Download analysis of yellow card reporting: annual report for 2008-2012

MHRA
151 Buckingham Palace Road
Victoria
London SW1W 9SZ
United Kingdom
www.mhra.gov.uk
Trends in UK spontaneous Adverse Drug
Reaction (ADR) reporting between
2008 – 2012
Executive Summary
This paper provides an analysis of UK spontaneous suspected ADR reports from
2008 to 2012. The analysis provides a greater insight into trends in electronic
reporting and the impact of the Yellow Card strategy as well as trends in reporting of
ADRs in the paediatric population and in the elderly over a ten year time period. It
forms the basis for reprioritising the Yellow Card strategy as we move forward to the
50th Anniversary of the scheme.
Key Findings
The data in 2008 to 2012 shows:












3.6% increase in ADR reports from 2011 to 2012 and a 4.1% increase in
reports from 2008 to 2012
Proportion of serious reports has increased from 84% in 2008 to 87% in 2012
with a higher proportion of serious reports from patients (87%) than from
healthcare professionals (74%).
Increase in the proportion of ADR reports with fatal outcome to 6% in 2012
from 5% in 2008 and 2009
5% increase in direct reporting from 2011 to 2012 accounting for 52% of all
reports received in 2012
Increase in the proportion of patient reporting even outside of publicised
campaigns involving the HPV vaccine and pandemic.
GP reporting continues to form the ‘backbone’ of the Yellow Card Scheme
and is at its highest level since 2007 with a 26% increase in the proportion of
direct reporting in 2012
In 2012 pharmacist reporting is at its highest ever level with a 19% increase in
the proportion of direct reporting in 2012.
Nurses are contributing the second largest proportion of reports accounting
for 17% of all direct reports in 2012
Electronic direct reporting has increased from 25% in 2008 to 68% in 2012;
showing a substantial increase in electronic reports received from patients
(40% in 2008 to 82% in 2012) and GPs (17% in 2008 to 72% in 2012).
Requirements of the new legislation have resulted in an increase in the
number of reports, specifically in the number of consumer reports received via
industry.
11% of the total number of reports relate to patients aged less than 18 years.
23% of the total number of reports relate to elderly (>65 years) patients.
Recommendations and key priorities
There are six key recommendations for the coming year as we move forward with the
strategy to strengthen the Yellow Card Scheme. These focus on:
Paediatric strategy - To increase reporting of ADRs occurring in children via the
Yellow Card Scheme.
Engaging with nurses - To increase ADR reporting via the Yellow Card Scheme in
light of new immunisation campaigns. Particular focus should be on education, ereporting and reporting for paediatric patients.
1
Engaging with HCPs and patients – To increase awareness of the change in
definition for adverse drug reactions to include medication errors, misuse and off
label use, and to promote the message of the new EU wide additional monitoring list.
Electronic reporting
- Continue to facilitate ADR reporting through HCP IT systems
- Continue with existing projects so that healthcare professional (HCP)
reporting continues to increase, particularly with hospital pharmacists.
- To develop a mobile technology infrastructure to facilitate reporting for
healthcare professionals
Promotion and Education - increase awareness through the Agency’s Outreach
and Professional Education Unit and work with the Yellow Card Centres to continue
local training, promotion and championing of the Yellow Card Scheme.
Communicate the findings of this analysis to further promote the Scheme and
educate and motivate reporters; publish more in peer reviewed journals. Increase
feedback to HCPs and patients on what the MHRA do with Yellow Card reports and
reporting requirements in light of the most frequently reported drug event
combinations and changes to legislation.
2
Table of Contents
Executive Summary ................................................................................................ 1
Recommendations and key priorities .................................................................... 1
Purpose of paper ..................................................................................................... 5
1 Introduction ...................................................................................................... 5
2 Spontaneous ADR reports received from 2008 to 2012................................. 6
2.1
Serious and fatal ADR reporting.................................................................. 7
2.2
Sources of ADR reports: Direct and Indirect .............................................. 9
2.3
Types of ADR reports: Electronic and Paper ............................................ 10
3 Prescription data ............................................................................................ 11
4 Direct Yellow Card reporting ......................................................................... 13
4.1
Types of direct reports - Paper and Electronic Yellow Card reporting ... 13
4.1.1 Telephone reporting ..................................................................................... 14
4.2
Source of direct reports – Reporter Qualification .................................... 15
4.3
Source of direct reports – Healthcare setting reporting .......................... 18
4.4
GP Yellow Card reporting .......................................................................... 20
4.4.1 GP reporting – Serious and Fatal ADRs ..................................................... 21
4.4.2 GP reporting – Electronic and Paper ADRs ................................................ 21
4.5
Pharmacist Yellow Card reporting ............................................................ 23
4.5.1 Pharmacist reporting – Serious and Fatal ADRs ....................................... 24
4.5.2 Pharmacist reporting – Electronic and Paper ADRs .................................. 24
4.6
Nurse Yellow Card reporting ..................................................................... 26
4.6.1 Nurse reporting – Serious and Fatal ADRs................................................. 28
4.6.2 Nurse reporting – Electronic and Paper ADRs ........................................... 29
4.7
Healthcare Professionals - Patient demographics ................................... 30
4.8
Patient Yellow Card reporting .................................................................... 32
4.8.1 Patient reporting – Serious and Fatal ADRs ............................................... 34
4.8.2 Patient reporting – Electronic and Paper Yellow Cards............................. 35
4.8.3 Patient reporting – Patient demographics .................................................. 36
5 Vaccine reporting ........................................................................................... 37
5.1
Source of vaccine reports .......................................................................... 37
5.2
Vaccine reactions ....................................................................................... 38
6 Regional Yellow Card reporting .................................................................... 40
7 New Pharmacovigilance Legislation and ADR reporting ............................ 42
8 Signal Assessment ........................................................................................ 45
8.1
Signals raised & investigated from 2008 until 2012 ................................. 45
8.2
Outcomes of signals identified .................................................................. 46
8.3
Patient signals ............................................................................................ 47
9. Conclusions ................................................................................................... 48
Recommendations and Key Priorities ................................................................. 49
Glossary................................................................................................................. 50
Annex 1: Yellow Card Scheme Background and ADR reporting guidelines ..... 52
Annex 2: Notes on interpretation of spontaneous reporting data ..................... 53
Annex 3: Guidance on seriousness of ADRs ...................................................... 54
Annex 4: Guidance on prescription data ............................................................. 55
Annex 5: Drug Safety Update article – Advice on Reporting ADRs ................... 56
Annex 6: Drug Safety Update article – Time to report. ....................................... 57
Annex 7: New EU Pharmacovigilance Legislation .............................................. 58
Annex 8: Paediatric patient reporting .................................................................. 61
8.1
Paediatric patient reporting – Sources of reports .................................... 62
8.2
Paediatric patient reporting – Most reported ............................................ 63
8.2.1 Paediatric Reactions .................................................................................... 63
8.2.2 Paediatric Medicines/vaccines .................................................................... 64
8.2.3 Paediatric Drug event combinations ........................................................... 64
3
8.3
Paediatric Medication errors and off label use ......................................... 65
Annex 9: Elderly patient reporting ....................................................................... 66
9.1
Elderly patient reporting – Sources of reports ......................................... 66
9.2
Elderly patient reporting – patient demographics .................................... 67
9.3
Elderly patient reporting – Most reported ................................................. 67
9.3.1 Elderly reactions .......................................................................................... 67
9.3.2 Elderly medicines ......................................................................................... 68
9.3.3 Elderly Drug event combinations ................................................................ 69
9.4
Elderly patients – Medication errors ......................................................... 69
4
ANALYSIS OF YELLOW CARD REPORTING: 2008-2012
Purpose of paper
To present the Committee with an analysis of Yellow Card reporting from 2008 to
2012. The report identifies trends in reporting, the impact of the Yellow Card strategy
and highlights new priority areas of focus for the Yellow Card strategy.
1
Introduction
Suspected Adverse Drug Reactions (ADRs) to medicinal products and vaccines are
reported to the CHM and the Medicines and Healthcare products Regulatory Agency
(MHRA) on a voluntary basis by healthcare professionals and, as of January 2005 by
members of the public through the Yellow Card Scheme. Reports are also submitted
as a legal requirement by pharmaceutical companies holding Marketing
Authorisations (MAHs). Information collected through the Yellow Card Scheme is an
important means of monitoring drug safety in clinical practice, acting as an early
warning system for the identification of previously unrecognised adverse reactions
and increasing knowledge of known ADRs.
This report provides an analysis of the ADR data received between 2008 and 2012
focussing on trends in the overall numbers of spontaneous ADR reports including
fatal and serious reports. This report also includes an analysis of the various
reporting sources (direct and indirect i.e. reported via industry), an overview of the
mechanisms of reporting (paper, electronic, telephone) and examines trends to
identify whether there has been an impact from Yellow Card Strategy activities.
This report also includes analysis of reporter sources, which focuses primarily on
Yellow Card reports received directly as MAHs are not obliged to provide detailed
information with regards to the type of healthcare professional who submitted the
report.
A ten year analysis of data received for both the paediatric and elderly patient
populations is also included in the annex of this report.
5
2
Spontaneous ADR reports received from 2008 to 2012
Summary
 The number of reports received from 2008 to 2012 is broadly consistent
 3.7% increase in reports in 2012 compared to 2008.
Table 1
Total number of ADR
reports and %
increase/decrease (direct
and indirect reports)
2008
2009
2010
2011
2012
25,012
25,454
(1.8%  )
23,305
(8.4 % )
25,135
(7.9% )
26,037
(3.6% )
Figure 2 provides a breakdown of the overall number of ADR reports received per
year for the past five years with the reporting source i.e. patients, healthcare
professionals or Industry.
In 2012 there was a 3.6% increase (902 reports) in the total number of UK
spontaneous ADR reports from the previous year and a 4.1% increase (1015 reports)
in 2012 when compared to 2008. An average of 24,588 ADR reports has been
received annually between 2008 and 2012. The lowest number of reports was
received in 2010; however this has increased by 11.7% over the next two years
taking ADR reporting to its highest level over this five year time period.
Figure 2
30000
70000
25000
60000
50000
20000
40000
15000
30000
10000
20000
5000
10000
0
0
2008
2009
2010
2011
Patient
Cumalative Number of
reports
Number of reports
Spontaneous ADR reporting by source 2008-2012
HCP
Industry
Patient
cumalative
Industry
Cumalative
HCP
cumalative
2012
Year
Overall, the number of reports has remained relatively consistent at approximately
25,000 reports per year over the past five years.
6
2.1 Serious and fatal ADR reporting
Summary
 The proportion of serious reports is relatively stable at an average of 84% of the
total number of reports from 2008 to 2012
 The proportion of ADR reports with fatal outcome has increased from 5% in 2008
to 7% in 2011 and 6% in 2012
Table 2.1.1
All serious reports*
Direct - HCP serious reports
Direct - Patient serious
reports
2008
21024 (84%)
8726 (71%)
Number and proportion of serious reports
2009
2010
2011
20837 (82%)
19611 (84%)
21813 (87%)
8960 (68%)
7720 (69%)
8521 (74%)
2001 (81%)
2741 (85%)
1702 (88%)
1452 (87%)
2012
22624 (87%)
8962 (74%)
1564(87%)
* Seriousness is based on whether the MedDRA reaction term is considered serious and if the reporter
considered the report to be serious (see Annex 3 for guidelines)
The proportion of patient reports which are considered serious is higher than that for
healthcare professional reports.
Table 2.1.2
Fatal reports
Industry - fatal reports
Direct - fatal reports
HCP - fatal reports
Patient - fatal reports
2008
1278 (5%)
1249 (9%)
303 (3%)
273 (2%)
30 (1%)
Number and proportion of fatal reports
2009
2010
2011
1184 (5%)
1476 (6%)
1871 (7%)
1337 (7%)
1701 (11%)
2642 (14%)
271 (3%)
312 (4%)
293 (3%)
247 (2%)
293 (3%)
279 (2%)
24 (1%)
19 (1%)
14 (1%)
2012
1558 (6%)
1751 (11%)
298 (3%)
280 (2%)
18 (1%)
The higher rate of reporting fatal outcomes from industry can be attributed to a
number of factors such as MAH legal obligations to submit ADR reports from
literature searches and special reporting requirements for specific medications. The
drug for which the largest number of fatal ADRs was received during this five year
time period is Clozapine. In order to use clozapine, patients, prescribers and
supplying pharmacists are required to register to a Patient monitoring scheme
(CPMS). The systems are run by Marketing Authorisation Holders for clozapine and
as a result the MAH will be aware of and should report all potential reactions to
clozapine involving changes in blood counts and unexplained deaths to the MHRA.
Additionally, a large number of fatal ADR reports have been received for
Ranibizumab as a result of the reimbursement method agreed with the manufacturer
in the UK. The Ranibizumab Reimbursement Scheme (RRS) is a web-based scheme
in which the manufacturer reimburses the NHS for the cost of ranibizumab after the
patient has received 14 Lucentis injections; as a result the RSS records the amount
of Lucentis treatments for each patient. The manufacturer is informed through the
RRS every time a patient treated with ranibuzumab dies and then reports such
occurrences to the MHRA as suspected ADR reports, in order to ensure compliance
with UK legislation. However, there is usually no suspicion in these reports that there
may be an association between ranibizumab and the fatal event.
7
Figure 2.1.3 shows the proportion of serious and fatal reports for all UK spontaneous
ADR reports.
Figure 2.1.3
Proportion of serious and fatal reports
100%
5%
5%
6%
7%
6%
79%
77%
78%
79%
81%
16%
18%
16%
13%
13%
2008
2009
2010
2011
2012
Percentage reports
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
Year
Non-serious reports
Serious reports
Fatal reports
The number of non-serious reports was highest in 2009 which can be attributed to
the number of non-serious reports received following the nationwide Human
Papilloma Virus (HPV) vaccination campaign.
8
2.2 Sources of ADR reports: Direct and Indirect
Summary
 The number of direct reports (includes patients and healthcare professional
reports) decreased in 2010 and increased again in 2011 and 2012.
Table 2.2.1
Direct reports
Indirect reports
2008
14421
10606
Number of direct and indirect reports
2009
2010
2011
15347 (6.4% )
12728 (17.1% )
12984 (2.0% )
10115 (4.6% )
10577 (4.6% )
12152 (14.9% )
2012
13636 (5.0% )
12402 (2.1% )
Figure 2.2.2 shows the number and proportions of direct and indirect reports received
over the last five years.
Figure 2.2.2
There has been a decrease in the number of indirect reports received in 2010 which
can be attributed to one MAH incorrectly submitting reports by the wrong report type.
The proportion of reports received directly from healthcare professionals and patients
was at its highest in 2009 as a result of higher public exposure of the Yellow Card
scheme through leaflets handed out to patients after the influenza vaccination
programme during the pandemic season, and also due to increased reporting
from nurses following the HPV campaigns (see 3.3 and 3.7). The more recent
increase in direct reports is following the Yellow Card strategy (see 3.5 and 3.6)
9
2.3 Types of ADR reports: Electronic and Paper
Summary

