Clinical Care 2015 by Ashville Media Group

THE LATEST DEVELOPMENTS IN IRISH HEALTHCARE | 2015

BETTER PATIENT CARE INTEGRATED PATHWAYS OF CARE

A UNIFIED & INTEGRATED APPROACH

IMPROVING ACCESS TO CARE, STANDARDS & OUTCOMES

LOCALISED INITIATIVES

STRATEGIES

INTEGRATED FACILITIES

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LEGAL CATEGORY: Prescription only medicine. 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. ▼ This medicinal product is subject to additional monitoring and it is therefore important to report any suspected adverse events related to this medicinal product. PHIR/NO/1014/0002

Further information is available on request and in the OLYSIO summary of product characteristics. Available at www.medicines.ie

Revealing OLYSIO in Hepatitis C treatment

OLYSIOW 150 mg hard capsules PRESCRIBING INFORMATION ACTIVE INGREDIENT: Simeprevir sodium equivalent to 150 mg of simeprevir. Please refer to Summary of Product Characteristics (SmPC) before prescribing. INDICATION(S): For treatment of chronic hepatitis C (CHC) in combination with other medicinal products in adult patients. DOSAGE & ADMINISTRATION: Oral. To be initiated/monitored by physician experienced in CHC management. Not for use as monotherapy. Adults: Recommended one capsule once daily for 12 weeks, swallowed whole with food. See SmPC for full posology and treatment stopping rules, if inadequate on-treatment virologic response. Do not reduce or interrupt OLYSIO treatment. Do not restart OLYSIO treatment if discontinued because of adverse reactions or inadequate ontreatment virologic response. A missed dose should be taken with food as soon as possible, within 12 hours of the usual dosing time, the next dose of OLYSIO should be taken at the regularly scheduled time. If a dose is missed by more than 12 hours, the patient should not take the missed dose and should resume dosing of OLYSIO with food at the regularly scheduled time. Caution in East Asian patients. HCV/HIV-1 co-infection; no dose adjustment required. Children: No data available. Elderly: No data >75 years; limited data >65. No dose adjustment required. Renal impairment: Mild/moderate: No dose adjustment required. Severe: Caution; some evidence of increased simeprevir exposure. Hepatic impairment: Mild/moderate: No dose adjustment required. Severe: significant increased simeprevir exposure; no dose recommendation. CONTRAINDICATIONS: Hypersensitivity to active substance or any excipient. SPECIAL WARNINGS & PRECAUTIONS: OLYSIO should not be used in patients with HCV genotypes 2, 3, 5 or 6. Check co-medication SmPCs before starting Olysio. Discontinue OLYSIO if co-medications discontinued. No data on use of OLYSIO in re-treating patients who have failed HCV NS3-4A protease inhibitor based therapy. Substantially reduced efficacy if hepatitis C genotype 1a with NS3 Q80K polymorphism at baseline, when in combination with peginterferon alfa and ribavirin; pre-treatment testing for Q80K is strongly recommended, also with sofosbuvir. Interferon-free regimens not investigated in phase 3 studies. Interferon free therapy with OLYSIO should only be used in patients who are intolerant to, or ineligible for, interferon therapy, and are in urgent need of treatment. No data with telaprevir or boceprevir; expected to be cross-resistant, therefore not recommended. Lower SVR12 rates/viral breakthrough/viral relapse more frequent with peginterferon alfa-2b/ ribavirin than peginterferon alfa-2a/ribavirin. Photosensitivity reactions: advise use of sun protective measures, avoid sun exposure/tanning devices, if photosensitivity reactions occur, consider discontinuation. Rash: monitor patients for progression; if severe, discontinue. Hepatic impairment: safety/efficacy not studied in moderate/severe hepatic impairment (Child-Pugh class B or C) or in decompensated patients; caution recommended. Lab tests: monitor HCV RNA levels at wks 4 and 12; refer to co-medication SmPCs. Hepatitis B Virus (HBV) co-infection and organ transplant patients: not studied. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. SIDE EFFECTS: Very common: dyspnoea, nausea, rash, pruritus. Common: constipation, blood bilirubin increased, photosensitivity reaction. PREGNANCY: If benefit justifies the risk. No human studies. Effective contraception required. Check co-medication SmPCs. LACTATION: Not known whether excreted in human milk. Check co-medication SmPCs, contraindications and warnings apply. INTERACTIONS: Moderate/strong inhibitors/inducers of CYP3A4 not recommended. OATP1B1 inhibitors (eg eltrombopag, gemfibrozil) may mildly increase simeprevir concentrations. Plasma concentrations of medicines which are substrates for OATP1B1 and P-gp transport may increase if co-administered. Not recommended: carbamazepine, oxcarbazepine, phenobarbital, phenytoin;

Once Daily

astemizole, terfenadine; systemic erythromycin, clarithromycin, telithromycin; systemic itraconazole, ketoconazole, posaconazole, fluconazole or voriconazole; rifampicin, rifabutin, rifapentine; systemic dexamethasone; cisapride; milk thistle (Silybum marianum), St John’s wort (Hypericum perforatum); efavirenz, other NNRTIs (elavirdine, etravirine, nevirapine); ritonavir, darunavir/ ritonavir, any HIV PI with/without ritonavir, cobicistat-containing products. Monitor levels: digoxin, ciclosporine, tacrolimus, sirolimus; warfarin (INR). Use lowest dose: rosuvastatin, pitavastatin, pravastatin, atorvastatin, simvastatin, lovastatin, sildenafil or tadalafil for pulmonary arterial hypertension. Caution/monitor: amiodarone, disopyramide, flecainide, mexiletine, propafenone, quinidine; oral amlodipine, bepridil, diltiazem, felodipine,nicardipine, nifedipine, nisoldipine, verapamil. Caution: oral midazolam or triazolam. Refer to SmPC for full details of interactions. LEGAL CATEGORY: Prescription only medicine. PRESENTATIONS, PACK SIZES, MARKETING AUTHORISATION NUMBER(S): OLYSIO 150mg capsules; 7 capsules (1 week); EU/1/14/924/001. MARKETING AUTHORISATION HOLDER: Janssen-Cilag International NV, Turnhoutseweg 30, B-2340 Beerse, Belgium. FURTHER INFORMATION IS AVAILABLE FROM: Janssen-Cilag Ltd, 50100 Holmers Farm Way, High Wycombe, Buckinghamshire HP12 4EG, UK. © Janssen-Cilag Ltd 2014 Adverse events should be reported. W This medicinal product is subject to additional monitoring and it is therefore important to report any suspected adverse events related to this medicinal product. 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: www.hpra.ie, E-mail: medsafety@hpra.ie. Adverse events should also be reported to Janssen-Cilag Ltd on +44 (0)1494 567447. Prescribing information last revised: May 2014 References: 1. OLYSIO Summary of product characteristics. Available at www.medicines.ie. 2. Jacobson I et al. AASLD, 2013. Poster 1122. 3. Forns X et al., Gastroenterology, 2014, epub. http://dx.doi.org/10.1053/j.gastro.2014.02.051. 4. Manns M, et al. HEPDART 2013. Poster 57. †

