WHO Drug Information Vol 22, No

WHO Drug Information Vol 22, No. 4, 2008 World Health Organization

WHO Drug Information

Contents International Harmonization Ergot-derived dopamine agonists: fibrotic reactions 286 ICDRA: medicines agencies decide Use of antibiotics in premature labour 287 future action 253 Intravenous immune globulin: ICHÐQ11 appears on the horizon: transfusion-related lung injury 288 development and manufacture of Alemtuzumab: infection-related deaths 288 drug substances 268 Theophylline: narrow therapeutic index and potential for misuse 289 Pharmacovigilance Update Cesium chloride and ventricular Strategies for developing pharmaco- arrhythmias 289 vigilance: an international focus 272 Drug-induced hyponatraemia 290 Harmonization and pharmacovigilance 273 Slimming health products adulterated Global markets and patient safety 273 with sibutramine 291 Pharmacovigilance and the Pan Phenytoin and fosphenytoin: serious American Network for Drug skin reactions 291 Regulatory Harmonization 274 Etoricoxib: hypertension risks 292 Lessons learned from the development Efalizumab: updated labelling 292 of pharmacovigilance in Spain 274 Oseltamivir: hepatic and skin disorders 293 Counterfeit and substandard medicines 276 Counterfeit and illegitimate medicines: Regulatory Action and News a view from the Americas 277 Rimonabant: suspension of marketing Pan American Network for Drug authorization 296 Regulatory Harmonization Anti- Vaccines for use in the 2009 influenza Counterfeiting Group 278 season 296 Argentine National Investigation Australian Adverse Drug Reaction Programme on Illegitimate Medicines 278 Committee (ADRAC) to be replaced 297 Administrative traceability requirements 50th orphan medicine receives positive in medicines purchasing 279 opinion 297 Industry commitment in the battle against Televancin: withdrawal of marketing fraud and counterfeiting 281 authorization application 298 Docetaxel: no extension of indication 298 Access to Medicines Ciclosporin eye drops: withdrawal of Better medicines for children: the way marketing authorization application 298 forward 282 Positive opinions on paediatric investigation plans 299 Biosimilar products: a regulatory update 300 Safety and Efficacy Issues Erlotinib: hepatic failure and hepatorenal syndrome 285 ATC/DDD Classification Botulinum toxin type A and distant toxin ATC/DDD Classification: temporary list 302 spread 285 ATC/DDD Classification: final list 305 Safety review of bisphosphonates 286

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Contents (... continued)

Recent Publications, Report on essential medicines for children 309 Information and Events Uganda’s antimalarials market 309 FIP and the future of hospital pharmacy 307 Right to access to medicines 309 Assessing, monitoring and evaluating New issue of WHO/HAI pricing bulletin 310 pharmaceutical situations 307 European Pharmaceutical Forum success 307 Proposed International Procurement and supply management Nonproprietary Names: toolbox 308 List 100 311

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252 WHO Drug Information Vol 22, No. 4, 2008

International Harmonization

ICDRA: medicines agencies decide future action

The Thirteenth International Conference of Drug Regulatory Authorities (ICDRA) held in Berne, Switzerland, from 16 to 19 September 2008 has once again provided drug regulators with a unique opportunity to meet and discuss the particular challenges of medicines regulation.

On this occasion, the ICDRA was hosted by the Swiss Agency for Therapeutic Products, Swissmedic, in collaboration with the World Health Organization (WHO). The event was highly appreciated for its continuing role in fostering a regulatory forum where matters of urgency and international relevance can be openly debated among regulatory officials from developed and developing countries. The ICDRA was attended by over 300 participants from 96 countries and led to adoption of recommendations which regulators consider important in assuring the quality, safety and efficacy of medical products. The recommendations are set out below and on the following pages.

Building mutual trust ¥ Should regulators assess and inspect as a key to access every innovative product that is proposed for their market? Regulatory approval of medicines — ¥ Can and should all regulators assess evaluation, registration, and marketing and inspect generic medicines? authorization — is based on scientific assessment. The approval process needs ¥ Does repetitive assessment and inspec- considerable resources and capacity if it tion provide added value? is to be carried out properly. This plenary session set out to show how mutual trust ¥ How can confidence be built into scien- constitutes a capacity building factor and tific assessments carried out by other parties? leads to improved access to medicines. Potential public health gains can be harnessed from a harmonized under- Moderator Canada: Meena Ballantyne standing of what is needed to ensure the quality, safety and efficacy of medicines. Presentations WHO Intergovernmental Working Group This session addressed the many questions faced by regulators in difficult, on Public Health, Innovation and Intellec- resource constrained environments, tual Property: Implications for regulators. Mandisa Hela, South Africa. including:

¥ How can regulators best contribute to How to benefit from other regulators’ work. A New Zealand view point . public health with the resources they have? Stewart Jessamine, New Zealand.

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Building trust, enhancing competence Regulatory systems in a among African medicines regulatory changing environment authorities: a WHO initiative. Jonathan Regulators are facing a rapidly changing Martey, Ghana. environment including demographics and burden of disease, scientific progress, Recommendations globalization of manufacturing and clinical WHO should: research, difficulties in availability of new and old drugs, and difficulties for indi- 1. Promote, in a targeted and prioritized vidual agencies to meet challenges on way, adoption and implementation of the their own. WHO Model Registration Package as minimum information requirements for Moderator product registration. European Union: Thomas Lönngren

2. Produce a guidance and draft regula- Presentations tion for managing confidentiality issues Changing environments and small regula- among regulatory authorities. tory authorities. Ngawang Dema, Bhutan. 3. Undertake joint assessments of selected applications, using the WHO Model Implications of rapid socioeconomic Registration Package. changes to the regulatory affairs. Cuong Truong Quoc, Viet Nam. 4. Foster the development of regional, collaborative post-market surveillance The changing environment and regulatory and pharmacovigilance systems to systems. Björn Beermann, Sweden. monitor the quality, safety and efficacy of health products. Regulatory paradigms for change: A Singapore perspective. John Lim, 5. Explore the potential development of Singapore. an interagency e-governance working group to harmonize electronic require- Regulatory systems: a Dutch viewpoint. ments to assist in the development of Aginus Kalis, Netherlands. regulatory management systems and the sharing of information in accordance with Recommendations established WHO international regulatory norms and standards. Member States should:

6. In partnership with well-resourced 1. Facilitate and speed up global regula- regulatory authorities: tory cooperation.

¥ establish formal mechanisms for the 2. Support and stimulate their regulatory exchange and use of regulatory infor- authorities to work with regional and mation among all authorities to global partners. strengthen capacity and to maximize efficiencies, and WHO should: ¥ facilitate cooperation between small and medium well-resourced regulatory 1. Continue to support and create new authorities to develop systems for the activities that stimulate cooperation and abbreviated assessment, approval and build trust among regulatory agencies. monitoring of health products.

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Crisis management: Moderators safeguarding health Republic of Korea: Inkyu Kim WHO: Bruce Plotkin In the course of their work, staff working in regulatory authorities may often experi- Presentations ence crises with medicinal products. Mechanisms for information sharing and Some of these crises can lead to loss of public health response under the Interna- public confidence and can be deeply tional Health Regulations (IHR). damaging to the reputation and effective- B. Plotkin, WHO. ness of the regulation of medicines. Communication during a crisis: nelfinavir This session explored ways in which the case study. Emer Cooke, EMEA, Euro- International Health Regulations can be pean Union. used as a mechanism for information- sharing during a medicinal product crisis. Nelfinavir: Where are we now? Experi- The Regulations stipulate that it is man- ence in Barbados. Maryam Hinds, datory to notify WHO of ‘all events which Barbados. may constitute a public health emergency of international concern’ and cover Nelfinavir: Where are we now? Experi- serious international safety events due to ence in Ghana. Delese Darko, Ghana medicinal products. Responding to vaccine safety events. The case study of nelfinavir, which has Karen Midthun, USA. been suspended due to contamination with a harmful substance, was presented. Recommendations This case represents a complex example of an international problem involving Member States should: multiple stakeholders and areas for improvement in the communications area. 1. Have in place a standard operating Experience in two different countries procedure (SOP) for communication in where the product had been withdrawn times of crisis. Main initial communication completely from the market and where difficulties which are linked to uncertainty the product had been reinstated into the of toxicity implications could be avoided treatment programmes were discussed. by use of such SOPs. Finally, a few examples were discussed on how vaccine crises are handled. There 2. Consider that many reports may be are no substantial differences between a required to generate a signal, depending medicine crisis and a vaccine crisis. on the seriousness of the event and the quality of the information. It was agreed that there should always be a crisis management plan in place. This 3. Through national health authorities, should consist of a process through which continue encouraging spontaneous organizations, in collaboration with reporting and vigilance systems and external stakeholders, prevent or effec- introduce crisis management systems. tively manage crises. Key elements are systematic and planned operation and 4. Play an important role in monitoring, involvement of all stakeholders is essen- analysing, and communication of vac- tial in order to provide an efficient, rapid cines safety. and effective response.

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5. Undertake passive and active surveil- six functions of the medicines chain lance after licensure including observa- supply (from registration to distribution). tional studies needed to detect and evaluate medicine and vaccine safety Phase II: Development of a national GGM concerns. framework and its official adoption by the Ministry of Health. WHO and Member States should: Phase III: Implementation of a national 1. Work further to integrate and coordi- GGM programme. nate information and other requirements in the International Health Regulations Presentation (IHR) (2005) with functions and activities WHO Good Governance for Medicines of medicines regulatory authorities and Programme: the Zambian experience. related networks. Such integration could Esnat Mwape, Zambia. include establishing links between medicines regulatory authorities and their Recommendation respective national IHR focal points, including potential access to the WHO 1. Develop, implement and monitor a IHR Event Information Site. Good Governance for Medicines implementation framework, including: Current topics ¥ Establishment and implementation of Moderators codes of conduct. European Union/Council of Europe: Susan Keitel ¥ Enforcement of anticorruption laws. Armenia: Emil Gabrielyan ¥ Provision of transparency and access to Good Governance for Medicines information. In late 2004, WHO implemented the Good Governance for Medicines (GGM) ¥ Protection of whistleblowers. programme in an attempt to curb corruption in the pharmaceutical sector. Its goal ¥ Improvement of inter-institutional col- is to increase transparency and promote laboration and cooperation. ethical practices in national medicines regulatory authorities and supply man- ¥ Provision of guidelines to define and agement systems. underpin public-private partnerships. The GGM programme started with four countries in the WHO South-East Asia Variations Region and has now extended to 27 Presentation countries in all WHO regions. WHO has now a technical package to guide coun- New proposal for the EU Variation Regu- tries in implementing the GGM pro- lation Ð point of view of an EU National Competent Authority. Christa Wirthumer- gramme and facilitates sharing of accu- mulated experiences within countries. Hoche, Austria. Recommendation The programme is based on a three- phase model process: 1. Create a robust and efficient variation Phase I: National assessment of trans- system as it is vital for the quality of a parency and vulnerability to corruption in medicine throughout its life-cycle.

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Radiopharmaceuticals 3. WHO to make the data available on its web site. Presentation Challenges in regulating radiopharma- WHO Certification Scheme ceuticals: view of the International Con- sultancy Group affiliated to IAE. Presentation Kadariah Mohamed Ali, Malaysia. WHO Certification Scheme for finished pharmaceutical products, where are we Recommendations today? Margareth Sigonda, Tanzania.

1. Encourage better regulatory oversight. Recommendations

2. Establish a prequalification system for 1. Review reports of recent meetings held radiopharmaceuticals. at WHO.

3. Establish an international common 2. Give feedback to WHO for further platform (website and electronic data- discussion. base) for harmonized dossiers to pre- qualify radiopharmaceuticals. Adverse reactions

4. Establish detailed mechanisms. Presentation Adverse reactions related to change of Involvement of consumers in medi- formulation: thyroxine case. Stewart cines surveillance reporting Jessamine, New Zealand. Presentation Involving consumers in medicines surveil- Regulatory aspects of lance reporting. Tan Lie Sie, Malaysia, paediatric medicines and Cynthia Lim, Philippines. This session was linked to the two day pre-ICDRA meeting “Better Medicines for Recommendation Children: the way forward”. The meeting 1. Increase efforts to include consumers was unique in inviting, for the first time, in medicines surveillance reporting by regulators, industry, clinicians, civil fostering consumer awareness, informing society and academics to meet and and educating the public and by promot- identify challenges and seek solutions to ing the programme to consumers. ensuring better access to medicines for children. The pre-ICDRA meeting was WHO Stability Testing Guideline attended by more than 240 participants from 75 countries. [A summary of the Presentation main themes to emerge from the meeting Revision of WHO stability testing guide- is presented on page 282.] lines. Tamás Paál, Hungary. Moderator Recommendations European Union: Agnès Saint-Raymond

1. Finalize the revision of the guideline Presentations and apply it in Member States. Recent legislative changes regarding paediatric medicines in the European 2. Provide information about the national Union. Agnès Saint-Raymond, European long-term conditions to WHO. Union.

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Clinical trials in neonates Ð challenges for 4. Devise mechanisms for ensuring trans- all stakeholders? Irja Lutsar, Estonia. parency and exchange of information on trials, licensing, and children’s medicines Paediatric medicines: a viewpoint from an (dose, adverse effects). African regulator. Richard Rukwata, Zimbabwe. 5. Improve information on safety of medicines used in children and building Report from the pre-ICDRA meeting infrastructure for pharmacovigilance. “Better medicines for children – the way forward”. Agnès Saint-Raymond, Euro- Other parties pean Union. For industry: continue integrating paediat- Recommendations from pre-conference ric dosage forms and delivery devices vaccines and biologicals track. David early in development of new medicines. Wood, WHO. For industry: continue integrating paediat- Recommendations ric needs, including developing countries needs in the development of new vac- Member States should: cines.

Assist WHO to form an ICDRA paediatric For the generic industry: develop missing working group to: dosage forms of off-patent medicines (including necessary fixed-dose combina- 1. Ensure global collaboration. tions).

¥ Agree on global regulatory standards. To health professionals: engage actively in sound, ethical research with children, ¥ Streamlining paediatric clinical trials. with the aim of avoiding duplication of research. 2. Implement efficient registration of children’s medicines. WHO should:

¥ Put children medicines as top priority. 1. Convene a global paediatric working group of regulators. ¥ Fast track strategies: e.g., hybrid appli- 2. Work with civil society to mobilize and cations, mutual recognition, cooperative empower consumers, parents, patients’ review, waivers, etc. groups and health professionals to advocate for better medicines for chil- 3. Develop consolidated views/advice on dren. dosage forms and delivery devices. 3. Develop strategies for addressing high ¥ Guideline on dosage forms. priority needs with achievable results including: zinc for diarrhoea, Pneumoniae ¥ Manipulations, extemporaneous formu- treatment, neonatal sepsis, HIV, TB, lations. malaria treatments, and analgesics. 4. Establish a drug development helpline ¥ Increase knowledge on paediatric excipients. to support new essential medicines for children.

