WHO Drug Information Vol. 27, No. 1, 2013

WHO Drug Information

Contents

Access to Blood Products Combined contraceptives: venous Access to safe and effective blood and arterial thromboembolism 19 products in low and middle income Fibrin sealant spray: gas embolism 19 countries 3 Corticosteroids: musculoskeletal adverse events 20 Current Topics Mechanism to combat substandard/ Regulatory Action and News spurious/falsely-labelled/falsified/ Herbal medicines: strengthening counterfeit medical products 6 assessment methodology and Speeding up access to quality improved communication 22 medicines in Africa 6 Advanced therapies: incentives and PQM technical support for strengthened interaction 22 prequalification of medicines 8 Methodologies in pharmacovigilance International Generic Drug Regulator’s and pharmacoepidemiology 23 Pilot Project 9 Nicotinic acid/laropiprant: suspension recommended 23 Safety and Efficacy Issues Bevacizumab approved for meta- Tolvaptan: risk of liver injury 10 static colorectal cancer 24 Roflumilast: risk of suicidal behaviour 10 Mercury free healthcare 24 Sodium picosulfate/magnesium Ocriplasmin: approved for vitreo- citrate: convulsions 11 macular traction 25 Risperidone and rhabdomyolysis 12 India: clinical trial conditions Docetaxel: serious respiratory- amended 25 related adverse reactions 13 eSubmission Gateway release II Zolpidem: impaired activity 14 and eSubmission web client 26 Combination treatment with telaprevir, Deferasirox approved for nontrans- peginterferon alfa and ribavirin: fusion-dependent thalassaemia 26 serious skin reactions 14 Pomalidomide approved for Dabigatran etexilate mesylate: not advanced multiple myeloma 27 for patients with mechanical Nalmefene approved for reduction prosthetic heart valves 15 of alcohol consumption 27 Sodium oxybate with alcohol or Mipomersen sodium and lomitapide drugs: respiratory depression 15 approved for inherited cholesterol Statins: risk of increased blood disorder 27 sugar levels and diabetes 15 Memantine: Imatinib mesilate: Immunomodulatory medicines: marketing authorization application progressive multifocal leuko- withdrawal 28 encephalopathy 16 Imatinib mesilate: marketing Thyroxine and fractures 17 authorizaation application Oral bowel cleansing products: withdrawal 29 serious electrolyte disturbances 18 ... (continued)

1 WHO Drug Information Vol. 27, No. 1, 2013

Contents (continued)

Recent Publications, Information International course on dengue 33 and Events Paediatric ACTs for the treatment of WHO/WIPO/WTO: health innovation uncomplicated malaria 33 and access to medicines 29 EPN study: availability and pricing of Consultation Document children’s medicines in Ghana 30 The International Pharmacopoeia IOM report on substandard and 4. Reference Substances and falsified medicines 30 Reference Spectra 35 HIFA: Information for healthcare providers 31 International Nonproprietary New pregnancy registry protocol 32 Names Malaria: rapid diagnostic testing 33 Recommended List No. 69 41

WHO Drug Information

Digital library

e-mail table of contents

subscriptions

available at:

http://www.who.int/druginformation

2 WHO Drug Information Vol. 27, No. 1, 2013

Access to Blood Products

Access to safe and effective not suitable for further manufacture. blood products in low and Generally accepted international standards require, among other things, middle income countries appropriate freezing and cold storage Blood products include blood and blood conditions, traceability of donors, testing components produced as single-donor to lower the residual viral risk, regulatory products for direct transfusion, so-called controls, quality systems and adherence labile blood components (i.e., red blood to good manufacturing practices (GMP). cells, platelets and plasma), as well as Improvement in quality standards, know- numerous plasma-derived medicinal how and production processes in blood products (e.g., albumin, polyvalent and establishments should therefore directly specific immunoglobulins, and blood contribute to reducing the rate of trans- coagulation factors) that are prepared mission by transfusion of blood-borne in fractionation facilities from pools of infectious diseases. thousands of plasma units. Even while the need for plasma products grows, a substantial and increasing In high-income countries (HIC), each unit volume of recovered plasma in LMIC is of whole blood collected is separated into currently being wasted. This volume has several therapeutic blood components to been estimated — based on the global both deliver the most effective treatment approximations of whole blood donations (component therapy) and to make most and the volume of recovered plasma efficient use of a precious and limited currently used for direct transfusion or for human resource. The plasma component fractionation — to be close to 9.3 million can be used directly for transfusion, or litres each year. This volume corresponds sent for further manufacture into thera- to more than 40% of world supply of peutic plasma protein concentrates. recovered plasma. Access to safe and effective blood The volume of discarded plasma is products is a major challenge in low and expected to increase substantially as middle income countries (LMIC) where the volume of blood collected to meet local blood establishments may have projected LMIC needs for red cells (the very basic facilities and systems, where primary determinant of the number of quality and safety standards need to be whole blood collections) increases and established or strengthened, and where as blood component therapy becomes blood supplies may be insufficient to meet more widely applied. This has been the medical needs. experience supported by decades of clinical data from HIC. World Health Assembly resolution WHA63.12, in addressing the avail- The challenge now is to support LMIC ability, quality and safety of blood investment in improving the quality of products, points out that in many LMIC the blood they collect by improving the a large percentage of human plasma, knowledge base, infrastructure, produc- separated from whole blood is currently tion standards and regulatory oversight in discarded. This wastage occurs in large blood establishments and by emphasizing part because the separated plasma is the positive impact that such a move

3 Blood Products and Components WHO Drug Information Vol. 27, No. 1, 2013 will have on public health. The short- epidemiology and demographics of term investment in improving local markers of blood-borne infections. production standards in blood establish- ments of countries currently discarding Overall, it is imperative for governments large volumes of plasma is a means to in LMIC to address the large wastage of improve access to essential plasma- blood and plasma estimated to occur, derived medicinal products while at the and it is clearly in their interest to do so. same time improving the quality and The process, methods, and timelines safety of the other blood components, the for improving blood collection systems safety and health of the blood donor and will vary in different countries. The gaps the long-term benefits to the public health between HIC and LMIC are significant, of national and worldwide populations. but differ from region to region. Suitable regulatory oversight is often lacking, and To examine and analyze the available in its absence progress will be faltering data, the drivers of technology transfer and at risk. Sustainability of aid provided and local production in blood establish- to many countries, largely because of the ments, and the potential benefits and AIDS pandemic, will only occur with the risks that arise from such an initiative, exertion of national will and locally appro- WHO convened a stakeholders’ work- priate regulatory and legislative action. shop in Geneva on 14–15 June 2012. Participants included representatives Another initiative intended to improve from national regulatory authorities, the safety, availability, quality, and blood collection organizations, patient accessibility of blood products is the organizations, national blood proposal endorsed by the WHO Blood programmes, plasma fractionators, Regulators Network to add whole blood members of the WHO Blood Regulators and red blood cells to the WHO Model Network, nongovernmental organizations, List of Essential Medicines (EML). This public health and funding agencies. proposal was also endorsed by the 63rd WHO Expert Committee on Biological The report of these deliberations will be Standardization and the 15th Interna- published in April 2013 and posted at tional Conference of Drug Regulatory the web site address: http://www.who.int/ Authorities. Whole blood and red cells bloodproducts. The report examines the meet the generally accepted definition volume of plasma separated from whole of medicines; they are among the most blood that is currently wasted worldwide widely prescribed therapies (an estimated and identifies challenges and opportuni- 90 million units annually worldwide), and ties and the key steps needed to improve are credited with saving millions of lives the current situation. each year.

The steps proposed should have multiple Blood is a national resource, derived from benefits, at the national, regional and voluntary public donations and processed global levels. They include strengthening into medicines to advance that same local production capacity in blood public’s health. Blood is a unique establishments in countries currently biological in that the “raw material” is discarding plasma, through transfer of the blood donor and the health of that technology and know-how, building donor is linked directly to the health of technical capacity and expertise of the recipient. The EML designates national regulatory authorities in the medicines as essential based on their whole-blood area, improving the health efficacy and safety, availability, ease of of the blood donor and blood-product use in different settings, comparative recipient, and providing data on the cost-effectiveness, and public health

4 WHO Drug Information Vol. 27, No. 1, 2013 Blood Products and Components need as judged by disease prevalence. introducing the sale of blood or payment The EML is important because in many of donors. In virtually all countries that countries it forms the basis of national have regulated blood as a medicine for drug policies. Governments and health decades, blood components derive from ministries often refer to the EML when voluntary, unremunerated donors. Listing making decisions regarding resource blood on a WHO-sponsored document allocation and health spending. should further emphasize the importance of voluntary non-remunerated blood Adding blood to the EML should encour- donation and the not-for-profit status of age investment in building local systems blood collecting organizations: policies to provide safe and effective blood which that WHO has endorsed for many years. is accessible to more patients. Although In all cases, the purpose of the EML is the cost of upgrading standards, infra- to reduce the burden of disease. The structure and regulatory oversight application to add blood to the EML will requires an initial investment, the result encourage governments to invest in is safer available blood, reduction in the infrastructure and the governance of risk of another epidemic of blood-borne blood systems, support safe blood disease transmission, and long-term collection and regulated blood prepara- societal benefit. Most HIC already tion, storage and shipment, and improve distinguish blood components as a public health. product in terms of preparation, storage and handling, from the process At the 15th International Conference of of transfusion which has traditionally Drug Regulatory Authorities, regulators been considered medical practice, and from more than 100 countries endorsed many already regulate blood components the recommendations that: as medicines. There is no conflict between the concepts • Member States should take steps to of blood as a medicine and blood dona- assure the quality, safety and avail- tion as an altruistic act. The opposite is ability of blood for transfusion, including true. Addition of whole blood and red oversight through regulation; and blood cells to the EML should benefit the development of voluntary non- • Member States are encouraged to remunerated donation by protecting the establish lists of essential medicines health of the blood donor and by raising and to include whole blood and blood the standards for safe collection, accurate components for transfusion on their screening and testing, and follow-up of lists. donors who require care. Countries that already regulate blood as a medicine These recommendations underline the oversee and protect the appropriate care objectives of Resolution WHA63.12 of the donor. Nor is there evidence that adopted in 2010 which supports access regarding blood as a medicine will pro- to quality, safe blood products at the mote commercialism of human tissue by global level.

5 WHO Drug Information Vol. 27, No. 1, 2013

Current Topics

Mechanism to combat The meeting also stressed the need substandard/spurious/falsely- to develop educational initiatives targeted at consumers, health profes- labelled/falsified/counterfeit sionals and industry to prevent SSFFC medical products medical products. It called for the development of methodologies and The Member State Mechanism on instruments to obtain more accurate Substandard/spurious/falsely-labelled/ information on the nature and magnitude falsified/counterfeit (SSFFC) Medical of the problem. Participants advocated Products was established in May 2011 by the establishment of guidelines on how the World Health Assembly at its sixty- to respond to the detection of SSFFC fifth session. The goal of the SSFFC medicines and on securing the distri- Mechanism is to promote international bution chain to avoid the infiltration of collaboration on strategies to address the SSFFC medical products. falsification of medicines from the stand- point of public health, excluding trade The manufacture, distribution and sale and intellectual property considerations. of SSFFC medical products is a problem that endangers the health of the popula- The first meeting of the Member State tion within all regions and Member States, Mechanism on SSFFC Medical Products, and impacts on the credibility of health was organized by the World Health services. Globalization, free trade and Organization (WHO) and the Argentine Internet technology have all affected Ministry of Health. On 21 November the way in which patients obtain their 2012, representatives from sixty-five medicines and have made it more com- WHO Member States met in Buenos plex for national regulatory authorities to Aires, Argentina, and agreed to pro- effectively control the distribution systems mote strengthening of action to combat in their countries. SSFFC medical products. The meeting ended with a call to all countries to jointly Through the Mechanism, WHO will also address this global public health problem enable strengthening of national and that affects millions of people worldwide. regional capacity by developing strategies to prevent SSFFC medical The 200 representatives at the meeting products reaching patients. agreed on a workplan that highlights the Reference: SSFFC Mechanism and activities importance of cooperation between dif- related to SSFFC medical products at http:// ferent national authorities and the sharing www.who.int/medicines of best practices and experiences. They agreed to establish a global committee comprising two delegates from each Speeding up access to quality WHO Region to support implementation medicines in Africa of a workplan which provides for the Ten African countries have joined a WHO reinforcement of national regulatory initiative that aims to speed up access to bodies through capacity-building and medicines and develop local expertise in networking. medicines regulation.

