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WHO Drug Information Contents Regulatory Focus Regulation of medicines in China 3 Boceprevir: HIV protease inhibitor interactions 33 Bortezomib: fatal if given intrathecally 33 Bevacizumab: suspension for metastatic breast cancer 34 Drotrecogin alfa: withdrawal 34 Dextropropoxyphene-containing analgesics cancelled 34 Vemurafenib approved for meta static or unresectable melanoma 35 Ecallantide: marketing authorization application withdrawal 35 Sitagliptin and pioglitazone: market ing authorization application withdrawal 35 Voclosporin: marketing authorization application withdrawal 36 Desloratadine: marketing authorization application withdrawal 36 Electronic CTD implementation 36
Better medicines for children: pharmaceutical formulations 15 Benznidazole: child-adapted dosage form approved 21 Use of drugs in paediatric health conditions increasing 23 Bevacizumab: severe infectious endophthalmitis and blindness Ursodeoxycholic acid: serious hepatic events Simvastatin with amiodarone: dosage review Fenofibric acid: the ACCORD lipid trial BCG vaccine: lymphadenitis Dabigatran etexilate mesylate: bleeding events Dabigatran etexilate: caution in the elderly and renally impaired Dabigatran: risk of bleeding Pneumovax 23®: revaccination recommendations Somatropin-containing medicines: positive benefit-risk balance Pholcodine-containing cough medicines Antipsychotics in children and ado lescents: cardiometabolic reactions Citalopram hydrobromide: dose dependent QT prolongation Brentuximab vedotin: new warning and contraindication Quetiapine: information updated Aliskiren: cardiovascular and renal events Natalizumab: progressive multifocal leukoencephalopathy
Paediatric Medicines
Regulatory Action and News
Safety and Efficacy Issues
24 24 24 25 25 26 26 26 27 28 28 29 30 31 31 32 32
ATC/DDD Classification
ATC/DDD Classification (temporary) 37 ATC/DDD Classification (final) 40
Pharmacovigilance Toolkit 42 Uppsala Monitoring Centre signals document: increased availability 42 Learning module: selective serotonin reuptake inhibitors 42 Medicines access survey 43 ATC/DDD methodology course 43 Access and Control Newsletter 43 Managing access to medicines and health technologies 44
Recent Publications, Information and Events
International Nonproprietary Names Recommended List No. 67 45
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Announcement The 15th International Conference of Drug Regulatory Authorities (ICDRA) will be hosted by the State Agency for Medicines, Estonia, in collaboration with the World Health Organization The ICDRA will take place in Tallinn, Estonia, 23 – 26 October 2012 Information and registration at: http://www.icdra.ee http://www.who.int/medicines/icdra
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Regulatory Focus Regulation of medicines in China Over the past decade, China has introduced significant changes to the regulation of medicines through modernizing its legislative framework in line with international practice and by re-organizing the nation’s medicines administrative agency, the State Food and Drug Administration (SFDA). Medicines regulatory agencies (MRAs) have been established at national, provincial, city and county levels and, by the end of 2010, there were 2898 administrative organs and 1076 public institutions employing human resources of 45,393 and 24,939 respectively (1). The State Food and Drug Administration (SFDA) is the responsible agency for medicines administration nationwide. The medicines regulatory agencies at provincial level are responsible for drug regulation in their administrative areas while the responsibilities of local level MRAs are legally defined or commissioned by upper level MRAs. Administratively, mainland China consists of 31 contiguous regions at provincial level, 333 at city level and 2856 at county level (2). As of November 2010, China registered an overall population of 1339,724,852 (3) and, in 2010, the country’s gross domestic product amounted to RMB 40120.2 billion (4). This article provides insight into changes taking place in the organizational structure, legislative framework and current situation of medicines regulation in China with a focus on medicines registration, manufacturing, distribution and use, advertising, and post-market safety monitoring as well as control of narcotics and psychotropic substances*. It also draws a picture of China’s pharmaceutical industry and offers a glimpse of the transformations taking place in the medicines regulatory scene set against a backdrop of international harmonization. * This article does not focus on traditional Chinese medicine, which would merit a separate article.
Medicines regulatory situation The State Council of the People’s Republic of China is the executive arm of the Central People’s Government. It is the highest body of both state power and state administration (5). Departments under the State Council are responsible for related medicines regulatory administrative work as defined within the limits of their duties and include the National Development and Reform Commission responsible for drug pricing, the Ministry
of Human Resources and Social Security responsible for formulating the China National Formulary for Essential Medicare and Industrial Injury Insurance, the Ministry of Agriculture responsible for supervision of raw material for narcotic drugs and the Ministry of Public Security which is responsible for monitoring the distribution of narcotic drugs and psychotropic substances. The State Food and Drug Administration (SFDA) was established in 1998
Article by Xiaoqiong Zheng, Information Centre, State Food and Drug Administration, Beijing, China. 3
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Table 1. State Food and Drug Administration functions • Formulate policies and programmes on the administration of drugs, medical devices, health foods and cosmetics, as well as food safety at the consumption level (restaurant, cafeteria, etc.) and supervise implementation. Take part in drafting relevant laws, regulations and normative documents. • Take charge of food hygiene licensing and food safety supervision at consumption level. • Formulate good practice for food safety at the consumption stage and supervise implementation; carry out investigation and monitoring work of food safety at consumption level, and release information related to supervision on food safety at consumption level. • Take charge of health foods, cosmetic hygiene licensing, hygiene supervision and relevant review and approval work. • Take charge of administrative and technical supervision of medicines and medical devices, take charge of formulating good practices for medicines, medical devices in aspects of research, production, distribution and use, and supervise implementation. • Take charge of registration and supervision of medicines and medical devices; draw up relevant national standards for medicines and medical devices, and supervise implementation; carry out adverse drug reaction (ADR) monitoring and adverse event monitoring of medical devices; be responsible for drug and medical device re-evaluation and removal. Take part in formulating the national essential medicines list and adopting the national essential medicines system. Organize implementation of a classification system for prescription and non-prescription medicines. • Take charge in formulating regulations for traditional Chinese medicines (TCMs) and ethno-medicines, and supervise implementation, draw up quality standards for TCMs and ethno-medicines, formulating good agricultural practices for Chinese crude drugs and processing standards for prepared slices of Chinese crude drugs and supervising their implementation. Implement protection for certain TCMs. • Supervise the quality and safety of medicines and medical devices; regulate radiopharmaceuticals, narcotics, toxics and psychotropics, and release quality and safety information on medicines and medical devices. • Organize the investigation and take legal action against violation of laws and regulations concerning food safety at consumption level, and in research, production, distribution and use of medicines, medical devices, health food and cosmetics. • Direct relevant local work regarding food and drug administration, emergency response, inspection and information sharing. • Draw up and improve qualification systems for licensing pharmacists, direct and supervise the registration of licensed pharmacists. • Carry out international information exchange and cooperation related to food and medicines regulation. • Undertake other work assigned by the State Council and the Ministry of Health.
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through the merger of medicines regulatory functions of the State Pharmaceutical Administration of China, the State Administration of Traditional Chinese Medicine of the People’s Republic of China (SATCM) — also under the Ministry of Health — and the Drug Administration Department of the Ministry of Health, namely the State Drug Administration (SDA) directly under the State Council. In 2003, with additional responsibilities for food regulation, the SDA became the current SFDA. In 2008, the SFDA reverted to Ministry of Health responsibility. The establishment of the SFDA to regulate medicines was a milestone in the history of medicines regulation in China and an important achievement in healthcare reform. From 1998 to 2011, the SFDA has been committed to public health through: • Strengthening the science based approach to medicines evaluation. • Promoting quality assurance systems in enterprises involved in research, production and distribution. • Facilitating the establishment of a national essential medicines system and the classification of prescription and non-prescription medicines. • Improving pharmacovigilance to safeguard public health. • Ensuring the quality, safety, efficacy and accessibility of medicines. In addition to medicines regulation, several other categories of health related products are also regulated by the SFDA (6). (Table 1.) Regulatory responsibility and capacity The scope of medicines regulation in China covers the whole life-cycle of medicines, including: • Production, manufacturer licensing, provision of Internet-based pharmaceutical information, Internet pharmaceutical trading, and medical institutions
producing pharmaceutical preparations, etc. • Product approval at clinical trial, production, and import levels. • Authorization of medicines advertising and promotion of over-the-counter (OTC) and prescription-only medicines. • Implementation of quality assurance systems and compliance with good laboratory practice (GLP), good clinical practice (GCP), good manufacturing practice (GMP) and good distribution practice (GDP). • Post-marketing safety surveillance through a nationwide network encompassing organization and electronic management systems for adverse drug reaction (ADR) reporting and monitoring. The SFDA makes decisions on marketing authorizations and authorization of products for clinical trial and import. Decisions are based on reviews provided by the Centre for Drug Evaluation (CDE), an affiliated public organization providing technical support under SFDA administrative supervision. Provincial MRAs assist the drug registration process through preliminary work by verifying the original dossier application, format review and on-site inspection. Drug testing institutes established or designated by drug regulatory departments are responsible for the drug testing which is required as part of drug review and approval and for drug quality control in accordance with the law (7). Pharmaceutical industry profile The Chinese pharmaceutical industry has made significant progress over the past decade. According to a White Paper The Status Quo of Drug Supervision in China released by the Information Office of the State Council in 2008, China had the capacity to produce 1500 types of drug substance and over one billion doses a year of 41 types of vaccine against infection caused by 26 kinds of virus and
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Table 2. Pharmaceutical industry profile Indicator January–November 2010 January–June 2011 1123.9 714.6 Among these: Among these: • APIs: 215.7 • APIs: 117.8 • FPPs: 318.56 • FPPs: 158.3 • Medical devices: 104.83 • Biological products: 59.1 • TCM preparations: 317.2 • TCM preparations: 119.2 International business 54.12 34.55 (billion US dollars) Among these: Among these: • Export: 35.80 • Export: 21.38 • Import: 18.32 • Import: 13.17 R&D percentage of gross 1.82% (figure for entire year) industrial output Fixed assets investment (billion yuan) Profit (billion yuan) 175.33 110.8 Gross industrial output (billion yuan)
111.4 62.9
Source: Department of Industry Coordination, National Development and Reform Commission at http://www.sdpc.gov.cn/ jjxsfx/t20110128_393383.htm National Development and Reform Commission at http://www.sdpc.gov.cn/zjgx/t20110323_400832.htm National Development and Reform Commission at http://www.ndrc.gov.cn/jjxsfx/t20110829_430931.htm National Bureau of Statistics of China. Ministry of Science and Technology of the People’s Republic of China. Ministry of Finance People’s Republic of China. Report on Investment in Scientific R&D, 2010, at http://www.sts.org.cn/tjbg/tjgb/ document/2011/20110928.htm
pathogenic bacteria (8). By the end of 2010, China counted more than 8000 pharmaceutical enterprises — including producers of prepared Chinese crude drugs, oxygen for medical use, diagnostic agents, blood derived products and vaccines (9) — of which 4678 were producers of active pharmaceutical ingredients (APIs) and finished pharmaceutical preparations (FPPs) (1). In 2010, the gross industrial output reached 1236.827 billion yuan with annual total sales of medicinal products at 682 billion yuan (10). An overview of the Chinese pharmaceutical industry profile is set out in Table 2. The challenges of regulating the Chinese pharmaceutical industry were highlighted in a speech given by the SFDA DeputyCommissioner Wu Zhen at the 2011 Annual Conference on National Medicines Regulation (11). Following international economic integration, China is now the third largest pharmaceutical market in the 6
world. This demands that the country’s regulatory activities are in line with international standards. Current efforts to reform health care inside China also present challenges for capacity building and regulation, while the quality and safety of services and products provided within the essential medicines programme need to be safeguarded.
Legislative framework and regulatory status China practises a unified, multilevel legislative system (12). The National People’s Congress and its Standing Committee exercise the state’s power to make laws. The State Council formulates administrative regulations and, at provincial level, the People’s Congresses as well as their standing committees establish local statutes. In the area of medicines regulation, the main legislative instrument is the Drug Administration Law of the People’s
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Republic of China. Based on this, the legal framework of medicines regulation is established and regularly improved.
cines regulation, it reflects the internal and external driving forces modelling medicines regulation in China, for example: • First released in1985 following enactment of the Drug Administration Law.