The total number of electronic reports has increased over the last five years from
33% in 2008 to 82% in 2012
Figure 2.3.1 shows the number and proportion of electronic and paper reports
received from 2008 to 2012. Figure 2.3.1 shows the number and proportion of
indirect paper electronic and paper reports received over the last five years
Figure 2.3.1
The MHRA is fully compliant with E2B reporting and since 2009 the majority of the
pharmaceutical companies have submitted their ADR reports electronically using
E2B. Efforts to increase the proportion of industry reports received via E2B resulted
in the proportion of industry reports received electronically increasing from 83% in
2009 to 98% in 2012.
10
3
Prescription data
IMS Disease Analyzer was used to determine the number of prescriptions issued in
the UK primary care setting (See Annex 4). The number of prescriptions issued and
the number of patients treated between 2008 and 2012 in UK primary care was
extracted from IMS Disease Analyzer and can be seen in Table 3.1.
Table 3.1
Number of Prescriptions
(millions)
Number of Patients (millions)
Average Number of
Prescriptions per Patients
2008
2009
2010
2011
2012
686.82
53.83
702.48
52.8
722.87
51.64
739.22
50.06
764.30
49.28
12.8
13.3
14
14.8
15.5
This data has been projected up to estimate UK numbers and broken down by age
group as per figure 3.2.
Figure 3.2
Proportion of Prescriptions by Age group
(Time period: 2008-2012; Medical Database: IMS Disease-Analyser)
75+
65-74
Patient age group
55-64
45-54
35-44
25-34
2009
18-24
2008
2010
13-17
2011
7-12
2012
2-6
<2
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
Percentage of prescriptions
The number of prescriptions issued increase with age and elderly patients continue
to be issued the greatest number of prescriptions every year from 2008 to 2012.
11
Figure 3.3 and 3.4 show the number of prescriptions issued against the number of
ADR reports received and by year and age group.
Figure 3.3
16000
780
14000
760
12000
740
10000
720
8000
700
6000
4000
680
2000
660
0
Number of prescriptions
Number of reports
Number of reports and precription data
(Time period: 2008-2012; Medical Database: IMS Disease-Analyser
640
2008
2009
2010
2011
2012
Year
Number of direct reports
Number of Prescriptions (millions)
Figure 3.4
Prescription data and ADR reports by age group 2010-2012
Percentage of reports/prescriptions
35%
Prescriptions
ADR reports received
30%
25%
20%
15%
10%
5%
0%
<2
2-6
7-12
13-17
18-24
25-34
35-44
45-54
55-64
65-74
75+
Age group
Figure 3.4 shows the numbers of ADR reports received and primary care
prescriptions by age group for 2010 to 2012. This seems to show a slightly different
picture with a greater proportion of ADRs reported in children than might be expected
from the proportion of primary care prescriptions in that age group; however, there
are a number of important limitations of the data which must be understood (Annex
4)
12
4
Direct Yellow Card reporting
4.1 Types of direct reports - Paper and Electronic Yellow Card reporting
Figure 4.1.1 shows the number of direct paper and electronic Yellow Card reports
that have been received between 2008 and 2012. The number of paper reports has
decreased over the years whilst the number of electronic reports has increased since
2010.
The MHRA’s Yellow Card strategy, which strengthens reporting of ADRs through the
Yellow Card Scheme, has a strong focus on facilitating reporting i.e. making reporting
convenient to access and easy to complete. Easier access to the Yellow Card
Scheme can help to enable the earlier detection of any potential drug safety issues,
allowing the MHRA to take prompt action to protect public health. The enhanced
electronic Yellow Card report form, designed to make the process of ADR reporting
quicker and easier for both health professionals and patients was launched in
February 2008. As part of this strategy several projects are currently underway to
facilitate electronic Yellow Card reporting through integration into clinical IT systems
used by healthcare professionals.
The Yellow Card website was also updated in early September 2012 to implement a
number of recommendations from the Health Technology Assessment completed by
the University of Nottingham∞. The newly improved Yellow Card website provides an
enhanced platform that supports the requirements of the new legislation, the Yellow
Card Strategy, and the NHS information standard on electronic Yellow Card reporting
from clinical IT systems.
Figure 4.1.1
∞
AJ Avery et al (2011), Evaluation of patient reporting of adverse drug reactions to the UK ‘Yellow Card
Scheme’: literature review, descriptive and qualitative analyses, and questionnaire surveys: Health
Technology Assessment 2011; Vol. 15: No. 20, Accessed at http://www.hta.ac.uk/project/1628.asp
13
The level of direct Yellow Card reporting fluctuates between given years due to a
variety of reasons such as a medicine/vaccine being new, stimulated
interest/publicity and variations in exposure to the medicine/vaccine.
4.1.1 Telephone reporting
As well as paper and electronic reporting methods, patients can also report directly
via the telephone. Table 4.1.1.1 shows the number of telephone reports received
from 2008 to 2012 and the proportion of reports from patients that this accounts for.
The proportion of patient reports received via the telephone is between 4-6% each
year with the exception of 2009.The total number of ADR reports received over the
telephone is relatively small. However as per the recommendations from the Health
Technology Assessment completed by the University of Nottingham, the MHRA
recognise the important of keeping all methods of reporting open to members of the
public
Table 4.1.1.1
Number of telephone reports
Proportion of patient reports
2008
130
5.3%
14
2009
69
2.1%
2010
124
6.4%
2011
91
5.4%
2012
78
4.3%
4.2 Source of direct reports – Reporter Qualification
Summary
Table 4.2.1
Direct reports
% of total reports
% GP reports
% Nurse reports
% Patient reports
% Pharmacist
reports
2008
14422
57.6%
24.4%
18.0%
17.1%
2009
15373
60.4% 
21.0% 
22.9% 
21.1% 
2010
12728
54.6% 
18.9% 
24.7% 
15.3% 
2011
12984
51.7% 
25.3% 
20.8% 
12.9% 
2012
13635
52.4% 
25.7% 
17.2% 
13.2% 
11.3%
10.9% 
Swine flu
vaccine (2584
reports, 17%)
Headache
(1420 reports,
9%)
Swine flu
vaccine &
headache (517
reports, 3%)
13.3% 
14.6% 
19.0% 
HPV (1752
reports, 14%)
Headache
(933 reports,
7%)
HPV (1049
reports, 8%)
Headache
(788 reports,
6%)
HPV (677
reports, 5%)
Nausea (843
reports, 6%)
HPV &
dizziness (369
reports, 3%)
HPV & pain in
extremity (232
reports, 2%)
HPV &
dizziness (179
reports, 1%)
Most reported
drug
Varenicline (2128
reports, 15%)
Most reported
reaction
Nausea (1274
reports, 9%)
Most reported
drug event
combination
Varenicline &
Nausea (424
reports, 3%)
Table 4.2.2
1
2
3
4
5
2008
Varenicline &
Nausea (424
reports, 2.9%)
Drug event combinations
2009
2010
2011
Swine flu vaccine
HPV & dizziness
HPV & pain in
& headache (517
(369 reports,
extremity (232
reports, 3.4%)
2.9%)
reports, 1.8%)
HPV & Dizziness
(332 reports,
2.3%)
Varenicline &
Depession (327
reports, 2.3%)
HPV & Dizziness
382 reports,
2.5%)
Swine flu vaccine
& pyrexia (358
reports, 2.3%)
HPV & Nausea
(311 reports,
2.4%)
HPV & Headache
(301 reports,
2.4%)
HPV & Nausea
(287 reports,
2.0%)
HPV & Headache
(256 reports,
1.8%)
HPV & Headache
(320 reports,
2.1%)
HPV & Nausea
(291 reports,
1.9%)
HPV & pain in
extremity (237
reports, 1.9%)
HPV & fatigue
(136 reports,
1.1%)
15
HPV & dizziness
(220 reports, 1.7%)
HPV & Headache
(205 reports, 1.6%)
HPV & Nausea (158
reports, 1.2%)
Varenicline &
Depressed mood
(114 reports, 0.9%)
2012
HPV & dizziness
(179 reports,
1.3%)
Varenicline &
Nausea (118
reports, 0.9%)
HPV & Headache
(111 reports,
0.8%)
Varenicline &
Depressed mood
(110 reports,
0.8%)
HPV & Nausea
(101 reports,
0.7%)
Figure 4.2.3 shows the breakdown in the proportion of direct ADR reports by different
reporter types from 2008 to 2012
Figure 4.2.3
*
2012 sees GP reporting returning to the higher numbers (2511 reports) received in
2008 (3515 reports) (see section 4.4) whilst reports received from nurses has
steadily decreased since 2009 (see section 4.7). Reports received from pharmacists
are at its highest with an increase of 37% (703 reports) from 2011 to 2012. (see
section 4.6)
Figure 4.2.3 shows trends in the number of reports received by reporter qualification
and a timeline of Yellow Card strategy activities which had a direct impact on the
level of reporting.
*
Reporter qualifications are grouped as follows: GP, Nurse (nurse & hospital nurse), Patient (patient,
parent, carer) Physician (physician, hospital doctor), Pharmacist (Pharmacist, hospital pharmacist,
pharmacist technician, pre-reg pharmacist, community pharmacist), Other hospital healthcare
professional (hospital healthcare professionals, radiographer, paramedic); Other Healthcare
professional (chiropodist, coroner, dentist, healthcare assistant, midwife, optometrist, medical student,
other healthcare professional,)
**An individual report may have multiple reporter sources therefore total numbers of cases cannot be
derived from the graph above.
- Non medical prescribers can not be distinguished by reporter qualification and so these are included
within the above groups i.e. a nurse prescriber report will be contained within the nurse reporter
qualification group.
16
Figure 4.2.3
Number of reports received from 2008-2012 by reporter source
GP
Nurse
Patient, Parent & Carer
Pharmacist
4000
Number of reports
3500
3000
2500
2000
1500
1000
500
0
2008
2009
2010
Year
Yellow Card Strategy Timeline
2011
February 2008 – Patient
reporting launch &
promotional campaign
June 2009 – Patient
and healthcare
professional campaign
developed
May 2010 – EHR
portal developed
October 2011 – New
Medicines Service
launched including
Yellow Card reporting
advice
2008
2009
2010
2011
February 2008 – Yellow
Card website updated
October to December
2009 – IDS leaflet drop
& Life channel video
December 2010 – SystmOne
reporting starts. October
2010- MIDatabank electronic
reporting successfully tested
HPV campaign
H1N1 Influenza Pandemic
17
2012
September 2012 –
Electronic Yellow Card
website updated
2012
October/November 2012
– Reporting pilot from
Cerner ‘Millennium’ system
starts. ‘Ask your
pharmacist week’
4.3 Source of direct reports – Healthcare setting reporting
In addition to comparing individual reporter types, such as GPs and hospital doctors,
reporters have been grouped into the below healthcare setting categories to simplify
comparisons between the different settings:



Primary Care: community pharmacist, GP, nurse, dentist, optometrist. These are
reporters that have everyday direct contact with patients in a primary care setting.
Secondary Care: This group is comprised of hospital reporters: hospital doctor,
hospital nurse, hospital pharmacist, hospital health professional. These are
essentially hospital reporters, from a secondary care setting.
Other: This category is composed of reporters that cannot be classified into a primary
or secondary care setting as it hasn’t been specified what kind of pharmacist,
physician or health professional they are.
Figure 4.3.1 shows the number of reports received over the last five years for each of the
healthcare settings
Figure 4.3.1
Number of reports by healthcare setting
14000
Number of reports
12000
10000
8000
6000
4000
2000
0
2008
2009
2010
2011
2012
Year
Primary Care
Secondary Care
Other
Overall, most direct healthcare professional reports are received from the Primary Care
sector (GPs, nurses and community pharmacists). The proportion of reports received each
year by healthcare setting has not changed over the last five years. Information relating to
non-medical prescribers cannot be distinguished as this information is not provided by the
reporters on the Yellow Card forms. In cases where these may have been provided, data is
aggregated under the report qualification (i.e. nurse prescriber data is within the nurse
qualification and primary care health setting)
18
Figure 4.3.2 shows the number of reports received by healthcare setting between 2008 and
2012.
Figure 4.3.2
Proportion of serious and fatal ADRs by healthcare setting 2008-2012
100%
1%
Percentage reports
90%
80%
4%
3%
17%
32%
37%
70%
60%
Fatal
50%
Non Serious
40%
30%
Serious
79%
65%
62%
20%
10%
0%
Primary Care
Secondary Care
Other
Healthcare setting
Higher proportions of reports with a fatal outcome (838 report) and serious reports (16608
reports) have been received from secondary care reporters over the last five years. This is to
be expected, as patients under hospital care are more likely to be experiencing more serious
or severe ADRs, which may result in a fatal outcome.
19
4.4 GP Yellow Card reporting
Summary

