WHO Drug Information Vol 22, No. 3, 2008 World Health Organization

WHO Drug Information

Contents

International Harmonization Abacavir: hypersensitivity reactions 201 Fluoroquinolones: risk of tendinitis ICH Pharmaceutical Quality System and tendon rupture 201 Q10 177 African Medicines Regulatory Harmonization Initiative (AMRHI): Regulatory Action and News a WHO concept paper 182 WHO Prequalification: GMP deviations and suspension 203 Safety and Efficacy Issues Import alert: Ranbaxy facilities 203 Medicines Prequalification Programme: Moxifloxacin: adverse hepatic reactions 191 listed products 204 Ezetimibe/simvastatin: safety review of Development of medicines for Alzheimer cancer risk 191 and Parkinson disease 205 Norfloxacin-containing medicines not for GMP regulations for radiopharma- use in urinary infections 192 ceuticals 205 Ceftriaxone: fatal outcome with calcium- containing solutions 193 Safety review of tumour necrosis factor Pharmaceutical Distribution blockers 194 Recombinant human bone morphogenetic and Trade protein: life-threatening complications 195 WHO Certification Scheme on the Electronic medical devices malfunction: quality of pharmaceutical products computed tomography scanning 195 moving in international commerce Desmopressin and hyponatraemia 196 Proposal for improvement of the WHO Micro-bubble contrast agents 197 Certification Scheme 207 Simvastatin used with amiodarone: Consultation on improvement of the rhabdomyolysis 197 Certification Scheme 214 Naltrexone injection site reactions 197 Adalimumab: hepatosplenic T-cell lymphoma 198 Recommended International Serious Risks/New Safety Information 198 Nonproprietary Names: Deferasirox: hepatic failure 199 Colchicine: fatal interactions and List 60 219 reactions 200

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International Harmonization

ICH Pharmaceutical Quality System Q10

The International Conference on Harmonization of Technical Requirements for Reg- istration of Pharmaceuticals for Human Use (ICH) guideline Pharmaceutical Quality System Q10 was adopted at the ICH meeting in Portland (Oregon, USA) in June 2008. Within Step 4 of the ICH Process, the guideline is recommended for adoption by regulatory bodies of the European Union, Japan and USA. The guideline describes a robust quality management system model that can be implemented throughout the different stages of the product lifecycle.

The ICH Q10 quality vision over the decades. In the 1980s, Toyota cars became the model of global choice In the 1930s, Walter Shewhart (1) devel- because they lasted longer than other oped Statistical Process Control methods cars in the same category and required and the PDSA spiral — plan what you much less service. About a decade later, want to do, do it, study the results, make it became clear that it was the way Toyota corrections (total quality management), designed and manufactured the cars that and start the cycle again (continuous led to high consistency in the process and improvement). product.

Shewhart’s student, W. Edwards Deming In 2003, the ICH Steering Committee (2) is credited with improving production agreed on a new quality vision to empha- in the United States during World War II. sise a risk- and science-based approach From 1950 onwards, he taught top to pharmaceutical production in an management in Japan on how to improve adequately implemented quality system. design, product quality, testing and sales As a consequence, the guidelines on in global markets through various meth- Pharmaceutical Development (Q8), ods, including the application of statistics. Quality Risk management (Q9) and Deming demonstrated that Shewhart’s Pharmaceutical Quality System (Q10) spiral is roughly analogous to the scien- were drafted. As these concepts and tific method: one has a theory (or hypoth- principles are rather new in the pharma- esis), and puts it to the test; studies the ceutical area, proper implementation is results and takes action based on those important to bring clarity, further explana- results. This is the road to scientific tion and remove ambiguities and uncer- learning. PDSA is the road to organiza- tainties. tional learning. Table 1 overleaf lists some frequently In the 1950s, Dr Joseph M. Juran (3) used terms defined in the ICH Pharma- started a production management system ceutical Quality System Q10 guideline. at Toyota which has continued to evolve

Article submiited by János Pogány, Budapest. Comments to: [email protected]

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Table 1. Pharmaceutical Quality System guideline definitions

Continual Improvement: Recurring activity to increase the ability to fulfil requirements Enabler: A tool or process which provides the means to achieve an objective Knowledge Management: Systematic approach to acquiring, analysing, storing, and disseminating information related to products, manufacturing processes and components Performance Indicators: Measurable values used to quantify quality objectives to reflect the performance of an organization, process, or system, also known as “performance metrics” in some regions Product Realisation: Achievement of a product with the quality attributes appropriate to meet the needs of patients, health care professionals, and regulatory authorities (including compliance with marketing authorisation) and internal customers’ requirements. Quality Objectives: A means to translate the quality policy and strategies into measurable activities Quality Policy: Overall intentions and direction of an organization related to quality as formally expressed by senior management. (ISO 9000:2005) Quality risk management: An active approach to identifying, scientifically evaluating and controlling potential risks to quality Senior Management: Person(s) who direct and control a company or site at the highest levels with the authority and responsibility to mobilize resources within the company or site (ICH Q10 based in part on ISO 9000:2005 Quality management systems)

Pharmaceutical Quality System of ICH Q10 that is additional to current regional GMP requirements is optional.” The Q10 glossary defines the Pharma- ceutical Quality System (PQS) as a Scope of the Pharmaceutical “management system to direct and con- Quality System trol a pharmaceutical company with regard to quality.” The PQS describes a PQS applies to all systems supporting the set of policies, processes and procedures development and manufacture of phar- required for designing (non-clinical and maceutical drug substances and drug clinical research) and execution (develop- products, including biotechnology and ment, manufacture, distribution and biological products, throughout the postmarketing activities) of changes in product life cycle. the pharmaceutical industries that employ science- and risk-based principles and Relationship of ICH Q10 to approaches related to product quality regional GMPs (ICH Q8 and ICH Q9) at each life cycle Figure 1 overleaf —drawn from com- stage. This also promotes continual ments of the European Union during the improvement leading to the fulfilment of development of the guideline and patient needs and improved business adapted to this review article — illustrates performance. the principal differences between ICH The guideline introduction states that Q10 and GMPs. “ICH Q10 is not intended to create new expectations beyond current regulatory Activities overlap to some extent (e.g. requirements. Consequently, the content clinical batches are manufactured accord-

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Figure 1. Relationship of ICH Q10 to regional GMPs

Management Organizational processes Ð quality system improvement Responsibility Quality System Risk Knowledge Human Resources ¥ Management Management Management Management Management Commitment

¥ Quality Policy Support processes Ð product/process management and improvement ¥ Quality Objectives Product/Process Change Control Quality Management of ¥ Quality Planning Improvement Assurance Suppliers and Contractors ¥ Resource Management Process CAPA Documentation Management of Validation Management Equipment and ¥ Quality Facilities Communication

¥ Management Product life-cycle processes Ð product realization Review Pharmaceutical Technology Manufacturing Discontinuation ¥ Quality Oversight Development Transfer

P r o d u c t l i f e c y c l e

Covered by ICH10 Covered by GMPs ing to GMPs during Pharmaceutical Management Responsibility Development, or Human Resource Management includes GMP training) but Management should establish a quality the diagram permits focusing presenta- policy to include expectations of compli- tion in this article to the pink rectangles. ance with applicable regulatory require- ments. The quality policy should be Enablers: Knowledge Management communicated to and understood by and Quality Risk Management personnel at all levels in the company. Knowledge Management and Quality Management should provide adequate Risk Management will facilitate achieve- and appropriate resources (human, ment of the following objectives of the financial, materials, facilities and equip- PQS: ment) to implement and maintain the PQS and continually improve its effective- ¥ Achieve product realization ness. Management should assess the conclu- ¥ Establish and maintain a state of control sions of periodic reviews of process performance and product quality and of ¥ Facilitate continual improvement the PQS.

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Continual improvement of are identified and evaluated, and the process performance and body of knowledge is continually ex- product quality panded. Data collection on performance indicators In the terminal stage of the product — quality attributes of the drug product lifecycle, a pre-defined approach should and the parameters of the manufacturing be used to manage activities such as process — starts with the design and retention of documentation and samples development of pharmaceutical quality and continued product assessment (e.g., from the very beginning of the product life complaint handling and stability) and cycle. In an eternally successful organiza- reporting in accordance with regulatory tion, “People routinely do things right first requirements. time”, (Philip Crosby). Product and process variability is explored. Pharma- Pharmaceutical Quality System ceutical development results in knowl- elements edge which establishes that the selected Process performance and product formulation is suitable for the intended quality monitoring system use and the manufacturing process can An effective monitoring system provides be scaled up to production level. Process assurance of the continued capability of and product monitoring conducted processes and controls to produce a throughout development can be used to product of desired quality and to identify establish a control strategy for manufac- areas for continual improvement. turing. Corrective Action and Preventive The goal of technology transfer activities Action (CAPA) System is to pass on product and process knowl- The pharmaceutical company should edge [analytical methods, active pharma- have a system for implementing correc- ceutical ingredients (APIs) and pharma- tive action (to prevent recurrence) and ceutical dosage forms] between pharma- preventive action (to prevent occurrence) ceutical development and manufacturing, resulting from the investigation of com- and within or between manufacturing plaints, product rejections, non-conform- sites to achieve product realization. ance, recalls, deviations, audits, regula- (According to this description, transfer of tory inspections and findings, and trend technology takes place within the same analysis from process performance and quality system. The effective transfer of product quality monitoring. Preventive knowledge and experience between two action also includes, e.g., benchmarking, quality systems may not follow the same reviews (contracts, purchasing, process- methodology, for example, when the API es), process capability studies, Statistical and the pharmaceutical product are Process Control (SPC) analysis, Failure manufactured by different companies.) Mode Efffects Analysis (FMEA) and This knowledge forms the basis for the employee training programmes. manufacturing process, control strategy, process validation approach and ongoing This methodology is useful where correc- continual improvement. tive action and preventive action is incorporated into the iterative pharmaceu- In the third stage, the PQS should assure tical design and development process. that the desired product quality is rou- CAPA is mainly used as an effective tinely met, suitable process performance system for the modification or control of a is achieved, the set of controls are manufacturing process by its results or appropriate, improvement opportunities effects (feed-back) or using its anticipated

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results or effects (feed-forward) and enhance the PQS and product and continual improvement. process understanding — such as new approaches to process validation and Change Management System monitoring in-process control strategies Innovation, continual improvement, the that may lead to real-time release mecha- outputs of process performance and nisms — as well as the use of quality risk product quality monitoring and CAPA management principles (e.g., ICH Q8, drive change. In order to evaluate, ICH Q9 and ICH Q10). approve and implement these changes properly, a company should have an Conclusion effective change management system. The concepts and principles of quality There is generally a difference in formality management have been widely used in of change management processes prior the car industry since the 1950s but they to the initial regulatory submission and are rather new in the pharmaceutical after submission, where changes to the industry. Although ICH Q10 is not in- regulatory filing might be required under tended to create any new expectations regional requirements. beyond current regulatory requirements, pharmaceutical industries — also outside Management Review of Process the ICH regions — are expected to Performance and Product Quality implement the PQS because it is an Management review should provide indispensible condition for those compa- assurance that process performance and nies that wish to become and/or remain product quality are managed over the life competitive in product quality and produc- cycle. Depending on the size and com- tivity within global and regional markets. plexity of the company, management review can be a series of reviews at PQS is equally applicable to innovator various levels of management and should and generic pharmaceutical companies include a timely and effective communica- as well as to drug substances and drug tion and escalation process to raise products. Implementation of PQS continu- appropriate quality issues to senior levels ously increases product and process of management for review. understanding and provides opportunities for science-based dossier assessment Continual improvement of the pharma- and the increased use of risk-based ceutical quality system approaches for regulatory inspections. Management should have a formal process for reviewing the PQS on a References periodic basis. The review should include, among others, the measurement of 1. http://www.skymark.com/resources/leaders/ achievement of PQS objectives and the Shewhart.asp assessment of performance indicators. 2. http://www.en.wikipedia.org/wiki/ Management should follow up emerging Image:W._Edwards_Deming.gif regulations, guidance and quality issues that can impact the PQS. ICH Q10 3. http://www.skymark.com/resources/leaders/ encourages innovations that might juran.asp

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African Medicines Regulatory Harmonization Initiative (AMRHI): a WHO concept paper

Essential medicines save lives and improve health when they are available, afford- able, of assured quality and properly used. However, lack of access to essential medicines remains one of the most serious global public health problems (1). Mil- lennium Development Goal number 8 declares that providing access to affordable essential drugs in developing countries is a fundamental human right (2). The objective of the WHO project on Harmonization of Medicines Regulation in Africa (AMRHI) is to improve health in the African Region by increasing access to safe and effective medicines of good quality. This can be accomplished by strength- ening the technical and administrative capacity of participating national medicines regulatory authorities. Collaborative mechanisms can provide a more transparent, streamlined process for the marketing authorization of pharmaceutical products and follow-up of products already marketed. Comments on this concept paper are most welcome and should be addressed to: Samvel Azatyan, Essential Medicines and Pharmaceutical Policies, World Health Organization, 1211 Geneva 27, Switzerland or [email protected]

Effective medicines regulation ineffective regulation transcend national borders and have global implications (3). Assuring the quality, efficacy and safety of medicines is an important task for Over two-thirds of the world’s population medicines regulatory authorities (MRA) live in countries with marginal or inad- and is performed through subjecting all equate regimes for assuring drug quality, pharmaceutical products to pre-marketing safety and efficacy. A recent WHO survey evaluation, marketing authorization and on the quality of antimalarials in seven post-marketing review. Countries may African countries revealed that between differ regarding registration systems since 20 and 90% of products failed quality not all can implement a comprehensive testing (4). Use of poor quality starting medicine evaluation and registration materials from unreliable sources is an system. ongoing problem in many countries (5). The prevalence of poor quality or even Currently, approximately 20% of countries harmful medicines is a waste of re- have fully operational medicines regula- sources that undermines already overbur- tion. Of the remainder, half have regula- dened health-care systems, puts public tion of varying capacity, and 30% have safety at risk and increases the likelihood either no or very limited medicines of drug resistance. regulation. The reality is that many low- income countries cannot ensure the Medicines regulation is a complex issue. safety, efficacy and quality of medicines It is the totality of all measures — legal, circulating on their markets because they administrative and technical — which are resource constrained in terms of governments take to ensure the safety, staffing, standards, systems, and training. efficacy and quality of drugs. This also A number of additional factors explain involves assessment of the relevance and observed weaknesses of drug regulation accuracy of product information. with regard to health systems or socio- The ability to regulate medicines effec- economic development. Problems of tively is determined by a number of

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factors, including: the state of economic A number of recent initiatives have been development, infrastructure and prevail- successful, most notably the establish- ing health-care system. A root problem is ment of the WHO Medicines Prequalifica- the lack of human and financial resources tion Programme (7). However, much devoted to regulation and the effective- more action is required in order to im- ness of collaboration with regulators prove the operation of medicines regula- abroad. Not all medicines regulatory tory authorities in resource-constrained authorities (MRAs) in developing coun- countries to detect and contain substand- tries have sufficient capacity to perform ard medicines. The formation of effective risk-benefit assessments. Among other networks between regulatory authorities things, this is often the result of inad- nationally and internationally facilitates equate political commitment exacerbated sharing of scarce resources and elimi- by interest groups that benefit from loose nates duplication of effort. Networking of regulation and retaining of the status quo institutions in developing and developed in the pharmaceutical sector. Hence, countries, both formal and informal, is an although the policy options to rectify this important element in building regulatory situation are relatively straightforward in capacity and trust, especially with regard principle, implementation may well be to innovative products (8). Harmonization much more complicated. of medicines regulation is a desirable goal for many reasons (9). Countries need resources, both human and financial. Lack of resources may be ¥ Companies have to generate only one compensated to some extent by effective data set for all regions and, conse- collaboration among countries and quently, the amount of human and information sharing. Therefore, political animal experimentation is reduced. leadership and commitment is critical. ¥ The cost of development of new drugs Meanwhile, it is important to mention that and their regulatory documentation is even if more financial resources are reduced, which would logically lead to allocated to ensuring appropriate regula- lower prices. tory development within a region, the availability and expertise of human ¥ Common regulatory standards for resources could remain a challenge over evaluation and inspection facilitate the medium term. regulatory communication and informa- tion sharing. The need for harmonization ¥ Local products are more likely to be The circulation of substandard medicines acceptable for export to other countries. in the developing world is a serious ¥ Faster access to medicines of high concern (6). The problem of substandard public health value (paediatric medi- medicines include inadequate or over- cines, medicines for major diseases or concentration of ingredients, contamina- for emergencies in national settings tion, poor quality ingredients, poor stabil- etc.). ity and inadequate packaging. Reasons for the existence of substandard medi- ¥ Increased competitiveness resulting cines are multiple: medicines manufac- from newly developed common mar- tured for export are not regulated to the kets. same standards as those for domestic use, while regulatory agencies in the less- Existing harmonization initiatives developed world are poorly equipped to Harmonization in a broad sense means assess and address this problem. harmonization of technical requirements

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for medicines regulation, i.e., legislation, capacity and a certain level of socioeco- guidelines, procedures, etc. These nomic development. It should also be requirements relate to the quality, safety noted that ICH was created for new and efficacy of medicinal products and innovative medicines and the ICH parties can differ in complexity from one type of are highly industrialized nations control- marketing authorization application to ling the majority of the innovative industry, another (i.e., innovator drugs vs. gener- whereas most developing countries have ics). In implementing medicines regula- generic markets with generic manufac- tion, it should be noted that this will only ture, or with no local manufacture at all. be effective if all aspects of regulation are addressed. The results of a WHO multi- Regional harmonization country study showed that several areas Cooperative action at the regional level in drug regulation receive relatively little has proved more effective in many cases attention in the implementation process. in strengthening regulatory capacity at the The informal sector, post-marketing national level. Regional initiatives in- surveillance (quality and safety) and volved in harmonization include the control of drug information were the most Association of South-East Asian Nations important of these (10). (ASEAN), the Andean Community, the Gulf Cooperation Council, Mercosur and Various international and regional initia- the Southern African Development tives exist in which regulators from Community (SADC). These offer different developing countries participate. WHO working models, ways of exchanging convenes the biennial International regulatory information and creating Conferences of Drug Regulatory Authori- common technical requirements, pooling ties (ICDRA) where many important information on drugs in actual circulation policy options, technical issues and (since markets have substantial regional actions related to harmonization have and country differences in terms of origin been debated, recommended and imple- and nature of products). In certain cases mented as a result. they share facilities (e.g. testing laborato- ries), and compare experience of side- The International Conference on Harmo- effects of particular drugs in the post- nization (ICH) has core members from marketing phase, identify substandard the research-based industry and regula- and counterfeit drugs, and so on. Practi- tory authorities from the European Union, cal and pragmatic steps to share regula- Japan and USA, with observers from tory resources, information and even Canada, EFTA and WHO. The ICH has facilities offer the most effective means to made significant progress in harmonizing protect public health from substandard technical requirements used in the products in developing countries. developed world, thus mitigating some of the problems associated with differing New regulatory pathways requirements of the three regulatory Considering the reality of inadequate blocks. regulatory capacity in many developing countries, and also in smaller well Although in recent years the ICH Global resourced/developed countries, harmoni- Cooperation Group has intensified its zation initiatives often rely on the ap- work and has opened up to non-ICH proval or opinions emitted by regulatory countries, the ICH has been less suc- authorities in well-resourced countries. cessful in involving and having an impact This could carry some concerns because on developing countries. This is because, the risk/benefit balance in developing in particular, harmonization implies a countries may be different from those in reasonable parity in existing regulatory developed countries. As there is little

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available evidence of differences in the instance, the Global Fund to Fight AIDS, risk/benefit profile of the majority of Tuberculosis and Malaria gives prefer- essential medicines in various environ- ence to medicines that have been pre- ments, consideration of the assessments qualified by the WHO process, as well as carried out in well resourced and fully by stringent regulatory authorities. This operational MRAs in developed countries has proved useful to developing countries is a better option than no guidance at all without the necessary resources to or limited assessment with no added conduct similar level assessments and value. inspections, with the added potential of being actively involved in the prequalifica- There exist several examples of how tion process through their national regula- regulators in developing countries may tory experts. benefit from assessments carried out by well resourced regulatory authorities. Active involvement in the WHO Medicines These initiatives include, but are not Prequalification Programme has contrib- limited to, US FDA tentative approval uted to building national regulatory process for antiretroviral medicines, capacity and improving regulations and European Union Article 58 process for regulatory processes. Several African priority medicines in developing countries, countries can serve as good examples. Canadian Access to Medicines Scheme However, the responsibility for decision- (known as the Jean Chrétien Pledge) and making, and the processes required for others. These initiatives could provide the that decision-making, as well as post- support needed for capacity building of marketing surveillance, must remain a national regulatory authorities of develop- matter of national sovereignty. ing countries through partnerships, or scientific and technical assistance. African Medicines WHO Medicines Prequalification Regulatory Harmonization Programme Initiative (AMRHI) The WHO Medicines Programme for The overall objective of AMRHI is to medicines was set up in 2001 to provide United Nations procurement agencies, improve health in the African Region by such as UNICEF, with a range of good increasing access to safe and effective medicines of good quality for the treat- quality products that meet international standards of quality, safety and efficacy. It ment of priority diseases. This can be does not intend to replace national accomplished by strengthening the technical and administrative capacity of regulatory authorities or national authori- zation systems for importing medicines participating national medicines regula- but draws on the best national regulatory tory authorities. Collaborative mecha- nisms can be established to create a expertise available while pro-actively including and involving regulators from more transparent, streamlined process for developing countries. Since its beginning, the marketing authorization of pharma- ceutical products and follow-up of prod- capacity building has been a major objective of the Prequalification Pro- ucts already marketed. gramme. Collaborative mechanisms for drug Over time, the growing list of products regulatory systems and processes at the found to meet international standards has regional/sub-regional levels should proved useful for anyone purchasing bulk translate into improved regulatory ap- medicines, including countries them- proval processes and operational selves and other organizations. For efficiencies at the national level. In this