Drug Administration Law
The Drug Administration Law was issued by the National People’s Congress. It was • Revised to reflect establishment of the enacted in 1985, and amended in 2001. SDA in 1998. The 2001 revision has achieved better harmonization with regard to international • Revised in response to China’s membership to the World Trade Organizapractice and provides a modern base tion in 2001. for control over the quality, safety and • Revised to reflect the Drugs/medicines refer to articles efficacy of medicines 2001 revision of the which are used in the prevention, in China. The Law Drug Administration treatment and diagnosis of human applies to all parties Law. diseases and intended for the reengaged in research and development, pro- gulation of the physiological func- • Updated following tions of human beings, for which adoption of the Admiduction, distribution, indications, usage and dosage nistrative Licensing use, and administration. In 2002, the State are established. These include Law of the People’s Chinese crude drugs, prepared Republic of China in Council also adopted slices of Chinese crude drugs, tra- 2004. Regulations for Impleditional Chinese medicine prepamentation of the Drug rations, chemical drug substances Under the Provisions, Administration Law of and their preparations, antibiotics, a series of measures the People’s Republic biochemical drugs, radiopharma- relating to procedures of China. ceuticals, sera, vaccines, blood and products have products and diagnostic agents. been issued, including The Drug Administra(Article102 of the Drug Administra- Supplementary provition Law 2001 comtion Law) prises 106 articles in sions for TCM registraten chapters, inclution (2008), Provisions New drugs refer to medicines for on-site inspection ding: General Proviwhich have not been marketed in drug registration sions, Control of Drug Manufacturers, Control within the territory of the People’s (2008), Provisions for Republic of China. (Article 83 of special review and of Drug Distributors, Control of Pharmaceu- the Regulation). approval for new drug ticals in Medical Instiregistration (2009) tutions, Control of Drugs, Control of Drug and Provisions for technology transfer of Packaging, Control of Drug Pricing and drugs (2009). Provisions for drug stanAdvertising, Inspection of Drugs, Legal dards is currently under development Liabilities, and Supplementary Provisions. (14). Based on the framework of the Drug Administration Law, a comprehensive legal system including regulations, provisions, and guidelines has been established. Applications are classified into new medicines, generic medicines, import medicines and their supplementary applications, as well as re-registration. (Article 11.12.) The first two classifications – new medicines and generic medicines – apply to domestic applicants, whereas requests 7
Medicines registration
Provisions for drug registration 2007 (13) is in its fifth edition and fourth update. As the most frequently revised rule in medi-
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from overseas applicants are handled according to those for imported medicines. Any application for changing a dosage form or route of administration, or claiming a new indication for marketed medicines, is submitted through the new drug application (NDA) process which covers applications for registration of medicines not previously marketed in China. (Article 12.12.) The SFDA has additionally formulated Requirements for application dossiers in CTD format for pharmaceutical products based on the common technical document (CTD) of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceutical for Human Use (ICH) taking into consideration the actual situation of drug research and development in China. The Requirements were issued in September 2010 (15). An application for generic medicines will apply to production of medicines having an existing national medicines standard for marketing approval by the SFDA. The application process for a biological product is the same as that for an NDA. (Article 12.12.) An application for an imported drug refers to the registration application for medicines manufactured abroad to be marketed in China. (Article 12.12.) Special review procedures to encourage innovation also exist. Speciality products are given priority in review and approval. A specific fast track procedure applies to the following products (Article 4.12): • Active ingredients extracted from plants, animals and minerals, etc. and their preparations not yet marketed in China. Newly discovered Chinese crude drugs and their preparations. • Chemical drug substances and their preparations and biological products not yet approved for marketing in China or abroad.
• New drugs offering significant clinical advantage for the treatment of diseases such as AIDS, malignant tumours and rare disorders, etc. • New drugs for the treatment of diseases for which effective therapeutic methods are not available.
Quality assurance
In China, good manufacturing practices (GMP) is a set of principles and procedures which should be followed in order to provide assurance that each medicinal product is safe and of the required quality. This comprises requirements relating to premises, equipment, personnel, documentation and quality control. These requirements are enforced through systems of factory inspection and mandatory licensing of factories which manufacture medicines. Since its first promulgation in 1988 (16), China’s Good Manufacturing Practice for Drugs was revised in 1992 and 1998. The latest version of GMP (2010 Revision) released by the Ministry of Health has been effective since 1 March 2011 (17). It consists of 14 chapters and 313 articles based on the concepts of quality risk management and whole process control of drug manufacturing. It attaches greater importance on the scientific nature, instructions, functions and manoeuverability consistent with WHO GMP. Overseas manufacturers of medicines supplied to China must provide evidence that goods are manufactured to a standard of GMP equivalent to that expected of Chinese manufacturers of the same goods. National drug standards in China include the Pharmacopoeia of the People’s Republic of China, drug registration specifications, etc., published by the Ministry of Health/SFDA, including technical requirements such as testing methods
National drug standards
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and manufacturing processes. (Article 136.12.) The 2010 edition of The Pharmacopoeia of the People’s Republic of China is available in three volumes and contains 4567 monographs (18).
overview of SFDA’s work in the area of medicines registration including production, clinical trials, and other key areas.
Pre-approval requirements for clinical trial applicants • Safety evaluation in pre-clinical studies should comply with GLP (19). • Clinical trials (including bioequivalence studies) should be conducted in compliance with GCP. (Article 30.12.) • Drugs used for clinical trials should be manufactured in facilities in compliance with GMP. (Article 35.12.) • A drug can be used for a clinical trial only after being tested and qualified. Vaccines, blood products and other biological products specified by the SFDA should be tested by drug testing institutes designated by the SFDA. (Article 36.12.) All clinical trials (including bioequivalence studies) need prior SFDA approval. • The approved clinical trial should be conducted in a certified research institution that operates in compliance with Chinese GCP. • For overseas applicants intending to conduct an international multicentre clinical trial in China, drugs used for the clinical trial should already be approved or in phase II or III clinical trial overseas. While approving the conduct of an international multicentre clinical trial, the SFDA may require the applicant to first conduct a phase I clinical trial in China. (Article 44.12.) • Any preventive vaccine trial not having first been registered overseas is prohibited in China. (Article 44.12.) SFDA publishes an Annual report on the evaluation and approval of drug registrations (20). The report provides an
Provisions for medicines use Medicines use is covered by the national essential medicines system and list. This includes classification of medicines into prescription and non-prescription categories.
Essential Medicines
Over the past three decades, the concept of essential medicines has evolved in China from a list to an integrated strategy based on a national medicines policy and is a key objective of healthcare reform (21). China released its first National Essential Medicines List in 1982 following the launch of the WHO Model List of Essential Drugs in 1975. In 2009, the National Essential Medicines Committee was established (22). The Provision for a National Essential Medicines List (interim) (23) and a Position paper on implementation of the National Essential Medicines System (24) were published in 2009. The Position Paper defines essential medicines as those which satisfy the health care needs and are available to the public at all times in adequate amounts and in appropriate dosage forms, affordable price and equitable access to the public. The National Essential Medicines List has been regularly updated and the current 2009 edition is the Seventh edition. Coverage of products has expanded from a focus on chemical pharmaceuticals in the first edition to TCM in the second edition, and was again extended to include prepared slices of Chinese crude drugs in the current 2009 edition.
Classification of prescription and non-prescription medicines At the National Health Conference in 1996, classification of prescription and
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non-prescription medicines was identified as a key feature of the reform and development of China’s healthcare system (25). In June 1999, the Provision for classification of prescription drugs and non-prescription drugs (interim) and the first list of non-prescription medicines (OTC) was released. In 2001, control over prescription and OTC classification management became a legal requirement under the Drug Administration Law. (Article 37.7.) In 2004, the SFDA took a dynamic management approach to the control of OTC medicines (26). Henceforth, OTC medicines could be switched to prescription-only status as a result of any safety related issues. To further standardize information and labelling of non-prescription medicines, the SFDA revised the model insert for non-prescription drugs in 2007 (27). By the end of 2011, the SFDA had issued 5697 package inserts for nonprescription drugs, including 1170 chemical drugs and 4527 TCMs (28). Control of narcotics and psychotropic substances The Regulation for control of narcotics and psychotropics was adopted by the State Council on 26 July 2005. It consolidates and amends the former two separate regulations for narcotic drugs and psychotropic substances released in 1987 and 1988. The more stringent provisions are in line with the respective International Conventions under the principle of balancing control measures and access (29). The main points include, among others: Coordinated supervision Departments under the State Council involved in narcotic and psychotropic control include the SFDA, Ministry of Agriculture (MoA) and Ministry of Public Security (MPS). The MoA and SFDA hold joint responsibility for narcotics and the MPS is responsible for oversight of distribution and the medicinal plans used
for narcotic medicines production (Article 5.25). MRAs above provincial level have established information monitoring networks and share information related to products (research, production, distribution, use, storage and transportation) with the public security agency at the same level. (Article 58.25.) Clinical trials Clinical trials of narcotics listed as a category 1 psychotropic should not be conducted in healthy subjects. (Article 13.25.) Production The SFDA and MoA draw up an annual cultivation plan based on production, clinical needs and national storage capacity. Cultivation enterprises are designated by the SFDA and MoA. (Article 14.25.) Distributors and distribution National wholesalers who distribute narcotic drugs and category 1 psychotropic substances among the provinces are licensed by the SFDA. (Article 24.25.) Narcotic drugs and category I psychotropic drugs are not permitted in retailing. (Article 30.25.) Information sharing Reports on product-related information are provided quarterly by city-level MRAs to upper level MRAs. (Article 59.25.) Electronic distribution oversight Real-time dynamic monitoring of production, purchase, sales, inventory and flow of narcotic drugs and category 1 psychotropic substances is realized through the Electronic Medicines Supervision and Regulation Network (30). Control of drug promotion and advertising Control of OTC and prescription-only medicine advertising ensures accurate content, compliance with the law and avoidance of misleading information. The legal basis for drug advertising is vested in the SFDA approved package insert/ labelling information. (Article 6.27.)
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Supervision of drug advertising is the responsibility of the SFDA and the State Administration for Industry and Commerce (SAIC). The current legislative framework for medicines advertising Provisions for drug advertisement examination (SFDA Order 27) and Drug advertisement examination and release standards (SAIC Order 27) (31) was issued jointly by the two departments and became effective in May 2007. Advertising is prohibited (Article 3.27) for: • Narcotics, psychotropic substances, toxic medicines and radiopharmaceuticals. • Pharmaceutical preparations produced by medical institutions. • Products specifically for military use. • Preparations under trial production. • Products that have been prohibited by the SFDA for production, sale or use. The SFDA implements a risk based regulatory approach in terms of content of advertisements and category of product (e.g., OTC or prescription-only medicines). The key points are: • Only OTC products can be advertised directly to the consumer and all advertising materials should state that purchase and use should be made in accordance with a pharmacist’s instructions or guidance. (Article 8.27.) • Prescription medicines can only be advertised in medical or pharmaceutical journals assigned by the Ministry of Health and SFDA. The advertisement should state that it is specifically directed to medical professionals. (Article 8.27.) • The prescription/trade name cannot be used within the advertising slogan. (Article 5.27.) • By the end of June 2011, 544 publications had been designated by the Ministry of Health/SFDA (32).
Drug safety monitoring
Establishing a reporting system on adverse drug reactions (ADRs) is required under Article 71 of the Drug Administration Law 2001. It is a legal obligation for manufacturers, distributors and medical institutes to report serious ADRs. Improving the ADR evaluation system is also highlighted in the 2010 State Council schedule. Among the five Priorities in the reform of the medicine and healthcare system, an ADR evaluation system is a necessary part of the essential medicines policy (33). The Provisions for ADR reporting and monitoring released in 2011 by the Ministry of Health clearly define the appropriate procedure, timeframe, and responsibilities of stakeholders (34). China’s ADR monitoring work was initiated in 1989 through establishment of the ADR Monitoring Centre within the Ministry of Health. Over the past two decades, in addition to development of the appropriate legislative framework, key progress made includes formal membership of China’s ADR Centre to the WHO International Drug Monitoring Programme in 1998. The first National annual report on ADR monitoring was released in 2009. The ADR network is expected to be expanded to 400 sub-centres nationwide with an on-line information reporting system functioning as of 2010 (35). In 2011, China signed an agreement with the WHO Collaborating Centre for International Drug Monitoring (Uppsala Monitoring Centre) with the aim of enhancing data exchange from China’s Adverse Drug Reaction Monitoring database and VigiBase — the WHO global database containing over 6 million ADR reports. The project agreement will also improve the Drug Dictionary of China, and signal detection and patient safety data mining techniques (36). According to the Guideline on strengthening the establishment of an ADR monitoring system released by the SFDA in 2011, the future China ADR monito-
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Roadmap for Drug Safety National drug safety plan 2011—2015 The Roadmap for Drug Safety adopted on 7 December 2011 sets out the overall objectives and priorities for pharmaceutical products, which should be produced under conditions satisfying good manufacturing practices (GMP). Priorities include: Standards improvement. Standards for chemical medicines and biological products will comply with international requirements. China should take the lead in developing international standards for traditional Chinese medicine (TCM) Quality control capacity building. A focus will be made on strengthening improvement of quality control institutions at national level, upgrading conditions at provincial level and strengthening mobile testing capacity of institutions at county level. Whole process oversight. Systems will be launched for quality assurance of medicines and medical devices. All marketed products will be subject to bar coding and all medicines controlled under electronic track and trace systems. Postmarketing system. A special focus will be made on the monitoring and assessment of new drugs, TCM injectables and high risk products. Essential medicines. The essential medicines system will be improved through ensuring safety and accessibility. The withdrawal and recall of medicines. This will be improved and a credit rating system established for enterprises. Efforts to combat substandard and counterfeit products willl continue. Medicines approval. An in-depth reform of the medicines administrative approval system will be carried out following strict criteria and standardized procedures. The revision and establishment of drug-related laws and regulations will be accelerated.
ring and reporting system will be based on international standards supported by information technology with an early warning capability, combined with four-level SFDA and stakeholder participation (37).
