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HPN February 2017

Issue 35

HOSPITAL PROFESSIONAL NEWS IRELAND Ireland’s Dedicated Hospital Professional Publication

IN THIS ISSUE: NEWS: HSE on Breach of Contract Page 5 REPORT: Cancer rates in decline says Annual Report Page 10

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PharmaSource was the first to market with our website. Others have tried to mimic but none can compare. Our site allows you to check stock levels in real time, confirm pricing, reprint monthly invoices and keep a record of what unlicensed medicines you have ordered for audit purposes. Placing your order with PharmaSource has never been easier.

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CLINICAL: 5th Annual 3U Diabetes Conference 2017 Page 17 CPD: Management of Dyslipidaemia Page 23 FEATURE: Dysphagia in Stroke Patients Page 31 CONFERENCE: Issues from 'bench to bedside' Page 34


FIRST LINE CLL GAZYVARO ▼(obinutuzumab) is the only antibody with proven superiority vs. MabThera 1 (rituximab) in first-line CLL ®

®

ENGINEERED FOR S U P E R I O R I T Y EFFECTIVE IN THE R E A L W O R L D 1 Indication: GAZYVARO in combination with chlorambucil is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL) and with comorbidities making them unsuitable for full-dose fludarabine based therapy.

ABRIDGED PRESCRIBING INFORMATION (For full prescribing information refer to the Gazyvaro Summary of Product Characteristics [SmPC]). Gazyvaro®▼ (obinutuzumab) 1,000 mg concentrate for solution for infusion Indication: Chronic Lymphocytic Leukaemia (CLL): In combination with chlorambucil for the treatment of adult patients with previously untreated CLL and with comorbidities making them unsuitable for full-dose fludarabine therapy. Follicular Lymphoma (FL): In combination with bendamustine followed by Gazyvaro maintenance for the treatment of patients with FL who did not respond or who progressed during or up to 6 months after treatment with rituximab or a rituximab-containing regimen. Dosage & Administration: Administer as an IV infusion through a dedicated line after dilution, with full resuscitation facilities immediately available and under supervision of an experienced physician. Do not administer as IV push or bolus. Prophylaxis and premedication for Tumour Lysis Syndrome (TLS): Patients with high tumour burden and/or a high circulating lymphocyte count (>25 x 109/L) and/or renal impairment (CrCl) <70mL/min) are considered at risk of TLS and should receive prophylaxis. Prophylaxis should consist of adequate hydration and administration of uricostatics e.g. allopurinol, or suitable alternative treatment such as urate oxidase (e.g. rasburicase), starting 12-24 hours prior to start of therapy. Patients should continue to receive repeated prophylaxis prior to each subsequent infusion, if deemed appropriate. Prophylaxis and premedication for infusion-related reactions (IRRs): Hypotension, as a symptom of IRRs, may occur during Gazyvaro infusions; consider withholding antihypertensives for 12 hours prior to and throughout each infusion and for the first hour after administration. Administer premedication before each infusion - see SmPC for further details. Duration of treatment: CLL, in combination with chlorambucil: 6 treatment cycles each of 28 days duration. Dose: Cycle 1: 1,000 mg split over Day 1 (100 mg) and Day 2 (900 mg; if the first bag is completed without modifications of the infusion rate or interruptions, the second bag may be administered on day 1, with no need for dose delay or repetition of premedication); 1,000 mg on Day 8; and 1,000 mg on Day 15 of a 28-day treatment cycle. Cycles 2 - 6: 1,000 mg on Day 1. FL: Induction with 6 cycles of 28 days in combination with bendamustine, followed by Gazyvaro single-agent maintenance (if patients responded or had stable disease after induction) once every 2 months for two years or until disease progression (whichever occurs first). Maintenance: 1,000 mg. Administration: Monitor closely for IRRs. CLL, in combination with chlorambucil: Cycle 1: Day 1 (100 mg): Administer at 25 mg/ hr over 4 hours. Do not increase the infusion rate. Day 2 (or Day 1 continued) (900 mg): If no IRR occurred during the previous infusion, administer at 50 mg/hr. Infusion rate can be escalated in increments of 50 mg/hr every 30 minutes to a maximum of 400 mg/hr. Cycle 1: Day 8 and Day 15 and Cycles 2 - 6: Day 1 (1,000 mg): If no IRR occurred during the prior infusion, when the final infusion rate was 100 mg/hr or faster, administer at 100 mg/hr, with escalation by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. FL, in combination with bendamustine: Cycle 1: Day 1(1,000 mg): Administer at 50 mg/ hr. The rate of infusion can be escalated in 50 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. Cycle 1: Day 8 and Day 15 and Cycles 2 - 6: Day 1 (1,000 mg): If no infusion related reaction occurred during the prior infusion when the final infusion rate was 100 mg/hr or faster, infusions can be started at a rate of 100 mg/hr and increased by 100 mg/hr increments every 30 minutes to a maximum of 400 mg/hr. Maintenance: Every two months for two years or until disease progression (whichever occurs first). Management of IRRs may require temporary interruption, reduction in rate of infusion, or treatment discontinuations – see SmPC for further details. Contraindications: Hypersensitivity to any component of this product. Warnings & Precautions: Include the trade name and batch number of the administered product in the patient records to improve traceability of biological medicinal products. IRRs: Most frequently observed during infusion of first 1,000 mg with most patients having no IRRs during subsequent administrations. Mitigation measures to reduce IRRs should be followed (see SmPC). IRRs may be related to cytokine release syndrome which has also been reported in Gazyvaro treated patients. Patients with a high tumour burden and/or high circulating lymphocyte count in CLL (> 25 x 109/L) may be at increased risk of severe IRRs. Patients with renal impairment (CrCl < 50 mL/min) and with both Cumulative Illness Rating Scale (CIRS) > 6 and CrCl < 70 mL/min are more at risk of IRRs, including severe IRRs. Do not administer further infusions if patient experiences acute life-threatening respiratory symptoms, a Grade 4 (life threatening) IRR or, a second occurrence of a Grade 3 (prolonged/recurrent) IRR (after resuming the first infusion or during a subsequent infusion). Carefully monitor patients who have pre-existing cardiac or pulmonary conditions throughout the infusion and post-infusion period. For patients at acute risk of hypertensive crisis evaluate the benefit and risks of withholding anti-hypertensive medicine. Hypersensitivity reactions including anaphylaxis: Anaphylaxis has been reported. Hypersensitivity may be difficult to distinguish from IRRs. If a hypersensitivity reaction is suspected during infusion, stop the infusion and permanently discontinue Gazyvaro. Patients with known IgE mediated hypersensitivity to obinutuzumab must not be treated. TLS: TLS has been reported – see Dosage & Administration for suggested prophylaxis. All patients considered at risk should be carefully monitored during the initial days of treatment with a special focus on renal function, potassium, and uric acid values. Neutropenia: Severe and life-threatening neutropenia including febrile neutropenia has been reported and patients with renal impairment (CrCl <50 mL/min) are more at risk. Patients with neutropenia should be closely monitored with regular laboratory tests until resolution. Treat in accordance with local guidelines and consider administration of G-CSF. Consider dose delays with severe or life-threatening neutropenia. For severe neutropenia lasting > 1 week, antimicrobial prophylaxis strongly recommended throughout the treatment period until resolution to Grade 1 or 2. Antiviral and antifungal prophylaxis should be also considered. Cases of late onset neutropenia (occurring >28 days after treatment end) and prolonged neutropenia (lasting >28 days after treatment end) have also been reported. Thrombocytopenia: Severe and life-threatening thrombocytopenia including acute thrombocytopenia (occurring within 24 hours after infusion) has been observed during treatment and patients with renal impairment (CrCl <50 mL/min) are more at risk. Fatal haemorrhagic events have also been reported in Cycle 1 of treatment. A clear relationship between thrombocytopenia and haemorrhagic events has not been established. Monitor patients closely especially during the first cycle; perform regular laboratory tests until event resolution, consider dose delays in cases of severe or life-threatening thrombocytopenia. Transfusion of blood products at the discretion of the treating physician. Use of any concomitant therapies which could worsen thrombocytopenia events should be taken into consideration particularly during the first cycle. Worsening

of pre-existing cardiac conditions: May occur as part of an IRR and can be fatal. Patients with a history of cardiac disease should be monitored closely and hydrated with caution to prevent fluid overload. Infections: Do not administer Gazyvaro in the presence of an active infection and exercise caution when considering use in patients with a history of recurring or chronic infections. Fatal infections have been reported. In patients with both CIRS>6 and CrCl<70 mL/min, an increased incidence and severity of infections was observed. Hepatitis B reactivation: HBV reactivation, some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with anti-CD20 antibodies including Gazyvaro. Perform HBV screening (including HBsAg and HBcAb-status) before initiating treatment. Patients with active hepatitis B disease should not be treated and those with positive hepatitis B serology should consult liver disease experts before start of treatment and be monitored and managed to prevent hepatitis reactivation. Progressive Multifocal Leukoencephalopathy (PML): PML has been reported and PML diagnosis should be considered in any patient presenting with new-onset or changes to pre-existing neurologic manifestations. Evaluation of PML includes consultation with a neurologist, brain MRI and lumbar puncture. Treatment should be withheld during investigation of potential PML; permanently discontinued if PML confirmed and refer patient to a neurologist. Immunisation: The safety of immunisation with live or attenuated viral vaccines following Gazyvaro therapy has not been studied and vaccination with live virus vaccines is not recommended during treatment and until B cell recovery. Drug Interactions: No formal drug-drug interaction studies have been performed. A risk for interactions with other concomitantly used medicinal products cannot be excluded. Obinutuzumab is not a substrate, inhibitor or inducer of CYP450, UGT enzymes and transporters such a P-glycoprotein; therefore no pharmacokinetic interactions expected with drugs known to be metabolised by these enzyme systems. Fertility, Pregnancy & Lactation: Women of childbearing potential must use effective contraception during and for 18 months after treatment. Gazyvaro should not be administered to pregnant women unless the possible benefit outweighs the potential risk. Side Effects and Adverse Reactions: Very common (≥ 1/10): Upper respiratory tract infection, sinusitis, neutropenia, thrombocytopenia, anaemia, cough diarrhoea, constipation, arthralgia, pyrexia, asthenia, IRRs. Common (≥1/100 to <1/10): urinary tract infection, nasopharyngitis, oral herpes, rhinitis, pharyngitis, lung infection, influenza, squamous cell carcinoma of skin, leukopenia, lymph node pain, TLS, hyperuricaemia, depression, ocular hyperaemia, atrial fibrillation, cardiac failure, hypertension, nasal congestion, rhinorrhoea, dyspepsia, colitis, haemorrhoids alopecia, pruritus, night sweats, eczema, back pain, musculoskeletal chest pain, pain in extremity, bone pain, dysuria, urinary incontinence, chest pain, WBC count decreased, neutrophil count decreased, weight increased. Elderly: Patients with CLL aged ≥75 years experienced more serious adverse events leading to death than patients < 75 years. No clinically meaningful differences in safety according to age in the pivotal study in iNHL. Refer to SmPC for full listings of adverse events. See SmPC section 4.8 for instructions on reporting of suspected adverse events. Legal Category: Product subject to medical prescription which may not be renewed (A). Presentations & Marketing Authorisation Number: 1,000 mg of obinutuzumab in 40 mL (25 mg/mL) pack of 1 vial (EU/1/14/937/001). Marketing Authorisation Holder: Roche Registration Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom. Gazyvaro is a registered trade mark. Further information is available from Roche Products (Ireland) Limited, 3004 Lake Drive, Citywest, Naas Road, Dublin 24. Telephone: (01) 4690700. Fax: (01) 4690791. Date of Preparation: June 2016 ▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you become aware of. In the event of a suspected adverse event, please report it to: The Drug Surveillance Centre, Roche Products (Ireland) Limited Telephone: (01) 4690700 Fax: (01) 469 0793 Email: ireland.drug_surveillance_centre@roche.com Alternatively, suspected adverse reactions should be reported to: The Pharmacovigilance Section, Health Products Regulatory Authority (HPRA) Telephone: (01) 676 4971 Fax: (01) 676 2517 Website: www.hpra.ie Email: medsafety@hpra.ie References: 1. Goede V et al. N Engl J Med 2014; 370:1101-1110 and Supplementary Appendix Date of item: September 2016. IE/GAZ/0515/0004(2)


3

HPN February 2016 Issue 35

Contents

Foreword

Mental Health roadmap on the way, says HSE P5

Editor

Kelly Jo Eastwood There are over 400 vacant Consultant positions in Ireland’s health service, which is facing a ‘medical brain’ drain. These are the words of Irish Hospital Consultants Association Secretary General Martin Varley.

New treatment reimbursed for metastatic colorectal cancer P8

6

Calls to reduce Type 2 Diabetes burden P12

As a consequence of that decision, the EAT determinations must now be implemented in full by the HSE including the payment of the unlawful salary deductions.

New aspects in Diabetes treatment P17

Mr Varley went on to say the vacant post situation is ‘undermining the quality and safety of patient care, increasing delays in providing care and is leading to longer waiting lists.’

17

Improving mortality with early detection P20

Turn to page 5 for the full story. We look at the European Society of Cardiology’s latest guidelines in our CPD section this issue, and reflect on the management of dysphagia in stroke patients on page 31.

Regulars Feature: Anticoagulants P28 20

CPD: Dyslipidaemia P23

Event Gallery: P45 45

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.

PUBLISHER IPN Communications Ireland Ltd Clifton House, Lower Fitzwilliam Street, Dublin 2 (01) 669 0562 MANAGING DIRECTOR Natalie Maginnis n-maginnis@btconnect.com EDITOR Kelly Jo Eastwood kjeastwood@hotmail.com 00447876548989 ACCOUNTS Rachel Wilson cs.ipn@btconnect.com

Elsewhere in this issue, we cover the key issues discussed at the Health Research Board’s conference, HRB30. Researching how healthcare itself is delivered, and engaging policymakers and healthcare professionals in health research were some of the emerging key themes. One of the speakers was Professor Mike Kelly, a former Director within the National Institute for Health and Care Excellence in the UK, who urged delegates to ‘think slow’ about how research moves to influence policy and practice, and the need for health researchers to engage with policy makers, journalists and end users to translate their research.

Feature: Chronic Pain P38

Clinical Profiles: P46

Mr Varley was speaking as the association welcomed the HSE decision to withdraw its appeal against the Employment Appeals Tribunal (EAT) determinations which found in favour of two IHCA members Dr Tom Hogan and Dr John McDermott.

COMMERCIAL MANAGER Sharon Kennedy Sharon@ipnirishpharmacynews.ie

Mobile: 0044 7765 236886

Keynote speaker Dr Tony Holohan, Chief Medical Officer, reinforced that bringing health research into practice is complex. “Medical and healthcare progress is linked to a strong health research community,” he said. “Nevertheless, the traditional model of laboratory to bedside to patient to population in a linear fashion seems limited. A wider appreciation of health and the factors that influence it such as social determinants, which go way beyond the reach of traditional healthcare, is needed.” Turn to page 34 for the full coverage. Finally, the pertinent issue of biosimilars continues to gather apace, as new and important interventions to current debates about biosimilar interchangeability have been made by the European Society for Medical Oncology (ESMO), the USA's Food and Drug Administration (FDA) and a collection of scientists from national medicines regulators.

Marcel Levi

The public positioning comes as an increasing number of biosimilar products coming to market in an environment where cost pressures highlight the need to utilise less expensive medicinal products where this can be done without detriment to patient treatment or safety.

Professor Ian Graham

You can read more about this on page 41.

CONTRIBUTORS

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

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


4 News

Reform still required on medicines savings As Hospital Professional News was going to press, leading experts on medicine usage trends across Europe were telling a conference that Ireland’s lack of medicines competition is forcing Irish patients to needlessly spend more on expensive drugs.

Abasaglar, has sold a total of 153 packs over the past 12 months, compared to more than almost 135,000 sales for the more expensive equivalent biologic medicine, Lantus. There are over 225,000 diabetes sufferers in Ireland (diabetes.ie).

The event was organised by the Healthcare Enterprise Alliance (HEA), the representative body of leading Irish pharmaceutical providers, and heard how measures included in the Government's recent pricing agreement with certain pharmaceutical manufacturers is failing to deliver the best possible value.

Only two better value biosimilar medicines have entered the Irish market in the past year. For biosimilar manufacturers, blockages and the lack of supportive biosimilar policies mean Ireland is neither attractive nor sustainable, and ultimately will not deliver the best possible savings for patients and taxpayers.

While the Government’s agreement can certainly be commended for attempting to generate savings of up to 30% for an off-patent biologic medicine, the HEA said it was ‘signalled at the time of its announcement that the inclusion of such a clause would only lead to a restriction on the entry of lower cost biosimilar medicines and reduce their uptake. Analysis of drug sales since the agreement support’s the HEA’s view.’ Data was presented which shows that in one instance, a better value biosimilar medicine introduced last September, Benepali, used to treat rheumatoid arthritis, sold just three packs in four months, compared to more than 19,000 sales for the more expensive equivalent biologic medicine, Enbrel. In Ireland, around 40,000 people, or 1% of the population, are living with arthritis (arthritisireland.ie). In the case of diabetes medicine, a better value biosimilar drug,

However, the Irish Pharmaceutical Healthcare Association (IPHA), which represents the research based pharmaceutical industry in Ireland, has strongly refuted the claims by the Healthcare Enterprise Alliance (HEA) that the new pricing Agreement negotiated with the State last summer is not bringing value. According to Oliver O’Connor, CEO of the IPHA, “The IPHA Agreement is now delivering savings of ¤12 million per month since it started on 1st August – on target for ¤140m in its first year. It is travesty for others to suggest we are not delivering value. There is no evidence that any other Association or other pharmaceutical companies are delivering savings to the State of anything like this scale. Nor have they set out any plans to do so,” he said. “The Agreement we negotiated with the State is delivering a package of measures with the

State that will deliver over ¤785 million in savings to the taxpayer up to 2020. That is the largest ever such package of savings the research-based pharmaceutical has delivered to State. “Savings from the entry of biosimilars into Ireland are part of this package and have already started. We estimate that these savings will be over ¤100m.” The IPHA CEO dismissed HEA claims that the Agreement was essentially blocking the uptake of biosimilars due to a 30% price cut in originator biologics when a competitor biosimilar comes on the market: “This claim is totally spurious. The 30% price cut on loss of exclusively is providing the State with savings already. These savings are not contingent on the subsequent uptake or market share of biosimilars. IPHA agreed

this mechanism specifically so that the State can invest in new medicines”. Mr O’Connor noted that many of the biosimilars that will launch in the near future are actually manufactured by IPHA companies. He also noted that as investment in the development of a biosimlar is significantly less than an originator biologic, the State should expect a biosimilar manufacture to launch with at least a 30% discount. “The pricing Agreement IPHA negotiated with the State is working and is delivering very substantial savings to the State. Prices are set at an average of 14 other EU member states and will be kept at this level each year. ” he concluded. More on this story in the March issue of HPN.

Calls for budget meeting on Hospital costs Labour spokesperson on Finance, and member of the Oireachtas Budgetary Oversight Committee, Joan Burton TD has requested a special meeting to examine the estimated costs of the proposed children's hospital. "I wrote to the Budgetary Oversight Committee Chair, John Paul Phelan to request a special meeting to discuss the extraordinary costs now projected for the new Children's Hospital,” she said. "I have read various report's, and it appears the costs have increased enormously, way in excess than previous figures that were estimated. The original figure of ¤650 million has risen by nearly ¤350 million - close to ¤1 billion before the ¤200 million cost of IT and equipment. "The implications of these additional costs and the impact this will have on other spending profiles and on the fiscal space needs to be discussed. "While there will be an immediate impact on health, it will also have consequences across the entire capital budget of state when we have a serious requirement to invest in housing, schools and transport infrastructure. "A 50% increase in the cost of this one project will have serious repercussions for the capital budget if replicated in other Departments." The HSE said that the current capital budget is "entirely insufficient" to deal with the range of challenges it faces. The HSE said it had made provision for ¤68m to spend this year on the hospital - due to be built over four years. It's entire capital budget is ¤384m.

February 2017 • HPN


5

HSE reverses decision on Breach of Contract The Irish Hospital Consultants Association (IHCA) has welcomed the decision by the HSE to withdraw its appeal against the Employment Appeals Tribunal (EAT) determinations which found in favour of two IHCA members Dr Tom Hogan and Dr John McDermott. As a consequence, the EAT determinations must now be implemented in full by the HSE including the payment of the unlawful salary deductions. Commenting on the decision, Mr Martin Varley, Secretary General of the IHCA said, “It is very unfortunate that Dr Hogan and Dr McDermott were forced to the steps of the High Court to have their contract terms honoured. The

Martin Varley, General Secretary, IHCA

persistent and repeated refusal of the HSE to honour the 2008 Consultant Contracts has seriously undermined trust between hospital consultants and the HSE and is one of the key reasons that the Irish health service is experiencing an unprecedented medical brain drain. Today there are over 400 vacant permanent consultant posts in the Irish health service which is undermining the quality and safety of patient care, increasing delays in providing care and is leading to longer waiting lists.”

Work underway on Mental Health roadmap It is understood that work is underway on a roadmap for improved out-of-hours access to mental health services.

Minister of State for Mental Health and Older People, Helen McEntee

Minister of State for Mental Health and Older People, Helen McEntee TD, has received a petition of almost 12,000 signatures from Shari McDaid, on behalf of the Mental Health Reform, A Lust for Life, Uplift and Future Voices at Leinster House. Minister McEntee said that “Improving access to mental health services is a key priority for me as Minister and work is underway in this area. Anyone who needs help should be able to get it. We need to ensure that 7-day access is in place, across the country, before we move towards the provision of 24/7 access. We must walk before we can run. I am glad to say that

and in due course 24/7 access, to mental health services across the country.

specific actions are in place around many of the issues raised in the petition. For instance, the HSE set up a Service Improvement Project with a dedicated Project Manager in November 2016, to help ensure

that each region provides access to a weekend service for people currently attending the service. I am now working with my Department and the HSE on a roadmap to achieve both 7/7,

“Services for all adults and those under 18, are being developed in the light of significant new investment being made available for mental health, balanced against an acknowledged difficulty for the Executive in securing suitably qualified and experienced staff for this care programme. My objective, and that of the HSE, is to improve all aspects of mental health care nationally for all children and adults, including better access outside of normal working hours.”

Enhances patient medicines management at OLOL Hospital Our Lady of Lourdes Hospital in Drogheda has been working to enhance the control and compliance of ordering medicines between pharmacy and the wards while enhancing patient care. The Medicines Management Process Improvement project team was established at the hospital recently and included nursing, portering and Pharmacy representatives. The team was led by Senior Pharmacist Orla Nolan.

Last month the ‘Medicines Management Process Improvement' project team members received certificates of completion on ‘Healthcare Process Improvement Programme (Level 2)' from the RCSI Quality & Process Improvement Centre (QPIC). RCSI QPIC team facilitated very practical and applied QI training, where the team members were enabled to discuss different

challenges in the existing process and work together to gain consensus on a better way forward for all. At the certification process, Orla Nolan presented significant results to-date around time ‘reclaimed' for patient care by eliminating ‘non value add' activities, reduction in ‘out of hours' ordering and saving in medicines cost due to a more streamlined process.

Ms. Caitriona Crowley, OLOL General Manager and Kieran Tangney Executive Director RCSI QPIC presented the awards and commended the team on working together to deliver significant process improvements which benefit the teams and their patients.

HPN • February 2017


6 News

Recommendations to tackle medicine shortages The European associations representing manufacturers of medicinal products, parallel distributors, pharmaceutical wholesalers and pharmacists have announced a series of recommendations on the provision of information, designed to help tackle medicines shortages. Focusing on the transparency and the availability of medicine shortage data, the Associationsâ&#x20AC;&#x2122; statement is part of their wider commitment to tackling the issue. Evidence suggests it is an increasing problem across the European Union, having a significant impact on patients, on health professionals, on healthcare systems and suppliers. The recommendations call for greater transparency and availability of medicines shortage data, early detection and assessment of potential shortages, consistency of reporting, increased access to the information available across all parts of the supply chain, improved data infrastructure, and collaborative governance processes. The recommendations aim to mitigate the impact of shortages on patients, provide patients and health professionals with upto-date, meaningful information and improve the ability of health systems to diagnose and solve supply issues as they arise. This statement builds on existing good practices and recommends

some specific features of ideal medicines shortages information systems. The European associations representing manufacturers of medicinal products, parallel distributors, pharmaceutical wholesalers and pharmacists hope that, taking into consideration the national specificities of each country, these recommendations can help enhance information systems at a national level, and potentially form the basis of future European level action. Shortages of medicinal products are a growing issue of concern across the European Union and indeed globally (2012, 2014). There is increasing evidence that shortages occur across the EU and that a wide range of medicines are affected. Several factors can give rise to the cause of medicines shortages. The causes of shortages are understood to be multifactorial, including problems in production, global consolidation of manufacturing, unintended impacts of pricing and tendering policies, as well as problems within the supply chain. This paper does not expand further on issues of causation and, by extension, solution. Rather, it addresses the need for better information collection, communication and transparency in order to: ameliorate patient care impacts via improved management of shortages; and, to enhance understanding of the extent and nature of medicines shortages.

Despite steps already taken to address some of the causes of medicine shortages, the problem persists. It is clear that without reliable information regulators, industry, parallel distributors, pharmaceutical wholesalers, health professionals and, of course, patients, cannot take steps to limit the negative effects that interruptions in medicines supply have upon patient care and health system performance. European associations representing manufacturers of medicinal products, parallel distributors, pharmaceutical wholesalers and pharmacists have

come together to work jointly on proposed principles for improving collection, communication and transparency of information on shortages of medicines. Everyone is in agreement that reliable information systems are an essential step in communicating the problems of shortages. Whilst it is recognised that such systems need to be implemented at national level, and therefore to be responsive to specific national concerns and regulation, a number of principles underpin efficient, effective and reliable information systems.

EDQM open consultation on Automated Dose Dispensing Guidelines The European Directorate for the Quality of Medicines and Healthcare (EDQM) has opened a consultation on prospective European guidelines on Automated Dose Dispensing. The consultation will close on the 24th February 2017. The purpose of the guidelines is to harmonise the standards and approaches to automated dose February 2017 â&#x20AC;˘ HPN

dispensing across Europe, to help ensure that this service is provided to a consistently high standard which ensures the safe supply of medicines to patients. The guidelines are intended to be utilised by pharmacies and manufacturers involved in automated dose dispensing, as well as by national authorities in countries where this service is provided.

Commenting on the consultation, Aida Batista, EAHP Director of Professional Development and Patient Safety policy lead, remarked, "Automatic Dose Dispensing can be a powerful tool for patient safety as well as medication adherence. However, there are common challenges to be met in respect to its introduction and use. Therefore, EDQM's initiative to

produce guidelines to help ensure this service is provided to a consistently high standard across Europe, is to be welcomed. EAHP encourages engagement by hospital pharmacy in the EDQM project and will be making its own response to the survey.â&#x20AC;?