6 WHO Drug Information Vol. 27, No. 1, 2013 Current Topics

The Accelerated Registration Pilot prequalification reports to make an Project is a new collaborative activity independent decision on whether to between medicines regulators in devel- register the medicine in that country. oping countries and international experts This provides an opportunity to take working with WHO’s Prequalification of advantage of WHO prequalification Medicines Programme. WHO’s list of without losing national autonomy. prequalified products is a vital tool for United Nations agencies and other The initiative establishes strong lines organizations involved in bulk purchasing of communication on assessment and of medicines.The list includes medicines inspection outcomes with medicines that have been evaluated for quality, regulatory authorities in developing safety and efficacy based on information countries and could serve as a model from manufacturers and inspection of for collaboration among the authorities manufacturing and clinical sites. themselves, particularly in countries with similar health needs. The Accelerated Registration Pilot Project encourages national regulatory In countries which lack experts in authorities to fast track the registration medicines regulation, particularly in the of medicines that have already been assessment of quality and efficacy of assessed and approved by WHO’s medicines, the pilot project is an oppor- prequalification procedure. In many tunity to build capacity and learn from countries, the same medicines are also best practices. It also provides a forum required to go through a national process for information sharing and exchange of quality assurance before their use is with WHO’s prequalification experts who authorized. This is a lengthy, expensive are drawn from well-resourced regulatory procedure that can discourage or delay authorities around the world. pharmaceutical companies from applying to import their products. A major focus is on getting products registered and maintaining a two-way The Global Fund to Fight AIDS, Tuber- flow of information once the product is culosis and Malaria encourages use of in use. WHO will inform the national the accelerated registration initiative and authority of any withdrawals, suspensions urges national authorities to use prequali- or delisting of prequalified medicines and fication conclusions to avoid duplicating they, in turn, will keep WHO informed work and spending time and money on a of any national deregistration or issues procedure that has already been carried about the medicine’s safety or efficacy. out. Some national medicines regulatory authorities may have limited resources The accelerated registration project and this project will help them to benefit has the potential to improve medicines from the international expertise and rigo- registration globally. Besides making rous standards of WHO’s Prequalification treatment available to patients more of Medicines Programme. rapidly, it also has a positive effect on training and capacity building in the Within the project, when a manufacturer partner countries, and gives them the applies to register a prequalified pro- ultimate responsibility for their own sys- duct in a participating country, it agrees tems. to share the complete prequalification Reference: WHO Prequalification of Medi- assessment and inspection file with a cines Programme is available at http://www. nominated person from the national who.int/prequal and http://www.who.int/fea- regulatory authority via a secure internet tures/2013/accelerated_registration/en/index. site.The national authority may use the html

7 Current Topics WHO Drug Information Vol. 27, No. 1, 2013

PQM technical support for form of tuberculosis is more difficult and prequalification of medicines lengthy to manage — often requiring up to two years of treatment. Poor-quality The Programme for Promoting the Quality medicines can lead to drug resistance of Medicines (PQM) is funded by the US and undermine desired treatment out- Agency for International Development comes. (USAID) and implemented by the US Pharmacopeial Convention (USP). Its aim By expediting the process of prequalifi- is to increase the availability of affordable, cation with WHO, PQM is able to expand high-quality medicines to treat patients the pool of viable manufacturers and, worldwide suffering from multidrug- in turn, increase the supply of quality- resistant tuberculosis by providing assured medicines. Ultimately, these technical assistance at no cost to manu- medicines can help prevent unnecessary facturers. The initiative has yielded its first patient deaths, particularly among antituberculosis medicine, cycloserine, vulnerable populations including many 250 mg capsule, which has now achieved women and children. prequalification status from the World Health Organization (WHO). In its efforts to improve access to quality- assured medicines, the PQM technical The WHO Prequalification of Medicines assistance programme also supports the Programme (PQP) evaluates and assures Global Drug Facility (GDF) — a pooled the quality of medicines bought by inter- procurement system for antituberculosis national aid programmes. This improves medicines operated by WHO. PQM, treatment results in developing countries in collaboration with GDF, USAID and and beyond. Given the policy of many WHO, identify promising manufacturers organizations and agencies that only who may then receive PQM technical medicines prequalified by WHO or assistance. approved by a stringent regulatory authority are suitable for procurement, PQM offers technical assistance for the increase in demand for prequalified twelve types of medications to treat products has stretched WHO’s resources. multidrug-resistant tuberculosis. PQM is currently working with approximately To address this resource gap, the PQM twenty manufacturers of finished products programme — which also works to or active pharmaceutical ingredients from combat substandard and counterfeit around the world to prepare products for medicines in developing countries and prequalification. Some of these manu- increase the supply of quality-assured facturers produce multiple second-line medicines — offers technical assistance tuberculosis medicines. by providing support to interested manufacturers to achieve prequalification. Through a series of workshops held in conjunction with WHO and GDF, PQM PQM may provide assistance during has been reaching out to manufacturers preparation of product dossiers for in regions of the world with a high burden submission to PQP by guiding manu- of tuberculosis or where manufacturers facturers toward compliance with WHO are working to improve their manufactu- good manufacturing practices or by ring practices. addressing WHO comments on manu- Reference: PQM Press Release, 7 February facturer submissions. Assistance is 2013 at http://www.usp.org/around-world/pqm- particularly focused on «second-line» uspusaid/increasing-supply-qa-medicines. antituberculosis medicines used for Information on US Pharmacopeial Convention multidrug-resistant tuberculosis. This (USP) is available at http://www.usp.org.

8 WHO Drug Information Vol. 27, No. 1, 2013 Current Topics

International Generic Drug Representatives discussed worksharing Regulator’s Pilot Project possibilities in the areas of active substance master files (ASMFs)/drug The International Generic Drug Regula- master files (DMFs), exchange of tor’s Pilot Project (IGDRP) was created confidential information, inspection of to promote regulatory collaboration and sites conducting bioequivalence and convergence in generic drug regulatory bioanalytical studies, conditions programmes in order to address associated with granting biowavers, challenges posed by increasingly and pharmaceutical quality issues. heavy workloads, globalization, and the growing complexity of scientific issues. Potential efforts to assist WHO in implementing proposed changes to Following on from its previous meeting in the WHO Prequalification of Medicines Washington, D.C. in April 2012, IGDRP Programme as it moves toward a new representatives from the medicines operating model were also canvassed, regulatory authorities of Australia, Brazil, as were the operational possibilities of Canada, China, Chinese Taipei, Japan, a number of secure platforms for the Republic of Korea, Mexico, Singapore, sharing of confidential information Switzerland and the United States of between agencies. The next meeting of America, as well as the World Health the IGDRP is tentatively scheduled for Organization and the European Direc- April or May 2013 in Australia. torate for the Quality of Medicines and Healthcare, met in Nanchang, China from Reference: Prequalification of Medicines 3–4 December 2012. Programme at http://www.who.int/prequal

9 WHO Drug Information Vol. 27, No. 1, 2013

Safety and Efficacy Issues

Tolvaptan: risk of liver injury Healthcare providers should perform liver tests promptly in patients who United States of America — Health- report symptoms that may indicate liver care professionals have been notified of injury, including fatigue, anorexia, right significant liver injury associated with the upper abdominal discomfort, dark urine use of tolvaptan (Samsca®). or jaundice. If hepatic injury is suspected, tolvaptan should be promptly discon- In a double-blind, placebo-controlled tinued, appropriate treatment should trial in about 1400 patients with auto- be instituted, and investigations should somal dominant polycystic kidney disease be performed to determine probable (ADPKD) and its open-label extension cause. Tolvaptan should not be re- trial, three patients developed significant initiated in patients unless the cause for increases in serum alanine amino- the observed liver injury is definitively transferase with concomitant, clinically established to be unrelated to treatment significant increases in serum total biliru- with tolvaptan. bin. In the trials, the maximum daily dose administered (90 mg in the morning and Reference: FDA Safety Communication, 25 30 mg in the afternoon) was higher than January 2013 at http://www.fda.gov/Safety/ the maximum 60 mg daily dose approved MedWatch/SafetyInformation/SafetyAlertsfo- for the treatment of hyponatraemia. rHumanMedicalProducts/ucm336669.htm

Tolvaptan is a selective vasopressin Roflumilast: risk of suicidal V2-receptor antagonist indicated for the behaviour treatment of clinically significant hyper- volaemic and euvolaemic hyponatraemia. United Kingdom — Roflumilast Samsca® is not approved for the treat- (Daxas®) is a phosphodiesterase-type-4 ment of ADPKD. (PDE4) inhibitor used for maintenance treatment of severe chronic obstructive Most of the liver enzyme abnormalities pulmonary disease (COPD) associated were observed during the first 18 months with chronic bronchitis. It is indicated for of therapy. Following discontinuation of adult patients with a history of frequent treatment, all three patients improved. exacerbations as an add-on to broncho- An external panel of experts assessed dilator treatment. The recommended these cases as being either probably or dose is one 500 microgram tablet daily. highly likely to be caused by tolvaptan. These findings indicate that tolvaptan From clinical trial data, roflumilast is has the potential to cause irreversible known to be associated with an increased and potentially fatal liver injury. These risk of psychiatric disorders such as data are not adequate to exclude the insomnia, anxiety, nervousness and possibility that patients receiving depression. Rare instances of suicidal tolvaptan for its indicated use of clinically ideation and behaviour, including significant hypervolaemic and euvolae- completed suicide, have also been mic hyponatraemia are at a potential observed. A recent review of post- increased risk for irreversible and potenti- marketing data (unpublished) has found ally fatal liver injury. that cases of suicidal behaviour have also

10 WHO Drug Information Vol. 27, No. 1, 2013 Safety and Efficacy Issues been reported in patients with and without suspected of being associated with a history of depression, usually in the first Pico-Salax®. Several articles in the weeks of treatment. literature reported incidents of seizures and hyponatraemia or emphasized the If patients have existing psychiatric risk of electrolyte disturbances when symptoms, or if concomitant treatment using sodium picosulfate/magnesium is intended with other medicines likely citrate (4–7). It is important to replace to cause psychiatric symptoms, roflumi- electrolytes as well as fluids when last treatment should only be started or rehydrating (8). Both the risk of hypo- continued after careful assessment of natraemia and decreased drug absorption the benefits and risks. are well described in the prescribing and consumer information for Pico-Salax® Reference: Drug Safety Update, Volume 6, (1). Number 6: S2, January 2013 at http://www. mhra.gov.uk/Safetyinformation/DrugSa- Extracted from the Canadian Adverse Reac- fetyUpdate/CON228753 tion Newsletter, Volume 23, Number 1, January 2013 at http://www.hc-sc.gc.ca/dhp- Sodium picosulfate/magnesium mps/medeff/bulletin/carn-bcei_v23n1-eng citrate: convulsions References Canada — Pico-Salax® contains sodium picosulfate and magnesium 1. Pico-Salax® (Magnesium oxide, citric acid and sodium picosulfate). North York (ON): citrate (also referred to as citric acid and Ferring Pharmaceuticals; 2012. magnesium oxide) and is available as a nonprescription oral purgative indicated 2. Hoy SM, Scott LJ, Wagstaff AJ. Sodium for the clearance of the bowel prior to picosulfate/magnesium citrate: A review x-ray examination, endoscopy or surgery of its use as a colorectal cleanser. Drugs (1). In addition to Pico-Salax®, there are 2009;69(1):123–36. four other marketed medications con- taining sodium picosulfate/magnesium 3. Sanders G, Mercer SJ, Saeb-Parsey K, et citrate in Canada: Picodan®, Purg- al. Randomized clinical trial of intravenous Odan®, Picoflo® and Oral Purgative®. fluid replacement during bowel preparation for surgery. Br J Surg 2001;88(10):1363–5.

Pico-Salax® acts as an osmotic laxative, 4. Frizelle FA, Colls BM. Hyponatremia stimulates peristalsis and has a powerful and seizures after bowel preparation: washing out effect within 3 to 6 hours or report of three cases. Dis Colon Rectum less of administration (1). The diarrhoea 2005;48(2):393–6. produced by the medication can lead to dehydration and loss of electrolytes, 5. Dillon CE, Laher MS. The rapid develop- particularly sodium which may result in ment of hyponatraemia and seizures in an hyponatraemia and convulsions (1–3). elderly patient following sodium picosulfate/ magnesium citrate (Picolax). Age Ageing Elderly and debilitated individuals are 2009;38(4):487. particularly at risk. Pico-Salax® may also decrease the absorption of oral 6. Parente F, Marino B, Crosta C. Bowel medications due to an increase in preparation before colonoscopy in the era of gastrointestinal transit rate, and may be mass screening for colo-rectal cancer: A associated with convulsions in patients practical approach. Dig Liver Dis 2009; taking anticonvulsants (1). 41(2):87–95. As of 30 June 2012, Health Canada 7. Sarre R. Bowel preparation. Australian has received 11 reports of convulsions Prescr 2005;28(1):16–7.