• Regulation and authorization of information provision, whether commercial or non-commercial. • Regulation and licensing of Internetbased medicines transactions, including third party e-commerce platform providers, business-to-business (B2B) and business-to-consumers (B2C). References 1. State Food and Drug Administration (2011). SFDA annual statistics report 2010. At http:// www.sfda.gov.cn/WS01/CL0108/66530.html 2. Ministry of Civil Affairs of the People’s Republic of China (2011). Statistical report on social service development in China 2010. At http://www.mca.gov.cn/article/zwgk/ mzyw/201106/20110600161364.shtml
Internet-related pharmaceutical distribution and information
Internet based activities related to medicines need to be licensed by the MRAs. Under the two legal documents released by the SFDA, Requirement for Internetbased service provision of pharmaceutical information 2004 and Requirements for review and licensing of Internet-based pharmaceutical transactions 2005, regulation involves two spheres:
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WHO Drug Information Vol. 26, No. 1, 2012 3. National Bureau of Statistics of China (2011). Bulletin of key figures for the 6th National Population Survey 2010. At http://www. stats.gov.cn/tjfx/jdfx/t20110428_402722253. 4. National Bureau of Statistics of China (2011). Preliminary verification bulletin on 2010 annual gross domestic product (GDP). At http://www.stats.gov.cn/tjdt/zygg/sjxdtzgg/ t20110907_402752625.htm 5. Constitution of the People’s Republic of China (Full text after amendment on 14 March 2004). At: http://www.npc.gov.cn/englishnpc/ Constitution/node_2825.htm 6. State Food and Drug Administration. Main responsibilities of SFDA. At http://eng.sfda. gov.cn/WS03/CL0756/ 7. Order of the President of the Peoples Republic of China (No. 45). Article 6 of the Drug Administration Law of the People’s Republic of China. At http://eng.sfda.gov.cn/WS03/ CL0766/61638.html 8. Information Office of the State Council of the People’s Republic of China (2008). Status quo of drug supervision in China. At http://www.gov.cn/english/2008-07/18/ content_1049011.htm 9. State Food and Drug Administration (2011). Database of Pharmaceutical manufacturers. Official website of SFDA at http://app1.sfda. gov.cn/datasearch 10. Southern Medicine Economic Research Institute of SFDA (2011). Medicinal Economic Newspaper. Capital-driven time is coming. At http://www.yyjjb.com/html/2011-07/13/ content_146414.htm 11. State Food and Drug Administration. Wu Zhen (2011). National Conference on Medicines Regulation. News Release. At http:// app1.sfda.gov.cn/WS01/CL0287/68457.html 12. National People’s Congress. At http:// www.npc.gov.cn/pc/11_4/2007–11/20/ content_1617713.htm 13. State Food and Drug Administration (2007). Provisions for drug registration. At http://www.sda.gov.cn/WS01/CL0053/24529. html
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14. State Food and Drug Administration. Zhang Wei (2010). Latest progress in development of the Chinese pharmaceutical industry and administration of drug registration. 2010 China–Japan Symposium on Global Clinical Trials and Ethnic Factors, China. At http:// www.pmda.go.jp/english/past/2010_sympo/ file/201005_03.pdf 15. State Food and Drug Administration. SFDA issues Requirements for application dossiers in CTD format for a pharmaceutical product. News Release. 11 October 2010. At http://eng.sfda.gov.cn/WS03/CL0757/62297. html 16. State Food and Drug Administration (2011).Good manufacturing practice for drugs (2010 Revision) issued. News Release. At http://eng.sfda.gov.cn/WS03/CL0757/62350. html 17. State Food and Drug Administration. Good manufacturing practice for drugs, (2010 Revision). ( MOH Decree No. 79.) At http://eng. sfda.gov.cn/WS03/CL0768/65113.html 18. State Food and Drug Administration (2010). The Third General Assembly of the Ninth Chinese Pharmacopoeia Commission and the Summing-up Conference on Compilation of The 2010 Chinese Pharmacopoeia. Beijing. News Release. At http://eng.sfda.gov. cn/WS03/CL0757/62334.html 19. State Food and Drug Administration. Notice for facilitating the implementation of GLP. Guo shi yao jian an(2006)587. At http:// www.sda.gov.cn/WS01/CL0055/10619.html 21. State Food and Drug Administration (2010). 2009 Report on the evaluation and approval of drug registrations. At http://www. sda.gov.cn/WS01/CL0236/54135.html 21. Xinhua News Agency (2009). Deepening reform in healthcare system and establishing the county’s essential medicines system. At http://news.xinhuanet.com/politics/2009-11/15/ content_12462632.htm 22. Ministry of Health (2009). National Essential Medicines Committee established. At http://www.moh.gov.cn/publicfiles/business/ htmlfiles/wsb/pwsyw/200905/40493.htm
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Regulatory Focus 23. Ministry of Health, National Development and Reform Commission, Ministry of Industry and Information Technology, Ministry of Supervision, Ministry of Finance, Ministry of Human Resources and Social Security, Ministry of Commerce, State Food and Drug Administration, State Administration of Traditional Chinese Medicine (2009). Provision for National Essential Medicines List (Interim). At http:// www.moh.gov.cn/publicfiles/business/htmlfiles/ mohbgt/s7692/200908/42512.htm 24. Ministry of Health, National Development and Reform Commission, Ministry of Industry and Information Technology, Ministry of Supervision, Ministry of Finance, Ministry of Human Resources and Social Security, Ministry of Commerce, State Food and Drug Administration, State Administration of Traditional Chinese Medicine (2009). Position Paper on implementation of the National Essential Medicines System. At http://www.moh.gov. cn/publicfiles/business/htmlfiles/mohywzc/ s3581/200908/42498. 25. State Drug Administration. Guo yao jian an(1999)460. Facilitating China’s classification of prescription and non-prescription medicines. At http://www.sda.gov.cn/WS01/ CL0055/9684.html 26. State Food and Drug Administration (2004). Guo shi yao jian an(2004)101, Conducting the switch of prescription and OTC. At http://www.sda.gov.cn/WS01/ CL0055/10268.html 27. State Food and Drug Administration (2004). Guo shi yao jian zhu(2007)54. Notification of release of the insert sheet model for over-the-counter medicines. At http:// former.sfda.gov.cn/cmsweb/webportal/W472/ A64019346.html 28. State Food and Drug Administration (2011). Database of model insert for over-thecounter medicine. Official website of SFDA at http://app1.sfda.gov.cn/datasearch/face3/dir.
WHO Drug Information Vol. 26, No. 1, 2012 29. The State Council (2005). Regulation for control of narcotics and psychotropics. At http://www.sfda.gov.cn/WS01/CL0784/23500. html 30. State Food and Drug Administration (2007). Notice on the establishment of a monitoring network for narcotics and psychotropics. Guo shi yao jian ban(2007)482, 3 August,2007. At http://former.sfda.gov.cn/ cmsweb/webportal/W945325/A64022736.html 31. State Food and Drug Administration. State Administration for Industry and Commerce (2007). Drug advertisement examination and release standards. At http://www.sfda.gov.cn/ WS01/CL0053/24526.html 32. State Food and Drug Administration (2011). Online database of SFDA web sites at http://app1.sfda.gov.cn/datasearch/face3/ dir.html 33. General Office of the State Council of the People’s Republic of China (2010). Guo ban han (2010)67. At http://www.gov.cn/ zwgk/2010-04/19/content_1586732.htm 34. Ministry of Health (2011). Provisions for ADR reporting and monitoring. At http://www. sfda.gov.cn/WS01/CL0053/62621.html 35. State Food and Drug Administration. Yan min. Development of ADR reporting and monitoring in China. 14th ICDRA, Singapore, at http://www.who.int/medicines/areas/quality_safety/regulation_legislation/icdra 36. The UPPSALA Monitoring Center (2011). SFDA in China and the UMC – Collaboration in sharing global patient safety information. At http://www.umc-products.com/DynPage. aspx?id=75618&news=10096 37. State Food and Drug Administration (2011). Guideline on strengthening the establishment of an ADR monitoring system. At http://www.sfda.gov.cn/WS01/CL0844/66936
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Paediatric Medicines Better medicines for children: pharmaceutical formulations Safe and effective pharmacotherapy in paediatric patients requires the timely development of medicines to suit the age, physiological condition and body size of the child. However, use of unlicensed and off-label medicines in children is widespread. Formulations developed specifically for children are urgently needed. In 2007, the World Health Organization (WHO) launched the “Make Medicines Child Size” project. The WHO Quality Assurance Programme has contributed to the project by developing norms and standards for global application. The WHO Expert Committee on Specifications for Pharmaceutical Preparations have recently endorsed a first guideline and several monographs related to paediatric medicines. The guideline aims to: • Inform regulatory authorities and manufacturers of issues that require special attention in the development of paediatric medicines taking into accounting new trends and developments as well as efforts undertaken by regulatory authorities. • Focus on conditions and special needs in developing countries. The guideline indicates sources of detailed instructions for the development of paediatric medicine formulations. (A list of guidelines and literature appearing in the guideline are reproduced on page 19.) The guideline covers paediatric dosage forms, dosage forms to be considered in particular, oral administration, rectal administration, parenteral administration, dermal and transdermal administration, inhalations and packaging and labelling. Extemporaneous preparations and compounding are not within the scope of the document. However, a separate supplementary guidance document entitled “Provision by healthcare specialists of patient-specific preparations that are not available as authorized products: points to consider” is under preparation.
Guideline development
A preliminary draft document “ Development of paediatric medicines: points to consider” was discussed at the Expert Committee’s Forty-second meeting in 2007. A further text was prepared based on the above draft and on “Formulations of choice for the paediatric population” published by the European Medicines Evaluation Agency in 2006. Preparatory work involved coordination with ongoing activities both within and outside WHO, in particular with the European Medicines Agency (EMA), UNICEF, and the WHO Essential Medicines Programme. After wide circulation for comment, “Development of paediatric medicines: points to consider in pharmaceutical formulation” was adopted at the Forty-sixth Expert Committee meeting in October 2011.
Paediatric dosage form selection
The guiding principles in selecting paediatric dosage forms should be, as for adults, the balance of risk/benefit taking into account the specific needs of the 0–18 year-old population. Convenient, reliable administration. The administered dose should be adjusted to the age and needs of the patient and manipulation of the dose should be kept to a minimum. Paediatric medicines
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Table 1. Paediatric dosage form indicators Dosage form Flexible solid dosage forms, e.g., orodispersible tablets Oral medicines for precise dose titration Parenteral formulations Rectal preparations Advantage Priority dosage form. Suitable for both developed and developing countries May be used for various APIs Potentially for use in children > 6 months Suitable for precise dose measurement or titration For severe diseases and conditions Severely ill children or children unable to swallow Platform technology for multiparticulate solids Requires a trained caregiver Cultural barriers to use WHO: QAS/11.399/Rev.1* Consideration Not suitable for medicines requiring a precise dose titration Compatibility of API and breast milk Reference
*Zhao N et al (2010). Tablet splitting: product quality assessment of metoprolol succinate extended release tablets. Working document. WHO/QAS/11.399/Rev.1
should preferably be ready-to-use formulations. Alternatively, the dosage form should be designed to subdivide into smaller, uniform doses of appropriate size for accurate dosing. Acceptability and palatability. The dosage form should be palatable, easy to administer and acceptable to the patient. It should also be developed to avoid any potential interactions with food and medicine or effects on bioavailability. If administration with common food or liquids is acceptable, information supported by evidence-based compatibility studies should be provided in the patient information leafet. Dosing frequency. A minimum dosing frequency should be preferred to facilitate compliance with the dosing schedule for older children or caregivers. Instructions on the dosing frequency should be based on the pharmacokinetic and pharmacodynamic properties of the active pharmaceutical ingredient (API) but may be influenced by the design of the dosage form.
End-user needs. Paediatric medicines should be easy to use and affordable with regard to: • Supply (e.g., ease of transportation, storage requirements). • Access to clean water. • Adequate product information (e.g., how to administer; compatibility and incompatibility with food ingredients).
Dosage forms
Although the most appropriate dosage form should be based on a case-bycase evaluation, in general, flexible solid dosage forms are likely to prove most suitable for global use and should be prioritized (Table 1).
Formulation design
Many items need to be considered in the design of formulations for paediatric use. Those mentioned in the Development of paediatric medicines document include quality, the Biopharmaceutics Classification System (BCS), excipients, colouring agents, antimicrobial preservatives,
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Table 2. Paediatric formulation design indicators Item 1. Quality 2. BCS Consideration (key) Acceptable level of impurities in APIs Degradation products in FPPs Safety margins on APIs and FPPs Safety studies in juvenile animals FPP compliance Dissolution testing to address gastric pH of the child BCS-based API classification Transporter function and metabolic enzymes (typically CYP3A4) Excipients affecting transit time (efflux) Selected references WHO: QAS/10.376 ICH :Q3A(R2);Q3B;Q3C EMA: CPMP/SWP/5199/02 EMEA/CHMP/SWP/431994/2007 CPMP/SWP/QWP/4446/00 The International Pharmacopoeia FIP/AAPS guidelines WHO. Technical Report Series, No.937, Annex 8.