Targin 15mg/7.5mg & Targin 30mg/15mg Now Available!1

TArgiN tablets ®

Pain relief and patient wellbeing

2

Dual action therapy to treat severe pain3

‰ Oxycodone:

Powerful treatment for severe pain4

‰ Naloxone:

Counteracts opioidinduced constipation4

Targeting severe pain Indications: Severe pain, which can be adequately managed only with opioid analgesics. Second line symptomatic treatment of patients with severe to very severe idiopathic restless legs syndrome after failure of dopaminergic therapy. Naloxone is added to counteract opioid-induced constipation by blocking the action of oxycodone at opioid receptors locally in the gut. Dosage and administration: All available strengths of Targin are licensed for analgesia in line with the therapeutic indication. Targin 15/7.5mg and 30/15mg tablets are not licensed for use in RLS. Analgesia Adults over 18 years: Usual starting dose for opioid naïve patients: 10 mg/5 mg taken orally at 12-hourly intervals.Patients already receiving opioids may be started on higher doses depending on their previous opioid experience. Targin 5 mg/2.5 mg is intended for dose titration when initiating opioid therapy & individual dose adjustment. The dosage is dependent on the severity of the pain and the patient’s previous history of analgesic requirements. Maximum daily dose of Targin is 160 mg oxycodone hydrochloride & 80 mg naloxone ydrochloride. The maximum daily dose is reserved for patients who have previously been maintained on a stable daily dose of and who have become in need of an increased dose. Special attention should be given to patients with mild renal or hepatic impairment. Targin is not intended for the treatment of breakthrough pain. Please refer to SmPC for further details. Restless Legs Syndrome Adults over 18 years: Usual starting dose is 5 mg/2.5 mg at 12-hourly intervals. Titration on a weekly basis is recommended in case higher doses are required.The dosage should be adjusted to the sensitivity of the individual patient. Maximum daily dose of Targin is 60 mg oxycodone hydrochloride and 30 mg naloxone hydrochloride. Targin is indicated for patients suffering from RLS for at least 6 months who have failed on previous doperminergic therapy. RLS symptoms should be present daily and during daytime (≥ 4 days/week). Patients should be clinically evaluated at least 3 monthly. When no longer required Targin should be tapered down over a period of approx 1 week to reduce the risk of a withdrawal reaction. Analgesia/Restless Legs Syndrome Targin must be swallowed whole & not broken, chewed or crushed. Paediatric population: No data available. Contra-indications: Hypersensitivity to active substances or excipients, any situation where opioids are contra-indicated,

severe respiratory depression with hypoxia and/or hypercapnoea; severe COPD, cor pulmonale, severe bronchial asthma, non-opioid induced paralytic ileus, moderate to severe hepatic impairment. History of opioid abuse. Precautions and warnings: Respiratory depression, elderly or infirm, opioid-induced paralytic ileus, severely impaired pulmonary function, sleep apnoea, myxoedema, hypothyroidism, adrenocortical insufficiency, toxic psychosis, cholelithiasis, prostate hypertrophy, alcoholism, delirium tremens, pancreatitis, hypo- or hypertension, pre-existing cardiovascular diseases, head injury, epileptic disorder, predisposition to convulsions, patients taking MAO inhibitors, history of alcohol/drug abuse, galactose intolerance, Lapp lactase deficiency, glucosegalactose malabsorption, mild hepatic or renal impairment, pre-operative use or within the first 12 - 24 hours post-operatively. Not suitable for treatment of withdrawal symptoms. Not recommended in cancer associated with peritoneal carcinomatosis or sub-occlusive syndrome in advanced stages of digestive & pelvic cancers. Concomitant use of alcohol and Targin may increase the undesirable effects of Targin and should be avoided. Caution advised if combining with other sedating medicinal products due to potential additive effects. Refrain from driving or operating machines if somnolence/sudden sleep onset experienced. Tolerance and dependence may occur. It may be advisable to taper dose when stopping treatment to prevent withdrawal symptoms. Caution is advised in treating restless legs syndrome patients with additional sleep apnoea syndrome with Targin due to the additive risk of respiratory depression. No data about the risk exist because in the clinical trial patients with sleep apnoea syndrome were excluded. There is no clinical experience with Targin in the longterm treatment of RLS beyond 1 year. Interactions: Substances having a CNSdepressant effect (e.g. other opioids, sedatives, hypnotics, anti-depressants, phenothiazines, neuroleptics, anti-histamines and anti-emetics) may enhance CNS-depressant effect of Targin (e.g. respiratory depression). Alcohol may enhance the pharmacodynamic effects of Targin; concomitant use should be avoided. Interaction with coumarin anticoagulants may increase/decrease INR. Inhibitors or inducers of CYP3A4 or CYP2D6 may affect the metabolism of oxycodone. Dose titration may be necessary. Pregnancy and lactation: Not

References: 1. Targin® Summary of Product Characteristics. 2. Überall M, et al. Journal of Pain Research 2015:8 459-475. Results of a 12-week prospective, randomised, open-label, blinded endpoint parallel group study measuring pain intensity, functionality, quality of life and tolerability of treatment. 3. Nadstawek J, et al. Int J Clin Pract, August 2008; 62 (8): 1159–1167. 4. Simpson K, Leyendecker P, Hopp M, et al. Fixed-ratio combination oxycodone/naloxone compared with oxycodone alone for the relief of opioid-induced constipation in moderate-to-severe noncancer pain. Curr Med Res Opin 2008;24(12):3503-3512.

recommended. Side-effects: Common: decreased/loss of appetite, insomnia, altered mood and personality changes, decreased activity, psychomotor hyperactivity, dizziness, headache, somnolence, vertigo, hot flush, abdominal pain, constipation, diarrhoea, dry mouth, dyspepsia, flatulence, hiccups, vomiting, nausea, pruritus, skin reactions, hyperhidrosis, dysuria, asthenic conditions, fatigue, depression, disturbance in attention, tremor, paraesthesia, visual impairment, hepatic enzymes increased, chest pain, chills, thirst, pain, blood pressure decreased, blood pressure increased. Other side effects which are potentially serious: hypersensitivity, anaphylactic response, restlessness, confusion, agitation, reduced libido, depression, euphoric mood, hallucinations, convulsions, speech disorder, syncope, paraesthesia, sedation, drug dependence, migraine, concentration impairment, visual impairment, palpitations, angina pectoris, tachycardia, decrease in blood pressure, increase in blood pressure, dyspnoea, respiratory depression, tooth disorder, dysphagia, ileus, melaena, gingival bleeding, hepatic enzymes increase, cholestasis, biliary colic, urticaria, erectile dysfunction, amenorrhoea, oedema, peripheral oedema, urinary retention, drug withdrawal syndrome, chest pain, injuries from accidents and drug tolerance. Refer to SPC for further details of other side-effects and oxycodone class-effects. Legal category: CD (Sch2) POM. Package quantities: Blisters of 56 tablets. Marketing Authorisation numbers: PA1688/010/001-4, PA1688/010/0067. Marketing Authorisation holder: Mundipharma Pharmaceuticals Limited, Millbank House, Arkle Road, Sandyford, Dublin 18. Tel: +353 (0)1 2063800. One of the Mundipharma/Napp independent associated companies. Date of preparation: March 2016. PI Code – UK/TARG-15013(1) Adverse events should 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. Adverse events should also be reported to Mundipharma Pharmaceuticals Limited on drugsafetyireland@mundipharma.ie or by phone on 01 2063800 (1800 991830 outside office hours) ® The Mundipharma device (logo) is a Registered Trade Mark. ® Targin is a Registered Trade Mark. © 2011-2012 Mundipharma Pharmaceuticals Limited. Date of item: July 2016. IRE/TRN-16006a

www.mundipharma.ie


8 News

IMO respond to Ireland's health workforce crisis Ireland faces significant issues in the area of medical staffing, possessing one of the lowest ratios of doctor to population in the developed world, at just 2.8 per 1,000 population, which compares to an EU average of 3.4.

of emigration amongst the medical profession.

practising in Ireland for the foreseeable future.

The organisation has examined the causes of these trends and made a series of recommendations to the Pay Commission in this regard.

Key recommendations from the IMO include:

Low medical staffing has been observed to have profoundly negative consequences for patient outcomes and the operation of healthcare systems, and is a contributing factor to hospital overcrowding. The limit that low medical staffing places on the ability of any given hospital to admit, diagnose, and treat patients who present to Irish healthcare services, is demonstrated by persistent capacity crisis within public hospitals in this country.

A factor contributing to the low number of doctors working in Ireland are unattractive working conditions and levels of remunerations that both drive emigration of doctors from Ireland, and inhibit the return of doctors who have already emigrated. The paucity of these conditions of work affect all levels of current and aspirant medical practitioners. A Medical Workforce Analysis, published by the Department of Public Expenditure and Reform last summer, highlighted that 87% of medical students are either intending to emigrate or contemplating it, while a Medical Council examination of the retention intentions of Irish trainee doctors revealed that just 58% of trainees see themselves

The Irish Medical Organisation has made a detailed submission to the Public Service Pay Commission which highlights the significant issues in the area of medical staffing, the low ratio of doctor to population and the high level

• The effects of the FEMPI Acts, 2009-2015, must be withdrawn, as they apply to medical practitioners. • The 30% unilateral pay cut imposed on consultant doctors in 2012 must be completely reversed, to restore pay parity among colleagues. • An independent review of doctors’ remuneration and working conditions in Ireland should be carried out, which will include an assessment of the attractiveness of the Irish health services as an employer in terms of pay and conditions, relative to other English-speaking jurisdictions, such as Australia and Canada. • Grants, support schemes, and tax benefits must be developed

for all NCHDs to ensure that all costs associated with an NCHD’s training are borne by the HSE. • A new contract for Consultants in Public Health Medicine should be drawn up and offered to new entrants and existing Specialists in Public Health Medicine, placing such physicians on par with their consultant colleagues in terms of remuneration, and with regard to out-of hours arrangements. • A supported recruitment and retention programme, specifically designed at attracting Irish trained doctors back to Ireland must be developed. • Tax relief on loan repayments for graduate entry medical students must be provided. • A new consultants’ contract must be negotiated. • A new NCHDs’ contract must be negotiated

HSE reimburses new Cancer treatment Professor Ray McDermott, Consultant Medical Oncologist, Tallaght Hospital Meath Hospital, Dublin and St Vincent’s Hospital, Dublin during the pivotal phase III RECOURSE study.

Lonsurf® (trifluridine/tipiracil) is now reimbursed in Ireland under the High Tech Scheme, within its marketing authorisation, as an option for treating metastatic colorectal cancer. LONSURF® is indicated in adults who have had previous treatment with, or were not considered candidates for available therapies including fluoropyrimidine - oxaliplatin- or irinotecan-based chemotherapies, anti-vascular endothelial growth factor (VEGF) agents and antiepidermal growth factor receptor (EGFR) agents, or when these therapies are not suitable3. LONSURF® was trialled in three centres in Ireland; Bon Secours Hospital, Cork, Adelaide and

February 2017 • HPN

This announcement comes at a time when there is a real need for further treatment options for patients with refractory metastatic colorectal cancer. With the changing funding landscape for new treatments in Ireland, the addition of new products in later lines of therapy could be crucial to those patients. “Data from the pivotal RECOURSE study provides evidence that LONSURF may offer Irish patients with refractory metastatic colorectal cancer extended survival as well as a reduction in risk of death compared to placebo”, said Professor Ray McDermott, Consultant Medical Oncologist, Tallaght Hospital, Dublin and one of the Irish RECOURSE investigators. “There are not many options left when a patient has had previous treatments. LONSURF is potentially a valuable new treatment that I can offer to my

patients with metastatic colorectal cancer regardless of their RAS status or resistance to previous lines of treatment”, continued McDermott. The HSE reimbursement comes after marketing authorisation was granted by the European Commission in May and the NICE recommendation in August 2016 based on data from the Phase III RECOURSE study. Servier is an international pharmaceutical company, with no shareholders, governed by a non-profit Foundation. The recommendation underpins the company’s commitment to research in the field of oncology and its philosophy of delivering life-enhancing medicines to the patients who need them. “With this approval, we are delivering on a promise to bring an oral new treatment to patients with advanced metastatic colorectal cancer across Europe,” said Mr Francois Druguet, Country Manager Servier Ireland. “We are excited about this important milestone, which demonstrates Servier’s commitment to improving the lives of patients living with cancer. LONSURF has also been shown to prolong progression-free survival and preserve performance

status, allowing patients to make time for more moments that matter.” In coming to their decision, the HSE considered evidence from the international, doubleblind, placebo-controlled Phase III RECOURSE study, which investigated the efficacy and safety of trifluridine/tipiracil plus best supportive care (BSC) compared to placebo plus BSC in 800 patients with previously treated mCRC.The trial met the primary endpoint of a statistically significant improvement in overall survival (OS). The median OS improved from 5.2 months with placebo (+BSC) to 7.2 months with trifluridine/tipiracil (+BSC). The hazard ratio for death in the trifluridine/tipiracil group versus the placebo group was 0.69 (95% confidence interval [CI], 0.59 to 0.81; P<0.0001), this translated into 1-year survival rates of 27.1% and 16.6%, respectively. The most frequently observed side effects (≥ 30%) in patients receiving trifluridine/tipiracil were neutropenia, nausea, decreased appetite, diarrhoea, fatigue, anaemia, thrombocytopenia, increase in total bilirubin, alkaline phosphatase and AST levels, and leucopenia.


Now for the treatment of pretreated mCRC

Make time for more moments that matter

trifluridine/tipiracil

Available on High Tech Scheme (from 01-02-2017)

LonsurfÂŽ is licensed to Servier by Taiho, co-developed globally and marketed in their respective territories.

qLonsurfÂŽ (trifluridine/tipiracil) Abbreviated prescribing information: COMPOSITION*: Lonsurf 15 mg/6.14 mg: film-coated tablet containing 15 mg trifluridine and 6.14 mg tipiracil (as hydrochloride). Lonsurf 20 mg/8.19 mg: film-coated tablet containing 20 mg trifluridine and 8.19 mg tipiracil (as hydrochloride). INDICATION*: Treatment of adult patients with metastatic colorectal cancer who have been previously treated with, or are not considered candidates for, available therapies including fluoropyrimidine-, oxaliplatinand irinotecan-based chemotherapies, anti-VEGF agents, and anti EGFR agents. DOSAGE AND ADMINISTRATION*: Recommended starting dose: 35 mg/m2/dose taken orally twice daily on Days 1 to 5 and Days 8 to 12 of each 28-day cycle, within 1 hour after completion of the morning and evening meals. Dosage calculated according to body surface area, not exceeding 80 mg/dose. Possible dosing adjustments based on individual safety and tolerability: 3 permitted dose reductions to a minimum dose of 20 mg/m2 twice daily, dose escalation permitted after a dose reduction. CONTRAINDICATIONS*: Hypersensitivity to the active substances or to any of the excipients. WARNINGS*: Bone marrow suppression: Complete blood cell counts must be obtained prior to initiation of therapy, prior to each cycle and as needed. Treatment must not be started if absolute neutrophil count <1.5 x109/L, if platelet counts <75x109/L, or if unresolved Grade 3 or 4 non-haematological clinically relevant toxicity. Patient should be monitored closely for infections, appropriate measures should be administered as clinically indicated. Gastrointestinal toxicity: anti-emetic, anti-diarrhoeal and other measures should be administered as clinically indicated, dose modifications should be applied as necessary. Renal impairment: not recommended if severe renal impairment or end-stage renal disease. Patients with moderate renal impairment should be more frequently monitored for haematological toxicities. Hepatic impairment: not recommended if moderate or severe hepatic impairment. Proteinuria: monitoring by dipstick urinalysis recommended prior to starting and during therapy. Excipients: contain lactose. INTERACTIONS*: Precautions: medicinal products that interact with nucleoside transporters CNT1, ENT1 and ENT2, inhibitors of OCT2 or MATE1, human thymidine kinase substrates (e.g. zidovudine), hormonal contraceptives. FERTILITY*. PREGNANCY AND BREASTFEEDING*: Not recommended. CONTRACEPTION*: For women and men, highly effective contraceptive measures must be used during treatment and for 6 months after stopping treatment. DRIVE & USE MACHINES*: Fatigue, dizziness or malaise may occur. UNDESIRABLE EFFECTS*: Very common: Neutropenia, leukopenia, anaemia, thrombocytopenia, decreased appetite, diarrhoea, nausea, vomiting, fatigue. Common: Lower respiratory tract infection, upper respiratory tract infection, febrile neutropenia, lymphopenia, monocytosis, hypoalbuminaemia, insomnia, dysgeusia, neuropathy peripheral, dizziness, headache, flushing, dyspnoea, cough, abdominal pain, constipation, stomatitis, oral disorder, hyperbilirubinaemia, Palmar-plantar erythrodysaesthesia syndrome, rash, alopecia, pruritus, dry skin, proteinuria, pyrexia, oedema, mucosal inflammation, malaise, hepatic enzyme increased, blood alkaline phosphatase increased, weight decreased. Uncommon: Septic shock, enteritis infectious, lung infection, biliary tract infection, influenza, urinary tract infection, gingival infection, herpes zoster, tinea pedis, candidiasis, bacterial infection, infection, cancer pain, pancytopenia, granulocytopenia, monocytopenia, erythropenia, leukocytosis, dehydration, hyperglycaemia, hyperkalaemia, hypokalaemia, hypophosphataemia, hypernatraemia, hyponatraemia, hypocalcaemia, gout, anxiety, neurotoxicity, dysaesthesia, hyperaesthesia, hypoaesthesia, syncope, paraesthesia, burning sensation, lethargy, visual acuity reduced, vision blurred, diplopia, cataract, conjunctivitis, dry eye, vertigo, ear discomfort, angina pectoris, arrhythmia, palpitations, embolism, hypertension, hypotension, pulmonary embolism, pleural effusion, rhinorrhoea, dysphonia, oropharyngeal pain, epistaxis, enterocolitis haemorrhagic, gastrointestinal haemorrhage, pancreatitis acute, ascites, ileus, subileus, colitis, gastritis, reflux gastritis, oesophagitis, impaired gastric emptying, abdominal distension, anal inflammation, mouth ulceration, dyspepsia, gastrooesophageal reflux disease, proctalgia, buccal polyp, gingival bleeding, glossitis, periodontal disease, tooth disorder, retching, flatulence, breath odour, hepatotoxicity, biliary dilatation, skin exfoliation, urticaria, photosensitivity reaction, erythema, acne, hyperhidrosis, blister, nail disorder, joint swelling, arthralgia, bone pain, myalgia, musculoskeletal pain, muscular weakness, muscle spasms, pain in extremity, sensation of heaviness, renal failure, cystitis noninfective, micturition disorder, haematuria, leukocyturia, menstrual disorder, general physical health deterioration, pain, feeling of body temperature change, xerosis, blood creatinine increased, electrocardiogram QT prolonged, international normalised ratio increased, activated partial thromboplastin time prolonged, blood urea increased, blood lactate dehydrogenase increased, protein total decreased, C-reactive protein increased, haematocrit decreased. Post-marketing experience: interstitial lung disease reported in Japanese patients. OVERDOSE*. PROPERTIES*: Trifluridine is an antineoplastic thymidine-based nucleoside analogue and tipiracil hydrochloride is a thymidine phosphorylase (TPase) inhibitor. Following uptake into cancer cells, trifluridine, is phosphorylated by thymidine kinase, further metabolised in cells to a deoxyribonucleic acid DNA substrate, and incorporated directly into DNA, preventing cell proliferation. However, trifluridine is rapidly degraded by TPase and readily metabolised by a first-pass effect following oral administration, hence the inclusion of the TPase inhibitor, tipiracil hydrochloride. PRESENTATION*: Pack of 20 or 60 film-coated tablets. LES LABORATOIRES SERVIER, 50 rue Carnot, 92284 Suresnes cedex France. www.servier.com. Marketing Authorisation: EU/1/16/1096/001-006. Legal Category: POM. Date of Text: April 2016. Further information available from: Servier Laboratories Ireland Ltd, Block 2, West Pier Business Campus, Old Dunleary Road, Dun Laoghaire, Co. Dublin, Tel (01) 6638110, Fax (01) 6638120, www.servier.ie. * For complete information, please refer to the Summary of Product Characteristics on www.medicines.ie. mCRC=metastatic ColoRectal Cancer Date of preparation of this item: January 2017. 1617C1LNPress.


Cancer incidence  On average, 37,591 cancers and other non-invasive tumours were diagnosed annually during the period 2012-2014.

10 News

 Excluding non-melanoma skin cancers (NMSC), 20,804 cases of invasive cancer were diagnosed annually (11,101 males, 9,703 females), representing 68% of all registered invasive cases.  Excluding NMSC, the top five most common invasive cancers diagnosed in men were prostate (30%), colorectal (13%) and lung cancer (12%), lymphoma (5%) and melanoma of the skin (4%) (Summary Figure 1).

Cancer rates may have plateaued:

 Excluding NMSC, the top five cancers in women were breast (30%), lung (11%) and colorectal cancer (10%), melanoma of the skin (5%) and uterine cancer (corpus uteri, 5%).

Latest report from the National Cancer Registry

 The lifetime risk (to age 75 years) of an invasive cancer diagnosis (excluding NMSC) was approximately 1 in 3 for men and 1 in 4 for women.

The latest annual report from the National Cancer Registry, Ireland’s premier source of cancer information, suggests that, although the total number of cancers continues to rise, mainly due to the ageing of our growing population, there is some positive news.

Summary Figure 1. Numbers, percentages and rank of the most commonly diagnosed invasive cancers (excluding NMSC): annual averages 2012-2014 MALES

FEMALES

ALL

The report shows that for men, the chances of developing cancer, which had been rising steadily since 1994, may have plateaued. Rates of the top three cancers in men (prostate, colorectal and lung), having adjusted for age, are now declining or static. For women too, the rate of the most common of the more serious cancers, breast cancer, has decreased since 2008, after a long period of increase from 1994. About 37,600 new tumours were registered annually in 20122014, of which 30,700 were malignant cancers, or 20,800 cancers excluding non-melanoma cancer of the skin, which is the commonest cancer overall but is rarely fatal. Cancer is the second most common cause of death in Ireland, and about 8,700 cancer deaths per year occurred during 2011-2013. Survival from cancer continues to improve and five-year net survival for all cancers (excluding nonmelanoma skin cancer) increased from 44% during 1994-1998 to 51% 1999-2003, 57% 2004-2008 and 61% 2009-2013. At the end of 2014 there were 139,526 persons still alive whose cancer had been diagnosed since 1994, equivalent to 3% of the Irish population. Cancer incidence  On average, 37,591 cancers and other non-invasive tumours were diagnosed annually during the period 2012-2014.  Excluding non-melanoma skin cancers (NMSC), 20,804 cases of invasive cancer were diagnosed annually (11,101 males, 9,703 females), representing 68% of all registered invasive cases.  Excluding NMSC, the top five most common invasive cancers diagnosed in men were prostate (30%), colorectal (13%) and lung cancer (12%), lymphoma (5%) and melanoma of the skin (4%) (Summary Figure 1).

February 2017 • HPN

low-incidence invasive cancers are not shown (c.10% of cases), therefore percentages do not sum to 100% † vulva, vagina, uterus (NOS) and placenta

mortality melanoma of skin, uterine declining or static rates in prostate,  Cancer Excluding NMSC, the top five cancer, female lung cancer and lungcancer and colorectal cancers. in women breast cancers An annual average were of 8,655 deaths from (males 4,590, femalesThere 4,065) occurred during the period 2011-2013, male liver cancer) also show was a steady and significant (30%), lung (11%) and colorectal accounting for melanoma 30% of all deaths period. ongoing or recent increases. fall during in the that male lung cancer rate cancer (10%), of thein Ireland during 1994-2014 and a marked skin (5%) and uterine cancer Cancer prevalence Page | 1 cancer decline in the prostate (corpus uteri, 5%). rate during 2011-2014. This was  As the number cancer of cases  The lifetime risk (to age 75 balanced against steady increases continues to rise in line with the years) of an invasive cancer in lymphomas and melanoma of population as expected, and diagnosis (excluding NMSC) the skin. mortality continues to fall, the was approximately 1 in 3 for number of persons living with The less marked recent decline men and 1 in 4 for women. cancer (or having a previous in the overall female cancer rate cancer diagnosis) continues to Cancer incidence trends since 2011 was heavily influenced increase. by a significant decline in the As might be expected in a country breast cancer rate since 2008,  139,526 (43%) of all cancer where both the population and following an earlier period of patients registered by the average age is increasing, the increase (strongly influenced by National Cancer Registry during number of new cancer cases mammographic screening). This 1994-2014 (excluding nonincreased almost year on year was balanced against steady melanoma skin cancer patients) during the period 1994-2014. increases in lung cancer, skin were still alive at the end of However, numbers of new cases melanoma, uterine cancer and 2014, or 3% of the total Irish registered slowed markedly from lymphoma population in 2014. 2011 in males and less markedly in females from 2009. Cancer mortality  Of these, 6,520 (4.7%) had been diagnosed with more than After accounting for population  Overall cancer mortality one distinct cancer type in a growth and age structure, this rates decreased steadily and different body site (as opposed translated into a statistically significantly over the period to multiple primaries of the same significant 2.3% annual decline in 1994-2013, by an average of site, recurrences or metastases). the male cancer rate during 20111.5% annually in males and 2014, and a less marked (non1.1% annually in females.  The top six most common significant) 0.9% annual decline cancer diagnoses among  However, reflecting a growing in the female rate during the same survivors were: breast and aging population, the total period, excluding non-melanoma (previously diagnosed in 23% numbers of cancer deaths skin cancers. of survivors), prostate (22%) continues to increase annually. and colorectal cancer (12%), The decline in the overall male skin melanoma (7%) and  Mortality rates for some cancer incidence rate during 2011non-Hodgkin lymphoma (4%). individual cancers (notably 2014 appears to be largely due to


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


12 News

IMO President criticises diversion of money to National Treatment Purchase Fund (NTPF) Dr John Duddy, President of the IMO

The Irish Medical Organisation has criticised the allocation of ¤20 million to the National Treatment Purchase Fund (NTPF) and the promise of an additional ¤50 million for the fund in 2018. The commitments were detailed by the Minister for Health, Simon Harris TD. The Minister was speaking at the National Treatment Purchase Fund (NTFP) Symposium where he launched the Fund’s Strategy for 2017-2019 Dr John Duddy, President of the IMO said that the allocation of public money to private hospitals removes vitally needed resources from public hospitals. He said, “Health finance is a zero-sum game. If the Minister gives money to private hospitals, he is doing so at the expense of public hospitals. That might help the Government massage waiting list figures in the

short term but it simply adds to the difficulty of sorting out our public hospitals in the medium to long term.” Dr Duddy also said he was disappointed to hear the Minister

discuss plans to work more closely with the NTPF in 2017. “Successive Ministers have used the NTPF as a tool to massage figures and give the impression of action. The reality is that it reflects

a mindset which puts public hospitals behind private hospitals in the queue for scarce resources and ultimately only increases the difficulties facing every on the public health service.”

Calls to reduce burden of Type 2 Diabetes Diabetes experts representing 38 countries have convened in Berlin to launch The Berlin Declaration, a global call to action urging policy makers to reduce the growing burden of type 2 diabetes. Their recommendations focus on four pillars of ‘Early Action’ in type 2 diabetes: preventing diabetes, diagnosing it early, controlling it early and ensuring early access to the right personalised interventions. If adopted by national health systems, the recommendations are expected to help countries meet voluntary global diabetes targets set by the United Nations1 and the World Health Organization.2 If policy makers fail to take action, health system costs are expected to increase by $129 billion by 2040. According to the Healthy Ireland survey, 854,165 adults over 40 in the Republic of Ireland are at increased risk of developing

February 2017 • HPN

(or have) Type 2 diabetes. More alarmingly, there are a further 304,382 in the 30 – 39 year age group that are overweight and not taking the weekly 150 minutes recommended physical activity, leaving them at an increased risk of chronic ill-health. This means that there are 1,158,547 adults in Ireland that need to consider making changes to their daily behaviours in terms of eating healthily and being more active. It is estimated that there are over 15,600 people over 80 years of age living with Type 2 diabetes based on the TILDA study which showed a prevalence of 11.9% in the over 75 age group. The International Diabetes Federation’s (2012) estimates that by 2030 there will be 278,850 people with the condition (prevalence of 7.5% in the population). Experts are issuing their call for early action at the Global

Diabetes Policy Forum on Early Action in Type 2 Diabetes in Berlin on 13-14 December 2016. The meeting is organised and funded by AstraZeneca in collaboration with the International Diabetes Federation (IDF), Primary Care Diabetes Europe (PCDE), and the World Heart Federation (WHF), and supported by German Diabetes Aid (GDA). The Forum is taking forward the work begun under the banner of ‘Early Action in Diabetes’ at the first Global Diabetes Policy Summit, held in Barcelona, Spain, in November 2015. Participants in this year’s Forum include leading clinical experts in diabetes as well as patient group representatives, policy makers and political leaders. The Berlin Declaration is the output of the work of 23 diabetes experts from 11 countries who volunteered to participate in four international working groups established at the 2015 Summit in Barcelona. The groups were

tasked to review best practice in policy making in diabetes prevention, early detection, early control and early access to the right interventions. Each group convened at least twice during 2016 in order to contribute to The Berlin Declaration. “I’m delighted that the International Diabetes Federation is helping to champion this important initiative,” said IDF president Dr Shaukat Sadikot. “What sets ‘Early Action’ apart from other campaigns is its focus on real action on the ground, aimed at producing concrete benefits for people with diabetes in countries at all levels of income. Every six seconds, someone in the world dies from diabetes. This sobering fact makes it absolutely critical that policy makers take action now, and that a broad range of stakeholders come together to encourage and support needed policy reform.”


