2013 at http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/01/news_detail_001694.jsp&mid=WC0b01ac058004d5c1Bevacizumab approved formetastatic colorectal cancerUnited States of America — The Foodand Drug Administration (FDA) hasapproved bevacizumab (Avastin®) foruse in combination with fluoropyrimidine/rinotecan or fluoropyrimidine/oxaliplatinbased chemotherapy for the treatment ofpatients with metastatic colorectal cancer(mCRC) whose disease has progressedon a first-line bevacizumab-containingregimen. Bevacizumab is a recombinanthumanized monoclonal IgG1 antibodythat binds to human vascular endothelialgrowth factor (VEGF), preventing theinteraction of VEGF to its receptors onthe surface of endothelial cells.This approval is based on the results ofa randomized, open-label, multinationaltrial enrolling patients with mCRC thatprogressed during or within three monthsof discontinuation of bevacizumab-basedcombination chemotherapy with fluoro-pyrimidine-oxaliplatin or fluoropyrimidine/irinotecan in the first line. No new safetysignals were observed in this trial. Thesafety data was consistent with theknown safety profile established inpreviously approved indications.Reference: FDA News Release, at 23 Janua-ry 2013 at http://www.fda.gov/Drugs/Informa-tionOnDrugs/ApprovedDrugs/ucm336763.htm?source=govdeliveryMercury free healthcareHealth Care Without Harm (HCWH) andthe World Health Organization (WHO) areco-leading a global initiative to achievevirtual elimination of mercury-basedthermometers and sphygmomanometersover the next decade and their substi-tution with accurate, economically viablealternatives. This initiative is based onthe Mercury in Health Care: 2005WHO Policy Paper which calls for short,medium and long-term steps to achievethe gradual substitution of mercury-basedmedical devices.This project is a component of the UNEnvironment Programme’s (UNEP)Mercury Products Partnership, which isled by the US Environmental ProtectionAgency. This broader UNEP ProductsPartnership seeks action to eliminatemercury in products such as batteries,lighting and lamps, electrical andelectronic devices, dental products,and measuring and control devices.With specific regard to the WHO/HCWHHealth Care collaborative initiative, theProducts Partnership has set theobjective of phasing out, by 2017, thedemand for mercury-containing feverthermometers and sphygmomanometersby at least 70% and to shift theproduction of all mercury-containing feverthermometers and sphygmomanometersto accurate, affordable, and safer non-mercury alternatives.
25WHO Drug Information Vol. 27, No. 1, 2013 Regulatory Action and NewsReference: EMA Press Release, 18 January2013 at http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/01/news_detail_001695.jsp&mid=WC0b01ac058004d5c1India: clinical trial conditionsamendedIndia — The Ministry of Health hasprovided rules for granting permissionand conducting inspections of clinicaltrials. Following notification of rules forproviding compensation to victims ofclinical trials, the Union Health Ministryhas now amended the Drugs andCosmetics (D&C) Rules to set conditionsfor giving permission to trials andinspection of sites.The Government issued the notificationto add a fresh rule (122 DAC) to theexisting guidelines issued by the DrugsController General of India (DCGI) whichlists all conditions for granting permissionfor clinical trials.Schedule Y, requires adherence to goodclinical practice guidelines and ethicalresearch committee approval beforeinitiating the study. It also makes trialregistration mandatory within the ClinicalTrials Registry of India before enrollingsubjects. An annual status report of eachclinical trial as to whether it is ongoing,completed or terminated must also besubmitted to the licensing authority andin case of termination of any clinicaltrial, the detailed reasons should becommunicated.The notification also stipulates the needfor reporting of serious adverse eventsduring trials, rules for medical manage-ment of the injury during trials and report-ing on compensation provided to victims.It also lays down rules relating to theinspection of sponsor premises, includingtheir employees, subsidiaries, agents,contractors, sub-contractors and trial sitesby authorized officers at any time with orUNEP has also been charged by theworld’s governments to explore thepossibility of establishing an internation-al legally binding instrument to addressmercury pollution.Reference: WHO/HCWH Health Care colla-borative initiative. Press Release. http://www.mercuryfreehealthcare.org/about.htmOcriplasmin: approved forvitreomacular tractionEuropean Union — The EuropeanMedicines Agency’s Committee forMedicinal Products for Human Use(CHMP) has recommended marketingauthorization for Jetrea®, a medicinalproduct indicated for the treatment ofadults with vitreomacular traction (VMT),an eye condition which can cause severevisual disturbance. This represents thefirst medicinal option for patients sufferingfrom this condition.The only active treatment optioncurrently available for VMT is vitrectomy,whereby the vitreous humour is removed.The post-vitrectomy patient may haveto undergo a period of four to six weekswithout being able to work or livenormally, out of which 7 to 14 daysmay be in a ‘head-down’ position toenhance the success rate of the surgicalprocedure. This ‘head-down’ posturingcan be very inconvenient for the patient,and carries a significant burden of care tofamily or friends.Jetrea® contains the new activesubstance ocriplasmin, a recombinanthuman protein derived from the yeastPichia pastoris. Ocriplasmin hasenzymatic activity against proteins inthe interface between the vitreoushumour and the retina. By breakingdown these proteins, ocriplasmin canloosen the adhesion between the vitreoushumour and the macula and can there-fore resolve traction at the macula.
