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HPN Issue 41

HOSPITAL PROFESSIONAL NEWS IRELAND Ireland’s Dedicated Hospital Professional Publication IN THIS ISSUE: NEWS: Waiting lists out of control Page 4 CLINICAL: Prostate Cancer Page 6 REPORT: National Cancer Strategy for Ireland Page 23 CLINICAL: Rheumatoid Arthritis Page 30 CLINICAL: Psoriasis Page 38 AWARDS: 2017 Hospital Professional Awards Page 53 CONFERENCE: EASL 2017 Page 84 June 2017

When life is

too busy for RA Given a choice, 53% of RA patients would chose a monthly regime1*

GO further with Simponi With Simponi, approximately 70% of patients remained on treatment after 5 years.2 Make your 1st choice count. patients on concomitant immunosuppressive therapy that, in addition to their underlying disease, could predispose them to infection. There have been reports of active TB in patients receiving Simponi, including patients previously treated for latent TB. Patients should be evaluated for active or latent TB before Simponi treatment. All such tests should be recorded on the Patient Alert Card provided with the product. If active TB is diagnosed, treatment with Simponi should not be initiated. If latent TB is diagnosed, treatment with anti-TB therapy must be initiated before initiation of Simponi. Patients on Simponi should be monitored closely for signs and symptoms of active TB and advised to seek medical advice if signs and/or symptoms of TB appear. Hepatitis B (HBV) reactivation: Reactivation of HBV occurred in patients receiving Simponi who were chronic carriers. Some cases had a fatal outcome. Patients should be tested for HBV infection before initiating treatment with Simponi Malignancies and lymphoproliferative disorders: Caution is advised when considering Simponi treatment in patients with history of malignancy or continuing treatment in patients who develop a malignancy, additional caution should be exercised in patients with increased risk for malignancy due to heavy smoking. A risk for the development of malignancies in children and adolescents cannot be excluded. Rare cases, usually fatal, of hepatosplenic T-cell lymphoma (HSTCL) have been reported, the majority of cases occurred in adolescent and young males nearly all on concomitant treatment with azathioprine (AZA) or 6-mercaptopurine (6-MP). The potential risk with the combination of AZA or 6-MP and Simponi should be carefully considered. A risk for the development for HSTCL in patients treated with TNF-blockers cannot be excluded. Colon dysplasia/carcinoma - Screen for dysplasia in all patients with UC who are at increased risk or had a prior history for dysplasia or colon carcinoma. In newly diagnosed dysplasia patients the risks and benefits of continued Simponi use should be carefully assessed. Melanoma and Merkel cell carcinoma (all TNF-blocking agents including Simponi) have been reported, periodic skin examination is recommended, particularly for patients with risk factors for skin cancer. Heart Failure: Simponi should be used with caution in patients with mild heart failure (NYHA class I/II). Patients should be closely monitored and Simponi must be discontinued in patients who develop new or worsening symptoms of heart failure. Some cases had a fatal outcome. Neurological events: Use of anti-TNF therapy, including Simponi, has been associated with cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disorders, including multiple sclerosis and peripheral demyelinating disorders. Discontinuation of Simponi should be considered if these disorders develop. Carefully consider the benefits and risks before initiation of therapy in patients with a history of demyelinating disorders. Surgery: Patients requiring surgery whilst on Simponi therapy should be closely monitored for infections. Autoimmune processes: If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with Simponi and is positive for antibodies against double-stranded DNA, treatment should be discontinued. Haematological reactions: There have been post-marketing reports of pancytopenia, leukopenia, neutropenia, aplastic anaemia, and thrombocytopaenia in patients receiving TNF-blockers. Cytopenias including pancytopaenia have been reported infrequently in clinical trials. Patients should be advised to seek medical attention if they develop signs and symptoms suggestive of blood dyscrasias. Discontinuation should be considered in patients with significant haematologic abnormalities. Vaccinations/therapeutic infectious agents: It is recommended that live vaccines or any therapeutic infectious agents should not be given concurrently. Allergic reactions: If an anaphylactic reaction or other serious allergic reaction occurs, administration of Simponi should be discontinued immediately, and suitable treatment initiated. The needle cover of the pre-filled pen contains latex and may cause allergic reactions in those sensitive to latex. Special populations: Older patients (≥ 65 years): Adverse events, serious adverse events and serious infections in patients aged ≥65 were comparable to those observed in younger patients. However, caution should be exercised when treating the elderly, particular attention should be paid to infections. There were no patients age 45 and over in the nr-Axial SpA study. Paediatric patients (<18 years): Vaccinations: it is recommended that prior to initiating Simponi therapy, paediatric patients be brought up to date with all immunisations in agreement with current immunisation guidelines. Excipients: Simponi contains sorbitol (E420). Patients with rare hereditary problems of fructose intolerance should not take Simponi. INTERACTIONS Combination of Simponi and other biological therapeutics used to treat the same conditions as Simponi, including anakinra and abatacept is not recommended. PREGNANCY AND LACTATION Administration of Simponi is not recommended during pregnancy or breast-feeding. Women of childbearing potential should use adequate contraception and continue its use for at least 6 months after the last Simponi treatment. SIDE EFFECTS Refer to SmPC for complete information on side effects Very Common (≥ 1/10): upper respiratory tract infection; Common (≥1/100): bacterial infections, lower respiratory tract infections, viral infections, bronchitis, sinusitis,

superficial fungal infections, abscess, anaemia, allergic reactions, autoantibody positive, depression, insomnia, dizziness, headache, paraesthesia, hypertension, asthma and related symptoms, dyspepsia, gastrointestinal and abdominal pain, nausea, gastrointestinal inflammatory disorders, stomatitis, alanine aminotransferase increased, aspartate aminotransferase increased, pruritus, rash, alopecia, dermatitis, pyrexia, asthenia, injection site reaction, chest discomfort, bone fractures were reported. Serious, including fatal adverse events have been reported including septic shock, lymphoma, leukaemia, melanoma, Merkel cell carcinoma, hepatosplenic T-cell lymphoma*, leukopenia, thrombocytopaenia, pancytopaenia, aplastic anaemia, serious systemic hypersensitivity reactions (including anaphylactic reaction), skin exfoliation, vasculitis (systemic), sarcoidosis, demyelinating disorders, congestive heart failure, arrhythmia, ischaemic coronary artery disease, thrombosis, interstitial lung disease and lupus-like syndrome. * Observed with other TNF-blocking agents. Paediatric population: pJIA: The safety of golimumab has been studied in a phase III study of 173 pJIA patients from 2 to 17  years of age. The average follow-up was approximately two years. In this study, the type and frequency of adverse events reported were generally similar to those seen in adult RA studies. PACKAGE QUANTITIES 1 x 50 mg pre-filled pen containing 50 mg of golimumab in 0.5 ml solution for injection 1 x 50 mg pre-filled syringe containing 50 mg of golimumab in 0.5 ml solution for injection 1 x 100 mg pre-filled pen containing 100 mg of golimumab in 1 ml solution for injection Legal Category: Prescription Only Medicine. Marketing Authorisation Number 50 mg Pre-filled Pen EU/1/09/546/001 50 mg Pre-filled Syringe EU/1/09/546/003 100 mg Pre-filled Pen EU/1/09/546/005 Marketing Authorisation Holder Janssen Biologics B.V., Einsteinweg 101, 2333  CB Leiden, The Netherlands Date of Revision of Text: February 2017. Simponi/PI-IRE/02-17 © Merck Sharp & Dohme Ireland (Human Health) Limited 2017. All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin 18 or from Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to MSD (Tel: 01-2998700) References: 1. Huynh, T.K. et al. Preferences of patients and health professionals for route and frequency of administration of biologic agents in the treatment of rheumatoid arthritis. Patient Preference and Adherence, 2014:8; 93-99. 2. Keystone EC, Genovese MC, Hall S et al. Safety and efficacy of subcutaneous golimumab in patients with active rheumatoid arthritis despite methotrexate therapy: final 5-year results of the GO-FORWARD trial. J Rheumatol. 2016;43:298–306. *Rheumatoid arthritis patients preferring subcutaneous therapies Date of preparation: July 2017.

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


SIMPONI 50 MG, 100 MG SOLUTION FOR INJECTION IN PRE-FILLED PEN SIMPONI 50 MG SOLUTION FOR INJECTION IN PRE-FILLED SYRINGE (GOLIMUMAB) ABRIDGED PRODUCT INFORMATION Refer to Summary of Product Characteristics before prescribing PRESENTATION Simponi 50 mg solution for injection in pre filled pen Simponi 50 mg solution for injection in pre filled syringe Simponi 100 mg solution for injection in pre filled pen INDICATIONS Rheumatoid Arthritis (RA): Simponi, in combination with methotrexate (MTX), is indicated for: the treatment of moderate to severe, active rheumatoid arthritis in adults when the response to disease-modifying anti-rheumatic drug (DMARD) therapy including MTX has been inadequate; the treatment of severe, active and progressive rheumatoid arthritis in adults not previously treated with MTX. Simponi, in combination with MTX, has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function; Psoriatic Arthritis (PsA): Simponi, alone or in combination with MTX, is indicated for the treatment of active and progressive PsA in adults when the response to DMARD therapy has been inadequate. Simponi has been shown to reduce the rate of progression of peripheral joint damage as measured by X-ray in patients with polyarticular symmetrical subtypes of the disease and to improve physical function. Ankylosing Spondylitis (AS): Simponi is indicated for the treatment of severe, active AS in adults who have responded inadequately to conventional therapy. Non-radiographic axial spondyloarthritis (nr-Axial SpA): Simponi is indicated for the treatment of severe, active nr-Axial SpA who have had an inadequate response to or are intolerant to NSAIDs. Ulcerative colitis (UC): Simponi is indicated for treatment of moderately to severely active UC in adult patients who have had an inadequate response to conventional therapy including corticosteroids and 6-mercaptopurine (6-MP) or azathioprine (AZA), or who are intolerant to or have medical contraindications for such therapies. Polyarticular juvenile idiopathic arthritis (pJIA): Simponi 50mg in combination with MTX is indicated for the treatment of polyarticular juvenile idiopathic arthritis in children with a body weight of at least 40 kg, who have responded inadequately to previous therapy with MTX. DOSAGE AND ADMINISTRATION Simponi should be injected subcutaneously. Treatment should be initiated and supervised by qualified physicians experienced in the diagnosis and treatment of RA, PsA, AS, nr-Axial SpA, UC or pJIA. After proper training in subcutaneous injection technique, patients may self-inject, if their physician deems it appropriate. RA: Simponi 50 mg given once a month, on the same date each month, concomitantly with MTX. PsA: Simponi 50 mg given once a month, on the same date each month, alone or in combination with MTX. AS and nr-Axial SpA: Simponi 50 mg given once a month, on the same date each month. Clinical response is usually achieved within 12-14 weeks of treatment (3 or 4 doses). Continued therapy should be reconsidered in patients who show no evidence of therapeutic benefit within this time period. In patients weighing more than 100 kg who do not achieve an adequate clinical response after 3 or 4 doses, increasing the dose of golimumab to 100 mg once a month may be considered, taking into account the increased risk of certain serious adverse reactions with the 100 mg dose compared with the 50 mg dose. UC: Patients weighing < 80 kg: Simponi given as an initial dose of 200 mg, followed by 100 mg at week 2, then 50 mg every 4 weeks. Patients weighing ≥ 80 kg: Simponi given as an initial dose of 200 mg, followed by 100 mg at week 2, then 100 mg every 4  weeks. During maintenance treatment, corticosteroids may be tapered, following clinical practice guidelines. Clinical response is usually achieved within 12-14 weeks of treatment (after 4 doses). pJIA: Simponi 50 mg administered once a month, on the same date each month, for children with a body weight of at least 40 kg. Clinical response is usually achieved within 12 to 14  weeks of treatment (after 3-4 doses). Missed dose: If a patient forgets to inject Simponi on the planned date, the forgotten dose should be injected as soon as the patient remembers. The patient should be instructed not to inject a double dose. Older patients (≥ 65 years): no dose adjustment required. Paediatric patients (<18 years): For indications other than pJIA, Simponi is not recommended. Patients with renal and hepatic impairment: Simponi is not recommended. CONTRAINDICATIONS Patients with a hypersensitivity to golimumab or any of the excipients; Patients with active tuberculosis (TB) or other severe infection such as sepsis and opportunistic infections; patients with moderate or severe heart failure (NYHA class III/IV). PRECAUTIONS AND WARNINGS Infections: Patients must be monitored closely for infection before, during and for 5 months after cessation of treatment. Exercise caution when considering Simponi in patients with chronic infection or a history of recurrent infection including use of concomitant immunosuppressive therapy. Simponi should not be given to patients with clinically important active infection. Patients should be advised of the potential risk factors. Bacterial infections (including sepsis and pneumonia), mycobacterial (including TB), invasive fungal and opportunistic infections, including fatalities, have been reported. The invasive fungal infection should be suspected if they develop a serious systemic illness. There was a greater incidence of serious infections, including opportunistic infections and TB, in patients receiving golimumab 100 mg compared with patients receiving golimumab 50 mg. Serious infections have occurred in


HPN Issue 41



Private Hospitals call for greater access for patients P4


Kelly Jo Eastwood This issue of Hospital Professional News is a bumper one; not only do we present The Peer Review for the first time, but we also carry full details of the finalists for this year’s hotly contested Hospital Professional Awards.

Peer Review Prostate Cancer P6 5

Peer Review Rheumatoid Arthritis P29 Peer Review Psoriasis P38

This is according to the Irish Hospital Consultants Association (IHCA), who this month announced details of its 2018 Pre Budget Submission.

Peer Review Chronic Pain P74

Dr Tom Ryan, President of the IHCA, said, “There are now over 589,000 people on waiting lists in Ireland’s public hospitals and there is no sign that these numbers are going to decrease. Waiting lists are spiralling out of control because there is not enough capacity in the system. Public hospitals urgently need additional acute beds, intensive care beds, theatre operating time, consultants and other frontline staff. This is essential to reduce the unacceptable waiting lists, the overcrowding of emergency departments and the increasing number of patients being treated on trolleys. Currently our health care system appears to be more focussed on balancing budgets and rationing care than treating patients.”


Peer Review Stroke P80 Regulars Feature: HIV Cascade of Care P25 Feature: Crohn’s Disease P43


Feature: Diabetes Cycle P72


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 EDITOR Kelly Jo Eastwood 00447876548989

In other news, Ireland’s new National Cancer Strategy 2017-2026 has been labelled a ‘potential game changer’ by Professor Bryan Hennessy, Clinical Lead, Cancer Trials Ireland, and Consultant Oncologist, Beaumont Hospital. “Implementation of the strategy could take us significantly closer to finding successful treatments for all types of cancer,” he said.

Clinical Synopsis: EASL 2017 P85 Clinical Profiles P97

Leading with the news, it has been discouraging to read that waiting lists in Ireland’s public hospitals are out of control and will not be brought back to manageable levels unless resources are redirected to increase acute hospital and mental health frontline capacity.


This issue of HPN is our Peer Review; an annual special edition which aims to demonstrate Hospital Professional News’ further endeavours to support current and future hospitals professionals to learn, grow and innovate. Hospital Professional News delivers education to thousands of healthcare professionals including Consultants, Pharmacists and clinical teams, demonstrating cutting edge research that has a direct impact on patient care. This issue feature article submissions to foster this network of shared learning, focusing on enhanced clinical outcomes. We have clinical topics covered ranging from Prostate Cancer to Crohn’s Disease and from Psoriasis to Schizophrenia. The fifth Hospital Professional Awards take place on Saturday, September 16th - showcasing the extraordinary talent and hard work Irish Hospital Professionals, including Consultants, Pharmacists, Clinical Specialists and their teams and multidisciplinary departments are undertaking throughout Ireland. The shortlist across 14 Award categories are detailed from page 53.

Mobile: 0044 7765 236886 DESIGN DIRECTOR Ian Stoddart Design HospitalProfessionalNews

HOSPITAL PROFESSIONAL NEWS IRELAND Ireland’s Dedicated Hospital Professional Publication HPN • Issue 41

4 News

Irish patients should have access to Private Hospitals Simon Nugent, CEO Private Hospitals Association

The Private Hospitals Association(PHA) has said it is perverse that Irish patients waiting on treatment can use private hospitals abroad under a HSE refund scheme but aren’t allowed to use ones in the Republic.

“Hospital waiting lists have reached all-time highs, with 1 in 8 people in Ireland (570,000) currently awaiting some form of hospital treatment. 14,000 Irish patients joined the queue since March this year alone,” Mr Nugent said.

Simon Nugent, CEO of the PHA, said the Minister for Health should change the HSE Policy and allow every patient seeking approval for treatment abroad to be first offered treatment here instead in our private hospital system.

“There is a network of 19 private hospitals dotted throughout the country that could make substantial in-roads into these waiting list numbers. It is perverse that waiting patients are being urged by the State to seek

treatment abroad but not here. The HSE is spending increasing amounts of money under the Cross-Border Directive treating patients elsewhere in the EU. Bizarrely, the only private hospitals in Europe where patients are not entitled to be treated are those in Ireland. You can choose Milan or Munich, Bristol or Budapest but if you go to any private hospital across Ireland you won’t be refunded by the HSE. “Private hospitals here seek parity under the HSE scheme. With the

Cross-Border Treatment Directive, the HSE will only refund the bills from a private or public hospital in an EU country up to the cost of doing the procedure in a public hospital in Ireland. The Minister for Health should instruct the HSE to simply apply the same rule within Ireland. Member states are not required by the EU to apply the Cross-Border Directive in their home country but neither do they forbid it. “It is unfair to patients to force them to go abroad, opening them to health risks too. The distance between home and where the procedure occurred is a clinical risk particularly if there are complications or a need for readmission. Patients requiring subsequent visits to the hospital abroad must apply again to the Scheme. Language barriers, minor variations in medical practice and cultural differences add to the risks. Arranging flights and transfers amounts to added stress for patients. There’s also an equity barrier – treatment overseas favours younger and wealthier people as costs must be paid up front before being reimbursed by the HSE,” Mr Nugent warned.

Approval for Antimicrobial Resistance Action Plan The Government has given approval for Ireland’s first National Action Plan on Antimicrobial Resistance 2017-2020. The overall goal of Ireland’s National Action Plan on AMR is to ensure, for as long as possible, the availability of effective antibiotic treatment options for both humans and animals, with safe medicines that are quality-assured, used in a responsible way, and accessible to all who need them. Minister for Health, Simon Harris TD, and Minister for Agriculture, Food and the Marine, Michael Creed TD secured the approval. Minister for Health, Simon Harris TD said, “This National Action Plan represents Ireland’s commitment to the development and implementation of a cross-sectoral ‘One Health’ approach to the problem of antimicrobial resistance. The Plan has been jointly developed by both Departments with the oversight and guidance of the Interdepartmental AMR Consultative Committee which was established by the Chief Medical Officer and Chief Veterinary Officer of our two respective Departments. Both Minister Creed and I are most appreciative of the valuable input of the Committee, whose membership encompasses the human health, animal health and environmental sectors, providing expertise across all sectors.” The Action Plan will be published in September and the implementation and evaluation processes will be designed encompassing ‘One Health’ and sector specific timeframes and responsible bodies for each activity over the lifetime of the Plan.

Promoting Gender Equality in Surgery The Irish Medical Organisation (IMO) has welcomed the publication of Progress: Promoting Gender Equality in Surgery, by the Royal College of Surgeons in Ireland. While in many ways the medical profession in Ireland has never been more diverse, surgical specialties remain very much male-dominated at consultant level.

Definitions of Success seminar held in conjunction with the Bar of Ireland, has revealed that perceptions of surgery as maledominated, and the absence of adequate supports to enable surgeons to properly balance family or personal commitments with their professional responsibilities, affect female participation within the discipline.

Research conducted by the IMO, and presented at its recent

This RCSI report identifies many similar difficulties, and

Issue 41 • HPN

recommends changes in workplace culture and practices, such as the introduction of mentorship programmes and policies that facilitate pregnant surgeons and those with families. The IMO calls on all relevant stakeholders to ensure the report’s recommendations are fully considered and embraced as a means of improving female participation in surgery. Speaking about the report, IMO

President, Dr. Ann Hogan, stated, “there are perceptions that women’s skill sets or abilities may not be compatible with or suited to certain specialties, and this report offers important guidance on how such perceptions can be challenged and rectified. Women represent a huge proportion of the medical workforce and the current gender disparity within surgery can no longer be ignored.”


Hospital waiting lists are ‘out of control’ Waiting lists in Ireland’s public hospitals are out of control and will not be brought back to manageable levels unless resources are redirected to increase acute hospital and mental health frontline capacity, according to the Irish Hospital Consultants Association (IHCA). The Association announced details of its 2018 Pre Budget Submission this month. Dr Tom Ryan, President of the IHCA, said, “There are now over 589,000 people on waiting lists in Ireland’s public hospitals and there is no sign that these numbers are going to decrease. Waiting lists are spiralling out of control because there is not enough capacity in the system. Public hospitals urgently need additional acute beds, intensive care beds, theatre operating time, consultants and other frontline staff. This is essential to reduce the unacceptable waiting lists, the overcrowding of emergency departments and the increasing number of patients being treated on trolleys. Currently our health care system appears to be more focussed on balancing budgets and rationing care than treating patients. “Ireland’s population has increased by 12% over the last 12 years, with the population aged 65 years and over increasing by 35%. There are more people than ever requiring healthcare and the upcoming budget must reflect this reality. Throughout the past decade the State has severely rationed healthcare, and with an increasing number of patients becoming reliant on private hospitals, in effect acute hospital

Dr Tom Ryan, President, Irish Hospital Consultants Association

services are being privatised by stealth. Notably the private hospitals understand the increase in existing and future demand for health care services and have expanded their bed capacity, unlike the public hospitals,” said Dr Ryan. “This situation did not arise overnight. But now the waiting lists are increasing at an alarming rate, as a consequence of decades of health care cuts. In addition, lack of acute hospital capacity is impacting adversely on essential surgical appointments, which have declined by over 100,000 (54%) in four years, and on the delivery of timely cancer care to patients. Urgent action is needed to prevent the health system descending into chaos.” Dr Ryan continued: “The cumulative cuts of nearly ¤1.9 billion in the current Health Capital Plan for 2016 to 2021, compared with 2008, is rapidly leading to a crumbling health service

infrastructure, with acute hospitals attempting to treat patients with equipment that is increasingly obsolete. The current levels of funding do not even meet the cost of maintaining and replacing existing equipment never mind providing for much needed additional capacity. Furthermore, when the new capital investment projects, including the Children’s Hospital and the plans to relocate maternity hospitals, are funded the existing Capital Plan of ¤3 billion will not have sufficient funding to replace obsolete equipment or develop additional capacity to provide care.”

In its 2018 submission, the Association highlights the failure of the State to address

the consultant recruitment and retention crisis which is significantly impacting on patient care. The 2008 Consultant Contract is not being honoured by the State. This, combined with the ongoing discrimination against new entrant consultants, and the failure to reverse the FEMPI salary cuts, has created an environment where the health services cannot recruit and retain a sufficient number of high calibre consultants. It is unacceptable that over 400 approved hospital consultant posts are either vacant or filled on a temporary/agency basis. This false economy must be ended as patients are being deprived of care while medical agency costs are exceeding ¤115m per year. The HSE’s admission that 70 non-specialist doctors have been appointed to Specialist Consultant posts since 2008 demonstrates the extent of the failure of current health service policies to address the ongoing exodus of highly trained consultants.”

be required, and to understand the concerns and requirements of different stakeholder groups.

operating in Ireland or the UK and those companies who may wish to develop a presence in Ireland.

Speakers will include representatives from human and veterinary medicines industry associations, from the Industrial Development Authority and the HPRA.

The event takes place on Thursday 31 August, 2017 at the Crowne plaza Hotel, Santry from 13.30 – 16.00 with registration from 13.00.

The IHCA has said that Budget 2018 must also provide a significant increase in funding for mental health services which are significantly understaffed and remain funded at 15% below 2008 levels.

HPRA to host Brexit event Following the UK’s triggering of Article 50 to leave the European Union, the HPRA, together with medicines agencies in Europe, is making preparations to ensure that they continue to deliver on their patient and animal health remit even if the UK fully exits the current systems on 29 March 2019. The HPRA wishes to engage with

stakeholders to explain how the organisation is responding to the possible implications of Brexit and hear from them the key issues and concerns they have. The aim of the meeting is to engage with stakeholders on their approach to potential Brexit scenarios, to outline their plans to increase their contribution to EU regulatory procedures as may

Manufacturers, distributors, and marketing authorisation holders

There is no fee to attend this event To register please use the following link - http://

HPN • Issue 41

6 Prostate Cancer

The burden of healthcare costs associated with prostate cancer in Ireland Burns, Richéal M. Leal, Jose, Wolstenholme, Jane, 1 O’Neill, Ciaran, 2 Sullivan, Frank J., 3 Drummond, Frances J., 4, 5 Sharp, Linda Affiliations 1 Health Economic Research Centre, Nuffield Department of Population Health, University of Oxford, Oxford - UK 2 J.E. Cairnes School of Business and Economics, National University of Ireland, Galway - Ireland 3 Prostate Cancer Institute, National University of Ireland, Galway - Ireland 4 National Cancer Registry, Cork - Ireland 5 Department of Epidemiology and Public Health, University College Cork, Cork - Ireland 6 Institute of Health and Science, Newcastle University, Newcastle upon Tyne - UK

Over the last two decades, in many Western countries, the incidence of prostate cancer (PCa) has been rising. It is the second most common cancer in men Worldwide (1*), with an estimated 1.1 million men diagnosed in 2012 (2*). PCa also imposes a significant economic burden on society with an estimated cost of ¤8.4 billion to the European Union in 2009, 7% of all cancer costs (3*). Trends in PCa incidence in Ireland and elsewhere are thought to be largely explained by the increased rates of prostate specific antigen (PSA) testing among asymptomatic men (4*5*-6*-7*). Although the European Randomised Study of Screening for Prostate Cancer (ERSPC) reported a 21% reduction of cancer-related death due to PSA screening compared to no screening (5*), these benefits must be balanced against the harmful consequences of overdiagnosis and overtreatment of PCa (8*-9*-10*). In comparison, the US PLCO trial found no such evidence of mortality reduction at 13 years’ followup (11*). The consequences of over-detection and overdiagnosis are of significant concern because not all PCas would have become clinically apparent within their lifetime; estimates of the pool of PCas susceptible to over-detection vary from 1%-2% in men aged 20-29 years to 59%-72% in men aged 90-99 years (12*). Furthermore, the recent results of the ProtecT randomised trial on detection and treatment for PCa suggests that there is no significant difference between

Issue 41 • HPN

Active Monitoring (AM) and more radical treatment modalities in prostate-cancer-specific mortality (13*). The Republic of Ireland (RoI) has one of the highest PCa rates in Europe and the fourth highest rate in the world (14*, 15*); this is largely due in part to the fact that population coverage of PSA testing is considered higher than in most other European countries (6*, 16*, 17*). The annual cost of PSA testing alone in the RoI was estimated to be ¤3.6 million in 2010 (18*). However, the total economic impact of PCa in the RoI is unknown and its estimation is challenging due to

the complexity of the healthcare delivery model (mixed public/ private model) (19*) and the limitations of published reference costs (20*). PCa-related costs vary across payers, thus providing further obstacles in estimating healthcare costs across all payer types (20*). Due to the steady increases in PCa in the RoI since 1994 and current projections for growth, it is important to understand the economic impact in order to assess both the drivers of cost and the potential for cost-containment strategies. The aim of this analysis was two-fold: first, we estimated resource use associated with

the different components of PCa healthcare in the RoI including detection, diagnosis, treatments and follow-up care, which has not been undertaken previously; second, combining these with unit costs, we estimated the overall healthcare expenditure for PCain 2010. Details of PCa (ICD-10 code: C61) cases diagnosed during 2007-2010 were obtained from the population-based National Cancer Registry Ireland (NCRI). Deaths from PCa and other causes during 20072010 were obtained from the Central Statistics Office (CSO) via the NCRI and linked to incident cases. Patient clinical,

7 diagnostic and treatment data were extracted from the NCRI database for the period 20072009. A PCa patient pathway was constructed based on available NCRI data, the most up-to-date literature (21*-22*23*), and expert clinical opinion (24*).1 Healthcare utilisation associated with each step of the pathway was derived from the NCRI database, a patient survey administered by the NCRI (25*) and a recent HTA appraisal of PSA testing (26*) (Tab. I). PCa detection was assumed to include two GP visits and two PSA tests prior to biopsy referral based on clinical (24*) and national guidance (27*) for Ireland. From survey responses, men were assumed to have had, on average, 1.25 biopsies (25*); this was verified by clinical expert opinion (24*). Rates of severe complications of biopsy, including infection and hospitalisation were sourced from the HTA of PSA testing for the detection of PCa (26*). These data were for the UK; no relevant data are available for Ireland. Treatments and procedures recorded by the NCRI for the first year of diagnosis included biopsies, radical prostatectomy

(RP), external beam radiation therapy (EBRT), brachytherapy (BT), other surgery (transurethral resection of the prostate [TURP]), hormone therapy (HT), chemotherapy (CT), active monitoring (active surveillance or watchful waiting [AM], which cannot be distinguished in NCRI data) and combinations thereof. The allocation of treatments at PCa diagnosis was estimated by averaging the national PCa treatment data over 2007-2009. EBRT was assumed to be intensity-modulated radiation therapy (IMRT) and HT was assumed to be goserelin. Components of AM were based on expert opinion (24*) and included four GP visits per year each including a PSA test, one out-patient appointment per year and one biopsy per year (27*). Post-treatment followup included medication, GP and out-patient attendance (22*, 23*, 27*), other surgical procedure and diagnostic tests (22*, 23*, 26*, 28*-29*-30*), and were assumed to continue for three years after the first year of diagnosis; these assumptions were based on a synthesis of the literature and expert clinical opinion (24*). Terminal (palliative) care included medication (30*,

31*), diagnostic treatment and end-of-life care based on an average length of stay of 13 days in an inpatient setting in Ireland (20*). Treatment complications were categorised into short term (<1-year post-treatment). and long term (>1-year post-treatment) and included incontinence (23*), impotence (23*), risk of cardiovascular disease (CVD) (30*) and risk of fracture (32*); based on published sources, these were assumed to vary by treatment modality (26*-27*-28*-29*). Consequences of complications were assumed to be hospitalisation, further diagnostic tests and treatments (33*). Unit costs The perspective of this analysis was that of the public payer. Hence, only direct healthcare costs were included. Costs were estimated by multiplying cancer-related contacts/resource utilisation by the respective unit costs. The unit costs associated with diagnosis, treatment, treatment complications (shortand long-term) and terminal

care were obtained from survey data (18*, 34*), Irish (35*), and UK reference costs (36*) and previously published sources (20*, 23*, 31*) (Supplementary Table I, available online at Medication costs, including HT costs, were sourced from the HSE Primary Care Reimbursement Service database and with the assistance of a communitycare pharmacist (37*). Costs of detection were calculated using project-specific survey instruments described in detail elsewhere (18*, 34*). Costs of EBRT and BT were sourced from an ongoing micro-costing analysis undertaken by an Irish hospital (24*). All costs were expressed in 2010 (¤) using standard methods of inflation recommended by Irish guidelines (HIQA & CSO) (38*) and non-Irish costs were adjusted using the purchasing power parity (PPP) method (39*). Analysis Incident cases (2007-2010) were broken down by year, age group and clinical stage at diagnosis (Supplementary Table II, available online at www.grhta. com). Full clinical and treatment

Table I - Resource use parameteres

HPN â&#x20AC;˘ Issue 41

8 Prostate Cancer Table II - Healthcare costs of prostrate cancer in Republic of Ireland, in 2010 (¤ millions)

data on all PCa cases diagnosed in 2010 were unavailable at the time of analysis, so the stage and treatment distribution was based on 2007-2009 data. The healthcare costs of PCa were estimated using two approaches: incidence-based (IB) and prevalence-based (PB); this was for purposes of comparison. The IB approach consisted of estimating solely the annual costs of those patients diagnosed in 2010 (n = 3287), whereas the PB approach consisted of estimating the costs of all men with PCa in 2010 regardless of the year of disease onset. The PB approach assumed that after four years’ post-diagnosis no further management would be necessary and hence, no PCa-related costs would occur. Therefore, to estimate overall costs, the costs for patients diagnosed in 2010 (IB) were combined with costs of patients diagnosed between 2007 and 2009 who were alive at the beginning of 2010 (PB) (n = 11,054). and terminal (palliative) costs for men who died from PCa in 2010 (n = 533). Both approaches involved estimating costs of resources used at the patient level, i.e., consistent with a bottom-up approach. Since several management options are available for patients with localised disease, scenario analysis was performed to

Issue 41 • HPN

investigate the impact on total cost of reallocating patients from more- to less-costly treatment regimens for this clinical subgroup, i.e., increasing proportions treated by AM or BT instead of RP and EBRT. HT and CT were not adjusted as these strategies for treatment/management of PCa are used in more advanced stages and therefore have limited treatment alternatives.

follow-up after the first year of diagnosis for patients diagnosed 2007-2009, but still treated in 2010, were estimated at ¤13 million. Costs associated with treatment complications were estimated at ¤4.8 million. The cost associated with terminal care for the 533 PCa deaths in 2010, of which 185 (35%) were due to cancers diagnosed in that year, was estimated at ¤3.7 million (UC ¤6958).


In 2010, the total healthcare costs associated with PCa (up to four years’ post-diagnosis), i.e., employing the PB approach, was approximately ¤45.6 million. The healthcare cost from PCa diagnosis up to four years’ postdiagnosis, including biopsy and treatment complications, was estimated at ¤13,818 per patient. The total estimated burden of newly diagnosed PCa in 2010, i.e., adopting the IB approach, was approximately ¤25.7 million.

Table II shows the healthcare costs in RoI associated with PCa in 2010 for both approaches. In 2010, the overall cost associated with PCa detection (n = 3287) was ¤366,369. PCa diagnosis, which included biopsies (¤432/patient) and diagnostic procedures (¤376/patient), was estimated at ¤3 million (unit cost [UC] ¤808). The healthcare cost per patient, in 2010, for the first year of PCa diagnosis was estimated at ¤7337, excluding treatment complications, or ¤7532, including treatment complications. Estimated treatment costs (for the first year) varied considerably; AM ¤430,572 (UC ¤655), EBRT ¤8.05 million (UC ¤6122), RP ¤3.6 million (UC ¤7324), BT ¤591,496 (UC ¤4999), TURP ¤2.6 million (UC ¤5709), HT ¤4.8 million (UC ¤4670), and CT ¤741,404 (UC ¤11,278). Post-treatment costs, which included three years’

PSA testing in cancer patients accounts for the smallest proportion of costs for both the IB and PB approaches; 1.4% and 0.8%, respectively. HT was delivered both in isolation and in combination with radical treatments and represented the largest proportion of the PB total costs (32%). EBRT and BT combined accounted for the 34% and 22% of costs in IB and PB approaches, respectively. Also, EBRT accounted for the

highest proportion of costs in newly diagnosed cases (IB approach). RP, although only administered to 15% of patients, represented 14% and 9% of the total costs in the IB and PB approaches, respectively. Scenario analyses are shown in Table III. Redistributing localised cancers from costlier treatments (RP (-10%) and EBRT (-15%) to BT (+15%) and AM (+10%) has a marginal impact on the overall burden of cost in all scenarios, a maximum reduction of ¤3.2 million (7%). In this study, we estimated costs and resource utilisation rates for PCa diagnosis and treatment in the RoI in 2010 using available Irish data. Total PCa healthcare expenditure was estimated at ¤45.6 million, equating to 0.027% of Ireland’s GDP and 0.32% of public expenditure on healthcare in 2010 (40*); this is similar to % of GDP attributable to PCa in the UK (0.024%) and lower than that of France, Italy and Sweden (0.049%, 0.038% and 0.039%, respectively) (3*). Clinical stage at diagnosis and variation in treatment modalities may in part account for variation across countries. However, with growing pressures on healthcare budgets, an aging population and steady growth in PCa incidence, driven in part by increased PSA testing in primary care and longer life

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:; e-mail: 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

10 Prostate Cancer Table III - Treatment scenario analyses for prevalent costs in 2010

patients with localised PCa with more aggressive, costlier treatment modalities over a 10-year follow-up period; thus, suggesting redistribution of care to AM, in particular, may be a viable cost-containment strategy. Monitoring of trends in treatment and examination of practice variation is warranted.

expectancy, understanding the components of the burden of cost and how they compare with European counterparts is vital for constructing policy responses. As expected, PCa treatment regimens accounted for most of costs (¤34 million, 74%); however, short- and long-term complications posttreatment also constituted a significant burden (¤4.8 million, 11%). Furthermore, we estimated that over half the PCa expenditure was attributable to diagnosis and first year of treatment (¤25 million). Using incidence data, the diagnosis and treatment of PCa in the RoI was estimated at ¤7337 (2010¤) per patient excluding treatment complications. Incidence costs of PCa in the UK of ¤3682 (2006¤), Germany ¤3698 (2006¤), Spain ¤3256 (2006¤), Italy ¤5226 (2006¤) and France ¤5851 (2006¤) were comparable after adjusting for PPP (41*). The cost of ¤13,818 per prevalent case (including four years’ follow-up) in the RoI is similar to the cost of ¤12,731 in France (2008¤ including five years’ follow-up) (42*). However, costs of PCa care in the RoI are among the highest in Europe. A European study estimated that across Europe the total cost of cancer in 2009 was ¤126 billion and the annual Irish direct healthcare cost of PCa in 2009 was ¤51 million. The study adopted a top-down approach using national fee schedules and expenditure data incorporating public and private healthcare expenditure (3*). Our estimates

Issue 41 • HPN

included public payer costs only, which may account, in part, for the discrepancy between estimates. Previous research found that approximately 30% of men diagnosed with PCa used private healthcare providers (43*). The unit costs used in our study for this subgroup may be conservative, as costs of treatments in the private setting are thought to be substantially higher than the public system; however, there are no data available on the unit cost differences across the two modes of healthcare delivery within the RoI. If adopting a 15% adjustment for private care in Ireland applied in Luengo-Fernandez et al (3*) to the proportion treated privately (approximately 30%) (43*), this would increase the total cost of PCa in the RoI to ¤47.7 million. The scenario analysis highlighted that potential annual savings ranging from ¤2.2 million to ¤3.2 million are possible if suitable patients with localised disease received less costly management options, namely AM and BT. Between 2007 and 2009, approximately 65% of PCa was diagnosed as localised disease (Stage I-II). Those receiving AM and BT accounted for 24% on average and those in receipt of RP and EBRT accounted for 55%. Whether greater use of AM or BT is clinically justified and aligns with European guidance needs further investigation (44*). However, the ProtecT trial findings (13*), suggest there is no mortality benefit for treating

This study has several limitations. Resource use estimates for post-biopsy complication rates were informed by published studies as data were not available in the RoI. For HT, we assumed goserelin was solely used and for CT we assumed docetaxel in combination with prednisolone was solely used; both assumptions were made due to limited treatment data available in the RoI and we acknowledge that other products are prescribed in the RoI. In the absence of published data in the RoI, sources from UK studies as well as expert opinion have informed the resource use parameters and costs associated with some elements of treatment. Other parameters were sourced from relevant literature, which focussed primarily on identifying data from the UK (as another public healthcare system); if UK data could not be identified, data from other countries was used. Although, our aim was to estimate all Irish costs using a bottom-up approach based on patient level data, this was not possible for all elements of care given the lack of data and resources to perform micro-costing exercises. For example, treatment unit costs were retrieved from the readily available HSE Casemix programme database which reports costs by diagnosisrelated groups (gross costing where patients are grouped according to similar levels of resource usage), rather than using a micro-costing approach to collect and value all resources associated with all treatments. Thus, it could be argued that

not all costs estimated in our study are fully consistent with a bottom-up approach. A more apt classification is a mixture of bottom-up and top-down (gross-costing) approach that was conditional on the availability of data. Finally, this analysis captured expenditures associated with PCa for those diagnosed and registered with the NCRI. However, registry completeness, although high, is not 100% (45*). Moreover, based on UK trial data, approximately 9% of those screened have a raised PSA (defined as >3 ng/mL) and 23% of those 9% are diagnosed with PCa (46*). Applying these proportions to the RoI suggests that the 3287 diagnosed in 2010 may only represent 23% of the men who underwent a biopsy after an abnormal PSA test. However, previous research suggests that approximately 17% of those tested had an abnormal PSA test in the RoI, nearly double the rates of the ProtecT trial (6*); further, biopsy rates for suspected PCa in the RoI are considerably higher than in the UK (47*). Thus, extra PCarelated expenditure associated with PSA testing and biopsies for those who did not have PCa could range between ¤1.5 million to ¤3 million; these costs were not included in our estimates but may account for the cost difference presented here and that of the Luengo-Fernandez et al study (3*). Conclusion The estimated burden of cost associated with PCa in the RoI for 2010 was ¤45.6 million employing a public payer’s perspective. Healthcare expenditures associated with PCa are substantial representing a sizeable proportion of the Irish healthcare budget in relation to disease prevalence. Increases in PCa incidence, in part due to PSA testing, have significant resource utilisation implications in the RoI as well as across Europe; this study aids in understanding the PCa pathway and associated costs in the RoI which may highlight areas of focus for cost containment strategies. Find the full version with references at


34.7 median OS1



of patients treated with ZYTIGA® plus low-dose prednisolone did not experience grade 3 or 4 corticosteroidassociated adverse event2

reduction in the risk of

48% radiographic progression3 WITH

of median follow up


ZYTIGA maintains a favourable safety profile and is generally well-tolerated1


ZYTIGA® 500 mg Tablets PRESCRIBING INFORMATION. ACTIVE INGREDIENT(S): Abiraterone acetate. Please refer to Summary of Product Characteristics (SmPC) before prescribing. INDICATION(S): Taken with prednisone or prednisolone for the treatment of metastatic castration resistant prostate cancer in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated. The treatment of metastatic castration resistant prostate cancer in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen. DOSAGE & ADMINISTRATION: Adults: 1000 mg (2 tablets) single daily dose. Not with food as this increases the systemic exposure (take dose at least two hours after eating; no food for at least one hour post-dose). Swallow whole with water. Take with recommended dose of prednisone or prednisolone of 10 mg daily. Medical castration with LHRH analogue should be continued during treatment in patients not surgically castrated. Children: No relevant use. Hypokalaemia: In patients with pre-existing, or who develop hypokalaemia during treatment with Zytiga, consider maintaining potassium level at ≥4.0 mM. Patients who develop Grade ≥ 3 toxicities (hypertension, hypokalaemia, oedema and other non-mineralocorticoid toxicities) stop treatment and start appropriate medical management. Do not restart Zytiga until symptoms of the toxicity have resolved to Grade 1 or baseline. Renal impairment: No dose adjustment, however no experience in patients with prostate cancer and severe renal impairment; caution advised. Hepatotoxicity: If hepatotoxicity develops (ALT or AST >5x upper limit of normal - ULN), stop treatment immediately until liver function returns to baseline; restart Zytiga at 500 mg (1 tablet) once daily and monitor serum transaminases at least every 2 weeks for 3 months and monthly thereafter (see Special warnings & precautions). If hepatotoxicity recurs on reduced dose, stop treatment. If severe hepatotoxicity develops (ALT or AST 20xULN), discontinue Zytiga and do not restart. Hepatic impairment: Mild (Child-Pugh class A) - no dose adjustment required. Moderate (Child-Pugh class B) - approximately 4x increased systemic exposure after single oral doses of 1,000 mg. Moderate/Severe (Child-Pugh class B or C) – no clinical data for multiple doses. Use with caution in moderate impairment, benefit should clearly outweigh risk. CONTRAINDICATIONS: Pregnancy or potential to be pregnant. Hypersensitivity to active substance or any excipients. Severe hepatic impairment (Child-Pugh Class C). SPECIAL WARNINGS & PRECAUTIONS: Zytiga may cause hypertension, hypokalaemia and fluid retention due to increased mineralocorticoid levels. Cardiovascular: Caution in patients with history of cardiovascular disease. In patients with a significant risk for congestive heart failure (history of cardiac failure, uncontrolled hypertension, ischaemic heart disease) consider an assessment of cardiac function before treating (echocardiogram). Safety not established in patients with left ventricular ejection fraction < 50% or NYHA Class II to IV (pre-chemotherapy) and III or IV (post-chemotherapy) heart failure. Before treatment cardiac failure should be treated and cardiac function optimised. Correct and control hypertension, hypokalaemia and fluid retention pre-treatment. Caution in patients whose medical conditions might be compromised by hypertension, hypokalaemia or fluid retention e.g. heart failure, severe or unstable angina pectoris, recent myocardial infarction or ventricular arrhythmia, severe renal impairment. Monitor blood pressure, serum potassium and fluid retention and other signs and symptoms of congestive heart failure before treatment, then every two weeks for 3 months, and monthly thereafter. QT prolongation observed in patients experiencing hypokalaemia with Zytiga treatment. Consider discontinuation if there is a clinically significant decrease in cardiac function. Hepatotoxicity & hepatic impairment: Measure serum transaminases pre-treatment and every two weeks for first three months, then monthly. If symptoms/signs suggest hepatotoxicity, immediately measure serum transaminases. If ALT or AST > 5x ULN, stop treatment and monitor liver function. Restart treatment after liver function returns to baseline; use reduced dose (see dosage and administration). No clinical data in patients with active or symptomatic viral hepatitis. Rare reports of acute liver failure and hepatitis fulminant, some fatal. Corticosteroid withdrawal: Monitor for adrenocortical insufficiency if prednisone or prednisolone is withdrawn. Monitor for mineralocorticoid excess if Zytiga continued after corticosteroids withdrawn. Bone density: Decreased bone density may be accentuated by Zytiga plus glucocorticoid. Prior use of ketoconazole: Lower response rates may occur in patients previously treated with ketoconazole for prostate cancer. Hyperglycaemia: Use of glucocorticoids could increase hyperglycaemia, measure blood sugar frequently in patients with diabetes. Use with chemotherapy: Safety and efficacy of concomitant use of Zytiga with cytotoxic chemotherapy not established. Intolerance to excipients: Not to be taken by patients with galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption. Take sodium content into account for those on controlled sodium diet. Potential risks: Anaemia and sexual dysfunction may occur in men with metastatic castration resistant prostate cancer including those

taking Zytiga. Skeletal muscle effects: Cases of myopathy reported. Some patients had rhabdomyolysis with renal failure. Caution is recommended in patients concomitantly treated with drugs known to be associated with myopathy/ rhabdomyolysis. SIDE EFFECTS: Very common: urinary tract infection, hypokalaemia, hypertension, diarrhoea, peripheral oedema. Common: sepsis, hypertriglyceridaemia, cardiac failure (including congestive heart failure, left ventricular dysfunction and decreased ejection fraction), angina pectoris, arrhythmia, atrial fibrillation, tachycardia, dyspepsia, increased alanine aminotransferase, increased aspartate aminotransferase, rash, haematuria, fractures (includes all fractures with the exception of pathological fracture). Other side effects: adrenal insufficiency, myocardial infarction, QT prolongation, hepatitis fulminant, acute hepatic failure, myopathy, rhabdomyolysis. Refer to SmPC for other side effects. FERTILITY/PREGNANCY/LACTATION: Not for use in women. Not known whether abiraterone or its metabolites are present in semen. A condom is required if the patient is engaged in sexual activity with a pregnant woman. If the patient is engaged in sexual activity with a woman of childbearing potential, a condom is required along with another effective contraceptive method. Studies have shown that abiraterone affected fertility in male and female rats, but these effects were fully reversible. INTERACTIONS: Caution with drugs activated by or metabolised by CYP2D6 particularly when there is a narrow therapeutic index e.g. metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, flecainide, codeine, oxycodone and tramadol, dose reduction should be considered. Avoid strong inducers of CYP3A4 (e.g. phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital, St John’s wort). Zytiga is a CYP2C8 inhibitor. Monitor for signs of toxicity if combined with drugs with a narrow therapeutic index eliminated predominately by CYP2C8. May increase concentrations of drugs eliminated by OATP1B1. Food (see Dosage & Administration). Caution with medicines known to prolong QT interval or induce torsade de pointes e.g. quinidine, disopyramide, amiodarone, sotalol, dofetilide, ibutilide, antiarrhythmic medicinal products, methadone, moxifloxacin and antipsychotics. Use of Zytiga with spironolactone is not recommended. Refer to SmPC for full details of interactions. LEGAL CATEGORY: POM. PRESENTATIONS, PACK SIZES & MARKETING AUTHORISATION NUMBERS: Blister Pack, 56 tablets, EU/1/11/714/002. MARKETING AUTHORISATION HOLDER: JANSSEN-CILAG INTERNATIONAL NV, Turnhoutseweg 30, B-2340 Beerse, Belgium. FURTHER INFORMATION IS AVAILABLE FROM: Janssen-Cilag Ltd, 50-100 Holmers Farm Way, High Wycombe, Buckinghamshire, HP12 4EG, UK. © Janssen-Cilag Ltd 2014. Prescribing information last revised: November 2016 Adverse events should be reported. Healthcare professionals are asked to report any suspected adverse events via: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website:, E-mail: Adverse events should also be reported to Janssen-Cilag Limited on +44 1494 567447 or at © Janssen-Cilag Limited 2016 References: 1. Ryan CJ, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapynaive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo controlled phase 3 study. Lancet Oncol 2015; 16: 152–60. 2. Fizazi, K., et al (2015). ASCO GU 2015 (abstract 169). 3. Rathkopf, DE et al. Updated Interim Efficacy Analysis and Long-term Safety of Abiraterone Acetate in Metastatic Castration-resistant Prostate Cancer Patients Without Prior Chemotherapy (COUAA-302). Eur Urol (2014), eururo.2014.02.056. Date of Preparation: February 2017 | PHIR/ZYT/1014/0004(5)

12 Breast Cancer Clinical use of biomarkers in breast cancer: Updated guidelines from the European Group on Tumor Markers (EGTM) M.J. Duffy. N. Harbeck, M. Nap, R. Molina, A. Nicolini, E. Senkus, F. Cardoso Clinical Research Centre, St. Vincent's University Hospital, Dublin and UCD School of Medicine, UCD Conway Institute, University College Dublin, bBreast Center of the University of Munich, Munich, Germany cDepartment of Pathology, Atrium Heerlen Medical Centre, Heerlen, The Netherlands dLaboratory of Biochemistry, Hospital Clinic, Barcelona, Spain e Department of Oncology, Transplantations and New Technologies in Medicine, University of Pisa, Pisa, Italy fDepartment of Oncology and Radiotherapy, Medical University of Gdańsk, Gdańsk, Poland gBreast Unit, Champalimaud Clinical Centre, Lisbon, Portugal a

Biomarkers currently play an indispensable role in the management of patients with breast cancer, especially in deciding the type of systemic therapy to be administered. In 2005, the European Group on Tumor Markers (EGTM) published guidelines on the use biomarkers in breast cancer[1]. However, since then, a number of important new developments have been reported, especially with tissue-based biomarkers. These include the use of multiparameter signatures for predicting patient outcome and the use of HER2 for the upfront identification of likely response to several different forms of antiHER2 therapy. In addition, new recommendations have been published for performing a number of breast cancer biomarker assays such as oestrogen receptors (ERs), progesterone receptors (PRs) and HER2. The aim of this article is therefore to expand on, and update the 2005 guidelines, focussing on tissuebased biomarkers.

Table 1 Gene/protein signatures previously proposed for predicting outcome in patients with newly diagnosed breast cancer. Table 1 Gene/protein signatures previously proposed for predicting outcome in patients with newly diagnosed breast cancer. Test Tissue required Molecule measured No. of analytes Studied in prospective randomised trial uPA/PAI-1 Fresh/frozen Protein 2 Yes and ongoing Oncotype Dx FFPE mRNA 21 Yes and ongoing MammaPrint Fresh/frozen/FFPE mRNA 70 Yes and ongoing Prosigna/PAM50 FFPE mRNA 50a Ongoing GGI FFPE mRNA 97 Ongoing BCI FFPE mRNA 11 No Mammostrat FFPE Protein 5 No IHC4 score FFPE Protein 4 No EndoPredict FFPE mRNA 11 Ongoing Rotterdam signature Fresh/frozen mRNA 76 No OncoMasTR FFPE mRNA 7 No Curbest 95GC FFPE mRNA 95 No FFPE, formalin-fixed and paraffin-embedded. GCI, Genomic Grade Index; BCI, Breast Cancer Index. aIn addition to 50 genes from the PAM50 panel, the test also contains eight control genes for normalisation, six positive controls and eight negative controls (Prosigna packet insert).

1. Oestrogen and progesterone receptor for predictive endocrine sensitivity

selective oestrogen receptor modulators (tamoxifen), thirdgeneration aromatase inhibitors (anastrozole, letrozole or exemestane), LH-RH agonists (leuprolide, goserelin), pure oestrogen receptor downregulators (fulvestrant), oophorectomy and other endocrine therapies. As predictive markers for endocrine therapy, ER and PR are used in the neoadjuvant, adjuvant and advanced disease settings[8–11].

Oestrogen receptor (ER) exists in two main forms, ERα and ERβ. Currently, a validated clinical role has only been established for ERα which will be referred to as ER in this article. Whereas the original ligand-binding ER assays are likely to have detected both ERα and ERβ, the current immunohistochemistry (IHC) measurements detect only ERα. Similarly, progesterone receptor (PR) exists in two forms, dubbed PRA and PRB. Currently used IHC assays detect both these forms of PR. The main clinical application of steroid hormone receptors, i.e. ERα and PR is in selecting patients with invasive breast cancer for treatment with endocrine therapy, i.e. administration of

Issue 41 • HPN

In early disease, a meta-analysis of individual data from 20 randomised clinical trials (n = 21,457) showed that treatment of ER-positive patients (i.e. ≥10 fmol/mg protein determined with a biochemical assay) for approximately 5 years with adjuvant tamoxifen significantly reduced the 15-year odds of disease recurrence by 39% and odds of breast cancer mortality by 30%[9]. In contrast to the findings with ER-positive

disease, treatment of ER-negative patients (<10 fmol/mg protein) with tamoxifen had no significant effect on either breast cancer recurrence or mortality. In this meta-analysis, PR did not provide independent predictive information. While not predictive of the benefit from tamoxifen in this meta-analysis, high levels of PR levels, however, were reported to be independently correlated with an increased probability of response to tamoxifen, longer time to treatment failure and longer overall survival in patients with metastatic breast cancer[12,13]. It should be stated that most of the studies included in the above meta-analysis used the original biochemical assays (ligand-binding and ELISA) to measure ER and PR. These assays were not standardised and it is unclear if all the laboratories participated in quality assurance programs.

Although 5 years of adjuvant tamoxifen treatment was the standard form of endocrine treatment for steroid hormone receptor–positive patients for several years, administration of tamoxifen or an aromatase inhibitor (i.e. letrozole) for 10 years was recently shown to be superior to a 5-year course[14,15]. This enhanced benefit, however, should be weighed against the potential additional side-effects of the extended treatment. Ideally, therefore, biomarkers should be available to identify those patients who are at high risk of developing late recurrences, as these women may benefit from the extended therapy. Equally important, theses biomarkers should help to identify women at low risk of late relapse, as these could be spared the sideeffects and costs of the extended treatment. Emerging data suggest that specific gene signatures may


IBRANCE® + AI and IBRANCE® + fulvestrant1

JOINING FORCES, CHANGING THE OUTLOOK As a 1st line breakthrough therapy for mBC, IBRANCE® + letrozole has demonstrated >2 years mPFS.*2 And, when combined with fulvestrant, it offers enhanced efficacy to a wide patient population.*3

IBRANCE® is indicated for the treatment of HR+/HER2- locally advanced or mBC:1 • in combination with an AI • in combination with fulvestrant in patients who have received prior ET In pre- or peri-menopausal women, the ET should be combined with a LHRH agonist1

IBRANCE® q(PALBOCICLIB) PRESCRIBING INFORMATION: Please refer to the Summary of Product Characteristics (SmPC) before prescribing IBRANCE® 75 mg, 100 mg or 125 mg hard capsules. Presentation: Hard capsules containing 75 mg, 100 mg or 125 mg palbociclib. Indications: Treatment of hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative locally advanced or metastatic breast cancer: in combination with an aromatase inhibitor; in combination with fulvestrant in women who have received prior endocrine therapy. In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinizing hormone releasing hormone (LHRH) agonist. Dosage: Therapy should be initiated and supervised by a physician experienced in the administration of anti-cancer medicinal products. The recommended dose is 125 mg of palbociclib once daily for 21 consecutive days followed by 7 days off treatment (Schedule 3/1) to comprise a complete cycle of 28 days. Treatment of pre/perimenopausal women with the combination of palbociclib plus letrozole should always be combined with an LHRH agonist (see SmPC section 4.4). Capsules should be swallowed (should not be chewed, crushed, or opened prior to swallowing). It should be taken with food, preferably a meal to ensure consistent palbociclib exposure (see SmPC section 5.2). Palbociclib should not be taken with grapefruit or grapefruit juice (see SmPC section 4.5). Dose modification of IBRANCE® is recommended based on individual safety and tolerability. Management of some adverse reactions may require temporary dose interruptions/delays, and/or dose reductions, or permanent discontinuation. For dose reduction guidelines for management of adverse reactions, haematologic and non-haematologic toxicities, refer to SmPC section 4.2. No dose adjustments of IBRANCE® are required for patients with mild hepatic impairment (total bilirubin ≤1 × upper limit of normal [ULN] and aspartate aminotransferase [AST] >1 × ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST. Administer IBRANCE® to patients with moderate and severe hepatic impairment only after careful consideration of the potential benefits and risks and with close monitoring of signs of toxicity (see SmPC section 5.2). No dose adjustments of IBRANCE® are required for patients with mild to moderate renal impairment (creatinine clearance [CrCl] ≥30 mL/ min). Administer IBRANCE® to patients with severe renal impairment only after careful consideration of the potential benefits and risks and with close monitoring of signs of toxicity (see SmPC section 5.2). No dose adjustment of IBRANCE® is necessary in patients ≥65 years of age (see section 5.2).

