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HPN January 2017

Issue 34

HOSPITAL PROFESSIONAL NEWS IRELAND Ireland’s Dedicated Hospital Professional Publication

IN THIS ISSUE: NEWS: Criticism for health budgets Page 5

As an adjunct to diet and exercise for appropriate patients with type 2 diabetes

SUPPORT YOUR PATIENTS WITH

CONFIDENCE

REPORT: Reducing medication discrepancies Page 12 CLINICAL: European Respiratory Society Conference Page 16 CPD: Venous Thromboembolism Page 23

sitagliptin/metformin

FEATURE: Model of Care for Epilepsy Page 28

sitagliptin

Legal Category: POM. Marketing Authorisation Holder: Merck Sharp & Dohme Limited, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK. Date of revision: January 2016. © Merck Sharp & Dohme Ireland (Human Health) Limited, 2016. All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin D18 X5K7 or from www.medicines.ie. Date of preparation: October 2016.

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Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie Adverse events should also be reported to MSD (Tel: 01-299 8700)

19/10/2016 09:46

NEWS: Electronic Health Record for UL Hospitals Page 37


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HPN January 2016 Issue 34

Contents

Foreword

New Maternity Service standards issued P4

Editor

EU regulation on paediatric medicine development P6

New Year's Day. A fresh start. A new chapter in life waiting to be written. New questions to be asked, embraced, and loved. Answers to be discovered and then lived in this transformative year of delight and self-discovery. Today carve out a quiet interlude for yourself in which to dream, pen in hand. Only dreams give birth to change.

Kelly Jo Eastwood

¤600,000 in funding towards lung disease P12

4

Innovation for Prostate Cancer detection discovered P20

Medical staff said they were at breaking point, with a record 612 patients on trolleys, and the rate of flu doubling at the start of January.

Investigating pregnancy after Breast Cancer P36

The HSE confirmed that one person has died as a result of flu - the predominant AH3 flu strain is affecting mostly older people. The pressure on hospital services has been exacerbated by a severe respiratory virus sweeping across the country, as well as the norovirus, or the winter vomiting bug.

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New clinical trial for Melanoma patients P42

A HSE spokesperson said that many hospitals were reporting a "significant surge" in demand as the number of cases of winter-related illnesses continued to rise.

Regulars CPD: Venous Thromboembolism P23 20

Feature: Epilepsy Model of Care P28

Event Gallery P43 42

Clinical Profiles P45

Hospital Professional News is Circulated to all independent, multiple and hospital pharmacist, pre reg pharmacists, students pharmacy student’s offi cial bodies, government officials and departments, Pharmacy Managers, Manufactures, Wholesalers. Buyers of pharmacy groups and healthcare outlets. Circulation is free to all pharmacists Subscription rate for Hospital Pharmacy News ¤60 plus vat per year All rights reserved by Hospital Professional News. All material published in Hospital Professional News is copyright and no part of this magazine may be reproduced, stored in a retrieval system of transmitted in any form without written permission. Pharmacy Communication Ireland have taken every care in compiling the magazine to ensure that it is correct at the time of going to press, however the publishers assume no responsibility for any effects from omissions or errors.

MANAGING DIRECTOR Natalie Maginnis n-maginnis@btconnect.com EDITOR Kelly Jo Eastwood kjeastwood@hotmail.com 00447876548989 ACCOUNTS Rachel Wilson cs.ipn@btconnect.com

However Dr Paedar Gilligan of the Irish Medical Organisation tells us this month that the root causes of this recurring overcrowding was a lack of beds, a lack of doctors and other staff and a poorly resourced GP infrastructure. “Politicians often complicate what is a very simple explanation for our overcrowding crisis. It’s not because of seasonal issues or a spike in flu cases,” he says.

Feature: Improving General Paediatric Surgery Services P31

PUBLISHER IPN Communications Ireland Ltd Clifton House, Lower Fitzwilliam Street, Dublin 2 (01) 669 0562

Hospitals across the country have warned patients to stay away from emergency departments unless absolutely necessary, as Ireland faced a flu epidemic and overcrowding hits crisis levels.

COMMERCIAL MANAGER Sharon Kennedy Sharon@ipnirishpharmacynews.ie

Mobile: 0044 7765 236886 CONTRIBUTORS Alok A. Khorana Marc Carrier

“It’s because politicians knowingly and deliberately took 1600 beds out of our hospitals, introduced policies that were a direct cause of doctors emigrating and failed to invest in General Practice. All this at a time when our population was rising and there are more elderly people than ever before in need of healthcare. It doesn’t get simpler than this; we’ve reduced the size of the container but we’re still trying to get more and more into it every day. It just won’t work.” Turn to page 8 for the full story. Orphan drugs also hit the headlines at the start of this year. A study by UK academics shows that orphan drug legislation designed to incentivise investment in treatments for rare diseases is generating products so profitable that investment in broader indications is being stifled. According to an analysis of 83 publicly quoted companies, which together market nearly 200 orphan drugs, compared to control companies matched by size, country and R&D investment, orphan drugs companies are five time more profitable and have a 10% to 15% higher market valuation. The analysis, published in PLOS One, shows not only are orphan drug companies more profitable, their profits have historically increased by 11% for each additional orphan drug that reaches the market. Turn to page 22 for the details.

David A. Garcia Agnes Y. Y. Lee St James's Hospital Medicine Unit

DESIGN DIRECTOR Ian Stoddart Design www.pharmacynewsireland.com www.facebook.com/ HospitalProfessionalNews

HOSPITAL PROFESSIONAL NEWS IRELAND Ireland’s Dedicated Hospital Professional Publication HPN • January 2017


4 News

Maternity Standards issued to promote safer care Marie Kehoe-O’Sullivan, HIQA Director of Standards and Quality Improvement

launched in January 2016. These standards have been designed to support the implementation of the National Maternity Strategy.

The Health Information and Quality Authority (HIQA) has published National Standards for Safer Better Maternity Services. The standards describe what safe, high-quality maternity services should look like. Following a number of high-profile failings in the delivery of safe,

high-quality care in maternity services, HIQA committed to the development of specific standards for maternity services to drive improvements in quality and safety. Ireland’s first National Maternity Strategy, ‘Creating a Better Future Together’ was

Marie Kehoe-O’Sullivan, HIQA’s Director of Standards and Quality Improvement, says, “HIQA developed the National Standards for Safer Better Maternity Services to make maternity care safer and better, and to ensure that the services delivered meet the needs of the women they are supposed to serve. The launch of maternity standards enables services to ensure that they are meeting the necessary outcomes to safeguard the people using their services and to improve the quality of care they provide.”

The maternity standards cover eight themes of care including, person-centred care and support, and better health and wellbeing, to improve outcomes for women and their babies. Marie Kehoe-O’Sullivan continued, “These standards are informed by national and international research and best practice, as well as the voices of women, patient advocates and front-line staff who participated in our advisory group, focus groups and public consultation. The standards put women at the centre of what maternity services do. By promoting practice that is up to date, effective and consistent, and based on best available evidence, they provide a framework of good practice for services to strive towards, but also for women to understand what safe, high-quality maternity care looks like and what they should expect from a service.”

13th National Health Summit The 13th National Health Summit takes place on February 7th, 2017 in Croke Park, Dublin. Everyone agrees that a single vision for healthcare in Ireland is an essential first step in a long-term plan to create the health service that is needed. The recently formed Oireachtas cross-party committee on the future of healthcare is an

unprecedented move in this direction and a welcome response to the obvious and well-known failings of the health service. But, will this new initiative turn out to be a mere talking shop? Or the answer to creating a long-term roadmap for reform of healthcare that will be implemented no matter who is in government over the next decade? That’s just one of the issues

that will be covered at The 13th National Health Summit in February.

• Delivering care in the right way and the right place focusing on health outcomes

The event brings together a range of experts and practitioners from the OECD, the UK and the Irish health service to explore, discuss and debate solutions to some of the toughest challenges being faced. There are also dedicated streams on 3 key themes:

• Putting power in the patients hands • Reshaping the workforce for our future healthcare service For further information and to register visit www.healthsummit.ie

First Audit on Hospital Mortality The National Office of Clinical Audit (NOCA) has launched the first National Audit of Hospital Mortality Report at an event held in the Royal College of Surgeons in Ireland. Hospital mortality is one of many potential outcome measures which can be used as a quality indicator to improve care. The first report presents an analysis of mortality from the National Audit of Hospital Mortality between 2013 and 2015. There are 44 acute publicly funded hospitals contributing January 2017 • HPN

data to the audit. The report presents information across five key diagnoses: acute myocardial infarction (AMI), heart failure, ischaemic stroke, haemorrhagic stroke and chronic obstructive pulmonary disease (COPD) & bronchiectasis in a clear and transparent manner which will be of interest to patients. Key Findings: This report presents a crude inhospital mortality rate between 2005 and 2015.

• In AMI there was a significant reduction in deaths per 100 admissions from 11.1 deaths in 2005 to 5.9 in 2015. • For heart failure, there was a small but significant reduction from 9.6 deaths in 2005 to 7.9 in 2015. • For ischaemic stroke, there was a small but significant reduction from 14.2 deaths in 2005 to 10.5 in 2015. • There was almost no change for haemorrhagic stroke and COPD & bronchiectasis.

This report also presents standardised mortality ratios (SMR) for in-hospital mortality in 2015 (2013-2015 combined for haemorrhagic stroke). All hospitals were within the expected range for AMI, heart failure, ischaemic and haemorrhagic stroke with one hospital outside the expected range for COPD & bronchiectasis. This hospital has welcomed the NAHM report and is currently carrying out a detailed review.


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Consultant criticise ‘inadequate’ funding increase The Irish Hospital Consultants Association (IHCA) has criticised the inadequate increase in the acute hospital and mental health services budgets following the publication of the 2017 HSE National Service Plan. Commenting on the 2017 HSE Service Plan, Dr Tom Ryan, IHCA President, says a 2.8% increase in the acute hospital budget is inadequate and completely insufficient to cater for existing patient demand. “We are very concerned that the budget allocation will not be sufficient and that it will fail to address the growing waiting lists and increased patient demand for healthcare due to demographic and other reasons,” he said. “The plan fails to address the critical capacity constraints that have arisen from years of cuts in health sector capital expenditure.” Dr Ryan adds, “The root causes of the crisis in our public hospitals are inadequate acute and ICU bed capacity and insufficient operating capacity which have not been addressed in this Service Plan. These constraints are not only leading to longer waiting lists but they are resulting in the cancellation of essential surgery with increased frequency.” Dr Ryan said that acute health infrastructure is crumbling, with many hospitals attempting to treat patients with inadequate facilities and equipment that is

Dr John Duddy, President, Irish Medical Organisation

increasingly obsolete. He said that it is disappointing that the National Service Plan does not provide funding to address the critical acute hospital and mental health capacity deficits which are preventing consultants and frontline staff from treating patients without delays.

Responding to the Service Plan, the President of the IMO, Dr John Duddy, said that the plan would offer no respite from the carousel of hospital overcrowding, increasing waiting lists, vacant consultant posts, emigration of doctors and under-resourced GP services.

“I am also very concerned that despite promises to address the recruitment and retention of nurses and midwifery staff, no effort is being made to address the hundreds of vacant consultant posts which exist across the country and are having a massive impact on patient care,” Dr Ryan said.

Dr Duddy said, “When the HSE itself starts pre-warning about budget shortages before the Service Plan is produced, you know you are facing a problem. Unfortunately, the HSE warnings are well placed this year and we have no confidence that patients will get the care and attention they deserve or that professionals will get the resources they require to do their jobs effectively.”

Meanwhile, The Irish Medical Organisation has warned that insufficient funds have been put aside for the health budget in the coming year.

in public hospitals and the negotiation of a new GP contract. He expressed disappointment that the Service Plan contained no significant proposals in either area. He said: “Unless and until we address the problems of bed capacity the overcrowding we see in our Emergency Departments will continue, elective surgeries will be cancelled and waiting lists will get longer. While noting the Minister’s comments that some funds are available for a new GP Contract there is absolutely no clarity around this number or even what is to be discussed in terms of any new contract. The vision of moving services from the acute setting to the community setting looks increasingly unlikely.

Dr Duddy warned that the key challenges for the service next year would be the overcrowding

Pharmacists could play bigger role in healthcare The Pharmaceutical Society of Ireland (PSI) has published a major report on how pharmacists can best meet the needs of patients and the public into the future, which contains significant recommendations for the planning and delivery of patient care and pharmacy services in Ireland. “Future Pharmacy Practice in Ireland - Meeting Patient Needs” is the result of a research project, commenced in late 2015, that included an extensive consultation process involving patients, healthcare professionals, including pharmacists, other regulatory bodies, and engagement with

policy-makers including the Department of Health, HSE, and wider stakeholders.

The new roles for pharmacists that are recommended in the latest report would see pharmacists:

The recommendations outline how pharmacists could provide greater assistance for patients in managing their chronic diseases (such as diabetes, asthma), as part of structured medicine management initiatives in hospitals and also in the community for patients taking multiple or complex medicines. The report anticipates that physical settings for services and patient care, delivered by pharmacists are also likely to evolve with changing healthcare delivery patterns and patient need.

Providing expertise in assisting patients to manage their chronic diseases and improve adherence to prescribed medicines by structured medicines initiatives, availing of ongoing disease monitoring and where appropriate, patients accessing medicines through supplementary prescribing by pharmacists, which allows therapy or medicines continuation in collaboration with a patient’s GP;

patient care pathway via structured initiatives such as medication reviews for at-risk and vulnerable patients in the community and local settings e.g. nursing homes; and the greater use and sharing of pharmacists’ medicines expertise through education of both patients and other healthcare professionals in acute settings, to increase safety, reduce medication errors, ease transfer of care and optimise the use and impact of medicines for patients.

Managing what are complex medicines regimes throughout the HPN • January 2017


6 News

New Innovation Office for HPRA The Healthcare Products Regulatory Authority (HPRA) is establishing a new resource to foster and support innovation in the life sciences sector.

Lorraine Nolan, Chief Executive, HPRA

The first initiative of its kind in Ireland, the goal of the Innovation Office is to provide regulatory advice and assistance to those developing novel health products or technologies. Ensuring that regulatory factors are considered early in the development process will help to support a timely trajectory from product concept to market access and through to patient use. The Innovation Office will be focused on directly assisting innovators to understand and comply with EU and national regulations when developing novel health products or new approaches for manufacturing or testing of such products. Ireland is ranked as the seventh most innovative economy globally. This HPRA initiative will add to a number of existing programmes and supports already in place at a national level to further develop Ireland’s world leading position. The HPRA’s Innovation Office will be a dedicated centre providing individuals, academics, SMEs, pharmaceutical and medical device companies, and other groups with an initial point of contact and access to regulatory information and advice. It will be of interest to those involved in the early development of innovative health products or technologies

ultimately lead to new products coming to market quicker as we build knowledge and awareness of both the processes involved and the supporting data that would be required to gain regulatory approval.” The HPRA’s Innovation Office will provide regulatory support in respect of all areas regulated by the HPRA including medicines, medical devices, drug-device combination products and cosmetics. It will also have a confidential dedicated online query service, managed by a team of experienced regulatory experts.

and queries can be submitted in respect of initial research and design, formulation, testing, clinical studies or manufacture. According to Lorraine Nolan, Chief Executive of the HPRA, the aim is to help ensure that innovators have a clear understanding of the regulatory pathway that would apply to a new product, device or technology and that they avoid, where possible, regulatory issues which could potentially occur

at the different stages of the development process. “Ireland’s high density of innovative companies and the extensive research and development presence within academia seek to bring potentially life changing and lifesaving health products to market. As a regulator, we firmly believe that the application of our scientific and regulatory expertise can facilitate such innovation. This will

The HPRA has developed a dedicated section on its website and published an information leaflet with details of the support and advice that is available through the Innovation Office. It is also hosting an Innovation Day in spring 2017 for interested parties to outline the support it is offering and to highlight developments in the area. Those who require regulatory support or further information should use the online enquiry form or e-mail the Innovation Office at innovationoffice@hpra.ie.

EU Paediatric Medicines Regulation A group of Members of the European Parliament (MEPs) are seeking to influence the European Commission's current considerations on whether to revise the EU's regulation on Paediatric medicine development with a set of their own suggestions for improvement. The group of 7 MEPs includes the Chair of the European Parliament's Health Committee, Giovanni La Via (European Peoples Party, Italy), and representatives of other political groupings in the Parliament. They consider that January 2017 • HPN

while the EU's 2007 Paediatric Regulation has boosted research into childhood medicine, there is still scope for further improvements. The benefits they note the Regulation as achieving include: • Obliging companies to conduct a Paediatric Investigation Plan (PIP) for each new molecule they want to market; • Improving the level of information available on the paediatric use of approved medicines; and,

• Increasing the relative number of paediatric clinical trials. However, the MEPs express hope that more may yet be achieved via amendments to regulation to improve the research landscape for paediatric oncology and neonatology. Supporting their view, they cite the fact that childhood cancer remains the first cause of death by disease in children aged one year and over and 6,000 young people die of cancer each year in Europe. Amongst the barriers in this

respect, include the suggestion that for those cancers that only occur in children, little financial incentive exists for the pharmaceutical industry to bring new treatments to market. The MEPs also consider that the Regulation's obligations on companies to conduct paediatric medicine development should be based on a drug's mechanism of action matched to a tumour's biology rather than on indication limiting the drug's use to a specific type of cancer.


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8 News

Stop blaming flu for overcrowding Dr Peadar Gilligan, Consultant in Emergency Medicine at Beaumont Hospital

people than ever before in need of healthcare. It doesn’t get simpler than this; we’ve reduced the size of the container but we’re still trying to get more and more into it every day. It just won’t work.” Meanwhile, Health Minister Simon Harris said he is "sorry" about the "extraordinarily difficult" situation in the health service recently. Speaking at the Midland Regional Hospital in Tullamore, Co Offaly, he said, “Our hospitals are going through an extraordinarily challenging period of time at the present. I really am sorry for Irish patients and indeed for the staff working in our hospitals experiencing the conditions that they are having to put up with at the moment.

Dr Peadar Gilligan, Consultant in Emergency Medicine at Beaumont Hospital and Chairman of the IMO Consultant Committee, has said that the crisis of overcrowding will continue until the cuts to bed numbers in public hospitals are reversed and policies are changed to make Ireland an attractive location for Irish trained doctors to want to work in.

or a spike in flu cases. It’s because politicians knowingly and deliberately took 1600 beds out of our hospitals, introduced policies that were a direct cause of doctors emigrating and failed to invest in General Practice. All this at a time when our population was rising and there are more elderly

He says that the root causes of this recurring overcrowding was a lack of beds, a lack of doctors and other staff and a poorly resourced GP infrastructure.

Stop blaming flu….Overcrowding and cancellations of procedures are inevitable until Government invests in extra beds for public hospitals and creates a working environment that is attractive to Irish trained doctors.

“Politicians often complicate what is a very simple explanation for our overcrowding crisis. It’s not because of seasonal issues

Tallaght Hospital Bone Health Day A Metabolic Bone Biochemistry and Medicine Bone Health Day was held in the Trinity Centre for Health Sciences, Tallaght Hospital, chaired by Dr Gerard Boran, Consultant Chemical Pathologist. Experts discussed recent medical advances and research in the study of bones. Ms Eilish Burke (Project Manager IDS-TILDA) presented her work on the bone health of adults with intellectual disability. In her study she identified and discussed the higher risk burden people with intellectual disability experience. She has identified levels of risk factors such as anti-epileptic medication use, poor physical activity levels, and rate of menopause among

January 2017 • HPN

women at rates that would impact on bone health. Despite these high risks reported doctor’s diagnosis was 8.1% however rates for DXA screening were low at 16.8% with just 11.1% of those having had screening within the last 2 years. The most significant factor to impact on attendance for screening was mobility issues. An examination of the calcium and vitamin D supplementation for those with a diagnosis of osteoporosis revealed that 3 in every 10 with a diagnosis of osteoporosis were not prescribed these preventative measures. Further examination of the data will explore this important issue further.

Eilish Burke, Project Manager, TILDA

"It isn’t acceptable, the health service must do better, and I want to see absolutely everything done to try and improve this situation. This situation is not helped by the significant outbreak of flu and the particular strain of flu that has seen the flu impacting particularly on older people.” Harris says he expects the HSE to redouble its efforts and to do more than outlined in the winter initiative. But Dr Gilligan criticised the response of successive Governments to the problem. “To those of us working in the system there is no surprise in the numbers, in fact it is nothing short of a miracle that they are not even higher,” he says. “It’s time to treat this matter with the seriousness it deserves rather than expressing disappointment and surprise each time it manifests itself. Full capacity protocols have their place in extreme cases but they too are now becoming the norm which will mean more problems down the line for patients as their long awaited procedures are postponed. Patients who are on trollies in our Emergency Departments need a hospital bed not more promises. Government must act now and commit the funds required to run our health services to meet the real demand not some notional level of activity.”


Profile

9

Taking the helm at Pfizer - Mr Paul Reid With more than two decades of experience under his belt, Paul Reid, Managing Director of Pfizer in Ireland, has a lot of knowledge about the pharmaceutical industry, and a lot to say about biosimilars, medicine pricing and other pressing issues affecting healthcare professionals today. Mr Reid’s career has spanned across four healthcare organisations in the past 22 years, including Rowa Pharmaceuticals, Nutricia, Aventis (which is now Sanofi-Aventis) and Pfizer. His interest in the industry was first piqued while working on his final year thesis. “As part of my final year thesis, when I was looking to graduate with a bachelor of science in management from Trinity, I completed a thesis entitled Research and Development: Pharmaceutical Companies Response to the Threat of Generics,” Mr Reid explained. “At the time, not many people in Ireland were really talking about the pharmaceutical industry – it was more of a US-based industry, with a lot of success coming out of the US. In Ireland in that time, generics were only in their infancy. So if you were to speak to the general public at the time I completed my thesis, in 1994, not many people would have heard of generics, or known what they meant. “The more reading I did on the subject, the more intrigued I became. As part of my preparation for my thesis, I met with the marketing manager at the time of Rowa Pharmaceuticals, which was one of four generics companies at that time. “We had a long interview, where I was trying to get as much information as I could so I could complete my thesis – and within a week of meeting him, he offered me a job.” Still a young college graduate, Mr Reid moved from Dublin to Bantry, where Rowa is based, to take up the marketing role, and he stayed there for two and a half years. “So that’s how I got into the industry,” said Mr Reid. “I love working in the industry, and it’s very fulfilling, and I’ve worked in nearly every commercial role

Mr Paul Reid, Managing Director, Pfizer

you can do – I’ve been medical rep, sales manager, marketing manager, product manager, marketing director, business unit director and now managing director for the last three and a half years in Pfizer. I’m 15 years with Pfizer. “It’s a business that continuously changes. Every year, you face new challenges. I think in particular, when you work in Pfizer, which is such a large multinational company with such a big presence in Ireland, we’re constantly looking for ways of growing the business but we’re also constantly looking at new ways of evolving the business. “It’s a good feeling to be able to speak proudly about what you do, the medicines that you’re bringing to the market, the medicines that are helping make patients better.” Mr Reid said he takes a lot of pride in the fact that Pfizer has a strong vaccination portfolio. “For me, I love the fact that we have a vaccine business as part of our overall portfolio, because then you’re talking about preventing disease,” he said. “Everyone’s talking about the cost of medicines at the moment, and saying that medicines are expensive and asking whether it’s good return for the State and the Government to be funding new medicines. But you can never question funding vaccines – vaccines save money in the long-term because, effectively, you’re preventing illness. “So as a company, we’ve been very big on pneumococcal vaccinations but recently we’ve been adding to our vaccine portfolio, and we’ve a big one in our pipeline, hopefully, which is a meningitis B vaccine. So I’m very much looking forward to the future with vaccines because I think, as a company, we can shout loud and proud about being able to prevent disease, as well as just treating it.” The MD pointed out that his company has also been quite busy of late acquiring new

businesses. “In the last 12 months, we’ve acquired Anacor, which is an interesting company, and which will hopefully bring us new medicines – one in particular for eczema, and there haven’t been too many new medicines in that space over the years,” he said. “We’ve also acquired Hospira, which also strengthens our business because we’re now bringing in a nice pipeline of biosimilar medicines. “We’ve also bought in some Baxter vaccine business, and we’re pending a final acquisition of Medivation, which will bring in an oncology portfolio, and particularly prostate medicine, which will beef up our oncology presence for the future. “So that’s all really good at a global level. In Ireland, I think

what makes us all proud is that we continue to be the number one company, and we’ve many of the leading medicines in areas such as arthritis, cancer, cardiovascular health, pain and vaccines too. We continue to be one of the leading employers with over 3,000 colleagues, and we have seven sites in the country,” Mr Reid continued. “As a country, within Pfizer, we’ve got a very significant footprint and that gives us a lot of visibility and a lot of recognition for what we do in the country. I think that’s a really good advantage for us working in the company, but I also think it’s a good advantage for the country, in terms of what we’re able to invest here, and how we can grow our operations here, which is all good for people living and working in this country.”

HPN • January 2017


10 Profile Mr Reid believes that cost savings from older medicines can be used to fund the creation of the new medicines designed to treat the rarer and more complex diseases. “Most new medicines, most new innovative medicines do finally make it to the point where they are accessible to Irish patients,” he said. “But it’s got slower, the timeline from actually looking into and securing funding for new medicines to actually being able to commercialise them and make them available to Irish patients. That length of time has got longer, and it has got more complex in terms of trying to secure reimbursement for new medicines which, typically, tend to be more expensive.

Ireland should never have the highest nor the lowest price of medicines relative to other EU countries, and I think the agreement now secures that our pricing in Ireland will be closely aligned to the 14 reference countries that are included. At the moment, biosimilars are a topic of huge debate amongst everyone involved in the industry, and Mr Reid believes that there is plenty of room for them within the market, provided that a balanced approach is taken. “In Pfizer, biosimilars are going to be a major area for us in the near to medium term future – as I said, we just bought Hospira and we’re beefing up our biosimilar portfolio,” he said. “Having said that, we’re very wise to the fact that it’s important to get a balanced and appropriate approach to biosimilar medicine. Pfizer’s position is that we believe in informed switches from biologic to biosimilar medicines, based on evidence. “Pfizer supports the current HPRA guidance to Healthcare Professionals on Biosmilar prescribing. Biosimilars are not January 2017 • HPN

interchangeable and not for substitution. The decision to prescribe a biosmilar should remain a clinical decision to be made by the treating physician on an individual patient basis, with patient awareness, supported by scientific evidence.” Although the new Agreement on the Supply and Pricing of Medicines was announced in the summer, discussions between interested parties are still taking place, while the merit and the implications of the agreement are still being debated. Mr Reid believes it is a good agreement, and that it will lead to both savings and increased access for patients. “I think it’s a really good agreement that has been reached,” Mr Reid said. “I genuinely believe it’s in the best interests of the patients and the industry and the State. It

provides for significant savings – IPHA are saying they’re going to deliver ¤785 million in savings and that’s really coming through price cuts and various other parameters included in the agreement. “It’s a good agreement, it does provide savings, and it does provide room for new medicines which, for me, is one of the biggest issues we face in the future: getting access and getting funding for new medicines, so that Irish patients will have timely access to innovative and life-saving medicines. “Ireland should never have the highest nor the lowest price of medicines relative to other EU countries, and I think the agreement now secures that our pricing in Ireland will be closely aligned to the 14 reference countries that are included within the agreement. I think that’s good, and I think it’s good that we maintain the average – we should be at the average of those 14 countries, and not at the lowest. Ireland is not an economy that should be reflecting the lowest prices in Europe.” Along with debate over the pricings agreement, there are often stories within the national medial about Irish patients suffering from rare diseases, who are struggling to access proper treatment because the medicines are not available in this country.

“Reducing medicine expenditure is really not what we should be focused on. We should be investing in health, and the State should be investing in health, and medicines are a big part of that. What you’re going to see now, and what you’re going to see over the last number of years is that we’re now living in an era where scientific innovation is much more intense, and treatment options are now starting to emerge for more rare, complex, debilitating diseases. “The day of the old blockbuster model is gone,” Mr Reid continued. “What that brings is increased R&D costs, we’re getting these more complex medicines through the R&D phases, which means companies are investing more and more money into developing these more complex medicines. And that’s going to mean that they’re going to be looking to secure higher prices for the length of patent. “What we should be trying to do is balance that with bringing up savings on our older medicines, and that savings can be used to fund these newer, more innovative medicines, which are meeting unmet medical needs. The debate shouldn’t just be about how to reduce medicine expenditure – it should be a balance between achieving the savings on the medicines that are off-patent and have had their time, versus finding and securing funding for the new medicines that are meeting these unmet medical needs.” Mr Reid highlighted the longstanding relationship his company has with pharmacists, and said he is looking forward to seeing how the role of the pharmacist evolves over the next few years.