11 Safety and Efficacy Issues WHO Drug Information Vol. 27, No. 1, 2013

8. McQuaid KR. Chapter 15. Gastrointestinal As of 30 June 2012, Health Canada has Disorders. In: Papadakis MA, McPhee SJ, received five reports of rhabdomyolysis Rabow MW, editors. Current Medical Diagno- independent of NMS suspected of being sis & Treatment 2013. 52nd ed. New York: associated with risperidone. All but one McGraw-Hill. patient had recovered at the time of reporting. No deaths were reported. Risperidone and rhabdomyolysis Reports of significant and transient elevation of CPK in stable patients Canada — Risperidone is an atypical without the presence of NMS involving antipsychotic agent indicated for the treat- risperidone and other antipsychotics ment or management of schizophrenia, have been described in the literature (3, inappropriate behaviour associated with 10, 11). However, the exact pathophy- severe dementia and manic episodes siological mechanism that mediates this associated with Bipolar I disorder (1). association remains unclear. There are All atypical antipsychotics marketed in individual vulnerability factors involved Canada can trigger neuroleptic malignant in the development of rhabdomyolysis syndrome (NMS), and rhabdomyolysis in the presence of antipsychotics (12). It can be part of this syndrome. has also been proposed, based on animal studies, that the accumulation of sero- Rhabdomyolysis refers to the dis- tonin in skeletal muscle can play a role in integration of striated muscle and the the development of muscle injury (11). consequent release of muscular cell contents such as myoglobin into extra- Health professionals should be aware cellular fluid and circulation. Myoglobin of the risk of rhabdomyolysis without the is normally bound to plasma globulins, of presence of NMS suspected of being which a small amount may be excreted associated with the use of risperidone. in the urine. When a massive amount of myoglobin is released, and the binding Extracted from the Canadian Adverse Reac- capacity of plasma proteins is surpassed, tion Newsletter, Volume 23, Number 1, myoglobin is filtered by the glomeruli and January 2013 at http://www.hc-sc.gc.ca/dhp- eventually reaches the tubules, where it mps/medeff/bulletin/carn-bcei_v23n1-eng can cause obstruction and may lead to References renal failure (2). Clinical signs and symp- toms of rhabdomyolysis include muscle 1. Risperdal® (risperidone) [product mono- pain, weakness, and dark red-coloured graph]. Toronto (ON): Janssen Inc.; 2011. urine. Typically, serum creatine phospho- kinase (CPK) levels are also markedly 2. Vanholder R, Sever MS, Erek E, et elevated and can be used to assess the al. Rhabdomyolysis. J Am Soc Nephrol presence and intensity of muscle damage 2000;11(8):1553–61. (2–3). 3. Yasui N, Kondo T, Otani K, et al. Rhab- domyolysis without neuroleptic malignant Other atypical antipsychotics including syndrome induced by additional treatment of clozapine, olanzapine, quetiapine, aripi- risperidone. Hum Psychopharmacol Clin Exp prazole and one paliperidone product are 1998;13(8):575–7. currently labelled for the risk of rhabdo- myolysis independent of NMS, as well as 4. Clozaril® (clozapine) [product monograph]. Dorval (QC): Novartis Pharmaceuticals part of NMS, in their respective Canadian Canada Inc.; 2012. product monographs (4–8). Risperidone and ziprasidone are not labelled for the 5. Zyprexa® (olanzapine) [product mono- risk of rhabdomyolysis independent of graph]. Toronto (ON): Eli Lilly Canada Inc.; NMS (1, 9). 2012.

12 WHO Drug Information Vol. 27, No. 1, 2013 Safety and Efficacy Issues

6. Seroquel® (quetiapine) [product mono- pulmonary toxicity, which may result in a graph]. Mississauga (ON): AstraZeneca variety of pathological syndromes ranging Canada Inc.; 2012. from unspecified dyspnea to pulmonary pneumonitis that may lead to permanent 7. Abilify® (aripiprazole) [product monograph]. pulmonary fibrosis and possible death Montreal (QC): Bristol-Myers Squibb Canada; 2012. (2–3). This type of drug-associated lung injury typically occurs as a result of 8. Invega® (paliperidone) [product mono- cellular dysfunction which can trigger graph]. Toronto (ON): Janssen Inc.; 2012. apoptosis or by impairing the cell and tissue repair sequence (4). 9. Zeldox® (ziprasidone) [product mono- graph]. Kirkland (QC): Pfizer Canada Inc.; As of 31 July 2012, Health Canada has 2011. received 31 reports of respiratory-related adverse reactions suspected of being 10. Holtmann M, Meyer AE, Pitzer M, et al. associated with docetaxel involving Risperidone-induced marked elevation of serum creatine kinase in adolescence: A case pneumonitis, interstitial lung disease report. Pharmacopsych 2003;36(6):317–8. (ILD), lung infiltration or respiratory failure. Among these cases, 23 patients 11. Meltzer HY, Cola PA, Parsa M. Marked required hospitalization. A fatal outcome elevations of serum creatine kinase activity was reported in nine cases. associated with antipsychotic drug treatment. Neuropsychopharmacol 1996;15(4):395–405. Several cases of serious respiratory- related adverse reactions in patients 12. Jermain DM, Crismon ML. Psychotropic using docetaxel, either alone or in com- drug-related rhabdomyolysis. Ann Pharmaco- bination with other antineoplastic agents, ther 1992;26(7–8):948–54. have been reported in the literature. Reported adverse reactions include Docetaxel: serious respiratory- pneumonitis or interstitial pneumonitis, related adverse reactions pulmonary infiltrates, acute respiratory distress syndrome, respiratory failure, Canada — Docetaxel (Taxotere®) is an ILD, interstitial infiltrates and pneumo- injectable chemotherapy drug that was cystis pneumonia. Some of these cases first marketed on 31 December 1995. It resulted in fatal outcomes (5). is currently indicated for the treatment of cancer: breast, non-small cell lung, ova- Extracted from the Canadian Adverse Reac- rian and prostate, as well as squamous tion Newsletter, Volume 23, Number 1, cell carcinoma of the head and neck (1). January 2013 at http://www.hc-sc.gc.ca/dhp- Currently, there is one generic product mps/medeff/bulletin/carn-bcei_v23n1-eng marketed in Canada. References Docetaxel belongs to a group of anti- 1. Taxotere® (docetaxel) [product mono- neoplastic medicines known as taxanes graph]. Laval (QC): sanofi-aventis Canada which act by disrupting the microtubular Inc.; 2012. network essential for cell division (1). Specifically, it promotes the assembly and 2. Briasoulis E, Pavlidis N. Noncardiogenic stabilization of microtubules and leads pulmonary edema: An unusual and serious to the production of microtubule bundles complication of anticancer therapy. Oncologist without normal function, resulting in the 2001;6(2):153–61. inhibition of mitosis in cells. 3. Danson S, Blackhall F, Hulse P, et al. Interstitial lung disease in lung cancer: Sepa- Several antineoplastic drugs, including rating disease progression from treatment docetaxel, have been known to induce effects. Drug Saf 2005;28(2):103-13.

13 Safety and Efficacy Issues WHO Drug Information Vol. 27, No. 1, 2013

4. Charpidou AG, Gkiozos I, Tsimpoukis S, et than for men. The FDA has prepared a al. Therapy-induced toxicity of the lungs: An list of questions and answers as an overview. Anticancer Res 2009;29(2):631–9. overview of this safety issue. 5. Read WL, Mortimer JE, Picus J. Severe interstitial pneumonitis associated with Reference: FDA Safety Communication, 10 docetaxel administration. Cancer 2002; January 2013 at http://www.fda.gov/Drugs/ 94(3):847–53. DrugSafety/ucm334033.htm

Zolpidem: impaired activity Combination treatment with telaprevir, peginterferon alfa and United States of America —The Food ribavirin: serious skin reactions and Drug Administration (FDA) has notified the public of new information United States of America —The Food about zolpidem, prescribed for insomnia. and Drug Administration (FDA) has New data show that blood levels in some received reports of serious skin reactions, patients may be high enough the morning some fatal, in patients taking the hepatitis after use to impair activities that require C drug telaprevir (Incivek®) in combina- alertness, including driving. Zolpidem- tion with the drugs peginterferon alfa containing products and generics include and ribavirin (Incivek® combination Ambien®, Ambien CR®, Edluar®, and treatment). Significantly, some patients Zolpimist®. died when they continued to receive Incivek® combination treatment after Healthcare professionals are urged developing a worsening, or progressive to caution all patients using zolpidem rash and systemic symptoms. As a products about the risks. Data show result, FDA has added a boxed warning the risk for next-morning impairment to the drug label stating that Incivek® is highest for patients taking the combination treatment must be imme- extended-release forms of these drugs diately stopped in patients experiencing (Ambien CR® and generics). Women a rash with systemic symptoms or a appear to be more susceptible to this risk progressive severe rash. Consideration because they eliminate zolpidem from should also be given to stopping any their bodies more slowly than men. other medications that may be associated with serious skin reactions. Typical The recommended dose of zolpidem for systemic symptoms and signs may women should now be lowered from include fever, nausea, diarrhoea, mouth 10 mg to 5 mg for immediate-release sores or ulcers, facial edema, red or products and from 12.5 mg to 6.25 mg inflamed eyes, swelling or hepatitis. for extended-release products (Ambien All patients with serious skin reactions CR®). The FDA has also informed the should also receive urgent medical care. manufacturers that, for men, the labeling should recommend that healthcare Incivek® is a hepatic C virus NS3/4A professionals consider prescribing the protease inhibitor indicated in com- lower doses ― 5 mg for immediate- bination with peginterferon alfa and release products and 6.25 mg for ribavirin for the treatment of genotype 1 extended-release products. chronic hepatitis C in adult patients with compensated liver disease, including The recommended dose for Intermezzo®, patients who have cirrhosis, are a lower dose zolpidem product approved treatment-naïve, or who have been for middle-of-the-night awakening, is not previously received interferon-based changing. At the time of approval treatment. Incivek® must always be used in November 2011, the label already in combination with peginterferon alfa and recommended a lower dosage for women ribavirin.

14 WHO Drug Information Vol. 27, No. 1, 2013 Safety and Efficacy Issues

Serious skin reactions, including drug of natural biological tissue, known as a rash with eosinophilia and systemic bioprosthetic valves, has not been eva- symptoms (or DRESS) and Stevens- luated and cannot be recommended. Johnson Syndrome (SJS) have been previously reported in patients taking References Incivek® combination treatment. If 1. Van de Werf, F, Brueckman M, Connolly serious skin reactions occur, all three SJ, et al. A comparison of dabigatran etexilate components of Incivek® combination with warfarin in patients with mechanical heart treatment must be immediately dis- valves: the randomized, phase II study to continued. evaluate the safety and pharmacokinetics of oral dabigatran etexilate in patients after heart Reference: FDA Safety Communication, 19 valve replacement (RE-ALIGN). Am Heart J December 2012 at http://www.fda.gov/Drugs/ 2012; 163:931–937. DrugSafety/ucm332731.htm 2. FDA Safety Communication, 19 December 2012 at http://www.fda.gov/Drugs/DrugSafety/ Dabigatran etexilate mesylate: ucm332912.htm not for patients with mechanical prosthetic heart valves Sodium oxybate with alcohol or

United States of America — Healthcare drugs: respiratory depression professionals have been notified that United States of America — The the anticoagulant dabigatran etexilate Food and Drug Administration (FDA) is mesylate (Pradaxa®) should not be used reminding healthcare professionals and to prevent major thromboembolic events patients that the combined use of sodium in patients with mechanical heart valves, oxybate (Xyrem®) with alcohol or central also known as mechanical prosthetic nervous system (CNS) depressant drugs heart valves. The RE-ALIGN clinical trial can markedly impair consciousness and conducted in Europe (1) was recently may lead to respiratory depression. stopped because Pradaxa® users were more likely to experience strokes, heart The use of alcohol with Xyrem® is a attacks, and blood clots forming on the new contraindication added to the label, mechanical heart valves than were users which already contraindicates its use of the anticoagulant warfarin. There was with insomnia drugs. Use with other also more bleeding after valve surgery CNS depressant drugs such as opioid in Pradaxa® users than in the warfarin analgesics, benzodiazepines, sedating users. antidepressants or antipsychotics, general anesthetics, and muscle Dabigatran is approved to reduce the relaxants should be avoided. risk of stroke and systemic embolism in patients with non-valvular atrial Sodium oxybate is approved to reduce fibrillation. It is not approved for patients cataplexy and treat daytime sleepiness in with atrial fibrillation caused by heart patients with narcolepsy. Sodium oxybate valve problems. The FDA is requiring a is also known as gamma-hydroxybutyrate contraindication of dabigatran for patients (GHB). GHB is a known drug of abuse with mechanical heart valves. Healthcare associated with central nervous system professionals should promptly transition (CNS) adverse events, including death. any patient with a mechanical heart valve Even at recommended doses, Xyrem® who is taking dabigatran to another medi- can cause confusion, depression, and cation. other neuropsychiatric events.

