WHO Drug Information Vol

WHO Drug Information Vol. 26, No. 1, 2012

WHO Drug Information

Contents

Regulatory Focus Boceprevir: HIV protease inhibitor Regulation of medicines in China 3 interactions 33 Bortezomib: fatal if given intrathecally 33 Paediatric Medicines Better medicines for children: Regulatory Action and News pharmaceutical formulations 15 Bevacizumab: suspension for Benznidazole: child-adapted dosage metastatic breast cancer 34 form approved 21 Drotrecogin alfa: withdrawal 34 Use of drugs in paediatric health Dextropropoxyphene-containing conditions increasing 23 analgesics cancelled 34 Vemurafenib approved for meta- Safety and Efficacy Issues static or unresectable melanoma 35 Bevacizumab: severe infectious Ecallantide: marketing authorization endophthalmitis and blindness 24 application withdrawal 35 Ursodeoxycholic acid: serious Sitagliptin and pioglitazone: market- hepatic events 24 ing authorization application Simvastatin with amiodarone: withdrawal 35 dosage review 24 Voclosporin: marketing authorization Fenofibric acid: the ACCORD lipid application withdrawal 36 trial 25 Desloratadine: marketing authorization BCG vaccine: lymphadenitis 25 application withdrawal 36 Dabigatran etexilate mesylate: Electronic CTD implementation 36 bleeding events 26 Dabigatran etexilate: caution in the ATC/DDD Classification elderly and renally impaired 26 ATC/DDD Classification (temporary) 37 Dabigatran: risk of bleeding 26 ATC/DDD Classification (final) 40 Pneumovax 23®: revaccination recommendations 27 Recent Publications, Somatropin-containing medicines: Information and Events positive benefit-risk balance 28 Pharmacovigilance Toolkit 42 Pholcodine-containing cough Uppsala Monitoring Centre signals medicines 28 document: increased availability 42 Antipsychotics in children and ado- Learning module: selective lescents: cardiometabolic reactions 29 serotonin reuptake inhibitors 42 Citalopram hydrobromide: dose- Medicines access survey 43 dependent QT prolongation 30 ATC/DDD methodology course 43 Brentuximab vedotin: new warning Access and Control Newsletter 43 and contraindication 31 Managing access to medicines and Quetiapine: information updated 31 health technologies 44 Aliskiren: cardiovascular and renal events 32 Natalizumab: progressive multifocal International Nonproprietary Names leukoencephalopathy 32 Recommended List No. 67 45

1 WHO Drug Information Vol. 26, No. 1, 2012

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

2 WHO Drug Information Vol. 26, No. 1, 2012

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 of Human Resources and Social Security responsible for formulating the The State Council of the People’s Repu- China National Formulary for Essential blic of China is the executive arm of the Medicare and Industrial Injury Insu- Central People’s Government. It is the rance, the Ministry of Agriculture res- highest body of both state power and ponsible for supervision of raw material state administration (5). Departments for narcotic drugs and the Ministry of under the State Council are responsible Public Security which is responsible for for related medicines regulatory adminis- monitoring the distribution of narcotic trative work as defined within the limits drugs and psychotropic substances. of their duties and include the National Development and Reform Commission The State Food and Drug Administra- responsible for drug pricing, the Ministry tion (SFDA) was established in 1998

Article by Xiaoqiong Zheng, Information Centre, State Food and Drug Administration, Beijing, China.

3 Regulatory Focus WHO Drug Information Vol. 26, No. 1, 2012

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 ra- diopharmaceuticals, 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.

4 WHO Drug Information Vol. 26, No. 1, 2012 Regulatory Focus through the merger of medicines regula- producing pharmaceutical preparations, tory functions of the State Pharmaceutical etc. Administration of China, the State Admi- • Product approval at clinical trial, pro- nistration of Traditional Chinese Medi- duction, and import levels. cine of the People’s Republic of China (SATCM) — also under the Ministry of • Authorization of medicines advertis- Health — and the Drug Administration ing and promotion of over-the-counter Department of the Ministry of Health, (OTC) and prescription-only medicines. namely the State Drug Administration (SDA) directly under the State Council. In • Implementation of quality assurance 2003, with additional responsibilities for systems and compliance with good food regulation, the SDA became the cur- laboratory practice (GLP), good clinical rent SFDA. In 2008, the SFDA reverted to practice (GCP), good manufacturing Ministry of Health responsibility. practice (GMP) and good distribution practice (GDP). The establishment of the SFDA to regu- • Post-marketing safety surveillance late medicines was a milestone in the his- through a nationwide network encom- tory of medicines regulation in China and passing organization and electronic an important achievement in healthcare management systems for adverse drug reform. From 1998 to 2011, the SFDA has reaction (ADR) reporting and monitor- been committed to public health through: ing.

• Strengthening the science based ap- The SFDA makes decisions on marke- proach to medicines evaluation. ting authorizations and authorization of products for clinical trial and import. • Promoting quality assurance systems Decisions are based on reviews provided in enterprises involved in research, by the Centre for Drug Evaluation (CDE), production and distribution. an affiliated public organization providing • Facilitating the establishment of a na- technical support under SFDA administra- tional essential medicines system and tive supervision. Provincial MRAs assist the classification of prescription and the drug registration process through non-prescription medicines. preliminary work by verifying the original dossier application, format review and • Improving pharmacovigilance to safe- on-site inspection. Drug testing institutes guard public health. established or designated by drug regulatory departments are responsible for • Ensuring the quality, safety, efficacy the drug testing which is required as part and accessibility of medicines. of drug review and approval and for drug In addition to medicines regulation, quality control in accordance with the law several other categories of health related (7). products are also regulated by the SFDA (6). (Table 1.) Pharmaceutical industry profile The Chinese pharmaceutical industry has Regulatory responsibility and capacity made significant progress over the past The scope of medicines regulation in decade. According to a White Paper The China covers the whole life-cycle of medi- Status Quo of Drug Supervision in China cines, including: released by the Information Office of the State Council in 2008, China had the • Production, manufacturer licensing, capacity to produce 1500 types of drug provision of Internet-based pharmaceu- substance and over one billion doses tical information, Internet pharmaceuti- a year of 41 types of vaccine against cal trading, and medical institutions infection caused by 26 kinds of virus and

5 Regulatory Focus WHO Drug Information Vol. 26, No. 1, 2012

Table 2. Pharmaceutical industry profile

Indicator January–November 2010 January–June 2011

Gross industrial output 1123.9 714.6 (billion yuan) 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) 175.33 110.8

Profit (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 world. This demands that the country’s 2010, China counted more than 8000 regulatory activities are in line with pharmaceutical enterprises — including international standards. Current efforts to producers of prepared Chinese crude reform health care inside China also pre- drugs, oxygen for medical use, diagnostic sent challenges for capacity building and agents, blood derived products and vac- regulation, while the quality and safety of cines (9) — of which 4678 were produ- services and products provided within the cers of active pharmaceutical ingredients essential medicines programme need to (APIs) and finished pharmaceutical pre- be safeguarded. parations (FPPs) (1). In 2010, the gross industrial output reached 1236.827 billion Legislative framework and yuan with annual total sales of medici- regulatory status nal products at 682 billion yuan (10). An overview of the Chinese pharmaceutical China practises a unified, multilevel legis- industry profile is set out in Table 2. lative system (12). The National People’s Congress and its Standing Committee The challenges of regulating the Chinese exercise the state’s power to make laws. pharmaceutical industry were highlighted The State Council formulates administra- in a speech given by the SFDA Deputy- tive regulations and, at provincial level, Commissioner Wu Zhen at the 2011 An- the People’s Congresses as well as nual Conference on National Medicines their standing committees establish local Regulation (11). Following international statutes. In the area of medicines regula- economic integration, China is now the tion, the main legislative instrument is the third largest pharmaceutical market in the Drug Administration Law of the People’s

6 WHO Drug Information Vol. 26, No. 1, 2012 Regulatory Focus

Republic of China. Based on this, the cines regulation, it reflects the internal legal framework of medicines regulation and external driving forces modelling me- is established and regularly improved. dicines regulation in China, for example:

Drug Administration Law • First released in1985 following enact- The Drug Administration Law was issued ment of the Drug Administration Law. 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 mem- practice and provides a modern base bership to the World Trade Organiza- for control over the tion in 2001. 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. engaged in research diseases and intended for the re- and development, pro- gulation of the physiological func- • Updated following duction, distribution, tions of human beings, for which adoption of the Admi- use, and administra- indications, usage and dosage nistrative Licensing tion. In 2002, the State are established. These include Law of the People’s Council also adopted Chinese crude drugs, prepared Republic of China in Regulations for Imple- slices of Chinese crude drugs, tra- 2004. mentation of the Drug ditional Chinese medicine prepa- Administration Law of rations, chemical drug substances Under the Provisions, the People’s Republic and their preparations, antibiotics, a series of measures of China. biochemical drugs, radiopharma- relating to procedures ceuticals, sera, vaccines, blood and products have The Drug Administra- products and diagnostic agents. been issued, including tion Law 2001 com- (Article102 of the Drug Administra- Supplementary provi- prises 106 articles in tion Law) sions for TCM registra- ten chapters, inclu- tion (2008), Provisions ding: General Provi- New drugs refer to medicines for on-site inspection sions, Control of Drug which have not been marketed in drug registration Manufacturers, Control within the territory of the People’s (2008), Provisions for of Drug Distributors, Republic of China. (Article 83 of special review and Control of Pharmaceu- the Regulation). approval for new drug ticals in Medical Insti- registration (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 stan- Advertising, Inspection of Drugs, Legal dards is currently under development Liabilities, and Supplementary Provisions. (14). Based on the framework of the Drug Ad- Applications are classified into new ministration Law, a comprehensive legal medicines, generic medicines, import system including regulations, provisions, medicines and their supplementary appli- and guidelines has been established. cations, as well as re-registration. (Article 11.12.) Medicines registration Provisions for drug registration 2007 (13) The first two classifications – new medi- is in its fifth edition and fourth update. As cines and generic medicines – apply to the most frequently revised rule in medi- domestic applicants, whereas requests

7 Regulatory Focus WHO Drug Information Vol. 26, No. 1, 2012 from overseas applicants are handled • New drugs offering significant clinical according to those for imported medi- advantage for the treatment of diseases cines. Any application for changing a such as AIDS, malignant tumours and dosage form or route of administration, rare disorders, etc. or claiming a new indication for marketed • New drugs for the treatment of dis- medicines, is submitted through the new eases for which effective therapeutic drug application (NDA) process which methods are not available. covers applications for registration of medicines not previously marketed in China. (Article 12.12.) Quality assurance In China, good manufacturing practices The SFDA has additionally formulated (GMP) is a set of principles and proce- Requirements for application dossiers in dures which should be followed in order CTD format for pharmaceutical products to provide assurance that each medicinal based on the common technical docu- product is safe and of the required quality. ment (CTD) of the International Confe- This comprises requirements relating to rence on Harmonization of Technical premises, equipment, personnel, docu- Requirements for Registration of Pharma- mentation and quality control. These ceutical for Human Use (ICH) taking into requirements are enforced through sys- consideration the actual situation of drug tems of factory inspection and mandatory research and development in China. The licensing of factories which manufacture Requirements were issued in September medicines. 2010 (15). Since its first promulgation in 1988 (16), An application for generic medicines will China’s Good Manufacturing Practice apply to production of medicines having for Drugs was revised in 1992 and 1998. an existing national medicines standard The latest version of GMP (2010 Revi- for marketing approval by the SFDA. sion) released by the Ministry of Health The application process for a biological has been effective since 1 March 2011 product is the same as that for an NDA. (17). It consists of 14 chapters and 313 (Article 12.12.) articles based on the concepts of quality An application for an imported drug refers risk management and whole process to the registration application for medi- control of drug manufacturing. It attaches cines manufactured abroad to be marke- greater importance on the scientific na- ted in China. (Article 12.12.) ture, instructions, functions and manoeu- verability consistent with WHO GMP. Special review procedures to encourage innovation also exist. Speciality products Overseas manufacturers of medicines are given priority in review and approval. supplied to China must provide evidence A specific fast track procedure applies to that goods are manufactured to a stan- the following products (Article 4.12): dard of GMP equivalent to that expected of Chinese manufacturers of the same • Active ingredients extracted from goods. plants, animals and minerals, etc. and their preparations not yet marketed National drug standards in China. Newly discovered Chinese National drug standards in China include crude drugs and their preparations. the Pharmacopoeia of the People’s Repu- • Chemical drug substances and their blic of China, drug registration specifi- preparations and biological products cations, etc., published by the Ministry not yet approved for marketing in China of Health/SFDA, including technical or abroad. requirements such as testing methods