26WHO Drug Information Vol. 27, No. 1, 2013Regulatory Action and Newswithout prior notice. The officers will alsohave powers to search and seize anyrecord, data, document, books, investiga-tional drugs related to the trials.The licensing authority may also imposeany additional conditions for issuance ofpermission in respect of specific clinicaltrials, if considered necessary regardingthe objective, design, subject population,subject eligibility, assessments, conductand treatment of a clinical trial.Actions that can be taken against thesponsors in the case of non-adherence tothe rules are also specified. The licensingauthority can repeal permission, debarthe investigator and sponsors after givingwarning letters in case any discrepancy isfound during the inspections.Reference: Ministry of Health and FamilyWelfare, February 2013 at http://www.cdsco.nic.in/clinical_trial.htmeSubmission Gateway release IIand eSubmission web clientEuropean Union — The EuropeanMedicines Agency’s (EMA) Gatewayrelease II and eSubmission web client arenow live for all applications for centralizedprocedure marketing authorization forhuman medicines.Gateway release II is an upgradedversion of eSubmission Gateway, theelectronic submission channel thatthe Agency launched in 2012 to allowapplicants to submit documentssupporting all types of applications forhuman medicines to the EMA securelyover the internet in the ElectronicCommon Technical Document (eCTD)format. The existing Gateway userswill see new features in the systemfunctionality such as an automatedconfirmation of the technical validationfeedback to the applicant and anautomated upload to the Agency’seCTD review system.As part of this project, the eSubmis-sion web client, which complementsthe Gateway, is now available as wellfor applicants with lower transmissionvolumes. This web-based tool may bemore suitable for small and medium-sized companies. Registered applicantscan now start submitting all types ofcentralised procedure eCTD humanapplications through the web client.Applicants who have registered and usedthe web client during the user acceptancetesting can continue submitting theirapplications without further registrationfrom 15 January 2013.The EMA strongly recommends usingGateway or the web client for all eCTDsubmissions. Submissions on physicalmedia (CD or DVD) will continue to beaccepted as an alternative methodfor the time being. It is essential thatapplicants only use one method ofsubmission as duplicate submissionsmight lead to negative technical validationand cause a delay in the processing ofthe application.Reference: EMA Press Release, 15 January2013 at http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/Deferasirox approved fornon-transfusion-dependentthalassaemiaUnited States of America — TheFood and Drug Administration (FDA)has expanded the approved use ofDeferasirox (Exjade®) to treat patientsaged 10 years and older for chronic ironoverload in non-transfusion-dependentthalassaemia (NTDT).NTDT is a milder form of thalassaemiathat does not require individuals to getfrequent red blood cell transfusions.However, over time, some patients withNTDT are still at risk for iron overload thatdamage vital organs.