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

SUPPORT YOUR PATIENTS WITH

CONFIDENCE

sitagliptin/metformin

sitagliptin

INCLUDING EVIDENCE FROM

TEC S TRIAL EVALUATING CARDIOVASCULAR

O U T C O M E S W I T H S I TA G L I P T I N

NOW EVEN MORE REASONS TO CHOOSE JANUVIA® FIRST AS A PARTNER TO METFORMIN1 Januvia or Janumet. For Januvia only– Renal Impairment: Lower dosages are recommended in patients with moderate and severe renal impairment, as well as in ESRD patients requiring haemodialysis or peritoneal dialysis- see Dosage. For Janumet only - Lactic acidosis and renal function: a very rare, but serious, metabolic complication can occur due to metformin accumulation. Cases in patients on metformin have occurred primarily in diabetic patients with significant renal failure. Reduce incidence by assessing other associated risk factors. If suspected, discontinue treatment and hospitalise patient immediately. Determine serum creatinine concentrations regularly, i.e. at least once a year in patients with normal renal function and at least two to four times a year in patients with serum creatinine levels at or above the upper limit of normal and in elderly patients. Decreased renal function in elderly patients is frequent and asymptomatic. Exercise special caution where renal function may become impaired, e.g. when initiating antihypertensive or diuretic therapy or when starting treatment with a non-steroidal anti-inflammatory drug (NSAID). Surgery: due to metformin hydrochloride content of Janumet, discontinue treatment 48 hours before elective surgery with general, spinal or epidural anaesthesia. Do not resume earlier than 48 hours afterwards and only after renal function is normal. INTERACTIONS For Janumet only - Alcohol: avoid alcohol and medicinal products containing alcohol due to risk of lactic acidosis. Cationic agents that are eliminated by renal tubular secretion (e.g., cimetidine): these may interact with metformin by competing for common renal tubular transport systems. Consider close monitoring of glycaemic control, dose adjustment within the recommended posology and changes in diabetic treatment when these agents are co-administered. Iodinated contrast agents in radiological studies: intravascular administration of these agents may lead to renal failure, resulting in metformin accumulation and a risk of lactic acidosis. Discontinue Janumet prior to, or at the time of the test and do not reinstitute until 48 hours afterwards, and only after renal function is found to be normal. Combination requiring precautions for use: glucocorticoids (given by systemic and local routes) beta-2-agonists, and diuretics have intrinsic hyperglycaemic activity. Inform the patient and perform more frequent blood glucose monitoring, especially at the beginning of treatment. If necessary, adjust dose of the anti-hyperglycaemic medicine during therapy with, or on discontinuation of the other medicine. ACE-inhibitors: as these may decrease the blood glucose levels, if necessary, adjust dose of the antihyperglycaemic during therapy with, or on discontinuation of the other medicine. PREGNANCY AND LACTATION: Do not use during pregnancy or breast-feeding. Animal data do not suggest an effect of treatment with sitagliptin on male and female fertility. Human data are lacking. SIDE EFFECTS Refer to SmPC for complete information on side effects There have been no therapeutic clinical trials conducted with Janumet tablets however Janumet is bioequivalent to co-administered sitagliptin and metformin. Sitagliptin: Serious adverse reactions including pancreatitis and hypersensitivity reactions have been reported. Hypoglycaemia has been reported in combination with sulphonylurea and insulin. The following adverse reactions were reported from both clinical trials and post-marketing experience: Sitagliptin only: Common: hypoglycaemia, headache, Uncommon: dizziness, constipation and pruritus. Sitagliptin with metformin: Common: hypoglycaemia, nausea, flatulence and vomiting; Uncommon: somnolence; upper abdominal pain, diarrhoea, constipation and pruritus. For Januvia and Janumet: Post-marketing experience additional side effects have been reported (frequency not known): hypersensitivity reactions, including anaphylaxis, angioedema, rash, urticaria, cutaneous vasculitis, exfoliative skin conditions including Stevens-Johnson syndrome (see precautions), and bullous pemphigoid; acute pancreatitis, including fatal and non-fatal haemorrhagic and necrotising pancreatitis (see precautions); impaired renal function, including acute renal failure (sometimes requiring dialysis); vomiting; pain in extremity, arthralgia, myalgia, back pain and arthropathy; interstitial lung disease. Januvia: Description of selected adverse reactions Adverse experiences reported regardless of causal relationship to medication and occurring more commonly in patients treated with sitagliptin included upper respiratory tract infection, nasopharyngitis, osteoarthritis and pain in extremity. In the Trial Evaluating Cardiovascular Outcomes with sitagliptin (TECOS), after a median follow up of 3 years, sitagliptin, when added to usual care, did not increase the risk of major adverse cardiovascular events, or the risk of hospitalisation for heart failure compared to usual care without sitagliptin in patients with type 2 diabetes and established cardiovascular disease. PACKAGE QUANTITIES Januvia 25 mg, 50 mg and 100 mg film-coated tablets 28 tablets Janumet 50mg/850mg and 50mg/1000mg film-coated tablets 56 tablets Legal Category: POM. Marketing Authorisation Numbers Januvia 25 mg: EU/1/07/383/002 Janumet 50 mg/850 mg: EU/1/08/455/003 Januvia 50 mg: EU/1/07/383/008 Janumet 50 mg/1000 mg: EU/1/08/455/010 Januvia 100mg: EU/1/07/383/014 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 18 or from www.medicines.ie. Date of preparation: October 2016. 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)

Reference: 1. Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232–242.

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

DIAB-1198859-0000

JANUVIA® (Sitagliptin) JANUMET® (Sitagliptin/metformin hydrochloride) ABRIDGED PRESCRIBING INFORMATION Refer to Summary of Product Characteristics (SmPC) before prescribing. PRESENTATION Januvia® 25 mg, 50 mg and 100 mg film-coated tablet each containing 25 mg, 50 mg or 100 mg of sitagliptin respectively. Janumet® 50 mg/850 mg and 50 mg/1000 mg tablets each containing 50 mg sitagliptin and 850 mg or 1000 mg metformin hydrochloride. INDICATIONS For adult patients with type 2 diabetes mellitus Januvia is indicated to improve glycaemic control: as monotherapy • in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance as dual oral therapy in combination with • metformin when diet and exercise plus metformin alone do not provide adequate glycaemic control • a sulphonylurea when diet and exercise plus maximal tolerated dose of a sulphonylurea alone do not provide adequate glycaemic control and when metformin is inappropriate due to contra-indications or intolerance • a PPARγ agonist (i.e. a thiazolidinedione) when use of a PPARγ agonist is appropriate and when diet and exercise plus the PPARγ agonist alone do not provide adequate glycaemic control as triple oral therapy in combination with • a sulphonylurea and metformin when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control. • a PPARγ agonist and metformin when use of a PPARγ agonist is appropriate and when diet and exercise plus dual therapy with these medicinal products do not provide adequate glycaemic control. Januvia is also indicated as add on to insulin (with or without metformin) when diet and exercise plus stable dosage of insulin do not provide adequate glycaemic control. Janumet: as an adjunct to diet and exercise to improve glycaemic control in patients inadequately controlled on their maximal tolerated dose of metformin alone or those already being treated with the combination of sitagliptin and metformin. • in combination with a sulphonylurea (i.e., triple combination therapy) as an adjunct to diet and exercise in patients inadequately controlled on their maximal tolerated dose of metformin and a sulphonylurea. • as triple combination therapy with a PPARγ agonist (i.e., a thiazolidinedione) as an adjunct to diet and exercise in patients inadequately controlled on their maximal tolerated dose of metformin and a PPARγ agonist. • as add on to insulin (i.e., triple combination therapy) as an adjunct to diet and exercise to improve glycaemic control in patients when stable dosage of insulin and metformin alone do not provide adequate glycaemic control. DOSAGE AND ADMINISTRATION Januvia - One 100 mg sitagliptin tablet once daily, with or without food. Janumet - The dose of antihyperglycaemic therapy with Janumet should be individualised on the basis of the patient’s current regimen, effectiveness, and tolerability while not exceeding the maximum recommended daily dose of 100 mg sitagliptin. For patients not adequately controlled on metformin alone, the usual starting dose should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) plus the dose of metformin already being taken. For patients switching from co-administration of sitagliptin and metformin, Janumet should be initiated at the dose of sitagliptin and metformin already being taken. For patients inadequately controlled on dual combination therapy with the maximal tolerated dose of metformin and a sulphonylurea or with maximal tolerated dose of metformin and a PPARγ agonist or with maximal tolerated dose of metformin and insulin, the dose should provide sitagliptin dosed as 50 mg twice daily (100 mg total daily dose) and a dose of metformin similar to the dose already being taken. All patients should continue their recommended diet with an adequate distribution of carbohydrate intake during the day. Januvia and Janumet - In combination with a sulphonylurea or with insulin, consider a lower dose of sulphonylurea or insulin, to reduce risk of hypoglycaemia. Renal impairment: For Januvia only: When considering sitagliptin with another anti-diabetic product, its use in patients with renal impairment should be checked. Moderate impairment (CrCl ≥30 to <50 mL/min), the dose is 50 mg once daily. Severe impairment (CrCl <30 mL/min) or with end-stage renal disease (ESRD), the dose is 25 mg once daily. Mild impairment, no dose adjustment. Assessment of renal function is recommended prior to initiation of Januvia and periodically thereafter. For Janumet only: Should not be used in patients with moderate or severe renal impairment (creatinine clearance < 60 ml/min). Hepatic impairment: For Januvia only - no dosage adjustment necessary for patients with mild to moderate hepatic impairment. Januvia has not been studied in patients with severe hepatic impairment and care should be exercised. However, because sitagliptin is primarily renally eliminated, severe hepatic impairment is not expected to affect the dose of sitagliptin. For Janumet only – do not use. Elderly < 75 years: For Januvia only - no dosage adjustment necessary. For Janumet only - use with caution as age increases. Monitoring of renal function is necessary to aid prevention of metformin-associated lactic acidosis. Children: no data available. CONTRAINDICATIONS For Januvia - Hypersensitivity to active substance or excipients. For Janumet - Hypersensitivity. Diabetic ketoacidosis and diabetic pre-coma. Moderate and severe renal impairment (creatinine clearance < 60 ml/min). Acute conditions with the potential to alter renal function such as dehydration, severe infection, shock. Intravascular administration of iodinated contrast agents. Acute or chronic disease which may cause tissue hypoxia such as cardiac or respiratory failure, recent myocardial infarction, shock. Hepatic impairment. Acute alcohol intoxication, alcoholism. Lactation. PRECAUTIONS AND WARNINGS For Januvia and Janumet - General: do not use in patients with type 1 diabetes or for diabetic ketoacidosis. Acute pancreatitis: Use of DPP 4 inhibitors has been associated with a risk of developing acute pancreatitis Inform patients of the symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of sitagliptin, but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, Januvia or Janumet and other potentially suspect medicinal products should be discontinued; if acute pancreatitis is confirmed, Januvia or Janumet should not be restarted. Caution should be exercised in patients with a history of pancreatitis. Hypoglycaemia when used with other anti-hyperglycaemic medicinal products: Rates of hypoglycaemia reported with sitagliptin were generally similar to rates in patients taking placebo. Hypoglcaemia has been observed when sitagliptin was used in combination with insulin or a sulphonylurea (see side effects). Therefore consider a lower dose of sulphonylurea or insulin to reduce the risk of hypoglycaemia when administering Janumet or Januvia. Hypersensitivity reactions: Serious hypersensitivity reactions have been reported, including anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset occurred within the first 3 months after initiation of treatment with some reports occurring after the first dose. If suspected, discontinue


14 Clinical Synopsis

Blood Disorders at 2016 ASH Annual Meeting The American Society of Hematology (ASH), the world’s largest professional society concerned with the causes and treatment of blood disorders, hosted more than 27,000 attendees from around the world to highlight groundbreaking scientific research and the latest advances in patient care at its 58th annual meeting, held in the San Diego Convention Centre. The 2016 ASH Annual Meeting featured nearly 5,000 scientific abstract presentations in malignant and non-malignant blood diseases – from cuttingedge advances in genome editing and discoveries about biological processes of the blood to practice-changing breakthroughs in immunotherapies and innovative treatment combinations. Below is a synopsis of some of the abstracts from the scientific programme. The Role of Sphingomyelin (SM) in Tissue Factor (TF) Encryption: ATP-Induced Activation of Acid Sphingomyelinase in Macrophages Decrypts Tissue Factor By Hydrolysis of SM in the Outer Leaflet Jue Wang, Ph.D*, Usha R Pendurthi, PhD and L. Vijaya Mohan Rao, Ph.D. Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, TX While tissue factor (TF)-mediated blood coagulation is essential for maintaining hemostasis, the aberrant activation of TF-mediated coagulation is a major determinant of thrombotic occlusions, the precipitating event in acute myocardial infarction, unstable angina, and ischemic stroke. Typically, TF on cell surfaces exists in inactive coagulant status (cryptic TF). Cell injury leads conversion of cryptic TF to coagulant active/prothrombotic TF. Molecular differences between cryptic and procoagulant TF and the mechanisms that are responsible for the conversion from one to the other form are poorly understood and often controversial. A majority of the evidence in the literature suggest that level of anionic phospholipids, such as phosphatidylserine (PS), in the outer leaflet of the plasma membrane plays a critical role in regulating TF procoagulant activity at the cell surface. However, other pathways, such as the thioredoxin system or thiol-disulfide exchange pathways involving protein-disulfide isomerase (PDI), were also shown to contribute to TF activation by inducing structural changes in TF. It is unknown at present whether TF on cell surfaces of naïve cells exists primarily in the cryptic state because of the limited availability of anionic phospholipids at the outer leaflet or phospholipids present in the outer leaflet play an active role in maintaining TF in the cryptic state. In the outer leaflet of mammalian plasma membrane, sphingomyelin (SM) constitutes up to 50% of the total phospholipids present on the cell surface. It is possible that a high SM content in the outer leaflet may be responsible for maintaining TF in its cryptic state at the cell surface in naïve cells, and the hydrolysis of SM on the outer leaflet mediated by factors released in cell injury contributes to TF activation. The present study was carried out to investigate this possibility. First, we tested the potential effect of SM on TF activity in a reconstituted system in which full-length TF was reconstituted into phospholipid vesicles composed of varying molar concentrations of SM with the remainder of the vesicle consisting of phosphatidylcholine (PC). SM, at 35 mol % or higher concentration in the proteoliposome, inhibited TF coagulant activity significantly as measured in factor X activation assay. Ceramide, having a similar sphingosine backbone as of SM, had no inhibitory effect on TF-FVIIa activation of FX. Measurement of FVIIa-TF amidolytic activity showed that SM does not inhibit the amidolytic activity of FVIIa-TF, indicating that SM neither affects FVIIa binding to TF nor TF-FVIIa cleavage of the small substrate peptide. SM also inhibited significantly TF activity of TF reconstituted in PC/PS (94%:6% mol/mol) vesicles. Next, human monocytederived macrophages (MDMs) were treated with varying concentrations of bacterial sphingomyelinase (b-SMase) to hydrolyze SM in the outer leaflet. b-SMase treatment increased cell surface TF activity in a dose-dependent manner. SMase treatment also enhanced the release of TF-bearing microparticles (MPs). SMase treatment had no significant effect on cell surface prothrombinase activity or annexin V binding to MDMs, indicating that b-SMase treatment did not increase PS availability at the cell surface under our experimental conditions. Similar to that observed in bone marrowderived mouse macrophages, ATP (200 µM) stimulation of MDMs increased cell surface TF activity by about 3-fold and triggered the release of TF+ MPs. Immunofluorescence confocal microscopy revealed that ATP stimulation induced in the translocation of acid(a)-SMase from intracellular compartments to the outer leaflet of the plasma membrane. Treatment of MDMs with sphingomyelinase inhibitors, desipramine and imipramine (1 and 5 µM), or silencing a-SMase with siRNA markedly reduced the ATP-induced increased TF activity at the cell surface and TF+ MPs release. Finally, ATP stimulation was shown to increase the hydrolysis of SM in the outer leaflet of MDMs markedly. a-SMase inhibitors or silencing of a-SMase attenuated the ATP-induced SM hydrolysis. In summary, our data indicate that SM plays a critical role in maintaining TF in the cryptic state in resting cells. Activation/translocation of a-SMase to the outer leaflet following the activation of ATP receptor P2X7 leads to hydrolysis of SM and thus relieves the inhibitory effect of SM on TF, leading to TF decryption and the release of TF+ MPs. Protein C Activation Is the Critical Thrombomodulin Function in Embryonic and Adult Survival in Mice Thijs E van Mens, MD, MBA1,2*, Helena Liang, PhD2,3*, Irene Hernandez, MS2*, Mark Zogg, BS2*, Jennifer May2*, Sreemanti Basu, PhD2*, Berend H. Isermann, MD, PhD2,4 and Hartmut Weiler, PhD2 1 Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands 2 Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 3 Sutton Research Laboratory, Sydney Medical School Northern, University of Sydney, Sydney, Australia 4 Institute of Clinical Chemistry and Pathobiochemistry, University of Magdeburg, Magdeburg, Germany Thrombomodulin (Thbd) is a multifunctional transmembrane molecule expressed on endothelial, hematopoietic, placental trophoblast, and various other cells. Thbd facilitates protein C and TAFI activation by thrombin, but also exerts thrombin- and protein C-independent functions to regulate complement activity and inflammatory signaling. Complete Thbd deficiency causes embryonic death through as yet unclear mechanisms, while ablation of the lectin-like Thbd domain, reduction of Thbd cofactor activity for protein C (pC) activation, or truncation of the cytoplasmic domain do not impair embryonic development1–3. Here we applied in vivo structure-function and genetic complementation analyses to differentiate between pCdependent and –independent Thbd functions. Three mouse strains with various function-selective Thbd mutations were generated, i.e. ThbdPro/ΔCS, ThbdEGF4-6, and ThbdLT. Of these, only the latter mutant with defective thrombin-binding reproduced the embryonic lethal phenotype of complete Thbd deficiency. To examine the developmental February 2017 • HPN


15 role of Thbd expression in cell types other than placental trophoblast, Thbd LoxP mice carrying a conditional Thbd allele were crossed with mice expressing Cre recombinase under control of the endogenous Meox2 gene promotor, resulting in selective ablation of Thbd in the embryo proper, but preservation in extra-embryonic placental tissue. This yielded a normal number of Thbd-deficient embryos at term pregnancy. Preservation of Thbd function in the embryonic placenta therefore was sufficient to prevent intrauterine lethality until birth. Immunohistochemistry of term embryos and adult mice (week 10-16) confirmed persistent absence of Thbd expression. Half of Thbd-null mice were lost prior to weaning (3 weeks). Surviving mice were smaller, yet exhibited normal weight gain thereafter. By 4 weeks of age, 19 of 28 Thbd-deficient animals developed grossly observable lesions, i.e. purple discoloration and swelling of tail segments, followed by, edematic swelling and discoloration of the tail and hind limb digits, distal tail necrosis and/or uni- or bilateral eye degeneration. More than half of the Thbd-null mice expired within the first 10 weeks of life, and only 2 of 28 mice survived to week 40. Neither gross anatomical inspection nor histological surveys of internal organs revealed evidence of severe thrombotic organ damage, and except for elevated IL-6, cytokine plasma levels were normal. Tamoxifen-induced Thbd LoxP gene ablation in adult mice (10-12 week old) reproduced the phenotype of Meox2Cre-Thbd-null mice. Genetic supplementation of activated PC by transgenic expression of a partially Thbd-independent murine pC zymogen variant (“hyperactivatable” protein C4), prevented perinatal lethality, partially restored normal birth weight, and largely prevented the phenotype of Thbd-null mice. However, Thbd-null females expressing the pC transgene exhibited pregnancy-induced morbidity and mortality with complete penetrance. When mated to wild type males (embryonic placenta expresses Thbd), 8 of 8 pregnancies ended in death or severe distress during gestation or postpartum. These findings indicate that the lack of protein C activation by Thbd-bound thrombin is the sole cause of lethality of embryonic and adult Thbd-null mice; and that Thbd expression in extra-embryonic placental tissue is sufficient to prevent intra-uterine lethality. The mortality of pregnant Thbd-null females expressing the protein C transgene constitutes a novel model for pregnancy-specific complications associated with defects in the function of natural anticoagulant pathways. References: 1.

Isermann B et al. Nat Med. 2003;9(3):331-337.

2.

Conway EM et al. Blood. 1999;93(10):3442-3450.

3.

Conway EM et al. J Exp Med. 2002;196(5):565-577.

4.

Isermann B et al. Nat Med. 2007;13(11):1349-1358.

The Macrophage-Specific CD163 Is an Endocytic Receptor for Von Willebrand Factor (VWF) Cleaving Protease ADAMTS13 Fabian Verbij, MSc1*, Nicoletta Sorvillo, PhD2*, Paul Kaijen3*, Johana Hrdinova, MSc4*, Rob Fijnheer, MD, PhD5*, Anja ten Brinke, PhD6*, Alexander B. Meijer, PhD7,8*, Floris P. van Alphen, BSc9*, Timo K. van der Berg, Dr.10*, Jonas H. Graversen11*, Soren K. Moestrup, MD, PhD11* and Jan Voorberg, PhD3 1 Department of Plasma Proteins, Sanquin, Amsterdam, Netherlands 2 Harvard Medical School, Children's Hospital Boston, Boston 3 Department of Plasma Proteins, Sanquin Research, Amsterdam, Netherlands 4 Plasma Proteins, Sanquin, Amsterdam, Netherlands 5 Hematology, Meander MC, Amersfoort, Netherlands 6 Department of Immunopathology, Sanquin, Amsterdam, Netherlands 7 Department of Plasma Proteins, Sanquin-AMC Landsteiner Laboratory, Amsterdam, Netherlands 8 Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht, Netherlands 9 dept. Plasma Proteins, Sanquin Research, and Landsteiner lab. AMC/UvA, Amsterdam, Netherlands 10 Blood cell research, Sanquin, Amsterdam, Netherlands 11 Department of Molecular Medicine, University of Southern Denmark, Odense, Denmark Von Willebrand Factor (VWF) cleaving protease ADAMTS13 is responsible for proteolysis of ultra large VWF multimers in the circulation. ADAMTS13 is synthesized by hepatic stellate cells in the liver. Also endothelial cells have been suggested to contribute to the synthesis of ADAMTS13. In patients with acquired thrombotic thrombocytopenic purpura auto-reactive antibodies are formed primarily against the spacer domain of ADAMTS13. Previously we have shown that monocyte-derived dendritic cells were able to endocytose ADAMTS13 via the macrophage mannose receptor and subsequently process it into peptides and present it on MHC class II. However, it is currently unclear which receptor contributes to the clearance of ADAMTS13 from the circulation. The half-life of ADAMTS13 was measured following plasma infusion in patients with congenital TTP and was found to vary between 2.1 and 3.3 days. Internalization of ADAMTS13 by tissue-resident macrophages may contribute to its clearance from the circulation. Here we investigated endocytic mechanisms contributing to the uptake of ADAMTS13 by macrophages. Human monocyte-derived macrophages (MDMs) were used to monitor the uptake of fluorescently labelled recombinant ADAMTS13 by flow cytometry. Internalization of ADAMTS13 was blocked upon addition of the cellpermeable dynamin-inhibitor dynasore. Partial blockage of ADAMTS13 internalization was observed employing mannan; uptake however was not affected by a blocking antibody directed towards the macrophage mannose receptor CD206. A pull-down with ADAMTS13 and subsequent mass spectrometric analysis identified the hemoglobin scavenger receptor CD163 as a candidate receptor for ADAMTS13. CD163 is primarily expressed by the monocyte-macrophage lineage and is highly expressed on type-2 macrophages present in the bone marrow, the red pulp of the spleen and in the liver on Kupffer cells. Blocking experiments with a monoclonal anti-CD163 antibody EDHu-1 resulted in a decreased ADAMTS13 internalization by macrophages. Pronounced inhibition of ADAMTS13 uptake by EDHu-1 was observed in macrophages in which the expression of CD163 was boosted upon incubation with IL-10. In agreement with these findings CD163-expressing CHO cells but not CHO CD163-/- cells were capable of rapidly internalizing ADAMTS13. Surface plasmon resonance revealed high affinity binding of ADAMTS13 to soluble CD163 containing scavenger receptor cysteine-rich (SRCR) domain 1-9. Our results position CD163 as a novel binding partner for ADAMTS13 and suggest that binding of ADAMTS13 to CD163 promotes its internalization by macrophages. HPN • February 2017


16 Clinical Synopsis Microbial Exposure Regulates the Development of Anti-Blood Group Antibodies Connie M. Arthur, PhD1, Harold Clifford Sullivan, MD1*, Christian Gerner-Smidt1*, Nourine Ahmed-Kamili1*, Ashley Bennett1*, Seema R. Patel, PhD1*, Steve Henry2* and Sean R. Stowell, MD, PhD1 1 Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 2 Aukland University of Technology, Aukland, New Zealand Introduction: Anti-ABO antibodies represent the earliest recognized immunological barrier to transfusion and transplantation. However, despite Landsteiner’s discovery of ABO blood group antigens over a century ago, the factors that regulate anti-ABO antibody formation remain relatively unknown. Anti-ABO antibodies develop spontaneously within the first few months of life, in the absence of a known antigenic exposure. However, antibody levels vary considerably between individuals suggesting that differences in exposure to environmental triggers may regulate anti-ABO antibody formation. As distinct microbes can stimulate very specific anti-carbohydrate antibodies, we hypothesized that variation in exposure to microbes that decorate themselves in ABO carbohydrates may regulate anti-blood group antibody formation. However, no model currently exists to examine the potential impact of microbial exposure on the development of naturally occurring anti-blood group antibodies. Methods: To examine the regulatory capacity of specific microbial exposure on naturally occurring antibody formation, we generated a model of ABO blood group antigens. As lower mammals do not express ABO antigens, we used recipients knocked out (KO) for the glycosyltransferase responsible for the synthesis of the carbohydrate B disaccharide (Bdis) antigen, an antigen very similar to the human blood group B antigen. Microbial flora was assessed in WT (Blood group B-like) or Bdis KO (Blood group O-like) by sequencing ribosomal DNA isolated from stool samples. Serum was assessed for Bdis reactivity at baseline and following Bdis+ microbial exposure using a glycan microarray. WT or Bdis KO recipients were transfused with Bdis+ RBCs followed by the evaluation of RBC clearance, antibody engagement and complement fixation by flow cytometry. Results: Similar to blood group O individuals, Bdis KO recipients spontaneously develop varied amounts of anti-Bdis antibodies within the first few weeks of life capable of inducing an acute hemolytic transfusion reaction following incompatible Bdis+ RBC transfusion. To determine whether specific microbial exposure is the primary regulating factor in anti-Bdis antibody formation, we separately housed Bdis KO recipients with low titer anti-Bdis antibodies, yielding an entire Bdis KO colony that never developed detectable anti-Bdis antibodies. Exposure of Bdis KO recipients that lacked detectable anti-Bdis antibodies to specific microbes that express the Bdis antigen induced robust anti-Bdis antibodies. However, the timing of microbial exposure was critical in dictating the likelihood of anti-Bdis antibody formation as younger mice produced anti-Bdis antibodies much more readily than adult mice following Bdis+ microbial exposure. Consistent with this, only Bdis KO recipients that experienced early Bdis+ microbial exposure possessed anti-Bdis antibodies with the capacity to induce an acute hemolytic transfusion reaction following Bdis+ RBC transfusion. Conclusions: These results demonstrate that Bdis KO recipients provide an attractive model to study naturally occurring antibody formation and suggest that anti-ABO antibodies are not an inevitable outcome of not expressing ABO blood group antigens. Instead, naturally occurring antibody formation appears to be temporally regulated by specific microbial exposure. As younger Bdis KO recipients developed antibody more readily than older Bdis KO recipients, in addition to Bdis+ microbial exposure, the actual timing of exposure appears to be a key regulator of anti-Bdis antibody formation. Thus variations in an individual’s microbiota, particularly during early immunological development, likely dictate the level of anti-ABO antibody formation. As a result, intentional manipulation of an individual’s microbial flora may provide a unique and previously unrecognized approach to prevent anti-ABO(H) antibody development in patients requiring transplantation or chronic transfusion. Targeting of JAK/STAT Signaling to Reverse Stroma-Induced Cytoprotection Against BCL2 Antagonist Venetoclax in Acute Myeloid Leukemia Riikka Karjalainen1*, Mihaela Popa, Dr2*, Minxia Liu1*, Mika Kontro3*, Mireia Mayoral Safont2*, Alun Parsons, MSc1*, Kimmo Porkka, MD, PhD3*, Krister Wennerberg1*, Emmet McCormack, Dr, PhD2*, Bjørn T. Gjertsen2 and Caroline A Heckman, PhD1 1 Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland 2 Department of Clinical Science, University of Bergen, Bergen, Norway 3 Hematology Research Unit Helsinki, University of Helsinki and Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland Several promising new, targeted agents are being developed for the treatment of AML. The BH3 mimetic venetoclax (ABT-199) is a specific inhibitor of BCL2, with results from a phase 2 study showing transient activity of venetoclax in relapsed/refractory AML (Konopleva et al, 2014). The bone marrow (BM) microenvironment is known to protect AML cells from drug therapy and we showed earlier that conditioned medium (CM) from BM stromal cells applied to AML patient cells conferred resistance to venetoclax, which could be reversed by the addition of the JAK1/2 inhibitor ruxolitinib (Karjalainen et al, 2015). Here, we investigated the mechanisms mediating the BM stromal cell induced resistance to venetoclax and its reversal by ruxolitinib. To identify the soluble factor(s) contributing to stroma-induced protection of BCL2 inhibition, we analyzed the cytokine content of 1) CM from the human BM stromal cell line HS-5, 2) CM from BM mesenchymal stromal cells (MSCs) isolated from AML patients, 3) supernatants from BM aspirates collected from AML patients, and 4) supernatants from BM aspirates collected from healthy donors. Although expression levels varied, the cytokines detected were similar among the different samples. In HS-5 CM, IL-6, IL-8 and MIP-3α were among the most abundant cytokines. In addition, gene expression analysis showed the receptors for these cytokines were expressed in AML patient samples. IL-6, IL-8 and MIP-3α were added individually to mononuclear cells collected from AML patients, which were then treated with venetoclax. However, none of the cytokines alone could mimic the reduced sensitivity to venetoclax conferred by the HS-5 CM suggesting that stromal cell induced cytoprotection is likely multi-factorial. Next we tested the effect of AML-derived BM MSCs on the ex vivo response of AML patient samples (n=8) to ruxolitinib or venetoclax alone or in combination in a co-culture setting. Apoptosis assays showed negligible effects of ruxolitinib at a concentration of 300 nM, while venetoclax at a dose of 100 nM induced reduction in the percentage of CD34+ AML cells. Co-treatment with venetoclax and ruxolitinib demonstrated synergistic effects in 6 out of 8 samples and significantly reduced the number of CD34+ AML cells. Mechanistic studies showed that ruxolitinib treatment inhibited the BM stromal medium-induced expression of BCL-XL mRNA on AML cells and the drugs in combination down-regulated BCL2, MCL1 and BCL-XL protein expression, which was in correlation with sensitivity to the drugs. To further evaluate the ability of the venetoclax and ruxolitinib combination to eradicate leukemic cells in vivo we used an orthotopic xenograft model of AML. NSG mice were injected with genetically engineered MOLM-13luc cells and after engraftment treated with venetoclax (25 mg/kg, i.p.), ruxolitinib (50 mg/kg BID, p.o) or both and imaged once per week for 4 weeks. At the end of the treatment period bioluminescent imaging showed significantly reduced leukemia burden in the ruxolitinib and venetoclax co-treated mice compared to controls demonstrating superior anti-tumor efficacy than either agent alone. In summary, our data demonstrate that the combined blockade of JAK/STAT and BCL2 pathways with ruxolitinib and ventoclax is synergistic in ex vivo co-culture models and in vivo in an AML mouse model. The addition of ruxolitinib was able to overcome intrinsic resistance to venetoclax by reducing expression of MCL1, a known escape mechanism of BCL2 inhibition. These results support further clinical investigation of this combination, particularly for relapsed/refractory AML.