8 WHO Drug Information Vol. 26, No. 1, 2012 Regulatory Focus and manufacturing processes. (Article overview of SFDA’s work in the area of 136.12.) The 2010 edition of The Phar- medicines registration including produc- macopoeia of the People’s Republic of tion, clinical trials, and other key areas. China is available in three volumes and contains 4567 monographs (18). Provisions for medicines use Pre-approval requirements for Medicines use is covered by the national clinical trial applicants essential medicines system and list. This includes classification of medicines into • Safety evaluation in pre-clinical studies prescription and non-prescription catego- should comply with GLP (19). ries. • Clinical trials (including bioequivalence studies) should be conducted in compli- Essential Medicines ance with GCP. (Article 30.12.) Over the past three decades, the concept of essential medicines has evolved in • Drugs used for clinical trials should be China from a list to an integrated strategy manufactured in facilities in compliance based on a national medicines policy and with GMP. (Article 35.12.) is a key objective of healthcare reform • A drug can be used for a clinical trial (21). only after being tested and qualified. Vaccines, blood products and other China released its first National Essen- biological products specified by the tial Medicines List in 1982 following the SFDA should be tested by drug test- launch of the WHO Model List of Essen- ing institutes designated by the SFDA. tial Drugs in 1975. In 2009, the National (Article 36.12.) Essential Medicines Committee was established (22). The Provision for a All clinical trials (including bioequivalence National Essential Medicines List (interim) studies) need prior SFDA approval. (23) and a Position paper on implementation of the National Essential Medicines • The approved clinical trial should be System (24) were published in 2009. The conducted in a certified research institu- Position Paper defines essential medi- tion that operates in compliance with cines as those which satisfy the health Chinese GCP. care needs and are available to the public • For overseas applicants intending to at all times in adequate amounts and in conduct an international multicentre appropriate dosage forms, affordable clinical trial in China, drugs used for the price and equitable access to the public. clinical trial should already be approved or in phase II or III clinical trial over- The National Essential Medicines List has seas. While approving the conduct of been regularly updated and the current an international multicentre clinical trial, 2009 edition is the Seventh edition. Cove- the SFDA may require the applicant to rage of products has expanded from a first conduct a phase I clinical trial in focus on chemical pharmaceuticals in the China. (Article 44.12.) first edition to TCM in the second edition, and was again extended to include prepa- • Any preventive vaccine trial not having red slices of Chinese crude drugs in the first been registered overseas is prohib- current 2009 edition. ited in China. (Article 44.12.) Classification of prescription and SFDA publishes an Annual report on the non-prescription medicines evaluation and approval of drug regis- At the National Health Conference in trations (20). The report provides an 1996, classification of prescription and

9 Regulatory Focus WHO Drug Information Vol. 26, No. 1, 2012 non-prescription medicines was identi- for narcotic medicines production (Article fied as a key feature of the reform and 5.25). MRAs above provincial level development of China’s healthcare have established information monitoring system (25). In June 1999, the Provision networks and share information related to for classification of prescription drugs products (research, production, distribu- and non-prescription drugs (interim) and tion, use, storage and transportation) with the first list of non-prescription medicines the public security agency at the same (OTC) was released. In 2001, control level. (Article 58.25.) over prescription and OTC classification management became a legal require- Clinical trials ment under the Drug Administration Law. Clinical trials of narcotics listed as a (Article 37.7.) category 1 psychotropic should not be conducted in healthy subjects. (Article In 2004, the SFDA took a dynamic ma- 13.25.) nagement approach to the control of Production OTC medicines (26). Henceforth, OTC The SFDA and MoA draw up an annual medicines could be switched to prescrip- cultivation plan based on production, clini- tion-only status as a result of any safety cal needs and national storage capacity. related issues. To further standardize Cultivation enterprises are designated by information and labelling of non-prescrip- the SFDA and MoA. (Article 14.25.) tion medicines, the SFDA revised the model insert for non-prescription drugs in Distributors and distribution 2007 (27). By the end of 2011, the SFDA National wholesalers who distribute had issued 5697 package inserts for non- narcotic drugs and category 1 psycho- prescription drugs, including 1170 chemi- tropic substances among the provinces cal drugs and 4527 TCMs (28). are licensed by the SFDA. (Article 24.25.) Narcotic drugs and category I psychotro- Control of narcotics and pic drugs are not permitted in retailing. psychotropic substances (Article 30.25.) The Regulation for control of narcotics and psychotropics was adopted by the Information sharing State Council on 26 July 2005. It con- Reports on product-related information solidates and amends the former two are provided quarterly by city-level MRAs separate regulations for narcotic drugs to upper level MRAs. (Article 59.25.) and psychotropic substances released in 1987 and 1988. The more stringent Electronic distribution oversight provisions are in line with the respec- Real-time dynamic monitoring of productive International Conventions under the tion, purchase, sales, inventory and flow principle of balancing control measures of narcotic drugs and category 1 psycho- and access (29). The main points include, tropic substances is realized through the among others: Electronic Medicines Supervision and Regulation Network (30). Coordinated supervision Departments under the State Council Control of drug promotion and advertising involved in narcotic and psychotropic Control of OTC and prescription-only control include the SFDA, Ministry of medicine advertising ensures accurate Agriculture (MoA) and Ministry of Public content, compliance with the law and Security (MPS). The MoA and SFDA avoidance of misleading information. The hold joint responsibility for narcotics and legal basis for drug advertising is vested the MPS is responsible for oversight of in the SFDA approved package insert/ distribution and the medicinal plans used labelling information. (Article 6.27.)

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Supervision of drug advertising is the Drug safety monitoring responsibility of the SFDA and the State Establishing a reporting system on Administration for Industry and Com- adverse drug reactions (ADRs) is requi- merce (SAIC). The current legislative fra- red under Article 71 of the Drug Admi- mework for medicines advertising Provi- nistration Law 2001. It is a legal obliga- sions for drug advertisement examination tion for manufacturers, distributors and (SFDA Order 27) and Drug advertisement medical institutes to report serious ADRs. examination and release standards (SAIC Improving the ADR evaluation system is Order 27) (31) was issued jointly by the also highlighted in the 2010 State Council two departments and became effective in schedule. Among the five Priorities in the May 2007. reform of the medicine and healthcare system, an ADR evaluation system is Advertising is prohibited (Article 3.27) for: a necessary part of the essential medi- • Narcotics, psychotropic substances, cines policy (33). The Provisions for ADR toxic medicines and radiopharmaceuti- reporting and monitoring released in 2011 cals. by the Ministry of Health clearly define the appropriate procedure, timeframe, and • Pharmaceutical preparations produced responsibilities of stakeholders (34). by medical institutions. • Products specifically for military use. China’s ADR monitoring work was initiated in 1989 through establishment of the • Preparations under trial production. ADR Monitoring Centre within the Ministry • Products that have been prohibited by of Health. Over the past two decades, the SFDA for production, sale or use. in addition to development of the appropriate legislative framework, key progress The SFDA implements a risk based made includes formal membership of regulatory approach in terms of content of China’s ADR Centre to the WHO Inter- advertisements and category of product national Drug Monitoring Programme in (e.g., OTC or prescription-only medi- 1998. The first National annual report on cines). The key points are: ADR monitoring was released in 2009. The ADR network is expected to be • Only OTC products can be advertised expanded to 400 sub-centres nationwide directly to the consumer and all ad- with an on-line information reporting sys- vertising materials should state that tem functioning as of 2010 (35). In 2011, purchase and use should be made in China signed an agreement with the accordance with a pharmacist’s instruc- WHO Collaborating Centre for Interna- tions or guidance. (Article 8.27.) tional Drug Monitoring (Uppsala Monito- • Prescription medicines can only be ring Centre) with the aim of enhancing advertised in medical or pharmaceu- data exchange from China’s Adverse tical journals assigned by the Ministry of Drug Reaction Monitoring database and Health and SFDA. The advertisement VigiBase — the WHO global database should state that it is specifically di- containing over 6 million ADR reports. rected to medical professionals. (Article The project agreement will also improve 8.27.) the Drug Dictionary of China, and signal detection and patient safety data mining • The prescription/trade name cannot techniques (36). be used within the advertising slogan. (Article 5.27.) According to the Guideline on streng- • By the end of June 2011, 544 publi- thening the establishment of an ADR cations had been designated by the monitoring system released by the SFDA Ministry of Health/SFDA (32). in 2011, the future China ADR monito-

11 Regulatory Focus WHO Drug Information Vol. 26, No. 1, 2012

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 satis- fying 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 • Regulation and authorization of infor- on international standards supported by mation provision, whether commercial information technology with an early war- or non-commercial. ning capability, combined with four-level • Regulation and licensing of Internet- SFDA and stakeholder participation (37). based medicines transactions, including third party e-commerce platform provid- Internet-related pharmaceutical ers, business-to-business (B2B) and distribution and information business-to-consumers (B2C). Internet based activities related to medicines need to be licensed by the MRAs. References Under the two legal documents released 1. State Food and Drug Administration (2011). by the SFDA, Requirement for Internet- SFDA annual statistics report 2010. At http:// based service provision of pharmaceuti- www.sfda.gov.cn/WS01/CL0108/66530.html cal information 2004 and Requirements for review and licensing of Internet-based 2. Ministry of Civil Affairs of the People’s pharmaceutical transactions 2005, regu- Republic of China (2011). Statistical report lation involves two spheres: on social service development in China 2010. At http://www.mca.gov.cn/article/zwgk/ mzyw/201106/20110600161364.shtml

12 WHO Drug Information Vol. 26, No. 1, 2012 Regulatory Focus

3. National Bureau of Statistics of China 14. State Food and Drug Administration. (2011). Bulletin of key figures for the 6th Natio- Zhang Wei (2010). Latest progress in develop- nal Population Survey 2010. At http://www. ment of the Chinese pharmaceutical industry stats.gov.cn/tjfx/jdfx/t20110428_402722253. and administration of drug registration. 2010 China–Japan Symposium on Global Clinical 4. National Bureau of Statistics of China Trials and Ethnic Factors, China. At http:// (2011). Preliminary verification bulletin on www.pmda.go.jp/english/past/2010_sympo/ 2010 annual gross domestic product (GDP). file/201005_03.pdf At http://www.stats.gov.cn/tjdt/zygg/sjxdtzgg/ t20110907_402752625.htm 15. State Food and Drug Administration. SFDA issues Requirements for application 5. Constitution of the People’s Republic of dossiers in CTD format for a pharmaceutical China (Full text after amendment on 14 March product. News Release. 11 October 2010. At 2004). At: http://www.npc.gov.cn/englishnpc/ http://eng.sfda.gov.cn/WS03/CL0757/62297. Constitution/node_2825.htm html 6. State Food and Drug Administration. Main responsibilities of SFDA. At http://eng.sfda. 16. State Food and Drug Administration gov.cn/WS03/CL0756/ (2011).Good manufacturing practice for drugs (2010 Revision) issued. News Release. At 7. Order of the President of the Peoples Repu- http://eng.sfda.gov.cn/WS03/CL0757/62350. blic of China (No. 45). Article 6 of the Drug html Administration Law of the People’s Republic of China. At http://eng.sfda.gov.cn/WS03/ 17. State Food and Drug Administration. Good CL0766/61638.html manufacturing practice for drugs, (2010 Revi- sion). ( MOH Decree No. 79.) At http://eng. 8. Information Office of the State Council sfda.gov.cn/WS03/CL0768/65113.html of the People’s Republic of China (2008). Status quo of drug supervision in China. 18. State Food and Drug Administration At http://www.gov.cn/english/2008-07/18/ (2010). The Third General Assembly of the content_1049011.htm Ninth Chinese Pharmacopoeia Commission and the Summing-up Conference on Compi- 9. State Food and Drug Administration (2011). lation of The 2010 Chinese Pharmacopoeia. Database of Pharmaceutical manufacturers. Beijing. News Release. At http://eng.sfda.gov. Official website of SFDA at http://app1.sfda. cn/WS03/CL0757/62334.html gov.cn/datasearch 19. State Food and Drug Administration. 10. Southern Medicine Economic Research Notice for facilitating the implementation of Institute of SFDA (2011). Medicinal Economic GLP. Guo shi yao jian an(2006)587. At http:// Newspaper. Capital-driven time is coming. www.sda.gov.cn/WS01/CL0055/10619.html At http://www.yyjjb.com/html/2011-07/13/ content_146414.htm 21. State Food and Drug Administration (2010). 2009 Report on the evaluation and 11. State Food and Drug Administration. Wu approval of drug registrations. At http://www. Zhen (2011). National Conference on Medi- sda.gov.cn/WS01/CL0236/54135.html cines Regulation. News Release. At http:// app1.sfda.gov.cn/WS01/CL0287/68457.html 21. Xinhua News Agency (2009). Deepening reform in healthcare system and establishing 12. National People’s Congress. At http:// the county’s essential medicines system. At www.npc.gov.cn/pc/11_4/2007–11/20/ http://news.xinhuanet.com/politics/2009-11/15/ content_1617713.htm content_12462632.htm