GP reporting is at its highest level in 2012 with 26% of reports being directly received
from GPs.
Table 4.4.1
Number of GP reports
% of total reports
Most reported drug
Most reported
reaction
2008
3515
24%
Varenicline
(711 reports,
20%)
Depression
(230 reports,
7%)
2009
3232
21% 
Oseltamivir
(368
reports,11%)
Headache
(191 reports,
6%)
2010
2404
19% 
Swine flu
vaccine (210
reports, 9%)
2011
3279
25% 
Varenicline
(188 reports,
6%)
2012
3511
26% 
Simvastatin
(156 reports,
4%)
Headache (115
reports, 5%)
Rash (218
reports, 7%)
Rash (274
reports, 8%)
Table 4.4.2
Drug event combinations
2008
2009
2010
2011
2012
1
Varenicline &
depression (123
reports, 4%)
Varenicline &
depression (64
reports, 2%)
Varenicline &
nausea (28
reports, 1.2%)
Ramipril & cough (35
reports, 1.1%)
Simvastatin & myalgia
(49 reports, 1.4%)
2
Varenicline &
nausea (83
reports, 2.4%)
Oseltamivir &
vomiting (54
reports, 1.7%)
Varenicline &
depressed mood
(24 reports, 1.0%)
Simvastatin & Myalgia
(29 reports, 0.9%)
Phenoxymethylpenicillin
& rash (49 reports,
1.4%)
Oseltamivir &
rash (42
reports, 1.3%)
Varenicline &
suicidal ideation
(19 reports, 0.8%)
Varenicline &
depression (28 reports,
0.9%)
Ramipril & cough (44
reports, 1.3%)
Varenicline &
depressed
mood (38
reports, 1.2%)
Varenicline &
depression (18
reports, 0.7%)
Phenoxymethylpenicillin
& rash (26 reports,
0.8%)
Amoxicillin & rash (28
reports, 0.8%)
HPV &
headache (38
reports, 1.2%)
Swine flu vaccine
& pyrexia (18
reports, 0.7%)
Amoxicillin & rash (26
reports, 0.8%)
Varenicline &
depression (23 reports,
0.7%)
3
4
5
Varenicline &
depressed
mood (74
reports, 2.1%)
Varenicline &
suicidal ideation
(68 reports,
1.9%)
Varenicline &
anxiety (56
reports, 1.6%)
GPs are considered an important backbone to Yellow Card Scheme and are the largest
reporting group, however GP reporting significantly declined in 2010 (2404 reports) making
nurses the largest reporting group for this year. Following a targeted Yellow Card Strategy
and the introduction of integrated Yellow Card reporting in GP systems (See section 4.4.2)
the level of reporting has increased by 25% in 2011 (3279 reports) and 26% in 2012 (3511
reports).
Although the number of reports received by this reporting population has increased in recent
years, the most reported drug event combinations show an increase in submissions for
established medicines and known drug-event combinations. In 2008 to 2009 GPs most
frequently submitted reports for Varenicline and HPV vaccines. These Drug event
combinations were replaced by more established medicines in 2011 and 2012 with smaller
numbers of drug-event combinations. .
20
4.4.1 GP reporting – Serious and Fatal ADRs
Figure 4.4.1.1 shows the proportion of serious and fatal reports received by GPs from 2008
to 2012. The proportion of serious reports has remained relatively stable at approximately
70% of all GP reports. Fatal reporting by GPs remains stable at approximately 2% of the total
number of GP reports each year.
Figure 4.4.1.1
Proportion of GP serious and fatal ADRs
100%
2%
2%
2%
2%
1%
28%
35%
29%
28%
28%
Percentage reports
90%
80%
70%
60%
Fatal ADRs
50%
Non Serious ADRs
40%
30%
Serious ADRs
70%
64%
68%
71%
70%
2008
2009
2010
2011
2012
20%
10%
0%
Year
4.4.2 GP reporting – Electronic and Paper ADRs
Since November 2010, GPs have been able to report suspected ADR reports directly using
the practice software SystmOne which is used in about 20% of GP practices across the UK.
This was the first GP software to develop a Yellow Card reporting feature that enables GPs
to quickly populate and securely send an electronic Yellow Card to the MHRA directly from
their practice software. Figure 3.5.2.1 shows the impact on the number of reports received
from GPs since the integration with SystmOne. In 2012, the MHRA received 2224 electronic
GP reports via SystmOne, accounting for 63% of all direct GP reporting. GP reporting
accounted for the largest source of direct Yellow Card reports in 2012 (26%). Work is
continuing to increase the number of reports received via SysmOne, as well as working with
additional clinical IT system providers such as the Cerner Millennium system as part of the
ongoing wider Yellow Card strategy.
Figure 4.4.2.1 shows the proportion of electronic and paper reports received from GPs from
2008 to 2012. This figure also shows a further breakdown of electronic reports by source.
21
Figure 4.4.2.1
GP report types 2008-2012
Paper Yellow Cards
Electronic Yellow Cards
SystmOne Yellow Cards
2008
Year
2009
2010
2011
2012
0
1000
2000
Number of Reports
3000
4000
Although the number of GP reports has increased in the last two years as a direct result
SystmOne Yellow Card reporting, the reactions reported are of a non-serious nature and are
well recognised reactions. The most reported reaction in 2011 and 2012 is the MedDRA nonserious term rash. The five most reported drug event combination also includes non-serious
listed reactions e.g. ramipril and cough. This pattern in reporting highlights the need for more
guidance to be communicated as part of our Yellow Card campaigns and promotion of the
Black triangle, clarification of the reporting criteria and areas of special interest for Yellow
Card forms (See Annex 1).
22
4.5 Pharmacist Yellow Card reporting
Summary

Pharmacist reporting has increased from 11% in 2008 and 2009 to 19% of all direct
reports in 2012.
Table 4.5.1
2008
2009
2010
2011
2012
Number of
Pharmacist reports
% of total reports
1631
11%
1671
11%
1690
13% 
1894
15% 
2597
19% 
Most reported drug
Varenicline
(139 reports,
9%)
Swine flu
vaccine (148
reports,9%)
Varenicline
(111 reports,
7%)
Most reported
reaction
Nausea (82
reports, 5%)
Nausea (81
reports, 5%)
Nausea (87
reports, 5%)
Varenicline
(63 reports,
3%)
Dyspnoea
(91 reports,
5%)
Varenicline
(79 reports,
3%)
Headache
(129 reports,
5%)
Table 4.5.2
Drug event combinations
2008
2009
2010
2011
2012
1
Varenicline &
nausea (23
reports, 1.4%)
Swine flu vaccine &
headache (24
reports, 1.4%)
Varenicline &
nausea (23
reports, 1.4%)
Warfarin & INR
ratio increased
(11 reports, 0.6%)
Varenicline & Nausea
(14 reports, 0.5%)
2
Varenicline &
depression (18
reports, 1.1%)
Swine flu vaccine &
pyrexia (20 reports,
1.2%)
Warfarin & INR
increased (19
reports, 1.1%)
Aspirin & GI
Haemorrhage (11
reports, 0.6%)
Simvastatin &
Rhabdomyolysis (11
reports, 0.4%)
3
Warfarin & INR
increased (15
reports, 0.9%)
Warfarin & INR
increased (18
reports, 1.1%)
Aspirin & GI
Haemorrhage
(13 reports,
0.8%)
Docetaxel &
injection site pain
(8 reports, 0.4%)
Naproxen & GI
Haemorrhage (10
reports, 0.4%)
4
Varenicline &
headache (14
reports, 0.9%)
Swine flu vaccine &
myalgia (16 reports,
1.0%)
Varenicline &
abnormal
dreams (11
reports, 1.1%)
Varenicline &
depression (7
reports, 0.4%)
Varenicline &
depressed mood (9
reports, 0.3%)
5
Aspirin & GI
Haemorrhage
(12 reports,
0.7%)
Swine flu vaccine &
oedema peripheral
(14 reports, 0.8%)
Varenicline &
depressed mood
(9 reports, 1.1%)
Lisinopril &
angioedema (7
reports, 0.4%)
Piperacillin and
Tazobactam &
clostridium difficile
infection (9 reports,
0.3%)
Figure 4.5.3 shows the trend in reporting for the different types of pharmacists over the last
five years. The number of reports received from each of these groups has increased in 2012
but more noticeably for both hospital pharmacists (22%, 240 reports increase from 2011 to
2012) and community pharmacists (75%, 388 reports increase from 2011 to 2012).
23
Figure 4.5.3
Pharmacist reports by qualification 2008-2012
Number of reports
1400
1200
1000
800
600
400
200
0
2008
2009
2010
2011
2012
Year
Community Pharmacists
Hospital Pharmacists
Pharmacists*
*Pharmacist group includes reports from pharmacists (unspecified location), pre-registration pharmacists and
pharmacy assistants.
4.5.1 Pharmacist reporting – Serious and Fatal ADRs
Figure 4.5.1.1 shows the proportion of serious and fatal reports received by pharmacists from
2008 to 2012. The proportion of serious reports has remained relatively stable at
approximately 80% of all pharmacist reports. Fatal reporting by pharmacists remains stable
at approximately 2% of the total number of pharmacist reports each year.
Figure 4.5.1.1
Proportion of Pharmacist serious and fatal ADRs
100%
Percentage reports
90%
2%
2%
2%
2%
2%
19%
23%
18%
17%
21%
80%
70%
Fatal ADRs
60%
Non Serious ADRs
50%
40%
Serious ADRs
79%
75%
80%
81%
78%
2008
2009
2010
2011
2012
30%
20%
10%
0%
Year
4.5.2 Pharmacist reporting – Electronic and Paper ADRs
In collaboration with Southampton University Hospitals NHS Trust and UK Medicines
Information (UKMI) service, the MHRA have integrated automated production of Yellow Card
reports using their MiDatabank software with medicines information pharmacists at over fifty
NHS hospitals in the UK. Figure 3.6.2.1 shows the impact on the number of reports received
24
for Pharmacists in 2011 and 2012 following efforts to increase reporting through MiDatabank
systems. In 2012, the MHRA received 445 reports through MiDatabank, which accounts for
50% of all electronic pharmacy reports and 17% of all direct pharmacist reports. To help
continue the installation of MiDatabank software, including Yellow Card reporting, this
programme has been supported by a number of activities such as communication via a letter
from Sir Professor Kent Woods CEO of the MHRA to NHS Chief Executives encouraging
prioritisation of the installation of this software within NHS Trusts.
The MHRA also set up a workshop and a poster on ADR reporting which was presented at
UKMI conferences, and a league table of reporting statistics is regularly provided to UKMI
centres. Work is continuing to increase the number of reports received via MiDatabank as
part of the ongoing wider Yellow Card strategy.
The New Medicine Service (NMS), launched in October 2011, is the fourth Advanced Service
to be added to the NHS community pharmacy contract in England. It aims to provide early
support to patients with long-term conditions who are starting a new medicine from certain
therapeutic groups, in order to maximise benefits and improve patient adherence. Successful
implementation of the NMS is envisaged by the Pharmaceutical Services Negotiating
Committee (PSNC) and NHS Employers to include an increase in the reporting of Yellow
Cards, thereby supporting improved pharmacovigilance, the monitoring of drug safety and
detection of new safety signals by the MHRA.
In addition to this initiative, the Yellow Card strategy has included an article published in the
Royal Pharmaceutical Journal±, work with key community pharmacy stakeholders, and active
encouragement of pharmacists to report suspected ADRs via the Yellow Card Scheme.
Figure 4.5.2.1 shows the proportion of electronic and paper reports received from all
pharmacists from 2008 to 2012. This figure also shows a further breakdown of electronic
reports from MiDatabank.
Figure 4.5.2.1
Pharmacist report types 2008-2012
2008
Year
2009
2010
2011
2012
0
500
1000
1500
2000
2500
3000
Number of Reports
Paper Yellow Cards
Electronic Yellow Cards
MIdatabank Yellow Cards
In 2012, Yellow Card strategy included partnership and engagement with key pharmacy
stakeholders such as the Professional Pharmacy Group and National Pharmacy Association.
This included initiatives such as ‘Ask Your Pharmacist Week’ to raise awareness of the
Yellow Card Scheme with community pharmacists and members of the public.
±
Jadeja M, McCreedy C. Positive effect of New Medicine Service on community Yellow Card Reporting. The
Royal Pharmaceutical Journal 2012; 289: 159
25
4.6 Nurse Yellow Card reporting
Summary