Contraindications: Hypersensitivity to the active substance or to any of the excipients (see SmPC section 6.1) use of preparations containing St. John’s Wort (see SmPC section 4.5). Warnings and Precautions: Ovarian ablation or suppression with an LHRH agonist is mandatory when pre/perimenopausal women are administered IBRANCE® in combination with an aromatase inhibitor, due to the mechanism of action of aromatase inhibitors. Palbociclib in combination with fulvestrant in pre/perimenopausal women has only been studied in combination with an LHRH agonist. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia. Appropriate monitoring should be performed (see SmPC sections 4.2 and 4.8). Since IBRANCE® has myelosuppressive properties, it may predispose patients to infections. Infections have been reported at a higher rate in patients treated with IBRANCE® in randomised clinical studies compared to patients treated in the respective comparator arm. Grade 3 and Grade 4 infections occurred respectively in 4.5% and 0.7% of patients treated with IBRANCE® in any combination (see SmPC section 4.8).Patients should be monitored for signs and symptoms of infection and treated as medically appropriate (see SmPC section 4.2). Physicians should inform patients to promptly report any episodes of fever. Strong inhibitors of CYP3A4 may lead to increased toxicity (see SmPC section 4.5). Avoid concomitant use of strong CYP3A inhibitors during treatment with palbociclib. Coadministration should only be considered after careful evaluation of the potential benefits and risks. If coadministration with a strong CYP3A inhibitor is unavoidable, reduce the IBRANCE® dose to 75 mg once daily. When the strong inhibitor is discontinued, increase the IBRANCE® dose (after 3–5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor (see SmPC section 4.5). Coadministration of CYP3A inducers may lead to decreased palbociclib exposure and consequently a risk for lack of efficacy. Therefore, concomitant use of palbociclib with strong CYP3A4 inducers should be avoided. No dose adjustments are required for coadministration of palbociclib with moderate CYP3A inducers (see SmPC section 4.5). Women of childbearing potential or their male partners must use a highly effective method of contraception while taking IBRANCE® (see SmPC section 4.6). IBRANCE® contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

*Based on results from a Phase III RCT. AI = aromatase inhibitor; ET = endocrine therapy; HR+/HER2– = hormone receptor positive, human epidermal growth factor receptor 2 negative; LHRH = luteinising hormone–releasing hormone; mBC = metastatic breast cancer; mPFS = median progression–free survival; RCT = randomised controlled trial. 1. IBRANCE® Summary of Product Characteristics. 2. Finn RS, et al. N Engl J Med 2016;375:1925-36. 3. Cristofanilli M, et al. Lancet Oncol. 2016;17(4):425-439. Date of Preparation: March 2017 PP-IBR-IRL-0026

Drug Interactions: The concomitant use of strong CYP3A inhibitors including, but not limited to: clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, voriconazole, and grapefruit or grapefruit juice, should be avoided (see sections 4.2 and 4.4). No dose adjustments are needed for mild and moderate CYP3A inhibitors. The concomitant use of strong CYP3A inducers including, but not limited to: carbamazepine, enzalutamide, phenytoin, rifampin, and St. John’s Wort should be avoided (see SmPC sections 4.3 and 4.4). No dose adjustments are required for moderate CYP3A inducers. The dose of sensitive CYP3A substrates with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus) may need to be reduced when coadministered with IBRANCE® as IBRANCE® may increase their exposure. Based on in vitro data, palbociclib is predicted to inhibit intestinal P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) mediated transport. Therefore, administration of palbociclib with medicinal products that are substrates of P-gp (e.g., digoxin, dabigatran, colchicine, pravastatin) or BCRP (e.g., rosuvastatin, sulfasalazine) may increase their therapeutic effect and adverse reactions. Based on in vitro data, palbociclib may inhibit the uptake transporter organic cationic transporter OCT1 and then may increase the exposure of medical product substrates of this transporter (e.g., metformin). Pregnancy & Lactation: Females of childbearing potential who are receiving this medicinal product, or their male partners should use adequate contraceptive methods (e.g., doublebarrier contraception) during therapy and for at least 3 weeks or 14 weeks after completing therapy for females and males, respectively (see SmPC section 4.5). There are no or limited amount of data from the use of palbociclib in pregnant women. Studies in animals have shown reproductive toxicity (see SmPC section 5.3). IBRANCE® is not recommended during pregnancy and in women of childbearing potential not using contraception. Based on male reproductive organ findings (seminiferous tubule degeneration in testis, epididymal hypospermia, lower sperm motility and density, and decreased prostate secretion) in nonclinical safety studies, male fertility may be compromised by treatment with palbociclib (see SmPC section 5.3). Thus, men may consider sperm preservation prior to beginning therapy with IBRANCE®. Driving and operating machinery: IBRANCE® may cause fatigue and patients should

exercise caution when driving or using machines. Side Effects: The most common (≥20%) adverse reactions of any grade reported in patients receiving palbociclib in randomised clinical studies were neutropenia, infections, leukopenia, fatigue, nausea, stomatitis, anaemia, alopecia, and diarrhoea. The most common (≥2%) Grade ≥3 adverse reactions of palbociclib were neutropenia, leukopenia, anaemia, fatigue, and infections. Dose reductions or dose modifications due to any adverse reaction occurred in 34.4% of patients receiving IBRANCE® in randomised clinical studies regardless of the combination. Very common adverse events (>1/10) are neutropenia, infections, leukopenia, fatigue, anaemia, nausea, stomatitis, alopecia, diarrhoea, thrombocytopenia, vomiting, rash, decreased appetite. Commonly reported adverse events (>1/100 to <1/10), are asthenia, pyrexia, dry skin, AST increased, dysgeusia, epistaxis, ALT increased, lacrimation increased, vision blurred, dry eye, febrile neutropenia. Refer to SmPC for further information on side effects. Refer to section 4.8 of the SmPC for further information on side effects, including description of selected adverse reactions. Legal Category: S1A. Marketing Authorisation Numbers: EU/1/16/1147/001 – 75mg (21 capsules); EU/1/16/1147/003 – 100mg (21 capsules) EU/1/16/1147/005 – 125mg (21 capsules). Marketing Authorisation Holder: Pfizer Limited, Sandwich, Kent, CT13 9NJ, United Kingdom. For further information on this medicine please contact: Pfizer Medical Information on 1800 633 363 or at For queries regarding product availability please contact: Pfizer Healthcare Ireland, Pfizer Building 9, Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24 + 353 1 4676500. qThis 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. Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 676 4971; Fax: +353 1 676 2517. Website:; e-mail: Last revised: 11/2016 Ref: IB 1_0

14 Breast Cancer be able to differentiate between patients with respect to their risk for early or late relapses following endocrine therapy. These include Prosigna (PAM50 and Risk of Recurrence score)[16], EndoPredict[17], IHC4[18], Breast Cancer Index (BCI)[18] and the HOXB13/IL17BR ratio[19]. Adjuvant treatment with thirdgeneration aromatase inhibitors (AIs) in postmenopausal hormone receptor–positive patients was shown to be superior to a 5-year course of tamoxifen in reducing the risk of recurrence albeit with modest effect (1–2%) in extending overall survival. This increased efficacy was found whether AIs were initially administered or sequentially used following 2–3 years of tamoxifen treatment [20]. Most expert panels, including the American Society of Clinical Oncology (ASCO) [21], the National Comprehensive Cancer Network (NCCN) [22] and the European Society of Medical Oncology (ESMO) [23] recommend the incorporation of an aromatase inhibitor, either upfront or in sequence with tamoxifen, in the adjuvant treatment of postmenopausal patients. According to the 2015 St. Gallen Consensus Group[24], tamoxifen alone may be suitable for low-risk women. In contrast, for high-risk women, the group recommended that an aromatase inhibitor should be considered and administered initially. For premenopausal receptorpositive patients, tamoxifen has been the standard treatment for several decades. However, based on recent findings from two clinical trials[25,26], the ASCO 2016 guidelines have recommended that high-risk patients should receive ovarian suppression in addition to standard adjuvant endocrine therapy, whereas low-risk patients should not have the additional ovarian suppression[27]. 2. ER and PR for determining prognosis While the primary value of steroid hormone receptors is as predictive biomarkers for endocrine therapy, the receptor status of a primary invasive breast cancer can also provide prognostic information. Indeed, several retrospective studies have shown that patients with ER or PR-containing tumours tend to have a better outcome than those lacking the receptors[28–36]. However, the favourably prognosis associated, at least with ER-positive tumours, mostly occurs during the first 5–7 years after initial diagnosis[28–30]. Thereafter, the risk of relapse tends to be greater in ER-positive than ER-negative tumours. Steroid

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hormone receptors alone thus cannot be used to identify women who may benefit from extended endocrine therapy. Furthermore, the impact of therapy on the prognostic impact of steroid hormone receptors prognosis is difficult to exclude, as almost all receptor-positive patients are treated with endocrine therapy in either early or advanced disease. Indeed, in some studies, the improved outcome with receptorpositive tumours was only found in patients treated with endocrine therapy[29,30]. 3. ER and PR: EGTM recommendation • In agreement with previously published guidelines[1,3,21–24,36], the EGTM panel recommends that ER and PR be measured on all newly diagnosed primary invasive breast cancers (for ER, LOE IA; SOR, A and for PR, LOE 1B; SOR, A/B). If ER or PR is found to be negative in the core needle biopsy specimen from a primary tumour, we suggest to re-assay them in the corresponding surgical sample. This suggestion however, is not evidence based but is based on several studies showing a discordance in hormone receptor status between a core needle biopsy and a corresponding surgical specimen. A possible reason for negative findings on the core needle but positive findings on the surgical specimens is an error in sampling. This may occur, especially in heterogeneous tumours, where the core biopsy specimen is not representative of the whole tumour. On the other hand, negative findings on the surgical specimen but positive findings with the core needle biopsy could relate to fixation artifacts, caused by a delay in exposure of the center of a surgical specimen to formalin[37]. • ASCO guidelines state that when discordant results are found between the primary and metastatic site, it is preferable to use the receptor status of the metastatic tumour, provided it is supported by the clinical situation and in agreement with the patients' wishes[38]. In contrast, both the European School of Oncology (ESO)-ESMO Consensus Conference for Advanced Breast Cancer (ABC) group[39] and NCCN[22] recommend administering endocrine therapy if any biopsy is receptor positive. It is important to state that the recommendation to measure ER/PR on metastatic sites when treating recurrent disease is not evidence based but would appear to be prudent, because of the possibility of an alteration in receptor status as a result of tumour progression.

Thus, based on a meta-analysis of 33 published studies containing a total of 4200 patients, Aurilio et al. [40] concluded that the discordance rates for ER between the primary and metastatic sites were 20% (95% confidenc interval [CI], 16–35%), with 24% of tumours converting from positive to negative and 14% converting from negative to positive status. In this meta-analysis, the pooled discordance for PR status between primary and metastatic sites was 33% (95% CI, 29–38) [40]. With PR, 46% of the samples changed status from positive to negative, whereas 15% changed status in the opposite direction. • Finally, both ER and PR should be measured by IHC using an analytically and clinically validated assay. 4. ER and PR: recommendation for further research • Development of biomarkers for increasing the positive predictive value of ER. • Identify biomarkers for selecting patients that preferentially benefit from an aromatase inhibitor vis-à-vis tamoxifen or vice versa. • Validate biomarkers for selecting patients who do not need extended adjuvant endocrine therapy. • Establish the optimum clinical cut-off points for both ER and PR, in particular to establish if these should be 1%, 10% or indeed a different percentage of positive cell nuclei staining[41]. • Develop and validate assays for ERβ with a view to ascertaining a potential clinical role for this form of ER in breast cancer[42]. • Establish the relative endocrine therapy predictive impact of the two forms of PR, i.e. PRA and PRB[33]. • Determine if ER mutations at recurrent sites have predictive ability. Recently, such mutations were found in approximately 20% of patients with metastatic breast cancer, most of whom were treated with an aromatase inhibitor[43]. It remains to be shown, however, if the presence of these mutations has a predictive impact. 5. HER2 for predicting the response to anti-HER2 therapies The main clinical use of HER2 measurement is in predicting the response to anti-HER2 therapy in the neoadjuvant, adjuvant and advanced disease settings[44]. Currently, four anti-HER2 therapies are approved for the treatment of HER2-positive breast cancer, trastuzumab, lapatinib, pertuzumab and trastuzumab

emtansine (T-DM1). Based on the available evidence, HER2 gene amplification/overexpression appears to be necessary but not sufficient for response to all of these anti-HER2 therapies. Recently, several expert panels, including ASCO[45], NCCN[22] and ABC[39], recommended that the first-line therapy for patients with HER2-positive advanced breast cancer should be trastuzumab, pertuzumab and a taxane, if not previously treated with trastuzumab. It was also suggested that this regimen is a treatment option for those who previously received trastuzumab. For those who progress during or after first-line anti-HER2 treatment, T-DM1 should be administered[45]. In the adjuvant setting, trastuzumab (in combination with chemotherapy) is the standard and still the only approved form of antiHER2 therapy administered. For the neoadjuvant setting, dual treatment with trastuzumab and pertuzumab is approved both in Europe and in the USA. According to the NCCN guidelines, a pertuzumab-containing regimen may be administered in the neoadjuvant setting to HER2-positive patients who are lymph node–positive or have tumours ≥2 cm[22]. 6. Measurement of HER2 Two main types of tests are available to measure HER2 gene amplification/protein overexpression, i.e. IHC and in situ hybridisation (ISH). ISH assays may use fluorescent ISH (FISH) or brightfield ISH. Guidelines for performing and interpreting HER2 results have been published by several expert panels including groups in the US (ASCO/CAP)[46], UK[47] and elsewhere[48]. 7. HER2: EGTM recommendation • HER2 gene amplification or overexpression should be determined on all patients with primary invasive breast cancer (LOE, IA; SOR, A). Where feasible, measurement should also be performed on any metastatic lesion. According to ASCO, if discordance exits between the two locations, the HER2 status of the metastatic site should be used in determining the management[40]. The ABC Consensus Guidelines and NCCN, however, state that if any biopsy is positive, the patients should receive anti-HER2 therapy[22,39]. As with ER and PR, the recommendation to measure HER2 on a metastatic lesion is not evidence based. However, like ER and PR, the HER2 status can vary between a primary and metastatic site. Thus, in the metaanalysis referred to above[40], 13%

15 of cancers that were positive in the primary cancer were found to be negative in the metastatic lesion, whereas 5% that were negative in the primary lesion were positive in the metastatic specimen. • As stated by the ASCO/CAP panel, measurement can be performed on either a core needle biopsy or on a surgical resection specimen[46]. As with ER/PR, if HER2 is found to be negative in the biopsy specimen from a primary tumour, it is recommended to re-assay it in the corresponding surgical sample (as tumour heterogeneity may have been responsible for the negative finding in the biopsy sample). Fine needle aspirates of primary cancers should not be used to measure HER2, as such samples do not allow reliable differentiation between invasive and in situ malignancy. • Measurement of HER2 in DCIS should not be performed. • HER2 measurement should be performed and positivity defined using the updated ASCO/CAP guidelines[46]. Ideally, an approved assay (e.g. by the FDA in the US or possessing the Conformité Européenne Mark in Europe) using IHC, brightfield ISH, or FISH assay should be used. • If the HER2 test result is still equivocal, after reflex testing with an alternative assay, consideration should be given to the feasibility of testing a separate tumour specimen[46]. • Serum levels of soluble HER2 protein or tumour levels of HER2 mRNA should not be used for predicting the response to antiHER2 therapy. 8. HER2: recommendations for further research • Identify additional markers to increase the positive predictive value of HER2. This should focus on HER2-positive patients who do not benefit from trastuzumab or other forms of anti-HER2 therapy, as well as the identification of the small number of patients who derive long-term benefit from anti-HER2 therapy. • Identify biomarkers for selecting the most appropriate form of antiHER2 therapy for a given patient. • Markers should be identified for selecting patients likely to particularly benefit from dual anti-HER2 therapies such as combined trastuzumab and either pertuzumab or lapatinib in the neoadjuvant setting or combined trastuzumab and pertuzumab in the advanced disease setting. The preliminary results suggesting that high levels of HER2 as measured

by a quantitative HER2 assay (HERmark) predicts an enhanced response to dual anti-HER2 therapy[49] should be confirmed. • Establish whether patients with equivocal scores should or should not receive anti-HER2 therapy. This question might be addressed by evaluating the potential predictive value of other assays for HER2 such as the use of ELISA for HER2 protein or RT-PCR for HER2 mRNA. • Finally, the potential biomarker value of HER2 mutations[50] in predicting the response or resistance to specific anti-HER2 therapies should be explored, especially in patients with highgrade lobular cancer, where the frequency of HER2 mutations may reach 15–20%[51,52]. 9. Ki67 A multiplicity of studies, including retrospective evaluation of randomised clinical trials and meta-analyses, have shown that elevated levels of Ki67 are independently associated with adverse outcome in patients with breast cancer (for review, see refs. [53–55] ). In one of the largest studies, Petrelli et al.[54] performed a systematic review of the literature which was followed by a metaanalysis of the individual studies. In total, 41 studies encompassing 64,196 patients were identified. Although different cut-off points over the range 10 to >25% cell staining were investigated, the threshold displaying the strongest prognostic significance for overall survival was found to be >25% cell staining (hazard ratio, [HR] 2.05; 95% CI, 1.7–2.5; p < 0.00001). The consistent relationship between high Ki67 values and poor outcome in patients with breast cancer has been found despite the reported poor interlaboratory precision for the assays employed, use of different methods to measure Ki67 and use of different cut-off points for differentiating between tumours with low and high Ki67 concentrations[56,57]. According to Denkert et al.[58], imprecision is particularly found at borderline or intermediate concentrations of Ki67. Indeed, these investigators suggested that clinical decisionmaking should not be based on Ki67 levels in the borderline range. However, in contrast to the poor precision at intermediate levels, a multicentre study carried out by the International Ki67 Working group concluded that good interlaboratory agreement was achievable using centrally stained core needle biopsies when Ki67 scores were higher or lower than intermediate scores (i.e. <10% or >20% cell staining) [59].

In addition to undergoing evaluation for prognostic value, Ki67 has also been investigated for potential therapy predictive use, especially in the neoadjuvant and adjuvant settings. In the neoadjuvant setting, most but not all reports found a significant association between high Ki67 levels and response to chemotherapy as measured by clinical or pathological response[58]. In the adjuvant setting, however, the relationship between Ki67 levels and the benefit from chemotherapy is less clear[58]. With endocrine therapy in the neoadjuvant setting, a number of studies have found that treatment-induced alterations in Ki67, even after short-term therapy, predict response and patient outcome[59–62]. Little data is available on the chemo or endocrine predictive value of Ki67 in the metastatic setting. 10. Ki67: EGTM recommendation • Although methodological problems exist in the determination of Ki67, because of its clearly established clinical value, wide availability and low costs relative to the available multianalyte signatures, Ki67 may be used in combination with established prognostic factors for determining prognosis, especially if values are low (e.g. <10% cell staining) or high (e.g. >25% cell staining; LOE, IB; SOR, B for using high cut-off point). The higher cut-off value is based on the metaanalysis discussed above[54] which concluded that a threshold of >25% cell staining was associated with a greater risk of death compared with lower values. The lower cut-off point, however, is not evidence derived, but based on the expert opinion of the authors. Until a standardised assay becomes available, measurement of Ki67 should adhere to the previously published recommendations of the International Ki67 in Breast Cancer Working Group[56]. 11. Ki67: recommendations for further research • Improve interlaboratory variation with assay standardisation. • Establish an optimum cut-off point or evaluate the use of Ki67 as a continuous variable. • Establish if different cut-off points are necessary for prognosis and therapy prediction. • Evaluate the potential of automated image analysis for reducing between-assay variability. 12. Multigene/multiprotein test In the last decade, several multianalyte tests have been proposed for predicting outcome

in patients with newly diagnosed primary invasive breast cancer (Tables 1 and 2). Some general points that apply to all or most of these multianalyte tests include the following (for review, see refs.[63–65]): • All appear to provide prognostic information for relapse-free survival independent of the traditional prognostic factors such as tumour size, tumour grade and lymph node status. • The majority were discovered and validated in ER-positive, HER2-negative, lymph node– negative patients between 40 and 65 years of age. Oncotype DX, MammaPrint, EndoPredict and Prosigna (see below), however, were also found to be prognostic in lymph node–positive patients (1–3 metastatic nodes), see below. • Only urokinase plasminogen activator (uPA)/PAI-1[66,67], Oncotype DX[68,69] and MammaPrint[70] have to-date been evaluated for clinical value as part of a randomised prospective trial. Prosigna[71], EndoPredict (NCT01805271) and Genomic Grade Index, (NCT01916837) however, are currently undergoing evaluation in such trials. • Results from the prospective OPTIMA prelim trial[71] suggest that although the proportion of patients identified as being at low or high risk are largely similar irrespective of which test is used, major differences were found with respect to classification of individual patients. Thus, the proportion of patients classified as low/intermediate risk was 82.1% for Oncotype DX, 72.0% for IHC4, 65.6% for Prosigna and 61.4% for MammaPrint[71]. • Most were developed and validated in European and North American patient populations. • The most important genes in the multigene profiles for predicting patient outcome are those involved in cell proliferation. • None can currently be recommended for predicting the response to a specific form of chemotherapy. • Although relatively expensive to perform, use of some multigene signatures (uPA/PAI-1, Oncotype DX and MammaPrint) were shown to be cost-effective in lymph node–negative patients as they reduce the use of adjuvant chemotherapy[72–75]. • It is unclear whether the routine employment of multianalyte tests leads to a better outcome for patients. • Several multianalyte tests are commercially available. These

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16 Breast Cancer Table 3 Guidelines on the use of biomarkers in patients with invasive breast cancer. EGTM recommendations. BCI, Breast Cancer Index; LOE, (level of evidence) based on Ref. [ 6 ] [6] SOR (strength of recommendation) based on Ref. [ 7 ] [7] . Table 3 Guidelines on the use of biomarkers in patients with invasive breast cancer. EGTM recommendations. BCI, Breast Cancer Index; LOE, (level of evidence) based on Ref. [ 6 ] [6] SOR (strength of recommendation) based on Ref. [ 7 ] [7] . Biomarker




For predicting the response to endocrine therapy in patients with early or advanced breast cancer. Mandatory in all patients.



In combination with ER for predicting response to endocrine therapy in patients with early or advanced breast cancer.Mandatory in all patients. IB




For predicting response to anti-HER2 therapy in patients with early or advanced breast cancer. Mandatory in all patients.




In combination with established clinical and pathological factors for determining prognosis in patients with newly diagnosed invasive breast cancer, especially if values are low or high.




For determining prognosis and aiding decision-making for the administration of adjuvant chemotherapy to patients with ER-positive, HER2-negative, lymph node–negative disease.



Oncotype DX

For determining prognosis and aiding decision-making for the administration of adjuvant chemotherapy in patients with ER-positive HER2-negative lymph, node–negative and lymph node–positive (1–3 nodes) disease.




For determining prognosis and aiding decision-making for the administration of adjuvant chemotherapy to patients with ER-positive, HER2-negative, lymph node–negative and lymph node–positive (1–3 nodes) disease.




For determining prognosis and aiding decision-making for the administration of adjuvant chemotherapy to patients with ER-positive HER2-negative, lymph node–negative and lymph node–positive (1–3 nodes) disease.




For determining prognosis and aiding decision-making for the administration of adjuvant chemotherapy to patients with ER-positive HER2-negative lymph node–negative and lymph node–positive (1–3 nodes) disease.




For determining prognosis and aiding decision-making for the administration of adjuvant chemotherapy in patients with ER-positive, HER2-negative, lymph node–negative disease.



include uPA/PAI-1 (Femtelle), Oncotype DX, MammaPrint, Prosigna, EndoPredict, BCI and Genome Grade Index (MapQuant Dx). Some of the best validated signatures are discussed below. TABLE 1 13. Urokinase plasminogen activator and PAI-1 for determining prognosis and therapy response Although not widely used, uPA and its inhibitor, PAI-1 are presently amongst the best validated prognostic biomarkers for breast cancer. Consistent with their ability to promote cancer progression, several retrospective and prospective studies have shown that high concentrations of uPA and PAI-1 protein are independent and potent predictors of adverse prognosis in patients with newly diagnosed invasive breast cancer[76]. Uniquely for breast cancer prognostic biomarkers, the clinical value of uPA/PAI-1 for predicting outcome in lymph node–negative breast cancer has been validated in two independent level of evidence-I studies (LOE I), i.e. in both a randomised prospective clinical trial in which uPA/PAI-1 evaluation was the main aim of the trial[[66], [67]] and a large pooled analysis of individual patient-related data (n = 8377) from retrospective and prospective studies[77]. Both uPA and PAI-1 are thus amongst the best validated prognostic biomarkers currently available for lymph node–negative breast cancer. As well as being prognostic, high levels of uPA and PAI-1 were also shown to be associated with benefit from adjuvant chemotherapy in patients with early breast cancer [[66], [67], [78], [79], [80], [81]] . Furthermore, in

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addition to their extensive clinical validation, uPA/PAI-1 measurement by ELISA has undergone detailed analytical validation[[82], [83]].

Diagnostica/Sekisui) using extracts of fresh or freshly frozen breast tumour tissue, either from biopsy or surgical specimen.

Currently, uPA and PAI-1 are undergoing further investigation in two randomised prospective trials, i.e. in the NNBC-3 and WSG-Plan B trials[[84], [85]]. The NNBC-3 trial compares 5-FU, epirubicin and cyclophosphamide followed by docetaxel with 5-FU, epirubicin and cyclophosphamide as adjuvant therapy for high-risk lymph node–negative patients (NCT01222052)[84]. In this trial, the risk of recurrence was determined by clinicopathological criteria or by a combination of uPA/PAI-1 levels and clinicopathological factors. In contrast to the NNBC-3 trial, the WSG-Plan B trial is comparing an anthracycline and taxanebased adjuvant chemotherapy combination with an anthracyclinefree taxane-based regimen in patients with HER2-negative breast cancer patients that are either high-risk node negative or node positive (NCT01049425)[85]. This trial also aims to compare the prognostic and predictive value of uPA/PAI-1 with that of Oncotype DX.

• Currently, IHC or PCR should not be used when measuring uPA or PAI-1 for clinical purposes.

14. uPA and PAI-1: EGTM recommendation • Levels of PA and PAI-1 protein levels may be combined with established factors for assessing prognosis and identifying ERpositive, HER2-negative and lymph node–negative breast cancer patients that are unlikely to benefit from adjuvant chemotherapy (LOE, IA; SOR, A). • For clinical use, uPA and PAI-1 should be measured by a validated ELISA (e.g. FEMTELLE, American

15. uPA and PAI-1: recommendation for further research • Future research should aim to establish, validate and standardise a method for measuring uPA and PAI-1 by IHC or other techniques using formalin-fixed and paraffinembedded tumour tissue. 16. Oncotype DX for determining prognosis and therapy response The Oncotype DX test (Genomic Health Inc, Redwood City, CA, USA) involves measurement of the expression of 16 prognostic/ predictive and five reference genes at the mRNA level by reverse transcriptase PCR in formalinfixed and paraffin-embedded breast tumour tissue [86]. Based on the relative expression levels of these 16 genes to the average expression level of the five control genes, a recurrence score (RS) was developed that predicts the risk of distant disease recurrence at 10 years for lymph node–negative, ER-positive breast cancer patients, receiving adjuvant tamoxifen. The RS which ranges continuously from 0 to 100, was used to stratify newly diagnosed patients with invasive breast cancer into three different risk outcome groups, i.e. low risk of recurrence (RS, <18; 51% of patients), intermediate risk of recurrence (RS, 18–31; 22% of patients) and high risk of recurrence (RS, >31; 27% of patients)[86]. Outcome analysis showed that the formation of

distant metastases at 10 years follow-up was 6.8% in the low-risk group, 14.3% in the intermediate-risk group and 31% in the high-risk group. Recently, the prognostic value of a low Oncotype DX RS was evaluated in a prospective study carried out as part of TAILORx trial (NCI-2009-00707)[68]. In this trial, women with lymph node–negative, hormone receptor–positive and HER-negative disease with an RS of ≤10 received endocrine therapy alone, those with a RS > 25 were treated with both endocrine therapy and chemotherapy, whereas those with an intermediate score (i.e. 11–25) were randomised to receive endocrine therapy with or without chemotherapy. Of the 10,253 eligible patients in the trial, 1626 (16%) exhibited an RS of <11. After a follow-up period of 5 years for this low-risk group, 93.8% were found to be free of invasive disease and 99.3% were free from recurrence at a distant site, while the overall survival was 98.0%. In another further prospective trial (WSG Plan B) which enrolled 3198 HER2-negative patients with node-positive or high-risk lymph node–negative disease (T2, grade2/3, high uPA/PAI-1 or age < 35 years), the 3-year diseasefree survival for patients with low RS (≤ 11) was found to be 98% [69]. This excellent outcome was achieved despite these high-risk patients not receiving adjuvant chemotherapy. Follow-up in this trial, however, was relatively short, the median being only 35 months. Find the full version with references at

Lung Cancer 17

Diagnosis, staging and treatment of patients with lung cancer The Guideline Development Group (GDG) was chaired by Dr Marcus Kennedy, Respiratory Physician, Cork University Hospital

Cancer is a major healthcare challenge. Each year in Ireland, approximately 20,804 people are diagnosed with invasive cancer. Cancer is the second leading cause of death in Ireland after diseases of the circulatory system.

the National Cancer Control Programme was set up to implement its recommendations. These eight regional cancer centres were designated to support implementation.

Deaths from cancer averaged about 8,655 deaths per year during 2011-2013, representing about 30% of all deaths in that period (NCRI, 2016a).


In Ireland, here are eight hospitals designated as cancer centres and one satellite breast unit (Letterkenny General Hospital). A cancer centre is characterised by the geographic concentration of all oncology disciplines with sub-specialised expertise on a tumour specific/ discipline basis to provide the critical mass and support to achieve best practice in cancer care. As well as these designated cancer centres, other hospitals provide cancer services such as chemotherapy. Cancer incidence data from the National Cancer Registry Ireland (NCRI) and population projections from the Central Statistics Office (CSO) have been combined by the NCRI to estimate the number of new cancer cases expected in five year bands from 2015 to 2040. The total number of new invasive cancer cases (including non-melanoma skin cancer) is projected to increase by 84% for females and 107% for males between 2010 and 2040, based only on changes in population size and age distribution (demography). If trends in incidence since 1994 are also taken into account, the number of cases is expected to increase by between 86% and 125% for females (depending on the method of projection used) and by between 126% and 133% for males (NCRI, 2014b). Following the publication of the 2006 National Cancer Strategy,

EPIDEMIOLOGY The biggest risk factor in the development of lung cancer is smoking. In Ireland, it is estimated that 5200 people die annually from smoking related diseases. The overall prevalence of cigarette smoking in Ireland in 2014 was 19.5%, compared to 21.5% for 2013. This equates to over 70,000 fewer smokers in 2014 compared to 2013 (Smoking in Ireland 2014: Synopsis of Key Patterns). Incidence The National Cancer Registry Ireland (NCRI), reported that on average approximately 37,500 neoplasms were registered annually in Ireland between 2012-2014 (NCRI, 2016). The annual average incidence of lung cancer in Ireland was 2,381 (C33-34 bronchus, lung and trachea) per annum (20122014) (NCRI, 2016) (Table 1). Lung cancer overtook colorectal cancer as the 2nd most common cancer diagnosed in females (average counts 2011-2013) for the first time in 2015 (NCRI, 2015). Lung cancer was the leading cause of cancer death in both sexes, comprising 18% of cancer deaths in women and 24% of cancer deaths in men during the period 2011-2013 (NCRI, 2016). Table 1. Annual average incidence of lung cancer in Ireland. (NCRI, 2016) Lung Cancer Cases (20122014) Lung cancer (C33-34) Females






According to the NCRI (2016) there was little change observed in the relative frequency or ranks of the common cancer types from the last annual report NCRI (2015). Figure 2 shows the relative frequencies of the most common invasive cancers diagnosed in females in Ireland from 2009-2013, including nonmelanoma skin cancer. Lung cancer made up 7.5% of all female cancers (NCRI, 2015). According to the NCRI (2016) there was little change observed in the relative frequency or ranks of the common cancer types from the last annual report NCRI (2015). Figure 3 shows the relative frequencies reported in 2015, of the most common invasive cancers diagnosed in males in Ireland from 2009-2013, including non-melanoma skin cancer. Lung cancer made up 8% of all male cancers. Mortality Table 2 shows the mortality rate from lung cancer in Ireland, 2011-2013. The number of deaths from lung cancer was 749 females and 1,079 males. (NCRI, 2016) Lung Death Female/Male 749/1,079 Rate/100,000 Female/Male


Survival A total of 1,389 patients diagnosed with lung cancer during 2013 were still alive at the end of that year (one-year prevalence). This suggests that 59% of all patients diagnosed with lung cancer were likely to be still undergoing or just completing first-course treatment at that point. Threeyear prevalence for lung cancer indicated that 2,592 patients were alive and likely to be still undergoing treatment or active clinical surveillance at the end of 2013. Lung cancer has very high mortality and, of the >37,000 cases diagnosed during 1994-

2013, only 12% were alive at the close of 2013 (NCRI, 2015). Cancer projections 2015-2040 Lung cancer case numbers increased significantly for females from 1994 to 2010, by 3.9% annually. For males the numbers increased by 0.7% annually from 1994 to 2005 and by 3.3% thereafter. Incidence rates of lung cancer increased by 2.3% annually in females and decreased by 0.7% annually in males (NCRI, 2014). Cancer of the lung is projected to increase by 95%-196% in females and by 72%-121% in males. Clinical and financial impact of lung cancer The diagnosis, staging, and treatment of patients with lung cancer requires multidisciplinary care in an acute hospital setting. The majority of patients will require diagnostic tests (radiology, pathology) and depending on the treatment plan may require surgery, radiotherapy and chemotherapy. A population-based cost analysis (Luengo-Fernandez et al., 2013) illustrated the economic burden of cancer on the European Union (EU). In 2009, cancer is estimated to have cost the EU ¤126 billion, with healthcare costs accounting for ¤51 billion (40%). They found that lung cancer had the highest economic cost (¤18.8 billion, 15% of overall cancer costs), followed by breast cancer (¤15.0 billion, 12%), colorectal cancer (¤13.1 billion, 10%), and prostate cancer (¤8.43 billion, 7%). Inpatient care was the major component of health-care costs in lung cancer (¤2.87 billion, 68%). The highest productivity losses attributable to mortality were identified for lung cancer (¤9.92 billion; 23% of the ¤42.6 billion in productivity losses because of all cancers). The costs of informal care were also highest for patients with lung cancer (¤3.82 billion; 16%

HPN • Issue 41

ypes from the last annual report NCRI (2015). Figure 4 shows the relative common invasive cancers diagnosed in females in Ireland from 2009noma18 skin Lung cancer.Cancer Lung cancer made up 7.5% of all female cancers Figure 4. Shows the relative frequencies of the most common invasive cancers diagnosed in females in Ireland, 2011-2013. (NCRI, 2015)

of the hemithorax) alone (considered reachable by standard bronchoscopy) who are otherwise fit should undergo flexible bronchoscopy in order to establish a histological or cytological diagnosis. (Grade B) Visible tumours should be sampled using more than one technique to optimise sensitivity. (Grade B) Consider bronchoscopy to provide a diagnosis for peripheral lesions, although percutaneous FNA biopsy has a higher diagnostic yield. (Grade B) Endoscopic assessment of the mediastinal lymph nodes with EBUS-TBNA with or without EUS-FNA should be offered to patients with suspected lung cancer prior to mediastinoscopy. (Grade A)

frequencies of the most common invasive cancers diagnosed in femalesIninpatients being considered for 15) active therapy, pleural effusion of the ¤23.2 billion total informal care provided). With lung cancer incidence expected to increase by 136% in females (Nordpred model) and 52% in males (NCRI, 2014b), there could be a significant increase seen in healthcare costs per person in Ireland. SUMMARY OF RECOMMENDATIONS Radiology Contrast enhanced CT scanning of the chest and upper abdomen to include the entire liver is recommended in all patients with suspected lung cancer, regardless of chest X-ray results. (Grade B) A tissue diagnosis of lung cancer should not be inferred from CT appearances alone. (Grade D) PET-CT is recommended for mediastinal and hilar lymph node staging in patients with potentially radically treatable non small cell lung cancer (NSCLC) prior to invasive staging. (Grade C) In patients with PET activity in a mediastinal lymph node and normal appearing nodes by CT (and no distant metastases), sampling of the mediastinum is recommended over staging by imaging alone. (Grade C) Percutaneous FNA, TTNB and core biopsy, FNA, guided bronchoscopy and VATS are all

Issue 41 â&#x20AC;˘ HPN

appropriate first line modalities for tissue diagnosis of peripheral lung nodules. (Grade C)

While percutaneous TTNA/biopsy has a higher diagnostic yield, bronchoscopy (including guided approaches where available) may provide a diagnosis for peripheral lesions. (Grade B) In patients with clinical stage 1A who are high risk surgical candidates, ablative techniques may be considered to achieve local control. (Grade D) Consider close follow up for patients who have undergone treatment with curative intent (including surgery and radiotherapy), to include periodic radiological evaluation with CT. (Grade C) A negative PET-CT reliably excludes adrenal metastases in patients with NSCLC. (Grade B) In NSCLC patients with with PET-CT positive for adrenal metastasis, histological confirmation should be considered unless there is overwhelming clinical and imaging evidence of widespread metastatic disease. (Grade B) In NSCLC patients with indeterminate adrenal lesions on PET-CT further assessment with adrenal specific CT or MRI criteria may be considered. If

non-invasive imaging findings are indeterminate, adrenal sampling such as EUS-FNA, percutaneous biopsy or adrenalectomy may be considered. (Grade D) Offer patients with signs/ symptoms suggestive of brain metastases contrast-enhanced CT of the head followed by contrast-enhanced MRI if normal or MRI as an initial test. (Grade B) Offer MRI or CT of the head in patients selected for treatment with curative intent in patients with stage III NSCLC. (Grade C) Do not routinely offer imaging of the brain in patients with stage I and II NSCLC. (Grade C) For patients with NSCLC with suspected bone metastasis evaluation with PET-CT is recommended over bone scintigraphy or CT. (Grade B) Bone scintigraphy is not necessary when PET-CT has not shown bone metastases. (Grade B) In patients with clinically limited-stage SCLC, PET-CT is suggested to exclude occult metastases. (Grade C) Respiratory Medicine Patients with central lesions (within proximal one-third

should be investigated with pleural aspiration. (Grade C)

If pleural fluid cytology is negative, and treatment will change depending on the nature of the pleural fluid, pleural biopsy using image guided or thoracoscopic biopsy is recommended. (Grade D)


In lung cancer patients with symptomatic (including breathlessness, haemoptysis and cough) malignant airway obstruction, any of the following therapeutic interventions may be considered: bronchoscopic debulking, tumour ablation modalities, airway stent placement and radiotherapy (external beam or brachytherapy). (Grade D) Pathology Distinguishing between small cell carcinoma and non-small cell carcinoma of the lung is recommended. For challenging cases, a diagnostic panel of immunohistochemical assays is recommended to increase the diagnostic accuracy. (Grade B) In individuals with pathologically diagnosed NSCLC, additional discrimination between adenocarcinoma and squamous cell carcinoma, even on cytologic material or small tissue samples is recommended. (Grade B)

Prescribing Information (Ireland) ▼Vargatef® (nintedanib) 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. Uncommon (≥ 1/1,000 < 1/100): Perforation, pancreatitis. 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 Crescent Building, Northwood, Santry, Dublin 9. Prepared in March 2017

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 or by email to Adverse events should also be reported to Boehringer Ingelheim Pharmacovigilance on 01 291 3960 or by email to

Reference: 1. VARGATEF® 100/150 mg Summary of Product Characteristics. Available at: Date accessed: July 2017. IRE/ONC-171020j | Date of preparation: July 2017

20 Lung Cancer EBUS ROSE should be made available whenever resources permit. (Grade B) Consider intra–operative frozen section analysis in primary diagnosis when pre operative diagnosis is not available. (Grade C) In selected cases intra-operative frozen section analysis for staging may be considered. (Grade C) Cytology samples can be used to provide material suitable for both NSCLC sub-typing and some molecular analysis, provided the samples are appropriately handled and processed. (Grade B) Fixation times of 6 to 12 hours for small biopsy samples and 8 to 18 hours for larger surgical specimens generally give best results, although expert consensus opinion is that fixation times of 6 to 48 hours should give acceptable results. (Grade D) Surgery

Pulmonary function testing (spirometry, diffusion capacity, lung volume) should be performed in all patients being considered for surgical resection. (Grade C)

start with pre-operative scoring (thoracoscore) and should ideally include attendance at a preoperative assessment clinic, where practical. (Grade D)

Postoperative predictive values should be calculated using broncho-pulmonary segment counting. If a mismatch is suspected ventilation perfusion scan should be performed. (Grade C)

Seek a cardiology review in patients with an active cardiac condition or ≥3 risk factors or poor cardiac functional capacity. (Grade C)

Offer patients surgery if they have an FEV1 & DLCO within normal limits (post-op predicted values >60%). (Grade C) Patients with ppoFEV1 and/or DLCO <30% should have formal cardiopulmonary exercise testing with measurement of VO2 max. (Grade C) Patients with ppoFEV1 and/ or DLCO >30 and <60% – supplementary functional exercise assessments should be considered. (Grade D)

Offer surgery without further investigations to patients with ≤2 risk factors and good cardiac functional capacity. (Grade B) Age >80 years should not automatically preclude surgery. Decisions should be based on oncological stage, co-morbidity and physiological testing. (Grade D) Multifocal In patients with suspected or proven multifocal lung cancer (without mediastinal or extrapulmonary disease), curative-intent treatment may be considered, following discussion at MDT. (Grade D)

lung cancer resection. (Grade B) In patients with malignant pleural effusion whose symmptoms improved following drainage, a number of options are available depending on performance status and documentation of lung re-expansion: - In patients with good perfomrance status withlung re-expansion, thoracoscopy with talc pleurodeis is recommended. (Grade C) - In patients with nonexpandable lung, tunneled catheters may be considered. (Grade C) - In patients with poor performance status with lung re-expansion, options include: tunnelled plerual catheter, serial thoracentesis, or beside talc pleurodesis. (Grade D) In patients with an isolated brain metastasis and a synchronous resectable primary NSCLC, sequential resection of the primary tumour and definitive treatment of the brain metastasis may be considered, following discussion at an MDT. (Grade C)

In patients with lung cancer being considered for surgery and a VO2 max <15mL/kg/min Synchronous predicted it is recommended that they are counselled about In patients with suspected or minimally invasive surgery, proven synchronous primary In patients with an isolated sublobar resections or nonlung cancer (without mediastinal adrenal metastasis and a operative treatment options for or extrapulmonary disease), synchronous resectable primary For patients with clinical stage their lung cancer. curative-intent treatment may berelative NSCLC,frequency sequential resection According to the NCRI (2016) there was little change observed in the or ranks I non small cell lung cancer (Grade C) considered, following discussion of the primary tumour and (NSCLC), video-assisted thoracic of the common cancer types from the last annual atreport NCRI (2015). Figure 5 shows the relative definitive treatment of the adrenal MDT. Lung cancer surgery remains the surgery (thoracoscopy) should metastasis may be considered, (Grade C) requencies reported in 2015, ofopportunity the most common invasive cancers diagnosed in males Ireland best for potential be considered as an alternative following discussion at an in MDT. cure in patients with significant Systematic mediastinal lymph to thoracotomy for anatomic (Grade C) rom 2009-2013, including non-melanoma cancer. Lung cancer co-morbidity. Efforts toskin contain node dissection should be made up 8% of all male pulmonary resection. Consider surgery as part of performed in all patients having a and manage that risk should (Grade B) cancers. multimodality management in patients with T1– 3 N2 (nonfixed, non-bulky, single zone) M0 disease. (Grade C) For patients with clinical stage I and II NSCLC who are medically fit for surgical resection, a lobectomy rather than sublobar resection is recommended. (Grade B)

Patients with clinical stage I SCLC and excellent performance status may be considered for resection following extensive staging investigation as part of a multimodality treatment regimen. (Grade C) Medical Oncology Preoperative chemoradiotherapy

Figure 5. Shows the relative frequencies of the most common invasive cancers diagnosed in males in Ireland, 2011-2013 (NCRI, 2015)

For patients with non small cell lung cancer (NSCLC) who are suitable for surgery, do not offer neo-adjuvant chemoradiotherapy outside a clinical trial. (Grade B) Preoperative chemotherapy Following discussion at an MDT, appropriate patients with NSCLC

igure 5. Shows the relative frequencies of the most common invasive cancers diagnosed in males in Issue 41 • HPN eland, 2011-2013 (NCRI, 2015)

1st-line XALKORI



can maximise your patients’ treatment outcomes for the journey ahead in ALK+ and ROS1+ advanced NSCLC 1-7

XALKORI® is the ONLY ALK inhibitor approved, and guideline-recommended, as 1st-line standard of care, offering your patients the opportunity to benefit from treatment with next-generation ALK inhibitors after progression1–5,8–10 XALKORI® followed by next-generation ALK inhibitors has demonstrated a median OS of >4 years from diagnosis3,4 XALKORI® provides clinically meaningful benefits in advanced ROS1+ NSCLC, and is the 1st and only treatment indicated for these patients6,7 XALKORI® (crizotinib) PRESCRIBING INFORMATION. Please refer to the Summary of Product Characteristics (SmPC) before prescribing Xalkori 200 mg or 250 mg hard capsules. Presentation: Hard capsules containing 200 mg or 250 mg crizotinib. Indications: First-line treatment of adults with anaplastic lymphoma kinase (ALK) positive advanced non-small cell lung cancer (NSCLC), treatment of adults with previously treated ALK-positive advanced NSCLC and the treatment of adults with ROS1-positive advanced NSCLC. Dosage: Therapy should be initiated and supervised by a physician experienced in the administration of anti-cancer medicinal products. An accurate and validated assay for either ALK or ROS1 is necessary for the selection of patients for treatment with XALKORI. Either ALK-positive or ROS1-positive NSCLC status should be established prior to initiation of crizotinib therapy. Assessment should be performed by laboratories with demonstrated proficiency in the specific technology being utilised. The recommended dose of Xalkori is 250 mg taken orally (twice daily) with or without food, continuously. Dosing interruption and/or dose reduction may be required based on individual safety and tolerability. If dose reduction is necessary, then the dose of XALKORI should be reduced to 200 mg taken twice daily. If further dose reduction is necessary, then the dose should be modified to 250 mg taken once daily based on individual safety and tolerability. For dose reduction guidelines for haematologic and non-haematologic toxicities, refer to SmPC section 4.2. Treatment should be used with caution in patients with mild and moderate hepatic impairment and should not be used in patients with severe hepatic impairment. No starting dose adjustment is recommended for patients with mild (60 ≤ creatinine clearance [CLcr] <90 mL/min) or moderate (30≤ CLcr < 60mL/min) renal impairment, since the population pharmacokinetic analysis indicated no clinically meaningful changes in steady-state crizotinib exposure in these patients. Crizotinib plasma concentrations may be increased in patients with severe renal impairment (CLcr <30mL/min). The crizotinib dose should be adjusted to 250 mg taken orally once daily in patients with severe renal impairment not requiring peritoneal dialysis or hemodialysis. The dose may be increased to 200 mg twice daily based on individual safety and tolerability after at least 4 weeks of treatment, refer to SmPC section 4.2. The safety and efficacy of crizotinib in paediatric patients has not been established. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Severe hepatic impairment. Special warnings and precautions for use: Drug induced hepatotoxicity (including cases with fatal outcome) has been reported. Monitor liver function tests including ALT, AST, and total bilirubin once a week during the first 2 months of treatment then once a month, as clinically indicated with more frequent testing for Grades 2, 3 or 4 elevations. Severe, life-threatening, and/or fatal interstitial lung disease (ILD)/pneumonitis has been reported. Monitor patients for pulmonary symptoms indicative of ILD/pneumonitis. Withhold crizotinib treatment if ILD/pneumonitis is suspected. Drug-induced ILD/pneumonitis should be considered in the differential diagnosis of patients with ILD-like conditions such as: pneumonitis, radiation pneumonitis, hypersensitivity pneumonitis, interstitial pneumonitis, pulmonary fibrosis, acute respiratory distress syndrome (ARDS), alveolitis, lung infiltration, pneumonia, pulmonary edema, chronic obstructive pulmonary disease, pleural effusion, aspiration pneumonia, bronchitis, obliterative bronchiolitis, and bronchiectasis. Crizotinib should be permanently discontinued in patients diagnosed with treatment-related ILD/pneumonitis. QTc prolongation has been observed in clinical studies in patients treated with XALKORI which may lead to an increased risk for ventricular tachyarrhythmias (e.g., Torsade de Pointes) or sudden death. The benefits and potential risks of crizotinib should be considered before beginning therapy in patients with pre-existing bradycardia, who have a history of or predisposition for QTc prolongation, who are taking antiarrhythmics or other medicinal products that are known to prolong QT interval and in patients with relevant preexisting cardiac disease and/or electrolyte disturbances. Crizotinib should be administered with caution in these patients and periodic monitoring of electrocardiograms (ECG), electrolytes and renal function is required. When using crizotinib, ECG and electrolytes (e.g., calcium, magnesium, potassium) should be obtained as close as possible prior to the first dose and periodic monitoring with ECGs and electrolytes is recommended, especially at the beginning of treatment in case of vomiting, diarrhoea, dehydration or impaired renal function. Correct electrolytes as necessary. If QTc increases by greater than or equal to 60 msec from baseline but QTc is <500 msec, crizotinib should be withheld and cardiologist advice should be sought. If QTc increases to greater than or equal to 500 msec, cardiologist advice must be immediately sought. For patients who develop QTc prolongation, see SmPC sections 4.2, 4.8 and 5.2. All-causality bradycardia was reported in clinical studies in 13% of patients treated with crizotinib. Symptomatic bradycardia (e.g., syncope, dizziness, hypotension) can occur in patients receiving crizotinib. The full effect of crizotinib on reduction of heart rate may not develop until several

weeks after start of treatment. Avoid using crizotinib in combination with other bradycardic agents (e.g., beta-blockers, non-dihydropyridine calcium channel blockers such as verapamil and diltiazem, clonidine, digoxin) to the extent possible, due to the increased risk of symptomatic bradycardia. Monitor heart rate and blood pressure regularly. Dose modification is not required in cases of asymptomatic bradycardia. For management of patients who develop symptomatic bradycardia, see SmPC sections 4.2 and 4.8. In clinical studies with crizotinib and during post marketing surveillance, severe, lifethreatening, or fatal adverse reactions of cardiac failure were reported (see section 4.8). Patients with or without pre-existing cardiac disorders, receiving crizotinib, should be monitored for signs and symptoms of heart failure (dyspnoea, oedema, rapid weight gain from fluid retention, fatigue, arrhythmias). Dosing interruption, dose reduction, or discontinuation should be considered as appropriate if such symptoms are observed. In clinical studies with crizotinib in patients with either ALK-positive or ROS1-positive NSCLC Grade 3 or 4 neutropenia has been very commonly (12%) reported. Grade 3 or 4 leukopenia has been commonly (3%) reported. Less than 0.5% of patients experienced febrile neutropenia in clinical studies with crizotinib. Complete blood counts including differential white blood cell counts should be monitored as clinically indicated, with more frequent repeat testing if Grade 3 or 4 abnormalities are observed, or if fever or infection occurs. In clinical studies with crizotinib, events of gastrointestinal perforations were reported. There were reports of fatal cases of gastrointestinal perforation during post-marketing use of crizotinib (see SmPC section 4.8). Crizotinib should be used with caution in patients at risk for gastrointestinal perforation (e.g., history of diverticulitis, metastases to the gastrointestinal tract, concomitant use of medications with a recognized risk of gastrointestinal perforation). Crizotinib should be discontinued in patients who develop gastrointestinal perforation. Patients should be informed of the first signs of gastrointestinal perforations and be advised to consult rapidly in case of occurrence. Blood creatinine increase and creatinine clearance decreased were observed in patients in clinical studies with crizotinib. Renal failure and acute renal failure were reported in patients treated with crizotinib in clinical trials and during post marketing. Cases with fatal outcome, cases requiring hemodialysis and cases of grade 4 hyperkalemia were also observed. Monitoring of patients for renal function at baseline and during therapy with crizotinib is recommended, with particular attention to those who have risk factors or previous history of renal impairment (see SmPC section 4.8). In clinical studies with crizotinib, Grade 4 visual field defect with vision loss has been reported. Optic atrophy and optic nerve disorder have been reported as potential causes of vision loss. Ophthalmological evaluation is recommmended if vision disorder persists or worsens in severity. Concomitant use of crizotinib with strong CYP3A4 inhibitors or with strong and moderate CYP3A4 inducers and CYP3A4 substrates with narrow therapeutic indices should be avoided. Avoid using crizotinib in combination with other bradycardic agents, medicinal products that are known to prolong QT interval and/or antiarrhythmics. Drug interactions: In vitro studies indicated that crizotinib is an inhibitor of CYP2B6. Therefore, crizotinib may have the potential to increase plasma concentrations of coadministered drugs that are metabolised by CYP2B6 (e.g., bupropion, efavirenz). In vitro studies indicated that crizotinib may induce pregnane X receptor (PXR)- and constitutive androstane receptor (CAR)-regulated enzymes (e.g. CYP3A4, CYP2B6, CYP2C8, CYP2C9, UGT1A1, However, there was no observed induction in vivo when crizotinib was coadministered with the CYP3A probe substrate midazolam. Caution should be exercised in administering crizotinib in combination with medicinal products that are predominantly metabolised by these enzymes. Of note, the effectiveness of concomitant administration of oral contraceptives may be reduced. In vitro studies indicated that crizotinib is a weak inhibitor of uridine diphosphate glucuronosyltransferase (UGT)1A1 and UGT2B7. Therefore, crizotinib may have the potential to increase plasma concentrations of coadministered drugs that are metabolised predominantly by UGT1A1(e.g. raltegravir, irinotecan) or UGT2B7 (e.g. morphine, naloxone). Based on an in vitro study, crizotinib is predicted to inhibit intestinal P-gp. Therefore, administration of crizotinib with medicinal products that are substrates of P-gp (e.g. digoxin, dabigatran, colchicines, pravastatin) may increase their therapeutic effect and adverse reactions. Crizotinib is an inhibitor of OCT1 and OCT2 in vitro. Therefore, crizotinib may have the potential to increase plasma concentrations of coadministered drugs that are substrates of OCT1 or OCT2 (metformin, procainamide). Prolonged QT interval has been observed with crizotinib. The concomitant use of crizotinib with medicinal products known to prolong QT interval or able to induce Torsades de pointes (e.g., class IA [quinidine, disopyramide] or class III [e.g., amiodarone, sotalol, dofetilide, ibutilide], methadone, cisapride, moxifloxacine, antipsychotics, etc.) should be carefully considered. A monitoring of the QT interval should be made in case of combinations of such medicinal products Use with caution due to the risk of excessive bradycardia when used in combination with other bradycardic agents (e.g. nondihydropyridine calcium channel blockers such as verapamil and diltiazem, betablockers, clonidine, guanfacine, digoxin, mefloquine, anticholinesterases, pilocarpine). Fertility, pregnancy and lactation: Not recommended in pregnancy or whilst breast-feeding. Adequate contraceptive methods should be used during therapy, and for at least 90 days after completing therapy.