13. State Food and Drug Administration 22. Ministry of Health (2009). National Essen- (2007). Provisions for drug registration. At tial Medicines Committee established. At http://www.sda.gov.cn/WS01/CL0053/24529. http://www.moh.gov.cn/publicfiles/business/ html htmlfiles/wsb/pwsyw/200905/40493.htm

13 Regulatory Focus WHO Drug Information Vol. 26, No. 1, 2012

23. Ministry of Health, National Development 29. The State Council (2005). Regulation for and Reform Commission, Ministry of Industry control of narcotics and psychotropics. At and Information Technology, Ministry of Super- http://www.sfda.gov.cn/WS01/CL0784/23500. vision, Ministry of Finance, Ministry of Human html Resources and Social Security, Ministry of Commerce, State Food and Drug Adminis- 30. State Food and Drug Administration tration, State Administration of Traditional (2007). Notice on the establishment of a Chinese Medicine (2009). Provision for Natio- monitoring network for narcotics and psy- nal Essential Medicines List (Interim). At http:// chotropics. Guo shi yao jian ban(2007)482, www.moh.gov.cn/publicfiles/business/htmlfiles/ 3 August,2007. At http://former.sfda.gov.cn/ mohbgt/s7692/200908/42512.htm cmsweb/webportal/W945325/A64022736.html

24. Ministry of Health, National Development 31. State Food and Drug Administration. State and Reform Commission, Ministry of Industry Administration for Industry and Commerce and Information Technology, Ministry of Super- (2007). Drug advertisement examination and vision, Ministry of Finance, Ministry of Human release standards. At http://www.sfda.gov.cn/ Resources and Social Security, Ministry of WS01/CL0053/24526.html Commerce, State Food and Drug Adminis- tration, State Administration of Traditional 32. State Food and Drug Administration Chinese Medicine (2009). Position Paper (2011). Online database of SFDA web sites on implementation of the National Essential at http://app1.sfda.gov.cn/datasearch/face3/ Medicines System. At http://www.moh.gov. dir.html cn/publicfiles/business/htmlfiles/mohywzc/ s3581/200908/42498. 33. General Office of the State Council of the People’s Republic of China (2010). Guo 25. State Drug Administration. Guo yao jian ban han (2010)67. At http://www.gov.cn/ an(1999)460. Facilitating China’s classifi- zwgk/2010-04/19/content_1586732.htm cation of prescription and non-prescription medicines. At http://www.sda.gov.cn/WS01/ 34. Ministry of Health (2011). Provisions for CL0055/9684.html ADR reporting and monitoring. At http://www. sfda.gov.cn/WS01/CL0053/62621.html 26. State Food and Drug Administration (2004). Guo shi yao jian an(2004)101, 35. State Food and Drug Administration. Conducting the switch of prescription and Yan min. Development of ADR reporting and OTC. At http://www.sda.gov.cn/WS01/ monitoring in China. 14th ICDRA, Singapore, CL0055/10268.html at http://www.who.int/medicines/areas/qua- lity_safety/regulation_legislation/icdra 27. State Food and Drug Administration (2004). Guo shi yao jian zhu(2007)54. Noti- 36. The UPPSALA Monitoring Center (2011). fication of release of the insert sheet model SFDA in China and the UMC – Collaboration for over-the-counter medicines. At http:// in sharing global patient safety information. former.sfda.gov.cn/cmsweb/webportal/W472/ At http://www.umc-products.com/DynPage. A64019346.html aspx?id=75618&news=10096

28. State Food and Drug Administration 37. State Food and Drug Administration (2011). Database of model insert for over-the- (2011). Guideline on strengthening the esta- counter medicine. Official website of SFDA at blishment of an ADR monitoring system. At http://app1.sfda.gov.cn/datasearch/face3/dir. http://www.sfda.gov.cn/WS01/CL0844/66936

14 WHO Drug Information Vol. 26, No. 1, 2012

Paediatric Medicines

Better medicines for children: The guideline aims to: pharmaceutical formulations • Inform regulatory authorities and manufacturers of issues that require special Safe and effective pharmacotherapy in attention in the development of paedi- paediatric patients requires the timely atric medicines taking into accounting development of medicines to suit the age, new trends and developments as well physiological condition and body size of as efforts undertaken by regulatory the child. However, use of unlicensed and authorities. off-label medicines in children is wide- spread. Formulations developed specific- • Focus on conditions and special needs ally for children are urgently needed. in developing countries. The guideline indicates sources of detailed instruc- In 2007, the World Health Organization tions for the development of paediatric (WHO) launched the “Make Medicines medicine formulations. (A list of guide- Child Size” project. The WHO Quality lines and literature appearing in the Assurance Programme has contributed guideline are reproduced on page 19.) to the project by developing norms and The guideline covers paediatric dosage standards for global application. The forms, dosage forms to be considered WHO Expert Committee on Specifications in particular, oral administration, rectal for Pharmaceutical Preparations have administration, parenteral administration, recently endorsed a first guideline and dermal and transdermal administration, several monographs related to paediatric inhalations and packaging and labelling. medicines. Extemporaneous preparations and com- Guideline development pounding are not within the scope of the A preliminary draft document “ Develop- document. However, a separate sup- ment of paediatric medicines: points to plementary guidance document entitled consider” was discussed at the Expert “Provision by healthcare specialists of Committee’s Forty-second meeting in patient-specific preparations that are not 2007. A further text was prepared based available as authorized products: points on the above draft and on “Formulations to consider” is under preparation. of choice for the paediatric population” published by the European Medicines Paediatric dosage form selection Evaluation Agency in 2006. Preparatory The guiding principles in selecting pae- work involved coordination with ongoing diatric dosage forms should be, as for activities both within and outside WHO, adults, the balance of risk/benefit taking in particular with the European Medicines into account the specific needs of the Agency (EMA), UNICEF, and the WHO 0–18 year-old population. Essential Medicines Programme. After wide circulation for comment, “Develop- Convenient, reliable administration. ment of paediatric medicines: points to The administered dose should be ad- consider in pharmaceutical formulation” justed to the age and needs of the patient was adopted at the Forty-sixth Expert and manipulation of the dose should be Committee meeting in October 2011. kept to a minimum. Paediatric medicines

15 Paediatric Medicines WHO Drug Information Vol. 26, No. 1, 2012

Table 1. Paediatric dosage form indicators

Dosage form Advantage Consideration Reference

Flexible solid Priority dosage form. Not suitable for dosage forms, e.g., Suitable for both medicines requiring a orodispersible developed and precise dose titration tablets developing countries

May be used for Compatibility of API various APIs and breast milk

Potentially for use in children > 6 months

Oral medicines for Suitable for precise dose Platform technology for WHO: precise dose titration measurement or titration multiparticulate solids QAS/11.399/Rev.1*

Parenteral For severe diseases Requires a trained formulations and conditions caregiver

Rectal preparations Severely ill children or Cultural barriers to use children unable to swallow

*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 formu- End-user needs. Paediatric medicines lations. Alternatively, the dosage form should be easy to use and affordable with should be designed to subdivide into regard to: smaller, uniform doses of appropriate size for accurate dosing. • Supply (e.g., ease of transportation, storage requirements). Acceptability and palatability. The • Access to clean water. dosage form should be palatable, easy to administer and acceptable to the • Adequate product information (e.g., patient. It should also be developed to how to administer; compatibility and avoid any potential interactions with food incompatibility with food ingredients). and medicine or effects on bioavailability. If administration with common food or Dosage forms liquids is acceptable, information sup- Although the most appropriate dosage ported by evidence-based compatibility form should be based on a case-by- studies should be provided in the patient case evaluation, in general, flexible solid information leafet. dosage forms are likely to prove most suitable for global use and should be prio- Dosing frequency. A minimum dosing ritized (Table 1). frequency should be preferred to facilitate compliance with the dosing schedule for Formulation design older children or caregivers. Instructions Many items need to be considered in the on the dosing frequency should be based design of formulations for paediatric use. on the pharmacokinetic and pharmaco- Those mentioned in the Development of dynamic properties of the active phar- paediatric medicines document include maceutical ingredient (API) but may be quality, the Biopharmaceutics Classifi- influenced by the design of the dosage cation System (BCS), excipients, colou- form. ring agents, antimicrobial preservatives,

16 WHO Drug Information Vol. 26, No. 1, 2012 Paediatric Medicines

Table 2. Paediatric formulation design indicators Item Consideration (key) Selected references

1. Quality Acceptable level of impurities in APIs WHO: QAS/10.376 Degradation products in FPPs ICH :Q3A(R2);Q3B;Q3C Safety margins on APIs and FPPs EMA: CPMP/SWP/5199/02 Safety studies in juvenile animals EMEA/CHMP/SWP/431994/2007 FPP compliance CPMP/SWP/QWP/4446/00 Dissolution testing to address The International Pharmacopoeia gastric pH of the child FIP/AAPS guidelines

2. BCS BCS-based API classification WHO. Technical Report Series, Transporter function and metabolic No.937, Annex 8. enzymes (typically CYP3A4) Excipients affecting transit time (efflux)

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 pharmaceutical products. WHO. Technical Report Series. Evaluation of certain food additives.

4. Colouring Use is generally discouraged Pollock I, Young E, Stoneham M agents Use may be justified in certain cases, (1989). Survey of colorings e.g. to avoid accidental dosing errors and preservatives in drugs. (several strengths) Pefferi G, Restani P (2003). Acceptable number for use is limited The safety of pharmaceutical Azo-dyes should be avoided excipients. Risk of allergic reactions associated with natural colourants

5. Antimicrobial Potential to cause adverse reactions in Public statement on antimicrobial preservatives infants and neonates preservatives in ophthalmic Avoid use whenever possible preparations for human use Keep to minimum concentration level (EMEA/622721/2009). Solid dosage forms do not need free-mercury-containing preservatives in ophthalmic preparations

6. Sweetening Safety in specific conditions (diabetes, agents fructose intolerance, phenylketonurea) Laxative effect

7. Taste Cultural differences in taste and acceptability Ernest TB et al (2007). Developing masking develop taste for maximum acceptability paediatric medicines: identifying Non-cariogenic sweeteners and flavours the needs and recognizing preferred the challenges.

8. Solubility Higher risks for parenteral preparations enhancers 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

17 Paediatric Medicines WHO Drug Information Vol. 26, No. 1, 2012 sweetening agents, taste making and tration route are highlighted and relevant solubility enhancers. references are listed. (See Table 2.)

Route of administration Next steps The common route of administration Although development of paediatric medi- discussed in the document covers oral, cines is still subject to limited knowledge rectal, parenteral, dermal and transder- in some areas, progress is rapidly being mal administration and inhalation. Special made. issues for consideration of each adminis-

Table 3. Route of administration and formulations

Administration Special considerations References

Oral

liquid preparations • preferred route for paediatric patients Strickly RG et al (2007). • drops • stabilizing agents are a major drawback Paediatric Drugs. A (microbial and chemical) • stability of multidose preparations review of commer- • powders and granules • risks of incorrect dosing cially available oral for reconstitution • dose-measuring device critical (drops) formulations. • suspensions • stability parameters of oral suspensions Siewert M et al (2003). FIP/AAPS guidelines Administration through for dissolution/ nasogastric tubes • no effects from saliva and gastric juice: in vitro release may afffect bioavailability testing of novel/ • potential absorption of API into special dosage tube material forms. Thomson SA et al Solid dosage forms (2009). Mini-tablets: • powders and multiparticulate • Improved stability, good dosage uni- new modality to preparations formity, options for different doses deliver medicines • immediate-release tablets • crushing tablets may affect bioavailability to preschool-age • capsules (only if allowed by manufacturer) children. • chewable tablets • chewable tablets may be chewed or Seager H (1998). swallowed whole (dissolution test Drug–delivery conditions same as for tablets) products and • effervescent dosage forms • control moisture and humidity in the zydis fast- manufacture, packaging dissolving and storage of effervescents dosage form. • effervescents: caution in renal insufficiency • dispersible and soluble tablets • dispersible and soluble tablets: flexibility ICH E11 for water-soluble APIs EMEA/622721/2009 • 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

Rectal

suppositories • important route of administration for children severely ill or unable to swallow rectal liquids • concordance and compliance of rectal preparation may be lower • cultural and regional acceptance barriers

18 WHO Drug Information Vol. 26, No. 1, 2012 Paediatric Medicines

Table 3. Route of administration and formulations (continued)

Administration Special considerations References

Parenteral • 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 • 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.