Nurse reporting increased in 2009 to 2011 and decreased in 2012 (17% of all direct
reports) to almost the same level of reporting in 2008 (18%).
Table 4.6.1
Number of Nurse
reports
% of total reports
Most reported
drug
Most reported
reaction
Most reported
drug event
combination
2008
2009
2010
2011
2012
2591
18%
HPV (865
reports, 33%)
Nausea (364
reports, 14%)
HPV & dizziness
(233 reports,
9%)
3517
23% 
HPV (1370
reports, 39%)
Headache (446
reports, 12%)
HPV &
dizziness (307
reports, 8%)
3144
25% 
HPV (1431
reports, 46%)
Dizziness (392
reports, 12%)
HPV & dizziness
(306 reports,
10%)
2707
21% 
HPV (837
reports, 31%)
Dizziness (288
reports, 11%)
HPV & pain in
extremity (202
reports, 7%)
2352
17% 
HPV (527
reports, 22%)
Dizziness (244
reports, 10%)
HPV & dizziness
(150 reports,
6%)
Table 4.6.2 – Vaccine DEC
1
2
3
4
5
Most reported vaccine drug event combination (DEC)
2008
2009
2010
2011
HPV & pain
HPV & Dizziness HPV & Dizziness
HPV &
in extremity
(233 reports,
(307 reports,
Dizziness (306
(202 reports,
8.9%)
8.7%)
reports, 9.7%)
7.5%)
HPV &
HPV & Nausea
HPV & Nausea
HPV & Nausea
Dizziness
(179 reports,
(228 reports,
(266 reports,
(187 reports,
6.9%)
6.5%)
8.5%)
6.9%)
HPV &
HPV & Headache HPV & Headache
HPV &
Headache
(153 reports,
(227 reports,
Headache (248 (160 reports,
5.9%)
6.5%)
reports, 7.9%)
5.9%)
HPV &
HPV & Syncope
HPV & pain in
HPV & pain in
Nausea (124
(99 reports,
extremity (151
extremity (198
reports,
3.8%)
reports, 4.3%)
reports, 6.3%)
4.6%)
HPV &
HPV & Pain in
HPV & Vomiting
HPV & Fatigue
Malaise (63
extremity (81
(139 reports,
(111 reports,
reports,
reports, 3.1%)
4.0%)
3.5%)
2.3%)
2012
HPV &
Dizziness (150
reports, 6.4%)
HPV &
Headache (77
reports, 3.3%)
HPV &
Nausea (77
reports, 3.3%)
HPV &
Syncope (73
reports, 3.1%)
HPV &
Malaise (60
reports, 2.6%)
Nurse reporting is typically dominated by vaccination campaigns and in recent years this has
been the HPV campaign as indicated by the top 5 drug event combinations over the last five
years. However, the number of reports received from nurses for these DEC’s has decreased
when comparing 2008 to 2012.
26
Table 4.6.2 – Non Vaccine DEC
4
2008
Varenicline &
nausea (130
reports, 5.0%)
Varenicline &
Depression (86
reports, 3.3%)
Varenicline &
depressed mood
(67 reports, 2.6%)
Varenicline &
Headache (65
reports, 2.5%)
5
Varenicline &
Vomiting (42
reports, 1.5%)
2
3
Varenicline &
Vomiting (29
reports, 0.8%)
Varenicline &
Vomiting (13
reports, 0.4%)
Varenicline &
Insomnia (16
reports, 0.6%)
2012
Varenicline &
Nausea (28
reports, 1.2%)
Varenicline &
Depression (26
reports, 1.1%)
Varenicline &
Headache (20
reports, 0.9%)
Varenicline &
Dizziness (15
reports, 0.6%)
Varenicline &
Depressed
mood (11
reports, 0.5%)
Figure 4.6.4 shows the trend in reporting for the different types of nurse over the last five
years.
Figure 4.6.4
Nurse reports 2008-2012
4000
HOSPITAL NURSE
NURSE
3500
Number of reports
1
Most reported Non Vaccine Drug event combinations
2009
2010
2011
Varenicline &
Varenicline &
Varenicline &
nausea (86 reports,
Depressed mood
Depressed mood
2.4%)
(40 reports, 1.3%)
(49 reports, 1.8%)
Varenicline &
Varenicline &
Varenicline &
Depressed mood
nausea (30 reports, nausea (28 reports,
(65 reports, 1.8%)
1.0%)
1.0%)
Varenicline &
Varenicline &
Varenicline &
Headache (49
Depression (19
Aggression (24
reports, 1.4%)
reports, 0.6%)
reports, 0.9%)
Varenicline &
Varenicline &
Varenicline &
Depression (40
Headache (16
Headache (22
reports, 1.1%)
reports, 0.5%)
reports, 0.8%)
3000
2500
2000
1500
1000
500
0
2008
2009
2010
2011
2012
Year
The numbers of reports received from general nurses have increased in 2009 and 2010. This
can be attributed to the launch of the HPV vaccination campaign. In 2011, reports from
nurses contributed towards the second largest proportion of direct Yellow Cards, however,
this proportion has declined by 355 reports (13%) in 2012 from 2707 reports (21% of all
direct Yellow Card reports) in 2011. This can be accounted for by the decline in Yellow Cards
received for HPV vaccines in 2012, which is expected as promotion and publicity around the
HPV vaccination campaign decreases as it enters its fourth year. Figure 4.6.5 better
represents the number of reports received by nurses from 2008 to 2012 for all other suspect
drugs against HPV vaccine. With the exclusion of HPV vaccine reports, nurse reporting is at
approximately 1700 reports per year.
27
Figure 4.6.5
4.6.1 Nurse reporting – Serious and Fatal ADRs
Figure 4.6.1.1 shows the proportion of serious and fatal reports received by nurses from
2008 to 2012. The proportion of serious reports has remained relatively stable at
approximately 50-60% of all nurse reports. Fatal reporting by nurses remains stable at
approximately 1% of the total number of nurse reports each year.
Figure 4.6.1.1
Proportion of patient serious and fatal ADRs
100%
0.5%
0.5%
0.5%
43.4%
48.1%
52.0%
0.7%
0.9%
42.4%
37.2%
Percentage reports
90%
80%
70%
60%
Fatal ADRs
50%
Non Serious ADRs
40%
30%
Serious ADRs
56.0%
51.4%
47.5%
2008
2009
2010
20%
56.9%
61.9%
2011
2012
10%
0%
Year
28
4.6.2 Nurse reporting – Electronic and Paper ADRs
Figure 4.6.2.1 shows the proportion of electronic and paper reports received from all nurses
from 2008 to 2012.
Figure 4.6.2.1
Percentage of reports
Proportion of nurse electronic and paper reports 2008-2012
100%
90%
80%
70%
60%
50%
40%
30%
20%
10%
0%
43%
46%
34%
61%
75%
Paper reports
Electronic reports
57%
54%
66%
39%
25%
2008
2009
2010
2011
2012
Year
The number of electronic reports increased in 2009 during the start of the HPV campaign
and reduced the year after. Although nurses are less likely to report electronically when
compared to GPs and Pharmacists, 2011 and 2012 electronic reporting from nurses increase
to the highest level of electronic reporting in this five year time period (26% increase from
2010 to 2011).
29
4.7 Healthcare Professionals - Patient demographics
Summary
Most reported non-vaccine healthcare professional reports are for the 55-75 year age group.
Approximately 60% of all healthcare professional reports from 2008 -2012 relate to female
patients.
The age breakdown of healthcare professional reports can be seen in figure 4.7.1. Over the
last five years there has been an increase in ADR reports in older age groups. The peak in
ADR reporting for 7-12 and 13-17 year olds correlates with the HPV vaccination programme.
Figure 4.7.1
HCP ADR reports by age from 2008-2012
Age Groups
75+
65-75
55-64
45-54
35-44
25-34
18-24
13-17
7-12
2-6
Under 2
HPV vaccine campaign
0.0%
2.0%
4.0%
6.0%
8.0%
10.0%
12.0%
14.0%
16.0%
% of ADR reports
Figure 4.7.2 shows the age groups for non-vaccine healthcare professional ADR reports in
the last five years. This shows a more consistent picture in the number of reports received in
the under 18’s age groups.
Figure 4.7.2
Non vaccine HCP ADR reports by age from 2008-2012
75+
Age Groups
65-75
55-64
45-54
35-44
25-34
18-24
13-17
7-12
2-6
Under 2
0.0%
2.0%
4.0%
6.0%
8.0%
10.0%
% of ADR reports
30
12.0%
14.0%
16.0%
18.0%
The majority of reports received are for the adult age groups (25 to 64 years), with a slightly
greater proportion in the 55-75 age groups. 6.4% (1109 reports) of healthcare professional
non-vaccine reports between 2008 and 2012 were for under 18s.
Reporting by gender has remained fairly constant over the last 5 years with approximately
60% of all reports relating to females, 37% relating to males and 3% where patient gender is
not specified.
31
4.8 Patient Yellow Card reporting
Summary
Table 4.8.1
2008
2009
2010
2011
2012
Number of patient
reports
% of total reports
2473
17.10%
3248
21.10% 
1943
15.30% 
1674
12.90% 
1796
13.20% 
Most reported drug
Simvastatin
(156 reports,
6%)
Swine flu
vaccine (1201
reports, 37%)
Most reported
reaction
Nausea (260
reports, 11%)
Headache (508
reports, 16%)
Swine flu
vaccine (331
reports, 17%)
Headache
(223 reports,
11%)
Flu vaccine
(63 reports,
4%)
Headache
(168 reports,
10%)
Varenicline
(64 reports,
4%)
Fatigue (187
reports,
10%)
Table 4.8.2
Drug event combinations
2008
2009
2010
2011
2012
1
Simvastatin &
myalgia (37
reports, 1.5%)
Swine flu vaccine &
headache (319
reports, 9.8%)
Swine flu vaccine
& pyrexia (68
reports, 3.5%)
HPV &
headache (20
reports, 1.2%)
HPV & fatigue (24
reports, 1.3%)
2
Varenicline &
depression (30
reports, 1.2%)
Swine flu vaccine &
pyrexia (207
reports, 6.4%)
Swine flu vaccine
& headache (52
reports, 2.7%)
Varenicline &
depression (19
reports, 1.1%)
Varenicline &
depression (23 reports,
1.3%)
3
Varenicline &
nausea (23
reports, 0.9%)
Swine flu vaccine &
nausea (178
reports, 5.5%)
Swine flu vaccine
& vomiting (47
reports, 2.4%)
HPV & fatigue
(18 reports,
1.1%)
HPV & headache (22
reports, 1.2%)
4
Simvastatin &
arthralgia (21
reports, 0.8%)
Swine flu vaccine &
pain in extremity
(176 reports, 5.4%)
Swine flu vaccine
& pain in
extremity (44
reports, 2.3%)
MMR vaccine
& pyrexia (14
reports, 0.8%)
Desogestrel &
depression (19 reports,
1.1%)
5
Simvastatin &
pain in extremity
(20 reports, 0.8%)
Swine flu vaccine &
fatigue (163
reports, 5.0%)
Swine flu vaccine
& fatigue (39
reports, 2.0%)
HPV & nausea
(13 reports,
0.8%)
levothyroxine & product
substitution issue (17
reports, 0.9%)
Patient Yellow Card reporting was introduced as a pilot scheme in January 2005 and after a
successful pilot was formally launched In February 2008 along with a nationwide campaign
aimed at raising awareness of the Yellow Card Scheme through community pharmacies. At
the same time, the enhanced electronic Yellow Card was re-launched, making on-line
reporting for patients and healthcare professionals easier and more user-friendly and
hopefully encouraging more on-line reporting.
Figure 4.8.3 shows the number of patient reports received over the last eight years with a
break down by reporter source (patient, parent or carer)
32
Figure 4.8.3
Patient reporting decreased after the first year of being launched and increased significantly
in 2008 when patient ADR reporting was formally established alongside a nationwide
campaign aimed at raising awareness of the Yellow Card Scheme through community
pharmacies.
In 2009, a year after the formal launch of the patient Yellow Card reporting increased again
as a result of the pandemic vaccines and antivirals campaign (see figure 4.6.4). From 2009
to 2012 patient Yellow Card reporting has decreased by 1305 reports (40%). Although
reporting from members of the public has decreased since 2009, there is a 7.3% (122
reports) increase in reports from 2011 to 2012. This recent increase may be attributable to
the impact of the Yellow Card Strategy.
IDS UK Ltd distribute healthcare leaflets to GP Surgeries throughout the UK. The MHRA
Patient Yellow Card was distributed during the period October to December 2009. The
leaflets were displayed in GP waiting rooms in a wall mounted multi-pocketed leaflet display
rack from which the patients can self-select.
During this time the MHRA also produced a Life Channel video, which is a high quality 30
second animated commercial with graphics, animations, sub titles and music sound track.
The video was broadcast throughout 462 GP waiting rooms with 3 played every hour. The
showing of the advertisement also coincided with sites where IDS also distributes leaflets.
The video was also used at conferences and exhibitions.
During the pandemic ‘season’ the MHRA launched a Pharmacovigilance strategy which
included the optimisation of the collection of suspected ADR reports from all reporters,
especially patients, parents and carers. To fulfil these requirements, the MHRA developed a
dedicated, web-based ADR reporting interface and worked with the Department of Health to
ensure that leaflets and other written material were made readily available to patients and
health professionals to encourage reporting of ADR reports through the Swine Flu ADR
Portal.
Figure 4.8.4 shows the reporting profile of all suspect drugs against pandemic
vaccines/medicines for all patient reports between 2008 and 2012. This figure shows a more
accurate profile for the number of patient reports that have been received without the
33
inclusion of pandemic reports. Patient reporting over the last five years after the formal
launch of the patient Yellow Card is stable at approximately 1500 reports per year.
Figure 4.8.4
Pandemic patient, parent and carer reports 2008-2012
3500
Pandemic
Number of reports
3000
All other drugs
2500
2000
1500
1000
500
0
2008
2009
2010
2011
2012
Year
4.8.1 Patient reporting – Serious and Fatal ADRs
Figure 4.8.1.1 shows the proportion of serious and fatal reports from patients and carers from
2008 to 2012. The proportion of serious reports has increased steadily from 79% in 2008 to
86% in 2012. Fatal reporting by members of the public remains stable at approximately 1%
of the total number of patient reports each year.
Figure 4.8.1.1
Proportion of patient serious and fatal ADRs
1%
100%
90%
19%
1%
1%
1%
1%
16%
12%
13%
13%
Percentage reports
80%
70%
60%
Fatal ADRs
50%
40%
Non Serious ADRs
80%
84%
87%
86%
86%
2009
2010
2011
2012
30%
20%
10%
0%
2008
Year
34
Serious ADRs
4.8.2 Patient reporting – Electronic and Paper Yellow Cards
Figure 4.8.2.1 shows the proportion of electronic and paper reports received from patients
from 2008 to 2012.
Figure 4.8.2.1
Proportion of patient electronic and paper reports 2008-2012
Percentage of reports
100%
18%
90%
23%
27%
18%
80%
70%
60%
60%
Paper reports
50%
82%
40%
30%
20%
73%
77%
82%
2010
2011
2012
Electronic reports
40%
10%
0%
2008
2009
Year
In 2009 electronic reporting increased dramatically by almost 1600 reports (~40%) due to
patient reports received via the Swine Flu ADR Portal. However electronic reporting has
remained the preferred method for reporting by patients and carers from 2010 onwards. A
number of enhancements were made in 2012 to the online Yellow Card form to facilitate
ease of reporting and take on board feedback from users of the website
35
4.8.3 Patient reporting – Patient demographics
The age breakdown of patient reports in figure 4.8.3.1. shows the majority of reports received
are for the adult age groups (25 to 64 years), with a slightly greater proportion in the 25-34
age group. 10% (1109 reports) of patient reports between 2008 and 2012 were for under
18s.
Figure 4.8.3.1
Age Groups
Patient ADR reports by age from 2008-2012
75+
65 to 74
55 to 64
45 to 54
35 to 44
25 to 34
18 to 24
13 to 17
7 to 12
2 to 6
Under 2
0.0%
Percentage of patient reports
2.0%
4.0%
6.0%
8.0%
10.0%
12.0%
14.0%
16.0%
% of ADR reports
Table 4.8.3.2 shows a breakdown of the patient gender for all patient parent and carer
reports from 2008 to 2012. It should be considered that only 1% of patient reports received
2008-2012 did not contain patient gender information. Most patients report for themselves
and it is therefore usually possible to deduce the patient gender in the majority of patient
reports, whereas this is not the case for healthcare professional and industry reports
Table 4.8.3.2
Year
2008
2009
2010
2011
2012
Female
63.3%
64.9%
63.6%
66.0%
63.3%
Male
35.2%
34.0%
35.5%
33.1%
35.4%
Unknown
1.5%
1.5%
0.7%
0.6%
1.0%
Analysis of the age profile between patient reports and healthcare professional reports show
generally increasing proportions of reports with age. The most frequently reported ages for
patients reports (25+ years) differs when compared with reports received by healthcare
professionals, where the most frequently reported age groups are for older patients (55 – 64
years). Reports for children (under 18 years old) make up 10% of all patient reports and
6.4% of all healthcare professional reports. It is expected that reports will be received for
elderly patients who are more likely to be subject to polypharmacy for age related conditions
such as cardiac and renal disorders. Generally, young children are exposed mainly to
vaccines and occasional courses of antibiotics or cough and cold medicines. Patient gender
is similar between patient reports (approximately 65% female reports) and healthcare
professional reports (approximately 60% female reports).
36
5
Vaccine reporting
Summary
Table 5.1
2008
2009
2010
2011
2012
2180
15%
1281
5145
33% ↑
1862
3472
27% ↓
1752
2062
16% ↓
1049
1550
11% ↓
677
59%
36%
50%
51%
44%
0
2584
866
63
10
0%
50%
25%
3%
Most reported vaccine
HPV vaccine
(1281 reports,
59%)
Swine flu
vaccine (2584
reports, 50%)
HPV vaccine
(1752 reports,
50%)
Most reported reaction
Dizziness (362
reports, 16%)
Headache
(901 reports,
17%)
Headache
(479 reports,
14%)
Most reported vaccine
event combination
HPV vaccine &
dizziness (332
reports, 15%)
HPV vaccine
& headache
(571 reports,
11%)
HPV vaccine
& dizziness
(369 reports,
11%)
HPV vaccine
(1049reports,
24%)
Pain in
extremity
(306 reports,
15%)
HPV vaccine
& pain in
extremity
(232 reports,
11%)
1%
HPV
vaccine (677
reports,
44%)
Number of vaccine
reports
% of total reports
Number of HPV reports
HPV - % total vaccine
reports
Number of Pandemic
vaccine reports
Pandemic vaccines - %
total vaccine reports
Dizziness
(235 reports,
15%)
HPV
vaccine &
dizziness
(179 reports,
12%)
In 2009, ADR reporting for vaccines was at its highest levels, comprising 33% of the total
reports received. The most reported vaccine in this year was swine flu vaccine and the
second most reported vaccine was HPV which accounted for 50% and 36% of all vaccine
reports respectively. In 2010, 2011 and 2012 the most reported vaccine was also HPV
vaccine, which was associated with the majority of vaccine reports at 50%, 51% and 44%
respectively.
It is expected that the number of vaccine reports will increase in 2013 due to a significant
change in the national immunisation programme, with the introduction of four major new
programmes based on the advice and recommendations of Joint Committee on Vaccination
and Immunisation (JCVI). The new immunisation campaigns include the intranasal influenza
vaccine Fluenz in children aged 2-16 years of age (autumn 2013), rotavirus vaccine Rotarix
in infants at 2 and 3 months of age (July 2013), shingles vaccine Zostavax in all 70 year olds
(September 2013), and a new adolescent booster of Meningitis Group C conjugate vaccine.
5.1 Source of vaccine reports
The reporting of suspected ADRs to vaccines by healthcare professionals and patients is
encouraged as part of the Yellow Card Scheme in order to gather more information on the
safety profile of vaccines. Given that nurses most frequently administer vaccines, it is
expected that reports received from nurses account for the largest source of reports at 52%
(7559 reports) of all vaccine reports. The second largest group of reporters are patients,
parents and carers (16% of all vaccine reports, 2375 reports).
37
5.2 Vaccine reactions
Figure 5.2.1 illustrates the ADR reporting profile of all spontaneous vaccine reports received
over the past five years. The SOCs containing the most ADRs was ‘General Disorders’ and
the ‘Nervous System Disorders’. SOCs This is due to the large number of ADR reports for
reactions such as ‘dizziness’, ‘headache’ and ‘syncope’ associated with HPV vaccination.
Figure 5.2.1
Number of vaccine reactions by System Organ Class (SOC) - 2008 to 2012
7000
Number of vaccine ADRs
6000
5000
4000
3000
2000
1000
Surg
Endo
Cong
Neopl
Hepat
Preg
SocCi
Renal
Repro
Ear
Inj&P
Card
Metab
Blood
Immun
Psych
Inv
Eye
Infec
Vasc
Resp
Musc
Skin
Gastr
Nerv
Genrl
0
System Organ Class (SOC)
Overall the profile is as expected for vaccine reports, with the majority of ADRs falling within
the General SOC (most frequently reported reactions: pyrexia and malaise), Nervous SOC
(most frequently reported reactions: headache and dizziness), Gastrointestinal SOC (most
frequently reported reactions: nausea and vomiting), Skin SOC (most frequently reported
reactions: erythema and rash), and Musculoskeletal SOC (most frequently reported reaction:
pain in extremity and myalgia).
The proportion of serious suspected ADR reports associated with vaccines over the last five
years can been seen in table 5.2.2.
38
Table 5.2.2
2008
1261
58%
Serious vaccine reports
2009
2010
2011
3253
2031
1504
63%
58%
73%
2012
1229
79%
The proportion of serious suspected ADR reports associated with vaccines over the last five
years is much lower than the proportion of serious reports for all (indirect and direct) drugs
and vaccines combined (approximately 85%).
Unsurprisingly over 80% of all vaccine ADR reports in 2009 and 2010 relate to female
patients as a result of the volume of HPV vaccine reports Figure 5.2.3 shows the age
breakdown for vaccine ADR reports from 2008 to 2012. As expected the majority of reports
were associated with patients aged less than 18 years. The large proportion of reports for the
age group under 2 years reflects the ages at which children receive their routine childhood
immunisations. Again, the effect of the HPV vaccination campaign can be seen, with a
substantial increase in the proportions of reports in the 7-12 and 13-17 year age groups.
Figure 5.2.3
Number of vaccine reports by age group
Unknown
65+
Number of reports
55-64
Age group
45-54
HPV vaccination campaign
35-44
25-34
18-24
13-17
7-12
2-6
Under 2
0
500
1000
1500
2000
2500
Number of reports
39
3000
3500
4000
4500
6
Regional Yellow Card reporting
Summary