Crizotinib may impair fertility and both men and women should seek advice for fertility preservation before treatment. Driving and operating machinery: Caution should be exercised when driving or operating machines as patients may experience symptomatic bradycardia (e.g., syncope, dizziness, hypotension), vision disorder, or fatigue while taking XALKORI. Undesirable effects: The most serious adverse reactions in patients with either ALK-positive or ROS1-positive advanced NSCLC are hepatotoxicity, ILD/pneumonitis, neutropenia and QT interval prolongation. Very common adverse events are neutropenia, anaemia, leukopenia, decreased appetite, neuropathy, dysgeusia, vision disorder, dizziness, bradycardia, diarrhoea, vomiting, nausea, constipation, abdominal pain, elevated transaminases, rash, oedema, fatigue. Commonly reported adverse events are hypophosphataemia, cardiac failure, electrocardiogram QT prolonged, syncope, interstitial lung disease, dyspepsia, oesophagitis, blood alkaline phosphatase increased, renal cyst, blood creatinine increased, blood testosterone decreased. Refer to SmPC for further information on side effects Legal Category: S1A. Marketing Authorisation Number: EU/1/12/793/001 - 200mg, 60 capsules; EU/1/12/793/003 250mg, 60 capsules. The Marketing Authorisation Holder: Pfizer Limited, Sandwich, Kent, CT13 9NJ, United Kingdom. For further information on this medicine please contact: Pfizer Medical Information on 1800 633 363 or at For queries regarding product availability please contact: Pfizer Healthcare Ireland, Pfizer Building 9, Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24 + 353 1 4676500. Last revised: 08/2016. Ref: XI 13_1 References: 1. Shaw AT, et al. Alectinib in ALK-positive, crizotinib-resistant, non-small-cell lung cancer: a single-group, multicentre, phase 2 trial. Lancet Oncol. 2016;17(2):234–42. 2. Kim DW, et al. Activity and safety of ceritinib in patients with ALK-rearranged non-small-cell lung cancer (ASCEND-1): updated results from the multicentre, open-label, phase 1 trial. Lancet Oncol. 2016;17(4):452–63. 3. Gainor JF, et al. Progression-free and overall survival in ALKpositive NSCLC patients treated with sequential crizotinib and ceritinib. Clin Cancer Res. 2015;21(12):2745-52.4. Watanabe S, et al. Progression-free and overall survival of patients with ALK rearrangement-positive non-small cell lung cancer treated sequentially with crizotinib and alectinib. Clin Lung Cancer. 2016. 5. Chiari R, et al. Clinical impact of sequential treatment with ALK-TKIs in patients with advanced ALK-positive non-small cell lung cancer: results of a multicenter analysis. Lung Cancer. 2015;90(2):255-60. 6. Shaw AT, et al. Crizotinib treatment of ROS1-positive advanced non-small cell lung cancer: results from the updated PROFILE 1001 analysis. Oral presentation at the European Society for Medical Oncology Congress, 7–11 October 2016, Copenhagen, Denmark. 7. Xalkori (crizotinib) Summary of Product Characteristics. 8. Solomon BJ, et al. First-line crizotinib versus chemotherapy in ALK-positive lung cancer. N Engl J Med. 2014;371(23):2167–2177. 9. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: non-small lung cancer - Version 2, 2017. 2016. 10. Novello S, et al. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology 2016: 27 (supplement 5):v1–v27. Date of preparation: March 2017. Job code: PP-XLK-IRL-0045. 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. Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 676 4971; Fax: +353 1 676 2517. Website:; e-mail:

22 Lung Cancer who are suitable for surgery can be considered for neoadjuvant chemotherapy. (Grade A) Concurrent chemoradiotherapy should be administered to patients with locally advanced NSCLC (suitable for radical radiotherapy) who have a good performance status (0-1). (Grade A) Induction or consolidation chemotherapy are not routinely recommended for patients receiving concurrent radical chemoradiation. (Grade B) Effectiveness of first-line cytotoxic chemotherapy In patients with a good performance status (PS) (i.e. Eastern Cooperative Oncology Group [ECOG] level 0 or 1) and stage IV NSCLC, a platinumbased chemotherapy regimen is recommended based on the survival advantage and improvement in quality of life (QOL) over best supportive care (BSC). (Grade A) In patients with stage IV NSCLC and a good performance status, two-drug combination chemotherapy is recommended. The addition of a third cytotoxic chemotherapeutic agent is not recommended because it provides no survival benefit and may be harmful. (Grade A) In patients receiving palliative chemotherapy for stage IV NSCLC, it is recommended that the choice of chemotherapy is guided by histological type of NSCLC. (Grade A) Effectiveness of first-line cytotoxic chemotherapy Bevacizumab plus platinumbased chemotherapy may be considered an option in carefully selected patients with advanced NSCLC. Risks and benefits should be discussed with patients before decision making. (Grade B)

Effectiveness of first-line targeted therapy Crizotinib should be considered as first line therapy in patients with ALK positive NSCLC tumours. (Grade B) In patients with stage IV non-squamous NSCLC who do not experience disease progression and have a preserved performance status after 4-6 cycles of platinumbased therapy, treatment with maintenance pemetrexed is suggested. (Grade B) In patients with stage IV NSCLC, switch maintenance therapy with chemotherapy agents other than pemetrexed has not demonstrated an improvement in overall survival and is not recommended. (Grade B) In patients with stage IV NSCLC who do not experience disease progression after 4-6 cycles of platinum-based double agent chemotherapy, there is insufficient evidence to recommend maintenance therapy with erlotinib. (Grade B) In elderly patients (age ≥70-79 years) with stage IV NSCLC who have good performance status and limited co-morbidities, treatment with a platinum doublet chemotherapy is recommended. (Grade B) In patients with stage IV NSCLC with a performance status of 2, single agent chemotherapy may be considered. Platinum doublet chemotherapy is suggested over single agent chemotherapy if the performance status of 2 is cancer related rather than comorbidity associated. (Grade B)

Effectiveness of first-line targeted therapy

Unfit patients of any age (performance status (3-4)) do not benefit from cytotoxic chemotherapy. However if patients harbor an EGFR or ALK mutation positive tumour, they may be considered for treatment with targeted therapies. (Grade C)

First line single agent EGFR tyrosine kinase inhibitors (TKI) should be offered to patients with sensitizing EGFR mutation positive NSCLC. Adding combination chemotherapy to TKI confers no benefit and should not be used. (Grade A)

Second line systemic anticancer therapy (SACT) with single agent drugs should be considered. The choice of agent to be used should be made on a case by case basis taking into account previous treatment, mutation status and comorbidities. (Grade B)

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In patients with either limited stage or extensive stage SCLC, platinum-based chemotherapy with either cisplatin or carboplatin plus etoposide is recommended. (Grade A) Non-platinum combinations can be considered in patients with limited stage and extensive stage SCLC (Grade A) There is no data to support maintenance therapy in limited stage or extensive stage SCLC. (Grade C) In patients with relapsed refractory SCLC, second line therapy should be considered. (Grade B) Re-initiation of the previously administered first-line chemotherapy regimen is recommended in patients who relapse >6 months from completion of initial chemotherapy. (Grade B) Single agent chemotherapy should be considered in patients with primary refractory SCLC to maintain or improve quality of life. (Grade B) Radiation Oncology Every patient with early stage disease (T1-T2 N0 M0) should be evaluated for fitness for surgery. If unfit for surgery, or surgery is declined, patients should be considered for radical treatment, preferably SBRT/SABR or radical radiotherapy. (Grade A) RFA can be considered for patients with clinical stage 1A tumours who are not suitable for surgery following discussion at a multidisciplinary team meeting. (Refer to Clinical question 2.2.3). (Grade D) In patients receiving combined chemoradiotherapy standard fractionation should be used to deliver a radical dose equivalant to 60 – 66 Gy. (Grade A) When a radical dose is considered 3D CRT is the minimum technique to be used. (Grade B) When available, CHART can be considered in patients with non operable stage I-III NSCLC not receiving chemotherapy. (Grade A) Perform three-dimensional treatment planning in patients

undergoing radical thoracic radiotherapy. 4DCT should be performed where available. (Grade B) The dose volume parameters for the organs at risk (e.g. oesophagus, lung) need to be taken into account. It is prudent to limit V20 to ≤30–35 % and mean lung dose to ≤20–23 Gy (with conventional fractionation) if one wants to limit the risk of radiation pneumonitis to ≤20% in definitively treated patients with non–small-cell lung cancer. (Grade B) In patients with R1 resection, regardless of N status, postoperative radiotherapy (PORT) should be proposed sequentially delivering a radical dose of 60 Gy in 30 fractions. (Grade B) In patients with a pN2 stage and a complete resection there is no consensus to the benefit of PORT. If considered, PORT should be delivered at a dose of 50 Gy standard fractionation. (Grade B) PORT is not indicated in patients with a complete resection R0 and N0 disease. (Grade B) Consolidation prophylactic cranial irradiation (PCI) is recommended in patients with limited-stage SCLC having a response to chemoradiotherapy. (Grade A) In combined modality care, thoracic RT is recommended in patients with limited-stage SCLC and should be initiated as early as possible. (Grade A) Consolidation PCI is recommended in patients with extensive stage SCLC having a response to chemotherapy. (Grade A) Consolidation thoracic RT may be considered in patients with extensive stage SCLC having a response to chemotherapy. (Grade A) Palliative Care Patients with stage IV NSCLC should be offered concurrent specialist palliative care and standard oncological care at initial diagnosis. (Grade B) This National Clinical Guideline is supported by the National Cancer Control Programme. Find the full version with references at

National Cancer Strategy 23

Cancer Strategy labelled a 'Game Changer' Ireland’s new National Cancer Strategy 2017-2026 has been labelled a ‘potential game changer’ by Professor Bryan Hennessy, Clinical Lead, Cancer Trials Ireland, and Consultant Oncologist, Beaumont Hospital.

Professor Bryan Hennessey, Clinical Lead, Cancer Trials Ireland, and Consultant Oncologist, Beaumont Hospital

“Implementation of the strategy could take us significantly closer to finding successful treatments for all types of cancer,” he said. “It acknowledges that cancer trials should be a core activity of cancer centres and recommends that they should be fully integrated into cancer care delivery. These actions will take cancer research to a new level. Cancer trials will not be outliers on the periphery, but central to the treatment options available to people with cancer.” The first Cancer Strategy, entitled Cancer Services in Ireland: A National Strategy, was published in 1996. Under the leadership of the late Professor James Fennelly, the Cancer Strategy Group identified the inferior Irish mortality figures for cancer compared to the European average and proposed a series of measures to reduce the death rate from cancer in the under 65 age group by 15% in the ten year period to 2005. The extensive appointment of a broad range of cancer specialists, and the reorganisation of services, under the Strategy resulted in this goal being achieved well before the target date. The implementation of the recommendations in the Hollywood report, published in 2003, also had a hugely significant impact on the delivery of radiation therapy in Ireland.

Breathtaking advances in basic and translational science have resulted in a proliferation of novel diagnostics and therapeutics and this trend will continue. Such advances present great opportunities, but their integration into cancer care will present organisational and financial challenges. At the same time, our population is aging rapidly, driving a relentless increase in cancer incidence, and challenging clinicians to treat patients who have complex medical needs.”

rate, a measure of the risk of developing cancer at any given age, has been increasing by only about 1% a year. Trends in death rates have been downwards over the same period (by 1.5% per year in men and 1.1% per year in women on average). There are a number of reasons why cancer incidence rates have been increasing slightly,including increases in risk factors such as obesity, alcohol consumption and sun exposure and the impact of screening.

Here we summarise the key points from the Strategy:

Much of the increase in the number of cancer cases and deaths is attributable to the growth in the population over

Cancer is a major cause of mortality in Ireland. Cancer and cardiovascular disease were each responsible for about one third of all deaths in 20134. In the population under 65, cancer was the cause of half of all deaths in women, and the cause of over one-third of all deaths in men. The percentage of deaths attributable to cancer has risen from 20% in the 1980s to over 30% at present.

“We are now faced with a different set of opportunities and challenges,” says Professor John Kennedy, Chairman of the Steering Group.

Four cancer types make up more than half of all newly diagnosed cancers (excluding non-melanoma skin cancer) - breast, colorectal, lung, and melanoma in women (56%), and prostate, colorectal, lung and melanoma in men (57%) (Figure2.1).

“Improving therapies have gratifyingly resulted in a greatly increased number of people who have survived cancer.

The number of cancer cases has been increasing by about 3% a year since 1994, but the age-standardised incidence

65 years of age; 62% of male patients with cancer and 53% of female patients during 19942014 were aged over 65. The population over 65 years is estimated to more than double, from 536,000 to 1,146,000, in the 25 years from 2011 to 20368. This ageing of the population will drive a large increase in the number of new cancer cases over the next few decades. Reducing the Cancer Burden Cancer prevention will be a cornerstone of this Cancer Strategy as it offers the most cost-effective, long term approach for cancer control. The proportion of cancer incidence attributable to modifiable lifestyle and environmental factors is

estimated to be in the 30% to 40% range. Of these risk factors, smoking has by far the biggest impact and, in implementing this Strategy, the committee will work towards the goal of making Ireland tobaccofree by 2025. ‘We also need to increase our efforts to reduce the number of avoidable cancers through the promotion of healthy lifestyles, in areas such as improved diet, more exercise and reduced alcohol intake. Prevention measures will be integrated with the overall health and wellbeing initiatives under the Healthy Ireland programme,’ says the Strategy report. Reducing health inequalities is a priority of this Strategy, as lifestyle risk factors generally follow social, deprivation, gender and age patterns. Health inequalities are also associated with poor symptom awareness, delayed presentation and low uptake of services, including screening. Detecting and diagnosing cancer early is a critical step in reducing mortality as a result of cancer. Efforts will continue to ensure that people take up the offer of cancer screening when invited through the BreastCheck, CervicalCheck and BowelScreen programmes. Broadened aged-based cohorts are envisaged for both BreastCheck and BowelScreen. Further improvements in overall survival rates will require HPN • Issue 41

24 National Cancer Strategy Professor John Kennedy, Chairman, Cancer Strategy Group Steering Committee

an emphasis on increasing the proportion of patients diagnosed at an earlier stage of their disease. Provision of Optimal Care A broad objective of the Strategy is to have models of care in place that ensure that patients receive the required care, in a timely fashion, from an expert clinical team in the optimal location. The concept of a continuum of care will underpin the approach to patient services, from prevention, early diagnosis and evidence-based, high quality patient-centred treatment, to appropriate follow-up and support. Much of our cancer treatment takes place in acute hospitals under the direction of specialist clinicians and multidisciplinary teams. This Strategy builds on progress made to date by supporting the key role of designated cancer centres in cancer treatment. Multidisciplinary team (MDT) working is a cornerstone of modern cancer care. MDT working has led to improved decision-making, more co-ordinated patient care and improvements in the overall quality of care. It is recommended that all patients diagnosed with cancer will have their case formally discussed at an MDT meeting. Current services are coming under pressure and patient numbers will continue to increase across the period of this Strategy. A rolling plan of capital investment will be required to ensure that highquality facilities are available for patients and staff, that our

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health personnel can progress in line with developments in cancer worldwide and that the potential for on-going improvements in outcomes is maximised. Advances in molecular technology have resulted in improved cancer diagnosis, the use of more targeted therapies and better monitoring of treatment outcomes. The role of inherited predisposition to cancer is also being increasingly defined through the use of genetic testing. Developments in genomics have impacts far wider than cancer, but are key to improving cancer outcomes. The challenge is to ensure that the potential benefits of molecular cancer diagnostics and cancer genetics/genomics will be realised for all patients across the ten year strategy period. Service improvements will be underpinned by evidence and best practice, and the centralisation of surgical services for more cancers will be progressed to ensure that optimal treatment is provided and outcomes are improved. Radiation oncology services will expand to meet demand. The growth in both the incidence of cancer, and the prevalence of patients on active treatment with new drugs, is giving rise to a significant increase in the volume and complexity of medical oncology and haematology work. As treatments become more complex, there will be a need for medical oncologists and haematologists to specialise in particular cancer sites and

treatment modalities. The total number of patients in receipt of Systemic Anti-Cancer Therapy (SACT) is expected to grow even faster than the number of new patients, as new drugs come on stream, as the duration of some treatments increases and as patients with advanced disease survive longer. In order to meet this rising demand, and to allow for a greater level of site specialisation, the number of medical oncologists and haematologists in Irish hospitals will need to be increased. New-to-market cancer therapeutics are exceedingly expensive. The NCCP, with the wider HSE and the Department of Health, work together in advancing the process of securing such drugs at affordable cost once the European Medicines Agency (EMA) has approved them for clinical use. The scale of the costs involved, set against expectations of the availability of the latest effective drugs, will pose an on-going management challenge during the period of the Strategy. Rare cancers, defined as those with an annual incidence of less than six cases per 100,000 comprise about 20% of all cancers, with approximately 5,200 new cases annually. There is a need for clear care pathways for the diagnosis and treatment of patients who have rare cancers, with particular emphasis on timely treatment planning at national MDT level, involving subspecialty expertise in diagnosis and treatment and with linkages to international centres of excellence for specialist advice and intervention.

Approximately 200 children and young adolescents (0-16 years of age) are diagnosed with cancer each year. All of these children are referred to the National Paediatric Haematology and Oncology Centre (NPHOC) to have their diagnosis established, treatment planned and followup mapped out. NPHOC also acts as an advisory and response service for 16 shared care centres throughout the country. The development of a new children’s hospital will provide the opportunity to establish an age-appropriate facility for adolescents and young adults with cancer. Services for this cohort, and transition arrangements to adult services, are a particular focus of this Strategy. A primary aim of all cancer services is the provision of safe, high quality and patientcentred care. This involves care that is safe, evidence-based, appropriate, timely, efficient, effective, equitable and personcentred. Safety is fundamental to quality healthcare and cancer services will be enabled to deliver safe care, while balancing competing pressures and demands. Meanwhile, the Irish Pharmaceutical Healthcare Authority (IPHA) has highlighted the fact that a timely reimbursement system must be in place if it is to deliver on its objectives. According to Oliver O’Connor, IPHA CEO, “Long term cancer survival rates are improving significantly, with deaths down by 21% since the 1990s. The use of innovative medicines are clearly playing a significant part in this. “IPHA enthusiastically shares the goal that we should aim to have Irish cancer survival rates among the best in Europe. To enable this to happen, the required medicines must be available to patients in the Irish health service among the fastest of European countries. This can be a shared endeavour between industry and Government,” he added.

HIV Care 25

The HIV Care Cascade P. McGettrick1,2, B. Ghavami-Kia1,2 , W. Tinago1, A. Macken1, J. O’Halloran1,2, J.S. Lambert1,2, G. Sheehan1,2, P.W.G. Mallon1,2 1 HIV Molecular Research Group, School of Medicine, University College Dublin, Dublin, Ireland, 2 Department of Infectious Diseases, Mater Misericordae University Hospital, Dublin, Ireland

With effective antiretroviral therapy (ART), people living with HIV (PLWH) who are engaged in care can expect to live longer and healthier lives than in the pre-ART era. In addition to personal health benefits from effective treatment regardless of CD4+ T-cell count.1, there is also a potential public health benefit, with those individuals on effective ART with suppressed plasma HIV RNA unlikely to contribute to onward sexual transmission of HIV.2–4 However, despite significant progress in our understanding of use of treatment as prevention, there remains a sustained global HIV epidemic, with numbers of new infections remaining static or increasing, even in resource-rich regions with full ART access.5,6 Building on the concept of treatment as prevention, the Joint United Nations Programme on HIV and AIDS (UNAIDS) in 2014 issued new targets for service providers to focus efforts in an attempt to bring the HIV epidemic under control. Commonly referred to as “90–90– 90,” these propose three targets: that 90% of the population living with HIV are aware of their diagnosis, that 90% of this diagnosed population are treated, and that 90% of those on ART are virally suppressed, with this strategy, if successfully implemented, expected to have a significant impact on the HIV epidemic by 2030.7 Against this backdrop, the HIV Care Cascade model, which examines population engagement with HIV care and treatment, is becoming increasingly utilized by HIV service providers to explore how closely individual clinic, country, or regional services align with the “90–90–90” targets. Although these models vary considerably

in their design and definitions, many present the cascade as five sequential steps, the first estimating of all PLWH in a given area, the second those diagnosed and linked to care, the third PLWH retained in care, the fourth those on ART, and the fifth those on ART with suppressed plasma HIV RNA. Previous models, particularly those from North America, have shown that although there are significant losses of subjects at each sequential step in the cascade, often the biggest loss occurs between the steps of those linked to and those retained in care, with one US study suggesting that approximately 50% of PLWH are not actively engaged in care despite 79% being aware of their diagnosis8; however, few have examined in detail the reasons for losses of subjects between steps in the cascade. Through the use of a HIV Care Cascade model, we explored how closely a service based within a European tertiary referral service aligned with the “90–90– 90” targets and aimed to elicit reasons underlying significant gaps or losses identified in the HIV Care Cascade model. Study design We conducted an analysis of data from the Mater Misericordiae University Hospital (MMUH) Infectious Diseases Cohort, a prospective cohort of subjects attending for ambulatory care at the MMUH, a tertiary teaching hospital located in Dublin’s north inner city which is one of the three specialist centers providing HIV services in Dublin, Ireland and one of the seven on the island of Ireland. All patients diagnosed with HIV linked to our clinic from its establishment in 1993 to the 1st December 2014 and attended on at least one occasion were included in

the analysis. Incarcerated individuals were included as prison authorities facilitate clinic attendances when possible to minimize disruption to HIV care. Data regarding ART dispensation were collected from the MMUH Infectious diseases pharmacy through which all ART was dispensed. Laboratory test results (CD4 count and HIV viral load) were collected from the electronic patient record and appointment records of those accessing clinic using private health insurance were obtained and recorded in the database. Ethics The local research ethics committee approved the study protocol and subjects enrolled in the cohort provided written, informed consent for use of their routine clinical data for research purposes. Analysis Categories within our HIV Care Cascade model were defined as follows: • “Linked to care” – a subject with a diagnosis of HIV with at least one attendance to the clinical service. • “Retained in care” (RIC) – those “linked to care” with two documented clinic attendances and/or laboratory tests (CD4+ T cell count and/or HIV viral load) at least three months apart within the 12 months preceding the analysis. • “On ART” – those retained in care with at least two ART dispensations at least three months apart within the preceding year. • “Virally suppressed” – defined as those on HAART with most recent HIV RNA readings less than 40 copies/ml in the preceding 12 months. • “Not Retained in Care” (NRIC) – those “linked to care” but

without a clinic visit or routine diagnostic test within the previous 12 months. An in-depth analysis of those NRIC was conducted examining age, ethnicity, and transmission risk. Attempts were made to contact these patients directly by telephone to assess current status and if not contactable, indirectly through local doctor and listed next of kin. The hospital electronic patient record was consulted in conjunction with the patient’s local doctor to determine those deceased and assess cause of death. Following this, their current status was classified as “emigrated,” “transfer-of-care,” “deceased,” “stopped attending but contactable,” and “lost to follow up” (LTFU), the latter being those who were un-contactable with no further information available from local doctor or next of kin. Data are presented as mean (standard deviation (SD)) or numbers (percentages (%)) as appropriate, with between group differences compared using χ2test for categorical variables and T-test for continuous variables. Results At the time of analysis, 1000 PLWH had been linked to care. Both genders were well represented (59.3% male) with the majority of subjects of either Caucasian (54.4%) or African (37.3%) origin and all three main transmission risk groups represented: heterosexual sex (50%), people who inject drugs (PWID, 22.2%), and men who have sex with men (MSM, 21.0%), respectively. Of the 1000 patients linked to care, 787 (78.7%) were classified as retained in care and 213 (21.3%) classified as not retained in care (NRIC). Compared to those retained in care, those NRIC were more

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26 HIV Care likely to be younger (38.3 (9.0) vs. 41.0 (9.5) years, p < 0.001) and of African origin (p = 0.045, see Table 1). However, there was no significant difference in transmission risk between those retained and not retained in care.

Table 1 Description of and comparisons within the HIV Care Cascade

Of the 787 retained in care, 720 (91.5%) were on ART of whom 644 (81.8%) were on ART with an undetectable HIV RNA (<40 copies/ml) (Figure 1). Those on ART who were virally suppressed were significantly older (mean (SD) age 42.0 (9.5) vs. 39.0 (8.7) years, p = 0.006) and were less likely to be PWID (80.6% PWID virally suppressed on ART vs. 92.0% non-PWID virally suppressed on ART; p < 0.001). There was no difference noted between other transmission risk groups or genders.

Gender (n (%))

A further analysis of those NRIC (n = 213) revealed that 56 (26.3%) emigrated, 27 (12.7%) transferred care to another institution, 15 (7.0%) stopped attending and had disengaged from HIV care, 38 (17.8%) had died, and 77 (36.1%) were LTFU. Of the 38 patients who had died, non-AIDS-related conditions accounted for 17 (44.7%) deaths, AIDS defining illnesses for 7 (18.4%) deaths, and unnatural death/misadventure the cause of death in a further 7 (18.4%) cases. The cause of death could not be ascertained during the analysis in seven cases due to incomplete data or death having occurred at another institution. Of the 15 who had stopped attending and disengaged from HIV care but were contactable, almost half (46,6%) were of African origin while 7 of the remaining 8 patients were PWID. Although prison authorities facilitate attendances to HIV clinic, two people cited imprisonment as a reason for disengagement. As a result of direct contact, 6 of the 15 in this group were successfully re-linked to care. Recalculating the cascade, excluding those who had died, emigrated, or transferred care, (total remaining population 879) the percentage of those linked to and who are retained in care rose to 89.5% (787/879) (Figure 2). Our HIV Care Cascade model demonstrates that once retained in care, treatment goals approaching the UNAIDS targets are possible with 91.5%

Issue 41 • HPN

Linked to care











Virally supressed




Age (mean (SD)) 41.0 (9.5) 38.3 (9.0) <0.001 37.6 (9.6) 0.003 42.0 (9.5) 0.006 Male 593 (59.3%) 466 (59.2%) 127 (59.6%) 45 (58.4%) 0.9 427 (59.3%) 390 (60.6%) Female 407 (40.7%) 321 (40.8%) 86 (40.4%) 32 (42.6) 293 (40.7%) 254 (49.4%) Transmission risk (n (%)) IVDU 222 (22.2%) 167 (21.2%) 55 (25.8%) 0.09 12 (15.6%) 0.4 155 (21.5%) 124 (19.3%) <0.001 MSM 210 (21.0%) 165 (21.0%) 45 (21.1%) 17 (22.1%) 146 (20.3%) 137 (21.3%) Heterosexual 501 (50.1%) 397 (50.4%) 104 (48.8%) 44 (57.1%) 367 (51.0%) 334 (51.9%) Unknown/other 67 (6.7%) 58 (7.3%) 9 (4.2%) 4 (5.2%) 52 (7.2%) 49 (7.7%) Ethnicity (n (%)) African 373 (37.2%) 281 (35.7%) 92 (43.2%) <0.001 43 (55.8%) 0.1 260 (36.1%) 235 (36.5%) 0.54 Caucasian 544 (54.4%) 448 (56.9%) 96 (45.1%) 21 (27.3%) 412 (57.2%) 368 (57.1%) South American 50 (5.0%) 29 (3.7%) 21 (9.9%) 10 (13.0%) 23 (3.2%) 19 (3.0%) Other/Unknown 33 (3.3%) 29 (3.7%) 4 (1.8%) 3 (3.9%) 25 (3.5%) 22(3.5%) Current status (n (%)) Emigrated 56(26.3%) Transferred care 27 (12.7%) Deceased 38 (17.8%) Stopped attending 15 (7.0%) LTFU 77 (36.1%)

Notes: ART; antiretroviral therapy. IVDU; intravenous drug user. LTFU; lost to follow-up. MSM; men who have sex with men. N; number. NRIC; not retained in care. RIC; retained in care. SD; standard deviation. *RIC vs. NRIC. **RIC vs. LTFU. ⇑virally suppressed (HIV RNA <40 cps/ml) vs. not virally suppressed.

on treatment and almost 90% of those on treatment virally suppressed, although, like other studies, we observed a significant drop in numbers between those linked to care and retained in care, a significant obstacle in achieving the second “90” goal of the UNAIDS 90–90–90 strategy. However, further analyses of this group demonstrated that the true numbers of patients lost to follow-up may be significantly lower than previously estimated from similar analyses, with only 10.5% subjects confirmed as truly lost to follow-up. As previous models have shown,

a substantial proportion of PLWH fail to remain engaged in care, with estimates of 45– 65% in US studies, with lack of engagement considered a significant barrier to the use of treatment- asprevention to control the HIV epidemic.8,9 The proportion of patients NRIC in our analysis (21.3%), although smaller than US studies, is broadly similar to previously reported Canadian models at approximately 20%10 and higher than those quoted for other high income European countries such as the UK and Denmark at 10.8 and 7.4%, respectively.11 However, our in-depth analysis of those “not

retained in care” in our cohort goes some way in explaining the difference between our cohort and those of neighbouring countries, with a much smaller number truly disengaged with care. Only 92 (9.2%) of the whole cohort intentionally disengaged from care or were truly lost to follow-up, the remainder having emigrated, transferred care, or died. Although there is no certainty that those who emigrated or transferred care to another institution actually remained in care once leaving our service, even if assuming that 9.2% of these individuals also









in treatment-naïve patients vs EFV/TDF/FTC, darunavir/r and atazanavir/r (in women)1-3

0 resistance to dolutegravir-based regimens in treatment-naïve trials to date1-5

with few clinically significant drug-drug interactions5

Build a regimen for your patients with DOLUTEGRAVIR AT THE CORE.

dolutegravir/abacavir/ lamivudine

Visit to learn more 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, adolescents and children aged 6 years and over, weighing at least 15 kg. Triumeq and Tivicay are contraindicated in patients with hypersensitivity to dolutegravir, abacavir or lamivudine or to any of the excipients, and with co-adminstration with Dofetilide5-6. 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



600 mg/lamivudine 300 mg tablets

See Summary of Product Characteristics before prescribing. Indication: HIV in over 12 years and ≥ 40 kg. 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. Monitor closely in mild hepatic impairment. 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, myalgia, 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: January 2017 Zinc code: UK/TRIM/0037/14(7)

Tivicay ® dolutegravir 10 mg, 25 mg and 50 mg tablets See Summary of Product Characteristics before prescribing Indication: HIV in >6 years and ≥15 kg as part of combination therapy. Dosing: Adults & adolescents ≥40 kg: 50 mg once daily with or without food if no proven/ suspected integrase resistance. Children 6 to <12 years: dose according to bodyweight: 15-<20 kg: 20 mg once daily (2x10 mg); 20-<30 kg: 25 mg once daily; 30-<40 kg: 35 mg once daily (1x25 mg+1x10 mg); When co-administered with efavirenz, nevirapine, tipranavir/ritonavir, etravirine (without boosted PI), carbamazepine, oxcarbazepine, phenytoin, phenobarbital, St John’s Wort or rifampicin, Tivicay 50 mg twice daily in adults/adolescents or the weight-based once daily dose twice daily in paediatric patients. Adults with proven/ suspected integrase resistance: 50 mg twice daily preferably with food. Limited data in paediatric patients with proven/suspected integrase resistance. 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 SmPC for full details. Headache, GI disturbance, insomnia, abnormal dreams, depression, dizziness, rash, pruritus, fatigue, elevations of ALT, AST and CPK, arthralgia, myalgia, hypersensitivity, suicidal ideation or suicide attempt. Basic NHS costs: £498.75 for 30 x 50 mg tablets EU/1/13/892/001. £99.75 for 30 x10 mg tablets (EU/1/13/892/003). £249.38 for 30x25 mg tablets (EU/1/13/892/005). 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: March 2017 Zinc code: UK/DLG/0055/13(10)

Adverse events should be reported. For the UK, reporting forms and information can be found at 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, Adverse events should also be reported to GlaxoSmithKline on 1800 244 255. References: 1. Walmsley S et al. J Acquir Immune Defi c 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:, accessed: March 2017. 6. TRIUMEQ (dolutegravir/abacavir/lamivudine) Summary of Product Characteristics. Available from:, accessed: March 2017.

TRIUMEQ and TIVICAY are registered trademarks of the ViiV Healthcare group of companies. ©2017 ViiV Healthcare group of companies. All rights reserved.

IE/DGR/0016/16(1) Date of preparation: March 2017

28 HIV Care Figure 2

disengaged from care, the overall rate of those not engaged in care would only rise to 9.96% of the total population linked to care, suggesting that there is not a large proportion of patients actively disengaging from care. Although national health care databases and registries have the ability to assess ongoing engagement with care in subjects transferring between health care institutions, this can be complex to accurately estimate and most will be unable to determine emigration status of specific individuals which may lead to overestimates of those truly not retained in care in some capacity (26.3% of those NRIC in our analysis). Excluding those who had died, transferred care, or emigrated, the proportion retained in care rises to 89.5% (787/879), with the proportion of those retained in care who are on ART at 81.9% (720/879), which, although less than the target set by the UNAIDS 90–90–90 goals, is likely underestimated as some will have been prescribed ART elsewhere. In addition, the numbers on ART will probably rise as more patients are commenced on ART with changes in treatment guidelines arising from results of recent trials suggesting a health benefit for ART at any CD4+ T-cell count.12 Interestingly, 6 of the 15 patients (40%) who had stopped

Issue 41 • HPN

attending HIV services reengaged with care as a direct result of being contacted for the purpose of the study. This unexpected benefit from performing our additional in-depth analysis suggests potential patient and public health benefits through regular monitoring of the HIV Care Cascade model, including direct contact with those who have stopped attending. Various initiatives to enhance engagement and retention, such as financial incentives, have had mixed results13 and the results from this analysis suggest that simpler approaches through directly engaging with those who stop attending may have significant benefits. However, these approaches would need to be validated in different health care settings. One of the most significant challenges in controlling the HIV epidemic, and one which we were unable to address in this study, is to both accurately assess and increase the proportion of PLWH who are aware of their diagnosis. It is currently estimated that 20–30% of PLWH in EU countries are unaware of their diagnosis and as such remain at risk of developing AIDSrelated conditions as well as contributing to onward HIV transmission, with those who have newly acquired HIV or in the advanced stages of infection through to disproportionately

contribute to onward HIV transmission.14–17 In Ireland, the number of new cases of HIV continues to rise with 491 new cases being diagnosed in 2015, representing a 30% year-on-year increase in new diagnosis18, a trend being replicated in many EU countries. Although such rises in newly diagnosed HIV may partly reflect increased testing and surveillance for HIV, combined with our analysis demonstrating targets of those retained in care on effective therapy being close to the UNAIDS 90–90–90 target, these data suggest that greater focus is required within European centers on increasing HIV testing and other prevention strategies if meaningful progress is to be made in controlling the HIV epidemic. Our study has limitations. In addition to lacking information on the true population prevalence of HIV infection, our single-site study may not reflect cascade of care models throughout Ireland, although there is a consistent, hospital-based approach to HIV management in Ireland that would support these data being broadly representative of the other six treatment centers. This cohort accounts for 13.6% of people diagnosed with HIV in Ireland since the early 1980s until the time of study,19 and its demographics are similar to that of the overall HIV cohort attending ambulatory care in

Ireland,20 which supports the view that, in the absence of national data, this study may be reflective of what is occurring on a national level . The use of laboratory tests as surrogate markers for retention in care has also been suggested to overestimate retention in the newly diagnosed HIV cohort. However, whether a similar over estimation occurs in a cohort of more established patients such as our own, who may not have as frequent laboratory tests as those newly diagnosed, is not clear.21 In addition, although we were able to establish estimates of those who had emigrated or transferred care, we were unable to accurately determine in all cases if those individuals were subsequently retained in care and can only assume similar rates of disengagement to those observed within our cohort. As the date at which disengagement occurred or after what time period in care was not recorded on an individual basis for those NRIC, the rate of loss to follow- up could not be determined. Despite these limitations, our approach of in-depth analysis of the HIV Care Cascade model provides useful insights, not only into HIV service provision, but also suggests areas where focus on public health activities may have a greater impact. Specifically, our data suggest that, as numbers NRIC may be significantly lower than previously estimated and with good proportions on successful treatment, the goals set by the UNAIDS 90–90–90 strategy, although not achieved to date, appear at least in part feasible; however, greater focus on testing and prevention activities for those either unaware of their HIV status or at risk of HIV acquisition will be required. Until such time, our analysis highlights the benefit of regularly analysing the HIV Care Cascade within clinical care, focusing on in-depth analysis of those NRIC to obtain a true representation of the cascade but also as a tool to optimize the numbers retained in care. Find the full version with references at

Rheumatoid Arthrits 29

Rheumatoid arthritis: An auto-immune inflammatory musculoskeletal disorder and more Patricia Minnock, Rheumatology Nurse Specialist, Rheumatology Rehabilitation Department, Our Lady's Hospice, Dublin Background The World Health Organisation classifies the disorders of the musculoskeletal system into five main groups: back pain; periarticular conditions also known as soft tissue or regional disorders; bone diseases; osteoarthritis, and inflammatory arthritis[4, 5]. The word arthritis comes from the Greek ‘arthron’ which means ‘joint’, and ‘itis’ meaning ‘inflammation’; plural: arthritides. Inflammatory arthritides are chronic and progressive autoimmune conditions that cause persistent joint inflammation and joint destruction as well as producing systemic symptoms[6].

synovial membrane which lines the cavity of all diarthrodial joints[12, 13]. Synovitis results in joints becoming red, swollen, tender, warm and painful; joint function is restricted by the associated symptoms of pain and stiffness. If left untreated, the protracted synovitis leads to joint destruction which is responsible for the deformity and disability associated with RA[12]. General Overview

The origins and effects of rheumatoid arthritis (RA) is an autoimmune response, which is described as a sustained specific immune response against selfantigens (auto-antigens)[10, 11]. It is recognised that the mechanisms which lead to the destruction of tissue, and the associated impairment or loss of joint and organ function during the course of RA, are essentially the same as the protective immune response against invasive microorganisms[11].

RA is primarily a disease of the synovial joints. There are also extra-articular (outside the joints) manifestations, such as rheumatoid nodules and a variety of systemic or constitutional features[14]. RA is characterised by the pattern or distribution of the joints involved. At presentation the classic distribution of joint involvement is a symmetrical synovitis of the multiple small joints (polyarthritis) of the hands and feet[15], hip and knee joints are also frequently implicated[14]. Affected joints become red, swollen, hot, and tender on palpation and movement; the associated joint stiffness experienced by patients, a phenomenon referred to as gelling, prevents their use. This prominent feature of increased stiffness upon waking (early morning stiffness) may last for more than an hour[16, 17]. The associated extraarticular manifestations and a variety of systemic/ constitutional features which also occur[14] include fatigue, malaise, and weight loss that may occur early in the disease presentation and sometimes overshadow the joint manifestations. Inflammation can involve other organ systems, including blood vessels, the nervous system, heart and lungs[17]. RA is associated with increased morbidity and mortality[13, 18], a considerable impact on patients’ quality of life[19-21], and a high cost to society[22, 23].

The immune response

Epidemiological aspects

As in all autoimmune diseases, the affected individual displays an inability to distinguish foreign molecules from some of the body's own molecules. In RA this results in a targeted response against synovial tissue that lines all diarthrodial (freely moveable) joints. This causes a ‘synovitis’, which is inflammation of the

The prevalence of RA in the adult population, estimated at 0.5-1%, is relatively constant across many populations[9, 24, 25]. The advised incidence for health planners is that 25–50 people from a population of 100,000 will develop typical RA[26]. It affects women 2-4 times more frequently than men and the peak age of

The estimated overall population prevalence of the inflammatory arthropathies is 2% (Table 1)[7]. National population samples are unavailable for most specific rheumatic conditions, estimates are mostly derived from published studies of smaller, defined populations[8, 9]. Rheumatoid arthritis (RA), the most recognised of these conditions, is the subject of this paper. An overview of the autoimmune pathogenesis, epidemiology, clinical manifestations, and management of this disease entity will be presented. Rheumatoid Arthritis: Pathogenesis

onset is 30 to 50 years[27-29]. It is hypothesised that this age of onset has risen in recent years[30], and that the incidence and severity has reduced over the past 3-4 decades[31]. The prevalence of RA increases with age[32], and gender differences diminish in the older age group[29, 33]. Genetic and environmental factors Evidence exists of both genetic and environmental contributions, and their interactions, to the development of RA[34]. While descriptive epidemiology suggests a genetic link, in contrast to other autoimmune diseases, such as insulin-dependent diabetes and multiple sclerosis, the familial recurrence risk in RA is smaller[35]. Multiple genetic factors are indicated, and a Mendelian inheritance pattern is not demonstrated[36]. The most definite genetic association with RA is the human leucocyte antigen (HLA) alleles of the major histocompatibility complex, a predisposition to and the severity of the disease expression is linked to the class II histocompatibility antigens, namely, HLA-DR4[24, 37, 38]. Other genetic factors shown to influence predisposition include variations in genes for various proteins such as cytokines, which are heavily implicated in driving the inflammatory process. It is likely therefore that, in addition to HLA, the development of RA is linked to several other genetic factors[24]. Environmental factors implicated in the aetiology of, and susceptibility to, RA include i) non-genetic body factors, ii) infective agents and iii) non infective agents[24]. Non genetic body (host) factors refer to hormonal and pregnancy influences. Evidence in relation to the exogenous effects of oestrogen on the incidence and severity of RA remains conflicting[39, 40], similarly, there is little conclusive evidence in relation to the role of infective agents. It is suggested that the decrease in incidence and prevalence of RA in several populations over the years is indirect evidence of a causal relationship between RA and an infective triggering agent[41-43]. Direct evidence on the relationship between the onset of RA and infectious agents is

inconclusive to date. The agents most usually implicated include the Epstein-Barr virus, parvovirus and bacterial agents such as Proteus, Mycoplasma and Yersinia[24]. Recent epidemiology studies have demonstrated a link between RA onset, its severity, and resistance to treatment, and the environmental risk factor, smoking[29, 44, 45]. Overall, there are surprisingly few studies on the role of diet. More recently, there is both interest and growing evidence on a potential protective role of omega-three fatty acids in RA, attributed to their beneficial role in inflammation[46]. In summary, the main risk factors for the disease occurrence and severity include any combination of genetic susceptibility, gender, age, infectious triggers, smoking, and hormonal factors. Clinical signs of RA The key signs of early RA include swelling, tenderness, warmth, and painful movement[32]. Joint tenderness is the most sensitive physical sign[16]. The joints most often involved early in the disease are the small joints of the hands and feet, commonly in symmetrical distribution, with gradual progression to the larger joints of the upper and lower limbs. Tendon sheath synovitis, predominately affecting the flexor tendon sheath of the hands, is another common finding[12]. The degree of joint swelling evident may not correlate with the amount of active synovitis or pain expressed by the patient. Joint swelling may be peri-articular or intra-articular, the latter is associated with the presence of a joint effusion[32, 47]. Articular features of RA The usual pattern of joint distribution or involvement includes the proximal interphalangeal joints (PIP), and the metacarpophalangeal joints (MCP) joints of the hands, wrists, elbows, shoulders, knees, ankles, subtalar, and metatarsophalangeal (MTP) joints of the feet. The cervical spine is the only characteristic axial location, with atlantoaxial subluxation a known complication[48], and tempromandibular joints are frequently involved[32]. The radiographic hallmarks of chronic

HPN • Issue 41

30 Rheumatoid Arthrits synovitis include periarticular osteoporosis, focal bone erosions at the joint margins and loss of joint space[6]. Inadequately treated articular inflammation can lead to progressive weakening or destruction of collateral structures, including the associated joint ligaments, tendons, cartilage, and bone. In addition, the pain associated with ongoing synovitis frequently leads to decreased range of movement at the affected joints. Initially, it is inflammation, and subsequently the progressive joint destruction, evident on x-ray, that drives disability in RA[49]. It is estimated that 90% of patients become disabled within 20 years of disease onset[6]. While the recognised classic presentation of RA is a symmetric polyarthropathy of the small joint of the hands and feet it may also present with an extra-articular or non-articular presentation[32]. Extra-articular features of RA Extra-articular features of RA affect over 40% of patients, and involve multiple organ systems (Table 2). The most common extra-articular manifestation is the development of subcutaneous rheumatoid nodules. This feature, found in about 30% of patients, is usually associated with the presence of a high titre rheumatoid factor antibody[32], and regarded as a cardinal diagnostic feature. They have been shown to be a marker for more severe disease but often appear late in the disease. Studies show a two to fourfold increase in mortality in patients with rheumatoid nodules[50, 51]; their early presence is regarded as a predictor of more severe extraarticular manifestations. Systemic extra-articular features of RA Systemic features (constitutional/ or extra-articular manifestations) of RA, such as fatigue, fever, anorexia and weight loss, may occur early in the course of the disease. In some cases these features persist, and can predominate the articular symptoms. Elderly patients in particular may present with polymyalgias, polyarthralgias and profound fatigue[32]. Laboratory indicators of systemic involvement in RA include elevated acutephase reactants; erythrocyte sedimentation count (ESR); C-reactive protein (CRP); anaemia; thrombocytopenia; elevation of certain liver function tests[17]. Comorbidities in RA People with RA die prematurely because chronically active

Issue 41 • HPN

inflammation predisposes to the development of multiple comorbid conditions[52]. These comorbidities are often associated with atypical features and worse outcome. Increased mortality correlates with disease severity and disease activity markers[53]. The most prevalent co-morbidities include i) • Cardiovascular: increased prevalence of myocardial infraction, heart failure, stroke • Infections: increased incidence of bacterial, tubercular, fungal, opportunistic, viral infection • Malignancies: increased incidence of lymphoma, lung and skin cancers • Osteoporotic fractures: rank highly among comorbidities contributing to mortality, future hospitalisations, and increased disability[53, 54]. Comorbidities and work disability in RA • Multiple comorbidities are strongly correlated with functional impairment • Functional disability is the most significant identifier of work disability[55]. Between 20-30% of patients become permanently work disabled within the first 2-3 years of disease[55, 56]. The multi-system features found in a small but important subset of patients[50], are summarised in Table 2. When present these can confound the correct diagnosis of this disease that has no single diagnostic pathognomonic feature. Diagnoses of RA Distinguishing a chronic illness such as RA from other selflimiting conditions can be difficult. There are no early onset disease specific features; the characteristic hallmarks of the disease develop over time. A salient characteristic of RA is its chronic and enduring nature; therefore it is not unusual that its diagnosis is delayed for months or even years. With the lack of a disease-specific feature or test the diagnosis of RA remains a composite of clinical and investigational features[57]. These features summarised in Table 3 provide a framework for diagnosis, and for monitoring and management of the course of this chronic rheumatic autoimmune disease. A history indicative of RA includes prolonged early morning stiffness that improves with activity,

polyarthritis, polyarthralgia (pain in many joints), and fatigue. Examination findings consistent with a diagnosis of RA include symmetric polyarthritis and rheumatoid nodules. Radiographic changes include periarticular osteopenia, joint space loss, and erosions. Although most serology studies are neither sensitive nor specific for RA they help exclude mimics of RA and confirm the presence of inflammation[16]. Management of RA The overarching goal of management is reversal of the pathogenic process; this is the basis of modern therapeutic biologic therapies[58]. A three step process is recommended in order to improve the diagnosis and outcome in arthritis: - i) the first step is the identification of the presence of inflammatory arthritis, ii) the next is distinguishing between definite diagnoses of arthritis (for example, rheumatoid arthritis, psoriatic arthritis), and iii) the third step is estimation of the risk of developing persistent or erosive irreversible arthritis and to propose an optimal treatment strategy[59] (See table 4 for glossary of terms and definitions). Management of RA is defined as all organisational, diagnostic, medical and educational procedures related to patients seeking help for arthritis of a peripheral joint[60]. The ultimate therapeutic goal in the treatment of RA is to induce complete remission. Therefore, the goals of management of RA is to prevent joint damage or at a minimum progression irrespective of residual subclinical changes[61], optimise physical function, improve quality of life and work capacity[62] [63] and reduce comorbidity risks[64]. Twelve key recommendations for the management of early RA were developed by The European League against Rheumatism (EULAR) based on evidence in the literature and expert consensus[65]. These provide a comprehensive summary of evidence based management including all steps in the process from early referral, diagnosis, prognosis and treatment. Presented, as published (Table 5) in a logical sequence[65], they incorporate two imperatives i) the need to initiate effective therapy immediately after diagnosis and ii), the requirement to set a treatment target and to assess the disease on the way towards that target, employing a treat-to-target strategy (T2T). The target should be a state of low disease activity or clinical remission[65].

Modern Pharmacological Approaches to Treatment Three major types of drug therapy are used in the treatment of RA: non-steroidal antiinflammatory drugs, disease modifying anti-rheumatic drugs, and glucocorticoids. Nonsteroidal anti-inflammatory drugs provide symptomatic relief of pain, stiffness and inflammation without influencing the causes of inflammation. Disease modifying anti-rheumatic drugs act by a variety of pathways with the common mechanism of inhibiting the main pro-inflammatory cytokines[16]. Inhibition of proinflammatory cytokines, mediators of inflammation, results in a decrease of disease activity, reduction in joint damage, preservation of function and improvement in systemic symptoms. Glucocorticoids have actions similar to both nonsteroidal anti-inflammatory drugs and disease modifying antirheumatic drugs; use in clinical practice is largely confined to short term for symptomatic relief. On account of their potential side effect profile, their long term use as disease modifying drugs is no longer recommended, therefore, they have been largely superseded by modern biologic disease modifying therapies[66, 67]. Evidence based treatment guidelines are presented in Table 5 and an Algorithm to guide their application in practice presented in Figure 4[65]. Disease modifying antirheumatic therapies: nonbiologic and biologic agents Diseases modifying antirheumatic drugs (DMARDS) fall into two separate groups: firstly, the conventional synthetic agents (non-biological drugs) (csDMARDS), and newer targeted synthetic agents (tsDMARDS), and secondly, the modern biologic disease modifying drugs (bDMARDS)[68]. The most commonly used csDMARDS include methotrexate (the main anchor drug)[69], hydxochloroquin, sulfasalazine and luflonomide, alone or in various combinations[70]. The current available tsDMARD is the Jak-inhibitor tofacitinib. The principle biologic disease modifying therapies include; TNF inhibitors (infliximab, etanercept, adalimumab, golimumab, certolizumab); a costimulation inhibitor (abatacept); an IL-6 receptor blocker (tocilizumab), and an anti-B-cell agent (rituximab)[65]. Early intervention with nonbiologic disease modifying anti-inflammatory drugs is the


For the treatment of rheumatoid arthritis in adults


THE FIRST METHOTREXATE AUTO-INJECTOR FOR PATIENTS WITH RHEUMATOID ARTHRITIS Featuring a unique double click mechanism at the start and end of each injection, a compact design and no button to press – designed to give confidence to you and your patients.

Available in 8 dose presentations, in 2.5mg increments from 7.5mg to 25mg – giving you a wide dosage range and the flexibility you need when treating your patients.

NEW methotrexate auto-injector PEN Nordimet (methotrexate) Solution for Injection in Pre-Filled Pen Please refer to the Summary of Product Characteristics for full prescribing information. Further information is available on request Presentation: Nordimet: Pre-filled pen containing 7.5 mg (in 0.3 ml), 10 mg (in 0.4 ml), 12.5 mg (in 0.5 ml), 15 mg (in 0.6 ml), 17.5 mg (in 0.7 ml), 20 mg (in 0.8 ml), 22.5 mg (in 0.9 ml) and 25 mg (1.0 ml) methotrexate in solution for injection. Indications: Active rheumatoid arthritis in adult patients. Polyarthritic forms of severe, active juvenile idiopathic arthritis, when the response to nonsteroidal anti-inflammatory drugs (NSAIDs) has been inadequate. Severe recalcitrant disabling psoriasis, which is not adequately responsive to other forms of therapy such as phototherapy, PUVA, and retinoids, and severe psoriatic arthritis in adult patients. Dosage and administration: Nordimet should only be prescribed by physicians with experience in the various properties of the medicinal product and its mode of action. Nordimet is injected once weekly, administered subcutaneously. Rheumatoid arthritis: Recommended initial dose is 7.5 mg of methotrexate once weekly. Depending on the individual activity of the disease & patient tolerability, the initial dose may be increased. A weekly dose of 25 mg should in general not be exceeded. Once the desired therapeutic result has been achieved, the dose should be reduced gradually to the lowest possible effective maintenance dose. Polyarthritic forms of severe, active juvenile idiopathic arthritis: The recommended dose is 10-15 mg/m² BSA per week. In therapy-refractory cases the weekly dose may be increased up to 20mg/m² BSA per week. Use in children < 3 years of age is not recommended. Psoriasis vulgaris and psoriatic arthritis: A test dose of 5 - 10 mg subcutaneously administered one week prior to initiation of therapy is recommended. Recommended initial dose 7.5 mg Date of preparation: January 2017 NOR/16/043i

methotrexate once weekly. Dose increased gradually but should not, in general, exceed a weekly dose of 25 mg of methotrexate. Once the desired therapeutic result has been achieved, dose should be reduced gradually to the lowest possible effective maintenance dose.The dose should be increased as necessary but should in general not exceed the maximum recommended weekly dose of 25 mg. Renal impairment, hepatic impairment or eld erly patients: Please refer to SmPC. Note: When switching from oral to parenteral use, a reduction in the dose may be required, due to the variable bioavailability of methotrexate after oral administration. Contraindications: Hypersensitivity to methotrexate or to any of the excipients. Severe hepatic impairment, if serum bilirubin is > 5 mg/dl (85.5 µmol/l). Alcohol abuse. Severe renal impairment (creatinine clearance < 30 ml/min). Pre-existing blood dyscrasias (e.g. bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anaemia). Immunodeficiency. Serious, acute or chronic infections such as tuberculosis & HIV. Stomatitis. Ulcers of the oral cavity and known active gastrointestinal ulcer disease. Pregnancy. Breast-feeding. Concurrent vaccination with live vaccines. Special warnings and precautions: Patients must be clearly advised that the therapy is to be administered once a week, and not every day. Patients receiving therapy should be appropriately monitored. Doses exceeding 20 mg/week can be associated with significant increase in toxicity, especially bone marrow suppression. The possible risks of effects on reproduction should be discussed with male and female patients of childbearing potential. Interactions: Consult SPC for detailed information on interactions. Undesirable effects: See SmPCs for full list of undesirable effects. Nordimet: Very common: Stomatitis. Dyspepsia. Appetite loss. Abdominal pain. Nausea. Raised liver enzymes. Common: Leukopenia. Anaemia.

Thrombopenia. Headache. Tiredness. Drowsiness. Pneumonia. Interstitial alveolitis/pneumonitis. Oral ulcers. Diarrhoea. Exanthema. Erythema. Pruritus. Uncommon: Pharyngitis. Pancytopenia. Precipitation of diabetes mellitus. Depression. Enteritis. Pancreatitis. Gastrointestinal ulceration and bleeding. Cirrhosis, Fibrosis and fatty degeneration of liver. Inflammation and ulceration of bladder. Renal impairment. Rare: Infection. Conjunctivitis. Sepsis. Allergic reactions. Anaphylactic shock. Hypogammaglobulinaemia. Visual disturbances. Pericarditis. Pericardial effusion. Pericardial tamponade. Thromboembolic events. Pulmonary fibrosis. Pneumocystis carinii pneumonia. Shortness of breath and bronchial asthma. Pleural effusion. Acute hepatitis. Renal failure. Anuria. Very rare: Lymphoma. Agranulocytosis. Severe courses of bone marrow depression. Acute aseptic meningitis. Convulsions. Paralysis. Impaired vision. Retinopathy. Haematemesis. Toxic megacolon. Hepatic failure. Stevens-Johnson syndrome. Toxic epidermal necrolysis. Not known: Eosinophilia. Encephalopathy/Leukoencephalopathy. Legal classification: POM. MA numbers: Nordimet: EU/1/16/1124/001 – 008. Further information available from: Nordic Pharma Ltd, Unit 3, Commerce Park, Brunel Road, Theale, Reading, United Kingdom. Date of prescribing information: January 2017. Code for PI: NOR/17/001i Adverse events should be reported. Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to Nordic Pharma Ireland: Phone no. +353 (0)1 4004141

32 Rheumatoid Arthrits cornerstone of treatment and in the early stages may halt the progressive synovitis, associated joint destruction and progressive disability. However, only a minority of patients achieve a good response on non-biologic therapies alone[70].

and sometimes silent comorbid conditions[53, 54, 75]. The Irish Rheumatology Nurse Forum (IRNF) working with the National Clinical Programme for Rheumatology

(NCPR) have outlined a proposal for the recruitment of additional rheumatology nurses to help achieve the objectives of the NCPR and bring service provision

for RA s in line with evidencebased practice and international standards of care, that is T2T. This is in keeping with the draft model of care for rheumatology[76].

Treat to Target Strategy in RA Treat to Target is the integration of clear outcome targets and tight disease control into standard practice under the direction of a rheumatologist in a more strategic and clinically successful manner. Intended to mirror the success of similar targeted treatment programs in hypertension, hyperlipidaemia and diabetes, combined insights have resulted in a clear set of recommendations with significant clinical benefits being implemented successfully in many parts of the world. The aim of a T2T strategy is to significantly reduce the overall burden of disease; it involves: -

Table 1: Inflammatory arthropathies: Estimated prevalence


Prevalence (%)

Rheumatoid arthritis


Crystal arthropathies


Ankylosing spondylitis


Psoriatic arthritis


Juvenile idiopathic arthritis


Systemic lupus erythematous


I. monitoring patients closely and titrating medication in order II. to achieve either the agreed goal of clinical remission or low disease activity III. usually within the first 6 months of diagnosis,[71]. Evidence exists that when clinicians act on the basis of the information gathered from clinical assessment of patients’ disease activity patient outcome can be significantly improved[72]. Nurse Led Treat to Target: A model of care delivery Within rheumatology services, nurse-led care continues to grow as a model of care delivery in the backdrop of the global shortage of rheumatologists, increased need for patient monitoring in the out-patient departments and the increasing standard of education and experience of rheumatology nurses[73, 74]. Clinical nurse specialist and advanced nurse practitioners are ideally placed to lead the implementation of a T2T strategy along with co-morbidity screening in the comprehensive care management of this chronic disease group. While the long-term prognosis of RA has improved since the availability of highly effective medications this is contingent on close monitoring and regular treatment adjustment to the targets of low disease activity or remission, as well as the systematic measuring of vital signs and laboratory measures, to detect otherwise unrecognised

Issue 41 • HPN

Table 2: Possible extra-articular and systemic manifestations of rheumatoid arthritis

Table 2: Possible extra-articular and systemic manifestations of rheumatoid arthritis General Fever Lymphadenopathy Anorexia /Weight loss Fatigue [17, 78-82]. Dermatological Palmar erythema Subcutaneous nodules Vasculitis (leukocytoclastic) (nailfold infracts) Digital ulceration Leg ulceration Raynaud’s phenomenon [17, 32, 50, 51, 87-89] Ocular Episcleritis Scleritis Choroid and retinal nodules Sjogrens syndrome (keratoconjunctivitis sicca) (10-35%) Steroid related cataracts Drug induced retinopathies [32, 91]. Pulmonary Pleuritis Pulmonary nodules Interstitial lung disease Bronchiolitis obliterans [32, 91, 98] Hepatic Elevated liver enzymes Drug induced hepatotoxicity[17, 69, 99].