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Vaccines and biologicals: Development of regulation 1. National regulatory authorities (NRAs) for herbal medicines should prioritize evaluation of vaccines for Currently, around 110 countries regulate diseases of most importance to child herbal medicines in response to a dra- survival. matically increased use globally and demand for more vigorous requirements Member States and WHO: to ensure quality, safety and efficacy. A 1. Networking among NRAs for the joint number of countries also review and evaluation and oversight of clinical trials strengthen existing regulations for herbal of new vaccines is proving an effective medicines in a continued effort to improve process in Africa. NRAs are requested to their use and efficacy. Regulation of continue to develop this type of collabora- herbal medicines varies from country to tion and WHO is requested to facilitate country, reflecting national circumstances the long-term sustainability of this and and legislative frameworks. A global other vaccine regulatory networking network of regulatory agencies responsi- initiatives. ble for regulation of herbal medicines, the “International regulatory cooperation for 2. Post-marketing effectiveness data is an herbal medicines (IRCH)” was estab- important aspect of vaccine evaluation. lished in 2006 under the coordination of WHO is requested to support capacity WHO and currently has 19 members. building and NRAs are requested to strengthen collaboration with public Moderators health agencies in this area. Singapore: Shen Kuan Yee 3. Vaccine pharmacovigilance is a regula- Lao PDR: Somthavy Changvisommid tory function that needs to be strengthened. NRAs are requested to prioritize Presentations capacity building for this function and Regulatory Framework: overview of the WHO is requested to support this activity regulation of herbal medicines in Switzer- through setting standard definitions, land. Karoline Mathys, Swissmedic, development of guidelines, training, and Switzerland. development of networks. Regulatory Framework: overview of the 4. NRAs are requested to expedite regulation of herbal medicines in Brazil national-level approval of WHO prequali- Bruno Rios, ANVISA, Brazil. fied vaccines. To facilitate this, WHO is requested to provide more detailed Overview of the regulation of herbal information about the quality, safety and medicines in Benin in supporting primary efficacy of prequalified vaccines. health care needs. Regina Badet, Depart- ment of Traditional Medicine and pharma- 5. Forty per cent of venomous snake bite copoeia, Ministry of Health, Benin. victims are children. There is a shortage of appropriate antivenoms globally. Overview: revising the regulatory frame- Improving the quality, quantity and distri- work of herbal medicines in China. bution of antivenoms is essential. NRAs Zhang Wei, State Food and Drug Admin- are requested to implement new WHO istration, China. guidance on the quality, safety and efficacy of antivenoms and WHO is Promotion of regulatory cooperation: requested to develop a prequalification perspectives from IRCH. Shen Kuan Yee, programme for antivenoms Deputy Director, Centre for Drug Adminis-

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tration, Health Products Regulation commonly used medicinal plants through Group, Health Sciences Authority, Singa- cooperation and in building national pore. research capacity for traditional medicines. Recommendations 5. Provide technical guidance to countries Member States should: on how to avoid interactions between conventional and herbal medicines. 1. Promote and improve use of traditional medicine (TM) as an important therapeu- 6. Continue to play a coordinating role in tic tool within health-care systems. International Regulatory Cooperation on Herbal Medicines (IRCH) functions by 2. Provide well balanced prescribing promoting the network to involve other information concerning TM including countries while encouraging member potential interactions with conventional countries of IRCH to incorporate their medicines. national lists of registered herbal products into the IRCH library and to share this 3. Promote research and use of TM as an with IRCH non-member countries. important therapeutic tool. 7. In cooperation with other relevant 4. Raise awareness of cases of adultera- international organizations, promote tion of TM with undeclared plants or introduction of intellectual property rights conventional medicines, or synthetic (“patent protection”) for all newly regis- substances. tered herbal products.

5. Countries with resources should Safety and pandemic support developing countries to achieve preparedness access to better technology tools for evaluation of the therapeutic potential of Pandemics and epidemics are public plants. health emergencies that put sudden and intense stress on all institutions involved. WHO should: Regulatory authorities will be faced with several issues that need to be dealt with 1. Provide policy and technical support to rapidly, efficiently and possibly with countries to facilitate integration of limited resources as pandemics are likely traditional medicine into the health-care to disrupt many aspects of public life. system. Medicines, vaccines and blood products 2. Support developing countries to access will have to be made available at short modern technologies to facilitate produc- notice for large populations. This includes tion and manufacturing of herbal medi- large scale quality control and intense cines. monitoring of therapeutic agents that might not have been previously adminis- 3. Support and coordinate North-South tered outside clinical development set- cooperation to improve access to better tings. technology to evaluate the therapeutic potential of plants. In the case of an avian influenza pandemic the safety of vaccines administered 4. Continue to support sub-regional group during the pre-pandemic phase needs to countries in developing monographs on be evaluated very rapidly.

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Adequate storage of therapeutic agents as a therapeutic in pandemic flu and its and safe and rapid distribution channels likely empirical use, WHO should: are further challenges to be taken on. ¥ Develop guidance on best practices for Moderators collection and use of convalescent Switzerland: Pia Carduff-Janosa plasma in a flu pandemic Indonesia: Lucky Slamet ¥ Promote pre-pandemic research on convalescent plasma Presentations Medicines and associated regulatory ¥ Encourage rapid sharing of scientific issues relevant in the pandemic context. and technical knowledge from both pre- Philip Bryan, United Kingdom. pandemic and pandemic experience

Vaccines and associated regulatory National regulatory authorities (NRAs) issues relevant in the pandemic context. should: Elwyn Griffiths, Canada. 1. Develop and share business continuity PaniFlow tool for monitoring drug/vaccine plans to enable essential functions to be adverse events during a pandemic. performed during the pandemic. Andres Schneider, Switzerland. 2. Develop and share regulatory plans to Blood supply and blood products: regula- enable rapid access to medicines, includ- tory issues in the pandemic context. ing vaccines, that may need to be im- M. Heiden, Germany. ported to respond to the pandemic. This should include emergency use provisions; Convalescent plasmas during a pan- information sharing agreements between demic. Jay Epstein, USA. NRAs and batch release procedures for vaccines to be implemented in the pan- Recommendations demic context.

WHO should: 3. NRAs are encouraged to actively participate in already existing networks 1. Establish, facilitate and intensify (such as the pandemic influenza vaccine international collaboration in safety regulatory network, blood regulators surveillance of pandemic vaccines and network). antivirals.

2. Request the WHO Collaborating Regulatory approaches to Centre for International Drug Monitoring/ proving interchangeability Uppsala Monitoring Centre, to provide free access to PaniFlow (a simplified Experience has demonstrated that online reporting form for primary report- prescribers and other health-care professionals as well as patients are reluctant to ers) for all countries who wish to use it, and to develop and implement a tool for change to generics unless there is a clear rapid signal detection on pooled data and reason to do so and this reluctance is a major hurdle for the introduction of keep all countries informed on findings in a timely manner. generics. Demonstrating qualitative and quantitative equality with the originator is therefore important for the introduction of 3. In recognition of the potential value and availability of convalescent plasma generics and subsequent drop in medicines prices and health-care costs.

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In light of knowledge gained in the last 3. Allocate more resources to medicines forty years on pharmaceuticals, scientific regulatory authorities (MRAs) for training evidence supports the need for regulating of assessors for evaluation of inter- the interchangeability of medicinal prod- changeability of multisource (generic) ucts. Many national competent authorities products. have issued guidelines on bioquequiva- lence studies and on the type of medici- 4. Enable MRAs to certify the contract nal product that can be exempted from in research organizations (CROs) conduct- vivo bioequivalence studies. ing bioequivalence studies

Interchangeability of medicinal products is WHO should: regulated in most EU Member Countries, Japan, USA and other countries. The 1. Promote mutual trust and international regulation of interchangeability of medici- cooperation mechanisms in order to nal products requires a strong team within recognize MRA inspections of CROs that each drug regulatory authority. Surveil- have been conducted based on interna- lance of performance and outcomes also tionally acceptable standards. requires expertise and resources. Strategies to fight Moderators counterfeit medicines Saudi Arabia: Salah Bawazir Counterfeiting of medicines, including the Spain: Carlos Lens entire range of activities from manufacturing to providing such products to patients, Presentations is a vile and serious criminal offence that Proof of interchangeability of pharmaceu- puts human lives at risk and undermines tical products and assurance of their the credibility of health systems. Because quality in Ukraine. Olga Baula, Ukraine. of its direct impact on health, counterfeit- Implementation of bioequivalence re- ing of medicines should be combated and quirements: lessons learned. Rodrigo punished accordingly. Christofoletti, Brazil. Combating counterfeit medicines requires Interchangeability and registration of the coordinated effort of all the different multisource (generic) products in Japan. public and private stakeholders that are Daisuke Koga, Japan. affected and are competent to address the different aspects of the problem. WHO biowaiver guideline in regulatory practice. Kamal Iddir, Tunisia. Counterfeiting medicines is widespread and has escalated to such an extent that Recommendations effective coordination and cooperation at the international level is essential for Member States should: regional and national strategies to be 1. Ensure that drug laws and regulatory more effective. frameworks contain the required provi- The above principles have been the basis sions to ensure submission of bioequiva- for the establishment of the International lence data to regulators. Medical Products Anti-Counterfeiting Taskforce (IMPACT). The Taskforce has 2. Promote generic prescribing based on identified five areas where action is assurance that all mulltisource (generic) needed in order to combat counterfeit products are therapeutically equivalent. medical products effectively. Accordingly,

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five working groups have been created, of the supply chain at all steps of the covering: legislative and regulatory pharmaceutical supply system. infrastructure, regulatory implementation, enforcement, technology, and communi- 5. In developing track and trace method- cation. ologies used to secure the supply chain, MRAs should take into account the need Moderators to ensure international compatibility in Nigeria: Dora Akunyili order to improve their effectiveness in tracking products that move across Brazil: Bruno Rios borders, whenever applicable. Presentations National Experience in combating coun- 6. WHO and MRAs should promote the terfeit medical products: development of collaborative networks based on the principle of Single Points of Justina Molzon, USA. Contact (SPOC). Eishah A. Rahman, Malaysia Domenico Di Giorgio, Italy 7. WHO should further assist MRAs to Danny Lee-Frost, United Kingdom strengthen their capacity to detect and combat counterfeit medical products and Recommendations to exchange information at the international level. 1. Medicines regulatory agencies (MRAs) should be more proactive in providing 8. WHO should further promote a harmo- other NRAs and the general public with nized definition of a counterfeit medical appropriate information on the scope of product that is based on the 1992 defini- the problem of counterfeit medical prod- tion of counterfeit medicine, that focuses ucts at the national level. on the protection of public health, and takes into account the need to safeguard 2. MRAs should ensure that all concerned legitimate generic medicines. governmental institutions are aware of the scope of the problems related to counter- 9. WHO should develop and implement feit medical products and of the activities initiatives aimed at disseminating aware- that are undertaken to address these at ness and triggering political will to combat national and international level. counterfeit medical products. 3. MRAs should develop and adopt multi- pronged anti-counterfeiting strategies Emerging regulatory issues addressing at least: (a) ensuring proper concerning biosimilars and regulatory oversight, (b) securing the biologicals supply chain, (c) increasing and applying penalties, (d) increasing public and health Draft WHO guidance states that, in professional vigilance and awareness, (e) contrast to a generics approach, the developing and applying effective authen- dossier for a similar biological product will tication and detection technologies, and need to contain information on the non- (f) improving coordination with all con- clinical and clinical data in addition to the cerned stakeholders at the national and quality data. However, the proposed international level. guidance considers that a non-clinical and clinical package could be abbrevi- 4. MRAs should clearly define the respon- ated; the extent of abbreviation will sibilities of manufacturers and operators depend on the level of similarity to the

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well established reference product with a nisms such as regional centres of excel- proven record of quality, efficacy and lence in regulatory evaluation of similar safety. biological products.

Experience gained by using a “biosimilar Member States should: approach” in the EU was considered in the development of the WHO guidelines 1. Strengthen NRA functions for the and one abbreviated regulatory pathway evaluation, pharmacovigilance and is proposed. However, during review of overall regulation of biotherapeutics. the document, a need for an alternative was identified and an additional abbrevi- Emerging diseases: ated pathway is under development. regulating blood products Moderators This session recognized the need world- European Union/EMEA: Nick Gates wide for blood product regulation to Republic of Korea: Chung Keel Lee ensure availability of safe blood and blood products in the face of known and Presentations emerging threats, including emerging Regulation of copies of therapeutic infectious diseases. biological medicinal products: WHO guidelines. Elwyn Griffiths, Canada. Moderators Regulatory considerations in Thailand. USA: Jay Epstein Prapassorn Thanaphollert, Thailand. Indonesia: Lucky Slamet

WHO guidelines: abbreviated licensing Presentations pathways for biological products. Martina Emerging Diseases, blood safety and Weise, Germany. supply: Chikungunya virus outbreak in 2005/2006. Isabelle Sainte Marie, France. Panel discussion: Experience with existing regulatory pathways for copies of Dengue outbreaks in Latin America. therapeutic biological medicinal products. Clarice Lobo, Brazil.

Elwyn Griffiths, Canada. Assessment criteria for blood regulatory Prapassorn Thanaphollert, Thailand. systems: effectiveness in risk manage- Martina Weise, Germany. ment. Christian Schaerer, Switzerland.

Recommendations Plasma Quality: How does it matter? WHO should: Rainer Seitz, Germany. 1. Develop guidance for regulatory Assessment criteria for blood regulatory evaluation of similar biological products systems: effectiveness in risk manage- that includes clarification of the scientific ment. Jay Epstein, USA (presenting for basis for the reduction, wherever possi- Peter Ganz, Canada). ble, of non-clinical and clinical data requirements for such products. Recommendations

2. Assist regulators in implementing WHO should: globally agreed regulatory principles into 1. Take steps to further develop and national regulations and, where appropri- strengthen national and regional blood ate and feasible, develop support mecha-

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regulatory authorities and promote 2. Formulate policies and, as far as cooperation among them. possible, legislation to enable priority medicines availability according to local 2. Provide well-harmonized “Assessment health care needs. Criteria for Blood Regulatory Systems” building on work of the Blood Regulators 3. Direct drug regulatory authorities to Network reveal medicine availability problems by giving priority to new applications for 3. Take full account of existing assess- products answering locally unmet health ment tools in use by NRAs by: needs.

¥ Convening a consultation of NRAs to WHO should: review the draft assessment tool, and 1. Provide a forum to discuss and facili- ¥ Ensuring coordination with related WHO tate both availability and affordability of guidance documents. medicines in all Member States. 4. Prioritize development of guidelines on good manufacturing practices (GMP) for Update on harmonization Blood Establishments. initiatives

5. Promote introduction of WHO recom- Moderators mended plasma standards by NRAs. Tanzania: Margareth Sigonda Canada: Mike Ward Regulators contribution to access Presentations Development of ICH Global Cooperation Moderator Group: a non-ICH regional harmonization Hungary : Tamás Paál and country perspective. Yuppadee Presentations Javroongrit, Thailand. Availability of human medicinal products in Europe Ð how big is the problem and Harmonization of drug regulation in East what can we do? View from the regulator. Africa: the way forward. Apollo Muhairwe, Kristin Raudsepp, Estonia. Uganda.

Can regulators facilitate access? A Harmonization of regulatory require- viewpoint from China. Zhang Wei, China. ments: a view point from an APEC country. Mike Ward, Canada. Panel Discussion Update on Pan American Network for Recommendations Drug Regulatory Harmonization. James Fitzgerald, PAHO/WHO. Member States should: Recommendations 1. Involve regulators in the formulation of policies and measures assuring patient 1. WHO should encourage and facilitate access to medicines. Regulators should, Member States’ use of the assessment in addition to their traditional roles, take tool for drug regulatory authorities as an responsibility for facilitating availability of important step in promoting effective medicines.

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regulatory strategies and harmonization Recommendations efforts. Member States should: 2. WHO should promote the principle of 1. Promote national mechanisms for interconnectivity by information sharing communication and collaboration be- and cooperation between harmonization tween ethics committees and regulatory initiatives and enabling organizations to agencies regarding the oversight of build synergies, leverage capacity and clinical trials. sustain efforts. 2. Provide mechanisms that allow experts 3. WHO and Member States should from well resourced regulatory agencies promote effective mechanisms of harmo- to assist in capacity building of regulation nization through the establishment or of clinical trials in less resourced regula- strengthening of secretariats or coordina- tory authorities. This may include expert tion points, steering committees and support from regulators of the manufac- procedures respecting expert working turing country to regulators of the trial groups, governance and transparency. host country.

4. WHO should facilitate the adoption by 3. Promote a risk-based approach to Member States of a common format for regulatory oversight of clinical trials. marketing applications as a means of promoting a common regulatory language WHO should: that supports the sharing of information, good review practices and access to 1. Promote regulation of clinical trials by medicines. supporting countries to establish robust legal and regulatory frameworks and 5. The topic of harmonization should be a systems to register and publish ongoing standing agenda item at each ICDRA. trials to achieve transparency.

Role of regulators in clinical 2. Facilitate the establishment of confi- trial approval dentiality provisions that will allow communications and cooperation between Moderator regulatory agencies from manufacturing Australia: Rohan Hammett and trial host countries. Presentations Registration of clinical trials in the na- Building regulatory capacity: tional registry or authorization by the best practices for the future national DRA Ð what should come first? Surinder Singh, India. Moderators India: Debasish Panda Roles and responsibilities of national Japan: Takayuki Okubo regulators and the ethics committees: ways for better cooperation and commu- Presentations nication. Lucky Slamet, Indonesia. Building regulatory capacity. Debasish Panda, India. Interactions between manufacturing and trial host country regulators. Pieter Neels, NRA assessment/benchmark system and Belgium. institutional development plan (IDP). Rafael Perez Christia, Cuba.