Yellow Cards received from YCC regions areas account for approximately 50% of all
direct reports from 2008 to 2012
The number of reports per 100,000 of the population for YCC region areas is slightly
higher than the number of reports received for non-YCC region areas over the five years.
Within this section, all regional data is based upon Strategic Health Authority (SHA) regions
and reporter postcodes which have been compared to postcode information provided by the
Yellow Card Centres (YCCs).
YCCs operate across the UK (except Northern Ireland) and undertake valuable work relating
to a number of areas including, promotion and education of health professionals on ADR
reporting. Below are the five YCCs and the city in which the centre is based:





YCC North West (Liverpool)
YCC West Midlands (Birmingham)
YCC Scotland (Edinburgh)
YCC Wales (Cardiff)
YCC Northern & Yorkshire (Newcastle)
In 2009 YCC North West which was previously known as YCC Mersey expanded its
boundaries to encompass Greater Manchester and Lancashire as well as maintaining its
Merseyside and Cheshire region.
Table 6.1 shows the numbers of direct reports received from each YCC region in 2008 to
2012 based upon strategic health authority (SHAs) in England and health boards in Scotland
and Wales that fall within an area covered by a YCC.
Table 6.1
YCC Region
North West
Northern & Yorkshire
Scotland
Wales
West Midlands
Number of
Reports
2008
1974
1828
1554
1071
1203
Number of
Reports
2009
2008
1788
1531
876
1252
Number of
Reports
2010
1620
1523
1093
957
909
Number of Number of
Reports
Reports
2011
2012
1477
1520
1938
2160
919
884
792
637
922
932
Table 6.2 shows the contribution of the number of reports from each of the YCC regions per
100,000 of the population from 2008 to 2012 based upon current UK population of 63.2
million. The number of reports received from the YCCs by population has decreased for all
YCCs over the last five years, with the exception of Northern and Yorkshire.
40
Table 6.2
Population
in millions
in each
region*
YCC Region
North West
6.4
Number of
reports/
population
(100,000)
in 2008
30
Number of
reports/
population
(100,000)
in 2009
31
Number of
reports/
population
(100,000)
in 2010
25
Number of
reports/
population
(100,000)
in 2011
23
Number of
reports/
population
(100,000)
in 2012
24
Northern & Yorkshire
Scotland
Wales
West Midlands
8.7
5.3
3.1
5.3
21
29
35
23
21
29
28
24
18
21
31
17
22
17
26
17
25
17
22
18
Total from YCC
regions
Total from non YCC
regions
28.8
26
26
21
21
21
34.4
17
20
15
17
17
Total from UK
63.2
21
23
18
19
19
* Population data supplied by each individual YCC as of 2012 and taken to be consistent for all 5 years.
Over the last year the YCCs have delivered over 130 teaching and educational workshop
sessions to health professionals and undergraduates. YCCs also actively engage with
numerous patient groups, such as the British Lung foundation, the National Osteoporosis
Society and Diabetes UK groups, to increase awareness of the Scheme and reporting from
patients.
Key highlights of activity have included:





YCC Scotland: working in close collaboration with Scottish healthcare bodies and NHS
Education in Scotland to develop a series of six e-learning modules for ADR reporting.
YCC Wales: working with the All Wales Medicines Strategy Group to promote drug safety
and reporting from nurses and dentists involved with medicines management.
Contribution to the Expert Patient Programme to educate both patients living with longterm health conditions and their carers.
YCC West Midlands: research into the reporting rates by GPs; resulting in increased
engagement with local GPs.
YCC Northern and Yorkshire: partnering with NHS direct to give a number of medicines
information sessions focused on engaging with patients and increasing Yellow Card
reporting.
YCC North West: contribution to the success of MiDatabank and launch of the e-learning
program for England’s Centre for Pharmacy Postgraduate Education (CPPE) aimed at
pharmacists, pharmacy technicians and pre-reg pharmacists.
41
7
New Pharmacovigilance Legislation and ADR reporting
As part of European pharmacovigilance legislation adopted in July 2012, a number of
changes were implemented which were expected to have an impact on the level of ADR
reporting from Industry, healthcare professionals and the general public (Annex 6). The
legislation makes two fundamental changes for pharmacovigilance and spontaneous
reporting schemes such as the Yellow Card Scheme. Firstly the definition of an adverse drug
reaction is redefined to include ADRs arising from medication error, off-label use, misuse and
abuse. Secondly, the new legislation requires all marketing authorisation holders to submit
ADRs from consumers and non-healthcare professionals.
Broadening the definition of adverse drug events has the potential to significantly increase
the number of Yellow Cards received. The new legislation requires member states to
strengthen reporting of adverse drug reactions, therefore supporting the aim of the Yellow
Card strategy. The MHRA is exploring how reports of medication error can be encouraged in
order to meet the commitment set out in the new legislation. NHS England is currently
responsible for collecting reports of medication error, and so the MHRA is collaborating with
NHS England to ensure that information is exchanged in a timely manner. This collaboration
involves strengthening clinical governance through establishing designated Safety Officers in
trusts, streamlining data transfer to the Yellow Card database through electronic methods
and improving the quality of information in the National Reporting and Learning System
(NRLS) database.
Figure 7.1 shows the impact of the number of reports that have been received following on
from the change in definition of adverse events to include medication errors, intentional
misuse and off label use when associated with an adverse event.
Figure 7.1
Number of reports for medication error, overdose and off label use
2500
New Legislation
160
2000
Number of reports
140
120
1500
100
80
1000
60
40
500
20
Jun-13
May-13
Apr-13
Mar-13
Feb-13
Jan-13
Dec-12
Nov-12
Oct-12
Sep-12
Aug-12
Jul-12
Jun-12
May-12
Apr-12
Mar-12
Feb-12
0
Jan-12
0
Cumalative number of reports
180
Month & Year
Number of reports
Cumalative Number of reports
Although the number of reports for these types of reactions fluctuates from month to month, it
can be seen that there has been a general increase in the number of reports received
following implementation of the new legislation. Figure 7.2 shows the number of reports
42
received from indirect sources prior to the implementation of new legislation and post
implementation.
Figure 7.2
Impact of New EU legislation on indirect reporting
2500
50000
New Legislation
Number of reports
2000
40000
35000
1500
30000
25000
1000
20000
15000
500
10000
5000
Jun-13
May-13
Apr-13
Mar-13
Feb-13
Jan-13
Dec-12
Nov-12
Oct-12
Sep-12
Aug-12
Jul-12
Jun-12
May-12
Apr-12
Mar-12
Feb-12
0
Jan-12
0
Cumalative number of reports
45000
Month & Year
Indirect Reports
Cumalative total of spontaneous reports
As part of the new legislation Marketing Authorisation holders are now required to submit
reports from consumers regardless of whether or not they are medically confirmed. Figure
7.3 shows the number of consumer reports that have been received in 2012.
43
Figure 7.3
Impact of new legislation - consumer reports
600
Consumer reports
500
NUmber of reports
New Legislation
Transitional
period
400
300
200
100
Jun-13
May-13
Apr-13
Mar-13
Feb-13
Jan-13
Dec-12
Nov-12
Oct-12
Sep-12
Aug-12
Jul-12
Jun-12
May-12
Apr-12
Mar-12
Feb-12
Jan-12
0
Month & Year
As expected July 2012 demonstrates that the number of reports received by consumer
has dramatically increased, due to the new reporting obligations placed on MAHs to report all
consumer reports. There is a peak in the number of consumer reports received from industry
in May 2013 where one MAH submitted a backlog of reports, which had been identified as
consumer reports.
44
8
Signal Assessment
8.1 Signals raised & investigated from 2008 until 2012
Signals of new and changing drug safety hazards are detected in a timely manner through
the Yellow Card Scheme. Changes in the frequency of Adverse Drug Reaction (ADRs)
already known to be associated with drugs are also closely monitored through the signal
detection process. The drug-event combinations from Yellow Card reports are assessed
each week to identify potential safety signals. For any signals of concern a Signal
Assessment Case Folder (SACF) is created. During this time period a total of 746 signals
were identified. All of these signals were subjected to detailed review.
Each signal investigated is assigned a priority in which a national position should be reached.
Priorities can either be top (3 months), increased (6 months) or standard (12 months). Figure
8.1.1 shows the total number of Signal Assessment Case Folders created from 2008 until
2012 broken down by priority.
Figure 8.1.1:
Total number of SACFs created from 2008 - 2012
450
Number of SACFs created
400
350
300
250
200
150
100
50
0
Top
Increased
Standard
Priority
Figure 8.1.2 provides a breakdown of the number of SACF created each year between 2008
until 2012.
45
Figure 8.1.2:
Number of SACF created over time
140
Top
Increased
Standard
Number of SACFs
120
100
80
60
40
20
0
2008
2009
2010
2011
2012
Year
The peak seen in SACFs in 2009 can be explained by a pilot whereby signals identified by
an MAH were communicated directly to us, this accounted for 27% of all signals identified in
2009. From 2010 there is a decrease in the number of signals identified; this is due to a
change in process where SACFs are only created when we have enough evidence to
confirm a true signal (this is in line with legislation changes). Issues where we do not believe
we have sufficient evidence to confirm the signal are tracked through meeting minutes and
our signal detection system.
8.2 Outcomes of signals identified
Of the signals identified in the last 5 years 84% have been completed. Below is a list of the
various outcomes that these signals have resulted in, it is important to note that one signal
can result in a number of different outcomes:




Variation implemented: Updates made to improve warnings in product information.
Communication delivered: The Reference Member State (RMS) or the Rapporteur is
notified of the signal and asked to investigate further. Further discussion at PRAC.
Other measures implemented: Advice from Expert Advisory Groups (EAGs), or raised
via the PSUR.
Await further evidence: No immediate action is required at present, wait for more
cases.
Figure 8.2.1 displays the outcomes of signals identified from 2008 until 2012. This graph
does not include the 16% of identified signals where assessment is still ongoing and
therefore an outcome is not yet available.
46
Figure 8.2.1:
Of the peak in SACFs in 2009, the majority of these clearly resulted in no immediate action
as further evidence was required. 5% of signals identified in 2009 were for Tamiflu, these
were all assigned a top priority and were reviewed alongside the MAH promptly.
8.3 Patient signals
Of the 746 signals investigated over the last 5 years, there were 285 reports from the general
public which contributed to raising these signals. In 29 of the signals investigated, the report
that actually initiated further investigation (i.e. the index case) was a report which had been
submitted from a member of the public. Figure 8.3.1 displays the number of Yellow Card
reports received from members of the public which have contributed to signals over the last 5
years.
Figure 8.3.1:
The pandemic campaign explains the increased contribution of reports received from
members of the public from 2009 - 2010. In 2011 this decreases and then picks up again in
2012. This increase in the patient contribution to signals is in line with the increase in the
proportion of Yellow Card reports received from the general public in 2012.
47
9. Conclusions
The main trend which has emerged from ADR reporting over the last five years is a
4.1% increase for ADR reporting from 25,012 in 2008 to 26,037 in 2012. This
includes an increase of 13% in reports received from members of the public between
2011 and 2012.
Seriousness of reports has increased from 84% in 2008 to 87% of all reports in 2012.
ADR reports with a fatal outcome have increased from 5% of reports in 2008 to 6% of
all ADR reports in 2012. Although the proportion of ADR reports with a fatal outcome
has increased over the past five years, analysis of this data shows that this increase
is a result of industry reporting (7 to 10%) with direct reports from healthcare
professionals and patients remaining constant at about 2%. A key factor is the
changes in pharmaceutical company reporting of ADRs particularly the coding of
adverse drug reactions and the use of the term ‘death’. With respect to spontaneous
reports of ‘death’, industry are advised to use the most specific term available to
describe the suspected reaction and the report must be followed up for further
information.
The proportion of direct reporting by HCPs and members of the public accounts for
52% of all reports in 2012 and GP reporting continues to form the ‘backbone’ of the
Yellow Card Scheme with a 26% increase in the proportion of direct reports in 2012
when compared to 2011.
Pharmacist reporting is at its highest ever level with a 19% increase in the proportion
of direct reports in 2012 compared to 2011. Underpinning this is the increased
reporting by hospital pharmacists and the impact of the Yellow Card strategy.
Nurses contribute to the second largest proportion of reports accounting for 17% of
all direct reports in 2012 however this has decreased since 2010 when nurse
reporting accounted for 25% of all direct reports. Nurse reporting is dominated by
vaccination campaigns and in 2010 this was the HPV vaccination campaign. It is
expected that this figure will increase with the significant change in the national
immunisation programme, with the introduction of four major new programmes based
on the advice and recommendations of JCVI.
The Agency has also seen an increase in the number of direct electronic reports from
25% in 2008 to 68% in 2012. Members of the public are the largest reporter group
with a substantial increase from 40% in 2008 to 82% in 2012. Electronic reports
received from GPs have also increased significantly from 17% in 2008 to 72% in
2012.
Following the introduction of the new legislation Marketing Authorisation Holders are
now required to submit reports from consumers regardless of whether or not they are
medically confirmed, which has resulted in an increase in the number of reports, and
specifically the number of consumer reports received via industry.
The information collected from the Yellow Card Scheme over the past five years has
contributed significantly to the Agency’s advice on issues such as dabigatran and
serious haemorrhages as well as hypomagnesaemia associated with proton pump
inhibitors for which warnings were issued in DSU. Safety concerns for which product
information for prescribers and patients were updated included issues such as the
risk of facial palsy associated with ustekinumab, renal failure associated with
sitagliptin and Drug Rash with Eosinophilia and Systemic Symptoms associated
with raltegravir.
48
Recommendations and Key Priorities
There are six key recommendations for the coming year as we move forward with the
strategy to strengthen the Yellow Card Scheme. These focus on:
Paediatric strategy - To increase reporting of ADRs occurring in children via the
Yellow Card Scheme.
Engaging with nurses - To increase ADR reporting via the Yellow Card Scheme in
light of new immunisation campaigns. Particular focus should be on education, ereporting and reporting for paediatric patients.
Engaging with HCPs and patients – To increase awareness of the change in
definition for adverse drug reactions to include medication errors, misuse and off
label use, and to promote the message of the new EU wide additional monitoring list.
Electronic reporting
- Continue to facilitate ADR reporting through HCP IT systems
- Continue with existing projects so that healthcare professional (HCP)
reporting continues to increase, particularly with hospital pharmacists.
- To develop a mobile technology infrastructure to facilitate reporting for
healthcare professionals
Promotion and Education - increase awareness through the Agency’s Outreach
and Professional Education Unit and work with the Yellow Card Centres to continue
local training, promotion and championing of the Yellow Card Scheme.
Communicate the findings of this analysis to further promote the Scheme and
educate and motivate reporters; publish more in peer reviewed journals. Increase
feedback to HCPs and patients on what the MHRA do with Yellow Card reports and
reporting requirements in light of the most frequently reported drug event
combinations and changes to legislation.
The Commission is invited to consider recent trends in ADR reporting and the areas
of on going work to strengthen the Yellow Card Scheme and is requested to support
the conclusions and recommendations of this report.
49
Glossary
ADR
Adverse Drug Reaction
A reaction which is harmful and unintended and which occurs at a dose
normally used for prophylaxis, diagnosis or treatment.
Healthcare Professional Setting
Primary Care: community pharmacists, dentists, GPs, nurses, optometrists
Secondary Care: hospital doctor, hospital health professional, hospital nurse,
hospital pharmacist
Other: includes reports where reporters are stated as coroner, pharmacist,
physician, other health professional as well as reports from industry which are
confirmed as coming from lawyers or literature
Other Healthcare Professionals
Other healthcare professionals: includes reports from smaller discrete
reporting groups – e.g. dentists, coroners, optometrists – as well as reports
from industry which are confirmed as coming from a healthcare professional,
but where insufficient information is provided for MHRA to be able to record
the specific type of healthcare professional involved.
MedDRA terms
The MHRA uses the Medical Dictionary for Regulatory Activities to classify
ADRs. The dictionary is comprised of medical/clinical terms, which are
recognised and agreed internationally. There is a hierarchy to the dictionary
structure
SOC
System Organ Class
Highest hierarchical level in the MedDRA clinical terminology used in Sentinel
(e.g. hepatobiliary disorders)
PT
Preferred Term
Medical/clinical term which is recognised and agreed internationally (e.g.
pancytopenia).
HLT
High Level Term
Serious reactions
A reaction is considered serious if it meets ≥ 1 of the following criteria:
 results in death
 Is life-threatening
 results in or prolongs hospitalisation
 results in persistent or significant disability or incapacity
 is a congenital anomal
In addition, medical judgement should be used to decide whether reactions
not meeting these criteria might be considered serious – for instance if a
reaction requires intervention to prevent hospitalisation.
50
On Sentinel, reactions are defined as serious in line with the above definition:
in addition, we count as serious any reports, which include one or more
reactions from a predefined list of ‘Alert terms’ (conditions which are
commonly drug-related and which we regard as serious, regardless of
whether the above criteria are met – for instance agranulocytosis)
Direct ADR reports
Reports received directly from the reporter, health professional or patient
Indirect/Industry ADR reports
Reports received via the pharmaceutical industry
51
Annex 1: Yellow Card Scheme Background and ADR reporting guidelines
The Vigilance and Risk Management of Medicines Division (VRMM) of the MHRA is
responsible for monitoring the safety of all medicines in the UK, in order to identify
and investigate possible hazards and take appropriate action to minimise the risks to
users, ensuring the benefit:risk balance remains favourable thus protecting public
health.
Although data from a wide range of sources are used, it is the spontaneous reporting
scheme, the Yellow Card Scheme that underpins UK Pharmacovigilance. Since its
introduction by Sir Derrick Dunlop in 1964, ADR reporting through the Scheme has
been extended from doctors and dentists to include; coroners, pharmacists, nurses
and most recently, patients. Patient reporting was introduced as a pilot scheme in
January 2005 and was established formally in 2008.
Healthcare professionals are asked to report
 All suspected adverse drug reactions for new medicines - identified by the
black triangle ▼ symbol.
 All suspected adverse drug reactions occurring in children, even if a medicine
has been used off-label.
 All serious* suspected adverse drug reactions for established vaccines and
medicines, including unlicensed medicines, herbal remedies, and medicines
used off-label.
 All medication errors that result in an adverse reaction
*Reactions which are fatal, life-threatening, disabling or incapacitating, result in or
prolong hospitalisation, or medically significant are considered serious.
OR
What to report?
It is particularly important to report reactions that are:
 Serious
 Not mentioned in the Patient Information Leaflet (PIL) or Summary of
medicinal Products Characteristics (SmPC)
 to medicines under additional monitoring (▼)
 to herbal, homeopathic and complementary remedies
 occur in children or the elderly
The MHRA also encourages reporting of ADRs in other areas of special interest,
such as herbal remedies, congenital abnormalities and instances of delayed drug
effect. Patients are encouraged to report suspected side effects of any medicine or
herbal remedy. Pharmaceutical companies are legally required to expedite reports of
serious suspected ADRs received from health professionals to the MHRA.
52
Annex 2: Notes on interpretation of spontaneous reporting data
The limitations of spontaneous reporting schemes are well known and it is inevitable
that spontaneous ADR reporting levels will fluctuate over time due to factors such as
media influence, promotion and publicity. However, the Yellow Card Scheme plays a
vital role in UK Pharmacovigilance and the Agency is committed to strengthening the
Scheme and will continue to raise awareness.
1. The numbers of registered reports may subsequently change due to various
factors such as the identification of duplicate reports. The figures shown herein
should therefore be recognised as subject to change in future reports.
2. Reports may describe reactions in patients who have received several drugs
administered together. Careful analysis of the data is required as it may be difficult to
attribute the reaction to one specific drug. This is particularly relevant where several
vaccines or drugs are administered in combination.
3. Some reported reactions are conditions that may occur naturally. In such cases
there may be a temporal relationship between the drug and the reaction and this may
not necessarily reflect causality. This is particularly relevant to vaccines.
4. Reporting rates are influenced by the seriousness of the reaction, their ease of
recognition, the extent of use of a particular drug and may be stimulated by
promotion and publicity. Most newly marketed drugs are highlighted with a black
triangle for a minimum of two years post-marketing in order to encourage reporting of
any suspected reactions associated with the drug. Reporting for these black triangle
drugs tends to be higher than for other drugs but gradually decreases over time.
5. Numerical comparisons should not be made between reactions associated with
different drugs on the basis of the data. Comparisons can be misleading unless they
take account of variations in the level of reporting, the extent of use of the drugs, and
a number of other confounding variables.
53
Annex 3: Guidance on seriousness of ADRs
The ‘seriousness’ of ADRs and Yellow Cards is discussed frequently in this report; it
is important to consider that the statistics on numbers and proportions of serious
reports are calculated by taking into account both:


CIOMS seriousness criteria – Enables the reporter to indicate if they
considered the ADR to be: life threatening, result in death, results in or
prolongs hospitalisation, results in persistent of significant disability, a
congenital anomaly or medically significant for another reason.
MedDRA seriousness – whether the reaction preferred term (PT) is flagged
as serious = Y in the current version of MedDRA (16.0). Currently around
46.7% of MedDRA PTs overall are classed as serious, however this
percentage varies considerably between SOCs
The version of MedDRA used by the MHRA is upgraded periodically. The current
version is 16.0. Each time a new version of MedDRA is introduced, more terms are
introduced, and this could have an effect on the overall proportions of reports
considered to be serious.
54
Annex 4: Guidance on prescription data
IMS Disease Analyzer – Mediplus
This database contains anonymised computerised longitudinal records of patients’
GP consultations and treatment. The practices are intended to be representative of
the geographical distribution of GPs in the UK and the figures can be projected up to
estimate UK numbers. The database contains the records of around 3 million
patients of which one third are currently active. Birth year is recorded rather than date
of birth which means that age categories cannot be well defined.

IMS Disease Analyzer database represents approximately 1.7% of the UK
general population, and all values in this report has been projected to reflect total
UK population.

This database is a medical care database and only includes patient medical
records from GP practices. Usage is based on an prescription being issued by
their GP or healthcare professional in that practice. However a presciption issued
does not necessarily mean the patient was exposed to the drug because the
prescription may not be dispensed or if dispensed may not be taken.

It is not representative of the total use of medical drugs or products. This
database does not include data from secondary care or hospitals, and also does
not include drugs purchased OTC in pharmacies (P-only products) or
supermarkets (GSL products). The data in this report could be considered as an
underestimation or overestimation of usage of some drugs.

Prescriptions for non-medicincal healthcare products are also included in the
database and the prescription numbers in this report include all prescriptions.

The data extraction was based on patients from GP practices that have provided
data continuously in IMS Disease Analyzer.

Interpret the data with caution when comparing it against adverse drug reaction
reports, taking into consideration under-reporting associated with all ADR
reporting schemes and that an issue of prescription is not necessarily an
indication of drug exposure.
55
Annex 5: Drug Safety Update article – Advice on Reporting ADRs
November 2012
Reporting suspected adverse drug reactions to vaccines and biological
medicines: please provide the brand name and batch number
Biological medicines are medicines derived or manufactured from a ‘living’ biological
system. They encompass a broad range of therapeutic areas, including blood
products, vaccines, antibodies and advanced therapies (such as gene and tissue
therapy).
Biological medicines and vaccines are fundamentally different from standard
chemical medicines in terms of their complexity. Unlike most small molecule drugs,
their characteristics are determined as much by the specific manufacturing process
as the active ingredient itself.
A wide variety of vaccines and biological medicines are available, and for many
products a range of manufacturers produce the same ‘active ingredient’. These
include a range of ‘biosimilar’ medicines, several vaccines which protect against a
given infection, and products such as human immunoglobulin.
Unlike most standard generic medicines, the characteristics of such products will not
be identical. For this reason, it is very important that safety surveillance is carried out
on a brand/product-specific basis. In addition, these products may vary from batchto-batch and so it is important that we receive information on batch number.
As a specific example, there are more than ten different brands of influenza vaccines
available in the UK each year. However, it is very often the case that suspected ADR
reports refer only to ‘influenza vaccine’. Following the guidance below will allow us to
accurately evaluate the safety profile of specific products.
Reporting suspected adverse drug reactions (ADRs)
To allow us to perform product/brand-specific pharmacovigilance, when reporting a
suspected ADR to a biological medicine (such as blood products, antibodies and
advanced therapies [such as gene and tissue therapy]) or vaccine, in addition to the
substance please ensure that you provide the brand name (or product license
number and manufacturer), and the specific batch-number, on the report.
Additionally, when providing patients with details of the vaccine or biological
medicine administered, it is good practice to give them details of the brand and batch
number. This will allow patients and carers to more accurately report suspected
ADRs to us.
Please report suspected ADRS to any medicine or vaccine to the Yellow Card
Scheme
56
Annex 6: Drug Safety Update article – Time to report.
June 2011
Time to report
Yellow Card reports of suspected adverse drug reactions are vital to the monitoring
of side effects to medicines and vaccines. We understand that completing a Yellow
Card is another demand on your valuable time, but the success of the Scheme relies
on your voluntary reporting.
The following tips could help you save time when reporting Yellow Cards:
Report electronically
Completing a Yellow Card does not necessarily take long if you have access to the
SystmOne GP software, which has built-in Yellow Card reporting. This has been also
introduced into version 3.1 of MiDatabank pharmacy software.
Also don’t forget that registering to report online at www.yellowcard.gov.uk saves
time in completing your details and allows you to save a partially completed Yellow
Card and return to it later.
Keep to the reporting guidelines
Focus on reporting:


All reactions for Black Triangle medicines
Serious reactions for established medicines
We also are particularly interested in receiving Yellow Cards for:





Adverse reactions in children or the elderly
Delayed drug effects
Congenital anomalies
Reactions to herbal remedies
Drug interactions
What information to include
Remember for a valid Yellow Card report, we need only four pieces of information:




Suspect drug(s)
Suspected reaction(s)
Patient information (at least one of age, sex, or a local patient identification
number)
Your name and contact details (in case we need to contact you for follow-up
information)
It is helpful to have further information such as reaction outcome, concomitant
medicines and relevant medical history, but should not prevent you from reporting the
suspected adverse reaction if these are unavailable.
Show your support of the Yellow Card Scheme by reporting suspected adverse drug
reactions for medicines and vaccines, and you can help make medicines safer.
See www.yellowcard.gov.uk
57
Annex 7: New EU Pharmacovigilance Legislation (Good Vigilance Practice
module)
The new EU pharmacovigilance legislation, Directive 2010/84/EU and Regulation
1235/2010, published in December 2010, was implemented nationally by July 2012.
The legislation makes a number of fundamental changes for pharmacovigilance and
spontaneous reporting schemes, hence for the Yellow Card Scheme. Firstly the
definition of an adverse drug reaction is redefined to include ADRs arising from
medication error, off-label use, misuse and abuse. Broadening the definition has the
potential for significantly increasing the number of Yellow Cards received.
“Directive 2010/84/EU
(5)…the definition of the term ‘adverse reaction’ should be amended to
ensure that it covers noxious and unintended effects resulting not only from
the authorised use of a medicinal product at normal doses, but also from
medication errors and uses outside the terms of the marketing authorisation,
including the misuse and abuse of the medicinal product.“
Article 107 (3) and of Directive 2001/84/EC introduces a requirement for marketing
authorisation holders to submit non-serious ADRs to Eudravigilance (or a member
state as a transitional arrangement until the Eudravigilance database functionality is
ensured). Member states will also be required to submit non-serious ADRs to the
Eudravigilance database. This will be inconsistent with current Yellow Card reporting
guidelines for health professionals that request all ADRs are reported for black
triangle medicines, but only serious reactions are reported for established medicines.
The new legislation includes requirements that member states need to put in place to
strengthen reporting of adverse drug reactions, therefore supporting the aim of the
Yellow Card strategy. The following are areas considered particularly relevant to
Yellow Card reporting.
Patient reporting will now be mandatory in all EU member states:
“Directive 2010/84/EU… (21) …patients are also well placed to report
suspected adverse reactions to medicinal products. It is therefore appropriate
to facilitate the reporting of suspected adverse reactions to medicinal
products by both healthcare professionals and patients, and to make methods
for such reporting available to them.”
“Regulation 1235/2010…
Article 107a
1. Each Member State shall record all suspected adverse reactions that occur
in its territory which are brought to its attention from healthcare professionals
and patients.”
58
Member states are instructed to encourage reporting from both health professionals
and patients:
“Directive 2010/84/EU… Article 102. The Member States shall:
take all appropriate measures to encourage patients, doctors, pharmacists
and other health-care professionals to report suspected adverse reactions to
the national competent authority; for these tasks, consumer organisations,
patients organisations and healthcare professionals organisations may be
involved as appropriate.”
Additional efforts must be made to gather specific information for ADR reports to
biological medicines:
“Directive 2010/84/EU… Article 102. The Member States shall…[continued]
(e) ensure, through the methods for collecting information and where
necessary through the follow-up of suspected adverse reaction reports, that
all appropriate measures are taken to identify clearly any biological medicinal
product prescribed, dispensed, or sold in their territory which is the subject of
a suspected adverse reaction report, with due regard to the name of the
medicinal product…and the batch number”
The legislation requires development of web-reporting for healthcare professionals
and patients:
“Regulation 1235/2010...Article 25
The Agency [EMA], in collaboration with the Member States, shall develop
standard web-based structured forms for the reporting of suspected adverse
reactions by health-care professionals and patients…”
Further support is also provided for patient reporting through provision of alternative
reporting methods:
“Directive 2010/84/EU… Article 102. The Member States shall…[continued]
(b) facilitate patient reporting through the provision of alternative reporting
formats in addition to web-based formats ”
The legislation also provides a potential route for pursuing mandatory reporting of
adverse drug reactions for health professionals:
“Directive 2010/84/EU… Article 102. The Member States shall…[continued]
For the purposes of point (a) and (e) [of Article 102 - see above]…the
Member States may impose specific requirements on doctors, pharmacists
and other health-care professionals”
Member states must also develop a web-portal to provide pharmacovigilance
information to the public and will include product information (Summaries of Product
Characteristics, SPCs and Patient Information Leaflets, PILs), access to ADR data
(such as Drug Analysis Prints), Public Assessment Reports, and committee papers:
“Directive 2010/84/EU… (20) In order to increase the level of transparency of
the pharmacovigilance processes, the Member States should create and
maintain medicines web-portals.
“Directive 2010/84/EU… Article 102. The Member States shall…[continued]
(d) ensure that the public is given important information on pharmacovigilance
concerns relating to the use of a medicinal product in a timely manner through
59
publication on the web-portal and through other means of publicly available
information as necessary”
Directive 2001/84/EC also introduces an EU wide requirement for additional
monitoring of medicinal products such as those with a new active substance and
biological medicinal products including biosimilars. Medicinal products subject to this
additional monitoring will be identified by a black symbol and a standardised
explanatory sentence in the product information. Interim arrangements for transition
from the Black triangle scheme to the EU additional monitoring scheme must be
implemented once more information on this becomes available, as well as work on
the transition to replacement the scheme once the EU wide version is officially
launched.
“Directive 2010/84/EU…
(10)…some medicinal products are authorised subject to additional
monitoring. This includes all medicinal products with a new active substance
and biological medicinal products, including biosimilars, which are priorities
for pharmacovigilance.”
(20) In order to increase the level of transparency of the pharmacovigilance
processes, the Member States should create and maintain medicines web-portals.
“Directive 2010/84/EU… Article 102. The Member States shall…[continued]
(d) ensure that the public is given important information on pharmacovigilance
concerns relating to the use of a medicinal product in a timely manner through
publication on the web-portal and through other means of publicly available
information as necessary”
Directive 2001/84/EC also introduces an EU wide requirement for additional
monitoring of medicinal products such as those with a new active substance and
biological medicinal products including biosimilars. Medicinal products subject to this
additional monitoring will be identified by a black symbol and a standardised
explanatory sentence in the product information. Interim arrangements for transition
from the Black triangle scheme to the EU additional monitoring scheme must be
implemented once more information on this becomes available, as well as work on
the transition to replacement the scheme once the EU wide version is officially
launched.
“Directive 2010/84/EU…
(10)…some medicinal products are authorised subject to additional monitoring. This
includes all medicinal products with a new active substance and biological medicinal
products, including biosimilars, which are priorities for pharmacovigilance.
60
Annex 8: Paediatric patient reporting
The next phase of Yellow Card strategy activities is focused on increasing paediatric
adverse drug reaction reporting. The Yellow Card Strategy aims to strengthen
reporting of suspected adverse drug reactions to the Yellow Card Scheme through
facilitating reporting, improving the education and motivation of reporters, as well
delivering promotional activities. The activities aim to increase the number and
quality of Yellow Cards received from healthcare professionals, patients, parents and
carers.
The Paediatric Pharmacovigilance Strategy will go further than the Yellow Card
Strategy in order to meet the commitments made in response to the Children and
Young People’s Health Outcomes Forum. The Paediatric Pharmacovigilance
Strategy will operate alongside the Yellow Card Strategy but build on the
relationships developed to lead to more long term developments. It will also focus on
areas out of scope for the Yellow Card Strategy. This section of the paper analyses
paediatric reports from industry, healthcare professionals and members of the public
from 2003 to 2012.
Summary