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regard, the project aims to increase the pay out-of-pocket for most medicines. capacity of national medicines regulatory Improved regulation, with more sophisti- authorities and specifically strengthen the cated requirements, usually eliminates administrative, structural and technical substandard cheap medicines from the elements of medicines regulation. In market but could lead to an increase in doing so, the project will help countries to prices. In this regard, it is suggested that enhance and facilitate their decision- action should focus initially on mutually making processes regarding the registra- agreed standards, technical assistance tion of medicines, as well as exercise and capacity building issues and aim for more control over medicines circulating gradual and carefully balanced harmoni- on the market. Regulatory capacity zation of actual markets. building and facilitation of information exchange are thus indispensable compo- The willingness of sub-regional secretari- nents of the project. ats and potential member countries to participate in the harmonization process Specifically, the project objectives in- should be assessed beforehand. It is also clude: very important that participating countries demonstrate their commitment to con- 1. To create a collaborative network tinue the harmonization process and to through partnership between regula- carry the financial burden of maintaining tory authorities of participating coun- the secretariat, investing in developing tries and/or selected sub-regional and maintaining technical capacity of their economic blocks. staff, paying for travel to joint assessment meetings, inspections, etc. The Initiative 2. To harmonize technical requirements should also operate as a catalyst for for the regulation of medical products sustainable processes. and build confidence so that agreed harmonized standards are respected Leadership and maintenance by participating authorities. One important question is whether a permanent secretariat of the harmoniza- 3. To establish a framework for joint tion process needs to be established. If evaluations of application dossiers and yes, how should it be managed and inspections of medicine manufacturing operated and whether it should be based sites. in one of the countries or should rotate at specified intervals of time. Experience 4. To strengthen the capacity for regula- has shown that well qualified, effective tory oversight. and stable secretariats are crucial for the continuity and success of regulatory 5. To develop information management networks. systems and promote the exchange of regulatory information. Rotating secretariats may have disadvan- tages as opposed to stable, permanent Political commitment secretariats. However, rotating national A fundamental issue is the political staff in terms of time-limited secondment commitment of Member States to partici- may be an option to consider. The secre- pate in the harmonization process. The tariat could also be reinforced by inviting, experience of existing harmonization on a secondment basis, competent and initiatives has shown that all such proc- experienced regulators from well-estab- esses have led to upgrading of public lished authorities from outside the region. services. In less resourced counties, Additionally, the secretariat must have unfortunately, consumers still continue to access to highly qualified legal advice

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from potential participating countries. The maintenance of already authorized organization of meetings of legal advisers products will be covered, including would be highly appropriate as a mecha- variations and renewals. A number of nism to discuss and share commonalities WHO guidelines that are directly relevant and differences in the respective legisla- to these questions exist and are updated tive areas. regularly. These guidelines are adopted by many countries both for local use and Of particular value would be the estab- for reasons of international harmonization lishment of a steering committee of (10). representatives of participating member countries to give oversight and act as a Differences in regulatory capacity coordinating body. Representatives of and national legislation donor organizations could have observer The issue of differences in capacity status. Governing bodies and procedures between national regulatory authorities of of the project should, as far as possible, different countries is also very important. represent a sustainable model for long The results of a recent WHO pilot project term management of a collaborating on a registration technical package have network. demonstrated that even in a relatively homogenous group of participating The issue of availability of sufficient countries, from a socioeconomic develop- resources in MRAs is of importance for ment perspective, there are serious the project. Most resource-constrained differences in regulatory capacity. countries currently base their regulatory decisions for NCE applications on the Most participating countries have exper- opinion taken by other well-resourced tise and experience in evaluating the countries. Evaluation of new innovative quality aspects of an application dossier medicines specific for country needs — but only one or two had expertise in such as medicines for neglected diseases evaluating the clinical (efficacy and and certain paediatric medicines — may safety) parts. In recent years, WHO has necessitate creating special collaborative conducted an assessment of the medi- mechanisms for assessment and ap- cines regulatory systems in some African proval. Member States using the WHO assess- ment tool. However, for many countries, The African medicine market is basically information is either absent or out of date. a “generic” market and local manufactur- ing, where it exists, is also limited to WHO role in implementing AMRHI generic medicines (with perhaps some There may be many ways of introducing exceptions in countries such as South medicines harmonization to Africa. Africa). Limiting the scope of the project However, WHO proposes focusing on two to generic applications in the first instance scenarios that seem the most feasible. may help to fast track the initiative be- In the first scenario, WHO’s involvement cause this will restrict the number of could be limited to assisting foundations, guidelines that need to be harmonized. funding agencies, or any other partner in developing and finalizing the proposal Such action could be considered a first and then hand over the project to an phase, followed by harmonization of appropriate party such as a professional regulatory guidelines specific to new international organization, or regional or medicines whose safety, efficacy and subregional agency for implementation. quality requirements, at least in the long term, should be the same. It also should The implementing agency, in this case, be decided to what extent harmonization would take full responsibility for selection

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of the partners, for performance of the WHO has well-established working planned activities and for reporting relations with medicines regulatory outcomes of the project to the donors. authorities, nongovernmental organiza- WHO would provide technical expertise in tions and many other partners and major the preparatory phase of the project but players. WHO can also build on the involvement would not go beyond this competence and know-how of other UN point. organizations such as UNICEF, UNIDO, or UNDP and the International Atomic In the second scenario, WHO would take Energy Agency (IAEA) for issues related the lead in the project, from both a to radiopharmaceuticals. Such partners managerial and organizational point of constitute valuable resources in the view, would develop and finalize the successful implementation of the harmo- project proposal and select partners for nization initiative together with the WHO the implementation phase in collaboration Regional Office for Africa and WHO with Member States. WHO’s competitive country offices in African Member States. advantage in running such an initiative is expressed by its constitutional mandate Implementation of AMRHI and role in medicines regulation standard setting. In the framework of this mandate, 1. Mapping exercise and during decades of work in the field, A logical start to the initiative is assess- WHO has gained valuable experience ment of the situation in potential partici- and, with its regional and country offices, pating countries with regard to: has established a global network of research institutions, collaborating cen- ¥ regulatory capacity and experience of tres and individual experts upon which it the MRA; can draw. ¥ volume and structure of the pharmaceu- tical market; and Historically, WHO has actively supported several harmonization initiatives such as ¥ existing respective regulations and ASEAN and SADC. In the case of the legislation (including international Pan American Network for Drug Regula- treaties and agreements). tory Harmonization (PANDRH), the secretariat is provided by the WHO With better understanding of the situation, Regional Office for the Americas. appropriate future activities can be planned. This mapping exercise should Providing technical support to countries also look beyond the regulatory frame- to strengthen national drug regulatory work to all environments and legal re- capacities is one of WHO’s key activities. quirements impacting medicines regula- To ensure that good quality pharmaceuti- tion, regulatory harmonization and inter- cals are available, WHO sets norms and national cooperation. Countries with standards, develops guidelines and legislation not enabling participation in advises Member States on issues related the project will also be identified. This to quality assurance of medicines in mapping exercise could be followed by national and international markets. WHO two consecutive meetings. assists countries in building national regulatory capacity through networking, 2. Brainstorming kick-off meeting training and information sharing. Further, This meeting with responsible representa- no other organization is involved in a tives of potential participating MRAs comparable amount of capacity building would assess commitment to participate worldwide. in the project. Representatives of the

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harmonization initiatives that are already 5. Establishment of the AMRHI secre- operational (EU, ICH, ASEAN, Gulf tariat and Steering Committee Cooperation, SADC and others) could As an outcome of the regional stakehold- attend this meeting to share experience ers meeting, an AMRHI secretariat, on expected buy-in for the participating Steering Committee and expert bodies countries. should be established. The secretariat will carry out routine implementation work, 3. Regional stakeholders meeting while the Steering Committee will be This meeting would involve other inter- acting as a coordinating body for the ested parties including, but not limited to: harmonization initiative.

¥ Local industry associations; 6. Common technical requirements (guidelines) for regulation of medicinal ¥ Importers/wholesalers of medicines; products and starting joint activities According to an agreed scope and speed ¥ Representatives of medical community; of harmonization, technical documents ¥ Representatives of pharmacist commu- identified for harmonization and a working nities; plan would be agreed. As a principle, preference should be given to the adop- ¥ Consumer groups; tion or amendment of existing regulatory guidelines rather than development of a ¥ Other interested ministries (finance, completely new set. trade); The working plan should be regularly updated to reflect newly arising needs ¥ Representatives of customs authorities; and developments. Step-by-step coop- eration should be based on progress ¥ Representatives of regional and sub- made in the harmonization of technical regional economic blocks; requirements for individual regulatory activities, e.g. following the harmonization ¥ Other interested parties identified during of GMP requirements, the exchange of the kick-off meeting. inspection reports, confidence building exercises for inspectors, and recognition 4. Roadmap of inspection findings may start. As a result of these meetings, a roadmap should be proposed describing the scope 7. Development of a training and and speed of implementation of the confidence building plan for regulators project and the sequence of proposed A Training plan should be developed in activities, as well as expected outcomes, line with harmonized standards and country buy-in, and support and effort procedures. Training should, as far as required to achieve successful functioning possible, respect the following principles. of the initiative. Decisions on secretariat, management structure and principle Trainers external to the participating MRA procedures should be adopted. Mecha- will support the developmental capacity of nisms for legally acceptable handling and local trainers recruited from the expert sharing of commercially-sensitive infor- staff of participating MRAs. Training at mation should be proposed. A draft national level — both of regulators and consensus document setting out a basis other stakeholders — will be led by staff for further development of the project of participating authorities. Training will be should be drafted and agreed. oriented to acquiring practical knowledge and confidence building. Learning by

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doing will be promoted. In order to References strengthen confidence between participat- ing MRAs, rotation of staff should be 1. World Health Organization. Equitable promoted and organized. An option to be access to essential medicines: a framework considered is the establishment of a for collective action. WHO Policy Perspectives on Medicines no. 8. March 2004. regional centre to provide sustainable training in regulatory affairs and related 2. World Health Organization. Health and the matters. Some preparatory work in this Millennium Development Goals. 2005. http:// direction has already been undertaken by whqlibdoc.who.int/publications/2005/ WHO in Africa. 9241562986.pdf.

8. Joint evaluation of application 3. World Health Organization. Effective dossiers and inspection of medicines regulation: ensuring safety, efficacy manufacturing sites and quality. WHO Policy Perspectives on A framework for assessment of applica- Medicines no. 7. November 2003. tion dossiers should be developed which 4. World Health Organization. World Health respects the agreed scope of harmonized Organization steps up action against sub- procedures and experience from existing standard and counterfeit medicines. Asian and regulatory networks. Each participating African countries move to improve the quality authority will be given the opportunity to of their medicines. Press Release, 11 Novem- participate in the assessment process ber 2003. and inspections according to available capacity. Harnessing available outcomes 5. Rägo L. Global disequilibrium of quality. In: of regulatory assessments and a risk- Prince R, ed. Pharmaceutical quality. Davis based approach to the assessment will Horwood International Publishing, 2005. be promoted. Procedures will be pro- 6. J.-M. Caudron, N. Ford, M. Henkens, C. posed for communication of assessment Mace, R. Kiddle-Monroe and J. Pinel. Sub- outcomes at different stages of drug standard medicines in resource-poor settings: evaluation between participating authori- a problem that can no longer be ignored. ties and applicants. Publicly available Tropical Medicine and International Health. evaluation outcomes will be identified and 2008. 13: 8,1062Ð1072. procedures will be proposed for dealing with objections from applicants against 7. World Health Organization. Prequalification evaluation outcomes. Programme. http://healthtech.who.int/pq/ 8. World Health Organization. Public health, 9. Information management innovation and intellectual property rights: and exchange systems report of the Commission on Intellectual Focal communication points and informa- Property Rights, Innovation and Public Health. tion exchange mechanisms will be 2006. proposed to support regular regulatory activities and processes and to manage 9. World Health Organization. Marketing emergencies. This will include communi- authorization of pharmaceutical products with cation among participating MRAs, com- special reference to multisource (generic) munication with the secretariat and with products: A manual for drug regulatory applicants/authorization holders. Internet authorities. WHO/DMP/RGS/98.5. communication could be used as the 10. World Health Organization. Effective drug principle communication platform. Atten- regulation. A multicountry study. 2002. tion should be paid to the security of commercially confidential data.

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Safety and Efficacy Issues

Moxifloxacin: adverse medicines should be strengthened hepatic reactions concerning the risk of diarrhoea, heart failure in women and older patients, European Union — Finalizing a review severe skin reactions and fatal liver injury. of the safety of moxifloxacin-containing Doctors are advised to prescribe oral medicines for oral use, the European moxifloxacin-containing medicines Medicines Agency (EMEA) has concluded according to the updated product informa- that these medicines should only be tion and to consider the official guidance prescribed in the treatment of acute on the appropriate use of antibiotics and bacterial sinusitis, acute exacerbation of the local prevalence of resistance. chronic bronchitis and community- The CHMP opinion will now be forwarded acquired pneumonia when other antibiot- to the European Commission for the ics cannot be used or have failed. The adoption of a decision applicable to all Agency also recommended strengthening oral moxifloxacin-contain medicines the warnings for oral moxifloxacin medi- authorized in the EU. cines. Reference: European Medicines Agency Moxifloxacin is a fluoroquinolone antibi- Presss Release, Doc. Ref. EMEA/CHMP/ otic for the treatment of acute exacerba- 382927/2008. 24 July 2008. http:// tion of chronic bronchitis, community- www.emea.europa.eu acquired pneumonia, acute bacterial sinusitis and, in some Member States, Ezetimibe/simvastatin: safety for mild to moderate pelvic inflammatory review of cancer risk disease. United States of America — The Food At its July 2008 meeting, the Committee and Drug Administration (FDA) is investi- for Medicinal Products for Human Use gating a report from the SEAS trial (CHMP) concluded that the benefits of (Simvastatin and Ezetimibe in Aortic oral moxifloxacin medicines continue to Stenosis) of a possible association outweigh its risks. However, due to safety between the use of Vytorin¨ (a combina- concerns, mainly related to an increased tion of simvastatin plus ezetimibe) and a risk of adverse hepatic reactions, the potentially increased incidence of cancer. CHMP recommended restricting their use in these indications. For acute bacterial Simvastatin (Zocor®), a “statin” class sinusitis and acute exacerbations of drug approved in 1991, decreases chronic bronchitis, they should only be production of cholesterol by the liver and prescribed when other antibiotics cannot is indicated to reduce LDL-cholesterol be used or have failed. For community levels and reduce the risk of cardiovascu- acquired pneumonia, they should only lar events such as heart attack and be given when treatment with other stroke. Ezetimibe (Zetia¨), approved in antibiotics cannot be used. 2002, inhibits the absorption of choles- terol in the intestine and is indicated to The CHMP also recommended that the reduce LDL-cholesterol levels. Vytorin¨, warnings of oral moxifloxacin-containing the combination product approved in

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2004, is indicated to reduce LDL-choles- terol achieved and incident cancer in terol levels. patients receiving a statin.

Recently, FDA obtained preliminary However, most large prospective studies results from the SEAS trial. This clinical of statin drugs have reported no differ- trial tested whether lowering LDL-choles- ence in cancer incidence between the terol with Vytorin¨ would reduce the risk active and placebo arms. For simvastatin, of major cardiovascular events, including the Heart Protection Study randomized aortic valve replacement, congestive 20 000 patients to a daily dose of simvas- heart failure, and ischemic cardiovascular tatin 40 mg or placebo for up to 5 years. events in individuals with aortic stenosis. The incidence rate for cancer was 7.9% A lower overall cardiovascular risk was in the simvastatin group and 7.8% in the not found with Vytorin¨. However, there placebo group, and the deaths from was an additional observation that a cancer occurred at similar rates in both larger percentage of subjects treated with groups. Vytorin¨ were diagnosed with and died from all types of cancer combined (includ- References ing skin cancer) when compared to placebo during the 5-year study. 1. Alsheikh-Ali A et al. Effect of the magnitude of lipid lowering on risk of elevated liver Interim data from two large ongoing enzymes, rhabdomyolysis, and cancer. J Am Coll Cardiol 2007;50: 409-18. cardiovascular trials of Vytorin® — the Study of Heart and Renal Protection 2. Heart Protection Study Collaborative Group. (SHARP) and the Improved Reduction in MRC/BFH Heart Protection Study of choles- High-Risk Subjects Presenting with Acute terol lowering with simvastatin in 20,536 high- Coronary Syndrome (IMPROVE-IT) — risk individuals: a randomized placebo- show no increased risk of cancer with the controlled trial. Lancet 2002;360: 7-22. combination of simvastatin plus ezetim- ibe. The SHARP trial is expected to be 3. FDA Early Communication about an completed in 2010. The IMPROVE-IT trial ongoing safety review of ezetimibe/simvastatin is scheduled for completion around 2012. (marketed as Vytorin¨), simvastatin (marketed as Zocor¨) and ezetimibe (marketed as Safety data from both of these trials are Zetia¨). 21 August 2008 at http:// being evaluated on a regular basis by www.fda.gov/medwatch independent data safety monitoring boards. FDA has determined that, to date, these findings in the SEAS trial plus the Norfloxacin-containing interim data from ongoing trials should medicines not for use in not prompt patients to stop taking urinary infections Vytorin¨ or any other cholesterol lowering drug. European Union — The European Medicines Agency (EMEA) has recom- FDA is aware of previous reports sug- mended restricting the use of oral nor- gesting a link between low on-treatment floxacin-containing medicines in urinary cholesterol levels and an increased risk of infections. The Agency’s Committee for cancer. A 2007 pooled analysis of 16 Medicinal Products for Human Use studies with 23 statin drug arms, pub- (CHMP) has concluded that the market- lished in the Journal of the American ing authorizations for oral norfloxacin- College of Cardiology, reported an asso- containing medicines, when used in the ciation between the level of LDL-choles- treatment of acute or chronic complicated pyelonephritis (kidney infection), should

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be withdrawn because the benefits of already taking oral norfloxacin for this these medicines do not outweigh their type of infection to an alternative antibi- risks in this indication. This is based on otic. Patients who are taking oral formula- the fact that the efficacy has not been tions of norfloxacin-containing medicines adequately demonstrated for this type of to treat complicated pyelonephritis infection. should discuss their treatment with their doctor if they continue to have symptoms Norfloxacin is a fluoroquinolone antibiotic. or at their next scheduled visit. Medicines containing norfloxacin are authorized in all European Union (EU) Reference: European Medicines Agency Member States under various trade Press Release. Doc. Ref. EMEA/380260/ names for the treatment of infections, 2008. 24 July 2008. http:/www.emea. including simple or complicated urinary europa.eu tract infections, infection of the prostate, uncomplicated gonorrhoea, several types Ceftriaxone: fatal outcome of gastroenteritis and conjunctivitis. with calcium-containing solutions The CHMP review of norfloxacin medi- cines was initiated on the request of Canada — There is a risk of precipitation the Belgian medicines regulatory agency. when ceftriaxone and calcium are admin- They questioned the efficacy of oral istered concurrently via intravenous route. formulations of the medicine for compli- Cases of fatal reactions with ceftriaxone- cated pyelonephritis, in comparison with calcium precipitates in lung and kidneys other fluoroquinolones. In current prac- have been described in neonates and tice, this disease is usually treated using infants (1Ð4). either injectable antibiotics, or other fluoroquinolones taken by mouth or given Ceftriaxone is a long-acting broad spec- by injection. trum cefalosporin antibiotic for parenteral use indicated for treatment of lower Following evaluation of information respiratory tract infections, renal and provided by the companies, the CHMP, urinary tract infections, bacterial septi- at its July 2008 meeting, noted that there cemia, skin and wound infections, bone was not enough clinical data to demon- and joint infections, gonorrhoea, intra- strate the efficacy of oral treatment with abdominal infections, and meningitis norfloxacin-containing medicines in when caused by susceptible organisms. complicated pyelonephritis. Therefore, Ceftriaxone is also indicated for prophy- the CHMP concluded that the use of oral laxis in patients undergoing certain norfloxacin-containing medicines in the surgical procedures. treatment of acute or chronic complicated pyelonephritis could no longer be sup- Although there are no reports to date of ported. intravascular precipitations in patients, other than neonates, the theoretical The recommendation of the CHMP does possibility exists for an interaction be- not have an impact on the use of oral tween ceftriaxone and calcium-containing norfloxacin-containing medicines in other solutions in other patients. types of infection. ¥ In patients aged less than 10 weeks, IV Doctors should not prescribe oral nor- Ceftriaxone and IV calcium-containing floxacin for complicated pyelonephritis solutions should not be administered and should consider switching patients within 5 days of each other.

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¥ In all other patients, IV Ceftriaxone and Safety review of tumour IV calcium-containing solutions should necrosis factor blockers not be administered within 48 hours of each other. United States of America — The Food and Drug Administration (FDA) is investi- ¥ Ceftriaxone and calcium-containing gating the possible association between solutions, including continuous calcium- use of tumor necrosis factor (TNF) containing infusion such as parenteral blockers (marketed as Remicade¨, nutrition, should not be mixed or co- Enbrel¨, Humira¨, and Cimzia¨) and the administered to any patient irrespective development of lymphoma and other of age, even via different infusion lines cancers in children and young adults. at different sites These individuals were treated with TNF blockers for Juvenile Idiopathic Arthritis Although most cases occurred with (JIA), Crohn disease or other diseases. simultaneous administration of the two JIA is the new name for what was called products, the interaction has also been Juvenile Rheumatoid Arthritis (JRA). reported when ceftriaxone and calcium- containing products were administered FDA is investigating approximately 30 at different times and through different reports of cancer in children and young infusion lines. This explains the recom- adults submitted to FDA’s Adverse Event mended interval between the administra- Reporting System over a ten-year inter- tion of the two products because val, beginning in 1998 after approval of ceftriaxone remains in circulation for a the first TNF blocker, and extending certain time after its administration (5). through 29 April 2008. These reports described cancer occurring in children References and young adults who began taking TNF blockers (along with other immuno- 1. Rapp RP, Kuhn R. Clinical pharmaceutics and calcium ceftriaxone. Ann pharmacother suppressive medicines such as meth- 2007;41:2072. Epub 6 nov 2007. DOI otrexate, azathioprine or 6-mercaptopu- 10.1345/aph.1K410. rine), when they were aged 18 or less, to treat Juvenile Idiopathic Arthritis (JIA), 2. Gin AS, Wheateon H, Dalton B. Comments: Crohn disease or other diseases. Ap- Clinical pharmaceutics and calcium- proximately half the cancers were lym- ceftriaxone. Ann pharmacother 2008;42:450- phomas and included both Hodgkin and 51. Epub 29 January 2008. DOI 10.1345/ non-Hodgkin lymphoma. Lymphoma is aph.1K410a. not a recognized complication of JIA or of Crohn disease. Other cancers reported 3. Minutes of “Commission Nationale de pharmacovigilance” meeting, January 31, included leukaemia, melanoma, and solid 2006. http://afssaps.sante.fr/htm/1/pharmaco/ organ cancers. cr060101.pdf. Accessed 2008-06-23. FDA is also aware of the risk of hepato- 4. Information for healthcare professionals. splenic T cell lymphoma in children and September 2007. www.fda.gov/cder/drug/ young adults with Crohn disease treated InfoSheets/HCP/ceftriaxone.htm. Accessed with Remicade¨ and immunosuppressive 2008-06-23. drugs such as azathioprine or 6-mercap- topurine. This risk was described in the 5. Communication from Medeffect, 31 July Remicade¨ prescribing information in 2008. http://www.hc-sc.gc.ca 2006.