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Building regulatory capacity in a regula- Presentations tory network: experience from twinning Risk management of GMP inspections: projects and EU worksharing. Dagmar Australian approach. Tony Gould, Aus- Stará, Slovak Republic. tralia.

Recommendations Coping with increasing need for inspections: ASEAN initiatives. Abida Haq, WHO should: Malaysia.

1. Systematically inform ministries of What is EMEA’s approach in GMP in- health of outcomes of NRA assessments. spections? Emer Cooke, European Union. 2. Evaluate ways for improving bench- marking activities within the assess- Recommendations ments. Member States should: 3. Strengthen NRAs in regulatory self- assessment approaches. 1. Work towards ensuring quality, efficacy and safety of drugs while making efforts Member States and NRAs should: to contain escalating costs of drug prices by minimizing duplication of inspection 1. Use WHO tools for conducting self activities through: evaluation as an adequate way for improving regulatory performance. ¥ Better networking.

2. Provide staff to support the WHO ¥ Improved information sharing. assessment process and take advantage of the experience resulting from this ¥ Enhanced collaboration. process. ¥ Increased mutual trust/confidence. GMP inspections: impact of information sharing and risk 2. Promote efficient use of inspectorate resources through use of a risk manage- management ment approach in GMP inspections, Increasingly, strategies are discussed on especially for overseas manufacturers, by how best to cope with the increasing taking advantage of information available need for inspections by national and from other drug regulatory authorities. regional bodies. This topic was also 3. Collaborate with WHO Member States discussed during several WHO consulta- and the WHO Medicines Prequalification tions and meetings of the WHO Expert Programme to share information about Committee on Specifications for Pharma- dates, purpose of inspection and major ceutical Preparations, which suggested outcomes. that this would be a good subject for discussion at the 13th ICDRA. Manufacturers should: Moderators 1. Actively collaborate in information USA: Justina Molzon sharing among national, regional and international bodies involved in inspec- South Africa: Joey Gouws tions.

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2. Increase availability of non-confidential regional and other relevant authorities information on the web sites of interested involved in inspections. authorities and on protected sites access-ed by national authorities.

WHO should:

1. Promote and enable networking and information sharing among national,

ICH-Q11 appears on the horizon: development and manufacture of drug substances

The US Food and Drug Administration Yokohama in October 2007 and the Final (FDA) and the Pharmaceutical Research Concept Paper Q11: Development and and Manufacturers of America (PhRMA) Manufacture of Drug Substances (chemi- hosted an ICH Quality satellite round cal entities and biotechnological / biologi- table in Rockville, Maryland, USA 27Ð 28 cal entities) was endorsed by the ICH September 2007. The objectives of the Steering Committee in April 2008. A six- meeting were: party expert working group (EWG) was established, including observers from the ¥ To discuss the technical and regional European Free Trade Association (EFTA), differences and similarities in describing Health Canada and WHO. The EWG the development and manufacturing of follows the process used by the CTD-Q drug substances in the common techni- EWG where biotechnological / biological cal document (CTD). and chemical experts work together.

¥ To determine how best to apply the The concept paper (2) summarizes the principles of ICH Q8, Q9 and Q10 goals of the guideline, as follows: guidelines for both small and large molecules. ¥ Harmonize and encourage the submis- ¥ To integrate these principles into devel- sion of relevant documents regarding oping future quality guidances. the manufacturing process information and its justification. The conclusion of the meeting was that ¥ Outline the science-based concepts the quality by design (QbD) approach, relevant to the design of a robust including the design space, is applicable manufacturing process that reliably to both chemical and biotechnological (1) delivers a quality drug substance. active pharmaceutical ingredients (APIs), although opportunities and challenges ¥ Provide examples as appropriate of are different in the two groups of pharma- acceptable approaches for demonstrat- ceutical substances. ing process and product understanding.

The business plan was approved by the ¥ Facilitate the regulatory evaluation ICH Steering Committee (ICH SC) in process for authorities.

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

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Organic active pharmaceutical ingredients (APIs) may be manufactured by isolation from herbal, animal or human sources, for example: The structure synthesized from Artemisia annua has been modified by chemical synthesis to obtain a molecule with improved pharmacological and pharmaceutical properties.

Artemisinin Artesunate

The majority of (small-molecule) APIs are manufactured by chemical synthesis.

Nevirapine

Biotechnological methods are used to produce “large molecules”, e.g., antibiotics.

Streptomycin

The three groups of manufacturing methods, including the use of (genetically engineered) micro-organisms in fermentation, are frequently combined in the pharmaceutical industries.

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¥ Recommend approaches for demon- ¥ Chemical and biotechnological molecu- strating process and product under- lar entities; standing. ¥ New chemical entities opposed to ¥ Address the complexity of different generic APIs; manufacturing processes and products. ¥ Accommodate variable approaches to ¥ Current practice versus quality by development and corresponding infor- design (QbD) approach mation to be provided as described in Q8 and Q8R. Many quality topics have not yet been the subject of ICH guidelines (e.g. drug ¥ Address enhanced approaches to substance synthesis) and the content of manufacturing that can also create a Common Technical Document (CTD) for basis for alternative approaches to the Registration of Pharmaceuticals for control the quality of a product and for Human Use: Quality Ð M4Q(R1) is not the application of innovative technolo- totally harmonized. gies for the manufacture of APIs (e.g. continuous manufacture). Innovator pharmaceutical industries always develop a new chemical entity ¥ Address systematic approaches to drug concurrently with the finished pharmaceu- substance development, application of tical product (FPP), while generic API quality risk management, and concepts industries are often isolated from the drug such as design space, control strategies product manufacturers and the open part (including real-time release) over the of the drug master file (DMF) is the lifecycle of the product. technical link between them. The CTD Ð Quality Questions and Answers/ Location Topics already covered by other ICH Issues (3) states that “Since the DMF guidelines such as analytical procedure systems differ in the three regions, ICH validation (Q2), quality of biotechnological does not address this issue.” products (Q5 series), and GMP activities (Q7) will be cross-referenced in the new A control strategy has always existed in guideline, as appropriate. the drug-substance industries but Q8 initiated a new way of thinking and many Step 1: Consensus building stage began companies have adopted risk assess- with the first meeting of the Q11-EWG in ment (impact of process on safety and Portland, Oregon (USA) in June 2008, efficacy of API) and aim at more process where the guideline topic/definitions were understanding and the associated design accepted. Draft No.0 was tabled for space as well as process analytical discussion in Brussels in November 2008. technology (PAT) monitoring of critical Initial discussions have revealed that manufacturing process parameters. ICH-Q11 may become the hardest ever document to elaborate because it will These illustrative examples intend to become a stand-alone document to cover demonstrate that ICH Q11 is an important a wide scope of not-yet-harmonized document both for industry and regulatory issues: agencies and its impact goes beyond the ICH regions. ¥ Information on development and manufacture of drug substances in regulatory submissions;

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Notes and references 2. The full text of the ICH-Q11 concept paper can be found at http://www.ich.org/LOB/media/ 1. Biotech drug substances were defined as MEDIA4523.pdf active pharmaceutical ingredients manufactured by biotechnological processes including, 3. http://www.ich.org/LOB/media/ but not limited to, macromolecules (such as MEDIA620.pdf proteins, peptides and nucleic acids) and excluding vaccines.

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Pharmacovigilance Update

Strategies for developing Spain, with 40 million inhabitants, there pharmacovigilance: an are nineteen Spanish-speaking countries in Central and South America and a international focus growing Spanish-speaking population, around 45 million, in the USA. The 8th International Society of Pharma- covigilance (ISoP) conference, Strategies The Scientific Programme included for developing Pharmacovigilance, held in issues concerning pharmacovigilance and Buenos Aires, Argentina, in October 2008 presented differences in organization, was hosted by the Argentine Society of complexity and effectiveness in different Pharmacovigilance. This was the first regions. Harmonization in pharmacovigi- ISoP meeting to be held in Latin America, lance was approached in such a way as which is a geopolitical region mainly to discuss and compare the regulations of composed of developing countries with a developed and developing regions. Two total population of more than 450 million sessions were devoted to enhancing people. Although political, economic and methodology and one to improving the even ethnic conditions vary in the differ- efficacy of systems to prevent the circula- ent Latin American countries, they are all tion of counterfeit and substandard affected in different degrees by similar medicines (a summary of which is set out problems concerning production, distribu- on page 276). The need to enhance tion and utilization of medicines. pharmacovigilance in pregnant women, The conference was attended by more children and older people was also than 350 participants from more than 50 stressed. countries. Among the audience were Different approaches to pharmacovigi- many medicines regulatory authorities, lance in vaccines and a round-table health professionals, and representatives discussion on strategies of risk manage- of academia and pharmaceutical labora- ment from a regulatory perspective dealt tories, student and patient organizations. with two main topics in international Thirty participants were also sponsored to pharmacovigilance. The need for monitor- attend a pre-conference course Pharma- ing of a relatively new group of medicines covigilance: from fundamental basics to was the basis for the session about practice. This course was organized by biological products and advanced thera- the Argentine Ministry of Health to allow pies. The crucial role of communication in health professionals from Argentina’s th pharmacovigilance was also approached provinces to attend the 8 ISoP confer- from different perspectives and focused ence. on public and media communication. The The 8th ISoP conference was organized evaluation of medicines for marketing as a bilingual event in English and Span- authorization and the impact of this ish. Spanish is one of the most widely complex process on patient safety were spoken languages in the world. Besides tackled in three plenary lectures dealing

This article was prepared by Raquel Herrera Comoglio on behalf of the Argentine Society of Pharmacovigilance (www.safv.org.ar). Speaker authorization for publishing the summaries and reviews of lectures is kindly acknowledged.

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with benefit/risk balance, off-label use, care and where medicines are often and the non-commercial sponsorship of lacking. Many countries trading in com- clinical research. mon markets often have varying priorities in their fight against different diseases. Summaries of two sessions and a plenary Depending on the situation, these may lecture that have special importance for focus on treating lifestyle diseases or on the Latin-American region are provided battling diseases of poverty and underde- below and on the following pages. velopment. There is also a broad diversity in the structure and quality of pharmaceu- The programme from the 8th ISoP confer- tical markets, in the number of different ence is available at http://www.isop products licensed, in the active ingredi- 2008.org/isop2008-final programme3.pdf. ents and in sales figures. Advertising and promotion of medicinal products to health professionals and direct-to-consumer ad- Harmonization and vertising are just a few of the challenges pharmacovigilance* facing societies within a context of varying financial and human resources, social The international harmonization of phar- security systems and infrastructure. macovigilance has an impact on drug licensing and utilization and on the health Regulators have a responsibility to and disease burden worldwide, but its ensure patient health and safety and they impact is greatest within trade alliances, are required to act within existing national like Mercosur or the European Union. The structures and environments. However, complex issue of pharmacovigilance their power to act decisively may also be harmonization has become a growing influenced or hindered by overriding concern for regulators and presents public health needs or politics. considerable challenges. The role of harmonization Global markets and patient safety** Harmonization should use the best In the context of market globalization, the evidence of favourable or unfavourable acceptance and perception of risk and drug effects to assess the benefit-to-harm benefit of drugs is influenced by social, relationship. Likewise, it should promote structural and legal factors in different equal and fundamental rights for popula- countries. The key question is whether tions and the proper use of drugs in all harmonization of pharmacovigilance and settings in order to achieve high stand- regulatory action can be consolidated ards of safety. given the varying degrees of pharmacovigilance development observed in the The main preconditions for harmonization different regions. are availability of high quality information and transparency. It is necessary to Pharmaceutical manufacturers act define different levels of information in globally in an unequal world where not all order to make appropriate decisions. For countries have the opportunity to benefit underdeveloped countries with difficult from medical progress or access to health Internet access, WHO’s role should be reinforced to achieve effective coverage * Session chaired by Ulrich Hagemann, of essential information. Pharmacovigilance Department, Federal Institute for Drugs and Medical Devices - In conclusion, harmonization should BfArM, Germany and Pedro Lipszyc, Buenos reflect and respect differences between Aires National University, Argentina. countries and societies, but patient safety ** Presentation by Ulrich Hagemann. must have the highest priority. Full access

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to data and exchange of information are ments for drug registration. The group is key elements for collaboration and working for the harmonization of interna- interchange between all stakeholders. tional standards of quality, safety and Regulators should also be supported efficacy and a pharmacovigilance working through international or regional networks group was established in 2006 in order to: and action tending to improve pharmacovigilance in poor or under resourced ¥ Develop and strengthen pharmaco- countries should continue to be strength- vigilance through activities and harmo- ened by support from independent nized regulatory action that promotes organizations. the safe and rational use of medicines as a necessary component of public Pharmacovigilance and the Pan health policies in the WHO Region of American Network for Drug the Americas. Regulatory Harmonization* ¥ Promote the development and dis- The objective of the Pan American semination of knowledge, criteria and Network for Drug Regulatory Harmoniza- methodologies used in pharmaco- tion (PANDRH) is to offer a forum to vigilance for training and education identify common activities among mem- activities directed to all stakeholders. bers. It aims to establish priorities in drug regulatory harmonization processes, ¥ Develop, analyse and propose the use facilitate continuity of technical agree- of tools to support harmonization of ments and encourage convergence of pharmacovigilance in the Region. drug regulatory systems within the Americas. In order to improve adverse drug reaction reporting, there must be strong political PANDRH is made up of representatives commitment from each component of the from drug regulatory authorities of the 35 health-care system. As an example, countries in the region, organisms for experience in Cuba has shown that economic integration such as CARICOM appointing a focal point responsible for and MERCOSUR, associations of the pharmacovigilance in each district hospi- pharmaceutical industry, academia and tal has led to a considerable increase in nongovernmental organizations. Its main the number of adverse drug reaction targets are: reports.

¥ To strengthen drug regulatory agencies Lessons learned from the develop- at country level. ment of pharmacovigilance in Spain* ¥ To promote constructive participation of Spontaneous reporting started in Catalo- all partners. nia in the 1980s, when pharmacovigi- ¥ To facilitate the establishment of a lance was almost completely unknown to network of regulatory authorities. health authorities or health professionals in Spain. Establishment of the Catalonia Key concerns are to improve the access pharmacovigilance system and research to safe and effective medicines of good was mainly the result of development of a quality in all countries of the region and to dynamic Clinical Pharmacology Unit at reduce unnecessary, duplicate require- the University Hospital in Catalonia.

* Presented by Julian Pérez Peña, National *Lecture presented by Joan-Ramon Laporte, Pharmacoepidemiology Development Center, Universidad Autonòma de Barcelona, Spain. Ministry of Public Health, Cuba.

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In Catalonia, spontaneous reporting was Examples of signals leading to market established, and continues to be devel- withdrawals: oped, as part of a broader communica- agranulocytosis Ð cinepacide tions strategy of drug monitoring between hepatitis Ð bendazac the Clinical Pharmacology Unit and Guillain Barré syndrome – gangliosides prescribers. It also encompasses a hepatitis Ð droxicam continuous education activity, mainly for hypersensitivity and hepatotoxicity Ð health professionals, health managers, glafenine policy makers, and politicians working in agranulocytosis Ð pyrithyldione the health sector. A major contribution of hepatotoxicity Ð ebrotidine the clinical pharmacology unit to public rhabdomyolysis Ð cerivastatin health was a change in prescription liver toxicity Ð nimesulide patterns in Catalonia. In 1984, many of hepatitis Ð green tea extract the most highly prescribed pharmaceuti- extrapyramidal and psychiatric cal products in the health system lacked reactions Ð veralipride. evidence of therapeutic efficacy, or were simply irrational fixed-dose combinations. Examples of signals leading to In comparison, the most highly prescribed changes in approved indications medicines in 2007 had better evidence of and conditions of use: efficacy. Parkinsonism and depression Ð cinnarizine and flunarizine The initial pharmacovigilance system taste disorders Ð citiolone received very strong institutional support acute dystonic disorders Ð clebopride from the Ministry of Health, which under- TB infection Ð infliximab stood the need for collaboration with (This last signal was generated by a Sao health professionals independent from Paulo University Hospital, where a the Ministry of Health and public adminis- Pharmacovigilance system was set up tration, and of communication and making with the collaboration of the Catalan alliances with people working in Universi- Institute of Pharmacology.) ties and hospital structures because of their closer access to prescribers. Spain’s Of note, many of the drugs involved had integration into the European Union was no evidence of efficacy, and this benefit- also positive in establishing regulatory risk assessment was straightforward. In measures for the licensing of new drugs addition, many of the adverse reactions and safety monitoring were type B (not related to the expected The programme was then extended to pharmacological effect, not dose-related, other Spanish regions and the Spanish etc.). Agency for Medicines and Health Prod- ucts (AEMPS) now maintains a central Traditionally, monitoring of medicines database, FEDRA, containing 140 000 safety has mainly relied on spontaneous reports. All the 17 Pharmacovigilance reporting, especially for detecting type B Regional Centres regularly publish effects. In Spain, spontaneous reporting bulletins with information on their findings also proved to be helpful in clearing the and on drug safety issues. market of irrational and useless medicines Ð and even harmful and ineffective In all these twenty-seven to twenty-eight drugs. However, although spontaneous years since its establishment, the Span- reporting has proved to be useful in ish pharmacovigilance system has detecting these type B reactions and produced many important results in the some type A effects, the surveillance of field of public health. medicines safety should include other

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pharmacoepidemiological methods. Since Reporting and publication of adverse the drug-induced disease burden consists drug reactions is a responsibility of mainly of type A effects, the challenge is a regulatory agencies. However, adverse risk evaluation of these, not only in effects of medicines are experienced first relative terms but in the amount of deaths hand in clinical practice, and therefore or hospitalizations caused by drugs in our pharmacovigilance is mainly a matter of societies. collaboration and communication within the health system and health care pro- The following represent examples of vider organizations and among all other pharmacoepidemiological methods used partners of the health care system. in recent years to asses some important drug safety problems: The Spanish pharmacovigilance system was conceived not only for regulatory 1. Randomized clinical trials (RCTs) and purposes but also as part of a broader meta-analysis of randomized clinical trials communication strategy between the for assessing the relationship between: university and prescribers.

