Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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