Inhalations

Liquids for nebulization • total lung deposition important for Krause J, Breitkreuts J clinical efficacy of preparation. (2008). Improving drug Metered dose inhalers (MDIs) • small airway diameter in children, deposition delivery in paediatric by impact in upper and central airways may medicine. Dry powder inhalers (DPIs) be significantly higher in children. 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.

Bibliography cifications for Pharmaceutical Preparations. 1. European Medicines Agency. Clinical Inves- Technical Report Series, No. 929, Annex 5. tigation of Medicinal Products in the Paediatric Guidelines for registration of fixed-dose com- Population, ICH Topic E11. January 2001 bination medicinal products (2005) at http:// CPMP/ICH/2711/99 at http://www.ema.europa. www.who.int/medicines eu/docs/en_GB/document_library/Scientific_ guideline/2009/09/WC500002926. 4. World Health Organization. Pharmaceu- tical development for multisource (generic) 2. World Health Organization. Guideline on pharmaceutical products. Working document quality risk management (working document QAS/08.251/Rev.1 at http://www.who.int/ QAS/10.376) at http://www.who.int/medicines medicines

3. World Health Organization. Thirty-ninth 5. International Conference on Harmonization. report of the WHO Expert Committee on Spe- Impurities in new drug substances. ICH Topic

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Q3A(R2) at http://www.ich.org/fileadmin/Pu- EMEA/566810/2008. at http://www.ema. blic_Web_Site/ICH_Products/Guidelines/Qua- europa.eu/docs/en_GB/document_library/ lity/Q3A_R2/Step4/Q3A_R2__Guideline.pdf Scientific_guideline/2009/09/WC500003754. pdf 6. European Medicines Agency. Impurities in new drug products, ICH Topic Q3B. CPMP/ 14. World Health Organization. Fortieth report ICH/2738/99 at http://www.ema.europa.eu/ of the WHO Expert Committee on Specifi- docs/en_GB/document_library/Scientific_gui- cations for Pharmaceutical Preparations. deline/2009/09/WC500002676.pdf Technical Report Series, No. 937, Annex 7: Multisource (generic) pharmaceutical pro- 7. European Medicines Agency. Impurities: ducts: guidelines on registration requirements guideline for residual solvents, ICH Topic to establish interchangeability (2006) at http:// Q3C. February 2009. CPMP/ICH/283/95 at www.who.int/medicines http://www.ema.europa.eu/docs/en_GB/docu- ment_library/Scientific_guideline/2009/09/ References WC500002674.pdf 1. Kearns GL et al. Developmental phar- 8. European Medicines Agency. Guide- macology – drug disposition, action and line on the limits of genotoxic impurities therapy in infants and children. N Eng J Med (CPMP/SWP/5199/02). EMEA/CHMP/ 2003;349(12):1157–1167. QWP/251344/2006 at http://www.ema.europa. eu/docs/en_GB/document_library/Scientific_ 2. European Medicines Agency. Reflection guideline/2009/09/WC500002903.pdf paper: formulations of choice for the paediatric population. (EMEA/CHMP/PEG/196810/2005) 9. European Medicines Agency. Q&A on the at http://www.nppg.scot.nhs.uk/misc/choicepa- CHMP Guideline on the limits of genotoxic per0605.pdf impurities. EMEA/CHMP/SWP/431994/2007 at http://www.ema.europa.eu/docs/en_GB/do- 3. Ernest TB et al. Developing paediatric cument_library/Scientific_guideline/2009/09/ medicines: identifying the needs and reco- WC500002903.pdf gnizing the challenges. J Pharm Pharmacol 2007;59:1043–1055. 10. European Medicines Agency. Note for guidance on specification limits of residues of 4. Krause J, Breitkreutz J. Improving drug metal catalysts (CPMP/SWP/QWP/4446/00). delivery in paediatric medicine. Pharma- 17 December 2002. http://www.ema.europa. ceutical Medicine 2008;22:41–50. eu/docs/en_GB/document_library/Scientific_ guideline/2009/09/WC500003588.pdf 5. Allen LV. Dosage form design and development. Clin Ther 2008;30(11):2102–2111. 11. World Health Organization. Fortieth report of the WHO Expert Committee on Specifica- 6. Siewert M et al. FIP/AAPS guidelines for tions for Pharmaceutical Preparations. Techni- dissolution/in vitro release testing of novel/ cal Report Series, No. 937, Annex 8, Proposal special dosage forms. Dissolution Technolo- to waive in vivo bioequivalence requirements gies 2003; February Issue, page 15. for WHO Model List of Essential Medicines immediate-release, solid dosage forms (2006) 7. Breitkreutz J, Boos J. Paediatric and at http://www.who.int/medicines geriatric drug delivery. Expert Opin Drug Deliv 2007;4(1):37–45. 12. European Medicines Agency. Public statement on antimicrobial preservatives in 8. Shehab N et al. Exposure to the phar- ophthalmic preparations for human use. 8 maceutical excipients benzyl alcohol and December 2009. EMEA/622721/2009 at http:// propylene glycol among critically ill neo- www.techtran.co.jp/techtr_j/globepharm/ nates. Pediatric Critical Care Medicine emea091208.pdf 2009;10(2):256-259. 13. European Medicines Agency. Guide- 9. “Inactive” Ingredients in Pharmaceutical line on the investigation of medicinal pro- Products: Update: http:/www.pediatrics.org/ ducts in the term and preterm neonate. cgi/content/full/99/2/268

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10. World Health Organization. Technical 15. Thomson SA et al. Mini-tablets: new mo- Report Series, Evaluation of certain food addi- dality to deliver medicines to preschool-aged tives. List of publications: http://www.who.int/ children. Paediatrics 2009;123(2):e235–e238. ipcs/publications/jecfa/reports/en/index.html. 16. Seager H. Drug-delivery products and the 11. Pollock I, Young E, Stoneham M. Survey Zydis fast-dissolving dosage form. J Pharm of colourings and preservatives in drugs. Brit. Pharmacol1998;50:375–382. Med J 1989;299:649–651. 17. Dolovich M. Influence of inspiratory flow 12. Pefferi G, Restani P. The safety of rate, particle size and airway caliber in aero- pharmaceutical excipients. Il Farmaco 2003; solized drug delivery to the lung. Respiratory 58:541–550. Care 2000;45:597–608. 13. Mennella JA, Beauchamp GK. Optimi- zing oral medications for children. Clin Ther 18. Schüepp K, Jauernig J, Janssens H. In 2008;30(11):2120–2132. vitro determination of the optimal particle size for nebulized aerosol delivery to infants. J 14. Strickly RG et al. Paediatric drugs – Aerosol Med 2005;18(2):225–235. A review of commercially available oral formulations. J Pharm Sci 2007;97(5):1731–1774.

Benznidazole: child-adapted America, and kills some 12,000 people dosage form approved each year, making it the leading para- sitic killer in the Americas. The Chagas Brazil’s National Health Surveillance parasite is primarily transmitted via the Agency (ANVISA) has granted registra- bite of the blood-sucking triatome bug. tion of a new paediatric dosage form of In addition to blood transfusion, organ benznidazole, developed through a par- transplant, or ingesting infected food, the tnership between the Pernambuco State parasite is also transmitted during preg- Pharmaceutical Laboratory (LAFEPE) nancy from mother to child. of Brazil and the Drugs for Neglected Diseases initiative (DNDi). Registration This new dosage form for children repre- of this formulation of benznidazole was sents real progress for several reasons. made on 12 December 2011. Children are at especially high risk of This new tablet is easier-to-administer infection, with a majority of them born and a safer treatment of Chagas disease from infected mothers. It is known that in infants and young children under the early treatment using benznidazole in the age of two, as they will receive accu- first year of life can eliminate the parasite rate dosage. Until now, benznidazole in more than 90% of infected newborns. was available only as a 100 mg tablet Thus, babies infected with Chagas for adults. Treatment for young children disease will benefit the most from this required cutting adult pills into tiny slivers new paediatric tablet. — up to 12 pieces depending on the child’s weight — and crushing and mixing The new 12.5 mg tablet is easily disper- them with water or juice, to be administe- sible and adapted for babies and child- red twice a day for 60 days. This difficult ren up to two years of age (20 kg body and inefficient method often results in weight). Treatment is designed to use improper dosing, risks of increased side- one, two, or three tablets, depending on effects, ineffective treatment, or treatment weight (recommended dosage, 5–10 mg/ stoppages. kg body weight/day). Chagas disease affects an estimated Tools to facilitate implementation of and eight to ten million people, mostly in Latin access to the new treatment include a

21 Paediatric Medicines WHO Drug Information Vol. 26, No. 1, 2012

Demand Forecast, a Procurement Guide, dosage form. The new tablet will be and a Tool Box providing training and produced by LAFEPE, a public pharma- educational materials for doctors, other ceutical manufacturer run by the State of health professionals, mothers, and care- Pernambuco in Brazil and the sole global givers regarding appropriate use of the producer of benznidazole. treatment. Reference: DNDi Drugs for Neglected In 2008, DNDi and LAFEPE entered a Diseases initiative at http://www.dndi.org joint development agreement for this

Use of drugs in paediatric health pharmaceutical company representatives. conditions increasing In the absence of experimental studies in paediatric populations, information In the past, treatment decisions involving provided by these sources may be based the use of drugs in infants, children and more on expert opinion or local practice youth were often derived from the data and experience (5). in drug studies involving adults (1, 2). However, the safety and efficacy of medi- Drug investigations in paediatric popu- cations may be significantly different in lations can be faced with multiple chal- paediatric patients than in adult patients lenges. Some examples include: owing to differences in developmental physiology, disease pathophysiology, • Defining appropriate ethical adaptations and developmental pharmacokinetics of clinical trials for studies involving and pharmacodynamics (2). This unders- infants, children and youth (1). tanding has led to the use of the phrase «children are not just small adults,» a • Ensuring adequate sample sizes (1, 2). statement that emphasizes the urgent • Choosing objective, clinically relevant need for evidence from high-quality trials endpoints that can be measured in a involving paediatric patients (2). valid and reliable manner (1, 2). The use of drugs to treat paediatric • Overcoming technical difficulties, such health conditions in Canada is increasing as the need for frequent blood sampling (3). Infants, children and youth repre- (1). sent nearly one-quarter of Canada’s • Improving pharmacoepidemiologic and population and, on average, receive four pharmacovigilance practices aimed to prescriptions a year from a range of more coordinate the development of reliable than 1200 different drugs (3, 4). None- information about drug benefits and theless, data on the efficacy and safety of harms to reduce uncertainties about the most medications prescribed for pediatric use of drugs in paediatric populations. patients are limited (2, 3, 5). • Expanding the availability of age-appro- When prescribing a medication for an priate product formulations (e.g., liquid «off-label» indication in infants, child- formulations). ren or youth, health professionals may consult available sources of information, Health Canada, like other regulatory such as peer-reviewed medical literature, authorities around the world, recognizes paediatric dosing manuals and textbooks, the need to strengthen information related drug formularies at children’s hospitals, to paediatric health. In pursuit of this ob- community pharmacists and the relevant jective, some of its key activities include:

22 WHO Drug Information Vol. 26, No. 1, 2012 Paediatric Medicines

• Coordinating the development of paedi- References atric information through the regulatory system and other means. 1. Matsui D, Kwan C, Steer E, et al. The trials and tribulations of doing drug research in • Coordinating how this information is children. CMAJ 2003;169(10):1033–4. made available and accessible. 2. Klassen TP, Hartling L, Craig JC, et al. • Raising awareness of child health Children are not just small adults: the urgent needs and safety issues related to the need for high-quality trial evidence in children. development and use of health prod- PLoS Medicine 2008;5(8):1180–2. ucts and food. 3. Abi Khaled L, Ahmad F, Brogan T, et al. • Promoting conditions that enable in- Prescription medicine use by one million formed decisions about the health and Canadian children. Paediatr Child Health nutrition of infants, children and youth. 2003;8(A):6A–56A.

To help improve safety data about health 4. Junker A. Canadian pediatric clinical trials products for the paediatric population, it activity 2005-2009. Maternal Infant Child is important for healthcare providers to Youth Res Network 2010;Aug:1–19. continue to report adverse reactions in both paediatric and adult populations. 5. Matsui D, Jardine M, Steer V, et al. Where physicians look for information on drug Extracted from Canadian Adverse Reaction prescribing for children. Paediatr Child Health Newsletter, Volume 22, Issue 1, January 2012 2003;8(4):219–21.