¥ Hormone replacement therapy and breast cancer, myocardial infarction, Counterfeit and thromboembolic disease, cerebro- vascular accidents. substandard medicines* The ISoP session Counterfeit Medicines ¥ SSRI antidepressants and suicide in and Illegitimate Drugs tackled the grow- children. ing problem of counterfeit and substand- ¥ Epoetins and hypertension and cardio- ard medicines. vascular risk. The World Health Organization defines a 2. Longitudinal follow-up of unselected counterfeit medicine as “a medicine which patients for assessing the relationship is deliberately and fraudulently misla- between risk of haemorrhage and use of belled with respect to identity and/or oral anticoagulants. source. Counterfeiting can apply to both branded and generic products and 3. Observational studies, meta-analysis of counterfeit products may include products observational studies and meta-analysis with the correct ingredients or with the of RCTs for assessing the risk of myocar- wrong ingredients, without active ingredi- dial infarction with rofecoxib, other COX-2 ents, with insufficient active ingredients or and other NSAIDs. with fake packaging.”

4. Spontaneous reporting, observational Although an accurate estimate of counter- studies, and meta-analysis of RCTs for feit medicines available in markets is gastrointestinal bleeding and NSAIDs and difficult to obtain, the number may be antiplatelet drugs. more than 10% of the global medicines 5. Meta-analysis of RCTs for assessing market, with a probable worth estimate of the risk of myocardial infarction and death 75 billion dollars in 2010. Medicines with inhaled anticholinergic drugs. * Session chaired and presented by Luis Special attention must also be paid to Alesso, Córdoba National University and drug utilization patterns; not only how Maria José Sánchez, Argentine Institute of much medicine is consumed, but how it is Medicines (INaMe), National Administration of consumed in real practice. Food, Drug and Medical Technology (ANMAT), Argentina.

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counterfeiting affects individuals from ate strength, pH, excipients or other both developing and developed countries. chemical properties. In Latin America, the extent of this problem is still unknown and weak borders In countries where governments supply between countries make appropriate medicines for the treatment of specific controls even more difficult to establish. diseases (such as haemophilia and AIDS), some high-priced medicines are Developing countries are more affected provided free of charge to patients by the by this threat because they have, in state health insurance systems. These general, weaker medicines regulatory products may sometimes be sold by systems, scarcity and/or erratic supply of patients to wholesalers and then reintro- basic medicines, unregulated markets duced into the market (a process called and unaffordable prices. An estimated “revolving”). 25% of the medicines consumed in developing countries are believed to be During this ISoP session, an urgent need counterfeit; and in some underdeveloped was identified for exhaustive and manda- countries, the figure is thought to be as tory guidance for medicines purchase, as high as 50%. well as national laws punishing drug counterfeiting or adulteration and market- Because it is a global, serious public ing of illegitimate, counterfeit and adulter- health problem, medicines counterfeiting ated medicinal products. should be considered as a crime and not only as an intellectual property issue or Counterfeit and illegitimate medicines: commercial fraud. As a potential cause of a view from the Americas* serious risk to health which may be life- The WHO/Pan American Health Organi- threatening, the battle against medicines zation (PAHO) states that a counterfeit counterfeiting demands the involvement product cannot be considered a medical of all social and economic actors from the product because it has been manufac- public and private sectors. tured and sold by withholding its real origin, evading regulatory controls with an Counterfeit medicines are part of a arbitrary and, above all, unpredictable broader phenomenon of substandard composition. Social and political condi- products which can threaten the populations which help medicines counterfeiting tion’s health. Altogether, counterfeit, to flourish include: adulterated medicines, stolen medicinal products, smuggled medicines, unregis- ¥ Inadequate legislation. tered medicines, and expired medicines are generally considered “illegitimate ¥ Weak regulatory oversight and enforce- medicines”. The definition illegitimate ment. medicines is a legal term, rather than one referring to the quality of a product. All ¥ Inadequate cooperation between drug illegitimate medicines are considered as regulators, police, customs, prosecu- substandard, even when they may have tors, health professionals, manufactur- been legally and properly produced (i.e. ers, wholesalers, and retailers. stolen medicines), because it is impossible to know if they have been correctly stored and transported. It should be noted that some legitimate medicines can * Presentation made by José Luis Castro, Pan also be considered substandard if tests American Health Organization/World Health prove that they do not have the appropri- Organization, Argentina.

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¥ Trading through several intermediaries/ tives of national regulatory agencies from brokers, wholesalers and the distribu- Argentina, Brazil, Canada, Colombia, tion chain. Dominican Republic, Paraguay, St. Lucia, and USA participate in this Group. The ¥ Unregulated trade, Internet-based sales, pharmaceutical industry is represented by transit through free zones. the Federación Latinoamericana de la ¥ No or limited patient access to reliable Industria Farmacéutica (FIFARMA) and health care and medicines supply. the Asociación Latinoamericana de industrias Farmacéuticas (ALIFAR). ¥ Lack of control over medicines destined for export. The PANDRH Anti-Counterfeiting Group is working on defining indicators for ¥ The high price of legal medicines. counterfeit medicines and on a proposal, ¥ Illiteracy and poverty and lack of infor- with a standardized procedure, for struc- mation or lack of access to information. tural strengthening of national regulatory authorities (NRAs) through a specific WHO/PAHO have undertaken many executive unit. It is also working on a activities to help prevent and fight medi- roadmap which would allow counterfeit cines counterfeiting: they support coun- medicines structured follow-up and on tries with technical advice to establish updating diagnostic studies and recom- pharmaceutical policies and regulations mendations for industry, NRAs and and by developing guidelines for quality governments in general. assurance, good manufacturing practices, purchasing, and distribution of medicines. In September 2007, with support from the WHO/PAHO coordinates the International Ministry of Health in Panama, the PAN- Medical Products Anti-Counterfeiting DRH Anti-Counterfeiting Group held a Taskforce (IMPACT) launched to gather workshop to establish national and all actors in the fight against counterfeit- multisectorial task forces and launch ing and target global action against this coordinated action against counterfeiting. public health threat. The Group is also working to define and establish a network of vital focal points of Adequate information exchange between communication within and among coun- governments and adviser groups is a tries and to draft an inspection guideline. priority and PAHO has set up an external This document was presented at the quality control programme for national PANDRH Meeting in Buenos Aires in laboratories in the Americas and has November 2007. developed a regional medicines prequalification system which is now being Argentine National Investigation harmonized with the WHO Medicines Programme on Illegitimate Medicines* Prequalification Programme. In Argentina, the first case of a counterfeit medicine (quinine sulfate) was docu- Pan American Network for mented in 1858 but it was not until 1997 Drug Regulation Harmonization that the National Institute of Medicines Anti-Counterfeiting Group Programme for the Investigation of The Pan American Network for Drug Illegitimate Medicines was created. The Regulation Harmonization (PANDRH) primary aim of the Programme is to Anti-Counterfeiting Group was created to counteract the commerce of counterfeit promote the development of strategies to prevent and fight counterfeit medical * Presentation made by Maria José Sánchez, products in the Americas. Representa- Argentina

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drugs in order to guarantee quality, cines for specific diseases (antiretrovirals, effectiveness and security of pharmaceu- anticancer drugs, products for haemo- tical products. It acts in joint action with philia). the National Administration for Medicines, Food and Medical Technology (ANMAT), In Argentina, there is no law specifically government prosecutors and the Federal punishing medicines counterfeiting or Police. The pharmaceutical Industry and marketing of illegitimate medicines and Academia also provide valuable collabo- the current legislation considers trade in ration. substandard medicines as a commercial offence. Currently, legislation has been The Programme is based on a strict proposed against medicines counterfeit- control of the legal medicines marketing ing and adulteration and, also, a proposal chain: it covers community and hospital has been made setting out the adminis- pharmacies, wholesalers, distributors, trative requirements for purchase of and both private and public health-care medicines. institutions. The methodology is primarily based on: Administrative traceability requirements in medicines purchasing* ¥ Visual inspection of pharmaceutical products. In Argentina, the only legislation covering purchasing by public health administration ¥ Request for documents proving product systems and public hospitals refers to the purchase. supplier’s fiscal status. There is no specific legal rule for medicines purchasing. ¥ Medicines sampling throughout the national distribution chain. In December 2004, at least 19 patients suffered iron poisoning and one of them The analysis of products discovered at died following the administration of a sites manufacturing counterfeit medicines counterfeit iron product in a public hospi- showed that there was no uniformity in tal in Argentina. This product, containing the characteristics of batches, and the iron citrate instead of iron sorbitex, had quantity of active ingredient varied 3.5 times more iron than the branded between zero and 200% of the amount product. The switch in active ingredient stated on the label. Both primary and was apparently made to obtain the same secondary packaging were, in general, colour as the original. The product was different from the original. Holograms also purchased from a third-party wholesale demonstrated differences with the origi- broker who had no links with the manu- nals. facturer. The wholesaler was prosecuted and the Argentine Medicines Agency, All 12 inspectors of the Argentine Pro- ANMAT, immediately published a list of gramme for the Investigation of Illegiti- recommendations to avoid the purchase mate Medicines are pharmacists and are of counterfeit products. But in May 2005, supported by technical, administrative a pregnant woman suffered serious liver and legal staff. Since Argentina is a failure and premature labour because of federal country, inspectors work in col- the administration of the same counterfeit laboration with the authorities from 23 product in the same public hospital. provinces. In the 1990s, the main problem involved counterfeiting of inexpensive medicines with a high consumption rate. Presentation made by Rodolfo Rodriguez, Nowadays, counterfeit or adulterated Córdoba Provincial Administration Health products are mainly high priced medi- Insurance (AProSS), Córdoba, Argentina.

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Table: illegitimate medicines identified in Argentina in 2008*

¥ Rituximab: A physician reported adulteration in a vial; no active principle was found at all. ¥ Riluzol: Following an adverse drug reaction report. Packaging was adulterated. ¥ Two rHu-eritropoyetin products: Adulterated products were found in a dialysis centre during an INaMe inspection. • Epoetin alfa recombinant: Following a physician’s report; adulterated packaging. ¥ Erlotinib: Following a patient report. Adulterated packaging and blister pack with capsules instead of coated tablets. Capsules did contain erlotinib 100 mg. ¥ Rituximab: A wholesaler reported adulteration in packaging. Reported products had not been legally imported and belonged to batches marketed in other Latin-Ameri- can countries. ¥ Trastuzumab: A nurse reported a different color in the vial content. Both packaging and vial had been adulterated; no active principle was found at all. ¥ Interferon Beta 1-A, Rituximab, parenteral Vitamins: Reported products had not been imported and belonged to batches marketed in other Latin-American countries (Interferon and rituximab) and Spain (Cervenit¨). ¥ Six batches of Concentrated VIII Factor, manufactured in Germany. Following patients’ reports (with samples). Samples showed adulteration (pierced stopper, manipulated top, content different from the original in quantity) and fungal development when reconstituted. Original ampoules had been re-utilized. • Efavirenz: Blisters did not show the expiration date, with ink traces saying “not for sale”. Blisters are believed to come from AIDS programmes providing free medicines (community pharmacy). ¥ One batch of ritonavir, identified in a community pharmacy because of adulterated packaging.

* www.anmat.gov.ar: National Administration of Food, Drugs and Medical Technology (ANMAT), Argentine Health Minister, legal rules Nû 193/08, 1185/08, 1416/08, 1943/08, 2599/08, 2831/08, 3307/08, 3351/08, 4125/08, 4143/08, 4244/08, 4543/08, 5647/08, 5650/08, 6110/08

Before and since then, many other and traceability systems. However, the illegitimate products have been found fight against the sale of illegitimate both in public and private health-care medicines also needs concurrent ap- institutions, some of them with a sound proaches from all partners involved. reputation. In 2008, ANMAT published, Health insurance systems have a key role among others, 15 legal resolutions in avoiding counterfeit or illegitimate withdrawing highly priced products based medicines purchasing. on laboratory, health care professional or patient reports (see table above). According to international and National recommendations, Córdoba Province Marketing authorization holders (MAH) of Health Insurance Administration branded marks add identification devices (AProSS) has established a mandatory

280 WHO Drug Information Vol 22, No. 4, 2008 Pharmacovigilance Update

list of requirements for wholesalers. It taken and executed by national regula- demands wholesalers to supply proof of tory authorities in the region, especially marketing authorization, wholesaler ANMAT (Argentina), ANVISA (Brazil), licensure, inspection results, and a list of INVIMA (Colombia) and COFEPRIS any disciplinary action against the whole- (Mexico) are recognized. saler. Packing lists and invoices are also With regard to measures to prevent requested in order to ensure legitimacy of counterfeiting and illegal trade of medi- medicines. This is an inexpensive and cines, a stricter authorization process for effective traceability system to avoid the marketing and approval of facilities and purchase of adulterated or illegitimate regular audits along the commercializa- medicines. tion chain (manufacturing laboratories, pharmaceutical wholesalers and distribu- Industry commitment in the battle tion companies, pharmacies and hospi- against fraud and counterfeiting* tals and health institutions) are essential. For many years, medicines manufactur- An accurate system of medicines trace- ers’ associations have participated in ability and legal rules and procedures to WHO and PAHO Working Groups against remove manufacturing machines and medicines counterfeiting, and the phar- equipment is also needed. In the search maceutical industry is actively engaged in and detection of illegal medicines in this battle worldwide. The Argentine unauthorized facilities, it is necessary to National Investigation Programme on collaborate jointly and synchronize Illegitimate medicines has been sup- actions among the health authorities, ported by manufacturers’ associations police and judicial system. and significant outcomes in terms of deactivation of clandestine laboratories, Manufacturers are involved in intensifying impounding medicines and prosecuting the communication network and providing individuals have been achieved. training to the highest possible number of regulatory agencies in the region. Manu- Argentine medicines manufacturers have facturers support and are committed to identified a need to improve procedures actions of vigilance and control of medi- for the public acquisition of medicines, cines marketing, the distribution chain, and to identify more funds for the control and of unauthorized marketing premises/ and monitoring of pharmaceutical whole- facilities. It is also essential to improve salers and pharmacies in provinces. The the education of patients and consumers outstanding role of the PANDRH Network and to pass clear and strict laws and and PAHO in promoting preventive regulations in order to track down and effective action, which are being under- sanction this crime against public health.

* Presented by Miguel Maito, Cilfa, Industrial Chamber of Argentine Pharmaceutical Labora- tories.