Triple therapy: OLYSIO, peg interferon and ribavirin. *SVR12 is deﬁned as undetectable HCV RNA 12 weeks after end of treatment. Week 4 on treatment virologic response is deﬁned as HCV RNA undetectable at week 4.

PHIR/NO/0714/0004 | Date of Preparation: August 2014

CONTENTS 35 ACUTE CORONARY SYNDROME The HSE National Clinical Programme for Acute Coronary Syndrome improves the standard of care for cardiac patients.

37 Cardiac Research: Equal effectiveness in two different carotid artery stenting procedures.

DR ÁINE CARROLL INTERVIEW Introducing integrated pathways of care to provide a more cohesive health service.

11 ASTHMA Prof Pat Manning on how the new national Model of Care for Asthma will improve patient care.

15 CANCER CARE Dr Jerome Kelly discusses why the extension of radiation oncology services in Cork and Galway are essential to cope with increasing demands.

19 Cancer Research: Exercise slows tumor growth and improves chemotherapy in mouse cancers.

Cancer Research: Personalised medicine for women with late stage ovarian cancer.

23 Cancer Research: Using ﬁreﬂy

39 Cardiac Research: Ancient herbal therapy can prevent and reverse hypertrophy in mice.

41 COPD

47 COPD Research: Outcomes of needbased lung transplantation system.

49 COPD Research: Familial transmission of COPD in adoptees.

51 CYSTIC FIBROSIS Prof Charles Gallagher outlines the six priorities of the National Clinical Programme for the treatment of cystic ﬁbrosis.

55 DERMATOLOGY

57 Dermatology Research: Personalised

melanoma vaccines treat unique mutations in patients’ tumours.

diagnostic aspirin use associated with lower risk of lymph node metastasis and reduced breast cancer speciﬁc mortality.

32 Cancer Research: Conservative management of lowrisk prostate cancer shows favourable survival rates.

2 | THE CLINICAL CARE JOURNAL

of the unfolded protein response in diabetes.

64 Diabetes Research: Gut immune system identiﬁed as a new and effective target in treating diabetes.

67 Diabetes Research: Increase in inﬂammation linked to high trafﬁc pollution for people on insulin.

recommendations for the directions of future COPD research.

of cause for tumor invasion in glioblastoma.

29 Cancer Research: Regular pre-

62 Diabetes Research: The role

45 COPD Research: New

24 Cancer Research: Discovery

Cancer Research: A molecule that irreversibly interferes with the activity of a common mutated cancer gene.

cell chromosomes and diabetes.

Prof Tim McDonnell explains how 12 new outreach centres have reduced hospital stays for COPD patients.

Dr Anne Marie Tobin leads a strategy to signiﬁcantly reduce waiting time and standardise care in dermatology services.

mechanism to study tumor response to therapy.

61 Diabetes Research: “Open” stem

69 CARE OF THE ELDERLY Dr Diarmaid O’Shea discusses the establishment of a specialist geriatric service (SGS) in each acute hospital as a model of best practice in the care and treatment of the older person.

73 Care of the Elderly Research: Changes in a blood-based molecular pathway identiﬁed in Alzheimer’s disease.

74 HOSPITAL ACQUIRED INFECTION Dr Fidelma Fitzpatrick discusses how focusing on three key areas – hand hygiene, antimicrobial stewardship and medical devices – has laid the foundation for a signiﬁcant reduction in HAIs.

79 HAEMODIALYSIS Dr Liam Plant discusses how the integrated clinical network of haemodialysis facilities is improving capacity, geographic spread and travel time for patients.

85 MENTAL HEALTH Dr Margo Wrigley outlines the importance of ensuring the reports and documents on the development of the mental health are implemented.

89 Mental Health Research:

119 RHEUMATOLOGY

Advances in technology allow investigation across the genome for involvement in schizophrenia.

Prof Oliver FitzGerald explains how the appointment of 24 musculo-skeletal physiotherapists has reduced orthopaedic and rheumatology waiting lists.

93 OBSTETRICS AND GYNAECOLOGY Prof Michael Turner discuss the positive impact that 30 national guidelines are having in obstetrics and gynaecology, and the further 20 guidelines that have been commissioned.

123 Rheumatology Research: A mosquito-borne virus causes RA like symptoms.

127 Rheumatology Research: BMI plays a role in sustained remission.

95 PAEDIATRICS AND NEONATOLOGY 107 Pain Management Research:

Prof Alf Nicholson outlines new strategies that have emerged following a major summit of paediatric healthcare personnel.

The relevance of co-ordination of care in pain management.

129 Rheumatology Research: Is there a conﬁned period in which RA is more susceptible to treatment?

109 Pain Management Research:

101 OPHTHALMOLOGY

Markovian models show promise for describing postoperative pain states.

Mr Paul Moriarty details the aim to provide patient care close to home for those with chronic eye disease.

111 Pain Management Research: Pain relief not sustained in patients treated with plateletrich plasma (PRP) injection for facet joint arthropathy.

113 PRIMARY CARE Minister for Health, Dr Leo Varadkar, plans to transfer the management of chronic disease from hospitals to the community in line with the proposed new model of primary care.

105 PALLIATIVE CARE

115 REHABILITATION

Dr Karen Ryan discusses the signiﬁcance of palliative care as an important core skill and competence for all healthcare staff in the health service.

Dr Jacinta Morgan outlines the need for a tertiary rehabilitation centre with six regional in-patient units to address the overwhelming demand for rehabilitation services.

132 STROKE Prof Peter Kelly looks at data showing a 7.5 per cent decrease in stroke deaths in the ﬁrst three years of the HSE National Clinical Programme for Stroke.