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FDA has requested the manufacturers to few events occurring prior to day 2. When provide information about all cases of airway complications occurred, medical cancer reported in children taking TNF intervention was frequently necessary. blockers. The manufacturer of Cimzia¨ is Treatments needed included respiratory required to conduct a study to assess support with intubation, anti-inflammatory long-term risks of the product, including medication, tracheotomy and most lymphoma and other cancers. commonly second surgeries to drain the surgical site. Reference: FDA Advise of safety review, 4 June 2008. http://www.fda.gov/medwatch/ Since the safety and effectiveness of rhBMP for treatment of cervical spine Recombinant human bone conditions has not been demonstrated, morphogenetic protein: life- and in light of the serious adverse events threatening complications described above, FDA recommends that practitioners either use approved alterna- United States of America — The Food tive treatments or consider enrolling as and Drug Administration (FDA) has investigators in approved clinical studies. received reports of life-threatening Both rhBMPs are contraindicated for all complications associated with recom- uses in patients who are skeletally binant human bone morphogenetic immature (<18 years of age) or pregnant, protein (rhBMP) when used in the cervical and in those with a known hypersensitiv- spine. It is of note that the safety and ity to the specific rhBMP, bovine Type 1 effectiveness of rhBMP in the cervical collagen or to other components of the spine have not been demonstrated and formulations. these products are not approved by FDA for this use. Reference: FDA Public Health Notification: Life-threatening Complications Associated FDA has received at least 38 reports of with Recombinant Human Bone Morphoge- complications during the last 4 years with netic Protein in Cervical Spine Fusion. 1 July the use of rhBMP in cervical spine fusion. 2008. http://www.fda.gov/medwatch These complications were associated with swelling of neck and throat tissue, Electronic medical devices which resulted in compression of the malfunction: computed airway and/or neurological structures in the neck. Some reports describe difficulty tomography scanning swallowing, breathing or speaking. United States of America —The Food Severe dysphagia following cervical spine and Drug Administration (FDA) is alerting fusion using rhBMP products has also users to the possibility that x-rays used been reported in the literature. during computed tomography (CT) Anatomical proximity of the cervical spine examinations may cause some implanted to airway structures in the body has and external electronic medical devices to contributed to the seriousness of the malfunction, and to provide recommenda- events reported and the need for emer- tions to reduce the potential risk. gency medical intervention. The mecha- nism of action is unknown, and character- The FDA has received a small number of istics of patients at increased risk have reports of adverse events in which CT not been identified. scans may have interfered with electronic medical devices, including pacemakers, Most complications occurred between 2 defibrillators, neurostimulators, and and 14 days post-operatively with only a implanted or externally worn drug infusion

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pumps. In these reports, the following adaptation can result in a shift of water adverse events were likely to have been intracellularly and cerebral oedema, caused by x-rays from CT scans: which may present with anorexia, nausea and vomiting, difficulty concentrating, • Unintended “shocks” (i.e., stimuli) from confusion, lethargy, agitation, headache, neurostimulators and seizures.

¥ Malfunctions of insulin infusion pumps The risk of hyponatraemia is greater with ¥ Transient changes in pacemaker output desmopressin intranasal preparations pulse rate than with the oral forms. In 2007, the TGA amended the indications for desmo- Note that malfunctions of this kind, which pressin nasal spray to restrict use only can result from direct exposure of the when it is not feasible to use an oral medical device to the high x-ray dose formulation. Sponsors were also required rates generated by some CT equipment, to amend all desmopressin product are different from those related to MRI information documents to strengthen scanning, which are caused by strong precautionary statements relating to the electric and magnetic fields. potential for hyponatraemia and to provide information on this potentially Reference: FDA Preliminary Public Health serious reaction (1). Notification: Possible Malfunction of Electronic Medical Devices Caused by Computed To date, ADRAC has received 68 reports Tomography (CT) Scanning, 14 July 2008 at of adverse reactions associated with the http://www.fda.gov/cdrh/safety.html. use of desmopressin, including 17 reports of convulsions (with or without reported Desmopressin and hyponatraemia), and 10 further reports of hyponatraemia hyponatremia alone. Of 12 reports of convulsions or hyponatremia following the Australia — Desmopressin (Minirin®, use of desmopressin nasal spray, 7 Octostim¨) is a synthetic analogue of involved children under 13 years of age. the natural antidiuretic hormone (ADH) arginine vasopressin and is currently Prescribers are reminded that desmo- available in nasal spray, nasal solution, pressin nasal spray and tablets should be tablet, sublingual wafer, and injection used in the treatment of nocturnal enu- form. Desmopressin nasal spray and resis only when an enuresis alarm has tablets are indicated for primary nocturnal failed or is contraindicated, and that enuresis (where an enuresis alarm has tablets should be used in preference to failed or is contraindicated) and cranial intranasal preparations because of a diabetes insipidus; desmopressin nasal possible increased risk of hyponatremia. solution and tablets are indicated for Avoidance of excessive fluid intake cranial diabetes insipidus and certain should be advised during treatment with blood disorders. desmopressin. The ongoing need for these products should be reviewed Desmopressin acts on the ADH receptors in the kidneys, mimicking the effects of periodically in patients taking desmo- ADH and therefore preventing excessive pressin long-term. loss of water. In the presence of exces- sive fluid intake in patients taking desmo- Extracted from the Australian Adverse pressin, dilutional hyponatraemia can Drug Reactions Bulletin, Volume 27, Number 4, August 2008 occur. If this occurs quickly then lack of

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Reference This risk is dose-related and increases when a dose of simvastatin greater than 1. Ferring Pharmaceuticals Pty Ltd. Product 20 mg per day is given with amiodarone. Information for: Minirin Nasal Spray, Minirin A revision of the simvastatin labelling in Tablets, Minirin, Octistim. 2002 described an increased risk of rhabdomyolysis when amiodarone is Micro-bubble contrast agents taken with simvastatin doses greater than 20 mg daily. United States of America — The Food and Drug Administration (FDA) has However, the FDA continues to receive issued an alert to healthcare profession- reports of rhabdomyolysis in patients als about changes that were made to the treated concurrently with amiodarone and prescribing information for micro-bubble simvastatin, particularly with simvastatin contrast agents. doses greater than 20 mg daily. Prescrib- ers should be aware of the increased risk The revised boxed warning and warnings of rhabdomyolysis when simvastatin is continue to highlight the risk of serious prescribed with amiodarone, and they cardiopulmonary reactions during or should avoid doses of simvastatin greater within 30 minutes following the adminis- than 20 mg per day in patients taking tration of these products and recommend amiodarone. that high risk patients with pulmonary hypertension or unstable cardiopulmo- Reference: Information for Healthcare nary conditions be closely monitored Professionals. Simvastatin (marketed as during and for at least 30 minutes post Zocor¨ and generics), Ezetimibe/Simvastatin administration of these contrast agents. (marketed as Vytorin¨), Niacin extended- Concurrent with these labelling changes, release /Simvastatin (marketed as Simcor¨), the FDA has required that manufacturers used with Amiodarone (Cordarone¨, of micro-bubble contrast agents conduct Pacerone¨). FDA Alert, 8 August 2008 at clinical studies to more thoroughly assess http://www.fda.gov/medwatch the risks for serious cardiopulmonary reactions. Naltrexone injection site reactions Reference: Information for Healthcare Professionals. Micro-bubble Contrast Agents United States of America — The Food (marketed as Definity¨ (Perflutren Lipid and Drug Administration (FDA) has Microsphere) Injectable Suspension and issued an alert to healthcare profession- Optison¨ (Perflutren Protein-Type A als about the risk of adverse injection site Microspheres for Injection). FDA Alert, 17 July reactions in patients receiving naltrexone 2008 at http://www.fda.gov/medwatch (Vivitrol¨). Physicians should instruct patients to monitor the injection site and Simvastatin used with contact them if they develop pain, swell- amiodarone: rhabdomyolysis ing, tenderness, induration, bruising, pruritus, or redness at the injection site United States of America — The Food that does not improve or worsens within and Drug Administration (FDA) has two weeks. Physicians should promptly issued an alert to healthcare profession- refer patients with worsening injection site als about the risk of a rare condition of reactions to a surgeon. muscle injury called rhabdomyolysis, which can lead to kidney failure or death, FDA has received 196 reports of injection when simvastatin is used with amiodar- site reactions including cellulitis, indura- one.

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tion, haematoma, abscess, sterile ab- mercaptopurine for inflammatory bowel scess, and necrosis. Sixteen patients disease. A risk for the development of required surgical intervention ranging hepatosplenic T-cell lymphoma in from incision and drainage in the cases of patients treated with adalimumab abscesses to extensive surgical debride- cannot be excluded. ment in the cases that resulted in tissue necrosis. ¥ HSTCL should be considered in the event that a patient receiving adalimu- Naltrexone is indicated for the treatment mab develops symptoms of lymphomas of alcohol dependence in patients who and / or hepatosplenomegaly with or are able to abstain from alcohol in an without peripheral lymphadenopathy or outpatient setting prior to initiation of significant peripheral blood lymphocyto- treatment. Naltrexone is administered sis. as an intramuscular (IM) gluteal injection. ¥ A warning will be added to the product Naltrexone should not be administered information (SPC/Package Leaflet) as a intravenously, subcutaneously, or inad- risk minimization measure. vertently into fatty tissue. Healthcare providers should ensure that the nal- Reference: Direct Healthcare Professional trexone injection is given correctly with Communication on reports of hepatosplenic T- the pre-packaged needle that is specifi- cell lymphoma in patients treated with cally designed for this drug. Humira¨ (adalimumab). Abbott Ltd. at http:// www.mhra.gov.uk Reference: Information for Healthcare Professionals. Naltrexone Injection Site Serious Risks/New Safety Reactions [naltrexone for extended-release Information injectable suspension (marketed as Vivitrol¨)]. FDA Alert, 12 August 2008 at http:// United States of America — The Food www.fda.gov/medwatch and Drug Administration (FDA) has published a table listing the names of Adalimumab: hepatosplenic products and potential signals of serious T-cell lymphoma risks/new safety information that were identified for these products during the United Kingdom — The manufacturer period January Ð March 2008 in the of adalimumab (Humira¨) is advising Adverse Event Reporting System (AERS) healthcare professionals of new safety database (see table on page 199). information. Adalimumab is a TNF alpha blocker authorized in adult patients for the The appearance of a drug on this list treatment of rheumatoid arthritis, psoriatic does not mean that FDA has concluded arthritis, ankylosing spondylitis, Crohn that the drug has the listed risk. It means disease and psoriasis. that FDA has identified a potential safety issue, but does not mean that FDA has ¥ From launch in December 2002, three identified a causal relationship between postmarketing reports of hepatosplenic the drug and the listed risk. If after further T-cell lymphoma (HSTCL), which is a evaluation the FDA determines that the rare aggressive form of non-Hodgkin drug is associated with the risk, it may lymphoma with a poor prognosis, have take a variety of actions including requir- been reported in patients receiving ing changes to the labelling of the drug, adalimumab. requiring development of a Risk Evalua- tion and Mitigation Strategy (REMS), or ¥ Two of these three patients were young gathering additional data to better charac- men also receiving azathioprine or 6- terize the risk.

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Potential Signals of Serious Risks/New Safety Information Identified by the Adverse Event Reporting System (AERS), January Ð March 2008

Product Name: Active Ingredient Potential Signal of Serious Risk/ (Trade), New or Product Class Safety Information

Arginine Hydrochloride Injection Paediatric overdose due to labelling / (R-Gene 10¨) packaging confusion Desflurane (Suprane¨) Cardiac arrest Duloxetine (Cymbalta¨) Urinary retention Etravirine (Intelence¨) Haemarthrosis Fluorouracil Cream (Carac¨) and Adverse events due to name Ketoconazole Cream (Kuric¨) confusion Heparin Anaphylactic-type reactions Icodextrin (Extraneal¨) Hypoglycaemia Insulin U-500 (Humulin R¨) Dosing confusion Ivermectin (Stromectol¨) and Warfarin Drug interaction Lapatinib (Tykerb¨) Hepatotoxicity Lenalidomide (Revlimid¨) Stevens Johnson Syndrome Natalizumab (Tysabri¨) Skin melanomas Nitroglycerin (Nitrostat¨) Overdose due to labelling confusion Octreotide Acetate Depot Ileus (Sandostatin LAR¨) Oxycodone Hydrochloride Controlled- Drug misuse, abuse and overdose Release (Oxycontin¨) Perflutren Lipid Microsphere (Definity¨) Cardiopulmonary reactions Phenytoin Injection (Dilantin¨) Purple Glove Syndrome Quetiapine (Seroquel¨) Overdose due to sample pack labelling confusion Telbivudine (Tyzeka¨) Peripheral neuropathy Tumor Necrosis Factor (TNF) Blockers Cancers in children and young adults

FDA wants to emphasize that the listing Deferasirox: hepatic failure of a drug and a potential safety issue on this Web site does not mean that FDA is United Kingdom — In agreement with suggesting prescribers should not pre- European Union regulatory authorities, scribe the drug or that patients taking the the manufacturer of deferasirox drug should stop taking the medication. (Exjade¨) has advised healthcare profes- Patients who have questions about their sionals of updated safety information. use of the identified drug should contact Deferasirox is indicated for the treatment their health care provider. FDA will of chronic iron overload due to frequent complete its evaluation of each potential blood transfusions, or when desferriox- signal/new safety information and issue amine (Desferal¨) is contraindicated or additional public communications as inadequate: appropriate. ¥ Postmarketing cases of hepatic failure, Reference: 5 September 2008 at http:// sometimes fatal, have been reported in www.fda.gov patients treated with deferasirox. The role of deferasirox as a contributing or aggravating factor cannot be excluded.

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It is recommended that serum trans- symptoms, respiratory symptoms and aminases, bilirubin and alkaline phos- constitutional symptoms. phatase are checked before the initia- tion of treatment, every 2 weeks during FDA has reviewed data from 2 studies the first month and monthly thereafter. If that support the recommendation for pre- there is a persistent and progressive therapy screening for the presence of the increase in serum transaminase levels HLA-B*5701 allele and the selection of that cannot be attributed to other alternative therapy in positive subjects. causes, deferasirox should be inter- Genetic tests for HLA-B*5701 are already rupted (see section 4.8 of revised SPC, available and all patients should be attached). screened for the HLA-B*5701 allele before starting or restarting treatment with ¥ Upper gastrointestinal ulceration and abacavir or abacavir-containing medica- haemorrhage have been reported in tions. Avoidance of abacavir therapy in patients, including children and adoles- HLA-B*5701 positive patients will signifi- cents, receiving deferasirox. Physicians cantly decrease the risk of developing and patients should remain alert for clinically-suspected abacavir HSR. For signs and symptoms of gastrointestinal HLA-B*5701-positive patients, treatment ulceration and haemorrhage during with an abacavir-containing regimen is deferasirox therapy and promptly initiate not recommended and should be consid- additional evaluation and treatment if ered only under exceptional circum- a serious gastrointestinal adverse event stances when the potential benefit out- is suspected. weighs the risk.

¥ Cases of renal tubulopathy (Fanconi Development of clinically-suspected syndrome) have been reported in abacavir HSR requires immediate and patients treated with deferasirox. Dose permanent discontinuation of abacavir reduction or interruption may be consid- therapy in all patients, including patients ered if there are abnormalities in levels negative for HLA-B*5701. This new safety of tubular markers and/or if clinically information will be reflected in updated indicated. product labelling. Reference: Communication from Novartis Reference: Information for Healthcare Pharmaceutical UK Ltd, EXJ08000052, July Professionals. Abacavir (marketed as 2008 at http://www.Mhra.gov.uk Ziagen¨) and Abacavir-containing Medica- tions. FDA Alert, 24 July 2008 at http:// Abacavir: hypersensitivity www.fda.gov/medwatch reactions Fluoroquinolones: risk of United States of America — The Food tendinitis and tendon rupture and Drug Administration (FDA) has issued an alert to healthcare profession- United States of America — The Food als about serious and sometimes fatal and Drug Administration (FDA) has hypersensitivity reactions (HSR) caused notified manufacturers that a boxed by abacavir therapy which are signifi- warning is necessary in the labelling for cantly more common in patients with a fluoroquinolones concerning the in- particular human leukocyte antigen (HLA) creased risk of tendinitis and tendon allele, HLA-B*5701. Abacavir HSR is a rupture. The agency also determined that multi-organ syndrome characterized by 2 it is necessary for manufacturers of the or more clinical signs or symptoms that drugs to provide a Medication Guide to can include fever, rash, gastrointestinal patients about possible side effects.

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The risk of developing fluoroquinolone- that drugs that inhibit this enzyme may associated tendinitis and tendon rupture increase blood colchicine concentrations is further increased in people older than and therefore increase the potential for 60, in those taking corticosteroid drugs, colchicine toxicity. The CYP3A4 inhibitor, and in kidney, heart, and lung transplant clarithromycin, was used concomitantly in recipients. 4 cases of severe colchicine toxicity reported to the TGA, 3 of which described Reference: FDA News, 8 July 2008. http:// a fatal outcome. In one of the fatal cases, www.fda.gov/medwatch clarithromycin was being used as part of “triple therapy” for Helicobacter pylori Colchicine: fatal interactions eradication in a patient undergoing and reactions treatment for gout with colchicine; this patient subsequently developed massive Australia — Colchicine is indicated for myelosuppression and multi-organ failure. the treatment of acute gout, but it has a Cases of fatal interactions between narrow therapeutic index with significant colchicine and clarithromycin have also potential for toxicity and severe drug been published (2, 3). interactions. In mid-2007, the Therapeutic Goods Administration (TGA) required To date, the TGA has received 243 updates to the Colgout¨ and Lengout¨ reports for colchicine, including 53 de- product information to limit colchicine scribing blood dyscrasias such as neutro- usage to only where NSAID treatment is penia (15 reports), thrombocytopenia contraindicated, has failed or has caused (10), pancytopenia (10), leukopenia (8) unacceptable side effects; and to limit the and agranulocytosis (4 reports), and an maximum cumulative dose to 6 mg over 4 additional report describing sepsis and days in otherwise healthy adults (with extensive severe maculopapular rash. washout intervals of at least 3 days if Of these cases, 21 had not recovered at additional treatment is needed). Alterna- the time of reporting and 9 described a tive treatments should be considered in fatal outcome associated with renal the elderly and those with renal or hepatic failure, multi-organ failure or overwhelm- impairment, but if colchicine is to be used ing sepsis. Colchicine was the sole in these patients the cumulative dose suspected drug in 16 of the reports of should not exceed 3 mg over 4 days. blood dyscrasia but other drugs were also suspected in all of the reports that The Adverse Drug Reactions Advisory described a fatal outcome. Committee (ADRAC) has previously Prescribers are reminded that colchicine warned of the potential for severe or fatal can be associated with significant toxicity toxicities with colchicine especially in and the risk-benefit should be considered overdose and in those with renal impair- on a case-by-case basis. In most cases, ment (1). Toxic effects of greatest con- it should be used for short-term periods cern include blood dyscrasias due to and only where NSAID therapy is con- bone marrow suppression, multi-organ traindicated or has failed. Colchicine is failure and, more rarely, myopathy and best avoided if patients are taking drugs rhabdomyolysis (which tend to occur in that inhibit CYP3A4 or have significant patients with impaired renal or hepatic renal or hepatic impairment. function on long-term treatment with prophylactic doses of colchicine). Extracted from the Australian Adverse Since colchicine is metabolized mainly by Drug Reactions Bulletin, Volume 27, CYP3A4, prescribers should be aware Number 5, October 2008

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References 3. Hung IF, Wu AK, Cheng VC, et al. Fatal interaction between clarithromycin and 1. ADRAC and Kubler PA. Fatal colchicine colchicine in patients with renal insufficiency: toxicity. MJA 2000; 172: 498-490. A retrospective study. Clin Infect Dis 2005; 41: 2. Cheng VC, Ho PL and Yuen KY. Two 291Ð300. probable cases of serious drug interaction between clarithromycin and colchicine. Southern Med J 2005; 98: 811-813.

Spontaneous monitoring systems are useful in detecting signals of relatively rare, serious and 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 previously. 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 validated before any regulatory decision can be made.

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Regulatory Action and News

WHO Prequalification: GMP Suspension from the WHO List of Pre- deviations and suspension qualified Medicinal Products will halt procurement by international and national World Health Organization — WHO’s procurement agencies of the products Medicines Prequalification Programme concerned until the Medicines Prequalifi- has issued a Notice of Concern letter to cation Programme is satisfied that all Sandoz South Africa Ltd. based on the corrective actions have been taken by the results of inspections performed at their manufacturer and verified by WHO. manufacturing facility in Kempton Park, South Africa. Additionally, one product Based on the information currently (isoniazid 150 mg + rifampicin 300 mg available, the documented deficiencies in tablet) which is manufactured at the manufacturing do not relate to the specific facility was suspended from the WHO List failure of the concerned Sandoz product of Prequalified Medicines. to meet its required specifications or to treat human illness. These actions were taken as a conse- WHO is advising consumers to continue quence of problems documented with taking their Sandoz medications until they manufacturing processes, where signifi- can be replaced with quality assured cant deviations from good manufacturing products from other manufacturers. practices (GMP) were documented in the However, where no alternative treatment manufacture and control of antituber- options are available, WHO strongly culosis medicines during the WHO in- advises consumers not to interrupt their spection in May 2008. A follow-up inspec- drug therapy, which could have serious tion by WHO was refused by the com- implications for their health. pany, thus it was not possible to verify the implementation of corrective action and Reference: Sandoz PQ note, 25 September come to a conclusion on the level of GMP 2008 at http://www.who.int/prequal compliance currently on site. Import alert: Ranbaxy facilities These actions are proactive measures that WHO is taking to ensure that all United States of America —The US prequalified medicinal products are Food and Drug Administration (FDA) has manufactured according to GMP require- issued two Warning Letters to Ranbaxy ments. A Notice of Concern is issued to Laboratories Ltd and simultaneously remind a manufacturer or research established an Import Alert for drugs organization of their obligations to assure manufactured or using materials from two quality and to inform suppliers and Ranbaxy facilities in India at Dewas or procurement agencies of potential risks Paonta Sahib. This means that any associated with a given product, manu- finished product or active pharmaceutical facturer or organization.A Notice of ingredient manufactured at these sites Concern is not cause for public concern. offered for import into the United States If WHO identifies a public health risk, will be detained at the border. appropriate additional steps are taken to The reason for these actions follows advise health professionals and the problems involving drug manufacturing public.