WITH ULTIBRO BREEZHALER EXACERBATION PREVENTION IS IN YOUR HANDS1 ®

®

One proven treatment for COPD patients,with patients,with * or without 3,4† exacerbations, demonstrating consistent superiority vs Salmeterol/Fluticasone1‡ 1,2

ULTIBRO® BREEZHALER® is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD).5 * Patients had at least one moderate or severe exacerbation in the previous 12 months. † Patients had no moderate or severe exacerbation in the previous 12 months. ‡ Fluticasone/Salmeterol 500/50 mg BID. Ultibro Breezhaler ▼This This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 of the SmPC for how to report adverse reactions. ABBREVIATED PRESCRIBING INFORMATION Please refer to Summary of Product Characteristics (SmPC) before prescribing. Presentation: Ultibro® Breezhaler® 85mcg / 43mcg inhalation powder hard capsules containing indacaterol maleate and glycopyrronium bromide respectively and separate Ultibro® Breezhaler® inhaler.Indications: A maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Dosage and administration: Recommended dose is the inhalation of the content of one capsule once daily, administered at the same time of the day each day, using the Ultibro® Breezhaler® inhaler. Capsules must not be swallowed. No dose adjustment required in elderly patients, for patients with mild and moderate hepatic impairment or for patients with mild to moderate renal impairment. No data available for use in patients with severe hepatic impairment and should only be used in patients with severe renal impairment or end-stage renal disease requiring dialysis if the expected benefit outweighs the potential risk. No relevant use in the paediatric population. Contraindications: Hypersensitivity to the active substances or to any of the excipients. Warnings/Precautions: Not to be administered concomitantly with medicinal products containing other LABA’s or LAMA’s. Asthma: ♦ULTIBRO® BREEZHALER® SHOULD NOT BE USED FOR TREATMENT OF ASTHMA. Acute use: ♦Not indicated for treatment of acute episodes of bronchospasm. Hypersensitivity: ♦Immediate hypersensitivity reactions have been reported after administration of indacaterol or glycopyrronium. If signs suggesting allergic reactions occur (in particular, angioedema, difficulties in breathing or swallowing, swelling of the tongue, lips and face, urticaria or skin rash), treatment should be discontinued immediately and alternative therapy instituted. Paradoxical bronchospasm: ♦If paradoxical bronchospasm occurs, Ultibro® Breezhaler® should be discontinued immediately and alternative therapy instituted. Anticholinergic effects related to glycopyrronium: ♦To be used with caution in patients with narrow-angle glaucoma and in patients with urinary retention. Patients with severe renal impairment: ♦Should only be used in patients with severe renal impairment, including those with end-stage renal disease requiring dialysis, if the expected benefit outweighs the potential risk. These patients should be monitored closely for potential adverse reactions. Cardiovascular effects: ♦To be used with caution in patients with cardiovascular disorders (coronary artery disease, acute myocardial infarction, cardiac arrhythmias, hypertension), in patients with known or suspected prolongation of the QT interval or patients treated with medicinal products affecting the QT interval and in patients with unstable ischaemic heart disease, left ventricular failure, history of myocardial infarction, arrhythmia (excluding chronic stable atrial fibrillation), a history of long QT syndrome or whose QTc (Fridericia method) was prolonged. ♦LABA’s may produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure, and/or symptoms, ECG changes. In case such effects occur, treatment may need to be discontinued. Hypokalaemia: ♦ LABA’s may produce significant hypokalaemia in some patients, which has the potential to produce cardiovascular effects. In patients with severe COPD, hypokalaemia may be potentiated by hypoxia and concomitant treatment which may increase the susceptibility to cardiac arrhythmias. Hyperglycaemia: ♦Inhalation of high doses of LABA’s may produce increases in plasma glucose. Upon initiation of treatment with Ultibro® Breezhaler® plasma glucose should be monitored more closely in diabetic patients. ♦ Ultibro® Breezhaler® has not been investigated in patients for whom diabetes mellitus is not well controlled. General disorders: ♦To be used with caution in patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to LABA’s. Excipients: ♦ Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Pregnancy and Lactation: ♦Ultibro® Breezhaler® should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the foetus. ♦Not known whether indacaterol, glycopyrronium and their metabolites are excreted in human milk. Use of Ultibro® Breezhaler® by breast-feeding women should only be considered if the expected benefit to the woman is greater than any possible risk to the infant. Interactions: ♦Concomitant use is not recommended with beta adrenergic blockers, anticholinergics or sympathomimetic agents. ♦Concomitant hypokalaemic treatment with methylxanthine derivatives, steroids, or non-potassium-sparing diuretics may potentiate the possible hypokalaemic effect of beta2-adrenergic agonists, therefore use with caution. ♦Inhibition of the key contributors of indacaterol clearance, CYP3A4 and P-gp, does not raise any safety concerns given the safety experience of treatment with indacaterol. ♦No clinically relevant drug interaction is expected when glycopyrronium is co administered with cimetidine or other inhibitors of the organic cation transport. Adverse reactions: ♦Very common: upper respiratory tract infection. ♦Common: nasopharyngitis, urinary tract infection, sinusitis, rhinitis, dizziness, headache, cough, oropharyngeal pain including throat irritation, dyspepsia, dental caries, gastroenteritis, musculoskeletal pain, pyrexia, chest pain. ♦Uncommon: hypersensitivity, angioedema, diabetes mellitus and hyperglycaemia, insomnia, paraesthesia, glaucoma, ischaemic heart disease, atrial fibrillation, tachycardia, palpitations, paradoxical bronchospasm, epistaxis, dry mouth, pruritus / rash, muscle spasm, myalgia, pain in extremity, bladder obstruction and urinary retention, peripheral oedema and fatigue. ♦Please refer to SmPC for a full list of adverse events for Ultibro® Breezhaler®. Legal Category: POM Pack sizes: Cartons containing 10 capsules (1x10 capsule blister strips) and one Ultibro® Breezhaler® inhaler or 30 capsules (3x10 capsule blister strips) and one Ultibro® Breezhaler® inhaler. Marketing Authorisation Holder: Novartis Europharm Limited, Frimley Business Park, Camberley GU16 7SR, United Kingdom. Marketing Authorisation Numbers: EU/1/13/862/007 & 003. Full prescribing information is available on request from Novartis Ireland Ltd, Vista Building, Elm Park Business Park, Dublin 4. Tel: 01 2601255 or at www. medicines.ie Date of Revision of API Text: 9th February 2016 References: 1. Wedzicha JA, Banerji D, Chapman KR, et al. Indacaterol–glycopyrronium versus salmeterol–fluticasone for COPD. N Engl J Med. 2016. 374:2222-2234. 2. Wedzicha JA, et al. Lancet Respir J 2013:1:199–209. 3. Mahler DA, et al. Eur Respir J 2014;43:1599–1609. 4. Vogelmeier CF, et al. Lancet Respir Med; 2013:1:51–60. 5. Ultibro® Breezhaler®. Summary of Product Characteristics. Accessed on www.medicines.ie, October 2016.

Date of Preparation: October 2016 IE02/ULT16-CNF057q


12 News

Reducing medication discrepancies Consultant team aligned clinical pharmacy service reduces medication discrepancies by 40% and improves patient safety A new study, that has just been published in the leading peerreviewed journal, the International Journal of Clinical Pharmacy, has shown how engineering clinical Pharmacy services to align collaboratively with a consultant team can significantly reduce unintentional medication discrepancies by 40%. The study was undertaken by clinical pharmacists at Naas General Hospital, Kildare, Ireland and the School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin. This is the first study to investigate a collaborative clinical Pharmacy model in a rural, model 3 hospital in Ireland. The investigators assessed a consultant team-based clinical Pharmacy service with pharmacists attending the post-admission ward rounds and targeting early medication reconciliation and review to support clinical decision making on the ward round. This resulted in a 40% reduction in the number of patients experiencing

an unresolved, unintentional medication discrepancy following hospital admission. Sharon Byrne, lead author of the paper and Clinical Pharmacist, says, “Collaborating with consultant teams and attending post-admission ward rounds allowed pharmacists to improve their collaborative working relationships with doctors to the benefit of patient safety. The ward round provides a forum to discuss medication reconciliation issues, to increase the pharmacist’s awareness of the case and therefore to contribute meaningfully to prescribing decisions and medicines optimisation including chronic and acute conditions, antimicrobial use and thromboprophylaxis.” Marie-Claire Jago-Byrne, Head of Pharmacy, said “In the study hospital with 11 consultants with admitting rights and eight pharmacists, it was possible to change the entire service at once and provide a service to all inpatients. Because the study

showed the benefits of a teambased service, it was feasible to make the service change permanent, with sustained implementation since the study completion in 2011.” Dr Kevin Moore, Clinical Director of Medicine and Consultant Physician, commented that, “The new model described in the study facilitates the early resolution of drug related issues, providing a safe basis for treatment decisions. The collaboration between doctors and pharmacists has improved the medication safety culture within the hospital.” Dr Tamasine Grimes, Associate Professor at Trinity College Dublin, commented, “This study is novel by providing a blue print for smaller hospitals with limited resources to provide a model of clinical Pharmacy that optimises patient safety and collaborative working relationships with physicians. This work demonstrates the benefit of academic-practice collaborations to inform

evidence-based health service development and implementation.” Mairead Galvin, currently acting Quality and Patient Manager in Midland Regional Hospital, Portlaoise, outlined that the findings of Irish practice-based research is an excellent decisionmaking resource for senior hospital management when supporting departmental service improvements. Consideration should be given as to how such quality improvements are spread throughout the health service so that all patients can benefit. The study intervention was delivered at hospital admission, with a hospital pharmacist working with a consultant medical team. In standard care, the hospital pharmacist was working on a particular ward(s), did not attend the post-admission ward round, and would not have had the same collaborative and inter-professional experience with the doctors.” The full study is available here http://rdcu.be/n4vr

Anne Marie awarded lung disease funding

Professor Anne Marie Healy, Investigator with AMBER Professor Anne Marie Healy, Investigator with AMBER, the Science Foundation Ireland funded materials science centre, hosted in Trinity College Dublin, has been awarded ¤600,000 (as part of NIH funded collaborations worth ¤8.8million overall) in research funding to develop a new inhaler for the treatment of lung disease. January 2017 • HPN

The funding was provided through the National Institutes of Health (NIH), one of the world’s foremost medical research centres based in the United States.

compounds within a dry powder inhaler, an easily deliverable format, that could benefit millions of patients with mucus-associated lung disease.

The funding will be used to develop a new dry powder inhaler for the treatment of lung disease, and could help millions of patients with cystic fibrosis, asthma and chronic obstructive pulmonary disease (COPD). This innovative type of inhaler will be the first ever of its kind to treat lung disease.

Professor Healy, Head of the School of Pharmacy and Pharmaceutical Sciences at Trinity, Investigator in AMBER and SSPC (The Synthesis and Solid State Pharmaceutical Centre, led by the University of Limerick) said, “I am delighted to be part of a translational NIH project, which aims to take the research from bench to bedside. Ireland has the highest incidence of cystic fibrosis in the world, with approximately 1 in 19 Irish people carrying one copy of the altered gene that causes the condition*. In addition, Ireland has the 4th highest prevalence of asthma in the world, with almost 5,000 asthma admissions to hospital on average each year**. Our proposed new treatment has the potential to greatly improve the respiratory function of these patients with lung disease, thus improving

Patients with cystic fibrosis produce thick sticky mucus instead of the thin, watery kind. This mucus can block the airways, causing difficulties with breathing and infections in the lungs. Mucolytic therapies (medications to break up the mucus) are limited in number, efficacy and tolerability. There have been no new mucolytic drugs introduced to treat lung disease in the past 20 years and only one in the past 50 years. The NIH funded research aims to design, develop and trial novel carbohydrate based

overall quality of life and reducing hospital admissions.” The funding allocated to Professor Healy, is part of two large NIH projects, co-ordinated by Professor John Fahy, Professor of Medicine from the University of California San Francisco (UCSF), and valued at $9.9 million (¤8.8 million). UCD’s Professor Stefan Oscarson (Professor of Chemical Biology, School of Chemistry and Chemical Biology) is also a partner. Clinical trials of the inhaler will start within the 5 year project framework. Professor Fahy added, “This NIH funded collaboration between UCSF, TCD and UCD addresses an unmet need for a well-tolerated and easily delivered mucolytic drug, with application to multiple lung diseases, particularly cystic fibrosis, asthma and COPD. I am delighted to be working with Professor Anne Marie Healy who brings expertise in the optimisation of drug formulations for delivery as dry powders”.


glutamyltransferase) or bilirubin, with a potentially higher risk for female patients. These increases were reversible in the majority of cases. Transaminase, ALKP and bilirubin levels should be Prescribing before Information investigated initiation(Ireland) of combination treatment and monitoring continued as required. ▼Vargatef 100 mg and 150 mg soft capsules capsules containing 100 mg or are 150measured, mg nintedanib (as esilate). is indicated IfSoft relevant liver enzyme elevations interruption, doseIndication: reduction orVargatef discontinuation of in combination with docetaxel for the treatment of adult patients with locally advanced, metastatic the therapyrecurrent with Vargatef maycellbe lung required, referof toadenocarcinoma the SPC. VEGFRtumour inhibition mightafterbe or locally non-small cancerplease (NSCLC) histology first-line chemotherapy. Dose and Administration: Treatment with Vargatef should be initiated associated with byan aincreased of bleeding.in Vargatef recommended in patients with recent and supervised physicianrisk experienced the use is of not anticancer therapies. The recommended dose of nintedanib 12 hours apart, days 2 towith 21 pulmonary bleedingis(>2002.5mgmltwice of reddaily blood)administered as well asapproximately patients with centrally locatedontumours of a standard 21 day docetaxel treatment cycle. Vargatef must not be taken on the same day of radiographic evidence of administration local invasion of(=major vesselsof nintedanib or radiographic evidence of cavitary docetaxel chemotherapy day 1).blood If a dose is missed, administration resume at the next scheduled time at the recommended dose. The individual daily doses of orshould necrotic tumours. Patients beyond taking theconcomitant anticoagulation, as warfarin or nintedanib should not be increased recommended dose to make upsuch for missed doses. The recommended maximum daily dose of regularly 400 mg should not beinexceeded. Patients may continue phenprocoumon should be monitored for changes prothrombin time, international therapy with nintedanib after discontinuation of docetaxel for as long as clinical benefit is observed or until unacceptable posology, methods of administration, dose normalized ratio (INR), andtoxicity clinicaloccurs. bleedingForepisodes. Patients with stable brain metastasisandshould of docetaxel, please refer to the corresponding product information for docetaxel. bemodifications closely monitored for signs and symptomsin case of cerebral bleeding. Treatment not recommended for Dose adjustments should be considered of adverse reactions of pre-specified severity: diarrhoea,with vomiting, nausea and other non-haematological orclosely haematological adverse reactions, and patients active brain metastasis. Patients should be monitored for thromboembolic aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) and bilirubin elevations – as initial the management treatment withvenous nintedanib should be events andmeasure Vargatefforshould be discontinuedof inadverse patientsreactions with life-threatening thromboembolic temporarily interrupted. Please refer to the Summary of Product Characteristics (SPC) for further reactions. should when treating patientsPaediatric with a higher cardiovascular riskefficacy includingin informationCaution including whenbetoused discontinue treatment. population: Safety and children aged 0-18 years have not been established. Elderly patients (≥ 65 years): No overall known coronary arteryanddisease. interruption shouldpatients. be considered in patientsof initial who develop differences in safety efficacyTreatment were observed for elderly No adjustment dosing required the basisofof acute a patient’s age. Race and body Based weight:onBased on populationofpharmacokinetic signs or onsymptoms myocardial ischaemia. the mechanism action patients analyses, no a priori dose adjustments necessary. Safety data for Black and African American treated VargatefRenal may have an increased perforations. Particular cautionvia patientswith are limited. impairment: Less risk thanof1 gastrointestinal % of a single dose of nintedanib is excreted the kidney. Adjustment of the starting dose in patients with mild to moderate renal impairment is should be exercised when treating with previous abdominal or a recent history with of a not required. The safety, efficacy patients and pharmacokinetics have not surgery been studied in patients severe organ renal impairment (< 30 ml/min creatinine clearance). Hepatic impairment: Nintedanib is hollow perforation. Treatment should only be initiated at least 4 weeks after major surgery. predominantly eliminated via biliary/faecal excretion (> 90%). Exposure increased in patients with hepatic impairment (Child Pugh A, Child Pugh B). No adjustment of the starting dose is needed for Therapy should be permanently discontinued in patients who develop gastrointestinal perforation. patients with mild hepatic impairment (Child Pugh A) based on clinical data. Limited safety data Nintedanib may9impair wound Treatment therefore be initiated or, in case toof available from patients withhealing. moderate hepatic should impairment (ChildonlyPugh B) are insufficient characterize this population. The safety, efficacy and judgement pharmacokinetics of nintedanib have not been perioperative interruption, resumed based on clinical of adequate wound healing. Caution investigated in patients with severe hepatic impairment (Child Pugh C). Treatment of patients with moderate (Child Pugh B) to severe (Child Pugh QTc C) hepatic impairment issoya-products not recommended. The should be exercised in patients who may develop prolongation. Dietary are known capsules must be taken orally, preferably with food, swallowed whole with water, and must not be tochewed causeorallergic reactions including severeHypersensitivity anaphylaxis intopersons withpeanut soya allergy. crushed. Contraindications: nintedanib, or soya,Patients or to anywith of the excipients. Warnings and Precautions: Patients with gastrointestinal disorders including known allergy to peanut protein carry enhanced risk for severe reactions orto discontinuation soya preparations.of diarrhoea, nausea and vomiting may an require interruption, dose reduction therapy. Diarrhoea be treated at first signsage, with anti-diarrhoeal Nintedanib exposureshould increased linearly with patient wasadequate inverselyhydration correlatedandto weight, and was medicinal products, e.g. loperamide. Supportive care for nausea and vomiting may include medicinal generally with higheranti-emetic in patientsproperties, of Asian racee.g.which may result inanti-histamines a higher risk ofor developing liver products glucocorticoids, 5-HT3 receptor antagonists and adequate hydration. In the event of dehydration, administration of electrolytes and enzyme close monitoring is recommended in patients with several of these risk factors. fluids iselevations; required. Plasma levels of electrolytes should be monitored, if relevant gastrointestinal adverse events occur. Combination intreatment docetaxel is associated with Interaction a higher frequency Close monitoring is recommended patients with weighing < 50 kg. Interactions: studies of neutropenia of CTCAE grade ≥ 3 as compared to treatment with docetaxel alone. Subsequent complications such as sepsis or febrile neutropenia have been observed. Blood counts should have only been performed in adults. P-glycoprotein (P-gp): Nintedanib is a substrate of P-gp.be during therapy, please refer to SPC. Hepatic function: Based on increased exposure, the Ifmonitored co-administered, potentmayP-gp inhibitors ine.g.patients ketoconazole or erythromycin may increase risk for adverse events be increased with mild hepatic impairment (Child exposure Pugh A). Treatment Vargatefshould is notberecommended in patients with moderate or severe hepatic toimpairment. nintedanib.with Patients monitored closely for tolerability of nintedanib. Potent P-gp Nintedanib was associated with an elevation of liver enzymes (ALT, AST, ALKP, gammaglutamyltransferase) or bilirubin, with a potentially higher risk forsfemale patients. Theseexposure increases inducers e.g. rifampicin, carbamazepine, phenytoin and St. John’ Wort may decrease to were reversible in the majority of cases. Transaminase, ALKP and bilirubin levels should be nintedanib. be carefully considered. Cytochrome (CYP)-as enzymes: investigated Co-administration before initiation ofshould combination treatment and monitoring continued required. If relevant liver enzyme elevations are measured, interruption, dose reduction or discontinuation of Likelihood drug-drug interactions with nintedanib be low.be the therapyofwith Vargatef may be required, pleasebased refer on to CYP the metabolism SPC. VEGFRconsidered inhibition tomight associated with anproducts: increasedThe riskpotential of bleeding. Vargatef is not recommended in patients withwas recent Other medicinal for interactions with hormonal contraceptives not pulmonary bleeding (> 2.5 ml of red blood) as well as patients with centrally located tumours with explored. Fertility, and Lactation: Nintedanib cause foetalevidence harm inofhumans; radiographic evidencePregnancy of local invasion of major blood vesselsmay or radiographic cavitary or necrotic tumours. Patients taking concomitant anticoagulation, such as warfarin or women should avoid pregnant whileforreceiving treatment and adequate phenprocoumon shouldbecoming be monitored regularly changes this in prothrombin time,use international normalized ratioduring (INR),and andforclinical bleeding episodes. Patients with ofstable brain Since metastasis should contraception at least 3 months after the last dose Vargatef. the effect of be closely monitored for signs and symptoms of cerebral bleeding. Treatment not recommended for patients with brain metastasis. Patients should be closely for thromboembolic nintedanib on active the metabolism and efficacy of contraceptives has monitored not been investigated, barrier events and Vargatef should be discontinued in patients with life-threatening venous thromboembolic methods appliedbe used as a when secondtreating form ofpatients contraception, to avoid pregnancy.riskThere is no reactions.should Cautionbeshould with a higher cardiovascular including known coronary Treatment interruption shouldbut be considered who develop information on artery the usedisease. of Vargatef in pregnant women, pre-clinicalin patients studies have shown signs or symptoms of acute myocardial ischaemia. Based on the mechanism of action patients treated with Vargatef an increased of gastrointestinal Particular caution reproductive toxicity may and have therefore nintedanibriskshould not be usedperforations. during pregnancy unless the should be exercised when treating patients with previous abdominal surgery or a recent history of a clinical condition requiresTreatment treatment.should Pregnancy be 4conducted at major least surgery. prior to hollow organ perforation. only betesting initiatedshould at least weeks after Therapy should be permanently discontinued in patients who develop gastrointestinal perforation. treatment. patients should be advised to notify doctoronly or pharmacist theyin become Nintedanib Female may impair wound healing. Treatment shouldtheir therefore be initiatedif or, case of perioperative interruption, resumed basedbecomes on clinical judgement ofreceiving adequateVargatef, wound healing. Caution pregnant during therapy. If the patient pregnant while she should be should be exercised in patients who may develop QTc prolongation. Dietary soya-products are known apprised the potential to thesevere foetus.anaphylaxis Terminationinofpersons the treatment Vargatef shouldwithbe to cause of allergic reactionshazard including with soyawith allergy. Patients known allergy to peanut protein carry an enhanced risk for severe reactions to soya preparations. considered. There is increased no information thepatient excretionage,ofwasnintedanib its metabolites human Nintedanib exposure linearlyonwith inverselyand correlated to weight,inand was generally higher instudies patients of Asian race which mayofresult in a higher risk of developing milk. Pre-clinical showed that small amounts nintedanib and its metabolites (≤ 0.5 %liverof enzyme elevations; close monitoring is recommended in patients with several of these risk factors. Closeadministered monitoring isdose) recommended in patients < 50 kg. studies the were secreted into milkweighing of lactating rats.Interactions: A risk to theInteraction newborns/infants have only been performed in adults. P-glycoprotein (P-gp): Nintedanib is a substrate of P-gp. be excluded.potent Breast-feeding shoulde.g.beketoconazole discontinued orduring treatmentmaywithincrease Vargatef.exposure Based Ifcannot co-administered, P-gp inhibitors erythromycin to Patients shouldthere be ismonitored closely tolerability of nintedanib. PotentareP-gp on nintedanib. preclinical investigations no evidence for forimpairment of male fertility. There no inducers e.g. rifampicin, carbamazepine, phenytoin and St. John’s Wort may decrease exposure to nintedanib. Co-administration Cytochrome (CYP)enzymes: human or animal data on potentialshould effectsbeofcarefully nintedanibconsidered. on female fertility available. Undesirable Likelihood of drug-drug interactions with nintedanib based on CYP metabolism considered to be low. effects:medicinal The mostproducts: frequentlyThereported reactions with specifichormonal for nintedanib were diarrhoea, Other potentialadverse for interactions contraceptives was not explored. Fertility, Pregnancy and Lactation: Nintedanib may cause foetal harm in humans; increased liver enzymes (ALT and AST) and vomiting. Very common 1/10): Neutropenia (includes women should avoid becoming pregnant while receiving this (≥treatment and use adequate contraception during and for at least 3 months after the last doseperipheral of Vargatef. Since the bleeding, effect of febrile neutropenia), decreased appetite, electrolyte imbalance, neuropathy, nintedanib on the metabolism and efficacy of contraceptives has not been investigated, barrier diarrhoea, vomiting, nausea,as abdominal pain,ofalanine aminotransferase increased,There aspartate methods should be applied a second form contraception, to avoid pregnancy. is no information on the use of Vargatef in pregnant women, but pre-clinical studies have shown aminotransferase bloodnintedanib alkaline should phosphatase increased, mucositis unless (including reproductive toxicityincreased, and therefore not be used during pregnancy the clinical condition shouldneutropenia, be conducted at least prior stomatitis), rash.requires Commontreatment. (≥ 1/100Pregnancy < 1/10):testingFebrile abscesses, sepsis,to treatment. Female patients should be advised to notify their doctor or pharmacist if they become pregnant during therapy. If the patient pregnant whilehypertension, receiving Vargatef, she should be thrombocytopenia, dehydration, venousbecomes thromboembolism, hyperbilirubinaemia, apprised of the potential hazard to the foetus. Termination of the treatment with Vargatef should be gamma-glutamyltransferase increased. Prescribers should consultandtheits Summary considered. There is no information on the excretion of nintedanib metabolitesofinProduct human milk. Pre-clinicalforstudies that small and its measures. metabolitesPack (≤ 0.5sizes: % of Characteristics furthershowed information on sideamounts effectsofandnintedanib recommended the administered dose) were secreted into milk of lactating rats. A risk to the newborns/infants cannot be120 excluded. Breast-feeding should be discontinued duringPOM. treatment with Vargatef. Based 100 mg capsules; 150mg 60 capsules. Legal category: MA numbers: 100 mg: on preclinical investigations there is no evidence for impairment of male fertility. There are no EU/1/14/954/002; 150onmg:potential EU/1/14/954/004. Marketing Authorisation Holder:Undesirable Boehringer human or animal data effects of nintedanib on female fertility available. effects: The most frequently reported adverse reactions specific for nintedanib were diarrhoea, Ingelheim International Binger 173, 55216 Rhein,Neutropenia Germany. Prescribers increased liver enzymesGmbH, (ALT and AST)Strasse and vomiting. VeryIngelheim common am (≥ 1/10): (includes febrile consult neutropenia), decreased appetite,Characteristics electrolyte imbalance, peripheralinformation. neuropathy,Additional bleeding, should the Summary of Product for full prescribing diarrhoea, vomiting, nausea, abdominal pain, alanine aminotransferase increased, aspartate information is available on request from Boehringer Ingelheim Ireland Ltd, The Hyde Building, aminotransferase increased, blood alkaline phosphatase increased, mucositis (including stomatitis), rash. Common (≥ 1/100 < 1/10): Febrile neutropenia, abscesses, sepsis, The Park, Carrickmines, Dublin 18. Prepared in December 2016 thrombocytopenia, dehydration, venous thromboembolism, hypertension, hyperbilirubinaemia, gamma-glutamyltransferase increased. Prescribers should consult the Summary of Product Characteristics furtherisinformation side effects and recommended measures. Pack sizes: This medicinalforproduct subject toonadditional monitoring. ®

100 mg 120 capsules; 150mg 60 capsules. Legal category: POM. MA numbers: 100 mg: EU/1/14/954/002; 150 mg: EU/1/14/954/004. Marketing Authorisation Holder: Boehringer Ingelheim International GmbH, Binger Strasse 173, 55216 Ingelheim am Rhein, Germany. Prescribers should consult the Summary of Product Characteristics for full prescribing information. Additional information is available on request from Boehringer Ingelheim Ireland Ltd, The Hyde Building, The Park, Carrickmines, Dublin 18. Prepared in December 2016 This medicinal product is subject to additional monitoring.

Adverse events should be reported to the Health Products Regulatory Authority at www.hpra.ie or by email to medsafety@hpra.ie. Adverse events should also be reported to Adverse events shouldPharmacovigilance be reported to theon Health Boehringer Ingelheim 01 291Products 3960 orRegulatory by email to Authority at www.hpra.ie or by email to medsafety@hpra.ie. PV_local_uk_ireland@boehringer-ingelheim.com Adverse events should also be reported to Boehringer Ingelheim Pharmacovigilance on 01 291 3960 or by email to PV_local_uk_ireland@boehringer-ingelheim.com

EXTENDING WHAT’S POSSIBLE VARGATEF®, the only triple angiokinase inhibitor for advanced adenocarcinoma of 1 the lung after first-line chemotherapy EXTENDING

WHAT’S POSSIBLE

VARGATEF® is indicated in combination with docetaxel for the treatment of adult patients with locally advanced, metastatic or locally recurrent non-small cell lung cancer of adenocarcinoma tumour histology after VARGATEF®, the1 only triple angiokinase first-line chemotherapy inhibitor for advanced adenocarcinoma of the lung after first-line chemotherapy1 VARGATEF® is indicated in combination with docetaxel for the treatment of adult patients with locally advanced, metastatic or locally recurrent non-small cell lung cancer of adenocarcinoma tumour histology after first-line chemotherapy1

Reference: 1. VARGATEF® 100/150mg Summary of Product Characteristics. Available at: http://www.medicines.ie/medicine/16211. Accessed October 2016. Reference: 1. VARGATEF 100/150mg Summary of Product Characteristics. Available at: http://www.medicines.ie/medicine/16211. IRE/VAR-161124a(2) Date of preparation: January 2017 Accessed October 2016. ®

IRE/VAR-161124a(2) Date of preparation: January 2017


14 News

Stroke care on European agenda Stroke care recently met to discuss the quality of Stroke prevention, care and support within the countries of Europe. Jon Barrick Stroke Alliance for Europe (SAFE) President and Valeria Caso President of the European Stroke Organisation (ESO) held the meeting at the European Union Health Commission. SAFE and ESO made a number of proposals aimed at gathering EU support for encouraging countries across Europe to improve stroke intervention. Stroke now accounts for more than 9% of all deaths in Europe and is the leading cause of long term severe disability.

Topics discussed included the Health Commissioners engagement with proceedings at a Stroke Summit meeting to be held in Brussels on May 11th 2017, the dissemination of the Burden of Stroke report with data on the stroke care pathway performance in each European country, and a report on the current situation around acute stroke care. Also discussed were support for the SAFE, ESO and others initiative to produce a stroke European action plan to be launched in May 2018, and the potential for creation of an economic burden of stroke report by 2019.

The Stroke European action plan will be the sequel to the Helsingborg declaration of 2006, which set objectives to be achieved by 2015. This is now redundant and many new developments and treatments have occurred since its first appearance, and there is now an opportunity to create initiatives to drive down the death and disability rates from stroke. Other topics covered were the need for greater awareness of stroke, more effort to be made in preventing stroke, and the need to allocate more resources for stroke research generally. SAFE and ESO were encouraged to provide more

examples of good practice to be shared country to country, and questions were asked concerning possibilities of good practice pilot activity. There was found to be a huge overlap between the work of SAFE and ESO, and that of the EU Health Commission, with all parties seeking to make sure stroke care is sustainable, efficient, and supports resilience within health care systems (the capacity to buffer change, learn and develop, enhance adaptive capacity in a situation of rapid treatment transformations).

Annual Stroke Study Day The Irish Heart Foundation Council on Stroke was established in 1997 and is dedicated to furthering excellence in stroke care in Ireland. The 20th Irish Heart Foundation Stroke study day will take place on Thursday 9th and Friday 10th March 2017 in the Croke Park Conference Centre, Dublin. There will be an expanded conference programme in celebration of their 20th anniversary. A number of key note speakers will present on Thursday afternoon followed by a drinks reception to which all delegates are invited to attend. The conference programme will continue on Friday 10th March and, in addition to the usual programme format, will include parallel sessions and guided poster tours. Full programme details will follow when speakers are confirmed, together with registration instructions.

Irish Melanoma Forum The Irish Melanoma Forum recently held their Annual Scientific Meeting in the Herbert Park, Dublin. It was attended by Consultant Oncologists, Surgeons, Radiologists, Nurse Specialists and those professionals with an interest in Melanoma.

Founded in 2011 by Dr Paul Donnellan, Consultant Medical Oncologist at Galway University Hospital, the Irish Melanoma Forum (IMF) aims to raise awareness of malignant melanoma in Ireland and educate the public regarding prevention, early

Mr Padraic Regan, Consultant Plastic Surgeon, UHG and Dr Myles Smith, Consultant Surgical Oncologist, Royal Marsden Hospital January 2017 â&#x20AC;˘ HPN

detection and treatment whilst fostering collaboration between health care professionals and researchers. This was the sixth year of the conference, which was Chaired by Dr.Derek Power from Cork

University Hospital. Keynote speakers included Dr Myles Smith, Royal Marsden Hospital, London and Dr Mary Laing, Consultant Dermatologist with University Hospital Galway.