136 CLINICAL LEADS’ CONTACT DETAILS

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THE LATEST DEVELOPMENTS IN IRISH HEALTHCARE | 2015

BETTER PATIENT CARE INTEGRATED PATHWAYS OF CARE

A UNIFIED & INTEGRATED APPROACH

IMPROVING ACCESS TO CARE, STANDARDS & OUTCOMES

LOCALISED INITIATIVES

STRATEGIES

INTEGRATED FACILITIES

NEW SERVICES

REDUCED WAITING LISTS

PRIORITIES

PLANNING

Further information is available on request and in the OLYSIO summary of product characteristics. Available at www.medicines.ie

All articles ©2015/2016. No part of this may be reproduced, stored in a retrieval system or transmitted in any form or by any means without written permission from the publisher. Opinions and comments expressed herein are not necessarily those of Ashville Media Group. Readers should make their own independent evaluation of the information contained within this publication and make such other investigations as they consider necessary (including obtaining independent financial advice) before acting in reliance on this information.

THE CLINICAL CARE JOURNAL | 3

ADVERTORIAL

TODAY’S HEALTH CHALLENGES THREATEN THE SUSTAINABILITY OF HEALTHCARE SYSTEMS There is a dramatic shift in healthcare today. Life expectancy is increasing in countries around the globe. By 2050, the proportion of the world’s population over age 60 will double, increasing to more than two billion. At the same time, chronic diseases are on the rise, and many people will spend the later parts of their lives coping with one or more chronic conditions. This places a burden on the patient, on those around them, and on the healthcare systems that support them. THE IRISH CONTEXT As with health systems in other European countries, the Irish health system is facing a combination of complex and urgent challenges. Ireland has experienced the second biggest cut in healthcare funding in the OECD for the period 2009 to 2011 yet, at the same time, the average healthcare spend per capita is well above the OECD average, with a number of

international organisations pointing to continued and significant inefficiencies or excessive costs in the Irish healthcare system. This is a particular concern when one considers that Ireland has a younger population base than almost all of our OECD peers. More than 50% of people aged 50 and over in Ireland are living with two or more chronic conditions – multi-morbidity – such as

diabetes, stroke or coronary heart disease. Between 2005 and 2012 there has been a 45% increase in hospitalisation for chronic obstructive pulmonary disease and a 112% increase in hospitalisation for Type 2 diabetes. The proportion of older people in Ireland is expected to double by 2050, which will have a very significant impact on the cost of healthcare in the future.

Pascale Richetta (Vice President, Western Europe and Canada Operations, AbbVie), Mary Harney (Chair, European Steering Group), and Leo Kearns (HSE) reviewing the ‘Sustainable Healthcare for Ireland – A Journey of Innovation and Partnership’ Report

ADVERTORIAL

There is greater scrutiny being applied to how health services are being run and delivered as the Government and taxpayers demand a more efficient health system that delivers better outcomes for patients.

“…interventions are becoming more complex and require the development of new models of care…” In the context of an ageing population therapeutic interventions are becoming more complex and require the development of new models of care to put it on a more sustainable footing. A NEW APPROACH There is an acknowledgment that the way in which we think about and deliver healthcare has to change and this is reflected in the Irish government’s ambitious and radical change agenda. As solutions to these challenges are being sought, improvements in the provision of healthcare services often have their origins in industry and the private sector. The success or failure of these ground-breaking innovations can be determined by the capacity and willingness of any given health system to adopt it at a particular time. AbbVie believes that addressing the world’s toughest health challenges involves everyone. Pan-European strategies on healthy ageing, combined with more effective management of public resources at the national level, can make a difference. Pascale Richetta, Vice President, Western Europe and Canada Operations, AbbVie explains, “We believe industry has a key role to play in partnering and collaborating with the Department of Health, the HSE and other key stakeholders in the Irish health system to help develop new models of care, improve health outcomes, and enhance efficiency

in the utilisation of public health resources. We are committed to stimulating debate in this area and have engaged in a number of activities designed to achieve this including commissioning a report by the Economist Intelligence Unit entitled ‘Never Too Early’ in 2012 and hosting a very successful multistakeholder event in partnership with Philips and EUPHA in Brussels called ‘Recipes for Sustainable Healthcare’ in 2013.” “Key learnings from our work to date indicates that three pillars: Prevention and Early Intervention; Citizen Empowerment; and a Reorganisation of Delivery of Care. If embraced, these could extend healthy life years, improve outcomes for patients and society and ensure the sustainability of healthcare systems. ” BUILDING A HEALTHY FUTURE FOR EVERYONE IN IRELAND, TOGETHER Last November, AbbVie launched a report that included specific recommendations for the development of a sustainable health care system in Ireland. Sustainable Healthcare for Ireland - A Journey of Innovation and Partnership was produced by a steering group of leading experts from healthcare, education and industry, and proposes the creation of a national framework to identify, adopt and scale up the practical and effective solutions for sustainable healthcare that already exist within the Irish health care system.

“They illustrate a change in focus from curative and treatment paradigms towards wellness, self-management of health status and early intervention.” The report looks in detail at twelve relevant initiatives, which showcase examples of innovation and best practice in the Irish healthcare system. They illustrate a change in focus from curative and treatment paradigms towards wellness, self-management of health status and early intervention.

RECOMMENDATIONS The report demonstrates that innovation is clearly evident within the current system. If applied or scaled up to a system-level these initiatives could contribute to making healthcare more sustainable. The report makes the following three recommendations: 1. The creation of a new National Framework to harness public and private thinking on solutions for sustainable healthcare where the health system and industry can meet to identify actual challenges and problem and discuss potential practical solutions. 2. The creation of a mechanism where innovative ideas such as those included in the report can be recognised, quickly adopted, scaled up and implemented to maximise their system wide impact. 3. The creation of a formal system to monitor and assess the innovative ideas that have been adopted using relevant criteria and KPIs to measure their impact. In conclusion, Todd Manning, General Manager of AbbVie Ireland explains, “In contributing ideas and solutions for sustainable healthcare those of us in the private sector will be mindful of the priorities and challenges of the policy makers, health managers and clinicians who will be responsible for their implementation. It is our hope that at the same time the health service will consider how it can engage positively with industry as the economic dimensions of cost savings, improved efficiencies, revenue generation and job creation from such partnerships cannot be ignored.” Sustainable Healthcare for Ireland – A Journey of Innovation and Partnership forms part of a pan-European white paper commissioned by AbbVie to look at concrete and practical solutions to the challenges facing health systems in 19 European countries. The panEuropean report will be available in March 2015. For more information, please email orla.kinsella@abbvie .com