3. Excipients Safety profile of paediatric excipient Breitkreutz J,Boos J (2007). Paedi in the target age groups atric and geriatric drug delivery. Route of administration Shehab N et al (2009), Exposure Single and daily dose of excipient to the pharmaceutical excipients Duration of treatment benzyl alcohol and propylene Acceptability for intended age group glycol among critically iII Potential alternatives neonates. American Academy Regulatory status in intended market of Pediatrics. “Inactive” ingredients in pharma ceutical products. WHO. Technical Report Series. Evaluation of certain food additives. 4. Colouring agents 5. Antimicrobial preservatives 6. Sweetening agents 7. Taste masking 8. Solubility enhancers Use is generally discouraged Use may be justified in certain cases, e.g. to avoid accidental dosing errors (several strengths) Acceptable number for use is limited Azo-dyes should be avoided Risk of allergic reactions associated with natural colourants Potential to cause adverse reactions in infants and neonates Avoid use whenever possible Keep to minimum concentration level Solid dosage forms do not need free-mercury-containing preservatives in ophthalmic preparations Safety in specific conditions (diabetes, fructose intolerance, phenylketonurea) Laxative effect Cultural differences in taste and acceptability Ernest TB et al (2007). Developing develop taste for maximum acceptability paediatric medicines: identifying Non-cariogenic sweeteners and flavours the needs and recognizing preferred the challenges. Higher risks for parenteral preparations vs. oral preparations Children vulnerable to the effects of ethanol Toxicity on brain maturation highly probable Chronic exposure linked to dependence in adults and adolescents Pollock I, Young E, Stoneham M (1989). Survey of colorings and preservatives in drugs. Pefferi G, Restani P (2003). The safety of pharmaceutical excipients.
Public statement on antimicrobial preservatives in ophthalmic preparations for human use (EMEA/622721/2009).
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sweetening agents, taste making and solubility enhancers.
tration route are highlighted and relevant references are listed. (See Table 2.)
Route of administration
The common route of administration discussed in the document covers oral, rectal, parenteral, dermal and transdermal administration and inhalation. Special issues for consideration of each adminis-
Next steps
Although development of paediatric medicines is still subject to limited knowledge in some areas, progress is rapidly being made.
Table 3. Route of administration and formulations Administration Oral liquid preparations • preferred route for paediatric patients • drops • stabilizing agents are a major drawback (microbial and chemical) • stability of multidose preparations • powders and granules • risks of incorrect dosing for reconstitution • dose-measuring device critical (drops) • suspensions • stability parameters of oral suspensions Administration through nasogastric tubes • no effects from saliva and gastric juice: may afffect bioavailability • potential absorption of API into tube material Solid dosage forms • powders and multiparticulate • Improved stability, good dosage uni- preparations formity, options for different doses • immediate-release tablets • crushing tablets may affect bioavailability • capsules (only if allowed by manufacturer) • chewable tablets • chewable tablets may be chewed or swallowed whole (dissolution test conditions same as for tablets) • effervescent dosage forms • control moisture and humidity in manufacture, packaging and storage of effervescents • effervescents: caution in renal insufficiency • dispersible and soluble tablets • dispersible and soluble tablets: flexibility for water-soluble APIs • sustained-release formulations • labelling instructions for sustained-release formulations (including coated tablets and matrix tablets): not to be broken or chewed • orodispersible dosage forms • orodispersibles may be moisture-sensitive Strickly RG et al (2007). Paediatric Drugs. A review of commercially available oral formulations. Siewert M et al (2003). FIP/AAPS guidelines for dissolution/ in vitro release testing of novel/ special dosage forms. Thomson SA et al (2009). Mini-tablets: new modality to deliver medicines to preschool-age children. Seager H (1998). Drug–delivery products and the zydis fast- dissolving dosage form. ICH E11 EMEA/622721/2009
Special considerations
References
Rectal suppositories rectal liquids • important route of administration for children severely ill or unable to swallow • concordance and compliance of rectal preparation may be lower • cultural and regional acceptance barriers
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Table 3. Route of administration and formulations (continued) Administration Parenteral
Special considerations
References
• preferred route of administration for seriously WHO. Multisource ill children and clinically unstable term and (generic) pharma- preterm neonates (developed world setting). ceutical products: • limited experience of needle-free injection guidelines on device use in children. registration require• increased blood perfusion in sustained- ments to establish release preparations. interchangeability • safety profile of each excipient and suitability (2006). for intended use.
Dermal and transdermal Transdermal patches Inhalations Liquids for nebulization • total lung deposition important for clinical efficacy of preparation. Metered dose inhalers (MDIs) • small airway diameter in children, deposition by impact in upper and central airways may Dry powder inhalers (DPIs) be significantly higher in children. Krause J, Breitkreuts J (2008). Improving drug delivery in paediatric medicine. Dolovich M (2000). Influence of inspiratory flow rate, particle size and airway caliber in aerosolized drug delivery to the lung. Schüepp K, Jauernig J, Janssens H (2005). In vitro determination of the optimal particle size for nebulized aerosol delivery to infants. • hydration of the skin and thickness of stratum corneum in children different from adults. • unintended systemic absortion through dermis a potential risk for many APIs. • safety profile of excipients. • test for local tolerance and acceptability.
Bibliography 1. European Medicines Agency. Clinical Investigation of Medicinal Products in the Paediatric Population, ICH Topic E11. January 2001 CPMP/ICH/2711/99 at http://www.ema.europa. eu/docs/en_GB/document_library/Scientific_ guideline/2009/09/WC500002926. 2. World Health Organization. Guideline on quality risk management (working document QAS/10.376) at http://www.who.int/medicines 3. World Health Organization. Thirty-ninth report of the WHO Expert Committee on Spe-
cifications for Pharmaceutical Preparations. Technical Report Series, No. 929, Annex 5. Guidelines for registration of fixed-dose combination medicinal products (2005) at http:// www.who.int/medicines 4. World Health Organization. Pharmaceutical development for multisource (generic) pharmaceutical products. Working document QAS/08.251/Rev.1 at http://www.who.int/ medicines 5. International Conference on Harmonization. Impurities in new drug substances. ICH Topic
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Paediatric Medicines Q3A(R2) at http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3A_R2/Step4/Q3A_R2__Guideline.pdf 6. European Medicines Agency. Impurities in new drug products, ICH Topic Q3B. CPMP/ ICH/2738/99 at http://www.ema.europa.eu/ docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002676.pdf 7. European Medicines Agency. Impurities: guideline for residual solvents, ICH Topic Q3C. February 2009. CPMP/ICH/283/95 at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/ WC500002674.pdf 8. European Medicines Agency. Guideline on the limits of genotoxic impurities (CPMP/SWP/5199/02). EMEA/CHMP/ QWP/251344/2006 at http://www.ema.europa. eu/docs/en_GB/document_library/Scientific_ guideline/2009/09/WC500002903.pdf 9. European Medicines Agency. Q&A on the CHMP Guideline on the limits of genotoxic impurities. EMEA/CHMP/SWP/431994/2007 at http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/ WC500002903.pdf 10. European Medicines Agency. Note for guidance on specification limits of residues of metal catalysts (CPMP/SWP/QWP/4446/00). 17 December 2002. http://www.ema.europa. eu/docs/en_GB/document_library/Scientific_ guideline/2009/09/WC500003588.pdf 11. World Health Organization. Fortieth report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. Technical Report Series, No. 937, Annex 8, Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid dosage forms (2006) at http://www.who.int/medicines 12. European Medicines Agency. Public statement on antimicrobial preservatives in ophthalmic preparations for human use. 8 December 2009. EMEA/622721/2009 at http:// www.techtran.co.jp/techtr_j/globepharm/ emea091208.pdf 13. European Medicines Agency. Guideline on the investigation of medicinal products in the term and preterm neonate.
WHO Drug Information Vol. 26, No. 1, 2012 EMEA/566810/2008. at http://www.ema. europa.eu/docs/en_GB/document_library/ Scientific_guideline/2009/09/WC500003754. pdf 14. World Health Organization. Fortieth report of the WHO Expert Committee on Specifications for Pharmaceutical Preparations. Technical Report Series, No. 937, Annex 7: Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (2006) at http:// www.who.int/medicines References 1. Kearns GL et al. Developmental pharmacology – drug disposition, action and therapy in infants and children. N Eng J Med 2003;349(12):1157–1167. 2. European Medicines Agency. Reflection paper: formulations of choice for the paediatric population. (EMEA/CHMP/PEG/196810/2005) at http://www.nppg.scot.nhs.uk/misc/choicepaper0605.pdf 3. Ernest TB et al. Developing paediatric medicines: identifying the needs and recognizing the challenges. J Pharm Pharmacol 2007;59:1043–1055. 4. Krause J, Breitkreutz J. Improving drug delivery in paediatric medicine. Pharmaceutical Medicine 2008;22:41–50. 5. Allen LV. Dosage form design and development. Clin Ther 2008;30(11):2102–2111. 6. Siewert M et al. FIP/AAPS guidelines for dissolution/in vitro release testing of novel/ special dosage forms. Dissolution Technologies 2003; February Issue, page 15. 7. Breitkreutz J, Boos J. Paediatric and geriatric drug delivery. Expert Opin Drug Deliv 2007;4(1):37–45. 8. Shehab N et al. Exposure to the pharmaceutical excipients benzyl alcohol and propylene glycol among critically ill neonates. Pediatric Critical Care Medicine 2009;10(2):256-259. 9. “Inactive” Ingredients in Pharmaceutical Products: Update: http:/www.pediatrics.org/ cgi/content/full/99/2/268
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WHO Drug Information Vol. 26, No. 1, 2012 10. World Health Organization. Technical Report Series, Evaluation of certain food additives. List of publications: http://www.who.int/ ipcs/publications/jecfa/reports/en/index.html. 11. Pollock I, Young E, Stoneham M. Survey of colourings and preservatives in drugs. Brit. Med J 1989;299:649–651. 12. Pefferi G, Restani P. The safety of pharmaceutical excipients. Il Farmaco 2003; 58:541–550. 13. Mennella JA, Beauchamp GK. Optimizing oral medications for children. Clin Ther 2008;30(11):2120–2132. 14. Strickly RG et al. Paediatric drugs – A review of commercially available oral formulations. J Pharm Sci 2007;97(5):1731–1774.
Paediatric Medicines 15. Thomson SA et al. Mini-tablets: new modality to deliver medicines to preschool-aged children. Paediatrics 2009;123(2):e235–e238. 16. Seager H. Drug-delivery products and the Zydis fast-dissolving dosage form. J Pharm Pharmacol1998;50:375–382. 17. Dolovich M. Influence of inspiratory flow rate, particle size and airway caliber in aerosolized drug delivery to the lung. Respiratory Care 2000;45:597–608. 18. Schüepp K, Jauernig J, Janssens H. In vitro determination of the optimal particle size for nebulized aerosol delivery to infants. J Aerosol Med 2005;18(2):225–235.