Niamh Devery and Jane Martin, Clinical Pharmacists, St Vincentâ&#x20AC;&#x2122;s Private Hospital


16 Clinical Synopsis

ESR International Congress The 26th International Congress of the European Respiratory Society was held last year in London The ERS International Congress has grown to be the largest meeting in the world in the respiratory field. The Chairs of the Scientific and Educational Councils, together with all ERS Officers, prepared a programme to challenge thinking minds, encourage debate and offer new insights across the spectrum of respiratory health and disease. The 2016 event has seen numbers rise with more partnerships developed with national and international societies. The Congress is the pinnacle of the year for the growing respiratory community, and others who attend, and represents a key opportunity to share knowledge across borders and professional disciplines. Below, we feature some of the extracts from the Poster Presentations. Notable abstracts on clinical problems related to asthma Inhalation technique education in asthma or COPD: The value of a visual instruction card Anneke H.M. Kemerink (Groningen, Netherlands), Anneke Kemerink, Luc H. Steenhuis, Titia J. Klemmeier, J. Sebastiaan Vroegop, Siebrig Schokker Background: Although the importance of teaching a correct inhalation technique in patients with asthma or COPD is recognised, the optimal method of inhalation technique education is unknown. To improve this, inhaler-specific visual instruction cards as an adjunct to standard education have been developed. Aim: To evaluate the value of these visual instruction cards in optimising inhalation technique in patients with asthma or COPD.Methods: Randomised controlled trial in 100 outpatients with asthma or COPD (49% male, mean age 63 years). Patients received either usual inhalation technique education (Usual Care) or received the visual instruction card in addition to the usual inhalation technique education (Usual Care+). At baseline and follow-up (at 6-8 weeks) inhalation technique was assessed using inhaler-specific checklists. Disease control was measured by ACQ or CCQ. Results: In both groups the proportion of patients with an adequate inhalation technique significantly improved. The improvement in the Usual Care+ group was significantly higher as compared to the Usual Care group (4% to 85% and 12% to 57% respectively, p<0.001). Disease control significantly improved in both groups. The improvement in ACQ was significantly higher in the Usual Care+ group as compared to the Usual Care group (-0.5 and -0.3 respectively, p<0.05). The CCQ showed a positive tendency in favour of the Usual Care+ group (–0.5 in the Usual Care+ and –0.3 in the Usual Care group, p=0.09).Conclusion: This study emphasises the importance of proper inhalation technique education, and in particular, the value of the newly developed visual instruction cards. Mapping out asthma in the out-patient clinic – The MAPOUT II study Asger Sverrild (Copenhagen, Denmark), Asger Sverrild, Vibeke Backer, Celeste Porsbjerg Background: Most studies in asthma only include selected groups of patients with many similarities in test results and clinical outcomes between subjects. The real life asthma population is far more heterogeneous with huge variations in clinical features and test results that are less well studied. Aim: The MAPOUT II study describes a clinically representative real-life asthma population in terms of clinical presentation and test outcomes over a 1-year follow-up.MethodsSubjects with possible asthma referred to a tertiary hospital clinic were enrolled over one year, and followed up 12 months later. Spirometry, FeNO, skin prick test, bronchoprovocation tests for airway hyperreactivity (AHR), induced sputum and ACQ were performed at baseline and at follow-up. Differences in clinical outcomes and test results were described at baseline and follow-up. Results: A total of 151 (79%) had objectively verified asthma. 60% were females; mean (min; max) age was 31 (15; 63); mean (min; max) ACQ was 1.4 (0.0; 4.6), mean (min; max) percent predicted FEV1 was 99 (45; 167), 60% were atopic; 71% had AHR and 19% had sputum eosinophils 33%. At follow-up 11% had sputum eosinophils 33%, and 54% of the asthmatics had AHR. Predictors of AHR at follow-up were lower FEV1, a higher ACQscore and presence of AHR at baseline. Subjects with AHR at follow-up continued to be more symptomatic than asthmatics without AHR. Conclusion: Asthmatics referred for specialist care are heterogeneous, and the majority of subjects presented with non-eosinophilic asthma and a normal FEV1, but with AHR that remained despite treatment with ICS. The results call for attention toward the large majority of subjects with noneosinophilic asthma, AHR and continuous symptoms. Improved characterization of obstructive airways diseases by parameterization of specific resistance loops Marko Topalovic (Leuven, Belgium), Marko Topalovic, Vasileios Exadaktylos, Geert Celis, Jean-Marie Aerts, Thierry Troosters, Wim Janssens Specific resistance loops appear in different shapes influenced by different resistive properties of the airways, yet theirs descriptive ability is compressed to a single parameter (slope). We aimed to develop different parameters reflecting the opening of the loop and explore mechanism behind it in obstructive airways diseases.Study included 134 subjects with completely performed pulmonary function tests, divided into groups: 1/ Healthy controls (N=22), 2/ Asthma, with non-obstructive lung function (N=22), 3/ COPD, including all disease stages (N=90). Opening of the expiratory part of the loop was described with geometrical parameters: 1/ area under the loop, 2/ roundness, 3/ asynchrony.No significant difference was found comparing developed parameters in asthma and healthy groups. However, significant difference was observed comparing these two groups with COPD. Grouping mild COPD subjects by open-not open shape revealed significant difference between geometrical parameters, but also lung function: FEV1, RV and RV/TLC. Multiple logistic regression indicated RV/TLC ratio as only predictor of loop opening with OR =0.84, 95%CI of (0.73 – 0.94), p value =0.0006 and R2 =0.35. Methacholine induced airway narrowing in asthma showed equal shape descriptors as COPD non-openers, but not slope. In contrast, all shape descriptors were significantly different comparing to COPD openers, yet slope was identical. RV/TLC was the main lung function determinant that differentiated obstructive asthma and COPD openers.This study introduces new parameters describing differences in the shape of specific resistance loops affected by different resistive mechanisms in obstructive airways diseases. Cognitive impairment in patients with eosinophilic granulomatosis with polyangiitis (EGPA): Service evaluation in a regional severe asthma centre in North-west England Sarah Diver (Stockport, United Kingdom), Sarah Diver, Binita Kane, Dorothy Ryan, Leanne Jo Holmes, Steve Fowler, Robert Niven Background: Cognitive decline in EGPA is rare. 30% of patients with small vessel vasculitis may have subclinical neuropsychological impairment1. Data is limited regarding EGPA alone. January 2017 • HPN


HPN Peer Review Call for Clinical Papers/Articles In order to achieve the highest quality and safety of care, we must support current and future hospitals professionals to learn, grow and innovate. Hospital Professional News delivers education to thousands of healthcare professionals including Consultants, Pharmacists and clinical teams, demonstrating cutting edge research that has a direct impact on patient care. Would you like to see your work in print in Ireland's leading hospital professional publication? HPN will be publishing a special Peer Review issue in August, 2017 and we are seeking original article submissions to foster this network of shared learning, focusing on enhanced clinical outcomes. Whether you are a Consultant, Registrar, Pharmacist or other healthcare professional working within any field/discipline, we want to hear from you. We are welcoming submissions from any therapeutic area that is of educational value to the HPN readers, your peers.

For example:  Cardiology  Oncology  Endocrinology  Biosimilars  Medicines Safety/Reconciliation  Respiratory  Neurology  Pharmacy  Aseptic Compounding

All enquiries welcome to: kelly@ipnirishpharmacynews.ie or Telephone 0044 7876548989


18 Clinical Synopsis Aim: To evaluate prevalence of cognitive impairment in patients with EGPA managed at a regional severe asthma centre in South Manchester, England. Methods: Cases identified where diagnosis of EGPA made by a specialist in eosinophilic vasculitis. Clinical consultations reviewed for subjective evidence of disease-related cognitive decline. Results: N = 16, 11 male, mean age 53. 25% had antibodies to myeloperoxidase (MPO). Cognitive impairment was present in 37.5% (6). Memory loss was described in all 6, poor concentration in 2, slowed speech in 1. 4 of 6 had magnetic resonance (MR) cerebral angiogram and 2 standard MR brain. Frontal white matter hyperintensities were seen on standard MR in 2. All other brain imaging was normal. 5 of 6 were reviewed by a neurologist. Discussion: Evaluation of our service indicates that disease-related cognitive impairment is more prevalent than literature suggests. Further objective evidence is required. This reinforces the importance of a multidisciplinary approach in EGPA. Reference: Frequency and patterns of subclinical cognitive impairment in patients with ANCA-associated small vessel vasculitides. Mattioli et al. J Neurol Sci. 2002. Adherence to asthma medication and preferences for once-daily treatment: Importance of treatment intrusiveness and patient beliefs Sarah Chapman (London, United Kingdom), Sarah Chapman, Peter Dale, Henrik Svedsater, Gillian Stynes, Nicola Vyas, David Price, Rob Horne Patients with asthma who do not adhere to treatment may experience poor control, and subsequently need greater healthcare.In a post-hoc analysis, we studied relationships between treatment adherence, asthma control, beliefs about medication, treatment intrusiveness, healthcare seeking and preference for OD vs BD maintenance medication using validated scales (Medication Adherence Report Scale [MARS], Asthma Control Test [ACT], Beliefs about Medicine Questionnaire-Necessity Concerns Differential [BMQ-NCD], Asthma Treatment Intrusiveness Questionnaire [ATIQ]).Patients were aged 18–55 yrs with self-reported asthma, 31 maintenance medications, recruited from 5 European countries (N=1010). Asthma was poorly controlled or uncontrolled in 46.1% of patients (ACT£15); median MARS score=3.40, showed that most patients reported some nonadherence. Most patients (73.5%) preferred OD medication that was as effective as their current medication over a slightly more effective BD medication. Self-reported nonadherence was associated with poorer asthma control (r=0.262, p<0.001) and increased HCP visits (r=–0.075, p<0.05). Nonadherence (MARS) and preference for OD treatment were associated with perceptions of treatment (BMQ-NCD) and treatment intrusiveness. Results suggest a complex inter-relationship between patients' beliefs about medication, intrusiveness, treatment adherence and preference for OD vs BD maintenance medication that all impact asthma control, and should be considered when evaluating treatment options. Funded by GSK (GHO-10-4705). The Nature of Pulmonary Hypertension Vascular remodelling is reversed following BMPR2 modified endothelial progenitor cell therapy in a MCT-induced PAH rat model Rebecca Harper (Adelaide, Australia), Rebecca Harper, Rebekah Ward, Claudine Bonder, Paul Reynolds Introduction: Pulmonary arterial hypertension (PAH) is caused by pulmonary vascular remodelling. Reduced expression of the bone morphogenetic protein receptor type-2 (BMPR2) is causally linked to PAH. Previously, we have augmented endothelial progenitor cells (EPCs) to over-express BMPR2 and transplanted them in a monocrotaline (MCT)-induced PAH rat model resulting in an amelioration of the disease. We now assess the effects of our BMPR2-EPC and EPC only therapy on vascular remodelling in this MCT-induced PAH rat model. Method: Rats (n=8) were injected with MCT, and then at day 10, rats were intravenously injected with EPCs only, AdBMPR2 transfected EPCs, or uninjected. After a further 8-10 days, PAH was assessed and lungs were extracted and processed into paraffin blocs. Immunohistochemical analysis on vessels 50µm or less was performed with a-smooth muscle actin (a-SMA) and proliferating cell nuclear antigen (PCNA). Results: After 8-10 days PAH was shown to be attenuated in the BMPR2-transduced EPC group, with a reduction in the mPAP of the EPCs Only group compared to MCT Only. Rats treated with EPCs Only had a significant reduction by 30.47% in vessel muscularisation and 39.59% reduction in cellular proliferation compared to MCT Only. Rats treated with BMPR2-EPCs had a 31.21% reduction in vessel muscularisation and a 52.97% reduction in cellular proliferation compared to MCT Only treated rats. Discussion: Amelioration of PAH can be achieved using BMPR2 modified EPCs. There's a significant reduction in distal vessel muscularisation and cellular proliferation following EPCs and BMPR2-EPCs treatment, with a greater effect seen in the BMPR2-EPCs group. Immunity in idiopathic pulmonary arterial hypertension (IPAH), a role for activated DCs? Thomas Koudstaal (Rotterdam, Netherlands), Thomas Koudstaal, Jennifer van Hulst, Tridib Das, Peter Heukels, Daphne Merkus, Michiel de Raaf, Ingrid Bergen, Harmjan Bogaard, Cantano Reis e Sousa, Geert van Loo, Rudi Hendriks, Karin Boomars, Mirjam Kool The presence of tertiary lymphoid organs (TLOs) in lungs of IPAH patients suggest a key role for (auto)immunity in its pathogenesis. Activated dendritic cells (DCs) play a crucial role in the induction of TLOs. DC activation leads to NF-kB activation, which is negatively regulated by the A20 enzyme. In this study, peripheral blood of PAH patients and healthy controls (HC) was examined for DC number and activation. Furthermore, mice harboring activated A20-deficient cDC1s (Dngr1-cre X Tnfaip3fl/fl mice (DNGR1-A20)) were examined at 31 weeks of age. PAH development was monitored using Right Heart Catheterization (RHC), Echocardiography, RV hypertrophy, and Histology. Peripheral CD141+ DCs (cDC1) of IPAH patients showed an increased activation status by CD86 expression compared to HC. DNGR1-A20KO mice showed an significantly increased RV hypertrophy, measured both by echocardiography and Fulton index. RHC showed a trend towards increased RVSP in the DNGR1-A20KOmice in comparison to the wildtype mice. Furthermore, lungs of DNGR1-A20KO mice exhibited increased perivascular infiltration, muscle wall thickening and collagen deposition around the pulmonary vessels compared to wildtype mice. Our IPAH patient data show a significantly increased activation of cDC1s in peripheral blood samples and our DNGR1-A20KO mouse model shows progression towards a PAH phenotype with significantly increased RVH and a trend of increased RVSP. The pulmonary vascular infiltrates show a possible role for (auto)immunity in the development of PH. In conclusion, investigating DC activation in the development or progression of PAH will be valuable to gain more insight in the mechanisms driving the pathophysiology of IPAH. – A new molecular genetic diagnostic approach for pulmonary arterial hypertension Christina Eichstaedt (Heidelberg, Germany), Christina Eichstaedt, Jie Song, Rebecca Rodríguez Viales, Nicola Benjamin, Satenik Harutyunova, Christine Fischer, Ekkehard Grünig, Katrin Hinderhofer Background: Mutations in the bone morphogenic protein receptor 2 (BMRP2), ALK1 and endoglin have previously been identified as main disease causing genes in pulmonary arterial hypertension (PAH). In clinical practice genetic assessment is performed by Sanger sequencing including these January 2017 • HPN


19 3 genes only although 7 further PAH-genes have previously been identified. In this study we developed a new PAH-specific gene panel. Methods: We included 37 patients with invasively confirmed PAH for genetic testing and 5 relatives of affected PAH-patients. A new PAH-specific gene panel was developed using next generation sequencing. The panel included the 10 known PAH-genes and 22 further candidates within the BMPR2/Alk1 pathway. Any potential pathogenic variants were reassessed by Sanger sequencing. Within repeated runs quality parameters have been adjusted. Results: Twenty-five of the 42 subjects (60%) had a mutation in BMPR2, ALK1 or endoglin genes identified by panel and Sanger sequencing. In addition, 3 new mutations and 13 unclassified variants were identified in 9 genes. A sensitivity of 100% was met after quality parameters were adjusted. The positive predictive value for all newly investigated genes based on panel results increased to 100% when Sanger technique was additionally applied. Conclusion: The new PAH-specific gene panel developed in this study allowed for the first time the assessment of all known 10 PAH-genes and further 22 candidates at once and reduced markedly overall sequencing costs and time. Sensitivity and positive predictive value reached 100% when Sanger technique was additionally applied. Thus, this technique might revolutionize the routine diagnostic genetic testing in PAH-patients. Antenatal sildenafil-simvastatin combination attenuates pulmonary hypoplasia and hypertension in nitrofen-induced congenital diaphragmatic hernia Laurence Dewachter (Brussels, Belgium), Céline Dewachter, Martine Makanga, Hidekazu Maruyama, Emeline Hupkens, Jean-Luc Vachiery, Robert Naeije, Laurence Dewachter Background. Congenital diaphragmatic hernia (CDH) has a high mortality rate mainly due to lung hypoplasia and persistent pulmonary hypertension of the newborn (PPHN). We recently reported that antenatal treatment with sildenafil or simvastatin prevented pulmonary hypoplasia and PPHN in experimental CDH. Objectives: We sought to evaluate the efficacy of antenatal sildenafil-simvastatin combination on pulmonary hypoplasia and PPHN associated to nitrofen-induced CDH. Methods: On embryonic day (E)9.5, nitrofen or vehicle was administered to pregnant rats. Nitrofen-treated rats were randomly assigned to antenatal sildenafil (100 mg/kg/day) and simvastatin (20 mg/kg/day) combination or placebo administration from E11 to E21. On E21, foetuses were delivered by caesarean section, killed and checked for left-sided CDH. Results: In nitrofen-induced CDH, simvastatin-sildenafil totally prevented left-sided CDH in the offspring, but failed to increase body weight and lungto-body weight ratio. Antenatal simvastatin-sildenafil improved lung parenchyma structure, with decreased alveolar septal thickness and increased radial alveolar count. Antenatal simvastatin-sildenafil restored pulmonary vascular density and external diameter, and reduced pulmonary arteriolar remodelling. This was associated with restored epithelial and vascular activation of apoptotic processes in the lungs. Antenatal combination therapy was more efficacious than antenatal therapy with simvastatin or sildenafil alone. Conclusions: Antenatal simvastatin-sildenafil combination therapy improves pathological features of lung hypoplasia and PPHN in experimental nitrofen-induced CDH. Lung cancer: therapeutic modalities, re-staging, and follow-up Pemetrexed in maintenance therapy of 164 patients with advanced non-small-cell lung cancer (NSCLC) Jana Skřiřková (Brno, Czech Republic), Jana Skricková, Zbynek Bortlicek, Karel Hejduk, Milos Pesek, Vitezslav Kolek, Marcela Tomiskova, Ivona Grygarkova, Leona Koubkova, Marketa Cernovska, Jaromir Roubec, Frantisek Salajka, Milada Zemanova, Helena Coupkova, Monika Satankova, Milosalav Marel Introduction: The effectiveness of continuation maintenance therapy with pemetrexed versus the watch-and-wait approach was proved by a large randomised phase III trial. We focused on continuance maintenance therapy with pemetrexed in routine clinical practice in the Czech Republic. Methods: The primary objective was to evaluate the overall survival, defined as the length of time from the start of maintenance therapy to the date of death. Data was summarised using the standard descriptive statistics, absolute and relative rates for categorial variables, averages for continuous variables, 95% confidence intervals, as well as median, minimum and maximum values. Kaplan-Meier survival curves were used to display the patient survival. The analysed cohort of NSCLC patients involved 164 patients. Results: The median age was 63,0 years; stage IV was the predominant clinical stage (85,4%), 53.7% of patients were men, 46.3% women. Adenocarcinoma was in 163 patients, and large-cell carcinoma in one. Treatment response was assessed in 138 patients. Among the assessed patients, 19.5% showed PR. SD was the most frequent response (48.8%); PD occurred in 15.2% patients. Adverse events led to the termination of treatment in 3.6% patients. The median number of cycles of maintenance therapy in our study was 5.0 (1.0; 24.0), and the median duration of maintenance therapy was 15.7 (3,0 – 58.2) weeks. The primary objective, median overall survival (median OS), was 18.7 months (95% CI: (14,6; 22,8). Conclusion: The continuation maintenance therapy with pemetrexed has been shown to be effective and well tolerated in the Czech population. Median overall survival (median OS), was 18.7 months (95% CI: (14,6; 22,8). Impact of second-line treatment on overall survival of advanced lung adenocarcinoma patients Chai Chee Shee (Petaling Jaya, Malaysia), Chai Chee Shee, Liam Chong Kin, Pang Yong Kek, Kow Keng Siong, Poh Mau Ern, Wong Chee Kuan, Tan Jiunn Liang Background Randomised control trials (RCTs) show good overall survival (OS) for advanced lung adenocarcinoma patients is much dependent on subsequent-line of treatment upon disease progression on first-line treatment. However, not many studies look into such outcome in real-world setting. Aims: To determine the impact of second-line treatment on OS for advanced lung adenocarcinoma patients who failed first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) or chemotherapy in the real world-setting. Methods: A retrospective analysis of advanced lung adenocarcinoma patients who developed disease progression on first-line EGFR-TKI or chemotherapy treatment at the University of Malaya Medical Centre from 1st August 2010 to 31th July 2014.ResultsOf 78 patients with EGFR mutant tumours and failed first-line EGFR-TKI, 23 patients (29.5%) received second-line chemotherapy while remaining 56 patients (70.5%) had best supportive care (BSC). Subgroup analysis showed that patients who received second-line chemotherapy had numerically better median OS (12.60 months) than those received BSC (9.03 months) (HR, 0.53; 95% CI, 0.24-1.21; p=0.134).Of 79 patients with EGFR wild-type tumours and failed first-line chemotherapy, 36 patients (45.6%) received second-line chemotherapy and 43 patients (54.4%) had BSC - the median OS for the former was 11.50 months and the latter was 5.47 months (HR, 0.58; 95% CI, 0.34-0.98; p=0.043). Conclusions: In the real-world setting, second-line active treatment significantly prolonged the OS. The OS in this study was shorter than that in RCTS due to presence of co-morbidities, poorer ECOG performance at diagnosis and lower rate of second-line treatment.

HPN • January 2017


20 News

Potential to improve Prostate Cancer detection Irish scientists have developed a new and innovative device which they are using to test a newly proposed method for the detection of prostate cancer, which should offer a significant improvement in tumour detection compared with existing methods. Using a specially constructed life-size ‘phantom’ test device which mimics the prostate and entire pelvic area, the researchers have been fine-tuning this new technique in advance of it being offered to patients in St James’s Hospital, Dublin, in a pilot clinical study. This research has been performed by Silvin Knight, a PhD student in the Imaging Physics Group, School of Medicine, Trinity College Dublin and the National Centre of Advanced Medical Imaging (CAMI), St James’s Hospital, working under the supervision of Professor Andrew Fagan, the Director of Imaging Physics in the CAMI centre and head of the group. Silvin’s work has been funded by the Irish Cancer Society and the Movember Foundation, and was recently published in the journal ‘Physics in Medicine and Biology’. Prostate cancer is the most common cancer among men in

Ireland with around 3,400 new cases of the disease identified each year. This makes up almost one third of all cancers diagnosed in men in Ireland. The new detection technique builds on the dynamic contrast enhanced (DCE) form of MRI (magnetic resonance imaging) proposed almost 20 years ago by scientists. This involves the injection of a ‘dye’ into a patient and taking a series of images as the dye leaks in and out of tissue in the prostate. As cancerous prostate tissue tends to be leakier than healthier tissue, the identification of leakier blood vessels in prostate tissue strongly indicates the presence of a tumour. DCE-MRI has been demonstrated in research studies to potentially offer a significant improvement in prostate cancer detection (of up to +42% in sensitivity, compared with biopsy alone), but to date scientists have been unable to properly test the technique’s accuracy, and so this potentially life-saving approach to prostate cancer detection has remained confined within a research setting. The research team’s test device will finally provide vital information

Currently it is difficult for doctors to definitively diagnose prostate cancer using existing techniques. These usually require patients to go through a painful and sometimes inaccurate biopsy procedure.

Irish Cancer Society-funded researcher Silvin Knight

on the effectiveness of DCE-MRI, while allowing the team to see the results of an improved version of DCE-MRI they are currently developing, which involves ‘compressed sensing’. This new technique uses advanced mathematics to determine the manner in which the DCE-MRI images are acquired and in how they are subsequently analysed in order to detect and determine the aggressiveness of the prostate tumour. The research team’s work should dramatically increase the possibility of DCE-MRI being incorporated into routine clinical examinations of the prostate, to the benefit of patients. Commenting on the project, Silvin said, “Currently it is difficult for doctors to definitively diagnose prostate cancer using existing techniques. These usually require patients to go through a painful and sometimes inaccurate biopsy procedure. “Using this new ‘phantom’ device will finally allow us to answer questions that have long eluded researchers about DCE-MRI. We can then build on these answers by trialling our improved ‘compressed sensing’ version of DCE-MRI. “In the coming months we will run a small pilot study in St James’s Hospital to test this new form of detection, and hope to

recruit some patients onto this trial. It will compare our new CS-DCE-MRI technique with existing biopsy results, with other imaging techniques, and with the analysis of removed prostates, to determine the level of improvement in prostate cancer detection.” Nine in ten prostate cancer patients survive their diagnosis after five years. However, early detection is a huge factor in saving lives. Currently the first tests men will undergo to detect if they have the disease involves PSA blood test – which measures a protein made by the prostate gland called prostate specific antigen – and a digital rectal examination.

22nd Congress of EAHP EAHP has announced the 22nd Congress of the EAHP will take place from 22nd-24th March 2017, in Cannes, with the theme of "Hospital pharmacists – catalysts for change". The scientific programme is relevant for hospital Pharmacists dealing with the challenge of rapid change in healthcare. The hospital Pharmacist's role in facilitating change will be addressed. EAHP's annual congress is the largest congress for hospital Pharmacy in Europe and attracts Pharmacists from all over the world. The EAHP Congress continues to provide delegates with an exceptional opportunity to meet, network and share expertise and best practice with colleagues while keeping up to date with the latest developments in hospital Pharmacy and learning about the latest products and innovations. Register before 31st January 2017 for the discounted rate. Visit www.eahp.eu for more details.

January 2017 • HPN


XOFIGO® prolongs the overall survival of patients with castration-resistant prostate cancer (CRPC) by intensive treatment at sites of bone metastases. Introduce Xofigo® for patient progressing on second-generation hormonal therapy1,2

v This medicinal product is subject to additional monitoring. Adverse events and product complaints should be reported. To report an adverse event or a product complaint about a Bayer product, please call Bayer on 01 2999 313. Adverse events and product complaints may also be reported to HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; e-mail: medsafety@hpra.ie. Xofigo 1100 kBq/mL solution for injection (radium Ra 223 dichloride) Please refer to full Summary of Product Characteristics (SmPC) before prescribing. Composition: Active ingredient: radium Ra 223 dichloride (radium-223 dichloride, 1100 kBq/ml, corresponding to 0.58 ng radium-223 at the reference date). Each vial contains 6 mL of solution (6.6 MBq radium-223 dichloride at the reference date). Contains sodium. Indication: Treatment of adults with castration-resistant prostate cancer, symptomatic bone metastases and no known visceral metastases. Dosage and Administration: Xofigo should be administered only by persons authorised to handle radiopharmaceuticals in designated clinical settings and after evaluation of the patient by a qualified physician. Recommended dose is an activity of 55 kBq per kg body weight, given at 4 week intervals for 6 injections. Safety and efficacy beyond 6 injections with Xofigo have not been studied. Xofigo is administered by slow intravenous injection (generally up to 1 minute). The intravenous access line or cannula must be flushed with isotonic sodium chloride 9mg/ml (0.9%) solution for injection before and after injection of Xofigo. No dosage adjustment is considered necessary in elderly patients, patients with hepatic impairment or in patients with renal impairment. Safety and efficacy of Xofigo in children and adolescents below 18 years of age have not been studied. Contraindications: No known contraindications. Warnings and Precautions: Bone marrow suppression, notably thrombocytopenia, neutropenia, leukopenia and pancytopenia, has been reported. Haematological evaluation of patients must be performed at baseline and prior to every dose. In case there is no recovery in values for absolute neutrophil count (ANC) and haemoglobin within 6 weeks after the last administration of Xofigo despite receiving standard of care, further treatment with Xofigo should only be continued after careful benefit/risk evaluation.

Patients with evidence of compromised bone marrow reserve e.g. following prior cytotoxic chemotherapy and/or radiation treatment (EBRT) or patients with advanced diffuse infiltration of the bone (EOD4; “superscan”), should be treated with caution as an increased incidence of haematological adverse reactions such as neutropenia and thrombocytopenia has been observed. Limited available data indicates that patients receiving chemotherapy after Xofigo had a similar haematological profile compared to patients receiving chemotherapy after placebo. Crohn’s disease and ulcerative colitis: due to the faecal excretion of Xofigo, radiation may lead to aggravation of acute inflammatory bowel disease, therefore Xofigo should only be administered to these patients after a careful benefit-risk assessment. In patients with untreated imminent or established spinal cord compression, treatment with standard of care, as clinically indicated, should be completed before starting or resuming treatment with Xofigo. In patients with bone fractures, orthopaedic stabilisation of fractures should be performed before starting or resuming treatment with Xofigo. In patients treated with bisphosphonates and Xofigo, an increased risk of development of osteonecrosis of the jaw (ONJ) cannot be excluded. In the phase III study, cases of ONJ have been reported in 0.67% patients (4/600) in the Xofigo arm compared to 0.33% patients (1/301) in the placebo arm. However, all patients with ONJ were also exposed to prior or concomitant bisphosphonates and prior chemotherapy. Xofigo contributes to a patient’s overall long-term cumulative radiation exposure and therefore may be associated with an increased risk of cancer and hereditary defects. No cases of Xofigo-induced cancer have been reported in clinical trials in followup of up to three years. Depending on the volume administered, Xofigo can contain up to 2.35 mmol (54 mg) sodium per dose. Undesirable effects: Very common: thrombocytopenia, diarrhoea, vomiting, nausea; Common: neutropenia, pancytopenia, leukopenia, injection site reactions; Uncommon: lymphopenia. Classification for supply: Medicinal product subject to restricted medical prescription. Marketing Authorisation Holder: Bayer Pharma AG. 13342 Berlin. Germany. MA number(s): EU/1/13/873/001. Further information available from: Bayer Ltd., The Atrium, Blackthorn Road, Dublin 18. Tel: 01 2999313. Date of Preparation: October 2015

References: 1. Mohler JL, Armstrong AJ, Bahnson RR, et al. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Prostate Cancer. Version 2.2016. National Comprehensive Cancer Network; 2016:1-108. 2. Mottet N, Bellmunt J, Briers E, et al. Guidelines on Prostate Cancer. European Association of Urology; 2015 :1-156. 3. Xofigo® (radium Ra 223 dichloride) solution for injection Summary of Product Characteristics (SmPC), Bayer Pharma AG, 13342 Berlin, Germany, 2016.

© 2016 Bayer Pharma AG. September 2016. L.IE.MKT.09.2016.0632


22 News

Study suggests orphan drug legislation might be too successful A study by UK academics shows that orphan drug legislation designed to incentivise investment in treatments for rare diseases is generating products so profitable that investment in broader indications is being stifled. According to an analysis of 83 publicly quoted companies, which together market nearly 200 orphan drugs, compared to control companies matched by size, country and R&D investment, orphan drugs companies are five time more profitable and have a 10% to 15% higher market valuation. Niche drugs are commanding high prices and all of the world's 10 most expensive drugs are orphans, with Alexion Pharmaceuticals Inc.'s Soliris (eculizumab), for treating atypical hemolytic uremic syndrome and paroxysmal nocturnal hemoglobinuria, heading the list, at more than $400,000 per year. "Although these [10 drugs] are prescribed to fewer patients, their high prices can result in revenues equivalent to traditional blockbusters," said Dyfrig Hughes, professor of pharmacoeconomics, and co-director of the Center for Health Economics & Medicines

Evaluation at Bangor University, Wales. Almost one-third of drugs approved for rare diseases now exceed $1 billion in annual sales. The global orphan drugs market is expected to reach $176 billion by 2020, accounting for 19% of prescription drug sales. The mean price of the top 100 orphan drugs by sales in 2014 was more than six times higher than a comparable sample of non-orphan drugs, at $137,782 per patient, per year vs. $20,875. As Hughes and his co-author Jannine Poletti-Hughes, lecturer in accounting and finance at Liverpool University, pointed out, in addition to premium pricing, owners of orphan drugs get incentives, including seven years of market exclusivity in the U.S. and 10 years in Europe, with the possibility of further extensions for pediatric use. Small companies developing orphan drugs get access to science advice from regulators, reduced or waived regulatory fees, and tax credits. Those incentives have paid off, with the FDA approving 503 treatments for rare diseases since

the orphan drug legislation came into effect in 1983, compared to fewer than 10 in the decade before. Orphan drugs accounted for 21 of 45 new innovative drugs approved by the FDA in 2015.