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Access to Medicines

Better medicines for Additionally, it identified gaps and challenges in paediatric research, gave an children: the way forward update on clinical trials in neonates, and Every second year, the World Health presented issues from the WHO Medi- Organization (WHO) convenes the cines Prequalification Programme. Other International Conference of Drug Regula- presentations focused on challenges in tory Authorities (ICDRA). The ICDRAs the development, regulation and supply provide drug regulatory authorities with a of vaccines and biologicals, as well as regulators-only forum to meet and dis- issues surrounding safety and pharmaco- cuss ways to strengthen collaboration. vigilance of vaccines in children. ICDRA pre-meetings are organized to discuss selected topics of interest linked A summary of the main themes to emerge to regulatory affairs for which participation from the presentations is outlined below. of regulators and other interested stake- A series of recommendations that have holders gives added value. arisen as a result of these discussions is presented on page 257. Detailed informa- The theme of the two day pre-meeting tion on each of the presentations can be linked to this year’s 13th ICDRA in Berne, accessed through the following link: http:// 14-15 September 2008, was “Better www.who.int/medicines/ Medicines for Children: the way forward”. The meeting was unique in being the first The current situation time that regulators, industry, clinicians, civil society and academics worldwide ¥ The global mortality rate in children were invited to meet and discuss chal- under five years remains inequitable lenges and seek solutions to ensuring and a significant problem. better access to medicines for children. The meeting involved more than 240 • Children’s medicines are an identified participants from 75 countries. priority, as stated in the World Health Assembly Resolution on Better Medi- Presentations were given by members of cines for Children (WHA60.20), and as academia, industry and regulatory agen- expressed in the Millennium Develop- cies. They offered perspectives on issues ment Goals. involving the safety, quality and dosing of medicines for children, and the ethical ¥ Advances in knowledge and technology challenges of conducting trials, particu- have led to: larly in children of the developing world. - better understanding of paediatric The conference was divided overall into growth and development and the two tracks with presentations focusing on associated changes in paediatric medicines, and biologicals and vaccines. physiology; Discussion included strategies for devel- - methodological advances in clinical oping fixed dose combinations for chil- trials and population health, including dren, alternate dosage forms for children adaptive and bridging trials; (both liquid and non-liquid formulations).

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- pharmacokinetic modelling techniques; through support of manufacturers, and preclinical and clinical testing, community education, and training of medical - databases of information on medicines personnel is essential. safety. ¥ Integrating immunization and other child ¥ Positive achievements and develop- health interventions in a campaign style ments have been made in regulatory delivery such as child health days for structures with incentives to promote high-priority health services has proven the development of medicines for successful if adequately supported by children, with some additional advances logistics, distribution, storage systems, in innovative technology for age appro- supply chain management, tracking and priate dosage forms. monitoring of supplies.

¥ Although clinical evidence on how best First steps to use medicines effectively and safely The following actions were identified as in children has started to be collated, essential in order to ensure availability many gaps in knowledge, particularly and affordable access to appropriate about the safety of medicines in children medicines for children: and optimal doses remain. ¥ Strengthening political commitment to For vaccines and biological products ensure that childhood survival remains a high topic of priority on the agenda. ¥ Many potential future vaccines for priority diseases are currently in devel- ¥ Movement towards primary health care, opment. However, despite advances in up-scaling high impact interventions at the field, barriers to research and community level, strengthening of development — including increased health systems, and continued advo- technological complexity and safety cacy. requirements, high clinical research ¥ A global collaborative stakeholder costs, and ongoing public concerns over approach Ð to include patients and vaccine safety — mean that vaccines carers, health professionals, academics still occupy only a small portion of the and manufacturers, as well as regula- pharmaceutical market. tors and policy makers is needed. ¥ Post marketing efficacy data and vac- ¥ Optimal age-appropriate dosage forms cine pharmacovigilance is an important should be developed as a priority. aspect of vaccine development. Ap- proaches to post marketing surveillance ¥ Better quality research involving chil- include passive (vaccine adverse event dren is required. Capacity building to reporting system) and active ap- strengthen ethical and high quality proaches (phase IV studies, FDA clinical trials globally and increasing the sentinel initiative and CDC’s Vaccine capacity and capability of ethics com- Safety Datalink), as well as the use of mittees to review and monitor clinical electronic databases. Advantages and trials is essential. Global standards for limitations are present with all methods. clinical trials in children need to be agreed and implemented. ¥ Forty per cent of venomous snake bite victims are children and there is a ¥ Unnecessary duplication of research shortage of appropriate antivenoms should be avoided. Existing literature, throughout world. Improving the quality, including clinical trials and pharmaco- quantity and distribution of antivenoms, kinetic studies in relevant populations

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needs to be collated and synthesized. ¥ Methods to ensure increased safety of Methods for ensuring transparency of medicines for children need to be information about existing clinical trials developed, in particular through moni- and licensed products need to be toring of adverse drug reactions. developed and implemented globally. In conclusion, the pre-ICDRA meeting ¥ Strengthening of manufacturing capacity dedicated to children’s medicines has and health systems infrastructure, successfully achieved its objectives and particularly for vaccines is needed. the recommendations will lead to follow- up activities. It is expected that a prog- ¥ Global strategies need to be developed ress report will be presented to the 14th to promote efficient and effective regis- ICDRA to be held in Singapore in 2010. tration/licensing of medicine for children, with due consideration of risks and benefits.

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Safety and Efficacy Issues

Erlotinib: hepatic failure dystonia, blepharospasm associated with and hepatorenal syndrome dystonia, strabismus, dynamic equinus due to spasticity in paediatric cerebral United States of America — Healthcare palsy patients, hyperhidrosis of the axilla professionals have been informed of and focal spasticity (3). Botox Cosmetic¨ cases of hepatic failure and hepatorenal is indicated for the treatment of facial syndrome, including fatalities, reported wrinkling (4). during use of erlotinib (Tarceva¨), particularly in patients with baseline hepatic Toxin spread may occur locally, when impairment. Patients with hepatic impair- botulinum toxin disperses to surrounding ment receiving erlotinib should be closely tissues, as in the case of dysphagia monitored during therapy and the product reported with the use of botulinum toxin should be used with extra caution in type A in patients with cervical dystonia patients with total bilirubin >3x ULN. (3). In addition, adverse reactions (ARs) suggestive of botulism have also been Dosing should be interrupted or discontin- reported and may occur as the result of ued if changes in liver function are systemic toxin spread beyond the site of severe, such as doubling of total bilirubin injection (2). Symptoms of botulism can and/or tripling of transaminases in the include muscle weakness or paralysis, setting of pretreatment values outside the dysarthria, dysphagia and dysphonia (5). normal range. New information from a Serious complications of botulism include pharmacokinetic study in patients with respiratory depression and dysphagia moderate hepatic impairment associated which may lead to aspiration pneumonia. with significant liver tumour burden has These manifestations may be fatal if been provided in the revised prescribing untreated (5,6). information. Reference: Communication from OSI Phar- Extracted from the Canadian Adverse Reac- maceuticals and Genentech. September 2008 tions Newsletter, Volume 18, Issue 4, October and information from FDA, 14 November 2008. 2008, at http://www.fda. gov/medwatch References

Botulinum toxin type A 1. Health Canada reviewing issue of distant and distant toxin spread toxin spread potentially associated with Botox¨ and Botox Cosmetic¨. Ottawa: Health Canada — Botulinum toxin health prod- Canada; 20 February 2008. ucts have recently been the subject of safety notices because of their suspected 2. Early communication about an ongoing association with the potential spread of safety review - Botox and Botox Cosmetic the toxin to sites in the body distant from (botulinum toxin type A) and Myobloc (botuli- the sites of administration (distant or num toxin type B). Rockville (MD): US Food and Drug Administration, 2008. systemic toxin spread) (1, 2). In Canada, botulinum toxin type A is marketed as 3. Botox (botulinum toxin type A for injection) Botox¨ and Botox Cosmetic¨. Botox¨ is [product monograph]. Markham (ON): Allergan indicated for the treatment of cervical Inc.; 2007.

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4. Botox Cosmetic (botulinum toxin type A for On 1 October 2007, FDA began request- injection) [product monograph]. Markham ing placebo-controlled clinical trial infor- (ON): Allergan Inc.; 2007. mation from the sponsors of alendronate, ibandronate, risedronate, and zoledronic 5. Brook I. Botulism: the challenge of diagno- acid in order to explore the potential risk sis and treatment. Rev Neurol Dis 2006; 3(4):182Ð9. for atrial fibrillation in male and female patients treated with these bisphos- 6. Palmer JL, Metheny NA. Preventing phonate drugs. aspiration pneumonia in older adults with dysphagia. Am J Nurs 2008;108(2):40Ð8. The data submitted by the four sponsors included data on 19 687 bisphosphonate- treated patients and 18 358 placebo- Safety review of treated patients who were followed for 6 bisphosphonates months to 3 years. The occurrence of atrial fibrillation was rare within each United States of America — On 1 study, with most studies containing 2 or October 2007, the Food and Drug Admin- fewer events. The absolute difference in istration (FDA) announced that it was event rates between each of the bisphos- reviewing safety data on a potential phonate and placebo arms varied from increased risk for atrial fibrillation in 0Ð3 per 1000. patients treated with a bisphosphonate drug (1). One large study of zoledronic acid showed a statistically significant increase Bisphosphonates are a class of drugs in the rate of serious atrial fibrillation used primarily to increase bone mass and events. However, across all studies, no reduce the risk for fracture in patients with clear association between overall bis- osteoporosis. Bisphosphonates are also phosphonate exposure and the rate of used to slow bone turnover in patients serious or non-serious atrial fibrillation with Paget disease of the bone and to was observed. Increasing dose or dura- treat bone metastases and lower elevated tion of bisphosphonate therapy was also levels of blood calcium in patients with not associated with an increased rate of cancer. Bisphosphonate products include: atrial fibrillation. alendronate (Fosamax¨, Fosamax Plus D¨), etidronate (Didronel¨), ibandronate References: (Boniva¨), pamidronate (Aredia¨), risedronate (Actonel¨, Actonel W/Cal- 1. http://www.fda.gov/cder/drug/early_comm/ cium¨), tiludronate (Skelid¨), and bisphosphonates.htm zoledronic acid (Reclast¨, Zometa¨). 2. FDA Information at www.fda.gov/medwatch/ An article and an accompanying letter to 12 November 2008 the editor in the 3 May 2007 issue of The New England Journal of Medicine de- Ergot-derived dopamine scribed increased rates of serious atrial agonists: fibrotic reactions fibrillation in two different studies of women ages 65 to 89 years old with United Kingdom/European Union — osteoporosis treated with the bisphos- The European Medicines Agency (EMEA) phonates, Reclast¨ and Fosamax¨. Data has recommended new warnings and showed an increased risk of serious atrial contraindications for ergot-derived fibrillation and this risk was reflected in dopamine agonists as a result of the risk the Reclast¨ labelling. of fibrosis, particularly cardiac fibrosis, associated with chronic use. The risk of

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cardiac fibrosis is higher with cabergoline ¥ Women who are planning pregnancy and pergolide than with the other ergot- should stop taking cabergoline one derived dopamine agonists. Cabergoline, month before they try to conceive. pergolide, and bromocriptine are indicated for the treatment of Parkinson References disease. 1. MHRA Drug Safety Update. Volume 2, Cabergoline (brand leader Dostinex¨) is Issue 3, October 2008 at http://www.mhra. used in hyperprolactinaemia. Bromo- gov.uk/mhra/drugsafetyupdate. criptine (brand leader Parlodel¨) is 2. http://www.emea.europa.eu/pdfs/human/ indicated for chronic endocrine disorders press/pr/32239508en.pdf. such as hyperprolactinaemia and ac- romegaly. This new advice applies only to 3. Zanettini R et al. Valvular Heart Disease and the Use of Dopamine Agonists for Parkin- treatment of chronic endocrine disorders son’s Disease. N Engl J Med 2007; 356Ð39. with these agents — it does not apply to the inhibition of lactation. 4. Schade R et al. Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation. N Engl J Cabergoline and bromocriptine Med, 2007; 356Ð29. ¥ Exclude cardiac valvulopathy as deter- Use of antibiotics mined by echocardiography before treatment. in premature labour United Kingdom —In the ORACLE ¥ Monitor patients for signs or symptoms Children Study (a 7-year follow-up of a of pleuropulmonary disease (e.g., dys- large randomized, placebo controlled pnoea, shortness of breath, persistent trial to investigate the effects of erythro- cough, or chest pain) and retroperito- mycin and co-amoxiclav in premature neal disorders during treatment. Renal labour) parents reported small increases insufficiency or ureteral or abdominal in the number of children with mild vascular obstruction might occur, with functional impairment or cerebral palsy pain in the loin or flank and leg oedema. born to mothers whose membranes were Abdominal masses or tenderness could intact and who had received antibiotics. suggest retroperitoneal fibrosis. In women who presented with spontane- Cabergoline ous premature labour without rupture of ¥ Monitor patients for signs of cardiac the membranes, prophylactic antibiotics fibrosis during treatment. had neither beneficial nor harmful short- term effects for babies. ¥ Echocardiography should be done Advice for healthcare professionals within 3Ð6 months of starting treatment and subsequently at 6Ð12-month ¥ This research was conducted in a very intervals. specific group of women and so the results do not mean that antibiotics are ¥ Stop treatment if echocardiography generally unsafe for use in pregnancy. shows new or worsened valvular regur- Untreated infections can be dangerous gitation, valvular restriction, or valve and potentially life threatening for leaflet thickening. pregnant women and their unborn babies, and antibiotics should continue ¥ Pregnancy should be excluded before to be prescribed in line with current administration of cabergoline. guidance and the product licence.

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¥ The study confirms existing practice that required débridement. Subsequently, the antibiotics should not be given routinely patient experienced hypotension and to women who are in premature labour dyspnoea and the infusion was stopped. with intact membranes and who have The results of a chest radiograph were no obvious infection. compatible with a diagnosis of TRALI. The patient was transferred to the inten- ¥ These results were unexpected and the sive care unit, where he required intuba- mechanism by which this reported tion. The result of an anti-human association occurred in women with leukocyte antigen test was pending at the intact membranes is unclear, particularly time of reporting. as no increase in functional impairment or cerebral palsy was reported in the Extracted from the Canadian Adverse Reac- children of mothers who received the tions Newsletter, Volume 18, Issue 4, October same antibiotics but whose membranes 2008. had ruptured. Additional research is required to shed light on these findings. References 1. Kleinman S, Caulfield T, Chan P et al. References Toward an understanding of transfusion- related acute lung injury: statement of a 1. MHRA Drug Safety Update. Volume 2, consensus panel. Transfusion 2004; Issue 3, October 2008 at http://www.mhra. 44(12):1774Ð89. gov.uk/mhra/drugsafetyupdate. 2. Oracle Children Study website at 2. Toy P, Popovsky MA, Abraham E et al. http://www.le.ac.uk/cm/rs/oracle/ Transfusion-related acute lung injury: definition and review. Crit Care Med 2005;33(4): Intravenous immune globulin: 721Ð6. transfusion-related lung 3. Rizk A, Gorson KC, Kenney L, et al. injury Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 2001; 41(2): Canada — Transfusion-related acute 264Ð8. lung injury (TRALI) is a clinical syndrome that presents as acute hypoxaemia and 4. Gamunex¨ (immune globulin intravenous noncardiogenic pulmonary oedema human 10%) [product monograph]. Toronto: Bayer Inc; 2005. during or within 6 hours after blood transfusion (1, 2). TRALI is an important cause of transfusion-associated death, Alemtuzumab: infection- even though it is probably still under- related deaths diagnosed and underreported (2). There have been few literature reports of TRALI Canada — Health Canada has informed in patients administered intravenous health-care professionals of important immune globulin (IVIG) (3). The Canadian safety information regarding the use of product monograph for Gamunex¨ alemtuzumab (Mabcampath¨) as consoli- (human IVIG 10%) recommends that IVIG dation therapy following combination recipients be monitored for pulmonary treatment with other chemotherapeutic or adverse reactions (4). biologic agents.