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LEADERSHIP

NEW INTEGRATED PATHWAYS OF CARE TO BE INTRODUCED The HSE National Clinical Care Programmes are moving to introduce innovative new integrated pathways of care which will work across the Hospital Groups and Community Healthcare Organisations, according to Dr. Aine Carroll, National Director of Clinical Strategy & Programmes. Maureen Browne reports.

he HSE National Clinical Care Programmes are moving to introduce innovative new integrated pathways of care which will work across the Hospital Groups and Community Healthcare Organisations, according to Dr. Aine Carroll, National Director of Clinical Strategy & Programmes. She said five new integrated care programmes were being identified with priority workstreams, the first of which is the integrated care pathway for older people. These are: • Patient Flow • Older persons • Chronic Disease prevention and management • Children’s Health • Maternal Health “Older persons are the absolute priority for 2015 and into next year and the

We are currently providing our services as if patients were dependent on us. We need to flip this idea on its head.

aim of the programme is that it will enable older people to access more appropriate care more rapidly and enable many who would otherwise go into long term care remain in their own homes. “Integrated care means different things to different people. At present, if you take older people with two or more chronic conditions who get ill after hours the default position is to call 999 and they are taken to the hospital Emergency Department where they may have to lie on trolleys for hours. They may not remember their allergies or their medication and if they are admitted on a Friday

they will be there for the weekend. The likely outcome is that they may end up going into long term care unnecessarily. “Rather than having hospital or primary care centred care, we need to move to a person centred model of care, where people who ﬁnd themselves ill and in need of attention will have access to a health professional who can be contacted, who knows their needs and can appropriately signpost the best way of taking care of these particular needs. “Our plan will involve the appointment of care co-ordinators who will work between hospitals and the

THE CLINICAL CARE JOURNAL | 7

LEADERSHIP

community and co-ordinate patients’ needs, whether they are hospital, primary care or community based. We need a proper team approach by a fully co-ordinated multi disciplinary team with the patient at the centre. “These co-ordinators will identify particular patient cohorts at risk of being admitted, using risk stratification. “We plan to map out available services, with clear signposts on how they can be accessed by people who need them and we hope that ultimately this will be nationally available. “We will develop integrated pathway of care and develop guidance for the management of multimorbidity with Finance, HR and ICT acting as key enablers of this initiative. “We also want to encourage patients in this cohort and indeed all older people to make plans with their families for their care as their needs change rather than being forced to make decisions at times of crisis.” “We have a number of chronic disease demonstrator projects up and running and there is an integrated care pathway for older people in development. A number of workstreams will feed into the integrated care programme for patient flows, starting with older people this year.” The current 33 HSE National Clinical Programmes and the nine supporting initiatives are to be re-organised to align and integrate with the five service divisions - Health & Well Being, Social Care, Mental Health, Acute Hospitals and Primary Care. “When the Clinical Programmes were established they were about improving quality access and the cost of services, all very worthy objectives. They developed quickly from a small number to the current 33 Programmes and nine supporting initiatives and have achieved a huge amount,” said Dr. Carroll. “The Acute Medicine and Surgery Programmes have done wonderful work in reducing the length of hospital stay and the Stroke Programme has resulted in Ireland moving from having one of the worst to one of the best thrombolysis rates in Europe.” She said the TCD Resilience Study had revealed that the health system was able to cope with cuts made to the health budget and what was effectively a staff moratorium because of the work of the clinical programmes and other initiatives. “We should be very proud of our clinicians and of my managerial colleagues who were will-

8 | THE CLINICAL CARE JOURNAL

We also want to encourage patients in this cohort and indeed all older people to make plans with their families for their care as their needs change rather than being forced to make decisions at times of crisis.

ing to go the extra mile despite the strains of cutbacks and moratoriums. “When I took over as National Director from Dr. Barry White, we realised we needed to align and integrate the programmes more and take the innovative outputs from the Clinical Programmes and manage them in a more co-ordinated approach. “We identified a number of challenges – there was a disconnect between the clinical strategy and the operational side of the organisation and there were challenges with finances, HR and ICT. Another issue which came up were that people were fatigued with all the changes in the system. In the next phase we knew we had to be much more aligned with the operational side of the Programmes and the priorities of the Programme should be aligned with the service priorities. “We had planned to group Programmes and appoint Group Leads, but that would not have fitted in with the new Directorate structures. The new Directorate structure offered the potential for creating five new groups of programmes. I worked with my national director colleagues to identify the key challenges nationally and internationally. They are mainly demographic pressures - patient flow, chronic disease prevention and management and older people. We also needed to look at children and maternity services. “We got agreement from the HSE Leadership team that implementing integrated care programmes for these groups would be our priority and we have been working at developing an operating model for integrated care programmes which would be aligned with the work of the different divisions and supported by finance, HR and ICT. “We have appointed five National Clinical Advisers and Group Leads – Dr. Orlaith O’Reilly for Health & Well Being, Dr. Siobhan Kennelly for Social Care, Dr. Margo Wrigley for Mental Health, Dr. Colm Henry for Acute Hospitals and most recently Dr. David Hanlon for Primary Care. The appointment of the primary care lead is a most

welcome development as integrated care cannot happen without primary care.” Each of the Programmes will have a Senior Programme Manager and an Executive Chair who will be individually extremely experienced in working across the system. “Within these integrated Programmes we have identified priority work streams which are co-sponsored between my Division and the service divisions. “A really critically important part of this work is a real emphasis on disease prevention and health and well being. We need to be making sure that we are keeping the citizens of this country well, fit and healthy and hopefully not needing to access services of any kind or putting off as long as possible the time when they need to access such services. We need to support the work of the Health & Well Being Division and we are fortunate in having policy support through Healthy Ireland.” Dr. Carroll said that the new initiatives (which were part of the reform projects under Leo Kearns’ team) would establish how services could work in an integrated manner across Community Health Organisations and Hospital Groups. It would also trial how integrated models of care could be supported through financial, HR and ICT modelling.” Dr. Carroll has strong views on how health providers are perceived as providing services. “It is not helpful for us or indeed our patients if we are seen as playing on different teams. We are currently providing our services as if patients were dependent on us. We need to flip this idea on its head. It is service providers who are dependent on patients because as service providers if we had no patients we would have no jobs. In industry it is said ‘the customer is always right’ and it should be the same in healthcare.”