"Following authorisation, the cost of marketing is comparatively small because the target population of physicians and patients are themselves so small," said Hughes.

The EMA has authorised 123 orphan drugs since the European legislation was enacted in 2000.

While the analysis can be said to illustrate orphan drug legislation is a success, it also suggests the system is not sustainable. As Hughes pointed out, common diseases increasingly are being classified as multiple rare conditions, each eligible for orphan designation.phan

The analysis, published in PLOS One, shows not only are orphan drug companies more profitable, their profits have historically increased by 11% for each additional orphan drug that reaches the market. For Hughes, who has acted as an external expert for the EMA's Committee of Orphan Medicinal Products, incentives have tipped the balance, allowing companies to make excessive profits. "This may have had the adverse and unintended consequence of directing R&D resources away from other areas of unmet clinical need, such as antibiotics," he said. The study compared 86 companies with orphan drug approvals in Europe, the U.S. or both, with 258 control companies, showing orphan drug marketing authorisation holders have a 9.6% higher return on assets than non-orphan drug companies.

He suggested a distinction could be made between drugs for specific use in one condition, for example a gene therapy for a particular inherited disorder, and those used in a number of conditions. "Gleevec [imatinib] for instance, has EMA orphan status for seven different cancers," Hughes noted. A further corrective would be to link market exclusivity to revenues. In Europe, individual countries can trigger a review of the profitability of individual products to limit the monopoly to six, rather than 10 years, allowing other companies to enter the market sooner.

Top honours for Cancer Research Congratulations to cancer researchers Mairéad Cooney and Maria Prencipe who went home with the top prizes at the 2016 Irish Cancer Society Research Awards. The awards, held on Thursday, December 1 in the Bank of Ireland Enterprise Centre, Trinity College Dublin, recognised some of the vital work being undertaken by researchers funded by the Irish Cancer Society. The charity is the leading investor in cancer research in Ireland, and currently funds 84 researchers across the country in the areas of cancer prevention, detection, treatment and survivorship. Mairéad, a PhD student at DCU and native of Navan, Co Meath, picked up the PhD Researcher of the Year award for her work, which focussed on the promotion of physical activity among people living with, or who have survived, cancer. As part of her project, Mairéad carried out an initial study which January 2017 • HPN

found that most healthcare professionals believed in the value of physical activity for patients but experienced challenges in its promotion, including lack of time and resources. A follow-up study of patients found that many felt isolated after their treatment, had limited access to exercise advice and services, and found getting active to be difficult for them. Mairéad’s research highlights the need to develop effective ways to support individuals living with and beyond cancer to remain active in the long term.

patients, whose cancer cells have spread from the prostate to other organs. One reason why prostate cancer cells survive treatment is the Serum Response Factor (SRF). Maria’s work showed that patients who did not respond to current treatments had much more SRF. Maria has found that a new drug which blocks SRF can stop the cancer cells from dividing and

surviving. When this drug is used in combination with current treatments, these are more effective in killing cancer cells. The findings are currently being tested in pre-clinical models in collaboration with the University of Washington. Following these experiments, it is hoped that the new drug will be available to prostate cancer patients in the near future.

She now plans to develop individualised self-management plans for the development of long-term physical activity among cancer patients and survivors. Maria, a post-doctoral researcher in UCD and native of Italy, took home the Post-Doctoral Researcher of the Year award for her project which looks at metastatic prostate cancer

(Back, L to R) Dr Damir Vareslija, RCSI; Silvin Knight, TCD (Front, L to R) Dr Aideen Ryan, NUI Galway; Maria Prencipe, UCD; Mairéad Cooney, DCU; and Lisa Dwane, TCD (Photo: Andres Poveda)


CPD 28: Venous Thromboembolism Continuing Professional Development

CPD

23

Alok A. Khorana,corresponding author Marc Carrier, David A. Garcia, and Agnes Y. Y. Lee

1. REFLECT - Before reading this module, consider the following: Will this clinical area be relevant to my practice?

3. PLAN - If I have identified a knowledge gap - will this article satisfy those needs or will more reading be required?

2. IDENTIFY - If the answer is no, I may still be interested in the area but the article may not contribute towards my continuing professional development (CPD). If the answer is yes, I should identify any knowledge gaps in the clinical area.

4. EVALUATE - Did this article meet my learning needs - and how has my practise changed as a result? Have I identified further learning needs?

60 Second Summary Thrombosis in cancer patients is associated with deleterious consequences. Most important is the strong association with short- and long-term mortality; indeed, thromboembolism is the second-leading cause of death in patients with malignancy. Whereas some studies have suggested that a limited occult cancer screening strategy, including medical history taking, physical examination, routine blood tests and a chest-X ray, is adequate to detect most occult cancers in patients with unprovoked VTE, others have shown that a more extensive occult cancer screening strategy (e.g. ultrasonography and/or computed tomography (CT) of the abdomen/pelvis, tumour markers, etc.) can increase the rate of detection and improve the sensitivity of screening. Although it is commonly stated that cancer patients are at high risk for VTE, there is significant variation in risk amongst subgroups of this population. Despite the multitude of reports linking cancer-associated VTE to individual risk factors or biomarkers, it should be noted that many of the published studies are univariate or limited multivariate analyses. An updated Cochrane systematic review of multiple randomised trials of outpatient prophylaxis in malignancy found that LMWH significantly reduced symptomatic VTE (RR 0.62, 95 % CI 0.41–0.93) but with a relatively high number needed to treat (NNT = 60) [27]. Cancer patients with VTE have higher rates of complications, including a 12 % annual risk of bleeding complications and up to a 21 % annual risk of recurrent VTE while on warfarin therapy [3]. Furthermore, epidemiologic and other studies have suggested that cancer-associated VTE may be relatively resistant to warfarin.

5. WHAT NEXT - At this time you may like to record your learning for future use or

assessment. Follow the 4 previous steps, log and record your findings. Published by HPN, sponsored by Leo Pharma. Copies can be downloaded from www.irishpharmacytraining.ie Disclaimer: All material published is copyright, no part of this can be used in any other publication without permission of the publishers and author. Leo Pharma has no editorial oversight of the CPD programmes included in these modules.

The only an of VTE in a

Guidance for the prevention and treatment of cancer-associated venous thromboembolism Thromboembolism frequently complicates the course of malignancy, particularly in the setting of medical and surgical anti-cancer treatments[1]. It can involve both the venous and arterial systems. The more common events are venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE). VTE generally presents after the diagnosis of cancer but it can be the presenting symptom that leads to diagnosis of malignancy. Incidentally diagnosed VTE, particularly involving visceral or splanchnic veins such as the portal or superior mesenteric vein, are increasingly contributing to the burden of cancer-associated thrombosis[2]. Arterial events, such as stroke or myocardial infarction, are also much more prevalent in patients with malignancy, as compared to the general population. Thrombosis in cancer patients is associated with deleterious consequences. Most important is the strong association with short- and longterm mortality; indeed, thromboembolism is the second-leading cause of death in patients with malignancy[3, 4]. VTE is also associated with recurrent VTE as well as bleeding, both at significantly higher rates than seen in noncancer patients[3]. Finally, VTE is associated with a threefold increase in hospitalisations and higher total health care costs[5]. Thus, appropriate prevention and treatment of cancer-associated thrombosis is vital to reduce its burden on patients with malignancy and on the health system at large. To provide guidance on the prevention and treatment of cancer-associated thrombosis, we

Abbreviated Prescribing I 0.4 ml/10,000 IU in 0.5 ml/ 12 in 0.8 ml/18,000 IU in 0.9 ml syringes) and innohep® 20,00 Please refer to the full S (www.medicines.ie) before pre Indications: Treatment of ve including deep vein thrombosis first developed a number of pivotal practical treatment of venous thromboe questions pertaining to the topic (Table 1). patients with active cancer. Fo Questions were developed by consensus from those with severe haemodyn surgery thrombolysis, may b the authors. The literature addressing the orabove Active ingredient: Tinzaparin s questions was reviewed by searching electronic Dosage and administration databases (PubMed, Medline), with a175focus anti-Xaon IU/kg body weigh oral anticoagulation is establis high quality cohort studies and randomized active cancer: 175 anti Xa IU/ controlled trials published in the lasttreatment 10 years, period of 6 months. T 6 months should be ev where available, as well as on recentbeyond systematic of innohep (175 IU/kg) con reviews. For each question, a brief summary discontinue innohep at least 2 and interpretation of pertinent literature shouldand not be resumed until at after the catheter has been existing guidelines, where available, orare efficacy of innohep in children provided, followed by guidance to the reader. no posology recommendatio impairment suspected, assess Guidance creatinine to estimate creatini CrCl level <30 ml/min not reco 1. What is the appropriate workupbeen to search established. Available evi with CrCl levels down to 20 m for occult malignancy in patients with treatment can be initiated with idiopathic VTE? risk. In this situation, the dose o on anti-factor Xa activity. If the Patients with acute unprovoked VTErange, have theadose of innohep sho Xa measurement sh four-fold increased risk of having an anti-factor underlying adjustment should be repeate occult cancer compared to patients For with guidance, mean levels betw [9] . patients witho provoking (e.g. recent surgery) risk factors volunteers and 0.5 andVTE 1.5 IU/anti-factor Xa I Up to 10 % of patients with unprovoked by a chromogenic assay. Elde may be diagnosed with cancer within the first in the treatmen recommended Inspect prod The year following their thrombotic eventof[9].administration: is obs greatest period of detection is withincloudiness the firstor 6precipitate is still suitable. Administer by S observed months[9–11] and the most frequently outer side of the thigh, lower b area around the navel, near s tumour types are cancers of the ovary, should be in supine po cumulative pancreas and liver[11]. The long term patient right side. The air-bubble withi incidence of cancer diagnosis (i.e. beyond 6–12 injection, the skin should be he in 1,000 IU increments facilitate months) has been reported to be comparable calculated dose, based on the p to the incidence described in the general up or down as appropriate. If ne population[12]. These data notwithstanding, achieve thethe appropriate dosag Contraindications: Hypersens utility and extent of occult cancer screening is immune-mediated heparin-ind controversial. There is presently no consensus major haemorrhage or conditi fulfilling any one of three c and wide variation in clinical practiceasregarding

whether to perform occult cancer screening References: 1. Petersen LJ et al

Continuous Professional Development Modules are sponsored by LEO Pharma LEO Pharma has no editorial oversight of the CPD programmes included in these modules.


24

CPD 28: Venous Thromboembolism

and what investigations should be included. The most recent version of the American College of Chest Physicians (ACCP) clinical practice guidelines does not provide a specific recommendation of occult cancer screening in patients with unprovoked VTE. Whereas some studies have suggested that a limited occult cancer screening strategy, including medical history taking, physical examination, routine blood tests and a chest-X ray, is adequate to detect most occult cancers in patients with unprovoked VTE, others have shown that a more extensive occult cancer screening strategy (e.g. ultrasonography and/or computed tomography (CT) of the abdomen/pelvis, tumour markers, etc.) can increase the rate of detection and improve the sensitivity of screening. Only two studies have directly compared limited and extensive screening[13, 14]. A recent prospective cohort study comparing a limited occult cancer screening strategy to a strategy also including a mammography in women and thoracic and abdominal CT did not show any difference in the number of cancers subsequently diagnosed (5.0 vs. 3.7 %, respectively) or in overall mortality (8.3 vs. 7.6 %, respectively) during 2.5 years of follow up[13]. The only reported randomized controlled trial included patients with negative limited occult cancer screening and randomized them to no further testing or additional testing[14]. The extensive screening strategy had a sensitivity of 93 % and increased detection of the number of cases of early-stage cancers (T1–2, N0) (64 vs. 20 %, p = 0.047). An absolute risk reduction of cancer-related mortality of 1.9 % in favour of the extensive screening group during the 2-year follow-up period was reported. Although the lack of statistical significance of the cancer-related mortality difference might be due to lack of power, methodological limitations and implied possible lead-time bias undermine the results. Furthermore, the components of an ideal extensive occult cancer screening program are still unknown. A decision analysis using the data from the randomised trial described above and a meta-analysis have reported that limited occult cancer screening in combination with a CT abdomen/pelvis had the best yield[9, 15]. However, the complication rates, costeffectiveness and difference in morbidity and mortality associated

Table 1: Guidance questions to be considered 1. What is the appropriate workup to search for occult malignancy in patients with idiopathic VTE? 2. How can high-risk cancer patients be identified for primary thromboprophylaxis? 3. What is the appropriate immediate and long-term treatment for people with cancer diagnosed with acute thromboembolism, including the role of DOACs? 4. What is the appropriate duration of anticoagulation? 5. What is the appropriate treatment strategy in patients with recurrent VTE on anticoagulation? with this extensive screening could not be determined[9]. The National Institute for Health Care Excellence (NICE) guidelines on managing VTE suggest that all patients diagnosed with unprovoked VTE should be given a physical examination, chest X-ray, basic laboratory investigations, and urinanalysis. A CT abdomen/ pelvis and, mammography for women, is also suggested in patients aged over 40[16]. However, these recommendations are controversial as it remains unclear whether extensive occult cancer screening and earlier cancer detection improves morbidity, mortality and quality of life in patients with newly diagnosed VTE. Finally, extensive screening carries a significant economic cost and can induce significant psychological burden. Further clinical trials are required to assess the risks and benefits of an extensive occult cancer screening program in patients with unprovoked VTE. Guidance Statements • Patients with unprovoked VTE should undergo a through medical history and physical examination, basic laboratory investigations (complete blood counts, metabolic profile and liver function tests) and chest X-ray. • We suggest that if not up-to-date, patients undergo age- and gender-specific cancer screening (i.e. cervical, breast, prostate and colon). (2) How can high-risk cancer patients be identified for primary thromboprophylaxis? Although it is commonly stated that cancer patients are at high risk for VTE, there is significant variation in risk amongst subgroups of this population. In a large recent systematic review of studies, the VTE estimate for the general cancer population was approximately 13 per 1000 person-years (95 % CI 7–23) [17]. In patients with metastatic disease

or those receiving thrombogenic regimens the risk was 68 per 1000 person-years (95 % CI 48–96) and as high as 200 per 1000 person-years (95 % CI 162–247) amongst patients with primary brain tumours. Discriminating between low- and high-risk patients is therefore crucial to optimize the risk-benefit ratio of thromboprophylaxis. Clinical risk factors, biomarkers or combinations of the two can be used to estimate VTE risk. Clinical risk factors include the primary site of cancer (with highest rates observed in patients with primary brain tumours and cancers of the pancreas, stomach, liver, lungs and kidneys and hematologic malignancies including lymphomas and myeloma), advanced stage and therapeutic interventions including surgery, type of chemotherapy, erythropoiesis-stimulating agents, and devices such as central venous catheters and inferior vena cava filters (reviewed in[1]). It should be noted that the advent of novel “targeted” anti-cancer therapies to supplement or replace traditional chemotherapybased regimens has not reduced the risk of VTE. Indeed, drugs targeting angiogenesis such as bevacizumab, sunitinib, sorafenib, the multi-targeted tyrosine kinase inhibitor ponatinib and the immunomodulator lenalidomide have been associated with arterial thromboembolism[18, 19], immunomodulatory agents such as thalidomide and lenalidomide have been associated with very high rates of VTE[20], and anti-epidermal growth factor antibodies such as cetuximab and panitumumab have also recently been associated with VTE[21]. A variety of candidate biomarkers have also been associated with VTE in malignancy. These include elevated platelet and leukocyte counts, decreased hemoglobin, elevated D-dimer, elevated prothrombin activation products, elevated soluble P-selectin, thrombin generation and elevated levels of TF-bearing microparticles (TFMP)[22].

Despite the multitude of reports linking cancer-associated VTE to individual risk factors or biomarkers, it should be noted that many of the published studies are univariate or limited multivariate analyses. Strategies utilising such individual factors to enroll patients onto clinical trials of thromboprophylaxis have not yielded the event rates that would have been predicted. For instance, in two large trials of outpatient prophylaxis, patients were selected based only on primary site and advanced stage; in these studies, event rates in the placebo arm ranged from 3.4 to 3.9 % and even thoughAbbreviated the studies Prescribing I 0.4 ml/10,000 IU in 0.5 ml/ 12 found a statistically significant in 0.8 ml/18,000 IU in 0.9 ml reduction with thromboprophylaxis syringes) and innohep® 20,00 in symptomatic VTE, results Please refer to the full S (www.medicines.ie) before pre were not adopted by the Indications: Treatment of ve oncology community due to low including deep vein thrombosis [23, 24] event rates . Basedtreatment on thisof venous thromboe patients with active cancer. Fo experience, the latest ASCO those with severe haemodyn guidelines recommend surgery against the or thrombolysis, may b Active ingredient: Tinzaparin s use of single risk factors to identify Dosage and administration high-risk patients[7]. 175 anti-Xa IU/kg body weigh

The only an of VTE in a

oral anticoagulation is establis

The ASCO panel and other active cancer: 175 anti Xa IU/ treatment period of 6 months. T guidelines including NCCN and beyond 6 months should be ev ESMO instead recommend the of innohep use (175 IU/kg) con of a validated risk assessment discontinue tool innohep at least 2 should not be resumed until at to discriminate between high- and or after the catheter has been low-risk patients (Tableefficacy 2). This of innohep in children posology recommendatio risk score was originallynoderived impairment suspected, assess from a development cohort of creatinine to estimate creatini 2701 patients and thenCrCl validated level <30 ml/min not reco beenofestablished. Available evi in an independent cohort with CrCl levels down to 20 m 1365 patients from a prospective treatment can be initiated with registry by Khorana andrisk. In this situation, the dose o on anti-factor Xa activity. If the colleagues (the so-called “Khorana range, the dose of innohep sho Score”) [25]. Subsequently, the anti-factor Xa measurement sh adjustment should be repeate Score was externally validated For guidance, mean levels betw prospectively by the Vienna volunteers and patients witho CATS consortium and 0.5 and 1.5 IU/anti-factor Xa I multiple retrospective by a chromogenic assay. Elde recommended in the treatmen cohort studies[1, 26]. of administration: Inspect prod

Continuous Professional Development Modules are sponsored by LEO Pharma LEO Pharma has no editorial oversight of the CPD programmes included in these modules.

cloudiness or precipitate is obs

How can risk stratification is stillbe suitable. Administer by S outer side of the thigh, lower b utilized to select patients for area around the navel, near s outpatient thromboprophylaxis? patient should be in supine po right side. The air-bubble withi An updated Cochrane systematic injection, the skin should be he review of multiple randomised in 1,000 IU increments facilitate trials of outpatient prophylaxis calculated dose, based on the p up or down as appropriate. If ne in malignancy found that LMWH achieve the appropriate dosag significantly reduced symptomatic Contraindications: Hypersens VTE (RR 0.62, 95 % CI immune-mediated 0.41–0.93) heparin-ind major haemorrhage or conditi but with a relatively high number as fulfilling any one of three c needed to treat (NNT = 60)[27].

References: 1. Petersen LJ et al


25 LMWH was associated with a 60 % non-significant increase in major bleeding (RR 1.57, 95 % CI 0.69–3.60). Thus patients with higher absolute risk of VTE would derive greater benefit and conversely patients with a lower baseline risk would derive less benefit or no benefit. Proof of this concept comes from subgroup analyses of the two largest randomized trials. Rates of VTE in high-risk patients (Khorana Score ≥3) enrolled in PROTECHT were 11.1 % in the placebo arm and 4.5 % in the nadroparin arm (NNT = 15, compared to 77 for lowand intermediate-risk patients) [28]. Similarly, in a per-protocol subgroup analysis of SAVEONCO, NNT was 25 for high-risk patients compared to 333 for low-risk patients[29]. No differences were observed in bleeding rates between high- and low-risk patients. Based on these findings, prophylaxis is not recommended in unselected general cancer patients (i.e. without risk stratification) or in those with a high risk of bleeding (e.g. primary brain tumours). One niche population in this regard is patients with multiple myeloma receiving imid-based regimens. In an updated Cochrane metaanalysis, LMWH was associated with a significant reduction in symptomatic VTE when compared with the vitamin K antagonist warfarin (RR 0.33, 95 % CI 0.14–0.83), while the difference between LMWH and aspirin was not statistically significant (RR 0.51, 95 % CI 0.22–1.17)[27]. It should be noted that there are other settings in which pharmacologic thromboprophylaxis is generally recommended by major guidelines panels. These include hospitalized cancer patients with other risk factors such as an acute medical illness or recent surgery. In acutely ill medical inpatients, unfortunately, no cancer-specific clinical trials have been conducted; recommendations are therefore made based upon extrapolation of data from randomized trials that included only a small minority of cancer patients[30]. Extended prophylaxis with LMWH for up to 4 weeks postoperatively should be considered for patients undergoing major abdominal or pelvic surgery for cancer who have high-risk features such as restricted mobility, obesity or history of VTE[7]. There are currently no substantial data on the use of DOACs in the prophylaxis setting; ongoing studies are addressing this issue.

Table 2: Predictive model for VTE according to Khorana et al. [25] Risk score

Patient characteristics Site of cancer Very high risk (stomach, pancreas)

2

High risk (lung, lymphoma, gynecologic, bladder, testicular)

1

Prechemotherapy platelet count ≥350,000/mm3

1

Hemoglobin level less than 10 g/dl or use of red cell growth factors

1

Prechemotherapy leukocyte count >11,000/mm3

1

Body mass index ≥35 kg/m2 or more

1

High-risk score ≥3

Intermediate risk score 1–2

Guidance Statements (See Table 3for dosing): Recommendations are made assuming no existing contraindications to pharmacologic prophylaxis. We suggest against routine thromboprophylaxis in unselected and low-risk cancer outpatients. We also suggest against routine thromboprophylaxis in patients with high risk for bleeding (e.g. primary brain tumors). • We suggest consideration of outpatient thromboprophylaxis with LMWH in high-risk (Khorana Score ≥3 or advanced pancreas) cancer outpatients receiving chemotherapy and with aspirin or LMWH in patients with myeloma receiving imid-based regimens. • We suggest routine consideration of inpatient thromboprophylaxis with LMWH or unfractionated heparin in cancer patients hospitalized with an acute medical illness. • We suggest inpatient thromboprophylaxis with LMWH or unfractionated heparin in cancer patients undergoing major surgery. • We suggest post-operative thromboprophylaxis with LMWH for up to 4 weeks in patients undergoing major abdominal or pelvic surgery for cancer with high-risk features such as immobility, obesity and history of VTE. (3) What is the appropriate immediate and long-term treatment for people with cancer diagnosed with acute VTE, including the role of DOACs? Cancer patients with VTE have higher rates of complications, including a 12 % annual risk of

Low-risk score 0

bleeding complications and up to a 21 % annual risk of recurrent VTE while on warfarin therapy[3]. Furthermore, epidemiologic and other studies have suggested that cancer-associated VTE may be relatively resistant to warfarin. Therefore LMWHs were evaluated as an alternate, extended-therapy option to warfarin. The CLOT trial reported by Lee et al. randomized 676 cancer patients with VTE to receive initial dalteparin followed by 6 months of either dalteparin or warfarin with target INR 2.5[31]. Fifteen percent of patients treated with warfarin developed recurrent VTE compared to 7.9 % of patients treated with dalteparin [hazard ratio (HR) 0.48, 95 % CI 0.30–0.77; NNT = 12). This study established the superiority of LMWH for long-term anticoagulation in cancer patients. This and subsequent smaller studies have been evaluated in a Cochrane systematic review that further supports the initial findings of the CLOT study[32]. A recent presentation of the CATCH trial, the largest treatment study of cancer-associated thrombosis, largely confirms these initial findings[33, 34]. In this global, randomized phase III clinical trial, 900 patients were randomized to either tinzaparin 175 IU/kg once daily for 6 months or initial tinzaparin 175 IU/kg once daily for 5–10 days overlapped and followed by dose-adjusted warfarin (target INR 2–3) for 6 months. Over the 6-month trial period, 31 patients (6.9 %) in the tinzaparin arm experienced recurrent VTE compared with 45 (10 %) in the warfarin arm [HR 0.65 (95 % CI 0.41–1.03; p = 0.07)]. Symptomatic non-fatal DVT occurred in 12 patients (2.7 %) in the tinzaparin arm and 24 (5.3 %) in the warfarin arm [HR 0.48 (95 % CI 0.24–0.96); p = 0.04]. Significantly fewer patients experienced clinically

relevant non-major bleeding with tinzaparin than warfarin (11 vs. 16 %, respectively; p = 0.03). There were no differences in rates of major bleeding, non-fatal PE or mortality between the two arms. Current guidelines recommend long-term anticoagulation with LMWH for cancer patients with VTE as the preferred approach and results of this latest trial support this strategy[7].

The only an of VTE in a

Continuous Professional Development Modules are sponsored by LEO Pharma LEO Pharma has no editorial oversight of the CPD programmes included in these modules.

Abbreviated

Prescribing

I

0.4 ml/10,000 IU in 0.5 ml/ 12 The past few years have seen the in 0.8 ml/18,000 IU in 0.9 ml emergence of several DOACs, syringes) and innohep® 20,00 which have been shownPlease to berefer to the full S (www.medicines.ie) before pre comparable to conventional Indications: Treatment of ve including therapy with warfarin for the deep vein thrombosis acute treatment of VTE.treatment Four of venous thromboe patients with active cancer. Fo agents (rivaroxaban, dabigatran, those with severe haemodyn surgery or thrombolysis, may b apixaban and edoxaban) have Active ingredient: Tinzaparin s received regulatory approval Dosage for and administration the treatment of VTE. However, 175 anti-Xa IU/kg body weigh oral anticoagulation is establis none of these agents were tested active cancer: 175 anti Xa IU/ in cancer-specific populations treatment period of 6 months. T beyond 6 months should be ev and, in all of the treatment studies, of innohep (175 IU/kg) con patients in the control arm received discontinue innohep at least 2 vitamin K antagonists (VKA) should not be resumed until at after the catheter has been rather than LMWH. Theordefinition of innohep in children of “active cancer” was efficacy also not no posology recommendatio consistent across studies, and suspected, assess impairment creatinine to estimate creatini some included cancer survivors. CrCl level <30 ml/min not reco Therefore, the efficacy and safety been established. Available evi with CrCl levels down to 20 m of DOACs in patients with cancercan be initiated with associated VTE remainstreatment uncertain. risk. In this situation, the dose o Indeed, the European Medecines on anti-factor Xa activity. If the range,notes the dose of innohep sho Agency label for apxiaban anti-factor Xa measurement sh that its efficacy and safety in should be repeate adjustment patients with active cancer For guidance, mean levels betw [35] volunteers has not been established . A and patients witho 0.5 and 1.5 IU/anti-factor Xa I recent meta-analysis evaluated 9 assay. Elde by a chromogenic recommended randomized trials involving 2310 in the treatmen of administration: Inspect prod patients with cancer-associated cloudiness or precipitate is obs [36] thrombosis treated withis DOACs . still suitable. Administer by S side of the thigh, lower b In comparison to VKA, outer LMWH area around the navel, near s showed a significant reduction in be in supine po patient should right 0.52; side. The air-bubble withi recurrent VTE events (RR: injection, the skin should be he 95 % CI 0.36–0.74) whereas in 1,000 IU increments facilitate DOACs did not (RR: 0.66; 95 dose, based on the p calculated or down as appropriate. If ne % CI 0.39–1.11) (Fig. 1).upLMWH achieve the appropriate dosag was associated with a nonContraindications: Hypersens significant increase in the risk immune-mediated heparin-ind major haemorrhage or conditi of major bleeding (RR: 1.06; 95 as fulfilling any one of three c % CI 0.5–2.23) whereas DOACs

References: 1. Petersen LJ et al


26

CPD 28: Venous Thromboembolism

showed a non-significant reduction (RR: 0.78; 95 % CI 0.42–1.44) compared to VKA. Annualized risks of recurrent VTE and major bleeding among patients randomized to VKA were higher in the LMWH studies as compared to the studies assessing DOACs, suggesting that a higher risk cancer population was enrolled in the LMWH studies. Ongoing and planned studies aim to determine the relative safety and efficacy of DOACs in cancer-associated VTE compared with LMWH. Incidental VTE, defined as VTE discovered on scans ordered for reasons other than suspected VTE (typically cancer staging or restaging) is an emerging major contributor to the burden of cancer-associated VTE. Although management of these events remains controversial, retrospective studies have found similar risks of mortality and recurrent VTE between patients with symptomatic and incidental PE[37–40]. Given the high risk of future, symptomatic VTE in these patients, many clinicians are reluctant to manage them without anticoagulation. However, there is some evidence that patients with isolated, incidental subsegmental PE may not need anticoagulant treatment[41]. Further confusion regarding incidental VTE surrounds the diagnosis of incidental visceral vein thrombi. Indeed, the majority of incidental VTE in malignancy involves visceral veins[38]. Visceral vein thrombi include portal, mesenteric, splenic, renal and gonadal vein thrombi. In a cohort study of gastrointestinal cancer patients, 100 % of visceral vein thrombi were incidentally discovered compared to 35 % of PE [42]. The consequences of incidental visceral vein thrombi are less well understood, although there appears to be at least an independent association with mortality [(HR) 2.6, 95 % CI 1.6–4.2] in patients with pancreas cancer[38]. It is unclear whether this association with mortality can be ameliorated by anticoagulation. Due to lack of evidence, decisions to treat or not treat visceral vein thrombi are made inconsistently, largely based on provider opinion and anecdotal experience. In a study by Ageno and colleagues, one-half of abdominal vein thrombi were not treated with anticoagulation[43]. Prospective clinical trials data in this setting are sorely lacking.