Health Canada has received a report of a Alemtuzumab is a recombinant human- 38-year-old man who had received ized monoclonal antibody and is currently Gamunex¨ for the treatment of strepto- authorized for the treatment of B-cell coccal thoracic cellulitis, which had also chronic lymphocytic leukaemia (B-CLL) in

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patients treated with alkylating agents Reference: MHRA Drug Safety Update. and who have failed fludarabine therapy. Volume 2, Issue 3, October 2008 at http:// Alemtuzumab is not authorized for use as www.mhra.gov.uk/mhra/drugsafetyupdate. consolidation therapy. Cesium chloride and Preliminary safety information from the ventricular arrhythmias CALGB10101 clinical trial conducted in the United States, reported 6infection- Canada — Nonradioactive cesium related deaths out of 51 patients who chloride (CsCl) is used orally as a natural received 3 chemotherapeutic agents health product. Although not authorized followed by consolidation therapy with for therapeutic use in Canada, unauthor- Mabcampath¨). The potential for an ized cesium products are accessible for increased risk of infection-related compli- purchase (e.g., on the Internet) and are cations may exist following treatment with used for the self-treatment of cancer. As multiple chemotherapeutic or biological of 28 May 2008, Health Canada received agents. 3 reports of prolonged QT interval and ventricular tachyarrhythmia suspected of The phase II CALGB10101 clinical trial being associated with the oral use of reported six infection-related deaths out CsCl. of 51 patients who received the three chemotherapeutic agents. The six fatal CsCl’s effects on cardiac rhythm have been demonstrated in animal studies, infections were reported as: Viral meningitis, Listeria meningitis, Legionella pneu- where it has been used to experimentally monia, cytomegalovirus infection, Pneu- induce ventricular arrhythmias (3). Al- though the mechanism is not fully under- mocystis jiroveci pneumonia, and Epstein Barr virus associated lympho-proliferative stood, CsCl is known to block a variety of disorder. potassium channels, including many of those involved in the cardiac action Reference: Health Canada. MedEffect Alert, potential (4,5). 18 November 2008 at http://www.hc-sc.gc.ca/ Extracted from the Canadian Adverse Reac- dhp-mps/medeff/advisories-avis/prof/_2008/ tions Newsletter, Volume 18, Issue 4, October mabcampath_nth-aah-eng.php 2008.

Theophylline: narrow References therapeutic index and 1. Lyon AW, Mayhew WJ. Cesium toxicity: a potential for misuse case of self-treatment by alternative therapy gone awry. Ther Drug Monit 2003;25(1):114-6. United Kingdom — Several products that contain theophylline or aminophylline 2. Pinter A, Dorian P, Newman D. Cesium- are available as pharmacy medicines that induced torsades de pointes. N Engl J Med can be dispensed without a prescription. 2002;346(5):383-4. Theophylline—a bronchodilator—inter- 3. Jones DL, Petrie JP, Li HG. Spontaneous, acts with several medicines and has a electrically, and cesium chloride induced narrow margin of safety between thera- arrhythmia and afterdepolarizations in the peutic and toxic doses. Therefore, com- rapidly paced dog heart. Pacing Clin Electro- munity pharmacists are reminded to physiol 2001;24(4 pt 1):474-85. check whether patients who buy theo- 4. Vyas H, Johnson K, Houlihan R, et al. phylline without a prescription are also Acquired long QT syndrome secondary to taking any other medicines (including cesium chloride supplement. J Altern Comple- theophylline on prescription). ment Med 2006;12(10):1011-4.

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5. Zhang S. Isolation and characterization of Older age is generally acknowledged to IKr in cardiac myocytes by Cs+ permeation. be a risk factor for hyponatraemia. Two- Am J Physiol Heart Circ Physiol 2006;290(3): thirds of the reports received since 2005 H1038-49. describe patients aged over 70 years and over 70% involved women. Onset of Drug-induced hyponatraemia hyponatraemia occurred within the first month in 74% of cases that provided this Australia — The Australian Adverse Drug information (median, 11 days). Reactions Committee (ADRAC) continues to receive reports of hyponatraemia (1) in The clinical presentation varied greatly association with various medicines. but the most commonly described disor- Severe hyponatraemia is a potentially ders were: neurological (including convul- devastating condition that can develop sions, postural hypotension, syncope, rapidly and without obvious prior symp- altered consciousness or coma, somno- toms, particularly in the elderly. Once lence, headache, ataxia, tremor, abnor- severe hyponatraemia develops, special- mal gait, visual disturbances and cerebral ist management is required to achieve a oedema), psychiatric (including confu- favourable outcome (2). sion, delirium, agitation and hallucina- tions) and gastrointestinal (including Since May 2005, ADRAC has received anorexia, nausea and vomiting). 307 reports of hyponatraemia, several of which also described syndrome of inap- This series of reports included two deaths propriate antidiuretic hormone secretion. which were considered attributable to 227 (74%) of the reports implicate a hyponatraemia. single drug as the suspected cause: mainly diuretics (126 reports) and antide- Although a few reports described hy- pressants (78 reports, 33 of which were ponatraemia as an incidental finding on with an SSRI or SNRI). routine laboratory testing in asymptomatic patients, there is evidence that even mild Severe hyponatraemia, which can cause levels of chronic hyponatraemia may significant and permanent neurological contribute to an increased rate of falls (3). injury or death (1), was documented in In fact, nine falls were documented in this 101 of the reports. Individual drugs most series of reports. commonly associated with the severe form were hydrochlorothiazide, indapa- Extracted from the Australian Adverse Drug mide, carbamazepine, paroxetine, venla- Reactions Bulletin, Volume 27, Number 5, faxine and sertraline. October 2008 at http//www.tga.gov.au/adr

Eighty of the 307 reports describe hypo- References natraemia in association with more than one agent; virtually all of these involved 1. Androgué HJ, Madias NE. Hyponatraemia. the combined use of a diuretic (hydro- NEJM 2000; 342:1581Ð1589. chlorothiazide or indapamide) with an 2. Douglas I. Hyponatraemia: why it matters, ACE inhibitor or an angiotensin II receptor how it presents, how we can manage it. blocker or with an SSRI or SNRI. The Cleveland Clinic J Med 2006; 73 (Suppl combination of carbamazepine with an 3):S4ÐS12. antihypertensive agent and a diuretic or 3. Decaux G. Is asymptomatic hyponatraemia with an antidepressant was also de- really asymptomatic? Am J Med 2006; 119 scribed. (7A):S79ÐS82.

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Slimming health products and a consequent increased dopaminer- adulterated with sibutramine gic neurotransmission, in line with the dopamine hypothesis of psychosis (2, 3). Singapore — In recent months, the Pharmacovigilance Branch of the Health Be mindful of Internet purchase Sciences Agency (HSA) has received of drug & health products three reports of adverse drug reactions Given the increasing trend of consumers (ADR) associated with two slimming turning to the Internet for purchase of health products. On further investigation, health products, health-care professionals the products namely, Relacore¨ and are encouraged to ask patients about the Lami¨, were found to contain consumption of such complementary sibutramine, an undeclared western drug medicines or health supplements. Very ingredient used as an appetite suppres- often, patients may not regard these sant in the management of obesity. products as medicines and not mention them to doctors. The information may be In June 2008, HSA issued a press state- important to physicians in making a ment to alert the public of the adulterated differential diagnosis of the adverse product labelled as Relacore¨. This was events experienced by patients. prompted by two ADR reports involving two adult patients (a male and female) in References their early twenties. Both patients admit- ted to purchasing the slimming product 1. J Psychosom Res. 2008 Jan;64(1): 107Ð9. over the Internet from a Chinese website. 2. Am J Psychiatry. 2000 Dec; 157(12): The product was subsequently tested by 2057Ð8. HSA’s analytical laboratory and found to contain 12.22 mg of sibutramine in each 3. J Clin Psychopharmacol. 2007 Jun; capsule. 27(3):315Ð7. 4. Product safety alert. Slimming health The adulterated product labelled as products (Relacore & Lami) adulterated with Relacore¨ (which could be a counterfeit sibutramine. 1 December 2008. at of the product sold in the USA) was http://www.hsa.gov.sg promoted as a dietary supplement. Phenytoin and fosphenytoin: Sibutramine-induced psychosis serious skin reactions Sibutramine is a noradrenaline and serotonin reuptake inhibitor indicated for United States of America — The Food weight loss. Commonly reported ADRs and Drug Administration (FDA) is investi- include insomnia, headache and anxiety. gating new preliminary data regarding a Tachycardia and hypertension have also potential increased risk of serious skin been reported in some patients. reactions including Stevens Johnson syndrome (SJS) and toxic epidermal Sibutramine is also known to exhibit necrolysis (TEN) from phenytoin significant dopamine reuptake inhibition (Dilantin¨, Phenytek¨) therapy in Asian and some authors have postulated that patients positive for a particular human this could possibly lead to the develop- leukocyte antigen (HLA) allele, HLA- ment of psychotic symptoms, especially B*1502. This allele occurs almost exclu- in the event of an overdose (1). This is sively in patients with ancestry across based on the postulation that the dopa- broad areas of Asia, including Han mine reuptake inhibition could result in Chinese, Filipinos, Malaysians, South excess dopamine in the synaptic clefts Asian Indians, and Thais. Because

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fosphenytoin is a prodrug and is con- benefits and risks of 90 mg etoricoxib verted to phenytoin after administration, (Arcoxia¨) in the treatment of rheumatoid any concern regarding this association arthritis and in ankylosing spondylitis. The is also applicable to fosphenytoin review included analyses from an obser- (Cerebyx¨). Phenytoin and fosphenytoin vational database (General Practice are used to control tonic-clonic (grand Research Database) study, which sug- mal) and complex-partial seizures in gest that a substantial number of patients epilepsy. A recent FDA information sheet with systolic BP >150mmHg and/or (12/12/2007), described an increased risk diastolic BP >90mmHg have been initi- of SJS/TEN with another anti-epileptic ated on etoricoxib despite earlier recom- drug, carbamazepine, in Asian ancestry mendations. patients with the HLA-B*1502 allele. Prescribers are therefore asked to note The FDA is working to identify additional the following updated and strengthened information to evaluate the possible risk safety recommendations: of SJS/TEN from phenytoin and fosphenytoin in patients with HLA-B*1502. ¥ Etoricoxib should not be used in pa- Until the evaluation is completed, health- tients with hypertension whose BP is care providers who are considering the persistently elevated above 140/90 use of phenytoin or fosphenytoin should mmHg and has not been adequately be aware of the risks and benefits de- controlled. scribed in the current prescribing informa- ¥ In all patients starting treatment with tion for this drug. etoricoxib, BP should be monitored within two weeks after initiation, and Because this new data suggests a periodically thereafter. possible association between HLA- B*1502 and phenytoin or fosphenytoin- Reference: Medicines and Healthcare induced SJS/TEN, and because of the Products Regulatory Agency, September known association between phenytoin 2008, at http://www.mhra.gov.uk/mhra. and SJS/TEN, health-care providers should consider avoiding phenytoin and Efalizumab: updated labelling fosphenytoin as alternatives for carbamazepine in patients who test positive United States of America — The Food for HLA-B*1502. and Drug Administration (FDA) has announced labelling changes to highlight Reference: FDA Alert, 24 November 2008 at the risks of life-threatening infections, www.fda.gov/medwatch/ including progressive multifocal leukoencephalopathy (PML), with the use of Etoricoxib: hypertension risks efalizumab (Raptiva ¨). The FDA is also requiring the submission of a Risk Evalu- United Kingdom/European Union — Health-care professionals have previously ation and Mitigation Strategy (REMS), been informed of the risk of hypertension- which will include a Medication Guide for patients and a timetable for assessment related adverse events associated with use of etoricoxib, and of the contraindica- of the REMS. tion for use of etoricoxib in patients with Efalizumab is a once-weekly injection hypertension whose blood pressure (BP) is not adequately controlled. approved for adults with moderate to severe plaque psoriasis who are candi- The European Medicines Agency (EMEA) dates for systemic (whole body) therapy has recently completed a review of the or phototherapy to control their psoriasis.

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The FDA has received reports of serious In 2007 the Uppsala Monitoring Centre infections leading to hospitalization and (UMC) undertook a review of the interna- death. The Boxed Warning will highlight tional adverse reaction reports attributed the risk of bacterial sepsis, viral meningi- to oseltamivir in the WHO Global Indi- tis, invasive fungal disease, progressive vidual Case Safety Report Database, multifocal leukoencephalopathy and other Vigibase, as well as the relevant literature opportunistic infections. and product information. This review did not identify any clearly defined signals of Additionally, labelling will be updated to unsuspected serious adverse reactions include data from juvenile animal studies not already in the product information or in mice (age equivalent to a 1Ð14 year old regulatory authority alerts, the latter human). These data indicate a potential concerning neuropsychiatric reactions. risk for the permanent suppression of the immune system with repeat administra- Reports of serious skin disorders tion of efalizumab in this age group. Reports of Stevens Johnson syndrome Raptiva¨ is not approved for children and toxic epidermal necrolysis have been under 18 years of age. reported in Vigibase. These disorders are listed under adverse reactions in product Efalizumab works by suppressing the information for Tamiflu¨ (oseltamivir) but immune system to reduce psoriasis flare- causality has not been established (2). ups. However by suppressing the body’s The Vigibase reports did not provide natural defence system, it can also additional information on causality. increase the risk of serious infections and malignancies in patients. Oseltamivir and hepatic disorders Despite the lack of a clear signal, reports Patients identified to begin therapy with in Vigibase of serious hepatic disorders Raptiva¨ should have received all their occurring in association with oseltamivir age-appropriate vaccinations before use were of concern. Reports of hepatic starting the drug. Vaccinations should not failure, hepatic necrosis, hepato-renal be administered to patients taking syndrome, jaundice and bilirubinaemia Raptiva¨ because immunity to the were statistically disproportionate to the vaccination virus may not be conferred. background data. Product information for oseltamivir (Tamiflu¨) indicated that Reference: FDA News, 16 October 2008 at hepatitis and abnormal liver function tests http://www.fda. gov/medwatch/ had been identified during post-marketing experience but that it was not possible to Oseltamivir: hepatic establish a causal relationship with and skin disorders oseltamivir exposure.

World Health Organization —The Patient characteristics antiviral agent oseltamivir is a selective At the time of the review, Vigibase held inhibitor of influenza virus A and B neu- 770 reports for oseltamivir. There were 46 raminidase. It is indicated for the treat- non-duplicated reports of hepatic reac- ment and prophylaxis of influenza virus tions including reports of hepatic failure infection types A and B although vaccina- and necrosis. Numbers of males and tion is preferred for prophylaxis. It should females affected were similar and the age be commenced early in the course of range was 18 to 88 years apart from two illness to achieve maximum benefit. infants aged 12 months. WHO has recommended its use for treating avian influenza A (H5N1) (1).

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Duration of oseltamivir use Thus oseltamivir appeared to be the most Data provided in 25 reports showed likely causal medicine in two reports of patterns of use, duration and reaction hepatic failure and one serious hepato- onset. Overall, oseltamivir was used for cellular reaction. It is of note that one one to five days in 17 patients. The patient with hepatic failure had pre- longest periods of use were 8 days and existing renal failure and was taking the 19 days. In 16 patients, onset of hepatic maximum recommended daily dose of manifestations occurred up to one week oseltamivir. after oseltamivir was discontinued. Hepatic reactions to medicines usually Causality become evident between five and ninety While oseltamivir appeared to be the days after first exposure (3). For this most likely causal medicine in three reason eight patients with onset one to reports of the most serious suspected two days after first exposure and one hepatic reactions, no details of investiga- patient for whom onset was 120 days tions for other potential causes, e.g., viral after exposure were excluded from studies, were provided. The other reports further analysis. of serious hepatic disorders could not readily be assigned a causality classifica- Dechallenge and rechallenge tion. There are difficulties in assigning No reports had valid dechallenge or causality to hepatic reports with oseltami- rechallenge data. vir for the following reasons:

Hepatic failure, hepatic necrosis and 1. Prodromal symptoms of hepatic serious hepatocellular reactions disorders may mimic influenza symptoms. Five reports of hepatic failure and/or hepatic necrosis were identified that 2. Dechallenge data is largely unhelpful contained information on time to onset as oseltamivir has usually been discontin- from first exposure that was appropriate ued before the reaction is evident. for drug-induced hepatotoxicity. Oseltami- 3. If patients have influenza symptoms vir was the only medicine considered they are likely to take other medicines suspect in two of these reports. There that can be hepatotoxic e.g., nonsteroidal were no reports of cholestatic hepatitis anti-inflammatory medicines and para- occurring within five and ninety days of cetamol. oseltamivir use. There were five reports of hepatocellular damage but these were 4. A number of patients were also taking poorly documented in terms of exposure antibiotics as well as oseltamivir and duration and other medicines were often many of these are also potentially hepato- co-suspect. toxic. The original copies of eight reports of Items (1) and (2) describe problems that jaundice and/or bilirubinaemia together make it almost impossible to assign a with elevated hepatic enzymes or hepati- “probable” rather than “possible” causality tis were requested from the countries of to hepatic reactions attributed to oseltami- origin in order to identify serious hepato- vir. However, one advantage is that the cellular reactions that are likely to pro- usual short duration of oseltamivir treat- gress to hepatic failure (4). Three such ment means that more serious injury may reports were obtained. Two of these be avoided in many cases, if the associa- patients progressed to the hepatic failure tion is causal. Most of these difficulties group described above. The third patient also apply when assessing causality of had not taken other suspect medicines serious skin disorders following exposure apart from low dose paracetamol. to oseltamivir.