DR AINE CARROLL, National Director of Clinical Strategy & Programmes.

In mHRPC after docetaxel . . .

SURVIVAL IN A DIFFERENT LIGHT Introducing JEVTANA®, a next generation taxane for the treatment of second-line mHRPC

JEVTANA® in combination with prednisone or prednisolone is indicated for the treatment of patients with mHRPC previously treated with a docetaxelcontaining treatment regimen. mHRPC=hormone-refractory metastatic prostate cancer.

Jevtana® (cabazitaxel) Prescribing Information Presentation: Vial containing 60mg cabazitaxel, with an accompanying vial of solvent. After dilution with the solvent, 1ml of solution contains 10mg cabazitaxel. Indications: Treatment, in combination with prednisone or prednisolone, of hormone refractory metastatic prostate cancer previously treated with a docetaxelcontaining regimen. Dosage and Administration: Use of Jevtana should be conﬁned to units specialising in the administration of cytotoxics and supervised by experienced anti-cancer chemotherapy specialists. Jevtana is administered as a 1 hour intravenous infusion every 3 weeks in combination with oral prednisone or prednisolone 10 mg administered daily throughout treatment. The recommended dose of Jevtana is 25 mg/m2. Pre-medication with the following intravenous medicinal products: anti-histamine (dexchlorpheniramine 5 mg or diphenhydramine 25 mg or equivalent), corticosteroid (dexamethasone 8 mg or equivalent), and H2 antagonist (ranitidine or equivalent) should be given at least 30 minutes prior to each administration of Jevtana. Anti-emetic prophylaxis is recommended and can be given orally or intravenously as needed. Elderly: No speciﬁc dose adjustment for the use of cabazitaxel in elderly patients is recommended Children: Not recommended. Hepatic impairment: see contraindications. Contraindications: Hypersensitivity to the active substance or excipients, baseline neutrophil count of <1,500 cells/mm3, liver impairment (bilirubin ≥ ULN, or AST and/or ALT ≥1.5 × ULN), concomitant vaccination with yellow fever vaccine.

in patients with haemoglobin <10 g/dl and appropriate measures taken as clinically indicated. Solvent contains 96% (15% v/v) ethanol which should be taken into account in high-risk groups such as patients with liver disease, or epilepsy. Gastrointestinal haemorrhage and perforation, ileus, colitis, including fatal outcome, have been reported. Caution is advised in patients most at risk: those with neutropenia, the elderly, concomitant use of NSAIDs, anti-platelet therapy or anti-coagulants, history of pelvic radiotherapy or gastrointestinal disease. Interactions: Avoid co-administration with strong CYP3A4 inhibitors as they may increase the plasma concentrations of cabazitaxel. Avoid co-administration with strong CYP3A4 inducers as they may lead to decreased plasma concentrations of cabazitaxel. There is a possible risk of interaction with OATP1B1 substrates (e.g. statins, valsartan, repaglinide). A time interval of 12 hours is recommended before the infusion and at least 3 hours after the end of infusion before administering the OATP1B1 substrates. Vaccination with a live attenuated vaccine should be avoided in patients receiving cabazitaxel. Response to killed or inactivated vaccines may be diminished. Pregnancy and Lactation: Cabazitaxel is not recommended during pregnancy and in women of childbearing potential not using contraception. Cabazitaxel should not be used during breast-feeding.

Please read section 6.6 of the Jevtana Summary of Product Characteristics (SPC) before mixing and diluting. Jevtana requires TWO dilutions prior to administration.

Adverse Reactions: Infections and infestations; Septic shock, sepsis, cellulitis, urinary tract infection, cystitis, upper respiratory tract infection, herpes zoster, candidiasis. Blood and the lymphatic system; Neutropenia, anaemia, infections (including sepsis and pneumonia), febrile neutropenia, thrombocytopenia, neutropenic sepsis. Skin and subcutaneous tissue; Alopecia, erythema, dry skin. Gastrointestinal; Diarrhoea, nausea, vomiting, constipation, abdominal pain, abdominal pain upper, abdominal distension, dyspepsia, gastroesophageal reﬂux disease, dry mouth, haemorrhoids, rectal haemorrhage, Colitis, enterocolitis, gastritis, neutropenic enterocolitis, gastrointestinal haemorrhage and perforation, ileus and intestinal obstruction. Nervous system; Peripheral sensory or motor neuropathy, paraesthesia, hyposaesthesia, dysgeusia,

Precautions and Warnings: Patients should be observed

closely for hypersensitivity reactions. Full blood counts must be monitored on a weekly basis during cycle 1 and before each cycle thereafter. Reduce dosage with: febrile neutropenia or neutropenic infection, Grade ≥ 3 neutropenia for more than one week (despite G-CSF use), Grade ≥ 2 peripheral neuropathy, Grade ≥ 3 diarrhoea or persisting diarrhoea. Ensure adequate hydration throughout treatment to prevent complications such as renal failure. Discontinue treatment in cases of renal failure ≥ Grade 3 (CTCAE 4.0). Caution recommended

For full information on Adverse Events please consult the Jevtana Summary of Product Characteristics.

dizziness, headache, lethargy, sciatica. Cardiac, vascular; Atrial fibrillation, tachycardia, hypotension (including orthostatic), deep vein thrombosis, flushing, hot flushes. Metabolism and nutrition; Anorexia, dehydration, hyperglycaemia, hypokalaemia. Eye; Increased lacrimation, conjunctivitis. Ear and labyrinth; Tinnitus, vertigo. Psychiatric; Anxiety, confusional state. Musculoskeletal, connective tissue and bone; Myalgia, arthralgia, pain in extremities, back pain, flank pain, musculoskeletal chest pain, muscle spasms. Respiratory, thoracic and mediastinal; Dyspneoa, cough, pneumonia, oropharyngeal pain. Renal and urinary disorders; Renal failure (including acute), dysuria, renal colic, haematuria, pollakiura, hydronephrosis, urinary retention, urinary incontinence, ureteric obstruction. Reproductive system and breast; Pelvic pain. General disorders and administration site reactions; Asthenia, fatigue, pyrexia, peripheral oedema, mucosal inflammation, pain, chest pain, oedema, chills, malaise. Immune system disorders and injury; Hypersensitivity reactions. Investigations; Weight decreased, elevated AST and transaminases. Legal Category: POM. Marketing Authorisation Number: EU/1/11/676/001. Marketing Authorisation Holder: sanofi-aventis groupe, 54, rue La Boetie, F-75008 Paris, France. Further information is available from: Sanofi 18 Riverwalk, Citywest Business