February 2017 • HPN


Feature 17

Important new aspects in Diabetes treatment 3U Partnership’s 5th Annual Diabetes Conference took place at RCSI on January 20th 2017. This meeting was organised for clinicians, scientists and other health care professionals involved in diabetes.

Dr Ruth Davis (3U Partnership) at the 5th Annual 3U Diabetes Conference 2017

The 3U Diabetes Partnership formed between RCSI, DCU and Maynooth University aims to create a Centre of Excellence with an international reputation. Dr Diarmuid Smith and Professor Seamus Sreenan are the leading clinicians and are directly involved in the organisation of this event. This meeting highlighted important new aspects of diabetes treatment. Researchers from the United States, the Netherlands, the United Kingdom and Ireland addressed the conference which focussed on hot topics in research into both type-1 and type-2 diabetes. 3U Diabetes conference sponsors Astra Zeneca with Professor Seamus Sreenan, RCSI, Dr Ruth Davis, 3U Partnership and Dr Donal O'Gorman

The Conference had an update from the National Clinical Lead in Diabetes, Dr Seán Dineen, with 2015 figures showing 5.2% of Irish adults have been diagnosed with the disease. Globally 9% of adults are believed to suffer from diabetes, with many of these remaining undiagnosed. The topic of precision medicine – the tailoring of medical decisions, practices, and treatment to the individual patient. – were discussed by Dr Judith Fradkin, Director, Division of Diabetes, Endocrinology and Metabolic Diseases at the NIDDK in Baltimore. Dr Fradkin gave details of the National Institutes of Health Precision Medicine Initiative which was developed on foot of the announcement by President Barack Obama, in his state of the Union address of 2015, of a commitment to support a more individualised approach to maintaining and improving health. President Obama, who is a long-time supporter of precision medicine, described it as – “delivering the right treatments, at the right time, every time to the right person.” Dr Donal O’Gorman, of the School of Health and Human Performance at DCU and director of the 3U diabetes consortium, commented, “We are very excited to have a focus on precision medicine for diabetes at our annual meeting

this year. This has been the main focus of our consortium over the last 18 months. “We firmly believe that every person with diabetes comes to that point through a different journey and that while large scale clinical trials can guide us in managing patient groups, their conclusions can not necessarily be applied to every individual. Diabetes, which means a high sugar level in the blood, has many different causes. A more rational approach to patient management is to take the individual’s situation into account.

“We need to consider why their blood sugar is high and address the underlying cause as well as taking into account factors that may mean that a treatment that suits many may not be appropriate for the individual. We feel that a greater understanding of the causes, from genetic to environmental, and the physiological disturbances that culminate in diabetes in the individual, will facilitate the most appropriate management for the individual – the right treatment for the right person at the right time. Ultimately this type of approach is

most likely to benefit the long term health of the person with diabetes and give the best chance of keeping them free of complications.” Researchers from the United States, the Netherlands, the United Kingdom and Ireland addressed the conference which focussed on hot topics in research into both type-1 and type-2 diabetes. Other talks at the 3U Partnership conference focussed on the role of geographical factors on diabetes, abnormalities in the liver, muscle and fat which can all contribute to diabetes and the role of the gut in HPN • February 2017


18 Feature

3U Team Dr Mary Fenton, Sheila McCormack, Dr Ruth Davis and Andrea Clarke

Dr Sean Dinneen, National Clinical Lead in Diabetes, National University of Ireland, Galway

Dr Jan Rigby from Maynooth University

Malgorzata Sypniewska and Justyna Tolwinska

diabetes, but its causation and its treatment. Diabetes is a priority research focus of the 3U Partnership, which brings together the academic strengths of Dublin City University, Maynooth University and RCSI to enhance education and research opportunities across the three partner institutions. The 3U Diabetes Consortium, comprising clinicians and scientists from the three institutions, is committed to developing cutting edge research into this chronic and costly disease in Ireland and aligns a number of interlinked areas of research into the condition extending from identifying and developing new molecules with therapeutic potential to providing world class diabetes care and treatments in the clinic. Dr O’Gorman, commented that, “We are again delighted to welcome such an outstanding group of researchers to the 3U for this year’s conference. The faculty, which includes the Minkowski award winner and

February 2017 • HPN

the winner of the Rising Star award from the 2016 European Association for the Study of Diabetes, comprises clinical and basic science researchers from North America and Europe who will share their current research findings with us and discuss the challenges of managing type 1 and type 2 diabetes. Because diabetes is one of the commonest chronic diseases in Ireland, maintaining the focus on the condition and supporting research into the condition is of paramount importance in helping improve patients’ lives.” The meeting was opened by Dr Ruth Davis, Director of the 3U Partnership, who said, “The 3U Diabetes meeting has become one of the most important events in the diabetes calendar over the last 5 years. It is also an important event for the three partner institutions and has allowed the consortium to develop collaborative links with leading institutions in the world of diabetes research. It is envisaged that these links will foster training opportunities for young Irish

Danielle Bruen, Robyn Bruen and Caoileann Murphy at the 5th Annual 3U Diabetes Conference 2017

researchers and contribute significantly to the evolution and sustainability of the important 3U Partnership.” Other talks at the 3U Partnership conference focussed on the role of

geographical factors on diabetes, abnormalities in the liver, muscle and fat which can all contribute to diabetes and the role of the gut in diabetes, but its causation and its treatment.


MAKE THE SWITCH TO BYDUREON® PEN

Out with the old

In with the improved

Instead of Bydureon Injection (Single-Dose Tray), prescribe BYDUREON® Pen for your patients with type 2 diabetes BYDUREON® Pen offers your type 2 diabetes patients: ✔ sustained Hba1c reductions3 ✔ low hypoglycaemia risk*4 ✔ convenient administration ✔ sustained secondary benefit +1,2 of weight loss + BYDUREON is not indicated for the management of weight loss, and weight change was a secondary endpoint in clinical trials. * Increased risk of hypoglycaemia when Bydureon is added to sulphonylurea. Consider reduction in dose of sulphonylurea to reduce the risk of hypoglycaemia.

Adverse events should be reported directly to: HPRA Pharmacovigilance, Earlsfort Terrace, Dublin 2. Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.hpra.ie Email: medsafety@hpra.ie. Adverse events should also be reported to AstraZeneca Medical Information on 1800 800 899. References: 1. Buse JB, Drucker DJ, Taylor K, et al. Exenatide once weekly produces sustained glycaemic control and weight loss over 52 weeks. Diab Care 2010;33:1255–61. 2. Drucker DJ, Buse JB, Taylor K, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet. 2008;372(9645):1240-1250 3. Klein EJ, Henry RR, Malloy J, et al. DURATION-1 extension: efficacy and tolerability of exenatide once weekly over 6 years in patients with type 2 diabetes mellitus. Poster presented at the 50th Annual Meeting of the European Association for the Study of Diabetes; September 15-19, 2014; Vienna, Austria. 4. BYDUREON® Summary of Product Characteristics available at www.medicines.ie.

Approval ID: 1019258.011 Date of preparation: November 2016

BYDUREON® (exenatide) 2MG POWDER AND SOLVENT FOR PROLONGED-RELEASE SUSPENSION FOR INJECTION PRESCRIBING INFORMATION Consult Summary of Product Characteristics (SmPC) before prescribing. Use: Treatment of type 2 diabetes mellitus in combination with metformin, sulphonylurea, thiazolidinedione, or combinations of metformin and sulphonylurea or metformin and thiazolidinedione, in adults who have not achieved adequate glycaemic control on maximally tolerated doses of these oral therapies. Presentation: Powder and solvent for prolonged-release suspension for injection containing 2mg exenatide. Dosage and administration: Adults: The recommended dose is 2mg exenatide once weekly, on the same day each week, at any time of day, with or without meals. Administer as subcutaneous injection in the thigh, abdomen, or back of the upper arm immediately after suspension of powder in the solvent. If dose is missed, administer as soon as practical, then resume once weekly dosing schedule. Two injections should not be given on the same day. Prolonged-release exenatide is for selfadministration, appropriate training is recommended. Patients switching from immediate-release to prolonged-release exenatide may experience transient elevations in blood glucose concentrations, which generally improve within first two weeks after therapy initiation. When prolonged-release exenatide is added to existing metformin and/or thiazolidinedione, the current dose of these oral therapies can be continued. Increased risk of hypoglycaemia when prolonged-release exenatide is added to sulphonylurea. Consider reduction in dose of sulphonylurea to reduce the risk of hypoglycaemia. Blood glucose self-monitoring may be necessary to adjust the dose of sulphonylurea. If a different glucose-lowering treatment is started after the discontinuation of prolonged-release exenatide, consideration should be given to the prolonged release of the product. Elderly: No dose adjustment required. >75 years: Very limited clinical experience. Consideration should be given to the patient’s renal function. Renal or hepatic impairment: No dose adjustment required for patients with mild renal impairment (creatinine clearance 50-80 ml/min) or hepatic impairment. Very limited experience in moderate renal impairment (creatinine clearance 30 50ml/min). Not recommended in patients with moderate renal impairment, severe renal impairment (creatinine clearance <30 ml/min) or end-stage renal disease. Children and adolescents: <18 years old: Safety and efficacy not established. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Warnings and precautions: Not to be used in patients with type 1 diabetes mellitus or for diabetic ketoacidosis. Must not be administered by intravenous or intramuscular injection. Renal impairment: Uncommon events of altered renal function with exenatide, including increase serum creatinine, renal impairment, worsened chronic renal failure and acute renal failure, sometimes requiring haemodialysis. Some occurred in patients experiencing events that may affect hydration and/or receiving medicinal products known to affect renal function/hydration status, including angiotensin converting enzyme inhibitors, angiotensin-II antagonists, non-steroidal anti-inflammatory medicinal products and diuretics. Reversibility observed with supportive treatment and discontinuation of potentially causative medicinal products, including exenatide. Severe gastrointestinal disease: Not recommended. Acute pancreatitis: Use of GLP-1 receptor agonists has been associated with a risk of developing acute pancreatitis. Spontaneously reported events of acute pancreatitis. Resolution of pancreatitis has been observed with supportive treatment, but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. Inform patients of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. If pancreatitis suspected, discontinue use; if acute pancreatitis is confirmed, prolonged-release exenatide should not be restarted. Caution should be exercised in patients with a history of pancreatitis. Concomitant medicinal products: Concurrent use of prolonged-release exenatide with insulin, meglitinides, alpha-glucosidase inhibitors, dipeptidyl peptidase-4 inhibitors or other GLP-1 receptor agonists have not been studied. The concurrent use of prolonged-release and immediate-release exenatide has not been studied and is not recommended. Weight loss: Rapid weight loss at a rate of >1.5kg per week has been reported with exenatide, which may have harmful consequences. Monitor for signs and symptoms of cholelithiasis. Discontinuation of treatment: The effect of Bydureon may continue as plasma levels of exenatide decline over 10 weeks. Choice of other medicinal products and dose selection should be considered accordingly until exenatide levels decline. Drug interactions: No dose adjustment required for medicinal products sensitive to delayed gastric emptying. Warfarin and cumarol derivatives: Increased INR (International normalised ratio) spontaneously reported during concomitant use of warfarin and prolonged-release exenatide. INR should be monitored during initiation of prolonged-release exenatide. HMG CoA reductase inhibitors: Concomitant use with exenatide was not associated with consistent changes in lipid profiles. Lipid profiles should be monitored as appropriate. Pregnancy and lactation: Women of childbearing potential should use contraception during treatment with prolonged-release exenatide. Discontinue at least 3 months before trying to get pregnant. Avoid use during pregnancy and breast-feeding. Undesirable Effects: Consult SmPC for full list of side effects. Very common (≥1/10): Hypoglycaemia (with sulphonylurea), diarrhoea, nausea. Common (≥1/100 to <1/10): Decreased appetite, dizziness, headache, vomiting, abdominal distention, abdominal pain, dyspepsia, constipation, flatulence, gastroesophageal reflux disease, pruritus and/or urticaria, injection site pruritus, fatigue, injection site erythema, asthenia. Uncommon (≥ 1/1000 to < 1/100): Dehydration, somnolence, intestinal obstruction, eructation, altered renal function (including acute renal failure, worsened chronic renal failure, renal impairment, increased serum creatinine), injection site rash. Rare (≥1/10,000 to <1/1000): Anaphylactic reaction. Frequency not known: Acute pancreatitis, angioneurotic oedema, macular and papular rash, injection site abscesses and cellulitis. INR ratio increased with concomitant warfarin use (some reports associated with bleeding). Patients may develop anti-exenatide antibodies following treatment with prolonged-release exenatide. These patients tend to have more injection site reactions (e.g. skin redness, itching). Small subcutaneous injection site nodules observed very frequently, consistent with the known properties of PLGA polymer microsphere formulations. Legal category: POM. Marketing authorisation number: EU/1/11/696/001 (single dose kit) and EU/1/11/696/003 (pre-filled pen). Further product information available on request from: Freephone 1800 800 899 or contact AstraZeneca UK Limited, Horizon Place, 600 Capability Green, Luton, Bedfordshire, LU1 3LU, United Kingdom. Bydureon is a trade mark of the AstraZeneca group of companies Date of API preparation: 03/2016.


20 News

Early detection advances improving mortality Professor John Field, Director of Research, Roy Castle Lung Cancer Research Programm

Advances in early detection have the potential to significantly improve mortality rates for people diagnosed with lung cancer, a leading expert in the field has told an Irish audience. The Irish Cancer Society event ‘Lung Cancer: Can Early Detection Save Lives?’ saw Professor John Field discuss the latest research on lung screening which suggests novel approaches to reduce lung disease and cancer death. This event was held as part of the Irish Cancer Society’s ‘DECODING CANCER’ series of public talks, which aims to dispel some of the myths around cancer and explore the many advances being made through research in prevention, early detection, treatment, and survivors’ quality of life. This year, more than 2,300 people in Ireland will hear the words “You have lung cancer”. Because the disease is often detected in advanced stages, just 3 out of every 20 lung cancer patients will survive 5 years after their diagnosis. Professor Field is Director of Research of the Roy Castle Lung Cancer Research Programme, Liverpool, and he is an internationally recognised expert in lung cancer who is making major contributions to our understanding of ways to improve survival through UK and European research. Currently in Ireland and the UK screening services are available for three cancers: cervical, breast and bowel. As a result, thousands of lives have been saved through the early detection of cancers. Now, as Chief Investigator for the UK Lung Cancer Screening Trial (UKLS), Prof Field has found hope in the potential use of new approaches to catching lung cancer earlier, when it may be much more treatable; approaches that combine making smokers more

February 2017 • HPN

If lung cancer is identified early and is suitable for surgical intervention, the patient potentially has a vastly greater chance of survival. attentive to signs of the illness and the use of Computed Tomography (CT) screening to detect lung cancer early. Speaking ahead of the event, Professor Field said, “Lung cancer kills more people than any other cancer. However, preliminary research suggests that CT screening could be a viable option when it comes to the early detection of lung cancer. If lung cancer is identified early and is suitable for surgical intervention, the patient potentially has a vastly greater chance of survival. “Already we are seeing promising results from a large scale lung cancer CT screening trial. In 2011 the US National Lung Screening Trial (NLST) showed a 20% decrease in deaths from lung cancer. The trial was conducted in people aged 55-74, with a smoking history of at least 30 years or having had smoked within the last 15 years.” In Ireland, an average of 1,800 people die from lung cancer each year – representing one in five (21%) of all cancer deaths. To

highlight the signs and symptoms of lung cancer, the Irish Cancer Society has developed an online Lung Health Checker (cancer.ie/ lung/checker). In less than two minutes members of the public can check their lung health using a series of short questions. While not a substitute for a doctor, the checklist is a useful way for anyone to spot the signs of poor lung health early, and as a result, do something about them. Through his work, Professor Field has seen how online resources like the Lung Health Checker can have real impact on early detection and care. He added, “Through our online questionnaire at www.MyLungRisk.org, based on the Liverpool Lung Project risk prediction model, the UKLS has shown that spotting early signs and symptoms of poor lung health and intervening sooner can have significant benefits. Many people who were suspected of poor lung health after taking the questionnaire went on to take part in the pilot UK Lung Cancer Screening Trial (UKLS). Of this cohort, the UKLS found that 83% had early stage lung disease

(Stage I & II), and of these patients, 85% were suitable for surgical interventions. “In Liverpool, the Central Commissioning Group (CCG) has undertaken a major lung cancer programme, called the Liverpool Healthy Lung Programme (LHLP). The LHLP invites the public to take a proactive approach to their lung health. Rather than reacting after a diagnosis of poor health, people aged 58-70 with a history of smoking or chronic obstructive pulmonary disease (which affects the lungs), are being invited to attend a lung health clinic at their local GP surgery. After this appointment, if the patient reaches a specific risk criteria, they are offered a Chest CT Scan at their local hospital. “’Breathe Freely’ public events in the region also give people an opportunity to get advice on how to look after your lungs and receive a free lung health check with a health professional. I am confident that steps like these will save lives through the early detection of lung cancers.”


Prescribing Information (Ireland) ▼Vargatef® 100 mg and 150 mg soft capsules Soft capsules containing 100 mg or 150 mg nintedanib (as esilate). Indication: 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 (NSCLC) of adenocarcinoma tumour histology after first-line chemotherapy. Dose and Administration: Treatment with Vargatef should be initiated and supervised by a physician experienced in the use of anticancer therapies. The recommended dose of nintedanib is 200 mg twice daily administered approximately 12 hours apart, on days 2 to 21 of a standard 21 day docetaxel treatment cycle. Vargatef must not be taken on the same day of docetaxel chemotherapy administration (= day 1). If a dose of nintedanib is missed, administration should resume at the next scheduled time at the recommended dose. The individual daily doses of nintedanib should not be increased beyond the recommended dose to make up for missed doses. The recommended maximum daily dose of 400 mg should not be exceeded. Patients may continue therapy with nintedanib after discontinuation of docetaxel for as long as clinical benefit is observed or until unacceptable toxicity occurs. For posology, methods of administration, and dose modifications of docetaxel, please refer to the corresponding product information for docetaxel. Dose adjustments should be considered in case of adverse reactions of pre-specified severity: diarrhoea, vomiting, nausea and other non haematological or haematological adverse reactions, and aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) and bilirubin elevations – as initial measure for the management of adverse reactions treatment with nintedanib should be temporarily interrupted. Please refer to the Summary of Product Characteristics (SPC) for further information including when to discontinue treatment. Paediatric population: Safety and efficacy in children aged 0-18 years have not been established. Elderly patients (≥ 65 years): No overall differences in safety and efficacy were observed for elderly patients. No adjustment of initial dosing required on the basis of a patient’s age. Race and body weight: Based on population pharmacokinetic analyses, no a priori dose adjustments necessary. Safety data for Black and African American patients are limited. Renal impairment: Less than 1 % of a single dose of nintedanib is excreted via the kidney. Adjustment of the starting dose in patients with mild to moderate renal impairment is not required. The safety, efficacy and pharmacokinetics have not been studied in patients with severe renal impairment (< 30 ml/min creatinine clearance). Hepatic impairment: Nintedanib is 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 patients with mild hepatic impairment (Child Pugh A) based on clinical data. Limited safety data available from 9 patients with moderate hepatic impairment (Child Pugh B) are insufficient to characterize this population. The safety, efficacy and pharmacokinetics of nintedanib have not been investigated in patients with severe hepatic impairment (Child Pugh C). Treatment of patients with moderate (Child Pugh B) to severe (Child Pugh C) hepatic impairment is not recommended. The capsules must be taken orally, preferably with food, swallowed whole with water, and must not be chewed or crushed. Contraindications: Hypersensitivity to nintedanib, peanut or soya, or to any of the excipients. Warnings and Precautions: Patients with gastrointestinal disorders including diarrhoea, nausea and vomiting may require interruption, dose reduction or discontinuation of therapy. Diarrhoea should be treated at first signs with adequate hydration and anti-diarrhoeal medicinal products, e.g. loperamide. Supportive care for nausea and vomiting may include medicinal products with anti-emetic properties, e.g. glucocorticoids, anti histamines or 5 HT3 receptor antagonists and adequate hydration. In the event of dehydration, administration of electrolytes and fluids is required. Plasma levels of electrolytes should be monitored, if relevant gastrointestinal adverse events occur. Combination treatment with docetaxel is associated with a higher frequency 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 be monitored during therapy, please refer to SPC. Hepatic function: Based on increased exposure, the risk for adverse events may be increased in patients with mild hepatic impairment (Child Pugh A). Treatment with Vargatef is not recommended in patients with moderate or severe hepatic impairment. Nintedanib was associated with an elevation of liver enzymes (ALT, AST, ALKP, gamma-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 investigated before initiation of combination treatment and monitoring continued as required. If relevant liver enzyme elevations are measured, interruption, dose reduction or discontinuation of the therapy with Vargatef may be required, please refer to the SPC. VEGFR inhibition might be associated with an increased risk of bleeding. Vargatef is not recommended in patients with recent pulmonary bleeding (> 2.5 ml of red blood) as well as patients with centrally located tumours with radiographic evidence of local invasion of major blood vessels or radiographic evidence of cavitary or necrotic tumours. Patients taking concomitant anticoagulation, such as warfarin or phenprocoumon should be monitored regularly for changes in prothrombin time, international normalized ratio (INR), and clinical bleeding episodes. Patients with stable brain metastasis should be closely monitored for signs and symptoms of cerebral bleeding. Treatment not recommended for patients with active brain metastasis. Patients should be closely monitored for thromboembolic events and Vargatef should be discontinued in patients with life threatening venous thromboembolic reactions. Caution should be used when treating patients with a higher cardiovascular risk including known coronary artery disease. Treatment interruption should be considered in patients who develop signs or symptoms of acute myocardial ischaemia. Based on the mechanism of action patients treated with Vargatef may have an increased risk of gastrointestinal perforations. Particular caution should be exercised when treating patients with previous abdominal surgery or a recent history of a hollow organ perforation. Treatment should only be initiated at least 4 weeks after major surgery. Therapy should be permanently discontinued in patients who develop gastrointestinal perforation. Nintedanib may impair wound healing. Treatment should therefore only be initiated or, in case of perioperative interruption, resumed based on clinical judgement of adequate wound healing. Caution should be exercised in patients who may develop QTc prolongation. Dietary soya products are known to cause allergic reactions including severe anaphylaxis in persons with soya allergy. Patients with known allergy to peanut protein carry an enhanced risk for severe reactions to soya preparations. Nintedanib exposure increased linearly with patient age, was inversely correlated to weight, and was generally higher in patients of Asian race which may result in a higher risk of developing liver enzyme elevations; close monitoring is recommended in patients with several of these risk factors. Close monitoring is recommended in patients weighing < 50 kg. Interactions: Interaction studies have only been performed in adults. P-glycoprotein (P-gp): Nintedanib is a substrate of P-gp. If co-administered, potent P-gp inhibitors e.g. ketoconazole or erythromycin may increase exposure to nintedanib. Patients should be monitored closely for tolerability of nintedanib. Potent P-gp inducers e.g. rifampicin, carbamazepine, phenytoin and St. John’s Wort may decrease exposure to nintedanib. Co-administration should be carefully considered. Cytochrome (CYP)- enzymes: Likelihood of drug-drug interactions with nintedanib based on CYP metabolism considered to be low. Other medicinal products: The potential for interactions with hormonal contraceptives was not explored. Fertility, Pregnancy and Lactation: Nintedanib may cause foetal harm in humans; women should avoid becoming pregnant while receiving this treatment and use adequate contraception during and for at least 3 months after the last dose of Vargatef. Since the effect of nintedanib on the metabolism and efficacy of contraceptives has not been investigated, barrier methods should be applied as a second form of contraception, to avoid pregnancy. There is no information on the use of Vargatef in pregnant women, but pre-clinical studies have shown reproductive toxicity and therefore nintedanib should not be used during pregnancy unless the clinical condition requires treatment. Pregnancy testing should be conducted at least prior to treatment. Female patients should be advised to notify their doctor or pharmacist if they become pregnant during therapy. If the patient becomes pregnant while receiving Vargatef, she should be apprised of the potential hazard to the foetus. Termination of the treatment with Vargatef should be considered. There is no information on the excretion of nintedanib and its metabolites in human milk. Pre-clinical studies showed that small amounts of nintedanib and its metabolites (≤ 0.5 % of the administered dose) were secreted into milk of lactating rats. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with Vargatef. Based on preclinical investigations there is no evidence for impairment of male fertility. There are no human or animal data on potential effects of nintedanib on female fertility available. Undesirable effects: The most frequently reported adverse reactions specific for nintedanib were diarrhoea, increased liver enzymes (ALT and AST) and vomiting. Very common (≥ 1/10): Neutropenia (includes febrile neutropenia), decreased appetite, electrolyte imbalance, peripheral neuropathy, bleeding, diarrhoea, vomiting, nausea, abdominal pain, alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, mucositis (including stomatitis), rash. Common (≥ 1/100 < 1/10): Febrile neutropenia, abscesses, sepsis, thrombocytopenia, dehydration, venous thromboembolism, hypertension, hyperbilirubinaemia, gamma-glutamyltransferase increased. Prescribers should consult the Summary of Product Characteristics for further information on side effects and recommended measures. Pack sizes: 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