Guidance Statements (see Table 3for dosing): • We suggest that patients with active cancer (i.e. known disease or receiving some form of anti-cancer therapy) and VTE be treated with LMWH for at least 6 months. • We suggest that patients with incidentally diagnosed DVT or PE be treated similarly to patients diagnosed with VTE based on symptoms i.e., with at least 6 months of LMWH monotherapy, with the exception of isolated subsegmental PE where decisions can be made on a case-by-case basis. We further suggest that treatment decisions in patients with incidentally diagnosed visceral vein thrombi be made on a case-by-case basis. (4) What is the appropriate duration and preferred agent for anticoagulation in cancer patients with VTE? The optimal duration of anticoagulation is not known as this has not been formally assessed beyond 6 months. In current practice, the consensus is to continue anticoagulation for at least 6 months and then reassess the need for continuing anticoagulation. In those with ongoing risk factors, such as metastatic or progressive disease or ongoing systemic chemotherapy, continuing anticoagulation may be indicated to prevent recurrence. Conversely, in those without ongoing risk factors, the risk of recurrent VTE is likely sufficiently low to justify stopping anticoagulation. Anticoagulation may be continued beyond 6 months if there is active malignancy and/or active, ongoing anti-neoplastic therapy. Results from a post-marketing study of extended treatment with dalteparin in patients with malignancy (DALTECAN) were recently reported. Of 334 patients, 109 (33 %) completed 12 months of dalteparin. Median treatment duration was 214 days. The highest major bleeding rate was in the first month of dalteparin therapy at 3.6 %, declining to 1.1 % during months 2–6, and 0.7 % over months 7–12 (p = 0.39 for months 2–6 vs. 7–12). The incidence of new or recurrent VTE was 11.1 %; again, highest for month 1 at 5.7 %, falling to 0.8 % per month for months 2–6 and 0.7 % per month for months 7–12. These data suggest that extended treatment is feasible and major bleeding is not a substantial concern; however, risk-benefit

ratio is unclear given relatively low rates of recurrent VTE past initial months of treatment. Given lack of randomized trial evidence, the best agent in this setting is unknown. Guidance Statements • Anticoagulation with LMWH monotherapy should be prescribed for a minimum period of 6 months after diagnosis of cancer-associated VTE. Anticoagulation therapy should be continued beyond 6 months if a patient has active malignancy (i.e. persistent malignant disease) or if ongoing anti-cancer therapy is planned. • For patients at low risk of recurrence we suggest that anticoagulation be discontinued after 6 months in the absence of active malignancy (i.e. patients are cured or in complete remission), provided that no anti-cancer therapy is ongoing or planned. • For patients at high risk of recurrence we suggest that anticoagulation be continued but with periodic re-evaluation of risks and benefits. (5) What is the appropriate treatment strategy in patients with recurrent VTE on anticoagulation? As noted earlier, recurrent VTE is not infrequent even in patients receiving appropriate anticoagulation in the setting of malignancy. Unfortunately, there are no randomized trials to provide an evidence-based approach. A recent paper and an ISTH guidance statement have described empiric approaches to this clinical problem [44, 45]. In general, LMWH monotherapy is considered the preferred approach. If patients are already on LMWH, dose escalation should be considered [44]. In a retrospective cohort study, the weight-adjusted dose of LMWH was increased by 20–25 % for at least 4 weeks. Patients on maintenance dose of LMWH were increased to full therapeutic dose for 6–12 weeks. Only 8.6 % of patients had a second recurrent VTE with this approach and 4.3 % had bleeding complications. Inferior vena cava (IVC) filters should only be used temporarily in patients with acute thrombosis who have absolute contraindications to anticoagulation. In a prospective randomized study of 200 patients (including 56 with cancer), patients who received filters had short-term protection from PE but higher rates of DVT and filter-site thrombosis compared to those randomized

to no filters (20.8 vs. 11.6 %, OR 1.87, 95 % CI 1.10–1.38). No short- or long-term survival benefit from IVC filter placement was seen. The potential risks of IVC filter placement are highlighted by non-randomized cohort studies that found IVC filters were associated with increased metastases and reduced survival in cancer patients[46]. Guidance Statements • We suggest that cancer patients with symptomatic recurrent VTE despite therapeutic anticoagulation with an agent other than LMWH be transitioned to therapeutic LMWH, assuming no contraindications to LMWH. • We suggest that cancer patients with symptomatic recurrent VTE despite optimal anticoagulation with LMWH continue with LMWH at a higher dose, starting at an increase of ~25 % of the current dose or resuming the therapeutic weight-adjusted dose if the patient was receiving a non-therapeutic dose at the time of recurrence.

The only an of VTE in a

• We suggest against the Abbreviated Prescribing I use of IVC filters except in 0.4 ml/10,000 IU in 0.5 ml/ 12 the presence of absolute in 0.8 ml/18,000 IU in 0.9 ml contraindications to syringes) and innohep® 20,00 Please refer to the full S pharmacologic anticoagulation before pre (e.g. active bleeding).(www.medicines.ie) If Indications: Treatment of ve necessary, retrievableincluding filtersdeep vein thrombosis should be used and atreatment plan of venous thromboe patients with active cancer. Fo created to retrieve the filter those with severe haemodyn when appropriate. surgery or thrombolysis, may b

Active ingredient: Tinzaparin s

Dosage VTE is an important cause of and administration anti-Xa IU/kg body weigh morbidity and mortality175 in anticoagulation patients oral is establis with malignancy. In thisactive chapter, cancer: 175 anti Xa IU/ treatment period of 6 months. T we have identified important beyond 6 months should be ev clinical questions and attempted of innohep (175 IU/kg) con discontinue to provide recommendations toinnohep at least 2 should not be resumed until at clinicians based on analysis of or after the catheter has been existing data, systematic reviews efficacy of innohep in children no posology and meta-analyses as well as recommendatio impairment suspected, assess consensus between authors creatinine to estimate creatini (Table 4). Many important CrCl issues level <30 ml/min not reco been remain to be addressed; in established. Available evi with CrCl levels down to 20 m particular, how best to enhance treatment can be initiated with appropriate utilization of outpatient risk. In this situation, the dose o on how anti-factor Xa activity. If the thromboprophylaxis and range, the dose of innohep sho to integrate the emerging classXa measurement sh anti-factor adjustment should be repeate of DOACs into prevention For guidance, mean levels betw and treatment of malignancy. volunteers and patients witho Considering the intense0.5scientific and 1.5 IU/anti-factor Xa I a chromogenic assay. Elde interest in this area thatbyhas recommended emerged in the past decade, we in the treatmen of administration: Inspect prod are cautiously optimistic that cloudinessthe or precipitate is obs is still suitable. Administer by S scientific community can continue outer side of the thigh, lower b to identify ways to enhance area around the navel, near s patient-centered care and reduce patient should be in supine po right the public health burden ofside. thisThe air-bubble withi injection, the skin should be he important and consequential in 1,000 IU increments facilitate complication of malignancy and calculated dose, based on the p up or down as appropriate. If ne its treatments.

Continuous Professional Development Modules are sponsored by LEO Pharma LEO Pharma has no editorial oversight of the CPD programmes included in these modules.

achieve the appropriate dosag Hypersens heparin-ind major haemorrhage or conditi as fulfilling any one of three c

Contraindications: References available on request. immune-mediated

References: 1. Petersen LJ et al


Up to 1 in 5 cancer patients will develop a VTE 1

Think cancer, think clots,

think innohep

®

Make innohep® the anticoagulant of choice for your cancer-associated thrombosis patients

Abbreviated Prescribing Information for innohep® 8,000 IU in 0.4 ml/10,000 IU in 0.5 ml/ 12,000 IU in 0.6 ml/14,000 IU in 0.7 ml/16,000 IU in 0.8 ml/18,000 IU in 0.9 ml, solution for injection (variable dose pre-filled syringes) and innohep® 20,000 IU/ml, solution for injection (vial) Please refer to the full Summary of Product Characteristics (SmPC) (www.medicines.ie) before prescribing. Indications: Treatment of venous thrombosis and thromboembolic disease including deep vein thrombosis and pulmonary embolus (PE) in adults. Extended treatment of venous thromboembolism and prevention of recurrences in adult patients with active cancer. For some patients with pulmonary embolism (e.g. those with severe haemodynamic instability) alternative treatment, such as surgery or thrombolysis, may be indicated. Active ingredient: Tinzaparin sodium 20,000 anti-Factor Xa IU/ml. Dosage and administration: Subcutaneous (SC) injection only. Adults: 175 anti-Xa IU/kg body weight once daily for at least 6 days and until adequate oral anticoagulation is established. Extended treatment in adult patients with active cancer: 175 anti Xa IU/kg body weight once daily for a recommended treatment period of 6 months. The benefit of continued anticoagulation treatment beyond 6 months should be evaluated. Neuraxial anaesthesia: Treatment doses of innohep (175 IU/kg) contraindicated. If neuraxial anaesthesia planned, discontinue innohep at least 24 hours before procedure is performed. innohep should not be resumed until at least 4-6 hours after the use of spinal anaesthesia or after the catheter has been removed. Paediatric population: The safety and efficacy of innohep in children below 18 years have not yet been established; no posology recommendations can be made. Renal impairment: If renal impairment suspected, assess renal function using a formula based on serum creatinine to estimate creatinine clearance (CrCl) level. Use in patients with a CrCl level <30 ml/min not recommended, as dosage in this population has not been established. Available evidence demonstrates no accumulation in patients with CrCl levels down to 20 ml/min. When required in these patients, innohep treatment can be initiated with anti-Xa monitoring, if the benefit outweighs the risk. In this situation, the dose of innohep should be adjusted, if necessary, based on anti-factor Xa activity. If the anti-factor Xa level is below or above the desired range, the dose of innohep should be increased or reduced respectively, and the anti-factor Xa measurement should be repeated after 3-4 new doses. This dose adjustment should be repeated until the desired anti-factor Xa level is achieved. For guidance, mean levels between 4 and 6 hours after administration in healthy volunteers and patients without severe renal insufficiency have been between 0.5 and 1.5 IU/anti-factor Xa IU/ml. Anti-factor Xa activity determinations were by a chromogenic assay. Elderly: Use innohep in standard doses. Precaution recommended in the treatment of elderly patients with renal impairment. Method of administration: Inspect product visually prior to administration. Do not use if cloudiness or precipitate is observed. The liquid may turn yellow by storage but is still suitable. Administer by SC injection; this can be done in abdominal skin, outer side of the thigh, lower back, upper leg or upper arm. Do not inject in the area around the navel, near scars or in wounds. For abdominal injections, the patient should be in supine position, alternating the injections between left and right side. The air-bubble within the syringe should not be removed. During the injection, the skin should be held in a fold. Syringes only: Doses are administered in 1,000 IU increments facilitated by the 0.05 ml graduations on the syringes. The calculated dose, based on the patient’s body weight, should therefore be rounded up or down as appropriate. If necessary, any excess volume should be expelled, to achieve the appropriate dosage before SC injection. Contraindications: Hypersensitivity to constituents. Current or history of immune-mediated heparin-induced thrombocytopenia (HIT) – type II. Active major haemorrhage or conditions predisposing to major haemorrhage, defined as fulfilling any one of three criteria: a) occurs in a critical area or organ (e.g. References: 1. Petersen LJ et al. Cancer Treatment Reviews 2009;35:754-764.

intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, intra-uterine or intramuscular with compartment syndrome), b) causes a fall in haemoglobin level of 20 g/L (1.24 mmol/L) or more, or c) leads to transfusion of 2 or more units of whole blood or red blood cells. Septic endocarditis. Treatment doses (175 IU/kg) contraindicated in patients who receive neuraxial anaesthesia. If neuraxial anaesthesia planned, discontinue innohep at least 24 hours before procedure performed. innohep should not be resumed until at least 4-6 hours after the use of spinal anaesthesia or after catheter has been removed. Monitor patients closely for signs and symptoms of neurological injury. Vial formulation contains 10 mg/ml benzyl alcohol and must not be given to premature babies and neonates. Precautions and warnings: Neuraxial anaesthesia: Patients undergoing epidural/ spinal anaesthesia or spinal puncture: Prophylactic use of heparin may be very rarely associated with epidural/spinal haematoma resulting in prolonged or permanent paralysis. Risk increased by use of epidural/spinal catheter, concomitant use of drugs affecting haemostasis and traumatic/repeated puncture. Extreme vigilance and frequent monitoring required. Haemorrhage: Caution in patients with increased risk of major haemorrhage. Intramuscular (IM) injections: Do not administer by IM injection; avoid concomitant IM injections due to risk of haematoma. HIT: Measure platelet counts before treatment and periodically thereafter (risk of immune-mediated Type II HIT). innohep must be discontinued in patients who develop immune-mediated Type II HIT. Platelet counts will usually normalise within 2 to 4 weeks after withdrawal of innohep. Regular monitoring of platelet count also applies to extended treatment for cancerassociated thrombosis, especially during the first month, considering that cancer and its treatments such as chemotherapy may also cause thrombocytopenia. Hyperkalaemia: Heparin can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, raised plasma potassium or taking potassiumsparing drugs, on long-term innohep. Measure plasma potassium in patients at risk before starting therapy; monitor regularly. Heparin-related hyperkalaemia usually reversible upon treatment discontinuation, although other approaches may need to be considered (e.g. decreasing potassium intake, discontinuing other drugs that may affect potassium balance). Prosthetic heart valves: Not recommended. No adequate studies therefore no dosage recommendations can be given. No adequate studies therefore no dosage recommendations can be given. Renal impairment: Use in patients with a CrCl level <30 ml/min not recommended, as dosage in this population not established. Available evidence demonstrates no accumulation in patients with CrCl levels down to 20 ml/min. When required in these patients, innohep treatment can be used cautiously with anti-Xa monitoring, if the benefit outweighs the risk. Although anti-Xa monitoring remains a poor predictor of haemorrhage risk, it is the most appropriate measure of the pharmacodynamic effects of innohep. Elderly: Caution advised as more likely to have reduced renal function. Interchangeability: Low molecular weight heparins (LMWHs) should not be used interchangeably. Switching to an alternative LMWH, especially during extended use, must be exercised with particular caution and specific dosing instructions for each proprietary product must be followed. Excipient warnings: Contains sodium metabisulfite (E223). Metabisulfites may rarely cause severe hypersensitivity reactions including bronchospasm. Use with caution in patients with asthma. Vial formulation contains benzyl alcohol which may cause toxic and anaphylactoid reactions in infants and children up to 3 years old. Drug interactions: Anticoagulant effect of innohep may be enhanced by other drugs affecting the coagulation system, such as those inhibiting platelet function, thrombolytic agents, vitamin K antagonists, activated protein C, small molecule anti-Xa and IIa inhibitors. Avoid or carefully monitor such combinations. Fertility, pregnancy and lactation: Pregnancy: Tinzaparin does not cross the

placenta. Can be used during all trimesters of pregnancy if clinically needed. Avoid use of vial formulation during pregnancy as it contains benzyl alcohol. Epidural anaesthesia: Treatment doses contraindicated due to risk of spinal haematoma. Delay epidural anaesthesia until at least 24 hours after last treatment dose of innohep due to risk of spinal haematoma. Prophylactic doses may be used as long as a minimum delay of 12 hours is allowed between last administration of innohep and needle or catheter placement. Use in pregnant women with prosthetic heart valves: Not recommended. Breast-feeding: Not known whether tinzaparin excreted into human milk. Although oral absorption of LMWHs is unlikely, risk to the breast-fed child cannot be excluded. In patients at risk, the incidence of VTE is particularly high during the first 6 weeks after child birth. Risk/benefit decision must be made whether to discontinue breast-feeding or to discontinue/abstain from innohep therapy. Fertility: No clinical studies. Side effects: Common: anaemia (incl. haemoglobin decreased), haemorrhage, haematoma, injection site reactions (incl. injection site haematoma, haemorrhage, pain, pruritus, nodule, erythema and extravasation). Uncommon: thrombocytopenia (type I) (incl. platelet count decreased), hypersensitivity, bruising, ecchymosis, purpura, hepatic enzyme increased (incl. increased transaminases, ALT, AST and GGT), dermatitis (incl. allergic dermatitis and bullous dermatitis), rash, pruritus. Rare: HIT (type II), thrombocytosis, anaphylactic reaction, hypoaldosteronism associated with hyperkalaemia and metabolic acidosis, toxic skin eruption (incl. Stevens-Johnson syndrome), skin necrosis, angioedema, urticaria, osteoporosis (in connection with long-term treatment), priapism. Patients with cancer on extended treatment: In a trial of patients with cancer on extended (6 months) treatment with innohep, the overall frequency of adverse events was comparable to that seen in other patients treated with innohep. Patients with cancer generally have an increased risk of haemorrhage, which is further influenced by older age, comorbidities, surgical interventions and concomitant medications. As expected, the incidence of haemorrhagic events was higher than previously observed in short-term use, and similar to the rates seen with extended use of anticoagulants in patients with cancer. Paediatric population: Limited information derived from one study and postmarketing data indicates that the pattern of adverse reactions in children and adolescents is comparable to that in adults. Legal category: Product subject to prescription. Marketing Authorisation Number and Holder: (syringes) innohep® 8,000 IU in 0.4 ml – PA 46/60/12, innohep® 10,000 IU in 0.5 ml – PA 46/60/10, innohep® 12,000 IU in 0.6 ml – PA 46/60/13, innohep® 14,000 IU in 0.7 ml – PA 46/60/11, innohep® 16,000 IU in 0.8 ml – PA 46/60/14, innohep® 18,000 IU in 0.9 ml – PA 46/60/4; (vial) innohep® 20,000 IU/ml – PA 46/60/3. LEO Laboratories Limited, Cashel Road, Dublin 12, Ireland. Last revised: November 2016 Further information can be found in the Summary of Product Characteristics or from: LEO Pharma, Cashel Road, Dublin 12, Ireland. email: medical-info.ie@leo-pharma.com Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.hpra.ie, E-mail: medsafety@hpra.ie Adverse events should also be reported to Drug Safety at LEO Pharma by calling +353 1 4908924 or e-mail medical-info.ie@leo-pharma.com ® Registered trademark

LEO® © LEO Pharma November 2016. IE/MAT-06219 v.1. All LEO trademarks mentioned belong to the LEO Group.

The only anticoagulant licensed for the treatment of VTE in all cancers


28 Feature

Models of Care for Epilepsy The key innovations of the Clinical Programme for Epilepsy include;

medicine and personalised care through a patient portal within the EPR;

The creation of a cohort of The development and registered advanced nurse implementation in 2 sites of the practitioners (RANPs) to Acute Seizure Integrated Care compliment the current Pathway (ICP). An audit of the medical expertise to help in the use of the ICP in one hospital chronic disease management demonstrated a reduction in THE NATIONAL CLINICA of epilepsy and to integrate it the admission rate from 45.9% with care in the community. when ICP wasnâ&#x20AC;&#x2122;t used, to This will provide timely access, 28.7% where it was used. intelligent support to general While a number of the practitioners, and outreach recommendations within the clinics in the community. It is Model of Care are currently anticipated that these services being addressed, full will reduce admissions The epilepsy care programme has a vision for the transformation of its epilepsy care in Irel implementation will see and length of stay in acute significant changes in the hospitals, both of which are The Epilepsy Programme has way epilepsy care is delivered key performance indicators three core aims; across the country. It will place To provide bestClinical value care for all people with epilepsy in the ri for thethe National community and hospital staff Programme for Epilepsy; the best available information - To improve place, at the right time, sharingworking together to support The development of the persons with Epilepsy in a care access to Epilepsy Electronic Patient setting appropriate to them Record. More than 6,500 expertBycare and and their needs. then a whole cohort of new experts in nursing will be helping to manage the require patients are now registered information The National Clinical centres when ne quality care in this chronic disorder will be centralized in epilepsy on Epilepsy EPR. Care 12 modules Programme for Epilepsy of functionality have been decentralized in a structured primary care programme where possible A sophisticated describes an integrated service developed to support delivery - To improve means of electronicofinformation management will be developed to become a defacto d which achieves positive epilepsy services. The outcomes for patients by within which the important evidence-based metrics underlying good clinical practice w Epilepsy EPR has also been the quality of enabling clinicians to work identified as a demonstrator delivering care at the emergency department interface will be pro careFront-line acrossphysiciansproject for the Individual Health together across boundaries integrated seizure care pathway thatthe will reduce admissions andsectors lengthtoofdeliver stay, whilst im Identifier through Office and different the healthcare of treatment CIO and is variability leading out Finally, on safe, safety by eliminating for theeffective 15% or and so ofperson very difficult to c development of precision spectrum fromepilepsythesurgery centred care. the national programme, will be enhanced and expanded over 2 sites

Key Messages of the Model of Care

The Model of Care sets out a vision for the transformation of epilepsy care in Ireland to provide the best patient centred care for all people with epilepsy in the right place, at the right time, sharing the best available information. This model of care is a blueprint for how Epilepsy services will be developed and continuously improved nationally. Epilepsy is a chronic disease characterised by unpredictable, sometimes lifelong, often dangerous seizures which result in involuntary alterations in behaviour and consciousness. The condition affects about one in every 100 people and is second only to stroke as the commonest chronic neurological disorder in Europe. Of the 40,000 sufferers in Ireland (10,000 of whom are under 16 years), only about 70% are well controlled on medication, leaving about 12-15,000 people who have breakthrough seizures, and are in regular contact with secondary and tertiary hospital services. There are 130 epilepsy deaths per year. Many patients with epilepsy suffer from mental health problems, and the condition has significant implications for social, vocational and occupational aspirations. January 2017 â&#x20AC;˘ HPN

prevention, class access to complex but potentially curative surgery through to The primary National Clinical Programme for Epilepsy describes an integrated service which ach managed outcomes for patients by enabling clinicians to work together across boundaries and di care todeliver complex Figure 1. Patient centred care across epilepsy services safe, effective and person centred care surgical care for difficult epilepsy Epilepsy - To improve value conscious care by shifting care where possible from expensive hospital cased care to the community.

Centre (RANP)

Primary Care/GP

Patient

Community Based Services

Fig 2; Patient centred care across epilepsy services

The benefits of such a service to patients include;

Acute Hospital Services


29 These care settings are grouped as follows; 1. Local level – this includes the patient’s GP, Primary Care Health and social care professionals and nurses, Community Rehabilitation Teams, the nearest Acute General Hospital and support provided by Epilepsy Ireland, the national advocacy service for people with epilepsy. 2. Group Epilepsy/Neurology Services – the hospitals with an epilepsy service (existing or proposed) collaborate to function as a Group Neurology Service, operating as a Clinical Network in each of the six Hospital Groups. These group centres will support hospitals within the group and Primary Care professionals in the management of patients with epilepsy in a planned and coordinated way. 3. National Tertiary Centres – in addition to the two neuroscience centres, Beaumont Hospital and Cork University Hospital, tertiary centres can be further developed across the service. Tertiary centres will generally have teams with sub specialism in some of the low volume / high complexity conditions within epilepsy. The focus of the acute care in epilepsy is to implement SOPs linked to evidence based guidelines around managing seizures outside of hospital (i.e. GP surgery or residential intellectual disability centre) in the ED/AMAU and on hospital wards (see proposed Integrated Care Pathway for

seizure management in the ED/AMAU - appendix 12.5). Each of the epilepsy centres will be led by a consultant neurologist with specific training in epilepsy care. This group/regional lead will be the responsible and accountable clinician for the delivery of the Epilepsy Programmes’ goals. The programme has been working with key stakeholders to define unambiguous guidelines for initial seizure management and subsequent referral onwards for specialist opinion follow-up. The programme will define best practice around existing international guidelines [30,31]. However, it is envisaged that Irish national evidence-based standards for specific aspects of care will be developed and submitted to the Irish National Clinical Effectiveness Committee for sanction (NCEC). Current utilisation of acute hospital care in epilepsy Studies in the last decade have shown that the majority of patients with epilepsy will be urgently admitted to secondary and tertiary care institutions (mostly through the Emergency Department) at some point in the history of their illness and a significant proportion will require multiple visits. Furthermore, symptomatic seizures secondary to acute medical or surgical illness, alcohol and drug intoxication, brain trauma and stroke add to the burden of seizure pathology presenting to all sectors of the Irish health system. Finally, a range of mimic disorders from psychogenic nonepileptic seizures (PNES), to blackouts caused by impaired vascular

responsiveness contribute to the diagnostic and therapeutic challenges. Despite the heavy burden of seizures in the Emergency Department, international studies suggest that the majority of patients are referred unnecessarily for admission to hospital and that the acute treatment of seizures is often ineffective and highly variable [ http://www.nashstudy.org. uk]. Furthermore, audits from Irish hospitals have shown that patients are often left as inpatients without specialist opinion and awaiting diagnostic tests. All of this evidence suggests that seizure admissions to hospitals are a cause of unnecessary medical intervention, variable care, delayed diagnosis and prolonged length of stay. In Ireland, composite data from the Hospital In-Patient Enquiry system (HIPE) revealed that in 2008 before the programme came into being, there were 6,982 discharges from acute Irish hospitals with a principal diagnosis of epilepsy; the total number of bed days used was 31,532 with an average (mean) length of stay (LOS) of 4.5 days (median 3.3 days) per discharge. The creation of a new model of care in Ireland using a seizure care pathway with early follow-up and prioritized diagnostics shows average length of stay has been reduced to 3.5 days by 2013 This demonstrates the massive efficiencies which can be achieved across acute hospitals. If the full economic rate (FER) of a bed day is costed at approximately ¤840 per night, in 2008, the admissions of 6,982 patients

cost the health service ¤26,391,960. In 2013 the admissions of an additional 941 patients i.e. 7923 cost the health service ¤23,293,620 demonstrating a significant gain in value to the service. Adults and children with epilepsy have an increased rate of mortality about 2-3 times that of the general population. This increase is highest in the first two to three years after diagnosis and generally related to the underlying cause of the disease. In those with longstanding refractoryepilepsy, increased mortality is related to epilepsy and is mainly due to Sudden Unexplained Death in Epilepsy (SUDEP), death due to complications of prolonged uncontrolled convulsive activity also known as Status Epilepticus (SE), and accidents and injuries related to unpredictable seizure activity. The National Sentinel Audit of Epilepsy Related Death in the UK found that epilepsy related death particularly SUDEP is underestimated by healthcare professionals. The audit demonstrated that 38% of deaths that were sudden and unwitnessed did not have a post mortem. They conclude that is difficult to estimate the number of epilepsy deaths from national data. Recent epidemiological data suggests that the biggest risk factor for SUDEP is uncontrolled seizure activity. The picture in Ireland is probably similar and therefore the figures given below are a conservative estimate of deaths related to SUDEP and SE in Ireland. In addition

Table 1: reduction in bed days achieved

Year

Discharges

Bed Days

AvLOS

Cost

2008

6982

31,532

4.5 days

26,391,960

2013

79231

27,974

3.5 days

23,293,620

2015

6009

27,372

3.4 days

22,992,480 # Average cost per discharge HPN • January 2017


30 Feature THE NATIONAL CLINICAL PROGRAMME FOR EPILEPSY Table 2. Morality figures from Irish Studies (Donohue et al 2013)

Epilepsy Prevalence estimates1

Estimated no of PWE 3

Rate of SUDEP cases / yr 2

Estimated no SUDEP cases /yr 3

Incidence & no of deaths from status epilepticus 4 based on 2010 Irish population

Estimated range of deaths per year from SE & SUDEP

8.3/1000 ≥ 5 years

34,171 PWE

0.6-1.3/1000 PWE

21-44 cases /year

Incidence; 706 cases

88-111

9.0/1000 ≥ 5 years

37,052 PWE

0.4-1.1/1000 PWE

15-41 cases /year

Deaths from SE; 67 deaths/year Incidence; 706 cases

82-108

Deaths from SE; 67 deaths/year

deaths to non-convulsive improvements seizure be a blueprint for epilepsy Tabledue 2. Morality figures from Irish Studiesin(Donohue et al will 2013) status epilepticus (NCSE) and control and standardized services and will ensure that accidents are not included in pathways for the treatment of the best value and most the status epilepticus in the ED. appropriate care is provided 1 figures Fromabove. Linehan et al 2010 for all." 2 from Based on work al 1998 at the event, Data Jawad and by Langan etSpeaking 3 Based 2010 has population estimates from wwwSimon cso ie colleagues in on Ireland Minister for Health Dr Áine Carroll, HSE National shown that in an elderly Harris, said, "The model of Director for Clinical Strategy 4 Based on work by Knake et al 2001 with incidence rate of 15 9/100,000 and Case Fatality Rate of hospitalized population, the care launched today takes and Programmes added, mortality from NCSE was 50% an integrated approach to “The success of the epilepsy over a five-year period. It is epilepsy healthcare. It spans programme is a real ‘good Models Care:and National and international evidence an1.5 aim Current of this programme to ofprimary acute settings and news story’ within the HSE reduce the number of lives lost reflects the varying needs of which shows that change is to epilepsy primarily through people with chronic disease. It possible. Not only changing

what we know, but changing what we do and how we do it. Seeing the shared care of patients across a number of care settings - outpatients, acute hospital, residential services, virtual encounters – 9encompass 3% for SE what integrated care should look like. It gives us hope that if change can be seen in this one area of practice, it can be replicated widely across the health service”

Responding to the challenge of maximising the benefits of medical advances for patients while minimising the burgeoning demand on healthcare systems, there is an international change in the chronic conditions like epilepsy are managed Chronic disease management (CDM) aim to Key Health Trends in Ireland 2016 move from episodic reactive health care delivery to one that prevents the occurrence of disease, and improves the of life ofthrough those whocare alreadyimprovement have a chronic illness by1,000 averting orhas delaying The Department of Health andquality health status to health in survival rates population increased Children has published the ninth delivery, staffing and costs. significantly over the period from breast and colorectal further deterioration focus of chronic disease management is on edition of ‘Health in Ireland, Key [12] In the case of epilepsy, thecancer 2006 to 2015, while the number in the last 15 years. Key trends include: Trends 2016’, a reference guide to of in-patient discharges per However, 5-year relative survival seizure management and health promotion significant trends in health 1,000 population has remained • Total hospital discharges rates from breast and cervical and health care over the internationally, past stable. continue to rise with 62.1% of of practice cancers arein lower in Ireland than Nationally and effective models epilepsy includerelatively the following decade, including population and this activity now carried out the average for OECD countries • In terms of elective procedures health status, as well as trends in components; on a day case basis (including where data is available. The for adults waiting more than service provision. dialysis). There has been a survival rate in Ireland for 8 months there has been an Epilepsy Nurse Specialists 55.0% increase in the number of colorectal cancer is slightly lower increase in the numbers waiting Health in Ireland, Key Trends 2016 day cases seen in public acute than the OECD average. over the period December 2015 provides summary statistics on Supported Self-Management hospitals since 2006. Improved to October 2016, with a slight health and health care over the • While there has been a reduction and lessCare invasive medical past It also highlights decrease in November 2016. For - ten years. Integration with Primary in the mortality rate from practice is largely responsible selected trends and topics and children waiting more than 20 respiratory diseases (including for the rapid growth in day Effective Clinical Information Systems includes new data which has weeks the number waiting for cancer of the trachea, bronchus patient activity. become available during the elective procedures increased and lung) of almost 3.6% since Supporting evidence the of above are in detail in the following sections including course of the year. An important for• all throughout the year. Theof number live births hasdescribed 2010 the rate in Ireland is 40.3% objective is to assess ourselves falling year-on-year since 2009 than the EU28 average. reference to how these could be adapted to the Irishhigher Health Service • The total number of people on and our progress in the broader and in 2015 the number of EU context. In this regard, several tables and graphs are presented comparing Ireland with the 28 Member States of the EU.

registered births was 65,909. Despite reductions in the numbers of births in recent years, the fertility rate in Ireland remains the 2nd highest in the EU behind France.

• From 2006 to 2014 the average length of stay decreased by 12.1%. In 2015 there was a slight increase in length of stay of 2.2%.

outpatient waiting lists increased in the period December 2015 to August 2016, with the number increasing at a slower pace from August 2016 to November 2016. The number of people waiting longer than 52 weeks increased throughout the year.