Campus, Dublin 24 or contact IEmedinfo@sanoﬁ.com Tel.: (01) 4035600. Please refer to the Summary of Product Characteristics which can be found on IPHA @ http://www.medicines. ie/ before prescribing. Information about adverse event reporting can be found at www.imb.ie Adverse events should be reported to the Sanoﬁ Drug Safety Department Date of Revision: March 2014

IE.CAB.14.03.02

Date of preparation: April 2014

IE.CAB.14.04.01

COMBINATION 50/5 μg 125/5 μg 250/10 μg

Rapid onset* and long lasting efficacy**

Asthma maintenance treatment

INNOVATION

Modern aerosol device with a patient-facing dose counter1 * Open label study, significant increase in FEV1 5 mins after dosing (p=o.oo1) (Aalbers et al: Onset of Bronchodilation with fluticasone/formoterol combination versus fluticasone/salmeterol in an open-label, randomised study; Adv Ther 2012) ** 6-12 month open label study, significant improvement in spirometric secondary endpoints vs baseline (Mansur et al, Long Term Safety and Efficacy of fluticasone/formoterol combination therapy in Asthma; JAMP -Vol 25, No0, 2012 p1-10)

ﬂutiform is indicated for the regular treatment of asthma in adults and adolescents (12 years and over), where use of a combination product (inhaled corticosteroid [ICS] and long-acting ß2-agonist [LABA]) is appropriate. ﬂutiform 250/10μg indicated in adults only.

fluticasone propionate/formoterol

ASTHMA

NATIONAL MODEL OF CARE FOR

ASTHMA TO BE PUBLISHED

Ireland has one of the highest rates of asthma in the world and a new National Model of Care for Asthma will set out a treatment plan for this common disease, according to Prof Pat Manning, Consultant Respiratory Physician and National Clinical Lead for the Programme. Maureen Browne reports.

he National Model of Care for Asthma developed by the HSE National Clinical Programme for Asthma has now been approved by the HSE Leadership Team and will be published shortly, according to Prof Pat Manning, Consultant Respiratory Physician and National Clinical Lead for the Programme. The majority of patients with asthma are managed at primary care level and the Model of Care sets out the care and treatment plan for patients with asthma through primary care and secondary care if needed, with a referral back again to primary care for ongoing management.

It clearly establishes how doctors, nurses and other health professionals can work effectively with engaged patients to make the clinical decisions most appropriate to their circumstances and to collaborate with specialist colleagues in providing a safe, seamless experience throughout their patient journey. The National Clinical Programme for Asthma is looking forward to the outcome of the contractual discussions between the HSE and GPs. As asthma is such a common disease and the Model of Care for Asthma is already developed, Prof Manning hopes that asthma will be one of the earlier chronic diseases to be taken on

board under the new arrangements. It is estimated that asthma affects one in ďŹ ve of the childhood population and is the most common chronic respiratory disease in the Republic of Ireland, affecting people of all ages and all socioeconomic groups. Ireland has the fourthhighest prevalence of asthma worldwide, and current estimates suggest that there are approximately 450,000 people with doctor-diagnosed asthma in Ireland (over one in eight of the population). Asthma is often under-diagnosed and uncontrolled, creating a substantial burden of ill-health on individuals as well as the healthcare system. Between 35 and 50 per cent of medical expen-

THE CLINICAL CARE JOURNAL | 11

ASTHMA

diture for asthma is as a consequence of exacerbations (an asthma outcome that is viewed as representing treatment failure).

NATIONAL ASTHMA GUIDELINES Prof Manning says that the initial focus of the work of the National Clinical Programme for Asthma to date was on the development and implementation of National Asthma Guidelines based on international best practice both for acute care and ongoing asthma management. The Emergency Adult Asthma Guidelines, which were ﬁrst published in November 2011, have now been revised and submitted to the National Clinical Effectiveness Committee and it is hoped to have approval and publication in the ﬁrst quarter of 2015. Emergency Paediatric Asthma Guidelines have also been developed and are available on www.hse.ie. Asthma Control in General Practice (guidelines for managing a patient with asthma in primary care) has been developed and approved by the ICGP. These guidelines were updated in May 2013 and are available on www.icgp.ie.

The majority of patients with asthma are managed at primary care level.

In collaboration with the ICGP, an educational programme for practice nurses has been developed around these asthma guidelines. The educational programme is delivered by HSE nurse specialists. Prof Manning went on to say that “almost 140 practice nurses have completed the programme and we would like to see more nurses doing the course next year. It will be particularly important when the National Model of Care is implemented, as much of it relates to primary care. “We are also training hospital nurses working in emergency departments, wards and medical assessment units with a focus on acute asthma management, peak ﬂow readings and inhaler technique. This practical, structured course is also available free of charge for practice nurses as well as hospital nurses, which means that the

12 | THE CLINICAL CARE JOURNAL

person receives the same asthma advice regardless of where they present acutely. “The focus for 2015 will be around supporting the implementation of the Model of Care in line with the national service plan commitment, while also planning initiatives for working with engaged patients to help them improve their self-care. This will require ongoing collaboration with specialist colleagues to streamline processes and pathways to improve the healthcare experience for our patients,” says Prof Manning.

Between

30-50%

of medical expenditure for asthma is as a consequence of exacerbations.