The MHRA have received a total of 77112 reports (11% of the total number of
reports) for patients aged less than 18 years from 2003 to 2012.
1.5% (1178 reports) of the reports relating to patients less than 18 years of age
contained a fatal outcome.
Using data from the 2011 UK Census the approximate reporting rates for the whole
population and under 18 year olds is show below in table 8.1. This approximate
reporting rate for paediatric patients is nearly half of the approximate reporting rate
for the total UK population.
Table 8.1:
Under 18 year olds
Total UK population
Population Size
Number of ADR reports
13.12 million
63.2 million
2653
25146
Reporting Rate
per ? population
20.2
39.8
Figure 8.2 shows a yearly breakdown of the number of paediatric reports received
over the last 10 years for both vaccine reports and non-vaccine reports.
Figure 8.2
61
2008, 2009 and 2010 saw an increase in the number of paediatric patient vaccine
reports which correspond to the launch of the HPV vaccination campaign in females
aged 12-17 years. The number of non-vaccines ADR reports received for this patient
population has been relatively stable (between 1000 and 1500 reports per year) over
the last ten years.
8.1 Paediatric patient reporting – Sources of reports
76% of paediatric reports received in the last ten years have been received directly
from healthcare professionals and members of the public. This is much higher than
for all ADR reports received in the last ten years where only 55% were received
directly and 45% were submitted from MAHs.
Figure 8.1.1 shows the proportion of direct reports by reporter in the past ten years
for all paediatric reports and non-vaccine paediatric reports. The largest reporter
group for all paediatric reports is nurses; accounting for 47% of all paediatric ADRs in
the last ten years. This is to be expected when considering the number of vaccine
reports that have been received for this population. The largest reporter group for
non-vaccine paediatric reports is Hospital doctors and physicians accounting for 35%
of these reports.
Figure 8.1.1
Figure 8.1.2 shows the breakdown of ADR reports by reporter for all non-vaccine
ADR reports compared to paediatric non-vaccine ADR reports.
Patients, parents and carers contributed to 9% of all paediatric reports since the
launch of patient reporting in 2008. However, Patients, parents and carers represent
12% of paediatric reports for all non-vaccine reports. GPs are the greatest
contributors to non-vaccine ADR reporting across all age groups whilst Hospital
doctors and physicians are the largest reporters of non-vaccine paediatric reports.
This is expected as hospital doctors and physicians are likely to see more serious
reactions with the paediatric population in the hospital setting.
62
Figure 8.1.2
8.2 Paediatric patient reporting – Most reported
8.2.1 Paediatric Reactions
Table 8.2.1.1 shows the top 10 reported reactions for non-vaccine ADR reports over
the last ten years in the paediatric population. Each of the top 10 reaction terms are
MedDRA non-serious reaction terms with the exceptions of convulsion and
aggression.
Table 8.2.1.1
Reaction PT
Vomiting
Rash
Headache
Urticaria
Convulsion
Aggression
Number of Reports
576
571
408
395
347
329
% of Non Vaccine Paediatric Reports
1.98%
1.96%
1.40%
1.36%
1.19%
1.13%
Nausea
Pyrexia
Pruritus
Diarrhoea
326
297
263
256
1.12%
1.02%
0.90%
0.88%
63
8.2.2 Paediatric Medicines/vaccines
Table 8.2.2.1 shows the top 10 suspect drugs reported for all non-vaccine paediatric
reports received in the last ten years with the number of reports containing a fatal
outcome.
Table 8.2.2.1
Drug Substance
Methylphenidate
Atomoxetine
Oseltamivir
Paracetamol
Valproic acid
Montelukast
Risperidone
Clozapine
Isotretinoin
Etonogestrel
Non Fatal ADR
Reports
707
655
376
232
258
238
231
211
207
195
Fatal ADR
Reports
9
1
2
45
8
1
3
10
6
4
Total Number of ADR
Reports
716
656
378
277
266
239
234
221
213
199
8.2.3 Paediatric Drug event combinations
Table 8.2.3.1 shows the top 10 reported drug/event combinations in non-vaccine
ADR reports over the last 10 years in the paediatric population.
Table 8.2.3.1
Drug Substance
Reaction PT
Number of Reports
Paracetamol
Oseltamivir
Atomoxetine
Atomoxetine
Overdose
Vomiting
Suicidal ideation
Aggression
100
100
98
97
Etonogestrel
Paracetamol
Valproic acid
Clozapine
Factor viii recombinant
Tetracaine
Atomoxetine
Pregnancy with implant contraceptive
Liver injury
Foetal anticonvulsant syndrome
Tachycardia
Factor VIII inhibition
Urticaria
Headache
68
64
61
59
58
53
49
The most frequently reported drug-event combination relates to paracetamol and
overdose. The majority of these reports were received from MAHs and are derived
from their obligation to carry out routine literature screening. A large number of these
reports relate to one specific literature article, received in 2008, entitled ‘Therapeutic
Misadventure with Paracetamol: Fact or Fiction’ from the American Journal of
Therapeutics which describes paediatric cases of overdose associated with
paracetamol. The sixth most frequent drug event combination of paracetamol and
liver injury also relates to cases from these literature articles.
Atomoxetine features in three of the top ten most frequent drug-event combinations.
Headache, suicide related events and aggression are all recognised side effects in
the product information.
64
The fifth most frequent drug-event combination relates to the implant contraception
‘Implanon’ and reports of lack of efficacy due to problems with insertion. A Drug
Safety Update Bulletin regarding this issue was published in October 2010 and a new
version of the product has now been introduced by the MAH with a new preloaded
applicator, designed to reduce the risk of insertion errors.
8.3 Paediatric Medication errors and off label use
The MHRA has received a total of 303 reports concerning cases in the
‘Maladministrations’, ‘Medication Errors NEC’ and ‘Medication Errors Due to
Accidental Exposures’ HLTs. These paediatric medication error reports represent
11.6% of all UK spontaneous ADR reports of medication errors on the database.
Table 8.3.1 shows the most frequently reported suspect drugs for these cases of
medication error.
Table 8.3.1
Drug Substance
Tacrolimus
Melatonin
Interferon beta
Mifamurtide sodium
Basiliximab
Methylprednisolone
Paracetamol
Omeprazole
Gene activated human
glucocerebrosidase
Number of reports
9
5
3
3
3
3
2
2
2
Bortezomib
Chlorhexidine and isopropyl
alcohol
2
2
Methylphenidate
Doxorubicin
Octreotide
Citalopram
2
2
2
2
65
Annex 9: Elderly patient reporting
This section of the paper analyses elderly patient reports from industry, healthcare
professionals and members of the public from 2003 to 2012.
Summary

Over the last 10 years (2003-2012), the MHRA has received 53375 reports (23%
of the total number of reports) for elderly patients.
86% (45900) of these reports were serious reports and 8% (4385 reports)
contained a fatal outcome (8%).

Figure 9.1 shows a yearly breakdown of the number and proportion of elderly reports
received in the last 10 years
Figure 9.1
Number of elderly reports received from 2003- 2012
7000
30.0%
25.0%
5000
20.0%
4000
15.0%
3000
10.0%
2000
Percetage of reports
Number of Reports
6000
5.0%
1000
0
0.0%
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
Received Year
Total Number of Elderly patient reports
Percentage of total reports
9.1 Elderly patient reporting – Sources of reports
Figure 9.1.1 and 9.1.2 show a breakdown of the sources of reports for elderly reports
over the last 10 years
Figure 9.1.
66
68% (36341 reports) of elderly reports have been submitted directly to the MHRA
and 32% (17034 reports) have been submitted via industry.
Figure 9.1.2
Of the reports submitted to the MHRA, 32% were from GPs, 22% were from
pharmacists and 19% were from Hospital doctors. Patient and carer reports
contributed to 8% of all elderly patient reports in the last 10 years. (Specifically with
7% (2696 reports) of reports received directly from elderly patients only)
9.2 Elderly patient reporting – patient demographics
73 % (39219 reports) of all elderly patient reports were for 65-79 year olds and 25 %
(13250 reports) reported patient ages greater than or equal to 80 years old. A further
2% of reports (906 reports) reported an unspecified age and indicated that the patient
belonged to the elderly patient group.
55% of all elderly reports were found to be related to reactions in females, 42% of
elderly reports were in males and 3% of these reports had an unknown gender.
9.3 Elderly patient reporting – Most reported
9.3.1 Elderly reactions
Table 9.3.1.1 shows the Top 10 reported reactions (Preferred Term (PT)) in the last
10 years for elderly patient reports
Table 9.3.1.1
Reaction PT
Dyspnoea
Diarrhoea
Nausea
Malaise
Dizziness
Rash
Headache
Vomiting
Confusional state
Myalgia
Number of Reports
2152
1914
1897
1883
1748
1554
1507
1460
1306
1220
67
% of Elderly reports
4%
4%
4%
4%
3%
3%
3%
3%
2%
2%
Each of the top 10 reactions terms except for myalgia are MedDRA non serious
reaction terms. The ‘Gastrointestinal Disorders’, ‘General Disorders and
Administration site Conditions’ and ‘Nervous System Disorders’ SOCs contained the
most reports with a respective 12%, 12% and 11% of all reactions reported in elderly
patients.
9.3.2 Elderly medicines
Table 9.3.2.1 shows the Top 10 Suspect drugs to be reported for all elderly patient
reports from 2003-2012 (all reporters direct & indirect)
Table 9.3.2.1
Suspect Drug Name
Simvastatin
Clozapine
Aspirin
Infliximab
Ranibizumab
Atorvastatin
Warfarin
Adalimumab
Ramipril
Alendronic acid
Number of reports
1576
1213
1177
1096
992
899
873
873
812
703
Simvastatin, clozapine, atorvastatin and ramipril were found to be the most
commonly reported suspect drugs reported by patients/carers, doctors and
pharmacists.
5800 elderly reports (11%) are associated with more than one suspect drug. Table
9.3.2.2 shows a breakdown of the number of reports containing multiple suspect
medications for elderly reports
Table 9.3.2.2:
Number of suspect drugs
1
2-10
11-20
21-30
>30
68
Number of reports
47576
5767
26
5
1
9.3.3 Elderly Drug event combinations
Table 9.3.3.1 shows the top 10 drug-event combinations for all elderly patient reports
from 2003-2012.
Table 9.3.3.1
Suspect Drug
Warfarin
Aspirin
Simvastatin
Aspirin
Ranibizumab
Aspirin
Warfarin
Varenicline
Clozapine
Simvastatin
Reaction PT
International normalised ratio increased
Gastrointestinal haemorrhage
Myalgia
Haematemesis
Death unexplained
Melaena
Drug interaction
Nausea
Lower respiratory tract infection
Rhabdomyolysis
Number of Reports
363
279
268
256
248
211
196
154
146
145
All of these drug-event combinations are well recognised with the exception of
ranibizumab and death unexplained. It is important to note that a large number of
fatal ADR reports have been received for ranibizumab as a result of the
reimbursement method agreed with the manufacturer in the UK.
9.4 Elderly patients – Medication errors
The MHRA have received a total of 573 medication error reports relating to ADRs in
the elderly. This represents 1% of all elderly patient reports and 15% (3757 reports)
of all medication error reports received in the last 10 years.
The majority of medication error reports received for elderly patients relate to
overdose and accidental overdose which accounts for 39% (224 reports) of
medication errors in elderly patient reports.
69