1.5.1 A nurse led model of care A Cochrane review of models of epilepsy care found strong evidence for positive outcomes by the The booklet is divided into • The number of day strategies case sixinvolvement chapters ranging across of epilepsy nurse specialists and self-management alone [26] Outcomes population, life expectancy and • There has been significant discharges in acute hospitals per measured included morbidity, mortality, seizure freedom, quality of life and knowledge of epilepsy and 2017 its treatment Epilepsy Nurse Specialists (ENS) have become an integral part of the epilepsy January • HPN


Feature 31

Improving Services for General Paediatric Surgery This article aims to set standards for comprehensive, quality non-specialist paediatric surgery (GPS) that is accessible to children and young people in the Republic of Ireland, and to make recommendations as to how improvements in the provision of the service can be achieved. The following informed the analysis of general paediatric surgery in this document:  Data presented at the Royal College of Surgeons in Ireland (RCSI) Millin Symposium (November 2008)  Review of Paediatric and Neonatal Services and Framework for Future Development (2013), National Clinical Programme for Paediatrics and Neonatology  Input from the National Clinical Programme for Surgery  Review of Hospital Inpatient Enquiry (HIPE) 2011 data - all of the HIPE analysis in this document is based on 2011 information. Currently 21 (47%) acute hospitals perform elective and or acute general paediatric surgery, with three (7%) providing elective day case surgery only for children over 5 years of age. Conditions that require general paediatric surgery are relatively common and do not require being undertaken in a specialist paediatric surgical unit. The most common acute procedures are laparoscopic or open appendicectomy, wound repair and abscess drainage. Most acute presentations are in older children (over 5 years of age) and are being managed by general surgeons who do not have specific general paediatric training (Ensuring the Provision of General Paediatric Surgery in the District General Hospital, Royal College of Surgeons of England 2010). The most common elective conditions are circumcision, resection of toenail, excision of lesion and orchidopexy. Medical circumcision has previously been a common procedure and is rarely indicated before 5 years of age. The only

emergency conditions treated that are time critical are testicular torsion and trauma. Children and young people under the age of 16 years account for 25% of the population (CSO, 2011). They require access to routine surgical and anaesthetic care at a location that is easily accessible to them and their family, and that meets the appropriate standards. The National Clinical Programme for Surgery (NCPS) undertook a detailed general paediatric surgery work load analysis of the HIPE data for 2011 with the objective of:

country providing care by local areas, whether they are: > Tertiary Centres > Regional Paediatric Surgical Facilities > Local Paediatric Surgical Facilities The NCPS analysis has divided the country, so that all children have local access for, at least, the most straightforward procedures as defined in the basket of cases in the Model of Care (http://www.hse.ie/eng/about/ Who/clinical/natclinprog/ paediatricsandneonatology/ Improvingstandardsforgeneral paediatricsurgery.pdf)

possible and have access to the appropriate level of care, with high quality resources delivered by the right staff with appropriate skills. The establishment of hospital groups is intended to permit greater autonomy for providers of hospital care and to allow hospitals to be more responsive to local needs. The Establishment of Hospital Groups as a transition to Independent Hospital Trusts Report (2013) states that “It is also acknowledged that inter-group working is as vital as the rationalisation of services within groups”.

Currently 21 (47%) acute hospitals perform elective and or acute general paediatric surgery, with three (7%) providing elective day case surgery only for children over 5 years of age. Conditions that The Paediatric Surgery Group require general paediatric surgery are relatively common and do not require being undertaken in a fully subscribes to the HIQA 1. Looking at the distribution of specialist paediatric surgicalpaediatric unit. The most common acute procedures are laparoscopic or open National Standards for Safer general surgery work Better Healthcare (2012) and by hospital group (as defined by appendicectomy, wound repair and abscess drainage. Most acute presentations are in older children its eight domains which include the report The Establishment of Networks for General person specific centred care; leadership; Hospital Groups as a Transition (over 5 years of age) and are being managed by general surgeons who do not have general Paediatric Surgery governance and management; to Independent Hospital Trusts paediatric training (Ensuring the Provision of General Paediatric Surgery in the effective District General care; safe care; the (2013) The use of clinical networks would promotion of better health and Hospital, Royal College of2.Surgeons of England 2010). The most common elective conditions are ensure an integrated approach for The distribution of general wellbeing by such methods as A network approach paediatric surgery workof lesion GPS accidents and acute circumcision, resection of toenail, excision andservices. orchidopexy. Medical preventing circumcision has will ensure that children are safely independent of hospital groups surgical illnesses; a workforce previously been a commonbut procedure and is the rarely indicated before age. The only treated as close to home5asyears of that is carefully planned, managed by distribution across emergency conditions treated that are time critical are testicular torsion and trauma.

Table1

Table 1 Provision of General Paediatric Number of Hospitals Surgery Elective and Acute GPS* 18 Elective Day Case GPS Only 3 No Elective or Acute GPS 24 TOTAL 45 *excludes three Dublin children’s hospitals

Percentage of Acute Hospitals 40% 7% 53% 100%

Children and young people under the age of 16 years account for 25% of the population (CSO, 2011). HPN • January 2017 They require access to routine surgical and anaesthetic care at a location that is easily accessible to


32 Feature and supported; an awareness and judicious use of resources whether they are human, financial or natural; and a service that is planned and executed based on quality information that is accurate, valid, timely, reliable, relevant, legible and complete recognising that this must be centrally supported and resourced. Governance Structures In hospitals that provide GPS for children there must be a commitment from the hospital group board and executive team that a high quality and resourced service is provided. Robust governance is critical with the identification of a lead / designated surgeon and anaesthetist in general paediatric surgery in any unit that accepts paediatric patients. Such units need to engage in audit /outcome multidisciplinary meetings held on a regular (monthly) basis and submit data into a national paediatric audit that includes local surgical facilities, regional surgical facilities and the tertiary paediatric hospitals. Surgeons must undertake a sufficient volume of GPS to maintain skills and competence. This is defined as the equivalent of at least one GPS list per month or ideally one per fortnight. Children need to be protected from harm during their medical care. Children and their parents should be involved in the process and be given the opportunity to feedback their observations and experiences of the services provided. Training Requirements and Implications Presently only a small minority of the surgical consultants currently working in the regional centres and local hospitals in Ireland have received formal paediatric surgical experience as part of their surgical training. However, when they retire they may be replaced by surgeons with no paediatric training, as paediatric surgical experience is not a requirement for general surgical training in Ireland (Grace et al., 2010). There may be difficulty in the future in providing GPS for children due to these training and recruitment issues. Training options required to meet service needs are: a. Proleptic training of 6 months attached to a Consultant Paediatric Surgeon

January 2017 • HPN

Or b. Six months training in tertiary paediatric surgery at registrar level Or c. Equivalent training abroad Or d. 12 months training in a RPSF In the consultants appointments process, due consideration must be given to the appointment of a surgeon with paediatric skills whenever an appointment is made of a consultant general surgeon in a hospital offering regional paediatric surgical services. Features of Regional Paediatric Surgical Facilities (RPSF) Designated RPSFs should be established based on the following standards:  24-hour anaesthetic, surgical and nursing services for children available 7 days a week. At times an RPSF may not have all the necessary staff to fulfil this role (e.g. due to leave etc.), and in those circumstances referral to the tertiary centre or another RPSF is appropriate.  Appropriate paediatric radiology and consultant paediatrician support.  Sufficient volume to generate at least one elective paediatric list per week.  Child and adult lists should be separated with children prioritised to the morning.  Close links with the tertiary paediatric surgeons.

 Managed care plans should be in place in order to refer complex cases to tertiary paediatric centres.  All acute surgery for children under two years of age should be admitted under the combined care of a designated surgeon and paediatrician. Ideally, most elective procedures should be performed as day cases with inpatient stay only if clinically indicated. Preterm or ex-preterm infants should not be considered for day case surgery unless they are medically fit and have reached at least 60 weeks post conceptual age. Infants with chronic lung disease or a history of apnoea should only be managed in tertiary units with facilities equipped for post-operative ventilation. Children, who require observation, should be admitted to the local inpatient paediatric unit. While local arrangements may vary between hospitals, all units must ensure that paediatricians in such hospitals are available for consultation in the management of children with surgical emergencies. Each unit should have agreed written protocols for management of children with possible surgical emergencies, ensuring clarity of responsibility if a child is transferring between the care of a surgeon and paediatrician. If it is determined that a child needs surgery, or is likely to need surgery, the following should apply: All children who require acute general paediatric surgery who have not reached their second birthday should be transferred for surgery to a RPSF or tertiary paediatric hospital unless:

 The ability to operate on a child under 12 months of age.

 The child’s condition is time critical e.g. testicular torsion, trauma

 On site in patient paediatric medical units.

OR

 Paediatric trained nursing staff.  Anaesthetists assisted by dedicated staff (assistants and anaesthetic nurses) with specific competencies.  A child and youth -friendly environment.  Peer review of practice and outcomes.  Child protection and appropriate staff training for same.

 The designated Consultant General Surgeon for GPS is competent to perform the operation within a time period appropriate to the child’s clinical condition. Staff with the appropriate anaesthetic and nursing competencies is also required. Day Case Surgery Hospitals (RPSFs, LPSFs and designated model 2 hospitals) should meet the following

standards in order to provide day case surgery for children:  The surgery should be undertaken by a surgeon experienced in the condition  A member of the surgical team must remain in the hospital until arrangements have been made for the discharge of all patients or, if necessary, a patient has been transferred to another unit for whatever reason  At least one member of the team involved in the treatment of day cases should hold the APLS/ PALS certificate and the other team members must have upto-date basic skills in paediatric resuscitation  While the child is in the unit at least one member of staff with up-to-date skills in basic paediatric life support should be present  Agreed and robust arrangements should be in place for paediatric assistance and transfer if necessary  Parents and carers should receive clear instructions on follow-up with written information on arrangements to deal with a post-operative emergency, including out of hours telephone numbers  Surgical day units must be staffed by nurses with competencies in the care of children  Units must develop and implement a pain management policy including advice on pain assessment and management at home and the provision of ‘take-home’ analgesia with clear instructions for its use  Play specialists should be available and the environment should be child and family friendly  Day case activity should be audited and regularly reviewed  Peer review of practice and outcomes should be undertaken  There is a clear protocol for contact with Paediatric Intensive Care Units (PICUs) and paediatric surgeons in the tertiary children’s hospitals to arrange transfer of patients should complications arise (PICU contact: 1890 213213 for advice and or referral www.picu.ie)


paediatric surgery will require additional paediatric surgeons in the tertiary paediatric c undertake outreach. Surgeons undertaking GPS in the RPSF can also provide an outreach s 33 for LPSF within their hospital group or network. Opportunities should also be available and anaesthetists to upskill in the children’s hospitals.  Anaesthesia services for children require specially trained clinical staff together with equipment, facilities and an environment appropriate to the needs of children.

Outreach Model for General Paediatric Surgery

Arrangements for Transfer The final decision on the need to transfer should be taken by a consultant in the local unit in consultation with the consultant anaesthetist. Typically this will be a consultant in general surgery or emergency medicine and depending on the circumstances, with input from a paediatrician  The consultant in the local unit should contact the on-call consultant paediatric surgeon in the RPSF or tertiary unit to discuss the case and arrange transfer  The child's parents must be involved in the decision and be given a clear explanation of the reasons for transfer  The ambulance service should be alerted to the possibility of transfer at as early a stage as possible  Each hospital should have a protocol for transfer of children which should be consistent with the recommended pathways for emergency GPS outlined in this policy and the Emergency Admission Decision Framework for paediatric patients. Outreach As with other paediatric tertiary specialties (e.g. cardiology, cleft, neurosurgery) it is expected that the paediatric surgeons in tertiary centres will undertake outreach clinics and theatre lists to RPSF hospitals. They will provide training/support to staff in these hospitals. The service would be undertaken by paediatric surgeons travelling for a full day once a month or once every 2-3 months to the outreach RPSF hospitals. The provision of an effective hub and spoke model for general paediatric surgery will require additional paediatric surgeons in the tertiary paediatric centres to undertake outreach. Surgeons undertaking GPS in the RPSF can also provide an outreach service to LPSF within their hospital group or network. Opportunities should also be available for surgeons and anaesthetists to upskill in the children’s hospitals.

Outreach Modelby for General Paediatric Surgery competent, trained staff in a anaesthetise and manage elective

Anaesthetic Services

Paediatric anaesthesia services in Ireland should be provided

safe working environment with adequate and appropriate facilities, drugs and equipment to safely

and acute paediatric surgery (see Paediatric Anaesthesia Model of Care, 2015).

Core Recommendations 1. Hospitals that provide GPS services should adopt the policies and standards as set out in this document. 2. All major neonatal and complex paediatric surgery should be performed in the tertiary paediatric surgery units. 3. Specific transfer guidelines must be in place to facilitate safe transfer in the event of an unexpected complication. Stabilisation prior to transfer is critical. Senior clinicians should be closely involved in pre transfer stabilisation. 4. GPS can be performed in tertiary, regional and local paediatric surgical facilities or within designated model 2 hospitals. 5. To achieve RPSF status, hospitals must have the capacity to provide 24-hour anaesthetic, surgical and nursing services to children 7 days a week. 6. At times an RPSF may not have all the necessary staff to fulfil this role (e.g. due to leave, etc.) and in those circumstances referral to the tertiary centre or another RPSF is appropriate. 7. A LPSF is a hospital that provides general paediatric surgery (case bundle as defined) largely on an elective basis. 8. Clear transfer pathways should exist between local, regional and tertiary facilities. 9.

RPSF Hospitals must identify paediatric surgical needs when appointing general surgeons and such appointments must always be linked and highlighted by the Consultant Appointments Committee. Designated lead surgeons and anaesthetists in GPS should be identified locally within hospital groups and must conduct regular multidisciplinary meetings with analysis and review of surgical outcomes.

10. General paediatric surgical training can be undertaken in a tertiary paediatric hospital, an RPSF, or as an appropriate proleptic appointment or an equivalent training abroad. 11. The provision of an effective hub and spoke model for general paediatric surgery will require additional paediatric surgeons in the tertiary paediatric centres to undertake outreach and in-reach sessions.

HPN • January 2017


34 Feature

From euphoria to despair The two faces of Bipolar Disorder Bipolar Disorder is a serious mental disorder that affects approximately 1-2% of Irish people. Bipolar Disorder is not restricted to any particular sex, race, or socio-economic class doctors, lawyers, teachers and taxi drivers may all be sufferers. Despite its seriousness, the illness is treatable, and with proper treatment and care the prognosis can be quite good.

Professor Patricia Casey, Consultant Psychiatrist, Mater Hospital and UCD Lecturer

Left untreated or undiagnosed however, the outcome is far poorer; there is a 15-17% mortality rate overall for the illness (up to 20 times that of the general population), with at least 25-50% of sufferers attempting suicide at some stage in their lives. What is Bipolar Disorder? Bipolar Disorder is primarily a genetic disorder that affects mood and mood regulation. Common symptoms are: depression, anxiety, suicidality and motor retardation through to excitability, elation, mania and psychosis. The phases of the illness i.e. depression to elation may manifest themselves weeks, months or even years apart. There are two main subtypes of the illness: Bipolar I and Bipolar II. While both have similar traits, Bipolar I is more serious – the true diagnosis of - Manic Depression and is marked by at least one episode of mania, a term used to describe extreme mood elevation, running into psychosis. Bipolar II has similar symptoms, but the elevated mood seen by this subtype is classified as ‘hypomania’, a much less severe or disruptive form. As Patricia Casey, Professor of Psychiatry at UCD and consultant psychiatrist, Mater Hospital, Dublin explains, “Bipolar I is where the person has full-blown mania. They’re very over-active, very over-talkative or very aggressive. They also get delusions; they may be deluded that they’re God or the queen, or a celebrity, or they may have suspicions that someone’s trying to harm them, or is talking about January 2017 • HPN

them or watching them. So there are psychotic symptoms present. In Bipolar II you get what’s called hypomania, which is a milder form of mania. Delusions aren’t present and people aren’t quite so overactive. They may still be overactive and their thoughts may still be racing but it’s much less than with bipolar I, the fullblown syndrome when psychotic symptoms are present.” What are the causes? As stated, bipolar disorder is a genetic illness; sufferers will likely have a relative who either suffers from the illness or another major depressive disorder. Further, between 15-30% of children of one bipolar parent are likely to develop the illness themselves. Professor Casey says, “We know

that genetic factors play a part, but quite how big a part, we don’t know. if there’s a family history of depression, that may increase the risk of bipolar disorder in firstdegree relatives, so there seems to be some kind of genetic link . But if a close family member has bipolar disorder, there’s absolutely no certainty that their children will get it, so it’s not a one-to-one link. There is a general predisposition and there’s an increased risk, but exactly what genes are involved, we don’t know. “Often the illness presents itself with a depressive episode, but you can’t actually make the diagnosis until the person has had a manic episode. So a person may present themselves with several episodes of depression first. The manic or depressive episode may come out of the blue, or it might be triggered

by substance abuse, for example with cannabis, amphetamines or some such substance, or by a traumatic event. “It’s only in recent years that we’ve discovered that there may be a link between childhood sexual abuse and Bipolar Disorder. How strong the linkage is, we don’t know, but from recent research, there certainly would appear to be a link.” What are the treatments? The treatment of choice for Bipolar Disorder is Lithium Carbonate, a commonly-occurring salt that was shown in the 1950s to have a sedative, or mood-stabilizing effect on patients. Anticonvulsants, antipsychotics and anti-depressants are also used to varying degrees of success. ECT (ElectroConvulsive Therapy) is also used


35 to a lesser extent for manic or severely depressed patients. Psychotherapy also plays a role in the form of Cognitive Therapy, Cognitive Behavioural Therapy (CBT) and counselling, though only in a supportive role. What about prognosis? Most sufferers of Bipolar Disorder, with proper treatment and care, go on to live relatively normal and successful lives. Hospitalizations are an unfortunate reality and are said to increase in likelihood with each admission, but can be minimised by adhering to professional advice. As Professor Casey says, “Treated, people can achieve complete stabilisation and can get on with their lives normally; untreated, the period between episodes reduces and the episodes last longer, and if treatment is then instigated they become more difficult to treat than if they had been treated earlier. So the prognosis isn’t good for those who are untreated – the episodes just keep recurring. There is also the risk of suicide for those who are untreated and possible health problems arising from risk-taking during the manic phase.” How can family & friends help? Family and friends can help by offering non-judgemental support, by being educated on the illness itself and by seeking professional advice if needed. Bipolar Disorder can be debilitating, so sometimes just having someone there offering emotional support can help: “If someone believes that a member of the family has a mental health problem, they should firstly encourage them to get help. They should also encourage the family member to adhere to treatment. If someone with bipolar disorder stops medication, they will relapse, as sure as night follows day. When that happens it becomes more difficult to treat next time around. “They should also encourage their loved one to link up with organisations like AWARE, which was set up specifically for people suffering with bipolar disorder, and provides up to the minute information about research, how to cope and practical things that can be done.” Symptoms “In a nutshell, with bipolar you can get the two extremes: when you’re unwell you get the highs, which are unpleasant, and the lows, which are also unpleasant,” says Dr Stephen Murphy, of The Park Clinic Medical Centre, Cabinteely.

“The lows are like a depressive illness. The mania end, is where people become psychotic and they have thoughts which possibly taken one at a time might seem reasonable, but there is no logic to them. They’re not realistic ideas, and the patients often become frustrated and irritated because people won’t follow what they’re trying to do. Sometimes they spend a lot of money, they can become sexually disinhibited, make rash decisions about where they live or their jobs or who they’ll be friendly with.” “They will often pursue risky sports or adventures. They’re also disinhibited with regard to their alcohol intake, and may experiment with illegal drugs. Occasionally they may also get some of the more commonly known psychotic systems, like hallucinations, both auditory and visual. And of course, one of the difficulties is that if they’re on medication, they may decide that don’t need that medication anymore.” “And then there’s the selfimportance, the seemingly limitless energy, and the lack of sleep. If you’re listening to a patient and you say to yourself ‘oh I must pay attention’, that’s usually a hint that you’re talking to someone who’s manic, because there’s no logic to their speech pattern.” Bipolar Disorder Lighthouse Project The Lighthouse Projects were launched with a specific focus to build an understanding of the benefits of an Electronic Health Record in the Irish healthcare system, with specific improvements in service delivery in 2016. These projects are also intended to enable learning within the system. The Bipolar Lighthouse project is unique to the other two projects as there is nothing currently in the space. It builds on the insights gained from the 4theHealthIreland Ecosystem meeting on March 1st 2016 which brought together stakeholders including service users, clinicians, academics and industry professionals. The specific feedback on the bipolar disorder lighthouse is available here. It is noted that a theme that emerged was that the issues relating to bipolar disorder and an EHR are those which face mental health practice in general; it is not proposed that there be a “bipolar EHR” different from other areas of mental health. However, it was also felt that for the purpose of the Lighthouse Project, bipolar

disorder was appropriate as it affects a clinically well defined population and interventions such as Early Warning Signs recognition have an evidence base. The Goal

include sleep diary, overall mood diary, activity scheduling, possible log of purchases (to monitor overspending). A means of contacting service proffessionals via patient portal.

A connected health approach to achieving and maintaining recovery in users of mental health services with a bipolar disorder. This will use technology to enable self-management and the detection of early warning signs of relapse, thus empowering the patient and easing contact with service providers. A patient portal will allow access to a care plan for service users and service providers, and allow the service user to monitor symptoms. This patient portal / mobile enabled solution that will be futureproofed and integrated into future Electronic Health Record with the Individual Health Identifier an integral feature of the project.

Mobile Accessible Via an App. The patient will be able to access patient portal and care plans from an app on their mobile.

Initial Users

Access to care plan for service user and service provider the aim to reduce unnecessary admission time for the patient and to ensure crises do not excessively disrupt the patients lives.

These will include patients with diagnosis of bipolar affective disorder and mental health professionals (including community psychiatric nurses; home based treatment team nurses; psychiatrists). The Structure wil include: Elements of the future Electronic Health Record by using the Individual Health Identifier. Record of the previous logins so service user can see who is accessing care plan. Patient portal which will allow access to care plan. Early Warning Sign monitoring. This will be personalised and will vary from person to person. It may

Health Care Professional Portal. The access to care plan can be accessed, with opt in consent of service user, by their healthcare professional to allow them to view the self-monitoring overview. The benefits include: Supporting the recovery model of mental health with an emphasis on strengths and developing personal resources Considerable evidence for benefits of early warning sign.

eHealth Ireland would like to create an EHR that will enable patients to have mobile access to record their medicinal compliance and quality of life. This will allow patients and clinicians to monitor and assess their condition for digital intervention. The development of a secure clinical communicator would allow patients and clinicians access to a support tool that could be used 24 hours a day as and when needed. This information could be analysed to provide important individualized treatment to patients and the population as a whole. HPN • January 2017


36 Clinical

Study opens in Ireland to investigate pregnancy after breast cancer PhD student Naoise Synnott

hopes that the drug, APR-246, can prevent the growth of triplenegative breast cancer cells. Each year, more than 250 people are diagnosed with triplenegative breast cancer. It is often aggressive, difficult to treat, and tends to be more common in younger women. The subtype accounts for approximately one in six breast cancer cases globally. Researchers from Breast-Predict, an Irish Cancer Society Collaborative Cancer Research Centre, have shown APR-246 can prevent the growth of triple-negative breast cancer cells.

An international cancer study has opened in Ireland to investigate the risks for young women who had breast cancer and attempt to get pregnant. Young women who have cancer can require ongoing hormone treatment for 5-10 years. This treatment prevents conception. The study will examine the risk of breast cancer returning among young women who interrupt their treatment for up to two years to attempt pregnancy. Internationally over 500 patients who had breast cancer will take part in the study. Cancer Trials Ireland is co-ordinating the study in Ireland which will involve 30 patients from Dublin, Cork, Limerick, Waterford and Galway. Dr Cathy Kelly, Consultant Medical Oncologist at The Mater Misericordiae University Hospital is leading the study in Ireland. She said that it was a highly significant study as it involved a consortium of 50 dedicated investigators from 19 countries around the world and was investigating an area of increasing concern for young women. “About 15% of women are diagnosed with breast cancer during their reproductive years,” she said. “Over the past few decades women have tended to delay having children for a variety of personal reason. As a result, for an increasing number of young women, they can get breast cancer before they have completed their plans for a family. January 2017 • HPN

“The best available evidence, based on reviewing records retrospectively, suggests that in certain instances pregnancy after breast cancer does not negatively impact disease outcome and is safe for the baby. “But we really need to have real time scientific evidence to confirm this and this study will give us that evidence. Hopefully it will be invaluable for future generations of women in this situation,” she said. Participants in the study have to be 42 years old or younger, have had early stage breast cancer, completed 18-30 months of hormone treatment and want to have a baby. Participants will interrupt their treatment for a maximum of 2 years during which time they will try to get pregnant. Participants will be carefully followed for at least 10 years after enrolling in the trial. Hospitals in Ireland participating in the trials include the Mater Misericordiae University Hopsital, Mater Private Hospital, St Vincent’s University Hospital, St James’s Hospital, University Hospital Galway, University Hospital Limerick, University Hospital Waterford and Cork University Hospital. The majority of young women with early breast cancer have hormonesensitive, or oestrogen receptorpositive (ER+) disease, meaning the cancer cells are fed by their own hormones. To reduce risks of the cancer returning, these women are treated with endocrine therapy that blocks the natural production of these hormones. Endocrine therapy may be prescribed for 5 to

10 years and impacts the ovaries, preventing conception. This study will evaluate whether it is safe for women who had hormone-sensitive breast cancer to interrupt their ongoing endocrine therapy for up to 2 years to attempt pregnancy without increasing their risk of a breast cancer relapse. The study will also provide the unique opportunity to collect precise information on pregnancy and offspring outcome after breast cancer. After making sure the woman meets the scientific criteria of the trial, and having confirmed their wish to participate in and understanding of the trial, there are several steps involved, including: Step 1: A three-month break in treatment before attempting conception Step 2: Up to a two-year treatment pause to allow for potential conception, delivery and breastfeeding Step 3: Treatment resumption and completion of full duration of endocrine therapy Enrolment will be over a period of 4 years and the study will take approximately 14 years to be completed. Cancer Trials Ireland is supported by the Health Research Board and the Irish Cancer Society. Meanwhile, a research team based in St Vincent’s University Hospital and University College Dublin believe they may have developed a drug to treat a deadly form of breast cancer. The team

The findings have been published in the International Journal of Cancer. The research was carried out by PhD student Naoise Synnott, under the supervision of Professor Joe Duffy and Professor John Crown. It involved laboratory tests in combination with current chemotherapy treatments and was funded by Breast-Predict and the Clinical Cancer Research Trust. It is now hoped that the drug will prove successful in clinical trials. Ms Synott sais, “At the moment the only form of drug treatment available to patients with triple-negative breast cancer is chemotherapy. “While this will work well for some patients, others may find that their cancer cells don’t respond as well as might be hoped to chemo, leading to patients suffering the side effects of this treatment without any of the desired outcomes.” Head of research at the Irish Cancer Society, Dr Robert O’Connor, hailed the development as a significant milestone in the ongoing work of Breast-Predict. “These research programmes focus on finding new ways to prevent as many cancers as we can, ensuring the most advanced personalised treatment options are available and that as many patients as possible thrive after treatment,” he said. “The number of people with cancer in Ireland is expected to double by 2040, and more research is vital if to tackle this growing epidemic of cancer.”


News 37

UL Hospitals introduces Electronic Health Record The opening of the new Emergency Department (ED) at University Hospital Limerick in May 2017 will represent a step closer following a significant upgrade to software systems in the department. With in excess of 60,000 presentations a year, the ED in Limerick is one of the busiest in the country. The systems upgrade will allow the Department to better manage increasing demand and has built in additional functionality that will better track patient journeys through the new clinical environment and collect data in real time. The new IMS MAXIMS system is functionally rich, easy to use, fully integrated into other hospital systems and has a comprehensive suite of reporting and analytical tools, allowing consultants and their teams the capability to maximise the operation of the ED. Effectively introducing an electronic healthcare record for unscheduled care in UHL, the system went live over the weekend with no disruption to patient care. According to Dr Damien Ryan, Consultant in Emergency Medicine, UL Hospitals Group, “The installation of the latest version of IMS MAXIMS will allow staff in the ED to have a modern, reliable information system which will allow us to capture more information about attendance patterns, patient flow and outcome. This system has the capability of allowing us in time to move to a paperless environment

thus future-proofing our ICT infrastructure for years to come.” Brian McKeon, Director of Informatics, Planning and Performance, UL Hospitals Group, added, “The new IMS Maxims ED system continues our journey towards fully digital care for the people of the Mid-West and throughout Ireland. It is integrated with our own group-wide patient management system, which has one identifier for all acute patients in the region. Our previous legacy system was unstable and had limited clinical data, but this new system will allow us to analyse real-time ED data through our cloud-based Business Intelligence platform. “The Medicine Directorate and eHealth Division staff here in the UL Hospitals Group have worked tirelessly to deliver this system in 2016. Always in the background, these talented and dedicated people are transforming the way we care for our patients into the future,” Richard Corbridge, Chief Information Officer, Health Service Executive, said, “This weekend the Emergency Department at University Hospital Limerick went live with a digital system that enables a step change in the way information can be used to deliver care in emergency situations. The new system enables real time information to support the management of patient flow and delivers bed side clinical information to staff, enabling safer more efficient care to be delivered.

Noreen Spillane, Chief Operations Officer, UL Hospitals Group; Paul Matthews, Project Manager, IMS MAXIMS; Dr Damien Ryan, Consultant in Emergency Medicine, UL Hospitals Group and Brian McKeon, Director of Informatics, Planning and Performance, UL Hospitals Group

The project is a great achievement, and a huge credit to the local and national teams and in particular the clinical leadership in Limerick who have championed the need for this system and the adoption of it.

technology to the health sector globally and is growing its Irish operations in 2016 and 2017. This go live shows that by working together we can build a better health service.”

“This is another example of the EHR being used to improve processes, while also improving patient safety through the use of technology. This delivery of this project has been a team effort with an Irish digital health company, IMS Maxims, a company that is leading the way in its innovative approach to the delivery of

Key functionality of the ED system includes recording the attendance, tracking, clinical triage and recorded outcomes for each and every patient. The solution caters for the design of the new ED, which will be laid out in zones and cubicles, and tracks each patient throughout the ED with enhanced data collection.