LEARNING PROGRAMME For any healthcare professional who wishes to update their knowledge, there is a self-learning asthma e-learning theoretical programme, which has six modules for completion. This learning programme is based on evidence-based national guidelines and developed by the National Clinical Programme for Asthma in conjunction with the Asthma Society of Ireland (ASI) and is freely available on www. hseland.ie and www.asthmasociety.ie. The vision of the National Clinical Programme for Asthma is that every child and every adult with asthma in Ireland should reach their maximal health and quality-of-life potential through the prevention, early detection and effective treatment of asthma. The aims of the programme are to maximise the health and quality of life of people with asthma and to prevent avoidable mortality due to asthma. The programme aims to see all patients diagnosed with asthma enrolled in a structured asthma programme that includes elements such as education about asthma, personal trigger factors and

medication, assessment of control, inhaler device and technique and smoking cessation/exposure to second-hand smoke. Prof Manning says that it is planned that all patients would receive guideline concordant care based upon level of control, to maximise the proportion of patients with asthma whose asthma was controlled and to reduce asthma mortality by 90 per cent over a 10-year period (2013-2023). It is hoped that over the next three years the work of the programme would see a reduction by 10 per cent (5,000 visits) in GP out-of-hours visits due to asthma and a reduced number of ED visits due to asthma by 10 per cent (2,000), while also reducing the number of asthma inpatient bed days by 10 per cent per year. PROF PAT MANNING is Consultant Respiratory Physician and National Clinical Lead for the National Programme for Asthma. For more information on the National Clinical Programme for Asthma visit www.hse.ie/asthma.

For patients with non-squamous NSCLC* JVU[PU\L Ă&#x201E;YZ[ SPUL [V

,_[LUK :\Y]P]HS ^P[OV\[ JVTWYVTPZPUN [VSLYHIPSP[` ESTABLISH SURVIVAL.

â&#x20AC;

Alimta/cisplatin followed by Alimta showed prolonged overall survival ZLWKRXW VLJQLĂ&#x20AC;FDQWO\ ZRUVHQLQJ WROHUDELOLW\ FRPSDUHG WR $OLPWD FLVSODWLQ IROORZHG E\ SODFHER Y PRQWKV IURP LQGXFWLRQ S 1 $GHQRFDUFLQRPD ODUJH FHOO FDUFLQRPD DQG RWKHU KLVWRORJLHV

ALIMTA* (PEMETREXED DISODIUM) REPUBLIC OF IRELAND ABBREVIATED PRESCRIBING INFORMATION. Presentation Type I glass vials with rubber stoppers containing pemetrexed disodium equivalent to 100 and 500mg of pemetrexed, as a sterile white to either light yellow or green-yellow lyophilised powder. Uses Alimta in combination with cisplatin is indicated for the treatment of chemotherapy naive patients with unresectable malignant pleural mesothelioma. Alimta in combination with cisplatin is indicated for ďŹ rst-line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology. Alimta is indicated as monotherapy for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer, other than predominantly squamous cell histology, in patients whose disease has not progressed immediately following platinum-based chemotherapy. Alimta is indicated as monotherapy for the second-line treatment of patients with locally advanced or metastatic non-small cell lung cancer, other than predominantly squamous cell histology. Dosage and Administration Posology: The drug is to be administered intravenously, under the supervision of a physician qualiďŹ ed in the use of cytotoxic anti-cancer therapy. Alimta in combination with cisplatin: The recommended dose of pemetrexed is 500mg/mÂ˛ of body surface area (BSA), given by ten-minute infusion, on day 1 of each 21-day cycle. The recommended dose of cisplatin is 75mg/mÂ˛ BSA, given by two-hour infusion, approximately 30 minutes after completion of the pemetrexed infusion on day 1 of each cycle. Adequate anti-emetic treatment and hydration for cisplatin treatment must be given. Alimta as single agent: The recommended dose of pemetrexed is 500mg/mÂ˛ BSA, given by ten-minute infusion, on day 1 of each 21-day cycle. Pre-medication: Supplement with 1000 micrograms intramuscular vitamin B12 and oral folic acid (350 to 1000 micrograms) to reduce toxicity (for full details see Summary of Product Characteristics [SPC]). To reduce the incidence and severity of skin reactions, a corticosteroid should be given the day prior to, on the day of, and the day after pemetrexed administration - this should be equivalent to 4mg of dexamethasone administered orally twice a day. Monitoring: Monitor prior to each dose for complete blood cell count, including a differential white cell count and platelet count. Absolute neutrophil count should be *1,500 cells/ mm3 and platelets *100,000 cells/mm3. Prior to each dose, collect blood chemistry tests to evaluate renal and hepatic function. Dose adjustments to pemetrexed and/or cisplatin at the start of a subsequent cycle should be based on nadir haematological counts or maximum nonhaematological toxicity. If necessary, delay or withhold treatment in the presence of haematological toxicity, neurotoxicity, and/or impaired hepatic/renal function. (For full information on dose modiďŹ cation see SPC.) Paediatric population: There is no relevant use of Alimta in the paediatric population in malignant pleural mesothelioma and non-small cell lung cancer. Renal impairment: Patients with creatinine clearance *45ml/min require no dose adjustment other than those recommended for all patients. Use in patients with creatinine clearance below 45ml/min is not recommended. See also â&#x20AC;&#x2DC;Warnings and Special Precautionsâ&#x20AC;&#x2122;. Hepatic impairment: Patients with hepatic impairment, such as bilirubin >1.5-times the upper limit of normal and/or aminotransferase >3.0-times the upper limit of normal (hepatic metastases absent) or >5.0-times the upper limit of normal (hepatic metastases present), have not been speciďŹ cally studied. Method of administration: Precautions should be taken before handling or administering Alimta. Alimta should be administered as an intravenous infusion over 10 minutes on the ďŹ rst day of each 21-day cycle. For instructions on reconstitution and dilution of Alimta before administration, see SPC. Contra-indications Hypersensitivity to pemetrexed or to any of the excipients. Concomitant yellow fever vaccine. Breast-feeding. Warnings and Special Precautions Myelosuppression is usually the dose-limiting toxicity. All patients must be instructed to take folic acid and vitamin B12 as a prophylactic measure. Pre-treatment with dexamethasone (or equivalent) can reduce the incidence and severity of skin reactions. Serious renal events, including acute renal failure, have been reported with pemetrexed alone or in combination with other chemotherapeutic agents. Many of the patients in whom these occurred had underlying risk factors, including dehydration or pre-existing hypertension or diabetes. The effect of third space ďŹ&#x201A;uid, such as pleural effusion or ascites, on pemetrexed is not fully deďŹ ned. A Phase 2 study of pemetrexed in 31 solid tumour patients with stable third space ďŹ&#x201A;uid demonstrated no difference in pemetrexed dose normalised plasma concentrations or clearance compared to patients without third space ďŹ&#x201A;uid collections. Thus, drainage of third space ďŹ&#x201A;uid collection prior to pemetrexed treatment should be considered, but may not be necessary. Serious cardiovascular events, including myocardial infarction and cerebrovascular events, have been uncommonly reported when pemetrexed is given in combination with other cytotoxic agents; most of these patients had pre-existing cardiovascular risk. Concomitant use of live attenuated vaccines is not recommended. Radiation pneumonitis has been reported in patients treated with radiation either prior, during, or subsequent to pemetrexed therapy. Pay particular attention to these patients and exercise caution with use of other radiosensitising agents. Radiation recall has been reported in patients who received radiotherapy weeks or years previously. Interactions Concomitant administration of nephrotoxic drugs and substances that are also tubularly secreted could potentially result in delayed clearance of pemetrexed. If necessary, creatinine clearance should be closely monitored. Patients must avoid taking non-steroidal anti-inďŹ&#x201A;ammatory drugs (NSAIDs) with long elimination half-lives for at least 5 days prior to, on the day, and at least 2 days following pemetrexed administration. If concomitant administration of NSAIDs is necessary, patients should be monitored closely for toxicity, especially myelosuppression and gastro-intestinal toxicity. In patients with normal renal function (creatinine clearance *80ml/min), high doses of NSAIDs (such as ibuprofen >1600mg/day) and aspirin at higher dosage (*1.3g daily) may decrease pemetrexed elimination and increase the occurrence of adverse events. Patients with mild to moderate renal insufďŹ ciency (creatinine clearance from 49 to 79ml/min) should avoid taking NSAIDs (eg, ibuprofen) or aspirin at higher