23 WHO Drug Information Vol. 26, No. 1, 2012

Safety and Efficacy Issues

Bevacizumab: severe infectious Ursodeoxycholic acid: serious endophthalmitis and blindness hepatic events Canada — Health Canada has informed Canada — Ursodeoxycholic acid (Urso- healthcare professionals of new safety diol®) is indicated for the management information regarding unauthorized use of cholestatic liver diseases. Canadian of bevacizumab (Avastin®) when repac- Product Monographs for ursodiol® kaged for intra-vitreal injection. products have been updated in October, 2011 to reflect data from a long-term Three clusters of serious ocular compli- clinical trial in primary sclerosing cholan- cations, including acute ocular inflam- gitis (PSC) finding an increase in serious mation, endophthalmitis, and infectious liver adverse events in patients taking endoph-thalmitis resulting in blindness, an unapproved ursodiol dose (twice the have been recently reported in California, recommended dose). Florida and Tennessee. Although these clusters continue to be investigated, it is • The recommended ursodiol dose is possible that the events of blindness from 13–15 mg/kg/day for adults with choles- streptococcal endophthalmitis in Florida tatic disease. were due to repackaging of bevacizumab • In a clinical trial in patients with PSC, without proper aseptic technique. long-term use of twice the recommend-

ed dose of ursodiol® was associated Bevacizumab is a recombinant huma- with improvement in serum liver tests nized monoclonal antibody that is direc- but did not improve survival, and was ted against vascular endothelial growth associated with higher rates of serious factor (VEGF). It is authorized for intra- adverse events (including death or liver venous administration in the following transplantation) compared to placebo. indications: • Improved serum liver tests do not • First-line treatment of patients with always correlate with improved liver metastatic carcinoma of the colon or disease status. rectum in combination with fluoro- pyrimidine-based chemotherapy. Reference: Communication from Aptalis Phar- ma Canada dated 1 December 2011 at http:// • Treatment of patients with unresectable www.hc-sc.gc.ca/dhp-mps/medeff/advisories- advanced, metastatic or recurrent non- avis/prof/_2011/avastin_8_hpc-cps-eng.php squamous non-small cell lung cancer in combination with carboplatin/paclitaxel Simvastatin with amiodarone: chemotherapy regimen. dosage review • Treatment of patients with glioblastoma United States of America — The Food after relapse or disease progression, and Drug Administration (FDA) has following prior therapy. advised of a dose limitation for simvas- Reference: Communication from Hoffmann- tatin from 10 mg to 20 mg when co-ad- La Roche dated 2 December 2011 at http:// ministered with the cardiac drug amioda- www.hc-sc.gc.ca/dhp-mps/medeff/advisories- rone. In June 2011, the FDA previously avis/prof/_2011/avastin_8_hpc-cps-eng.php recommended that the dose limitation for

24 WHO Drug Information Vol. 26, No. 1, 2012 Safety and Efficacy Issues simvastatin be decreased from 20 mg to Reference: FDA Drug Safety Communica- 10 mg, and has now reconsidered that tion, 9 November 2011 at http://www.fda.gov/ recommendation. Unlike other interacting Drugs/DrugSafety/ucm278837.htm drugs, there were no pharmacokinetic or clinical trial data to support the simvasta- BCG vaccine: lymphadenitis tin dose reduction approved with amiodarone. Therefore FDA has determined Singapore — The Health Sciences that the simvastatin dose limitation, when Authority (HSA) has updated healthcare taken with amiodarone, should be res- professionals on suspected reports of tored to 20 mg. lymphadenitis following the administration of the Bacillus Calmette-Guérin (BCG) In patients who are taking both simvasta- Vaccine Staten Serum Institute (SSI)®. tin and amiodarone, the dose of simvas- This observation arose from the active tatin should not exceed 20 mg per day. surveillance and monitoring of vaccine The simvastatin drug labels (Zocor® and adverse events (VAEs) at the sentinel site generics, Vytorin®) have been updated to at KK Women’s and Children’s Hospital reflect this correction. (KKH).

Reference: FDA Drug Safety Communication, In 2009, HSA collaborated with KKH to 15 December 2011 at http://www.fda.gov/ initiate active surveillance for VAEs rela- Drugs/DrugSafety/ucm283137.htm ted to H1N1 vaccines in pregnant women and children. This was subsequently Fenofibric acid: the ACCORD expanded to include all VAEs following lipid trial childhood immunization. United States of America — The Food In Singapore, BCG vaccine is routinely and Drug Administration (FDA) has given to newborns as part of the National advised that the cholesterol-lowering Childhood Immunization Schedule. Since medicine fenofibric acid (Trilipix®) may June 2003, the BCG vaccine manufactu- not lower a patient’s risk of having a heart red by SSI is the sole BCG vaccine regis- attack or stroke. This is based on data tered in Singapore. BCG Vaccine SSI® from the Action to Control Cardiovascular contains an attenuated strain of Mycobac- Risk in Diabetes (ACCORD) Lipid trial, terium bovis (BCG), Danish strain 1331. which evaluated the efficacy and safety of fenofibrate plus simvastatin combination In 2009, there were 26 reports of BCG- therapy versus simvastatin alone in pa- associated lymphadenitis of which 23 tients with type 2 diabetes mellitus. FDA cases (88%) presented as suppurative reviewed this trial as part of its ongoing lymphadenitis. Of these, 22 cases requir- investigation of the safety and efficacy of ed surgical intervention such as excision Trilipix®. or incision and drainage. In 2010, there were 25 reports of lymphadenitis. Sixteen In the ACCORD Lipid trial, there was no cases (64%) presented as suppurative significant difference in the risk of expe- lymphadenitis which required surgical riencing a major adverse cardiac event intervention. From January 2011 to between the group treated with fenofi- October 2011, the reports of lymphaden- brate plus simvastatin compared with itis increased to 53. simvastatin alone. In addition, a subgroup analysis showed that relative to treatment An increase in the number of suspected in men, there was an increase in the reports of BCG-associated suppurative risk for major adverse cardiac events in lymphadenitis has also been identified women receiving the combination therapy in some countries such as Ireland and versus simvastatin alone. Latvia in recent years. However, the

25 Safety and Efficacy Issues WHO Drug Information Vol. 26, No. 1, 2012 overall rate and pattern of VAEs remain undergone elective total hip or total knee consistent with the expected frequency of replacement surgery. In June 2011, the occurrence listed in the package insert of indication for Pradaxa® was extended BCG Vaccine SSI®. to include the prevention of stroke and systemic embolism in patients with non- Reference: Health Sciences Authority (HSA) valvular atrial fibrillation. Safety Announcement at http://www.hsa.gov. sg/publish/hsaportal/en/health_products_regu- Bleeding is a known side-effect for lation/safety_information/product_safety_ dabigatran as it is an extension of its alerts/safety_alerts_2011/reports_of_lympha- pharmacological effect. Based on clini- denitis.html cal evidence, the risk of major or severe bleeding from dabigatran is rare, even Dabigatran etexilate mesylate: though life-threatening or even fatal bleeding events outcomes may occur. The local pack- United States of America — The Food age insert of Pradaxa® currently car- and Drug Administration (FDA) has eva- ries warnings of this risk, including the luated post-marketing reports of serious recommendation to monitor for signs of bleeding events in patients taking dabi- bleeding or anaemia (1). Additionally, the gatran etexilate mesylate (Pradaxa®). local package insert recommends dose Dabigatran etexilate mesylate is a direct adjustments in the elderly and those thrombin inhibitor used to reduce the risk with impaired renal function as well as of stroke in patients with non-valvular close clinical surveillance in patients with atrial fibrillation, the most common type of low body weight (<50kg) and high body heart rhythm abnormality. weight (>110kg). Dabigatran is contraindicated in patients with severe renal Bleeding that may lead to serious or impairment. even fatal outcomes is a well-recognized complication of all anticoagulant therapies To date, HSA has received seven suspec- and the Pradaxa® drug label contains a ted adverse reaction reports associated warning about significant and sometimes with dabigatran. These included one case fatal bleeding. of bleeding, one case of deep vein throm- bosis and blood clot in the heart and one Reference: FDA Drug Safety Communica- case of stroke, all occurring in patients tion, 7 December 2011 at http://www.fda.gov/ between 77 and 86 years of age. The Drugs/DrugSafety/ ucm282724.htm time to onset of these cases were a few months after initiation of dabigatran. No Dabigatran etexilate: caution in the concomitant medicines were reported and elderly and renally impaired none of these cases had a fatal outcome.

Singapore — The Health Sciences Reference: The Health Sciences Authority Authority (HSA) has alerted healthcare (HSA). Safety Announcement, at http://www. professionals to serious cases of bleeding hsa.gov.sg/publish/hsaportal/en/health_pro- associated with the use of dabigatran and ducts_regulation/safety_information reminded them to closely monitor patients who are prescribed this medication, Dabigatran: risk of bleeding especially the elderly and those with renal impairment. Australia — Dabigatran (Pradaxa®) is a potent short-acting anticoagulant for Dabigatran (Pradaxa®) has been licen- which there is no antidote or reversal sed locally since August 2009 for the agent. As with warfarin, bleeding events primary prevention of venous thrombo- can occur. Clinicians are urged to give embolic events in adult patients who have careful consideration to the suitability of

26 WHO Drug Information Vol. 26, No. 1, 2012 Safety and Efficacy Issues patients for dabigatran particularly with Adverse events reported to the TGA for regard to recognized risks of bleeding. dabigatran June 2009 – October 2011

Dabigatran is a potent oral anticoagulant. Type of adverse event Number It is a direct thrombin inhibitor that inhibits Total adverse events 297 free and clot-bound thrombin. It has a Serious adverse events 196 mean half-life of 12–17 hours. It is renally Serious bleeding adverse events 70 excreted and the rate of elimination is Serious gastrointestinal bleeding 48 related to renal function. There is a close Serious intracranial bleeding 6 correlation between plasma dabigatran Events in patients aged 75 years levels and anticoagulant effect. or older: Total adverse events 166 Dabigatran may be considered an alter- Serious adverse events 108 native to warfarin and it carries similar risks of bleeding. In clinical trials the risk regarding the considerations of the TGA of bleeding per year of treatment with in approving dabigatran please see the dabigatran was 16.6% when taking 150 Australian Public Assessment Report mg twice daily, and 14.7% taking 110 (AusPAR) (3). mg twice daily compared with 18.4% for warfarin. References 1. Guidelines for management of bleeding with In April 2011, the Therapeutic Goods dabigatran. New Zealand: PHARMAC; 2011. Administration (TGA) approved dabigatran for use for the prevention of stroke 2. Pradaxa Product Information. Boehringer and systemic embolism in patients with Ingelheim Pty Limited. August 2011. non-valvular atrial fibrillation and at least one risk factor for stroke. Since then, 3. Dabigatran etexilate mesilate-AusPAR. The- the TGA has received an increase in rapeutic Goods Administration. 14 May 2011 the number of bleeding-related adverse at http://www.tga.gov.au events reports for dabigatran (see table). Pneumovax 23®: revaccination The analysis of these reports shows that recommendations some of the bleeding adverse events occurred during the transition from war- Australia — Pneumovax 23® vaccination farin to dabigatran; many of the adverse is used to prevent life-threatening infec- events are occurring in patients on the tions by pneumococcal bacteria. reduced dosage regimen; and the most common site of serious bleeding for In March 2011, a cluster of seven severe dabigatran is the gastrointestinal tract, local injection site reactions was reported whereas for warfarin it is intracranial. to the Therapeutic Goods Administration (TGA) by NSW Health and as a result Australian experts are currently develo- a recall of the batch of Pneumovax® ping guidelines for the management of implicated in these reactions was ordered bleeding in patients taking dabigatran. In by the TGA on 25 March 2011. the meantime clinicians are referred to the New Zealand guidelines (1). In April 2011, as a result of a continued increase in severe injection site reaction It is strongly recommended that clinicians reports, the TGA issued advice to health read the Product Information before professionals not to administer a second prescribing dabigatran. The Product or subsequent dose of Pneumovax 23® Information is available from the TGA web vaccine pending the outcome of a review, site (2). For more detailed information which has now been completed.