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Summary and recommendations hepatic disorder had not been diagnosed There are reports of hepatic reactions earlier because they were presumed to attributed to oseltamivir in Vigibase that have influenza and those who are devel- are more serious than those described in oping an adverse reaction to oseltamivir. the product information. Where identifi- Oseltamivir will not provide any benefit at able, the reports appeared to be predomi- this stage and discontinuation may avoid nantly of hepatocellular disorders. There more serious outcomes. is no clear evidence of causality because it is difficult to discriminate influenza and 3. Prompt discontinuation of oseltamivir if early symptoms of hepatic disease, a serious skin disorder occurs. Patients because of common concurrent use of should also be advised to consult their other hepatotoxic medicines and because medical attendant prior to taking this of the usual short duration of oseltamivir medicine if they have renal impairment, use. as they may need to take a reduced dose. There is a strong argument for alternative explanations (described above) for these References reports, particularly the likelihood that oseltamivir was used to treat prodromal 1. World Health Organization: Clinical management of human infection with avian symptoms of hepatic disease rather than influenza A (H5N1) virus, at http:// influenza. However, given the potential www.who.int/csr/disease/avian_influenza/ widespread and unsupervised use of guidelines/Clinical Management07.pdf oseltamivir a cautious approach should be considered. This could involve: 2. Tamiflu capsules® (Roche). Physician’s Desk Reference. Revised January 2008. 1. Alerting patients to the possibility of 3. Lee WM. Drug-induced hepatotoxicity. N hepatic and serious skin reactions as well Engl J Med 2003;349(5): 474-485. as other documented adverse effects, at the time of prescription. 4. Reuben A. Landmarks in Hepatology. Hy‘s Law. Hepatology 2004;39(2): 574Ð578. 2. Discontinuation of oseltamivir with 5. Report from Vigibase at the WHO Collabo- hepatic function testing where patients rating Centre for International Drug Monitor- are slow to recover from presumed ing, Uppsala, Sweden. influenza, or relapse. Such testing would identify both those patients whose

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

Rimonabant: suspension of 59/2007-like virus) is a current vaccine marketing authorization virus used in live attenuated vaccines]. United Kingdom/European Union — ¥ an A/Brisbane/10/2007 (H3N2)-like virus The European Medicines Agency (EMEA) [A/Brisbane/10/2007 and A/Uruguay/ has completed a review of rimonabant 716/2007 (an A/Brisbane/10/2007-like (Acomplia¨), a treatment for obesity, after virus) are current vaccine viruses]. concerns about its psychiatric safety. The ¥ a B/Florida/4/2006-like virus [B/Florida/ review has found that the benefits of 4/2006 and B/Brisbane/3/2007 (a B/ rimonabant do not outweigh the risks of Florida/4/2006-like virus) are current psychiatric reactions in clinical use. The vaccine viruses]. marketing authorization for this medicine will be suspended across the European Vaccine viruses (including reassortants) Union. and reagents for use in the laboratory Prescribers should not issue any pre- standardization of inactivated vaccine scriptions for rimonabant and should may be obtained from: Immunobiology review the treatment of those who are Section, Office of Laboratory and Scien- currently taking this medicine. tific Services, Therapeutic Goods Admin- istration, P.O. Box 100, Woden ACT, Patients who are currently enrolled in 2606 Australia (fax: +61 2 6232 8564, clinical trials of rimonabant may wish to web site: http://www.tga.gov.au); Division contact the trial investigator for more of Virology, National Institute for Biologi- information. cal Standards and Control, Blanche Lane, South Mimms, Potters Bar, Hert- References fordshire, EN6 3QG England (fax: +44 1707 641050, e-mail: enquiries@ 1. MHRA Drug Alert, DDL/001/23Oct08 at nibsc.ac.uk, web site: http://www.nibsc. https://www.cas.dh.gov.uk/ and http:// www.mhra.gov.uk/Safetyinformation/ and ac.uk/flu_site/index.html); or Division of [email protected] Product Quality, Center for Biologics Evaluation and Research, Food and Drug 2. EMEA Press Release, Doc. Ref. EMEA/ Administration, 1401 Rockville Pike, CHMP/537777/2008. 23 October 2008. http:// Rockville, MD 20892, United States (fax: www.emea.europa.eu +1 301 480 9748).

Vaccines for use in the 2009 Requests for reference strains for anti- influenza season genic analysis should be addressed to the WHO Collaborating Centre for Refer- World Health Organization — It is ence and Research on Influenza, 45 recommended that vaccines for use in the Poplar Road, Parkville, Victoria 3052, 2009 influenza season (southern hemi- Australia (fax: +61 3 9389 1881, web site: sphere winter) contain the following: http://www.influenzacentre.org); the WHO Collaborating Centre for Reference and ¥ an A/Brisbane/59/2007 (H1N1)-like virus Research on Influenza, National Institute [A/South Dakota/6/2007 (an A/Brisbane/ of Infectious Diseases, Gakuen 4-7-1,

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Musashi-Murayama, Tokyo 208-0011, information about listed drugs and inviting Japan (fax: +81 42 561 0812 or +81 42 consumers to sit on all its committees. As 565 2498, web site: http://www.nih.go.jp/ part of this effort, the TGA says it will be niid/index.html); the WHO Collaborating publishing consumer medicines informa- Center for Surveillance, Epidemiology tion for all drugs and make this available and Control of Influenza, Centers for on the TGA web site. Disease Control and Prevention, 1600 Clifton Road, Mail Stop G16, Atlanta, GA The legislative amendments needed are 30333, United States (fax: +1 404 639 expected to be introduced in the autumn 0080, web site: http://www.cdc. gov/flu/); 2009 sitting of the Australian Parliament. or the WHO Collaborating Centre for Reference and Research on Influenza, References: National Institute for Medical Research, 1. http://www.tga.gov.au/docs/html/tganews/ The Ridgeway, Mill Hill, London NW7 news57/tganews57.htm 1AA, England (fax: +44 208 906 4477, web site: http:/ www.nimr. mrc.ac.uk/wic). 2. http://www.tga.gov.au/regreform/ Updated epidemiological information is common.htm available on the WHO website at http:// 3. http://www.6minutes.com.au/dirplus/images/ www.who.int/influenza. 6minutes/newspluspharma/13_11_2008.pdf

Reference: Weekly Epidemiological Record (WER), 83(41) 365Ð372, 10 October 2008. 50th orphan medicine receives positive opinion Australian Adverse Drug European Union — Efforts in combating Reaction Committee (ADRAC) rare diseases reached a new milestone to be replaced this October, with the 50th positive opinion on an orphan medicine being Australia — The Australian Adverse adopted by the EMEA’s Committee for Drug Reaction Committee (ADRAC) is to Medicinal Products for Human Use be abolished and a new committee set up (CHMP). to take a more pro-active approach to drug safety and post-marketing surveil- To date, a total of 569 medicines have lance of medicines. been awarded orphan-designation ADRAC will be replaced by a Medicines status by the European Commission, based on recommendations of the Safety Committee as part of a ‘whole-of- lifecycle’ approach to pharmacovigilance EMEA’s Committee for Orphan Medicinal for prescription medicines. The new Products (COMP). approach will also bring in drug audits, the appointment of an individual ‘drug Developed specifically for the diagnosis, monitor’ to oversee safety of specific treatment or prevention of rare diseases, these medicines have the potential to drugs and a more flexible protocol that will allow drugs to be suspended rather offer relief to many thousands of Euro- than withdrawn or recalled when safety pean citizens suffering from chronic and often debilitating diseases who would issues arise. otherwise have few treatment options In the reforms planned for next year, the available. Therapeutic Goods Administration (TGA) says it will also improve access to drug A listing of the 50 orphan medicines to data and increase transparency, with the have received a positive CHMP opinion is regulatory body pledging to release more available at http://www.emea.europa.eu/

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pdfs/human/comp/56357508en.pdf and Taxotere¨ and Docetaxel Winthrop¨ Orphan drugs and rare diseases at a were expected to be used for the glance http://www.emea.europa.eu/pdfs/ adjuvant treatment of patients with human/comp/29007207en.pdf operable breast cancer whose tumours overexpress HER2 in the following Reference: EMEA website http://www.emea. combinations: europa.eu/htms/human/orphans/intro.htm ¥ in combination (given simultaneously) Telavancin: withdrawal of with trastuzumab following a chemo- marketing authorization therapy regimen based on doxorubicin application and cyclophosphamide. European Union — The European ¥ in combination with trastuzumab and Medicines Agency (EMEA) has been carboplatin. formally notified of the decision to withdraw the application for a centralized Taxotere¨ and Docetaxel Winthrop¨ are marketing authorization for the medicinal currently indicated for the treatment of product telavancin (Vibativ¨) 15 mg/ml breast cancer, non-small cell lung cancer powder for concentrate for solution for and prostate cancer, gastric adenocarci- infusion. noma and head and neck cancer.

Vibativ¨ was expected to be used for the Withdrawal is based on the CHMP’s treatment of complicated skin and soft opinion that the study design did not tissue infections in adults. In its official adequately define the contribution of letter, the company stated that the with- Taxotere¨ and Docetaxel Winthrop¨. drawal was based on the CHMP’s communication that the data provided were Reference: Press Release, Doc. Ref. EMEA/ not sufficient to allow it to conclude a 610719/2008 17 November 2008. http:// positive benefit-risk balance for Vibativ¨ www.emea.europa.eu for the applied indication at that time. Ciclosporin eye drops: Reference: Press Release, Doc. Ref. EMEA/ withdrawal of marketing 562428/2008 24 October 2008. http:// www.emea.europa.eu authorization application European Union — The European Docetaxel: no extension Medicines Agency (EMEA) has been of indication formally notified by the manufacturer of withdrawal of the application for a European Union —The European centralized marketing authorization for Medicines Agency (EMEA) has been the medicine ciclosporin 0.05% eye drops notified by the manufacturer of its deci- (Vekacia¨). Vekacia¨ was expected to sion to withdraw the application for an be used for the treatment of vernal extension of indication for the centrally keratoconjunctivitis and was designated authorized medicines containing do- as an orphan medicine on 6 April 2006. cetaxel (Taxotere¨ 20 mg/0.5 ml and 80 mg/2 ml, concentrate and solvent for Withdrawal of the application was based solution for infusion and Docetaxel on the CHMP’s view that the data pro- Winthrop¨ 20 mg/0.5 ml and 80 mg/2 ml, vided did not allow the Committee to concentrate and solvent for solution for conclude on a positive benefit-risk bal- infusion). ance for Vekacia¨ at that time.

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Reference: Press Release. Doc. Ref. EMEA/ metabolism). The PDCO subsequently 610677/2008. 17 November 2008. http:// adopted on its own motion a positive www.emea.europa.eu opinion on full waiver for this medicine in all subsets of the paediatric population, Positive opinions on on the grounds that the specific medicinal paediatric investigation plans product does not represent a significant therapeutic benefit over existing treat- European Union — A paediatric investi- ments for paediatric patients. gation plan (PIP) sets out a programme for the development of a medicine in the The PDCO adopted an opinion on the paediatric population. The PIP aims to modification of an agreed PIP for Clopi- generate the necessary quality, safety dogrel in the therapeutic area of and efficacy data through studies to cardiovascular diseases. Modifications to support the authorization of the medicine an agreed PIP can be requested by the for use in children of all ages. These data applicant when the plan is no longer have to be submitted to the EMEA as part appropriate or there are difficulties that of an application for a marketing authori- render the plan unworkable. zation for new medicinal products or products covered by a patent. In some The PDCO adopted positive opinions for cases, a PIP may include a waiver to product-specific waivers recommending study one or more age groups of children, that the obligation to submit data ob- or a deferral when it is appropriate to tained through clinical studies with conduct studies in adults prior to initiating children be waived in all subsets of the studies in the paediatric population, or paediatric population for the following when studies in the paediatric population medicines: would take longer to conduct than studies in adults. ¥ Lenalidomide (oncology); Ibuprofen - diphenhydramine hydrochloride, from The Paediatric Committee (PDCO) (pain); HIN1, H3N2, and B vaccine; adopted positive opinions on PIPs for the Omega-3-acid (ethyl esters of eico- following medicines: sapentaenoic acid (EPA) - docosa- hexaenoic acid (DHA)) - simvastatin ¥ Everolimus (oncology); TGplPTH1-34 (cardiology, endocrinology and metabo- (Osteogenic Gel I-040302) (endo- lism). crinology, gynaecology, fertility and metabolism); AEB0713-(1H-indol-3-yl)- Waivers can be issued if there is evi- 4-(2-(4-methyl-1-piperazinyl)-4- dence showing that the medicinal quinazolinyl)-1H-pyrrole-2,5-dione product concerned is likely to be ineffec- acetate(1:1), (dermatology); Alipogene tive or unsafe in the paediatric population, tiparvovec (cardiovascular diseases); or that the disease or condition targeted Human Normal Immunoglobulin (immu- occurs only in adult populations, or that nology and rheumatology); Telbivudine the medicinal product does not represent (gastroenterology); Maraviroc (infec- a significant therapeutic benefit over tious diseases); Tigecycline (infectious existing treatments for paediatric patients. diseases). Guideline on neonates The PDCO adopted a negative opinion The PDCO reviewed comments made on a PIP for sitagliptin phosphate mono- during the public consultation on the hydrate-metformin hydrochloride (endo- guideline on the investigation of medicinal crinology, gynaecology, fertility and products in preterm and term neonates.

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The guideline aims to provide guidance Biosimilar products such as Valtropin¨ for the development of medicines for use and Omnitrope¨ (both are somatropins) in neonates. It is based on several and Binocrit¨ (which contains epoetin concept papers released by the Paediat- alpha) are registered in the European ric Working Party (PEG) — the Agency’s Union. There are no biosimilar products former expert working party on paediatric registered in Singapore as yet but such medicines, which addressed the impact products will eventually enter the market, of immaturity of different organ systems subject to approval by HSA. when investigating medicines in neonates. How are biosimilar products different from generic chemical products? Neonates represent a particularly vulner- Biosimilar products may commonly be able subgroup of the paediatric popula- mistaken for generic versions of the tion. Whilst they account for a low per- reference biological product. Unlike centage of the total use of medicines in generic chemical drugs, whereby the childhood, up to 90% of medicines are chemical structure is identical to that of used without a marketing authorization or the reference chemical product, a off-label in this population. biosimilar product does not usually have an identical structure to the reference Reference: Press Release, Meeting highlights biological product. Hence, even though from the Paediatric Committee, 15-17 October these biological/biotechnology-derived 2008. Doc. Ref. EMEA/PDCO/552811/2008. proteins may be approved by regulatory 24 October 2008. http://www.emea.europa.eu authorities to be similar in terms of quality, safety and efficacy to a reference biologi- Biosimilar products: cal medicine to which it has been com- a regulatory update pared, there is a chance that these products may cause adverse reactions Singapore — A biosimilar medicine is a which may be different from that of their medicinal product which is similar to a reference products. One such adverse biological medicine that has already been reaction may be differing immunological registered with a drug regulatory authority response of the patient. and is submitted for medicinal product registration by an independent applicant How are biosimilar after the patent period for the original products assessed? product has expired. Biosimilar products are assessed based on comparability data between the As the cost of innovative biological biosimilar product and the reference products is generally high, thereby product in terms of quality of product, limiting use, the expiration of patents on nonclinical studies (e.g. animal pharma- many biological products such as human codynamic studies and toxicity studies) growth hormone and erythropoietin has and clinical studies (e.g. pharmacokinetic prompted the development and licensing and pharmacodynamic studies in human of biosimilar products. A biosimilar prod- subjects). The eventual approval for the uct would have an abbreviated nonclinical biosimilar product may be for the same and clinical development programme indication and patient group as that of the leveraging on the existing information of corresponding reference product regis- the original product and focusing on tered in Singapore, or it may be for more demonstration of similarity with the restricted indications and patient groups. original product, also known as the reference product.

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Important information concerning biosimilar products

Biosimilar products are similar but NOT identical to an existing biological product.

A biosimilar product may have the same or a more restricted indication for use compared to the existing biological product.

When prescribing a biosimilar product, the brand name of the product should be clearly stated on the prescription.