Actavis Launch Imatinib Actavis Group 400 mg Actavis has launched Imatinib Actavis Group 400 mg in a pack size of 30 filmcoated tablets. Imatinib Actavis Group is a prescription only medicine indicated for the treatment of the following cancers - Chronic myeloid leukaemia - Philadelphia chromosome positive acute lymphoblastic leukaemia - Myelodysplastic/myeloproliferative diseases - Hypereosinophilic syndrome (HES) and/or chronic eosinophilic leukaemia - Dermatofibrosarcoma protuberans Imatinib Actavis Group is now available from Uniphar and United Drug. For further information please contact your Actavis representative, call Actavis in Cork on 021-461 9040 or visit www.actavis.ie HPN • January 2017


38 Feature Skin microbiome before development of atopic dermatitis: Early colonization with commensal staphylococci at 2 months is associated with a lower risk of atopic dermatitis at 1 year Atopic dermatitis (AD) is a common inflammatory skin condition that begins early in life. Patients with AD with established disease experience frequent colonization and increased infections with Staphylococcus aureus, as well as potentially life threatening eczema herpeticum with herpes simplex virus. The hygiene hypothesis relates the development of atopic disorders (AD, allergic rhinitis, and asthma) to reduced microbial exposure at a young age.1 Epidemiologic studies examining the incidence of asthma have linked exposure to farming environments to lower rates of allergic disorders.2-4 However, the potential role of microbe exposure in early childhood to the development of AD and the subsequent atopic march toward the development of allergic rhinitis and asthma remains to be elucidated. There is significant interest in the potential effects of microbes on the development of skin immunity, as well as disease.5-9 Recent work in mice has shown that cutaneous exposure to commensal bacteria early in life can induce tolerance to these microbes.6 Given these epidemiologic associations between environmental exposure and development of atopic diseases, we investigated the skin microbiome in a birth cohort. We analysed bacterial 16S rRNA gene sequences from swabs collected from 4 skin sites in infants in a birth cohort (Babies After SCOPE: Evaluating the Longitudinal Impact Using Neurological and Nutritional Endpoints [BASELINE]) at 3 different time points to determine whether differences in the skin microbiome were associated with AD development. Methods Study subjects The Cork BASELINE Birth Cohort Study is the pediatric followon from the Cork Centre for the Screening for Pregnancy Endpoints (SCOPE) study.10,11 The Cork BASELINE Birth Cohort Study recruited within a white Irish population in Cork, Ireland, from August 2009 to October 2011. These women were subject to the inclusion criteria of the SCOPE study: low-risk primigravidous

TABLEI. I.Demographic Demographic for study subjects TABLE datadata for study subjects Healthy control Subjects 6/4 1/9

Patients with AD 5/5 3/7

Female/male sex Cesarean section/vaginal delivery BF/FF/C 2/3/5 1/2/7 Rural/urban 5/5 4/6 Pet/no pet 5/5 3/7 Emollient use (month 2), 2/8 6/4 yes/no Bathing frequency (month 2), 5/5 6/4 < weekly/> weekly Antibiotic use (month 2), 1/9 1/9 yes/no Antibiotic use (6 mo), yes/no 5/5 3/7 TEWL Day 2 9.668 6 0.776 9.749 6 0.618 Month 2 10.402 6 1.619 11.124 6 2.135 Month 6 11.412 6 2.149 10.08 6 1.342 BF, Breast-fed exclusively; C, combination feeding; FF, formula fed exclusively; TEWL, transepidermal water loss mothers with singleton pregnancies who delivered at or near term. Maternal consent was obtained at 20 weeksâ&#x20AC;&#x2122; gestation and verified at delivery.

FIG 1: Journal of Allergy and Clinical Immunology 2017 139, 166-172DOI: (10.1016/j.jaci.2016.07.029)

Fig 1

Ethical approval for the Cork BASELINE Birth Cohort Study was granted by the Clinical Research Ethics Committee of the Cork Teaching Hospitals (refECM5 [9] 01/07/2008). The BASELINE study is registered with the US National Institutes of Health Clinical Trials Registry (http://www.clinicaltrials. gov; ID: NCT01498965). Clinical diagnosis of AD All infants were assessed at birth and 2, 6, 12, and 24 months of age. Assessment included parental questionnaires and physical examination. Screening questions specific for AD were included in the questionnaires administered at 2, 6, and 12 months. AD was diagnosed (at 6, 12, and 24months) by experienced health care personnel using the UK Working Party Diagnostic Criteria.12-14 When AD was present, the SCORAD clinical tool was used to assess severity.15,16 The

January 2017 â&#x20AC;˘ HPN Journal of Allergy and Clinical Immunology 2017 139, 166-172DOI: (10.1016/j.jaci.2016.07.029)


39 FIG 2: Journal of Allergy and Clinical Immunology 2017 139, 166-172DOI: (10.1016/j. jaci.2016.07.029)

Fig 3

FIG 3: Journal of Allergy and Clinical Immunology 2017 139, 166-172DOI: (10.1016/j. jaci.2016.07.029)

and month 6. Skin samples and negative controls were collected with premoistened swabs, as Journal of Allergy and Clinical Immunology 2017 139, 166-172DOI: (10.1016/j.jaci.2016.07.029) previously described.19 After all Copyright © 2016 The Authors Terms and Conditions infants had been assessed at 1 year, 10 infants with clinical AD at months 2, 6, and/or 12 were selected for analysis as patients with AD. Healthy control subjects were 10 infants without AD at any study time points selected at random.

Nottingham Eczema Severity 4 most common Score was also used to assess Irish/European mutations, as Fig 4 17 AD severity at 122017 months. previously described.18 f Allergy and Clinical Immunology 139, 166-172DOI: (10.1016/j.jaci.2016.07.029) Demographic data and clinical © 2016 The Authors Terms and Conditions None of the subjects in this study details are shown in Table I. were found to have FLG mutations. Filaggrin genotyping Sampling for microbiome Cord blood samples were analysis collected at birth and stored We randomly selected 50 infants for analysis. Filaggrin (FLG) from the birth cohort and obtained genotyping was carried out on all study subjects with testing for the skin swabs at day 2, month 2,

Sample sites were selected based on the presentation of AD at different ages. Cheeks are a site of AD predilection in infants, and the nasal tip (Nt) is typically spared. The antecubital fossa (Af) and popliteal fossa (Pf) are typicalsites of AD predilection in children and adolescents. Sample processing/sequencing 16S rRNA V1-V3 sequencing was performed on swab samples, as previously described.19 Swabs were incubated in Yeast Cell Lysis Solution (MasterPure Kit, MPY80200; Epicentre, Madison, Wis) and Ready-Lyse Solution (R1802M, Epicentre) for 1 hour at

378C. Two 5-mm stainless steel beads (Qiagen, Hilden, Germany) were added and processed in a TissueLyser (Qiagen) for 2 minutes at 30 Hz. The solution was treated with MPC Protein Precipitation Reagent (MasterPure Kit MPY80200, Epicentre) to remove cellular debris. Subsequent steps were performed with the PureLink Genomic DNA Kit (Invitrogen, Carlsbad, Calif). Barcoded primers flanking V1 (27F, 59 AGAGTTTGATCCTGGCTCAG-39) and V3 (534R, 59-ATTACCGCGGCTGCTGG-39) were used for PCR. PCR products were purified with the Agencourt AMPure XP Kit (A63880; Beckman Coulter, Brea, Calif) and quantitated with the Quant-iT dsDNA High-Sensitivity Assay Kit (Q33120, Invitrogen); equivalent amounts of these PCR products were pooled, purified with a Qiagen MinElute column (28004, Qiagen) into 30 mL of TE buffer (10 mM Tris$Cl, 1 mM EDTA, pH 8.0), and sequenced at the National Institutes of Health Intramural Sequencing Center on a 454 GS FLX (Roche, Mannheim, Germany) platform. Reagents and collection procedure controls were tested and demonstrated no significant background contamination. Data analysis Sequences were pre-processed with mothur version 1.35.1.20 Briefly, 454 flowgram data were trimmed and denoised, and chimera checking was completed with the mothur implementation of UCHIME.21 Sequences were classified by using the Ribosomal Database Project naive Bayesian classifier.22 Sequences classified as chloroplast or mitochondria were discarded. Sitespecific definition of operational taxonomic units (OTUs; groups of sequences that share a specific level of similarity) and downstreamanalyseswas performed in mothur. Within the samples from each time point or site, pairwise distances were calculated, and OTUs were defined at 97% nucleotide

FIG 4: Journal of Allergy and Clinical Immunology2017 139, 166-172DOI: (10.1016/j.jaci.2016.07.029)

HPN • January 2017


40 Feature Fig E1 FIG E1: Journal of Allergy and Clinical Immunology2017 139, 166-172DOI: (10.1016/j.jaci.2016.07.029)

co-ordinates analyses based on these theta values, samples that are more similar to each other cluster more closely together. At each time point, the facial site samples clustered together (P > .05, AMOVA) but are distinctly separate from the extremity site samples (P < .006). The extremity sites clustered together at day 2 and month 2 but had different centroids at month 6 (P <.006,) Changes in bacterial colonization over time Skin microbiomes differ between children and adults; however, studies with longitudinal skin sampling in infants are infrequent.27,28 Alterations in skin bacterial abundances at different sampling time points were apparent in our cohort.

llergy and Clinical Immunology 2017 139, 166-172DOI: (10.1016/j.jaci.2016.07.029) similarity. Within-sample (Shannon Results 2016 The Authors Terms and Conditions

diversity) and between-sample (theta index) measurements were performed based on these OTU definitions, with subsampling to 1000 sequences per sample.23 Rarefaction curves level off by this value, suggesting adequate sequencing coverage; any samples with fewer than 1000 sequences after preprocessing were removed from analysis.

Differentially abundant OTUs were detected by using the metastats command in mothur. The sequences classified to the Staphylococcus genus by using the RDP naive Bayesian classifier were then placed on a phylogenetic reference tree using ‘‘-keep-atmost 1000 max-pitches 1000.’’ Taxonomy was assigned by using the guppy program in pplacer,24 with a likelihood cutoff set to 0.65, as previously described.19 Statistics All data analysis was performed in R software; results are presented as means 6 SEMs, unless otherwise indicated. Ninety-five percent CIs were estimated. Post hoc tests (ie, pairwise comparisons in analysis of molecular variance [AMOVA]) were adjusted by using Bonferroni correction. For detection of differentially abundant OTUs, Metastats results are filtered for OTUs with a mean abundance of 0.05% or greater, and P values were calculated by using a false discovery rate adjustment.

January 2017 • HPN

Site-specific bacterial colonization patterns Because different skin microenvironments and anatomic regions harbor distinct microbial communities in adults and older children,25,26 we initially compared the major bacterial taxa present at the 4 sites on infants. Relative abundances of these bacterial taxa showed differences between the 2 facial sites (cheeks and Nt) and the extremity sites. Calculation of differentially abundant species between the site types confirmed that Staphylococcus species were relatively more abundant on extremity sites at all time points and Gemella species were relatively more abundant on facial sites. Other taxa were only differentially represented at some time points, with facial sites higher in Propionibacterium species at day 2 and Streptococcus species at later time points. We validated these findings with biodiversity calculations, examining samples from each time point. We analyzed how similar the bacterial community structures were between the samples using the theta similarity index, which accounts for both the presence and proportion of bacterial species.23 A theta index value of 1 indicates that the 2 bacterial communities have identical structures; a value of 0 indicates maximal dissimilarity. In principal

For each skin site, the bacterial community structures showed striking shifts based on the sampling time point. At both extremity sites, the samples clustered separately between day 2 and month 6 (P 5.024 for Af and P 5.003 for Pf, AMOVA). For both facial sites, day 2 and month 6 samples clustered significantly (P <.003 for each), as did those between month 2 and month 6 (P < .003 at the cheeks and P 5.06 at Nt). To examine interpersonal variation, we calculated the mean similarity between samples at a single site and time point. For both facial sites, bacterial communities between subjects were most similar at month 6, converging to a more common bacterial population across subjects. Extremity sites did not present this same pattern; instead, the most similar bacterial community structures were observed at month 2 (Fig 2, C). We analyzed the bacterial diversity of all samples by using the Shannon diversity index (a higher value signifies more taxonomic groups, a more even distribution of these groups, or both). At each time point, diversity was similar between Af, cheeks, and Nt (P > .05, Wilcoxon rank sum test; Fig 3). Pf had a substantially altered pattern, significantly different from the other sites at all time points, except Af at day 2. At the facial sites, bacterial diversity increased significantly over the time studied (P < .001 for each site between

day 2 and month 6, Wilcoxon rank sum test). Combined with the increasingly similar bacterial community structures on the face, this suggests that over time, the microbial population converges and stabilizes at facial sites. Samples from the Af also significantly increased in diversity between the time points (P 5.033). Colonization of Af with commensal staphylococci at month 2 is associated with decreased incidence of AD at 1 year To identify any bacterial differences associated with AD in this cohort, we compared infants with AD at any time within the first year of life versus control subjects for each site and sampling time. At all time points, the bacterial community structures of infants with AD at any time within the first year of life did not cluster separately from control infants, and no significant differences in Shannon diversity were identified between the groups. Because the patients had clinical disease presenting at different time points, we also compared samples based on whether the subjects presented with disease at each time point. Overall, there was almost no distinction between affected and unaffected samples in within- or between-sample diversity, either before or at the time point when the patients were affected. Interestingly, the month 2 Af samples demonstrated statistically significant clustering grouped by those infants who went on to be affected at month 12 in this study (P 5 .003, AMOVA). OTU-based analysis suggested that a single OTU was differentially abundant between the groups; this OTU was classified as Staphylococcus (Fig 4, A). When considering all sequences classified to the Staphylococcus genus, the relative abundances were significantly different between the 2 groups, with subjects who went on to be affected colonized by significantly less staphylococci (mean, 0.065; 95% CI, 0.035-0.094) compared with those who went on to be unaffected (mean, 0.495; 95% CI, 0.458- 0.531; P < .003, Wilcoxon rank sum test; Fig 4, B). Given the specific association between S aureus and AD flares, we classified the Staphylococcus sequences to the species level; in these samples the most prevalent species were Staphylococcus epidermidis and Staphylococcus cohnii (Fig 4, C). In contrast to older patients with AD or patients with more severe AD,29 essentially no S aureus sequences were present in the samples in our cohort, even at the sites and times that patients were affected.


41 There were no statistically significant differences within individual Staphylococcus species levels in the month 2 Af samples between the later affected and later unaffected samples. Birth method and feeding method have little effect on skin microbiota Differences have previously been reported between the skin microbiota of infants born by means of cesarean section versus vaginal birth.28 We investigated whether birth method was associated with differences in the skin microbiota in our cohort. There was no clustering of samples at any site or time point based on birth method, except Af samples at day 2. Shannon diversity was similar between the 2 birth methods as well. Feeding method has been associated with differences in the intestinal microbiome composition of infants.30,31 However, feeding method (breast, formula, or combination) and sex did not affect skin bacterial colonization patterns in this cohort. Discussion Although infections with S aureus and herpes simplex virus can complicate the course of established AD, the role of microbes in the cause, genesis, and pathogenesis of AD remains unclear. Recent murine studies have shown that cutaneous microbes can influence the development of skin immunity and disease.5,6,9 Determining whether cutaneous microbes play a role in the initiation of AD could provide an opportunity to reduce the development of atopic disorders. To investigate the skin microbiome in infants before the development of AD, we used 16S rRNA gene sequencing of skin samples from a birth cohort and determined that shifts occur in the skin microbiome over the first 6 months of life, with site-specific bacterial communities changing in composition and diversity over time. We also identified a difference in staphylococcal colonization at a site of AD predilection that predates the presentation of disease, with patients who went on to be affected at a later date colonized by fewer Staphylococcus species. Birth method and feeding method did not appear to affect skin bacterial communities at the sites and time points studied in this cohort, but other studies are needed to confirm these findings. Prior studies of human skin have shown that skin microbial communities are site specific.32,33 Although there is heterogeneity of bacterial communities across the

skin surface, specific skin sites in different subjects often share common patterns of bacterial composition. This biogeography of the skin microbiome has been observed in older children and adults.26,34 In previous infant skin microbiome studies, site-specific differences were not evident in the first 3 months of life because infants were studied at a single time point immediately after delivery or were sampled at a single time point and analyzed in age cohorts of 1 to 3, 4 to 6, and 6 to 12 months.27,28 The present study differed by sampling the same cohort of infants over a 6-month interval (day 2, month 2, and month 6) and observed sitespecific differences as early as the second day of life, a time point not previously investigated. The bacterial diversity of 1 skin site, the Pf, shifted at time points differentially from the 3 other sites studied. Because this specific skin site has not been examined in a cohort this young, the results might be related to a unique aspect of infant skin physiology, exposure, or both or specific to this cohort. Interestingly, the body site differences in bacterial communities also reflect observed site differences in immune cell density and composition from human skin.35-38 Investigating site-specific differences in host-microbial interactions can enhance our understanding of the predilection of certain skin regions for dermatologic diseases. In addition to the biogeography of the skin microbiome, skin bacterial communities can shift significantly during different periods of the lifecycle, such as puberty.26 The physiology of infant skin changes over the first year of life, with alterations in stratum corneum hydration, skin pH, and sebum production.39 In this study the shifts in skin bacterial communities in the first months of life were the inverse of skin microbiome alterations that have been observed later in childhood. The increasing Shannon diversity observed in the first year of life in this infant cohort supports previous work that showed increased evenness or similar numbers in each taxa in bacterial communities from 3 skin sites in a cross sectional study.27 During puberty, significant shifts in skin bacterial communities likely reflect the changes in skin physiology and systemic hormones.26 Changes in the skin microbiome observed in these infants potentially reflect the influences of waning maternal hormones, as well as the continued development of infant skin. For example, lipophilic Propionibacterium species are relatively abundant on the facial

sites at neonatal day 2 but decrease substantially at later time points. This corresponds to the high sebaceous activity triggered by maternal hormones in the first days of life, which wane significantly in the weeks after birth.40 These findings lead to additional questions, including whether neonatal skin disorders, such as cephalic pustulosis (also known as neonatal acne), attributed to maternal hormones potentially might also be affected by alterations in skin bacteria. A previous study in mice reported that having antigen-specific tolerance to commensals depends on early colonization, suggesting that there is a ‘‘critical window’’ for inducing regulatory T cells, which prevent a later inflammatory response to these bacteria.6 Scharschmidt et al6 showed that application of a commensal species of Staphylococcus on neonatal skin induced these immunomodulatory effects. The relatively low abundance of pathogenic staphylococcal species on the Af of 2-month-old infants who later had AD at 12 months of age is intriguing in the context of this prior work in mice. Whether cutaneous exposure to commensal staphylococci during early infancy can have a similar effect remains unknown, and further investigation is needed to understand whether this might influence the development of AD. The absence of S aureus in AD lesions of this cohort was somewhat surprising, given that this species is associated with AD.29,41-43 A culture-based analysis of infant skin demonstrated S aureus colonization in approximately 21% of AD lesions among infants in their first year of life.44 The differences might be related to inherent differences in the study populations and/or the severity of sampled skin lesions between the study groups. Differences in birth method have been studied in relation to the incidence of atopy and the neonatal skin microbiome.28,45 An earlier study showed skin microbiome differences based on birth method in neonates sampled a few minutes after delivery. The small sample size and rare number of cesarean deliveries in the current study potentially contribute to the lack of statistically significant differences between the skin microbiota of infants born vaginally or by means of cesarean section at the earliest time point in this study, day 2 of life. Although this study analyzed different sites over a longer timeframe than the previous work, a larger study would be needed to address this question. Birth method might determine skin

colonization very early in life; however, environmental exposures and skin physiology might predominate in shaping bacterial communities after this initial delivery. The skin barrier and FLG mutations are additional aspects of skin physiology that have been studied in relation to atopy. Although approximately 10% of subjects in BASELINE publications and the Irish population have FLG mutations, the current cohort had fewer FLG mutations than expected because of sampling effects. Because a large proportion of patients with AD do not carry FLGnull alleles, the results in the current cohort avoid the potential effects of FLG mutations and remain relevant to AD. With interest in the potential immunologic effects of neonatal exposures to skin microbes,6,46 characterizing the early skin microbiome in neonates with and without FLG mutations and the timeframe for possible development of immune tolerance would be of significant clinical importance. There are increasing efforts to understand the potential relationship between the skin microbial landscape and the development of skin immunity and human disease. Early studies of the skin microbiome will identify possible associations between specific microbes and human health and disease, but extensive further research will be required to unravel the pathophysiology and key mechanisms involved. Longitudinal sampling of the same subjects as internal controls and the initiation of sampling soon after birth were features of this study that improve the ability to identify distinct microbial patterns that could provide insight into the skin microbial milieu before the development of skin disease. As a result, we were able to define the site specificity and longitudinal shifts of the skin microbiome in the first 6months of life, as well as the difference in relative abundances of commensal staphylococci before the development of AD. Additional investigations are needed to test whether site-specific differences in skin microbes influence the development of AD. References available on request Elizabeth A. Kennedy, BS,a Jennifer Connolly, MSc,b Jonathan O’B. Hourihane, DM,b Padraic G. Fallon, PhD,c,d W. H. Irwin McLean, DSc, FRS,e Deirdre Murray, PhD,b Jay-Hyun Jo, PhD,a Julia A. Segre, PhD,f Heidi H. Kong, MD, MHSc,a* and Alan D. Irvine, MD, DScc,d,g* Bethesda, Md, Cork and Dublin, Ireland, and Dundee, United Kingdom

HPN • January 2017


42 News

New clinical trial for Irish Melanoma patients Dr Derek Power, Oncology Clinical Trials Unit, Cork University Hospital and Dr Declan Soden, Cork Cancer Research Centre, University College Cork. Image: Tomás Tyner, UCC

in accordance with its licenced use as a 1st or 2nd line treatment with electrochemotherapy being additionally applied to shrink the skin melanoma nodule.

Cork Cancer Research Centre, based at UCC, has announced the launch of a new clinical trial for the treatment of malignant melanoma, aimed at significantly improving patient outcomes. In Ireland there are approximately 630 new cases of melanoma diagnosed each year with 110 people losing their lives to the disease annually. Melanoma mortality is increasing very rapidly with the number of deaths per annum expected to reach 150 by 2020. The new treatment being investigated involves a combination of Ipilimumab (“Ipi”, tradename Yervoy), a Bristol-Myers Squibb (BMS) drug, and tumour Electroporation, which is pioneered at CCRC. It aims to open up cancer cells with electrical pulses to facilitate the immunotherapy treatment to be even more effective, enabling the patient’s immune system to respond against the cancer. The study is supported by UCC, BMS and Breakthrough Cancer Research. The trial, which is sponsored by BMS, has just commenced at Cork University Hospital (CUH) and is the first of its kind in the world. It is being led by Principal Investigator and Consultant Oncologist Dr Derek Power and Scientific Investigator Dr Declan Soden of the Cork Cancer Research Centre, who will enrol suitable patients from around the country. IPI has been successfully used to date as a treatment of advanced melanoma in adults, significantly improving survival rates in up to 18% of patients who received the drug (*1). IPI is the first in a line of new immunotherapies that prevent tumours from shutting down the patient’s immune

January 2017 • HPN

system when it’s attacking the cancer. Electrochemotherapy (Electroporation combined with chemotherapy), which is pioneered at the Cork Cancer Research Centre with funding from Breakthrough Cancer Research, has received considerable attention in the last few years as an emerging therapy for use in cancer tumours. It involves delivering short bursts of electricity directly to the tumour making it porous and dramatically increasing its absorption of chemotherapy drugs. The new study entitled “Enhanced Malignant Melanoma Immunological engagement using sequential therapy with Ipilimumab and electrochemotherapy”, or EMMIE for short, is a single centre trial aiming to establish the safety and efficacy of treating patients with advanced melanoma. The trial of the new treatment regime has been approved by the Health Products Regulatory Authority, (formerly known as the Irish Medicine Board), the state agency which regulates and monitors the safe use of human and animal medicines in Ireland, and is being run with the support of BMS, who are providing the immunotherapy free of charge to University College Cork, and the Oncology Clinical Trials Unit in Cork University Hospital. Support for this approach has also just been validated in a clinical paper published in Cancer Immunology Research (*2), which showed a 50% increase in survival rates in a trial group who received combined IPI with a locally ablative treatment. Patients eligible to be included in the study will receive the licensed medicine, Ipilimumab,

Principal Investigator on the trial and Clinician and Consultant Medical Oncologist with Mercy and Cork University Hospitals, Dr Derek Power, welcomed the new developments in immunotherapy stating, “It is only in the last few years that cancer researchers have unravelled one of the key protective mechanisms that cancers use to stop the immune system from recognising and destroying these abnormal cells. Cancer cells send out signals around the tumour to turn off locally present immune cells, which has, as a result, prevented immunotherapies, like Ipilimumab, from working. Overcoming this immune ‘cloaking’ of the tumour has become the key to making immune therapy work for patients.” Dr Power continued, “Ipilimumab is already being used daily for patients across Ireland with established impacts for these patients. CCRC are at the forefront of research in relation to their electrochemotherapy treatment and we are excited at the synergy that will be created with the combined regime of these two treatments. We are already seeing good immune responses from Electrochemotherapy and with the addition of Ipilimumab we are excited to see the results from this enhanced treatment for patients.” Dr Declan Soden, Principal Investigator and Manager at the Cork Cancer Research Centre welcomed the trial, adding, “Our research at the CCRC has shown that treating tumours with a short burst of energy can make them leaky or porous. This allows for a more focused absorption of chemotherapy allowing for a substantial reduction in the concentration required and essentially eliminating drugbased side effects for patients. Our studies have expanded from patients with skin cancers (breast, malignant melanoma)

to endoscopically accessible cancers like colon, oesophageal. We hope to treat patients with other poor prognosis cancers using this approach in the near future.” “This electrical pulse can also very significantly spark an immune engagement against the cancer, which in combination with immunotherapies like IPI, has been found to lead to better outcomes for the patients. The success of this trial should lead to other studies for patients suffering from poor prognosis cancer where there are currently limited options available” concluded Dr Soden. Doctors with patients who may be suitable for this trial should refer them to Dr Power of the Oncology Clinical Trials Unit in Cork University Hospital or Dr Declan Soden of the Cork Cancer Research Centre in University College Cork. (1) The statement is taken from Dirk Schadendorf et al JCO 2015 Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma. Pooled analysis of OS adds to the evidence supporting the durability of long-term survival in a proportion of ipilimumabtreated patients with advanced melanoma. We observed a median OS of 11.4 months and an apparent plateau in the OS curve around year 3, when survival rates ranged from 20% to 26%, with follow-up to 10 years in some patients. (2) Support for this approach has come from a clinical paper just published in Cancer Immunology Research Local Tumor Treatment in Combination with Systemic Ipilimumab Immunotherapy Prolongs Overall Survival in Patients with Advanced Malignant Melanoma, Cancer Immunology Research 4(9) Sept 2016. Researchers went back and reviewed data on melanoma patients who had received systemic IPI along with concurrent targeted ablative treatment of their melanoma tumours. The data showed a doubling of survival in the group who received combined IPI with a locally ablative treatment (93wks v 42wks) (Cancer Immunology Research 4(6) Sept 2016).


Event Gallery 43 Leading expert to lead ¤5m project in medical devices Professor William Wijns, an expert in cardiology, has joined NUI Galway as Professor of Medical Devices. He will spearhead a ¤5 million research project, which will develop wearable sensors to alert patients at high risk of heart attacks to triggers such as stress or high blood pressure. Professor Wijns joins the University through the Science Foundation Ireland Research Professorship Programme, which supports national strategic priorities by recruiting world-leading research and leadership talent to Ireland. “The medical technology sector in Ireland is recognised as one of five global emerging hubs,” explains Professor Lokesh Joshi, Vice-President for Research at NUI Galway. “Eight of the world’s top ten med-tech companies are based here, and the West of Ireland in particular is at the heart of the Irish med-tech system. NUI Galway is the powerhouse for much of this progress and we have developed a range of interdisciplinary research centres

Professor William Wijns, NUI Galway Professor of Medical Devices

and initiatives, working closely with partners in industry, healthcare and government agencies. We welcome Professor Wijns with great anticipation of the opportunities his transformative approach brings to the translation of research into practice to ultimately deliver better health outcomes for patients.” Professor Wijns’ research focuses on heart attacks and sudden death caused by unexpected blockage of arteries supplying the heart with blood and oxygen. This occurs in people exposed to risk factors such as family history, hypertension, smoking, diabetes or high cholesterol, who exhibit a vulnerable narrowing in the walls of their arteries, without being aware of it. Trigger mechanisms like anger, mental stress, high blood pressure, strenuous exercise and sleep

disorders cause the narrowing to rupture inside the conduit, obstructing the artery. His work will look at developing medical devices that can monitor these “trigger” activities electronically, at a distance, using wearable sensors in high-risk subjects who are known to carry this vulnerable

narrowing of the artery, and in doing so, anticipate and prevent heart attacks. Professor Wijns will also join the Cardiology Department at Saolta University Healthcare group, where he will collaborate with other clinicians engaged in translational cardiovascular research.

MSD Celebrates 40 years in Ballydine MSD in Ballydine, Co. Tipperary, celebrated its 40th birthday last year, which was also the 125th anniversary of the founding of MSD globally. The healthcare company’s Ballydine facility, which has been a vibrant part of the

Ballydine community since 1976, is now one of the region’s largest employers with over 450 highly-skilled people employed at the site. MSD in Ballydine develops innovative methods for the

formulation and supply of new products and houses a formulation R&D and manufacturing facility onsite. The plant exports to over 30 countries with main markets being Europe, USA and Japan. Its employees are a crucial part

Pictured at MSD in Ballydine’s 40th Celebrations in Hotel Minella, Clonmel are the MSD in Ballydine Leadership Team, from L-R: Siobhan McGrath, Dermot O’Brien, Michael Brady, Pat Fitzgerald, John Carolan, Mari Murphy, Ger Carmody (Plant Manager), Kieran Butler, Sean Owens and Andrew Corby.

of the site’s success, and two of the original employees, Frank Cantwell and John Casey, who started with the company in 1976, are still working there. Amongst its workforce, MSD in Ballydine has nine married couples, an All-Ireland Camogie Champion, and thirteen employees with at least 35 years-service. Ger Carmody, Associate Vice President of Operations, MSD in Ballydine, said, “We’re proud to be part of the Ballydine community and over the past 40 years, our team has been actively engaged in initiatives in the local community and we are committed to making a difference through a range of community, workplace and environmental CSR programmes, which include supporting causes that matter to our people and neighbours. This has included initiatives in promoting STEM in local Schools through Junior Achievement, support for Science Week and our Bright Ideas Competition. We have recently supported many local charities including the Irish Cancer Society, the South East Mountain Rescue, St. Vincent de Paul, The Red Cross, the Alzheimer’s Society, Kilsheelan Tidy Towns, Carrick on Suir River Rescue and Barnardos.”

HPN • January 2017


44 Event Gallery Masters of Pharmacy graduates from RCSI From 15th to 17th November, RCSI (Royal College of Surgeons in Ireland) conferred a total of 925 candidates with their respective undergraduate and postgraduate awards at four separate ceremonies over two days as part of the College’s November conferring ceremonies. The first ceremony, on 15th November, saw the graduation of 99 candidates from full-time undergraduate programmes including BSc Pharmacy, BSc Physiotherapy and medicine (MB, BCh, BAO (NUI, RCSI), LRCP&SI). 101 candidates were then conferred at the Diploma, Masters and Doctoral Degree ceremony at RCSI. The November Conferrings continued on Thursday 17th

November with two further ceremonies, for graduates from the School of Nursing & Midwifery and Masters Degree candidates. At this ceremony, the seventh Honorary Doctorate of RCSI was presented to Professor Áine Hyland, Emeritus Professor of Education and former VicePresident of University College Cork, who delivered an address to the graduating student body.

Ciaran O’Hara, from Ballyheigue, and Hugh Herlihy from Castle Island, Co Kerry who both graduated with Master of Pharmacy (MPharm) from RCSI

Roisin McKeon (Masters in Pharmacy), Killoe, Longford

With a long-standing commitment to inclusion and diversity in Irish education, Professor Hyland has been active in education circles in Ireland and internationally for over 50 years. She is a member of the European Universities’ Association Institutional Evaluation Team and of the Steering Committee of the European Quality Assurance Forum.