27 Safety and Efficacy Issues WHO Drug Information Vol. 26, No. 1, 2012

Laboratory analysis of the recalled batch to remind prescribers to strictly follow (N3336) did not detect any problems rela- the approved indications and doses and ted to vaccine manufacture or handling. to carefully consider the warnings and The TGA has now determined that the precautions for somatropin-containing adverse events were not a batch- medicines. related problem. The TGA considers that the increased numbers of reports of Somatropin is a human growth hormone, severe reactions were a result of: manufactured using recombinant DNA technology. It promotes growth during • The known high rates of local reactions, childhood and adolescence, and also including severe injection site reactions, affects the way the body handles pro- which occur more commonly after a teins, fat and carbohydrates. It is used to repeat dose of Pneumovax 23®. treat a number of conditions associated with impaired growth and short stature. • The increased number of people having These include children who fail to grow a repeat dose following the inclusion of adequately due to a lack of growth hor- Pneumovax 23® vaccine in the Na- mone, Turner syndrome or chronic renal tional Immunization Programme in 2005 insufficiency and short children born small with revaccination after five years. for gestational age. • The increased reporting that followed Reference: EMA Press Release, EMA/ the publicity of the batch recall. CHMP/965945/2011, 15 December 2011 at http://www.ema.europa.eu The TGA is advising that revaccination with Pneumovax 23® can be undertaken Pholcodine-containing cough in accordance with the approved Product medicines Information (PI). In summary, revaccination should: European Union — The European Medi- cines Agency’s Committee for Medicinal • not be given routinely to immunocom- Products for Human Use (CHMP) has petent individuals (that is, those with a confirmed that the benefits of pholcodine- healthy immune system). containing cough medicines outweigh • be considered for patients at a high their risks and that these medicines risk of serious pneumococcal disease, should remain available for the treatment provided that at least five years has of non-productive (dry) cough in children passed since the previous dose of and adults. Pneumovax 23®. The review of pholcodine-containing me- Reference: Pneumovax 23®: updated revac- dicines was initiated because of concerns cination recommendations. 23 December that there could be cross-sensitisation 2011 at http://www.tga.gov.au/safety/alerts- between pholcodine and neuromuscular medicine-pneumovax-111223.htm blocking agents (NMBAs). It was suspected that this in turn could lead to ana- Somatropin-containing medicines: phylactic reactions in some patients recei- positive benefit-risk balance ving NMBAs during emergency surgery who had previously taken pholcodine- European Union — Following a review containing cough medicines. of somatropin-containing medicines, the European Medicines Agency’s Committee Following a thorough review of all avai- for Medicinal Products for Human Use lable data on the safety and efficacy of (CHMP) has confirmed that the benefit- pholcodine-containing cough medicines, risk balance of these medicines remains the Committee found no firm evidence positive. However, the CHMP wished to substantiate the hypothesis of cross-

28 WHO Drug Information Vol. 26, No. 1, 2012 Safety and Efficacy Issues sensitization between pholcodine and case reports, open studies of clinical NMBAs and a subsequent increased risk experience and controlled clinical trials of anaphylactic reactions during surgery. (4, 5). Second-generation antipsychotics have been prescribed for children and Reference: EMA Press Release, EMA/ adolescents with mental health problems CHMP/898043/2011, 18 November 2011 at such as schizophrenia, bipolar I disorder, http://www.ema.europa.eu autism, pervasive developmental disorder, disruptive behaviour disorders (inclu- Antipsychotics in children and ding conduct disorder and attention-deficit adolescents: cardiometabolic hyperactivity disorder), developmental reactions disabilities and Tourette syndrome (6). Use of these drugs in the paediatric popu- Canada — Health Canada has received lation has increased substantially over the 29 reports of cardiometabolic adverse last decade (6–8). According to one esti- reactions suspected of being associated mate, antipsychotic drug prescriptions for with second-generation antipsychotics children and youth in Canada increased (SGAs) in children and adolescents under by 114% from 2005 to 2009 (4). Despite 18 years of age. In Canada, no SGAs are this increased use, data regarding their authorized for use in children or adoles- safety are limited (2). cents, with one recent exception authorized for use only in adolescents 15 to The cardiometabolic effects of SGAs in 17 years old for the treatment of schizo- pediatric patients, including age-inappro- phrenia. priate weight gain, obesity, hypertension, and lipid and glucose abnormalities, are Excess weight and obesity in the popula- of concern (8). Furthermore, children and tion are increasing problems throughout adolescents with mental health problems the Western world, and this rise has also often have multiple cardiovascular risk been observed in children and adoles- factors, including poor nutrition, inade- cents (1). Weight gain and obesity are quate exercise, substance abuse and known to be associated with diabetes, lack of adequate healthcare monitoring dyslipidaemia and hypertension (2). In (2, 9). Some studies have shown that addition, weight gain is a well-established youth using antipsychotic agents may adverse reaction to second-generation be at a higher risk of weight gain and antipsychotics (SGAs) (1). metabolic effects than adults who use the same drugs (2, 7, 10). If weight gain In Canada, there are seven marketed is established in youth, it tends to persist second-generation antipsychotics: cloza- into adulthood (10). pine, risperidone, olanzapine, quetiapine, paliperidone, ziprasidone and aripipra- Because of differences in absorption, dis- zole. Recently, aripiprazole (Abilify®) was tribution and metabolism of antipsychotics authorized for the treatment of schi- in the paediatric population, higher doses zophrenia in adolescents 15 to 17 years per weight are required than in adults old (3). to achieve similar efficacy (2). Cardio- metabolic effects are problematic during Previously, there were no authorized childhood because they tend to be predic- indications for the use of SGAs in children tors of adult obesity, metabolic syndrome, or adolescents under 18 years of age in hypertension, cardiovascular morbidity Canada. Paediatric drug use, in many and malignant disease (2, 7, 8). circumstances, has been based primarily on information extrapolated from studies Adverse effects such as weight gain have involving adults, as well as from other been found to vary significantly by SGA types of scientific evidence, including agent. Clozapine and olanzapine seem

29 Safety and Efficacy Issues WHO Drug Information Vol. 26, No. 1, 2012 to be associated with the highest risk of 8, Correll CU, Manu P, Olshanskiy V, et al. clinically significant weight gain in child- Cardiometabolic risk of second-generation ren and adults (1, 2, 7). Risperidone and antipsychotic medications during first-time quetiapine generally show modest risk, use in children and adolescents. JAMA whereas ziprasidone and aripiprazole are 2009;302(16):1765–73. associated with the lowest risk. Limited 9. Varley CK, McClellan J. Implications of data are available for paliperidone (4). marked weight gain associated with atypical The risk of lipid elevation and increased antipsychotic medications in children and blood sugar appears to be greatest with adolescents. JAMA 2009;302(16):1811–2. olanzapine (11). 10. Ratzoni G, Gothelf D, Brand-Gothelf A, Extracted from Canadian Adverse Reaction et al. Weight gain associated with olanzapine Newsletter, Volume 22, Issue 1, January 2012 and risperidone in adolescent patients: a com- parative prospective study. J Am Acad Child References Adolesc Psychiatry 2002;41(3):337–43.

1. Newcomer JW. Second-generation (aty- 11. Ho J, Panagiotopoulos C, McCrindle B, pical) antipsychotics and metabolic effects: et al. Management recommendations for me- a comprehensive literature review. CNS tabolic complications associated with second Drugs 2005;19(Suppl 1):1–93. generation antipsychotic use in children and youth. J Can Acad Child Adolesc Psychiatry 2. De Hert M, Dobbelaere M, Sheridan EM, 2011;20(3):234–41. et al. Metabolic and endocrine adverse effects of second-generation antipsychotics in children and adolescents: a systemic review Citalopram hydrobromide: dose- of randomized, placebo controlled trials and dependent QT prolongation guidelines for clinical practice. Eur Psychiatry 2011;26:144–58. Canada — Health Canada has informed healthcare professionals that the 3. Abilify® (aripiprazole) [product monograph]. antidepressant citalopram hydrobromide Montréal (QC): Bristol-Myers Squibb Canada; (Celexa®, also marketed as generics), 2011. should no longer be used at doses greater than 40 mg per day due to study 4. Pringsheim T, Panagiotopoulos C, Davidson results indicating a dose-dependent J, et al. Evidence-based recommendations for potential for QT prolongation. Previously, monitoring safety of second generation anti- the Canadian Product Monograph stated psychotics in children and youth. J Can Acad that certain patients may require 60 mg Child Adolesc Psychiatry 2011;20(3):218–33. per day. 5. Zito JM, Derivan AT, Kratochvil CJ, et al. Off-label psychopharmacologic prescribing for Citalopram hydrobromide is a selective children: history supports close clinical moni- serotonin reuptake inhibitor (SSRI) indi- toring. Child Adolesc Psychiatry Mental Health cated for the symptomatic relief of de- 2008;2(24):1–11. pressive illness available as 20 mg and 40 mg tablets. 6. Panagiotopoulos C, Ronsley R, Elbe D, et al. First do no harm: promoting an evidence- A thorough QT study, conducted accor- based approach to atypical antipsychotic use ding to international standards, assessing in children and adolescents. J Can Acad Child Adolesc Psychiatry 2010;19(2):124–37. the effects of citalopram 20 mg per day and 60 mg per day on the QT interval 7. Correll CU. Assessing and maximizing the has shown that citalopram causes dose- safety and tolerability of antipsychotics used dependent QT prolongation. Patients at in the treatment of children and adolescents. particular risk for developing prolonga- J Clin Psychiatry 2008;69(Suppl 4):26–36. tion of the QT interval include those with

30 WHO Drug Information Vol. 26, No. 1, 2012 Safety and Efficacy Issues underlying heart conditions and those • John Cunningham virus (JCV) infec- who are predisposed to low blood levels tion resulting in progressive multifocal of potassium and magnesium. Hypokal- leukoencephalopathy (PML) and death aemia and hypomagnesaemia should be has been reported in Adcetris®-treated corrected before administering citalopram patients. The factors leading to reac- hydrobromide. tivation of latent JC virus are not fully understood. Reference: Safety Alert – Medeffect. 25 January 2012 at http://www.hc-sc.gc.ca/ Healthcare professionals should instruct dhp-mps/medeff/advisories-avis/prof/_2012/ patients to report changes in mood or celexa_2_hpc-cps-eng.php unusual behavior, confusion, loss of memory, changes in walking or talking, Brentuximab vedotin: new warning decreased strength or weakness on one and contraindication side of the body, or changes in vision. Reference: FDA Drug Safety Communication, United States of America — The Food 13 January 2012 at http://www.fda.gov/Drugs/ and Drug Administration (FDA) has DrugSafety/ advised that two additional cases of progressive multifocal leukoencephalopathy (PML) have been reported with the lym- Quetiapine: information updated phoma drug brentuximab vedotin (Adce- United Kingdom — The manufacturer tris®). Due to the serious nature of PML, of quetiapine and quetiapine prolonged a new boxed warning has been added to release has informed healthcare pro- the drug label. fessionals of an update to the special warnings and precautions section of Brentuximab vedotin is used to treat the summary of product characteristics Hodgkin lymphoma and a rare lymphoma concerning weight gain, hyperglycaemia known as systemic anaplastic large cell and metabolic risk. lymphoma. It is an antibody-drug con- jugate, allowing the antibody to direct the Weight gain has been reported in patients drug to a target on CD30 lymphoma cells. who have been treated with quetiapine, and should be monitored and managed In addition, a new contraindication war- as clinically appropriate in accordance ning against use of brentuximab vedotin with antipsychotic guidelines. with the cancer drug bleomycin due to increased risk of pulmonary (lung) toxicity Hyperglycaemia and/or development or has been added to the drug label. A exacerbation of diabetes occasionally clinical trial compared the combination associated with ketoacidosis or coma has of Adcetris® plus Adriamycin® (doxo- been reported rarely, including some fatal rubicin), bleomycin, vinblastine, and cases. In some cases, a prior increase dacarbazine (ABVD) to the combination in body weight has been reported which of Adcetris® plus Adriamycin® (doxorubi- may be a predisposing factor. cin), vinblastine, and dacarbazine (AVD) Patients treated with any antipsychotic as front-line therapy for HL. An excessive agent including quetiapine, should be ob- number of patients in the Adcetris plus® served for signs and symptoms of hyper- ABVD treatment group experienced non- glycaemia, (such as polydipsia, polyuria, infectious pulmonary toxicity. polyphagia and weakness) and patients with diabetes mellitus or with risk factors • Concomitant use of brentuximab ve- for diabetes mellitus should be monitored dotin and bleomycin is contraindicated regularly for worsening of glucose control. due to pulmonary toxicity. Weight should be monitored regularly.

