Who Drug Information

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


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


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 internatio-
nal 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 adminis-
tration nationwide. The medicines regulatory agencies at provincial level are res-
ponsible 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.

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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 de-
vices, 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 implemen-
tation.
• 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 regu-
lations 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 regu-
latory 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


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


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:
• First released in1985 following enact-
Drug Administration Law
ment of the Drug Administration Law.
The Drug Administration Law was issued
by the National People’s Congress. It was • Revised to reflect establishment of the
enacted in 1985, and amended in 2001. SDA in 1998.
The 2001 revision has achieved better
harmonization with regard to international • Revised in response to China’s 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
efficacy of medicines Drugs/medicines refer to articles
2001 revision of the
in China. The Law which are used in the prevention,
Drug Administration
applies to all parties treatment and diagnosis of human
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


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


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 implemen-
tation 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


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 produc-
tive 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.)

10


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 initia-
ted 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 appro-
priate 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


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 internatio-
nal 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 medi-
cines need to be licensed by the MRAs. References
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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


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
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gov.cn/WS03/CL0756/ (2011).Good manufacturing practice for drugs
(2010 Revision) issued. News Release. At
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app1.sfda.gov.cn/WS01/CL0287/68457.html 21. Xinhua News Agency (2009). Deepening
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12. National People’s Congress. At http:// the county’s essential medicines system. At
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14


Paediatric Medicines
Better medicines for children: The guideline aims to:
pharmaceutical formulations • Inform regulatory authorities and manu-
facturers 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 pharma-
ceutical 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


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


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 inspira-
tory 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.

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WC500002903.pdf gnizing the challenges. J Pharm Pharmacol
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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


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


• Coordinating the development of paedi- References
atric information through the regulatory
1. Matsui D, Kwan C, Steer E, et al. The trials
system and other means.
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


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 ami-
odarone. 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

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