Cardiac Pericarditis Myocarditis Nodules on valves Ischaemic heart disease [15, 52, 83-86]. Neuromuscular Entrapment neuropathy Peripheral neuropathy Mononeuritis multiplex Cervical myopathy Steroid mypopathy [6, 17, 90]. Hematological/Biochemistry Normocytic hypochromic anemia Thrombocytosis Felty's syndrome Lymphomas Serology : Positive for rheumatoid factor and anti-CCP antibodies (30%) [51, 92-97] Renal Drug induced renal toxicity Renal vasculitis Glomerulonephritis Amyloidosis [15] Others Hodgkin disease Non-Hodgkin lymphoma and Squamous cell skin cancer Osteoporosis [95, 100]


Figure 3: 2016 European League against Rheumatism (EULAR) recommendations on rheumatoid arthritis (RA) management

Figure 3: 2016 European League against Rheumatism (EULAR) recommendations on rheumatoid arthritis (RA) management

HPN â&#x20AC;˘ Issue 41 Page 13 of 18

34 Rheumatoid Arthrits

Table 3: Clinical and investigational diagnostic features of rheumatoid arthritis [16] Standard Procedures for Diagnosis • History of swelling /pain Table 3: Clinical and investigational diagnostic • Physical examination features of rheumatoid arthritis • Laboratory tests: Elevated ESR,[16] CRP • Laboratory evidence of specific auto-antibodies (rheumatoid factor and anti-CCP) [97] • Imaging evidence of damage/inflammation (radiography, MRI, ultrasonography) • Extra-articular disease and co-morbid conditions Physical Signs • Evidence of synovitis • Joint tenderness (positive squeeze test) • Joint swelling/effusions/warmth • Symmetrical involvement • Nodules (occasionally)

Presenting Symptoms Table 3: Clinical and investigational diagnostic features of rheumatoid arthritis [16] • Joint pain Standard Procedures for Diagnosis Presenting Symptoms • Joint swelling: Small joints, symmetrical • History of swelling /pain • Joint pain • Joint stiffness • Physical examination • Joint swelling: Small joints, symmetrical • Difficulty making a fist, especially on waking

• Laboratory tests: Elevated ESR, CRP

Laboratory evidence of specific auto-antibodies • •Fatigue (rheumatoid factor and anti-CCP) [97]

Imaging evidence of damage/inflammation • •Good response to anti-inflammatory drugs (radiography, Clinical Features MRI, ultrasonography) Extra-articular disease and co-morbid conditions • •Evidence of synovitis Signs (ESR/CRP) •Physical Inflammation Evidence abnormalities of synovitis • •Serological • •Rheumatoid factor,(positive anti CCP squeeze auto antibodies Joint tenderness test) • •X-ray (joint space increased due to Jointevidence swelling/effusions/warmth soft involvement tissue swelling, periarticular •effusion, Symmetrical characteristic erosions) •osteoporosis, Nodules (occasionally) • MRI / Ultrasound abnormalities • Systemic features: Fatigue, Fever, Weight Loss

Table 4: Glossary and definitions

• Joint stiffness • Difficulty making a fist, especially on waking • Fatigue

• Good response to anti-inflammatory drugs Clinical Features • Evidence of synovitis • Inflammation (ESR/CRP) • Serological abnormalities • Rheumatoid factor, anti CCP auto antibodies • X-ray evidence (joint space increased due to effusion, soft tissue swelling, periarticular osteoporosis, characteristic erosions) • MRI / Ultrasound abnormalities • Systemic features: Fatigue, Fever, Weight Loss

Term Poor prognostic factors

Definition Table 4: Glossary and definitions Table 4: Glossary and definitions • Moderate (after csDMARD therapy) to high disease activity according to composite measures Definition • High acute phase reactantTerm levels • Moderate (after csDMARD therapy) to high disease activity according to • High swollen joint counts Poor prognostic factors composite measures • Presence of RF and/or ACPA, especially at high levels • High acute phase reactant levels • Combinations of the above • High swollen joint counts • Presence of early erosions • Presence of RF and/or ACPA, especially at high levels • Failure of two or more csDMARDs • Combinations of the above Low-dose glucocorticoid ≤7.5 mg/day (prednisone equivalent) Meanings of treatment reduction • Presence of early erosions Tapering Usually reduction of drug dose or increase of application interval (‘spacing’) • Failure of two or more csDMARDs May include discontinuation (tapering 0), but then only after reduction Low-doseto glucocorticoid ≤7.5slow mg/day (prednisone equivalent) Cessation, discontinuation Disease activity states Remission Low disease activity Moderate, high disease activity DMARD nomenclature Synthetic DMARDs

Biological DMARDs

Stopping of a particular drug Meanings of treatment reduction


Usually reduction of drug dose or increase of application interval (‘spacing’)

May include discontinuation (tapering to 0), but then only after slow reduction ACR-EULAR Boolean or index-based remission definition Low disease activity state according to any of the validatedStopping composite Cessation, discontinuation of adisease particular drug activity measures that include joint counts Disease activity states Respective disease activity state according to any of the validated composite Remission ACR-EULAR Boolean or index-based remission definition disease activity measures that include joint counts Low disease activity

Low disease activity state according to any of the validated composite disease activity measures that include joint counts methotrexate, leflunomide, • Conventional synthetic E.G. Moderate, high disease Respective disease activity state according to any of the validated composite sulfasalazine, hydroxychloroquine DMARDs (csDMARDs) activity disease activity measures that include joint counts • Targeted synthetic DMARDs E.G. tofacitinib, baricitinib DMARD nomenclature (tsDMARDs) Synthetic DMARDs methotrexate, leflunomide, • Conventional synthetic E.G. • Biological originator DMARDs (boDMARDs) sulfasalazine, hydroxychloroquine DMARDs (csDMARDs) • Biosimilar DMARDs (bsDMARDs)

• Targeted synthetic DMARDs E.G. tofacitinib, baricitinib (tsDMARDs) Table 5: EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying anti-rheumatic drugs [65] Biological DMARDs • Biological originator DMARDs (boDMARDs) 11 of 18 • Biosimilar DMARDs (bsDMARDs) 1 Therapy with DMARDs should be started Page as soon as the diagnosis of RA is made

2 3 4 5 6 7 8 9 10 11 12

Treatment should be aimed at reaching a target of sustained remission or low disease activity in every patient Monitoring should be frequent in active disease (every 1–3 months); if there is no improvement by at most 3 months after the start of treatment or the target has not been reached by 6 months, therapy should be adjusted Page 11 of 18 MTX should be part of the first treatment strategy In patients with a contraindication to MTX (or early intolerance), leflunomide or sulfasalazine should be considered as part of the (first) treatment strategy Short-term glucocorticoids should be considered when initiating or changing csDMARDs, in different dose regimens and routes of administration, but should be tapered as rapidly as clinically feasible If the treatment target is not achieved with the first csDMARD strategy, in the absence of poor prognostic factors, other csDMARDs should be considered If the treatment target is not achieved with the first csDMARD strategy, when poor prognostic factors are present, addition of a bDMARD*1,2 or a tsDMARD*3 should be considered; current practice would be to start a bDMARD§ bDMARDs*1,2 and tsDMARDs#3 should be combined with a csDMARD; in patients who cannot use csDMARDs as comedication, IL-6 pathway inhibitors and tsDMARDs may have some advantages compared with other bDMARDs If a bDMARD* or tsDMARD§ has failed, treatment with another bDMARD or a tsDMARD should be considered; if one TNF-inhibitor therapy has failed, patients may receive another TNF-inhibitor or an agent with another mode of action If a patient is in persistent remission after having tapered glucocorticoids, one can consider tapering bDMARDs, especially if this treatment is combined with a csDMARD If a patient is in persistent remission, tapering the csDMARD could be considered

The symbols (*, §, #) indicate different levels of evidence which are correspondingly provided together with voting results and levels of agreement in table 3. 1 TNF-inhibitors: adalimumab, certolizumab pegol, etanercept, golimumb, infliximab boDMARDs or the respective EMA-approved/FDA-approved biosimilars. 2 Abatacept, rituximab (as first bDMARD under special circumstances—see text), or tocilizumab or respective EMA-approved/FDA-approved biosimilars, as well as other IL-6 pathway inhibitors, sarilumab and/or sirukumab, once approved. 3 Jak-inhibitors (where approved). boDMARDs, biological originator DMARDs; bsDMARD, biosimilar DMARDs; csDMARDs, conventional synthetic DMARDs; DMARDs, disease-modifying antirheumatic drugs; EULAR, European League Against Rheumatism; Jak, Janus kinase; MTX, methotrexate; RA, rheumatoid arthritis; TNF, tumour necrosis factor; tsDMARDs, targeted synthetic DMARDs.

Find the full version with references at Issue 41 • HPN




IN DMARD-IR AND TNF-IR RA PATIENTS, WHEN COMBINATION WITH MTX IS NOT AN OPTION ABRIDGED PRESCRIBING INFORMATION. For full prescribing information, refer to the Summary of Product Characteristics [SmPC]. RoActemra® (tocilizumab) 20mg/ml Concentrate for Solution for Infusion (RoActemra IV) and RoActemra® 162mg solution for injection in pre-filled syringe (RoActemra SC). Indications: RoActemra SC: In combination with methotrexate (MTX) for (i) the treatment of severe, active and progressive rheumatoid arthritis (RA) in adults not previously treated with MTX (ii) the treatment of adult patients with moderate to severe active RA who have had an inadequate response or intolerance to one or more disease-modifying anti-rheumatic drugs (DMARDs) or tumour necrosis factor (TNF) antagonists. RoActemra IV: In combination with MTX for the treatment of (i) severe, active and progressive RA in adults not previously treated with MTX, (ii) adult patients with moderate to severe active RA who have had an inadequate response or intolerance to one or more DMARDs or TNF antagonists, (iii) active systemic juvenile idiopathic arthritis (sJIA) in patients ≥ 2 years of age, who responded inadequately to previous therapy with NSAIDs and systemic corticosteroids, (iv) juvenile idiopathic polyarthritis (pJIA) (rheumatoid factor positive or negative and extended oligoarthritis) in patients ≥ 2 years of age, who responded inadequately to previous therapy with MTX. RoActemra IV/SC can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate for all indications. RoActemra IV/SC has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function when given in combination with MTX for the treatment of adult RA patients. Dosage & Administration: Treatment should be initiated by HCPs experienced in the diagnosis and treatment of RA, sJIA or pJIA and all patients should be given the Patient Alert Card. Assess suitability of patient for subcutaneous home use and instruct patient to inform HCP if they experience symptoms of an allergic reaction before administering the next dose. Limited data available regarding switching patients from RoActemra IV to RoActemra SC. RA: RoActemra IV: 8mg/kg diluted to a final volume of 100ml, given once every 4 weeks by IV infusion over 1 hour. For patients >100kg, doses >800mg per infusion are not recommended. No data on doses above 1.2g. RoActemra SC: 162mg once every week, irrespective of weight. Patients may self-inject after training. Alternate injection site frequently. sJIA (RoActemra IV only): Patients <2 years of age – no data. Patients ≥2 years, 8mg/kg diluted to final volume of 100ml for patients ≥ 30kg or 12mg/kg diluted to final volume of 50ml for patients < 30kg once every 2 weeks by IV infusion over 1 hour. Clinical improvement generally seen within 6 weeks of starting RoActemra; reconsider continued therapy if no improvement. pJIA (RoActemra IV only): Patients <2 years of age - no data. Patients >2 years of age, 8mg/kg diluted to final volume of 100ml for patients ≥ 30 kg or 10 mg/kg diluted to final volume of 50ml for patients <30kg once every 4 weeks by IV infusion over 1 hour. Clinical improvement generally seen within 12 weeks of starting RoActemra; reconsider continued therapy if no improvement. For pJIA/sJIA: check patient’s weight at each visit. Dose adjustments: For raised liver enzymes, modify concomitant DMARDs if appropriate, reduce or interrupt dose of RoActemra; for low absolute neutrophil count (ANC) or low platelet count reduce or interrupt RoActemra. In some instances discontinue RoActemra (see SmPC). In patients not previously treated with RoActemra, initiation is not recommended in patients with an absolute neutrophil count (ANC) below 2 x 109/l. Special Populations: No data available for RoActemra SC in patients <18 years of age. Closely monitor renal function in patients with moderate to severe renal impairment. No data in patients with hepatic impairment. No dose adjustments in patients >65 years. Contraindications: Hypersensitivity to any component of the product; active, severe infections. Special Warnings & Precautions: Cases of serious infections (sometimes fatal) have been reported; interrupt therapy until controlled. Do not initiate treatment in patients with active infections. Caution in patients with recurring/chronic infections, or other underlying conditions (e.g. diverticulitis, diabetes and interstitial lung disease) which predisposes to infection. Vigilance for the timely detection of serious infection is recommended - signs and symptoms of acute inflammation may be lessened, associated with suppression of the acute phase reaction. Consider effects of RoActemra on C-reactive protein (CRP), neutrophils and signs and symptoms of infection when evaluating a patient for a potential infection. Patients and parents/ guardians of sJIA and pJIA patients should contact their HCP when symptoms suggestive of infection appear. Screen for latent TB and treat if required prior to starting therapy. Patients to seek medical attention if sign/symptoms suggestive of TB occur during or after treatment. Viral reactivation (e.g. hepatitis B) reported with biologic therapies. Caution in patients with a history of intestinal ulceration or diverticulitis. Serious hypersensitivity reactions, including anaphylaxis, reported and may be more severe and potentially fatal in patients who have experienced hypersensitivity reactions during previous treatment even if they have received premedication with steroids and anti-histamines. Appropriate treatment should be available for immediate use in the event of an anaphylactic reaction during treatment with RoActemra. If an anaphylactic reaction or other serious hypersensitivity/serious infusion related reaction occurs, immediately stop administration and permanently discontinue RoActemra. Use with caution in patients with active hepatic disease/impairment. In clinical trials, transient or intermittent mild-moderate elevations of hepatic transaminases reported commonly with RoActemra treatment, without progression to hepatic injury. An increased frequency of these elevations was observed when potentially hepatotoxic drugs (e.g. MTX) were used in combination with RoActemra. When clinically indicated, consider other liver function tests including bilirubin. Not recommended in patients with baseline ALT or AST > 5 x ULN; caution in patients with ALT or AST > 1.5 x ULN (see SmPC for frequency of monitoring and dose modifications/interruptions). Decreases in neutrophil and platelet counts have occurred following treatment with RoActemra 8 mg/kg in combination with MTX. Risk of neutropenia may increase in patients previously treated with TNF antagonist. Continued therapy not recommended in patients with ANC < 0.5 x 109/l or platelet count < 50 x 103/μl. Do not initiate RoActemra treatment where ANC is below 2 x 109/l. Caution in patients with low platelet count; monitor neutrophils and platelets in RA, sJIA and pJIA patients according to SmPC. Elevations in lipid parameters seen; assess every 4 to 8 weeks; if elevated, follow local guidelines. Be vigilant for symptoms of new-onset central demyelinating disorders. Immunomodulatory medicines may increase malignancy risk in RA patients. Live and live attenuated vaccines should not be given concurrently (see SmPC). RA patients have an increased risk for cardiovascular disorders - manage risk factors (e.g. hypertension, hyperlipidaemia) as part of usual standard of care. Not recommended for use with other biological agents. RoActemra (for IV use) contains 1.17 mmol (or 26.55 mg) sodium per maximum dose of 1200 mg – to be considered by patients on a controlled sodium diet. Macrophage activation syndrome (MAS), a serious life-threatening disorder, may develop in sJIA patients – RoActemra not studied in patients during an active MAS episode. Trade name and batch number should be clearly recorded in patient file to improve traceability of biological medicines. Drug Interactions: Studies only performed in adults. Monitor patients taking medicines individually adjusted and metabolised via CYP450 3A4, 1A2 or 2C9 when starting/stopping RoActemra, as doses may need to be increased to maintain therapeutic effect. Effects of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy (refer to SmPC for further details on cytochrome CYP450 and other drug interactions). Fertility, Pregnancy & Lactation: Women must use contraception during and up to 3 months after treatment. No adequate data from use in pregnant women. Animal study showed increased risk of spontaneous abortion/embryo-foetal death at high dose. RoActemra should not be used during pregnancy unless clearly necessary. No lactation data in humans. A decision on whether to continue/discontinue breastfeeding or RoActemra therapy should be made taking into account the relative benefits to the child and mother. Refer to SmPC. Effects on ability to drive and use machines: RoActemra has minor influence on the ability to drive and use machines (dizziness). Undesirable Effects: Prescribers should consult SmPC for full details of ADRs. RoActemra IV: RA: The most commonly reported ADRs (occurring in ≥ 5% of patients treated with tocilizumab monotherapy or in combination with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT. The most serious ADRs were serious infections, complications of diverticulitis, and hypersensitivity reactions. ADRs occurring in RoActemra trials: Very Common (≥ 1/10): upper respiratory tract infections, hypercholesterolaemia. Common (≥1/100 - <1/10): cellulitis, pneumonia, oral herpes simplex, herpes zoster, abdominal pain, mouth ulceration, gastritis, rash, pruritus, urticaria, headache, dizziness, hepatic transaminases increased, weight increased, total bilirubin increased, hypertension, leucopenia, neutropenia, peripheral oedema, hypersensitivity reactions, conjunctivitis, cough and dyspnoea. Uncommon (≥1/1000 - <1/100): diverticulitis, stomatitis, gastric ulcer, hypertriglyceridaemia, nephrolithiasis, hypothyroidism. sJIA: ADRs were similar to those seen in RA patients. sJIA patients experienced a higher frequency of nasopharyngitis, decrease in neutrophil counts, hepatic transaminases increased, and diarrhoea. Very Common (≥ 1/10): upper respiratory tract infections, nasopharyngitis, decrease in neutrophil count. Common (≥1/100 - <1/10): diarrhoea, infusion related reactions, headache, platelet count decreased, cholesterol increased. pJIA: ADRs were similar to those seen in RA and sJIA patients. Nasopharyngitis, headache, nausea, and decreased neutrophil count more frequently reported in the pJIA population. Very Common (≥ 1/10): upper respiratory tract infections, nasopharyngitis, headache. Common (≥1/100 - <1/10): nausea, diarrhoea, infusion related reactions, hepatic transaminases increased, decrease in neutrophil count. Uncommon (≥1/1000 - <1/100): platelet count decreased, cholesterol increased. RoActemra SC: The safety and immunogenicity was consistent with the known safety profile of IV. Injection site reactions (including erythema, pruritus, pain and haematoma) were mild to moderate in severity. Serious or Potentially Serious: serious infections, active tuberculosis, invasive pulmonary infections, interstitial lung disease (including pneumonitis and pulmonary fibrosis), GI perforations (as complications of diverticulitis), serious hypersensitivity reactions, Stevens-Johnson syndrome. See SmPC section 4.8 for instructions on the reporting of suspected adverse reactions. Legal Category: Subject to medical prescription which may not be renewed (A). Presentations & Marketing Authorisation Numbers: 80mg of tocilizumab in 4ml (20mg/ml) pack of 1 (EU/1/08/492/001); 200mg of tocilizumab in 10ml (20mg/ml) pack of 1 (EU/1/08/492/003); 400mg of tocilizumab in 20ml (20mg/ml) pack of 1 (EU/1/08/492/005); 162mg tocilizumab solution for injection (in 0.9ml) in pre-filled syringe (EU/1/08/492/007). Marketing Authorisation Holder: Roche Registration Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom. RoActemra 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 2017. Reference: 1. Nisar MK et al. The role of tocilizumab monotherapy in the management of rheumatoid arthritis: a review. Int. J. Clin. Rheumatol. (2012) 7(1): 9-19. Date of item: August 2017. IE/RACTE/0517/0035(1)

Envarsus ® 0.75mg, 1mg, 4mg prolonged-release tablet Tacrolimus (as monohydrate) Please refer to Summary of Product Characteristics (SmPC) before prescribing Prescribing information Presentation Envarsus prolonged-release tablets containing 0.75mg, 1mg and 4mg of tacrolimus (as monohydrate) Indications Prophylaxis of transplant rejection in adult kidney or liver allograft recipients and treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adult patients Dosage and administration Envarsus is a once-a-day oral formulation of tacrolimus. Envarsus therapy requires careful monitoring by adequately qualified and equipped personnel. This medicinal product should only be prescribed, and changes in immunosuppressive therapy be initiated, by physicians experienced in immunosuppressive therapy and the management of transplant patients. Patients should be maintained on a single formulation of tacrolimus with the corresponding daily dosing regimen; alterations in formulation or regimen should only take place under the close supervision of a transplant specialist. The recommended initial doses presented below are intended to act solely as a guideline. Envarsus is routinely administered in conjunction with other immunosuppressive agents in the initial post-operative period. The dose may vary depending upon the immunosuppressive regimen chosen. Envarsus dosing should primarily be based on clinical assessments of rejection and tolerability in each patient individually aided by blood level monitoring. If clinical signs of rejection are apparent, alteration of the immunosuppressive regimen should be considered. As tacrolimus is a substance with low clearance, adjustments to the Envarsus dose regimen may take several days before steady state is achieved. Envarsus doses are usually reduced in the post-transplant period. Post-transplant changes in the condition of the patient may alter the pharmacokinetics of tacrolimus and may necessitate further dose adjustments. Prophylaxis of kidney transplant rejection: Envarsus therapy should commence at a dose of 0.17 mg/kg/day administered once daily in the morning. Administration should commence within 24 hours after the completion of surgery. Prophylaxis of liver transplant rejection: Envarsus therapy should commence at a dose of 0.11 – 0.13 mg/kg/day administered once daily in the morning. Administration should commence within 24 hours after the completion of surgery. Conversion of Prograf- or Advagraf-treated patients to Envarsus allograft transplant patients: Allograft transplant patients maintained on twice daily Prograf (immediate-release) or Advagraf (once daily) dosing requiring conversion to once daily Envarsus should be converted on a 1:0.7 (mg:mg) total daily dose basis and the Envarsus maintenance dose should, therefore, be 30% less than the Prograf or Advagraf dose. Envarsus should be administered in the morning. When converting from tacrolimus immediate-release products (e.g. Prograf capsules) or from Advagraf prolonged-release capsules to Envarsus, trough levels should be measured prior to conversion and within two weeks after conversion. Dose adjustments should be made to ensure that similar systemic exposure is maintained after the switch. In comparison to Caucasians, black patients may require higher tacrolimus doses to achieve similar trough levels. In clinical studies patients converted from twice daily Prograf were converted to Envarsus using a 1:0.85 (mg:mg) conversion. Conversion from ciclosporin to tacrolimus: Care should be taken when converting patients from ciclosporin-based to tacrolimus-based therapy. The combined administration of ciclosporin and tacrolimus is not recommended. Envarsus therapy should be initiated after considering ciclosporin blood concentrations and the clinical condition of the patient. Dosing should be delayed in the presence of elevated ciclosporin blood levels. In practice, tacrolimus-based therapy has been initiated 12 to 24 hours after discontinuation of ciclosporin. Monitoring of ciclosporin blood levels should be continued following conversion as the clearance of ciclosporin might be affected. Treatment of allograft rejection: Increased doses of tacrolimus, supplemental corticosteroid therapy, and introduction of short courses of mono-/polyclonal antibodies have all been used to manage rejection episodes. If signs of toxicity such as severe adverse reactions are noted, the dose of Envarsus may need to be reduced. Treatment of allograft rejection after kidney or liver transplantation: For conversion from other immunosuppressants to once daily Envarsus, treatment should begin with the initial oral dose recommended in kidney and liver transplantation respectively for prophylaxis of transplant rejection. Therapeutic drug monitoring: Dosing should primarily be based on clinical assessments of rejection and tolerability in each individual patient aided by whole blood tacrolimus trough level monitoring. As an aid to optimise dosing, several immunoassays are available for determining tacrolimus concentrations in whole blood. Comparisons of concentrations from the published literature to individual values in clinical practice should be assessed with care and knowledge of the assay methods employed. In current clinical practice, whole blood levels are monitored using immunoassay methods. The relationship between tacrolimus trough levels and systemic exposure (AUC 0-24) is well correlated and is similar between the immediate-release formulation and Envarsus. Blood trough levels of tacrolimus should be monitored during the post-transplantation period. Tacrolimus blood trough levels should be determined approximately 24 hours post-dosing of Envarsus, just prior to the next dose. Blood trough levels of tacrolimus should also be closely monitored following conversion from tacrolimus products, dose adjustments, changes in the immunosuppressive regimen, or

co-administration of substances which may alter tacrolimus whole blood concentrations. The frequency of blood level monitoring should be based on clinical needs. As tacrolimus is a substance with low clearance, following adjustments to the Envarsus dose regimen it may take several days before the targeted steady state is achieved. Data from clinical studies suggest that the majority of patients can be successfully managed if tacrolimus blood trough levels are maintained below 20ng/ml. It is necessary to consider the clinical condition of the patient when interpreting whole blood levels. In clinical practice, whole blood trough levels have generally been in the range of 5-20 ng/ml in kidney transplant patients in the early post-transplant period, and 5-15 ng/ml during subsequent maintenance therapy. See SmPC for dosage adjustments in special populations. Method of administration: Envarsus should be taken once daily in the morning, swallowed whole with fluid (preferably water) immediately following removal from the blister. Envarsus should generally be taken on an empty stomach to achieve maximal absorption. Contraindications Hypersensitivity to active substance or excipients. Hypersensitivity to macrolides. Warnings and precautions Medication errors, including inadvertent, unintentional or unsupervised substitution of immediate- or prolongedrelease tacrolimus formulations, have been observed with tacrolimus. This has led to serious adverse reactions, including graft rejection, or other adverse reactions which could be a consequence of either underor over-exposure to tacrolimus. Patients should be maintained on a single formulation of tacrolimus with the corresponding daily dosing regimen; alterations in formulation or regimen should only take place under the close supervision of a transplant specialist. Envarsus is not recommended for use in children below 18 years of age due to the limited data on safety and/or efficacy. During the initial post-transplant period, monitoring of the following parameters should be undertaken on a routine basis: blood pressure, ECG, neurological and visual status, fasting blood glucose levels, electrolytes (particularly potassium), liver and renal function tests, haematology parameters, coagulation values, and plasma protein determinations. If clinically relevant changes are seen, adjustments of the immunosuppressive regimen should be considered. Gastrointestinal perforation has been reported in patients treated with tacrolimus, adequate treatments should be considered immediately after suspected symptoms or signs occur. Extra monitoring of tacrolimus concentrations is recommended during episodes of diarrhoea. Cardiomyopathies have been observed in tacrolimus treated patients on rare occasions. Most cases have been reversible, occurring with tacrolimus blood trough concentrations much higher than the recommended maximum levels. Other factors observed to increase the risk of these clinical conditions included pre-existing heart disease, corticosteroid usage, hypertension, renal or hepatic dysfunction, infections, fluid overload, and oedema. Accordingly, high-risk patients receiving substantial immunosuppression should be monitored, using such procedures as echocardiography or ECG pre- and post-transplant (e.g. initially at 3 months and then at 9-12 months). If abnormalities develop, dose reduction of Envarsus or change of treatment to another immunosuppressive agent should be considered. Tacrolimus may prolong the QT interval, caution should be exercised in patients with diagnosed or suspected Congenital Long QT Syndrome. Patients treated with tacrolimus have been reported to develop EBV-associated lymphoproliferative disorders. Risk factors include using a combination of immunosuppressives, such as antilymphocytic antibodies (e.g. basiliximab, daclizumab) concomitantly, or EBV-Viral Capsid Antigen (VCA)-negative patients. Therefore, in this patient group, EBV-VCA serology should be ascertained before starting treatment with Envarsus. Careful monitoring with EBV-PCR is recommended. Positive EBV-PCR may persist for months and is per se not indicative of lymphoproliferative disease or lymphoma. As with other potent immunosuppressive compounds, the risk of secondary cancer is unknown. Exposure to sunlight and UV light should be limited. Patients treated with immunosuppressants, including Envarsus are at increased risk for opportunistic infections (bacterial, fungal, viral, and protozoal). Among these conditions are BK virus associated nephropathy and JC virus associated progressive multifocal leukoencephalopathy (PML).These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms. Patients treated with tacrolimus have been reported to develop posterior reversible encephalopathy syndrome (PRES). If symptoms indicating PRES such as headache, altered mental status, seizures, and visual disturbances, a radiological procedure (e.g. MRI) should be performed. If PRES is diagnosed, adequate blood pressure and seizure control, and immediate discontinuation of systemic tacrolimus is advised. Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. All patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease or concomitant medicinal product associated with PRCA. Dose reduction may be necessary in patients with severe liver impairment. Envarsus contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. (Refer to SmPC for full list of interactions). Side effects Very common: tremor, renal impairment, hyperglycaemic conditions, diabetes mellitus, hyperkalaemia, infections, hypertension,

insomnia, headache, diarrhoea, nausea, abnormal liver function tests Common: anaemia, thrombocytopenia, leukopenia, abnormal red blood cell analyses, leukocytosis, anorexia, metabolic acidoses, other electrolyte abnormalities, hyponatraemia, fluid overload, hyperuricaemia, hypomagnesaemia, hypokalaemia, hypocalcaemia, decreased appetite, hypercholesterolaemia, hyperlipidaemia, hypertriglyceridaemia, hypophosphataemia, confusion and disorientation, depression, anxiety symptoms, hallucination, mental disorders, depressed mood, mood disorders and disturbances, nightmare, nervous system disorders, seizures, disturbances in consciousness, peripheral neuropathies, dizziness, paraesthesias and dyaesthesias, writing impaired, eye disorders, blurred vision, photophobia, tinnitus, ischaemic coronary artery disorders, tachycardia, thromboembolic and ischaemic events, vascular hypotensive disorders, haemorrhage, peripheral vascular disorders, parenchymal lung disorders, dyspnoea, pleural effusion, cough, pharyngitis, nasal congestion and inflammations, gastro-intestinal (GI) signs and symptoms, vomiting, GI and abdominal pains, GI inflammatory conditions, GI haemorrhages, GI ulceration and perforation, ascites, stomatitis and ulceration, constipation, dyspeptic signs and symptoms, flatulence, bloating and distension, loose stools, bile duct disorders, hepatocellular damage and hepatitis, cholestasis and jaundice, rash, pruritus, alopecias, acne, increased sweating, arthralgia, back pain, muscle cramps, pain in limb, renal failure, acute renal failure, toxic nephropathy, renal tubular necrosis, urinary abnormalities, oliguria, bladder and urethral symptoms, febrile disorders, pain and discomfort, asthenic conditions, oedema, disturbed body temperature perception, increased blood alkaline phosphatase, increased weight, primary graft dysfunction. In clinical studies in kidney transplant patients receiving Envarsus, the most frequent adverse reactions (at least in 2% of patients) were tremor, diabetes mellitus, blood creatinine increased, urinary tract infection, hypertension, BK virus infection, renal impairment, diarrhoea, toxicity to various agents, and toxic nephropathy. Among the most frequent adverse reactions (at least in 2% of patients) in clinical studies in liver transplant patients receiving Envarsus were tremor, headache, fatigue, hyperkalaemia, hypertension, renal failure, blood creatinine increased, dizziness, hepatitis C, muscle spasms, tinea infection, leukopenia, sinusitis, and URTI. Uncommon: coagulopathies, pancytopenia, neutropenia, abnormal coagulation and bleeding analyses, dehydration, hypoglycaemia, hypoproteinaemia, hyperphosphataemia, psychotic disorder, encephalopathy, central nervous system haemorrhages and cerebrovascular accidents, coma, speech and language abnormalities, paralysis and paresis, amnesia, cataract, hypoacusis, heart failures, ventricular arrhythmias and cardiac arrest, supraventricular arrhythmias, cardiomyopathies, abnormal ECG investigations, ventricular hypertrophy, palpitations, abnormal heart rate and pulse investigations, deep limb venous thrombosis, shock, infarction, respiratory failures, respiratory tract disorders, asthma, acute and chronic pancreatitis, peritonitis, increased blood amylase, paralytic ileus, gastrooesophageal reflux disease, impaired gastric emptying, dermatitis, photosensitivity, joint disorders, haemolytic uraemic syndrome, anuria, dysmenorrhoea and uterine bleeding, decreased weight, influenza like illness, increased blood lactate dehydrogenase, feeling jittery, feeling abnormal, multi-organ failure, chest pressure sensation, temperature intolerance. Rare: thrombotic thrombocytopenic purpura, hypoprothrombinaemia, hirsutism, hypertonia, blindness, neurosensory deafness, pericardial effusion, acute respiratory distress syndrome, pancreatic pseudocyst, subileus, veno-occlusive liver disease, hepatic artery thrombosis, toxic epidermal necrolysis (Lyell’s syndrome), fall, ulcer, chest tightness, decreased mobility, thirst. Very rare: myasthenia, impaired hearing, abnormal echocardiogram, hepatic failure, Stevens Johnson Syndrome, nephropathy, haemorrhagic cystitis, increased fat tissue. Not Known: pure red cell aplasia, agranulocytosis, haemolytic anaemia, allergic and anaphylactoid reactions (Refer to SmPC for full list of adverse reactions) Legal category POM Packs and prices 0.75mg £44.33 1x30 tablets, 1mg £59.10 1x30 tablets, 4mg £236.40 1x30 tablets Marketing authorisation numbers EU/1/14/935/001, EU/1/14/935/004, EU/1/14/935/007. Full prescribing information is available on request from the UK Distributor Chiesi Limited, 333 Styal Road, Manchester, M22 5LG Date of preparation July 2015

For the UK: Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to Chiesi Limited, (address as above) Tel: +44(0)161 488 5555. For Ireland: Adverse events should be reported to HPRA Pharmacovigilance, Earlsfort Terrace, IRL, Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website:, e-mail: Adverse events should also be reported to Chiesi Limited, (address as above) Tel: +44(0)161 488 5555.

References: 1. Bunnapradist S, Ciechanowski K, West-Thielke P, et al. Conversion From Twice-Daily Tacrolimus to Once-Daily Extended Release Tacrolimus (LCPT): The Phase III Randomized MELT Trial. Am J Transplant 2013;13:760-9. 2. Budde K, Bunnapradist S, Grinyo JM, et al. Novel Once-Daily Extended-Release Tacrolimus (LCPT) Versus Twice-Daily Tacrolimus in De Novo Kidney Transplants: One-Year Results of Phase III, Double-Blind, Randomized Trial. American Journal of Transplantation 2014;14:2796-2806. 3. Bunnapradist S et al. LCPT once-daily extendedrelease tacrolimus tablets versus twice-daily capsules: a pooled analysis of two phase 3 trials in important de novo and stable kidney transplant recipient subgroups. Transplant International. 2016;29:603-11. Envarsus® is a registered trademark of Veloxis Pharmaceuticals A/S Ltd. Prograf® is a registered trademark of Astellas Pharma Europe Ltd. Date of preparation: March 2017 CHENV20170355

Prolonged-release tacrolimus tablets

TACROLIMUS REDEFINED For those patients who need a different tacrolimus...

Why wait?

In a post-hoc pooled analysis from two Phase 3 trials 1,2, elderly (≥65 years) kidney transplant recipients treated with Envarsus® were associated with fewer treatment failures vs. Prograf®.3 • The sub-populations did not reach statistical significance in the individual Phase 3 studies • The analyses were not adjusted for multiple comparisons • Caution should be exercised when interpreting p-values due to potential multiplicity Prolonged-release tacrolimus tablets

Prescribing information and references can be found on reverse. Date of Prep: March 2017 CHENV20170355

38 Psoriasis

An Insight into the clinical aspects Psoriasis Aine Sinead Kelly, Caitriona Ryan Department of Dermatology, St Vincentâ&#x20AC;&#x2122;s University Hospital, Dublin Corresponding author: Caitriona Ryan, MD, Department of Dermatology, St Vincentâ&#x20AC;&#x2122;s Univerisity Hospital, Elm Park, Dublin Phone: 01 2214189

Introduction Psoriasis is an immune mediated polygenic skin disorder affecting approximately 1-3% of the population1. In the most common form of psoriasis, the characteristic lesion is a sharply demarcated erythematous plaque with silver scale. These plaques are often localised to the extensor surfaces and scalp but can be widespread in more extensive disease. Psoriasis is considered to be a familial condition. Linkage and association studies have identified up to 41 psoriasis susceptibility regions in different chromsomal locations2-4. The most important of these seems to be the PSORS1 gene5. Psoriasis is associated with the HLA Cw6 allele. This allele is also strongly linked to the age of onset of psoriasis. In one study, HLA Cw6 allele was expressed in 90% of patients with early onset psoriasis, in 50% with late onset disease and only 7% of a control population. Patients can present at any age but typically two peaks in age of onset have been described: 20-30 years of age and 50-60 years of age, respectively6. 30% of patients have or will develop psoriatic arthritis and clinicians treating psoriasis patients should have a low threshold for referral7. There is growing evidence in the literature that psoriasis is more than a disease of the skin and that it has important systemic manifestations similar to other chronic inflammatory diseases. Psoriasis patients have an increased incidence of depression and anxiety in psoriasis patients8. They also have a clinically significant increased risk of cardiovascular disease and cardiovascular risk factors when compared to the general population9. Dermatologists and general practitioners should work in tandem to screen for these risk factors and treat them according to national and international guidelines. Clinical presentation Chronic plaque psoriasis accounts for 90% of psoriasis10. The elbows, knees, scalp, pre-sacrum and perinatal cleft are sites of predilection and should always be

Issue 41 â&#x20AC;˘ HPN

Figure 1 Erythrodermic Psoriasis

Figure 1 Erythrodermic Psoriasis

Figure 2 Palmoplantar pustulosis

examined. The reported incidence of nail changes in psoriasis is 10-55% and is an important clue when the diagnosis of psoriasis is not obvious11, 12.Guttate psoriasis presents as small discrete papules and plaques which are tear drop shaped and typically follow a sore throat. Psoriasis can present as an erythroderma(erythema involving 90% of cutaneous surfaces (figure 1) and should be suspected in those with a history of previous psoriasis, and nail changes. Generalised pustular

Figure 1 Erythrodermic Psoriasis

Figure 2 Palmoplantar pustulosis psoriasis starts abruptly with

erythema and pustulation. The skin is painful and the patient may have systemic symptoms. Both erythrodermic and generalised pustular psoriasis should be considered as dermatological emergencies. Urgent referral to secondary services or admission to an emergency department is Figure 2 Palmoplantar pustulosis necessary. Brown/ yellow pustules localised to the palms is known as palmoplantar pustular psoriasis (pustulosis) figure 2 . Up to 90% of palmoplantar pustulosis

patients are smokers. Research from Sweden found that current smokers had a 74-fold increased risk of developing palmoplantar pustulosis compared with nonsmokers13. Palmoplantar psoriasis occurs more commonly in females with frequencies in women ranging from 58 to 94 percent14-16. Intertriginous or flexural psoriasis lesions are characterised by shiny, pink to red, thin plaques with little to no scale. The most common sites are axilla, inguinal fold, gluteal cleft and inframammary

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40 Psoriasis

Figure 2 Palmoplantar pustulosis

Figure 3 Pitting & Oncholysis in Psoriatic Nail

excess alcohol consumption are independent risk factors for the development of cardiovascular disease and both are increased in psoriasis. A meta-analysis of twenty eight studies showed an association between psoriasis and current or former smoking. This suggests that smoking is an independent risk for the development of psoriasis27.

Figure 3 Pitting & Oncholysis in Psoriatic Nail areas. The genitalia are currently involved in a third of of psoriasis patients with two thirds of patients reporting current or previous genital disease.. Genital psoriasis has a high impact on quality of life and sexual health and psoriasis patients should be asked specifically about genital disease during each consultation17. Psoriatic arthritis The most common extra cutaneous manifestation of psoriasis is psoriatic arthritis (PsA). Certain clinical features may suggest a slightly higher predisposition to PsA in patients including scalp psoriasis and nail psoriasis (nail changes including pitting, onycholysis, onychoschizia, subungal hyperkeratosis and oil spots, figure 3), episodes of dactylitis (sausage finger), and a family history of PsA. Patterns of psoriatic arthritis include distal arthritis, asymmetric oligoarthritis, symmetric polyarthritis, arthritis mutilans and spondyloarthritis. These patients may also have soft tissue inflammation and entesitis (inflammation of the tendon insertion.) The average time for onset of joint disease from development of psoriasis Is 7 to 12 years years18. There is strong evidence to suggest a delay in diagnosis of psoriatic arthritis can impact on a patients’ long term outcome. Irreversible changes in the joint can occur within the first year of psoriatic arthritis development in 40-60% of patients19. Timely diagnosis and treatment may reduce joint pain and inflammation, reduce joint deformity, physical limitations and disabiility. Thus screening of all patients with psoriasis for psoriatic arthritis is pertinent at every visit. Morning stiffness lasting more than 30 minutes is a strong indicator of psoriatic arthritis.Patients should be asked about joint pains and back stiffness particularly early in the morning or after a long journey20. Ideally a PEST

Issue 41 • HPN

questionnaire should be completed by psoriasis patients annually. Cardiovascular co-morbidities Beyond its association with psoriatic arthritis, the association between psoriasis and cardiovascular disease has now been established and is an area of intensive research. There is now considerable evidence that patients with moderate to severe psoriasis have an increased risk of conditions such as cardiovascular disease, obesity, hypertension, hyperlipidemia, diabetes mellitus and the metabolic syndrome8. Patients with psoriasis have an excess in mortaility when compared to the general population21. A seminal cohort study using the United Kingodom General Practice Research Database (GPRD) showed that patients with psoriasis had an increased adjusted relative risk for myocardial infarction after controlling for other cardiovascular risk factors, particularly in younger patients and those with more severe psoriasis22. A similar study using the GPRD showed the incidence of risk factors for cardiovascular disease such as hypertension, diabetes, obesity and hyperlipidemia was increased compared with the general population23. Recent studies examining the association of psoriais and these cardiovascular risk factors have supported these findings from the GPRD24, 25. Psoriasis patients are more likely to be obese. However, it is unclear whether obesity predates or is a consequence of psoriasis. A prospective study in 78,626 women followed for 14 years showed a biologic gradient between increasing BMI and risk of incident psoriasis26. This suggests obesity may precede the development of the disease. The frequencies of smoking and

All psoriatic patients should have opportunistic blood pressure monitoring when attending appointments with their General Physician. They also require an annual lipid profile and HBA1c or fasting glucose to assess for dyslipidaemia and diabetes or insulin resistance. There are no dedicated guidelines for the management of coronary risk in patients with psoriasis. There should be a low threshold to start cardio-protective medications28. The psychosocial burden of disease Patients with psoriasis may experience significant psychological and social disbility. This varies amongst patients and doesn’t always correlate with psoriasis severity. Psoriasis patients may avoid certain social situations e.g. swimming, and can be restricted In their clothing choices e.g avoid wearing black. Studies show that psoriasis paients have a higher risk of sexual dysfunction as compared to the general population. Psoriasis patients with genital psoriasis have higher incidence of dyspareunia, lower frequency of intercourse, and a worsening of their psoriasis following intercourse36. In a study of 5604 psoriasis patients, 12 % were unemployed. Of these 12%, 92% cited psoriasis and/ or psoriatic arthritis as the sole reasons for not working29. A recent meta-analysis of 98 studies showed the prevalence of depressive symptoms amongst psoriasis patients was 28%. The prevalence of clinical depression in this analysis was 12% using International Classification of Diseases code38. Psychologicial distress can make psoriasis disease worse. Many dermatology centres screen patients for anxiety and depression at each clinic visit. Recent studies in mindfulness and cognitive behavioural therapy in psoriasis patients have shown significant improvements in patients mental health and the clincial severity of their psoriasis using mindfulness and behavioural therapy30.

Up to thirty per cent of psoriasis patients abuse alcohol by drinking in excess. This can lead to a wide spectrum of health and social problems, including ischaemic heart disease, atrial fibrillation, sudden death, liver cirrhosis, cerebrovascular disease and stroke, acute and chronic kidney injury, peptic ulcers, depression, suicide and anxiety. A large objective study found that mortality from alcohol related causes is significantly higher in psoriasis patients than in the general population. There is increased incidence of non alcholic fatty liver disease in psoriasis patients31. This can compound the psoriasis patients inclination towards excess consumption of alcohol. Alcohol excess can thus limit treatment options in these patients. Physicians should be aware that patients who abuse alcohol often evade detection until medical, legal or social problems arise. Self – reports of alcohol consumption often underestimate intake. Screening questionnaires such as AUDIT, CAGE and MAST can also be helpful32. Furthermore both smoking and alcohol excess has been shown to both worsen psoriasis and decrease the efficacy of treatments. The misuse of alcohol has also been shown to be a risk factor for the development of psoriasis. Social behaviours such as cigarette smoking and excess alcohol consumption are modifiable risk factors for both psoriasis and cardiovascular disease. Psoriasis patients should be opportunistically counselled and supported to modify their behaviours. Conclusion Once thought as a skin condition only, psoriasis has come to be appreciated as a complex systemic inflammatory disorder. In recent years the association of psoriasis with cardiovasular disease is becoming increasingly studied and understood. Psoriatic patients have increased incidence of both cardiovascular risk factors and events. Screening of psoriasis patients and implementation of appropriate interventions is necessary and the joint responsibility of their dermatologist and their GP. Furthermore, depression and anxiety are very prevalent in psoriasis patients and signs are often not appreciated by physicians. Patients should be assessed and treated or referred appropriately for pschological and mental health issues. Find the full version with references at





3,523 427 PATIENTS








STELARA® 45 mg and 90 mg solution for injection and 130 mg concentrate for solution for infusion PRESCRIBING INFORMATION. ACTIVE INGREDIENT(S): Ustekinumab. Please refer to Summary of Product Characteristics (SmPC) before prescribing. INDICATION(S): Plaque psoriasis adults: Treatment of moderate to severe plaque psoriasis in adults who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapies including ciclosporin, methotrexate or PUVA. Plaque psoriasis paediatrics: Moderate to severe plaque psoriasis in adolescent patients from 12 years of age, who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies. Psoriatic arthritis: Alone or in combination with methotrexate for treatment of active psoriatic arthritis in adult patients when response to previous non-biological disease-modifying anti-rheumatic drug (DMARD) therapy has been inadequate. Crohn’s Disease: Treatment of adult patients with moderately to severely active Crohn’s disease who had inadequate response with/lost response to/were intolerant to either conventional therapy or TNFα antagonist or have contraindications to such therapies. DOSAGE & ADMINISTRATION: Adults: Under guidance and supervision of a physician experienced in diagnosis and treatment of psoriasis/psoriatic arthritis/Crohn’s disease. Psoriasis or psoriatic arthritis. Subcutaneous (s.c.) injection. Avoid areas with psoriasis. Self-injecting patients or caregivers ensure appropriate training. Physicians are required to followup and monitor patients. Plaque psoriasis, adults & elderly: Patients ≤ 100kg, 45 mg at week 0 followed by a 45 mg dose at week 4, then every 12 weeks. Patients >100 kg, 90 mg at week 0 followed by a 90 mg dose at week 4, then every 12 weeks (45 mg was less effective in these patients). Plaque psoriasis paediatrics (12 years and older): Patients <60 kg, 0.75 mg/kg at week 0, followed by 0.75 mg/kg at week 4 then every 12 weeks thereafter. Patients ≥60 - ≤100kg, 45 mg at week 0 followed by 45 mg at week 4, then every 12 weeks. Patients >100 kg, 90mg at week 0, followed by 90mg at week 4, then every 12 weeks. Psoriatic arthritis, adults & elderly: 45 mg at week 0 followed by a 45 mg dose at week 4, then every 12 weeks. Alternatively, 90 mg may be used in patients with a body weight >100 kg. Consider discontinuation if no response after 28 weeks. Crohn’s Disease Initial single intravenous infusion dose based on body weight (260 mg or 390 mg or 520 mg) diluted in 0.9% w/v sodium chloride solution and given over at least one hour. At week 8 after intravenous dose, 90 mg s.c. dose is given; followed by every 12 weeks (or 8 weeks based on clinical judgement). Consider discontinuation if no response at 16 weeks. Immunomodulators

and/or corticosteroids may be continued but consider reducing/discontinuing corticosteroids if responding to Stelara. If therapy interrupted, resume s.c. every 8 weeks if safe/effective. Children: <12 years - Not recommended for psoriasis. <18 years - Not recommended for psoriatic arthritis and Crohn’s disease. Renal & Hepatic impairment: Not studied. CONTRAINDICATIONS: Hypersensitivity to product; clinically important, active infection. SPECIAL WARNINGS & PRECAUTIONS: Infections: Potential to increase risk of infections and reactivate latent infections. Caution in patients with a chronic infection or history of recurrent infection, particularly TB. Patients should be evaluated for tuberculosis prior to initiation of STELARA. Consider anti-tuberculosis therapy prior to initiation of STELARA in patients with past history of latent or active tuberculosis. Patients should seek medical advice if signs or symptoms suggestive of an infection occur. If a serious infection develops, closely monitor and STELARA should not be administered until infection resolves. Malignancies: Potential to increase risk of malignancy. No studies in patients with history of malignancy or in patients who develop malignancy while receiving STELARA. Monitor all patients, in particular those older than 60, patients with a medical history of prolonged immunosuppressant therapy or those with a history of PUVA treatment for non-melanoma skin cancer. Concomitant immunosuppressive therapy: Caution, including when changing immunosuppressive biologic agents. Hypersensitivity reactions: Serious hypersensitivity reactions (anaphylaxis and angioedema) reported, in some cases several days after treatment. If these occur appropriate therapy should be instituted and STELARA discontinued. Latex sensitivity: Needle cover contains natural rubber (latex), may cause allergic reactions. Immunotherapy: Not known whether STELARA affects allergy immunotherapy. Serious skin conditions: Exfoliative dermatitis reported following treatment. Discontinue STELARA if drug reaction is suspected. SIDE EFFECTS: Common: upper respiratory tract infection, nasopharyngitis, dizziness, headache, oropharyngeal pain, diarrhoea, nausea, vomiting, pruritus, back pain, myalgia, arthralgia, fatigue, injection site erythema, injection site pain. Other side effects: cellulitis, serious hypersensitivity reactions (including anaphylaxis, angioedema), skin exfoliation, exfoliative dermatitis. Studies show adverse events reported in ≥12 year olds with plaque psoriasis were similar to those seen in previous studies in adults with plaque psoriasis. Refer to SmPC for other side effects. FERTILITY: The effect of ustekinumab has not been evaluated. PREGNANCY: Should be avoided. Women of childbearing potential: Use effective contraception during treatment and for at least 15 weeks post-treatment.

LACTATION: Limited data in humans. INTERACTIONS: In vitro, STELARA had no effect on CYP450 activities. Vaccinations: Live vaccines should not be given concurrently with STELARA, and should be withheld for at least 15 weeks after last dose of STELARA. STELARA can resume at least 2 weeks after such vaccinations. No data on secondary transmission of infection by live vaccines in patients receiving STELARA. Concomitant immunosuppressive therapy: Psoriasis: Safety and efficacy of STELARA in combination with other immunosuppressants, including biologics, or phototherapy have not been evaluated. Psoriatic arthritis: concomitant MTX did not appear to affect STELARA. Crohn’s disease: concomitant immunosupressive or corticosteroid therapy did not appear to affect STELARA. Refer to SmPC for full details of interactions. LEGAL CATEGORY: Prescription Only Medicine. PRESENTATIONS, PACK SIZES, MARKETING AUTHORISATION NUMBER(S): 45 mg, 1 x vial, EU/1/08/494/001. 45 mg, 1 x 0.5 ml prefilled syringe, EU/1/08/494/003, 90 mg, 1 x 1.0 ml pre-filled syringe, EU/1/08/494/004. 130 mg, 1 x vial, EU/1/08/494/005. MARKETING AUTHORISATION HOLDER: JANSSENCILAG INTERNATIONAL NV, Turnhoutseweg 30, B-2340 Beerse, Belgium. FURTHER INFORMATION IS AVAILABLE FROM: Janssen-Cilag Limited, 50 – 100 Holmers Farm Way, High Wycombe, Buckinghamshire, HP12 4EG, UK. Prescribing information last revised: 11/2016 Adverse events should be reported. Healthcare professionals are asked to report any suspected adverse events via: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website:, E-mail: Adverse events should also be reported to JanssenCilag Limited on +44 1494 567447 or at © Janssen-Cilag Limited 2016 * Psoriasis Longitudinal Assessment and Registry † Outcome and Retention Rate of Biologic Treatments for Psoriasis ‡ British Association of Dermatologists Biologic Interventions Register § Continuous Assessment of Psoriasis Treatment Use REgistry with biologics References: 1. Menter A, et al. J Eur Acad Dermatol Venerol 2016;30:1148−58. 2. Vilarrasa E, et al. J Am Acad Dermatol 2016;74:1066−72. 3. Warren RB, et al. J Invest Dermatol 2015;135:2623–40. 4. Gniadecki R, et al. Br J Dermatol 2015;172:244–52. 5. van den Reek J, et al. Br J Dermatol 2014;171:1189−96. PHIR/STE/0417/0009 | Date of Preparation: May 2017

42 Dermatitis

Shiitake Flagellate Dermatitis: the First Case Reported in Ireland N Byrne1*, C Foley1, M Cotter2, S O’Gorman1, E Storan1, P Marren1 1 Department of Dermatology, University Hospital Galway, Galway 2 Department of Pathology, University Hospital Galway, Galway Abtract: Shiitake (Lentinula edodes) is the second most commonly consumed mushroom worldwide. The first case of shiitake mushroom flagellate dermatitis was described in Japan in 1977 and it is now being reported in the western world. We describe the first reported case in Ireland.

Figure 1 The Flagellate dermatitis appeared as oedematours, erythematous, linear eruptions, arranged in parallel streaks on the back (a) and upper legs (b)

Introduction Shiitake (Lentinula edodes) is the second most commonly consumed mushroom worldwide1. It is used in Asian medicine for its anticarcinogenic, antihypertensive and lipid lowering properties2. Furthermore, extracts of these mushrooms are used in overthe-counter dietary supplements designed to improve the immune system1. The first case of shiitake mushroom induced flagellate dermatitis was described in Japan in 1977 and it is now being reported in the western world3. After literary review and consultation with the Irish National Poisons Information Centre, we believe this is the first reported case of shiitake flagellate dermatitis in Ireland. Case Report A 53-year-old lady presented to the dermatology outpatient clinic with an intensely itchy widespread linear rash. Past medical history included hyperlipidaemia and a known allergy to hair dye. She had not used any hair dye recently nor taken any new medications. Clinical examination revealed a florid, oedematous,

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erythematous linear eruption, arranged as extensive parallel streaks on the neck, trunk and limbs, Figure 1. There was no dermographism. Mucosal surfaces were normal. Blood tests showed an elevated CRP 42 mg/L (norm.: 0 – 5). The other routine laboratory parameters were normal, including electrolytes, renal function, complete blood count and liver function. Skin biopsies demonstrated a non-specific spongiotic dermatitis with marked oedema of the papillary and reticular dermis. On detailed questioning the patient reported eating shiitake mushrooms at an Asian restaurant two days prior to the onset of the rash. Based on the classical clinical pattern of whiplash-like eruptions and history of eating shiitake mushrooms, we made a diagnosis of shiitake mushroom induced flagellate dermatitis. She was treated with a five day course of oral prednisolone, followed by topical steroid therapy. Chlorphenamine was prescribed for the pruritis. The rash resolved after four weeks. Subsequent patch testing confirmed an allergy to p-Phenylenediamine, the main constituent of hair dyes.

Flagellate dermatitis is characterized by pruritic, erythematous linear grouped papules resembling whiplash marks, affecting the neck, trunk and limbs. In addition to shiitake mushroom ingestion, it has been associated with bleomycin, dermatomyositis and adult onset Still’s disease4. Discussion Controversy surrounds the exact pathogenesis of shiitake flagellate dermatitis. Most agree that the polysaccharide lentinan is the culprit. This theory is supported by reports of flagellate dermatoses in patients treated with intravenous lentinan in Japan as adjuvant chemotherapy5. In addition, Lentinan is broken down by heat which may explain why the dermatitis usually only occurs following ingestion of raw or partially cooked shiitake mushrooms1. Disagreement begins when debating exactly how the lentinan causes the dermatitis. Some believe the polysaccharide has a direct toxic effect, causing interleukin-1 secretion, leading to vasodilatation, haemorrhage and eruption6. Others argue an allergic process given the relative

rarity of the disorder despite widespread consumption but patch testing to shiitake has had variable results7-9. There is a delay between ingestion and the eruption usually 24 to 48hrs – which can complicate the diagnosis. Laboratory findings are nonspecific10. Diagnosis is based on the classical appearance and history of shiitake ingestion. Histology from skin biopsies are non-specific showing features such as epidermal spongiosis and perivascular, cuff-shaped lymphocytic dermal infiltrates4. The condition is self-limiting. Symptomatic treatment includes emollients, topical steroids, and antihistamines. Short courses of oral steroids may be required in severe cases such as ours. In shiitake flagellate dermatitis the skin lesions resolve within two to four weeks, without scarring. In contrast, flagellate dermatitis caused by bleomycin can cause hyperpigmentation which lasts for several months4. Repeated consumption of shiitake typically elicits recurrence so should be avoided10. Shiitake flagellate dermatitis is a rare entity in the Western world but the popularity of Asian cuisine is increasing and the online sales of health food supplements is soaring. So while the debate as to the exact pathogenesis of the dermatitis continues, one thing remains clear – we are going to see more cases of shiitake flagellate dermatitis.

Find the full version with references at

Crohn's Disease 43

Overview of Crohn's Disease Management Crohn’s disease is one of the two main forms of inflammatory bowel disease (IBD). The second main form of inflammatory bowel disease is ulcerative colitis. Crohn’s disease causes inflammation of the digestive system. Inflammation is the body’s reaction to injury or irritation, and can cause redness, swelling and pain. In the case of Crohn’s, while it is due to an immune response, it does not appear to be an autoimmune disease meaning that it is not caused by the immune system being triggered by the body itself. Crohn’s disease got its name from an American doctor Burrill Crohn who first reported cases in 1932 in Mount Sinai hospital in New York.

colon is affected, in a pattern like ulcerative colitis. In others, multiple parts of the intestinal tract are affected. Rarely, the mouth, throat, oesophagus or stomach may be affected. A patch of inflammation may be as small as a few centimetres or extend most of distance along the intestinal tract. As well as affecting the lining of the bowel, Crohn’s may also go deeper into the bowel wall. In some cases, the inflammation in the intestinal tract triggers inflammation outside the intestine leading to other inflammatory complaints affecting the joints, eye, skin and endocrine system to name the most common.

Crohn’s is a chronic condition with many experiencing it as an ongoing and life-long condition often with periods of remission as well as relapses or flare-ups. There is currently no cure for Crohn’s but medication and sometimes surgery can give long periods of relief.

Crohn’s disease is a very individual condition ranging from very few symptoms to others with frequent flare-ups or constant disease. The part of the intestinal tract most affected with Crohn’s influences the symptoms.