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processes where significant deviation in addition to its routine monitoring from good manufacturing practices activities to confirm if products prequali- (GMP) have been documented in manu- fied by WHO from Ranbaxy continue to facture and control of both finished meet all the necessary requirements to products and active pharmaceutical ensure quality, safety and efficacy. ingredients during FDA inspections in Additionally, the WHO Medicines Pre- early 2008 (1). qualification Programme:

These are proactive measures that the ¥ has written to Ranbaxy requesting FDA is taking to ensure that all drugs that clarification of the issues raised by FDA; reach the American public are manufac- ¥ is in close contact with FDA concerning tured according to GMP requirements. the Ranbaxy products based on the Based on the information currently confidentiality agreement between the available, the FDA documented deficien- two institutions; cies in manufacturing do not relate to the specific failure of any Ranbaxy product to ¥ is in contact with other national regula- meet its required specifications or to treat tory authorities to follow the matter human illness. FDA is not recalling any closely; product presently in distribution in the USA, but is advising consumers to ¥ is taking steps to identify any potential continue taking their medications until irregularities or deficiencies that may affect Ranbaxy products, either under they can be replaced with products from another manufacturer. evaluation or prequalified by WHO; ¥ is liaising with other UN agencies (such World Health Organization — Ranbaxy as UNICEF) and partners. Laboratories Ltd has submitted several antiretroviral products for WHO prequalifi- In the current situation, where no alterna- cation since 2001. Currently 18 Ranbaxy tive treatment options are available, WHO products have been prequalified by WHO strongly advises consumers not to inter- and seven products are under evaluation. rupt their drug therapy, which could have serious implications for their health. The current Import Alert issued by the Switching to non-prequalified products is FDA lists 30 products, out of which two not recommended as their quality has not (lamivudine and zidovudine) are present been documented by WHO. in several WHO prequalified products. The WHO Medicines Prequalification References Programme has performed several inspections at the Ranbaxy Paonta Sahib 1. http://www.fda.gov/bbs/topics/NEWS/2008/ site Ð most recently in June 2008. During NEW01886.html each of the inspections, some non 2. Ranbaxy PQ note, 17 September 2008 at compliance with GMP was observed. http://www.who.int/prequal However, following each inspection the company submitted corrective action plans to rectify this non compliance and in Medicines Prequalification general the site was considered to be Programme: listed products operating at an acceptable level of World Health Organization —The WHO compliance with WHO GMP. Medicines Prequalification Programme, in close cooperation with national regulatory WHO is closely monitoring the case and agencies and partner organizations, planning a series of extraordinary actions was established to make quality priority

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medicines available for the benefit of Reference: WHO Medicines prequalification those in need. Programme at http://healthtech.who.int/pq/

This is achieved through evaluation and Development of medicines inspection activities and by building for Alzheimer and Parkinson national capacity for sustainable manu- disease facturing and monitoring of quality medi- cines. European Union — The European Medicines Agency (EMEA) has released The list of prequalified medicinal products two guidelines for companies developing used for HIV/AIDS, malaria, tuberculosis medicines for the treatment of Alzheimer and for reproductive health produced by disease and other dementias and for the Programme is used principally by Parkinson disease, in light of recent United Nations and other agencies to scientific progress in the understanding of guide their procurement decisions. The these diseases and conditions. list has now become a vital tool for any agency or organization involved in bulk Advances in clinical science, physiopa- purchasing of medicines. thology and molecular biology have stimulated new interest in the develop- List update: September 2008 ment of more effective symptomatic or disease-modifying treatments, i.e. early HA322: Abacavir 300 mg (as sulfate) treatments that may prevent the emer- tablets Ranbaxy Ltd - India gence or slow down the progression of disease. The guidelines were developed HA393: Abacavir 300 mg (as sulfate) in response to the need of companies tablets Matrix Laboratories - India developing these new types of medicines for guidance on appropriate clinical trial HA396: Nevirapine 200 mg tablets designs. Matrix Laboratories - India As life expectancy increases, neuro- degenerative diseases and dementia will HA403: Efavirenz 600 mg ablets affect more and more people over the Matrix Laboratories - India coming decades, and these guidelines HA404: Zidovudine 300 mg tablets are expected to help improve the avail- Matrix Laboratories - India ability of medicines to treat such diseases and conditions. The guidelines will come HA405: Lamivudine/Stavudine 150 mg/ into effect on 1 February 2009. 30 mg tablets Matrix Laboratories - India Reference: Press Release, EMEA releases HA406: Lamivudine/Stavudine 150 mg/ guidelines on development of medicines for 40 mg tablets Matrix Laboratories - India Alzheimer disease and Parkinson disease. Doc. Ref. EMEA/460300/2008, 4 September HA407: Lamivudine/Nevirapine/Stavu- 2008 at http://www.emea.europa.eu dine 150 mg/200 mg/30 mg tablets Matrix Laboratories - India GMP regulations for HA408: Lamivudine/Nevirapine/Stavu- radiopharmaceuticals dine 150 mg/200 mg/40 mg tablets Matrix Laboratories - India European Union — Revised good manufacturing practice (GMP) require- HA434: Lopinavir/Ritonavir 100 mg/25 ments for the production of radiopharma- mg tablets Abbott Laboratories - Ger- ceuticals have been published by the many European Commission (EC).

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The updates to the annex are intended to labelling and packaging materials, critical make it compliant with GMP Part II, which intermediates and the finished radiophar- laid out additional requirements for maceutical. Specifications must also be actives substances used as starting put in place for any piece of equipment materials. In addition, the EC has sought that could critically impact on the quality to bring the regulations up-to-date with of the finished product. advances in the manufacture of radio- pharmaceuticals. The cleaning, sanitization, sterilization or maintenance of equipment should be An initial draft was published for public documented to show the product name, consultation in December 2006. This batch number, date and time of the process has now been completed and activity and signature for the persons companies have until 1 March 2009 to involved in these activities. become compliant with the new require- ments. The regulations are broken down Documents must be kept for a minimum into subcategories including quality of three years, unless a different assurance, personnel, production and timeframe is specified by national laws. documentation. These are intended to Retention to ensure accountability ex- provide the necessary regulation to tends to keeping sufficient samples of prevent cross-contamination, the spread each batch of bulk formulated product for of radioactive material and ensure the at least six months after expiry of the quality of the product. finished medicinal product.

Quality assurance is particularly important Samples of starting materials, excluding in the manufacture of radiopharmaceuti- solvents gases or water used in the cals as the half-lives of some mean they manufacturing process must be kept for need to be administered shortly after at least two years after the release of the production. Consequently there is not product. This period can be shortened if enough time to test the product. the material has a period of stability of less than two years. Underlying all the regulations is the need for accurate, up-to-date documentation of Reference: Communication on EMEA web- site, 15 September 2008, at http:// procedures. Manufacturers must estab- www.emea.europa.eu lish specifications for raw materials,

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WHO Certification Scheme on the quality of pharma- ceutical products moving in international commerce

Quality assurance of pharmaceutical products should be based on a reliable system of marketing authorization, independent analysis of finished product quality and con- firmation through independent inspection that all manufacturing operations are car- ried out in conformity with good manufacturing practices. In the 1960s, a large number of African and Asian countries joining the World Health Organization did not have the necessary infrastructure or trained and skilled human resources to ensure the quality of medicines imported into their territories and they requested WHO to help them by establishing the WHO Certification Scheme on the quality of pharmaceuti- cal products moving in international commerce. This was designed as a tool for exchange of confirmatory information between medicines regulatory agencies.

At its Forty-second meeting held in October 2007, the WHO Expert Committee on Specifications for Pharmaceutical Preparations identified a number of concerns with operation of the WHO Certification Scheme. These have been documented in a background paper entitled Proposal for improvement of the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Com- merce (reproduced below).

A consultation on the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce was convened at WHO in Geneva on in July 2008 to discuss improvement of the Scheme. Final observations and recommedations are set out in the second part of this article (page 214). Comments on these proposals are now invited and should be forwarded to: Dr S. Kopp, Quality Assurance, Department of Essential Medicines and Pharmaceutical Policies, World Health Organization, 1211 Geneva 27, Switzerland. e-mail: [email protected]. A final report will be presented to the WHO Expert Committee at its Forty-third meeting in October 2008.

Proposal for improvement of 1969 in resolution WHA 22.50. The 1969 the WHO Certification Scheme Certification Scheme provided for: In 1969, WHO developed a guideline (a) the exporting country to establish, entitled Good practice in the manufacture after inspection, an up-to-date list of and quality control of drugs. The good manufacturers complying with GMP manufacturing practices (GMP) guideline which could be exchanged between together with the first version of the governments; and Certification Scheme on the quality of pharmaceutical products moving in (b) the issuance of batch certificates by international commerce was endorsed by responsible health authorities of the the World Health Assembly (WHA) in July exporting country.

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However, six years after the Scheme was The current Scheme endorsed, it was realized that mainte- Five years later the Scheme was refined, nance of the list of manufacturers comply- based on information gathered from field ing with GMP and issuance of batch trials and was adopted in 1997 in resolu- certificates by health authorities was not tion WHA50.3. Under the current 1997 feasible. As a result, a revised version of Scheme, three different types of certifi- the WHO Certification Scheme on the cate can be requested by importing Quality of Pharmaceutical Products countries. Moving in International Commerce was adopted in 1975 by the World Health 1. Certificate of a Pharmaceutical Assembly in resolution WHA 28.65. Product (Product Certificate): issued Under this scheme, maintenance of the by the competent authority when a list of manufacturers complying with GMP product in question is under consideration was dropped. for a product licence (registration) in the importing country or when administrative The 1975 version of the Scheme is based action is required to renew, extend, vary on certification by the responsible health or review such a licence. authorities of the exporting country of: 2. Statement of Licensing Status of a (a) the registration status of a particular Pharmaceutical Product: issued by the product in the exporting country; and competent authority of the exporting (b) GMP compliance of the responsible country when an importing agent is manufacturer. bidding in international tender.

Additionally, responsibility to issue batch 3. Batch Certificate of a Pharmaceuti- certificates became that of the manufac- cal Product: issued by the manufacturer turer. in case of non-biological products and by the competent authority in the case of In 1988, the World Health Assembly in vaccines and other biological products. resolution WHA 41.18 endorsed an expanded Certification Scheme. The Participation in the Scheme amended Scheme covered drug sub- The Certification Scheme requires that a stances and finished dosage forms WHO Member State send a letter to the intended for human use as well as Director-General of WHO expressing its veterinary products administered to food- intention to participate in the Scheme and producing animals. The Scheme also indicating: required the competent authority in the exporting country to provide copies of all ¥ the conditions under which it will partici- approved product information and label- pate, i.e. (a) as exporting country, (b) as ling as determined by the registration importing country, or (c) both as export- certificate issued by the regulatory ing and importing country; authority in the country of manufacture. ¥ any reservations it may have; Four years after the 1988 expanded version was adopted, the WHA endorsed ¥ provision of the name(s) and address of a modified version of the Scheme in 1992 the national drug regulatory authority in resolution WHA45.29 and recom- (ies)/competent authority(ies) author- mended that it be field tested in a number ized to issue certificates; and of WHO Member States in order to obtain feedback on its feasibility (1).

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¥ willingness to comply with the following Discussion and conclusions prerequisites of the Certification Scheme. A summary of problems identified in implementation of the Scheme and Prerequisites for exporting countries measures to be taken are set out in the (countries issuing certificates) table on pages 210Ð211. The WHO Certification Scheme (2) states that a Member State intending to use the International trade in pharmaceutical Scheme to support the export of pharma- products encompasses many thousands ceutical products should first satisfy itself of products and the value of the global that it possesses: market is currently estimated to reach over US$ 600 billion. During the last few ¥ an effective national licensing system decades many pharmaceutical manufac- not only for pharmaceutical products turing industries have flourished in both but also for manufacturers and distribu- developed and developing countries. tors; Some manufacturers produce only for local consumption, whereas a large ¥ GMP requirements consonant with number also produce for export. Confi- those recommended by WHO to which dential information available indicates all manufacturers of finished products that, particularly in developing countries, are required to conform; there are many pharmaceutical manufac- turers that do not meet WHO GMP ¥ effective control to monitor the quality of requirements. Some of these manufactur- pharmaceutical products registered or ers also operate as contract manufactur- manufactured within the country, includ- ers for manufacturers in developed ing access to an independent quality countries. control laboratory; When the Scheme was formulated three ¥ a national pharmaceutical inspectorate, decades ago the assumption was that it operating as an arm of the national drug would operate in situations where a regulatory authority, and having the pharmaceutical product is sold directly technical competence, experience and from the country of manufacture to the resources to assess whether GMP and country of final destination. At present other controls are being effectively such direct trade is rare and pertains only implemented, and the legal power to to a small sector of international trade. To conduct appropriate investigation to a large extent pharmaceutical manufac- ensure that manufacturers conform to turing/trade has taken on a global dimen- these requirements by, for example, sion in that different stages of the manu- examining premises and records and facturing activities take place in different taking samples; countries of the world before the product reaches the final destination. ¥ the administrative capacity to issue the required certificates, to institute inquiries On the other hand, it is currently esti- in the case of complaint, and to notify mated that out of 193 WHO Member expeditiously both WHO and the com- States about 20% are said to have a well- petent authority in any Member States developed national drug regulatory known to have imported a specific system that can ensure the quality of product that is subsequently associated drugs circulating in their national markets. with potentially serious quality defects Over 50 % of remaining countries are or other hazard. said to have a varying level of develop- ment and capacity to regulate their

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Table. Summary of problems identified in implementation of the Scheme and measures to be taken

Problem Measures to be taken

Exporting countries that do not fulfil the ¥ Request countries to submit a verifiable prerequisites required by the self-assessment report before they Certification Scheme issue certificates become party to the Scheme. to support export Alternatively: consider the possibility of ISO certification; or Certification by a well-established/ known regional drug regulatory authority cooperation/block, e.g. (ASEAN, EU, ICH, SADC). ¥ Require governments of Member States to submit a letter declaring the competent authority meets the prerequisites set out in the Certification Scheme.

Countries not party to the Scheme issue ¥ WHO should write a letter to the govern- certificates to support export of ments of those countries asking them to be pharmaceutical products party to the Scheme. ¥ Inform authorities of importing countries of the names of those countries that issue certificates without being party to Scheme. ¥ Advise countries not to accept certificates from countries that are not party to the Scheme.

There have been cases in which forged ¥ Ask exporting countries to develop secured certificates have been supplied to certificates by using a watermark/hologram, competent authorities of importing countries or any other technology. ¥ Request each exporting country to submit to WHO samples of their certificates so that WHO can compile those certificates and distribute them to Member States with the list of names of competent authorities to serve as reference material.

Information on who released the batch for ¥ Certificates should be transparent in disclos- marketing is not disclosed in certificates ing information that has impact on quality issued by exporting countries of products. ¥ A certificate issued for a product manufac- tured by a contract manufacture should indicate the name and address of (a) the product licence holder, and (b) the name and address of the contract manufacturer. ¥ A certificate issued for a product intended for export only (not registered in the exporting country should indicate (a) the name and site address of the manufacturer who released the batch, and (b) the reason why it is not registered in the exporting country.

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Problem Measures to be taken

Certificates are issued for products that are ¥ Manufacturers producing pharmaceutical produced by manufacturers that do not products should be required to provide a comply with WHO GMP requirements certificate of GMP compliance, e.g. issued by any known and reliable national inspec- torate such as the US FDA. ¥ Importing countries should inspect any manufacturer suspected to be non- compliant with WHO GMP requirements. Addresses of some authorities have changed ¥ WHO should send a circular letter to countries asking them to reapply for partici- pation in the Scheme. WHO should take countries off the list if they do not reapply. ¥ Membership to the Scheme should have a time limit, i.e. renewable every five or 10 years. Member States issue certificates for products ¥ In principle Member States should not issue not manufactured under their jurisdiction, certificates for products that are not pro- i.e. in their country duced under their jurisdiction, i.e. in their country. The country where the product has been manufactured should issue the certificate. ¥ If a certificate is issued for such a product then the name and address of the manufac- turer (the one who released the batch) and the site address where the product has been manufactured should be indicated in the certificate. Exporting countries issue other certificates ¥ WHO should advise importing country such as free sale certificates authorities not to request or accept free sale certificates. They should request and accept only those certificates indicated in the WHO Certification Scheme. ¥ WHO should ask exporting countries not to issue certificates other than those men tioned in the WHO Certification Scheme. ¥ WHO should organize seminars and work shops from time to time for drug regulatory authorities in order to promote the Scheme and give advice to countries. Importing countries require legalization of ¥ This is due to lack of confidence in the certificates, additional stamps, etc. genuineness of certificates. This issue will remain until countries build up confidence in the Scheme and the certificates being issued under the Scheme. ¥ Exporting countries should develop secured certificates and should provide samples of certificates, signature and stamp of author ity to serve as reference.

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pharmaceutical markets. Around 30% of Scheme. As a result, a large number of remaining countries are known to have importing country authorities have now either limited or no capacity to regulate reverted to on-site inspection of manufac- the pharmaceutical market (9). turing facilities and are conducting study tours to see how regulatory authorities This means drug regulatory practices operate. Information available shows that, differ from country to country in their through such inspection, importing standards, emphasis, and rigour of countries have been able to detect enforcement. Consequently, certificates manufacturers that do not comply with issued by a national regulatory authority WHO GMP requirements. should be accepted with caution unless there is full knowledge or proof of the Inspection by importing countries would competence of the regulatory authority to become unnecessary or diminished if fulfil the prerequisites mentioned in the exporting countries provided importing WHO Certification Scheme. countries with proof that they fulfil the prerequisites. This could be achieved if The Scheme is a non-binding agreement exporting countries submit to importing and participation of Member States is countries the results of an independent made on a voluntary basis. Although assessment of their regulatory system or exporting countries have to fulfil certain if governments of exporting countries prerequisites in order to issue certificates, issued letters declaring that their authori- the Scheme does not have an active ties fulfil the prerequisites. mechanism to ensure that countries meet the requirements. Everything is left to the In order to make the Scheme useful and judgement of the individual exporting provide the expected assurance to country and this loophole has encour- importing countries about the quality of aged non-compliant exporting countries medicines they import, the Scheme to issue certificates. needs to be revised, taking into account the needs of importing countries as the Moreover, the provisions of the Scheme Scheme was originally planned and by allow the authorities of exporting coun- considering the problems and weak- tries to decide which government institu- nesses observed in implementation of the tion will be responsible for the issuance of Scheme. a product certificate. Where there is a single central drug regulatory authority The circulation of counterfeit and sub- that is responsible for the licensing of standard pharmaceutical products in the products and manufacturers, the situation international market has become a is simple but becomes more complicated serious global problem affecting both in countries with a federal system of developed and developing countries. government where state drug regulatory However, the problem is more serious in authorities do not carry out licensing of those countries with weak regulatory and products and manufacturers but are quality assurance systems. As mentioned authorized to issue certificates. above, the WHO Certification Scheme cannot provide full assurance on the The fact that countries not complying with quality of imported products due to its prerequisites are issuing certificates and inherent limitations. Countries have to the lack of a mechanism to verify the establish their own operational drug competence of regulatory authorities, regulatory system to ensure the quality of coupled with the presence of fake certifi- medicines circulating within their territo- cates, have greatly eroded the confi- ries. dence of importing countries in the

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Strategies to improve use ¥ Member States (exporting drugs/issuing certificate) to submit with the application of the Certification Scheme a verifiable assessment report proving Revise the Certification Scheme to that the competent authorities meet the make it responsive to the needs of prerequisites of the Certification countries that rely on it Scheme, or make a declaration that the competent authority(-ies) meet(s) the ¥ Establish a committee composed of prerequisites stated in the WHO guide- regulatory authorities of importing and lines exporting countries as well as experts with experience in the use of the Certifi- ¥ Member States submit the names and cation Scheme to review the existing address of competent authorities document and prepare Draft I of the authorized to issue certificate. revised Certification Scheme. ¥ Submit samples of certificates with built- ¥ Circulate Draft I of the revised Certifica- in security system (e.g. watermark, tion Scheme among Member States for hologram) together with stamps and comment. signature(s) of authorized person(s). ¥ Prepare Draft II of the revised Certifica- tion Scheme by incorporating comments ¥ Notify WHO of any change of address received from Member States. or any change of authorized competent authority. ¥ Discuss Draft II of the revised Certifica- tion Scheme in a larger group of ex- Prepare a list of Member States perts, for instance, at the next Interna- party to the Scheme tional Conference of Drug Regulatory Authorities (ICDRA) where regulatory ¥ Prepare a list of Member States that authorities from both developed and have renewed their membership to the developing countries are represented. Scheme including the letter of applica- tion for membership and a sample of ¥ Prepare Draft III by incorporating com- the certificate received from the Mem- ments obtained from the ICDRA. ber State. ¥ Submit Draft III to the WHO Expert ¥ Distribute the prepared list to Member Committee on Specifications for Phar- States to serve as reference. maceutical Preparations for discussion and adoption. ¥ Update the list every defined year. If new Member States join the Scheme Revise criteria for membership then notify countries with a circular to the Scheme letter. ¥ WHO to write a circular letter to Member Create awareness and States to renew their membership and understanding of the Scheme indicate that membership is valid for limited period. ¥ Initiate informational and promotional programmes such as seminars or ¥ Applying countries to indicate in the workshops, for member States to letter their participation as (a) importing promote global implementation. country (receiving certificate), (b) exporting country (issuing certificate), or ¥ Assess the operation of the Scheme (c) both exporting and importing country from time to time to evaluate to what (issuing and receiving certificate). extent countries are using it.

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Delisting and negative publication 3. World Health Organization. Proceedings of the Ninth International Conference of Drug ¥ Establish a mechanism to remove Regulatory Authorities (ICDRA), Berlin, Member States from the list in case of Germany, 1999. non-compliance with the provisions of the Scheme. 4. World Health Organization. Expert Commit- tee on Specifications for Pharmaceutical ¥ Publish and circulate to Member States Preparations. Technical Report Series, No. any fake certificate reported. 908, 2003. 5. World Health Organization. Expert Commit- Strengthen national regulatory system tee on Specifications for Pharmaceutical Preparations. Technical Report Series, No. ¥ Support countries with a weak regula- 917, 2004. tory system to have their own quality assurance system by developing human 6. World Health Organization. Expert Commit- resources and providing technical and tee on Specifications for Pharmaceutical administrative assistance. Preparations. Technical Report Series, No. 929, 2005. References 7. World Health Organization. Expert Commit- 1. World Health Organization. Expert Commit- tee on Specification for Pharmaceutical tee on Specifications for Pharmaceutical preparations. Technical Report Series, No. Preparations. Technical Report Series, No. 943, 2006 823, 1992. 8. World Health Organization. Consultation on 2. World Health Organization. Expert Commit- New approaches and risk evaluation for tee on Specifications for Pharmaceutical manufacture of medicines. 2007 Preparations. Technical Report Series, No. 863, 1996. 9. World Health Organization. Effective medicine regulation - what countries do? (WHO//MAC), 1999.

Consultation on improvement of the Certification Scheme Specifications for Pharmaceutical Prepa- rations. The Forty-second Expert Committee on Specifications for Pharmaceutical Prepa- The Forty-second Expert Committee rations discussed and identified a number recommended that a group be formed to of perceived problems with the operation consider the recommendations in the of the WHO Certification Scheme on the document and feedback received upon its quality of pharmaceutical products circulation. together with that given by the moving in international commerce. These Expert Committee. A WHO consultation were set out in a background document met in Geneva 22Ð24 July 2008: Proposal for improvement of the WHO Certification Scheme on the Quality of ¥ to consider the problems stated, sug- Pharmaceutical Products Moving in gestions and feedback received in International Commerce, (reproduced on response to the document Proposal for previous pages), together with potential improvement of the WHO Certification solutions. Thie present text is offered for Scheme on the Quality of Pharmaceuti- consultation before being presented to cal Products Moving in International the Forty-third Expert Committee on Commerce; and

214 WHO Drug Information Vol 22, No. 3, 2008 Pharmaceutical Distribution and Trade

¥ to make recommendations for consid- ¥ Importing countries should consider eration by the Forty-third WHO Expert inspecting any manufacturer suspected Committee on Specifications for Phar- to be non-compliant with WHO GMP maceutical Preparations. requirements.