EXTENDING WHAT’S POSSIBLE VARGATEF®, the only triple angiokinase 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

▼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 Boehringer Ingelheim Pharmacovigilance on 01 291 3960 or by email to PV_local_uk_ireland@boehringer-ingelheim.com

Reference: 1. VARGATEF® 100/150 mg Summary of Product Characteristics. Available at: http://www.medicines.ie/medicine/16211. Date accessed: February 2017. IRE/VAR-161124a(3) | Date of preparation: February 2017


22 News

Plans unveiled to tackle hospital waiting lists The HSE has outlined plans to continue to drive down waiting times for patients. “It is not acceptable for patients to have to wait excessively long periods for necessary procedures or for outpatient appointments. Continuing to drive down the length of time patients are waiting for procedures is a priority for me in 2017,” said Minister for Health Simon Harris as he spoke at the National Treatment Purchase Fund (NTPF) Annual Conference. The Minister unveiled plans for more than 3,000 patients, who have been waiting over 18 months for day-case treatment, to be given appointments from next month under a new initiative to clear waiting lists. The patients, who include people waiting for cataract and other minor surgeries, dental extractions and treatment of skin lesions, will receive their treatment in private hospitals. Appointments will begin in April and it is hoped to clear the inpatient and daycase waiting list of anyone waiting longer than 18 months by June. The NTPF is an independent statutory body established by the Minister for Health. Its key functions are: • Collecting, collating and validating information on persons waiting for public hospital treatment; • Agreeing pricing arrangements with private & voluntary nursing homes under the Nursing Homes Support Scheme • Furnishing advice to the Minister for Health on related issues • Performing any other function assigned by the Minister for Health, since July 2012 this includes responsibility for the publication of outpatient waiting lists The NTPF previously arranged for the provision of hospital treatment to classes of persons determined by the Minister. Since 2011 this function has been suspended. In carrying out its functions, the NTPF works closely with the Department of Health, the HSE, acute public hospitals and private nursing homes across the health system. “I believe that we are all here today because we share a common

February 2017 • HPN

Under this initiative, the NTPF estimates that around 3,000 patients waiting 18 months or more for daycase procedures will be treated, with the aim that no patient will be waiting more than 18 months for daycase treatment by 30 June 2017. goal which is to put patients at the centre of our health service,” the Minister went on to say. “It is important for us to remember that patients can often be at their most vulnerable when they are waiting for a medical procedure and it is our responsibility, our collective responsibility, to enable patients to access acute hospital services in a timely manner.” Increasing Demand for Services Ireland has an ageing population. We are living longer and are healthier than ever before, and while this is something to be celebrated, it also means that there are increasing demands on our healthcare resources, he added. Every year there are over 3.2 million outpatient attendances in Ireland’s hospitals, 94,000 patients having elective inpatient procedures and 1 million having a planned day case procedure. And the demand continues to rise. For example, since 2000 the number of daycase discharges carried out have effectively quadrupled for the over 65 age group and almost doubled for patients under 65. The outpatient lists are also increasing with an average weekly increase of 1,200 this year. Waiting List Achievements for 2016 Despite this marked increase in activity and demand, during 2016 there were concerted efforts to reduce the number of long-waiting patients on the inpatient/daycase waiting list. The NTPF data for December 2016 show evidence of this with the overall Inpatient/ Daycase and the Outpatient waiting lists both decreasing since November. Minister Harris added, “In August 2016, I asked the HSE to develop and implement an Action Plan on Waiting Lists focused on those

patients waiting longest. The Action Plan set a target to reduce the number of patients waiting 18 months or over for an inpatient or daycase procedure by 50%, to no more than 1,800 patients by the end of 2016. “Ten days ago I was delighted to announce that the HSE had achieved the target set in its Waiting List Action Plan and had reduced by half the number of patients waiting longer than 18 months for inpatient treatment or day case procedures. “The figures published on 9th January by the NTPF showed that since I approved the Action Plan last August, the number of people on the Inpatient/Daycase waiting list has reduced by 11,519, leading to no more than 1,800 people waiting over 18 months for treatment. The actual number of people waiting for procedures at the end of December was 1,738. “In addition during 2016, the NTPF rolled out the Endoscopy Waiting List Initiative to arrange for the provision of endoscopy procedures to patients waiting over 12 months. By the end of December, over 5,500 people had come off the waiting list and the NTPF managed to clear over 99% of the people waiting the longest. Waiting List Plan for 2017 The plan, which entails close collaboration between the NTPF, the HSE and the Department includes: 1. Firstly the NTPF allocation for 2017 will utilise capacity in the private acute hospital sector to provide treatment for the longest waiting patient on the Inpatient/ Daycase waiting list; 2. In addition, the Minister has asked the HSE to submit an Action Plan to improve waiting lists in the public acute hospital sector for inpatients and daycases and outpatients;

3. Finally, during 2017 the HSE and the NTPF will work strategically and collaboratively together to ensure the best use of public and private hospital capacity to reduce patients waiting times. 1. NTPF Allocation Under this initiative, the NTPF estimates that around 3,000 patients waiting 18 months or more for daycase procedures will be treated, with the aim that no patient will be waiting more than 18 months for daycase treatment by 30 June 2017. Patients will be matched to the most appropriate pathway of care based on their individual procedure and the relevant hospital involved. In addition to current Daycase Waiting List Initiative, the NTPF is working closely with the HSE, supported by my Department, to finalise an approach for the remaining 2017 allocation. 2. HSE Waiting List Action Plan for Inpatients/Day Case and Outpatients “In tandem with this, in order to ensure that all long-waiters experience improved waiting times, I have also asked the HSE to develop new Waiting List Action Plans for 2017, in respect of both the Inpatient/Daycase Waiting List and the Outpatient Waiting List. The focus of these Plans will be on ensuring that no patient is waiting more than 15 months on either List by the end of October 2017,” he added. 3. Strategic Collaboration between NTPF and HSE “My vision is that during 2017 the HSE and the NTPF will combine their respective strengths and expertise and establish a strategic collaboration to ensure the best use of both public hospital capacity and the private hospital system to reduce waiting times for patients.”


CPD 29: Dyslipidemia Continuing Professional Development

CPD

23

Authors/Task Force Members: Zˇ eljko Reiner* (ESC Chairperson) (Croatia) Alberico L. Catapano* (EAS Chairperson)* (Italy), Guy De Backer (Belgium), Ian Graham (Ireland), Marja-Riitta Taskinen (Finland), Olov Wiklund (Sweden), Stefan Agewall (Norway), Eduardo Alegria (Spain), M. John Chapman (France), Paul Durrington (UK), Serap Erdine (Turkey), Julian Halcox (UK), Richard Hobbs (UK), John Kjekshus (Norway), Pasquale Perrone Filardi (Italy), Gabriele Riccardi (Italy), Robert F. Storey (UK), David Wood (UK).

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 Cardiovascular disease (CVD) kills over four million people in Europe each year. At least 80% of CVD could be prevented by eliminating health risk behaviours. CVD remains a leading cause of morbidity and mortality, despite improvements in outcomes for CVD. More patients are surviving their first CVD event and are at high risk of recurrences. In addition, the prevalence of some risk factors, notably diabetes and obesity, is increasing. The cost-effectiveness of CVD prevention has been calculated in various contexts. According to the WHO, policy and environmental changes could reduce CVD in all countries for <US$1 per person per year, while interventions at the individual level are considerably more expensive. One of the advantages of the SCORE system is that it can be recalibrated for use in different populations by adjustment for secular changes in CVD mortality and risk factor prevalences. Calibrated country-specific versions exist for Belgium, Cyprus, Czech Republic, Germany, Greece, Poland, Slovakia, Spain, Switzerland and Sweden, and country-specific electronic versions for Bosnia and Herzegovina, Croatia, Estonia, France, Romania, Russian Federation and Turkey can be found at http://www.heartscore.org. In both the 2011 EAS/ESC guidelines for the management of dyslipidaemias and the American Heart Association/American College of Cardiology (AHA/ACC) guidelines on the treatment of blood cholesterol to reduce atherosclerotic CV risk in adults, the importance of LDL-C lowering to prevent CVD is strongly emphasized. The approaches that are proposed to reach that LDL-C reduction are different. Plasma lipid levels are to a very large extent determined by genetic factors. In its more extreme forms this is manifested as familial hyperlipidaemia. A number of monogenic lipid disorders have been identified; among these, FH is most common and strongly related to CVD.

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 MSD. 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. MSD has no editorial oversight of the CPD programmes included in these modules.

ESC/EAS Guidelines for the Management of Dyslipidaemias European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Guidelines for the management of dyslipidaemias were published last year. Cardiovascular disease (CVD) kills over four million people in Europe each year. At least 80% of CVD could be prevented by eliminating health risk behaviours. “Lipids are probably the most fundamental risk factor for CVD,” said Professor Ian Graham (Ireland), Task Force Chairperson (ESC). “The relationship between lipids, particularly low density lipoprotein (LDL) cholesterol, and CVD is strong, graded, and unequivocally causal. Heart attacks rarely occur in populations with extremely low lipid levels, even if people smoke.” The new guidelines stress the need to lower lipid levels in populations and in high risk individuals. “Those at high risk should be the top priority for doctors treating patients oneto-one,” said Professor Graham. “But most deaths are in patients with only slightly high cholesterol because there are vast numbers of them. It means that population approaches for lowering lipids - such as lifestyle changes - are also needed.” WHAT IS CARDIOVASCULAR DISEASE PREVENTION? Definition and rationale Cardiovascular disease (CVD) kills >4 million people in Europe each year. It kills more women [2.2 million (55%)] than men [1.8 million (45%)], although cardiovascular (CV) deaths before the age of 65 years are more common in men (490 000 vs. 193 000).1 Prevention is defined as a coordinated set of actions, at the population level or targeted at an individual, aimed at

eradicating, eliminating or minimizing the impact of CV diseases and their related disability. CVD remains a leading cause of morbidity and mortality, despite improvements in outcomes for CVD. More patients are surviving their first CVD event and are at high risk of recurrences. In addition, the prevalence of some risk factors, notably diabetes and obesity, is increasing. The importance of CVD prevention remains undisputed and should be delivered at different levels: (i) in the general population by promoting healthy lifestyle behaviour2 and (ii) at the individual level, in those at moderate to high risk of CVD or patients with established CVD, by tackling an unhealthy lifestyle (e.g. poorquality diet, physical inactivity, smoking) and by reducing increased levels of CV risk factors such as increased lipid or blood pressure levels. Prevention is effective in reducing the impact of CVD; the elimination of health risk behaviours would make it possible to prevent at least 80% of CVD and even 40% of cancers, thus providing added value for other chronic diseases.3,4 Considerable evidence has quantified the relative efforts and costs in relation to health impact. The efforts may be depicted in the health impact pyramid (Figure 1 on page 24), where interventions with the broadest impact on populations represent the base and interventions with considerable individual effort are at the top.36 The cost-effectiveness of CVD prevention has been calculated in various contexts. According to the WHO, policy and environmental changes could reduce CVD in all countries for <US$1 per person per year, while interventions at the individual level are considerably more expensive.37 A report from the National Institute for Health and Care Excellence (NICE)

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24

CPD 29: Dyslipidemia

Figure 1

because such people are already at high-risk and need intensive risk factor advice.

From: 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias Eur Heart J. 2016;37(39):2999-3058. doi:10.1093/eurheartj/ehw272

TREATMENT TARGETS

Figure Legend:

Health impact pyramid.

Date of download: 2/7/2017

Š 2016 European Society of Cardiology and European Atherosclerosis Association. All rights reserved. For permissions please email: journals.permissions@oup.com.

be adapted to his/her total CV risk: the higher the risk, the more intense the action should be.

and automatically qualify for risk factor evaluation and management. SCORE chart: 10-year risk of fatal cardiovascular disease (CVD) in populations at high CVD risk based on the following risk factors: age, gender, smoking, systolic blood pressure, and total cholesterol. To convert the risk of fatal CVD to risk of total (fatal + nonfatal) hard CVD, multiply by 3 in men and 4 in women, and slightly less in old people. Note: the SCORE chart is for use in people without overt CVD, diabetes, chronic kidney disease, familial hypercholesterolaemia or very high levels of individual risk factors because such people are already at high-risk and need intensive risk factor advice.

CV risk in the context of these guidelines means the likelihood of a person developing a fatal or non-fatal atherosclerotic CV event over a defined period of time.

One of the advantages of the SCORE system is that it can be recalibrated for use in different populations by adjustment for secular changes in CVD mortality and risk factor prevalences. Calibrated country-specific versions exist for Belgium, Cyprus, Czech Republic, Germany, Greece, Poland, Slovakia, Spain, Switzerland and Sweden, and country-specific electronic versions for Bosnia and Herzegovina, Croatia, Estonia, France, Romania, Russian Federation and Turkey can be found at http://www.heartscore. org. Other risk estimation systems can also be recalibrated, but the process is easier for mortality than for total events. The European Guidelines on CVD prevention in clinical practice (version 2012)6 recommend use of the SCORE system because it is based on large, representative European cohort datasets.

All current guidelines on the prevention of CVD in clinical practice recommend the assessment of total CAD or CV risk, because atherosclerotic CVD is usually the product of a number of risk factors, and prevention of CVD in a given person should

Risk charts such as SCORE are intended to facilitate risk estimation in apparently healthy persons with no documented CVD. Patients who have had a clinical event such as acute coronary syndrome (ACS) or a stroke are at very high risk of a further event

estimated that a UK national programme reducing population CV risk by 1% would prevent 25 000 CVD cases and generate savings of ¤40 million per year.38 Coronary artery disease (CAD) mortality rates could be halved by only modest risk factor reduction,39 and it has been suggested that eight dietary priorities alone could halve CVD death.40 There is consensus that all the levels of the pyramid should be targeted but that emphasis should be put on the second level. Targeting lower levels in the health impact pyramid will also address the socio-economic divide in CV health, which has not diminished despite major improvements in the treatment of CVD in recent decades.9,10 TOTAL CARDIOVASCULAR RISK ESTIMATION

SCORE chart: 10-year risk of fatal cardiovascular disease (CVD) in populations at low CVD risk based on the following risk factors: age, gender, smoking, systolic blood pressure, and total cholesterol. To convert the risk of fatal CVD to risk of total (fatal + non-fatal) hard CVD, multiply by 3 in men and 4 in women, and slightly less in old people. Note: the SCORE chart is for use in people without overt CVD, diabetes, chronic kidney disease, familial hypercholesterolaemia, or very high levels of individual risk factors

In both the 2011 EAS/ESC guidelines for the management of dyslipidaemias125 and the American Heart Association/ American College of Cardiology (AHA/ACC) guidelines on the treatment of blood cholesterol to reduce atherosclerotic CV risk in adults,71 the importance of LDL-C lowering to prevent CVD is strongly emphasized. The approaches that are proposed to reach that LDL-C reduction are different. The task force charged with the development of the 2016 EAS/ESC updated guidelines on dyslipidaemias examined this issue in depth. It was recognized that the US expert panel confined itself to a simple, hard source of evidence coming from results in RCTs. Despite this, there has not been an RCT to support the AHA/ ACC recommendation for the use of high-dose statins in all highrisk people regardless of baseline LDL-C level. The European Task Force felt that limiting the current knowledge on CV prevention only to results from RCTs reduces the exploitation of the potential that is available for prevention of CVD. It is the concordance of the conclusions from many different approaches (from basic science, clinical observations, genetics, epidemiology, RCTs, etc.) that contributes to the understanding of the causes of CVD and to the potential of prevention. The task force is aware of the limitations of some of the sources of evidence and accepts that RCTs have not examined different LDL-C goals systematically, but felt that it was appropriate to look at the totality of the evidence. Indeed, the task force accepts that the choice of any given target goal for LDL-C may be open to debate given the continuous nature of the relationship between LDL-C reduction and reduction in risk. Particular consideration was given to results from systematic reviews confirming the dose-dependent reduction in CVD with LDL-C lowering; the greater the LDL-C reduction, the greater the CV risk reduction.65,66 The benefits related to LDL-C reduction are not specific for statin therapy.63 No level of LDL-C below which benefit ceases or harm occurs has been defined.

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25 Supplementary Figure A

There is considerable individual variability in the LDL-C response to dietary and drug treatments,61 which is traditionally taken to support a tailored approach to management. Total CV risk reduction should be individualized, and this can be more specific if goals are defined. The use of goals can also aid patient–doctor communication. It is judged likely that a goal approach may facilitate adherence to treatment, although this consensus opinion has not been fully tested. For all these reasons the European Task Force retains a goal approach to lipid management and treatment goals are defined, tailored to the total CV risk level. There is also evidence suggesting that lowering LDL-C beyond the goals that were set in the previous EAS/ESC guidelines is associated with fewer CVD events.126 Therefore, it seems appropriate to reduce LDL-C as low as possible, at least in patients at very high CV risk. The lipid goals are part of a comprehensive CV risk reduction strategy. The rationale for the nonlipid targets are given in the 2016 ESC Joint Prevention guidelines.485 The targeted approach to lipid management is primarily aimed at reducing LDL-C. For patients at a very high total CV risk, the goal is an LDL-C <1.8 mmol/L (70 mg/ dL). At least a 50% reduction from baseline (if >1.8 mmol/L) should also be achieved. For subjects at high total CV risk, the goal is an LDL-C level <2.6 mmol/L (100 mg/ dL). At least a 50% reduction from baseline [if >2.6 mmol/L (100 mg/ dL)] should also be achieved. In people at moderate total CV risk, the LDL-C goal is <3 mmol/L (115 mg/dL). When secondary targets are used the recommendations are Secondary targets have also been defined by inference for non-HDL-C and for apoB; they receive a moderate grading, as they have not been extensively studied in RCTs. Clinicians who are using apoB in their practice can use targets levels of <100 mg/ dL and <80 mg/dL for subjects at high or at very high total CV risk, respectively. The specific goal for non-HDL-C should be 0.8 mmol/L (30 mg/dL) higher than the corresponding LDL-C goal; adjusting lipid-lowering therapy in accordance with these secondary targets may be considered after having achieved an LDL-C goal

From: 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias Eur Heart J. 2016;37(39):2999-3058. doi:10.1093/eurheartj/ehw272

Figure Legend:

A systematic review and meta-analysis of the therapeutic equivalence of statins. ATOR = atorvastatin; FLUVA = fluvastatin; LOVA = lovastatin; PRAVA = pravastatin; SIMVA = simvastatin; ROSU = rosuvastatin; PITA = pitavastatin.

Date of download: 2/7/2017

in patients at very high CV risk, although the clinical advantages of this approach with respect to outcomes remain to be addressed. To date, no specific goals for HDL-C or TG levels have been determined in clinical trials, although increases in HDL-C predict atherosclerosis regression and low HDL-C is associated with excess events and mortality in CAD patients, even when LDL-C is <1.8 mmol/L (70 mg/dL). However, clinical trial evidence is lacking on the effectiveness of intervening in these variables to reduce CV risk further. – non-HDL-C <2.6 mmol/L (100 mg/dL) and <3.4 mmol/L (130 mg/ dL) in subjects at very high and high total CV risk, respectively (Class IIa, Level B).100,130 – apoB <80 mg/dL and <100 mg/ dL in those at very high and high total CV risk, respectively (Class IIa, Level B).100,131 Clinicians should use clinical judgment when considering further treatment intensification in patients at high or very high total CV risk. DRUGS FOR TREATMENT OF HYPERCHOLESTEROLAEMIA Statins Mechanism of action Statins reduce the synthesis of cholesterol in the liver by

© 2016 European Society of Cardiology and European Atherosclerosis Association. All rights reserved. For permissions please email: journals.permissions@oup.com.

competitively inhibiting HMG-CoA reductase activity. The reduction in intracellular cholesterol concentration induces an increased expression of LDLR on the surface of the hepatocytes, which results in increased uptake of LDL-C from the blood and a decreased plasma concentration of LDL-C and other apoBcontaining lipoproteins, including TG-rich particles. The degree of LDL-C reduction is dose dependent and varies between the different statins (supplementary Figure A and supplementary Table A).191 There is also considerable interindividual variation in LDL-C reduction with the same dose of drug.61 Poor response to statin treatment in clinical studies is to some extent caused by poor compliance, but may also be explained by a genetic background involving variations in genes of both cholesterol metabolism and of statin uptake and metabolism in the liver.192,193 Furthermore, conditions causing high cholesterol (e.g. hypothyroidism) should be considered. Indeed, interindividual variations in statin response warrant monitoring of individual response on initiation of therapy. A systematic review and metaanalysis of the therapeutic

equivalence of statins. ATOR = atorvastatin; FLUVA = fluvastatin; LOVA = lovastatin; PRAVA = pravastatin; SIMVA = simvastatin; ROSU = rosuvastatin; PITA = pitavastatin. EFFICACY OF CARDIOVASCULAR DISEASE PREVENTION IN CLINICAL STUDIES Statins are among the most studied drugs in CVD prevention, and dealing with single studies is beyond the scope of the present guidelines. A number of largescale trials have demonstrated that statins substantially reduce CV morbidity and mortality in both primary and secondary prevention, in both genders and in all age groups. Statins have also been shown to slow the progression or even promote regression of coronary atherosclerosis. Meta-analyses. A large number of meta-analyses have been performed to analyse the effects of statins in larger populations and in subgroups.64–66,68,129,194–200 In the large Cholesterol Treatment Trialists (CTT) analysis data, >170 000 participants and 26 RCTs with statins were included.64 A 10% proportional reduction in all-cause mortality and 20% proportional reduction in CAD death per 1.0 mmol/L (40 mg/dL) LDL-C reduction was reported.

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26

CPD 29: Dyslipidemia

The risk of major coronary events was reduced by 23% and the risk of stroke was reduced by 17% per 1 mmol/L (40 mg/dL) LDL-C reduction. The benefits were similar in all subgroups examined. The benefits were significant within the first year, but were greater in subsequent years. There was no increased risk for any non-CV cause of death, including cancer, in those receiving statins. Other meta-analyses have confirmed these results, coming to essentially the same conclusions. Most of the meta-analyses include studies in primary as well as secondary prevention. The absolute benefit from statin treatment may be less evident in patients in primary prevention, who are typically at lower risk. Several meta-analyses have specifically studied statins in primary prevention.66,68,199 The largest of these was published as a Cochrane review in 2013.200 The analysis included 19 studies with different statins and with somewhat varying inclusion criteria. In this analysis, all-cause mortality was reduced by 14%, CVD events by 27%, fatal and non-fatal coronary events by 27% and stroke by 22% per 1 mmol/L (40 mg/dL) LDL-C reduction. The relative risk reduction in primary prevention is about the same as that observed in secondary prevention. Similar results were also observed in analyses of statin treatment in people with low risk of vascular disease.66 However, it should be emphasized that in subjects with lower risk, the absolute risk reduction is also lower. Current available evidence from meta-analyses suggests that the clinical benefit is largely independent of the type of statin but depends on the extent of LDL-C lowering, therefore the type of statin used should reflect the LDL-C goal in a given patient. DRUGS FOR TREATMENT OF HYPERTRIGLYCERIDAEMIA Triglycerides and cardiovascular disease risk Although the role of TGs as a risk factor for CVD has been strongly debated, recent data favour the role of TG-rich lipoproteins as a risk factor for CVD.87 Large prospective studies have reported that non-fasting TGs predict CAD risk more strongly than fasting TGs.98,99 Recent data from genetic studies utilizing a Mendelian randomization design have consistently linked both non-fasting TG levels as well as remnant cholesterol to increased risk of CVD events and all-cause mortality.86,107 Remnant cholesterol is a calculated parameter in these

studies and equals TC − (HDL-C + LDL-C). These genetic data have strengthened the position of remnant cholesterol as a causal factor driving atherosclerosis and CVD events.75 Recently, remnant cholesterol has turned out to be a good surrogate marker of TGs and remnants.90 The burden of HTG as a CVD risk factor is highlighted by the fact that about one-third of adult individuals have TG levels >1.7 mmol/L (150 mg/dL).258 HTG can have different causes, among which its polygenic nature is most important in relation to CVD prevention.

Fatty acids n-3 fatty acids [eicosapentaenoic acid (EPA) and DHA] are used at pharmacological doses to lower TGs. n-3 fatty acids (2–4 g/day) affect serum lipids and lipoproteins, in particular VLDL concentration. The underlying mechanism is poorly understood, although it may be related, at least in part, to their ability to interact with PPARs and to a decreased secretion of apoB.

Statins Since statins have significant effects on mortality as well as most CVD outcome parameters, these drugs are the first choice to reduce both total CVD risk and moderately elevated TG levels. More potent statins (atorvastatin, rosuvastatin and pitavastatin) demonstrate a robust lowering of TG levels, especially at high doses and in patients with elevated TGs. In subgroup analyses from statin trials, the risk reduction is the same in subjects with HTG as in normotriglyceridaemic subjects.

Familial dyslipidaemias Plasma lipid levels are to a very large extent determined by genetic factors. In its more extreme forms this is manifested as familial hyperlipidaemia. A number of monogenic lipid disorders have been identified; among these, FH is most common and strongly related to CVD. In general in patients with dyslipidaemia, most commonly the pattern of inheritance does not suggest that there is a major single gene disorder (monogenic) causing the abnormality, but rather that it stems from inheriting more than one lipoprotein gene variant that, on its own, might have relatively little effect, but in combination with another or others has a greater influence on TC, TGs or HDL-C. The pattern of inheritance is polygenic.295 It is common to find that high LDL-C, high TGs or low HDL-C affect several family members.

FIBRATES Mechanism of action Fibrates are agonists of peroxisome proliferatoractivated receptor-α (PPAR-α), acting via transcription factors regulating various steps in lipid and lipoprotein metabolism. By interacting with PPAR-α, fibrates recruit different cofactors and regulate gene expression. As a consequence, fibrates have good efficacy in lowering fasting TG levels as well as post-prandial TGs and TG-rich lipoprotein (TRL) remnant particles. The HDL-C raising effects of fibrates are modest.263 Nicotinic acid Nicotinic acid has been reported to decrease fatty acid influx to the liver and the secretion of VLDL by the liver. This effect appears to be mediated in part by the action on hormone-sensitive lipase in the adipose tissue. Nicotinic acid has key action sites in both liver and adipose tissue. In the liver, nicotinic acid inhibits diacylglycerol acyltransferase-2 (DGAT-2), resulting in decreased secretion of VLDL particles from the liver, which is also reflected in reductions of both IDL and LDL particles.277 Nicotinic acid raises HDL-C and apoA1 primarily by stimulating apoA1 production in the liver.277 The effects of nicotinic acid on lipolysis and fatty acid mobilization in adipocytes are well established.

MANAGEMENT OF DYSLIPIDAEMIA IN DIFFERENT CLINICAL SETTINGS

FAMILIAL COMBINED HYPERLIPIDAEMIA Familial combined hyperlipidaemia (FCH) is a highly prevalent dyslipidaemia (1:100) and an important cause of premature CAD. FCH is characterized by elevated levels of LDL-C, TGs or both. The phenotype varies even among members of the same family. FCH shares considerable phenotype overlap with type 2 diabetes and MetS. FCH is a complex disease and the phenotype is determined by interaction of multiple susceptibility genes and the environment. The phenotype even within a family shows high inter- and intraperson variability based on lipid values (TGs, LDL-C, HDL-C and apoB). Therefore, the diagnosis is commonly missed in clinical practice; the combination of apoB >120 mg/dL + TGs >1.5 mmol/L (133 mg/dL) with a family history of premature CVD can be used to identify subjects who most probably have FCH.296 Currently, research is ongoing to define genetic markers; hopefully this approach will facilitate diagnosis of this frequent genetic dyslipidaemia.