Reference: FDA Safety Communication, 17 The use of dabigatran in patients with December 2012 at http://www.fda.gov/Drugs/ another type of valve replacement made DrugSafety/ucm332029.htm

15 Safety and Efficacy Issues WHO Drug Information Vol. 27, No. 1, 2013

Statins: risk of increased blood areas with irregular borders, surrounded sugar levels and diabetes by macrophages and irregular astrocytes with large, multiple nuclei (2). Patients Canada — Health Canada has with PML can have a variety of symptoms announced a labelling update for all including muscle weakness, sensory statins regarding the risk of increased deficit, cognitive dysfunction, language blood sugar levels and a small increased impairment and/or coordination and gait risk of diabetes among patients already difficulties (3). at risk for the disease. PML is caused by a human polyomavi- Based on the review of all available data, rus, the JC virus. Approximately 50% of Health Canada concluded that the risk the world’s population are infected with of diabetes appears to be mainly in the virus by the time they reach age 20, patients with pre-existing risk factors for although most remain asymptomatic diabetes, such as high levels of glucose (4). After initial virus infection, the virus or triglycerides, obesity or high blood remains quiescent in the kidneys, bone pressure. Health Canada continues marrow and lymphoid tissue (3). to believe the overall cardiovascular benefits of statin drugs in reducing blood In immunocompromised individuals cholesterol outweigh their risks. the quiescent virus can reactivate, enter the bloodstream and then gain entry A new warning about increased blood to the central nervous system where it sugar levels and the risk of diabetes, infects oligodendrocytes and astrocytes. including information on how to identify Infection of these cells leads to cell death, high-risk patients, has been added to the and the resulting demyelination produces drug labels for the six statins currently the neurological signs and symptoms of marketed in Canada: atorvastatin, lovas- PML (5). Viruses isolated from the brains tatin, rosuvastatin, simvastatin, pravasta- of individuals with PML have a genomic tin and fluvastatin. rearrangement in the regulatory region that is not found in the strains responsible Reference: Health Canada Safety Alert, 24 for initial infection (4,5). January 2013 at http://healthycanadians.gc.ca/ recall-alert-rappel-avis/hc-sc/2013/16949a- Cell-mediated immunity disorders are eng.php the major immunological disorders that predispose individuals to the develop- Immunomodulatory medicines: ment of PML (4). Cases have been progressive multifocal leuko- reported in patients with HIV, lympho- encephalopathy proliferative disorders, malignancies, patients on immunosuppressive therapy Australia — Immunomodulatory medi- after solid organ transplantation and in cines have been associated with the rheumatic diseases such as systemic development of progressive multifocal lupus erythematosus (6,7). leukoencephalopathy. Awareness of risk factors and early recognition of symptoms Immunosuppressive medications that is important as early diagnosis is likely to have been associated with PML include improve the prognosis (1). cyclophosphamide, corticosteroids, mycophenolate mofetil and monoclonal Progressive multifocal leukoencephalo- antibodies including natalizumab, pathy (PML) is a rare, but often fatal, rituximab and alemtuzumab (8). demyelinating disease of the central nervous system. PML lesions are typic- The early signs of PML are often related ally asymmetrical demyelinated plaque to cognitive dysfunction, manifesting

16 WHO Drug Information Vol. 27, No. 1, 2013 Safety and Efficacy Issues as mental slowness, disorientation and 2. Major EO. Progressive multifocal leuko- behavioural changes (2). Motor and encephalopathy in patients on immuno- sensory disturbance, characterized by modulatory therapies. Annu Rev Med lack of coordination, gait disturbance, 2010;61:35–47. ataxia, hemiparesis or visual deficits may 3. Tan CS, Koralnik IJ. Progressive multifocal also be found at the time of presentation leukoencephalopathy and other disorders (2). Seizures, language difficulties and caused by JC virus: clinical features and headaches can occur but are less pathogenesis. Lancet Neurol 2010;9:425–37. common. These signs and symptoms progress over the course of a few weeks 4. Berger JR, Khalili K. The pathogenesis of and death can occur weeks to months progressive multifocal leukoencephalopathy. after diagnosis. Discov Med 2011;12:495–503. Australian and New Zealand reports of 5. Tyler KL. Progressive multifocal leuko- PML associated with immunomodula- encephalopathy: can we reduce risk in tory medicines (to 30 November 2012) patients receiving biological immunomodula- tory therapies? Ann Neurol 2010;68:271–4. Rituximab* 13 6. Molloy ES, Calabrese LH. Progressive Natalizumab 13 multifocal leukoencephalopathy: a national Alemtuzumab 1 estimate of frequency in systemic lupus Cyclophosphamide* 1 erythematosus and other rheumatic diseases. Prednisolone* 1 Arthritis Rheum 2009;60:3761–5. Mycophenolate mofetil# 1 Tacrolimus# 1 7. Holman RC, Torok TJ, Belay ED, Janssen Dexamethasone# 1 RS, Schonberger LB. Progressive multifocal leukoencephalopathy in the United States, * Co-suspect medicines in same report. 1979-1994: increased mortality associa- # Co-suspect medicines in same report. ted with HIV infection. Neuroepidemiology 1998;17:303–9. Improved chance of survival is associated with early diagnosis, younger age at diag- 8. Piccinni C, Sacripanti C, Poluzzi E, Motola D, Magro L, Moretti U, et al. Stronger asso- nosis and if the disease is limited to one ciation of drug-induced progressive multifocal lobe of the brain (1). Current treatment of leukoencephalopathy (PML) with biological PML is limited and is generally supportive immunomodulating agents. Eur J Clin in nature. A treatment strategy for PML Pharmacol 2010;66:199–206. in HIV-negative patients is to restore the host adaptive immune response by stop- Thyroxine and fractures ping or decreasing immunosuppression (3). Australia — Health professionals are advised that the product information for Recovery of the immune system can trig- thyroxine (Eutroxsig® and Oroxine®) ger immune reconstitution inflammatory has recently been updated to include a syndrome (IRIS). In HIV-negative patients precaution about the increased risk of with PML-IRIS, the current treatment is osteoporotic fracture associated with corticosteroids to reduce the inflammatory excessive thyroxine doses. Control of response (3). hypothyroidism should be monitored References regularly, especially in the elderly, and the thyroxine dose adjusted accordingly. 1.Vermersch P, Kappos L, Gold R, Foley JF, Olsson T, Cadavid D, et al. Clinical outcomes Chronic hyperthyroidism promotes bone of natalizumab-associated progressive turnover, characterized by increases in multifocal leukoencephalopathy. Neurology bone resorption and in urinary excretion 2011;76:1697–704. of calcium and phosphorus. Increased

17 Safety and Efficacy Issues WHO Drug Information Vol. 27, No. 1, 2013 bone resorption may result in osteo- Extracted from the Medicines Safety Update, porosis and an increased risk of fracture. Volume 4, Number 1, February 2013 at http:// A similar risk appears to exist for hypo- www.tga.gov.au/safety thyroid patients receiving higher-than- References needed doses of thyroxine. The elderly may be at particularly increased risk, 1.Turner MR, Camacho X, Fischer HD, since thyroxine replacement needs Austin PC, Anderson GM, Rochon PA, et al. decrease with age, and age is an Levothyroxine dose and risk of fracture in additional risk factor for osteoporosis (1). older adults: nested case-control study. BMJ 2011;342:d2238. Fracture risk with thyroxine 2.Flynn RW, Bonellie SR, Jung RT, MacDo- replacement therapy nald TM, Morris AD, Leese GP. Serum thyroid- Two recent large studies have examined stimulating hormone concentration and morbi- the risk of fracture in patients on long- dity from cardiovascular disease and fractures term thyroxine replacement. A nested in patients on long-term thyroxine therapy. case-control study in 213 511 Canadian J Clin Endocrinol Metab 2010;95:186–193. thyroxine users aged over 70 followed patients for a mean of 3.8 years (1) and Oral bowel cleansing products: an observational cohort study in 17 684 serious electrolyte disturbances Scottish thyroxine users aged 18 and over, was conducted with a median Australia — The use of oral bowel follow-up of 4.5 years (2). Although cleansing products is part of the prepara- neither study measured both thyroxine tion for a number of medical, diagnostic and TSH levels, each found an associa- and surgical procedures. These products tion between either high or excessive (as create a cathartic effect by osmotic measured by TSH suppression) thyroxine action, resulting in a transfer of fluid and dose and fracture. As well as increasing electrolytes to the gut lumen. Marked the risk of osteoporosis, excess thyroxine dehydration, electrolyte abnormalities and may also increase the risk of falls associated complications may occur as secondary to arrhythmia or muscle a result in otherwise well patients. The weakness, particularly in the elderly (1). Therapeutic Goods Administration (TGA) has previously alerted prescribers to the The Product Information for thyroxine risk of severe electrolyte disturbances in (Oroxine®, Eutroxsig®) has recently been association with the use of sodium updated with a new precaution about picosulfate-containing products (1). the effects of thyroxine on bone mineral density. It is recommended that patients Since January 2002, the TGA has re- receiving thyroxine are given the mini- ceived a total of 51 adverse event reports mum dose necessary to achieve the for these products of which 18 were re- desired clinical and biochemical ports of serious electrolyte disturbances. response. Prescribers should keep in While it is known that the elderly, the frail mind that replacement thyroxine needs and those with cardiac failure or renal decrease in the elderly and serum TSH impairment are potentially at higher risk should be monitored regularly and of an adverse event, health professionals thyroxine doses adjusted accordingly. The are reminded that serious adverse events risk of fracture may be greater in patients can occur in patients under the age of 60 with other risk factors for osteoporosis, years who are otherwise fit and healthy, including postmenopausal women, those and that this should be considered when with a family history or past history of prescribing/dispensing these products. fracture or osteoporosis, smokers, and All patients should be reminded of the patients with vitamin D deficiency. importance of hydration and electrolyte

18 WHO Drug Information Vol. 27, No. 1, 2013 Safety and Efficacy Issues replacement while taking these products The risk of venous thromboembolism and to seek medical attention if they with these medicines is low but well experience any signs of severe dehydra- known and warnings are included in the tion, such as excessive thirst, dizziness, product information to alert patients and confusion and decreased urine output or prescribers to the risks. The PRAC will dark coloured urine. evaluate all available evidence on the benefits and risks of these medicines Extracted from the Medicines Safety Update, and give a recommendation on whether Volume 4, Number 1, February 2013 at http:// marketing authorization should remain www.tga.gov.au/safety as at present, be varied, suspended or Reference: Electrolyte disturbances with revoked, in the interest of all patients in sodium picosulfate bowel cleansing products. the European Union. Aust Adv Drug React Bull 2002;21:1. The PRAC has also formally started Combined contraceptives: venous a review of combined contraceptives and arterial thromboembolism containing chlormadinone, desogestrel, dienogest, drospirenone, etonogestrel, European Union — The European gestodene, nomegestrol, norelgestromin Medicines Agency’s Pharmacovigilance and norgestimate, often referred to Risk Assessment Committee (PRAC) has as third and fourth generation contra- formally started a safety review of Diane ceptives. 35® (cyproterone acetate 2 mg, ethiny- lestradiol 35µg), associated names and Reference: EMA Press Release, EMA/ its generics at its February 2013 meeting. 82707/2013, 8 February 2013 at http://www. ema.europa.eu/ema/index.jsp?curl=pages/ The Europe-wide review has been news_and_events/news/2013/02/news_de- initiated at the request of the French tail_001711.jsp&mid=WC0b01ac058004d5c1 medicines regulatory agency (ANSM), following the announcement of its plan Fibrin sealant spray: gas embolism to suspend the marketing authorizations for Diane 35® and its generics for acne European Union — The European Medi- treatment in France over the next three cines Agency’s Committee for Medicinal months. This was the result of an Products for Human Use (CHMP) has analysis of known data, including reports recommended a number of new instruc- of venous and arterial thromboembolism tions for healthcare professionals using recorded in the French national pharma- the fibrin sealants Tisseel®, Tissucol®, covigilance database in association with Artiss® and Beriplast P® (and associated Diane 35® and its generics over a period names) to optimize the safe use of these of more than 20 years. medicines when applied as spray during surgery. These medicines have been authorized at the level of individual Member States This follows the CHMP advice on two for many years. They are widely used other fibrin sealants, Evicel® and Quixil®, across Europe. However, their authorized adopted in November 2012. uses differ between Member States. In many countries they are authorized as a Fibrin sealants are used in a wide range contraceptive in women with hormone- of surgical procedures to help reduce related conditions such as acne, hirsutism local bleeding. They can be applied by and alopecia. In France, they are only dripping or spraying the solution onto authorized for the treatment of acne, but bleeding tissue, where they form a fibrin ANSM has noted widespread off-label clot, stopping bleeding and thereby use as a contraceptive. helping the wound to heal.