The following text constitutes a summary Responsibilities: of the meeting conclusions. WHO: Major discussion points ¥ Inform Member States about the Participants recognized the value of the Scheme and its prerequisites, including Certification Scheme in assuring the monitoring the period of validity of the quality of pharmaceutical products and Scheme’s membership. the benefits it brought to international commerce. However, they also recog- ¥ To provide tools for DRA assessment. nized that the Scheme had some limita- tions. In considering these matters the ¥ To enhance international collaboration participants were guided by proposals set among DRAs, and assist in capacity out in the background document. The building. group identified nine key issues. Member States: 1. Issuing (“exporting”) countries that do ¥ To improve on regulatory infrastructure not fulfil the prerequisites required by the Certification Scheme issue certificates to by strengthening DRAs. support export. In some countries, certifi- 2. Countries not party to the Scheme cates are issued for products that are produced by manufacturers that do not issue certificates to support export of comply with WHO good manufacturing pharmaceutical products. practices (GMP) requirements. Recommendations: Recommendations: ¥ Promote the Scheme Ð extend invitation to officially join the Scheme to countries ¥ Membership of the Scheme should not that are issuing certificates but which be open-ended. It should be renewable, are not party to the Scheme. every five years. ¥ To advise importing countries, when ¥ A mechanism of independent assess- products are imported into their country, ment of drug regulatory authorities to include a requirement for a valid CPP (DRAs) should be in place to ensure of a country that is party to the Scheme. that the prerequisites stated in the Scheme are met by participating “certifi- Responsibilities: cate-issuing” Member States. WHO: ¥ WHO should encourage countries to ¥ Promote the Scheme. perform self-assessment of DRAs periodically. Member States: ¥ Abide by the Scheme. ¥ In addition, when necessary, Member State regulatory capacity should be 3. Information on who released the batch further strengthened, e.g. through for marketing is not disclosed in certifi- WHO, regional and international col- cates issued by exporting countries. laboration.

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Recommendations: Member States:

¥ Certificates should be transparent in ¥ To correctly operate the Scheme. disclosing information that has an impact on the quality of products. 5. The list of competent authorities is out of date; details of some authorities have ¥ The certificate should include batch changed. The current list of countries that release site information in item 2A.3 participate in the Scheme in its present (Status of product-licence holder) of the form is not readily available. model CPP (World Health Assembly resolution WHA50.3) [“option c” will Recommendations: become new “d” and a new “c” will be created.] ¥ WHO should send a circular letter to participating countries asking them to Responsibilities: update the contact details and to specify if the country is the using and/or issuing WHO: body.

¥ When the Scheme is modified, new ¥ An updated list of competent authorities information on batch release site should should be compiled from the responses be introduced in item 2A.3 of the model to the letters of those countries actually CPP and footnotes 8 and 9 to CPP participating in the Scheme, with appro- suitably changed. priate contact addresses of DRAs Member States: (competent authorities) responsible for issuing certificates and for all communi- ¥ To issue information regarding batch cations related to the operation of the release. Scheme. In case of lack of response WHO should send reminders to coun- 4. Member States issue certificates for tries. products not under their jurisdiction, e.g. for products not authorized for marketing ¥ The list should be published as a stand- in their countries or not manufactured in alone publication and also made avail- their countries. able on the WHO web site. Recommendations: Responsibilities: WHO: ¥ Member States should not issue certifi- cates for products that are not under ¥ To send letters, update the list, publish their jurisdiction, i.e. for products not and distribute. authorized for marketing in their coun- tries or not manufactured in their coun- Member States: try, unless there is a legal provision put ¥ To respond to the circular letter. in place for medicines produced for “export only”. 6. The Scheme is at present directed to individual Member States, whereas Responsibilities: regulatory and procurement groupings of WHO: multistate organizations (e.g. European Medicines Agency (EMEA) and Organiza- ¥ To provide information on the Scheme. tion of Eastern Caribbean States/ Phar- maceutical Procurement Service (OECS/

216 WHO Drug Information Vol 22, No. 3, 2008 Pharmaceutical Distribution and Trade

PPS)) also need to be able to operate 8. Exporting countries issue other certifi- within the Scheme; this applies to both cates such as free sale certificates. issuing and receiving parties. Recommendations: Recommendation: • WHO should advise accepting (“import- ¥ Revise the Scheme to allow for those ing”) country authorities not to request parties to join the Scheme in their or accept free sale certificates and respective official functions. issuing (“exporting”) countries not to issue certificates other than those Responsibilities: mentioned in the WHO Certification Scheme. WHO and its Governing Bodies to revise the Scheme. ¥ Use of other certificates other than the ones included in the Scheme should be 7. There have been cases in which forged avoided. certificates have been supplied to compe- tent authorities of importing countries. Responsibilities: WHO and Member States should organ- Recommendations: ize seminars and workshops from time to • Encourage issuing (“exporting “) coun- time for DRAs in order to promote the tries to develop secured certificates by Scheme and give advice. using a watermark, hologram, or any other technology. 9. Importing countries require legalization of certificates, additional stamps, etc. ¥ Include a unique numbering system for ease of identification. Recommendation: ¥ Revise the current guidelines of the ¥ Competent authorities should provide a Scheme in order to strengthen it and to mechanism for specimen of certificates. emphasize that legalization of the CPP is not required and in many instances is • If a certificate is “suspicious” then of little value. contacts between the DRA and suspect- ing party (procurement/DRA) are Responsibilities: encouraged. WHO should promote this part of the ¥ Avoid use of photocopies; only original Scheme in training seminars and to take CPP or identical copies clearly marked the above into account in the revision process. as “duplicate” can be accepted. Member States should not request such Responsibilities: legalization. Medicines regulatory authority Proposed next steps ¥ See above. Implementation of recommendations, proposed time-scale and steps towards WHO: action:

¥ To consider including provision of serial - Recommendations reported to 13th number system when revising the ICDRA in September 2008 for informa- Scheme. tion and possible feedback.

217 Pharmaceutical Distribution and Trade WHO Drug Information Vol 22, No. 3, 2008

- Report and recommendations presented 2. Any new applicants to the Scheme will to 43rd WHO Expert Committee meeting be informed by the WHO Secretariat that in October 2008 with a view to adoption. revision of the Scheme is being consid- ered. If these recommendations are adopted, the following steps will be: 3. The proposal for revision of the Scheme and modified guidelines should 1. WHO Secretariat will follow up with a be presented to the WHO Executive circular letter to Member States party to Board and World Health Assembly. the Scheme requesting information as outlined in point 5, and informing them that revision of the Scheme is being considered.

218 Prepublication copy Recommended INN: List 60

International Nonproprietary Names for Pharmaceutical Substances (INN)

RECOMMENDED International Nonproprietary Names: List 60

Notice is hereby given that, in accordance with paragraph 7 of the Procedure for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances [Off. Rec. Wld Health Org., 1955, 60, 3 (Resolution EB15.R7); 1969, 173, 10 (Resolution EB43.R9); Resolution EB115.R4 (EB115/2005/REC/1)], the following names are selected as Recommended International Nonproprietary Names. The inclusion of a name in the lists of Recommended International Nonproprietary Names does not imply any recommendation of the use of the substance in medicine or pharmacy. Lists of Proposed (1–96) and Recommended (1–57) International Nonproprietary Names can be found in Cumulative List No. 12, 2007 (available in CD-ROM only).

Dénominations communes internationales des Substances pharmaceutiques (DCI)

Dénominations communes internationales RECOMMANDÉES: Liste 60

Il est notifié que, conformément aux dispositions du paragraphe 7 de la Procédure à suivre en vue du choix de Dénominations communes internationales recommandées pour les Substances pharmaceutiques [Actes off. Org. mond. Santé, 1955, 60, 3 (résolution EB15.R7); 1969, 173, 10 (résolution EB43.R9); Résolution EB115.R4 (EB115/2005/REC/1)] les dénominations ci-dessous sont choisies par l’Organisation mondiale de la Santé en tant que dénominations communes internationales recommandées. L’inclusion d’une dénomination dans les listes de DCI recommandées n’implique aucune recommandation en vue de l’utilisation de la substance correspondante en médecine ou en pharmacie. On trouvera d’autres listes de Dénominations communes internationales proposées (1–96) et recommandées (1–57) dans la Liste récapitulative No. 12, 2007 (disponible sur CD-ROM seulement).

Denominaciones Comunes Internacionales para las Sustancias Farmacéuticas (DCI)

Denominaciones Comunes Internacionales RECOMENDADAS: Lista 60

De conformidad con lo que dispone el párrafo 7 del Procedimiento de Selección de Denominaciones Comunes Internacionales Recomendadas para las Sustancias Farmacéuticas [Act. Of. Mund. Salud, 1955, 60, 3 (Resolución EB15.R7); 1969, 173, 10 (Resolución EB43.R9); Resolución EB115.R4 (EB115/2005/REC/1)], se comunica por el presente anuncio que las denominaciones que a continuación se expresan han sido seleccionadas como Denominaciones Comunes Internacionales Recomendadas. La inclusión de una denominación en las listas de las Denominaciones Comunes Recomendadas no supone recomendación alguna en favor del empleo de la sustancia respectiva en medicina o en farmacia. Las listas de Denominaciones Comunes Internacionales Propuestas (1–96) y Recomendadas (1–57) se encuentran reunidas en Cumulative List No. 12, 2007 (disponible sólo en CD-ROM).

1 Recommended INN: List 60 Prepublication copy

Latin, English, French, Spanish: Recommended INN Chemical name or description; Molecular formula; Graphic formula

DCI Recommandée Nom chimique ou description; Formule brute; Formule développée

DCI Recomendada Nombre químico o descripción; Fórmula molecular; Fórmula desarrollada

adipiplonum adipiplon 7-{[2-(3-fluoropyridin-2-yl)-1H-imidazol-1-yl]methyl}-2-methyl- 8-propyl[1,2,4]triazolo[1,5-c]pyrimidine

adipiplon 7-{[2-(3-fluoropyridin-2-yl)-1H-imidazol-1-yl]méthyl}-2-méthyl- 8-propyl[1,2,4]triazolo[1,5-c]pyrimidine

adipiplón 7-{[2-(3-fluoropiridin-2-il)-1H-imidazol-1-il]metil}-2-metil- 8-propil[1,2,4]triazolo[1,5-c]pirimidina

C18H18FN7

N NN H3C N F

N N CH3 N

agatolimodum agatolimod P-thiothymidylyl-(3'→5')-2'-deoxy-P-thiocytidylyl-(3'→5')-2'-deoxy- P-thioguanylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxy-P- thiocytidylyl-(3'→5')-2'-deoxy-P-thioguanylyl-(3'→5')-P-thiothymidylyl- (3'→5')-P-thiothymidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-P- thiothymidylyl-(3'→5')-2'-deoxy-P-thioguanylyl-(3'→5')-P- thiothymidylyl-(3'→5')-2'-deoxy-P-thiocytidylyl-(3'→5')-2'-deoxy-P- thioguanylyl-(3'→5')-P-thiothymidylyl-(3'→5')-P-thiothymidylyl- (3'→5')-P-thiothymidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxy-P- thioguanylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-deoxy-P-thiocytidylyl- (3'→5')-2'-deoxy-P-thioguanylyl-(3'→5')-P-thiothymidylyl-(3'→5')- thymidine

agatolimod P-thiothymidylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-2'-déoxy-P- thioguanylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'-déoxy-P-thiocytidylyl- (3'→5')-2'-déoxy-P-thioguanylyl-(3'→5')-P-thiothymidylyl-(3'→5')-P- thiothymidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-P-thiothymidylyl- (3'→5')-2'-déoxy-P-thioguanylyl-(3'→5')-P-thiothymidylyl-(3'→5')-2'- déoxy-P-thiocytidylyl-(3'→5')-2'-déoxy-P-thioguanylyl-(3'→5')-P- thiothymidylyl-(3'→5')-P-thiothymidylyl-(3'→5')-P-thiothymidylyl- (3'→5')-P-thiothymidylyl-(3'→5')-2'-déoxy-P-thioguanylyl-(3'→5')-P- thiothymidylyl-(3'→5')-2'-déoxy-P-thiocytidylyl-(3'→5')-2'-déoxy-P- thioguanylyl-(3'→5')-P-thiothymidylyl-(3'→5')-thymidine

2 Prepublication copy Recommended INN: List 60

agatolimod P-tiotimidilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')-2'-desoxi-P- tioguanilil-(3'→5')-P-tiotimidilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')- 2'-desoxi-P-tioguanilil-(3'→5')-P-tiotimidilil-(3'→5')-P-tiotimidilil- (3'→5')-P-tiotimidilil-(3'→5')-P-tiotimidilil-(3'→5')-2'-desoxi-P- tioguanilil-(3'→5')-P-tiotimidilil-(3'→5')-2'-desoxi-P-tiocitidilil-(3'→5')- 2'-desoxi-P-tioguanilil-(3'→5')-P-tiotimidilil-(3'→5')-P-tiotimidilil- (3'→5')-P-tiotimidilil-(3'→5')-P-tiotimidilil-(3'→5')-2'-desoxi-P- tioguanilil-(3'→5')-P-tiotimidilil-(3'→5')-2'-desoxi-P-tiocitidill-(3'→5')- 2'-desoxi-P-tioguanilil-(3'→5')-P-tiotimidilil-(3'→5')-timidina

C236H303N70O133P23S23

DNA, d(P-thio)(T-C-G-T-C-G-T-T-T-T-G-T-C-G-T-T-T-T-G-T-C-G-T-T)

alacizumabum pegolum* alacizumab pegol immunoglobulin di-Fab’ fragment, anti-[Homo sapiens VEGFR2 (vascular endothelial growth factor receptor 2, KDR, kinase insert domain receptor, FLK1, CD309)] pegylated humanized monoclonal antibody di-Fab’ CDP791 (or g165 DFM-PEG); VH-gamma1CH1 [humanized VH (Homo sapiens FR/Mus musculus CDR) [8.8.10] - Homo sapiens IGHG1*01 CH1-hinge (hinge PPCP12-15>AA)] (220- 214')-disulfide with kappa light chain [humanized V-KAPPA (Homo sapiens FR/Mus musculus CDR) [6.3.9] -Homo sapiens IGKC*01]; (226-bis-[maleimide-PEG (polyethylene glycol) 20 kDa]-226'')-dimer

alacizumab pégol immunoglobuline fragment di-Fab’, anti-[Homo sapiens VEGFR2 (récepteur 2 du facteur de croissance endothélial vasculaire, KDR, récepteur à domaine insert kinase, FLK1, CD309)] anticorps monoclonal di-Fab’ humanisé pégylé CDP791 (or g165 DFM-PEG); VH-gamma1CH1 [VH humanisé (Homo sapiens FR/Mus musculus CDR) [8.8.10] -Homo sapiens IGHG1*01 CH1-charnière (charnière PPCP12-15>AA)] (220-214')-disulfure avec la chaîne légère kappa [V-KAPPA humanisé (Homo sapiens FR/Mus musculus CDR) [6.3.9] -Homo sapiens IGKC*01]; dimère (226-bis-[maléimide-PEG (polyéthylène glycol) 20 kDa]-226'')

alacizumab pegol inmunoglobulina fragmento di-Fab’, anti-[Homo sapiens VEGFR2 (receptor 2 del factor vascular de crecimiento endotelial, KDR, receptor con dominio inserto kinasa, FLK1, CD309)] anticuerpo monoclonal di-Fab’ humanizado pegilado CDP791 (o g165 DFM- PEG); VH-gamma1CH1 [VH humanizado (Homo sapiens FR/Mus musculus CDR) [8.8.10] -Homo sapiens IGHG1*01 CH1-región bisagra (región bisagra PPCP12-15>AA)] (220-214')-disulfuro con la cadena ligera kappa [V-KAPPA humanizada (Homo sapiens FR/Mus musculus CDR) [6.3.9] -Homo sapiens IGKC*01]; dímero (226-bis- [maleimida-PEG (polietilen glicol) 20 kDa]-226'')

3 Recommended INN: List 60 Prepublication copy

Heavy chain / Chaîne lourde / Cadena pesada EVQLVESGGG LVQPGGSLRL SCAASGFTFS SYGMSWVRQA PGKGLEWVAT 50 ITSGGSYTYY VDSVKGRFTI SRDNAKNTLY LQMNSLRAED TAVYYCVRIG 100 EDALDYWGQG TLVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF 150 PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSVVTVPS SSLGTQTYIC 200 NVNHKPSNTK VDKKVEPKSC DKTHTCAA 228

Light chain / Chaîne légère / Cadena ligera DIQMTQSPSS LSASVGDRVT ITCRASQDIA GSLNWLQQKP GKAIKRLIYA 50 TSSLDSGVPK RFSGSRSGSD YTLTISSLQP EDFATYYCLQ YGSFPPTFGQ 100 GTKVEIKRTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 150 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 200 LSSPVTKSFN RGEC 214

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro C22 - C96; C144 - C200; C220 and light chain C214

Glycosylation sites / Sites de glycosylation / Posiciones de glicosilación Heavy chain residue C226 is the site of PEG attachment.

aleplasininum aleplasinin 2-{1-[(4-tert-butylphenyl)methyl]-5-(3-methylphenyl)-1H-indol-3-yl}- 2-oxoacetic acid

aléplasinine acide [1-{[4-(1,1-diméthyléthyl)phényl]méthyl}-5-(3-méthylphényl)- 1H-indol-3-yl]oxoacétique

aleplasinina ácido 2-{1-[(4-terc-butilfenil)metil]-5-(3-metilfenil)-1H-indol-3-il}- 2-oxoacético

C28H27NO3

O H C CH 3 3 CO2H

H3C N CH3

almorexantum almorexant (2R)-2-[(1S)-6,7-dimethoxy-1-{2-[4-(trifluoromethyl)phenyl]ethyl}- 3,4-dihydroisoquinolin-2(1H)-yl]-N-methyl-2-phenylacetamide

almorexant (2R)-1-[(1S)-6,7-diméthoxy-1-{2-[4-(trifluorométhyl)phényl]éthyl}- 3,4-dihydroisoquinoléin-2(1H)-yl]-N-méthyl-2-phénylacétamide

almorexant (2R)-2-[(1S)-6,7-dimetoxi-1-{2-[4-(trifluorometil)fenil]etil}- 3,4-dihidroisoquinolin-2(1H)-il]-N-metil-2-fenilacetamida

C29H31F3N2O3

F3C H H H H3CO N N CH3 O H3CO

4 Prepublication copy Recommended INN: List 60

amolimogenum bepiplasmidum* amolimogene bepiplasmid plasmid DNA vector expressing a hybrid peptide consisting of a 25 amino acid targeting signal sequence fused to the N-terminus of a 236 amino acid peptide derived from fragments of the E6 and E7 genes from HPV types 16 and 18, driven by a cytomegalovirus promoter

amolimogène bépliplasmide vecteur constitué d’ADN plasmidique exprimant un peptide hybride composé d’une séquence signal de 25 résidus fusionnée à l’aminoacide N-terminal d’un peptide de 236 résidus constitué de fragments du produit des gènes E6 et E7 du Papillomavirus humain de type 16 et 18 sous contrôle d’un promoteur de cytomégalovirus

amolimogén bepiplásmido vector formado por DNA de plásmido que expresa un péptido híbrido que consiste en una secuencia señal de 25 aminoácidos unida al extremo N-terminal de un péptido de 236 aminoácidos constituido por fragmentos del producto de los genes E6 y E7 del Papillomavirus humano tipos 16 y 18, controlado por un promotor de cytomegalovirus

amsilarotenum amsilarotene 4-[3,5-bis(trimethylsilyl)benzamido]benzoic acid

amsilarotène acide 4-{[3,5-bis(triméthylsilyl)benzoyl]amino}benzoïque

amsilaroteno ácido 4-{[3,5-bis(trimetilsilil)benzoil]amino}benzoico

C20H27NO3Si2

CO2H O H3C CH3 Si H3C N H

Si CH3 H3C CH3

anacetrapibum anacetrapib (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{4'-fluoro-2'-methoxy- 5'-(propan-2-yl)-4-(trifluoromethyl)-[1,1'-biphenyl]-2-yl}methyl)- 4-methyl-1,3-oxazolidin-2-one

anacétrapib (4S,5R)-5-[3,5-bis(trifluorométhyl)phényl]-3-{[4'-fluoro-2'-méthoxy- 5'-(1-méthyléthyl)-4-(trifluorométhyl)biphényl-2-yl]méthyl}- 4-méthyloxazolidin-2-one

anacetrapib (4S,5R)-5-[3,5-bis(trifluorometil)fenil]-3-{[4'-fluoro-2'-metoxi- 5'-(propan-2-il)-4-(trifluorometil)bifenil-2-il]metil}-4-metiloxazolidin- 2-ona

5 Recommended INN: List 60 Prepublication copy

C30H25F10NO3

CF3 O O H F C 3 N

H CH 3 OCH3

CF3 H3C

CH 3 F

anrukinzumabum* anrukinzumab immunoglobulin G1, anti-[Homo sapiens interleukin 13 (IL13)] humanized monoclonal IMA-638; gamma1 heavy chain [humanized VH (Homo sapiens FR/Mus musculus CDR) [8.7.12] -Homo sapiens IGHG1*03, 97R>K (CH1 120), 117L>A (CH2 1.3), 120G>A (CH2 1] (221-218')-disulfide with kappa light chain [humanized V-KAPPA (Homo sapiens FR/Mus musculus CDR) [10.3.9] -Homo sapiens IGKC*01]; (227-227'':230-230'')-bisdisulfide dimer

anrukinzumab immunoglobuline G1, anti-[Homo sapiens interleukine 13 (IL13)] anticorps monoclonal humanisé IMA-638; chaîne lourde gamma1 [VH humanisé (Homo sapiens FR/Mus musculus CDR) [8.7.12] - Homo sapiens IGHG1*03, 97R>K (CH1 120), 117L>A (CH2 1.3), 120G>A (CH2 1]] (221-218')-disulfure avec la chaîne légère kappa [V-KAPPA humanisé (Homo sapiens FR/Mus musculus CDR) [10.3.9] -Homo sapiens IGKC*01]; dimère (227-227'':230-230'')- bisdisulfure

anrukinzumab inmunoglobulina G1, anti-[Homo sapiens interleukina 13 (IL13)] anticuerpo monoclonal humanizado IMA-638; cadena pesada gamma1 [VH humanizada (Homo sapiens FR/Mus musculus CDR) [8.7.12] - Homo sapiens IGHG1*03, 97R>K (CH1 120), 117L>A (CH2 1.3), 120G>A (CH2 1]] (221-218')-disulfuro con la cadena ligera kappa [V-KAPPA humanizada (Homo sapiens FR/Mus musculus CDR) [10.3.9] -Homo sapiens IGKC*01]; dímero (227- 227'':230-230'')-bisdisulfuro