Benznidazole: child-adapted dosage form approved Brazil’s National Health Surveillance Agency (ANVISA) has granted registration of a new paediatric dosage form of benznidazole, developed through a partnership between the Pernambuco State Pharmaceutical Laboratory (LAFEPE) of Brazil and the Drugs for Neglected Diseases initiative (DNDi). Registration of this formulation of benznidazole was made on 12 December 2011. This new tablet is easier-to-administer and a safer treatment of Chagas disease in infants and young children under the age of two, as they will receive accurate dosage. Until now, benznidazole was available only as a 100 mg tablet for adults. Treatment for young children required cutting adult pills into tiny slivers — up to 12 pieces depending on the child’s weight — and crushing and mixing them with water or juice, to be administered twice a day for 60 days. This difficult and inefficient method often results in improper dosing, risks of increased sideeffects, ineffective treatment, or treatment stoppages. Chagas disease affects an estimated eight to ten million people, mostly in Latin
America, and kills some 12,000 people each year, making it the leading parasitic killer in the Americas. The Chagas parasite is primarily transmitted via the bite of the blood-sucking triatome bug. In addition to blood transfusion, organ transplant, or ingesting infected food, the parasite is also transmitted during pregnancy from mother to child. This new dosage form for children represents real progress for several reasons. Children are at especially high risk of infection, with a majority of them born from infected mothers. It is known that early treatment using benznidazole in the first year of life can eliminate the parasite in more than 90% of infected newborns. Thus, babies infected with Chagas disease will benefit the most from this new paediatric tablet. The new 12.5 mg tablet is easily dispersible and adapted for babies and children up to two years of age (20 kg body weight). Treatment is designed to use one, two, or three tablets, depending on weight (recommended dosage, 5–10 mg/ kg body weight/day). Tools to facilitate implementation of and access to the new treatment include a 21
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Demand Forecast, a Procurement Guide, and a Tool Box providing training and educational materials for doctors, other health professionals, mothers, and caregivers regarding appropriate use of the treatment. In 2008, DNDi and LAFEPE entered a joint development agreement for this
dosage form. The new tablet will be produced by LAFEPE, a public pharmaceutical manufacturer run by the State of Pernambuco in Brazil and the sole global producer of benznidazole. Reference: DNDi Drugs for Neglected Diseases initiative at http://www.dndi.org
Use of drugs in paediatric health conditions increasing In the past, treatment decisions involving the use of drugs in infants, children and youth were often derived from the data in drug studies involving adults (1, 2). However, the safety and efficacy of medications may be significantly different in paediatric patients than in adult patients owing to differences in developmental physiology, disease pathophysiology, and developmental pharmacokinetics and pharmacodynamics (2). This understanding has led to the use of the phrase «children are not just small adults,» a statement that emphasizes the urgent need for evidence from high-quality trials involving paediatric patients (2). The use of drugs to treat paediatric health conditions in Canada is increasing (3). Infants, children and youth represent nearly one-quarter of Canada’s population and, on average, receive four prescriptions a year from a range of more than 1200 different drugs (3, 4). Nonetheless, data on the efficacy and safety of most medications prescribed for pediatric patients are limited (2, 3, 5). When prescribing a medication for an «off-label» indication in infants, children or youth, health professionals may consult available sources of information, such as peer-reviewed medical literature, paediatric dosing manuals and textbooks, drug formularies at children’s hospitals, community pharmacists and the relevant
pharmaceutical company representatives. In the absence of experimental studies in paediatric populations, information provided by these sources may be based more on expert opinion or local practice and experience (5). Drug investigations in paediatric populations can be faced with multiple challenges. Some examples include: • Defining appropriate ethical adaptations of clinical trials for studies involving infants, children and youth (1). • Ensuring adequate sample sizes (1, 2). • Choosing objective, clinically relevant endpoints that can be measured in a valid and reliable manner (1, 2). • Overcoming technical difficulties, such as the need for frequent blood sampling (1). • Improving pharmacoepidemiologic and pharmacovigilance practices aimed to coordinate the development of reliable information about drug benefits and harms to reduce uncertainties about the use of drugs in paediatric populations. • Expanding the availability of age-appropriate product formulations (e.g., liquid formulations). Health Canada, like other regulatory authorities around the world, recognizes the need to strengthen information related to paediatric health. In pursuit of this objective, some of its key activities include:
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• Coordinating the development of paediatric information through the regulatory system and other means. • Coordinating how this information is made available and accessible. • Raising awareness of child health needs and safety issues related to the development and use of health products and food. • Promoting conditions that enable informed decisions about the health and nutrition of infants, children and youth. To help improve safety data about health products for the paediatric population, it is important for healthcare providers to continue to report adverse reactions in both paediatric and adult populations. Extracted from Canadian Adverse Reaction Newsletter, Volume 22, Issue 1, January 2012
References 1. Matsui D, Kwan C, Steer E, et al. The trials and tribulations of doing drug research in children. CMAJ 2003;169(10):1033–4. 2. Klassen TP, Hartling L, Craig JC, et al. Children are not just small adults: the urgent need for high-quality trial evidence in children. PLoS Medicine 2008;5(8):1180–2. 3. Abi Khaled L, Ahmad F, Brogan T, et al. Prescription medicine use by one million Canadian children. Paediatr Child Health 2003;8(A):6A–56A. 4. Junker A. Canadian pediatric clinical trials activity 2005-2009. Maternal Infant Child Youth Res Network 2010;Aug:1–19. 5. Matsui D, Jardine M, Steer V, et al. Where physicians look for information on drug prescribing for children. Paediatr Child Health 2003;8(4):219–21.
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Safety and Efficacy Issues Bevacizumab: severe infectious endophthalmitis and blindness Canada — Health Canada has informed healthcare professionals of new safety information regarding unauthorized use of bevacizumab (Avastin®) when repackaged for intra-vitreal injection. Three clusters of serious ocular complications, including acute ocular inflammation, endophthalmitis, and infectious endoph-thalmitis resulting in blindness, have been recently reported in California, Florida and Tennessee. Although these clusters continue to be investigated, it is possible that the events of blindness from streptococcal endophthalmitis in Florida were due to repackaging of bevacizumab without proper aseptic technique. Bevacizumab is a recombinant humanized monoclonal antibody that is directed against vascular endothelial growth factor (VEGF). It is authorized for intravenous administration in the following indications: • First-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with fluoropyrimidine-based chemotherapy. • Treatment of patients with unresectable advanced, metastatic or recurrent nonsquamous non-small cell lung cancer in combination with carboplatin/paclitaxel chemotherapy regimen. • Treatment of patients with glioblastoma after relapse or disease progression, following prior therapy. Reference: Communication from HoffmannLa Roche dated 2 December 2011 at http:// www.hc-sc.gc.ca/dhp-mps/medeff/advisoriesavis/prof/_2011/avastin_8_hpc-cps-eng.php
Ursodeoxycholic acid: serious hepatic events Canada — Ursodeoxycholic acid (Ursodiol®) is indicated for the management of cholestatic liver diseases. Canadian Product Monographs for ursodiol® products have been updated in October, 2011 to reflect data from a long-term clinical trial in primary sclerosing cholangitis (PSC) finding an increase in serious liver adverse events in patients taking an unapproved ursodiol dose (twice the recommended dose). • The recommended ursodiol dose is 13–15 mg/kg/day for adults with cholestatic disease. • In a clinical trial in patients with PSC, long-term use of twice the recommended dose of ursodiol® was associated with improvement in serum liver tests but did not improve survival, and was associated with higher rates of serious adverse events (including death or liver transplantation) compared to placebo. • Improved serum liver tests do not always correlate with improved liver disease status. Reference: Communication from Aptalis Pharma Canada dated 1 December 2011 at http:// www.hc-sc.gc.ca/dhp-mps/medeff/advisoriesavis/prof/_2011/avastin_8_hpc-cps-eng.php
Simvastatin with amiodarone: dosage review United States of America — The Food and Drug Administration (FDA) has advised of a dose limitation for simvastatin from 10 mg to 20 mg when co-administered with the cardiac drug amiodarone. In June 2011, the FDA previously recommended that the dose limitation for
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Safety and Efficacy Issues Reference: FDA Drug Safety Communication, 9 November 2011 at http://www.fda.gov/ Drugs/DrugSafety/ucm278837.htm
simvastatin be decreased from 20 mg to 10 mg, and has now reconsidered that recommendation. Unlike other interacting drugs, there were no pharmacokinetic or clinical trial data to support the simvastatin dose reduction approved with amiodarone. Therefore FDA has determined that the simvastatin dose limitation, when taken with amiodarone, should be restored to 20 mg. In patients who are taking both simvastatin and amiodarone, the dose of simvastatin should not exceed 20 mg per day. The simvastatin drug labels (Zocor® and generics, Vytorin®) have been updated to reflect this correction. Reference: FDA Drug Safety Communication, 15 December 2011 at http://www.fda.gov/ Drugs/DrugSafety/ucm283137.htm
BCG vaccine: lymphadenitis
Singapore — The Health Sciences Authority (HSA) has updated healthcare professionals on suspected reports of lymphadenitis following the administration of the Bacillus Calmette-Guérin (BCG) Vaccine Staten Serum Institute (SSI)®. This observation arose from the active surveillance and monitoring of vaccine adverse events (VAEs) at the sentinel site at KK Women’s and Children’s Hospital (KKH). In 2009, HSA collaborated with KKH to initiate active surveillance for VAEs related to H1N1 vaccines in pregnant women and children. This was subsequently expanded to include all VAEs following childhood immunization. In Singapore, BCG vaccine is routinely given to newborns as part of the National Childhood Immunization Schedule. Since June 2003, the BCG vaccine manufactured by SSI is the sole BCG vaccine registered in Singapore. BCG Vaccine SSI® contains an attenuated strain of Mycobacterium bovis (BCG), Danish strain 1331. In 2009, there were 26 reports of BCGassociated lymphadenitis of which 23 cases (88%) presented as suppurative lymphadenitis. Of these, 22 cases required surgical intervention such as excision or incision and drainage. In 2010, there were 25 reports of lymphadenitis. Sixteen cases (64%) presented as suppurative lymphadenitis which required surgical intervention. From January 2011 to October 2011, the reports of lymphadenitis increased to 53. An increase in the number of suspected reports of BCG-associated suppurative lymphadenitis has also been identified in some countries such as Ireland and Latvia in recent years. However, the
Fenofibric acid: the ACCORD lipid trial United States of America — The Food and Drug Administration (FDA) has advised that the cholesterol-lowering medicine fenofibric acid (Trilipix®) may not lower a patient’s risk of having a heart attack or stroke. This is based on data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid trial, which evaluated the efficacy and safety of fenofibrate plus simvastatin combination therapy versus simvastatin alone in patients with type 2 diabetes mellitus. FDA reviewed this trial as part of its ongoing investigation of the safety and efficacy of Trilipix®. In the ACCORD Lipid trial, there was no significant difference in the risk of experiencing a major adverse cardiac event between the group treated with fenofibrate plus simvastatin compared with simvastatin alone. In addition, a subgroup analysis showed that relative to treatment in men, there was an increase in the risk for major adverse cardiac events in women receiving the combination therapy versus simvastatin alone.
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overall rate and pattern of VAEs remain consistent with the expected frequency of occurrence listed in the package insert of BCG Vaccine SSI®. Reference: Health Sciences Authority (HSA) Safety Announcement at http://www.hsa.gov. sg/publish/hsaportal/en/health_products_regulation/safety_information/product_safety_ alerts/safety_alerts_2011/reports_of_lymphadenitis.html
Dabigatran etexilate mesylate: bleeding events United States of America — The Food and Drug Administration (FDA) has evaluated post-marketing reports of serious bleeding events in patients taking dabigatran etexilate mesylate (Pradaxa®). Dabigatran etexilate mesylate is a direct thrombin inhibitor used to reduce the risk of stroke in patients with non-valvular atrial fibrillation, the most common type of heart rhythm abnormality. Bleeding that may lead to serious or even fatal outcomes is a well-recognized complication of all anticoagulant therapies and the Pradaxa® drug label contains a warning about significant and sometimes fatal bleeding. Reference: FDA Drug Safety Communication, 7 December 2011 at http://www.fda.gov/ Drugs/DrugSafety/ ucm282724.htm
undergone elective total hip or total knee replacement surgery. In June 2011, the indication for Pradaxa® was extended to include the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. Bleeding is a known side-effect for dabigatran as it is an extension of its pharmacological effect. Based on clinical evidence, the risk of major or severe bleeding from dabigatran is rare, even though life-threatening or even fatal outcomes may occur. The local package insert of Pradaxa® currently carries warnings of this risk, including the recommendation to monitor for signs of bleeding or anaemia (1). Additionally, the local package insert recommends dose adjustments in the elderly and those with impaired renal function as well as close clinical surveillance in patients with low body weight (<50kg) and high body weight (>110kg). Dabigatran is contraindicated in patients with severe renal impairment. To date, HSA has received seven suspected adverse reaction reports associated with dabigatran. These included one case of bleeding, one case of deep vein thrombosis and blood clot in the heart and one case of stroke, all occurring in patients between 77 and 86 years of age. The time to onset of these cases were a few months after initiation of dabigatran. No concomitant medicines were reported and none of these cases had a fatal outcome. Reference: The Health Sciences Authority (HSA). Safety Announcement, at http://www. hsa.gov.sg/publish/hsaportal/en/health_products_regulation/safety_information
Dabigatran etexilate: caution in the elderly and renally impaired Singapore — The Health Sciences Authority (HSA) has alerted healthcare professionals to serious cases of bleeding associated with the use of dabigatran and reminded them to closely monitor patients who are prescribed this medication, especially the elderly and those with renal impairment.