The concept of FCH is also valuable clinically in assessing CV risk. It emphasizes both the importance of considering family history in deciding how rigorously to treat dyslipidaemia and that elevated LDL-C levels are riskier when HTG is also present. Statin treatment decreases CV risk by the same relative amount in people with HTG as in those without. Because the absolute risk is often greater in those with HTG, they may therefore benefit greatly from hypocholesterolaemic therapy. FAMILIAL HYPERCHOLESTEROLAEMIA Heterozygous familial hypercholesterolaemia FH is a common monogenic dyslipidaemia causing premature CVD due to lifelong elevation of plasma levels of LDL-C. If left untreated, men and women with heterozygous FH (HeFH) typically develop CAD before the ages of 55 and 60 years, respectively. However, if diagnosed early and properly treated, the risk for CAD may be dramatically reduced, with some studies even suggesting a normal life expectancy. The frequency of HeFH in the population has earlier been estimated at 1/500; however, recent studies from whole populations suggest that the frequency is higher, in some populations as high as 1/137.297 Based on extrapolations from available data, the frequency of HeFH can be estimated to be between 1/200 and 1/250, putting the total number of cases at between 14 and 34 million worldwide.121,298 Only a minor fraction of these are identified and properly treated. The risk of CHD among individuals with definite or probable HeFH is estimated to be increased at least 10-fold. FH is a monogenic disease caused by loss of function mutations in the LDLR or apoB genes or a gain of function mutation in the PCSK9 gene; 95% of FH is caused by mutations in LDLR. More than a thousand different mutations have been identified in LDLR causing FH. The different mutations cause reduced function or complete loss of function. Complete loss of receptor function is associated with more severe disease. A total of 4–5% of FH is caused by mutations in apoB causing reduced binding to LDLR and ∼1% is caused by mutations in PCSK9 causing increased catabolism of LDLR. (Continues in the March issue of HPN) References available on request

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28 Feature

Management of bleeding in patients treated with direct oral anticoagulants Anticoagulants are frequently prescribed agents for the prevention and treatment of a myriad of cardiovascular conditions. Conventional anticoagulant agents, such as vitamin K antagonists (VKAs; warfarin, phenprocoumon, or coumadin) and heparin or low molecular weight (LMW) heparin, are increasingly replaced by direct oral anticoagulants (DOACs) directly inhibiting factor Xa (e.g., rivaroxaban, apixaban, or edoxaban) or factor IIa (e.g., dabigatran). This new generation of anticoagulants is termed novel oral anticoagulants (NOACs) or DOACs. A large number of clinical studies have shown that these agents can prevent or treat acute or chronic thromboembolic diseases[1]. The most important complication of treatment with anticoagulant agents is hemorrhage, which may be serious, may cause long-term debilitating disease, or may even be life-threatening[2]. Bleeding in a patient on anticoagulants may require specific (additional) management; if the bleeding situation is sufficiently severe, swift reversal of the anticoagulant effect of the anticoagulant agent may even be required. Depending on the clinical situation, including the site and/ or the severity of the bleeding, this reversal may take place in a few hours, but in some cases immediate reversal is needed[3]. Generally, each (immediate) reversal of anticoagulant treatment needs also to take into consideration the indication for the antithrombotic agents. For example, the immediate interruption of anticoagulants in a patient with recent venous thromboembolism will markedly increase the short-term risk of recurrent venous thrombosis or pulmonary embolism. Likewise, in a patient with advanced heart disease and atrial fibrillation, interruption of anticoagulants may increase the risk of cerebral or systemic embolism. Each of these specific clinical settings requires a careful and balanced individual assessment of the benefits and dangers of reversing anticoagulants (and potential strategies to keep the period of reversal as brief as possible). Here we will briefly describe the epidemiology of bleeding complications due to anticoagulants and

February 2017 â&#x20AC;˘ HPN

various strategies to reverse the anticoagulant effect of antithrombotic agents, focusing on the new generation of anticoagulants (DOACs). Relevance, incidence, and risk factors for bleeding in patients on anticoagulant treatment The relevance of hemorrhagic complications in patients on anticoagulants is clearly demonstrated in a series of observational studies. In a large study of 34,146 patients with acute ischemic coronary syndromes, anticoagulant-associated bleeding was associated with a 5-fold increased risk of death during the first month and a 1.5-fold higher mortality between 30 days and 6 months[4]. Major hemorrhage was an independent predictor of mortality across all subgroups that were analyzed. Currently, VKAs are still the most frequently used oral anticoagulant agents for long-term prevention and treatment of a wide range of cardiovascular diseases. In wellcontrolled patients in clinical trials,

treatment with VKAs increases the risk of major bleeding by 0.5â&#x20AC;&#x201C;1.0 %/year and increases the risk of intracranial hemorrhage by about 0.2â&#x20AC;&#x201C;0.3 %/year[5]. However, in three real-life surveys this incidence varied from 1.4 to 3.4 %/year[6]. One needs to realize that the relatively uncomplicated trial populations may poorly reflect the real-life setting in which anticoagulants are prescribed. For example, in six pivotal trials that demonstrated the superiority of warfarin over placebo in the prevention of thromboembolic complications in patients with atrial fibrillation, 28,787 patients were screened but only 12.6% of these patients were included in the studies[7]. The incidence of hemorrhagic complications with use of the new generation of oral anticoagulants with direct inhibitory properties towards thrombin or factor Xa is not very different. The severity and incidence of bleeding events in DOAC-treated patients has been evaluated in a number of clinical studies, which

demonstrated similar or lower rates of major bleeding with DOACs compared with traditional anticoagulants[8, 9, 10, 11]. The safety and efficacy of DOACs versus warfarin were evaluated in a meta-analysis of 14 prospective and retrospective studies in AF patients undergoing catheter ablation (4782 patients in total[12]. Overall, no significant difference was observed in terms of thromboembolic events or major bleeding events between the warfarin and dabigatran treatment arms, although minor bleeding events occurred significantly less frequently with dabigatran compared with warfarin. Of note, DOAC treatment was associated with a reduced intracranial hemorrhage incidence compared with warfarin therapy, whereas some analyses showed an increased risk for gastrointestinal bleeds[12, 13, 14]. The recent guidelines from the European Society of Cardiology on anticoagulant management of atrial fibrillation recommend non-VKAs based on their more favorable incidence of


Table 1 Pharmacological options for reversing the effect of the direct-acting oral anticoagulants

hemorrhagic complications [15]. Likewise, DOACs are also advocated for the treatment of venous thromboembolism in recent guidelines[16]. Although these clinical study results are encouraging, there is very limited real-world evidence with regards to the incidence and severity of DOAC-related bleeding events; most of the currently available data are based on postmarketing studies. Some clinical studies have reported on their experience with bleeding complications in patients treated with DOACs compared with patients on warfarin[17, 18]. Data from the EINSTEIN studies on rivaroxaban demonstrated that patients who presented with major bleeding on rivaroxaban had a relatively milder presentation and a better recovery compared with patients on warfarin. A prospective chart review of 15 emergency department patients treated with dabigatran and 123 patients treated with warfarin showed that patients on dabigatran had a shorter length of stay, fewer major bleeding events, and fewer life-threatening complications compared with patients on warfarin. Additionally, dabigatran use was more commonly associated with gastrointestinal hemorrhage, and less frequently associated with intracranial bleeding, compared with warfarin, in this patient population. This finding is in contrast to results from an analysis of insurance claim and administrative data from the FDA Mini-Sentinel database, which showed that dabigatran was associated with reduced incidence of gastrointestinal bleeds compared with warfarin[19]. The Australian Therapeutic Goods Administration has been monitoring the safety profile of dabigatran, and reported 361 serious bleeding events with this agent between 2011 and 2013[20]. The most commonly reported bleeding site was the gastrointestinal tract, while a smaller proportion of intracranial bleeds were reported for dabigatran versus warfarin[20]. The most important risk factor for hemorrhage in users of anticoagulants is the intensity of the anticoagulant dose[21]. Studies suggest that with a target international normalized ratio (INR) of >3.0 the incidence of major bleeding is twice as large as in studies with a target INR of 2.0–3.0[22]. In a meta-analysis of studies in patients with prosthetic heart valves, a lower INR target range resulted in a lower frequency of major bleeding and intracranial hemorrhage with a similar antithrombotic efficacy[23]. For dabigatran a clear relationship

Table 1 Pharmacological options for reversing the effect of the direct-acting oral anticoagulants

Inhibitor

29

Conventional dose

Nonspecific reversal (prohemostatic interventions)

Prothrombin complex concentrates

50 U/kg

Activated prothrombin complex concentrates

50 U/kg

Recombinant factor VIIa

90 μg/kg

Specific reversal

Directed at dabigatran

Idarucizumab

5g

Directed at rivaroxaban, apixaban, and edoxaban

between dose and incidence of bleeding complications has been demonstrated in a clinical study in patients with atrial fibrillation[8], and all other DOACs have also demonstrated a similar doseadverse event relationship[14]. Patient characteristics constitute another important determinant of the bleeding risk. Older patients have a 2-fold increased risk of bleeding[24], and the relative risk of intracranial hemorrhage (in particular at higher intensities of anticoagulation) was 2.5 (95 % CI 2.3–9.4) in patients aged >85 years compared with patients 70–74 years old[25]. Comorbidity may also significantly increase the risk of bleeding. A case– control study in 1986 patients on anticoagulants showed that comorbidity (such as mild renal insufficiency, hepatic dysfunction, or diabetes) increased the risk of bleeding by about 2.5[7]. Another very important determinant of the risk of bleeding is the combined use of medication that affects both the coagulation system and platelet function. Two metaanalyses, comprising six trials with a total of 3874 patients and 10 trials with a total of 5938 patients, found a relative risk of major bleeding when antithrombotic agents were combined with aspirin of 2.4 (95 % CI 1.2–4.8) and 2.5 (95 % CI 1.7–3.7), respectively[26]. A population-based case–control study confirmed the high risk of

Andexanet-alfa

600–800 mg

Ciraparantag

100 mg

upper gastrointestinal bleeding in patients using anticoagulants in combination with aspirin and/ or clopidogrel[27]. It should be noted that the combined use of the new anticoagulant agents and antiplatelet agents was discouraged in the clinical trials, whereas this is increasingly common in clinical practice and may also have a serious impact on the risk of hemorrhage. Nonsteroidal anti-inflammatory agents (NSAIDs) are also associated with an enhanced risk of gastrointestinal bleeding. The combined use of anticoagulants and NSAIDs may result in an 11-fold higher risk of hospitalization for gastrointestinal bleeding as compared with the general population[28]. This risk is not significantly lower when using selective inhibitors of COX-2. As DOACs are associated with a higher risk of gastrointestinal bleeding compared with conventional anticoagulants (see above), the effect of combined treatment with these agents and aspirin or NSAIDs may be even larger. Reversal of DOACs One of the main advantages of DOACs are the relatively stable pharmacokinetic and pharmacodynamic properties, which obviates the need for repeated control of the intensity of anticoagulation and dose adjustments. This means that

for some clinical situations these drugs may represent an important improvement, but as already indicated the risk of (major) bleeding is still present. Clinical trials in patients using DOACs agents excluded many patients with common comorbidities and discouraged the simultaneous use of agents affecting platelet function. The risk of hemorrhage in these trials may therefore represent an underestimation of real-life bleeding risk. Dependent on the severity of the clinical situation and in view of the relatively short half-life of the direct factor Xa inhibitors (5–15 h), cessation of medication may often be sufficient to reverse the anticoagulant effect in case of bleeding. Some authors argue that in most cases this will suffice and more immediate reversal is hardly ever really needed in clinical practice[29]. However, if immediate reversal of anticoagulation is deemed necessary, additional measures may be required. In general, these can be divided into nonspecific and specific interventions to reverse the anticoagulant effect (Table 1). A practical approach to the patient presenting with bleeding while using DOACs, based on recommendations of the European Heart Rhythm Association[15], is presented in Table 2. Nonspecific measures include (activated) prothrombin complex

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30 Feature concentrates (PCCs) or recombinant factor VIIa (rFVIIa). The prothrombotic potential of activated PCCs and rFVIIa might be higher than that of nonactivated PCCs, so nonactivated PCCs may be preferred[30, 31]. In addition, a recent retrospective series of bleeding patients treated with PCCs for anticoagulant reversal showed a 20 % risk of thromboembolic complications, although part of the risk may have been due to the underlying thromboembolic risk for which the anticoagulant was prescribed in the first place and the clinical situation of the patients[32]. Specific measures are directly targeting the anticoagulant agent, by means of (Fab fragments of) monoclonal antibodies (in the case of dabigatran) or molecules that competitively bind to the anticoagulant agents (in the case of factor Xa inhibitors). Reversal of direct oral factor Xa inhibitors Preclinical data suggest that rFVIIa and PCCs (activated and nonactivated) may be useful for the reversal of NOAC-induced anticoagulation. Experimental studies have demonstrated that the amelioration of coagulation parameters is associated with a beneficial effect on blood loss [33, 34]. In addition, a number of studies in human healthy subjects have revealed that the administration of PCC resulted in a correction of the prolonged prothrombin time and restored depressed thrombin generation after rivaroxaban treatment in a controlled trial in healthy human subjects. Similarly, a three-factor PCC (Profilnine®; Grifols Biologicals Inc., Los Angeles, CA, USA) was also evaluated for rivaroxaban reversal in a study in healthy volunteers and was shown capable of correcting some of the rivaroxaban-induced effects on coagulation parameters[35, 36, 37]. Recent studies confirmed these findings also at lower doses of PCCs[38, 39]. More specific reversal of anti-factor Xa agents can be achieved with new agents that competitively bind to the anti-factor Xa agents. Ciraparantag binds directly to the factor Xa agent (in particular edoxaban) via hydrogen bonds from or to various parts of the molecule[40, 41]. This antidote was shown to block the anticoagulant effect of edoxaban and restored the prothrombin time in vitro. Further development is ongoing. Similarly, andexanetalfa is a recombinant protein analog of factor Xa that binds to factor Xa inhibitors but does not trigger prothrombotic activity.

February 2017 • HPN

Table 2 Practical guide for how to manage bleeding complications in patients on direct oral anticoagulants

Andexanet virtually immediately reversed the anticoagulant activity of apixaban and rivaroxaban in healthy subjects without evidence of clinical toxic effects[42]. A clinical study in patients who present with bleeding while taking anti-factor Xa DOACs is ongoing. Monitoring the reversal of the anticoagulant effect of factor Xa inhibitors is most simply done by measuring the prothrombin time, although there is some variability between prothrombin time reagents and for some agents the anti-factor Xa assay is more reliable[43]. Of note, the INR is not a suitable test to quantitate the (residual) anticoagulant effect by factor Xa agents. Reversal of direct oral thrombin inhibitors The other group of DOACs directly targets thrombin (factor IIa) and is represented by dabigatran. Preclinical studies show variable effects for the efficacy of (activated) PCCs and factor VIIa to reverse the anticoagulant effect and to ameliorate experimental bleeding in animals exposed to dabigatran[33, 44, 45]. Relatively high doses of PCCs, however, seem to have a reversing effect. Similarly, human volunteer studies show a limited effect of conventional doses of PCC to normalize coagulation parameters after ingestion of dabigatran[35, 37]. There are no systematic clinical trials investigating the effect of PCCs to reverse dabigatran-associated hemorrhage in clinical practice. However, some case series are helpful. The effectiveness of dabigatran-related bleeding management using a nonactivated four-factor (4F)-PCC (Octaplex®; Octapharma, Vienna, Austria) was recently evaluated by Diaz et al.[46]. Five patients receiving dabigatran, 76–88 years of age, were administered 4 F-PCC to manage dabigatran-related GI bleeding complications. Treatment with 4 F-PCC was able to adequately control bleeding in four of five patients; the fifth patient died of septic shock and coagulopathy secondary to severe hemorrhage. No thromboembolic events were reported in the next 6 months of follow-up in these patients. Interestingly, the authors also reported that, in the one patient presenting with a prolonged activated partial thromboplastin time (aPTT) as a result of dabigatran treatment, administration of 4 F-PCC was

Oral thrombin inhibitors (dabigatran)

Oral factor Xa inhibitors (rivaroxaban, apixaban, edoxaban)

None life-threatening bleeding

Check last intake; restoration of normal coagulation to be expected at 12–24 h (in case of creatinin clearance > 80 ml/min) or 24–36 h (in case of creatinin clearance 50–80 ml/min)

Local hemostatic interventions, fluid management, transfusion

Consider tranexamic acid (1000 mg 3dd) or DDAVP (0.3 μg/kg)

Life-threatening bleeding

All of the above

All of the above

Idarucizumab

Andexanet alfa

Ciraparantag (under investigation)

Prothrombin complex concentrate (no evidence)

Prothrombin complex concentrate (healthy volunteer data)

Activated PCC (no evidence)

Activated PCC (no human evidence)

Recombinant factor VIIa (no evidence)

Recombinant factor VIIa (healthy volunteer data)

Suggested management strategy in case of hemorrhagic complications in patients using direct oral anticoagulants, modified from[15] PCC prothrombin complex concentrate, dd daily, DDAVP de-amino D-arginine vasopressin

able to partially normalize this laboratory parameter. Similar clinical case reports have been reviewed elsewhere[47]. A direct reversing agent for dabigatran has been developed recently and is based on a Fab fragment of a monoclonal antibody (idaricuzimab) directly binding to dabigatran and eliminating its anticoagulant effect[48]. Experimental studies show a rapid and almost immediate reversal of dabigatran-induced anticoagulation[49, 50]. In healthy human subjects that were exposed to dabigatran, this antidote also showed a complete elimination of the anticoagulant effect of dabigatran[51]. In a clinical trial in 90 patients on dabigatran who had serious bleeding or required an urgent invasive procedure, idarucizumab completely reversed the anticoagulant effect of dabigatran almost instantaneously[52]. Monitoring of the anticoagulant effect of thrombin inhibitors in routine clinical practice is difficult. The aPTT is not very useful. An ecarin clotting time may be more accurate but is not readily available

in most routine clinical settings. Most convenient and practically applicable for monitoring of the anticoagulant effect may be the diluted thrombin time, which needs to be standardized for the specific agent that was used[53]. Conclusion For the new generation of DOACs, several reversal strategies are under evaluation and specific antidotes or reversing agents are being developed, although most interventions need further evaluation in clinical trials. Such strategies can be used in case of serious hemorrhage complicating the use of DOACs or if a patient on DOACs needs to undergo an immediate invasive procedure. Abbreviations aPTT, activated partial thromboplastin time; DOAC, direct oral anticoagulant; 4F, four-factor; INR, international normalized ratio; NOAC, novel oral anticoagulant; NSAID, nonsteroidal antiinflammatory agent; PCC, prothrombin complex concentrate; RFVIIa, recombinant factor VIIa; VKA, vitamin K antagonist

References on request


Feature 31

Dysphagia and Malnutrition in Stroke Patients Tackling malnutrition and dehydration amongst the key issues

A stroke or cerebrovascular accident (CVA) is defined as a loss of function caused by a disruption of the blood supply to a part of the brain. This can lead to brain damage and possibly death (RCP, 2012). There are two main causes of strokes: • Ischaemic: the blood supply/ flow is stopped due to a blood clot. The mechanism of ischaemic stroke is similar to that of a myocardial infarction (heart attack). Ischaemic stroke accounts for 85% of all cases. • Haemorrhagic: a weakened blood vessel supplying the brain bursts and causes brain damage. It includes primary intracerebral and subarachnoid haemorrhages and accounts for 15% of all cases (RCP, 2012). Prevalence of stroke There are approximately 152,000 cases of stroke in the UK per year, more than one every 5 minutes. It is estimated that there are approximately 1.1 million stroke survivors living in the UK. Stroke incidence is approximately 25% higher in men than women. However, although stroke incidence is higher for men, there are more strokes in women since women generally live longer than men (Stroke Association Statistics, 2013) Stroke remains the fourth most common cause of death in the UK, after cancer, heart and respiratory disease, accounting for more than 55,000 deaths in 2010 (Townsend et al, 2012), with implications on healthcare resources (RCP Audit, 2010). One in five strokes is fatal. Stroke causes about 7% of deaths in men and 10% in women. In Ireland, there are approximately 10,000 strokes each year. Of these, five out of six strokes happen in people over the age of 60. Each year, approximately 2,000 Irish people die from stoke which accounts for more deaths than breast cancer, prostate cancer and bowel cancer combined. An estimated 30,000 people are living in the community with disabilities as a result of a stroke. This makes stroke the third biggest cause of death in Ireland and the biggest

cause of acquired disability (Irish Heart Foundation, 2014). Malnutrition is prevalent in stroke patients The overall prevalence of malnutrition in stroke patients ranges from 6.1% to 62% (Foley et al. 2009a). A recent study carried out in UK hyper acute stroke units found that the prevalence of patients at high risk of malnutrition is 29% (Gomes et al. 2014). This value agrees with the proportion of stroke patients at risk of malnutrition previously reported by Stratton and colleagues of 30% for those in the acute and community setting (Stratton et al. 2003). Dysphagia and dehydration There are a number of clinical consequences of stroke, one of which is dysphagia (difficulty swallowing). Dysphagia is common following stroke and it is present in 40-50% of patients who survive the first few days (Stroke Association, 2012; Bogaardt et al. 2009). Dysphagia after stroke may involve difficulties with both the oral and pharyngeal phases of swallowing and increases the risk of respiratory complications

and aspiration pneumonia (Sura et al. 2012) and mortality (Singh & Hamdy 2006). It can add an average of 1.6 days to a typical hospital stay (Cichero & Altman, 2012) and prolong length of stay 13 days due to associated complications such as infections e.g. pneumonia, urinary tract infections (Ingeman et al.2011).

is a predictor of poor outcomes including discharge to long term-care (Lakshminarayan et al. 2010; Finlayson et al. 2011, Crary et al. 2013). DYSPHAGIA AND DEHYDRATION Identifying Malnutrition and Dysphagia in Stroke

Dysphagia is also a strong predictor of malnutrition risk (Sura et al. 2012) and dysphagic stroke patients are 2.4 times more likely to be malnourished compared with those who have normal swallowing (p <0.008) (Foley et al. 2009b). The serious consequences of malnutrition and dysphagia in stroke mean that it is extremely important to identify those patients who are at risk.

The NICE Clinical Guideline for Stroke (NICE CG68, 2008) and the Royal College of Physicians (RCP) National Clinical Guideline for Stroke (RCP, 2012) support the identification and management of malnutrition and dehydration in stroke patients. They recommend that:

Dysphagia has also been associated with dehydration; it is estimated that 62% of stroke patients suffer from dehydration at some point during their admission (Rowat et al. 2012). Patients often limit their drinking, probably due to concerns about choking and may need enteral or intravenous fluids to meet their requirements (Vivanti et al. 2009). Dehydration

• Stroke patients should also have their hydration assessed on admission, reviewed regularly and managed so that normal hydration is maintained

• All patients should be screened for malnutrition at the time of admission and weekly thereafter

• People with dysphagia should be given food, fluids and medications modified in a form that can be swallowed without aspiration

HPN • February 2017


32 Feature • People unable to take adequate nutrition and fluids orally should receive tube feeding with a nasogastric tube within 24 hours of admission and be referred for detailed nutritional assessment, individualised advice and monitoring • Nutrition support should be initiated for people with stroke who are at risk of malnutrition. This may include oral nutritional supplements (ONS), specialist dietary advice and/or enteral tube feeding (ETF). Early assessment of nutritional risk, with appropriate nutritional management, may improve survival of stroke patients (Yoo et al. 2008). Delays in assessment, treatment and rehabilitation of stroke patients will increase the risk of secondary complications, hinder recovery, increased likelihood of malnutrition and dehydration, and lead to long-term disability or even death. THE EVIDENCE FOR NUTRITION INTERVENTION Diet Modification Texture modification of food and fluids is widely used for the management of dysphagia

(Stoke Association, 2012). Guidelines have been produced based on best available current evidence and a consensus of expert opinion, which support the use of thickeners to thicken fluid and foods (Dysphagia Diet Food Texture Descriptors, 2012; Irish Consistency Descriptors for Modified Fluids and Fluids Consensus Document 2009). There is evidence to suggest that increasing the bolus viscosity improves swallowing function in neurological patients (including stroke survivors) which can lead to a significant reduction in aspiration (Clavé et al. 2006). Food and fluids need to be modified with a thickener to a consistency which provides patients with best control over the rate at which foods and fluids pass through the pharynx (Thomas and Bishop, 2007). If consistency recommendations are not followed, patients may consume food/fluids which they do not have sufficient control over and thus put them at risk of aspiration (Garcia et al. 2010). Modified texture diets are often nutritionally deficient due to the need to add liquid to reduce the consistency of the meal for certain consistencies (Wright et al. 2005;

Foley et al. 2006; Keller et al. 2012). If these diets, which are deficient in energy and protein, are administered for prolonged periods without appropriate nutrition support, they in themselves can lead to dehydration and malnutrition. Nutrition Support A randomised control trial by Ha et al. examined whether individualized nutrition support (including ONS in the acute stage of stroke) could prevent or minimize weight loss at 3 months in patients at risk of malnutrition. The nutritional intervention provided was energy- and protein fortified meals, or ONS (0.8-1.5 kcal/ml, 0.04-0.1 g/ml protein), or enteral tube feeding (1-4 kcal/ ml) based on nutritional needs. The study showed that weight loss (≥5%) was significantly lower in patients receiving ONS during the first week in hospital (p = 0.013). Moreover, there is a trend towards decreased weight loss at 3 months with ONS however this was not statistically significant (Ha et al. 2010a). Energy and protein supplementation (via fortified diet, ONS or ETF) was also linked with a significant improvement in handgrip strength (Ha et al. 2010b).

Nutritional Management of Stroke Patients When managing people with stroke, ONS, ETF, texture modified diets and thickened fluids should be considered as per NICE CG32 and RCP guidelines (NICE, 2006; RCP, 2012). There are a variety of products which may be suitable for patients following a stroke. These include enteral tube feeds for patients who are unable to meet their nutritional requirements through oral diet alone or have an unsafe swallow; powdered thickeners for patients who require texture modified food or fluids and/or pre thickened oral nutritional supplements for those that are at nutritional risk and oral nutritional supplements patients who can tolerate normal consistency fluids but require nutritional support. The management of stroke patients by a multidisciplinary team, which includes a Speech and Language therapist and Dietitian, is key to successful outcomes for the stroke patient with dysphagia.

News University Hospital Limerick New Board SC, Alec Gabbett, Graham Knowles and Jim Canny (further biographical detail below). Incoming President of University of Limerick, Prof Desmond Fitzgerald, will join the board on taking up his appointmentwith UL.

Professor Des Fitzgerald, President, University of Limerick Minister for Health Simon Harris has announced the appointment of a new board for UL Hospitals Group for a four-year term. The inaugural meeting of the new board took place at UHL on January 19th. The new appointments, which followed a competition run through the Public Appointments Service, include Dr Mary Gray, Michael Mulcahy

February 2017 • HPN

The Board is chaired by Limerick native Professor Niall O’Higgins. He has served in this role since June 2012 and his term has been extended until May 31st, 2017 to allow for a smooth transition from the previous to the new board. Dara Purcell has been reappointed secretary of the UL Hospitals Board. All six hospitals in the Mid-West - University Hospital Limerick, University Maternity Hospital Limerick, Ennis Hospital, Nenagh Hospital, St. John's Hospital and Croom Orthopaedic Hospital - are united in one single hospital system, UL Hospitals. A common model of governance covering finance, staffing and resources is delivered under the

Chief Executive of UL Hospitals Group and the Board of Directors. The Hospital Board of Directors has been established to promote the success of UL Hospitals by leading and directing its activities, involving four main elements:  Strategic planning  Policy making  Supervision and challenge of executive management  Accountability to stakeholders The Board also has an important role in creating and maintaining a high profile for UL Hospitals at community and national level. Chairman of the Board Professor O’Higgins, stated, “I am very pleased to welcome the members of the new Board. In addition to experience and in a range of specialist fields, each brings an enthusiasm and commitment to accelerate the development of the UL Hospitals Group. By their

dedication to public service, the members of the new Board are determined to improve services for patients within the hospitals, to strengthen bonds between the hospitals and the University of Limerick and to work closely with the community programmes in enhancing care for both in-patients and out-patients.” Colette Cowan, CEO, of UL Hospitals Group, added, “The executive team at UL Hospitals was delighted to meet the new board members for our first meeting this month and I look forward to working closely with them over the next four years. We could not have wished for a better group of people to guide, advise and, of course, challenge us on our plans to develop hospital services in the MidWest. The board brings an enormous wealth and breadth of clinical, professional, management, academic and business experience to the table and we fully intend to draw on that for the good of our patients.”