Difference between Ulcerative colitis and Crohn’s Disease Ulcerative colitis only affects the inner lining of the colon, also known as the large intestine. In Crohn's disease, inflammation can appear anywhere in the digestive tract, from the mouth to the anus. Crohn’s generally affects all the layers of the bowel walls, not just the inner lining so tends to have more serious symptoms. Causes The exact cause is not known but researchers and experts think Crohn’s is caused by a combination of factors, including: • Genetic factors • an abnormal reaction of the digestive system to bacteria in the intestine • an unknown trigger or perhaps set of triggers that may include viruses, other bacteria, diet, stress, or other environmental factors. How does Crohn’s disease affect the intestinal tract? Any part of the intestinal tract can be affected in Crohn’s disease. The most common area is the last part of the small intestine (terminal ileum) and the first part of the large intestine (colon), near the appendix. For some only the


In general, the most common symptoms during a flare-up are: • Abdominal pain and diarrhoea. Sometimes mucus, pus or blood is mixed with the diarrhoea. • Tiredness and fatigue. This can be due to the illness itself, from the weight loss associated with flare-ups or surgery, anaemia from blood loss or simply due to a lack of sleep due to pain, diarrhoea and other symptoms which inevitably affect sleep. • Feeling generally unwell. Some people may have a raised temperature and feel feverish. • Mouth ulcers • Loss of appetite and weight loss. • Anaemia (a reduced level of red blood cells). Crohn’s makes anaemia more likely due to blood loss, not eating enough because of symptoms like pain and diarrhoea and because the body is not fully absorbing the nutrients from the food. Anaemia is a major factor in tiredness. Prevalence It’s estimated that Crohn’s disease affects one in every 650 people in the UK. The figures in Ireland are not thought to be significantly different. Crohn’s appears to be slightly more common in women than in men. The Irish Society

for Colitis and Crohn’s disease indicated there were 5.9 new cases of Crohn’s disease in Ireland per 100,000 population in 2011 and compared to 14.9 new cases of ulcerative colitis per 100,000 the same year. The incidence of Crohn's disease is higher than ulcerative colitis in children. The peak age of incidence of Crohn’s is between the ages of 15 and 35, with a second (smaller) peak from the 50s to 70s. IBD diagnosed in children can behave differently and can be treated differently to that diagnosed in adults It’s more common in urban rather than rural areas and in northern developed countries, although the numbers are beginning to increase in developing nations. It is also more common in smokers. Main types of Crohn’s disease Crohn’s is often categorised to which part or parts of the intestinal tract are most affected. The main types are: Terminal ileal and ileocaecal Crohn’s in the ileum (the last part of the small intestine) is known as ileal or sometimes ‘terminal ileal’ Crohn’s because it affects the terminus or end of the ileum. If it affects the beginning of the large bowel it is known as ileocaecal Crohn’s. In this type of Crohn’s, pain is often experienced in the lower right side of the abdomen, especially after eating. There is often weight loss, and diarrhoea may occur. Because Crohn’s in the ileum can make it difficult for the body to absorb bile salts, bile salts can build up leading to irritation

the bowel lining; Diarrhoea often occurs and is most likely to be watery. The diarrhoea is unlikely to be bloody, as any blood lost will be digested by the time it reaches the rectum. About four in 10 people with Crohn’s have ileal or ileocaecal disease. Small bowel Abdominal pain and diarrhoea are also common symptoms if Crohn’s occurs further up the small bowel. Again, the diarrhoea is unlikely to be blood stained, but weight loss and anaemia may be experienced. Nearly a third of people with Crohn’s have it in the small bowel. Colonic Crohn’s disease in the colon (large intestine or large bowel) is known as ‘Crohn’s colitis’. This is a common form of Crohn’s disease. The main symptom tends to be blood stained diarrhoea. Because of the inflammation, the colon cannot hold as much waste as normal so very frequent bowel movements occur (six or more a day), especially if the rectum is inflamed. Gastroduodenal Crohn’s in the upper intestinal tract (the oesophagus, stomach or duodenum) is much less common. Symptoms that indicate Crohn’s in the upper intestinal tract include indigestion-like pain, nausea, loss of appetite, and weight loss. Perianal Crohn’s in the area around the anus can occur on its own or at the same time as inflammation in other parts of the body. It can cause symptoms such as:

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44 Crohn's Disease Joints

• Fissures: tears in the lining of the anal canal which can cause pain and bleeding, especially during bowel movements. • Skin tags: small fleshy growths around the anus. • Haemorrhoids: swollen areas in the anal canal. • Abscesses: collections of pus that can become swollen and painful. Most often found in the area around the anus and can cause a fever or lead to a fistula. • Fistulas: narrow tunnels or passageways between the intestinal tract and the skin or another organ. In perianal Crohn’s, fistulas often run from the anal canal to the skin around the anus. They appear as tiny openings in the skin that leak pus or sometimes faecal matter. They can irritate the skin and are painful, but can usually be treated with medication and/or surgery. Oral Crohn’s Crohn’s can occasionally affect the mouth. True oral Crohn’s which typically causes swollen lips and mouth fissures, is rare. However, about one in five people with Crohn’s tend to develop mouth ulcers. Complications Complications of Crohn’s can also be troublesome. Complications may occur in the intestinal tract or other areas of the body. Complications in the intestinal tract may include strictures, perforations and fistulas. Complications of Crohn’s disease affecting the intestinal tract Strictures Ongoing inflammation and then healing in the bowel may cause

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scar tissue to form. This can create a narrow section of the bowel, known as a stricture. A stricture can make it difficult for food to pass leading to a blockage. Symptoms include severe cramping abdominal pain, nausea, vomiting and constipation. The abdomen may become bloated and distended and the intestinal tract may make loud noises. Strictures are usually treated surgically mainly with operation known as a stricturoplasty. Perforations Very occasionally, a severe blockage caused by a stricture may lead to a perforation or rupture of the bowel, making a hole. The contents of the bowel can leak through the hole and form an abscess. This causes pain and a fever. An abscess may also develop into a fistula. Fistulas (Fistulae) A fistula can form when inflammation in Crohn’s spreads through the whole thickness of the bowel wall and continues to tunnel through the layers of other tissues. These tunnels or passageways can connect the bowel to other loops of bowel, to the surrounding organs, such as the bladder and vagina, or to the outside skin, including the skin around the anus (discussed earlier). Fistulas may be treated medically or with surgery. Complications of Crohn’s disease affecting other parts of the body Crohn’s disease can also cause problems outside the intestinal tract. Some people with Crohn’s develop conditions affecting the joints, eyes or skin. These often occur during active disease, but they can develop before any signs of bowel disease or during times of remission.

Inflammation of the joints affects up to one in three people with IBD. In people with Crohn’s, arthritis is more commonly associated with Crohn’s colitis (Crohn’s disease in the colon). The inflammation usually affects the large joints of the arms and legs, including the elbows, wrists, knees and ankles. Fluid collects in the joint space causing painful swelling, although there can be pain without obvious swelling. Symptoms generally improve with treatment for intestinal symptoms and there is mainly no lasting joint damage. A small percentage develop swelling and pain in the smaller joints of the hands or feet. This may be longer lasting and persist while the inflammatory bowel disease is in remission. More rarely, ankylosing spondylitis can develop in which the joints in the spine and pelvis become inflamed. This can flare up independently of the Crohn’s. Medication and physiotherapy can be helpful in treating arthritic symptoms.

people with Crohn’s who have had sections of the small intestine removed. Some of the drugs used for Crohn’s such as sulphasalazine and azathioprine can also cause anaemia. Symptoms of anaemia include tiredness and fatigue and if not treated can lead to shortness of breath, headaches and general weakness. Depending on the cause of anaemia, iron, B12 or folic acid supplements are the most common treatments. Crohn’s disease link to cancer Severe or extensive Crohn’s disease affecting all or most of the colon for many years can mean a slightly increased risk than normal of developing colon cancer Diagnosis Diarrhoea, abdominal pain, and weight loss lasting for several weeks or longer indicate Crohn’s is a possibility particularly if a family history of inflammatory bowel disease. Tests and physical examinations can confirm a diagnosis. These include:


Blood Tests and Stool Tests

Crohn’s can cause skin problems. The most common skin problem is erythema nodosum, which affects about one in seven people with Crohn’s. Painful red swellings appear, usually on the legs, and then fade leaving a bruiselike mark. This condition tends to occur during flare-ups and generally improves with treatment for the Crohn’s. More rarely, a skin condition called pyoderma gangrenosum affects people with Crohn’s disease. This starts as small tender blisters, which become painful, deep ulcers. These can occur anywhere on the skin, but most commonly appear on the shins or near stomas. It is usually treated with steroids or immune-suppressants but may need biological therapy.

Simple blood tests can show inflammation and anaemia; both of which are indicators of Crohn’s. Stools can also be tested for signs of bleeding or inflammation, and to check whether diarrhoea is caused by an infection.

Anaemia Anaemia means fewer red blood cells than normal and/or lower levels of haemoglobin in the blood. Haemoglobin is a protein found in red blood cells to help carry oxygen around the body. There are several different types of anaemia. People with inflammatory bowel disease are most likely to develop iron deficiency anaemia. This is caused by a lack of iron in the diet or poor absorption of iron from food and can be made worse by ongoing intestinal blood loss due to inflammation. Another type of anaemia is vitamin deficiency anaemia, caused by a low intake or poor absorption of certain vitamins, such as vitamin B12 or folic acid. This particularly affects

Endoscopy There are several types of endoscopy which have different names based on the type of scope used and part of the intestinal tract being examined. For example: • An upper GI endoscopy: a thin flexible tube with a camera in its tip is inserted through the mouth to examine the oesophagus, stomach and duodenum. • A sigmoidoscopy or colonoscopy: for symptoms in ileum or colon a sigmoidoscope (a short endoscope) or a colonoscope (a longer and more flexible endoscope) will be inserted through the anus to examine the rectum and colon. Endoscopies should not be painful but may be uncomfortable so the patient may be given a sedative to help relax. Biopsies (small samples of tissue) are often taken during the endoscopy. These can then be examined under a microscope to confirm the diagnosis. Barium X-ray Tests Barium sulphate is a harmless white chalky substance that coats the lining of the intestinal tract and so give a clearer outline in an

45 x-ray. It can be given as a drink to help show up problems in the stomach or small intestine, or in an enema to show up inflammation in the colon. MRI and CT Scans MRI (Magnetic Resonance Imaging) and CT (Computerised Tomography) scans can determine the extent of the inflammation. MRI scans use magnets and radio waves, and CT scans use a special kind of x-ray to build up a ‘3D’ image of the body. Ultrasound is sometimes also used to aid diagnosis. Could symptoms be IBS (Irritable Bowel Syndrome) People with Crohn’s can get bowel symptoms when the disease is not active. This might be due to Irritable Bowel Syndrome (IBS), which tends to be more common in people with Crohn’s than in the general population. There is no blood loss in IBS, but it can cause abdominal pain, bloating and a varying bowel habit with diarrhoea and/or constipation. If you are having symptoms like these, and tests do not show active inflammation or an infection, then it may be IBS. Treatment varies from changing diet to over the counter products like peppermint oil and mebeverine. Treatment Treatment for Crohn’s may be medical, surgical or a combination of both. For mild Crohn’s, no drug treatment may be needed. Dietary therapy may be another option for some. Treatment will depend on the type of Crohn’s. Medication used treat Crohn’s disease

• Biological or ‘anti-TNF’ drugs such as infliximab (Remicade®) and adalimumab (Humira®). Biological therapies are generally reserved for people in poor general health with severe symptoms of Crohn's disease, especially if corticosteroids and immunosuppressants are unsuitable or ineffective. Biological treatment usually lasts at least 12 months, unless these drugs stop being effective sooner or the patient cannot tolerate. After this time, condition will be assessed to determine if further treatment is necessary. Symptomatic drugs

Drug treatment for Crohn’s aims to reduce symptoms and control flare-ups, and then to prevent a relapse once the disease is under control. This can mean taking medication on an on-going basis, sometimes for many years.

Help control and reduce common symptoms such as pain, diarrhoea and constipation. They include

Anti-inflammatory drugs

• Bulking agents such as ispaghula husk (Fybogel®)

Help to reduce inflammation and include: • 5 ASAs or aminosalicylates such as mesalazine (brand names include Asacol®, Pentasa® and Salafalk®) and sulphasalazine (Salazopyrin®) • Corticosteroids, often just called steroids, such as prednisolone, hydrocortisone and budesonide (Entocort®) • Immuno-suppressants such as azathioprine (Imuran®), methotrexate and tacrolimus

• Anti-diarrhoeal such as loperamide (Imodium®) and cholestyramine (Questran®)

• Painkillers such as paracetamol and aspirin. Surgical treatment for Crohn’s Over the last 20 years, advances such as the development of biological drugs have produced better results for Crohn’s disease meaning surgery is less often needed. There have also been changes in the way surgery for Crohn’s is now managed. For example, extensive re-sections (removal of diseased sections

of the intestine) are now less common. However, surgery remains an important treatment option, often in combination with medical therapies. It is estimated that about seven out of 10 people with Crohn’s will still need surgery at some point in their lives. Surgery may sometimes be the only option when other treatments cannot sufficiently control their symptoms. Occasionally, an urgent operation is required, for example a severe blockage in the intestines or a hole or tear in the bowel. Dietary treatment for Crohn’s disease Enteral nutrition (also known as dietary treatment or nutritional therapy) involves a liquid diet replacement usually for a few weeks. These feeds contain all the essential nutrients in a simple form that the body can absorb with little or no digestion. They come in a range of flavours. An alternative may be to take the feed overnight through a naso-gastric tube (a fine tube passed through the nose down into the stomach). Enteral nutrition is widely used for children with Crohn’s disease, because it helps their growth and avoids the use of steroids. There is less evidence for the effectiveness of enteral nutrition in adults, particularly for active Crohn’s disease. Research has shown it to be less effective than steroids. However, enteral nutrition may be recommended for adults who prefer not to use drug therapy, and it can be useful as a

supplement for people who need extra nutrition. Are complementary and alternative approaches helpful? Some people with Crohn’s disease have found complementary and alternative medicines helpful for controlling symptoms such as such as abdominal pain and bloating. However, there are few reliable scientific studies to show the effectiveness of such therapies and it is possible that their symptoms may have gone into remission coincidentally, given the unpredictable course of Crohn’s or there may be a placebo effect. One area where there has been some scientific research is the use of omega 3 fish oils. However, a recent review concluded that fish oils were probably not effective at keeping people with Crohn’s in remission, as although some studies found symptoms improved, two larger studies showed no benefit. A small study on acupuncture for active Crohn’s also showed very slight improvement, but not enough to be significant. Other research has suggested that the herbal medicine wormwood may help with steroid reduction, but more research is needed in this area. There is ongoing research into the use of probiotics for inflammatory bowel disease, but so far they have not been found helpful for Crohn’s. Find the full version with references at

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Rapid Clinical Response from week 31,2 Lasting Clinical Remission at two years3 Well Tolerated Safety Profile1-3 consistent with 7 years’ cumulative safety data in psoriatic disease4-6 Convenient Dosing1 with 1 IV infusion and 4-6 S/C maintenance doses per year2

STELARA® 45 mg and 90 mg solution for injection and 130 mg concentrate for solution for infusion PRESCRIBING INFORMATION. ACTIVE INGREDIENT(S): Ustekinumab. Please refer to Summary of Product Characteristics (SmPC) before prescribing. INDICATION(S): Plaque psoriasis adults: Treatment of moderate to severe plaque psoriasis in adults who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapies including ciclosporin, methotrexate or PUVA. Plaque psoriasis paediatrics: Moderate to severe plaque psoriasis in adolescent patients from 12 years of age, who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies. Psoriatic arthritis: Alone or in combination with methotrexate for treatment of active psoriatic arthritis in adult patients when response to previous non-biological disease-modifying anti-rheumatic drug (DMARD) therapy has been inadequate. Crohn’s Disease: Treatment of adult patients with moderately to severely active Crohn’s disease who had inadequate response with/lost response to/were intolerant to either conventional therapy or TNFα antagonist or have contraindications to such therapies. DOSAGE & ADMINISTRATION: Adults: Under guidance and supervision of a physician experienced in diagnosis and treatment of psoriasis/psoriatic arthritis/Crohn’s disease. Psoriasis or psoriatic arthritis.

Subcutaneous (s.c.) injection. Avoid areas with psoriasis. Self-injecting patients or caregivers ensure appropriate training. Physicians are required to follow-up and monitor patients. Plaque psoriasis, adults & elderly: Patients ≤ 100kg, 45 mg at week 0 followed by a 45 mg dose at week 4, then every 12 weeks. Patients >100 kg, 90 mg at week 0 followed by a 90 mg dose at week 4, then every 12 weeks (45 mg was less effective in these patients). Plaque psoriasis paediatrics (12 years and older): Patients <60 kg, 0.75 mg/kg at week 0, followed by 0.75 mg/kg at week 4 then every 12 weeks thereafter. Patients ≥60 - ≤100kg, 45 mg at week 0 followed by 45 mg at week 4, then every 12 weeks. Patients >100 kg, 90mg at week 0, followed by 90mg at week 4, then every 12 weeks. Psoriatic arthritis, adults & elderly: 45 mg at week 0 followed by a 45 mg dose at week 4, then every 12 weeks. Alternatively, 90 mg may be used in patients with a body weight >100 kg. Consider discontinuation if no response after 28 weeks. Crohn’s Disease Initial single intravenous infusion dose based on body weight (260 mg or 390 mg or 520 mg) diluted in 0.9% w/v sodium chloride solution and given over at least one hour. At week 8 after intravenous dose, 90 mg s.c. dose is given; followed by every 12 weeks (or 8 weeks based on clinical judgement). Consider discontinuation if no response at 16 weeks. Immunomodulators and/or corticosteroids may be continued

but consider reducing/discontinuing corticosteroids if responding to Stelara. If therapy interrupted, resume s.c. every 8 weeks if safe/effective. Children: <12 years - Not recommended for psoriasis. <18 years - Not recommended for psoriatic arthritis and Crohn’s disease. Renal & Hepatic impairment: Not studied. CONTRAINDICATIONS: Hypersensitivity to product; clinically important, active infection. SPECIAL WARNINGS & PRECAUTIONS: Infections: Potential to increase risk of infections and reactivate latent infections. Caution in patients with a chronic infection or history of recurrent infection, particularly TB. Patients should be evaluated for tuberculosis prior to initiation of STELARA. Consider anti-tuberculosis therapy prior to initiation of STELARA in patients with past history of latent or active tuberculosis. Patients should seek medical advice if signs or symptoms suggestive of an infection occur. If a serious infection develops, closely monitor and STELARA should not be administered until infection resolves. Malignancies: Potential to increase risk of malignancy. No studies in patients with history of malignancy or in patients who develop malignancy while receiving STELARA. Monitor all patients, in particular those older than 60, patients with a medical history of prolonged immunosuppressant therapy or those with a history of PUVA treatment for nonmelanoma skin cancer. Concomitant immunosuppressive therapy: Caution,

Take part in life

including when changing immunosuppressive biologic agents. Hypersensitivity reactions: Serious hypersensitivity reactions (anaphylaxis and angioedema) reported, in some cases several days after treatment. If these occur appropriate therapy should be instituted and STELARA discontinued. Latex sensitivity: Needle cover contains natural rubber (latex), may cause allergic reactions. Immunotherapy: Not known whether STELARA affects allergy immunotherapy. Serious skin conditions: Exfoliative dermatitis reported following treatment. Discontinue STELARA if drug reaction is suspected. SIDE EFFECTS: Common: upper respiratory tract infection, nasopharyngitis, dizziness, headache, oropharyngeal pain, diarrhoea, nausea, vomiting, pruritus, back pain, myalgia, arthralgia, fatigue, injection site erythema, injection site pain. Other side effects: cellulitis, serious hypersensitivity reactions (including anaphylaxis, angioedema), skin exfoliation, exfoliative dermatitis. Studies show adverse events reported in ≥12 year olds with plaque psoriasis were similar to those seen in previous studies in adults with plaque psoriasis. Refer to SmPC for other side effects. FERTILITY: The effect of ustekinumab has not been evaluated. PREGNANCY: Should be avoided. Women of childbearing potential: Use effective contraception during treatment and for at least 15 weeks post-treatment. LACTATION: Limited data in humans. INTERACTIONS: In

vitro, STELARA had no effect on CYP450 activities. Vaccinations: Live vaccines should not be given concurrently with STELARA, and should be withheld for at least 15 weeks after last dose of STELARA. STELARA can resume at least 2 weeks after such vaccinations. No data on secondary transmission of infection by live vaccines in patients receiving STELARA. Concomitant immunosuppressive therapy: Psoriasis: Safety and efficacy of STELARA in combination with other immunosuppressants, including biologics, or phototherapy have not been evaluated. Psoriatic arthritis: concomitant MTX did not appear to affect STELARA. Crohn’s disease: concomitant immunosupressive or corticosteroid therapy did not appear to affect STELARA. Refer to SmPC for full details of interactions. LEGAL CATEGORY: Prescription Only Medicine. PRESENTATIONS, PACK SIZES, MARKETING AUTHORISATION NUMBER(S): 45 mg, 1 x vial, EU/1/08/494/001. 45 mg, 1 x 0.5 ml pre-filled syringe, EU/1/08/494/003, 90 mg, 1 x 1.0 ml pre-filled syringe, EU/1/08/494/004. 130 mg, 1 x vial, EU/1/08/494/005. MARKETING AUTHORISATION HOLDER: JANSSEN-CILAG INTERNATIONAL NV, Turnhoutseweg 30, B-2340 Beerse, Belgium. FURTHER INFORMATION IS AVAILABLE FROM: Janssen-Cilag Limited, 50 – 100 Holmers Farm Way, High Wycombe, Buckinghamshire, HP12 4EG, UK. Prescribing information last revised: 11/2016

Adverse events should be reported. Healthcare professionals are asked to report any suspected adverse events via: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website:, E-mail: Adverse events should also be reported to Janssen-Cilag Limited on +44 1494 567447 or at © Janssen-Cilag Limited 2016 References: 1. Feagan BG et al, N Engl J Med 2016;375:1946-60. Ustekinumab as Induction and Maintenance Therapy for Crohn’s Disease. 2. Stelara Summary of Product Characteristics. Available at 3. Sandborn, W.J. et al. ECCO 2017. OP010. 4. Kimball AB, et al. JEADV 2012:27(12):1535–1545. 5. Langley RG, et al. Br J Dermatol 2015:172(5):1371–1383. 6. Kavanaugh A, et al. Ann Rheum Dis 2016 [e-pub ahead of print] PHIR/STE/0417/0009 | Date of Preparation: May 2017

CPD 35: ERAS Continuing Professional Development



Enhanced recovery after surgery: Current research insights and future direction Aliza Abeles, Richard Mark Kwasnicki, Ara Darzi, Department of Surgery and Cancer, St Mary’s Hospital, Imperial College London, London W2 1NY, United Kingdom Author contributions: Abeles A and Kwasnicki RM analysed the literature and wrote the manuscript; Darzi A reviewed and edited the manuscript.

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 The concept of enhanced recovery after surgery (ERAS) was initially proposed by Kehlet who explored the possible determinants of post-operative morbidity in the late 1990s. He identified potential risk factors that needed to be recognised and treated peri-operatively to minimise the effects of surgical stress on the patient. He also championed the idea of working within a multidisciplinary framework. Together these have led to a series of interventions which have been formulated into standardised protocols to span a patient’s entire journey through the surgical process with distinct elements in the pre-operative, intraoperative and post-operative phase.

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 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.

ERAS and laparoscopic surgery The concept of enhanced recovery after surgery (ERAS) was initially proposed by Kehlet[1] who explored the possible determinants of post-operative morbidity in the late 1990s. He identified potential risk factors that needed to be recognised and treated peri-operatively to minimise the effects of surgical stress on the patient. He also championed the idea of working within a multidisciplinary framework. Together these have led to a series of interventions which have been formulated into standardised protocols to span a patient’s entire journey through the surgical process with distinct elements in the pre-operative, intra-operative and post-operative phase (Table 1).

Minimally invasive surgery has been shown to reduce post-operative pain, length of hospital stay and complications. Recent studies have examined the use of laparoscopic techniques within an enhanced recovery programme.

Colorectal surgery was the first specialty to implement ERAS in the early 2000s. Early studies proved feasibility and demonstrated that patients benefited from shorter length of hospital stay and reduced post-operative ileus and cardiopulmonary complications, compared with standard care[2-4]. ERAS has also been shown to be feasible and safe in the emergency colorectal setting, leading to shorter length of stay and faster recovery of bowel function[5].

The principles of ERAS have been adopted by most specialties, each formulating their own specific protocols and guidelines. The generic overarching ideas of pre-operative, intra-operative and post-operative elements are included, but the actual interventions and evidence base are specialty specific.

A 2012 consensus review of ERAS guidelines for colonic surgery examined the evidence base for each ERAS intervention and provided graded recommendations[6]. Though given strong recommendation grading, not all the interventions have high levels of evidence for their efficacy (Table 2).

Despite the evidence of improved postoperative outcomes and recovery, ERAS implementation varies in different centres. Given the barriers to implementation and the difficulty in determining the relative importance of each individual component within the ERAS protocol the idea of a flexible and individualised method rather than a rigid protocol has been postulated, with each centre and hospital determining which elements to include for their specific protocols Enhanced recovery after surgery is an evolving principle that aims to improve patient outcomes following surgery, with minimally-invasive surgery as an integral core. Current problems that are being discussed by ERAS proponents include barriers of implementation of ERAS protocols and the difficulty of measuring postoperative outcomes and improvements.

Minimally invasive surgery is one element that has been strongly recommended with a high level of evidence for oncological outcomes and moderate evidence in terms of patient recovery. Minimally invasive surgery has been shown to reduce post-operative pain, length of hospital stay and complications[7-9]. Recent studies have examined the use of laparoscopic techniques within an enhanced recovery programme. For example, the LAFA-study[10] showed that laparoscopic surgery, as part of an enhanced recovery programme, significantly shortened length of hospital stay compared with open surgery. Other outcomes including morbidity, readmission rates and quality of life were similar between the groups. The EnROL Trial[11] found a statistically significant difference between length of hospital stay and 30 d readmissions favouring the laparoscopic group compared with the open surgery group, but no differences between groups for physical fatigue or other secondary outcomes.

Newer minimally invasive techniques in the form of single incision laparoscopic surgery (SILS), robotic surgery and natural orifice transluminal endoscopic surgery have recently emerged. Although still in the early stages with ongoing research in progress, SILS has been shown to reduce conversion rate to laparotomy and reduce length of hospital stay[12]. Robotic surgery has advantages over purely laparoscopic surgery including the ability for seven degrees of freedom and tremor filtration which could benefit more demanding surgery, e.g., rectal resections. Robotic surgery has been shown to be both safe and feasible with short term outcomes comparable to conventional laparoscopic surgery but longer operative time and higher costs[13,14]. ROLARR (Robotic vs Laparoscopic Resection for Rectal

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Table 1

An example of a generic enhanced recovery after surgery protocol Pre-operative

cancer) is an RCT which aims to compare the benefits of robotic vs laparoscopic surgery, the results of which have not yet been published. The ultimate benefits of laparoscopic surgery and ERAS are essentially the same; improved outcomes and faster recovery. Given that laparoscopic surgery has been shown to improve outcomes both separately from, and as a part of ERAS, it can be seen as a significant and integral component to any ERAS protocol where minimally invasive surgery is applicable. Specialty specific ERAS The principles of ERAS have been adopted by most specialties, each formulating their own specific protocols and guidelines. The generic overarching ideas of pre-operative, intra-operative and post-operative elements are included, but the actual interventions and evidence base are specialty specific. Specialties with similar operative procedures, i.e., those within the lower abdominal/pelvic cavity, tend to have similar elements within their protocols, for example colonic surgery[6] and gynaecological oncology surgery[15,16] recommend no pre-operative bowel preparation, avoidance of nasogastric tube insertion and use of minimally invasive surgical techniques when expertise is available. Similar recommendations exist for urological surgery[17], however long-term oncological results following use of minimally invasive techniques are still awaited. A review of enhanced recovery in pancreatic surgery highlighted placement of intraperitoneal drains as a controversial and highly debated element within ERAS protocols for pancreatectomy[18]. Intraperitoneal drains have been used historically to help in the recognition of a pancreatic fistula or anastomotic leak. This leak of pancreatic fluid can cause erosion of vessels, haemorrhage and sepsis. A recent metaanalysis concluded that those patients without drains had higher mortality but lower overall complications[19]. Current ERAS guidelines recommend systemic post-operative drainage with early removal in patients at low risk of pancreatic fistula, but these

Pre-admission counselling Fluid and carbohydrate loading

Intra-operative Post-operative Short acting anaesthetic agents

Mid-thoracic epidural anaesthesia

Mid thoracic epidural anaesthesia

No Nasogastric tubes

No drains

Prevention of nausea and vomiting

No prolonged fasting

No/selective bowel preparation Avoidance of salt and water overload Avoidance of salt and water overload Antibiotic prophylaxis

Maintenance of normothermia


Early removal of catheter Early oral nutrition

No Premedication

Early mobilisation

Non-opioid oral analgesia

Stimulation of gut motility

Audit of compliance and outcomes

recommendations could change as further evidence is highlighted in future studies[20]. Within bariatric surgery pre-operative factors have been suggested to have important post-operative benefits, these include pre-operative weight loss, pre-operative exercise and adequate nutritional supplementation[21]. Studies have shown that pre-operative weight loss is a positive predictor of postoperative weight loss[22]. Together with adequately improving known nutritional deficiencies, which are common in obese patients, these elements seem essential additions to any bariatric ERAS protocol. Other specialty specific elements include pre-operative respiratory physiotherapy prior to thoracic surgery[23]. This improves exercise capacity and lung function in patients who will lose lung volume after surgery. Use of pre-emptive analgesia and local anaesthetics infiltration within orthopaedic surgery is thought to allow early mobilisation and increased limb movement secondary to decreased somatic sensation[24,25]. Using generic elements as a basis for specialty guidelines with added specific interventions allows for a more comprehensive ERAS protocol with improved outcomes and recovery for each specialty. Barriers to the implementation of ERAS Despite the evidence of improved post-operative outcomes and recovery, ERAS implementation varies in different centres. McLeod et al[26] reported that of the 18 specific ERAS guideline recommendations, only two reached a compliance rate of

greater than 75%. Pędziwiatr et al[27] implemented an ERAS protocol over a period of time and found that although only 65% compliance was reached for the first cohort, compliance rose to 89.6% by the third cohort, i.e., a gradual improvement was shown over time. Recently the ERAS Compliance Group found that ERAS protocol compliance in elective colorectal cancer resections were around 75%, but there was variation between centres and elements[28]. Compliance with ERAS protocols was associated with better outcomes and exhibited a form of “dose-dependency” whereby, as compliance increased, complications decreased. Laparoscopic surgery and balanced intravenous fluid therapy were specifically shown to be associated with a reduced risk of complications. Certain elements are easier to implement than others, for example if they already form part of routine practice, e.g., prophylactic antibiotics, thromboprophylaxis and using minimally-invasive techniques. Some elements are more difficult to implement despite increased efforts[27], including: No bowel preparation, early urinary catheter removal, no opioids and restrictive fluid therapy. An early study into ERAS protocol compliance indicates that compliance with post-operative factors significantly influenced outcomes[29], but it was difficult to determine which specific elements had an independent influence on outcomes. Conversely, a review by Ahmed et al[30] found that studies achieved similar outcomes despite not including all components of

recommended ERAS protocols. Furthermore, a systematic review[31] looking at RCTs of ERAS vs standard care was unable to show that ERAS protocols with more elements were more successful than those with fewer elements. Given the barriers to implementation and the difficulty in determining the relative importance of each individual component within the ERAS protocol the idea of a flexible and individualised method rather than a rigid protocol has been postulated, with each centre and hospital determining which elements to include for their specific protocols[29,31,32]. Factors thought to encourage the implementation of ERAS and improve compliance include; appointment of specific ERAS coordinators, use of engaged multidisciplinary teams, specific ERAS units/wards, specific teaching sessions about the benefits of ERAS and regular auditing[27,29,30]. Whichever elements are included, auditing compliance with the ERAS protocol, as well as measuring patient outcomes, form an essential part of the ERAS audit cycle[6]. Outcome measures The impetus behind ERAS is improving post-operative recovery therefore it is necessary to measure recovery objectively. Many outcome measures have been used, yet the most frequently reported is length of hospital stay[33]. However, this surrogate measure of recovery can be influenced by external

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51 Table 2

Enhanced recovery after surgery society recommendations for colonic surgery and their evidence level[6] ERAS element with high/moderate level evidence ERAS element with low level evidence Stopping smoking 4 wk prior to surgery Pre-operative information and counselling

circumstances, for example patients’ expectations of discharge date, social or support networks not being in place or even hospital administration issues with inability to process discharge summaries or dispense necessary medications. Furthermore, despite meeting the necessary clinical markers required for discharge, e.g., blood tests and physiological observations, the patient is unlikely to be back to their functional baseline, since hospital discharge is based on the patient being safe to convalesce in the community. Other clinical outcomes studied include thirty-day mortality, thirty-day re-admission and post-operative complications[34,35]. These outcomes are often recorded as part of the clinical notes and can be used in conjunction with length of hospital stay. However, they only offer insight into the major complications or postoperative issues in patients who are readmitted or treated. There is little information to represent how patients are recovering at home in the long term. Since 2009 the NHS in the United Kingdom has invited patients to fill in a patient reported outcomes questionnaire after hip replacement, knee replacement, groin hernia and varicose vein surgery. Such questionnaires measure a patient’s health status and health related quality of life at a single point in time is collected before and after the procedure. This has been introduced to provide an indication of the quality of care being delivered. These outcome measures are more patient-focused, relating to daily living within their own environment and their return to normal function. King et al[33] assessed the influence of an ERAS protocol on quality of life. A validated QOL questionnaire (EORTC QLQ-C30) was used by patients undergoing surgery with an ERAS protocol compared to a historic control group. No statistically significant difference between the two groups in terms of quality of life was found. Another study measured post-operative fatigue as a long-term outcome to compare ERAS vs conventional care[36]. It was shown that post-operative fatigue levels increased in both groups significantly, which reached a maximum level just before discharge. However, the peak level reached was significantly smaller in the ERAS group. They

No routine use of bowel preparation Stopping drinking alcohol 4 wk prior to surgery Allowing clear fluids up until 2h before and Peri-operative oral nutritional supplements and solids 6h before anaesthetic induction carbohydrate loading No routine use of sedative premedication Standard anaesthetic that allows rapid awakening Routine thromboprophylaxis Post-operative nausea and vomiting prophylaxis Antimicrobial prophylaxis and skin preparation Routine urinary drainage Balanced intravenous fluids guided by flow measurements Using stress reducing elements of ERAS to minimise hyperglycaemia Use of mid thoracic epidural blocks in open surgery Early mobilisation Us of spinal analgesia or PCA in laparoscopic surgery Laparoscopic surgery No routine use of nasogastric tubes Maintenance of normothermia No routine intra-abdominal drains Early post-operative enteral feeding Insulin treatment of severe hyperglycaemia in ICU Use of chewing gum to prevent post-operative ileus ERAS: Enhanced recovery after surgery; PCA: Patient controlled analgesia; ICU: Intensive care unit.

also exhibited a significantly smaller Fatigue Consequence Score during the first thirty post-operative days. More recently proponents of ERAS have started to focus research on the theme of patient experience[37], and qualitative studies undertaken have highlighted areas for improvement including post-discharge support and follow-up[38]. Another consideration is the economic potential of ERAS. Studies have shown that implementing an ERAS protocol is cost effective[39]. Recent systematic reviews by Lemanu et al[40] and Lee et al[41] note however, that there are few RCTs documenting cost data, there are inconsistencies in the reporting of cost data, and suggest the need for well-designed trials in order to fully determine the true cost-effectiveness of ERAS. A recent systematic review by Neville et al[42] aimed to identify useful recovery parameters within ERAS, noting that validated outcome measures were lacking for this complex recovery process. It was found that multiple different outcome measures are in use and that they tend to reflect short term recovery focusing on biological and physiological outcomes. The paucity of outcomes in the longer term was highlighted, for example few studies actually report any outcomes after thirty days post-surgery. A suggestion has

been made for longer-term follow-up for post-surgical patients with a focus on patients’ functional status including physical activity measurement and exercise capacity to help quantify recovery more fully. Another review by Feldman et al[43] postulates that phases of recovery overlap and cannot be defined as a single event within a specific time frame. This means that different outcome measures are relevant at different time periods, but that no single outcome measure is perfect to quantify total recovery. Instead, a core set of outcome measures for each stage of recovery is proposed which reflect the perspectives of each member of the multi-disciplinary team as well as the patient. It is now clear that different outcomes are relevant at different stages of the recovery process. One measure of recovery that is poorly represented by current outcome measures is physical activity. This is an important indicator of functional recovery both in hospital and back at home whilst convalescing. There is a potential to fill this gap by providing means of continual measurement in a non-invasive and objective manner. Prehabilitation Physiotherapy and mobilisation recommendations are frequently given in the post-operative period

with a view to improving recovery and function. However, physical “conditioning” prior to operative stresses have been considered with the idea of enhancing patients’ functional capacity and thus improving outcomes post-operatively[44,45]. For example, studies have implemented pre-operative exercise regimens and assessed subsequent post-operative functional activity and outcomes[46]. However, the benefit of prehabilitation is uncertain with systematic reviews reporting contradictory evidence. The review by Valkenet et al[47] included twelve studies [orthopaedic surgery, cardiac surgery and open abdominal aortic aneurysm (AAA) repair]. The risk of developing post-operative pulmonary complications was lower in those patients receiving inspiratory muscle training prior to cardiac and AAA surgery (RR = 0.40, 95%CI: 0.23-0.72). Conversely, there was no significant difference between post-operative complication rates or length of stay in joint replacement surgery. Lemanu et al[48] included eight studies in their review (cardiothoracic surgery, abdominal surgery and orthopaedic surgery), which found that there was poor adherence with the prehabilitation interventions with little evidence of physiological and clinical outcome improvements. One review focused more specifically on total

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Table 3 Additional enhanced recovery after surgery elements using sensor technology Additional ERAS element What this adds Pre-operative physical activity monitoring Measuring patient's baseline function to assess for surgical fitness and to predict support required post operatively Prehabilitation Exercise training prescribed to patients to improve their baseline functional capacity, together with nutritional advice and psychological support Post-operative physical activity monitoring Providing feedback to clinicians of patient recovery, monitoring compliance with mobilisation recommendations and picking up complications/allowing safer hospital discharge Activity feedback Providing motivation to patient to encourage them to mobilise in the initial post-operative phase, thereby reducing complications and enhancing recovery ERAS: Enhanced recovery after surgery.

body exercise as a prehabilitation intervention[49]. In this review of twenty one studies, improvements were seen in post-operative pain, length of stay and physical function in those undergoing the prehabilitation intervention. These differing conclusions may be due to the heterogeneity of the included studies with different physiological outcomes recorded and different prehabilitation interventions being used. A tri-modal prehabilitation intervention was used in a randomised controlled trial with patients undergoing colorectal resection[44]. The intervention consisted of fifty minutes’ total body exercise, alternating between aerobic and resistance training three times a week, nutrition counselling with protein supplementation and provision of stress reducing strategies. The trial found that the prehabilitation group had increased functional walking capacity both pre-operatively and at eight weeks post-operatively compared with the rehabilitation group. There was no difference in self-reported physical activity, health related quality of life, thirty day complications, anxiety or depression between groups. The evidence for prehabilitation is in its preliminary stages, with mainly low powered, observational studies. It is difficult to quantify or characterise the benefits of a prehabilitation programme, or indeed which interventions should be included. Randomised controlled trials looking at prehabilitation in colorectal cancer patients[50] and in vascular patients undergoing elective abdominal aortic aneurysm repair[51] are currently underway, which will

help towards informing the decision of whether or not prehabilitation should become part of the ERAS protocol. Use of technology A variety of technologies have been used within the perioperative period as helpful adjuncts within ERAS, for example oesophageal Doppler for monitoring fluid balance[52], pneumatic calf compression to provide thromboprophylaxis[53] and the use of forced air warming units to maintain normothermia[54]. Furthermore, recent advances in technology have led to the emergence of small, wearable sensors that can measure, store and transmit large amounts of patient and environmental data[55,56]. These sensors have been used to objectively and continuously monitor physical activity in the home environment following discharge from hospital[57] and within the hospital setting[58]. Studies in the early post-operative period have offered insight on patient mobility and functional recovery[59]. Cook et al[60] monitored patient steps after elective cardiac surgery. An association was found between number of steps taken by a patient and their length of hospital stay and post-operative discharge destination. WasowiczKemps et al[61] measured daily physical activity following laparoscopic cholecystectomy in a controlled study where advice was given to resume normal activity quickly following their operation. Recovery to baseline daily activity took more than one week in 64% of patients but women in the intervention group resumed normal daily activity quicker than those in the control group. One

study comparing laparoscopic vs open distal gastrectomy used an objective physical activity monitor to evaluate post-operative recovery[62]. Recovery of activity on each post-operative day was higher in the laparoscopic group. Studies assessing longer term physical activity monitoring[63,64] have shown this is both feasible and beneficial for collecting data on longer-term outcomes. Providing feedback on activity levels to participants has been shown to increase physical activity in a randomised controlled trial in young healthy Finnish men[65]. A randomised controlled trial assessing interventions for patients with intermittent claudication[66] showed that wearing a feedbackenabled physical activity monitor improved claudication and walking distance as well as quality of life scores at three months. There is therefore the potential to use sensor technology to complement and augment ERAS, leading to improved patient experience and outcomes. Knowing patients’ pre-operative activity levels might correlate to their baseline function and wellbeing, which could provide an indication of anticipated support the patient may require post-operatively. Monitoring physical activity in the hospital post-operatively can help monitor compliance with post-operative mobilisation recommendations as well as measure inpatient activity providing an indication of functional recovery and screening for complications. Over time, monitoring physical activity unobtrusively can give useful longterm outcome measures that truly reflects a patient’s recovery in the community[67]. Activity feedback

to patients both in hospital and in the community may help to encourage an increase in their activity levels, as well as motivate them to be more engaged in their own recovery and care. Sensor technology could, therefore, help overcome the current barriers to ERAS and help assess and improve patient outcomes and experience throughout the surgical period, in keeping with Kehlet’s initial ERAS concept. Additional elements to add to specialty specific protocols could include pre-operative activity monitoring, prehabilitation and post-operative activity monitoring with feedback (Table 3). Enhanced recovery after surgery is an evolving principle that aims to improve patient outcomes following surgery, with minimallyinvasive surgery as an integral core. Current problems that are being discussed by ERAS proponents include barriers of implementation of ERAS protocols and the difficulty of measuring post-operative outcomes and improvements. Evidence for prehabilitation is being explored in randomised controlled trials, as initial studies are contradictory and based on observational studies with few participants. Technological advances have enabled wearable devices to continuously and objectively collect data about the wearer’s well-being. This could provide an opportunity to assess ERAS compliance, monitor patient outcomes and offer a variety of promising therapeutic interventions. Find the full version with references at

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Awards Hospital Professional

Awards 53


The Hospital Professional Awards 2017 - Celebrating Excellence The Hospital Professional Awards are now in their fifth consecutive year, celebrating the innovation and excellence in care of the entire secondary care sector within Ireland. The Hospital Professional Awards offer a unique programme to bring these leading professionals – Consultant, Pharmacists, Clinical Specialists, Researchers, Academics and Innovators - together to showcase the ongoing projects currently being undertaken throughout Ireland's hospitals to disseminate results, promote learning and best practice so that the excellence in specialist work is shared in every hospital setting in Ireland. Winners of a Hospital Professional Award will be chosen by an esteemed judging panel for their evidence-based research and/or work in the enhancement of a field and/or therapeutic area for the ultimate benefit of Ireland's hospital patients or the growth of the profession as a whole. The applications for this year’s awards surpassed the previous two years with just under 100 submissions representing Ireland’s leading hospital specialists and departments and teams.

Whilst the short listing process was extremely difficult – with some strong entries failing to make it to the shortlist – it is important to highlight that it is not just about winners and losers. Everyone who entered this year’s awards deserves commendation. Over the following pages we feature the finalists in each of our 14 Award Categories

These Awards decorate best practice within secondary care, with Award Categories ranging from Consultant-led project and team initiatives to specialised therapeutic area innovations and leading Pharmacy and Pharmacistdriven excellence. Investing in the further development of secondary care within Ireland, the education and clinical learning derived from entries to the Hospital Professional Awards will highlight the quantifiable projects that have been driving benefits to both clinical peers and patients with the objective of greater shared outcomes. The 2017 Hospital Professional Awards will be held on September 16th, 2017 in

the Clayton Hotel, Dublin and will be hosted by Irish actress and comedienne Deirdre O’Kane with over 450 in attendance. These Awards have been met with great enthusiasm from suppliers, healthcare professionals including Consultants and Pharmacists. They have raised the profile of the industry within Ireland. Our sponsors are amongst the elite of the industry, all of whom see the awards as the perfect vehicle to show their support in this arena. Make sure you catch the October issue of Hospital Professional News which will have exclusive coverage of all the winners and of the night itself.

HPN • Issue 41

Awards 54 Awards

Hospital Professional


Idis Hospital Pharmacist of the Year 2017

Part of the Clinigen Group

Dawn Davin Hospital: Tallaght Hospital

Nomination Overview: Dawn Davin is a Senior Clinical Pharmacist working in the area of Nephrology at Tallaght Hospital. She is involved in many aspects of the pharmacy department as well as collaborating closely with the wider nephrology multidisciplinary team. Involved with the collaborative prescribing model (Pharmaceutical Care at Tallaght Hospital [PACT]) since its inception, she applies prescribing skills to the complexities of nephrology patients. Dawn enjoys being involved with collaborative projects and has recently won awards from two UK renal organisations. Dawn recently obtained a post graduate qualification in prescribing from QUB, which has contributed positively and extensively to the development of her current role in the provision of the PACT model for the provision of team based pharmacy services to renal in-patients. This includes medication reconciliation, prescription review & intervention, collaborative prescribing, and involvement at the point of discharge. It has also facilitated a greater collaborative platform for undertaking research and improving the delivery of patient care.

Dawn Davin, Senior Clinical Pharmacist

Colm McDonald Hospital: St James’s Hospital

Nomination Overview: Colm McDonald has been employed as a Senior Pharmacist in General Clinical Services at St. James’s since 2003, currently working as the Respiratory Specialist Senior Pharmacist and Respiratory TB pharmacist in St James's Hospital. Colm brings his wide variety of Clinical Pharmacy qualifications and experience in a consistent approach to patient care and improving the experience of his colleagues at all levels, as well as nursing and medical staff in the hospital. In the fourteen years since Colm joined the Pharmacy department he has gained a huge range of experience in different specialist roles. In each of these roles Colm has been extremely dedicated to ensure patients receive the best pharmacy care. Colm has been responsible for the Respiratory TB pharmacy service since its introduction in St James’s Hospital in September 2007. In 2016, Colm established the morning “huddle” for dispensary staff to ensure effective communication in the pharmacy dispensary. This “huddle” ensures streamlined processes for the dispensary service and allows a forum for ideas and concerns to be shared. Colm McDonald, Respiratory Specialist Senior Pharmacist/Respiratory TB Pharmacist

Caroline Gallagher

Hospital: St Vincent’s University Hospital Nomination Overview: Caroline is a Senior Pharmacist/Acting Dispensary Manager in the Pharmacy Dept of St Vincent’s University Hospital. Caroline moved to St. Vincent’s University Hospital in 2005 from St James’s Hospital where she completed an MSc in Hospital Pharmacy from Trinity College Dublin. While undertaking a busy clinical role in the liver transplant unit, Caroline also acts as a projects lead with the new build in SVUH. She is involved with future planning for Pharmacy, and is also the ICT systems administration lead for Ascribe, the dispensary management system. Caroline has acted as the dispensary manager in SVUH and embraced LEAN methodology to enhance efficiencies therein. Caroline has a patient-facing role in her work on the liver ward, and in the dispensary. Caroline Gallagher, Senior Pharmacist/ Acting Dispensary Manager

Issue 41 • HPN




Hospital Professional

Multidisciplinary Award 2017

Clare Meaney & Mary McCartan Hospital: Hospital: National Rehabilitation Hospital Entry Overview: The pharmacy team at National Rehabilitation Hospital (NRH) is dedicated to sourcing, dispensing and reviewing the patient’s medications during their stay. One category of medicines the team looked at was the insulin pens/devices. Several audits of medication management processes were carried out by the Pharmacy and Nursing department in early 2016 as part of the update to the hospitals medication management policy. One of the medication administration audits identified that currently the insulin pens do not have a seal on them to indicate if a pen has not been opened, nor does it state it is for “individual or single patient use only”. This was highlighted as a patient safety issue and driven forward to inform healthcare professionals about the purpose and safe practices regarding the necessity and usage of flag labels for insulin pens/devicesat ward level. By introducing this safety initiative, the administration, documentation and education should decrease errors and risk for both the patient and staff.

Claire Meaney, Senior Hospital Pharmacy Technician

Mary McCartan, Senior Pharmacist

Infection Prevention Control Team Hospital: Midland Regional Hospital, Tullamore

Aideen Lanigan, Pharmacist; Marie Philbin Antimicrobial Pharmacist; Liz Winters Infection Prevention & Control Nurse; Fiona Hanlon Surveillance Scientist; Dr Tomasz Blasiak Registrar in Medicine; Miriam O'Connor SHO in Medicine

Entry Overview: Infection control is in the public eye and tightly regulated by HIQA, and so a number of multidisciplinary and multi-departmental approaches need to be taken to deal with the challenges. The team are currently tackling the issue of bloodstream infections and aiming to be among the top hospitals in the country for avoiding these. One aspect is the approach to standards and processes around invasive medical devices. Other groups and departments within the hospital are brought in for joint work on route cause analysis to maximise the learning from any infection that has been detected. The team ensures that everything has a process that has been developed for each care bundle. Work is always underway to ensure that the team meet the targets set by HIQA for their inspections. Data on hand hygiene and antimicrobial consumption is audited on an ongoing basis and fed back to line managers and hospital managers and other stakeholders so that the hospital can constantly improve.

Missing from the Photo are: Michelle Bergin ADON Infection Prevention & Control; Geraldine Talty CNM2 Surveillance; Dr Cathal O'Sullivan Consultant Microbiologist; Dr Eoin Bergin Consultant Physician; Alice Farrelly CNM2 Medicine; Grace Doyle Staff Nurse Medicine; Dr Waqar Shah Consultant in Emergency Medicine; Brendan Reddy Quality & Patient Safety Manager; Ann Calvert CNM3 ED

Gerry Hughes Hospital: St James’s Hospital Entry Overview: In an age where antimicrobial resistance is becoming one of the largest threats to global public health, continuous innovation, drive and promotion in the field of antimicrobial stewardship (AMS) is needed more than ever. The St James’s Hospital (SJH) AMS programme continually seeks to practice and promote excellent AMS within the hospital. Over recent years, the programme has continued its efforts to fight the threat of resistance and promote excellence in the field of AMS. Targeted stewardship ward rounds, publishing of prescribing guidelines in mobile application format, providing feedback to utilisers of antibiotics in the hospital, running a programme of continuous audit and surveillance and managing the global shortage of key antimicrobial agents are just some of the key ongoing operational achievements of the programme over past years. In June 2016, the SJH AMS operational committee hosted the first Irish national antimicrobial stewardship study event, AMS InSight.

Dr Geraldine Moloney, Elmarie Cottrell, Dr Akke Vellinga, Professor Dilip Nathwani, Dr Robert Cunney, Professor Colm Bergin, Dr Alida Fe Talento, Gerry Hughes, Dr Enrique Sanchez and Dr Ajay Oza

HPN • Issue 41

Awards 56 Awards

Hospital Professional


Roche Oncology Pharmacist of the Year 2017

Annette Whiriskey Hospital: Tallaght Hospital

Nomination Overview: Annette is a Senior Clinical Pharmacist at the forefront of the haematology service at Tallaght Hospital. She developed a special interest in the area during her Masters in Hospital Pharmacy in 2013 and has never looked back. Annette describes the role of a haematology pharmacist as exciting, demanding and challenging given the progressive change in this rapidly evolving area. She regularly assists the hospital’s three consultants optimise patient’s treatment. This involves keeping abreast of the HSE’s National Cancer Control Programme’s guidance as well as accessing compassionate supplies of medication and assisting in the set-up of clinical trials. She works closely with the Haematology Day Ward, In-patient Wards, the Pharmacy Aseptic Unit and the Dispensary. Her communication skills are key to ensure processes run smoothly between these areas. Process improvement and the development of robust systems are always at the forefront of her mind. Annette Whiriskey, Senior Clinical Pharmacist

Bridget Lynam Hospital: Beaumont Hospital

Nomination Overview: For over two years, Bridget Lynam has worked as a Senior Aseptics/Oncology Pharmacist at Beaumont Hospital. When she started, Beaumont Pharmacy was experiencing acute staff shortages, but Bridget took this all in her stride and slotted into the team seamlessly at a particularly difficult time. The Aseptic Compounding Unit (ACU) has also experienced a significant increase in workload since 2014, and Bridget has been a hugely important member of the pharmacy service to Oncology and Heamatology during these demanding times. She has always maintained an exemplary level of service with excellence in patient care always at the focus of her work, no matter what task she has undertaken.She has brought a wealth of knowledge from her previous experience, and used this to make some practical but powerful changes to the ACU in Beaumont. Bridget is also heavily involved in managing expanded access programmes and a wide-range of oncology clinical trials in her day to day duties. Bridget Lynam, Senior Aseptics/Oncology Pharmacist

Éilis Crimmins

Hospital: Midland Regional Hospital, Tullamore Nomination Overview: Éilis has worked as the Senior Pharmacist in the Oncology Haematology and Aseptic Compounding Pharmacy at the Midland Regional Hospital Tullamore since 2009. At a local level at the Hospital, Éilis is active in ensuring that medication safety for patients is paramount. This is through clinical checking of Oncology and Haematology prescriptions, ensuring that doses and treatment choices are correct for the patient and evidence based. As part of the pharmacy team, she writes and checks treatment protocols to minimise errors and improve medicine management of different diagnosis. Éilis has been a member of the Hospital Pharmacy Association of Ireland Aseptics Specialist Interest Group (ASSIG) since 2010, becoming the chairperson in 2013.As chairperson, Éilis’ aim was to enhance the education and training of hospital pharmacists and technicians. She founded an annual education meeting where hospital pharmacists and technicians would have the opportunity to share knowledge and experience in the area of Aseptics. She also helped to launch national guidance on this specialised area and promoted its use through a series of education events. Éilis Crimmins, Senior Pharmacist

Issue 41 • HPN




Hospital Professional

Excellence in Patient Safety Award 2017 Eileen Relihan, Medication Safety Facilitator Hospital: St James’s Hospital Entry Overview: Eileen has recently been involved in the development and delivery of the Medication Safety Minute, a novel initiative recently launched at SJH which delivers a pro-active, bite-sized medication safety message to hospital staff by e-mail, via the hospital’s intranet page and to a wider audience via twitter #MedSafetyMin. This initiative was developed as a joint project between Dr Barry O’Connell, Clinical Director Medical Directorate, Dr Una Kennedy, Consultant, Emergency Medicine and Eileen Relihan.

Eileen Relihan, Medication Safety Facilitator

Mary O'Sullivan, ICU Pharmacist & Claire Mullins, Hospital Pharmacy student Hospital: St Vincent’s University Hospital Entry Overview: The multidisciplinary team in ICU reflected on what actions family/ next of kin could be involved with, to enhance patient care in ICU. This project aimed to ensure the best medication history is obtained for an individual patient in ICU. Medication history can impact on a patient’s diagnosis, and help direct their therapy. As part of the medication reconciliation process, patients and their care givers can be an important source of information. The project describes use of software in ICU to enhance communication and transparency of information for staff managing patient care in ICU.

Mary O'Sullivan, ICU Pharmacist

Claire Mullins, Masters in Hospital Pharmacy student

Ciaran Meegan, Deirdre Lenehan, Laura Cosgrove Hospital: Mater Misericordiae University Hospital

Professor Ciaran Meegan, Head of Pharmacy Services and Deirdre Lenehan, Drug Safety Facilitator

Entry Overview: Helping Patients and Prescribers – Development of a Direct Oral Anticoagulant Therapy Record and Anticoagulant Recognition Cards: The MMUH has a reputation for actively working, both locally and nationally, on medication safety issues. In the MMUH any staff member may report a medication variance to share experiences and learn from mistakes. The level of reporting in the MMUH has increased substantially in the last number of years, including an almost 50% increase most recently between 2015 and 2016. The DSC decided to develop a DOAC Therapy Record to provide all the necessary information about DOAC therapy to the Prescriber and the Patient in an on-going accessible manner. This Therapy Record will promote the safe use of these high risk medicines because it will be used continually by the patient in conjunction with their Hospital Specialist or General Practitioner.

Mary Mccartan, Pharmacist & Claire Meaney, Senior Hospital Pharmacy Technician Hospital: Pharmacy Department, National Rehabilitation Hospital Entry Overview: The role of Flag Insulin labels in patient safety: The NRH provides a comprehensive range of specialist rehabilitation services from patients throughout Ireland. There are variable injuries in the NRH from head injuries, spinal cord injury, traumatic brain injury, stroke injuries and limb loss. The impact of these injuries can range from moderate to severe. The pharmacy department in the NRH is one of the teams that contribute towards a patient’s rehabilitation process from the time of admission to discharge. By introducing this safety initiative, the administration, documentation and education should decrease errors and risk for both the patient and staff. This new safety initiative has highlighted that needles and Insulin pens/devices should never be shared or be used for more than one person, even when the needle is changed.

Mary McCartan, Senior Pharmacist

Claire Meaney, Senior Hospital Pharmacy Technician

HPN • Issue 41

Awards 58 Awards

Hospital Professional


Hospital Specialist of the Year Award 2017

Miriam Coghlan Hospital: University College Dublin Nomination Overview: Miriam Coghlan is a senior Hepatitis C Pharmacist based across the hepatology and infectious disease teams at St Jamesâ&#x20AC;&#x2122;s hospital, Dublin (SJH). She leads a team that includes a junior pharmacist and technician as well as being team lead on the weekly HIV/Hepatitis C co-infection clinic. Miriam has demonstrated an innovative approach to a brand new area for clinical pharmacists. She has accepted challenges and developed her role from the ground up, developing first her own skills in this area and then expanding her team and focusing on educating fellow staff members across all disciplines about these medications. Her commitment to continually expanding her knowledge is clear from not only her attendance of international and national conferences but also submitting posters to these conferences. Her contribution to the national registry as well as her own research as part of her PhD research demonstrates how she is committed to not just her role within SJH but also to expanding the research base within the wider hepatitis c treatment community. Miriam Coghlan, Senior Hepatitis C Pharmacist

Joanna Carroll Hospital: Tallaght Hospital Pharmacy Nomination Overview: Joanne Carroll is a Senior Pharmacist who has been working in Beaumont Hospital, incorporating St Josephâ&#x20AC;&#x2122;s since December 2015. Joanna has always developed pharmacy services, regardless of here she has worked previously. Her most recent work development was to establish a day hospital service with no other examples in the country to follow, therefore looking to the UK and Canada, Joanna integrated herself with the medical team producing impressive results for 2016. Joanna is described as a dedicated pharmacist who has spent the last 14 years developing, expanding and contributing to the pharmacy profession on a wide scale. She has utilised all she earned from her early days in Merlin Park University Hospital honing her skills in the dispensary, deputising for the Chief Pharmacist when needed, developing rheumatology care of the older person by producing patient information leaflets, as well as guidelines on the prevention of glucocorticoid induced osteoporosis, amongst many other innovations. Joanna Carroll, Senior Pharmacist

Laura McCabe Hospital: Mater Misericordiae University Hospital

Laura McCabe, Medicines Information Services Manager

Issue 41 â&#x20AC;˘ HPN

Nomination Overview: Laura McCabe is the Mater Misericordiae University Hospital (MMUH) Medicines Information (MI) Service Manager. Laura has a key role in education and teaching, both within the MMUH Pharmacy Department and externally. Laura is involved in educating undergraduate medical students and was recently invited to present on biosimilar medicines in rheumatological disease to Rheumatology Specialist Registrars (SpRs) at a National study day, hosted in the MMUH. She is also an honorary clinical lecturer for the RCSI Pharmacy undergraduate programme and is an active member of the UK Medicines Information (UKMI) network. In all of the above examples, Laura has worked as a team member, and often as the team leader, engaging and involving key stakeholders from the outset to ensure success of each initiative. Laura has demonstrated a consistent ability to respectfully involve and motivate staff. Laura has consistently strived to improve patient care. Optimisation of patient safety and welfare married with supporting safe and effective prescribing are the key drivers of every project she endeavours to undertake.