Dabigatran: risk of bleeding Australia — Dabigatran (Pradaxa®) is a potent short-acting anticoagulant for which there is no antidote or reversal agent. As with warfarin, bleeding events can occur. Clinicians are urged to give careful consideration to the suitability of
Dabigatran (Pradaxa®) has been licensed locally since August 2009 for the primary prevention of venous thromboembolic events in adult patients who have 26
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Safety and Efficacy Issues Adverse events reported to the TGA for dabigatran June 2009 – October 2011 Type of adverse event Number
patients for dabigatran particularly with regard to recognized risks of bleeding. Dabigatran is a potent oral anticoagulant. It is a direct thrombin inhibitor that inhibits free and clot-bound thrombin. It has a mean half-life of 12–17 hours. It is renally excreted and the rate of elimination is related to renal function. There is a close correlation between plasma dabigatran levels and anticoagulant effect. Dabigatran may be considered an alternative to warfarin and it carries similar risks of bleeding. In clinical trials the risk of bleeding per year of treatment with dabigatran was 16.6% when taking 150 mg twice daily, and 14.7% taking 110 mg twice daily compared with 18.4% for warfarin. In April 2011, the Therapeutic Goods Administration (TGA) approved dabigatran for use for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation and at least one risk factor for stroke. Since then, the TGA has received an increase in the number of bleeding-related adverse events reports for dabigatran (see table). The analysis of these reports shows that some of the bleeding adverse events occurred during the transition from warfarin to dabigatran; many of the adverse events are occurring in patients on the reduced dosage regimen; and the most common site of serious bleeding for dabigatran is the gastrointestinal tract, whereas for warfarin it is intracranial. Australian experts are currently developing guidelines for the management of bleeding in patients taking dabigatran. In the meantime clinicians are referred to the New Zealand guidelines (1). It is strongly recommended that clinicians read the Product Information before prescribing dabigatran. The Product Information is available from the TGA web site (2). For more detailed information
Total adverse events 297 Serious adverse events 196 Serious bleeding adverse events 70 Serious gastrointestinal bleeding 48 Serious intracranial bleeding 6 Events in patients aged 75 years or older: Total adverse events 166 Serious adverse events 108
regarding the considerations of the TGA in approving dabigatran please see the Australian Public Assessment Report (AusPAR) (3). References 1. Guidelines for management of bleeding with dabigatran. New Zealand: PHARMAC; 2011. 2. Pradaxa Product Information. Boehringer Ingelheim Pty Limited. August 2011. 3. Dabigatran etexilate mesilate-AusPAR. Therapeutic Goods Administration. 14 May 2011 at http://www.tga.gov.au
Pneumovax 23®: revaccination recommendations Australia — Pneumovax 23® vaccination is used to prevent life-threatening infections by pneumococcal bacteria. In March 2011, a cluster of seven severe local injection site reactions was reported to the Therapeutic Goods Administration (TGA) by NSW Health and as a result a recall of the batch of Pneumovax® implicated in these reactions was ordered by the TGA on 25 March 2011. In April 2011, as a result of a continued increase in severe injection site reaction reports, the TGA issued advice to health professionals not to administer a second or subsequent dose of Pneumovax 23® vaccine pending the outcome of a review, which has now been completed. 27
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Laboratory analysis of the recalled batch (N3336) did not detect any problems related to vaccine manufacture or handling. The TGA has now determined that the adverse events were not a batchrelated problem. The TGA considers that the increased numbers of reports of severe reactions were a result of: • The known high rates of local reactions, including severe injection site reactions, which occur more commonly after a repeat dose of Pneumovax 23®. • The increased number of people having a repeat dose following the inclusion of Pneumovax 23® vaccine in the National Immunization Programme in 2005 with revaccination after five years. • The increased reporting that followed the publicity of the batch recall. The TGA is advising that revaccination with Pneumovax 23® can be undertaken in accordance with the approved Product Information (PI). In summary, revaccination should: • not be given routinely to immunocompetent individuals (that is, those with a healthy immune system). • be considered for patients at a high risk of serious pneumococcal disease, provided that at least five years has passed since the previous dose of Pneumovax 23®. Reference: Pneumovax 23®: updated revaccination recommendations. 23 December 2011 at http://www.tga.gov.au/safety/alertsmedicine-pneumovax-111223.htm
to remind prescribers to strictly follow the approved indications and doses and to carefully consider the warnings and precautions for somatropin-containing medicines. Somatropin is a human growth hormone, manufactured using recombinant DNA technology. It promotes growth during childhood and adolescence, and also affects the way the body handles proteins, fat and carbohydrates. It is used to treat a number of conditions associated with impaired growth and short stature. These include children who fail to grow adequately due to a lack of growth hormone, Turner syndrome or chronic renal insufficiency and short children born small for gestational age. Reference: EMA Press Release, EMA/ CHMP/965945/2011, 15 December 2011 at http://www.ema.europa.eu
Pholcodine-containing cough medicines European Union — The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has confirmed that the benefits of pholcodinecontaining cough medicines outweigh their risks and that these medicines should remain available for the treatment of non-productive (dry) cough in children and adults. The review of pholcodine-containing medicines was initiated because of concerns that there could be cross-sensitisation between pholcodine and neuromuscular blocking agents (NMBAs). It was suspected that this in turn could lead to anaphylactic reactions in some patients receiving NMBAs during emergency surgery who had previously taken pholcodinecontaining cough medicines. Following a thorough review of all available data on the safety and efficacy of pholcodine-containing cough medicines, the Committee found no firm evidence to substantiate the hypothesis of cross-
Somatropin-containing medicines: positive benefit-risk balance European Union — Following a review of somatropin-containing medicines, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has confirmed that the benefitrisk balance of these medicines remains positive. However, the CHMP wished 28
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sensitization between pholcodine and NMBAs and a subsequent increased risk of anaphylactic reactions during surgery. Reference: EMA Press Release, EMA/ CHMP/898043/2011, 18 November 2011 at http://www.ema.europa.eu
Antipsychotics in children and adolescents: cardiometabolic reactions Canada — Health Canada has received 29 reports of cardiometabolic adverse reactions suspected of being associated with second-generation antipsychotics (SGAs) in children and adolescents under 18 years of age. In Canada, no SGAs are authorized for use in children or adolescents, with one recent exception authorized for use only in adolescents 15 to 17 years old for the treatment of schizophrenia. Excess weight and obesity in the population are increasing problems throughout the Western world, and this rise has also been observed in children and adolescents (1). Weight gain and obesity are known to be associated with diabetes, dyslipidaemia and hypertension (2). In addition, weight gain is a well-established adverse reaction to second-generation antipsychotics (SGAs) (1). In Canada, there are seven marketed second-generation antipsychotics: clozapine, risperidone, olanzapine, quetiapine, paliperidone, ziprasidone and aripiprazole. Recently, aripiprazole (Abilify®) was authorized for the treatment of schizophrenia in adolescents 15 to 17 years old (3). Previously, there were no authorized indications for the use of SGAs in children or adolescents under 18 years of age in Canada. Paediatric drug use, in many circumstances, has been based primarily on information extrapolated from studies involving adults, as well as from other types of scientific evidence, including
case reports, open studies of clinical experience and controlled clinical trials (4, 5). Second-generation antipsychotics have been prescribed for children and adolescents with mental health problems such as schizophrenia, bipolar I disorder, autism, pervasive developmental disorder, disruptive behaviour disorders (including conduct disorder and attention-deficit hyperactivity disorder), developmental disabilities and Tourette syndrome (6). Use of these drugs in the paediatric population has increased substantially over the last decade (6–8). According to one estimate, antipsychotic drug prescriptions for children and youth in Canada increased by 114% from 2005 to 2009 (4). Despite this increased use, data regarding their safety are limited (2). The cardiometabolic effects of SGAs in pediatric patients, including age-inappropriate weight gain, obesity, hypertension, and lipid and glucose abnormalities, are of concern (8). Furthermore, children and adolescents with mental health problems often have multiple cardiovascular risk factors, including poor nutrition, inadequate exercise, substance abuse and lack of adequate healthcare monitoring (2, 9). Some studies have shown that youth using antipsychotic agents may be at a higher risk of weight gain and metabolic effects than adults who use the same drugs (2, 7, 10). If weight gain is established in youth, it tends to persist into adulthood (10). Because of differences in absorption, distribution and metabolism of antipsychotics in the paediatric population, higher doses per weight are required than in adults to achieve similar efficacy (2). Cardiometabolic effects are problematic during childhood because they tend to be predictors of adult obesity, metabolic syndrome, hypertension, cardiovascular morbidity and malignant disease (2, 7, 8). Adverse effects such as weight gain have been found to vary significantly by SGA agent. Clozapine and olanzapine seem 29
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WHO Drug Information Vol. 26, No. 1, 2012 8, Correll CU, Manu P, Olshanskiy V, et al. Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents. JAMA 2009;302(16):1765–73. 9. Varley CK, McClellan J. Implications of marked weight gain associated with atypical antipsychotic medications in children and adolescents. JAMA 2009;302(16):1811–2. 10. Ratzoni G, Gothelf D, Brand-Gothelf A, et al. Weight gain associated with olanzapine and risperidone in adolescent patients: a comparative prospective study. J Am Acad Child Adolesc Psychiatry 2002;41(3):337–43. 11. Ho J, Panagiotopoulos C, McCrindle B, et al. Management recommendations for metabolic complications associated with second generation antipsychotic use in children and youth. J Can Acad Child Adolesc Psychiatry 2011;20(3):234–41.
to be associated with the highest risk of clinically significant weight gain in children and adults (1, 2, 7). Risperidone and quetiapine generally show modest risk, whereas ziprasidone and aripiprazole are associated with the lowest risk. Limited data are available for paliperidone (4). The risk of lipid elevation and increased blood sugar appears to be greatest with olanzapine (11). Extracted from Canadian Adverse Reaction Newsletter, Volume 22, Issue 1, January 2012 References 1. Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 2005;19(Suppl 1):1–93. 2. De Hert M, Dobbelaere M, Sheridan EM, et al. Metabolic and endocrine adverse effects of second-generation antipsychotics in children and adolescents: a systemic review of randomized, placebo controlled trials and guidelines for clinical practice. Eur Psychiatry 2011;26:144–58. 3. Abilify® (aripiprazole) [product monograph]. Montréal (QC): Bristol-Myers Squibb Canada; 2011. 4. Pringsheim T, Panagiotopoulos C, Davidson J, et al. Evidence-based recommendations for monitoring safety of second generation antipsychotics in children and youth. J Can Acad Child Adolesc Psychiatry 2011;20(3):218–33. 5. Zito JM, Derivan AT, Kratochvil CJ, et al. Off-label psychopharmacologic prescribing for children: history supports close clinical monitoring. Child Adolesc Psychiatry Mental Health 2008;2(24):1–11. 6. Panagiotopoulos C, Ronsley R, Elbe D, et al. First do no harm: promoting an evidencebased approach to atypical antipsychotic use in children and adolescents. J Can Acad Child Adolesc Psychiatry 2010;19(2):124–37. 7. Correll CU. Assessing and maximizing the safety and tolerability of antipsychotics used in the treatment of children and adolescents. J Clin Psychiatry 2008;69(Suppl 4):26–36.
Citalopram hydrobromide: dosedependent QT prolongation Canada — Health Canada has informed healthcare professionals that the antidepressant citalopram hydrobromide (Celexa®, also marketed as generics), should no longer be used at doses greater than 40 mg per day due to study results indicating a dose-dependent potential for QT prolongation. Previously, the Canadian Product Monograph stated that certain patients may require 60 mg per day. Citalopram hydrobromide is a selective serotonin reuptake inhibitor (SSRI) indicated for the symptomatic relief of depressive illness available as 20 mg and 40 mg tablets. A thorough QT study, conducted according to international standards, assessing the effects of citalopram 20 mg per day and 60 mg per day on the QT interval has shown that citalopram causes dosedependent QT prolongation. Patients at particular risk for developing prolongation of the QT interval include those with
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underlying heart conditions and those who are predisposed to low blood levels of potassium and magnesium. Hypokalaemia and hypomagnesaemia should be corrected before administering citalopram hydrobromide. Reference: Safety Alert – Medeffect. 25 January 2012 at http://www.hc-sc.gc.ca/ dhp-mps/medeff/advisories-avis/prof/_2012/ celexa_2_hpc-cps-eng.php
• John Cunningham virus (JCV) infection resulting in progressive multifocal leukoencephalopathy (PML) and death has been reported in Adcetris®-treated patients. The factors leading to reactivation of latent JC virus are not fully understood. Healthcare professionals should instruct patients to report changes in mood or unusual behavior, confusion, loss of memory, changes in walking or talking, decreased strength or weakness on one side of the body, or changes in vision. Reference: FDA Drug Safety Communication, 13 January 2012 at http://www.fda.gov/Drugs/ DrugSafety/
Brentuximab vedotin: new warning and contraindication United States of America — The Food and Drug Administration (FDA) has advised that two additional cases of progressive multifocal leukoencephalopathy (PML) have been reported with the lymphoma drug brentuximab vedotin (Adcetris®). Due to the serious nature of PML, a new boxed warning has been added to the drug label. Brentuximab vedotin is used to treat Hodgkin lymphoma and a rare lymphoma known as systemic anaplastic large cell lymphoma. It is an antibody-drug conjugate, allowing the antibody to direct the drug to a target on CD30 lymphoma cells. In addition, a new contraindication warning against use of brentuximab vedotin with the cancer drug bleomycin due to increased risk of pulmonary (lung) toxicity has been added to the drug label. A clinical trial compared the combination of Adcetris® plus Adriamycin® (doxorubicin), bleomycin, vinblastine, and dacarbazine (ABVD) to the combination of Adcetris® plus Adriamycin® (doxorubicin), vinblastine, and dacarbazine (AVD) as front-line therapy for HL. An excessive number of patients in the Adcetris plus® ABVD treatment group experienced noninfectious pulmonary toxicity. • Concomitant use of brentuximab vedotin and bleomycin is contraindicated due to pulmonary toxicity.
Quetiapine: information updated United Kingdom — The manufacturer of quetiapine and quetiapine prolonged release has informed healthcare professionals of an update to the special warnings and precautions section of the summary of product characteristics concerning weight gain, hyperglycaemia and metabolic risk. Weight gain has been reported in patients who have been treated with quetiapine, and should be monitored and managed as clinically appropriate in accordance with antipsychotic guidelines. Hyperglycaemia and/or development or exacerbation of diabetes occasionally associated with ketoacidosis or coma has been reported rarely, including some fatal cases. In some cases, a prior increase in body weight has been reported which may be a predisposing factor. Patients treated with any antipsychotic agent including quetiapine, should be observed for signs and symptoms of hyperglycaemia, (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control. Weight should be monitored regularly.