When dispensing/administering a biosimilar product, only the product with the correct brand name should be dispensed/administered. There should NOT be any substitution with another product with the same international nonproprietary name (INN) without seeking clarification from the prescribing doctor.

When reporting an adverse reaction, the brand name and batch number of the product should be clearly stated.

How should a biosimilar product be How are adverse drug reactions prescribed and dispensed? (ADRs) to biosimilars reported? The decision by a doctor whether to In view of the complexity of biological prescribe a biosimlar product or the molecules and for the reasons mentioned innovator biological product is dependent above, it is pertinent to report the brand on factors relevant to the patient and the name of the biosimilar which is suspected institution in which he practises. However to cause an ADR rather than the name when prescribing such products, it is of the substance (e.g. Genotropin¨ important to use the brand name of the instead of somatropin), together with the selected product. A biosimilar product batch number of the product used. may have the same international nonproprietary name (INN) as the reference References biological product but they should not be 1. http://www3.niaid.nih.gov/research/re- presumed to be identical. Using the brand sources/DAIDSClinRsrch/Glossary.htm name will help avoid the issue of auto- matic substitution of the product when 2. Drug Safety Update Vol. 1, Issue 7 February 2008 from MHRA and CHM dispensed in the pharmacy, or during administration of the product. 3. Adverse Drug Reaction News, Vol. 10 No. 3, December 2008. http://www.hsa.gov.sg

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ATC/DDD Classification

ATC/DDD Classification (Temporary)

The following anatomical therapeutic chemical (ATC) classifications and defined daily doses (DDDs) were agreed by the WHO International Working Group for Drug Statis- tics Methodology in 27Ð28 October 2008. Comments or objections to the decisions from the meeting should be forwarded to the WHO Collaborating Centre for Drug Statistics Methodology at [email protected]. If no objections are received, the new ATC codes and DDDs will be considered final and included in the January 2010 issue of the ATC index.The inclusion of a substance in the lists does not imply any recommendation of use in medicine or pharmacy.

ATC level INN/Common name ATC code

New ATC level codes (other than 5th levels): Agents for atopic dermatitis, excluding corticosteroids D11AG Peripheral opioid receptor antagonists A06AH

New ATC 5th level codes: Aciclovir, combinations D06BB53 Alvimopan A06AH02 Asenepine N05AH05 Bacitracin J01XX10 Bazedoxifene G03XC02 Becaplermin A01AD08 Benzethonium chloride D08AJ08 Bromfenac S01BC11 Casopitant A04AD13 Cefcapene J01DD17 Cevimeline N07AX03 Cilostazol C04AX33 Corifollitropin alfa G03GA09 Dalbavancin J01XA04 Dapsone D10AX05 Dexmethylphenidate N06BA11 Doxercalciferol H05BX03 Eltrombopag B02BX05 Eperisone M03BX09 Everolimus L01XE10 Fluocinolone acetonide S02BA08 Golimumab L04AB06 Iclaprim J01EA03 Lansoprazole, amoxicillin and clarithromycin A02BD07

302 WHO Drug Information Vol 22, No. 4, 2008 ATC/DDD Classification

ATC level INN/Common name ATC code Lisinopril and amlodipine C09BB03 Meningococcus, tetravalent purified polysaccharide antigen conjugated J07AH08 Meptazinol N02AX05 Methylnaltrexone bromide A06AH01 Mitiglinide A10BX08 Nabiximols N02BG10 Nalfurafine V03AX01 Oritavancin J01XA05 Pazopanib L01XE11 Pegloticase M04AX02 Phenazone S02DA03 Potassium acetate B05XA17 Pralatrexate L01BA05 Regadenoson C01EB21 Saxagliptin A10BH03 Silodosin G04CA04 Sodium fluoride (18F) V09IX06 Sodium levofolinate V03AF10 Stavudine, lamivudine and nevirapine J05AR07 Tamsulosin and dutasteride G04CA52 Valsartan, amlodipine and hydrochlorothiazide C09DB03 Vinflunine L01CA05

INN/Common name Previous ATC code New ATC code

ATC code changes: Alitretinoin D11AX19 D11AG04 Clotiapine N05AX09 N05AH06 Cromoglicic acid D11AX17 D11AG03 Paricalcitol A11CC07 H05BX02 Pimecrolimus D11AX15 D11AG02 Tacrolimus D11AX14 D11AG01

Previous name New name New ATC code

ATC name changes: Angiotensin II antagonists and calcium Angiotensin II antagonists channel blockers and calcium channel blockers, including combinations with diuretics C09DB Diazepines, oxazepines and Diazepines, oxazepines, thiaze- thiazepines pines and oxepines N05AH

303 ATC/DDD Classification WHO Drug Information Vol 22, No. 4, 2008

New DDDs:

INN/common name DDD Unit Adm.R ATC code

Cefcapene 0.45 g O J01DD17 Cefotiam 1.2 g O J01DC07 Cevimeline 90 mg O N07AX03 Cilostazol 0.2 g O C04AX33 Dabigatran etexilate 0.22 g O B01AE07 Doripenem 1.5 g P J01DH04 Eperisone 0.15 g O M03BX09 Febuxostat 80 mg O M04AA03 Icatibant 30 mg P C01EB19 Meptazinol 1.2 g O,P N02AX05 Methylnaltrexone bromide 6 mg P A06AH01 Micafungin 0.1 g P J02AX05 Mitiglinide 30 mg O A10BX08 Polymyxin B 0.3 MU O A07AA05 Rilonacept 23 mg P L04AC04 Romiplostim 30 mcg P B02BX04 Sodium levofolinate 30 mg (1) P V03AF10 Tafluprost 0.3 ml (2) S01EE05

(1) Expressed as levofolinic acid (2) Single dose package

Change of DDDs

INN/common name Previous DDD New temporary DDD ATC Code

Risperidone* 1.8 mg P depot 2.7 mg P depot N05AX08

*Please note that the changes will not be implemented before January 2010

304 WHO Drug Information Vol 22, No. 4, 2008

ATC/DDD Classification

ATC/DDD Classification (Final)

The following anatomical therapeutic chemical (ATC) classifications and defined daily doses (DDDs) were agreed by the WHO International Working Group for Drug Sta- tistics Methodology in March 2008. They will be included in the January 2009 issue of the ATC index. The inclusion of a substance in the lists does not imply any recommendation of use in medicine or pharmacy. The WHO Collaborating Centre for Drug Statistics Methodology can be contacted at [email protected]

ATC level INN/Common name ATC code

New ATC 5th level codes: Alipogene tiparvovec C10AX10 Arbekacin J01GB12 Capsaicin M02AB01 Catumaxomab L01XC09 Ciclosporin S01XA18 Decitabine L01BC08 Degarelix L02BX02 Doripenem J01DH04 Eslicarbazepine N03AF04 Icatibant C01EB19 Liraglutide A10BX07 Mepolizumab L04AC06 Oxycodone, combinations N02AA55 Panipenem and betamipron J01DH55 Peginterferon alfa-2a, combinations L03AB61 Perindopril and amlodipine C09BB04 Plerixafor L03AX16 Pneumococcus purified polysaccharide antigen and Haemophilus influenzae, conjugated J07AL52 Prucalopride A03AE04 Rilonacept L04AC04 Romiplostim B02BX04 Tocilizumab L04AC07 Tocofersolan A11HA08 Ustekinumab L04AC05 Zucapsaicin M02AB02

305 ATC/DDD Classification WHO Drug Information Vol 22, No. 4, 2008

Previous name New name New ATC code

ATC name changes: Capsicum preparations and similar Capsaicin and similar agents M02AB agents Clostridiopeptidase Collagenase D03BA02* Clostridiopeptidase, combinations Collagenase, combinations D03BA52* House dust House dust mites V01AA03*

* Correction of names to be decided at the Working Group meeting in October 2009

New DDDs:

INN/common name DDD Unit Adm.R ATC code

Anidulafungin 0.1 g P J02AX06 Arbekacin 0.2 g P J01GB12 Cefmetazole 4 g P J01DC09 Cerolizumab pegol 14 mg P L04AB05 Clevudine 30 mg O J05AF12 Eculizumab 64 mg P L04AA25 Fluticasone furoate 0.11 mg N R01AD12 Fosaprepitant 95 mg (1) P A04AD12 Raltegravir 0.8 g O J05AX08 Rivastigmine 9.5 mg TD N06DA03 Tiotropium bromide 5 mcg Inhal solution R03BB04 Vildagliptin 0.1 g O A10BH02

(1) Expressed as fosaprepitant.

306 WHO Drug Information Vol 22, No. 4, 2008 Recent Publications, Information and Events

FIP and the future The WHO Operational package for of hospital pharmacy assessing, monitoring and evaluating country pharmaceutical situations is intended as a useful tool for researchers, The Global Conference on the Future of policy-makers, planners and others who Hospital Pharmacy was convened as part need to use standardized measurement of the 68th Annual Congress of the tools to gather data and other information. International Pharmaceutical Federation The tools presented have already been (FIP). Hospital pharmacists from around used for several years at global and the world met 30Ð31 August 2008 in country levels. In addition, the operational Basel, Switzerland and successfully package can be used by international developed 74 consensus statements agencies and donors, by professional reflecting the profession’s preferred vision groups and nongovernmental organiza- of practice in the hospital setting. tions.

The FIP Global Conference on the Future Reference: WHO Operational package for of Hospital Pharmacy has been in assessing, monitoring and evaluating country planning for nearly three years, during pharmaceutical situations. Guide for coordina- which time a survey of hospital pharmacy tors and data collectors. WHO/TCM/2007.2 at practice was conducted. The survey, http://www.who.int/entity/medicines/publica- describing the nature and scope of tions/WHO_TCM_ 2007.2.pdf pharmacy practice worldwide, included responses from 85 nations representing European Pharmaceutical 86% of the world’s population. Forum success All of the approved consensus state- The final report of the Pharmaceutical ments, along with evidence-based Forum was presented on 18 October literature reviews that support the state- 2008 in Brussels setting out principles ments, will be published in early and recommendations on three key 2009 in a special supplement of the challenges in the pharmaceutical sector. American Journal of Health-System Firstly, how to improve information on Pharmacy. Free access to the full pro- diseases and treatments, secondly, how ceedings will be made possible to compare medicines and identify the through the Journal web site. most effective ones, and thirdly, how to balance access and reward for innovation Reference: http://www.fip.org/globalhosp within limited health-care budgets.

Assessing, monitoring and The Pharmaceutical Forum brought evaluating pharmaceutical together European Union countries and situations stakeholders, including patient organizations, health professionals, industry and Pharmaceutical sector assessment allows insurers. The final report comprises a set the monitoring and evaluation of access of principles and recommendations to to essential medicines, safety, effective- increase cooperation in three key areas. ness and good quality, and proper use.

307 Recent Publications, Information and Events WHO Drug Information Vol 22, No. 4, 2008

The Forum adopted the following recom- Optimal use of resources mendations: A toolbox of knowledge should help to use limited resources optimally and Enhance quality of information address specific mechanisms like risk- Core quality principles for the develop- sharing/conditional pricing and tendering ment of information to patients will im- and adopted Guiding Principles to help prove the quality of information by provid- national authorities find a balance being a clear and defined framework and tween expenditure, access and innova- also identify information of poor quality. tion. The Forum invites all health actors to refer to the agreed principles. The ban on Reward for innovation advertising of prescription medicines The expected value of innovation and should continue. potential reward mechanisms for innovative medicines have been analysed in Increase accessibility order to better match public health needs More information to citizens in effective and long-term investments in research communication formats should be pro- and development. vided (by electronic and non-electronic means), taking account of local traditions, Follow-up health-care systems and languages. Member States and stakeholders are invited to implement the recommenda- Generation of information by making tions of the Forum. The Commission will the best use of all actors provide support to the strengthening of The Forum recommends that Member the cooperation tools. States, the Commission and health actors consider strengthened collaboration in Reference: Report of the European Pharma- the field of information to patients. Such ceutical Forum, Brussels, 2 October 2008 at collaboration should respect the minimum http://ec.europa.eu/pharmaforum ethical requirements of transparency, disclosure of financial and other support Procurement and supply and a definition of responsibilities. management toolbox Relative effectiveness Member States, payers and patients face Since the Procurement & Supply Man- the common challenge of containing agement Toolbox web site went live in health care budgets, including pharma- December 2007, 27 new tools have been ceutical costs, while promoting and added making a total of 116 English tools. sustaining innovation. They therefore need to recognize the value of identifying A separate toolbox has now been devel- the most effective medicines. oped in French and contains 27 tools. The tool categories are: Pricing and reimbursement Final pricing and reimbursement deci- 1. Policy sions are usually required before patients 2. Selection can access new health solutions and 3. Quantification innovative companies can obtain reward 4. Procurement for their research. Although pricing and 5. Inventory Management reimbursement decisions are made by 6. Use individual Member States, they share the 7. Monitoring & Evaluation concern on balancing access and reward 8. Pricing with limited resources. 9. Capacity Building

308 WHO Drug Information Vol 22, No. 4, 2008 Recent Publications, Information and Events

The web site now also contains demo people can access them, and how much videos, which illustrate how to use the they pay, this study provides an evidence different features of the web site (http:// base for policy makers in Uganda and www.psmtoolbox.org/demos.php). internationally to guide initiatives to replace older, ineffective medicines with Reference: Vincent Habiyambere at WHO/ affordable high quality ACTs. AMDS [email protected] and IDA Solutions [email protected]. Website Reference: Understanding the Antimalarials at http://www.psmtoolbox.org Market: Uganda 2007 — An Overview of the Supply Side http://www.mmv.org and Report on essential [email protected] medicines for children Right to access to medicines A draft report of the meeting of the Second Subcommittee on Selection and A resolution calling on the African Com- Use of Essential Medicines for Children, mission on Human and Peoples’ including the draft second Model List of Rights to recognize the human right to Essential Medicines for Children has now access for needed medicines was passed been published as an agenda paper for at a meeting of African Human Rights the March 2009 Expert Committee organizations in Abuja, Nigeria, Meeting. on 10 November 2008.

Reference: Information from World Health The NGO forum is composed of approxi- Organization at http://www.who.int/ mately 100 human rights organizations in selection_medicines/committees/expert/17/en/ Africa with observer status before the index.html African Human Rights Commission. The resolution will now be transmitted to the Uganda’s antimalarials market African Commission for consideration in its biannual meeting. The Medicines for Malaria Venture (MMV) has just released a new report mapping The resolution adopted by the Forum the antimalarials market in Uganda. The calls on the African Commission to report highlights a new focus in gathering recognize “access to needed medicines an evidence base about the structure and as a fundamental component of the size of the antimalarials market in order to right to health ...”. It specifically calls on guide new initiatives to increase access the Commission to recognize duties to to high quality malaria medicines. respect, protect and fulfil rights to access to medicines, including by taking “full Understanding the Antimalarials Market: advantage of all flexibilities in the WTO Uganda 2007 — An Overview of the Agreement on Trade Related Aspects of Supply Side provides a wealth of interest- Intellectual Property that promote access ing facts about the structure of the to affordable medicines.” A full copy of the antimalarials market in rural Uganda. The resolution is available at http://wcl. study identifies the types of antimalarials american.edu/pijip/go/humanrights and available on the market, availability of http://www.wcl. american.edu/pijip/go/ product by outlet type, range of prices, resolution-abuja affordability, supply chain structure, and price mark-ups. Reference: African NGO Forum Resolution on Right to Access to Needed Medicines at http:// By mapping a detailed record of the www.wcl.american.edu/pijip/go/resolution- range of antimalarials available, where abuja.

309 Recent Publications, Information and Events WHO Drug Information Vol 22, No. 4, 2008

New issue of WHO/HAI ¥ Actions taken by the Lebanese Govern- pricing bulletin ment to lower prices and improve transparency. In September, the United Nations Millen- nium Development Goals (MDG) Gap ¥ The improved availability of artemether/ Task Force reported that medicines are lumefantrine in Kenya. too costly and availability is often poor. The lead article in the WHO/HAI Pricing • What’s new in the 2nd edition of the Bulletin outlines key findings in the UN survey manual. report, and lists national and global targets to reduce prices and improve ¥ Key findings from a medicine price and availability. availability survey in Thailand.

Other articles in the bulletin: Reference: Health Action International website http://www.haiweb.org and http:// ¥ New legislation aimed at making medi- www.haiweb.org/GlobalDatabase/Main.htm cines more affordable in the Philippines.

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