Awards Hospital Professional



MSD Infectious Diseases Project of the Year 2017

Marie O Halloran Hospital: Hospital: Pharmacy Department, Mater Misericordiae University Hospital Nomination Overview: Examining Polypharmacy and Potential Drug-Drug Interactions in an Older HIV Positive Population: Polypharmacy and potential drug-drug interactions are well documented phenomena in older adults but there is less published data on the incidence of these in an older HIV positive population, and a lack of awareness on how to manage same in a HIV positive population. There is evidence to suggest that people with HIV may age faster than people without HIV, secondary to complex mechanisms. As a result polypharmacy and potential drug-drug interactions may emerge in this population even earlier than traditionally believed. In addition, many previously published studies omit over the counter or herbal products which may underestimate polypharmacy and potential drug-drug interactions. This study included these groups of medicines. It is foreseen this initiative will draw attention to the fact that the HIV population is older than ever before, and are being affected by diseases of old age. It is likely these patients will need dual input from specialists in both Medicines for the Elderly and Infectious diseases in their management, thus changing the dynamics of their care. Due to the high levels of polypharmacy and potentially significant drug interactions, this study has also confirms the vital role of pharmacist review and interventions in this clinical setting.

Marie O'Halloran, Acting Senior Clinical Pharmacist

David Fitzgerald, Senior Antimicrobial Pharmacist & Team Hospital: National Maternity Hospital

Noreen O'Callaghan, Senior Neonatal Pharmacist, Montse Corderroura, Senior Pharmacist, David Fitzgerald, Senior Antimicrobial Pharmacist, Anne Clohessy, Senior Pharmacist, Linda Simpson, Senior Pharmaceutical Technician

Nomination Overview: Examining the aetiology and diagnostic criteria of maternal pyrexia in labour with a view to improved antibiotic management: a prospective case-control study: This study aimed to provide information on the aetiology of peripartum maternal pyrexia, along with the diagnostic accuracy of obstetric SIRS criteria as predictors of infection related to peripartum pyrexia, in order to assist decisions to guide antibiotic therapy for mothers and newborns. The objectives were: 1.To determine the infection rate related to peripartum maternal pyrexia. 2.To evaluate the diagnostic accuracy of the obstetric SIRS criteria and cardiotocography (CTG) for identification of infection related to peripartum maternal pyrexia. 3.To investigate associations between epidural analgesia and peripartum maternal pyrexia, along with other potential risk factors, using cases and controls. This project challenges current thinking on the diagnosis and management of maternal pyrexia around the time of labour. This research is particularly relevant at this time, given the recent launch in March 2017 of the World Health Organisation’s Global Maternal and Neonatal Sepsis Initiative which aims to develop and test effective strategies to manage maternal sepsis.

Ms Roisin O’Connor: Senior Pharmacist, Infectious Diseases Hospital: GUIDE clinic, St James’s Hospital Nomination Overview: Malaria Treatment Quality Improvement Study at St James’ Hospital (SJH): The aim of this quality improvement study was to ensure appropriate and timely treatment of malaria in St James’s Hospital (SJH). The interventions delivered were chosen to meet the specific training and resource needs identified during analysis of local medication error data. Staff feedback suggests that competence and confidence in the management of malaria has been greatly enhanced at the front-line. This initiative demonstrates some of the many skills and attributes that Roisin brings to both the pharmacy team and the Infectious Diseases multi-disciplinary team, both of which she is an integral member. Her excellent working relationships within these teams can be seen in the diversity of contributors to the initiatives including the dispensary staff in pharmacy (who ensured that the prescribing aids were sent with the dispensed anti-malarial medicines), the medical and nursing team in GUIDE (who collaborated in designing and delivering the training sessions and updating and approving the guidelines), the Medication Safety facilitator (who collaborated on the analysis of local error data and gave invaluable input in the design and display of the guidelines and prescribers aid to maximise impact and readability), and the staff in the clinical pharmacy department.

Roisin O'Connor, Senior Pharmacist in Infectious Diseases

HPN • Issue 41

Awards 60 Awards

Hospital Professional


Medisource Hospital Pharmacy Technician of the Year Award 2017

Ann O’Brien

Hospital: Mater Misericordiae University Hospital Nomination Overview: Ann commenced work in the Pharmacy Department, MMUH, in 2005. With no prior hospital experience. Ann immediately set to work, settling in and quickly learning the ropes in the busy Dispensary. Ann’s strong sense of kindness and overall dependability make her a wonderful colleague to work aside. We rely on her to get the job done and know we can always ask her for help when the going gets tough. Overall, Ann epitomises the core values of the hospital - accountability, compassion and excellence, and her commitment to patient care set her apart.

Ann O’Brien, Hospital Pharmacy Technician

Trish Scully

Hospital: Midland Regional Hospital, Tullamore Nomination Overview: Trish Scully is the Senior Pharmaceutical Technician working in the Regional Oncology Haematology Pharmacy at Midland Regional Hospital Tullamore. The Regional Oncology Haematology Pharmacy at MRHT is a busy unit, which provides services to the midland region of Ireland. Trish is a great individual to work withcompassionate, patient, hardworking, respectful and humble. No task is too much and is always at hand to help all members of the Aseptic Compounding team from pharmacists to multitask attendants. Trish has demonstrated team spirit, when resources are low and ensures that the service continues to improve.

Trish Scully, Hospital Pharmacy Technician

Ann Marie Cahill

Hospital: St Vincent’s University Hospital Nomination Overview: Annmarie Cahill is the Senior Pharmaceutical Technician in Dispensary of St Vincent’s University Hospital (SVUH) Pharmacy Dept. She is responsible for co-ordinating and delegating dispensary activity, including cardiac arrest, intubation and anaphylaxis medication management. She is the team lead for dispensary involved with planning and preparation for accreditation (an on-going process SVUH is committed to).

Ann Marie Cahill, Hospital Pharmacy Technician

Issue 41 • HPN


Pamela Barry

Hospital: Beaumont Hospital Nomination Overview: Pamela has worked in Beaumont Hospital for 9 years and over that period she has proven herself to be an incredibly valuable part of the Pharmacy Team. Pamela has gained a wealth of experience in the full scope of activities undertaken in the Pharmacy Department during her time here and she has shown consistent dedication to her work no matter what area she has been involved in. Recently, she has spent a considerable amount of time in the Aseptic Unit and was involved in the implementation of the needle-free system in the unit. Showing her commitment to excellence in patient care in this sector of pharmacy, she self-funded her attendance at the Aseptic Preparation and Dispensing of Medicines in Leeds University in 2016. Pamela Barry, Hospital Pharmacy Technician

Patricia Dalton Hospital: Tallaght Hospital

Nomination Overview: Patricia (‘Trish’) Dalton is a hard-working, reliable and enthusiastic team player who strives for excellence in all her endeavours. As a Senior Pharmaceutical Technician and Dispensary Team Leader, Trish champions the health and well-being of patients at Tallaght Hospital, and places their pharmaceutical care needs at the core of everything she does. Trish’s caring personality also shines through in her interactions with Pharmacy colleagues and other hospital staff, to whom she is perpetually considerate, supportive and dedicated.

Patricia Dalton, Hospital Pharmacy Technician

Sandra Cullen Hospital: Connolly Hospital

Nomination Overview: Sandra Cullen is a Senior Pharmacy Technician who in January 2017 took on the new role of Financial Stewardship Technician. She has 13 years of hospital pharmacy experience in a range of different roles. In addition to her wealth of knowledge and expertise, Sandra is an empathetic, insightful and compassionate colleague who inspires and cajoles with her inimitable mix of humour and positivity. Sandra is a creative and enthusiastic member of the Pharmacy team and has contributed significantly to the development of the Pharmacy service over the past decade. She has been a leader among her peers in developing the Pharmacy Technician role in performing kardex reviews on wards and in pioneering the Accredited Pharmacy Technician Checking role.

Sandra Cullen, Hospital Pharmacy Technician

HPN • Issue 41

Awards 62 Awards

Hospital Professional


Young Hospital Professional of the Year 2017

Ciara Gavin, Clinical Pharmacist Hospital: St James’s Hospital Pharmacy Department Nomination Overview: Ciara Gavin is a clinical pharmacist who works for the Pharmacy department of St James Hospital, based in Dublin. She is qualified as a pharmacist for six years, having graduated in the UK from the University of East Anglia in 2010. Ciara is an acute medical admissions senior pharmacist, based on an extremely busy admissions ward in St James's Hospital. She works tirelessly for the Acute Medical Admission Units (AMAU) to ensure a safe and efficient transition of patient care from the community into the hospital. Ciara is a fantastic asset to the clinical pharmacy team, but also an invaluable member of the multidisciplinary team of the AMAU. She is involved in several projects, involving the allied health professionals including a new exciting project based within the AMAU St James's Hospital which incorporates the teachings of Dartmouth Medical School.

Ciara Gavin, Clinical Pharmacist

Gráinne Johnston, Clinical Pharmacist Hospital: Mater Misericordiae University Hospital Pharmacy Department Nomination Overview: Gráinne works as a basic grade clinical pharmacist in the Pharmacy Department at the Mater Misericordiae University Hospital (MMUH). She began her work in MMUH in 2014 as an intern and progressed to working as a qualified basic grade pharmacist in December 2015, to immediately undertaking the Trinity College MSc in Hospital Pharmacy in January 2016. Since starting work in the MMUH, Gráinne has always strived for clinical excellence in order to enhance patient outcomes. Through working on a number of wards involving different specialties, Gráinne identified a number of areas where patient safety and patient outcomes could be enhanced.

Gráinne Johnston, Clinical Pharmacist

Eimear McManus, Pharmacist Hospital: National Rehabilitation Hospital Pharmacy Department Nomination Overview: Eimear has been a member of staff in the Pharmacy Department at the National Rehabilitation Hospital in Dun Laoghaire for two and a half years. Eimear joined the NRH in 2015 after working for a number of years in community pharmacy. Over the past two and a half years, she was shown a big commitment to developing her professional knowledge by undertaking a MSc. in Clinical Pharmacy with University College Cork which she is due to complete this October. Health Literacy is an area Eimear is passionate about and she has shown great commitment to developing the pharmacy as a health literacy friendly department. She has taken a number of steps to ensure that we are providing the best possible service we can to patients with limited health literacy. Eimear McManus, Pharmacist (Centre) pictured with Nessa Walsh, Pharmacy Intern (left) and Sheena Cheyne, Pharmacy Manager (right)

Issue 41 • HPN

Awards Hospital Professional



Consultant-Led Team of the Year Award 2017

Dr Eoin Bergin, Consultant Nephrologist Hospital: Midland Regional Hospital, Tullamore Nomination Overview: The Renal Dialysis Unit at the Midland Regional Hospital, Tullamore has provided a high quality renal service based on multidisciplinary teamwork to renal patients in the Midlands area since 2005. Originally intended to reduce the demand on Dublin Hospitals, patient demand for the unit has grown to the extent that it now expanded back from the new hospital into the “Scott Dialysis Unit” which was the original site of the unit before the hospital moved location in 2008. Dr Bergin has also been an essential part of the hospital team having been chair of the pharmacy and therapeutics committee for a number of years. Under his guidance there have been many progressive initiatives in the hospital, including the projects mentioned above involving nurse prescribers and the pharmacy team. He leads a coherent team that shares his values of putting the patient at the centre of care.

Dr Eoin Bergin, Consultant Nephrologist

Professor Frank Murray, Consultant Gastroenterologist & Dr Deirdre McEnroy-Mullins, Locum Consultant Gastroenterologist Hospital Department: Beaumont Hospital Hepatology Department & Pharmacy Department Nomination Overview: In November 2016, in response to the increased demand on the service, the committed workforce within this department at Beaumont Hospital recognised the need for a formal meeting to discuss issues arising with treatment of both current and future patients using the collective knowledge, and skills of the department. The MDT consists of a consultant, hepatology nurse specialists and the pharmacist who meet at weekly intervals to discuss patients’ treatment. The introduction of the MDT has proven to be a vital method of enhancing communication within the hepatology service. Complex patients are identified and discussed prior to initiating HCV treatment; this reduces issues such as poor compliance and drug-drug interactions (DDIs) between proposed HCV medication and concomitant medications, therefore avoiding any issues once treatment is initiated. Professor Frank Murray, Consultant Gastroenterologist

Professor Seán Murphy, Director Acute Stroke Service; Dr Fionnuala Ni Áinle, Consultant Haematologist; Dr Michael Marnane, Consultant Neurologist Hospital Department: Acute Stroke Service, Haematology Department, Neurology Department and Pharmacy Department, Mater Misericordiae University Hospital Nomination Overview: The MMUH Medicines Information (MI) and Drug safety services have collaborated with the MMUH Neurology, Haematology teams and Acute Stroke service to successfully implement a number of key initiatives that have undoubtedly enhanced the care of patients requiring anticoagulation due to underlying irregular heart-beat, blood clots and other potentially life-threatening conditions. Their examples of innovation and leadership clearly illustrate the concerted teamwork of a highly skilled group of professionals whose vision from the outset was to improve patient safety with the use of anticoagulants. The success of each initiative is a clear reflection of the collaborative efforts of a team led by Consultants with expertise in the fields of Haematology, Neurology and Stroke and specialist Pharmacists who offer a wealth of experience in MI and Drug Safety. Professor Seán Murphy, Director, Acute Stroke Services

HPN • Issue 41

Awards 64 Awards

Hospital Professional


Accord Innovation in Aseptic Compounding Award 2017

Beaumont Hospital Aseptic Compounding Unit Project Lead: Grant Carroll, Chief II Pharmacist, Chemotherapy/Aseptics Entry Overview: Beaumont Hospital Pharmacy Aseptic Compounding Unit (ACU) dispenses approximately 14,000 items of individualised systemic anticancer therapy each year. With a sharp 25% increase in activity between 2013 and 2014 the ACU completed a SWOT analysis and committed to a long-term Quality Improvement (QI) project to ensure they could continue to provide a safe, efficient and high-quality service to patients. The importance of continued improvement and research is recognised as a significant part of the operation of a Cancer Centre and the ACU plays a significant part in this. Beaumont Hospital Aseptic Compounding team led by Grant Carroll, Chief II Pharmacist, Chemotherapy/Aseptics

Mater Misericordiae University Hospital Aseptic Compounding Department Project Lead: Brid Ryan, Aseptic Compounding Service Manager Entry Overview: As a Designated Cancer Centre of Excellence, Mater Misericordiae University Hospital manufactures over 18,000 items of chemotherapy and sterile products per annum and provides Oncology / Haematology services to an increasing number of patients. Aseptic Compounding Services developed in order manufacture sterile intravenous preparations in line with Good Manufacturing Practice (GMP) for the treatment of cancer for administration in the secondary care setting. The Aseptic Compounding Service, in conjunction with Pharmacy Department Management and the MMUH Drug Expenditure Committee, recognised the need to develop new hospital processes for the use of novel medicines under managed access programmes.

Brid Ryan, Aseptic Compounding Service Manager

St Vincent’s University Hospital Aseptic Compounding Unit Team Project Lead: Fiona Begley, Chief II Pharmacist, Maeve Moran, Acting Chief II Pharmacist & Team Entry Overview: Since 2010 activity in the pharmacy Aseptic Compounding Unit (ACU) in St Vincent’s University Hospital has increased with respect to the number of items compounded in the unit.

St Vincent's University Hospital Aseptic Compounding Unit Team

Issue 41 • HPN

It was established that a need to consolidate efforts was required, in order to maximise the quality, safety and efficiency of the ever increasing requirements of the service. A number of different improvements have been implemented with continuous development and further streamlining of these improvements on an on-going basis, including the implementation of an electronic treatment ordering system and inprocess improvements. The unit strives to continually improve the service it provides. Many innovations and improvements have been identified and several small as well as some large changes have been implemented or are in progress.

Awards Hospital Professional



Innovation & Service Development Award 2017 Sinead Curtis & Ciara Ni Dhubhlaing, Senior Pharmacists

Hospital: Pharmacy Department, St Patrick’s University Hospital Nomination Overview: The aim of this project was to assess the impact of a pharmacist review at discharge upon medication discrepancies from a psychiatric inpatient unit and develop this service. The findings of the study add an Irish context to the growing evidence demonstrating the risk to patients moving between care environments. The study has led to the identification of a significant number of discrepancies that would have gone undetected had the usual standard of care at the study hospital been implemented. Understanding the type and frequency of discrepancies can empower practitioners to better understand ways to prevent them. Senior Pharmacists Ciara Ni Dhubhlaing and Clare Butler

Project Lead: Ciarán Muldowney, Senior Pharmacist Hospital: St Vincent’s University Hospital Nomination Overview: Ciarán Muldowney, Senior Pharmacist in St. Vincent’s University Hospital, devised the concept for this innovation and developed it for delivery to the point of patient care. The focus of this project is to optimise the quality of life of affected patients with Multiple Sclerosis, by empowering them to manage their own care at home with oral medication, rather than attending hospital for IV therapy for 3 consecutive days. A secondary benefit would be that day care resources would be freed up within the hospital. This initiative demonstrates how high quality clinical trial evidence can be put into practical use to benefit patients, decrease overall hospital workload and reduce costs. Ciarán Muldowney, Senior Pharmacist

Project Lead: Diabetes Department Hospital: St Luke’s General Hospital, Kilkenny Nomination Overview: This innovation represents a pilot programme offering brief and long-term art psychotherapy to support individuals with a diagnosis of Type 1 Diabetes. The objective was to provide a service to support Paediatric Patients (Inpatient & Outpatient) with their diabetes diagnosis, illness management and coping mechanisms with a view to improve adherence and compliance. The preliminary findings of the evaluation carried out through a semi-structured interview is suggesting the service was integral as a part of the paediatric patients care and treatment of diabetes. It provided more engagement to the overall diabetes service and supported staff in providing treatment to the whole of the person and not just the illness. Left to right: Olive O' Grady Diabetes Nurse Specialist, Áine Fitzgerald Diabetes Nurse Specialist, Kate O'Connor, Senior Dietitian, Dr. Asif Wasim Paediatric Consultant, Majella Doherty Dietetics Manager, Geraldine Hanlon Paediatric Diabetes Nurse Missing: Adrienne O'Shea -Art Psychotherapist Edelle Nolan : Clinical Supervisor & Arts Co-Coordinator

Project Lead: Cancer Services Pharmacy Team Hospital: St Vincent’s Private Hospital Entry Overview: This project aimed to introduce a clinical pharmacist to the Haematology/Oncology outpatients ward of St. Vincent’s Private Hospital. By increasing the efficiency with which the prescriptions issues such as errors, omissions, missing scripts were resolved and up skilling of technicians to carry out some checking steps in the compounding process enough pharmacist time was made available to enable a continuous provision of the new service without affecting negatively the ACU capacity. The process changes also allowed the staff within the ACU to concentrate in the optimisation of the compounding processes by removing most of the clinical tasks to the ward.

Aseptic Compounding Team, St Vincent's Private Hospital led by Emma O'Grady

HPN • Issue 41

Awards 66 Awards


Hospital Professional

Daiichi-Sankyo Hospital Pharmacy Team of the Year Award 2017

Tallaght Hospital Pharmacy Department Project Lead: Tim Delaney, Superintendent Pharmacist/Head of Department

Nomination Overview: Tallaght Hospital Pharmacy Department provides a range of service to In-Patients, Out-Patients and Day Case patients. The team mission is to deliver safer, better, more cost-effective patient care through optimisation at all stages of the medication use process (purchasing, dispensing and aseptic manufacture, medicines information, risk management and medication reconciliation by team-based pharmacists.) As an academic department, their service is supported by education and training to advanced practice level, and practice is continually reviewed in line with emerging evidence from our research and clinical audit programmes.

The Pharmacy Team, Tallaght Hospital Pharmacy Department

St Vincent’s University Hospital Pharmacy Department Project Lead: Paul Tighe, Head of Pharmacy

Nomination Overview: In addition to the usual running of the Pharmacy department, St Vincent’s University Hospital (SVUH) successfully completed its third Joint Commission International (JCI) survey, which took place in Sept 2016. There is also an on-going focus on strategic development of the campus, including the physical new build for the pharmacy department, with the planned move of National Maternity Hospital to the SVUH site. Examples of initiatives undertaken in the past year to enhance pharmaceutical care provided by the SVUH pharmacy department include the launch of a Medicines Guide App, overhaul of supply of MDAs from pharmacy, Design for safety - AMU Drug Room and patient own lockers for medication and provision of oral methylprednisolone instead of IV for MS exacerbations to facilitate patients being managed at home rather than in hospital.

The Pharmacy Team, St Vincent’s University Pharmacy Department Issue 41 • HPN

67 Clinical Pharmacy Team, Midland Regional Hospital, Tullamore Project Lead: Oisín Ó hAlmhain, Chief II Pharmacist

Nomination Overview: The clinical pharmacy team in the Midland Regional Hospital Tullamore need no additional motivation to get going than that of putting the patient first, and getting the job done well. The team look after a diverse range of inpatients alongside a number of disciplines and specialties from 4 counties with an estimated population of 250,000. A buddy system has been introduced which pairs more experienced clinical pharmacists with more recent graduates. This helps senior staff to delegate as well as providing reassurance and experienced knowledge to more junior members of the team.The clinical pharmacy service is currently focussed around ensuring that medicines reconciliation on admission is accurate, and that problems identified at this point are resolved appropriately in order to improve patient safety throughout the patient admission and thereafter.

The Pharmacy Team, Midland Regional Hospital Clinical Department

St. Vincent’s Private Hospital ACU Team Project Lead: Nuno Silva, ACU Manager/Chief II Pharmacist

Nomination Overview: The Aseptic Compounding (ACU) team provides both Clinical Services and Compounding Services to the Haematology/ Oncology patients of St. Vincent’s Private Hospital. Despite the inherent pressures felt in any busy ACU, during 2016/2017 a number of projects and changes took place to improve the quality and safety of the service provided by the ACU. Most of projects /changes are a team effort with several team members collaborating to ensure its completion such as the introduction of Coveralls and changes in the gowning procedure; Introduction of a Outpatient Pharmacy Service; Review and update of Drug Preparation Sheets and the Review and comparison of available closed transfers system.

The Pharmacy Team, St Vincent’s Private Hospital Pharmacy Department

Pharmacy Department, Our Lady’s Children’s Hospital, Crumlin Project Lead: Michael Fitzpatrick, Chief Pharmacist

Nomination Overview: The Pharmacy Department at Our Lady’s Children’s Hospital Crumlin plays a vital and unique role in the provision of advice and pharmaceutical care to paediatric patients and in the discharge planning of patients. The paediatric discharge process can be complex and time consuming. The team are committed to ensuring seamless discharge of patients into the community with minimum disruption to medicine supply, especially for unlicensed or specialist medicines. The team is highly skilled and possesses a wide range of expertise, talents and skills. Many pharmacists have experience in specific clinical areas and are always willing to share their knowledge with other team members. Recently, the team rolled out a new medication kardex in the hospital. This involved collaboration with other institutions to develop an appropriate tool for prescribing for the unique requirements of paediatric patients.

The Pharmacy Team, Our Lady’s Children’s Hospital Crumlin

HPN • Issue 41

Awards 68 Awards


Hospital Professional

Daiichi-Sankyo Hospital Pharmacy Team of the Year Award 2017 (Continued)

Pharmacy Department, National Rehabilitation Hospital Project Lead: Sheena Cheyne, Chief Pharmacist

Nomination Overview: The pharmacy department in the NRH, National Rehabilitation Hospital has a small team, but provides many services including purchasing medications, dispensing for in patients (individually dispensed medicines), supply of week end leave medications (60% patients go home every week end) and for discharge. Pharmacists attend Consultant ward rounds and provide an antimicrobial stewardship round with the Consultant microbiologist. Medicine reconciliation is completed at admission and discharge. Patient education is provided in groups and in individual sessions. Recent projects include education for staff members and refurbishment of the department.

The Pharmacy Team, National Rehabilitation Hospital

Pharmacy Department, Mater Misericordiae University Hospital Project Lead: Professor Ciaran Meegan, Head of Pharmacy Services Nomination Overview: The Mater Misericordiae University Hospital (MMUH) Pharmacy Department provides a suite of patient centred, safety-oriented services with cost effectiveness as a cornerstone. Recent key activities and achievements of the Pharmacy team demonstrate the impact of the MMUH pharmacy team and services on the hospital, to patients and to the profession. These include the implementation of Electronic Parenteral Nutrition (PN) Ordering, Researching Electronic Prescribing for Chemotherapy and Medicines Optimisation, amongst other innovations. The Pharmacy Team, Mater Misericordiae University Hospital

Pharmacy Department, Beaumont Hospital Project Lead: Nuala Doyle, Head of Pharmacy

Nomination Overview: Beaumont Hospital Pharmacy Department faces many structural and electronic challenges. The team have made significant changes by streamlining the manual processes across the services including within clinical services, focusing and refining the A number of QI projects introduced in the dispensary. The Beaumont Hospital Pharmacy team are genuinely interested in achieving an efficient, lean, effective, cost saving and cost rationalisation department that they can be proud of. The difficult task they have whole heartedly undertaken alongside the recent innovations, dedications, and the motivation, inspiration and pride in their work makes enhancements they have made to both the profession and their patients worthwhile.

Issue 41 â&#x20AC;˘ HPN

The Pharmacy Team, Beaumont Hospital

Awards Hospital Professional



Excellence in Psychiatry Award 2017 Dr Feargal Leonard, Consultant Psychiatrist Hospital: Mental Health Service for the Elderly, Department of Psychiatry, Cavan General Hospital, Cavan Nomination Overview: This entry highlights the development of a joint working initiative between Mental Health Services, Services for Older People and Privately Operated Nursing Homes in ‘Person Centred Care’ for the management of Behavioural and Psychological Symptoms of Dementia (BPSD). The initiative showcases innovative practice which has enhanced the development of care for persons with dementia living within the participating nursing homes. It also involves all members of the MHSE multidisciplinary team working collaboratively in developing new methods of working with nursing home colleagues, such as the use of a best practice guideline on antipsychotic medication prescribing.

Dr Feargal Leonard, A/Executive Clinical Director

Professor Fiona McNicholas, Professor in Child Psychiatry Hospital: Department of Psychological Medicine, Our Lady’s Children’s Hospital, Crumlin Nomination Overview: The team involved with this project involves a multidisciplinary group of clinicians, researchers, patient advocates, and young people themselves in work towards the safe and effective psychiatry management of mental health illness in a rare genetic disorder - 22Q11DS. This research programme has been initiated and developed over the last five years due to the very high rate of mental health disorders in this cohort, coupled with the lack of any dedicated mental health service for a group of individuals required to face many challenging transitions as they journey through life. This application demonstrates through effective and collaborative team work, effective leadership, patient involvement, the development of a large body of research in a rare genetic disorder carrying a very high rate of psychiatry illness and thus pertinent to psychiatry services. Professor Fiona McNicholas, Professor in Child Psychiatry

Christine Pelz Hospital: Greystones Community Mental Health Team, Newcastle Hospital, Co. Wicklow Nomination Overview: The Greystones Community Mental Health Team seeks to improve local mental health service provision on an ongoing basis. In addition to regular team meetings, the team meet twice per annum specifically to focus on the development of our local service delivery and to explore ways in which the needs of the local population can be best met. The issues arising time and time again centred around social isolation, low self-esteem, lack of meaningful accessible leisure activities, concordance with medication, engagement with the mental health team and stigma. Through discussion and as highlighted in the Irish and international media, attention was drawn to the many health benefits that choral singing can have. Sam Kavanagh, Choral Conductor, Ellen Conalty, Community Mental Health Nurse, Edel O'Hara Leahy, Senior Clinical Psychiatrist, Caroline Gill, Staff Nurse, CBT Therapist and Christine Pelz, Mental Health Social Worker

Professor Michael Fitzgerald, Professor in Child Psychiatry Hospital: Our Lady’s Hospital for Sick Children Crumlin/National Children’s Hospital/Tallaght Hospital Entry Overview: Professor Michael Fitzgerald has altered the psychiatry multidisciplinary model. While the multidisciplinary model is the current dominant model, and has some advantages, it has also serious disadvantages in paralysing the individual creativity and responsibility of individual team members. It is not responsive to the waiting lists and to the distress of the children and families on the waiting lists. In taking the lead, Professor Fitzgerald has distributed the new referrals to the member of the team most relevant to them. This meant that each team member had their own list. The multidisciplinary team was used in a linear rather than a horizontal way. He has also improved psychotherapy services in Ireland for children and adults through visiting the various areas of the Eastern Health Board to supervise trainee psychiatrists, psychologists etc., e.g., St. Loman’s Hospital, Vergemount Hospital, St. James’s.

Professor Michael Fitzgerald, Professor in Child Psychiatry

HPN • Issue 41

70 Medicines Ireland

Medicines Ireland 89

Medicines for Ireland manifesto calls for radical overhaul of medicines policy in Ireland Owen McKeon, County CountryManager, Manager, Mylan Ireland

A National Medicines Strategy for Ireland which provides a longterm roadmap for how Ireland procures, supplies and affords medicines for Irish patients, is one of the key proposals contained in Medicines for Ireland’s policy manifesto published last month (July). Medicines for Ireland is a newly launched grouping of key medicine suppliers, including some of the largest suppliers of medicines to the HSE. Against a backdrop of growing difficulties experienced by Irish patients in affording and accessing life-savings medicines, the group has come together to propose and push for a radical reform of the current system of medicine supply. Medicines for Ireland’s manifesto has six core proposals which are critical to ensuring a properly functioning market and to safeguarding patients. These are:  A National Medicine Strategy which sets out a long-term plan for medicine usage and supply in Ireland;  Establishment of new National Medicines Office to implement this strategy and oversee the ¤2 billion annual medicine spend;  A new Medicine Pricing Agreement, which sets medicine prices, between the Department of Health and pharmaceutical industry ending the existing situation where only part of the industry participates in these negotiations; Issue 41 • HPN

 A Biosimilar Strategy, driven by the HSE, to kick-start switching to more affordable but equally effective biosimilar medicines. This has the potential to unlock hundreds of millions in savings in the years ahead;  Driving real competition in the medicines market through dynamic pricing schemes, particularly for high-volume medicines; and  Measures to tackle the growing problem of medicine shortages (currently over 140 medicines out of stock). The group’s policy proposals aim to radically overhaul the way medicine policy is set in Ireland, which they believe is outdated, lags far behind European best practice and is undermining patient access and affordability. The group cite the experience in New Zealand which has had a national medicines strategy for over a decade and approach the issue of medicine supply in a more planned and structured way than is the case in Ireland. Issues which must be addressed urgently in Ireland include:  The lack of a long-term plan for medicine supply in Ireland to ensure Ireland can continue to afford new, but more expensive, innovative medicines and the need for a cohesive body to implement it;  The ad hoc approach to medicine procurement and how to afford it into the future, especially hospital and hightech medicines, which has seen the latter’s cost to the

State more than double from ¤315 million to over ¤662 million in less than 10 years;  An archaic National Medicine Pricing Agreement which is negotiated without the largest suppliers of medicines to the HSE being party to the negotiations and the agreement;  The growing problem of medicines shortages, with the number and range of out of stock medicines increasing year-on-year; and  The failure of the HSE to make significant savings by switching to more affordable (up to 30% cheaper) biosimilar medicines. Of the biosimilars available in Ireland currently, they are less than 1% of the market with more expensive biologics making up the remaining 99%. Owen McKeon, Country Manager, Mylan Ireland and a founding member of Medicines for Ireland states "we are calling in Ireland for radical reform of pricing and reimbursement to deliver greater patient access to medicines and better value for money for the HSE. I call on the HSE and the Minster to examine our proposals carefully, all based on independent European data and experience. Such as; a new comprehensive road map to activate switching to more affordable but equally effective, and proven measures to tackle the growing problem of medicine shortages. Change is always necessary and possible, but in Ireland we have been too slow to reform our approach to medicine procurement. Too

often we only adapt and reform years or even decades after such changes are commonplace elsewhere. We cannot afford to do this when it comes to healthcare and medicine reforms. The membership of Medicines for Ireland has a track record of reform, having been to the fore in the introduction and implementation of providing patients with more affordable medicines, particularly through generic substitution in recent years. We are eager to continue this reform momentum so that Ireland’s medicine policy is fit for purpose and reflective of changes that are already wellembedded across the globe. We urge all decision-makers to carefully examine the proposals, including an amendment to EU regulations that would enable medicines to get to Irish patients on patent day off one thereby enabling thousands of new jobs and R&D into Ireland, all via the timely production of biosimilars in Ireland / Europe. I call on govt / MEPs to support and to move to implement these reforms as a matter of urgency. The lives of patients and their continued access to the best quality of care is at stake." Jeffrey Walsh, Joint Chairperson of Medicines for Ireland and Commercial Manager, Pinewood Healthcare, added, “The slow pace of change is frustrating for patients and those who want to see the current shortcomings addressed. As medicine suppliers, we feel the same frustration and that’s why we have developed our manifesto with real, fundamental, and actionable reform in mind. “Much has been said about the problems in the supply of medicines – lack of affordability, delayed or denied access, growing shortages. It all points to the unsustainability of continuing our current approach. Medicines for Ireland have designed our policy proposals to empower the Department of Health to reform now, rather than when the existing problems are even more acute. We can develop a better way but urgent reform must now be a priority for all stakeholders”, concluded Walsh. HPN • Issue 41

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








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 Date of preparation: October 2016. Adverse events should be reported. Reporting forms and information can be found at 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


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

72 Diabetes

Potential Impact of Cycle of Care on Diabetes Services in Secondary Care J Finnegan1, P McGing2, M Hatunic1 1 Endocrinology Department, Mater Misericordiae University Hospital, Dublin 2 Clinical Chemistry Department, Mater Misericordiae University Hospital, Dublin Abstract: Diabetes Cycle of Care is a new initiative recently introduced by the Health Service Executive (HSE). In this review we found that a quarter of patients attending a secondary care diabetes outpatient clinic in a large teaching hospital could potentially be managed in primary care upon implementation of Diabetes Cycle of Care.

Introduction Prevalence of Type 2 diabetes (T2DM) is increasing internationally and nationally1,2. Diabetes and its associated complications account for a significant workload and financial burden to the health service3. Optimising glycaemic control and managing cardiovascular risk factors reduces the risk of developing complications associated with diabetes4. The endocrine service in the Mater Misericordiae University Hospital provides specialist care to over 8000 patients with diabetes. As the prevalence of diabetes in Ireland is rising so is the demand for specialist care. The Diabetes Cycle of Care is a new initiative recently introduced by the HSE5. It will provide bi-annual structured diabetes review, through primary care services, for patients with type 2 diabetes with stable glycaemic control6. Our objective was to assess the proportion of patients attending diabetes clinics that have T2DM and analyse how many of them could potentially be suitable for the Cycle of Care. Methods We retrospectively audited ten consecutive outpatient diabetes clinics. Patients’ medical data was obtained using the hospital’s Electronic Patient Record (Patient Centre). Results of the most recent bloods tests for HbA1c, Lipids, and eGFR was gathered from the Laboratory Information System (Telepath v1.9). Information on the patients’ age, type of diabetes, and treatment, was obtained from clinic letters on Patient Centre. Data was analysed using Microsoft Excel to identify uncomplicated patients with T2DM, suitable for Cycle of Care, as per the ICGP guide

Issue 41 • HPN

including HbA1c <58 mmol/mol and eGFR >60 ml/min6. Results A total of 465 patients attended 10 diabetes clinics, approximately one-third (35.2%) of whom had Type 1 diabetes (T1DM) and twothirds T2DM (64.3%) (Table). The average age of patients attending clinics with T1DM was 45.1 years. Mean HbA1c was 62.7(16.8SD) mmol/mol and 42.7% had an HbA1c of ≤58 mmol/mol. Patients with T1DM had average total cholesterol of 4.44 mmol/l; 67.1% had LDL less than 2.6 mmol/l. There were 43.9% patients with T1DM on lipid lowering therapy. The majority of patients with T1DM had an eGFR >60ml/min (80.5%), 7.3% had stage III CKD (eGFR 30-59ml/min) and 2.4% of patients had stage IV CKD (eGFR 15-29ml/min), just 32.3% were on an ACEi/ARB. Patients with T2DM had an average age of 62.9 years with mean HbA1c 56.1 (17.7SD) mmol/mol. Just over a fifth (20.6%) of these patients were taking insulin, with 79.4% of patients using oral medication or diet to maintain glycaemic control. The average HbA1c in patients with T2DM on insulin was 64.3 mmol/mol compared to 53.9 mmol/mol in their counterparts taking oral hyperglycaemic agents (OHA)/ diet control. Hba1c of ≤58 mmol/ mol was achieved by 51.6% of patients on insulin and 73.6% of patients taking OHA/diet alone. In patients with T2DM the mean total cholesterol was 4.10 mmol/l and 72.4% of patients had LDL cholesterol of less than 2.6 mmol/l. The majority of patients with T2DM are on a lipid lowering medication (71.4%). The prevalence of CKD was higher

in patients with T2DM; 30.2% have impaired renal function: 23.6% have stage III CKD (eGFR 30-59ml/min), 5.3% have stage IV CKD (eGFR 15-29ml/min), and 1.3% have stage V CKD (eGFR <15ml/min). There were 65.1% patients with T2DM treated with an ACEi/ARB. Interestingly 122 patients (26.2%) attending clinics with T2DM on OHA/diet, with intact renal function (eGFR ≥60ml/min) had a Hba1c of ≤ 58 mmol/mol . Discussion A high percentage (69.1%) of patients with T2DM achieved a target HbA1c of ≤ 58 mmol/ mol and large numbers of patients were taking lipid lowering medication and ACEi/ ARBs (65.1%). This review

shows a significant number of patients with T2DM attending our specialist diabetes clinics are meeting their glycaemic targets. The majority of patients with T2DM are taking the appropriate medications to reduce cardiovascular risk. Based on the data from this study 26.2% of patients currently attending the specialist diabetes outpatient clinics could be appropriately managed in primary care should the Cycle of Care be implemented. This positive development would allow specialist services to allocate more time and resources to managing patients with more complex disease. Find the full version with references at

(linagliptin) 5mg tablets

(linagliptin/metformin (linagliptin/metformin HCI) HCI)

TrajentaÂŽ (linagliptin) and JentaduetoÂŽ (linagliptin/metformin HCl) Legal Category POM Marketing Authorisation Numbers and Holder: EU/1/11/707/003, EU/1/12/780/005, EU/1/12/780/019. Boehringer Ingelheim International GmbH, D-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 Crescent Building, Northwood Park, Santry, Dublin 9, Ireland. IE/TRJ/00279a(2)b. Date of preparation: May 2017.

(linagliptin) 5mg tablets

(linagliptin/metformin HCI)

74 Chronic Pain

European Pain Federation position paper on appropriate opioid use in chronic pain management T. O'Brien, LL Christrup, AM Drewes, MT Fallon, HG Cress, HJ McQuay, G Mikus, BJ Morlion, J Perez-Cajaraville, E Pogatzki-Zahn, G Varrassi, JCD Wells Marymount University Hospital & Hospice, Cork Abstract: Poorly controlled pain is a global public health issue. The personal, familial and societal costs are immeasurable. Only a minority of European patients have access to a comprehensive specialist pain clinic. More commonly the responsibility for chronic pain management and initiating opioid therapy rests with the primary care physician and other non-specialist opioid prescribers. There is much confusing and conflicting information available to non-specialist prescribers regarding opioid therapy and a great deal of unjustified fear is generated. Opioid therapy should only be initiated by competent clinicians as part of a multi-faceted treatment programme in circumstances where more simple measures have failed. Uncontrolled pain is a major public health concern. Despite multiple pain management guideline documents and initiatives by the WHO and others, there is still a reluctance to apply evidencebased and validated strategies in pain management. A major element contributing to this unacceptable situation is the pervasive negative bias that exists in respect of opioid use. In this regard, it is important to state that we are solely concerned with the legitimate use of opioid medication by competent and responsible clinicians, in carefully selected and supervised patients. Opioids are only considered in circumstances where non-opioid and adjuvant therapies have failed. The correct dose of an opioid is the lowest possible dose that achieves the desired outcome. The purpose of opioid use, as part of a multi-faceted approach to pain management, is to achieve and maintain an optimal level of pain and symptom relief with the minimal level of side effects. Ultimately, this is intended to rehabilitate the pain patient so that he/she may again engage more fully with life across a range of domains – family, work, social etc.

the care experience for patients experiencing pain across Europe. Pain is an unpleasant sensory and emotional experience. (IASP Taxonomy 2012) The individual experience and manifestation of pain is influenced by a complex series of interactions involving sensory, pathophysiological, affective, socio-cultural, behavioural and cognitive elements (Fig. 1; Dalal and Bruera 2012). Both chronic non-cancer pain and cancer pain remain significant public health concerns (Breivik et al., 2006; Ripamomti et al., 2012). The personal and socioeconomic impact of chronic pain is considered to be at least as great as that of other established healthcare priorities, including cardiovascular disease and cancer (Breivik et al., 2013). Pain reduces patient quality of life, preventing

many from leading an independent lifestyle. This can also negatively affect the lives of their family, friends and co-workers (West et al., 2012). The Declaration of Montreal states that pain management is inadequate across most of the world (IASP, 2012). Opioid analgesics are indispensable for the management of pain (Gilson et al., 2011). Opioids are highly effective and safe analgesics and their appropriate use by competent clinicians is a crucial element in modern pain management. Opioids are not a panacea for all painful conditions and are only introduced when strictly necessary and with due regard to an ongoing risk benefit analysis. Opioids are not used in isolation, but form part of a multi-faceted strategy that includes all necessary adjuvant analgesics, non-drug interventions, psychological

European Journal of Pain Volume 21, Issue 1, pages 3-19, 19 DEC 2016 DOI: 10.1002/ejp.970

European Journal of Pain Volume 21, Issue 1, pages 3-19, 19 DEC 2016 DOI: 10.1002/ejp.970

Issue 41 • HPN

In many instances, the absence of systematic screening of patients for pain results in the underrecognition and under-treatment of pain. It is over twenty years since the American Pain Society recommended routine assessment and recording of patients’ pain as a first step in improving pain management (APSQoCC, 1995). Whilst identifying pain is no guarantee of improved pain management, it is a vital first step (Mularski et al., 2006), and failure

European Pain Federation position paper on appropriate opioid use European Pain Federation position paper on appropriate opioid useininchronic chronicpain pain management management

This guideline document is produced by the European Pain Federation (EFIC) in order to provide a fair, balanced and evidence-based summary regarding the role of opioid use in pain management. The guideline is intended primarily for non-specialist prescribers and summarises all of the relevant data where such exists. Where data are lacking, the views and expert recommendations presented reflect the extensive clinical experience of a diverse range of European clinicians and scientists who have collaborated on this project. In so doing, we hope to better inform clinicians, regulators, legislators, administrators and the general public. We all have a shared responsibility to improve

Figure 1. The multi-dimensional concept of ‘total pain’

support and rehabilitation. All healthcare professionals must be adequately trained in basic pain assessment and management, and must take steps to maintain the essential competencies and skills required. When deemed medically necessary by a senior responsible clinician, opioids must be readily accessible under supervision for those who legitimately require such therapy.



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76 Chronic Pain to do so means that pain will not be addressed at all. All patients undergoing medical assessment for whatever purpose should be screened for pain. However, clinicians do not routinely seek a pain history and patients do not always volunteer one, even when asked. The reasons for this are summarised in Boxes 2 and 3 below (Dar et al., 1992; Anderson et al., 2000, 2002; Cleeland et al., 2000; Anderson, 2010). Box 2. Why do clinicians not routinely seek a pain history? • Lack of training and expertise • Time constraints • Excessive focus on disease indices • Not part of standard clinical assessment • Gender and ethnic differences Box 3. Why do patients not always report pain, even if asked? • May believe that pain is inevitable • Pain may not be the primary symptom • Cognitive impairment • Regard pain as an unavoidable consequence of their disease and/or treatment • Wish to be seen in a positive way • Do not wish to challenge the position of the clinician • Fearful of the anticipated consequences: o Hospitalisation/investigations o Anticipated therapies, including opioid medications Barriers to appropriate opioid use Worldwide, one of the most significant barriers to optimal pain management is lack of access to vital opioid medications, due to inappropriate restrictions on their availability and accessibility (INCB, 2016). Opioids are clearly not a panacea for all pains and this position paper is solely concerned with the scientific use of opioid medications in selected and supervised chronic pain patients as part of a comprehensive, multi-modality, multi-disciplinary approach to treatment. In this context alone, opioid therapy is an essential and indispensable

Issue 41 • HPN

tool in achieving and maintaining an optimal level of pain control in selected patients. Due regard must be paid to the patients psychological and emotional status – there is always more to achieving and maintaining analgesia than simply prescribing analgesics. The overall objective is to enable rehabilitation of the pain patient in order for them to resume their usual work and leisure activities. There are enormous variations in opioid use across the globe, and even within regions, similar variations are observed. According to the World Health Organization (WHO): ‘the central principle of balance represents a dual obligation of governments to establish a system of control that ensures adequate availability of controlled substances for medical and scientific purposes, while simultaneously preventing abuse, diversion and trafficking. While misuse of controlled substances poses a risk to society, the system of control is not intended to be a barrier to their availability for medical and scientific purposes, nor interfere in their legitimate medical use for patient care’ (WHO, 2011). A measure of the average per capita consumption of opioids in a given country is not in itself a reliable quality indicator of pain management in that country, yet it does provide some indirect evidence of the awareness among healthcare professionals of the role of opioids in pain management. Although a significant cumulative increase in opioid use has been reported in recent years, this has mainly occurred in a selected limited number of developed countries. Access to opioids varies enormously with the greatest use noted in North America, Western Europe and Oceania. Ninety-two per cent of the world's morphine is consumed by 17% of the world's population, leaving a mere 8% for distribution amongst 83% of the world's population. Consequently, millions of people are allowed to suffer pain unnecessarily. (INCB, 2016). Cherny et al. note that throughout Europe there are ‘excessively zealous or poorly considered laws and regulations to restrict the diversion of medicinal opioids into illicit markets profoundly interfere with the medical availability of opioids for the relief of pain. Often, the logistics of the treatment of pain with opioids is so burdensome or complex for physicians, nurses or pharmacists as to be a major

disincentive to involvement’ (Cherny et al., 2010). The solution to this major public health issue does not rest solely with any one country, professional group or other constituency. All concerned must work together to implement in a meaningful way the recommendations of the WHO (WHO, 2011) and the Council of Europe (CoE, 2003) in respect of opioid availability and accessibility for legitimate medical and scientific purposes. The European Pain Federation (EFIC) believes that a clearly focused, balanced and coordinated approach at local, regional, national and international level is required if we are to address the gross inequities that currently exist. There is an urgent need to shift the focus from a predominantly opioid-centric approach to a more patient-centric approach. Opioids: separating fact from fallacy Unfortunately, despite all of the available research, extensive clinical experience and published evidence, unjustified and exaggerated concerns regarding the safety of opioids continue to serve as a significant impediment to their appropriate availability, accessibility and rational use (INCB, 2016). For absolute clarity, the observations made in this article concerning the use of opioids relate exclusively to the medical use of opioid medications in adequately assessed and supervised patients for the sole purpose of achieving and maintaining a satisfactory level of pain and symptom control and are based on the strict understanding and implementation of the core principles of opioid prescribing. Clinical pharmacology of opioids There are three classical types of G-protein coupled opioid receptors: δ-, κ- and μ-receptors. Opioids act at these receptors as agonists, antagonists or partial agonists. Opioid agonists bind to the receptors to induce cellular hyperpolarisation. The majority of clinically relevant opioid analgesics are agonists of μ-receptors in the central nervous system (Pathan and Williams, 2012). Opioids mainly elicit their analgesic action through binding to central μ-opioid receptors. Opioid-related side effects are mediated via both

central and peripheral μ-opioid receptors. Genetic variability in μ-opioid receptors, complex regulation of receptor expression, different binding affinities of the opioids, and additional κand δ-opioid receptors all contribute to the need for individualisation of pain treatment (Brunton et al., 2011). The majority of patients respond to low or moderate doses of opioids. The non-specialist prescriber should seek expert opinion if a patient needs rapidly escalating doses and/or if the effective dose is in excess of oral morphine equivalent of 120 mg/24 h. Table 2 presents pharmacological data on common opioids, including the dose equivalent to 30 mg morphine (Brunton et al., 2011; DrugBank 2015). Please note that tables of equivalence are intended as a guideline only and do not represent clinically precise equivalence. Further dosing guidance can be obtained using one of a number of opioid dosage conversion apps that are available for smartphones and tablets (Haffey et al., 2013). Table 2. Clinical pharmacology of common opioids and approximate dose equivalent to oral morphine 30 mg Guidelines for initiating opioid analgesia The decision to initiate opioid therapy is made by a senior responsible clinician following a comprehensive assessment of the individual patient and a detailed analysis of the nature of the pain and its impact. For chronic noncancer pain, opioid therapy is only initiated when more simple strategies have failed following a reasonable trial. All patients must be fully informed on the proposed therapeutic strategy, including all potential risks and benefits and must be educated on the appropriate use and storage of the opioid medication. It is good practice at the outset to identify and document the expected therapeutic outcomes, both favourable in terms of pain relief and restoration of function, and potential adverse effects. This will be important when determining if the opioid therapy is successful or not. The recommended practice involves use of a μ-receptor agonist administered in a slowrelease formulation from the WHO analgesic ladder, based

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Targin® (oxycodone hydrochloride / naloxone hydrochloride) 5 mg/2.5 mg, 10 mg/5 mg, 15 mg/7.5 mg, 20 mg/10 mg, 30 mg/15 mg, 40 mg/20 mg, 60 mg/30 mg and 80 mg/40 mg prolonged release tablets. PRESCRIBING INFORMATION Republic of Ireland. Please read the Summary of Product Characteristics (SmPC) before prescribing. 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 (RLS) 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, 30/15mg, 60/30mg and 80/40mg 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. Lower strengths are available 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 hydrochloride. 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. Targin should not be administered for longer than absolutely necessary. When the patient no longer requires opioid therapy, it may be advisable to taper the dose gradually. 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 dopaminergic 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, severe respiratory depression with hypoxia and/or hypercapnia; 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, opioidinduced paralytic ileus, severely impaired pulmonary function, sleep apnoea, myxoedema, hypothyroidism, Addison’s disease (adrenal cortical insufficiency), toxic psychosis, cholelithiasis, prostate hypertrophy, alcoholism, delirium tremens, pancreatitis, hypo- or hypertension, pre-existing cardiovascular diseases, head injury (risk of raised intracranial pressure), epileptic disorder, predisposition to convulsions, patients taking MAO inhibitors, history of alcohol/drug abuse, galactose intolerance, Lapp lactase deficiency, glucose-galactose 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. May affect ability to drive and use machinery. 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. Oxycodone alone has an abuse profile similar to other strong agonist opioids. 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 long-term treatment of RLS beyond 1 year. Interactions: Substances having a CNS-depressant effect (e.g. other opioids, sedatives, hypnotics, anti-depressants, antipsychotics, phenothiazines, neuroleptics, antihistamines 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 recommended. Side-effects: Common (≥ 1/100): 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, vomiting, nausea, flatulence, hiccups, pruritus, skin reactions, hyperhidrosis, dysuria, asthenia, fatigue. Additionally, in RLS trial: depression, disturbance in attention, tremor, paraesthesia, visual impairment, blood pressure decreased, blood pressure increased, hepatic enzymes increased, chest pain, chills, thirst, pain. Uncommon (< 1/100) but potentially serious: hypersensitivity, anaphylactic responses, confusional state, depression, libido decreased, restlessness, euphoric mood, hallucination, agitation, drug dependence, aggression, convulsions, speech disorder, syncope, paraesthesia, sedation, concentration impaired, migraine, hyperalgesia, visual impairment, angina pectoris, palpitations, tachycardia, blood pressure decreased, blood pressure increased, dyspnoea, respiratory depression, tooth disorder, dysphagia, ileus, melaena, gingival bleeding, dental caries, hepatic enzymes increased, biliary colic, cholestasis, urticaria, urinary retention, erectile dysfunction, amenorrhoea, chest pain, drug withdrawal syndrome (including neonatal), peripheral oedema, oedema, drug tolerance, injuries from accidents. Refer to SPC for further details of other side-effects. Legal category: CD (Sch2) POM. Package quantities: Blisters of 56 tablets. Marketing Authorisation numbers: PA1688/010/001-4, PA1688/010/006-9. 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 2017. PI Code – UK/TARG15013(2).

‰ ‰

References: 1. Targin® SmPC. 2. Nadstawek J, et al. Int J Clin Pract, August 2008; 62 (8): 1159–1167. 3. O’Brien T, Christrup LL, Drewes AM et al. European Pain Federation position paper on appropriate use in chronic pain management. Eur J Pain 2017;21:319. 4. Dowell D, Haegerich T, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain—United States, 2016. 5. Faculty of Pain Medicine. Opioids Aware: A resource for patients and healthcare professionals to support prescribing of opioid medicines for pain ( 6. OxyContin (prolonged-release oxycodone tablets). Summary of Product Characteristics. 7. Kosten TR, George TP. The neurobiology of opioid dependence: implications for treatment. Sci Pract Perspect 2002;1:13–20. 8. Rosenblum A, Marsch LA, Joseph H et al. Opioids and the treatment of chronic pain: controversies, current status, and future directions. Exp Clin Psychopharmacol. 2008;16:405–16.

Adverse events should be reported to HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website:; E-mail: Adverse events should also be reported to Mundipharma Pharmaceuticals Limited on or by phone on 01 2063800 (1800 991830 outside office hours)


Powerful treatment for severe pain 1,2

Naloxone: Counteracts opioidinduced constipation 1

Targets severe pain

® The Mundipharma device (logo) is a Registered Trade Mark. ® Targin is a Registered Trade Mark. © 2011-17 Mundipharma Pharmaceuticals Limited. Date of item: August 2017. IRE/TRN - 17004.

Considerations when Prescribing an Opioid. w Patients should be carefully selected and regularly monitored to ensure that opioids are prescribed appropriately.3-5

w Patients should be made aware of the potential opioid side effects and the potential for misuse, abuse and addiction.3,4

w Clear treatment goals related to pain and function should be agreed with the patient.


w Start at lowest possible dose and up-titrate stepwise according to individual patient response.3

w The lowest effective dose should be prescribed.2,3-6 w Patients should be monitored throughout opioid treatment to reassess the benefits and risks of continued therapy. If benefits do not outweigh risks, reconsider the treatment plans and doses of opioids should be tapered down or discontinued.3-5

w If discontinuing treatment, the dose should be gradually decreased by 10% every week or every 2 weeks dependent on patient response)3 to prevent symptoms of withdrawal.5

w Addiction is possible even when opioids are taken as directed.7 The exact prevalence of addiction in patients treated with opioids for chronic pain is difficult to determine.8 Signs of addictive behaviour should be monitored and addressed.4,5

78 Chronic Pain on a single-prescriber policy. Patients are kept under close medical surveillance and may be encouraged to keep a pain and activity diary. The aim of this section is to outline a practical, step-by-step guide to the clinical processes and considerations involved in initiating analgesic therapy with opioids. A flowchart summarizing this algorithm is presented in Fig. 2.

3. Impact of the pain(s) on the patient's life – occupational, social, recreational

Figure 2. A step-by-step guide to the initiation of opioid analgesia (below).

7.2 Definition of therapeutic goals

7.1 Clinical assessment 1. Patient suitability for opioid treatment should be assessed prior to initiation of therapy and consider: 1. Nature of the pain(s) and documented response to previous treatments 2. Pain intensity and its likely sensitivity to opioids

4. Psychosocial assessment including mood, family/social supports, psychiatric morbidities and addiction risk including previous opioid use, if any 5. Significant co-morbidities such as gastro-intestinal, hepatic, renal, respiratory disease etc.