34 Conference

Highlighting issues of Bench to Bedside ‘Bench to bedside’ – it’s a term used to describe how scientific discoveries translate into clinical practice. But we need to look beyond that linear model in the complex environment of health systems and human behaviours. We need to research more about how healthcare itself is delivered, and we need to engage the public, policymakers, healthcare professionals and patients alike in health research.

Professor Mike Kelly, former Director, National Institute for Health and Care Excellence

Dr Tony Holohan, Chief Medical Officer with the Department of Health, reinforced that bringing health research into practice is complex, and needs active participation from providers and patients. He outlined how Healthy Ireland provides a framework for engagement and information to fuel research and stressed the need to build a culture of listening to and involving patients.

Those were key themes that emerged during the Health Research Board (HRB30) conference, which celebrated the Health Research Board’s 30 years of supporting health research in Ireland. Healthcare outcomes from research: it’s complicated Research can lead to better outcomes for patients and, more generally, it can keep the public healthier. But the line between a study or a discovery and these health outcomes is not always straight. At the HRB 30 conference, Professor Mike Kelly, a former Director within the National Institute for Health and Care Excellence in the UK urged delegates were to ‘think slow’ about how research moves to influence policy and practice, and the need for health researchers to engage with policy makers, journalists and end users to translate their research. You’ve carried out a decent piece of health research. It gets peer-reviewed and published in a decent journal, where lots of influential people could find it when they are drawing up guidelines. Job done? Hardly, according to Professor Kelly, who issued a wake-up call to researchers about the need to engage with policy makers and journalists to help research have impact. ‘If you are a successful academic in the world of policy it is actually about shoe leather', he said. Professor Kelly was involved in developing guidelines on the promotion of good health and the prevention of disease.

February 2017 • HPN

Working across a range of topics including tobacco, alcohol, obesity, mental health and a range of communicable diseases, Professor Kelly could see a big issue. ‘The problem is that in each of areas the answers are far from simple, and yet the politicians and policy makers want simple answers to these complicated problems', he said. As humans, we tend to have cognitive short-cuts that allow us to ‘think fast’ about some topics or tasks, noted Professor Kelly, whereas we go back to first principles and ‘think slow’ about others. ‘We can’t do that first-principle thinking with everything we do, because if we did we would never make a decision. But some things in life do require us to slip into that slow-thinking mode', said Professor Kelly, who is a Senior Visiting Fellow at the University of Cambridge. ‘The trouble with many public health and policy problems is this draw to think fast all the time about causes, [as if] there is a simple cause of the effect let’s act on the cause’. For non-communicable diseases, this often gets reduced down to the very simple idea of getting people to change their behaviours.

Dr Tony Holohan, Chief Medical Officer, Department of Health

‘If we can get people to change their behaviour, they will stop smoking, they will take more exercise, they will eat more healthily and Bob’s your uncle, gone is obesity epidemic and the epidemic of heart disease and the rest of it', said Professor Kelly. But despite public health messages for decades telling people to avoid what is bad for their health and to get more active, change has been elusive: ‘If it was so easy to change behaviour we would have done it long ago’. Academic researchers also need to change their ‘fast’ thinking about how their work can have an impact – publishing findings and sitting back to let them move on and have an effect is generally not enough.

“Medical and healthcare progress is linked to a strong health research community,” said Dr Holonan. “Nevertheless, the traditional model of laboratory to bedside to patient to population in a linear fashion seems limited. A wider appreciation of health and the factors that influence it such as social determinants, which go way beyond the reach of traditional healthcare, is needed.” New paradigms, new beginnings Minister for Health, Simon Harris, TD, emphasised the need to communicate about how health research improves outcomes for patients. The talks that followed his opening speech delivered the goods. Dr Shoo K. Lee, a Scientific Director at the Canadian Institutes


35 Professor Louise Kenny, Consultant Obstetrician at University College Cork

and have made ground-breaking discoveries about links between MND and other conditions, as well as showing how patients with MND who receive multi-disciplinary care tend to do better.

of Health Research, outlined how building a network of neonatal intensive care units (NICUs) first in Canada and then internationally allowed research to improve health outcomes without the need for new technology. Dr Shoo and colleagues combined scientific studies and business-inspired approaches to quality and implementation, and they involved parents directly in the care of their babies. They improved health outcomes by reconfiguring existing resources and technology, and by challenging assumptions that only healthcare professionals can deliver healthcare. Also on the topic of pregnancy and babies, the HRB 30 conference heard from Professor Louise Kenny from the INFANT Centre about how HRB investment has supported developments designed to improve how we monitor for complications such as pre-eclampsia and fetal growth restriction. “Perinatal complications account for 10% of the global disease burden, yet R&D investment for many decades in the perinatal healthcare space [has been] small and not strategic,” said Professor Kenny, who is a Consultant Obstetrician at University College Cork. “Equitable investment in perinatal healthcare could reduce global disease burden by 3% in a decade.” Professor Kenny and her colleagues at the Science Foundation Ireland INFANT Centre in Cork are looking to tackle health issues for pregnant mothers and their babies, and

HRB investment into studies and infrastructure has been making a difference. She spoke about the decade-long SCOPE trial, which recruited 4,000 first-time mothers with low-risk pregnancies. The cohort included 1700 mothers in Ireland, and the aim was to find reliable signals in mid-pregnancy that can alert to potential complications later on, particularly pre-eclampsia. Professor Fidelma Dunne from NUI Galway described how the HRB-funded Atlantic DIP project in the west of Ireland uncovered stark figures about how often and how deeply diabetes in pregnancy affects the health of the mother and baby, and how their interventions have turned the dial back: pregnancy outcomes for women with pre-existing diabetes in the region are now almost comparable to the background population.

Professor Kathleen Bennett described studies on how longterm aspirin use can reduce the risk of metastatic breast cancer, and ongoing research to identify who will benefit from long-term aspirin. She also showed findings from research about why women with breast cancer stop taking prescribed long-term hormone therapy. Changing behaviours and cultures for health In many respects our health can depend on our behaviours and attitudes, and Dr Molly Byrne spoke at the conference about the HRB-supported Health Behaviour Change Research Group that she leads. They are developing evidence-based Interventions for cardiac sexual health, hand hygiene, supporting young people with Type 1 diabetes and many other areas. Attitudes and behaviours are also key to strengthening entire health systems, the HRB 30 Conference heard from Professor Eilis McAuliffe, who described research that has shown the benefit of ‘task sharing’ in healthcare, where less broadly trained staff do specific tasks to

make more of resources, and that pay is not always the motivation for staff. Her work as a HRB Research Leader will now assess how collective leadership can help to build a culture of reporting to improve safety reporting in healthcare. Communicating nuance Two major strands emerged at the HRB30 Conference: the complexity of health research and the need to communicate more widely about that research so that its evidence can have an impact. As both a health researcher and a journalist, Dr Sara Burke has a foot in both camps and she brought a rounded perspective. Her own HRB-funded research has uncovered evidence about the impact of specific healthcare policy decisions and funding cuts on healthcare delivery in Ireland. Meanwhile, Dr Burke has worked for several years as successful writer and broadcaster about health issues in Ireland. She described to the conference how health issues in the media are often portrayed black and white, yet the reality is many shades of grey, and research needs to shine a light on those shades. Dr Burke’s research is directly informing the Department of Health and the Oireachtas Committee on Future of Healthcare, and she urged health researchers to ensure they communicate the evidence they find, so that it is used to inform healthcare policy decisions.

Gathering and using data Professor Ella Arensman described how research is helping us to understand the prevalence and patterns of self-harm and suicide in Ireland, and to direct resources to emergency departments for people who have self-harmed. Clinician-scientist Professor Orla Hardiman and her team have discovered new genes involved in Motor Neurone Disease and clusters of occurrence in Ireland,

Professor Fidelma Dunne, NUI Galway

HPN • February 2017


36 News

Local funding for collaborative research on bone regeneration CÚRAM Investigator, Dr Manus Biggs, is one of three Irish researchers to receive a newly launched Biotechnology and Biological Sciences Research Council (BBSRC) - Science Foundation Ireland joint research grant of over ¤1 million, awarded between NUI Galway and the University of Glasgow. The BBSRC and Science Foundation Ireland have entered an agreement to welcome, encourage and support research applications that cut across national boundaries involving collaborative teams led by researchers from the UK and Ireland. Dr Biggs will co-lead a research programme in conjunction with Professor Matthew Dalby, Professor of Cell Engineering (Institute of Molecular Cell and Systems Biology) at the University of Glasgow. The programme will focus on the development of nanobiomimetic electrically active scaffolds for bone regeneration, with an aim of producing rapid, large area bone grafts in the laboratory environment. Bone tissue regeneration remains an important challenge in the field of tissue engineering and sees a transplantation frequency second only to that of blood. Bone grafting is the current standard treatment; however, given the inherent

Dr Manus Biggs, CURAM Investigator

mechanical stress) with nano mechanical stimulation to develop new bone cells from stem cells.

limitations of this approach, bone tissue engineering and advanced biomaterials that mimic the structure and function of native tissues hold potential as alternative strategies to regeneration. Current studies in regenerative bone scaffolds suggest that further biomimicry is required before a complete solution to bone regeneration can be delivered. Further evidence has been gathered on the importance of minute electrical and mechanical cues on cell differentiation and function.

“This project will further our current understanding of the joint role of electromechanical stimulation on stem cell function. We need to focus on understanding the cellular response to these subtle electrical and mechanical cues,” says Dr Biggs “We can then understand more fully how these influence cell function and tissue regeneration.” This joint programme will focus on combining piezoelectric regenerative scaffolds, (piezoelectric materials have the ability to generate an electric charge in response to applied

CÚRAM is the Science Foundation Ireland Centre for Research in Medical Devices, based at NUI Galway. Supported by Science Foundation Ireland (SFI) and industry partners, CÚRAM’s goal is to radically improve quality of life for patients with chronic illness by developing the next generation of smart, implantable medical devices. The Centre’s innovative approach incorporates biomaterials, drug delivery, cell based technologies, glycosciences and device design to enhance, develop and validate both traditional and new combinational medical devices, from molecular design stage to implant manufacturing. CÚRAM's devices are being developed with strong clinical collaborations to enable rapid translation of research findings to clinical application.

Hepatitis C eradicated in Haemophilia patients It is estimated that between 20,000 and 50,000 people in Ireland are infected with the Hepatitis C virus. There is very effective treatment now available for Hepatitis C, which eliminates the virus in over 50% of cases. However, there is still a need for a coordinated approach to surveillance, treatment and support.

with 105 also infected with HIV. To date, 112 have died of either HIV or hepatitis C.

decided not to take treatment, because they were very elderly or there were other reasons.

C virus (prevalence in population of injecting drug users in Ireland ranges from 62%-81%).

The Irish Haemophilia Society’s Chief Executive, Brian O’Mahony, said it was the largest medical disaster in the history of the State and it devastated the haemophilia community.

It was announced in December of last year that Hepatitis C has virtually been eradicated in people who have haemophilia.

In July, 2015, the IHS received an assurance from the Department of Health that all State-infected patients, including patients with haemophilia, would be treated no later than the end of 2017.

The chairwoman of the national hepatitis C treatment programme, Professor Suzanne Norris, said the HSE’s aim was to make hepatitis C a rarity in Ireland by 2030 by providing treatment to all infected persons.

The National Hepatitis C Strategy lays out a clear plan with timelines to reduce transmission of Hepatitis C and to improve the care of patients infected with Hepatitis C in Ireland. Implementation of the Strategy will be challenging in the current climate, however a number of the recommendations are already well underway. Other cost neutral recommendations which promote an enhanced, integrated approach towards care and management of Hepatitis C infected service users will be the initial focus of implementation.

All of the haemophiliacs who needed treatment for hepatitis C have now been offered it, with excellent success rates. From the 1970s to 1991, 240 haemophiliacs were infected with hepatitis C by contaminated blood products,

February 2017 • HPN

Mr O’Mahony said that the target had been exceeded, with all haemophiliacs offered treatment. The success rates are more than 90%. A small number of people

Many people are still unaware of the risk factors for contracting Hepatitis C and unknowingly engage in behaviours that put them at risk of contracting the virus. Injecting drug use is the leading risk behaviour for transmission of Hepatitis C. In particular, the sharing of injecting equipment poses the greatest risk of exposure to the Hepatitis


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dolutegravir/abacavir/ lamivudine TRIUMEQ is indicated for the treatment of HIV-infected adults and adolescents above 12 years of age weighing at least 40 kg. Before initiating treatment with abacavir-containing products, HLA-B*5701 status must always be documented. Abacavir should not be used in patients known to carry the HLA-B*5701 allele due to the risk of hypersensitivity reaction. TIVICAY is indicated in combination with other antiretroviral medicinal products for the treatment of HIV-infected adults and adolescents above 12 years of age. Triumeq and Tivicay are contraindicated: in patients with hypersensitivity to dolutegravir, abacavir or lamivudine or to any of the excipients, and with co-administration with dofetilide.5,6 These medicinal products are subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. Prescribing Information Triumeq® dolutegravir 50mg/abacavir 600mg/lamivudine 300mg tablets See Summary of Product Characteristics before prescribing. Indication: HIV in over 12 years and ≥ 40kg. Screen for HLA-B*5701 prior to use. Do not use if HLA-B*5701 positive. Dose: one tablet once daily with or without food. Elderly: Limited data in 65+ yrs. Creatinine clearance <50ml/min or moderate/severe hepatic impairment: Not recommended. Contraindications: Hypersensitivity to any ingredient. Co-administration with dofetilide. Warnings/precautions: Both abacavir and dolutegravir are associated with risk of hypersensitivity reactions (HSR). Do not initiate in HLA-B*5701+ or previous suspected abacavir HSR. Stop Triumeq without delay if HSR suspected. Never reintroduce any dolutegravir- or abacavir-containing product after suspected HSR. Risks of immune reactivation syndrome, osteonecrosis, increased weight, lipids, glucose. Monitor LFTs in Hepatitis B/C co-infection. Inconclusive data on relationship between abacavir and MI; minimise all modifiable CV risk factors (e.g. smoking, hypertension, hyperlipidaemia). Not recommended if dolutegravir required b.d. (with etravirine [without boosted PI], efavirenz, nevirapine, rifampicin, boosted tipranavir, carbamazepine, oxcarbazepine, phenytoin, phenobarbital and St John’s Wort). Use with cladribine not recommended. Use with Mg/Al-containing antacids, calcium, multivitamins or iron requires dosage separation. Caution with metformin: monitor renal function and consider metformin dose adjustment. Pregnancy/lactation: Not recommended. Avoid breast-feeding. Side effects: See SPC for details. Headache, insomnia, sleep/dream disorders, GI disturbance, fatigue, hypersensitivity, anorexia, depression, dizziness, somnolence, lethargy, malaise, cough, nasal symptoms, rash, pruritus, alopecia, arthralgia, muscle disorders, asthenia, fever, elevations of ALT, AST and CPK, blood dyscrasias, suicidal ideation or suicide attempt, rhabdomyolysis, lactic acidosis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis. Basic NHS costs: 30 tablets: £798.16 EU/1/14/940/001. MA holder: ViiV Healthcare UK Ltd, 980 Great West Road, Brentford, Middlesex TW8 9GS. Further information is available from Customer Contact Centre, GlaxoSmithKline UK Ltd, Stockley Park West, Uxbridge, Middlesex UB11 1BT. POM S1A

Triumeq is a registered trademark of the ViiV Healthcare Group of Companies Date of approval: July 2016 Zinc code: UK/TRIM/0037/14(5)

dolutegravir 50mg tablets Tivicay® See Summary of Product Characteristics before prescribing Indication: HIV in >12 years and ≥40kg as part of combination therapy. Dosing: 50mg once daily with or without food if no proven/suspected integrase resistance. 50mg twice daily with efavirenz, nevirapine, tipranavir/ritonavir, etravirine (without boosted PI), carbamazepine, oxcarbazepine, phenytoin, phenobarbital, St John’s Wort or rifampicin. Adults with proven/suspected integrase resistance: 50mg twice daily preferably with food. Elderly: Limited data in 65+ yrs. Caution in severe hepatic impairment. Contraindications: Hypersensitivity to any ingredient. Co-administration with dofetilide. Warnings/precautions: Risk of hypersensitivity reactions. Discontinue dolutegravir and other suspect agents immediately if suspected. Risks of osteonecrosis, immune reactivation syndrome. Monitor LFTs in Hepatitis B/C co-infection and ensure effective Hepatitis B therapy. Caution with metformin: monitor renal function and consider metformin dose adjustment. Use with etravirine requires boosted PI or increased dose of dolutegravir. Use with Mg/Al-containing antacids, calcium, multivitamins or iron requires dosage separation. Pregnancy/ lactation: Not recommended. Avoid breast-feeding. Side effects: See SPC for full details. Headache, GI disturbance, insomnia, abnormal dreams, depression, dizziness, rash, pruritus, fatigue, elevations of ALT, AST and CPK, hypersensitivity, suicidal ideation or suicide attempt. Basic NHS costs: 30 tablets £498.75 EU/1/13/892/001. MA holder: ViiV Healthcare UK Ltd, 980 Great West Road, Brentford, Middlesex TW8 9GS. Further information available from Customer Contact Centre, GlaxoSmithKline UK Ltd, Stockley Park West, Uxbridge, Middlesex UB11 1BT. POM S1A Tivicay is a registered trademark of the ViiV Healthcare Group of Companies Date of approval: August 2015 Zinc code: UK/DLG/0055/13(7)

References: 1. Walmsley S et al. J Acquir Immune Defic Syndr. 2015;70(5):515-519. 2. Molina J-M et al. Lancet HIV. 2015;2(4):e127-e136. 3. Orrell C et al. Presented at: Annual International AIDS Conference; July 18-22, 2016; Durban, South Africa. Abstract THAB0205LB. 4. Raffi F et al. Lancet Infect Dis. 2013;13(11):927-935. 5. TIVICAY (dolutegravir) Summary of Product Characteristics. Available from: www.medicines.ie, accessed: September 2016. 6. Triumeq (dolutegravir/avacavir/lamivudine) Summary of Product Characteristics. Available from: www.medicines.ie, accessed: September 2016.

Adverse events should be reported. For the UK, reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to GlaxoSmithKline on 0800 221 441.

Adverse events should be reported. For Ireland, adverse events should be reported directly to the HPRA; Freepost, Pharmacovigilance Section, Health Products Regulatory Authority, Earlsfort Terrace, Dublin 2, Tel: +353 1 676 4971, medsafety@hpra.ie. Adverse events should also be reported to GlaxoSmithKline on 1800 244 255.

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TRIUMEQ and TIVICAY are registered trademarks of the ViiV Healthcare group of companies. ©2016 ViiV Healthcare group of companies All rights reserved.

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Date of preparation: September 2016 IE/DGR/0016/16

10/19/2016 1:42:14 PM


38 Feature

Myths and Misconceptions around Pain The latest research contradicts some of the popular assumptions about joint pain. These misconceptions often get in the way of effective therapies. A lot of incorrect assumptions about joint pain are in circulation. “The sometimes overly pessimistic misconceptions can prevent patients from getting into therapy even though it could improve their condition and reduce their pain,” pain expert Serge Perrot criticized. Perrot, a Professor from Descartes University and Cochin Hospital, Paris, France, made these remarks at a symposium focusing on severe and chronic joint pain being staged in Dubrovnik by the European Pain Federation EFIC. The expert talked about some of the most common myths concerning joint pain. Myth #1: The more extensive the joint damage, the more severe the pain. The misconception that the intensity of pain correlates with the extent of anatomical joint damage is especially persistent. Professor Perrot, “This statement is true at most in connection with very severe lesions.” Data shows that half of the individuals with radiologically verifiable joint damage live free of pain whereas, conversely, one in every two patients with knee pain has an intact joint. Prof Perrot: “So the question has to be this: Are there joint changes that induce pain?” Various cohort studies (MOST, Framingham) prove, for example, that a constriction of the intra-articular space is more likely to result in knee pain than osteophytes are, i.e. degenerative, structural changes in the bone. According to MRT studies (Torres, Osteoarthritis Cartilage 2006), intense pain is strongly correlated with synovialitis (inflammation of the synovial membrane) or bone marrow injuries but not with osteophytes, changes in cartilage, bone cysts, subluxations of the meniscus or lacerated ligaments.

February 2017 • HPN

Myth #2: Joint pain is synonymous with inflammation. Anyone who automatically assumes that inflammation is the reason for joint pain is equally off track. Professor Perrot provided more precise information, “Inflammations play a role mainly in acute pain but not in chronic and mechanical pain.” Viewed pathophysiologically, joint pain is both, namely, an inflammation of the synovial membrane and bone pain caused by a constriction of the intra-articular space that increases the local pressure. According to one study (Laslett, EULAR 2011, London), treatment with a 5mg IV of zoldedronic acid can reduce bone pain by 15 points on the 100-point VAS scale. Injuries to bone marrow are reduced by 37%. For pain caused by an inflammation of the synovial membrane, treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) can help. Treatment of bone marrow oedemas also helps mitigate the pain.

Myth #3: Joint pain emanates from the joint. The assumption that joint pain has to emanate from the joint would seem obvious but is in fact incorrect. Professor Perrot, “Joint pain is a complex experience in which social factors, pain behaviour, feelings, thoughts, the perception of pain and damage to nociceptive tissue come into play.” He cited arthritis as an example that demonstrates just how much a matter of the mind pain ultimately is: Spontaneous arthritic pain is exhibited in the brain in the medial prefrontal cortex and affects the person’s emotional state. Pain induced by a stimulus exhibits itself in brain regions that process somatosensorily nociceptive processes. In the central nervous system, joint pain sensitizes the brain, thereby creating excess local sensitivity. Myth #4: Joint pain comes with age. Professor Perrot added, “80% of arthritis patients are 50 or

older but age alone does not determine whether a person suffers from joint pain and how severe that pain is.” Besides age, two other cofactors for the intensity of arthritis pain are obesity and local injuries. People with the genotype Ile585Val TRPV1 are less sensitive to pain in the lower part of their body and therefore have a significantly lower risk of suffering from painful arthritis in their knees. With inflammatory joint diseases, gender can determine the level of pain: Women suffer more from these diseases than men do. Hormones can also be involved in joint pain: A blockage of oestrogen, for instance in connection with breast cancer treatment, can quickly result in inflammatory changes to wrists and ankles. Myth #5: Joint pain is not treatable. Even if freedom from pain is not a realistic goal of therapy in some cases: Joint pain does not have to be accepted without any hope of relief. Even intense pain is not synonymous with serious


39 Professor Serge Perrot, Descartes University and Cochin Hospital, Paris

damage to the joint. “Joint pain is highly heterogeneous. The pain phenotypes therefore have to be precisely analysed to be able to initiate a suitable treatment,” the expert emphasised. He recommended that pain management should in any case consist of a combination of pharmacological and non-drug therapies. Inadequate treatment in Chronic Musculoskeletal Pain Elderly patients with chronic musculoskeletal pain often receive inadequate medical treatment. A recent Polish study suggests that this situation does not change until patients are referred to specialised pain clinics. “Prior to referral, the patients receive systemic non-steroidal anti-inflammatory drugs (NSAIDs) all too often and opioids all too rarely. Yet the opioid buprenorphine, for instance, is a highly effective drug for combatting pronounced pain and is just as safe used on elderly patients as on younger ones,” said study author Dr Magdalena Kocot-Kepska from the Collegium Medicum of Jagiellonian University in Krakow (Poland) at the symposium. In this study, researchers evaluated data from 165 patients over the age of 80 who were referred to a pain clinic due to chronic complaints. 70% of this group consisted of patients suffering from chronic musculoskeletal pain. Six out of seven patients were women. Prior to admission to the clinics, 71% of the patients were treated with non-steroidal anti-inflammatory drugs

(NSAIDs). That was the case even though nearly all of them (95%) suffered from cardiovascular diseases and these analgesics are not indicated in the case of cardiovascular problems. After being admitted to the pain clinic, 35% were given strong opioids, but only a good one in five of these patients displayed slight side-effects. Dr Kocot-Kepska, “A good deal of clarification and clear-cut treatment guidelines are still needed. The concerns about opioids and the excessive use of NSAIDs definitely have to be reconsidered, especially in elderly, most vulnerable patients.” Weight loss reduces joint pain for osteoarthritic patients Reduction of body weight reduces the pain level of patients suffering from advanced osteoarthritis. This is shown by a Scottish study that was also presented at the EFIC symposium in Dubrovnik. After losing weight, patients had to take steroidal anti-inflammatory drugs only three times a week instead of four times to combat breakthrough pain, according to the study authors. In this study 30 people (twelve men, 18 women) were examined to determine how programmed weight reduction would affect their pain level. For 14 weeks, the study participants followed a diet and swam 30 minutes a day under the supervision of a physiotherapist. The participants weighed an average of 95 kilograms initially and the majority of them succeeded in

losing about 6.7% of their body weight. At the same time the pain level on the 10-point VAS pain scale fell from 6 to 4 points among the men and from 7 to 6 points among the women.

EFIC was formed in 1993, and has grown in size and scope over the last 21 years. It has become established as the European voice of all those who study and treat pain.

2017 European Pain Federation Congress

During the Congress he speakers will explore the scientific application of clinical pain management, looking ahead and highlighting how best to apply pain treatment in the future. There is an excellent, broad-based Scientific Programme Committee, chaired by Thomas Toelle. The SPC is working on an attractive and ambitious programme, which will cover all the different multi-disciplinary aspects of research and medical practice in this field. Refresher Courses, Plenary Lectures, Topical Seminars, workshops and daily poster presentations will both encourage interaction and inspire exchange between participants.

The European Pain Federation EFIC is a multidisciplinary professional organisation in the field of pain research and medicine, consisting of the 37 chapters of the International Association for the Study of Pain (IASP®), which are the IASP approved official National Pain Societies in each country. Established in 1993, The European Pain Federation EFIC constituent chapters represent Pain Societies from 37 European countries and close to 20,000 physicians, basic researchers, nurses, physiotherapists, psychologists and other healthcare professionals across Europe, who are involved in pain management and pain research. Chris Wells, President of the European Pain Federation EFIC, has announced the 10th Congress of the European Pain Federation EFIC. This will be held in Copenhagen, Denmark from 6th to 9th September 2017. This congress follows on from a series of successful meetings throughout Europe over the last 22 years; however, this year the European Pain Federation EFIC is planning major changes in both form and content.

Sources: EFIC 2016 – Topical Symposium on Acute and Chronic Joint Pain: Abstract M. Kocot Kepska, A. PrzeklasaMuszynska, J. Dobrogowski: Strong opioids for chronic musculoskeletal pain in elderly - retrospective study of multidisciplinary pain clinic patients; Abstract EFIC 2016 – Topical Symposium on Acute and Chronic Joint Pain: M. Paul: Effect of programmed weight loss on joint pain in osteoarthritis – non pharmacological intervention

This innovative and informative event will once again be the leading pain congress in Europe. The European Pain Federation

Source: EFIC 2016 – Topical Symposium on Acute and Chronic Joint Pain: Professor Serge Perrot

HPN • February 2017


News 41

New positions on biosimilar interchangeability The European Society for Medical Oncology (ESMO), the USA's Food and Drug Administration (FDA) and a collection of scientists from national medicines regulators have each made new and important interventions to current debates about biosimilar interchangeability. The public positioning comes as an increasing number of biosimilar products coming to market in an environment where cost pressures highlight the need to utilise less expensive medicinal products where this can be done without detriment to patient treatment or safety. In the case of small and large chemical medicines, moving patients to cheaper generic versions of the originator product has been a long-standing and successful means to reduce a

health system's medicines bills. In the case of biologic medicines however, the level to which a reference product and a biosimilar product can be considered interchangeable is sometimes made subject of debate. Because of this, healthcare professional organisations and regulators are increasingly making known their positions on the matter. The USA's medicines regulator, the Food and Drug Administration (FDA), opened the New Year by publishing long-awaited draft guidelines on the interchangeability of a biosimilar with its reference product. The draft guidelines call for developers of biosimilars to produce a switching study (or studies) to demonstrate that the risk in terms of safety or

diminished efficacy between a biosimilar and its reference product is not greater than the risk of using the reference product without such switch. In short, an interchangeable product is expected to produce the same clinical result as the reference product in any given patient. Achieving the status of 'interchangeable' is especially important in the USA as only such designated biosimilars can then be substituted for the reference product by a pharmacist without the intervention of a health care provider. Meanwhile, the European Society for Medical Oncology (ESMO) has made an intervention into the current discussions on biosimilar interchangeability and substitution by publishing a formal position

paper. The paper embraces the opportunity biosimilars provide in keeping medicines costs sustainable for health systems, but also strongly emphasises the need for physicians to retain authority in respect to any switch of a patient between reference and biosimilar product, or between different biosimilars. The ESMO position paper states: "Automatic substitution, which might be practice for generics, should... be avoided in the field of biosimilars. Interchangeability and switching should only be permitted if: (1) the physician is well-informed about the products; (2) the patient is fully briefed by the physician and (3) a nurse is closely monitoring the changes and tracking any adverse events".