27WHO Drug Information Vol. 27, No. 1, 2013 Regulatory Action and NewsThe FDA is also authorizing marketingof FerriScan® as an imaging companiondiagnostic for Exjade® therapy inpatients with NTDT. The agencypreviously cleared FerriScan® formeasuring liver iron concentration (LIC),but its use in Exjade® clinical studiesto select patients for therapy, and tomanage therapy, defined its role as anecessary imaging companion diagnostic.FerriScan® measures LIC non-invasivelyusing magnetic resonance imaging.Exjade® was previously approved fortreatment of chronic iron overload due toblood transfusions in patients aged2 years and older.Reference: FDA News Release, at 23January 2013 at http://www.fda.gov/Drugs/NewsEvents/ucm130958.htmPomalidomide approved foradvanced multiple myelomaUnited States of America — The Foodand Drug Administration (FDA) hasapproved pomalidomide (Pomalyst®)to treat patients with multiple myelomawhose disease progressed after beingtreated with other cancer drugs.Pomalyst® is intended for patients whohave received at least two prior therapies,including lenalidomide and bortezomib,and whose disease did not respond totreatment and progressed within 60 daysof the last treatment.Pomalyst carries a boxed warning thatthe drug should not be used in pregnantwomen because it can cause severelife-threatening birth defects, and that thedrug can cause blood clots. Because ofthe embryo-fetal risk, it is available onlythrough the Pomalyst® Risk Evaluationand Mitigation Strategy (REMS)Programme.Common side effects include neutro-penia, anaemia, constipation, diarrhoea,thrombocytopenia, upper respiratory tractinfections, back pain and fever.Reference: FDA News Release, at 8 February 2013 at http://www.fda.gov/Drugs/NewsE-vents/ucm130958.htmNalmefene approved for reductionof alcohol consumptionEuropean Union —The EuropeanMedicines Agency’s Committee for Medi-cinal Products for Human Use (CHMP)has recommended the granting of amarketing authorization for nalmefene(Selincro®), a medicinal product intendedfor the reduction of alcohol consumptionin adults with alcohol dependence. Nal-mefene is an opioid receptor antagonist.Selincro® is indicated to help loweralcohol consumption in adults withalcohol dependence who have aconsumption of more than 60 g ofalcohol per day for males, and morethan 40 g of alcohol per day for females,who do not have physical withdrawalsymptoms and who do not requireimmediate detoxification.The Committee also recommendedthat Selincro® should be prescribed inconjunction with continuous psychosocialsupport that focuses on treatmentadherence and reducing alcoholconsumption. The medicine should onlybe prescribed to patients who continue tohave a high drinking risk level two weeksafter initial assessment.Reference: EMA Press Release, EMA/CHMP/786305/2012, 14 December 2012 athttp://www.ema.europa.eu/ema/Mipomersen sodium andlomitapide approved forinherited cholesterol disorderUnited States of America — The Foodand Drug Administration has approvedmipomersen sodium (Kynamro®)injection as an addition to lipid-lowering
28WHO Drug Information Vol. 27, No. 1, 2013Regulatory Action and Newsmedications and diet to treat patientswith homozygous familial hyper-cholesterolemia (HoFH). The additionof Kynamro® helps to reduce low-density lipoprotein-cholesterol (LDL-C),apolipoprotein B, total cholesterol, andnon-high density lipoprotein-cholesterol(non HDL-C).In December 2012, the FDA alsoapproved lomitapide (Juxtapid®)to reduce LDL-C, total cholesterol,apolipoprotein B, and non HDL-C inpatients with HoFH.HoFH, an inherited condition that occurswhen the body is unable to remove LDL-C from the blood causing abnormallyhigh levels of circulating LDL-C. Forthose with HoFH, heart attacks anddeath often occur before age 30.The most common adverse reactionsin the clinical trial included injection sitereactions, flu-like symptoms, nausea,headache and serum transaminases.Reference: FDA News Release, at 29 Janua-ry 2013 at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm337195.htmMemantine: Imatinib mesilate:marketing authorizationapplication withdrawalEuropean Union —The European Medi-cines Agency (EMA) has been notifiedby the manufacturer of its decision towithdraw its application for centralizedmarketing authorization for the medicinememantine (Memantine FGK®), 7 mg,14 mg, 21 mg and 28 mg, prolonged-release hard capsule. It was intended tobe used for the treatment of patients withmoderate to severe Alzheimer disease.In its letter, the company stated that it iswithdrawing the application for strategicreasons.Reference: EMA Press Release, 15 January2013 at http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/01/news_detail_001689.jsp&mid=WC0b01ac058004d5c1Imatinib mesilate: marketingauthorization applicationwithdrawalEuropean Union —The EuropeanMedicines Agency (EMA) has beennotified by the manufacturer of itsdecision to withdraw the application fora centralized marketing authorization forthe medicine imatinib mesilate (Ruvise®),100- and 400-mg film-coated tablets. Itwas intended to be used for adults asadd-on therapy for the treatment ofpulmonary arterial hypertension (PAH).The company has withdrawn theapplication since additional data arerequired to address CHMP questionsrelating to the benefit-risk assessmentof imatinib in PAH patients. These datawill not be available within the time-frameallowed in the centralized procedure.Reference: EMA Press Release, 24 January2013 at http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2013/01/