1. Agreement on expected therapeutic goals – pain intensity scores and restoration of function/ activities 2. Planned management of anticipated opioid related side effects, particularly in respect of bowel dysfunction 3. Likelihood of achieving therapeutic goals such as the maximum pain score that is acceptable to an individual patient and functional goals such as

resuming hobbies and/or returning to work etc. 7.3 Choose an appropriate opioid 1. Opioid selection should be individualized to the patient. There is no single opioid that is superior to all other opioids on the individual level and therefore opioid therapy is initiated on a trial-and-error basis. As response cannot be predicted in advance, physician preference in terms of familiarity and availability is important and also patient preference (where identified) should be respected where possible. Transdermal opioid delivery systems are not suitable for patients with acute, uncontrolled pain. The following shall be taken into consideration when selecting an opioid: 1. Physician/patient preference in terms of familiarity, availability 2. Drug–drug interactions and comorbidities identified e.g. avoid methadone and buprenorphine if

history of prolonged QT interval/structural heart disease/ arrhythmia etc. 3. No direct clinical trial evidence to suggest any one opioid is superior to any other in initial therapy on individual basis. However, some patients may experience severe side effects to one opioid and not to another and this cannot be predicted (opioid trial phase). 4. Initiate therapy at the outset to minimize opioid induced bowel dysfunction – laxatives and/or peripherally acting opioid receptor antagonists 7.4 Initiate a short-term trial 1. Single-prescriber, singledispenser policy if possible. 2. Close medical surveillance particularly during the initial titration phase 3. Monitor with pain, activity and side-effect diary

European Pain Federation position paper on appropriate opioid pain European Pain Federation position paper on appropriate opioiduse usein in chronic chronic pain management management

Figure 2

European Pain Federation position on appropriate opioid use in chronic pain management

European Journal of Pain Volume 21, Issue 1, pages 3-19, 19 DEC 2016 DOI: 10.1002/ejp.970

opean Journal of Pain me 21, Issue 1, pages 3-19, 19 DEC 2016 DOI: 10.1002/ejp.970 // Issue 41 • HPN

79 4. Initial course of opioid treatment should be considered as a shortterm therapeutic trial of between several weeks and a few months. 5. Outcomes to consider include: 1. Progress towards pre-defined therapeutic goals. 2. Presence, absence and tolerability of opioid-related side effects. 3. Changes in daily physical and social activity. 4. Changes in underlying pain condition. 5. Changes in comorbidities or psychiatric health status. 6. Identification of misuse, abuse or addictive behaviours (e.g. loss of control and/or preoccupation with obtaining opioids despite adequate analgesia and presence of side effects). 7.5 Start at lowest possible dose and up-titrate stepwise 1. Initially all patients who are prescribed opioids for the first time should start on the lowest available convenient dose schedule using a long-acting oral formulation (for good compliance and ease of administration) 2. Particular caution is required in frail patients in the setting of significant co-morbidities, e.g. renal dysfunction 3. Caution is required in patients using other centrally acting drugs such as benzodiazepines – ideally, the co-prescription of opioids and benzodiazepines should be avoided if possible 4. Long-acting opioids offer a more convenient option for the patient resulting in: o Enhanced compliance. o Reduction in breakthrough pain episodes. o Reduced likelihood of addiction/ abuse or misuse. 7.6 Treatment of side effects 1. From the beginning, treatment of predictable opioid-induced side effects is an integral part of effective opioid administration 2. This is particularly relevant in terms of reducing the burden of opioid induced bowel dysfunction 3. All patients should receive laxative medications and/ or peripherally acting opioid antagonists when initiating opioid therapy 4. A smaller proportion of patients will experience short-term nausea

at the initiation of opioid therapy. A dopamine receptor antagonist is useful in such circumstances. In summary, the main objective of the short-term opioid therapy is to find the best balance between analgesic efficacy and tolerability. That is, to provide the patient with pain relief, while at the same time ensuring that they are comfortable in terms of side effects, with minimal impairment of physical and psychosocial functional status and no aberrant drug-related behaviour. Patients need to be reviewed regularly for signs of inefficacy, continuous dose escalation, noncompliance, unapproved co-medications, deterioration in functional status or addiction/abuse or misuse. If any such signs are seen, or there is an unfavourable balance between side effects and analgesia, a full re-evaluation must be undertaken and an alternative therapeutic strategy pursued. Opioid switching In circumstances where an individual patient fails to achieve satisfactory pain control and/or they are troubled by unacceptable side effects, a trial of an alternative opioid is indicated. In clinical practice, one of two strategies to affect the switch may be employed as follows: 1. The equi-analgesic dose of the current opioid and the proposed new opioid is established by reference to published equivalence tables. Once the equivalent dose is established, it is further reduced by a factor of 25–50% to establish the new baseline starting dose (Drewes et al., 2013). This reduction is necessary to allow for incomplete cross-tolerance and inter-individual variation in response. Equivalence tables are for guidance only as they may underestimate the potency of the new opioid (Fine and Portenoy, 2009). Fatal outcomes can occur during opioid rotation, even when prescribers have not deviated from published guidelines (Webster and Fine, 2012). Once the previous opioid is withdrawn and the new opioid introduced, the clinician will continue to monitor the patient and will titrate the dose as required, based on observed clinical response. 2. Alternatively, the dose of the established opioid may be reduced sequentially over a number of days and stopped. Simultaneously, the new opioid is introduced at the lowest possible dose and gradually titrated over a number of days to the optimal dose that achieves

a satisfactory outcome with an acceptable side-effect burden. Managing long-term use of opioids Patients on long-term opioid therapy must be kept under close clinical surveillance. At all times, the opioid dose is kept to the minimal level that achieves the desired outcome. Equally, side effects must be kept under review, especially in terms of bowel dysfunction (which is not dosedependent and is the only opioid side effect with a mechanismbased therapy). As with any other medication, opioid therapy should only continue if it is clinically beneficial, with an acceptable side-effect profile that does not further compromise patient quality of life. Long-term opioid treatment of up to 6 months will benefit approximately 25% of patients with painful conditions such as osteoarthritis, diabetic polyneuropathy, postherpetic neuralgia and chronic low back pain (Häuser et al., 2014). In such patients, regular clinical reviews are required to assess pain control, impact on lifestyle (daily activities, sleep disturbance and participation), physical and psychological well-being, side effects and continued need for treatment (Häuser et al., 2014). After 6 months of opioid therapy, a dose reduction (or ‘drug holiday’) should be considered and discussed with the patient, to determine whether continued opioid treatment is appropriate (Häuser et al.,2015). The response to non-pharmacological treatment, such as pain-related physiotherapy, psychotherapy and systematic lifestyle modification, should also be assessed (Häuser et al.,2015). Discontinuation of opioid therapy should be considered if the individual goals of treatment are not met; if side effects are intolerable and/ or untreatable; if the individual goals are reached by additional treatment (e.g. surgery or physiotherapy); or if the patient shows signs of opioid misuse, abuse or addiction (Häuser et al.,2014). In relation to the latter point, using opioids for pain control in drug-dependent patients is complex and should always prompt referral to a specialist service. A situation may arise where the clinician decides that discontinuing opioids is required, but the patient disagrees and seeks to continue the therapy. It may be difficult for the clinician to determine if the

patient's insistence represents a genuine desire for pain relief, inappropriate drug seeking behaviour or a combination of both (Alford, 2016). In such circumstances, the clinician is the responsible prescriber and must be fully satisfied that continued opioid prescription is the correct management strategy. If not, the decision must be respectfully explained to the patient that opioid prescriptions are to be withdrawn. Other therapeutic options and more specialist multi-disciplinary assessment should be undertaken in such circumstances. Conclusions Pain is a global public health problem. In Europe, the reasons are many and varied but ultimately relate to a lack of understanding of the nature and impact of chronic pain and a failure to apply evidence based strategies to pain management. The situation is further compounded by an inappropriate and exaggerated fear concerning the legitimate scientific use of opioid medications as part of a comprehensive pain management strategy in carefully selected and supervised patients. In many countries, overly stringent and ill-considered restrictions and regulations intended to prevent illicit, non-medical use of opioids, results in patients suffering unnecessarily. Opioids should only be introduced when less potent analgesics and adjuvant therapies have failed to achieve and maintain adequate pain relief and rehabilitation. A positive educational programme is required to change attitudes towards the proper medical use of opioids, both in the medical community and for patients, their families and wider society. The European Pain Federation (EFIC) is committed to improving the understanding of opioids and their role in pain management, and believes that appropriate education and training will enable PCPs to prescribe opioids responsibly. The medical profession is compassionate enough and bright enough to learn how to prescribe opioids when they are indicated in ways that maximise benefit and minimise harm. Though managing chronic pain is complicated and time-consuming, we owe it to our patients to ensure access to comprehensive pain management, including the medically appropriate use of opioids (Alford, 2016). Find the full version with references at

HPN • Issue 41

80 Stroke

Stroke services and guideline compliance – Ireland vs UK A comparison of service organisation and guideline compliance between two adjacent European health services Dr Paul McElwaine, Department of Medical Gerontology, Trinity College Dublin, Mercer’s Institute, St James’s Hospital, Dublin

It is generally accepted that better organisation of stroke services results in better outcomes for stroke patients.1,2 Accordingly, modern stroke care is often highly structured, utilising models of care and protocols3 derived from evidence-based guidelines.4–8 However, interpretation of guidelines and how they are implemented and thus consequent development of services may differ between health services. The island of Ireland is divided into two government authorities the Republic of Ireland (ROI) and Northern Ireland (NI), which is a component of the United Kingdom. Stroke services in each area have developed separately; the NI health service being a component part of the larger UK National Health Service (NHS) and the ROI being governed by the Irish Health Service Executive (HSE). In an analysis of the second Irish National Stroke Audit (2nd NSA) carried out in the Republic we compared services between the two jurisdictions in terms of resources provided and concordance with European and UK guidance, specifically with NI but with reference to the UK where NI data unavailable. Methods The 2nd NSA was performed in 2015 under the auspices of the Irish National Clinical Programme for Stroke Care (CPSC).9 The audit was designed to collect data on patient care and outcome measures that were consistent with Irish National Guidelines and the previous iteration of the national audit in 2008.10 It was also designed to allow comparison with other local European health systems. Data were collected in a format to permit comparison with published European Stroke

Issue 41 • HPN

Organisation (ESO) guidelines and recommendations.3,6 Due to the close proximity and similar healthcare structure, results were also compared with data from UK audits, both the seven UK Royal College of Physicians Audits 1998–201111,12 and the current continuous Sentinel Stroke National Audit Programme (SSNAP) which has operated since 2014 and data from which is published quarterly. SSNAP collects clinical data prospectively for every stroke patient along the stroke care pathway up to 6 months and includes a biennial acute organisational audit providing a view of the quality of stroke services in the acute setting. The UK and Ireland have very similar health systems in

terms of organisation and medical training structures. The 2nd NSA comprised of two components The first was an organisational audit comprised of a questionnaire sent to senior administrators and lead stroke clinicians followed by an inspection visit by teams from the national programme consisting of senior specialist medical, nursing and therapy staff representing the CPSC to confirm and clarify reports provided. The second component was a chart audit of a representative sample of individual patients who had received acute stroke care in hospitals over two, 3-month periods 1 January 2014 to 31 March 2014 and 1 July 2014 to 30

September 2014. Chart audit was performed by medical, specialist nursing and therapy staff from each hospital with a superaudit of random chosen centres performed by staff from the CPSC to ensure consistency across sites. The tool was approved by an expert working group prior to dissemination, many of whom had been involved in prior national audits or audits in other jurisdictions. The tool was also reviewed by national quality assurance organisation and was trialled in four hospitals prior to final revisions and national dissemination. The audit was also conducted in association with an independent

NEW aspirin • atorvastatin • ramipril

The 1st polypill licensed for secondary prevention of cardiovascular events in Ireland Trinomia 100 mg/20 mg/10 mg, 100 mg/20 mg/5 mg, 100 mg/20 mg/2.5 mg hard capsules (acetylsalicylic acid, atorvastatin (as atorvastatin calcium trihydrate) and ramipril) Abbreviated Prescribing Information Please consult the Summary of Product Characteristics (SmPC) for full prescribing information. Presentation: Hard capsules containing: two 50 mg acetylsalicylic film-coated tablets, two 10 mg atorvastatin film-coated tablets and one 10 mg ramipril filmcoated tablet; or two 50 mg acetylsalicylic film-coated tablet, two 10 mg atorvastatin film-coated tablets and one 5 mg ramipril film-coated tablet; or two 50 mg acetylsalicylic film-coated tablet, two 10 mg atorvastatin film-coated tablets and one 2.5 mg ramipril film-coated tablet. Uses: Secondary prevention of cardiovascular accidents as substitution therapy in adult patients adequately controlled with the monocomponents given concomitantly at equivalent therapeutic doses. Dosage: Oral administration. 1 capsule per day, preferably after a meal. Swallow with liquid. Do not chew or crush. Avoid grapefruit juice. Patients currently controlled with equivalent therapeutic doses of acetylsalicylic acid, atorvastatin and ramipril can be directly switched. Treatment initiation should take place under medical supervision. Cardiovascular prevention, target maintenance dose of Ramipril is 10 mg once daily. Daily dose in renal impairment based on creatinine clearance - ≥ 60 ml/min, maximum daily dose is 10 mg ramipril; 30-60 ml/min, maximum daily dose is 5 mg ramipril. Contraindicated in hemodialysis and/or with severe renal impairment (creatinine clearance <30 ml/min). Administer with caution with hepatic impairment. Perform liver function tests before initiation of treatment and periodically thereafter. Maximum daily dose of is 2.5 mg ramipril and initiate treatment under close medical supervision. Contraindicated in severe or active hepatic impairment. Start treatment in very old and frail patients with caution. Contraindications: Hypersensitivity to any component, to other salicylates, to NSAIDs, to any other ACE inhibitors, tartrazine, soya or peanut. History of previous asthma attacks or other allergic reactions to salicylic acid or other NSAIDs. Active, or history of recurrent peptic ulcer and/or gastric/intestinal haemorrhage, other kinds of bleeding. Haemophilia and other bleeding disorders. Severe kidney and liver impairment. Hemodialysis. Severe heart failure. Concomitant treatment with methotrexate at a dosage of 15 mg or more per week. Concomitant use with aliskiren-containing products with diabetes mellitus or renal impairment. Nasal polyps associated with ashma induced or exacerbated by acetylsalicylic acid. Active liver disease or unexplained persistent elevations of serum transaminases. Pregnancy, lactation and in women of child-bearing potential not using appropriate contraceptive measures. Concomitant treatment with tipranavir, ritonavir, ciclosporin. History of angioedema.. Extracorporeal treatments leading to contact of blood with negatively charged surfaces. Significant bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney. Hypotensive or haemodynamically unstable states. Children and adolescents below 18 years of age. Warnings and Precautions: Only for use as a substitution therapy in patients adequately controlled with the monocomponents given concomitantly at equivalent therapeutic doses. Special populations requiring particularly careful medical supervision: Hypersensitivity to other analgesics/antiinflammatory/ antipyretic/antirheumatics or other allergens. Other known allergies, bronchial asthma, hay fever, swollen nasal mucous membranes and other chronic respiratory diseases. History of gastric or enteric ulcers, or of gastrointestinal bleeding. Reduced liver and/or renal function. Particular risk of hypotension: strongly activated renin-angiotensin-aldosterone system, transient or persistent heart failure post MI, risk of cardiac or cerebral ischemia, in case of acute hypotension medical supervision including blood pressure monitoring is necessary. Deterioration of cardiovascular circulation. Glucose 6 phosphate dehydrogenase deficiency. Risk of elevated levels of uric acid. Consumption of substantial quantities of alcohol and/or have a history of liver disease. Diagnosed pregnancy, stop treatment immediately, and, if appropriate, start alternative therapy. ACE inhibitors cause higher rate of angioedema in black patients than in non-black patients. The blood pressure lowering effect of ACE inhibitors is somewhat less in black patients than non-black patients. Monitoring during treatment is required for: Concomitant treatment with NSAIDs, corticosteroids, SSRIs, antiplatelet drugs, anticoagulants. Signs or symptoms suggestive of liver injury. Stop treatment temporarily prior to elective major surgery and when any major medical or surgical condition occurs. Particularly careful monitoring is required in patients with renal impairment, risk of impairment of renal function, particularly with congestive heart failure or after a renal transplant. Risk of development of hyperkalaemia – regular monitoring of serum potassium recommended. Specific side-effects: Perform liver function tests before use and monitor periodically and with liver injury or increased transaminase levels. Use with caution with substantial alcohol use or history of liver disease. Potential risk of hemorrhagic stroke. May affect the skeletal muscle and cause myalgia, myositis, and myopathy that may progress to rhabdomyolysis, ask patients to promptly report skeletal muscle effects (muscle pains,

cramps or weakness) especially if accompanied by malasie or fever and measure CK levels, stop treatment if significantly elevated or if severe muscular symptoms occur. Prescribe with caution in patients with pre-disposing factors for rhabdomyolysis. Benefit/risk of treatment should be considered and clinical monitoring recommended. Do not measure CK following strenuous exercise or in presence of plausible alternative cause of CK increase. If CK levels significantly elevated at baseline, re-measure levels 5 to 7 days later to confirm the results. Risk of rhabdomyolsis with use of potent CYP3A4 inhibitors, transport proteins or HIV protease inhibitors. Consider alternative treatments if risk of myopathy. Consider lower starting or maximum dose and appropriate clinical monitoring with potent CYP3A4 inhibitors and medicinal products that increase the plasma concentration of atorvastatin respectively. Do not co-administer with systemic fusidic acid or within 7 days of stopping fusidic acid. Where use of systemic fusidic acid considered essential, discontinue statin treatment during fusidic acid treatment. Reports of rhabdomyolysis in patients receiving fusidic acid and statins in combination. Where prolonged systemic fusidic acid needed, consider need for co-administration of Trinomia and fusidic acid on case by case basis with close medical supervision. Discontinue statin treatment if interstitial lung disease occurs. Monitor patients at risk of diabetes mellitus. Discontinue treatment if angioedema occurs and initiate emergency treatment promptly. Concomitant use of ACE-inhibitors and angiotensin II receptor blockers or aliskiren is not recommended and should not be used in patients with diabetic nephropathy. Anaphylactic reactions during desensitization, consider temporary discontinuation of Trinomia during desensitization. Monitor white blood cells for neutropenia/agranulocytosis and more regularly in the initial phase of treatment, impaired renal function, concomitant collagen disease and other mediciens that can change the blood picture. Cough. Contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Interactions: Acetylsalicylic acid: other platelet aggregation inhibitors, other NSAIDs,and antirheumatics, systemic glucocorticoids, diuretics, alcohol, SSRIs, uricosuric agents, anticoagulant and thrombolytic therapy, digoxin, antidiabetic agents including insulin, methotrexate, valproic acid, , antacids, ACE inhibitors, ciclosporin, vancomycin, interferon α, lithium, barbiturates, zidovudine, phenytoin, laboratory tests. Atorvastatin: CYP3A4 inhibitors, CYP3A4 inducers, transport protein inhibitors, gemfibrozil/fibric acid derivatives, ezetimibe, colestipol, fusidic acid, colchicine, digoxin, oral contraceptives, warfarin. Ramipril: potassium salts, heparin, potassium-retaining diuretics and other plasma potassium increasing active substances, antihypertensive agents and other substances that may decrease blood pressure, vasopressor sympathomimetics and other substances, allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may change the blood cell count, lithium salts, antidiabetic agents including insulin. Monitor as appropriate. Consider lower maximum dose of atorvastatin with potent CYP3A4 inhibitors. Pregnancy and Lactation: Contraindicated in pregnancy and breast-feeding. Women of child-bearing potential should use effective contraception during treatment. Side Effects: Ramipril: Common (≥ 1/100, <1/10): dyspepsia, nausea, diarrhoea, vomiting, digestive disturbances, abdominal discomfort, gastrointestinal inflammation, non-productive tickling cough, bronchitis, sinusitis, dyspnoea, headache, dizziness, rash in particular maculo-papular, blood potassium increased, myalgia, muscle spasms, chest pain, fatigue, hypotension, orthostatic blood pressure decreased, syncope. Atorvastatin: Common: dyspepsia, nausea, diarrhoea, constipation, flatulence, pharyngolaryngeal pain, epistaxis, nasopharyngitis, headache, allergic reactions, hyperglycaemia, myalgia, muscle spasms, pain in extremity, joint swelling, back pain, arthralgia, liver function test abnormal, blood creatine kinase increased. ASA: Very Common (≥ 1/10): Gastrointestinal complaints such as heartburn, nausea, vomiting, stomach ache and diarrhea, minor blood loss from the gastrointestinal tract (micro-bleeding). Common: Paroxysmal bronchospasm, serious dyspnoea, rhinitis, nasal congestion. For less frequent side effects see SmPC. Pack Sizes: Blister containing 28 film-coated tablets. Legal Category: POM. Product Authorisation Numbers: PA 1744/002/001-003. Product Authorisation Holder: Ferrer Internacional, S.A., Gran Vía Carlos III, 94, 08028 Barcelona, Spain. Marketed by: A. Menarini Pharmaceuticals Ireland Ltd. Further information is available on request from A. Menarini Pharmaceuticals Ireland Ltd, 2nd Floor, Castlecourt, Monkstown Farm, Monkstown, Glenageary, Co. Dublin A96 T924 or may be found in the SmPC. Date of Preparation: February 2017 Date of item: April 2017. IR-Tri-03-2017

82 Stroke non-governmental organisation, the Irish Heart Foundation, to permit external scrutiny and validation of the process. The organisational audit document included 46 core questions with multiple sub-sections relating to the structure, staffing and operation of the service. The chart audit document included 77 core questions to be completed for each subject. Each hospitals admitting 20 or more acute strokes (ICD, 10 codes: I61, I63 and I64, including sub-categories) in the previous year was requested to complete the organisational audit and hospital chart audit on between 25 and 40 consecutive patients admitted during the periods outlined, depending on the number of patients admitted. Organisational data were compared with published Irish and ESO guidelines and SSNAP data published for NI and UK hospitals for the period April 2013 to March 2014. Patient data were also assessed for concordance with guidelines. Individual patient data was not available for NI for the time period in question and these results were compared with overall UK data. Collected NSA data was initially recorded on paper audit forms and all data were sent to an independent organisation for data entry and tabulation. SSNAP is published online at the organisation’s website. Quantitative results for the Irish and NI/UK audits were statistically evaluated and compared using relative risks (RR) and chi-square statistic to estimate scale of discrepancies and to compare proportions. In comparing staffing levels, chi squares were applied after converting ratios to proportions using the published total bed numbers. Results Data for 874 patients was audited in the ROI of 6035 total strokes (14.5%) admitted to Irish hospitals in 2014. These were compared with 74,307 in the UK SSNAP which collects prospective data on stroke admissions for England, Wales and Northern Ireland. Twenty-seven hospitals in Ireland were found to have admitted 20 strokes or more in 2013 (median 177, range 56–412) and were audited. Twenty-one (78%) of these were found to

Issue 41 • HPN

Table 1. Comparison of specialists managing stroke patients, ROI versus UK (chi square statistic) Primary specialty of consultant

Republic of Ireland, `n=874 (%)









Internal medicine








UK, n=74,307 (%)

Note: n: number of patients have stroke units using the three core elements required by the European Stroke Organisation definition, that is a discreet area of a defined ward used exclusively for stroke, specialist medical, nursing and therapy staff and regular multidisciplinary team meetings.3 This compared with 10 of 10 (100%) in Northern Ireland. One NI hospital that reported a 10-bed stroke unit used solely for care beyond 72 h and utilised a thrombolysis bypass process was excluded from our analysis, although acute stroke patients were potentially repatriated to the hospital earlier than 72 h on occasion. All remaining Northern Irish were self-categorised as combined units. In contrast, 10 of the ROI units categorized themselves as acute, the remained as combined. On inspection it was found that most of the acute units in the ROI also provided substantial post-acute care usually influenced by the availability of unoccupied rehabilitation beds to transfer patients to and the distinction between acute and combined units was unclear. There were 152 stroke beds available for acute care across NI and 150 in ROI. The number of stroke beds per head of population (on 2011 census data from both areas) was 1 per 12,037 for NI and 1 per 30,633 for ROI, representing 2.5 times the number of acute beds per head of population in NI. This compares with 1:20,874 for the United Kingdom as a whole. Direct admission to a stroke unit/ high dependency bed reported in 66% of patients in NI versus 40% in ROI and 75% in the UK as a whole (RR 2.4 (95% CI 2.3– 2.5), UK vs. ROI). Fifty-seven percent of UK patients were admitted to the stroke unit within 4 h compared to 11% of patients in ROI (RR 2.0 (95% CI 2.0–2.1)). Fifty-four percent of patients in ROI received care in a stroke unit at

some time post-stroke compared to 96% of patients in the UK (RR 11.5 (95% CI 10.6–12.5)). Complete comparable data for stroke unit admission for NI was not available. All units in NI and ROI had multidisciplinary team meetings to review stroke patients’ care at least weekly. Capacity for investigation, physiological monitoring and staffing within stroke units differed significantly between jurisdictions. Twenty-four hour CT imaging was available in all sites in ROI and 99% of sites in the UK including all sites in NI. However, capability for 24-h physiological monitoring was available in 54% of units in ROI compared to 91% of UK units (RR 5.1 (95% CI 4.7–5.5)). Twenty-three of 27 ROI sites and all NI sites reported a senior physician with specialist knowledge of stroke care. However, patients in the ROI were significantly less likely to be managed under a senior clinician (consultant grade) with specific stroke training that is geriatrician or neurologist (Table 1). Stroke nurse specialists were employed in all the NI units and in 23 of the 27 ROI units. Nursing numbers were compared for staff on duty per 10 acute or combined beds at 10 a.m. weekday mornings, the time of the week when units would have greatest staff numbers present. In ROI, this averaged 2.9/10 beds compared with 2.3/10 beds in NI and 2.4/10 beds in the UK (p1/4 0.03 Chi Sq). There were however significantly more care assistants in the UK and NI 1.6/10 beds compared with 0.9/10 beds in Ireland (p¼0.02 Chi Sq). Thus, there was no significant difference in ratio of total nursing/care attendant staff between jurisdictions. Only two (10%) of the ROI units and

none of the NI units met the ESO recommended 1:2 total nursing ratio for low dependency stroke beds and none met the 1.5:1 ratio suggested for high acuity beds in ESO guidelines.3 Ratio of allied health professionals per 10 stroke unit beds is outlined in Table 2. It appears that there are a significantly higher proportion of Dieticians and Speech and Language Therapists in ROI than either NI or the UK. However, AHPs in the ROI frequently also have responsibility for stroke patients outside the units and thus actual time per stroke unit patient may be considerably less in ROI given the substantial deficit in stroke unit capacity. The UK also reports numbers of therapy assistants that are not recorded in Ireland for the purposes of determining staff to patient ratios. In general, there was a lower proportion of non-university degree qualified staff in therapy services in the ROI. All units had local ambulance arrangements for transfer of suspected strokes and prenotification of Emergency Departments. Thrombolysis including redirect policy to intervention sites is available in 100% of sites in NI versus 96% in ROI, with a reported thrombolysis rate of non-haemorrhagic strokes of 15.1% (NI) versus 10.9% (ROI) (p¼0.3). Rates of intra-cerebral haemorrhage were 12.5% in NI versus 15.1% ROI (p¼0.5). Patients have access to early supported discharge (ESD) in 73% of NI sites compared to 15% in ROI, translating to 21% (65/312) of all discharged patients using an ESD service in NI versus 5% (41/743) in ROI (RR 3.8 (95% CI 2.6–5.5)). There was no consistent means in differentiating outcomes between

84 Stroke ROI and the UK. Inpatient mortality was not significantly different, ROI versus UK, 14% versus 15.8% (RR 0.9 (95% CI 0.1â&#x20AC;&#x201C;1.1)). However, this may be influenced by the availability of home care and early supported discharge services between countries. Whilst the majority of hospitals in both Northern Ireland and the Republic of Ireland met key elements of the definition of stroke unit care there were significant deficits in staff levels in both countries. In the ROI whilst the majority of hospitals were found to have stroke units, the relatively small size of units and lower resource meant that a substantial proportion of patients were not able to fully access the specialised stroke care provided. The study has some limitations. Data collection in the ROI audit was similar to previous UK Sentinel Audit methods,12 that is physical auditing of patient charts. However, this differs from current SSNAP practice where data collection is online and thus less subject to bias from deficiencies in note keeping, data coding, etc. Charts were audited by local staff and whilst the audit group repeat audited charts in a number

of randomly chosen hospitals, data collection errors may still have occurred. Errors may also have occurred in classification of stroke unit type. Some smaller hospitals in ROI were not included in the audit if they were subject to an ambulance redirect policy for stroke patients. These hospitals admitted less than 1% of all strokes in 2014 rending operation of effective stroke units or services impracticable. They were excluded from the analysis. Units in ROI were frequently classified as acute however many of these units relied on off-site rehabilitation units for their patients and where delays in transfer were encountered many provided prolonged rehabilitation on-site leaving them closer in definition to combined stroke units. There were no dedicated onsite stroke rehabilitation units in ROI at the time of the audit. In NI, there is much clearer designation of acute and rehabilitation beds within combined stroke units on acute hospital sites. So it is likely that the number of beds available in acute services is overstated. Realistically not all beds, within large combined stroke units in particular, are able to manage

patients in the early phase of their stroke. Whilst our intention was to compare data from ROI on patient care with NI and UK data, most NI hospitals were not recording care data routinely to SSNAP in 2014 which was not consistent with practice in the remainder of the UK. A previous study has compared the management of stroke between cohorts of patients in two individual hospitals in the Republic of Ireland and Northern Ireland,14 but these were not necessarily representative of stroke care nationally. We designed the study to enable us to collect data that would be suitable for comparison with both previous Irish National Audit data but also with ESO and UK data to allow us to determine the quality of organisation and care by international standards. Accordingly, the audit tools used were detailed and comprehensive including elements to permit comparison with ESO, UK and Irish guidelines which differ slightly in some elements. Self-reported organisational audits were validated by site visits conducted jointly by members of the CPSC audit team and clinicians nominated by the Irish Heart Foundation. Our study demonstrates the challenges and difficulties in trying to implement evidence-based care for stroke patients. Guidelines in respect of acute interventions are typically strongly evidence based with support from randomised controlled trial data.4 It is therefore easier to establish strict guidelines and thus measure against them. Whilst the evidence for stroke units is also strong and the components that represent stroke unit care are agreed,2,6 it is sometimes difficult to make an arbitrary call as to whether a hospital meets criteria or not. Both ESO and American Stroke Association guidelines3,15 have tried to address this by establishing different levels of stroke unit care based on criteria agreed using Delphi processes but conclusions based on such processes have limitations for example questions have been raised about the evidence in the ESO guidelines for having transcranial Doppler available 24/7?3 The other issue is in resource allocation. At first glance there is little difference between Irish and UK facilities. Notwithstanding that all 10 sites in NI have stroke units

Issue 41 â&#x20AC;˘ HPN

versus 78% of sites in ROI, the ratio of nurse and AHP staffing to bed is not dissimilar. Nursing levels in both in ROI and NI were low compared with guideline recommendations. This is important because of the reported association between nursing levels and patient mortality recently reported from UK.16 The significant difference between jurisdictions is in the numbers of properly staffed beds available to cater for case load. While acknowledging the practicalities of providing stroke unit care in hospitals that admit small numbers of stroke cases per year, there is little benefit in a hospital having a designated stroke unit if an individual cannot routinely expect to be admitted and cared for there. Furthermore, it is important to stress that there is a difference between stroke beds being available for admissions on site and the quality of access to these beds. Access is limited by fluctuations in acuity of stroke case mix, bed availability and staffing levels. The CPSP was implemented in the Republic of Ireland at a time of the worst economic crisis in the history of the state. Over the period 2009â&#x20AC;&#x201C;2013 health service funding was cut by approximately 20%,17 so to have improved the organisation and delivery of stroke care to the extent it has was somewhat of an achievement. However, many of the changes were made by reallocating and re-designating resources and accordingly in many cases services have been developed that just bring them into line with the guidelines, that is the guidelines were used as a target and whilst they are specific as to the components of good stroke care, they mention little about extent of such care. It is important therefore that in further iterations of guidelines specific recommendations are included as a necessity to provide adequate beds within stroke units and that these beds be accessible by all patients who need them. In doing so we can help avoid the situation where health services and hospitals can achieve a level of compliance with guidelines but still be unable to provide adequate care for a large proportion of their population. Find the full version with references at

Clinical Research 85

New Guidelines Presented at European Association for the Study of the Liver The European Association for the Study of the Liver (EASL) presented four new Clinical Practice Guidelines (CPGs) at The International Liver Congress™ 2017 in Amsterdam, The Netherlands. CPGs define the use of diagnostic, therapeutic and preventive modalities, including non-invasive and invasive procedures, in the management of patients with various liver diseases. They are intended to assist physicians and other healthcare providers, as well as patients and interested individuals, in the clinical decision making process by describing a range of generally accepted approaches for the diagnosis, treatment and prevention of specific liver diseases. This annual congress is the biggest event in the EASL calendar, attracting scientific and medical experts from around the world to learn about the latest in liver research. Attending specialists present, share, debate and conclude on the latest science and research in hepatology, working to enhance the treatment and management of liver disease in clinical practice. This year, the congress attracted approximately 10,000 delegates from all corners of the globe. The new CPGs include:  Revised guidelines on the ‘Management of Hepatitis B virus infection’ The new EASL HBV CPGs are the first international guidelines to include the new antiviral drug tenofovir alafenamide (TAF), as well as the latest scientific evidence on stopping antiviral therapy in distinct patient populations on long-term treatment. HBV infection remains a global public health burden with changing epidemiology due to several factors including vaccination policies and migration. All patients with chronic HBV are at increased risk of progression to cirrhosis and hepatocellular carcinoma (HCC), depending on host and viral factors. The main goal of therapy is to improve survival and quality of life by preventing disease progression, and consequently HCC development. The induction of long-term suppression of HBV replication represents the main endpoint of current treatment strategies, while loss of HBsAg (a surface antigen of HBV which indicates current infection) is an optimal endpoint. “Hepatitis B virus infections are major health threats that affect about 240 million individuals worldwide. The updated EASL guidelines integrate the latest scientific advances on diagnosis and therapy of Hepatitis B, thereby providing clear guidance to clinicians and patients for the management of this potentially life-threatening disease,” said Professor Frank Tacke, member of the Clinical Practice Guideline panel and EASL Governing Board Member. Based on an extensive systematic review of the most current literature by a panel of leading global experts, the updated HBV CPGs provide: - New definitions of disease phases that will better guide clinicians on treatment indications - Expanded indications for initiating treatment in order to prevent mother-to-child transmission, based on the latest scientific evidence - Clear cut recommendations for special patient populations (e.g., children, extrahepatic disease manifestations, prevention of HBV re-activation) - Practical rules for response-guided therapy in patients receiving pegylated interferon for HBV  New guidelines on the ‘Management of Acute (fulminant) Liver Failure’  New ESGE/EASL guidelines on the ‘Role of endoscopy in Primary Sclerosing Cholangitis’  New guidelines on ‘The treatment and management of patients with Primary Biliary Cholangitis’ “The EASL Primary Biliary Cholangitis guidelines are meant to support clinicians in establishing a long-term commitment with patients and their disease, providing indications on how to stratify the risk from diagnosis to disease progression. The guidelines will also help identify which patients require second line treatment, in which advances are fortunately being made,” said Professor Marco Marzioni, Professor of Gastroenterology, Università Politecnica delle Marche – "Ospedali Riuniti" University Hospital of Ancona, Italy and one of the authors of the guidelines. He continued, “The EASL-ESGE guidelines have been developed by the two societies to identify the optimal approach for the management of Primary Sclerosing Cholangitis. As extra-hepatic bile ducts are involved in the disease, a multi-disciplinary approach is a key factor for the success of management. The guidelines provide a tool to fine tune the endoscopic and medical treatments of patients with Primary Sclerosing Cholangitis.” Potential link between direct-acting antiviral treatment for Hepatitis C and liver cancer According to data from eight studies also presented at The Congress, there remains continued debate on whether patients are at risk of developing liver cancer after achieving sustained virologic response (SVR) with a direct-acting antiviral (DAA) regimen for Hepatitis C virus (HCV). Investigators presented the results of their studies that show both sides of the argument – DAA therapy is associated with a higher risk of liver cancer compared with interferon-based therapy, versus there is no difference in liver cancer risk following cure with either therapy. Whilst remarkable progress has been made in the development of successful antiviral therapies for HCV infection, some recent studies suggest that curing patients does not eliminate the risk of developing liver cancer. There also appears to be an unexpectedly high rate of liver cancer (also known as hepatocellular carcinoma [HCC]) recurrence in patients who previously had their tumour treated successfully and had received DAAs.

HPN • Issue 41

86 Clinical Research This claim was further supported by a Spanish study led by Dr Maria Reig and Dr Mariño, Hospital Clinic Barcelona, Spain in which patients with HCV and HCC who had previously been cured of HCC received DAA therapy. After a median 12.4 month follow-up, following treatment with DAAs, the rate of HCC coming back (recurrence) was 31.2% (24/77) and of those who received HCC treatment at recurrence, 30% (6/20) of patients presented progression in the immediate 6-month follow-up. “Our study offers further support to previous findings that there is an unexpected high recurrence rate of hepatocellular carcinoma associated with DAAs, and that this association may result in a more aggressive pattern of recurrence and faster tumour progression,” said Dr Maria Reig, Barcelona Clinic Liver Cancer Group, Hospital Clinic Barcelona, Spain, and lead author of the study. “These data indicate that there needs to be further research conducted in this area, clarifying the mechanism for the association between liver cancer recurrence and DAA therapy.” Identifying those patients at risk of liver cancer is essential, a task that Dr Etienne Audureau, Public Health, Henri Mondor University Hospital, Créteil, France, and colleagues attempted to achieve by developing a prognostic tool for HCC. They found that in patients with severe scarring of the liver due to HCV (compensated cirrhosis), failure to achieve SVR was the most influential factor in predicting liver cancer. In addition, risk factors for liver cancer differ according to SVR status. The investigators recommend that in patients with compensated cirrhosis, eradication of HCV should be achieved before liver function is impaired and people who have achieved SVR should be monitored for liver cancer after 50 years of age. The mechanisms behind the development of liver cancer following HCV cure are not yet understood. One group of investigators led by Professor Thomas Baumert, Inserm Institute for Viral and Liver Diseases, University of Strasbourg, France, aimed to investigate if HCV infections produce epigenetic and transcriptional changes that persist after the infection is cured, and whether these epigenetic changes drive liver disease and HCC following cure. They found that the epigenetic and transcriptional changes are only partially reversed by DAAs and persist after HCV cure, suggesting that these changes are a driver for liver cancer that develops after HCV infection has been cured. The investigators concluded that these findings open a new perspective to develop novel biomarkers to identify patients at high risk of HCC and provide an opportunity to develop urgently needed strategies for HCC prevention. On the other side of the debate, a systematic review, meta-analyses, and meta-regression study, by Professor Gregory Dore and Dr Reem Waziry from The Kirby Institute, UNSW Sydney, and colleagues, found no evidence for higher risk of HCC occurrence or recurrence following DAA treatment, compared with interferon-based HCV therapy. A total of 41 studies, including 26 on HCC occurrence and 15 on HCC recurrence (in total, n=13,875 patients) were included. In studies assessing HCC occurrence, average follow up was shorter and average age was higher in DAA studies compared to interferon studies; incidence was lower with longer follow-up and younger age. In studies assessing HCC recurrence, average follow up was also shorter. Ultimately, in the meta-regression analysis, no evidence in favour of a differential HCC occurrence or recurrence was found between DAA and interferon regimens, after adjusting for study follow-up and age. “Recent studies have reported contradicting evidence on risk of hepatocellular carcinoma following direct-acting antiviral therapy; our aim was to bring some clarity to this,” said Professor Dore, Kirby Institute and lead author of the study. “These data show the higher incidence of HCC observed following DAA therapy can be explained by the shorter duration of follow-up and older age of participants, rather than the DAA treatment regimen.” A Scottish study, led by Dr Hamish Innes, School of Health and Life Sciences, Glasgow Caledonian University, Scotland, found that the risk of liver cancer following SVR was not associated with the use of DAAs, but baseline risk factors. Furthermore, risk of HCC development was similar in patients taking interferon-free regimens versus interferoncontaining regimens, following a multivariate adjustment (IRR: 0.96, p=0.929) and no significant differences in HCC risk were found when treatment regimen was defined in terms of DAA containing regimens versus DAA free regimens. These data indicate that rather than the treatment regimens themselves, it is the baseline risk factors that determine risk of hepatocellular carcinoma. Another interesting study in Japanese patients with HCV genotype 1 infection, found a reduced incidence of liver cancer following achievement of SVR after 12 weeks of therapy with an interferon-free regimen (ledipasvir plus sofosbuvir) to a similar degree as that obtained with an interferoncontaining regimen (simeprevir with peginterferon plus ribavirin). This study, which was conducted by Dr Masaaki Korenaga, Kohnodai Hospital, National Center for Global Health and Medicine, Chiba, Japan, and colleagues, also found that unexpected development of liver cancer following SVR in patients without previous liver cancer could potentially be predicted by imaging procedures (computer tomography or enhanced magnetic resonance imaging). Similarly, a Chinese study led by Dr George Lau, from the Beijing 302-Hong Kong Humanity and Health Hepatitis C Diagnosis and Treatment Centre, in Beijing, China, found no increase in the incidence of liver cancer in patients who achieved SVR12 with DAA compared to peginterferon plus ribavirin. A Sicilian study conducted by Dr Vincenza Calvaruso, University of Palermo, Palermo, Italy, and colleagues, demonstrated that patients who achieved SVR with DAAs had a similar risk of developing liver cancer when compared to historical controls of patients with compensated cirrhosis who achieved SVR after interferon-based therapy. In addition, those who achieved SVR with DAAs had a lower risk of developing liver cancer than those patients whose HCV infection was not cured. “The original observations made by researchers from the Barcelona Clinic Liver Cancer Group have sparked a huge number of studies aimed at verifying the potential association between DAA treatment and increased HCC recurrence after cure,” said Professor Francesco Negro, Divisions of Gastroenterology and Hepatology of Clinical Pathology, University Hospital of Geneva, and EASL Governing Board Member. “At this stage, there is no reason to alter treatment guidelines until the issue is definitively clarified. We cannot exclude, however, that we may have to revise post-SVR surveillance in some specific patient subgroups.”

Issue 41 • HPN

The only licensed treatment for the reduction in recurrence of overt hepatic encephalopathy (OHE)1

At home they are still at risk; ...TARGAXAN® rifaximin-a reduces the risk of recurrence of overt hepatic encephalopathy.1

Long-term secondary prophylaxis in hepatic encephalopathy (HE)2 TARGAXAN® 550 mg film-coated tablets. REFER TO FULL SUMMARY OF PRODUCT CHARACTERISTICS (SmPC) BEFORE PRESCRIBING. Presentation: Film-coated tablet containing rifaximin 550 mg. Uses: Targaxan is indicated for the reduction in recurrence of episodes of overt hepatic encephalopathy in patients ≥ 18 years of age. Dosage and administration: Adults 18 years of age and over: 550 mg twice daily, with a glass of water, with or without food for up to 6 months. Treatment beyond 6 months should be based on risk benefit balance including those associated with the progression of the patients hepatic dysfunction. No dosage changes are necessary in the elderly or those with hepatic insufficiency. Use with caution in patients with renal impairment. Contraindications: Contraindicated in hypersensitivity to rifaximin, rifamycin-derivatives or to any of the excipients and in cases of intestinal obstruction. Warnings and precautions for use: The potential association of rifaximin treatment with Clostridium difficile associated diarrhoea and pseudomembranous colitis cannot be ruled out. The administration of rifaximin with other rifamycins is not recommended. Rifaximin may cause a reddish discolouration of the urine. Use with caution in patients with severe (Child-Pugh C) hepatic impairment and in patients with MELD (Model for End-Stage Liver Disease) score > 25. In hepatic impaired patients, rifaximin may decrease the exposure of concomitantly administered CYP3A4 substrates (e.g. warfarin, antiepileptics, antiarrhythmics, oral contraceptives). Both decreases and increases in international normalized ratio (in some cases with bleeding events) have been reported in patients maintained on warfarin and prescribed rifaximin. If co-administration is necessary, the international normalized

ratio should be carefully monitored with the addition or withdrawal of treatment with rifaximin. Adjustments in the dose of oral anticoagulants may be necessary to maintain the desired level of anticoagulation. Ciclosporin may increase the rifaximin Cmax Pregnancy and lactation: Rifaximin is not recommended during pregnancy. The benefits of rifaximin treatment should be assessed against the need to continue breastfeeding. Side effects: Common effects reported in clinical trials are dizziness, headache, depression, dyspnoea, upper abdominal pain, abdominal distension, diarrhoea, nausea, vomiting, ascites, rashes, pruritus, muscle spasms, arthralgia and peripheral oedema. Other effects that have been reported include: Clostridial infections, urinary tract infections, candidiasis, pneumonia cellulitis, upper respiratory tract infection and rhinitis. Blood disorders (e.g. anaemia, thrombocytopenia). Anaphylactic reactions, angioedemas, hypersensitivity. Anorexia, hyperkalaemia and dehydration. Confusion, sleep disorders, balance disorders, convulsions, hypoesthesia, memory impairment and attention disorders. Hypotension, hypertension and fainting. Hot flushes. Breathing difficulty, pleural effusion, COPD. Gastrointestinal disorders and skin reactions. Liver function test abnormalities. Dysuria, pollakiuria and proteinuria. Oedema. Pyrexia. INR abnormalities. Legal category: UK - POM, Ireland - Prescription only. Cost: UK - Basic NHS price £259.23 for 56 tablets. Ireland - €262.41 for 56 tablets Marketing Authorisation number: UK - PL 20011/0020. Ireland - PA 102/29/1 For further information contact: Norgine Pharmaceuticals Limited, Norgine House, Moorhall Road, Harefield, Middlesex, United Kingdom UB9 6NS Telephone: +44(0)1895 826606 E-mail: Ref: UK/XIF5/0116/0173(1) Date of preparation: October 2016.

United Kingdom - Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to medical information at norgine Pharmaceuticals Ltd on 01895 826606. Ireland - Healthcare professionals are asked to report any suspected adverse reactions via HPra Pharmacovigilance, earlsfort Terrace, Irl - dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website:; e-mail: adverse events should also be reported to Medical Information at norgine Pharmaceuticals on +44 1895 826606. References: 1. TARGAXAN ® 550 Summary of Product Characteristics. Available for the UK from: uk/emc/medicine/27427 [Accessed October 2016]. Available for Ireland from: http://www.medicines. ie/medicine/15936/SPC/TARGAXAN+550mg+filmcoated+tablets/ [Accessed October 2016]. 2. Mullen KD, et al. Clin Gastroenterol Hepatol 2014;12(8): 1390-97. Product under licence from Alfa Wassermann S.p.A. TARGAXAN is a registered trademark of the Alfa Wassermann group of companies, licensed to the Norgine group of companies. NORGINE and the sail logo are registered trademarks of the Norgine group of companies. UK/XIF5/0416/0201(1) Date of preparation: October 2016.

88 Depression

Treatment Overview: Depression in Adults Professor Brendan Kelly Professor of Psychiatry, Trinity College Dublin; Consultant Psychiatrist at Tallaght Hospital

Professor Brendan Kelly, Professor of Psychiatry, Trinity College Dublin

behavior therapy or ‘CBT’), and social interventions, all of which can be combined to suit the needs and circumstances of any given individual. Psychological treatments

Depression is a common mental illness. The WHO estimates that by 2020 depression will be the second most common cause of disability worldwide, after heart disease. Over the course of a life-time, the chance of developing depression at some point is between 10% and 17%. Over the course of any given year, the chance of developing depression is between 3% and 7%. The risk is almost twice as high in women (10.0%) as in men (6.6%). Depression reduces individuals’ ability to work leading to sick leave and, commonly, under-employment. As a result, depression accounts for a substantial proportion of the economic cost of mental illness in Ireland which, in 2006, exceeded ¤3 billion including more than ¤1 billion for direct costs of care and another ¤1 billion due to underemployment and non-employment. In England, the cost of mental ill health is £105.2 billion per year, with depression accounting for a substantial proportion: the cost of depression in England was £7.5 billion in 2007, and, by 2026, will have risen to £12.2 billion. Individuals with depression commonly require assistance and support in order to deal with their symptoms, enter recovery, and maintain wellness into the future. In the first instance, it is important that the individual with depression is able to talk openly about their symptoms, without fear of criticism or judgment. It is also important that any issues relating to alcohol use or other drug use are identified at the outset and, if possible, resolved: treatment of depression is rendered extremely difficult in the presence of alcohol or drug misuse. Treatment of depression is, for the most part, based on a bio-psychosocial approach to management; i.e. there are ‘biological’ treatments (such as medication), psychological treatments (such as cognitive

Issue 41 • HPN

The most commonly-used psychological treatment for depression is CBT, which focuses on the use of cognitive strategies (i.e. strategies related to thinking patterns and habits) and behavioural strategies (i.e. strategies related to actions and behavioural habits), in an effort to re-frame depressive thoughts, enhance coping strategies, reduce symptoms and promote recovery. Usually, the psychotherapist will meet the patient once per week and point out errors or unhelpful thinking patterns which may deepen or prolong depression. Together, the patient and psychotherapist identify ways to address these errors and habits, and incrementally improve symptoms of depression. There is strong evidence that CBT is highly effective in the management of depression, generalized anxiety disorder, panic disorder, social phobia and post-traumatic stress disorder. For some patients with mild or moderate depression, the benefits of CBT can exceed those of anti-depressant medication. Interpersonal psychotherapy is another psychotherapeutic approach to depression which emphasises that the occurrence of depression is not the patient’s fault, and that the disorder has occurred in the patient’s specific psychosocial context, which is significant in terms of recovery. Interpersonal psychotherapy is a time-limited, manual-based, focused, pragmatic therapy which, like CBT, generally lasts for a few months and is undertaken with a trained psychotherapist. There is now strong evidence that interpersonal psychotherapy is highly effective in the treatment of depression, both on its own and in combination with anti-depressant medication. Therapies based on mindfulness, too, offer very specific benefits for many individuals with depression. Mindfulness means paying attention to the present moment, simply and directly. It involves maintaining a careful awareness of your thoughts, emotions and actions, but not judging them. It involves staying focussed on the present moment as

much as possible, and when your mind wanders, gently re-directing it back to now: the feeling of the chair you’re sitting on, the smell of fresh coffee, the person with whom you are speaking. The concept of mindfulness is rooted in Buddhist and early Hindu psychology and is an essential element of meditative practice in both traditions. Over the past fifteen years, the concept of mindfulness has penetrated deeply into the public mind in many Western countries. Today, it seems that mindfulness is everywhere: on the Internet, in bookshops, and in therapy centres across the country. The popularity of mindfulness is easy to understand. Many people feel distracted much of the time, sending text messages, receiving emails, trying to attend to myriad tasks all at once. The practice of mindfulness is the opposite of these things. In other words: don’t just do something; sit there. There are many ways to cultivate mindfulness. One way is simply to provide a verbal label for specific things throughout the day; e.g. you could mentally label the position of your body each time it changes (i.e. ‘standing’, ‘sitting’, ‘walking’). This promotes simple bodily awareness, rather than criticism or analysis. The same technique can be applied to emotions or thoughts, simply labelling each one as it occurs, but not trying to interpret, change or linger on it. Mindfulness is a powerful way to improve psychological wellbeing. The benefits can be subtle but profound. One might still feel irritation at the usual day-to-day problems, but one is less like to respond impulsively. One may still feel disappointed at minor upsets, but the disappointment is proportionate rather than catastrophic. Most of all, one may feel a new kind of inner stillness, a deepened awareness of the present moment, and a reduction in the black cloud of foreboding that many people now report feeling virtually all of the time. Recent years have seen considerable research in the use of mindfulness not just to increase wellbeing, but also to treat psychological disorders and mental illness. There is now a strong evidence base for mindfulnessbased psychological therapies for mild and moderate depression, anxiety disorders, self-harming behaviour and various other common problems. There is also emerging evidence for mindfulness-

based techniques for certain cases of substance misuse, obsessive-compulsive disorder and eating disorders. Properly used, mindfulness can help promote holistic health in chronic medical illness and deepen psychological care during cancer treatment and in terminal care settings. Most of all, though, specific courses of mindfulness-based therapies, provided over an eight-week period, are now accepted as effective tools for preventing relapse of depression. Regarding social interventions for depression, there are well-described relationships between depressive symptoms, stressful life-events and deficits in social support. Specific social interventions include provision of social support, measures to increase social engagement (i.e. going out) and introduction of befriending services for individuals who are isolated, poorly-integrated and experiencing socially-disabling symptoms. Elements of national social policy may also be relevant: social welfare arrangements, for example, have significant effects on depressive symptoms, with the receipt of government entitlement benefits by unemployed women showing a significant association with reduced depressive symptoms in the long-term. For all individuals with depression, a consideration of the social environment and graded social re-engagement is an essential step on the road to recovery. Self-help groups and organisations such as Aware ( are also important and very helpful for many. Antidepressant medication Biological treatments for depression include administration of medications and treatment of co-existing medical or substance-related disorders (e.g. alcohol abuse). Anti-depressant medications are the medications most commonly used in the management of depression. Most guidelines now recommend newer medications (selective-serotonin re-uptake inhibitors) as first-line treatments for depression, ahead of older medications (such as tricyclic anti-depressants and monoamine oxidase inhibitors). St John’s wort, a herb, is another useful treatment (although users should note that it significantly reduces the effectiveness of the contraceptive pill, possibly resulting in pregnancy). Overall, though, newer antidepressant medications have fewer side effects than older ones, and are safer.

89 Choice of medication will depend on severity of the depression, the patient’s treatment history and patient preference. It is important that the decision to start an antidepressant medication is made jointly between the patient and the doctor or mental health team, and is carefully reviewed after around six weeks, to see if progress is occurring. If progress is not satisfactory, treatment needs to be adjusted or re-considered.

medications in certain groups (e.g. treatment of depression in children and adolescents). There is also occasional controversy about antidepressant medication in a more general sense. In 2010, the College of Psychiatrists of Ireland noted that ‘effective treatment of depression is an important means of reducing suicide rates’, and addressed the relationship between anti-depressant medication and suicidal thoughts:

All of these medications have various effects on brain neurotransmitters. That is not to suggest that the cause of depression in any given individual can be simply ascribed to any specific ‘chemical imbalance’ in the brain. The biology of the brain is as-yet poorly understood, so any simple biological explanations for depression over-state how much is really understood about the brain. What is clear, however, is that anti-depressant medications have some effects on brain chemicals and a majority of individuals find that these effects helpful in terms of depression.

‘Untreated depression can have a fatal outcome. Those experiencing moderate to severe depression frequently describe having thoughts of self-harm. Antidepressants are effective in the treatment of depression. The effective treatment of depression is an important means of reducing suicide rates. A huge volume of research in recent years has failed to establish a causal link between antidepressant use and suicide. At an individual level, the period early in treatment may be a time of relatively high risk, as treatment tends to start when the person’s depression is severe and treatment takes some weeks to work. As treatment takes effect and energy and motivation return, people who have recently commenced antidepressant treatment may be more able to act on suicidal thoughts that are inherent to their condition. That the early recovery period is potentially a period of increased risk for suicidality is something of which all doctors should be aware. The College of Psychiatry of Ireland, in unison with the advice of the Irish Medicines Board, recommends close monitoring of all individuals commenced on antidepressant therapy. There is no evidence of a link between antidepressant use and homicide.’

More precisely, approximately twothirds of patients with moderate or severe depression respond to the first anti-depressant prescribed. In these patients, the medication should be continued for six to nine months after recovery from a single depressive episode. For individuals who have experienced multiple depressive episodes, there is evidence to support continuation of treatment for up to two years. If there is no or insufficient response to the first anti-depressant prescribed after several weeks, it is recommended to either increase dose, switch to a different anti-depressant, or engage in a broader re-consideration of therapeutic options. In the event of poor response after a second antidepressant, alternative treatment strategies may be required (e.g. an anti-psychotic medication or lithium, a mood-stabilising medication). Many individuals experience no side-effects whatsoever from antidepressant medications. Others experience mild adverse effects (e.g. transient nausea or sickness in the stomach) but opt to stay on the medication on the basis that the positive effects (improved mood) exceed any side-effects. Other side-effects may include headache, drowsiness, weight change and various others depending on the specific medication. In all cases, potential side effects should be discussed carefully prior to treatment. Specific side-effects vary between different medications and are detailed on the information sheets provided with the medications themselves. In addition, specific issues have been reported with specific

It is important that both patients and families are aware of these matters and, indeed, aware of all of the possible adverse effects of all therapies (medications and psychological therapies alike), so as to ensure that treatment choices are informed, collaborative, sensible, safe and effective. The need for this kind of balanced information and a reasonable approach is especially important in relation to one of psychiatry’s best-known and leastunderstood treatments, electroconvulsive therapy (ECT). Electro-convulsive therapy (ECT) ECT is an effective treatment for severe, treatment-resistant or life-threatening depression. ECT is often shown in movies and on television as it was administered in the 1950s: in a haphazard fashion, without anaesthetic, and against the patient’s wishes. Today, ECT is used less commonly, is given under general anaesthetic, and the vast majority of treatments are entirely voluntary.

Like many treatments across all areas of medicine, it is not understood how ECT works. There is, however, strong evidence that, for a small minority of patients whose depression is severe, treatment-resistant, or lifethreatening, ECT provides rapid and substantial relief, and can, in some, prove life-saving. The treatment involves the patient receiving a general anaesthetic twice per week for four to six weeks, and, while under anaesthetic, an electric current being applied across the brain, producing brain activity similar to that seen in an epileptic seizure or fit. Does ECT work? The literature on ECT is wide and varied, and much is driven by ideology rather than scientific research. In recent years, however, a very clear picture has emerged. In England, the National Institute of Clinical Excellence (NICE) reviewed the entire evidencebase for ECT and now recommends ECT for the treatment of (a) severe depressive illness, (b) a prolonged or severe episode of mania, or (c) catatonia (severe physical manifestations of mental disorder), in order to gain fast and short-term improvement of severe symptoms once all other treatment options have failed, or when the situation is life-threatening. Predictors of good response to ECT include severe depression, delusions and prominent biological symptoms (e.g. loss of weight, loss of appetite, early morning waking and diurnal mood variation). Potential side-effects include headache and memory difficulties, and while these are short-lived in the majority of cases, some people report persistent memory problems. Careful explanation of side-effects is essential prior to treatment, to allow patients to weigh up the positives against the negatives, and make informed choices. Many critics of the over-use and inappropriate use of ECT in the past choose to apply their arguments to today’s practices too, and ignore the fact that the balance of scientific evidence is now clearly in favour of ECT in the very specific, very limited circumstances outlined by NICE. Despite this clear evidence, many contemporary critics tend to focus selectively on parts of the scientific literature that suit their argument, rather than overviews of the entire body of literature, such as that provided by NICE. While it is clearly important that dissenting views are considered with care, anyone who has experienced the intensely debilitating and life-threatening symptoms of severe depression will appreciate that no treatment should be dismissed without clear-eyed, objective evaluation of the evidence. In the case of ECT, the balance of evidence, as presented by NICE, is

now very clear: ECT is a potentially life-saving treatment for depression when it is severe, treatmentresistant, and/or life-threatening. As a doctor and scientist it does not rest easy with me that we do not know how ECT works, and I am deeply disturbed that ECT has been overused and misused throughout the history of psychiatry. Today, however, ECT is highly regulated by the Mental Health Commission and it would be a profound violation of rights to withhold ECT from appropriate patients in the future. ECT is a safe, essential treatment for a minority of patients who might otherwise die. Overall treatment approaches Overall, it is important that treatment choices for depression take account of all elements of the bio-psychosocial approach to management. Combinations of therapies are likely to be required for many people; e.g. psychological therapy and anti-depressant medications. It is imperative that therapeutic choices and plans are communicated clearly to patients and their families, and that care is genuinely holistic and person-centred at all times. Providing consistent psychological support is a vital element in the management of any mental illness, and can turn a potentially debilitating episode of depression into an episode of illness that is faced together, addressed collaboratively, and resolved in a fashion that is effective, acceptable, and produces sustained wellness for the future. Outcomes in depression vary from person to person, depending on their circumstances and the severity of the depression. The vast majority of people with mild and moderate depression recover fully. Overall, 80% of people with depression recover fully, while 20% experience ongoing problems. In severe depression, the lifetime risk of suicide is 10%-15% but it is much lower in less severe depression. Prognosis is better if the person does not use alcohol or drugs, adheres to their personal treatment plan, and takes active steps to maintain mental wellness following recovery; i.e. has a healthy diet and lifestyle, maintains good physical health, sustains links with family and friends, and addresses any emergent mental health problems early on. Brendan Kelly is Professor of Psychiatry at Trinity College Dublin, Consultant Psychiatrist at Tallaght Hospital, and author of ‘Hearing Voices: The History of Psychiatry in Ireland’ (Irish Academic Press, 2016) (

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HPN • Issue 41

90 Schizophrenia

Treatment Overview: Schizophrenia Professor Brendan Kelly Professor of Psychiatry, Trinity College Dublin; Consultant Psychiatrist at Tallaght Hospital episode psychosis, for which NICE recommends medication in conjunction with psychological interventions such as family interventions and individual cognitive behaviour therapy (CBT). NICE also recommends that the choice of medication is made by the patient and healthcare professional (and, if appropriate, carer) together, taking account of likely benefits and possible side-effects such as weight gain, movement problems (e.g. restlessness), and potential effects on the heart or hormones (e.g. raised prolactin). The first effective medication for schizophrenia, chlorpromazine, was developed in the 1950s and was followed by a number of related medications (in both tablet and injected forms) which made it possible for some long-term patients to leave large institutions and live with greater independence in the community. These medications included fluphenazine, trifluoperazine, flupentixol, haloperidol, zuclopenthixol, sulpiride and pimozide. Schizophrenia will affect just under 1% of people at some point in their lives. There are 15 to 20 new cases per 100,000 population per year, an incidence equal to that of Type 1 diabetes in Western Europe. In Ireland, schizophrenia accounted for 20% of all psychiatric admissions in 2015, yielding the second-highest admission rate of any diagnosis (78 admissions per 100,000 population per year), second only to depressive disorders (105 admissions per 100,000 population per year).

mental disorder. As with all mental disorders, treatment is based on a bio-psycho-social approach: biological interventions include administration of medications, treatment of co-existing medical illness or substance misuse problems, and, in a small minority of cases, electro-convulsive therapy (ECT). Psychological and social interventions include specific psychotherapies for patients and families, as well as enhancing personal supports and social participation.