19 Safety and Efficacy Issues WHO Drug Information Vol. 27, No. 1, 2013

The review of fibrin sealants was initiated Reference: EMA Press Release, EMA/ following reports of gas embolism with CHMP/772180/2012, 14 December 2012 Evicel® and Quixil® in association with at http://www.ema.europa.eu/ema/index. the use of spray devices that use a jsp?curl=pages/news_and_events/news pressure regulator to administer these medicines. These events appear to be Corticosteroids: musculoskeletal related to the use of the spray device at adverse events higher-than-recommended pressures and/or in closer-than-recommended New Zealand — Healthcare profession- proximity to the tissue surface. als are reminded that corticosteroids are associated with multiple musculoskeletal The Committee recommended that : adverse reactions including avascular necrosis of the bone, osteoporosis and • The product information should be up- tendinopathies (1). dated with clear and consistent advice Avascular necrosis of the bone is for healthcare professionals regarding an uncommon adverse reaction recommended pressure and distance to associated with corticosteroids (1, 2). use during spraying application. Higher doses of corticosteroids are associated with a greater risk of • Marketing authorization holders for avascular necrosis even when used for these medicines should ensure that short periods (2). Importantly, avascular they are used with pressure regula- necrosis has also been reported with tors that do not exceed the maximum topical application of corticosteroids (3). pressure required to deliver the fibrin sealant, and that they contain labels Osteoporosis is a common adverse stating the recommended pressure and reaction associated with long-term distance. corticosteroid treatment, where up to 50% of patients are affected (1, 4). • The product information should include Bone loss is more rapid during the a warning that the risk of gas embo- early stages of therapy, is dose- lism appears to be higher when fibrin dependent and primarily occurs in sealants are sprayed using air, as trabecular bone (1, 4, 5). Daily doses compared to CO2, and patients should of greater than 7.5 mg prednisolone (or be closely monitored for signs of gas equivalent) have been associated with embolism. a higher risk of fracture than daily doses of less than 2.5 mg prednisolone (or • Healthcare professionals in the Euro- equivalent) (5). pean Union (EU) will receive a letter outlining the updated information on the Tendinopathies associated with safe use of these medicines. corticosteroid use are predominantly reported in the Achilles and patellar However, for Beriplast P® (and asso- tendons (6). Tendon ruptures have also ciated names), the CHMP concluded been reported. Tendinopathies have been that there is no risk associated with this associated mainly with oral and intra- product because it does not require articular corticosteroid use (6). a gas-assisted spray device during application, therefore there is no risk of In New Zealand, 40 reports of gas embolism with this product when musculoskeletal adverse events used in accordance with prescribing ad- associated with corticosteroids were vice and with the recommended device. reported to the Centre for Adverse

20 WHO Drug Information Vol. 27, No. 1, 2013 Safety and Efficacy Issues

Reaction Monitoring (CARM) between ment and dose is regularly reviewed. January 2000 and June 2012. The Use of more than one medicine with the majority of the reports were associated potential to cause adverse musculo- with prednisone (30 reports). skeletal effects is likely to increase the risk of an adverse reaction, such as The remaining reports were associated avascular necrosis, osteoporosis and with dexamethasone (nine reports), tendon disorders. triamcinolone (two reports) and methyl- prednisolone (one report). In two cases, Extracted from Prescriber Update, Volume the patient was on more than one 33, Number 4, December 2012 at http://www. corticosteroid. It is worth noting that in medsafe.govt. all but one case of tendon rupture the References patient was also taking a quinolone antibiotic (7). 1. Martindale: The Complete Drug Reference Online. London: Pharmaceutical Press. URL: The types of musculoskeletal adverse www.medicinescomplete.com. reactions reported in these 40 reports are shown below. Avascular necrosis (55.6%) 2. Nixon JE. Early diagnosis and treatment of and osteonecrosis (13.3%) were the steroid induced avascular necrosis of bone. most commonly reported musculoskeletal BMJ 1984;288: 741–4. adverse reactions. Of the reported cases of avascular necrosis, two-thirds reported 3. McLean CJ, Lobo RF, Brazier DJ. Cata- racts, glaucoma, and femoral avascular avascular necrosis of the femoral head. necrosis caused by topical corticosteroid ointment. Lancet 1995;345: 330. CARM reports of musculoskeletal adverse reactions associated with 4. Lukert BP, Raisz LG. Glucocorticoid- corticosteroids for the period induced osteoporosis: pathogenesis and January 2000 to June 2012 management. Annals of Internal Medicine 1990;112: 352–64. Avascular necrosis 55.6% Osteonecrosis 13.3% 5. van Staa TP, Leufkens HG, Abenhaim L, Tendon rupture 11.1% et al. Oral corticosteroids and fracture risk: Myalgia 6.7% relationship to daily and cumulative doses. Arthritis 4.4% Rheumatology 2000;39: 1383–9. Septic arthritis 4.4% Osteoporosis 2.2% 6. Blanco I, Krahenbuhl S, Schlienger RG. Fracture pathological 2.2% Corticosteroid associated tendinopathies: an analysis of the published literature and spontaneous pharmacovigilance data. Drug Healthcare professionals are encourag- Safety 2005;28: 633–43. ed to educate patients about possible adverse reactions associated with 7. Medsafe. Quinolones — a tendency to corticosteroid use and to ensure treat- rupture. Prescriber Update 2012;33(3): 23–4.

Spontaneous monitoring systems are useful in detecting signals of relatively rare, serious or unexpected adverse drug reactions. A signal is defined as “reported information on a possible causal relationship between 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 seriousness of the event and the quality of the information”. All signals must be vaidated before any regulatory decision can be made.

21 WHO Drug Information Vol. 27, No. 1, 2013

Regulatory Action and News

Herbal medicines: strengthening Patient and consumer organizations assessment methodology and involved in the Agency’s activities have improved communication expressed strong support for this initiative which will represent a valuable European Union — In 2012, the source of information on the European European Medicines Agency’s Committee view on herbal medicines and add to on Herbal Medicinal Products (HMPC) the vast amount of information released adopted 15 Community herbal mono- by the different national regulatory autho- graphs and released seven monographs rities on use of herbal medicines resulting for public consultation. A total of 114 final from their scientific work within the EU monographs have been made available network of medicines agencies. since the HMPC was established in 2004. Reference: EMA Press Release, 12 The monographs published to date cover February 2013 at http://www.ema.europa. a large number of therapeutic areas and eu/ema/index.jsp?curl=pages/news_ the work plan of the HMPC for 2013 and_events/landing/news_and_events. contains 30 draft or final monographs. jsp&mid=WC0b01ac0580022519 A Community herbal monograph Advanced therapies: incentives comprises the HMPC’s scientific opinion and strengthened interaction on a given herbal substance and pre- parations thereof, based on the European Union — In 2013, The evaluation of all available scientific data European Medicines Agency’s Committee and information on the historic use of for Advanced Therapies (CAT) expects these herbal ingredients in the EU vis- to review three or four marketing à-vis requirements of the legislation. The authorization applications (MAAs) for information contained in such mono- advanced-therapy medicinal products graphs is used by Member States to (ATMPs). This compares to three support the evaluation of marketing applications received in 2012, which applications from companies. led to the authorization for treatment of lipoprotein lipase (LPL) deficiency, As part of the 2012–2015 work pro- a very rare inherited disorder. gramme, the HMPC will look into strengthening its assessment method- While the number of MAAs for advanced ology and aiming for continued high therapies is still limited, an analysis quality standards for its new or revised of ATMPs under clinical evaluation assessments. The first monographs published in 2012 in the journal having undergone systematic review/ Molecular Therapy shows that the revision will be published in 2013. research and development pipeline is large. This is confirmed by the amount of The Agency has also started working on scientific advice provided to companies making the main information contained by the CAT and the number of ATMPs in the monographs as well as the studies which have been classified. and data used by the HMPC to issue its recommendations more accessible to the Among the ATMPs under development, general public. three quarters are cell-based medicinal

22 WHO Drug Information Vol. 27, No. 1, 2013 Regulatory Action and News products while one quarter represents The first of these two databases, the gene therapies. Products are being Drug Consumption Database, is a developed for cancer, cardiovascular comprehensive and structured source diseases and haematology-related of information on drug consumption in conditions. Europe. It is the result of reviewing, compiling and updating knowledge about In December 2012, the Committee European sources of data on drug published a reflection paper clarifying utilization in out- and in-patient healthcare the legal basis of the classification of settings. Information is currently available medicines as advanced therapies and for 17 EU countries (Belgium, Bulgaria, provides information on how these Czech Republic, Denmark, Finland, medicines are classified as gene-therapy, France, Germany, Hungary, Italy, Latvia, somatic-cell-therapy, tissue-engineered Netherlands, Norway, Poland, Portugal, or combined medicines. Some border- Spain, Sweden, and United Kingdom) up line cases and areas where scientific to October 2012. Work is in progress to knowledge is limited or evolving rapidly expand data. are also discussed. The second database, the PROTECT ADR database, is a listing of all ADRs In 2012, 17 applications were sub- contained in section 4.8 of the summary mitted for a scientific recommendation of product characteristics (SmPC) of on advanced-therapy classification. The medicinal products centrally authorized CAT classified 14 of these as ATMPs, in the EU. It is based on the Medical compared with the 12 submitted and Dictionary for Regulatory Activities 12 adopted in 2011. A similar number is (MedDRA) terminology. The goal of this expected in 2013. database is to improve the efficiency of the detection process of ADRs by As part of its work programme 2010– allowing quick identification and filtering 2015, CAT will continue to hold meetings or flagging of listed and unlisted ADR. on specific topics with interested parties This database is updated every six such as scientific associations or trade months and currently contains information organizations. up to 30 June 2012.

Reference: EMA Press Release, 13 February Reference: EMA Press Release, 12 February 2013 at http://www.ema.europa.eu/ema/index. 2013 at http://www.ema.europa.eu/ema/index. jsp?curl=pages/news_and_events/landing/ jsp?curl=pages/news_and_events/landing/ news_and_events news_and_events

Methodologies in pharmacovigil- Nicotinic acid/laropiprant: ance and pharmacoepidemiology suspension recommended European Union — The PROTECT European Union — The European project, a public-private partnership for Medicines Agency’s Committee innovative methodologies in pharmaco- for Medicinal Products for Human vigilance and pharmacoepidemiology, Use (CHMP) has confirmed the coordinated by the European Medicines recommendation to suspend the Agency (EMA), has reached a crucial marketing authorization for nicotinic acid/ stage with the delivery of two databases laropiprant (Tredaptive®, Pelzont® and which will offer access to important data Trevaclyn®) used to treat adults with resources for pharmacovigilance activities dyslipidaemia. The CHMP decision and pharmacoepidemiological studies. follows the recent recommendation by