Challenges of Gram Negative Resistance MSD recently hosted a meeting entitled ‘The Challenges of Gram Negative Resistance’ on September 8th, 2016 in Dublin. The visiting speaker was Professor David Livermore, Prof of Medical Microbiology, University of East Anglia, Lead on Antibiotic Resistance, Public Health England. Attendees included Clinicians, Medical Scientists and Antimicrobial Specialist Pharmacists.

East Anglia, Lead on Antibiotic Resistance, Public Health England and Professor Martin Cormican, Consultant Microbiologist & Professor of Bacteriology, NUIG,

Michael Phelan, Business Unit Director, MSD 4: Professor David Livermore, Prof of Medical Microbiology, University

1

2

1: Delegates who attended the recent Challenges of Gram Negative event 2: Dr André Oliveira, Medical Advisor , MSD 3: Niamh McEvoy , Brand Manager Antimicrobials, MSD ; Professor David Livermore, Prof of Medical Microbiology, University of

3

January 2017 • HPN

of East Anglia, Lead on Antibiotic Resistance, Public Health England and Professor Martin Cormican, Consultant Microbiologist & Professor of Bacteriology, NUIG

4


Clinical R&D 45 ROCHE’S EMICIZUMAB FOR HAEMOPHILIA A MEETS PRIMARY ENDPOINT IN PHASE III STUDY Roche has announced that the primary endpoint has been met for the phase III HAVEN 1 study evaluating emicizumab prophylaxis in people 12 years of age or older with haemophilia A and inhibitors to factor VIII. The study showed a statistically significant reduction in the number of bleeds over time in people treated with emicizumab prophylaxis compared to those receiving no prophylactic treatment. The study also met all secondary endpoints, including a statistically significant reduction in the number of bleeds over time with emicizumab prophylaxis treatment in an intra-patient comparison in people who had received prior bypassing agent prophylaxis treatment. The most common adverse events with emicizumab were injection site reactions, consistent with prior studies. Haemophilia A affects around 600 people in Ireland and of those nearly 200 have severe disease, requiring intensive care and treatment. Despite the improvements in the management of haemophilia A, inhibitory antibodies against factor VIII develop in approximately 20–35% of individuals with severe disease, which renders the treatment less effective or ineffective and remains a major concern. “The development of inhibitors that render factor VIII replacement less effective, or ineffective, is one of the greatest challenges in the treatment of haemophilia A today, putting patients at high risk for lifethreatening bleeds and repeated bleeds that may cause long-term joint damage,” said Dr Mike Starnawski, Medical Director at Roche in Ireland. “We are pleased to see that, in our first pivotal trial, emicizumab prophylaxis significantly reduced the number of bleeds over time in people in this difficult-to-treat setting. We look forward to working with health authorities to bring this treatment to the haemophilia community as soon as possible.” As previously reported, two patients had thromboembolic events and two patients developed thrombotic microangiopathy (TMA). The common aspect between all cases of thromboembolic events and TMA is that they occurred in patients who were on emicizumab prophylaxis and in addition received activated prothrombin complex concentrate to treat breakthrough bleeds. Neither thromboembolic event required anti-coagulation therapy. Both cases of TMA have completely

resolved, and one patient restarted emicizumab.

(5%), and increased aspartate aminotransferase (4%).

NIVOLUMAB APPROVED IN EUROPE FOR TREATMENT IN BLOOD CANCER AS NEW DATA SHOW PROMISING RESULTS OF CANCER REDUCTION

Hodgkin lymphoma (HL) is a cancer of the lymphatic system. Generally, lymphoma cells grow in lymph glands (nodes) and this causes the glands to get bigger or swell. Hodgkin lymphoma can start in any part of your body, but the most common place for it to start is the neck, armpit or chest. The lymphoma cells can sometimes spread to other lymph glands. They can also get into your bloodstream and spread to other organs, for example in your liver, stomach or bowel. HL incidence rates have increased in Ireland, with 133 people diagnosed with the cancer in Ireland in 2013. Approximately half of all patients with HL are under 35 years old when diagnosed, only 16% of all patients with HL are 65 years old or over. The disease is the fourth most common cancer in patients aged 15-34 (after testicular cancer, melanoma and breast cancer).

Bristol-Myers Squibb have announced the breakthrough immunotherapy, Opdivo®(nivolumab), has been approved for the treatment of classical Hodgkin lymphoma (cHL), a rare and often-aggressive blood cancer. Specifically, the approval is for patients whose cancer is progressing (relapsed or refractory) despite autologous stem cell transplantation (ASCT) and treatment with brentuximab vedotin (BV). The approval comes as new data presented at the American Society for Hematology (ASH) congress show that nearly 95% of patients in this setting, were still alive at one year. At this advanced stage, Hodgkin lymphoma is a terminal condition with limited therapy options currently available. The primary endpoint of the study showed that considerable cancer reduction was seen in over twothirds of patients on nivolumab (68%, 95% CI: 56%, 78%), measured as objective response rate (ORR). In addition, 8% (95% CI: 3%, 16%) of these patients saw a complete response (CR), where no recognisable sign of cancer remained.* “This is a significant step forward for Hodgkin lymphoma patients,” said Dr. Graham Collins, Consultant Haematologist, Oxford University Hospitals Foundation Trust. “Historically, once a patient’s cancer progresses to this stage they are generally placed on palliative end-of-life care. The launch of nivolumab changes the treatment landscape, offering an innovative approach to treating this cancer.” Nivolumab has an innovative mode of action that works by harnessing the ability of the immune system to fight cancer. In the CheckMate 205 study, presented at the 58th American Society of Hematology (ASH) Annual Meeting in San Diego, USA, 12-month progression-free survival (PFS) was demonstrated in over half of patients (54.6%, 95% CI: 40.9%, 66.4%) with the median duration of response lasting for over a year (13.1 months, 95% CI: 8.7, not reached).* The safety profile of nivolumab was consistent with previously reported data in this tumour type. Grade 3/4 drug-related adverse events occurred in 29% of patients, the most common were increased lipase (8%), neutropenia

“We are delighted that nivolumab has been approved across Europe for the treatment of classical Hodgkin lymphoma. Patients with the potential to benefit are those who have failed standard therapies and have no alternative options. The approval comes at a time when pivotal new data presented at ASH are demonstrating the potential this treatment can offer to patients with this type of blood cancer.” said Benjamin Hickey, General Manager, UK and Ireland, Bristol-Myers Squibb. “We are fully committed to working with reimbursement authorities to ensure that all eligible patients in Ireland are able to benefit from this treatment as quickly as possible.”

ROCHE’S OBINUTUZUMAB SHOWED SUPERIOR PROGRESSION-FREE SURVIVAL Positive results from the pivotal phase III GALLIUM study in people with previously untreated follicular lymphoma, the most common type of indolent (slow-growing) nonHodgkin lymphoma (iNHL) were communicated at the 58th ASH Annual Meeting & Exposition (San Diego, December 3-6, 2016). The study compared the efficacy and safety of obinutuzumab plus chemotherapy (CHOP, CVP or bendamustine) followed by obinutuzumab alone, headto-head with rituximab plus chemotherapy followed by rituximab alone. Results from a pre-planned interim analysis showed that obinutuzumab-based treatment significantly reduced the risk of the disease worsening or death (progression-free survival; PFS, as assessed by investigator) compared to rituximab-based treatment: HR=0.66 (95% CI: 0.510.85; p=0.0012). Treatment with

obinutuzumab also significantly delayed the need for new treatment: HR=0.68 (95% CI: 0.51-0.91; p=0.0064). Adverse events with either obinutuzumab or rituximab were consistent with what was seen in previous clinical trials when each was combined with various chemotherapies. The most common grade ≥3 adverse events in the obinutuzumab group were neutropenia (43.9%), infections (20.0%) and infusionrelated reactions (12.4%). Data from the GALLIUM study will be submitted to health authorities for approval consideration. Therefore obinutuzumab is not yet authorised for use in people with previously untreated follicular lymphoma. “People with follicular lymphoma continue to need better initial treatment options because their disease is incurable and becomes more difficult to treat with each relapse,” said Dr Mike Starnawski, Medical Director of Roche in Ireland. An average of 660 cases of non-Hodgkin’s lymphoma (NHL) were diagnosed per year in the country between 2007 and 2011, of which approximately 126 were follicular lymphoma. “GALLIUM is the second study in which obinutuzumab showed superior progression-free survival compared to rituximab, when each was combined with chemotherapy”, stated Dr Starnawski. In the first head-to-head comparison of obinutuzumab and rituximab, the CLL11 study in people with previously untreated chronic lymphocytic leukaemia and comorbidities, obinutuzumab plus chlorambucil significantly extended PFS compared to treatment with rituximab plus chlorambucil (median PFS 26.7 months vs 15.2 months, respectively; HR=0.39 (95% CI: 0.31–0.49; p<0.001). The most common side effects of obinutuzumab plus chlorambucil were infusion reactions, low white blood cell counts, low platelet counts, low red blood cell counts, fever, cough, nausea, and diarrhoea. In addition, data from the phase III GOYA study, comparing obinutuzumab plus CHOP chemotherapy head-to-head with rituximab plus CHOP chemotherapy in first line diffuse large B-cell lymphoma (DLBCL) were also presented at ASH 2016. This study did not meet its primary endpoint of obinutuzumab significantly reducing the risk of disease worsening or death (progression-free survival; PFS) compared to rituximab plus CHOP chemotherapy (R-CHOP). Adverse events with obinutuzumab and rituximab were consistent with those seen in previous clinical trials when each was combined with various chemotherapies. HPN • January 2017


46 Clinical R&D BAYER’S XARELTO® SIGNIFICANTLY REDUCED BLEEDING COMPARED TO VKA IN AF-PATIENTS ALSO RECEIVING ANTIPLATELET THERAPY AFTER PERCUTANEOUS CORONARY INTERVENTION Bayer AG has announced results from the Phase IIIb PIONEER AF-PCI study, which demonstrated that two different treatment strategies with its oral Factor Xa inhibitor Xarelto® (rivaroxaban) both significantly reduced the risk of bleeding compared to a vitamin K antagonist (VKA) treatment strategy in patients with non-valvular atrial fibrillation (AF) after percutaneous coronary intervention (PCI) with stent placement. Specifically, rivaroxaban 15 mg once daily in combination with single antiplatelet therapy significantly reduced the rate of clinically significant bleeding by 41 per cent (relative risk reduction; equivalent to 9.9 per cent absolute risk reduction) compared to VKA plus dual antiplatelet therapy (DAPT) through 12 months of randomised therapy in these patients. Rivaroxaban 2.5 mg twice daily in combination with DAPT reduced the rate of clinically significant bleeding compared to VKA + DAPT by 37 per cent (relative risk reduction; equivalent to 8.7 per cent absolute risk reduction) through 12 months of randomised therapy, which was also statistically significant. Similar rates for the exploratory efficacy endpoint (cardiovascular death, MI, stroke, and stent thrombosis) were observed; however, the study was not powered for statistical significance on efficacy. Results from PIONEER AF-PCI – the first randomised trial of a non-vitamin K antagonist oral anticoagulant (NOAC) in this patient population – were presented today as a Late-Breaking Clinical Trial at American Heart Association (AHA) Scientific Sessions 2016 in New Orleans, LA, USA and published simultaneously in The New England Journal of Medicine. Furthermore, a supporting subanalysis of PIONEER AF-PCI showing significantly fewer rates of all-cause mortality or recurrent hospitalisation due to adverse events for patients taking rivaroxaban plus antiplatelet therapy compared to those on VKA plus antiplatelet therapy was also simultaneously published in Circulation. “Patients with non-valvular AF who undergo PCI are at increased risk of blood clots, which can trigger severe consequences including stroke, myocardial infarction and stent thrombosis. In order to reduce the risk of these, patients are currently being treated with a combination therapy that January 2017 • HPN

increases their risk of bleeding,” said C. Michael Gibson, M.S., M.D., Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center in Boston, USA and the Principal Investigator of the PIONEER AF-PCI study. “Now, the PIONEER AF-PCI study demonstrated that statistically one bleeding event could be prevented if 11 patients were treated with the 15 mg once-daily rivaroxaban treatment strategy, thus offering physicians essential guidance to make more informed treatment decisions for this patient population in the future.”

daily (or 10 mg od for patients with moderate renal impairment [CrCl: 30 – 50 ml/min]) plus clopidogrel (or prasugrel or ticagrelor) for 12 months

“PIONEER AF-PCI answers an important medical question because it is potentially relevant for the 20-45% of AF patients that also have coronary artery disease and are at risk of having to have a PCI. The actual rate of PCI procedures in AF patients is approximately 1% per year,” said Dr Michael Devoy, Head of Medical Affairs & Pharmacovigilance of Bayer AG’s Pharmaceuticals Division and Bayer Chief Medical Officer.

• Arm 3: Triple therapy consisting of dose-adjusted VKA (target INR of 2.0–3.0) plus DAPT (as in arm 2) for a pre-specified duration of 1, 6 or 12 months (investigator determined), followed by doseadjusted VKA (target INR of 2.0–3.0) in combination with low-dose ASA to end of month 12

Despite this, there was a lack of clinical evidence to guide best possible treatment strategies in these patients. Current Guidelines and consensus / position papers recommend a combination of antiplatelet and anticoagulant therapies for the initial phase after PCI in patients with AF – a treatment approach that has been associated with an increased risk of bleeding, including intracranial bleeding. PIONEER AF-PCI adds to the extensive investigation of rivaroxaban, which, by the time of its completion, is expected to include more than 275,000 patients in both clinical trials and real-world settings. PIONEER AF-PCI was an openlabel, randomised Phase IIIb study, designed to determine the safety of two rivaroxaban treatment regimens versus a dose-adjusted vitamin K antagonist (VKA) treatment strategy after percutaneous coronary intervention (PCI) with stent placement in patients with non-valvular atrial fibrillation (AF). PIONEER AF-PCI included 2, 124 patients worldwide in 26 different countries. The primary endpoint of the study was the occurrence of clinically significant bleeding, defined as a composite of TIMI major bleeding, TIMI minor bleeding and bleeding requiring medical attention through 12 months of randomised therapy. All patients were randomised in a 1:1:1 ratio into three treatment arms: • Arm 1: Rivaroxaban 15 mg once

• Arm 2: Rivaroxaban 2.5 mg twice daily plus a pre-specified duration of 1, 6 or 12 months (investigator determined) of DAPT consisting of low-dose acetylsalicylic acid (ASA) + clopidogrel (or prasugrel or ticagrelor), followed by rivaroxaban 15 mg once daily (or 10 mg od for patients with moderate renal impairment) in combination with low-dose ASA to end of month 12

GENMAB ANNOUNCES PHASE III STUDY OF DARATUMUMAB IN COMBINATION WITH CARFILZOMIB IN MULTIPLE MYELOMA Genmab A/S (Nasdaq Copenhagen: GEN) has announced that daratumumab (DARZALEX®) will be investigated in a Phase III clinical study in combination with carfilzomib (KYPROLIS®) and dexamethasone in patients with relapsed/ refractory multiple myeloma. The study will be conducted under a master clinical trial collaboration and supply agreement between Genmab’s licensing partner for daratumumab, Janssen Biotech, Inc., and Onyx Pharmaceuticals, Inc., a wholly-owned subsidiary of Amgen, Inc. The agreement covers all potential opportunities for combining daratumumab and carfilzomib (a proteasome inhibitor) for the treatment of patients with cancer. The first study under this collaboration agreement will be a 450 patient Phase III, randomized, open-label, registration study that will seek to determine if daratumumab in combination with carfilzomib (56 mg/m2 twice weekly) and dexamethasone improves progression-free survival (PFS), compared to carfilzomib and dexamethasone alone in patients with multiple myeloma who have received one to three prior therapies. The study is anticipated to start dosing patients in 2017 and will be sponsored by Amgen. “The new Phase III study combining daratumumab with carfilzomib and dexamethasone is an exciting addition to the broad and expansive development program for daratumumab and illustrates the strategy to explore

as many clinical development opportunities for daratumumab as possible, and potentially establish daratumumab as the backbone treatment in multiple myeloma,” said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab. As part of an earlier collaboration agreement between Janssen and Amgen, a separate, ongoing Phase I study (MMY1001 EQUULEUS) is evaluating the safety and pharmacokinetics of daratumumab in combination with a number of backbone multiple myeloma therapies including carfilzomib in newly diagnosed and relapsed/refractory patients with multiple myeloma.

IRISH ULTIBRO SMPC NOW INCLUDES FLAME RESULTS Recently published in the New England Journal of Medicine (NEJM), the FLAME study results have now been EU approved for inclusion in the clinical section 5.1 of the Irish Summary of Product Characteristics (SmPC). In the 52-week FLAME study comparing Ultibro Breezhaler (n=1,675) and fluticasone/ salmeterol (n=1,679), Ultibro Breezhaler met the primary study objective of non-inferiority in rate of all COPD exacerbations (mild, moderate or severe) compared to fluticasone/salmeterol. The number of all COPD exacerbation per patient-years was 3.59 for Ultibro Breezhaler (4,531 events) and 4.03 for fluticasone/salmeterol (4,969 events). Ultibro Breezhaler further showed superiority in reducing the annualised rate of all exacerbations (mild, moderate and severe) by 11% versus fluticasone/ salmeterol (p=0.003). Compared to fluticasone/ salmeterol, Ultibro Breezhaler reduced the annualised rate of both moderate or severe exacerbations by 17% (p<0.001), and of severe exacerbations (requiring hospitalisation) by 13% (not statistically significant, p=0.231). The number of moderate or severe COPD exacerbations/ patient-years was 0.98 for Ultibro Breezhaler (1,265 events) and 1.19 for fluticasone/salmeterol (1,452 events). Ultibro Breezhaler prolonged time to first moderate or severe exacerbation with a 22% reduction in risk of an exacerbation (p<0.001) and prolonged time to first severe exacerbation with a 19% reduction in risk of an exacerbation (p=0.046). The incidence of pneumonia was 3.2% in the Ultibro Breezhaler arm compared to 4.8% in the fluticasone/salmeterol arm (p=0.017). Time to first pneumonia was prolonged with Ultibro Breezhaler compared to fluticasone/salmeterol (p=0.013). Please refer to the newly updated SmPC on www.medicines.ie .


47 UNIQUE RESULTS SHOW DIVITUM™ ABLE TO EVALUATE ANTI-TUMOR ACTIVITY OF CANCER DRUG New clinical study results presented at the San Antonio Breast Cancer Symposium, the world’s leading breast cancer conference, 6-10 December 2016, demonstrate that Biovica’s DiviTum™ biomarker assay can evaluate the efficacy of the novel breast cancer drug palbociclib (Ibrance®, Pfizer). The US study, performed by Dr Cynthia Ma, St Louis, investigated 50 women with clinical stage II or III estrogen receptor positive, HER2 negative breast cancer, treated with anastrozole in combination with palbociclib prior to surgery. DiviTum™ was used to measure levels of thymidine kinase (TK) activity, an enzyme closely linked to cell proliferation rate, in blood samples collected before and after treatment. Results demonstrate a highly significant correlation between the antiproliferative effect of palbociclib and the reduction in TK levels measured by DiviTum™ post 2 weeks of adding palbociclib and at the time of surgery. The assay may thus serve as an early indicator of treatment response by CDK 4/6 inhibitors like palbociclib. “Our study provides the first clinical evidence of a method, DiviTum™, for palbociclib treatment effect in breast cancer. The results are very promising and support future studies of DiviTum™ to evaluate and identify patients for response to CDK 4/6 inhibitors,” says Dr Cynthia Ma, MD, PhD, Associate Professor of Medicine, Washington University School of Medicine, St Louis, US. Breast cancer is the most common form of cancer among women today, affecting approximately 362,000 individuals in EU and 233,000 in the US each year. Around 1,600 new cases are diagnosed every day and 136,000 deaths occur annually (EU+US). Palbociclib was FDA-approved in February 2015. In the drug’s first year on the US market, more than 20,000 women were prescribed the medicine, whose sales are estimated to exceed $ 2 billion in 2016. In November 2016 palbociclib was approved in the EU. “These first results correlating DiviTum™ to palbociclib efficacy are highly promising since there

are no other biomarkers available for CDK 4/6 inhibitors today. We aim to provide DiviTum™ as a tool for clinicians to optimize the survival and quality-of-life benefits gained by patients treated with this new class of drugs,” says Anders Rylander, CEO Biovica.

SCIENTISTS DEVELOP SMART KNEE DEVICE Recuperation from knee surgery, such as arthroscopy or knee replacement, can take some time, varying from three months to one year depending on the patient. A new ‘smart knee’ device could improve and accelerate recovery from knee surgery, thanks to scientists at Tyndall National Institute and GermanSerbian software SME, Nissatech Innovation Center. The intelligent device, which is attached to the knee during postop care, is currently being trialled in a Budapest Hospital, and could be on the market in two years if clinicians and patients alike enjoy the benefits predicted by the scientists and their research in this area. “Typically after knee surgeries, patients need to undergo a rehabilitation process to strengthen muscles and regain their mobility. Much of the post op exercises are expected to take place at home where they cannot be observed by medical staff,” explains Principal Investigator for the gateone project at Tyndall, Thomas Healy. “The ‘smart knee’ system remotely monitors the patients progress, through a knee movement sensor developed at Tyndall National Institute, and based on the progress the patient makes, the rehabilitation program can be adapted and personalized to the patient. The sensor and the data provided to the physician is invaluable in the recovery process, which is the real value of the ‘smart knee’,” he added. The ‘smart knee’ is just one of many innovations that is being shared with the international SME community through the gateone project. Encouraging small and medium sized businesses to take advantage of the world-class technologies, the EU funded gateone project is sharing a concept portfolio with SMEs across Europe and providing funding to help bridge the gap from R&D to market-ready products.

Tyndall selected four of its key technology platforms to be part of the gateone portfolio, including wearable technologies, microneedle-based transdermal delivery systems, energy management systems and electrochemical sensors. The Smart Knee is the first Tyndall demonstrator through gateone to be provided to an SME for real environment trials and leverages work developed by Tyndall researcher Salvatore Tedesco in CONNECT, the Science Foundation Ireland Research Centre for Future Networks and Communications. The EU Innovation Union Scoreboard 2016 has confirmed Ireland’s credentials as the ‘leader’ in innovation in small and medium sized companies. Tyndall is eager to continue this excellent performance and is calling on SMEs to take advantage of the opportunities presented through gateone, to continue to grow this sector of the economy. The gateone project is funded through the European Horizon 2020 plan, the largest European research fund of its kind, with a fund of ¤80 billion, financing EU research projects over 7 years.

INTAS PHARMACEUTICALS COMPLETES DEAL TO ACQUIRE ACTAVIS UK & IRELAND Intas Pharmaceuticals Ltd. (“Intas”), through its wholly owned subsidiary Accord Healthcare Ltd. (“Accord”), announced it has completed the deal to acquire Actavis UK Ltd. & Actavis Ireland Ltd. (“Actavis UK & Ireland”) from Teva Pharmaceutical Industries Ltd. (“Teva”), for an enterprise value of £603 million payable in cash. The transaction is part of the European Commission’s anti-trust divestiture requirements arising from Teva’s acquisition of Allergan’s generics business. Following the completion of the acquisition, Accord strengthens its footprint in the UK and Ireland retail market to become a leading player in the industry at European level, while Intas becomes a top 20 generic player globally. The combination with Actavis UK Ltd. and Actavis Ireland gives Accord an exciting opportunity to build on its already strong position in the market, providing the Company with increased access to UK and Irish retail and hospital markets. The combination of these two high performing businesses, expands Accord’s UK manufacturing

presence with the addition of the GMP Barnstaple site owned by Actavis, resulting in a combined regional base revenue of more than half a billion euros per year, and a workforce of more than 1,000 employees. “The completion of this acquisition captures a great opportunity for growth and demonstrates Intas’ commitment to greater European expansion”, says Mr Binish Chudgar, Vice Chairman and Managing Director of Intas. “The joining of these two companies, means we can continue our successful European operating path, which started more than a decade ago. We are a leading generics player in the UK market, with a clear plan for continued growth and development of the Barnstaple site and the Actavis team. Through our subsidiary, Accord Healthcare, we are welcoming the Actavis team into the Intas family and will ensure a smooth integration of the two businesses”, Chudgar added. James Burt, Executive Vice President Europe & MENA for Accord comments “Under the banner ‘Growing Together’, we are excited to be starting on a journey with Actavis to work towards our vision of having a fully integrated, comprehensive offering of affordable medicines and ensuring patient access to effective healthcare across Europe.” Sara Vincent, Actavis SVP UK and Ireland comments “We are excited to join the Intas/Accord family. This is a great opportunity to build on the strengths of both organisations and we look forward to the future growth opportunities” This acquisition further demonstrates Accord’s commitment to UK manufacturing, adding to the recent significant investment to reinstate a facility in Newcastle. The Barnstaple plant will become one of Accord’s four UK sites, ensuring the company has one of the most extensive local supply chains to service pharmacies, clinicians, hospitals and wholesalers across UK and Ireland, and into Europe.

HPN • January 2017


INTRODUCING ZEPATIER® (elbasvir and grazoprevir) A fixed-dose combination of a second-generation NS3/4A protease inhibitor and NS5A inhibitor 1,2

MULTIPLE PATIENT TYPES1 CHALLENGING COMORBIDITIES1 POWERFUL CURE* INDICATION: ZEPATIER is indicated for the treatment of chronic hepatitis C (CHC) genotype 1 or 4 infection in adults.1

95

% (291/306)

of the overall treatment-naïve (TN) patient population achieved SVR12 with 12 weeks of ZEPATIER, no RBV1

98% (135/138) of TN patients with compensated cirrhosis achieved SVR12 with 12 weeks of ZEPATIER, no RBV1,3 • Integrated analysis included data from C-EDGE TN, C-EDGE COINFECTION, C-SURFER, and C-WORTHY

C-EDGE TN—Double-blind, placebo-controlled,TN patients with or without cirrhosis, ZEPATIER for 12 weeks. G1 (n=288), G4 (n=18)1 *Cure of hepatitis C virus (HCV) infection=sustained virologic response, the primary end point in all studies, defined as HCV ribonucleic acid (RNA) less than the lower limit of quantification (LLOQ) at 12 weeks after the cessation of treatment (SVR12).1,4 G=genotype; RBV=ribavirin.

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 of the SPC for how to report adverse reactions. ABRIDGED PRODUCT INFORMATION Refer to Summary of Product Characteristics before prescribing. PRESENTATION Film-coated tablets containing 50 mg elbasvir and 100 mg grazoprevir. INDICATIONS Treatment of chronic hepatitis C (CHC) genotype 1a, 1b or 4 infection in adults. DOSAGE AND ADMINISTRATION See SPC for full details. Treatment should be initiated and monitored by a physician experienced in the management of CHC. Recommended dose is one tablet once daily. HCV genotype

Treatment and duration

1a

ZEPATIER for 12 weeks ZEPATIER for 16 weeks plus ribavirin should be considered in patients with baseline HCV RNA level >800,000 IU/ml and/or the presence of specific NS5A polymorphisms causing at least a 5-fold reduction in activity of elbasvir to minimise the risk of treatment failure.

1b

ZEPATIER for 12 weeks

4

ZEPATIER for 12 weeks ZEPATIER for 16 weeks plus ribavirin should be considered in patients with baseline HCV RNA level >800,000 IU/ml to minimise the risk of treatment failure.

No dose adjustment required in patients with mild, moderate, or severe renal impairment (including patients receiving haemodialysis or peritoneal dialysis). CONTRAINDICATIONS Hypersensitivity; moderate or severe hepatic impairment (Child-Pugh B or C); co-administration with OATP1B inhibitors or CYP3A inducers or P-gp inducers. PRECAUTIONS AND WARNINGS Assess hepatic function prior to therapy, at treatment week 8, and as clinically indicated. For patients receiving 16 weeks of therapy, also assess hepatic function at week 12. Advise patients to seek medical advice immediately if they have fatigue, weakness, lack of appetite, nausea and vomiting, jaundice or discoloured faeces. Consider discontinuing therapy if ALT levels >10 x ULN. Discontinue therapy if ALT elevation is accompanied by signs or symptoms of liver inflammation, increased conjugated bilirubin, alkaline phosphatase, or INR. Not recommended in genotypes 2, 3, 5 and 6. Safety and efficacy not studied in HCV/HBV co-infected patients. Contains lactose and 69.85 mg of sodium per dose. Children and adolescents: not recommended. INTERACTIONS Co-administration with strong CYP3A inhibitors not recommended. Concentrations of dabigatran may increase when co-administered with elbasvir, with possible increased bleeding risk. Clinical and laboratory monitoring is recommended. When co-administered with ZEPATIER, daily the dose of atorvastatin, fluvastatin, lovastatin or simvastatin should not exceed 20 mg and the daily dose of rosuvastatin should not exceed 10 mg. When co-administered, monitor

tacrolimus whole blood concentrations, changes in renal function, and for tacrolimus-associated adverse events. PREGNANCY AND LACTATION Use in pregnancy only if the potential benefit justifies the potential risk to the foetus. When used with ribavirin, women of childbearing potential must use effective contraception during treatment and for a period post -treatment. Breast-feeding should be discontinued during Zepatier therapy. SIDE EFFECTS Refer to SmPC for complete information on side-effects. In clinical studies, the most commonly reported adverse reactions were fatigue and headache. Less than 1% of subjects treated with ZEPATIER with or without ribavirin had serious adverse reactions (abdominal pain, transient ischaemic attack and anaemia). Very common: headache; fatigue Common: decreased appetite; insomnia, anxiety, depression; dizziness; nausea, diarrhoea, constipation, upper abdominal pain, abdominal pain, dry mouth, vomiting; pruritus, alopecia; arthralgia, myalgia; asthenia, irritability. Serum Late ALT elevations: During clinical studies with ZEPATIER with or without ribavirin, < 1% of subjects experienced elevations of ALT > 5 x ULN, generally at or after treatment week 8. These were typically asymptomatic, resolving with on-going therapy or after completion of therapy. PACKAGE QUANTITIES Packs of 28 tablets. Legal Category: POM. Marketing Authorisation Number EU/1/16/1119/001. Marketing Authorisation Holder Merck Sharp & Dohme Limited, Hertford Road, Hoddesdon, Hertfordshire, EN11 9BU United Kingdom. Date of revision: July 2016. © Merck Sharp and Dohme Ireland (Human Health) Limited 2016. All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin D18 X5K7 or from www.medicines.ie. Date of preparation: September 2016. References: 1. Data on file, MSD. 2. Clark VC, Peter JA, Nelson DR. New therapeutic strategies in HCV: second-generation protease inhibitors. Liver Int. 2013;33(suppl 1):80–84. 3. Kwo P, Jacobson I, Lawitz E, et al. Elbasvir/grazoprevir in cirrhotic patients with HCV infection. Poster presented at: 25th Asian Pacific Association for the Study of the Liver; February 20-24, 2016; Tokyo, Japan. 4. European Association for the Study of the Liver. Recommendations on treatment of hepatitis C 2015. J Hepatol. 2015;63:199–236. Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie Adverse events should also be reported to MSD (Tel: 01-299 8700)

Before prescribing ZEPATIER, please read the Summary of Product Characteristics.

Red Oak North, South County Business Park, Leopardstown, Dublin D18 X5K7 Ireland

(elbasvir and grazoprevir) tablets

INFC-1186850-0006

ZEPATIER® ▼ (elbasvir/grazoprevir)

HPN January 2017  
HPN January 2017  
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