Hospital Pharmacy Technicians Annual Conference The National Hospital Pharmacy Technicians Association (NAHPT) Annual Conference will take place this year on Saturday, April 1st, 2017 in the Crowne Plaza Hotel, Santry. Registration will open from 8.30am and the conference agenda includes presentations, workshops and pharmaceutical exhibition. There will also be two categories within the poster competition, sponsored by Actavis. For registration on line visit www.pharmtech.ie or contact President Laura Lyons for more information on llyons@mater.ie

Clinical trials programme expansion Leading healthcare company, MSD, has announced that it is to expand its clinical trials programme in Ireland, with a particular focus on the latest developments in the treatment of cancer. The announcement, which will see MSD commit up to ¤25 million to Irishbased clinical trials and related R&D activities over the next three years, was made to coincide with MSD’s global sponsorship of World Cancer Day - a worldwide initiative designed to raise awareness of cancer and reduce the global burden through prevention, detection, and treatment. According to Ger Brennan, Managing Director of MSD Human Health, “Today’s announcement

marking World Cancer Day is a signal of the potential we believe exists for growing Ireland’s standing in healthcare research and development globally. The Irish Government has openly stated its ambition to make the pharmaceutical sector a cornerstone of economic policy and one of the main priorities for Irish economic growth going forward. Key to this will be embracing the potential of leadingedge R&D and putting in place the structures to maximise the potential returns for not just the Irish patient population, but also the economy generally.” MSD’s Medical Director, Dr. Colm Galligan, noted, “While there has

been some progress in recent years, there remains significant potential to expand access to clinical trials for Irish patients. A report commissioned by Cancer Trials Ireland estimates that clinical trials can add from 6 to 15 quality adjusted years for participants[i]. Despite this, recent data shows that only 3% of cancer patients in Ireland participate in a clinical trial. [ii] Reaching our full potential will require a collaborative approach from industry, Government and healthcare professionals, with a focus on dedicated time, resources and infrastructure. “The concept of ‘protected time’ for researcher doctors is long established in many other

countries, where clinicians dedicate a set amount of time to clinical research each year. Current burdens on the healthcare system in Ireland mean that clinicians, understandably, are focused on basic service provision. To truly accelerate R&D in Ireland, renewed incentives would be a welcome step in ensuring Ireland takes a leading role in innovative research and clinical trials.” There are now 21 clinical trials being run by MSD in Ireland, including trials for MSD’s breakthrough oncology product, as well as new discoveries and innovations in other therapeutic areas, such as Alzheimer’s disease.

HPN • February 2017


42 News

Applying economics to healthcare Health economics applies economic reasoning to the analysis of health and healthcare. It is an applied field of study that allows for the systematic and rigorous examination of the problems faced in promoting health for all. Many hospital and pharmaceutical industry professionals are taking on the challenge of health economics as they observe the benefits of applying it to a variety of challenges in health and medicine. As the population continues to grow, the demand for quality and cost-effective health care similarly grows, leaving the field of health economics vital to sustaining our health care system. NUI Galway currently offer an MSc in Health Economics and has yielded noteworthy results, as those undertaking the course have been enjoying comprehensive training in both the theory and application of health economics techniques, and graduate with the skills and experience for a successful career in research, professional practice or policy analysis. Recent graduates have secured employment in large multinational pharmaceutical companies, in government departments, and in research centres. Market Access Manager with MSD, Mr Peter Tierney became aware of the discipline and the benefits medicine can bring to the healthcare system whilst undertaking a module on public health in the final year of his MPharm degree. He tells Hospital Professional News, “One of the fundamental principles of Pharmacy is that best clinical evidence must inform to the provision of pharmaceutical care in order to achieve optimal outcomes for patients. Additionally in order for the overall healthcare system to function efficiently it is important, bearing in mind the finite resources available, that all decisions are made only after carefully considering best evidence and cost/affordability. The MSc in Health Economics offered me the opportunity to study how to combine rational decision making with best clinical evidence.” Patient Access Manager with Novartis, Louise Duggan, also recently completed the course and echoes these sentiments. “I felt by undertaking this course, I would obtain new skills so I could better evaluate healthcare from various perspectives such as societal, patient, healthcare

February 2017 • HPN

professionals and payers,” she says. “The funding and provision of healthcare is complex. It is obvious that there are some best practices taking place in international healthcare systems that we need to implement, such as electronic patient/data records and better capacity management. I think these capabilities will be the key to unlocking so many issues in evaluating and funding healthcare provision in Ireland.” The programme at NUI Galway consists of taught modules, an internship and a minor dissertation. Taught modules include Economics of Health and Social Care, Economic Evaluation in Healthcare, Health Systems and Policy Analysis and Applied HTA and Decision Modelling amongst other topics. For Mr Tierney, the course broadened an understanding of the delivery of healthcare beyond just medicines. “It equipped me with an in-depth understanding of economic modelling as it relates to health technology assessments. The course also further developed my understanding of the macroeconomic environment and the challenges facing the Department of Health and the HSE in the delivery of healthcare in Ireland.” In relation to his current position with MSD, the course assisted in equipping him with the skillset necessary to successfully achieve and maintain patient access to innovative drugs across a number of therapeutic areas. “My job is to secure and maintain national reimbursement of pharmaceuticals thus ensuring that Irish patients can access the best medicines,” he says. “For Irish patients to continue to benefit from these medicines it is important that the access is sustainable for all stakeholders. Combining what I learnt in the MSc with my MPharm I am in a much better position to understand and articulate the value that pharmaceuticals and Pharmacy bring to the overall healthcare system.” Another recent graduate student is Helen O’Donnell, currently undertaking a PhD in Pharmacoeconomics with Trinity College Dublin in conjunction with the National Centre for Pharmacoeconomics (NCPE). While having previously worked within community Pharmacy, economics has always interested Helen.

“The mix of analytical, quantitative and clinical aspects greatly appealed to me,” she says. “Changing career was a big decision. Therefore I felt that a one-year taught program would allow me to obtain a broad base of knowledge and experience in economics which would help me to make a correct decision regarding my future career path. The 12 week work placement organised as part of the course was also a significant factor in my decision. “The course helped me to realise that health economics does not equate to health care economics and made me appreciate the importance of the topic to society. On a practical level, I developed quantitative skills in statistics and econometrics and gained practical experience of using two common statistical packages SPSS and STATA. “My enjoyment of the course gave me the confidence to pursue a PhD position with the NCPE. The applied knowledge and skills I gained on the course and the experience of conducting the master’s thesis have given me a firm foundation for my future research.” Understanding international healthcare systems is another key component of the course and one which was important to Louise Duggan, who adds, “My ultimate professional goal is to continue to improve patient outcomes in Ireland. Novartis has been recognized as having the best pipeline in the world, with over 140 projects in clinical development. I am very proud to work in a company that provides Irish patients with medicines that makes a real difference to patients’ lives.” Louise concludes by stating, “The funding and provision of healthcare is complex. It is obvious that there are some best practices taking place in international healthcare systems that we need to implement, such as electronic patient/data records and better capacity management. I think these capabilities will be the key to unlocking so many issues in evaluating and funding healthcare provision in Ireland. “Having attended this course, I have a better understanding of the pressures that healthcare providers face, from a policy, patient demand and finite budget perspective. Novartis now, in partnership with the MSc in NUI Galway host an annual meeting in November that focuses on topical issues relating

to the funding and provision of healthcare in Ireland.” For more information on the MSc in Health Economics please contact Brendan Kennelly at brendan.kennelly@nuigalway.ie or by visiting http://www.nuigalway.ie/ health-economics/ Hospital Pharmacist Case Study Pauline Duggan Hospital Pharmacist, Naas General Hospital Pauline Duggan has commenced the programme with a three-fold learning objective:  To gain knowledge of the tools of health economics and how to apply economic theories and models to healthcare providers;  To learn how to allocate already scarce resources, while still trying to maximise health benefits to the population, and;  To learn about economic evaluation and how to understand their use in the decision making process. “Most hospital pharmacists use pharmacoeconomics to assist with making decisions involving formularies and how medicines can be used in a more costeffective or cost-beneficial manner. We are constantly looking at ways in which to reduce costs without impacting on patient health. “With the increasing focus on drug pricing, the medicines management programme and the decisions being made by National Centre for Pharmacoeconomics in relation to new drugs, getting the economics right is becoming as important as the clinical efficacy. “An aging population has led to an increase in the prevalence of chronic disease and the range of medications being prescribed is ever expanding. Providing healthcare in an efficient manner is becoming more important and I was interested in understanding how this can be achieved. “Providing healthcare in an efficient manner is becoming more and more important especially when it comes to the allocation of limited resources. As a hospital pharmacist, I feel we are ideally placed to have an impact on decision making in the provision of healthcare in Ireland.”


MSc (Health Economics)

Choose NUI Galway for an MSc (Health Economics) and you will gain far more than just a qualification. Our program was developed in response to industry needs and is delivered by enthusiastic, research-active faculty. Applications from people with experience in the pharmaceutical industry or the health care system are especially welcome. Applicants without a background in economics will be offered an opportunity to take a course in economics before starting the programme. Working professionals can complete the program on a part-time basis over a two year period.

Find out more: brendan.kennelly@nuigalway.ie www.nuigalway.ie/health-economics

#GetTheEdge


44 Event Gallery Professional Diploma in Clinical Leadership programme The President of RCSI, Professor John Hyland has opened Ireland’s first Professional Diploma in Clinical Leadership at the RCSI Institute of Leadership. The programme, directed by Mr Dermot O’Flynn and Dr Mary Collins, is unique in that it is an interdisciplinary specialist accredited postgraduate programme designed for newly appointed or 'soon to be appointed' senior clinicians, clinical managers, supervisors, clinical nurse managers and allied health professionals in the private, public or non-profit sector who wish to quickly develop their clinical leadership skills.

The development of systems thinking and transformational leadership will be a major focus of the new programme, which will also incorporate advances in positive psychology and organisational scholarship. As such, it will be the first clinical leadership programme in Ireland to incorporate these developments. Mr O’Flynn, Director of Professional Development at the Institute of Leadership said 'participants will undertake a unique programme of study which will be evidence-based, cutting-edge and designed to meet the immediate development needs of both themselves and their organisations'.

Professor John Hyland, President of RCSI; Professor Ciaran O'Boyle, Director of the Institute of Leadership; Dr Mary Collins, Programme Director; Mr Dermot O'Flynn, Programme Director; and Professional Diploma in Clinical Leadership participants

Irish Thoracic Society Bursaries Pictured at the presentation of the ITS GSK Travel Bursaries to the BTS Winter Meeting are Dr Marcus Butler, Irish Thoracic Society, Dr Dorothy Ryan, Beaumont Hospital, Dr Matshediso Mokoka, Beaumont Hospital, RCSI and Mr Tom Lane, GSK. Also pictured (right) at the presentation of the ASI ITS Research Bursary 2016 are Ms Averil Power, CEO, Asthma Society, Prof Anthony O'Regan, Galway University Hospital,Galway, Ms Jennifer Heaney, Novartis and Dr Jacqueline Rendall, President, Irish Thoracic Society. Prof O'Regan's project will be exploring the prevalence and impact of nasal disease in persistent asthma in the West of Ireland. Annual Scientific Meeting Meanwhile, the 2016 Irish Thoracic Society Annual Scientific Meeting was held in the Fitzpatrick Castle Hotel, Dublin. The conference reflected the excellent work in respiratory medicine and healthcare throughout the island and ‘state of the art’ education on a range of topics. Guest lectures from Professor Wisia Wedzicha, Imperial College London; Professor Luke O’Neill, Trinity College Dublin; Professor Richard Costello, RCSI, Beaumont Hospital Dublin, and Professor Karina Keogh, Mayo Clinic, Rochester were very well received by all.

February 2017 • HPN

Professor Richard Costello, RCSI Beaumont Hospital Dublin, delivering his guest lecture ‘Does Adherence to Therapy Matter’ at the ITS Annual Scientific Meeting, kindly supported by Teva

Professor JJ Gilmartin, Dr Michael O’Mahony and Professor Anthony O’Regan, Galway University Hospitals with Professor Luke O’Neill, Trinity College Dublin, Guest Speaker at the ITS Annual Scientific Meeting

Mr Barry Walsh and Ms Cliona O’Donoghue, Boehringer Ingelheim, Professor Wisia Wedzicha, Imperial College London (keynote speaker) and Dr Marcus Butler, St Vincent’s University Hospital Dublin


45 Leadership Foundation invite for Professor O’Driscoll

Bon Secours hosts Study Day

Professor Lorraine O’Driscoll has been invited, by Leadership Foundation for Higher Education, to become a Role Model for others undertaking their programme. Leadership Foundation for Higher Education is a UK-led programme that offers training in leadership skills that are important in third level institutes both in Ireland and the UK. The vision is to draw on leadership skills developed in academia and academia, by role models, to guide and inspire others.

Professor O'Driscoll

Saturday January, 28th 2017 saw Bons Secours Hospital Cork host Ireland’s largest Annual GP Study Day at which 280 doctors attended. The speakers on the day covered a very broad range of topics and included Dr Ailís Ni Riain (GP Engagement Project), Dr Mark

Davis Heartsink patients – working with people who are difficult to help, Ms Mary Condell Assisted Decision Making (Capacity Act 2015) in addition to the Bon Secours Hospital Cork Consultant speakers who presented a range of case studies chaired by GPs, in Cardiology/Neurology/ Endocrinology/Rheumatology/ Respiratory Medicine/ Dermatology/Haematology/ Microbiology/Gastroenterology/ Emergency Medicine. Additionally the hospital consultants delivered talks on topical areas such as Colorectal Cancer, Breast Screening, Ovarian Cancer, Acute Sports injurie and Acute Paediatric presentations.

Workshop held on Integrated Care Programme for Older Persons A joint workshop was held between staff of HSE Community Healthcare Organisation Area 1 (CHO 1)and Sligo University Hospital (SUH) on the Integrated Care Programme for Older Persons (ICPOP) recently. The workshop was co- facilliated by representatives from CHO 1/ SUH ICP OP Implementation Team and the National ICPOP. The ICPOP is based on a ten step framework, the central objective of which is to integrate existing services and develop new community based care models to improve health and social

services for older persons in our society. This is achieved through joint working between all agencies and in particular between acute hospital services and community services. The aim of the workshop was to commence mapping of existing resources and to inform an action plan for 2017 for older persons services across CHO 1(commencing with Sligo/Leitrim) and SUH. Dr Siobhan Kennelly clinical lead on the national programme updated the attendees on the national ICPOP. Speaking at the workshop she stated, “By 2021

there will be an extra 136,000 people aged over 85 than today. Another way to think about this: we’ll add roughly 20,000 more people aged over 75 every year for the next 20 years.” * Planning around how to meet their needs now is essential if we are to sustain vital health and social care services. The support of local implementation of integrated solutions to older persons care using population based planningsuch as thosebeing developed and delivered across CHO 1 and SUH is key to the approach being use by ICPOP as a national programme”.

Jo Shortt, Senior Project Manager at SUH spoke on the achievements to date with regards to joint working across CHO 1/ SUH stating “Today is about linking current service provision to greatest need, with a focus of keeping our older persons out of hospital where appropriate and safe. Where patients require admission, we need to ensure that our expert team can assess and treat this patient group as quickly as possible to reduce hospital stay and improve our patient outcomes. Working together across hospital and community will be crucial to this.”

¤1.1m distribution deal for Limerick firm Fleming Medical, a key supplier of medical devices has recently signed a distribution agreement with Muscat Pharmacy to distribute its Medicare range of products in Oman. The deal represents a value of ¤1.1million over the next three years and builds on the company’s strategy to grow its presence in the Middle East. Fleming Medical was part of an Enterprise Ireland delegation of 20 Irish companies led by Minister for Employment & Small Business, Pat Breen TD that attended Arab Health 2017 in Dubai, the largest healthcare exhibition & medical congress in the Middle East. Founded by MD, Mark Fleming 30 years ago in Limerick, the company operates successfully in more than 20 countries worldwide, trading in quality healthcare

devices and consumables under the Medicare brand, among others. As a leading healthcare business and recognised innovator, Fleming Medical is a trusted partner for Irish and international pharmacy and healthcare industries. “We are delighted to announce our appointment of Muscat Pharmacy as our distributor in Oman – we are very excited in seeing our Irish products on the shelves in Omani Pharmacies. This announcement is further strengthening both the Fleming Medical & Medicare brands on an international stage – we look forward to exploring more new markets in the next few years,” said Mark Fleming, MD Fleming Medical.

Mike Hogan, Director MENA Enterprise Ireland, Mr Patrick Hennessy (Ambassador of Ireland to the UAE), Dr Mohammed H. Darwish, Honorary Consul of Ireland to Oman, Mr Pat Breen, Minister for Employment & Small Business, Mohamed ?????????????????????

HPN • February 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 AFPCI 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 February 2017 • HPN

a combination therapy that 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 AFPCI 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.”

• Arm 1: Rivaroxaban 15 mg once 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

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.”

• 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

“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 lowdose ASA to end of month 12

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

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:

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

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). “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.”


DEMONSTRATED POWERFUL PAIN RELIEF1,a For the symptomatic relief of1 Osteoarthritisb

30-60mg once daily

Rheumatoid Arthritisc Ankylosing Spondylitisc

60-90mg once daily

For the short-term treatment of1 Postoperative Moderate Dental Surgery Pain

90mg

Acute Gouty Arthritis

120mg

once daily, maximum 3 days

once daily, maximum 8 days

60-90mg once daily

ARCOXIA® Film-coated Tablets Prescribing Information Refer to the Summary of Product Characteristics (SmPC) before prescribing. Presentation: Arcoxia 30 mg (blue-green), 60 mg (dark green), 90 mg (white), 120 mg (pale green) film-coated tablets containing 30 mg, 60 mg, 90 mg and 120 mg etoricoxib respectively. Indication: Adults and adolescents 16 years of age and older for the symptomatic relief of osteoarthritis (OA), rheumatoid arthritis (RA), ankylosing spondylitis (AS), and pain and signs of inflammation associated with acute gouty arthritis. Adults and adolescents 16 years of age and older for short-term treatment of moderate pain associated with dental surgery. Dosage and method of administration: Shortest duration of treatment and lowest effective dose should be used as cardiovascular risk may increase with dose and duration of exposure. Need for symptomatic relief and response to therapy should be re-evaluated periodically especially in patients with OA. Administer orally with or without food. OA: 30 mg o.d. If insufficient relief, 60 mg once daily (o.d.) may increase efficacy. RA and AS: 60 mg o.d. If insufficient relief, 90 mg o.d. may increase efficacy, once clinically stabilised titration to 60 mg may be appropriate. Acute gouty arthritis: 120 mg o.d., maximum 8 days treatment. Postoperative dental surgery pain: 90 mg o.d., limited to maximum of 3 days. Do not exceed recommended dose or duration of treatment. Elderly: No dosage adjustments necessary. Exercise caution. Hepatic impairment: do not exceed 60 mg dose in mild dysfunction. Do not exceed 30 mg dose in moderate dysfunction. Renal impairment: No dosage adjustments required in creatinine clearance ≥ 30 ml/min. Contraindications: Hypersensitivity to ingredients, active peptic ulceration or active gastro-intestinal (GI) bleeding, patients who after taking acetylsalicylic acid or non-steroidal anti-inflammatory drugs (NSAIDs) including cyclooxygenase-2 (COX-2) inhibitors experience bronchospasm, acute rhinitis, nasal polyps, angioneurotic oedema, urticarial or allergic-type reactions, pregnancy and lactation, severe hepatic dysfunction, estimated renal creatinine clearance < 30 ml/min, children and adolescents under 16 years, inflammatory bowel disease, congestive heart failure, patients with hypertension whose blood pressure is persistently elevated above 140/90 mmHg and has not been adequately controlled, established ischaemic heart disease, peripheral arterial disease, and/or cerebrovascular disease. Special warnings and precautions: Gastrointestinal effects: Upper GI complications, some resulting in fatal outcome have occurred with etoricoxib. Caution in patients at risk of developing GI complications with NSAIDs; elderly using other NSAID or acetylsalicyclic acid concomitantly or patients with history of GI disease. Increased risk of GI adverse effects when taken concomitantly with acetylsalicyclic acid. Cardiovascular effects: Class of drugs may be associated with risk of thrombotic events. Careful consideration in patients with significant risk factors for cardiovascular events (hypertension, hyperlipidaemia, diabetes mellitus, smoking). Do not discontinue anti-platelet therapies. Renal effects: Consider monitoring of renal function in patients with pre-existing significantly impaired renal function, uncompensated heart failure or cirrhosis. Fluid retention, oedema and hypertension: Caution in patients with history of heart failure, left ventricular dysfunction or hypertension and in pre-existing oedema. Take measures to discontinue treatment if deterioration of condition. Control hypertension before initiating treatment and monitor blood pressure within two weeks after initiation and periodically thereafter. Hepatic Effects: Monitor patients with symptoms and/ or signs of liver dysfunction, or in whom abnormal liver test has occurred. Discontinue if signs of hepatic insufficiency or persistent abnormal liver function test. General: Caution when initiating treatment in patients with dehydration. Serious skin reactions, some fatal, including exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported very rarely in association with NSAIDs and some selective COX-2 inhibitors. Serious hypersensitivity reactions (anaphylaxis and angioedema) have been reported. Discontinue at first appearance of skin rash, mucosal lesions or any other sign of hypersensitivity. Etoricoxib may mask fever and other signs of inflammation. Caution when coadministering with warfarin or other oral anticoagulants. Contains lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take Arcoxia. Interactions: Pharmacodynamic Interactions: Oral anticoagulants: Closely monitor prothrombin time International Normalised Ratio in patients also receiving oral anticoagulants, particularly in first days of treatment initiation or etoricoxib dose change. Diuretics, ACE inhibitors and Angiotension II antagonists: Effectiveness of diuretics and other antihypertensive drugs may be reduced. Caution when combining ACE inhibitor or Angiotensin II inhibitor with cyclooxygenase inhibitors due to possible deterioration of renal function, including acute renal failure, especially in the elderly. Consider monitoring renal function after initiation of concomitant therapy, and periodically thereafter. Acetylsalicyclic acid: Not recommended with doses of acetylsalicylic acid above those for cardiovascular prophylaxis (low dose) or with other NSAIDs due to possible increased rate of GI ulceration or other complications. Cyclosporin and tacrolimus: Coadministration of cyclosporin or

tacrolimus with any NSAID may increase nephrotoxic effect. Monitor renal function if concomitantly used. Pharmacokinetic (PK) Interactions: Effect of etoricoxib on other drugs: Lithium: NSAIDs decrease lithium renal excretion and therefore increase lithium plasma levels. If necessary monitor blood lithium closely and adjust lithium dosage. Methotrexate: Monitor for methotrexate-related toxicity when administered concomitantly. Oral contraceptives: Etoricoxib has shown to increase concentration of ethinyl estradiol when coadministered with oral contraceptives; this can increase the incidence of adverse events associated oral contraceptives. Hormone Replacement Therapy: Evidence of increases in estrogenic concentration in concomitant use; consider when selecting post-menopausal hormone therapy for use with etoricoxib. Prednisone/ prednisolone: No clinically important effects. Digoxin: Monitor patients at high risk for digoxin toxicity when administered concomitantly due to possible increase of digoxin Cmax. Drugs metabolised by sulfotransferases: Etoricoxib inhibits human sulfotransferase. Care when concomitantly administering with other drugs primarily metabolised by human sulfotransferases (e.g. oral salbutamol, minoxidil). Drugs metabolised by CYP isoenzymes: Not expected to inhibit cytochrome P450 enzymes. Effect of other drugs on Etoricoxib: Etoricoxib is metabolised by CYP enzymes. Ketoconazole: 400mg o.d. for 11 days did not have clinically important effect on single dose PK of 60 mg etoricoxib. Voriconazole (oral) and Miconazole (oral gel): Coadministration of either with etoricoxib caused slight increased exposure of etoricoxib but not clinically significant. Rifampicin: Co-administration produced decrease in etoricoxib concentrations. Etoricoxib doses higher than those studied are not recommended. Antacids: Does not affect PK of etoricoxib. Pregnancy and lactation: Not recommended. If woman becomes pregnant during treatment, etoricoxib must be discontinued. Do not use during breast feeding. Not recommended when attempting to conceive. Driving and using machines: Patients who experience dizziness, vertigo or somnolence when on treatment should refrain from driving or operating machinery. Undesirable effects: Very common (≥1/10): Abdominal pain. Common (≥1/100, <1/10): Alveolar osteitis, oedema/fluid retention, dizziness, headache, palpitations, arrhythmia, hypertension, bronchospasm, constipation, flatulence, gastritis, heartburn/acid reflux, diarrhoea, dyspepsia/ epigastric discomfort, nausea, vomiting, oesophagitis, oral ulcer, ALT increase, AST increased, ecchymosis, asthenia/ fatigue, flu-like disease. Other important undesirable effects: Upper respiratory infection, leukopenia, hypersensitivity, atrial fibrillation, tachycardia, congestive heart failure, angina pectoris, myocardial infarction, cerebrovascular accident, transient ischaemic attack, hypertensive crisis, vasculitis, gastroduodenal ulcer, peptic ulcers including gastrointestinal perforation and bleeding, pancreatitis, hepatitis, hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema/ anaphylactic/ anaphylactoid reactions including shock. Additional information available on request. Overdose: Remove unabsorbed material from GI tract, clinical monitoring, institute supportive therapy, if required. Not dialyzable by haemodialysis; not known whether dialyzable by peritoneal dialysis. Legal classification: POM. Marketing Authorisation numbers and pack sizes: Arcoxia 30 mg film-coated tablets: PA1997/1/1 28 pack, 60 mg film-coated tablets: PA1997/1/2 28 pack, 90 mg film-coated tablets: PA1997/1/3 5 and 28 pack, 120 mg film-coated tablets: PA1997/1/4 7 and 28 pack. Marketing Authorisation Holder: Merck Sharp & Dohme BV, Waarderweg 39, 2031 BN Haarlem, The Netherlands. Date of Preparation: August 2016. IRE/A16 0006 References: 1. Arcoxia SmPC, www.medicines.ie. a Doses greater than those recommended for each indication have either not demonstrated additional efficacy or have not been studied. Due to cardiovascular risks, the shortest duration possible and the lowest effective daily dose of ARCOXIA should be used.1 b The recommended dose for osteoarthritis is 30 mg once daily. An increased dose of 60 mg once daily may increase efficacy. The dose for osteoarthritis should not exceed 60 mg daily.1 c The recommended dose for Rheumatoid Arthritis and Ankylosing Spondylitis is 60 mg once daily. An increased dose of 90 mg once daily may increase efficacy. The dose for Rheumatoid Arthritis and Ankylosing Spondylitis should not exceed 90 mg daily. Once stabilised, down-titration to a 60 mg once daily dose may be appropriate.1 Date of Preparation: August 2016 IRE/A16 0007e

Grünenthal Pharma Ltd., Dublin, Ireland, www.grunenthal.ie


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 Feb 2017  
Hpn Feb 2017  
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