23 Regulatory Action and News WHO Drug Information Vol. 27, No. 1, 2013 the Pharmacovigilance Risk Assessment of discontinuation of bevacizumab-based Committee (PRAC) to suspend these combination chemotherapy with fluoro- medicines. pyrimidine-oxaliplatin or fluoropyrimidine/ irinotecan in the first line. No new safety Doctors should no longer prescribe signals were observed in this trial. The Tredaptive®, Pelzont® or Trevaclyn® and safety data was consistent with the should review patient treatment options. known safety profile established in previously approved indications. A review of nicotinic acid/laropiprant was initiated in December 2012 after Reference: FDA News Release, at 23 Janua- new data from a large, long-term study ry 2013 at http://www.fda.gov/Drugs/Informa- called HPS2-THRIVE became available. tionOnDrugs/ApprovedDrugs/ucm336763. The results of the study, which are still htm?source=govdelivery preliminary, indicated that taking nicotinic acid/laropiprant together with a statin Mercury free healthcare has no significant additional benefit in reducing the risk of major vascular Health Care Without Harm (HCWH) and events such as heart attack and stroke, the World Health Organization (WHO) are compared with statin-alone therapy. In co-leading a global initiative to achieve addition, a higher frequency of non- virtual elimination of mercury-based fatal but serious side effects was seen thermometers and sphygmomanometers in patients taking these medicines. over the next decade and their substi- tution with accurate, economically viable Reference: EMA Press Release, 18 January alternatives. This initiative is based on 2013 at http://www.ema.europa.eu/ema/ the Mercury in Health Care: 2005 index.jsp?curl=pages/news_and_events/ WHO Policy Paper which calls for short, news/2013/01/news_detail_001694. medium and long-term steps to achieve jsp&mid=WC0b01ac058004d5c1 the gradual substitution of mercury-based medical devices. Bevacizumab approved for metastatic colorectal cancer This project is a component of the UN Environment Programme’s (UNEP) United States of America — The Food Mercury Products Partnership, which is and Drug Administration (FDA) has led by the US Environmental Protection approved bevacizumab (Avastin®) for Agency. This broader UNEP Products use in combination with fluoropyrimidine/ Partnership seeks action to eliminate rinotecan or fluoropyrimidine/oxaliplatin mercury in products such as batteries, based chemotherapy for the treatment of lighting and lamps, electrical and patients with metastatic colorectal cancer electronic devices, dental products, (mCRC) whose disease has progressed and measuring and control devices. on a first-line bevacizumab-containing regimen. Bevacizumab is a recombinant With specific regard to the WHO/HCWH humanized monoclonal IgG1 antibody Health Care collaborative initiative, the that binds to human vascular endothelial Products Partnership has set the growth factor (VEGF), preventing the objective of phasing out, by 2017, the interaction of VEGF to its receptors on demand for mercury-containing fever the surface of endothelial cells. thermometers and sphygmomanometers by at least 70% and to shift the This approval is based on the results of production of all mercury-containing fever a randomized, open-label, multinational thermometers and sphygmomanometers trial enrolling patients with mCRC that to accurate, affordable, and safer non- progressed during or within three months mercury alternatives.

24 WHO Drug Information Vol. 27, No. 1, 2013 Regulatory Action and News

UNEP has also been charged by the Reference: EMA Press Release, 18 January world’s governments to explore the 2013 at http://www.ema.europa.eu/ema/ possibility of establishing an internation- index.jsp?curl=pages/news_and_events/ al legally binding instrument to address news/2013/01/news_detail_001695. mercury pollution. jsp&mid=WC0b01ac058004d5c1

Reference: WHO/HCWH Health Care colla- India: clinical trial conditions borative initiative. Press Release. http://www. amended mercuryfreehealthcare.org/about.htm India — The Ministry of Health has Ocriplasmin: approved for provided rules for granting permission and conducting inspections of clinical vitreomacular traction trials. Following notification of rules for European Union — The European providing compensation to victims of Medicines Agency’s Committee for clinical trials, the Union Health Ministry Medicinal Products for Human Use has now amended the Drugs and (CHMP) has recommended marketing Cosmetics (D&C) Rules to set conditions authorization for Jetrea®, a medicinal for giving permission to trials and product indicated for the treatment of inspection of sites. adults with vitreomacular traction (VMT), an eye condition which can cause severe The Government issued the notification visual disturbance. This represents the to add a fresh rule (122 DAC) to the first medicinal option for patients suffering existing guidelines issued by the Drugs from this condition. Controller General of India (DCGI) which lists all conditions for granting permission The only active treatment option for clinical trials. currently available for VMT is vitrectomy, Schedule Y, requires adherence to good whereby the vitreous humour is removed. clinical practice guidelines and ethical The post-vitrectomy patient may have research committee approval before to undergo a period of four to six weeks initiating the study. It also makes trial without being able to work or live registration mandatory within the Clinical normally, out of which 7 to 14 days Trials Registry of India before enrolling may be in a ‘head-down’ position to subjects. An annual status report of each enhance the success rate of the surgical clinical trial as to whether it is ongoing, procedure. This ‘head-down’ posturing completed or terminated must also be can be very inconvenient for the patient, submitted to the licensing authority and and carries a significant burden of care to in case of termination of any clinical family or friends. trial, the detailed reasons should be communicated. Jetrea® contains the new active substance ocriplasmin, a recombinant The notification also stipulates the need human protein derived from the yeast for reporting of serious adverse events Pichia pastoris. Ocriplasmin has during trials, rules for medical manage- enzymatic activity against proteins in ment of the injury during trials and report- the interface between the vitreous ing on compensation provided to victims. humour and the retina. By breaking It also lays down rules relating to the down these proteins, ocriplasmin can inspection of sponsor premises, including loosen the adhesion between the vitreous their employees, subsidiaries, agents, humour and the macula and can there- contractors, sub-contractors and trial sites fore resolve traction at the macula. by authorized officers at any time with or

25 Regulatory Action and News WHO Drug Information Vol. 27, No. 1, 2013 without prior notice. The officers will also As part of this project, the eSubmis- have powers to search and seize any sion web client, which complements record, data, document, books, investiga- the Gateway, is now available as well tional drugs related to the trials. for applicants with lower transmission volumes. This web-based tool may be The licensing authority may also impose more suitable for small and medium- any additional conditions for issuance of sized companies. Registered applicants permission in respect of specific clinical can now start submitting all types of trials, if considered necessary regarding centralised procedure eCTD human the objective, design, subject population, applications through the web client. subject eligibility, assessments, conduct and treatment of a clinical trial. Applicants who have registered and used the web client during the user acceptance Actions that can be taken against the testing can continue submitting their sponsors in the case of non-adherence to applications without further registration the rules are also specified. The licensing from 15 January 2013. authority can repeal permission, debar the investigator and sponsors after giving The EMA strongly recommends using warning letters in case any discrepancy is Gateway or the web client for all eCTD found during the inspections. submissions. Submissions on physical media (CD or DVD) will continue to be Reference: Ministry of Health and Family accepted as an alternative method Welfare, February 2013 at http://www.cdsco. for the time being. It is essential that nic.in/clinical_trial.htm applicants only use one method of submission as duplicate submissions eSubmission Gateway release II might lead to negative technical validation and eSubmission web client and cause a delay in the processing of the application. European Union — The European Medicines Agency’s (EMA) Gateway Reference: EMA Press Release, 15 January release II and eSubmission web client are 2013 at http://www.ema.europa.eu/ema/index. now live for all applications for centralized jsp?curl=pages/news_and_events/ procedure marketing authorization for human medicines. Deferasirox approved for non-transfusion-dependent Gateway release II is an upgraded thalassaemia version of eSubmission Gateway, the electronic submission channel that United States of America — The the Agency launched in 2012 to allow Food and Drug Administration (FDA) applicants to submit documents has expanded the approved use of supporting all types of applications for Deferasirox (Exjade®) to treat patients human medicines to the EMA securely aged 10 years and older for chronic iron over the internet in the Electronic overload in non-transfusion-dependent Common Technical Document (eCTD) thalassaemia (NTDT). format. The existing Gateway users will see new features in the system NTDT is a milder form of thalassaemia functionality such as an automated that does not require individuals to get confirmation of the technical validation frequent red blood cell transfusions. feedback to the applicant and an However, over time, some patients with automated upload to the Agency’s NTDT are still at risk for iron overload that eCTD review system. damage vital organs.

26 WHO Drug Information Vol. 27, No. 1, 2013 Regulatory Action and News

The FDA is also authorizing marketing thrombocytopenia, upper respiratory tract of FerriScan® as an imaging companion infections, back pain and fever. diagnostic for Exjade® therapy in patients with NTDT. The agency Reference: FDA News Release, at 8 February previously cleared FerriScan® for 2013 at http://www.fda.gov/Drugs/NewsE- vents/ucm130958.htm measuring liver iron concentration (LIC), but its use in Exjade® clinical studies to select patients for therapy, and to Nalmefene approved for reduction manage therapy, defined its role as a of alcohol consumption necessary imaging companion diagnostic. European Union —The European FerriScan® measures LIC non-invasively Medicines Agency’s Committee for Medi- using magnetic resonance imaging. cinal Products for Human Use (CHMP) has recommended the granting of a Exjade® was previously approved for marketing authorization for nalmefene treatment of chronic iron overload due to (Selincro®), a medicinal product intended blood transfusions in patients aged for the reduction of alcohol consumption 2 years and older. in adults with alcohol dependence. Nal- mefene is an opioid receptor antagonist. Reference: FDA News Release, at 23 January 2013 at http://www.fda.gov/Drugs/ Selincro® is indicated to help lower NewsEvents/ucm130958.htm alcohol consumption in adults with alcohol dependence who have a Pomalidomide approved for consumption of more than 60 g of advanced multiple myeloma alcohol per day for males, and more than 40 g of alcohol per day for females, United States of America — The Food who do not have physical withdrawal and Drug Administration (FDA) has symptoms and who do not require approved pomalidomide (Pomalyst®) immediate detoxification. to treat patients with multiple myeloma whose disease progressed after being The Committee also recommended treated with other cancer drugs. that Selincro® should be prescribed in conjunction with continuous psychosocial Pomalyst® is intended for patients who support that focuses on treatment have received at least two prior therapies, adherence and reducing alcohol including lenalidomide and bortezomib, consumption. The medicine should only and whose disease did not respond to be prescribed to patients who continue to treatment and progressed within 60 days have a high drinking risk level two weeks of the last treatment. after initial assessment.

Pomalyst carries a boxed warning that Reference: EMA Press Release, EMA/ the drug should not be used in pregnant CHMP/786305/2012, 14 December 2012 at women because it can cause severe http://www.ema.europa.eu/ema/ life-threatening birth defects, and that the drug can cause blood clots. Because of Mipomersen sodium and the embryo-fetal risk, it is available only lomitapide approved for through the Pomalyst® Risk Evaluation inherited cholesterol disorder and Mitigation Strategy (REMS) Programme. United States of America — The Food and Drug Administration has approved Common side effects include neutro- mipomersen sodium (Kynamro®) penia, anaemia, constipation, diarrhoea, injection as an addition to lipid-lowering

27 Regulatory Action and News WHO Drug Information Vol. 27, No. 1, 2013 medications and diet to treat patients 14 mg, 21 mg and 28 mg, prolonged- with homozygous familial hyper- release hard capsule. It was intended to cholesterolemia (HoFH). The addition be used for the treatment of patients with of Kynamro® helps to reduce low- moderate to severe Alzheimer disease. density lipoprotein-cholesterol (LDL-C), apolipoprotein B, total cholesterol, and In its letter, the company stated that it is non-high density lipoprotein-cholesterol withdrawing the application for strategic (non HDL-C). reasons. In December 2012, the FDA also Reference: EMA Press Release, 15 January approved lomitapide (Juxtapid®) 2013 at http://www.ema.europa.eu/ema/ index.jsp?curl=pages/news_and_events/ to reduce LDL-C, total cholesterol, news/2013/01/news_detail_001689. apolipoprotein B, and non HDL-C in jsp&mid=WC0b01ac058004d5c1 patients with HoFH. HoFH, an inherited condition that occurs Imatinib mesilate: marketing when the body is unable to remove LDL- authorization application C from the blood causing abnormally withdrawal high levels of circulating LDL-C. For those with HoFH, heart attacks and European Union —The European death often occur before age 30. Medicines Agency (EMA) has been notified by the manufacturer of its The most common adverse reactions decision to withdraw the application for in the clinical trial included injection site a centralized marketing authorization for reactions, flu-like symptoms, nausea, the medicine imatinib mesilate (Ruvise®), headache and serum transaminases. 100- and 400-mg film-coated tablets. It was intended to be used for adults as Reference: FDA News Release, at 29 Janua- add-on therapy for the treatment of ry 2013 at http://www.fda.gov/NewsEvents/ pulmonary arterial hypertension (PAH). Newsroom/PressAnnouncements/ucm337195. htm The company has withdrawn the Memantine: Imatinib mesilate: application since additional data are required to address CHMP questions marketing authorization relating to the benefit-risk assessment application withdrawal of imatinib in PAH patients. These data European Union —The European Medi- will not be available within the time-frame cines Agency (EMA) has been notified allowed in the centralized procedure. by the manufacturer of its decision to Reference: EMA Press Release, 24 January withdraw its application for centralized 2013 at http://www.ema.europa.eu/ema/ marketing authorization for the medicine index.jsp?curl=pages/news_and_events/ memantine (Memantine FGK®), 7 mg, news/2013/01/