31 Safety and Efficacy Issues WHO Drug Information Vol. 26, No. 1, 2012

Given the observed changes in weight, at baseline. Aliskiren 300 mg was given blood glucose and lipids seen in clinical in addition to standard of care, including studies, there may be possible worsening an angiotensin converting enzyme (ACE) of the metabolic risk profile in individual inhibitor or angiotensin receptor blocker patients, which should be managed as (ARB). clinically appropriate. A higher incidence of adverse events Reference: Medicines and Healthcare Pro- related to non-fatal stroke, renal compli- ducts Regulatory Agency (MHRA). Commu- cations, hyperkalaemia and hypotension nication from AstraZeneca UK at http://www. were observed in this high-risk popu- mhra.gov.uk/Safetyinformation/Safetywar- lation. ningsalertsandrecalls/Safetywarningsandmes- sagesformedicines/index.htm Reference: Medicines and Healthcare Pro- ducts Regulatory Agency (MHRA). Communi- Aliskiren: cardiovascular cation from Novartis dated 23 December 2011 and renal events at http://www.mhra.gov.uk/Safetyinformation/ Safetywarningsalertsandrecalls/Safetywar- United Kingdom — The manufacturer of ningsandmessagesformedicines/index.htm aliskiren (Rasilez®) has informed healthcare professionals of new safety informa- Natalizumab: progressive multi- tion following the interim results from the focal leukoencephalopathy Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE). United States of America — The Food Analyses of these data are ongoing. and Drug Administration (FDA) has However, as a precautionary measure, advised that testing positive for anti-John it is advised that routine (non-urgent) Cunningham virus (JCV) antibodies has review is carried out for patients taking been identified as a risk factor for pro- Aliskiren-containing medicines. gressive multifocal leukoencephalopathy (PML). PML is a rare but serious brain Additionally, aliskiren or aliskiren- infection associated with use of natali- containing fixed combination products zumab (Tysabri®) for the treatment of should not be used in patients with multiple sclerosis or Crohn disease. diabetes in combination with angiotensin converting enzyme (ACE) inhibitors or Natalizumab has been approved for the angiotensin receptor blockers (ARB). As treatment of relapsing forms of multiple a consequence: sclerosis since November 2004 and for the treatment of moderately to severely • Healthcare professionals should stop active Crohn disease since January 2008. aliskiren-containing treatment in patients who are diabetic and also taking Patients with three known risk factors an ACE inhibitor or an ARB. Alternative have an estimated risk of PML of antihypertensive treatment should be 11/1,000 users. The risk factors are: considered as necessary. • Presence of anti-JCV infection antibod- • Aliskiren-containing products should ies. not be initiated in diabetic patients who • Longer duration of Tysabri® treatment, are also taking either an ACE inhibitor especially beyond 2 years. or ARB. • Prior treatment with an immunosup- The ALTITUDE study was conducted in pressant medication (e.g., mitoxan- type 2 diabetic patients at high risk of trone, azathioprine, methotrexate, fatal and non-fatal cardiovascular and cyclophosphamide, or mycophenolate renal events. In most patients arterial mofetil). blood pressure was adequately controlled

32 WHO Drug Information Vol. 26, No. 1, 2012 Safety and Efficacy Issues

Reference: FDA Drug Safety Communication, Bortezomib: fatal if given 20 January 2012 at http://www.fda.gov/Drugs/ intrathecally DrugSafety Canada — Health Canada has aler- Boceprevir: HIV protease inhibitor ted healthcare professionals to the risk interactions of fatal outcome associated with the inadvertent intrathecal administration United States of America — The Food of the antineoplastic drug bortezomib and Drug Administration (FDA) has (Velcade®). notified healthcare professionals of drug interactions between the hepatitis C Since the first global approval of borte- virus (HCV) protease inhibitor boceprevir zomib in May 2003, three cases of (Victrelis®) and certain ritonavir-boosted inadvertent intrathecal administration with human immunodeficiency virus (HIV) fatal outcome have been reported world- protease inhibitors (atazanavir, lopinavir, wide; these occurred in France and Italy. darunavir) which can potentially reduce Each case occurred when an intrathecal the effectiveness of these medicines oncology chemotherapy was scheduled when used together. at the same time as bortezomib intravenous administration. Health Canada Boceprevir is a hepatitis C virus (HCV) has not received any Canadian reports protease inhibitor used with the medi- involving inadvertent intrathecal adminis- cines peginterferon alfa and ribavirin to tration. treat chronic hepatitis C infection in adults who have not been treated before or who Bortezomib should only be administered have failed previous treatment. Ritona- via the approved intravenous (IV) route; vir is an HIV protease inhibitor used to Bortezomib is fatal if given intrathecally. “boost” other HIV protease inhibitors, Healthcare professionals are encouraged: increasing their levels in the blood and making them more effective. • To administer chemotherapy intended via the intrathecal route at a different A drug interaction study showed that ta- time than other parenteral chemother- king boceprevir (Victrelis®) with ritonavir apy. (Norvir®) in combination with atazanavir (Reyataz®) or darunavir (Prezista®), or • To use different connectors for medi- with lopinavir/ritonavir (Kaletra®) reduced cinal products to be administered via blood levels of the HIV medicines and the intrathecal or intravenous route. boceprevir in the body. • To clearly label syringes with the name of the medicinal product and route of Drug interactions between boceprevir and administration to be used and ensure ritonavir-boosted atazanavir, lopinavir, procedures are in place to enforce a and darunavir can potentially reduce the double check of syringe labelling before effectiveness of these medicines when administration. co-administered. Reference: Safety Alert – Medeffect. 26 Reference: FDA Drug Safety Communication, January 2012 at http://www.hc-sc.gc.ca/ 8 February 2012 at http://www.fda.gov/Drugs/ dhp-mps/medeff/advisories-avis/prof/_2012/ DrugSafety/ucm291119.htm velcade_hpc-cps-eng.php

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.

33 WHO Drug Information Vol. 26, No. 1, 2012

Regulatory Action and News

Bevacizumab: suspension Buflomedil-containing medicines: for metastatic breast cancer suspension Canada — Health Canada has taken European Union — The European the decision to suspend authorization of Medicines Agency’s Committee for Medi- bevacizumab (Avastin®) for use in the cinal Products for Human Use (CHMP) treatment of metastatic breast cancer. has concluded, following a review of the safety and efficacy of buflomedil, that the This decision does not affect Health risks of these medicines, particularly the Canada’s authorization of bevacizumab risks of severe cardiological and neurolo- for other types of cancer. Bevacizumab gical adverse reactions, do not outweigh remains authorized in Canada for use in their limited benefits in the treatment of the treatment of metastatic colon, rectal, patients with chronic peripheral arterial and lung cancers, as well as in the treat- occlusive disease (PAOD). The Com- ment of glioblastoma. mittee therefore recommended that the marketing authorizations of all buflomedil- Reference: Information Update 2011–59, containing medicines be suspended in 28 November 2011 at http://www.hc-sc.gc.ca/ all European Union (EU) Member States dhp-mps/medeff/advisories-avis/prof/_2011/ where they are currently authorized. avastin_8_hpc-cps-eng.php The review of buflomedil was initiated Drotrecogin alfa: withdrawal following the suspension of the marketing United States of America — The Food authorization in France by the French and Drug Administration (FDA) has an- regulatory authority in February 2011. nounced the worldwide voluntary market Reference: EMA Press Release, EMA/ withdrawal of drotrecogin alfa (activated) CHMP/570796/2011, 17 November 2011 at [Xigris®] by the manufacturer. http://www.ema.europa.eu

In a recently completed clinical trial Dextropropoxyphene-containing (PROWESS-SHOCK trial), drotrecogin alfa failed to show a survival benefit. In analgesics cancelled this trial of 1696 patients, 851 patients Australia — The Therapeutic Goods were enrolled in the drotrecogin alfa arm Administration (TGA) has cancelled and 845 patients were enrolled in the all pain-killers containing dextropro- placebo arm. Results based on prelimi- poxyphene (Capadex®, Di-Gesic®, nary analyses that were submitted to the Doloxene® and Paradex®) from the FDA showed a 28-day all cause mortality Australian Register of Therapeutic Goods rate of 26.4% (223/846) in Xigris®-treated (ARTG), as of 1 March 2012. patients compared to 24.2% (202/834) in placebo-treated patients. Following a review of the available evidence, the TGA found that the safety Reference: FDA Drug Safety Communication, risks of using analgesics containing dex- 25 October 2011 at http://www.fda.gov/Drugs/ tropropoxyphene outweighed the bene- DrugSafety fits. Cancellation from the ARTG means

34 WHO Drug Information Vol. 26, No. 1, 2012 Regulatory Action and News that these prescription medicines can Ecallantide: marketing authoriza- no longer be supplied by their Australian tion application withdrawal sponsors. European Union — The European Medi- Dextropropoxyphene has recently been cines Agency (EMA) has been notified shown to increase the risk of serious ar- by the manufacturer of its decision to rhythmias. This effect is more pronounced withdraw the application for ecallantide with high doses or overdoses. An exten- (Kalbitor®), 10 mg/ml solution for injec- sive review of the safety and efficacy of tion. Ecallantide was intended to be dextropropoxyphene has been conducted used for symptomatic treatment of acute by the TGA which has determined that attacks of hereditary angioedema (HAE) the overall risk of serious adverse reac- in adults and adolescents 16 years of age tions outweighs any benefits that may and older. be provided by these medicines. This position is consistent with medicine regu- The company stated that they were lators in Europe, New Zealand, USA and unable to provide sufficient information elsewhere, where dextropropoxyphene- to address the outstanding clinical issues containing medicines have been removed identified during the evaluation of their from the market. application.

Reference: Therapeutic Goods Administra- Reference: EMA Press Release, EMA/ tion Safety Announcement, 2 December 2011 891024/2011, 15 November 2011 at http:// at http://www.tga.gov.au/newsroom/media- www.ema.europa.eu 2011-dextropropoxyphene-111122.htm

Vemurafenib approved for meta- Sitagliptin and pioglitazone: static or unresectable melanoma marketing authorization application withdrawal European Union — The European Medi- cines Agency’s Committee for Medicinal European Union — The European Medi- Products for Human Use (CHMP) has cines Agency (EMA) has been notified recommended the granting of a marketing by the manufacturer of its decision to authorization for a novel protein-kinase withdraw the application for sitagliptin and inhibitor to treat patients suffering from pioglitazone (Janacti® and related trade metastatic or unresectable melanoma names)100/30 mg and 100/45 mg fixed- with BRAF V600 mutations. dose combination tablets. In Europe, doctors diagnose almost Janacti® was intended to be used for the 60 000 new cases of melanoma per treatment of adult patients with type 2 year and approximately 8300 men and diabetes mellitus. 7600 women die from this type of cancer annually. In the pivotal clinical trial, The company stated that they are with- vemurafenib (Zelboraf®) was compared drawing the application following a review to the standard first-line treatment of of the regulatory and commercial pros- dacarbazine. The medicine was shown pects for the fixed-dose combination to improve progression-free survival by product. There are currently no ongoing about four months and overall survival by clinical trials with Janacti®. about three months in patients who tested positive for BRAF V600 mutations. Reference: EMA Press Release, EMA/ 887576/2011, 14 November 2011 at http:// Reference: EMA Press Release, EMA/ www.ema.europa.eu CHMP/975685/2011, 16 December 2011 at http://www.ema.europa.eu

35 Regulatory Action and News WHO Drug Information Vol. 26, No. 1, 2012

Voclosporin: marketing authoriza- Reference: EMA Press Release, EMA/ tion application withdrawal 840073/2011, 19 October 2011 at http://www. ema.europa.eu European Union — The European Medi- cines Agency (EMA) has been notified Electronic CTD implementation by the manufacturer of its decision to withdraw the application for voclosporin Saudi Arabia — The Saudi Food and (Luveniq®), 10 mg soft capsules. Drug Authority (SFDA) has informed pharmaceutical companies and their Voclosporin was intended to be used agents to prepare for implemention of the for the treatment of patients with chro- electronic common technical document nic non-infectious uveitis involving the (eCTD) when submitting product files for posterior or intermediate segments of the evaluation. eyes as characterized by a high degree of inflammation and in whom corticosteroids The timeframe determined for implemen- are inappropriate, do not provide ade- ting the eCTD is as follows. quate control, or cannot be tapered below 10 mg/day. Voclosporin was designated • As of 20 December 2011: non- eCTD an orphan medicinal product on 14 Sep- electronic submission (NeeS) can be tember 2007. submitted according to Guidance for Registration (version 3). The company stated that they were unable to demonstrate to the satisfaction • As of 1 September 2012, the NeeS will of the CHMP an overwhelming effect be mandatory and the SFDA will not showing that the benefits of Luveniq® accept any other format. outweigh its risks, and thus would qualify • Starting 5 January 2013, either eCTD for a recommendation for authorization or NeeS can be submitted. with one pivotal study only. • As of 4 January 2014, the NeeS will be Reference: EMA Press Release, EMA/ accepted but submissions in eCTD are 833913/2011, 18 October 2011 at http://www. preferred ema.europa.eu • Starting from 3 January 2015, only Desloratadine: marketing authori- eCTD will be accepted. zation application withdrawal More information about the difference European Union — The European Medi- between eCTD and NeeS is available in cines Agency (EMA) has been notified Guidance for Registration and the GCC by the manufacturer of its decision to Module 1 Specifications guideline which withdraw the application for desloratadine are available from [email protected] (Desloratadine Krka®), 5 mg film coated and at www.sfda.gov.sa. In addition, the tablets. SFDA will conduct workshops to assist Desloratadine Krka® was intended to be pharmaceutical companies in following used for the relief of symptoms asso- these technical requirements. ciated with allergic rhinitis and urticaria. Reference: Saudi Food and Drug Authority. Desloratadine Krka® is a generic of News Release dated 14 Jaunary 2012. At Aerius® which has been authorized in the http://www.sfda.gov.sa/En/Drug/News/1122- European Union since 15 January 2001. en-14-1.htm In its official letter, the company stated that their marketing strategy is the reason for withdrawal.