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Given the observed changes in weight, blood glucose and lipids seen in clinical studies, there may be possible worsening of the metabolic risk profile in individual patients, which should be managed as clinically appropriate. Reference: Medicines and Healthcare Products Regulatory Agency (MHRA). Communication from AstraZeneca UK at http://www. mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/index.htm
at baseline. Aliskiren 300 mg was given in addition to standard of care, including an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). A higher incidence of adverse events related to non-fatal stroke, renal complications, hyperkalaemia and hypotension were observed in this high-risk population. Reference: Medicines and Healthcare Products Regulatory Agency (MHRA). Communication from Novartis dated 23 December 2011 at http://www.mhra.gov.uk/Safetyinformation/ Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/index.htm
Aliskiren: cardiovascular and renal events United Kingdom — The manufacturer of aliskiren (Rasilez®) has informed healthcare professionals of new safety information following the interim results from the Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE). Analyses of these data are ongoing. However, as a precautionary measure, it is advised that routine (non-urgent) review is carried out for patients taking Aliskiren-containing medicines. Additionally, aliskiren or aliskirencontaining fixed combination products should not be used in patients with diabetes in combination with angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB). As a consequence: • Healthcare professionals should stop aliskiren-containing treatment in patients who are diabetic and also taking an ACE inhibitor or an ARB. Alternative antihypertensive treatment should be considered as necessary. • Aliskiren-containing products should not be initiated in diabetic patients who are also taking either an ACE inhibitor or ARB. The ALTITUDE study was conducted in type 2 diabetic patients at high risk of fatal and non-fatal cardiovascular and renal events. In most patients arterial blood pressure was adequately controlled 32
Natalizumab: progressive multifocal leukoencephalopathy
United States of America — The Food and Drug Administration (FDA) has advised that testing positive for anti-John Cunningham virus (JCV) antibodies has been identified as a risk factor for progressive multifocal leukoencephalopathy (PML). PML is a rare but serious brain infection associated with use of natalizumab (Tysabri®) for the treatment of multiple sclerosis or Crohn disease. Natalizumab has been approved for the treatment of relapsing forms of multiple sclerosis since November 2004 and for the treatment of moderately to severely active Crohn disease since January 2008. Patients with three known risk factors have an estimated risk of PML of 11/1,000 users. The risk factors are: • Presence of anti-JCV infection antibodies. • Longer duration of Tysabri® treatment, especially beyond 2 years. • Prior treatment with an immunosuppressant medication (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, or mycophenolate mofetil).
WHO Drug Information Vol. 26, No. 1, 2012 Reference: FDA Drug Safety Communication, 20 January 2012 at http://www.fda.gov/Drugs/ DrugSafety
Safety and Efficacy Issues
Bortezomib: fatal if given intrathecally Canada — Health Canada has alerted healthcare professionals to the risk of fatal outcome associated with the inadvertent intrathecal administration of the antineoplastic drug bortezomib (Velcade®). Since the first global approval of bortezomib in May 2003, three cases of inadvertent intrathecal administration with fatal outcome have been reported worldwide; these occurred in France and Italy. Each case occurred when an intrathecal oncology chemotherapy was scheduled at the same time as bortezomib intravenous administration. Health Canada has not received any Canadian reports involving inadvertent intrathecal administration. Bortezomib should only be administered via the approved intravenous (IV) route; Bortezomib is fatal if given intrathecally. Healthcare professionals are encouraged: • To administer chemotherapy intended via the intrathecal route at a different time than other parenteral chemotherapy. • To use different connectors for medicinal products to be administered via the intrathecal or intravenous route. • To clearly label syringes with the name of the medicinal product and route of administration to be used and ensure procedures are in place to enforce a double check of syringe labelling before administration. Reference: Safety Alert – Medeffect. 26 January 2012 at http://www.hc-sc.gc.ca/ dhp-mps/medeff/advisories-avis/prof/_2012/ velcade_hpc-cps-eng.php
Boceprevir: HIV protease inhibitor interactions United States of America — The Food and Drug Administration (FDA) has notified healthcare professionals of drug interactions between the hepatitis C virus (HCV) protease inhibitor boceprevir (Victrelis®) and certain ritonavir-boosted human immunodeficiency virus (HIV) protease inhibitors (atazanavir, lopinavir, darunavir) which can potentially reduce the effectiveness of these medicines when used together. Boceprevir is a hepatitis C virus (HCV) protease inhibitor used with the medicines peginterferon alfa and ribavirin to treat chronic hepatitis C infection in adults who have not been treated before or who have failed previous treatment. Ritonavir is an HIV protease inhibitor used to “boost” other HIV protease inhibitors, increasing their levels in the blood and making them more effective. A drug interaction study showed that taking boceprevir (Victrelis®) with ritonavir (Norvir®) in combination with atazanavir (Reyataz®) or darunavir (Prezista®), or with lopinavir/ritonavir (Kaletra®) reduced blood levels of the HIV medicines and boceprevir in the body. Drug interactions between boceprevir and ritonavir-boosted atazanavir, lopinavir, and darunavir can potentially reduce the effectiveness of these medicines when co-administered. Reference: FDA Drug Safety Communication, 8 February 2012 at http://www.fda.gov/Drugs/ DrugSafety/ucm291119.htm
Spontaneous monitoring systems are useful in detecting signals of relatively rare, serious or unexpected adverse drug reactions. A signal is defined as “reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented 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 vaidated before any regulatory decision can be made.
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Regulatory Action and News Bevacizumab: suspension for metastatic breast cancer Canada — Health Canada has taken the decision to suspend authorization of bevacizumab (Avastin®) for use in the treatment of metastatic breast cancer. This decision does not affect Health Canada’s authorization of bevacizumab for other types of cancer. Bevacizumab remains authorized in Canada for use in the treatment of metastatic colon, rectal, and lung cancers, as well as in the treatment of glioblastoma. Reference: Information Update 2011–59, 28 November 2011 at http://www.hc-sc.gc.ca/ dhp-mps/medeff/advisories-avis/prof/_2011/ avastin_8_hpc-cps-eng.php
Buflomedil-containing medicines: suspension European Union — The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has concluded, following a review of the safety and efficacy of buflomedil, that the risks of these medicines, particularly the risks of severe cardiological and neurological adverse reactions, do not outweigh their limited benefits in the treatment of patients with chronic peripheral arterial occlusive disease (PAOD). The Committee therefore recommended that the marketing authorizations of all buflomedilcontaining medicines be suspended in all European Union (EU) Member States where they are currently authorized. The review of buflomedil was initiated following the suspension of the marketing authorization in France by the French regulatory authority in February 2011. Reference: EMA Press Release, EMA/ CHMP/570796/2011, 17 November 2011 at http://www.ema.europa.eu
Drotrecogin alfa: withdrawal United States of America — The Food and Drug Administration (FDA) has announced the worldwide voluntary market withdrawal of drotrecogin alfa (activated) [Xigris®] by the manufacturer. In a recently completed clinical trial (PROWESS-SHOCK trial), drotrecogin alfa failed to show a survival benefit. In this trial of 1696 patients, 851 patients were enrolled in the drotrecogin alfa arm and 845 patients were enrolled in the placebo arm. Results based on preliminary analyses that were submitted to the FDA showed a 28-day all cause mortality rate of 26.4% (223/846) in Xigris®-treated patients compared to 24.2% (202/834) in placebo-treated patients. Reference: FDA Drug Safety Communication, 25 October 2011 at http://www.fda.gov/Drugs/ DrugSafety
Dextropropoxyphene-containing analgesics cancelled Australia — The Therapeutic Goods Administration (TGA) has cancelled all pain-killers containing dextropropoxyphene (Capadex®, Di-Gesic®, Doloxene® and Paradex®) from the Australian Register of Therapeutic Goods (ARTG), as of 1 March 2012. Following a review of the available evidence, the TGA found that the safety risks of using analgesics containing dextropropoxyphene outweighed the benefits. Cancellation from the ARTG means
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that these prescription medicines can no longer be supplied by their Australian sponsors. Dextropropoxyphene has recently been shown to increase the risk of serious arrhythmias. This effect is more pronounced with high doses or overdoses. An extensive review of the safety and efficacy of dextropropoxyphene has been conducted by the TGA which has determined that the overall risk of serious adverse reactions outweighs any benefits that may be provided by these medicines. This position is consistent with medicine regulators in Europe, New Zealand, USA and elsewhere, where dextropropoxyphenecontaining medicines have been removed from the market. Reference: Therapeutic Goods Administration Safety Announcement, 2 December 2011 at http://www.tga.gov.au/newsroom/media2011-dextropropoxyphene-111122.htm
Ecallantide: marketing authorization application withdrawal European Union — The European Medicines Agency (EMA) has been notified by the manufacturer of its decision to withdraw the application for ecallantide (Kalbitor®), 10 mg/ml solution for injection. Ecallantide was intended to be used for symptomatic treatment of acute attacks of hereditary angioedema (HAE) in adults and adolescents 16 years of age and older. The company stated that they were unable to provide sufficient information to address the outstanding clinical issues identified during the evaluation of their application. Reference: EMA Press Release, EMA/ 891024/2011, 15 November 2011 at http:// www.ema.europa.eu
Vemurafenib approved for metastatic or unresectable melanoma European Union — The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended the granting of a marketing authorization for a novel protein-kinase inhibitor to treat patients suffering from metastatic or unresectable melanoma with BRAF V600 mutations. In Europe, doctors diagnose almost 60 000 new cases of melanoma per year and approximately 8300 men and 7600 women die from this type of cancer annually. In the pivotal clinical trial, vemurafenib (Zelboraf®) was compared to the standard first-line treatment of dacarbazine. The medicine was shown to improve progression-free survival by about four months and overall survival by about three months in patients who tested positive for BRAF V600 mutations. Reference: EMA Press Release, EMA/ CHMP/975685/2011, 16 December 2011 at http://www.ema.europa.eu
Sitagliptin and pioglitazone: marketing authorization application withdrawal European Union — The European Medicines Agency (EMA) has been notified by the manufacturer of its decision to withdraw the application for sitagliptin and pioglitazone (Janacti® and related trade names)100/30 mg and 100/45 mg fixeddose combination tablets. Janacti® was intended to be used for the treatment of adult patients with type 2 diabetes mellitus. The company stated that they are withdrawing the application following a review of the regulatory and commercial prospects for the fixed-dose combination product. There are currently no ongoing clinical trials with Janacti®. Reference: EMA Press Release, EMA/ 887576/2011, 14 November 2011 at http:// www.ema.europa.eu
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WHO Drug Information Vol. 26, No. 1, 2012 Reference: EMA Press Release, EMA/ 840073/2011, 19 October 2011 at http://www. ema.europa.eu
Voclosporin: marketing authorization application withdrawal European Union — The European Medicines Agency (EMA) has been notified by the manufacturer of its decision to withdraw the application for voclosporin (Luveniq®), 10 mg soft capsules. Voclosporin was intended to be used for the treatment of patients with chronic non-infectious uveitis involving the posterior or intermediate segments of the eyes as characterized by a high degree of inflammation and in whom corticosteroids are inappropriate, do not provide adequate control, or cannot be tapered below 10 mg/day. Voclosporin was designated an orphan medicinal product on 14 September 2007. The company stated that they were unable to demonstrate to the satisfaction of the CHMP an overwhelming effect showing that the benefits of Luveniq® outweigh its risks, and thus would qualify for a recommendation for authorization with one pivotal study only. Reference: EMA Press Release, EMA/ 833913/2011, 18 October 2011 at http://www. ema.europa.eu
Electronic CTD implementation Saudi Arabia — The Saudi Food and Drug Authority (SFDA) has informed pharmaceutical companies and their agents to prepare for implemention of the electronic common technical document (eCTD) when submitting product files for evaluation. The timeframe determined for implementing the eCTD is as follows. • As of 20 December 2011: non- eCTD electronic submission (NeeS) can be submitted according to Guidance for Registration (version 3). • As of 1 September 2012, the NeeS will be mandatory and the SFDA will not accept any other format. • Starting 5 January 2013, either eCTD or NeeS can be submitted. • As of 4 January 2014, the NeeS will be accepted but submissions in eCTD are preferred • Starting from 3 January 2015, only eCTD will be accepted. More information about the difference between eCTD and NeeS is available in Guidance for Registration and the GCC Module 1 Specifications guideline which are available from sdr.drug@sfda.gov.sa and at www.sfda.gov.sa. In addition, the SFDA will conduct workshops to assist pharmaceutical companies in following these technical requirements. Reference: Saudi Food and Drug Authority. News Release dated 14 Jaunary 2012. At http://www.sfda.gov.sa/En/Drug/News/1122en-14-1.htm
Desloratadine: marketing authorization application withdrawal European Union — The European Medicines Agency (EMA) has been notified by the manufacturer of its decision to withdraw the application for desloratadine (Desloratadine Krka®), 5 mg film coated tablets. Desloratadine Krka® was intended to be used for the relief of symptoms associated with allergic rhinitis and urticaria. Desloratadine Krka® is a generic of Aerius® which has been authorized in the European Union since 15 January 2001. In its official letter, the company stated that their marketing strategy is the reason for withdrawal.