28 WHO Drug Information Vol. 27, No. 1, 2013

Recent Publications, Information and Events

WHO/WIPO/WTO: health innovation over the years, with increasing and access to medicines attention given to medical technologies and their invention and dissemination. For the first time, the three global Public health and innovation policies, intergovernmental bodies dealing with and the rules of trade, competition and health, intellectual property and trade procurement, all play a part. have pool-ed their expertise on a study of policies needed to advance medical and The policy-making focus has broadened health technologies and to ensure they from the basic questions of ensuring reach the people who need them. access to essential medicines, and developing treatments for neglected Promoting access to medical techno- diseases that are available and affordable logies and innovation: intersections for those who are primarily affected — between public health, intellectual the poor. This is part of the right to health. property and trade was launched by the World Health Organization (WHO), World More recently, attention has turned to Intellectual Property Organization (WIPO) other aspects of how to meet this right: and World Trade Organization (WTO). including the measures that are needed to provide incentives for medical innova- Public health remains a clear impera- tion — such as medicines, vaccines and tive for the international community, and medical devices — and how to ensure promoting both medical innovation and equitable access to all of these vital access to the fruits of that innovation medical technologies. is indispensable for progress towards improved and more equitable health Part of the picture is the international outcomes. But to achieve this result patent system and how governments demands greater practical cooperation implement it domestically according to and dialogue within the international the needs of their countries. The system. patent system is designed to support innovation, and offers a mechanism to The book covers a broad range of ensure that these innovations are complex, yet linked issues relating to accessible to society. public health and innovation in medical technologies, with the ultimate goal of The research and development accessibility — making medical advances pharmaceutical industry therefore relies available globally to all who are sick. It heavily on exclusive patent rights in provides solid information for anyone order to recoup the investment made in concerned with these issues. research and development, as shown by the high number of applications for Its target audiences are policymakers, patents on medical technologies under legislators, government officials, WIPO’s Patent Cooperation Treaty. delegates to international organizations, nongovernmental organizations, and The secretariats of the three organiza- researchers. The study reflects the tions have drawn on their experience and debate about health that has evolved the data available to them to produce

29 Recent Publications, Information and Events WHO Drug Information Vol. 27, No. 1, 2013 this study and to support discussions on children to the success of MDG 4, policy options and legal issues. the World Health Assembly passed Resolution WHA60.20 in 2007, to The book looks at the need for inter- include essential children’s medicines national cooperation, who is involved, and in national medicine lists, procurement how to address the challenges that the and reimbursement schemes. sector is facing. It examines in detail the range of policy issues from health and In January 2011, the Ecumenical human rights and national, regional and Pharmaceutical Network (EPN) global regulation policies, to intellectual conducted a study to determine the property, trade and tariffs, procurement, availability and pricing of selected free trade agreements and other aspects essential medicines for children in of policy. church health facilities in Ghana. The EPN study followed up on a 2007 World It studies a range of issues, such as Health Organization (WHO) survey of patents in the pharmaceutical sector; children’s medicines availability in 14 traditional medical knowledge, the African capitals, which had revealed poor importance of knowing what is patented availability of medicines for children in and where, and how easy it is to find both public and private facilities. out, and questions of affordability and availability of medicines and market This study was the first significant attempt failure. to collect data on the availability of child- ren’s medicines in health facilities in Gha- It looks at the development of medical na. Previous studies have focused on the technologies, modern research and availability of medicines in general, or on development, ways of providing incen- all health facilities, with no focus on either tives for innovation, and ways of dealing children’s medicines or faith-based health with market failures, in particular with facilities. A similar study was carried out new products for treating neglected by EPN in Chad, Kenya and Uganda. diseases. It also includes comprehensive sections on trade and intellectual property Results of the study show that zinc rules and the flexibilities they contain sulphate, chlorpheniramine syrup and for governments to meet various public vitamin A had the lowest availabilities and health objectives. over 40% of the facilities surveyed were not stocking zinc sulphate dispersible Reference: World Health Organization tablets, vitamin A capsules and chlorphe- (WHO), World Intellectual Property Organi- niramine syrup at all. Unavailability of zation (WIPO) and World Trade Organization these crucial medicines could largely (WTO). Promoting access to medical techno- compromise the quality of healthcare logies and innovation: intersections between offered to children. public health, intellectual property and trade. Available from WHO Press at bookorders@ Reference: Ecumenical Pharmaceutical who.int Network. A study to determine the availa- bility of essential medicines for children in EPN study: availability and pricing church health facilities in Ghana. http://www. of children’s medicines in Ghana epnetwork.org/childrens-medicines The continuous availability of affordable IOM report on substandard and medicines for children is necessary for falsified medicines countries to reduce infant mortality, in keeping with Millennium Development The US Institute of Medicine (part of the Goal (MDG) 4. In recognition of the American Academies of Science) has importance of availability of medicines for published a report on Countering the pro-

30 WHO Drug Information Vol. 27, No. 1, 2013 Recent Publications, Information and Events blem of falsified and substandard drugs. HIFA: Information for The very careful development and review healthcare providers process of IOM reports is comparable to that of WHO Expert Committee reports. Access to reliable, unbiased information on medicines is fundamental to health The report identifies, in particular, care. Prescribers and users often lack the distinction between substandard, such information, especially in low- falsified and counterfeit medicines. This resource settings. Some have no is a very helpful approach to enabling a information at all, or the information meaningful discussion. The report then that they do have is commercially biased. focuses on the public health impact of As a result, countless people suffer substandard and falsified medicines harm, and sometimes death, as a result while the term counterfeit medicines is of prescribing errors such as the wrong reserved for trade-mark infringements, medicine, or the wrong dose. Further- which are considered outside the scope more, irrational prescribing promotes the of the report. Chapter three of the report emergence of drug resistance. Countless contains a comprehensive overview of people are already dying from multidrug- the extent of the problem of substandard resistant tuberculosis and other drug- and falsified medicines. resistant strains that have emerged largely because of irrational prescribing. The report also makes a number of There is a real and growing threat to the recommendations for the Food and Drug human species from new microbes that Administration (FDA), who commissioned are resistant to all known treatments. the report, and for national authorities, covering various ways and means to Each year, Healthcare Information for strengthen regulatory oversight and All (HIFA) includes a focus on a specific to promote supply chain security. For group of healthcare providers. The HIFA example, a three-step approach is Steering Group has announced the recommended, starting with registration/ focus of the HIFA 2013–15 challenge licensing of all medicine importers in a to be Meeting the information needs of country, followed by registration/ prescribers and users of medicines. A licensing of all national institutions that new page on the HIFA website has been buy/sell medicines (secondary whole- created for this purpose at http://www. salers, pharmacies, etc.) and ultimately hifa2015.org/2013-15-challenge-prescri- the use of unique identifiers of individual bers-and-users-of-medicines/ packages as a final step. This approach is in line with recent EU directives coming The HIFA vision is that every prescriber into force. and user of medicines will have access to the information and knowledge they The report also proposes the develop- need to use medicines effectively. HIFA ment of an international code of practice. is bringing together a working-group of This type of non-binding international rule volunteers to take this forward. The group would identify and promote regulatory will: and other governance measures that have proven to be effective in containing • Promote discussion on HIFA2015 on substandard and falsified medicines, and relevant issues, including drivers and could serve as an action guide. barriers to the availability and use of Reference: US Institute of Medicine. Counte- reliable information on medicines. ring the problem of falsified and substandard drugs. http://www.iom.edu/Reports/2013/ • Promote discussion on issues that are Countering-the-Problem-of-Falsified-and- particularly relevant to different groups Substandard-Drugs.aspx of prescribers and users.

31 Recent Publications, Information and Events WHO Drug Information Vol. 27, No. 1, 2013

• Harness insights and perspectives from pregnant women coming for care but also HIFA members and incorporate these enables later comparison of birth defects into the HIFA Knowledge Base (cur- among women who have been exposed rently under development). to a medicine with those who have not. The second feature is the generic Reference: Communication from the HIFA applicability of the approach irrespective Steering Group at http://www.hifa2015.org/ of drug or disease, and the third is the about/administration/ improvement of staff capacity to manage and monitor pregnancies and newborns. New pregnancy registry protocol These qualities add to the practicality and cost-effectiveness of the protocol. A new protocol has been published in BMC Pregnancy and Childbirth for The materials developed are available collecting data on the risks of birth to any country wishing to join the WHO defects due to medicines for diseases Pregnancy Registry, on condition that such as HIV and malaria. The major there is a commitment to train the staff to components of first-line treatments for use the materials, to obtain reliable data these diseases are not recommended on drug exposure and to conduct a during the first trimester, yet many women systematic surface examination of the may take these medications before they newborn. The Registry builds capa- are aware that they are pregnant. Sixty- city within the health system to improve eight pecent of the world’s HIV population maternal and neonatal care as well as to reside In sub-Saharan Africa and serve as a sentinel surveillance system approximately 25 million pregnant for the safety of medicines used in women are at risk of malaria. pregnant women.

The protocol is neither disease nor drug- The specific objectives of the WHO specific. The power of the approach lies Pregnancy Registry are to: in its broad application to a variety of settings in which women may have more • Build capacity to obtain reliable than one infectious disease or condition information on obstetric, medical, and during the course of pregnancy and may drug history during pregnancy and also have been exposed to many drugs. diagnose, assess, monitor and manage Its methods, case record forms and pregnancy and the outcomes of preg- training materials (including a DVD nancy including congenital malforma- showing how to conduct a surface tions, stillbirths and prematurity. examination of a newborn) have been tested for feasibility in five countries • Quantify the baseline risk of (four in Africa and one in South America), major congenital malformations in the and further refined and used in the WHO absence of drug exposure during the Pregnancy Registry. The approach is course of pregnancy. integrated within the reproductive health system of the countries, specifically ante- • Quantify the risk of major congenital natal clinics and labour/delivery facilities. malformations associated with expo- sure to medicines during the course of There are three important features of pregnancy. the pregnancy registry protocol which stand out from most other registries. The • Identify other obstetric, therapeutic and first is the simplicity of including women clinical factors that may contribute to agreeing to take part at their first facility the risk of major congenital anomalies visit for care during their pregnancy. This and other adverse birth outcomes in not only represents the population of pregnant women.

32 WHO Drug Information Vol. 27, No. 1, 2013 Recent Publications, Information and Events

• Support a culture of drug safety aware- Reference: Special Programme for Research ness among women and their provid- and Training in Tropical Diseases. TDR News. ers in participating countries and avoid 13 December 2012. http://www.who.int/tdr preventable adverse drug-related pregnancy outcomes. Paediatric ACTs for the treatment of uncomplicated malaria • Develop an ongoing surveillance sys- tem of maternal and newborn health The Medicines for Malaria Venture (MMV) that strengthens the health system to has announced the release of a new improve maternal and neonatal out- independent study focused on assessing comes. critical barriers to the acceptance and uptake of quality antimalarial medicines Reference: Special Programme for Research and Training in Tropical Diseases. TDR for children. eNewsletter, December 2012 at http://www. who.int/tdr The study examines six francophone countries in Central and West Africa, and draws on a WHO-endorsed framework for Malaria: rapid diagnostic testing evaluating barriers to access to essential Malaria rapid diagnostic test performance medicines. It suggests interventions that is the fourth report in a series of could enhance acceptance and uptake laboratory-based evaluations of rapid of WHO-recommended medicines for diagnostic tests (RDTs) for malaria. It children. provides a comparative measure of their performance in a standardized way to Reference: News Release. Acceptance and distinguish between well and poorly uptake of quality antimalarial medicines for children. http://www.mmv.org/newsroom/publi- performing tests. This information can cations be used by malaria control programmes and to guide UN procurement policy for International course on dengue these diagnostic tools. The 13th International Course on Dengue In Round 4, 48 products were evaluated. will be held 12–23 August 2013 in Overall, the majority of resubmitted pro- Havana, Cuba. Through theoretical and ducts either maintained or improved their practical sessions, the main aspects performance in Round 4, indicating pro- related to dengue will be covered: dengue duct improvement by the manufacturers. epidemiology, clinical management, Also included in the report is an algorithm diagnosis, virology and immunology, to assist in the RDT selection process, vector control, environmental risk factors a field tool to assess RDT packaging, and community participation. safety and ease-of-use, and a pictorial guide to common anomalies seen in Important aspects to be discussed are production lots. trends of dengue at global level, impact of climate change, new dengue clinical The evaluation programme is co- classification, opportunities for diagnosis, sponsored by the Foundation for impact of virus diversity, immuno- Innovative New Diagnostics (FIND), genetics, complexity of dengue immunity the Special Programme for Research and pathogenesis, dengue vaccines, and Training in Tropical Diseases (TDR) integrated surveillance and control, and the WHO Global Malaria Programme difficulties, options, challenges, econo- (GMP). Testing is performed at the mic burden, new options for control, and US Centers for Disease Control and insecticide resistance, among others. Prevention (CDC).