29WHO Drug Information Vol. 27, No. 1, 2013WHO/WIPO/WTO: health innovationand access to medicinesFor the first time, the three globalintergovernmental bodies dealing withhealth, intellectual property and tradehave pool-ed their expertise on a study ofpolicies needed to advance medical andhealth technologies and to ensure theyreach the people who need them.Promoting access to medical techno-logies and innovation: intersectionsbetween public health, intellectualproperty and trade was launched by theWorld Health Organization (WHO), WorldIntellectual Property Organization (WIPO)and World Trade Organization (WTO).Public health remains a clear impera-tive for the international community, andpromoting both medical innovation andaccess to the fruits of that innovationis indispensable for progress towardsimproved and more equitable healthoutcomes. But to achieve this resultdemands greater practical cooperationand dialogue within the internationalsystem.The book covers a broad range ofcomplex, yet linked issues relating topublic health and innovation in medicaltechnologies, with the ultimate goal ofaccessibility — making medical advancesavailable globally to all who are sick. Itprovides solid information for anyoneconcerned with these issues.Its target audiences are policymakers,legislators, government officials,delegates to international organizations,nongovernmental organizations, andresearchers. The study reflects thedebate about health that has evolvedover the years, with increasingattention given to medical technologiesand their invention and dissemination.Public health and innovation policies,and the rules of trade, competition andprocurement, all play a part.The policy-making focus has broadenedfrom the basic questions of ensuringaccess to essential medicines, anddeveloping treatments for neglecteddiseases that are available and affordablefor those who are primarily affected —the poor. This is part of the right to health.More recently, attention has turned toother aspects of how to meet this right:including the measures that are neededto provide incentives for medical innova-tion — such as medicines, vaccines andmedical devices — and how to ensureequitable access to all of these vitalmedical technologies.Part of the picture is the internationalpatent system and how governmentsimplement it domestically according tothe needs of their countries. Thepatent system is designed to supportinnovation, and offers a mechanism toensure that these innovations areaccessible to society.The research and developmentpharmaceutical industry therefore reliesheavily on exclusive patent rights inorder to recoup the investment made inresearch and development, as shownby the high number of applications forpatents on medical technologies underWIPO’s Patent Cooperation Treaty.The secretariats of the three organiza-tions have drawn on their experience andthe data available to them to produceRecent Publications, Informationand Events
30WHO Drug Information Vol. 27, No. 1, 2013children to the success of MDG 4,the World Health Assembly passedResolution WHA60.20 in 2007, toinclude essential children’s medicinesin national medicine lists, procurementand reimbursement schemes.In January 2011, the EcumenicalPharmaceutical Network (EPN)conducted a study to determine theavailability and pricing of selectedessential medicines for children inchurch health facilities in Ghana. TheEPN study followed up on a 2007 WorldHealth Organization (WHO) survey ofchildren’s medicines availability in 14African capitals, which had revealed pooravailability of medicines for children inboth public and private facilities.This study was the first significant attemptto collect data on the availability of child-ren’s medicines in health facilities in Gha-na. Previous studies have focused on theavailability of medicines in general, or onall health facilities, with no focus on eitherchildren’s medicines or faith-based healthfacilities. A similar study was carried outby EPN in Chad, Kenya and Uganda.Results of the study show that zincsulphate, chlorpheniramine syrup andvitamin A had the lowest availabilities andover 40% of the facilities surveyed werenot stocking zinc sulphate dispersibletablets, vitamin A capsules and chlorphe-niramine syrup at all. Unavailability ofthese crucial medicines could largelycompromise the quality of healthcareoffered to children.Reference: Ecumenical PharmaceuticalNetwork. A study to determine the availa-bility of essential medicines for children inchurch health facilities in Ghana. http://www.epnetwork.org/childrens-medicinesIOM report on substandard andfalsified medicinesThe US Institute of Medicine (part of theAmerican Academies of Science) haspublished a report on Countering the pro-this study and to support discussions onpolicy options and legal issues.The book looks at the need for inter-national cooperation, who is involved, andhow to address the challenges that thesector is facing. It examines in detail therange of policy issues from health andhuman rights and national, regional andglobal regulation policies, to intellectualproperty, trade and tariffs, procurement,free trade agreements and other aspectsof policy.It studies a range of issues, such aspatents in the pharmaceutical sector;traditional medical knowledge, theimportance of knowing what is patentedand where, and how easy it is to findout, and questions of affordability andavailability of medicines and marketfailure.It looks at the development of medicaltechnologies, modern research anddevelopment, ways of providing incen-tives for innovation, and ways of dealingwith market failures, in particular withnew products for treating neglecteddiseases. It also includes comprehensivesections on trade and intellectual propertyrules and the flexibilities they containfor governments to meet various publichealth objectives.Reference: World Health Organization(WHO), World Intellectual Property Organi-zation (WIPO) and World Trade Organization(WTO). Promoting access to medical techno-logies and innovation: intersections betweenpublic health, intellectual property and trade.Available from WHO Press at firstname.lastname@example.orgEPN study: availability and pricingof children’s medicines in GhanaThe continuous availability of affordablemedicines for children is necessary forcountries to reduce infant mortality, inkeeping with Millennium DevelopmentGoal (MDG) 4. In recognition of theimportance of availability of medicines forRecent Publications, Information and Events