36 WHO Drug Information Vol. 26, No. 1, 2012

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 Methodo- logy at [email protected]. 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 INN Common name ATC code

New ATC 5th level codes: aclidinium bromide R03BB05 alcaftadine S01GX11 alendronic acid and alfa- calcidol, 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 disopro- xil, 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

37 ATC/DDD Classification WHO Drug Information Vol. 26, No. 1, 2012

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) ethyl- enedicysteine V09CA06

New ATC level codes (other than 5th level): Direct factor Xa inhibitors B01AF Fluoroquinolones S01AE

ATC code changes: INN Common name Previous ATC New ATC besifloxacin S01AX23 S01AE08 ciprofloxacin S01AX13 S01AE03 diamorphine N02AA09 N07BC06 droperidol N01AX01 N05AD08* gatifloxacin S01AX21 S01AE06 histrelin H01CA03 L02AE05 levofloxacin S01AX19 S01AE05 lomefloxacin S01AX17 S01AE04 lopinavir and ritonavir ** J05AE06 J05AR10 moxifloxacin S01AX22 S01AE07 norfloxacin S01AX12 S01AE02 ofloxacin S01AX11 S01AE01 rivaroxaban B01AX06 B01AF01

* Existing code ** New ATC level name (previous name: lopinavir)

ATC name changes: Previous New ATC code

Other cephalosporins Other cephalosporins and penems J01DI

New DDDs: DDD Unit Adm.R ATC code abiraterone 1 g O L02BX03 amifampridine 40 mg O N07XX05 apixaban 5 mg O B01AF02 belatacept 12.5 mg P L04AA28 belimumab 25 mg P L04AA26 boceprevir 2.4 g O J05AE12

38 WHO Drug Information Vol. 26, No. 1, 2012 ATC/DDD Classification

New DDDs (continued)

DDD Unit Adm.R ATC code ciclesonide 0.2 mg N R01AD13 collagenase clostridium histolyticum 0.9 mg P M09AB02 delavirdine 1.2 g O J05AG02 dextromethorpen, combinations 40 mg1 O N07XX59 exenatide 0.286 mg P depot inj. A10BX04 fidaxomicin 0.4 g O A07AA12 histamine dihydrochloride 0.5 mg P L03AX14 inosine pranobex 3 g O J05AX05 leuprorelin 0.134 mg P depot implant L02AE02 lorazepam 2.5 mg P N05BA06 nabiximols 42 mg SL N02BG10 naproxen and esomeprazole 0.5 g2 O M01AE52 pyrvinium 0.35 g O P02CX01 retigabine 0.9 g O N03AX21 rifaximin 0.6 g O A07AA11 telaprevir 2.25 g O J05AE11 tobramycin 0.112 g Inhal. powder J01GB01 triptorelin 0.1 mg P L02AE04 vinpocetine 15 mg O N06BX18 von Willebrand factor 6 TU P B02BD10

1 expressed as dextromethorphan 2 refers to naproxen

Herbal medicinal products* ATC level INN Common name ATC code New ATC 5th level codes: Agni casti fructus G02CX03 Cimicifugae rhizoma 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).

39 WHO Drug Information Vol. 26, No. 1, 2012

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 [email protected].

INN Common name ATC code

New ATC 5th level codes: 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 ATC name changes:

Previous New ATC code

Antigrowth hormones Somatostatin and analogues H01CB Calcium, combinations with Calcium, combinations with other drugs vitamin D and/or other drugs A12AX Enzyme inhibitors Aromatase inhibitors L02BG

40 WHO Drug Information Vol. 26, No. 1, 2012 ATC/DDD Classification

New DDDs:

DDD Unit Adm.R ATC code

aspoxicillin 4 g P J01CA19 aztreonam 0.225 g Inhal. solution J01DF01 bekanamycin 0.6 g P J01GB13 carumonam 2 g P J01DF02 cefbuperazone 2 g P J01DC13 cefminox 4 g P J01DC12 conestat alfa 3.5 TU P B06AC04 desvenlafaxine 50 mg O N06AX23 fingolimod 0.5 mg O L04AA27 flomoxef 2 g P J01DC14 histrelin 0.137 mg* implant H01CA03 isepamicin 0.4 g P J01GB11 ribostamycin 1 g P J01GB10 tapentadol 0.4 g O N02AX06 ticagrelor 0.18 g O B01AC24 vernakalant 0.2 g P C01BG11

* DDD assigned according to the total content of the implant.

Herbal medicinal products* ATC level INN Common name ATC code

New ATC 5th level codes: Hyperici herba 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).

41 WHO Drug Information Vol. 26, No. 1, 2012

Recent Publications, Information and Events

Pharmacovigilance Toolkit as VigiBase(®) — which contains over seven million such reports. After receiving The World Health Organization has a signal, national regulatory authorities announced the launch of a Pharmacovi- may consider possible action — for ins- gilance Toolkit. This has been developed tance further evaluation of source data, or by the WHO Collaborating Centre for a study for the testing of a hypothesis. Pharmacovigilance Training and Advo- cacy, Ghana, in collaboration with the In 2011, the WHO Advisory Committee WHO Advisory Committee on Safety of on the Safety of Medicinal Products Medicinal Products, the Uppsala Monito- recommended that signal articles be ring Centre, Sweden, and the WHO made public. A first step in making UMC Quality and Safety of Medicines Pro- signals publicly available will be taken in gramme, Geneva. early 2012 when, for the first time, they will be included in WHO Pharmaceuticals The Toolkit brings together existing Newsletter which is issued every second resources that are used in the practice month. Currently, 450 professionals of pharmacovigilance. Its main objective receive the restricted signal document, is to bring current information, guidelines mainly staff at national pharmacovigilance and practical advice to all pharmacovigi- centres. The new arrangement with allow lance practitioners. for a wider audience

In addition to a dedicate web site, the References Toolkit is available on a USB key in a similar format for use in areas with poor 1. Uppsala Monitoring Centre/WHO Collabora- internet connectivity. The Toolkit is cur- ting Centre for International Drug Monitoring, rently available in English but efforts are Sweden, at http://www.who-umc.org underway to have it translated into other 2. World Health Organization. WHO Pharma- languages. ceuticals Newsletter. At http://www.who.int/ medicines Reference: The Pharmacovigilance Toolkit. At www.pvtoolkit.org Learning module: selective serotonin reuptake inhibitors Uppsala Monitoring Centre signals document: increased availability The United Kingdom Medicines and Healthcare Products Regulatory Agency Among the objectives of the WHO Pro- (MHRA) has just launched a learning gramme for International Drug Monitoring module on selective serotonin reuptake is the early identification of international inhibitors (SSRI) for clinical practitioners. drug safety problems not identified in clinical trials, known as signals. These SSRIs form the most widely prescribed signals are published in the Uppsala class of antidepressants. This module Monitoring Centre’s (UMC) SIGNAL docu- identifies the most important hazards of ment, and represent varying levels of sus- SSRIs and informs on actions that health picions derived from examination of the professionals should take in order to data in the WHO Global Individual case minimize and manage the risks. For each safety reports database — also known adverse effect, the package outlines:

42 WHO Drug Information Vol. 26, No. 1, 2012 Recent Publications, Information and Events

• The main features of the adverse effect. ATC/DDD methodology course • Factors that increase the risk. The WHO Collaborating Centre for Drug • How the risk can be reduced. Statistics Methodology will organize its annual course in ATC/DDD methodo- • Specific treatment for the adverse logy in Oslo from 7 to 8 June 2012. The effect. course gives an introduction to the Anato- A self-assessment exercise, together with mical Therapeutic Chemical (ATC) clas- full feedback, complements the learning sification system and the technical unit material which is suitable for doctors, of measurement, the Defined Daily Dose pharmacists and nurses involved in the (DDD). The purpose of the ATC/DDD care of patients with depression. Clini- and how to use the methodology is also cians starting out in psychiatry will find it covered in the course which consists of especially valuable. lectures, discussions and working groups. The course is open for all interested Used in conjunction with authoritative parties. However, basic knowledge in guidelines on disease management, this common medical terminology is recom- module will help maximize the benefits of mended. SSRI treatment. The Centre also arranges courses on Reference: Healthcare products Regulatory request from countries which plan to Agency (MHRA). SSRI learning module. At start using the ATC/DDD methodology. http://www.mhra.gov.uk/ConferencesLearnin- gCentre/LearningCentre/Medicineslearning- For example, courses have previously modules/Reducingmedicinerisk/SSRIlearning- been arranged in Ecuador, Japan and module/index.htm Morocco.

Medicines access survey Lectures will cover the following topics:

A team of researchers at the National • Background, overview and develop- Institute of Public Health in Mexico have ment of the ATC/DDD methodology conducted an analysis of availability, • The main principles for establishing affordability and prices of medicines in new ATC codes and assigning DDDs Mexico City during 2009/2010 using the Health Action International (HAI)/WHO • Procedures for applications (ATC suggested methodology. codes, DDDs and changes). The second day will focus on application The analysis showed that in the public of the ATC/DDD methodology in drug sector medicines included in the sample consumption statistics. Working group were unavailable in more than 50% of sessions will address various ATC/DDD those health establishments visited. In problems and points to consider related the private sector, originator product to the application of the methodology in prices were on average 4.5 times higher drug consumption statistics. than their corresponding interchangeable generics (e.g., the originator product, Reference: WHO Collaborating Centre for fluoxetin, was 172 times more expensive Drug Statistics Methodology. At http://www. than its generic counterpart). Almost 50% whocc.no/courses/ of all treatments analysed were unaffor- dable. Access and Control Newsletter Reference: Mexico: Medicines access survey. The Access and Control Newsletter At http://www.haiweb.org/medicineprices/sur- provides the latest news from WHO on veys.php access to medicines controlled under

43 Recent Publications, Information and Events WHO Drug Information Vol. 26, No. 1, 2012 the international drug treaties. It aims to in 1982. It was revised in 1997 with over provide information on improving access 10,000 copies distributed in over 60 for medical use and evaluation of the countries worldwide. The third edition, dependence-producing properties of Managing Access to Medicines and other substances and medicines made from Health Technologies reflects the dramatic these substances. changes in politics, public health priorities, advances in science and medicine, The current number includes: greater focus on health care systems, increased donor funding, and the advent • Roundtable in Bosnia and Herzegovina. of information technology that have • Serbian National WHO Counterpart for profoundly affected access to essential pain treatment — access to opioids. medicines over the past 14 years. • Psychiatrists are stakeholders in im- The revised edition has many new areas proving access to controlled medicines. that have been added or enhanced, inclu- • Prequalification of morphine and ding six new chapters: methadone. • Intellectual property and access to • ATOME Project: workshops on improv- medicines ing access to controlled medicines. • Traditional and complementary medi- • Life Before Death: Short movies on the cines policy global crisis of pain treatment. • Pharmaceutical pricing policy Reference: WHO Access and Control News- letter, No 9, January 2012 at http://www.who. • Pharmaceutical benefits in insurance int/medicines/areas/quality_safety/Access_ programmes Contr_Newsletter/en/index.html • Drug seller initiatives Managing access to medicines and • Pharmacovigilance health technologies Reference: Management Sciences for Health. Managing Drug Supply is the leading Managing Access to Medicines and other reference on how to manage essential Health Technologies. At http://www.msh.org/ medicines in developing countries. Mana- resource-center/managing-drug-supply-digital- ging Drug Supply was originally published edition.cfm