C6452H9954N1714O2024S46

Heavy chain γ1 / Chaîne lourde γ1 / Cadena pesada γ1 EVQLVESGGG LVQPGGSLRL SCAASGFTFI SYAMSWVRQA PGKGLEWVAS 50 ISSGGNTYYP DSVKGRFTIS RDNAKNSLYL QMNSLRAEDT AVYYCARLDG 100 YYFGFAYWGQ GTLVTVSSAS TKGPSVFPLA PSSKSTSGGT AALGCLVKDY 150 FPEPVTVSWN SGALTSGVHT FPAVLQSSGL YSLSSVVTVP SSSLGTQTYI 200 CNVNHKPSNT KVDKKVEPKS CDKTHTCPPC PAPEALGAPS VFLFPPKPKD 250 TLMISRTPEV TCVVVDVSHE DPEVKFNWYV DGVEVHNAKT KPREEQYNST 300 YRVVSVLTVL HQDWLNGKEY KCKVSNKALP APIEKTISKA KGQPREPQVY 350 TLPPSREEMT KNQVSLTCLV KGFYPSDIAV EWESNGQPEN NYKTTPPVLD 400 SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH EALHNHYTQK SLSLSPGK 448

Light chain κ / Chaîne légère κ / Cadena ligera κ DIQMTQSPSS LSASVGDRVT ITCKASESVD NYGKSLMHWY QQKPGKAPKL 50' LIYRASNLES GVPSRFSGSG SGTDFTLTIS SLQPEDFATY YCQQSNEDPW 100' TFGGGTKVEI KRTVAAPSVF IFPPSDEQLK SGTASVVCLL NNFYPREAKV 150' QWKVDNALQS GNSQESVTEQ DSKDSTYSLS STLTLSKADY EKHKVYACEV 200' THQGLSSPVT KSFNRGEC 218'

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 22-95 22''-95'' 23'-92' 23'''-92''' 138'-198' 138'''-198''' 145-201 145''-201'' 218'-221 218'''-221'' 227-227'' 230-230'' 262-322 262''-322'' 368-426 368''-426''

6 Prepublication copy Recommended INN: List 60

baminerceptum* baminercept human tumor necrosis factor receptor superfamily member 3 (lymphotoxin-β receptor, TNF C receptor)-(2-195)-peptide (fragment of extracellular domain) fusion protein with human immunoglobulin heavy constant γ1 chain Fc fragment [227 residues, hinge (195-205) des-(1-4),C5>V, CH2 (206-315), CH3 (316-421) des-K107]

baminercept membre 3 de la superfamille des récepteurs du facteur de nécrose tumorale humain (récepteur de la lymphotoxine-β ou récepteur du TNF C)-(2-195)-peptide (fragment du domaine extracellulaire) protéine de fusion avec le fragment Fc de la chaîne lourde constante γ1 de l’immunoglobuline humaine [227 residues, dés-(1-4)- [C5>V]charnière (195-205), CH2 (206-315), des-K107-CH3 (316-421)]

baminercept miembro 3 de la superfamilia de receptores del factor de necrosis tumoral humano (receptor de la linfotoxina-β o receptor del TNF C)- (2-195)-péptido (fragmento del dominio extracelular) proteína de fusión con el fragmento Fc de la cadena pesada constante γ1 de la inmunoglobulina humana [227 restos, des(14)-[C5>V]bisagra (195-205), CH2 (206-315), desK107-CH3 (316-421)]

C4074H6282N1134O1274S68

Monomer / Monomère / Monómero AVPPYASENQ TCRDQEKEYY EPQHRICCSR CPPGTYVSAK CSRIRDTVCA 50 TCAENSYNEH WNYLTICQLC RPCDPVMGLE EIAPCTSKRK TQCRCQPGMF 100 CAAWALECTH CELLSDCPPG TEAELKDEVG KGNNHCVPCK AGHFQNTSSP 150 SARCQPHTRC ENQGLVEAAP GTAQSDTTCK NPLEPLPPEM SGTMVDKTHT 200 CPPCPAPELL GGPSVFLFPP KPKDTLMISR TPEVTCVVVD VSHEDPEVKF 250 NWYVDGVEVH NAKTKPREEQ YNSTYRVVSV LTVLHQDWLN GKEYKCKVSN 300 KALPAPIEKT ISKAKGQPRE PQVYTLPPSR DELTKNQVSL TCLVKGFYPS 350 DIAVEWESNG QPENNYKTTP PVLDSDGSFF LYSKLTVDKS RWQQGNVFSC 400 SVMHEALHNH YTQKSLSLSP G 421

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 12-27 12'-27' 28-41 28'-41' 31-49 31'-49' 52-67 52'-67' 70-85 70'-85' 73-93 73'-93' 95-101 95'-101' 108-117 108'-117' 111-136 111'-136' 139-154 139'-154' 201-201' 204-204' 236-296 236'-296' 342-400 342'-400'

Glycosylation sites / Sites de glycosylation / Posiciones de glicosilación Asn-9 Asn-9' Asn-146 Asn-146' Asn-272 Asn-272'

bentamapimodum bentamapimod 2-(1,3-benzothiazol-2-yl)-2-[2-({4-[(morpholin-4-yl)methyl]phenyl}= methoxy)pyrimidin-4-yl]acetonitrile

bentamapimod (benzothiazol-2-yl)[2-({4-[(morpholin-4-yl)méthyl]phényl}= méthoxy)pyrimidin-4-yl]acétonitrile

bentamapimod 2-(1,3-benzotiazol-2-il)-2-[2-({4-[(morfolin-4-il)metil]fenil}metoxi)= pirimidin-4-il]acetonitrilo

C25H23N5O2S

N H CN O O N N and enantiomer et énantiomère y enantiómero N S

7 Recommended INN: List 60 Prepublication copy

berubicinum berubicin (8S,10S)-10-[(3-amino-4-O-benzyl-2,3,6-trideoxy-α-L-lyxo- hexopyranosyl)oxy]-6,8,11-trihydroxy-8-(2-hydroxyacetyl)- 1-methoxy-7,8,9,10-tetrahydrotetracene-5,12-dione

bérubicine (8S,10S)-10-[(3-amino-4-O-benzyl-2,3,6-tridéoxy-α-L-lyxo- hexopyranosyl)oxy]-7,8,9,10-tétrahydro-6,8,11-trihydroxy- 8-(hydroxyacétyl)-1-méthoxytétracène-5,12-dione

berubicina (8S,10S)-10-[(3-amino-4-O-bencil-2,3,6-tridesoxi-α-L-lixo- hexopiranosil)oxi]- 6,8,11-trihidroxi-8-(hidroxiacetil)-1-metoxi- 7,8,9,10-tetrahidrotetraceno-5,12-diona

C34H35NO11

O OH O OH OH

H OCH3 O OH O O

CH3 O NH 2

besifloxacinum besifloxacin 7-[(3R)-3-aminoazepan-1-yl]-8-chloro-1-cyclopropyl-6-fluoro-4-oxo- 1,4-dihydroquinoline-3-carboxylic acid

bésifloxacine (+)-acide 7-[(3R)-3-aminohexahydro-1H-azépin-1-yl]-8-chloro- 1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydroquinoléine-3-carboxylique

besifloxacino ácido 7-[(3R)-3-aminoazepan-1-il]-1-ciclopropil-8-cloro-6-fluoro- 4-oxo-1,4-dihidroquinolina-3-carboxílico

C19H21ClFN3O3

Cl N N H2N H F CO2H O

betrixabanum betrixaban N-(5-chloropyridin-2-yl)-2-[4-(N,N- dimethylcarbamimidoyl)benzamido]-5-methoxybenzamide

bétrixaban N-(5-chloropyridin-2-yl)-2-({4- [(diméthylamino)iminométhyl]benzoyl}amino)-5-méthoxybenzamide

betrixabán N-(5-cloropiridin-2-il)-2-[4-(N,N-dimetilcarbamimidoil)benzamido]-5- metoxibenzamida

8 Prepublication copy Recommended INN: List 60

C23H22ClN5O3

OCH3 O Cl CH3 N H N H3C O N N H NH

briobaceptum* briobacept aspartyl[1-valine,20-asparagine,27-proline](human tumor necrosis factor receptor superfamily member 13C (BAFF receptor, BlyS receptor 3 or CD268 antigen)-(1-71)-peptidyl (part of the extracellular domain))valyl(human immunoglobulin G1 Fc fragment, Homo sapiens IGHG1-(104-329)-peptide) (79-79':82-82')-bisdisulfide dimer

briobacept aspartyl[1-valine,20-asparagine,27-proline](membre 13C de la superfamille des récepteurs du facteur de nécrose tumorale humain (récepteur du BAFF, récepteur 3 du BlyS ou antigène CD268)- (1-71)-peptidyl (fragment du domaine extracellulaire))valyl(fragment Fc de l’immunoglobuline G1 humaine, Homo sapiens IGHG1-(104- 329)-peptide) (79-79':82-82')-bisdisulfure du dimère

briobacept aspartill[1-valina,20-asparagina,27-prolina](miembro 13C de la superfamilia de receptores del factor de necrosis tumoral humano (receptor del BAFF, receptor 3 del BlyS o antígeno CD268)-(1-71)- peptidil (fragmento del dominio extracelular))valil(fragmento Fc de la inmunoglobulina G1 humana, Homo sapiens IGHG1-(104-329)- péptido) (79-79':82-82')-bisdisulfuro del dímero

C2910H4542N814O878S24

Monomer / Monomère / Monómero DVRRGPRSLR GRDAPAPTPC NPAECFDPLV RHCVACGLLR TPRPKPAGAS 50 SPAPRTALQP QESVGAGAGE AAVDKTHTCP PCPAPELLGG PSVFLFPPKP 100 KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 150 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ 200 VYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV 250 LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPG 249

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 20-33 20'-33' 25-36 25'-36' 79-79' 82-82' 114-174 114'-174' 220-278 220'-278'

cabazitaxelum cabazitaxel 1-hydroxy-7β,10β-dimethoxy-9-oxo-5β,20-epoxytax-11-ene- 2α,4,13α-triyl 4-acetate 2-benzoate 13-[(2R,3S)-3-{[(tert- butoxy)carbonyl]amino}-2-hydroxy-3-phenylpropanoate]

cabazitaxel (-)-12b-acétate 12-benzoate et 9-[(2R,3S)-3-{[(1,1- diméthyléthoxy)carbonyl]amino}-2-hydroxy-3-phénylpropanoate] de (2aR,4S,4aS,6R,9S,11S,12S,12aR,12bS)-11-hydroxy-4,6- diméthoxy-4a,8,13,13-tétraméthyl-5-oxo-3,4,4a,5,6,9,10,11,12,12a- décahydro-7,11-méthano-1H-cyclodéca[3,4]benzo[1,2-b]oxète- 9,12,12b(2aH)-triyle

cabazitaxel 4-acetato 2-benzoato 13-[(2R,3S)-3-{[(terc-butoxi)carbonil]amino}- 2-hidroxipropanoato] de 1-hidroxi-7β,10β-dimetoxi-9-oxo-5β,20- epoxitax-11-eno-2α,4,13α-triil

9 Recommended INN: List 60 Prepublication copy

C45H57NO14

OCH3 O H OCH3 H C 3 CH H HO H 3

O CH3 H H H CH3 HN H O O O O OH H O CH 3 O O CH3 CH H C 3 3 O

cariprazinum cariprazine 3-(trans-4-{2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl}cyclohexyl)- 1,1-dimethylurea

cariprazine N'-(trans-4-{2-[4-(2,3-dichlorophényl)pipérazin-1-yl]éthyl}cyclohexyl)- N,N-diméthylurée

cariprazina N'-(trans-4-{2-[4-(2,3-diclorofenil)piperazin-1-il]etil}ciclohexil)- N,N-dimetilurea

C21H32Cl2N4O

CH3 H N N H3C O N Cl N Cl

carmegliptinum carmegliptin (4S)-1-{(2S,3S,11bS)-2-amino-9,10-dimethoxy-1,3,4,6,7,11b- hexahydro-2H-benzo[a]quinolizin-3-yl}-4-(fluoromethyl)pyrrolidin- 2-one

carmégliptine (4S)-1-[(2S,3S,11bS)-2-amino-9,10-diméthoxy-1,3,4,6,7,11b- hexahydro-2H-pyrido[2,1-a]isoquinoléin-3-yl]-4-(fluorométhyl)= pyrrolidin-2-one

carmegliptina (4S)-1-{(2S,3S,11bS)-2-amino-9,10-dimetoxi-1,3,4,6,7,11b- hexahidro-2H-benzo[a]quinolizin-3-il}-4-(fluorometil)pirrolidin-2-ona

C20H28FN3O3

O H2N H H F N H H3CO N H

H CO 3

10 Prepublication copy Recommended INN: List 60

cobiprostonum cobiprostone 7-{(2R,4aR,5R,7aR)-2-[(3S)-1,1-difluoro-3-methylpentyl]-2-hydroxy- 6-oxooctahydrocyclopenta[b]pyran-5-yl}heptanoic acid

cobiprostone acide 7-{(2R,4aR,5R,7aR)-2-[(3S)-1,1-difluoro-3-methylpentyl]- 2-hydroxy-6-oxooctahydrocyclopenta[b]pyran-5-yl}heptanoïque

cobiprostona ácido 7-{(2R,4aR,5R,7aR)-2-[(3S)-1,1-difluoro-3-metilpentil]- 2-hidroxi-6-oxooctahidrociclopenta[b]piran-5-il}heptanoico

C21H34F2O5

O H CO2H H H O

HO F F H CH3 CH3

conestatum alfa* conestat alfa human plasma protease C1 inhibitor (C1 esterase inhibitor) (N,O-glycosylated recombinant protein expressed in the mammary gland of transgenic rabbits), glycoform α

conestat alfa inhibiteur de la protéase plasmatique C1 humain (inhibiteur de l’esterase C1) (protéine N,O-glycosylée recombinante exprimée dans la glande mammaire de lapines transgéniques), glycoforme α

conestat alfa inhibidor de la proteasa plasmática C1 humana (inhibidor de la esterasa C1) (proteína N,O-glicosilada recombinante expresada en glándula mamaria de coneja transgénica), glicoforma α

C2355H3745N613O728S17

NPNATSSSSQ DPESLQDRGE GKVATTVISK MLFVEPILEV SSLPTTNSTT 50 NSATKITANT TDEPTTQPTT EPTTQPTIQP TQPTTQLPTD SPTQPTTGSF 100 CPGPVTLCSD LESHSTEAVL GDALVDFSLK LYHAFSAMKK VETNMAFSPF 150 SIASLLTQVL LGAGENTKTN LESILSYPKD FTCVHQALKG FTTKGVTSVS 200 QIFHSPDLAI RDTFVNASRT LYSSSPRVLS NNSDANLELI NTWVAKNTNN 250 KISRLLDSLP SDTRLVLLNA IYLSAKWKTT FDPKKTRMEP FHFKNSVIKV 300 PMMNSKKYPV AHFIDQTLKA KVGQLQLSHN LSLVILVPQN LKHRLEDMEQ 350 ALSPSVFKAI MEKLEMSKFQ PTLLTLPRIK VTTSQDMLSI MEKLEFFDFS 400 YDLNLCGLTE DPDLQVSAMQ HQTVLELTET GVEAAAASAI SVARTLLVFE 450 VQQPFLFVLW DQQHKFPVFM GRVYDPRA 478

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 101-406 108-183

Glycosylation sites / Sites de glycosylation / Posiciones de glicosilación Asn-3 Thr-26 Ser-42 Asn-47 Thr-49 Asn-59 Thr-61 Thr-66 Thr-70 Thr-74 Asn-216 Asn-231 Asn-250 Asn-330

11 Recommended INN: List 60 Prepublication copy

dacetuzumabum* dacetuzumab immunoglobulin G1, anti-[Homo sapiens CD40 (TNF receptor superfamily member 5, TNFRSF5)] humanized monoclonal SGN-40 (or huS2C6); gamma1 heavy chain [humanized VH (Homo sapiens FR/Mus musculus CDR) [8.8.7] -Homo sapiens IGHG1*03, 97R>K (CH1 120)] (217-219')-disulfide with kappa light chain humanized V-KAPPA (Homo sapiens FR/Mus musculus CDR) [11.3.9] -Homo sapiens IGKC*01]; (223-223'':226-226'')-bisdisulfide dimer

dacétuzumab immunoglobuline G1, anti-[Homo sapiens CD40 (membre 5 de la superfamille des récepteurs du TNF, TNFRSF5)] anticorps monoclonal humanisé SGN-40 (ou huS2C6); chaîne lourde gamma1 [VH humanisé (Homo sapiens FR/Mus musculus CDR) [8.8.7] - Homo sapiens IGHG1*03, 97R>K (CH1 120)] (217-219')-disulfure avec la chaîne légère kappa [V-KAPPA humanisé (Homo sapiens FR/Mus musculus CDR) [11.3.9] -Homo sapiens IGKC*01]; dimère (223-223'':226-226'')-bisdisulfure

dacetuzumab inmunoglobulina G1, anti-[Homo sapiens CD40 (miembro 5 de la superfamilia de receptores del TNF, TNFRSF5)] anticuerpo monoclonal humanizado SGN-40 (o huS2C6); cadena pesada gamma1 [VH humanizado (Homo sapiens FR/Mus musculus CDR) [8.8.7] - Homo sapiens IGHG1*03, 97R>K (CH1 120)] (217-219')- disulfuro con la cadena ligera kappa [V-KAPPA humanizada (Homo sapiens FR/Mus musculus CDR) [11.3.9] -Homo sapiens IGKC*01]; dímero (223-223'':226-226'')-bisdisulfuro

C6452H9964N1732O1998S42

Heavy chain / Chaîne lourde / Cadena pesada EVQLVESGGG LVQPGGSLRL SCAASGYSFT GYYIHWVRQA PGKGLEWVAR 50 VIPNAGGTSY NQKFKGRFTL SVDNSKNTAY LQMNSLRAED TAVYYCAREG 100 IYWWGQGTLV TVSSASTKGP SVFPLAPSSK STSGGTAALG CLVKDYFPEP 150 VTVSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSL GTQTYICNVN 200 HKPSNTKVDK KVEPKSCDKT HTCPPCPAPE LLGGPSVFLF PPKPKDTLMI 250 SRTPEVTCVV VDVSHEDPEV KFNWYVDGVE VHNAKTKPRE EQYNSTYRVV 300 SVLTVLHQDW LNGKEYKCKV SNKALPAPIE KTISKAKGQP REPQVYTLPP 350 SREEMTKNQV SLTCLVKGFY PSDIAVEWES NGQPENNYKT TPPVLDSDGS 400 FFLYSKLTVD KSRWQQGNVF SCSVMHEALH NHYTQKSLSL SPGK 444

Light chain / Chaîne légère / Cadena ligera DIQMTQSPSS LSASVGDRVT ITCRSSQSLV HSNGNTFLHW YQQKPGKAPK 50' LLIYTVSNRF SGVPSRFSGS GSGTDFTLTI SSLQPEDFAT YFCSQTTHVP 100' WTFGQGTKVE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150' VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200' VTHQGLSSPV TKSFNRGEC 219'

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 22-96 22''-96'' 23'-93' 23'''-93''' 139'-199' 139'''-199''' 141-197 141''-197'' 217-219' 217''-219''' 223-223'' 226-226'' 258-318 258''-318'' 364-422 364''-422''

daporinadum daporinad (2E)-N-[4-(1-benzoylpiperidin-4-yl)butyl]-3-(pyridin-3-yl)prop- 2-enamide

daporinad (2E)-N-[4-(1-benzoylpipéridin-4-yl)butyl]-3-(pyridin-3-yl)prop- 2-énamide

daporinad (2E)-N-[4-(1-benzoilpiperidin-4-il)butil]-3-(piridin-3-il)prop-2-enamida

C24H29N3O2

N H N

O N

O

12 Prepublication copy Recommended INN: List 60

darinaparsinum darinaparsin L-γ-glutamyl-S-(dimethylarsanyl)-L-cysteinylglycine

darinaparsine L-γ-glutamyl-S-(diméthylarsanyl)-L-cystéinylglycine

darinaparsina L-γ-glutamil-S-(dimetilarsanil)-L-cisteinilglicina

C12H22AsN3O6S

H NH O 2 H N HO2C N CO2H H O H S

As CH3 H3C

dexnebivololum dexnebivolol (1R)-2-({(2R)-2-[(2S)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]- 2-hydroxyethyl}amino)-1-[(2R)-6-fluoro-3,4-dihydro-2H-chromen- 2-yl]ethanol

dexnébivolol (1R,1'R)-1,1'-[(2R,2'S)-bis(6-fluoro-3,4-dihydro-2H-1-benzopyran- 2-yl)]-2,2'-azanediyldiéthanol

dexnebivolol (1R)-2-({(2R)-2-[(2S)-6-fluoro-3,4-dihidro-2H-cromen-2-il]- 2-hidroxietil}amino)-1-[(2R)-6-fluoro-3,4-dihidro-2H-cromen- 2-il]etanol

C22H25F2NO4

H OH HO H H O N O H H F F

emricasanum emricasan (3S)-3-{(2S)-2-[N-(2-tert-butylphenyl)oxamoylamino]propanamido}- 4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid

emricasan acide (3S)-3-({(2S)-2-[({[2-(1,1-diméthyléthyl)phényl]amino}= oxoacétyl)amino]propanoyl}amino)-4-oxo- 5-(2,3,5,6-tétrafluorophénoxy)pentanoïque

emricasán ácido (3S)-3-{(2S)-2-[N-(2-terc-butilfenil)oxamoilamino]= propanamido}-4-oxo-5-(2,3,5,6-tetrafluorofenoxi)pentanoico

C26H27F4N3O7

F CO2H F O O H H N N N O F H H HCH CH3 O 3 O F H C 3 CH 3

13 Recommended INN: List 60 Prepublication copy

eribaxaban eribaxaban (2R,4R)- N1-(4-chlorophenyl)- N2-[2-fluoro-4-(2-oxopyridin- 1(2H)-yl)phenyl]-4-methoxypyrrolidine-1,2-dicarboxamide

éribaxaban (2R,4R)-N1-(4-chlorophényl)-N2-[2-fluoro-4-(2-oxopyridin- 1(2H)-yl)phényl]-4-méthoxypyrrolidine-1,2-dicarboxamide

eribaxabán (2R,4R)- N1-(4-clorofenil)- N2-[2-fluoro-4-(2-oxopiridin-1(2H)-il)fenil]- 4-metoxipirrolidina-1,2-dicarboxamida

C24H22ClFN4O4

H OCH3 H H N Cl N O N F O N H O

ezatiostatum ezatiostat ethyl [(4S)-4-amino-5-ethoxy-5-oxopentanoyl]-S-benzyl-L-cysteinyl- D-2-phenylglycinate