In England, the estimated societal cost of schizophrenia was £7 billion (¤10 billion) in 2004/2005, while in Ireland the cost of schizophrenia in 2006 was ¤460.6 million, comprising direct costs of care amounting to ¤117.5 million and indirect costs of ¤343 million, including ¤43.8 for informal care borne by families.

There is now considerable evidence to support the benefits of pro-active, early intervention in first episode psychosis, including schizophrenia. Management involves a multi-disciplinary team working together with the patient, family, and primary care team to diagnose and treat the first episode of illness, prevent the development of subsequent episodes, and establish an ongoing management plan aimed at optimising social function and minimising the effects of the illness on patient and family.

The true cost of schizophrenia, however, can only be described in human terms, relating to reduced quality of life, limited opportunity for personal development, ongoing symptoms, and increased mortality (see below), as well as the suffering and stress experienced by family members and carers. Schizophrenia is a treatable

Issue 41 • HPN

Medication The fundamental principles of treatment in acute schizophrenia are similar to those in many

other areas of medicine. Medication should be used at a dose that combines optimal effectiveness with a minimum of side effects. The use of multiple medications is to be avoided as much as possible, although it can be necessary in certain circumstances. Medication regimes should be rational and understandable, with an emphasis on once-daily dosing where possible. Measures should be taken to assist with complex treatment regimes, and these may involve pharmacy blister packing, tablet boxes, tablet counters, or supervision by a family member or therapist. Side effects should be identified early and openly discussed with patient and family, as appropriate. The UK-based National Institute for Health and Care Excellence (NICE) provides specific treatment recommendations in its review of ‘psychosis and schizophrenia in adults: prevention and management’, published in February 2014 and (like all NICE guidelines) freely available from its website. The NICE advice covers a ranges of areas relating to schizophrenia, but places especially strong emphasis on early intervention for first

It was soon recognised, however, that these medications could have significant adverse effects, including movement disorders (such as restlessness or Parkinsonism), dry mouth, constipation, sedation, effects on the heart (increasing risk of sudden cardiac death), and various other effects (e.g. dizziness, impotence). A range of strategies were introduced to manage adverse effects and research focused on developing newer treatments that would combine good clinical effects with fewer side effects. A new generation of ‘atypical’ antipsychotics was duly developed and introduced to clinical practice, so there is now a broad range of anti-psychotic medications available for schizophrenia, with different combinations of benefits and adverse effects. Atypical antipsychotic medications currently available include risperidone, olanzapine, quetiapine, aripiprazole, amisulpride, ziprasidone and paliperidone. In practice, first episode schizophrenia is now most often treated with an atypical antipsychotic medication, though conventional anti-psychotic agents are still sometimes used. These newer atypical agents appear to be as effective as older agents

Truxima®▼ (rituximab) 500mg concentrate for solution for infusion. Prescribing Information Republic of Ireland. Please read the Summary of Product Characteristics (SPC) before prescribing. Presentation: Type I glass vials, with butyl rubber stopper. Each vial contains 500mg of rituximab in 50 mL. Indications and dosage: Adult patients: Follicular non-Hodgkin’s lymphoma (FL): (i) as induction treatment in combination with chemotherapy for previously untreated or relapsed refractory patients with stage III-IV FL: 375 mg/m2 body surface area (BSA) on day 1 of each chemotherapy cycle for up to 8 cycles. (ii) as maintenance therapy in previously untreated patients responding to induction therapy: 375 mg/m2 BSA once every 2 months (starting 2 months after the last dose of induction therapy) until disease progression or for a maximum of 2 years. In relapsed/refractory patients responding to induction therapy: 375 mg/m2, once every 3 months (starting 3 months after the last dose of induction therapy) until disease progression or for a maximum of 2 years. (iii) as monotherapy in patients with stage III-IV FL who are chemo-resistant or are in the second or subsequent relapse after chemotherapy and for retreatment in patients responding to monotherapy: 375 mg/m2 BSA, administered once weekly for 4 weeks. Diffuse large B-cell non-Hodgkin’s lymphoma (DLBCL): for treatment of CD20 positive DLBCL in combination with CHOP: 375 mg/m2 BSA on day 1 of each chemotherapy cycle for 8 cycles. Administer after i.v. infusion of the glucocorticoid component. Chronic lymphocytic leukaemia (CLL): in combination with chemotherapy, for previously untreated and relapsed/refractory CLL: 375 mg/m2 BSA, on day 0 of the first treatment cycle, followed by 500 mg/m2 BSA on day 1 of subsequent cycles for 6 cycles in total. Prophylactic hydration and uricostatics recommended 48 hours prior to Truxima. Where lymphocyte counts >25x109/L, administration of prednisone/prednisolone 100mg i.v. shortly before Truxima is recommended. Rheumatoid arthritis (RA): in combination with methotrexate (MTX), for adults with severe active RA who have had an inadequate response or intolerance to other DMARDs including one or more TNF inhibitor therapies. 1000mg i.v. infusion followed by a second 1000 mg i.v. infusion two weeks later. Evaluate need for further courses after 24 weeks (see SPC). Premedication with i.v. 100 mg methylprednisolone should be given 30 minutes prior to each infusion. Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA): in combination with glucocorticoids, for the induction of remission in adult patients with severe, active GPA (Wegener’s) and MPA: 375 mg/m2 BSA once weekly for 4 weeks. All indications: No dose reductions of Truxima are recommended. Standard dose reductions for any concomitant chemotherapeutic medicinal product should be applied. Administration: Give RA, GPA and MPA patients the patient alert card with each infusion. Administer prepared Truxima as an i.v. infusion, through a dedicated line, with full resuscitation facilities immediately available, under the supervision of an experienced healthcare professional. Do not administer as an i.v. push or bolus. Administer anti-pyretic and an antihistaminic before each infusion. Consider glucocorticoid (GCC) premedication if Truxima is not given with GCC-containing chemotherapy. Monitor closely for onset or evidence of cytokine release syndrome (CRS). Interrupt infusion immediately if evidence of a severe reaction (e.g. severe dyspnoea, bronchospasm or hypoxia). Evaluate NHL patients for tumour lysis syndrome (TLS). First infusion: Recommended initial rate of 50 mg/h for the first 30 minutes, which can then be escalated in increments of 50 mg/h every 30 minutes up to 400 mg/h. Subsequent infusions: Recommended initial rate of 100 mg/h and increased by 100 mg/h increments every 30 minutes, up to 400 mg/h. Alternative faster infusion schedule in RA only (4mg/mL in 250mL infusion volume): if no serious infusion related reaction (IRR) during first or subsequent infusions at standard rates (above), initiate at 250 mg/h for the first 30 minutes and escalate to 600 mg/h over 90 minutes. Faster infusion not suitable for patients who have clinically significant cardiovascular disease, arrhythmias or previous serious IRR to biologic therapy or rituximab. Contraindications: Hypersensitivity to the active substance, murine proteins, or any of the other excipients; active, severe infections; severely immunocompromised patients. Severe heart failure (NYHA class III/IV) or severe, uncontrolled cardiac disease in patients with RA, GPA or MPA. Precautions and warnings: To improve the traceability of biological medicinal products, the trade mark and the batch number of the administered product should be recorded in the patient file. Progressive multifocal leukoencephalopathy (PML): Very rare cases of fatal PML have been reported. Monitor patients for new or worsening neurological symptoms suggestive of PML and suspend until PML excluded. Permanently discontinue if confirmed. See SPC for further information. Infusion related reactions (IRRs): Rituximab is associated with IRRs, including CRS, TLS, anaphylactic and hypersensitivity reactions, including severe reactions with fatal outcome. Severe IRRs are characterised by pulmonary events and may include features of tumour lysis or rapid TLS in addition to reactions such as fever, chills, rigors, hypotension, urticaria and angioedema. Use extreme caution and closely

is rituximab is rituximab WHY PAY MORE monitor first infusion when treating patients with >25x109/L circulating malignant cells or high tumour burden (higher risk of severe CRS). Consider reduced infusion rate or split dosing where lymphocyte counts >25x109/L. See SPC for further details on severe IRRs. IRRs of all kinds have been observed in 77% of patients treated with rituximab. Common IRRs are generally reversible with a reduction in rate, or interruption, of rituximab infusion and administration of an antipyretic, an antihistaminic and occasionally, oxygen, i.v. saline or bronchodilators. Temporary or permanent discontinuation may be necessary if severe or if the same adverse events recur a second time. In most cases the infusion can be resumed at a 50% reduction in rate when symptoms have completely resolved. Anaphylaxis and other hypersensitivity reactions have been reported following i.v. administration of proteins to patients. IRRs may also be associated with myocardial infarction, atrial fibrillation, pulmonary oedema and acute reversible thrombocytopenia. Consider withholding antihypertensives for 12 hours prior to infusion due to risk of hypotension. Treat with caution and closely monitor patients with a history of pulmonary insufficiency or pulmonary tumour infiltration. Cardiac disorders: Closely monitor patients with a history of cardiac disease and/or cardiac chemotherapy. Infections: Patients are at an increased risk of developing infections, including serious infections with fatal outcome. Do not administer if active and/or severe infection present or if severely immunocompromised. Caution in patients with a history of, or susceptibility to recurring/chronic infections. Determining immunoglobulin levels in RA, GPA and MPA before treatment is recommended. Hepatitis B (HBV) reactivation has been reported, including cases with a fatal outcome. HBV screening should be performed before initiation of Truxima. Patients with active hepatitis B disease should not be treated. Patients with positive serology for HBV should consult liver specialists and be monitored and managed to prevent reactivation. Haematological toxicities: Caution in patients with neutrophil counts <1.5 x 109/L and/or platelet counts <75 x 109/L as clinical experience in this population is limited. Perform regular blood counts during Truxima therapy in all indications, and prior to each course and regularly up to 6-months after cessation of treatment in RA and GPA/MPA. Immunisations: Live viral vaccines are not recommended. Response to non-live vaccinations may be reduced. See SPC for further information. Skin reactions: Severe skin reactions such as Toxic Epidermal Necrolysis (TEM) and Stevens-Johnson Syndrome (SJS), including fatal outcomes, have been reported - permanently discontinue treatment. Malignancy: The possible risk for the development of solid tumours with the use of immunomodulatory drugs cannot be excluded. Concomitant/ sequential use of other DMARDs in RA: The concomitant use of Truxima and anti-rheumatic therapies other than those specified for RA is not recommended. Monitor patents for signs of infection if biologic agents and/or DMARDs are used following Truxima therapy. Interactions: Limited data are available (see SPC). Patients with human anti-mouse antibody or human anti-chimeric antibody titres may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies. Fertility, pregnancy and lactation: Women of childbearing potential should use adequate contraception and continue its use for at least 12 months after Truxima treatment. Truxima should not be administered during pregnancy. Do not breastfeed in the 12 months following treatment. Side effects: Very common (≥1/10) and common (≥1/100 to <1/10) side effects: Viral infection, bacterial infection, bronchitis, acute bronchitis, sepsis, pneumonia, febrile infection, herpes zoster, respiratory tract infections, fungal infection, sinusitis, hepatitis B, infections of unknown aetiology, neutropenia/febrile neutropenia, leucopenia, thrombocytopenia, anaemia, pancytopenia, granulocytopenia, infusion related reaction (hypertension, nausea, rash, pyrexia, pruritus, urticaria, throat infection, hot flush, hypotension, rhinitis, rigors, tachycardia, fatigue, oropharyngeal pain, peripheral oedema, erythema), angioedema, hypersensitivity, hyperglycaemia, weight decrease, face oedema, increased LDH, hypocalcaemia, paraesthesia,


hypoaesthesia, insomnia, vasodilatation, dizziness, anxiety, agitation, lacrimation disorder, conjunctivitis, tinnitus, ear pain, myocardial infarction/myocardial arrhythmia, atrial fibrillation, cardiac disorder, orthostatic hypotension, bronchospasm, respiratory disease, chest pain, dyspnoea, cough/increased cough, vomiting, diarrhoea, abdominal pain, dysphagia, stomatitis, constipation, dyspepsia, anorexia, throat irritation, alopecia, sweating/night sweats, skin disorder, hypertonia, myalgia, back pain, neck pain, pain, fever, chills, asthenia, headache, tumour pain, flushing, malaise, cold syndrome, shivering, multi-organ failure, decreased IgG levels, urinary tract infection, gastroenteritis, tinea pedis, hypercholesterolemia, migraine, sciatica, depression, oesophageal reflux, mouth ulceration, arthralgia/musculoskeletal pain, muscle spasms, muscle weakness, osteoarthritis, bursitis, decreased IgM levels. Additional side effects in ≥ 5% GPA/MPA patients in clinical trials: Nasopharyngitis, cytokine release syndrome, hyperkalaemia, tremor, acne, epistaxis, nasal congestion, pain in extremities, decreased haemoglobin. Uncommon (< 1/100) but potentially serious, including fatal, side-effects: Serious viral infection, Pneumocystitis jirovecii, progressive multifocal leukoencephalopathy, reactivation of hepatitis B, infusion related reactions (generalised oedema, bronchospasm, wheezing, laryngeal oedema, angioneurotic oedema, generalised pruritus, anaphylaxis, anaphylactoid reaction), tumour lysis syndrome, cytokine release syndrome, serum sickness, coagulation disorders, aplastic anaemia, haemolytic anaemia, late neutropenia, depression, peripheral neuropathy, cranial neuropathy, severe vision loss, facial nerve palsy, loss of other senses, left ventricular failure, supra-ventricular tachycardia, ventricular tachycardia, angina/angina pectoris, heart failure, atrial flutter, atrial fibrillation, myocardial ischaemia, bradycardia, severe cardiac disorders, vasculitis, leukocytoclastic vasulitis, asthma, broncholiolitis obliterans, hypoxia, respiratory failure, pulmonary infiltrates, interstitial lung disease, gastrointestinal perforation, Steven’s-Johnson syndrome, toxic epidermal necrolysis, renal failure. Cases of posterior reversible encephalopathy syndrome (PRES) / reversible posterior leukoencephalopathy syndrome (RPLS) have been reported. Please refer to the SPC for further information and a full list of side effects. Overdose: Intravenous doses of up to 5000 mg have been administered in a dose escalation study in CLL patients, which did not identify any safety signals. The infusion should be interrupted immediately and patient monitored closely, if overdose is experienced. Legal category: POM. Presentation: 1 vial of 500 mg. Marketing Authorisation number: EU/1/16/1167/001.Marketing Authorisation holder: Celltrion Healthcare Hungary Kft, 1051 Budapest, Bajcsy-Zsilinszky út 12., 4. em. 410.Hungary. For medical information enquiries, please contact ®Truxima is a registered trade mark of Celltrion, Inc. and is used under licence. ®The Mundipharma device (logo) is a Registered Trade Mark. © 2017 Mundipharma Pharmaceuticals Limited. PI Code UK/TRU-17025. Date of Preparation March 2017.

▼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 for how to report side effects. Distributed in Ireland by: Mundipharma Pharmaceuticals Limited, Millbank House, Arkle Road, Sandyford, Dublin 18, Ireland. Phone +353-1-2063800 Date of Item: June 2017. IRE/TRX-17024. ® TRUXIMA is a registered trade mark of Celltrion, Inc. and is used under licence. ® MUNDIPHARMA and the ‘mundipharma’ logo are registered trade marks of Mundipharma AG.

Not just similar Truxima is rituximab

92 Schizophrenia in the management of delusions and hallucinations, and seem to have fewer adverse effects in the recommended dosage ranges. In particular, they are associated with a reduced incidence of movement disorders and reduced incidence of difficulties with clear thinking. Side effects can, however, include weight gain, impaired glucose tolerance, and diabetes mellitus, as well as dry mouth, sedation, possible effects on the heart, dizziness and impotence. And, as with all anti-psychotics, ‘neuroleptic malignant syndrome’ can occur; this is a rare adverse effect (very high temperature, confusion) that needs to be managed in hospital and can be fatal if not treated. For all patients, it is recommended that, prior to commencing these medications, the person has a ECG performed, weight and height checked, and a set of basic blood tests done, including blood glucose. These should be monitored annually. In first episode schizophrenia, a six to eight-week trial of an optimal dosage of an atypical medication should be combined with appropriate social and psychological treatment. If this does not produce satisfactory clinical results, therapeutic options should be reviewed and discussed with patient and family. It is important to establish if the patient is not taking the medication for any reason, and to address whatever concerns might be leading to this. Another antipsychotic medication (tablets or injections) can be tried for a further six to eight weeks. In the unlikely event that these steps do not produce sufficient clinical improvement, clozapine can be considered. Clozapine is an anti-psychotic medication which can greatly help persons with difficult-to-treat schizophrenia, but it is reserved for treatmentresistant situations owing to its possible effects on the person’s white blood cell count. As a result, clozapine is a highly regulated medication and requires a careful programme of blood-testing while the person is on it. This blood testing programme is highly effective in detecting and addressing this problem. Other potential side effects include weight gain, constipation, seizures, cardiac effects, and problems with saliva secretion. Even so, a great number of people have benefitted hugely from this medication, which has been genuinely transformative in the lives of many people with schizophrenia who had extremely distressing symptoms prior to clozapine. At all stages of treatment it is essential to discuss the treatment plan with patient and carers;

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discuss adverse effects of medication (if any); and provide social and personal support for patient and family. There can, however, be particular challenges if the person presents in a highly agitated psychotic state, in a situation of great distress, and possibly presents a risk to self or others. In this situation, management centres initially on environmental and psychological measures: talking calmly and clearly to the patient, increasing personal space, and ensuring the availability of a comfortable, non-threatening environment for patient and carers. There are many possible causes of acute agitation so care needs to be taken to ensure that the person is not suffering from something other than schizophrenia or something in addition to schizophrenia (e.g. intoxication with drugs, or delirium following an injury or illness). If the person presents a risk to self or others, or if treatment is urgently needed and cannot be otherwise provided, involuntary procedures can be instigated under the Mental Health Act 2001. In very acute circumstances of risk, the Gardaí can be called, but this is rare event. The Gardaí then have the option of instigating involuntary admission under the Mental Health Act 2001. Finally with regard to medication, decisions to discontinue medication are taken on an individual basis. To date, insufficient attention has been given to correct protocols for reducing and stopping medication, the adverse effects linked with these decisions and with medication discontinuation, and the management of resultant therapeutic challenges. There is a strong need for further research and consideration of these matters. ECT ECT is not a common treatment for schizophrenia but has a role in certain situations. NICE guidelines, based on an extensive review of evidence, recommend ECT for severe depressive illness, prolonged or severe episodes of mania, or catatonia (which can occur in schizophrenia), once certain conditions are met. According to NICE, ECT should be administered to gain fast, short-term improvement of severe symptoms after all other treatment options have failed, or when the situation is life-threatening. Particular caution is advised in pregnant women and older or younger patients; an individual risk-benefit assessment should be performed (balancing adverse

effects, such as memory problems, with benefits); and patients should be reassessed regularly during programmes of ECT. More than one course of ECT should be considered only for patients with severe depressive illness, catatonia or mania who have previously had good responses to ECT. ECT should not be used as a long-term treatment to prevent recurrence of depression or in the general management of schizophrenia, according to NICE. ECT should, then, be reserved for rare, severe situations in certain persons with schizophrenia. In Ireland, schizophrenia, schizotypal and delusional disorders accounted for fewer than 9% of all programmes of ECT administered in 2013, the vast majority being prescribed for depressive disorders (82%). Nonetheless, there remains a small minority of patients with schizophrenia, especially those with catatonia, for whom ECT is indicated, effective and – occasionally – life-saving. Ongoing treatment Even if response to treatment is good following a first episode of psychosis, there is a high risk of relapse if medication is stopped within one to two years. In addition, ongoing management of schizophrenia involves much more than medication, and requires a multi-disciplinary team working together with the patient, family, GP and primary care team to treat the first episode of illness, prevent the development of subsequent episodes, and establish an ongoing collaborative plan aimed at optimising social function and minimising the effects of the illness on the patient and the family. Continued treatment with antipsychotic medication is part of a package of therapies that can help prevent relapse. Medication may be administered as tablets, injections or both. It is important to discuss treatment with patient and family, and to seek out evidence of adverse effects of medication or non-concordance with treatment. Treatment for depression may also be needed for some people, and this might involve medication at times, as well as psychological therapy and support. Long-term use of anti-psychotic medication use may be associated with the development of side effects (see above). Each side effect is addressed in its own way. In general, if a side effect develops, it is wise to consider the possibility of other causes also; e.g. weight gain may be due to poor dietary habits rather than medication. Appropriate

measures should be instigated to address the underlying cause. Some medication can contribute to the development of diabetes, and this requires fundamental reconsideration of the chosen treatment, as well as management of the diabetes. If the side effect appears to be due to the medication, it may be a good first step to consider reducing the dose or switching to another medication, if this is clinically appropriate and acceptable. There are also specific strategies for the management of particular unwanted effects, such as movement disorders, and a psychiatrist or GP can advise about these. Additional medication can play a role in managing these problems, although the use of complex combinations of different medications is to be avoided where possible, and social or psychological measures should accompany all interventions. There is particular concern in recent times about the effects of certain anti-psychotic medications on the heart, and so some medications require cardiac monitoring under specialist supervision. It is often the negative symptoms of schizophrenia, such as social withdrawal or impaired motivation, that prove most distressing for family and carers in the longterm. Current medications that are effective in the alleviation of symptoms such as hallucinations or delusions tend to have a much weaker effect on negative symptoms. There is a strong need to develop further medications that combine enhanced clinical effectiveness with fewer side effects, as these are likely to also prove more acceptable to patients, enhance adherence to treatment, and improve overall therapeutic outcomes. In addition to pharmacological management, there is a series of other interventions that are critical in the management of schizophrenia. Psychoeducation for patient and family helps develop understanding of the illness and its treatment, and enhances the therapeutic alliance between family and health-care providers. Other psychological approaches of proven benefit include CBT, family therapy, art therapy (especially for negative symptoms) and self-help groups and forums. Recent years have seen particular interest in CBT for certain patients with schizophrenia, focusing on helping them deal with persistent delusions and hallucinations. NICE now recommends offering structured CBT to assist patients with establishing links between

93 earlier, and women 12 years earlier, than the rest of the population. This excess is not accounted for by unnatural deaths; the leading causes are heart disease and cancer. As a result, there is a need for ongoing and enhanced focus on the physical health of persons with schizophrenia, including (but not limited to) support in stopping smoking, promotion of improved diet and lifestyle, and screening for cardiac risk-factors (e.g. high blood pressure and cholesterol). In addition, treatment with antipsychotic medication reduces the likelihood of premature death in schizophrenia - providing yet another reason to persist with treatment in this complex, misunderstood but eminently treatable disorder. Brendan Kelly is Professor of Psychiatry at Trinity College Dublin, Consultant Psychiatrist at Tallaght Hospital, and author of ‘Hearing Voices: The History of Psychiatry in Ireland’ (Irish Academic Press, 2016) (

References thoughts, feelings, actions, and their symptoms and functioning, and re-revaluating others people’s perceptions, beliefs or reasoning as they relate to target symptoms. Other aspects of CBT in psychosis include monitoring one’s own thoughts, feelings or behaviours with respect to symptoms; promoting alternative coping strategies; diminishing distress; and improving functioning. Social interventions for schizophrenia include the assessment of social and occupational needs, provision of appropriate information and training, and advice on financial and practical matters relating to housing, occupation, and social function. Many people with schizophrenia, especially if it follows a chronic course, experience difficulties obtaining and sustaining accommodation. It is important to ensure that accommodation is appropriate to the needs of the patient and that there are no preventable psychosocial stressors likely to hinder recovery. It is also important to recognise the role of support and encouragement from family and friends during both the illness and the recovery phase. Occupational engagement is another key area for many people with schizophrenia, especially those with recurring episodes of

psychosis. The development of acceptable and gainful occupation for people with schizophrenia is dependent on the abilities and aptitudes of the individual person, and the availability of appropriate financial and human resources. In the case of acute schizophrenia there may well be a return to previous employment or education following an episode of illness. In the case of chronic schizophrenia, there may be a need for further training or a reformulation of employment or training plans. The provision of specific employment programmes can help with rehabilitation and ongoing treatment for people with persistent symptoms or psychosocial disability associated with mental illness. Day centres may form a further focus for daily activity and also provide an opportunity for detailed clinical assessment and liaison with family and carers. Outcome Schizophrenia is a relatively common mental disorder which can be disabling but is treatable. Seventy per cent of people who experience a psychotic episode will be well within one year, although many will have a second episode. Discontinuing medication within the first 18 months makes the person five times more likely to experience a relapse.

The lifetime risk of suicide in schizophrenia is approximately 10%, which is higher than the general population risk (which is under 1%). Risk is especially high in young males during the first few years of schizophrenia, and if there are persistent delusions or hallucinations, drug misuse, or previous attempts at suicide. In practical terms, these statistics mean that (a) the vast majority of people with schizophrenia will not die by suicide; (b) suicide cannot be predicted in any given individual with schizophrenia (as it is still a rare event); and (c) risk will likely be diminished if the person persists with treatment and does not misuse drugs. Schizophrenia is associated with reduced rates of social interaction, marriage, reproduction, and workforce participation, with the result that two thirds of people with chronic schizophrenia are unemployed. Tragically, most of this ‘secondary disability’ is not attributable to the illness itself, but to society’s prejudicial responses to it. Finally, one of the other longterm challenges in schizophrenia is the recurring finding that the illness is associated with poor physical health. Life expectancy is considerably reduced in schizophrenia: on average, men with schizophrenia die 15 years

1. Daly A, Craig S. HRB Statistics Series 29: Activities of Irish Psychiatric Units and Hospitals 2015. Health Research Board, 2016. 2. Behan C, Kennelly B, O’Callaghan E. The economic cost of schizophrenia in Ireland: a cost of illness study. Irish Journal of Psychological Medicine 2008; 25: 80-87. 3. NICE. Psychosis and Schizophrenia in Adults: Prevention and Management. NICE, 2014 ( guidance/cg178). 4. NICE Guidance on the Use of Electroconvulsive Therapy. NICE, 2009 ( guidance/ta59). 5. Mental Health Commission. The Administration of ElectroConvulsive Therapy in Approved Centres: Activity Report 2013. Mental Health Commission, 2015. 6. NICE Psychosis and Schizophrenia in Adults: Prevention and Management. NICE, 2014 ( guidance/cg178). 7. Crump C, Winkleby MA, Sundquist K, Sundquist J. Comorbidities and mortality in persons with schizophrenia: a Swedish national cohort study. American Journal of Psychiatry 2013; 170: 324-33.

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94 ASCO Education

American Society of Clinical Oncology Cancer Updates Alice T. Shaw, MD, PhD, Director of Thoracic Oncology at Massachusetts General Hospital Cancer Center in Boston

Findings from a phase III clinical trial point to a more effective initial treatment for patients with ALK-positive non-small cell lung cancer (NSCLC). Compared to the current standard of care crizotinib (Xalkori), the newer ALK inhibitor alectinib (Alecensa) halted cancer growth for a median of 15 months longer and caused fewer severe side effects. The study was featured at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting. “This is the first global study to compare alectinib with crizotinib in ALK-positive lung cancer and establishes alectinib as the new standard of care for initial treatment in this setting,” said lead study author Alice T. Shaw, MD, PhD, Director of Thoracic Oncology at Massachusetts General Hospital Cancer Center in Boston, MA. “Alectinib was especially beneficial in controlling and preventing brain metastases, which can have a major impact on patients’ quality of life.” About 5% of NSCLCs are ALKpositive, meaning they have a genetic rearrangement where the ALK gene is fused with another gene. In the United States, about 12,500 people are diagnosed with ALK-positive NSCLC each year. Crizotinib, the first medicine to specifically target ALK, was approved by the FDA in 2011. Although the majority of patients initially benefit from crizotinib, the cancer typically starts growing again within a year. Alectinib is a more potent, next-generation inhibitor of ALK. It was initially

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approved in 2015 for use in patients with advanced NSCLC that worsens despite crizotinib. In this open label clinical trial (ALEX), researchers randomly assigned 303 patients with stage IIIB or IV, ALK-positive NSCLC to receive alectinib or crizotinib. The patients had not received prior systemic therapy for advanced NSCLC. Alectinib reduced the risk of cancer progression or death by 53% compared with crizotinib. Based on independent review, alectinib extended the median time to progression by about 15 months (median progression-free survival was 25.7 months with alectinib and 10.4 months with crizotinib). “Nobody imagined it would be possible to delay advanced lung cancer progression by this much. Most targeted therapies for lung cancer are associated with a median progression-free survival of roughly 12 months,” said Dr Shaw. While both treatments cross the blood-brain barrier, alectinib was more effective in preventing brain metastases than crizotinib, because it can better penetrate into the brain. At 12 months, the incidence of brain metastases was much lower with alectinib than with crizotinib (9% vs. 41%). Overall, severe side effects were less common with alectinib than with crizotinib, occurring in 41% vs. 50% of patients. The most common side effects of alectinib were fatigue, constipation, muscle aches, and swelling, whereas crizotinib caused gastrointestinal

problems and liver enzyme abnormalities. The researchers will continue to follow patients on this study to see if those treated with alectinib live longer than those treated with crizotinib. Meanwhile, several ongoing clinical trials are comparing other next-generation ALK inhibitors to crizotinib in the first-line setting. Global Study Sets New RiskBased Standard to Personalize Chemotherapy for Colon Cancer After Surgery After surgery for lymph-node positive colon cancer (stage III), some patients may only need half of the long-standing standard course of chemotherapy. In an analysis of six clinical trials with over 12,800 patients, 3 months of chemotherapy was nearly as effective as 6 months in patients with relatively lower recurrence risk and caused fewer side effects, particularly nerve damage. Chemotherapy lowers the chance of cancer recurrence after colon cancer surgery. Since 2004, the standard (adjuvant) treatment after surgery has been a combination of chemotherapies (FOLFOX or CAPOX), given over a period of six months. The goal of this study, which pooled data from 6 studies conducted in North America, Europe, and Asia, was to determine if 3 months of chemotherapy was as effective as 6 months. While the primary endpoint was not proven statistically, a shorter, 3-month

course of chemotherapy was associated with a less than 1% lower chance of being colon cancer free at 3 years compared to the standard 6-month course (74.6% vs. 75.5%). In patients considered at low risk of cancer recurrence (60% of patients in the study), the difference was even smaller (83.1% in patients receiving a 3-month course vs. 83.3% in patients receiving a 6-month course). “Our findings could apply to about 400,000 colon cancer patients worldwide every year. For 60% of these patients, who have lower risk for cancer recurrence, 3 months of chemotherapy will likely become the new standard of care,” said senior study author Axel Grothey, MD, an oncologist at the Mayo Clinic Cancer Center in Rochester, Minn. “Patients with higher risk colon cancer, however, should discuss these results with their doctor to see if a shorter course of therapy would be right for them, taking into account their preference, age, and ability to tolerate chemotherapy.” A key side effect of one of the chemotherapies in the regimen – oxaliplatin – is nerve damage, which can result in permanent numbness, tingling, and pain. The longer a patient receives oxaliplatin, the greater the chance for severe and long-lasting nerve damage. Nerve damage (numbness/tingling of the hands and feet) was substantially less common in patients receiving a 3-month course of chemotherapy vs. a 6-month month course (15% vs. 45% with FOLFOX and 17% vs. 48% with CAPOX). “Many side effects of chemotherapy, such as hair loss, go away over time, but nerve damage is a side effect some patients have to deal with for the rest of their lives,” said Dr Grothey. This study is a prospective, pre-planned analysis of pooled data from six concurrent, phase III clinical trials conducted in 12 countries. It was established more than 10 years ago as so-called IDEA collaboration (International Duration Evaluation of Adjuvant

95 therapy). A steering committee oversaw the study design, and an independent statistical center reviewed the results from all six clinical trials (findings from three of which are being presented at the ASCO Annual Meeting). The study received public funding only. “We needed this large number of patients to answer the study question, but at the time this study began in 2007 it was not possible to run one study of that size anywhere in the world,” said Dr Grothey. “With more than 12,834 patients, this is the largest collaboration of its kind in oncology.” Patients were followed for a median time of 39 months. For all patients combined, the rate of disease-free survival at 3 years was slightly lower with 3 months of chemotherapy than with 6 months of chemotherapy (74.6% vs. 75.5%). The type of chemotherapy regimen selected affected the difference in 3-year disease-free survival between the 3-month and 6-month treatment duration (75.9% vs. 74.8% with CAPOX and 73.6% vs 76.0% with FOLFOX), although the difference was relatively small in both cases. In the subset of patients with lower risk colon cancer (defined as cancer spread to 1-3 lymph nodes and not completely through the bowel wall), the disease-free survival rate at 3 years was almost identical for those who received 3 (83.1%) and 6 months of chemotherapy (83.3%). The rate of clinically meaningful (grade 2 or greater) nerve damage differed depending on the type of chemotherapy regimen received, but was consistently higher for people who received 6 months versus 3 months of chemotherapy (45% vs. 15% with FOLFOX and 48% vs. 17% with CAPOX). “Aside from nerve damage, longer chemotherapy also means more diarrhea and fatigue, more doctor appointments, blood draws, and time away from work and social interactions,” said Dr. Grothey. “This is extremely important work that will affect the lives of many of my patients hopefully tomorrow, and will allow us to provide a more personalized approach to our patients with colon cancer. Although addressing the question, ‘can we give less treatment?’ is of major importance to patients and their doctors, it is rare to see this type of study. Given that these questions are unlikely to be

David Hyman, MD, Chief of Early Drug Development at Memorial Sloan Kettering Cancer Center in New York

of interest to the pharmaceutical industry, federal support for these trials is critical,” said Dr Baxter. New Drug Shows Durable Efficacy Across Diverse Pediatric and Adult Cancers Scientists may have developed the first targeted, oral, tumortype agnostic therapy – a cancer medicine that works comparably well across many kinds of cancer, regardless of patient age. In clinical trials of adults and children with 17 different types of advanced cancer, larotrectinib treatment resulted in responses in 76% of patients. Response to larotrectinib has been durable, with 79% of responses ongoing 12 months after starting treatment. Larotrectinib is a selective inhibitor of tropomyosin receptor kinase (TRK) fusion proteins, which are a product of a genetic abnormality when a TRK gene in a cancer cell fuses with one of many other genes. It is estimated that this abnormality occurs in about 0.5% – 1% of many common cancers, but in greater than 90% of certain rare cancers, such as salivary gland cancer, a form of juvenile breast cancer, and infantile fibrosarcoma. “TRK fusions are rare, but occur in many different cancer types. In fact, at this point it is hard to find a cancer type where TRK fusions have not been reported,” said lead study author David Hyman, MD, Chief of Early Drug Development at Memorial Sloan Kettering Cancer Center in New York. “These findings embody the original promise of precision oncology: treating a patient based on the type of mutation, regardless of where the cancer originated. We believe that the dramatic response of tumors with TRK fusions to larotrectinib supports widespread genetic testing in patients with advanced cancer to see if they have this abnormality.” Researchers analyzed data from

55 patients with TRK fusions enrolled in three ongoing phase I and phase II clinical trials. All patients (12 children and 43 adults) had locally advanced or metastatic cancer, including colon, lung, pancreatic, thyroid, salivary, and gastrointestinal cancers, as well as melanoma and sarcoma. “This dataset, subject to independent central radiology review, will be submitted to FDA for larotrectinib’s regulatory approval. If approved, larotrectinib could become the first therapy of any kind to be developed and approved simultaneously in adults and children, and the first targeted therapy to be indicated for a molecular definition of cancer that spans all traditionally-defined types of tumors,” said Dr Hyman. In the first 50 patients with 17 different cancer types who have been on the study long enough to have at least two scans, 38 (76%) of these patients had a response. Of those, three patients with pediatric sarcomas previously not amenable to surgery went on to receive potentially curable surgery after larotrectinib shrank the tumors. The median duration of treatment response has not yet been reached, as the majority of patients are still responding to treatment. At 12 months into treatment, 79% of responding patients remain progression free. To date, the longest duration of treatment response has been 25 months and is ongoing. The most common side effects were fatigue and mild dizziness, which was expected as the normal TRK protein has a role in controlling balance. No patients needed to stop treatment due to side effects. “Because larotrectinib was designed to target only TRK, it has been very well tolerated and does not cause many of the side effects associated with chemotherapy

and multi-targeted therapy,” said Dr. Hyman. TRK fusions were first discovered in colon cancer in 1982, but only recent technological advances, particularly next-generation sequencing (NGS), have enabled systematic detection of this abnormality. To date, scientists have found more than 50 different partner genes that fuse with one of three TRK genes (NTRK 1, 2, and 3). TRK fusions arise early in cancer development and remain present as tumors grow and spread. The abnormal TRK fusion proteins are constantly “turned on,” sending cancer cells signals to keep growing and dividing. “TRK fusions are like an ignition switch for cancer,” said Dr. Hyman. Although there are other experimental treatments that block TRK along with other proteins, larotrectinib is the first to selectively block TRK. This characteristic improves potency of the drug, while lowering side effects. The FDA granted larotrectinib a breakthrough therapy designation in 2016 for the treatment of pediatric and adult TRK fusionpositive unresectable or metastatic solid tumors that had worsened despite systemic therapy or that have no acceptable alternative treatments. The designation serves to expedite the development and review of promising new drugs for treating serious or life-threatening illnesses. The researchers have identified what they believe to be the primary means by which tumors may grow resistant to larotrectinib, and they are studying another TRK-targeted therapy, LOXO-195, for the treatment of patients with cancer that regrows after initially responding to larotrectinib. Find the full version with references at

HPN • Issue 41

96 News HPRA making plans to deliver health remit At the end of March this year, the United Kingdom (UK) notified the European Council that it intends to withdraw from the European Union (EU). Together with other Member States and the European Medicines Agency (EMA), the Healthcare Products Regulatory Authority (HPRA) is making preparations to ensure that they continue to deliver on their patient and animal health remit even if the UK fully exits the current systems on 29 March 2019. The UK continues to play a full role within the European regulatory network during the ongoing discussions in relation to its withdrawal from the EU. Although the eventual outcomes of these negotiations are unknown, there are potentially significant implications for the European network as a whole and particularly for Ireland with its shared market place. “Protecting the availability of medicines for Irish patients and the integrity of our market are key strategic aims of the HPRA’s Brexit-related activities while also

optimising our role within the European regulatory network and maintaining our strong working relationships with UK colleagues,” they say. The HPRA has established an internal working group under the direction of Rita Purcell, Deputy Chief Executive, to ensure that we are prepared for the UK’s withdrawal from the EU. The HPRA will provide information on this page to keep stakeholders informed of developments. Proposed stakeholder meeting The HPRA intends to hold a stakeholder meeting to engage with stakeholders on their approach to potential Brexit scenarios and to understand the concerns and requirements of different stakeholder groups. This meeting, which will focus on medicines for human and veterinary use, will take place on the afternoon of 31 August 2017 at the Crowne Plaza in Santry, Dublin, starting at 13.30. Visit for further details.

Ensuring market availability A major priority for the HPRA is to ensure the availability and the continued uninterrupted supply of human and veterinary medicines and medical devices in Ireland. The HPRA will provide support to marketing authorisation holders (MAHs) so as to maintain the availability of medicines and is available to meet with and discuss issues with MAHs, as required. To assist with this the HPRA has requested MAHs which hold a marketing authorisation in Ireland for a medicinal product for human use, where the UK is the RMS or a CMS, to respond to a survey. The survey seeks to identify any products where supply and availability may be interrupted in the event of the UK withdrawing from the EU and to ensure that plans are in place to proactively address this. Those who have not yet submitted their responses should submit them as soon as possible to Increasing share of regulatory workload Recognising the considerable

contribution currently made by the UK to the work of the European medicines network, the HPRA is ready to assume a greater role in EU regulatory activities postBrexit as may be required. The EMA has established working groups to operationalise agreed principles and rules for redistribution of the centralised workload, see EMA: United Kingdom’s Withdrawal from the European Union (Brexit’). The HPRA already plays a significant role in the European Medicines regulatory network. Their representation in the EMA’s committees and working parties mirrors that of the larger agencies in Europe. HPRA has a strong profile in terms of assessment work, ranking in the top 2 in the veterinary medicines assessments over the past 10 years and ranking in the top 10 in Europe for human medicines post authorisation work. Their inspection activities are recognised as providing a strong regulatory environment in Ireland and are heavily relied on for inspection of sites on behalf of the EMA.

The HPAI Leadership Academy launch Elaine Conyard, HPAI Executive, Gearoid Hardy, Leadership Consultant, Deirdre Lynch, HPAI Executive & Immediate Past President, Anne-Martina Mulligan, Key Accounts Manager, Hospitals, MSD Ireland

videos with supporting materials. Participants need only a screen and somewhere comfortable to sit.

The Leadership Academy, sponsored by MSD Ireland, was introduced at the Hospital Pharmacists Association of

Issue 41 • HPN

Ireland (HPAI) annual conference earlier this year and will include 5 Leadership Master Classes delivered through eLearning

The learnings are based on the idea that Leadership is a state of mind rather than a position of authority and that anyone can exhibit leadership in their role. The challenge is to identify the opportunities to do so and seize them. Each Master Class will consist of approximately 45 minutes of video

broken into smaller chunks, so that they can be watched at the participants own pace. There will be supporting materials including a lecture guide pack, blogs and recommended further reading. The aim of The Academy is for all pharmacists to have an opportunity, at their own pace, to have the benefit of a 2-day Leadership course from a leading expert (Gearóid Hardy) in the field. The course may be eligible for CPD and/or as part of the development of the hospital Pharmacy team led out by the chief pharmacist. Gearoid Hardy has over 35 years’ experience working in a variety of industries including; banking, IT, healthcare, manufacturing and pharmaceutical. He has international experience in both the academic and professional sector. His leadership credentials come from the Kennedy School of Government at Harvard and he is currently completing a Doctorate in the area of Healthcare teams.

Clinical R&D 97 NEW INDICATION FOR CLONMEL HEALTHCARE Clonmel Healthcare are delighted to announce an additional indication for Pregabalin Clonmel 25mg, 50mg, 75mg, 100mg, 150mg, 200mg and 300mg Capsules, Hard Pregabalin Clonmel Capsules, Hard are currently indicated for: 1 •

Epilepsy - Pregabalin Clonmel is indicated as adjunctive therapy in adults with partial seizures with or without secondary generalisation.

Generalised Anxiety Disorder - Pregabalin Clonmel is indicated for the treatment of Generalised Anxiety Disorder (GAD) in adults.

• For the treatment of peripheral and central neuropathic pain in adults. Pregabalin Clonmel Capsules, Hard are available in a 56 and/ or 84 pack size and are GMS reimbursable. Full prescribing information is available on request or alternatively please go to www.clonmel-health. ie. Medicinal product subject to medical prescription. Please contact Clonmel Healthcare on 01-6204000 if you require any additional information on Pregabalin Capsules, Hard. Ref 1. Pregabalin Clonmel Capsules, Hard Summary of Product Characteristics PA 126/278/1-6, 8 PA Holder: Clonmel Healthcare Ltd, Waterford Road, Clonmel, Co. Tipperary Legal Category: Prescription Only Medicine. Date Prepared: July 2017. 2017/ADV/PRE/026

SANOFI GENZYME AND ALNYLAM REPORT POSITIVE RESULTS Sanofi Genzyme, the specialty care global business unit of Sanofi, and Alnylam Pharmaceuticals, Inc, the leading RNAi therapeutics company, have announced new positive results from the ongoing phase 2 open-label extension (OLE) study with fitusiran in patients with hemophilia A and B, with or without inhibitors (N=33). These results were presented in an oral presentation at the International Society on Thrombosis and Haemostasis (ISTH) 2017 Congress, held from July 8 - 13, 2017 in Berlin, Germany. Fitusiran is an investigational RNAi therapeutic targeting antithrombin (AT) for the treatment of patients with hemophilia A and B, that is designed to lower levels of AT with the goal of promoting sufficient thrombin generation upon

activation of the clotting cascade to restore hemostasis and prevent bleeding. The updated clinical results in the fitusiran phase 2 OLE study showed that the safety and tolerability profile of fitusiran remains encouraging, with no thromboembolic events, including during co-administration of replacement factor or bypassing agents. The majority of adverse events (AEs) were mild or moderate in severity, with the most common AEs consisting of transient, mild injection site reactions (ISRs). In addition, once-monthly subcutaneous (SC) administration of fitusiran achieved lowering of AT, increases in thrombin generation, and, in a post-hoc exploratory analysis, reductions in the median estimated annualized bleeding rate (ABR) in patients with and without inhibitors. Based on these results, the companies announced last week the initiation of the ATLAS phase 3 program for fitusiran in patients with hemophilia A and B with or without inhibitors. The ongoing fitusiran phase 2 OLE study includes patients (N=33) with hemophilia A (N=27) and hemophilia B (N=6). The study includes 14 patients with inhibitors, including one with hemophilia B. Fitusiran was administered as a low volume (less than 1 mL), monthly, subcutaneous, fixed dose of 50 mg (N=13) or 80 mg (N=20). All results are as of a June 15, 2017 data transfer date. Patients were treated for up to 20 months in the phase 2 OLE, with a median of 11 months on study. The majority of AEs were mild or moderate in severity, with the most common non-laboratory AEs consisting of transient, mild ISRs (18 percent of patients). There was one discontinuation due to an AE, an asymptomatic alanine aminotransferase (ALT) elevation in a patient with chronic hepatitis C virus (HCV) infection. Serious adverse events (SAEs) considered possibly related to drug were reported in two patients: asymptomatic ALT elevation in one patient with chronic HCV infection, as noted above, and seizure with confusion in one patient with a prior history of seizure disorder. Asymptomatic ALT increases greater than 3x the upper limit of normal (ULN), without concurrent elevations in bilirubin greater than 2x ULN, were observed in 11 patients, all of whom were hepatitis C antibody positive; at current follow-up, all ALT elevations are resolved (N=10) or resolving (N=1). No thromboembolic events, laboratory evidence for pathological clot formation, or instances of antidrug antibody (ADA) formation were reported.

NEW RESEARCH POINTS TO TREATMENT BREAKTHROUGH FOR GLOBALLY DEVASTATING VIRUSES An international collaboration, including scientists from Trinity College Dublin has potentially unlocked the door to better treatment of viral diseases, including the flu and the common cold. The researchers discovered that an ancient, 1.5 billion year old cell biological process found in plants, fungi and mammals enhances viral disease in mice and the researchers believe it is highly likely it has the same effect on viruses in humans. They identified a protein, called Nox2 oxidase that was activated following infection with viruses, including influenza, rhinovirus (i.e. common cold), dengue and HIV, irrespective of the strain of the virus. Once activated the Nox2 oxidase suppressed the body’s key antiviral reaction and its ability to fight and clear the viral infection which in turn resulted in a stronger or more virulent disease in mice. The study also investigated a new prototype drug to treat these debilitating viral diseases. They found that the Nox2 oxidase protein activated by the viruses is located in a cell compartment called endosomes. They carefully modified a chemical that inhibited or restrained the activity of the Nox2 oxidase, to enable it to reach this endosome compartment. Their customised drug was found to be very effective at suppressing disease caused by influenza infection. In the 2015/16 flu season in Ireland 1856 people were hospitalised as a result of flu, there were 84 deaths from flu and at peak flu season, 80 in every 100,000 of the population had the flu, according to the HSE influenza surveillance reports. The global burden is also staggering with more than 5million cases of infection annually with up to 10% resulting in death. The collaboration was led by RMIT University scientists in Melbourne and includes researchers and clinicians from eight universities across Australia, the United States and Trinity College Dublin in Ireland. Dr Selemidis, head of the Oxidant and Inflammation Biology Group at RMIT University said, “Current treatment strategies are limited as they specifically target circulating viruses and have either unknown or very little effect against new viruses that enter the human population." “The study identifies a protein of the immune system that

contributes to the disease caused by flu viruses irrespective of their strain. It also developed a novel drug delivery system to target this protein, which drastically alleviated the burden of viral disease. This work identifies a treatment strategy that has the potential to alleviate the symptoms caused by some of the most devastating viruses worldwide, including the flu,” Dr Eunice To said.

MARKETING AUTHORISATION FOR LEO PHARMA’S KYNTHEUM® LEO Pharma have announced that the European Commission has granted marketing authorisation for Kyntheum® (brodalumab), a novel biologic treatment for adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy. Brodalumab is the first and only treatment for moderate-to-severe psoriasis to target the IL-17 receptor. By binding to this specific receptor on the cells of the skin, rather than targeting free inflammatory mediators, brodalumab blocks the biological activity of several pro-inflammatory IL-17 cytokines involved in plaque formation. This mechanism of action is different to all other psoriasis biologics currently available. “Approximately 73,000 people in Ireland are living with psoriasis, a debilitating, chronic disease which can also carry an increased risk for other associated conditions, especially in more severe psoriasis patients. Despite clinical advances in treatment, many patients still fail to achieve total skin clearance, measured as PASI 100,” commented Dr Caitriona Ryan, Consultant Dermatologist in St Vincent's Hospital and Aesthetic Surgery. “Today’s decision marks an important advancement in the management of moderate-tosevere psoriasis. Brodalumab’s differentiated mode of action offers Dermatologists a new option supported by trial data which indicate the potential to give some patients full skin clearance.” With brodalumab 210mg, psoriasis plaques start to clear at week 2 as the inflammation decreases. In the clinical trials, 37%-44% of patients treated with brodalumab achieved complete skin clearance (PASI 100) at week 12, compared with 19%-22% with ustekinumab [AMAGINE-2: 44% (n=272/612) versus 22% (n=65/300), p<0.001; AMAGINE-3: 37% (n=229/624) versus 19% (n=58/313), p<0.001]. High levels of skin clearance were sustained with continuous brodalumab treatment through week 52. After one year of treatment, half of patients had complete skin clearance (PASI 100).

HPN • Issue 41

98 Clinical R&D ACCORD LAUNCH IRINOTECAN HYDROCHLORIDE 20 MG/ ML CONCENTRATE FOR SOLUTION FOR INFUSION Accord Healthcare is delighted to announce the launch of Irinotecan Hydrochloride 20mg/ml Concentrate Solution for Infusion in three pack sizes 2ml, 5ml and 25ml. Irinotecan Hydrochloride 20 mg/ ml Concentrate for Solution for Infusion is indicated for the treatment of patients with advanced colorectal cancer, either in a combination with other medicines or alone. Irinotecan Hydrochloride 20 mg/ ml Concentrate for Solution for Infusion is now available from Uniphar/Allphar. For further information please contact your Accord representative, call Accord in Cork on 021-461 9040 or visit Your Accord Hospital Representatives are: Tracy Kivlehan 086-8389 829 & Oliver Lawrence 087 949 3918.

STUDY GIVES NEW HOPE OF TARGETED TREATMENT FOR TRIPLE NEGATIVE BREAST CANCER Research led by Irish scientists has found a potential new approach to treating one of the most difficult-to-treat forms of breast cancer, which currently has limited treatment options. Scientists from BREAST-PREDICT, an Irish Cancer Society Collaborative Cancer Research Centre, in collaboration with an EU-funded research consortium called RATHER, have shown that a new drug, called THZ-1, can prevent the growth of triple negative breast cancer. Their findings have recently been published in the journal Cancer Research. Triple negative breast cancer affects approximately one in five women diagnosed with breast cancer, and is more often diagnosed in younger women. This aggressive subtype lacks three important proteins or biomarkers in the tumour cells, namely estrogen receptor, progesterone receptor and HER2. This means that patients with this type of breast cancer cannot receive ‘targeted therapies’ such as hormone therapy (e.g. Tamoxifen) or Herceptin. Instead, the only Issue 41 • HPN

effective treatment for these patients is chemotherapy, making this type of cancer one of the most difficult to treat. Although many of these patients do respond well to chemotherapy, resistance of the tumour to this treatment is a common problem. Patients with resistant disease have a poor prognosis, and their tumours are more likely to return and spread following treatment. Doctors and researchers are urgently looking for new treatment options for these patients. This most recent study focused on a protein called CDK7, which the researchers found to be present at high levels in triple negative breast cancers. Interestingly, patients with high levels of CDK7 present in their tumour were more likely to experience a disease relapse following standard chemotherapy treatment. This means that high CDK7 levels could be used as a ‘biomarker’ to identify patients unlikely to respond well to chemotherapy. This type of test could be very useful to their doctors, as they could then prioritise these patients for a more aggressive treatment regime. The researchers also tested a drug that acts on CDK7, called THZ-1, to investigate if this could be a novel treatment for triple negative breast cancer. Remarkably, treating triple negative breast cancer cells grown in the laboratory with THZ-1 halted their growth, both on its own and in combination with other treatments. The researchers proposed THZ-1 as a novel treatment option for this aggressive cancer type, particularly in combination with existing treatments, to improve their success rate. Commenting on the findings, Prof William Gallagher, the lead investigator on the study and Professor of Cancer Biology at UCD, said, “This study has uncovered an important new treatment possibility for patients with triple negative breast cancer, a particularly aggressive subtype of the disease. This success was only possible through a concerted team-based approach from multiple national and international collaborators.” This study was supported by the Irish Cancer Society Collaborative Cancer Research Centre BREAST-PREDICT

and the EU-funded RATHER project, an international research consortium focused on tackling difficult-to-treat subtypes of breast cancer; both of which are co-ordinated by Prof. Gallagher. While further research is needed on this novel treatment before it can be used in breast cancer patients, this work is a key step in opening up a wider range of new and less toxic treatment options for triple negative breast cancer patients.


Daiichi Sankyo Europe GmbH (hereafter, “Daiichi Sankyo”) have announced that the European Committee for Medicinal Products for Human Use (CHMP) has recommended approval of a label update for the company’s oral, once-daily direct factor Xa-inhibitor LIXIANA®, to provide guidance on its use in patients undergoing transoesophageal echocardiography (TEE)-guided and delayed cardioversion (treatment to restore a normal heart rhythm). The label update is based on results from the ENSURE-AF study, the largest, prospective randomised clinical trial of an anticoagulant for cardioversion in patients with NVAF. The study enrolled 2,199 patients, and compared once-daily LIXIANA with enoxaparin/warfarin with a median time in therapeutic range (INR 2-3) of 70.8 %. These data support the use of LIXIANA as a possible alternative to conventional treatment with enoxaparin and warfarin. LIXIANA’s rapid onset of action allows for prompt cardioversion in the TEE-guided approach as early as two hours after LIXIANA intake, helping to avoid delays or postponements of the procedure. “ENSURE-AF provides important insight into the use of LIXIANA in the setting of TEE-guided and delayed cardioversion in NVAF patients,” said Wolfgang Zierhut, MD, Executive Director, EU Cardiovascular Medical Affairs. “We are pleased that the CHMP has recognised the importance of the ENSURE-AF data for LIXIANA in this common procedure, by recommending this label update. Daiichi Sankyo is committed to supporting patients and physicians by advancing understanding of the

efficacy and safety of LIXIANA in different clinical settings, through studies such as ENSURE-AF.” Cardioversion is a procedure used to restore normal, regular heart rhythm in AF patients. Due to an associated risk of thrombotic events such as stroke, guidelines recommend anticoagulation before and after the procedure. The delayed onset of action and fluctuations in INR associated with VKA treatments such as warfarin, can result in costly and inconvenient delays to cardioversion in patients. Initial treatment with enoxaparin (followed by overlapping VKA treatment) until the VKA reaches the therapeutic range of INR 2-3, represents the best possible conventional treatment. The primary efficacy endpoint of the ENSURE AF study was a composite of stroke, systemic embolic events, myocardial infarction and cardiovascular mortality, which occurred in five patients in the LIXIANA 60/30 mg arm versus 11 in the enoxaparin-warfarin arm. The primary safety endpoint was major and clinically relevant nonmajor bleedings (CRNM), which occurred in 16 patients in the LIXIANA arm versus 11 patients in the enoxaparin-warfarin arm. The difference between the treatment arms was statistically non-significant. Event rates of thromboembolism and major and CRNM bleedings were low in the LIXIANA and exceptionally well-controlled warfarin arms. There was no difference between the TEEguided approach and the delayed cardioversion setting. These data support the use of LIXIANA as a possible alternative to conventional treatment with enoxaparin and warfarin, and may facilitate prompt cardioversion in the TEE-guided approach as early as two hours after LIXIANA intake. This label update makes LIXIANA the only NOAC with specific label guidance for early cardioversion within two hours after LIXIANA intake in the TEEguided approach.

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