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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 Statistics Methodology in October 2011. Comments or objections to the decisions should be forwarded to the WHO Collaborating Centre for Drug Statistics Methodology at whocc@fhi.no. The new ATC codes and DDDs will be considered final and be included in the January 2013 issue of the ATC Index. The inclusion of a substance in the lists does not imply any recommendation for use in medicine or pharmacy. ATC level New ATC 5th level codes: INN Common name ATC code
aclidinium bromide R03BB05 alcaftadine S01GX11 alendronic acid and alfacalcidol, sequential M05BB06 apixaban B01AF02 atorvastatin and ezetimibe C10BA05 boseprevir J05AE12 cefuroxime S01AA27 ciclesonide R01AD13 cobicistat V03AX03 dextromethorphan, combinations N07XX59 electrolytes in combination with other drugs B05BB04 elvitegravir J05AX11 emtricitabine, tenofovir disoproxil, elvitegravir and cobicistat J05AR09 faropenem J01DI03 fidaxomicin A07AA12 florbetapir (18F) V09AX05 fluoxetine and psycholeptics N06CA03 flutemetamol (18F) V09AX04 glycopyrronium bromide R03BB06 ingenol mebutate D06BX02 ivacaftor R07AX02 lomitapide C10AX12 meningococcus A, purified polysaccharide antigen conjugated J07AH10
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ATC level
INN Common name
ATC code
mirabegron G04BD12 nafcillin J01CF06 ormeloxifen G03XC04 pioglitazone and sitagliptin A10BD12 ridaforolimus L01XE19 rubidium (82Rb) chloride V09GX04 simvastatin and fenofibrate C10BA04 sitagliptin and simvastatin A10BH51 technetium (99mTc) ethylenedicysteine V09CA06 B01AF S01AE New ATC S01AE08 S01AE03 N07BC06 N05AD08* S01AE06 L02AE05 S01AE05 S01AE04 J05AR10 S01AE07 S01AE02 S01AE01 B01AF01
New ATC level codes (other than 5th level): Direct factor Xa inhibitors Fluoroquinolones
ATC code changes: INN Common name besifloxacin ciprofloxacin diamorphine droperidol gatifloxacin histrelin levofloxacin lomefloxacin lopinavir and ritonavir ** moxifloxacin norfloxacin ofloxacin rivaroxaban
Previous ATC S01AX23 S01AX13 N02AA09 N01AX01 S01AX21 H01CA03 S01AX19 S01AX17 J05AE06 S01AX22 S01AX12 S01AX11 B01AX06
* Existing code ** New ATC level name (previous name: lopinavir) ATC name changes: Previous Other cephalosporins New ATC code Other cephalosporins and penems J01DI DDD 1 40 5 12.5 25 2.4 Unit g mg mg mg mg g Adm.R O O O P P O ATC code L02BX03 N07XX05 B01AF02 L04AA28 L04AA26 J05AE12
New DDDs:
abiraterone amifampridine apixaban belatacept belimumab boceprevir 38
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New DDDs (continued) ciclesonide collagenase clostridium histolyticum delavirdine dextromethorpen, combinations exenatide fidaxomicin histamine dihydrochloride inosine pranobex leuprorelin lorazepam nabiximols naproxen and esomeprazole pyrvinium retigabine rifaximin telaprevir tobramycin triptorelin vinpocetine von Willebrand factor 1 expressed 2 refers
DDD 0.2
Unit mg
Adm.R N
ATC code R01AD13
0.9 mg P M09AB02 1.2 g O J05AG02 40 mg1 O N07XX59 0.286 mg P depot inj. A10BX04 0.4 g O A07AA12 0.5 mg P L03AX14 3 g O J05AX05 0.134 mg P depot implant L02AE02 2.5 mg P N05BA06 42 mg SL N02BG10 O M01AE52 0.5 g2 0.35 g O P02CX01 0.9 g O N03AX21 0.6 g O A07AA11 2.25 g O J05AE11 0.112 g Inhal. powder J01GB01 0.1 mg P L02AE04 15 mg O N06BX18 6 TU P B02BD10
as dextromethorphan to naproxen
Herbal medicinal products* New ATC 5th level codes: ATC level INN Common name Agni casti fructus Cimicifugae rhizoma ATC code G02CX03 G02CX04
* Assessed and approved by regulatory authorities based on dossiers including efficacy, safety, and quality data (e.g. the well-established use procedure in EU).
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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 Statistics Methodology in March 2011. They have been included in the January 2012 version of the ATC Index. The inclusion of a substance in the lists does not imply any recommendation for use in medicine or pharmacy. The WHO Collaborating Centre for Drug Statistics Methodology can be contacted at whocc@fhi.no. New ATC 5th level codes: ATC name changes: Previous Antigrowth hormones Calcium, combinations with other drugs Enzyme inhibitors New Somatostatin and analogues Calcium, combinations with vitamin D and/or other drugs Aromatase inhibitors ATC code H01CB A12AX L02BG INN Common name ATC code
aclidinium bromide R03BB05 abiraterone L02BX03 aflibercept S01LA05 axitinib L01XE17 bosutinib L01XE14 brentuximab vedotin L01XC12 catridecacog B02BD11 crizotinib L01XE16$ dapagliflozin A10BX09 dexlansoprazole A02BC06 levomethadone N07BC05 losartan and amlodipine C09DB06 meloxicam, combinations M01AC56 mipomersen C10AX11 naproxen and misoprostol M01AE56 pasireotide H01CB05 perampanel N03AX22 ruxolitinib L01XE18 sipuleucel-T L03AX17 tafamidis N07XX08 telaprevir J05AE11 tesamorelin H01AC06 vemurafenib L01XE15
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ATC/DDD Classification
New DDDs: aspoxicillin aztreonam bekanamycin carumonam cefbuperazone cefminox conestat alfa desvenlafaxine fingolimod flomoxef histrelin isepamicin ribostamycin tapentadol ticagrelor vernakalant DDD 4 0.225 0.6 2 2 4 3.5 50 0.5 2 0.137 0.4 1 0.4 0.18 0.2 Unit g g g g g g TU mg mg g mg* g g g g g Adm.R P Inhal. solution P P P P P O O P implant P P O O P ATC code J01CA19 J01DF01 J01GB13 J01DF02 J01DC13 J01DC12 B06AC04 N06AX23 L04AA27 J01DC14 H01CA03 J01GB11 J01GB10 N02AX06 B01AC24 C01BG11
* DDD assigned according to the total content of the implant.
Herbal medicinal products* ATC level New ATC 5th level codes: INN Common name Hyperici herba ATC code N06AX25
* Assessed and approved by regulatory authorities based on dossiers including efficacy, safety, and quality data (e.g. the well-established use procedure in EU).
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Recent Publications, Information and Events Pharmacovigilance Toolkit The World Health Organization has announced the launch of a Pharmacovigilance Toolkit. This has been developed by the WHO Collaborating Centre for Pharmacovigilance Training and Advocacy, Ghana, in collaboration with the WHO Advisory Committee on Safety of Medicinal Products, the Uppsala Monitoring Centre, Sweden, and the WHO Quality and Safety of Medicines Programme, Geneva. The Toolkit brings together existing resources that are used in the practice of pharmacovigilance. Its main objective is to bring current information, guidelines and practical advice to all pharmacovigilance practitioners. In addition to a dedicate web site, the Toolkit is available on a USB key in a similar format for use in areas with poor internet connectivity. The Toolkit is currently available in English but efforts are underway to have it translated into other languages. Reference: The Pharmacovigilance Toolkit. At www.pvtoolkit.org
as VigiBase(®) — which contains over seven million such reports. After receiving a signal, national regulatory authorities may consider possible action — for instance further evaluation of source data, or a study for the testing of a hypothesis. In 2011, the WHO Advisory Committee on the Safety of Medicinal Products recommended that signal articles be made public. A first step in making UMC signals publicly available will be taken in early 2012 when, for the first time, they will be included in WHO Pharmaceuticals Newsletter which is issued every second month. Currently, 450 professionals receive the restricted signal document, mainly staff at national pharmacovigilance centres. The new arrangement with allow for a wider audience References 1. Uppsala Monitoring Centre/WHO Collaborating Centre for International Drug Monitoring, Sweden, at http://www.who-umc.org 2. World Health Organization. WHO Pharmaceuticals Newsletter. At http://www.who.int/ medicines
Uppsala Monitoring Centre signals document: increased availability Among the objectives of the WHO Programme for International Drug Monitoring is the early identification of international drug safety problems not identified in clinical trials, known as signals. These signals are published in the Uppsala Monitoring Centre’s (UMC) SIGNAL document, and represent varying levels of suspicions derived from examination of the data in the WHO Global Individual case safety reports database — also known 42
Learning module: selective serotonin reuptake inhibitors The United Kingdom Medicines and Healthcare Products Regulatory Agency (MHRA) has just launched a learning module on selective serotonin reuptake inhibitors (SSRI) for clinical practitioners. SSRIs form the most widely prescribed class of antidepressants. This module identifies the most important hazards of SSRIs and informs on actions that health professionals should take in order to minimize and manage the risks. For each adverse effect, the package outlines:
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Recent Publications, Information and Events
• The main features of the adverse effect. • Factors that increase the risk. • How the risk can be reduced. • Specific treatment for the adverse effect. A self-assessment exercise, together with full feedback, complements the learning material which is suitable for doctors, pharmacists and nurses involved in the care of patients with depression. Clinicians starting out in psychiatry will find it especially valuable. Used in conjunction with authoritative guidelines on disease management, this module will help maximize the benefits of SSRI treatment. Reference: Healthcare products Regulatory Agency (MHRA). SSRI learning module. At http://www.mhra.gov.uk/ConferencesLearningCentre/LearningCentre/Medicineslearningmodules/Reducingmedicinerisk/SSRIlearningmodule/index.htm
ATC/DDD methodology course The WHO Collaborating Centre for Drug Statistics Methodology will organize its annual course in ATC/DDD methodology in Oslo from 7 to 8 June 2012. The course gives an introduction to the Anatomical Therapeutic Chemical (ATC) classification system and the technical unit of measurement, the Defined Daily Dose (DDD). The purpose of the ATC/DDD and how to use the methodology is also covered in the course which consists of lectures, discussions and working groups. The course is open for all interested parties. However, basic knowledge in common medical terminology is recommended. The Centre also arranges courses on request from countries which plan to start using the ATC/DDD methodology. For example, courses have previously been arranged in Ecuador, Japan and Morocco. Lectures will cover the following topics: • Background, overview and development of the ATC/DDD methodology • The main principles for establishing new ATC codes and assigning DDDs • Procedures for applications (ATC codes, DDDs and changes). The second day will focus on application of the ATC/DDD methodology in drug consumption statistics. Working group sessions will address various ATC/DDD problems and points to consider related to the application of the methodology in drug consumption statistics. Reference: WHO Collaborating Centre for Drug Statistics Methodology. At http://www. whocc.no/courses/
Medicines access survey A team of researchers at the National Institute of Public Health in Mexico have conducted an analysis of availability, affordability and prices of medicines in Mexico City during 2009/2010 using the Health Action International (HAI)/WHO suggested methodology. The analysis showed that in the public sector medicines included in the sample were unavailable in more than 50% of those health establishments visited. In the private sector, originator product prices were on average 4.5 times higher than their corresponding interchangeable generics (e.g., the originator product, fluoxetin, was 172 times more expensive than its generic counterpart). Almost 50% of all treatments analysed were unaffordable. Reference: Mexico: Medicines access survey. At http://www.haiweb.org/medicineprices/surveys.php
Access and Control Newsletter
The Access and Control Newsletter provides the latest news from WHO on access to medicines controlled under
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the international drug treaties. It aims to provide information on improving access for medical use and evaluation of the dependence-producing properties of substances and medicines made from these substances. The current number includes: • Roundtable in Bosnia and Herzegovina. • Serbian National WHO Counterpart for pain treatment — access to opioids. • Psychiatrists are stakeholders in improving access to controlled medicines. • Prequalification of morphine and methadone. • ATOME Project: workshops on improving access to controlled medicines. • Life Before Death: Short movies on the global crisis of pain treatment. Reference: WHO Access and Control Newsletter, No 9, January 2012 at http://www.who. int/medicines/areas/quality_safety/Access_ Contr_Newsletter/en/index.html
in 1982. It was revised in 1997 with over 10,000 copies distributed in over 60 countries worldwide. The third edition, Managing Access to Medicines and other Health Technologies reflects the dramatic changes in politics, public health priorities, advances in science and medicine, greater focus on health care systems, increased donor funding, and the advent of information technology that have profoundly affected access to essential medicines over the past 14 years. The revised edition has many new areas that have been added or enhanced, including six new chapters: • Intellectual property and access to medicines • Traditional and complementary medicines policy • Pharmaceutical pricing policy • Pharmaceutical benefits in insurance programmes • Drug seller initiatives • Pharmacovigilance Reference: Management Sciences for Health. Managing Access to Medicines and other Health Technologies. At http://www.msh.org/ resource-center/managing-drug-supply-digitaledition.cfm
Managing access to medicines and health technologies Managing Drug Supply is the leading reference on how to manage essential medicines in developing countries. Managing Drug Supply was originally published
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