ézatiostat (2R)-[(4S)-4-amino-5-éthoxy-5-oxopentanoyl]-S-benzyl-L-cystéinyl- 2-phénylglycinate d’éthyle

ezatiostat (2R)-[(4S)-4-amino-5-etoxi-5-oxopentanoil]-S-bencil-L-cisteinil- 2-fenilglicinato de etilo

C27H35N3O6S

H NH O H 2 H H3C O N O CH3 N H O O H O S

fasobegronum fasobegron 4'-(2-{[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino}ethyl)- 3-methoxy-[1,1'-biphenyl]-4-carboxylic acid

fasobégron acide 4'-(2-{[(2R)-2-(3-chlorophényl)-2-hydroxyéthyl]amino}éthyl)- 3-méthoxybiphényle-4-carboxylique

fasobegrón ácido 4'-(2-{[(2R)-2-(3-clorofenil)-2-hidroxietil]amino}etil)-[1,1'-bifenil]- 3-metoxi-4-carboxílico

C24H24ClNO4

H OH H N

OCH3

Cl CO2H

14 Prepublication copy Recommended INN: List 60

favipiravirum favipiravir 6-fluoro-3-hydroxypyrazine-2-carboxamide

favipiravir 6-fluoro-3-hydroxypyrazine-2-carboxamide

favipiravir 6-fluoro-3-hidroxipirazina-2-carboxamida

C5H4FN3O2

O F N NH2

N OH

fermagatum fermagate diiron(III) tetramagnesium carbonate dodecahydroxide—water (1/4)

fermagate tétrahydrate de carbonate et bis[(OC-6-11)-hexahydroxyferrate(3-)] de tétramagnésium

fermagato dodecahidróxidocarbonato de dihierro(III) y tetramagnesio— agua(1/4)

CH12Fe2Mg4O15 . 4 H2O

3- OH HO OH 2+ 2- 4 Mg CO3 2 Fe . 4 H2O HO OH OH

flopristinum flopristin (3R,4R,5E,10E,12E,14S,16R,26aR)-16-fluoro-14-hydroxy- 4,12-dimethyl-3-(propan-2-yl)-3,4,8,9,14,15,16,17,24,25,26,26a- dodecahydro-1H,7H,22H-21,18-azenopyrrolo= [2,1-c][1,8,4,19]dioxadiazacyclotetracosine-1,7,22-trione

flopristine (3R,4R,5E,10E,12E,14S,16R,26aR)-16-fluoro-14-hydroxy- 4,12-diméthyl-3-(1-méthyléthyl)-8,9,14,15,16,17,24,25,26,26a- décahydro-3H-21,18-nitrilo-1H,22H-pyrrolo= [2,1-c][1,8,4,19]dioxadiazacyclotétracosine-1,7,22(4H)-trione

flopristina (3R,4R,5E,10E,12E,14S,16R,26aR)-16-fluoro-14-hidroxi- 4,12-dimetil-3-(propan-2-il)-3,4,8,9,14,15,16,17,24,25,26,26a- dodecahidro-1H,7H,22H-21,18-azenopirrolo= [2,1-c][1,8,4,19]dioxadiazaciclotetracosina-1,7,22-triona

C28H38FN3O6

O H3C CH N O 3 N H H O H O CH3 F CH3 H H H N HO O

15 Recommended INN: List 60 Prepublication copy

folitixorinum folitixorin N-{4-[(6aRS)-3-amino-1-oxo-1,4,5,6,6a,7-hexahydroimidazo= [1,5-f]pteridin-8(9H)-yl]benzoyl}-L-glutamic acid

folitixorine acide N-{4-[(6aRS)-3-amino-1-oxo-1,4,5,6,6a,7- hexahydroimidazo[1,5-f]ptéridin-8(9H)-yl]benzoyl}-L-glutamique

folitixorina ácido N-{4-[(6aRS)-3-amino-1-oxo-1,4,5,6,6a,7- hexahidroimidazo[1,5-f]pteridin-8(9H)-il]benzoil}-L-glutámico

C20H23N7O6

O H CO2H

O N H and epimer at C* N et l'épimère en C* N CO2H y el epímero al C* H2N N HN * HN H

ibodutantum ibodutant 6-methyl-N-{1-[({(1R)-1-[({1-[(tetrahydro-2H-pyran- 4-yl)methyl]piperidin-4-yl}methyl)amino]-3-phenyl-1-oxopropan- 2-yl}amino)carbonyl]cyclopentyl}-1-benzothiophene-2-carboxamide

ibodutant N-[1-({(1R)-1-benzyl-2-oxo-2-[({1-[(tétrahydro-2H-pyran- 4-yl)méthyl]pipéridin-4-yl}méthyl)amino]éthyl}carbamoyl)cyclopentyl]- 6-méthyl-1-benzothiophène-2-carboxamide

ibodutant N-[1-({(1R)-1-bencil-2-oxo-2-[({1-[(tetrahidro-2H-piran- 4-il)metil]piperidin-4-il}metil)amino]etil}carbamoil)ciclopentil]-6-metil- 1-benzotiofeno-2-carboxamida

C37H48N4O4S

O O H S N N N O H H O H N H3C

imegliminum imeglimin (4R)-6-(dimethylamino)-4-methyl-4,5-dihydro-1,3,5-triazin-2-amine

iméglimine (+)-(6R)-1,6-dihydro-N,N,6-triméthyl-1,3,5-triazine-2,4-diamine

imeglimina (4R)-6-(dimetilamino)-4-metil-4,5-dihidro-1,3,5-triazin-2-amina

C6H13N5

H CH3

N NH

CH3 H2N N N CH3

16 Prepublication copy Recommended INN: List 60

laromustinum laromustine 2-(2-chloroethyl)-1,2-bis(methanesulfonyl)- N-methylhydrazinecarboxamide

laromustine 2'-(2-chloroéthyl)-N-méthyl-1',2'-bis(méthylsulfonyl)= carbamohydrazide

laromustina 2-(2-cloroetil)-1,2-bis(metanosulfonil)-N-metilhidrazinacarboxamida

C6H14ClN3O5S2

O CH3 O O S

H3C N N N Cl H O S CH3 O

levonebivololum levonebivolol (1S)-2-({(2S)-2-[(2R)-6-fluoro-3,4-dihydro-2H-chromen-2-yl]- 2-hydroxyethyl}amino)-1-[(2S)-6-fluoro-3,4-dihydro-2H-chromen- 2-yl]ethanol

lévonébivolol (1S,1'S)-1,1'-[(2R,2'S)-bis(6-fluoro-3,4-dihydro-2H-1-benzopyran- 2-yl)]-2,2'-azanediyldiéthanol

levonebivolol (1S)-2-({(2S)-2-[(2R)-6-fluoro-3,4-dihidro-2H-cromen-2-il]- 2-hidroxietil}amino)-1-[(2S)-6-fluoro-3,4-dihidro-2H-cromen- 2-il]etanol

C22H25F2NO4

HO H H OH H O N O H H F F

linopristinum linopristin N-{(6R,9S,10R,13S,15aS,22S,24aS)-22-{[4- (dimethylamino)phenyl]methyl}-6-ethyl-10,23-dimethyl- 18-[(morpholin-4-yl)methyl]-5,8,12,15,21,24-hexaoxo-13-phenyl- 1,2,3,5,6,7,8,9,10,11,12,13,14,15,15a,16,19,21,22,23,24,24a- docosahydropyrido[2,1-f]pyrrolo[2,1-l][1,4,7,10,13,16]= oxapentaazacyclononadecin-9-yl}-3-hydroxypyridine-2-carboxamide

linopristine (6R,9S,10R,13S,15aS,22S,24aS)-22-{[4-(diméthylamino)= phényl]méthyl}-6-éthyl-9-{[(3-hydroxypyridin-2-yl)carbonyl]amino}- 10,23-diméthyl-18-[(morpholin-4-yl)méthyl]-13-phényl- 1,2,3,6,7,9,10,13,14,16,19,22,23,24a-tétradécahydro- 12H-pyrido[2,1-f]pyrrolo[2,1-l][1,4,7,10,13,16]= oxapentaazacyclononadécine-5,8,12,15,21,24(15aH)-hexone

linopristina N-{(6R,9S,10R,13S,15aS,22S,24aS)-22-{[4-(dimetilamino)fenil]= metil}-6-etil-13-fenil-10,23-dimetil-18-[(morfolin-4-il)metil]- 5,8,12,15,21,24-hexaoxo- 1,2,3,5,6,7,8,9,10,11,12,13,14,15,15a,16,19,21,22,23,24,24a- docosahidropirido[2,1-f]pirrolo[2,1-l][1,4,7,10,13,16]= oxapentaazaciclononadecin-9-il}-3-hidroxipiridina-2-carboxamida

17 Recommended INN: List 60 Prepublication copy

C50H63N9O10

H3C CH3 N H N H3C H N CH O 3 N N O O H O O HN O O O OH H HN O N H H H H CH3 N

lucatumumabum* lucatumumab immunoglobulin G1, anti-[Homo sapiens CD40 (TNF receptor superfamily member 5, TNFRSF5)] human monoclonal antibody CHIR-12.12; gamma1 heavy chain [Homo sapiens VH [8.8.13] - IGHG1*03 (CH1 S10>A), no C-terminal lysine] from clone CHIR- 12.12 (223-219’)-disulfide with kappa light chain [Homo sapiens V-KAPPA (IGKV2-28-IGJK3*01, K12>R) [11.3.9] -IGKC*01] from clone CHIR-12.12; (229-229”:232-232”)-bisdisulfide dimer

lucatumumab immunoglobuline G1, anti-[Homo sapiens CD40 (membre 5 de la superfamille des récepteurs du TNF, TNFRSF5)] anticorps monoclonal humain CHIR-12.12; chaîne lourde gamma1 [Homo sapiens VH [8.8.13] -IGHG1*03 (CH1 S10>A), pas de lysine C-terminale] du clone CHIR-12.12 (223-219’)-disulfure avec la chaîne légère kappa [Homo sapiens V-KAPPA (IGKV2-28-IGJK3*01, K12>R) [11.3.9] -IGKC*01] du clone CHIR-12.12; dimère (229- 229”:232-232”)-bisdisulfure

lucatumumab inmunoglobulina G1, anti-[Homo sapiens CD40 (miembro 5 de la superfamilia de receptores del TNF, TNFRSF5)] anticuerpo monoclonal humano CHIR-12.12; cadena pesada gamma1 [Homo sapiens VH [8.8.13] -IGHG1*03 (CH1 S10>A), sin lisina C-terminal] del clon CHIR-12.12 (223-219’)-disulfuro con la cadena ligera kappa [Homo sapiens V-KAPPA (IGKV2-28-IGJK3*01, K12>R) [11.3.9] - IGKC*01] del clon CHIR-12.12; dímero (229-229”:232-232”)- bisdisulfuro

Heavy chain / Chaîne lourde / Cadena pesada QVQLVESGGG VVQPGRSLRL SCAASGFTFS SYGMHWVRQA PGKGLEWVAV 50 ISYEESNRYH ADSVKGRFTI SRDNSKITLY LQMNSLRTED TAVYYCARDG 100 GIAAPGPDYW GQGTLVTVSS ASTKGPSVFP LAPASKSTSG GTAALGCLVK 150 DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT 200 YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP 250 KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 300 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ 350 VYTLPPSREE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV 400 LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK 450

Light chain / Chaîne légère / Cadena ligera DIVMTQSPLS LTVTPGEPAS ISCRSSQSLL YSNGYNYLDW YLQKPGQSPQ 50 VLISLGSNRA SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCMQARQTP 100 FTFGPGTKVD IRRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150 VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200 VTHQGLSSPV TKSFNRGEC 219

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Light Chain Intrachain: C23-C93, C149-C199 Heavy Chain Intrachain: C22-C96, C147-C203, C264-C324, C369-C428 Interchain: Light Chain: C219-Heavy Chain 223, Heavy Chain 1 C229-Heavy Chain 2 C229, Heavy Chain 1 C232 - Heavy Chain 2 C232

18 Prepublication copy Recommended INN: List 60

milatuzumabum* milatuzumab immunoglobulin G1, anti-[Homo sapiens CD74 (major histocompatibility complex class II invariant chain)] humanized monoclonal IMMU-115 (or hLL1); gamma1 heavy chain [humanized VH (Homo sapiens FR/Mus musculus CDR) [8.8.13] -Homo sapiens IGHG1*03] (223-219')-disulfide with kappa light chain [humanized V-KAPPA (Homo sapiens FR/Mus musculus CDR) [11.3.9] -Homo sapiens IGKC*01]; (229-229'':232-232'')-bisdisulfide dimer

milatuzumab immunoglobuline G1, anti-[Homo sapiens CD74 (chaîne invariante du complexe majeur d’histocompatibilité de classe II)] anticorps monoclonal humanisé IMMU-115 (ou hLL1); chaîne lourde gamma1 [VH humanisé (Homo sapiens FR/Mus musculus CDR) [8.8.13] - Homo sapiens IGHG1*03] (223-219')-disulfure avec la chaîne légère kappa [V-KAPPA humanisé (Homo sapiens FR/Mus musculus CDR) [11.3.9] -Homo sapiens IGKC*01]; dimère (229-229'':232-232'')- bisdisulfure

milatuzumab inmunoglobulina G1, anti-[Homo sapiens CD74 (cadena invariable del complejo mayor de histocompatibilidad de clase II)] anticuerpo monoclonal humanizado IMMU-115 (o hLL1); cadena pesada gamma1 [VH humanizado (Homo sapiens FR/Mus musculus CDR) [8.8.13] - Homo sapiens IGHG1*03] (223-219')-disulfuro con la cadena ligera kappa [V-KAPPA humanizada (Homo sapiens FR/Mus musculus CDR) [11.3.9] -Homo sapiens IGKC*01]; dímero (229- 229'':232-232'')-bisdisulfuro

C6518H10066N1758O2020S40

Heavy chain / Chaîne lourde / Cadena pesada QVQLQQSGSE LKKPGASVKV SCKASGYTFT NYGVNWIKQA PGQGLQWMGW 50 INPNTGEPTF DDDFKGRFAF SLDTSVSTAY LQISSLKADD TAVYFCSRSR 100 GKNEAWFAYW GQGTLVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK 150 DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT 200 YICNVNHKPS NTKVDKRVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP 250 KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN 300 STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ 350 VYTLPPSREE MTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV 400 LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK 450

Light chain / Chaîne légère / Cadena ligera DIQLTQSPLS LPVTLGQPAS ISCRSSQSLV HRNGNTYLHW FQQRPGQSPR 50' LLIYTVSNRF SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YFCSQSSHVP 100' PTFGAGTRLE IKRTVAAPSV FIFPPSDEQL KSGTASVVCL LNNFYPREAK 150' VQWKVDNALQ SGNSQESVTE QDSKDSTYSL SSTLTLSKAD YEKHKVYACE 200' VTHQGLSSPV TKSFNRGEC 219'

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 22-96 22''-96'' 23'-93' 23'''-93''' 139'-199' 139'''-199''' 147-203 147''-203'' 219'-223 219'''-223'' 229-229'' 232-232'' 264-324 264''-324'' 370-428 370''-428''

mirabegronum mirabegron 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]= amino}ethyl)phenyl]acetamide

mirabégron 2-(2-aminothiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phényléthyl]= amino}éthyl)phényl]acétamide

mirabegrón 2-(2-amino-1,3-tiazol-4-il)-N-[4-(2-{[(2R)-2-fenil-2-hidroxietil]amino}= etil)fenil]acetamida

C21H24N4O2S

H OH H N S O NH2 N N H

19 Recommended INN: List 60 Prepublication copy

monepantelum monepantel N-{2-cyano-1-[(2S)-5-cyano-2-(trifluoromethyl)phenoxy]propan-2-yl}- 4-(trifluoromethylsulfanyl)benzamide

monépantel N-{(1S)-1-cyano-2-[5-cyano-2-(trifluorométhyl)-1-méthylphénoxy]- 4-[(trifluorométhyl)sulfanyl]benzamide

monepantel N-{2-ciano-1-[(2S)-5-ciano-2-(trifluorometil)fenoxi]propan-2-il}- 4-(trifluorometilsulfanil)benzamida

C20H13F6N3O2S

O CF H3C CN 3 O N H F3C S CN

nelivaptanum nelivaptan (2S,4R)-1-{(3R)-5-chloro-1-[(2,4-dimethoxybenzene)sulfonyl]- 3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-hydroxy- N,N-dimethylpyrrolidine-2-carboxamide

nélivaptan (2S,4R)-1-{(3R)-5-chloro-1-[(2,4-diméthoxyphényl)sulfonyl]- 3-(2-méthoxyphényl)-2-oxo-2,3-dihydro-1H-indol-3-yl}-4-hydroxy- N,N-diméthylpyrrolidine-2-carboxamide

nelivaptán (2S,4R)-1-{(3R)-5-cloro-1-[(2,4-dimetoxibenceno)sulfonil]- 3-(2-metoxifenil)-2-oxo-2,3-dihidro-1H-indol-3-il}-4-hidroxi- N,N-dimetilpirrolidina-2-carboxamida

C30H32ClN3O8S

H3CO O H3C S O N CH O 3 OCH3 N O H

N OH Cl O H CH3

nesbuvirum nesbuvir 5-cyclopropyl-2-(4-fluorophenyl)-6-[N-(2-hydroxyethyl)= methanesulfonamido]-N-methyl-1-benzofuran-3-carboxamide

nesbuvir 5-cyclopropyl-2-(4-fluorophényl)-6-[(2-hydroxyéthyl)(méthylsulfonyl)= amino]-N-méthyl-1-benzofurane-3-carboxamide

nesbuvir 5-ciclopropil-2-(4-fluorofenil)-6-[N-(2-hidroxietil)metanosulfonamido]- N-metil-1-benzofuran-3-carboxamida

20 Prepublication copy Recommended INN: List 60

C22H23FN2O5S

O CH3 O S

N O HO F

NH O CH3

odanacatibum odanacatib (2S)-N-(1-cyanocyclopropyl)-4-fluoro-4-methyl-2-{[(1S)-2,2,2- trifluoro-1-{4'-(methanesulfonyl)-[1,1'-biphenyl]-4-yl}ethyl]amino}= pentanamide

odanacatib (2S)-N-(1-cyanocyclopropyl)-4-fluoro-4-méthyl-2-({(1S)-2,2,2- trifluoro-1-[4'-(méthylsulfonyl)biphényl-4-yl]éthyl}amino)pentanamide

odanacatib (2S)-N-(1-cianociclopropil)-4-fluoro-4-metil-2-{[(1S)-2,2,2-trifluoro- 1-{4'-(metanosulfonil)-[1,1'-bifenil]-4-il}etil]amino}pentanamida

C25H27F4N3O3S

CH3 F CH3 F C H H 3 H NCN N H O

H3C S OO

omacetaxini mepesuccinas omacetaxine mepesuccinate 1-[(1S,3aR,14bS)-2-methoxy-1,5,6,8,9,14b-hexahydro- 4H-cyclopenta[a][1,3]dioxolo[4,5-h]pyrrolo[2,1-b][3]benzazepin-1-yl] 4-methyl (2R)-2-hydroxy-2-(4-hydroxy-4-methylpentyl)butanedioate

mépésuccinate d’omacétaxine (2R)-2-hydroxy-2-(4-hydroxy-4-méthylpentyl)butanedioate de 1-[(1S,3aR,14bS)-2-méthoxy-1,5,6,8,9,14b-hexahydro- 4H-cyclopenta[a][1,3]dioxolo[4,5-h]pyrrolo[2,1-b][3]benzazépin-1-yle] et de 4-méthyle

mepesuccinato de omacetaxina (2R)-2-hidroxi-2-(4-hidroxi-4-metilpentil)butanodioato de 1-[(1S,3aR,14bS)-2-metoxi-1,5,6,8,9,14b-hexahidro- 4H-ciclopenta[a][1,3]dioxolo[4,5-h]pirrolo[2,1-b][3]benzazepin-1-ilo] y de 4-metilo

21 Recommended INN: List 60 Prepublication copy

C29H39NO9

O CH3 HO CH 3 HO O H C OCH3 3 O O H H O N O

otelixizumabum* otelixizumab immunoglobulin G1, anti-(human CD3E) humanized/chimeric monoclonal TRX4 (ChAglyCD3); humanized gamma1 heavy chain 299N>A [humanized VH (Homo sapiens FR/Rattus sp. CDR) (119 residues [8.8.12])- Homo sapiens IGHG1*01, 180N>A (CH2 84.4)] (222-216’)-disulfide with chimeric lambda light chain 111G>R [Rattus sp. V-LAMBDA (110 residues [8.3.9])-Homo sapiens IGLC2*01, 1G>R (1.5)] ; (228-228”: 231-231”)-bisdisulfide dimer

otélixizumab immunoglobuline G1, anti-(CD3E humain) anticorps monoclonal humanisé/chimérique TRX4 (ChAglyCD3); chaîne lourde gamma1 humanisée 299N>A [VH humanisé (Homo sapiens FR/Rattus sp. CDR) (119 residus [8.8.12])- Homo sapiens IGHG1*01, 180N>A (CH2 84.4) (222-216’)-disulfure avec la chaîne lambda chimérique 111G>R [Rattus sp. V-LAMBDA (110 residues [8.3.9])-Homo sapiens IGLC2*01, 1G>R (1.5)] ; dimère (228-228”: 231-231”)- bidisulfure

otelixizumab inmunoglobulina G1, anti-(CD3E humano) anticuerpo monoclonal humanizado/quimérico TRX4 (ChAglyCD3); cadena pesada gamma1 humanizada 299N>A [VH humanizada (Homo sapiens FR/Rattus sp. CDR) (119 residuos [8.8.12])- Homo sapiens IGHG1*01, 180N>A (CH2 84.4) (222-216’)-disulfuro con la cadena lambda quimérica 111G>R [Rattus sp. V-LAMBDA (110 residuos [8.3.9])-Homo sapiens IGLC2*01, 1G>R (1.5)] ; dímero (228- 228”: 231-231”)-bisdisulfuro

C6448H9954N1718O2016S42

Heavy chain / Chaîne lourde / Cadena pesada EVQLLESGGG LVQPGGSLRL SCAASGFTFS SFPMAWVRQA PGKGLEWVST 50 ISTSGGRTYY RDSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAKFR 100 QYSGGFDYWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150 YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200 ICNVNHKPSN TKVDKKVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250 DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYAS 300 TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350 YTLPPSRDEL TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400 DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449

Light chain / Chaîne légère / Cadena ligera DIQLTQPNSV STSLGSTVKL SCTLSSGNIE NNYVHWYQLY EGRSPTTMIY 50' DDDKRPDGVP DRFSGSIDRS SNSAFLTIHN VAIEDEAIYF CHSYVSSFNV 100' FGGGTKLTVL RQPKAAPSVT LFPPSSEELQ ANKATLVCLI SDFYPGAVTV 150' AWKADSSPVK AGVETTTPSK QSNNKYAASS YLSLTPEQWK SHRSYSCQVT 200' HEGSTVEKTV APTECS 216'