33 Recent Publications, Information and Events WHO Drug Information Vol. 27, No. 1, 2013

The new global initiatives for dengue and of Dengue and its Vector, Pedro Kourí the experiences of several countries and Tropical Medicine Institute, Havana, geographical regions will also be updated Cuba, in collaboration with the Cuban and general lectures as well as round Ministry of Public Health, the Cuban tables and symposia are scheduled. Two Society of Microbiology and Parasitology mini-courses on GIS and dengue and and the Pan American Health Organiza- modeling of transmission and prediction tion (PAHO). of dengue as well as other activities and meetings will be also organized. Reference: PAHO/WHO Collaborating Centre for the Study of Dengue and its Vector. http:// The course is provided by the PAHO/ instituciones.sld.cu/ipk/anuncioc/ WHO Collaborating Centre for the Study

34 WHO Drug Information Vol. 27, No. 1, 2013

Consultation Document

The International Pharmacopoeia

4. Reference Substances and Reference Spectra

Draft proposal for the Supplementary Information section of The Interna- tional Pharmacopoeia (January 2013). Please address any comments to Quality Assurance and Safety: Medicines, World Health Organization, 1211 Geneva 27, Switzerland or e-mail to [email protected]. Working documents are available for comment at http://www.who.int/medicines.

[Note from the Secretariat: The Supplementary Information section of The Internatio- nal Pharmacopoeia provides the user with texts for guidance and information and will not constitute part of the standards.]

4.1 International Chemical Reference Substances

4.1.1 Introduction International Chemical Reference Substances (ICRS) are primary chemical refe- rence substances for use in physical and chemical tests and assays described in The International Pharmacopoeia or in other World Health Organization (WHO) quality assurance documents adopted by the WHO Expert Committee on Specifications for Pharmaceutical Preparations. ICRS are used to identify, determine the purity or assay pharmaceutical substances and preparations or to verify the performance of test methods.

This chapter describes principles to be applied during the establishment and use of ICRS, which guarantee that the reference substances are suitable for their intended purpose.

This chapter is not applicable to WHO International Biological Reference Preparations.

4.1.2 Terminology

Chemical reference substance The term chemical reference substance, as used in this text, refers to an authenti- cated, uniform material that is intended for use in specified chemical and physical tests, in which its properties are compared with those of the product under examina- tion and which possesses a degree of purity adequate for its intended use.

Primary chemical reference substance A designated primary chemical reference substance is one that is widely acknowledged to have the appropriate qualities within a specified context and whose assigned content when used as an assay standard is accepted without requiring comparison with another chemical substance.

35 Consultation Document WHO Drug Information Vol. 27, No. 1, 2013

Secondary chemical reference substance A secondary chemical reference substance is a substance whose characteristics are assigned and/or calibrated by comparison with a primary chemical reference subs- tance.

4.1.3 Purpose of ICRS

The purpose of establishing ICRS is to provide users of The International Pharmaco- poeia or other WHO quality assurance documents adopted by the WHO Expert Com- mittee on Specifications for Pharmaceutical Preparations with authenticated subs- tances for reference. Many analytical tests and assays are based on comparison of physical or chemical properties of a sample with those of a reference standard. ICRS serve as such reference standards and thus enable the analyst to achieve accurate and traceable results. Furthermore ICRS may be used to assess system suitability during analyses and to calibrate analytical instruments.

ICRS may also be employed to establish secondary reference substances according to the WHO General guidelines for the establishment, maintenance and distribution of chemical reference substances. In cases of doubtful results or dispute, however, the tests performed using ICRS are the only authoritative ones.

4.1.4 Establishment of ICRS

All operations related to the establishment and distribution of ICRS should be carried out according to the relevant guidelines. Among these, the WHO General guidelines for the establishment, maintenance and distribution of chemical reference substances and International Organization for Standardization (ISO) Guide 34 – General require- ments for the competence of reference material producers (including related guides) have a prominent position.

Production

Source material for the establishment of ICRS may be synthesized and purified for this purpose or may be selected from the regular pharmaceutical production of the mono- graphed substance provided that the purity and homogeneity are suitable. In some cases, for example, in order to improve the stability of the reference substance, it may be useful to select an alternative salt (or salt vs base), solvate or hydrate. The content assigned to the standard takes into account which substance is selected.

Compliance with the relevant tests of the corresponding monograph as published in The International Pharmacopoeia is required where applicable.

Reference standards are dispensed into suitable containers under appropriate filling and closure conditions, to ensure the integrity of the reference material. The con- tainers employed are preferably single-use in order to minimize the risk of decom- position, contamination and moisture uptake. Where multiple-use containers are employed appropriate use and handling controls should be implemented to assure their suitability.

WHO encourages pharmaceutical manufacturers to donate suitable candidate mate- rials and thus to contribute to the availability of ICRS.

36 WHO Drug Information Vol. 27, No. 1, 2013 Consultation Document

Analytical characterization

The source material should be tested with suitable analytical techniques aiming to characterize all relevant quality attributes. The identity is confirmed and the purity is determined, usually based on results obtained with the validated methods of the respective monographs. However, the use of further analytical techniques may be appropriate in order to fully characterize the candidate material. Absolute methods (for example, volumetric titrations, differential scanning calorimetry) should be employed to complement and verify the results of relative methods where the properties of a sample are compared with those of a reference substance (for example, chromato- graphic methods). The extent of testing and the number of laboratories involved in characterizing the material depends on the intended use of the reference substance to be established. If required, assay standards are characterized in interlaboratory trials to increase the accuracy of the assigned value and to determine the associated uncertainty.

A thorough purity investigation is usually performed with the aim to identify and quantify all components of the candidate material (i.e., main component, organic and inorganic impurities, water and residual solvents). The elucidation of the composition of the candidate material is usually considered as accomplished when all components have been identified and quantified, if relevant. The cumulative percentage of all components should yield 100% (mass balance approach).

The purity of a candidate material is usually calculated on the “as is” basis, so that the analyst can use the substance without pretreatment, for example, drying.

Provided that all components themselves are expressed as a percentage of the weight of sample taken the “as is” content can be calculated as follows: purity = 100 - organic impurities% - inorganic impurities% - water% - residual solvent%

When chromatographic methods are used to test for related substances impurity concentrations are often determined in relation to the principal compound. The “as is” content of organic impurities, to be substituted in the formula above, can be calculated as follows: organic impurities% = chromatographic result * (100 - water % - residual solvent % - inorganic impurities %)/100

The content assigned to a quantitative ICRS depends on the purity of the candidate material and on the selectivity of the method for which the standard will serve as a reference. If the standard is intended to be used with a method that has the same selectivity than the method used to determine its purity the calculated purity will be assigned as the content of the ICRS. However, if the intended method is less discriminative, it may be necessary to add to the purity the content of impurities that cannot be discriminated from the response of the parent compound. The following example illustrates this:

A candidate material is analysed with different analytical methods to identify and quantify all relevant components. The results reveal that, besides the labelled subs-

37 Consultation Document WHO Drug Information Vol. 27, No. 1, 2013 tance, the following components are present: 2.0% water (analysed by Karl Fischer titration, calculated on an “as is” basis); 1.0% enantiomer of the labelled substance (analysed by chiral HPLC, calculated in relation to the sum of the peak areas of both enantiomers); and two organic impurities, each 0.75% (analysed by an achiral HPLC method, calculated in relation to the sum of the peak area of all peaks, ignoring solvent and injection peaks). The purity of the standard is calculated to 95.55% (purity = 100% – (2.5% x 0.98) – 2%). The candidate material is intended to be used as a reference in an assay test, which stipulates the use of the same HPLC method as already applied to determine the organic impurities in the characterization of the candidate material. A content of 96.53% is assigned to the reference substance (assigned content = 100% – (1.5% x 0.98) – 2%). The concentration of the enantiomer is not taken into consideration as the method, for which the reference substance is intended, is not selective for the enantiomer.

Labelling: The labelling should provide all information necessary to use the reference substance as intended, i.e. the name of the reference substance, the batch number, storage conditions, etc. If intended for quantification the assigned content or potency (for microbiological assays) is also given. The accompanying leaflet is considered to be part of the labelling.

Release and adoption ICRS are established and released under the authority of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. The Committee adopts new ICRS and new lots as being suitable for use as described in The International Pharmaco- poeia or in other WHO quality assurance documents.

Stability monitoring and distribution At the WHO custodian centre for ICRS the established reference substances are stored and distributed under conditions suitable to ensure their stability.

The stability of ICRS is monitored by regular re-examinations. Their frequency and extent is based on the:

• liability of the ICRS to degradation • container and closure system • storage conditions • hygroscopicity • physical form • intended use

The analytical methods employed to verify the stability are often chosen among those performed during the establishment of the reference standard. The maximum per- mitted deviation from the assigned value should be predefined and, if exceeded, the batch should be re-established or replaced.

4.1.5 Use and storage of ICRS by the user

The letters RS after the name of a substance in a test or assay described in The International Pharmacopoeia or in other WHO quality assurance documents adopted by the WHO Expert Committee on Specifications for Pharmaceutical Preparations indicate the use of the respective ICRS.

38 WHO Drug Information Vol. 27, No. 1, 2013 Consultation Document

ICRS are suitable for the analytical purpose described in The International Pharma- copoeia or other WHO quality assurance documents adopted by the WHO Expert Committee on Specifications for Pharmaceutical Preparations. Directions for use of ICRS are also given in the leaflet enclosed with the substance when distributed. When used for other purposes the responsibility for assessing the suitability rests with the user or the authority that prescribes or authorizes this use. If reference standards other than ICRS are used for purposes described in The International Pharmacopoeia or in other WHO quality assurance documents adopted by the WHO Expert Committee on Specifications for Pharmaceutical Preparations the suitability of these substances has to be demonstrated by the user. The user has to consider an assigned content in assay determinations or when it is indicated in the method description. ICRS are supplied in adequate quantities for immediate use after opening of the container. Users should purchase only sufficient amount for short-term use. It is generally recommended that the user stores ICRS protected from light and moisture and preferably at a temperature of about 5 ± 3 °C. When special storage conditions are required this is stated on the label or in the accompanying leaflet. If an unopened container is stored under the recommended conditions it remains suitable for use as long as the respective batch is valid. Information on current batch numbers is provided on the web site of the WHO custodian centre for ICRS (see under ordering information). Reference standards that are normally stored at 5 ± 3 °C are dispatched at ambient temperature since short-term excursions from the storage recommendations are considered not deleterious to the reference standard. Reference standards stored at -20 °C are packed on ice or dry ice and dispatched by courier. Reference standards stored at -80 °C or stored under liquid nitrogen are packed on dry ice and dispatched by courier.

4.1.6 Ordering information

Since April 2010 the European Directorate for the Quality of Medicines and Health- Care (EDQM), Council of Europe, is responsible for the establishment, preparation, storage and distribution of ICRS for The International Pharmacopoeia. A list of ICRS currently available can be found on their web site (see http://www.edqm.eu).

Orders for International Chemical Reference Substances should be sent to:

European Directorate for the Quality of Medicines & HealthCare 7 allée Kastner CS 30026 F-67081 Strasbourg France Fax: +33 (0)3 88 41 27 71 — to the attention of EDQM Sales Section E-mail: [email protected]

The current price for ICRS is 70 Euros per package. Extra charges will be added for the delivery of the reference substances. For details see the above-mentioned web site.

39 Consultation Document WHO Drug Information Vol. 27, No. 1, 2013

The WHO International Standard for endotoxin is available from the National Institute for Biological Standards and Control (NIBSC).

National Institute for Biological Standards and Control Blanche Lane South Mimms Potters Bar GB-Hertfordshire EN6 3QG United Kingdom of Great Britain

4.2 International Infrared Reference Spectra

International Infrared Reference Spectra (IIRS) are provided for use in identification tests as described in monographs of The International Pharmacopoeia or other WHO quality assurance documents adopted by the WHO Expert Committee on Specifica- tions for Pharmaceutical Preparations.

The reference spectra are produced from authenticated material using an appropriate sample preparation technique. They are recorded with a Fourier transform infrared spectrophotometer (FTIR). Instructions for the preparation of spectra are given in 1.7 Spectrophotometry in the infrared region; Identification by reference spectrum. A spectrum of the test substance is considered to be concordant with a reference spectrum if the transmission minima (absorption maxima) of the principal bands in the test spectrum correspond in position, relative intensities and shape to those in the reference spectrum.

40