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 22-96 22''-96'' 22'-91' 22'''-91''' 138'-197' 138'''-197''' 146-202 146''-202'' 215'-222 215'''-222'' 228-228'' 231-231'' 263-323 263''-323'' 369-427 369''-427''

22 Prepublication copy Recommended INN: List 60

pegloticasum*

pegloticase tetramer α4 of des-(1-5)-[6-threonine,45-threonine,290-lysine, 300-serine]uricase (EC 1.7.3.3, urate oxidase) from Sus scrofa (porcine), non acetylated, of which some of the lysine 6-amine residues are engaged in a carbamate linkage with a monomethylic ether of polyoxyethylene (macrogol)

pégloticase tétramère α4 du des-(1-5)-[6-thréonine,45-thréonine,290-lysine, 300-sérine]uricase (EC 1.7.3.3, urate oxydase) de Sus scrofa (porc) non acétylé dont certaines fonctions 6-amine de lysines sont engagées dans une liaison carbamate avec un éther monométhylique de polyoxyéthylène (macrogol)

pegloticasa tetrámero α4 de la des-(1-5)-[6-treonina,45-treonina,290-lisina, 300-serina]uricasa (EC 1.7.3.3, urato oxidasa) de Sus scrofa (porc) no acetilada algunas de cuyas funciones 6-amino de las lisinas forman uniones carbamato con un éter monometílico de polioxietileno (macrogol)

C6196H9720N1632O1792S32

O O R H C ON 3 H n

H2N-R: Peptide monomer / Peptide monomère / Peptido monómero TYKKN DEVEFVRTGY GKDMIKVLHI QRDGKYHSIK EVATTVQLTL 50 SSKKDYLHGD NSDVIPTDTI KNTVNVLAKF KGIKSIETFA VTICEHFLSS 100 FKHVIRAQVY VEEVPWKRFE KNGVKHVHAF IYTPTGTHFC EVEQIRNGPP 150 VIHSGIKDLK VLKTTQSGFE GFIKDQFTTL PEVKDRCFAT QVYCKWRYHQ 200 GRDVDFEATW DTVRSIVLQK FAGPYDKGEY SPSVQKTLYD IQVLTLGQVP 250 EIEDMEISLP NIHYLNIDMS KMGLINKEEV LLPLDNPYGK ITGTVKRKLS 300 SRL 303

preladenantum preladenant 2-(furan-2-yl)-7-(2-{4-[4-(2-methoxyethoxy)phenyl]piperazin- 1-yl}ethyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine

préladénant 2-(furan-2-yl)-7-(2-{4-[4-(2-méthoxyéthoxy)phényl]pipérazin- 1-yl}éthyl)-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine

preladenant 2-(furan-2-il)-7-(2-{4-[4-(2-metoxietoxi)fenil]piperazin-1-il}etil)- 7H-pirazolo[4,3-e][1,2,4]triazolo[1,5-c]pirimidin-5-amina

C25H29N9O3

O N N N N N N N N

H2N O O CH3

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radiprodilum radiprodil 2-{4-[(4-fluorophenyl)methyl]piperidin-1-yl}-2-oxo-N-(2-oxo- 2,3-dihydro-1,3-benzoxazol-6-yl)acetamide

radiprodil 2-{4-[(4-fluorophényl)méthyl]pipéridin-1-yl}-2-oxo-N-(2-oxo- 2,3-dihydrobenzoxazol-6-yl)acétamide

radiprodil 2-{4-[(4-fluorofenil)metil]piperidin-1-il}-2-oxo-N-(2-oxo-2,3-dihidro- 1,3-benzoxazol-6-il)acetamida

C21H20FN3O4

H N O O N O N F H O

remogliflozini etabonas remogliflozin etabonate 5-methyl-1-(propan-2-yl)-4-({4-[(propan-2-yl)oxy]phenyl}methyl)- 1H-pyrazol-3-yl 6-O-(ethoxycarbonyl)-β-D-glucopyranoside

étabonate de rémogliflozine 6-O-(éthoxycarbonyl)-β-D-glucopyranoside de 5-méthyl-4-{[4-(1- méthyléthoxy)phényl]méthyl}-1-(1-méthyléthyl)-1H-pyrazol-3-yle

etabonato de remogliflozina 6-O-(etoxicarbonil)-β-D-glucopiranósido de 5-metil-1-(propan-2-il)- 4-({4-[(propan-2-il)oxi]fenil}metil)-1H-pirazol-3-ilo

C26H38N2O9

CH3

O CH3

CH3

CH3 H3C O O N

O O O N CH3 OH HO OH

retosibanum retosiban (3R,6R)-6-[(2S)-butan-2-yl]-3-(2,3-dihydro-1H-inden-2-yl)-1-[(1R)-1- (2-methyl-1,3-oxazol-4-yl)-2-(morpholin-4-yl)-2-oxoethyl]piperazine- 2,5-dione

rétosiban (3R,6R)-3-(2,3-dihydro-1H-indén-2-yl)-1-[(1R)-1-(2-méthyloxazol- 4-yl)-2-(morpholin-4-yl)-2-oxoéthyl]-6-[(1S)-1-méthylpropyl]= pipérazine-2,5-dione

retosibán (3R,6R)-6-[(2S)-butan-2-il]-3-(2,3-dihidro-1H-inden-2-il)-1-[(1R)-1-(2- metil-1,3-oxazol-4-il)-2-(morfolin-4-il)-2-oxoetil]piperazina-2,5-diona

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C27H34N4O5

CH3 CH O H 3

HN H O N N H H O O N O H3C

riociguatum riociguat methyl N-(4,6-diamino-2-{1-[(2-fluorophenyl)methyl]-1H-pyrazolo= [3,4-b]pyridin-3-yl}pyrimidin-5-yl)-N-methylcarbamate

riociguat (4,6-diamino-2-{1-[(2-fluorophényl)méthyl]-1H-pyrazolo[3,4-b]pyridin- 3-yl}pyrimidin-5-yl)méthylcarbamate de méthyle

riociguat (4,6-diamino-2-{1-[(2-fluorofenil)metil]-1H-pirazolo[3,4-b]piridin- 3-il}pirimidin-5-il)metilcarbamato de metilo

C20H19FN8O2

NH2 CH3 N O N CH3 N O F N NH N 2

N

rolofyllinum rolofylline 1,3-dipropyl-8-(tricyclo[3.3.1.03,7]nonan-3-yl)-3,7-dihydro-1H-purin- 2,6-dione

rolofylline 1,3-dipropyl-8-(tricyclo[3.3.1.03,7]non-3-yl)-3,7-dihydro-1H-purine- 2,6-dione

rolofyllina 1,3-dipropil-8-(triciclo[3.3.1.03,7]nonan-3-il)-3,7-dihidro-1H-purina- 2,6-diona

C20H28N4O2

O H H3C N N

O N N CH 3

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tenatumomabum* tenatumomab immunoglobulin G2b, anti-[human tenascin C (TNC, hexabrachion, HBX) Mus musculus] monoclonal antibody ST2146; gamma2b heavy chain (Mus musculus VH [8.8.13]-IGHG2B*02 from clone ST2146) (135-219')-disulfide with kappa light chain (Mus musculus V-KAPPA [11.3.9]-IGKC*01 from clone ST 2146); (229-229'':232-232'':235- 235'':238-238'')-tetradisulfide dimer

ténatumomab immunoglobuline G2b, anti-[tenascine C humaine (TNC, hexabrachion, HBX) Mus musculus] anticorps monoclonal murin ST2146; chaîne lourde gamma2b (Mus musculus VH [8.8.13]- IGHG2B*02 du clone ST2146) (135-219')-disulfure avec la chaîne légère kappa (Mus musculus V-KAPPA [11.3.9]-IGKC*01 du clone ST 2146); dimère (229-229'':232-232'':235-235'':238-238'')- tétradisulfide

tenatumomab inmunoglobulina G2b, anti-[tenascina C humana (TNC, hexabrachion, HBX) Mus musculus] anticuerpo monoclonal murino ST2146; cadena pesada gamma2b (Mus musculus VH [8.8.13]- IGHG2B*02 del clon ST2146) (135-219')-disulfuro con la cadena ligera kappa (Mus musculus V-KAPPA [11.3.9]-IGKC*01 del clon ST 2146); dímero (229-229'':232-232'':235-235'':238-238'')-tetradisulfuro

Heavy chain / Chaîne lourde / Cadena pesada EIQLQQSGPE LVKPGASVKV SCKASGYAFT SYNMYWVKQS HGKSLEWIGY 50 IDPYNGVTSY NQKFKGKATL TVDKSSSTAY MHLNSLTSED SAVYYCARGG 100 GSIYYAMDYW GQGTSVTVSS AKTTPPSVYP LAPGCGDTTG SSVTLGCLVK 150 GYFPESVTVT WNSGSLSSSV HTFPALLQSG LYTMSSSVTV PSSTWPSQTV 200 TCSVAHPASS TTVDKKLEPS GPISTINPCP PCKECHKCPA PNLEGGPSVF 250 IFPPNIKDVL MISLTPKVTC VVVDVSEDDP DVQISWFVNN VEVHTAQTQT 300 HREDYNSTIR VVSTLPIQHQ DWMSGKEFKC KVNNKDLPSP IERTISKIKG 350 LVRAPQVYIL PPPAEQLSRK DVSLTCLVVG FNPGDISVEW TSNGHTEENY 400 KDTAPVLDSD GSYFIYSKLN MKTSKWEKTD SFSCNVRHEG LKNYYLKKTI 450 SRSPGK 456

Light chain/ Chaîne légère / Cadena ligera DIVMTQAAPS VPVTPGESVS ISCRSSKSLL HSNGNTYLYW FLQRPGQSPQ 50 LLIYRMSNLA SGVPDRFSGS GSGTAFTLRI SRVEAEDVGV YYCMQHLEYP 100 LTFGAGTKLE LKRADAAPTV SIFPPSSEQL TSGGASVVCF LNNFYPKDIN 150 VKWKIDGSER QNGVLNSWTD QDSKDSTYSM SSTLTLTKDE YERHNSYTCE 200 ATHKTSTSPI VKSFNRNEC 219

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro Bold and underlined Cysteins are those involved in disulphide bridges.

tertomotidum tertomotide human telomerase reverse transcriptase (EC 2.7.7.49)-(611-626)- peptide (telomerase catalytic subunit fragment)

tertomotide télomérase transcriptase réverse humaine (EC 2.7.7.49)-(611-626)- peptide (fragment de la sous-unité catalytique de la télomérase)

tertomotida transcriptasa inversa humana telomerasa (EC 2.7.7.49)-(611-626)- péptido (fragmento de la subunidad catalítica de la telomerasa

C85H146N26O21

HGlu Ala Arg Pro Ala Leu Leu Thr Ser

Arg Leu Arg Phe Ile Pro Lys OH 10 16

26 Prepublication copy Recommended INN: List 60

tigatuzumabum* tigatuzumab immunoglobulin G1, anti-[Homo sapiens TNFRSF10B (tumor necrosis factor receptor superfamily member 10b, DR5, TRAIL-R2, CD262)] humanized monoclonal TRA-8 (or CS-1008); gamma1 heavy chain [humanized VH (Homo sapiens FR/Mus musculus CDR) [8.8.12] -Homo sapiens IGHG1*03] (222-213')-disulfide with kappa light chain [humanized V-KAPPA (Homo sapiens FR/Mus musculus CDR) [6.3.8] -Homo sapiens IGKC*01]; (228-228'':231-231'')- bisdisulfide dimer

tigatuzumab mmunoglobuline G1, anti-[Homo sapiens TNFRSF10B (membre 10b de la superfamille des récepteurs du facteur de nécrose tumorale, DR5, TRAIL-R2, CD262)] anticorps monoclonal humanisé TRA-8 (ou CS-1008); chaîne lourde gamma1 [VH humanisé (Homo sapiens FR/Mus musculus CDR) [8.8.12] - Homo sapiens IGHG1*03] (222- 213')-disulfure avec la chaîne légère kappa [V-KAPPA humanisé (Homo sapiens FR/Mus musculus CDR) [6.3.8] -Homo sapiens IGKC*01]; dimère (228-228'':231-231'')-bisdisulfure

tigatuzumab inmunoglobulina G1, anti-[Homo sapiens TNFRSF10B (miembro 10b de la superfamilia de receptores del factor de necrosis tumoral, DR5, TRAIL-R2, CD262)] anticuerpo monoclonal humanizado TRA-8 (o CS-1008); cadena pesada gamma1 [VH humanizada (Homo sapiens FR/Mus musculus CDR) [8.8.12] - Homo sapiens IGHG1*03] (222-213')-disulfuro con la cadena ligera kappa [V-KAPPA humanizada (Homo sapiens FR/Mus musculus CDR) [6.3.8] -Homo sapiens IGKC*01]; dímero (228-228'':231-231'')- bisdisulfuro

C6406H9924N1716O2012S46

Heavy chain / Chaîne lourde / Cadena pesada EVQLVESGGG LVQPGGSLRL SCAASGFTFS SYVMSWVRQA PGKGLEWVAT 50 ISSGGSYTYY PDSVKGRFTI SRDNAKNTLY LQMNSLRAED TAVYYCARRG 100 DSMITTDYWG QGTLVTVSSA STKGPSVFPL APSSKSTSGG TAALGCLVKD 150 YFPEPVTVSW NSGALTSGVH TFPAVLQSSG LYSLSSVVTV PSSSLGTQTY 200 ICNVNHKPSN TKVDKRVEPK SCDKTHTCPP CPAPELLGGP SVFLFPPKPK 250 DTLMISRTPE VTCVVVDVSH EDPEVKFNWY VDGVEVHNAK TKPREEQYNS 300 TYRVVSVLTV LHQDWLNGKE YKCKVSNKAL PAPIEKTISK AKGQPREPQV 350 YTLPPSREEM TKNQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPVL 400 DSDGSFFLYS KLTVDKSRWQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK 449

Light chain / Chaîne légère / Cadena ligera DIQMTQSPSS LSASVGDRVT ITCKASQDVG TAVAWYQQKP GKAPKLLIYW 50' ASTRHTGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ YSSYRTFGQG 100' TKVEIKRTVA APSVFIFPPS DEQLKSGTAS VVCLLNNFYP REAKVQWKVD 150' NALQSGNSQE SVTEQDSKDS TYSLSSTLTL SKADYEKHKV YACEVTHQGL 200' SSPVTKSFNR GEC 213'

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 22-96 22''-96'' 23'-88' 23'''-88''' 133'-193' 133'''-193''' 146-202 146''-202'' 213'-222 213'''-222'' 228-228'' 231-231'' 263-323 263''-323'' 369-427 369''-427''

velaglucerasum alfa* velaglucerase alfa human glucosylceramidase (EC 3.2.1.45 or beta-glucocerebrosidase), glycoform α

vélaglucérase alfa glucosylcéramidase humaine (EC 3.2.1.45 ou bêta-glucocérébrosidase), glycoform α

velaglucerasa alfa glucosilceramidasa humana (EC 3.2.1.45 o beta-glucocerebrosidasa), glicoforma α

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C2532H3850N672O711S16

ARPCIPKSFG YSSVVCVCNA TYCDSFDPPT FPALGTFSRY ESTRSGRRME 50 LSMGPIQANH TGTGLLLTLQ PEQKFQKVKG FGGAMTDAAA LNILALSPPA 100 QNLLLKSYFS EEGIGYNIIR VPMASCDFSI RTYTYADTPD DFQLHNFSLP 150 EEDTKLKIPL IHRALQLAQR PVSLLASPWT SPTWLKTNGA VNGKGSLKGQ 200 PGDIYHQTWA RYFVKFLDAY AEHKLQFWAV TAENEPSAGL LSGYPFQCLG 250 FTPEHQRDFI ARDLGPTLAN STHHNVRLLM LDDQRLLLPH WAKVVLTDPE 300 AAKYVHGIAV HWYLDFLAPA KATLGETHRL FPNTMLFASE ACVGSKFWEQ 350 SVRLGSWDRG MQYSHSIITN LLYHVVGWTD WNLALNPEGG PNWVRNFVDS 400 PIIVDITKDT FYKQPMFYHL GHFSKFIPEG SQRVGLVASQ KNDLDAVALM 450 HPDGSAVVVV LNRSSKDVPL TIKDPAVGFL ETISPGYSIH TYLWRRQ 497

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 4-16 18-23

Glycosylation sites / Sites de glycosylation / Posiciones de glicosilación Asn-19 Asn-59 Asn-146 Asn-270 Asn-462

veltuzumabum* veltuzumab immunoglobulin G1, anti-[Homo sapiens CD20 (MS4A1, membrane- spanning 4-domains subfamily A member 1, B lymphocyte surface antigen B1, Leu-16, Bp35)] humanized monoclonal IMMU-106 (or hA20); gamma1 heavy chain [humanized VH (Homo sapiens FR/Mus musculus CDR) [8.8.14] -Homo sapiens IGHG1*03] (224-213')-disulfide with kappa light chain [humanized V-KAPPA (Homo sapiens FR/Mus musculus CDR) [5.3.9] -Homo sapiens IGKC*01]; (230-230'':233-233'')-bisdisulfide dimer

veltuzumab immunoglobuline G1, anti-[Homo sapiens CD20 (MS4A1, membre 1 de la sous-famille A à 4 domaines transmembranaires, antigène de surface B1 des lymphocytes B, Leu-16, Bp35)] anticorps monoclonal humanisé IMMU-106 (ou hA20); chaîne lourde gamma1 [VH humanisé (Homo sapiens FR/Mus musculus CDR) [8.8.14] - Homo sapiens IGHG1*03] (224-213')-disulfure avec la chaîne légère kappa [V-KAPPA humanisé (Homo sapiens FR/Mus musculus CDR) [5.3.9] -Homo sapiens IGKC*01]; dimère (230-230'':233-233'')-bisdisulfure

veltuzumab inmunoglobulina G1, anti-[Homo sapiens CD20 (MS4A1, miembro 1 de la subfamilia A con 4 dominios transmembranarios , antígeno de superficie B1 de los linfocitos B, Leu-16, Bp35)] anticuerpo monoclonal humanizado IMMU-106 (ou hA20); cadena pesada gamma1 [VH humanizado (Homo sapiens FR/Mus musculus CDR) [8.8.14] - Homo sapiens IGHG1*03] (224-213')-disulfuro con la cadena ligera kappa [V-KAPPA humanizado (Homo sapiens FR/Mus musculus CDR) [5.3.9] -Homo sapiens IGKC*01]; dímero (230-230'':233-233'')-bisdisulfuro

C6458H9918N1706O2026S46

Heavy chain / Chaîne lourde / Cadena pesada QVQLQQSGAE VKKPGSSVKV SCKASGYTFT SYNMHWVKQA PGQGLEWIGA 50 IYPGMGDTSY NQKFKGKATL TADESTNTAY MELSSLRSED TAFYYCARST 100 YYGGDWYFDV WGQGTTVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV 150 KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ 200 TYICNVNHKP SNTKVDKRVE PKSCDKTHTC PPCPAPELLG GPSVFLFPPK 250 PKDTLMISRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY 300 NSTYRVVSVL TVLHQDWLNG KEYKCKVSNK ALPAPIEKTI SKAKGQPREP 350 QVYTLPPSRE EMTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP 400 VLDSDGSFFL YSKLTVDKSR WQQGNVFSCS VMHEALHNHY TQKSLSLSPG 450 K 451

Light chain / Chaîne légère / Cadena ligera DIQLTQSPSS LSASVGDRVT MTCRASSSVS YIHWFQQKPG KAPKPWIYAT 50' SNLASGVPVR FSGSGSGTDY TFTISSLQPE DIATYYCQQW TSNPPTFGGG 100' TKLEIKRTVA APSVFIFPPS DEQLKSGTAS VVCLLNNFYP REAKVQWKVD 150' NALQSGNSQE SVTEQDSKDS TYSLSSTLTL SKADYEKHKV YACEVTHQGL 200' SSPVTKSFNR GEC 213'

Disulfide bridges location / Position des ponts disulfure / Posiciones de los puentes disulfuro 22-96 22''-96'' 23'-87' 23'''-87''' 133'-193' 133'''-193''' 148-204 148''-204'' 213'-224 213'''-224'' 230-230'' 233-233'' 265-325 265''-325'' 371-429 371''-429''

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viquidacinum viquidacin (3R,4R)-4-{(3S)-3-[3-fluoro-6-methoxyquinolin-4-yl]- 3-hydroxypropyl}-1-{2-[(thiophen-2-yl)sulfanyl]ethyl}piperidine- 3-carboxylic acid

viquidacine acide (3R,4R)-4-[(3S)-3-(3-fluoro-6-méthoxyquinoléin-4-yl)- 3-hydroxypropyl]-1-[2-(thiophén-2-ylsulfanyl)éthyl]pipéridine- 3-carboxylique

viquidacina ácido (3R,4R)-4-{(3S)-3-[3-fluoro-6-metoxiquinolin-4-il]- 3-hidroxipropil}-1-{2-[(tiofen-2-il)sulfanil]etil}piperidina-3-carboxílico

C25H29FN2O4S2

OCH3

H CO2H H OH

S H N N S F

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AMENDMENTS TO PREVIOUS LISTS MODIFICATIONS APPORTÉES AUX LISTES ANTÉRIEURES MODIFICACIONES A LAS LISTAS ANTERIORES

Recommended International Nonproprietary Names (Rec. INN): List 59 Dénominations communes internationales recommandées (DCI Rec.): Liste 59 Denominaciones Comunes Internacionales Recomendadas (DCI Rec.): Lista 59 (WHO Drug Information, Vol. 22, No. 1, 2008)

p. 43 suprimáse insertése albinterferón alfa2b albinterferón alfa-2b

p. 48 supprimer insérer céftaroline fosamil ceftaroline fosamil

* Electronic structure available on Mednet: http://mednet.who.int/ * Structure électronique disponible sur Mednet: http://mednet.who.int/ * Estructura electrónica disponible en Mednet: http://mednet.who.int/

Procedure and Guiding Principles / Procédure et Directives / Procedimientos y principios generales The text of the Procedures for the Selection of Recommended International Nonproprietary Names for Pharmaceutical Substances and General Principles for Guidance in Devising International Nonproprietary Names for Pharmaceutical Substances will be reproduced in proposed INN lists only. Les textes de la Procédure à suivre en vue du choix de dénominations communes internationales recommandées pour les substances pharmaceutiques et des Directives générales pour la formation de dénominations communes internationales applicables aux substances pharmaceutiques seront publiés seulement dans les listes des DCI proposées. El texto de los Procedimientos de selección de denominaciones comunes internacionales recomendadas para las sustancias farmacéuticas y de los Principios generales de orientación para formar denominaciones comunes internacionales para sustancias farmacéuticas aparece solamente en las listas de DCI propuestas.

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