MAINTAIN CONTROL.

dosage, for 2 days before, on the day of, and 2 days following pemetrexed administration. In patients with mild to moderate renal insufďŹ ciency eligible for pemetrexed therapy, NSAIDs with long elimination half-lives should be interrupted for at least 5 days prior to, on the day of, and at least 2 days following pemetrexed administration. There is a possible interaction between oral anticoagulants and pemetrexed; therefore, increase the frequency of International Normalised Ratio (INR) monitoring if treating with oral anticoagulants. Fertility, Pregnancy, and Lactation Contraception in males and females: Women of childbearing potential must use effective contraception during treatment with pemetrexed. Pemetrexed can have genetically damaging effects. Sexually mature males are advised not to father a child during the treatment and up to 6 months thereafter. Contraceptive measures or abstinence are recommended. Pregnancy: There are no data from the use of pemetrexed in pregnant women but pemetrexed, like other antimetabolites, is suspected to cause serious birth defects when administered during pregnancy. Animal studies have shown reproductive toxicity. Pemetrexed should not be used during pregnancy unless clearly necessary, after a careful consideration of the needs of the mother and the risk for the foetus. Breastfeeding: It is not known whether pemetrexed is excreted in human milk and adverse reactions on the suckling child cannot be excluded. Breast-feeding must be discontinued during pemetrexed therapy. Fertility: Owing to the possibility of pemetrexed treatment causing irreversible infertility, men are advised to seek counselling on sperm storage before starting treatment. Driving, etc It has been reported that pemetrexed may cause fatigue. Patients should be cautioned against driving or operating machinery. Undesirable Effects Summary of the safety proďŹ le: The most commonly reported undesirable effects related to pemetrexed, whether used as monotherapy or in combination, are bone marrow suppression, manifested as anaemia, neutropenia, leucopenia, and thrombocytopenia; and gastro-intestinal toxicities, manifested as anorexia, nausea, vomiting, diarrhoea, constipation, pharyngitis, mucositis, and stomatitis. Other undesirable effects include renal toxicities, increased aminotransferases, alopecia, fatigue, dehydration, rash, infection/sepsis, and neuropathy. Rarely seen events include Stevens-Johnson syndrome and toxic epidermal necrolysis. Rare cases of anaphylactic shock have been reported. Infections and infestations: Common: Infection. Haematological: Very common: Anaemia, leucopenia, thrombocytopenia, neutropenia. Common: Febrile neutropenia and infection without neutropenia. Uncommon: Pancytopenia. Rarely, haemolytic anaemia has been reported in patients treated with pemetrexed. Gastro-intestinal: Very common: Nausea, vomiting, stomatitis/pharyngitis, anorexia, diarrhoea, constipation. Common: Dyspepsia, abdominal pain, heartburn. Uncommon: Colitis (including bleeding, sometimes fatal, intestinal perforation, intestinal necrosis, and typhlitis). Oesophagitis/radiation oesophagitis has been reported during trials. General: Very common: Fatigue. Common: Fever, conjunctivitis, pain, oedema. Metabolism and nutrition: Common: Dehydration. Nervous system: Very common: Neuropathy - sensory. Common: Neuropathy - motor, dizziness, taste disturbance. Renal and urinary: Very common: Creatinine elevation, creatinine clearance decreased. Common: Renal failure, renal disorders. Hepatobiliary: Common: SGPT (ALT) elevation and SGOT (AST) elevation, increased GGT. Rare: Cases of hepatitis, potentially serious, have been reported during trials. Skin and subcutaneous tissue: Very common: Rash/desquamation, alopecia. Common: Urticaria, allergic reaction/ hypersensitivity, erythema multiforme, pruritus. Rare: Radiation recall; bullous conditions have been reported, including Stevens-Johnson syndrome and toxic epidermal necrolysis, which in some cases were fatal. Uncommon: Cases of peripheral ischaemia, leading sometimes to extremity necrosis, have been reported. Cardiovascular and cerebrovascular: Uncommon: Myocardial infarction, angina pectoris, cerebrovascular accident, supraventricular arrhythmias, transient ischaemic attack, pulmonary embolism. (Usually when given in combination with other cytotoxic agents and with pre-existing cardiovascular risk.) Common: Chest pain. Respiratory: Uncommon: Interstitial pneumonitis with respiratory insufďŹ ciency (sometimes fatal), radiation pneumonitis. For full details of these and other side-effects, please see the Summary of Product Characteristics, which is available at http://www.medicines.ie/. Legal Category POM Marketing Authorisation Numbers and Holder EU/1/04/290/001, EU/1/04/290/002 Eli Lilly Nederland BV, Grootslag 1-5, NL-3991 RA Houten, The Netherlands. Date of Preparation or Last Review November 2012 Full Prescribing Information is Available From Eli Lilly and Company Limited, Lilly House, Priestley Road, Basingstoke, Hampshire, RG24 9NL. Telephone: Basingstoke (01256) 315 000 E-mail: ukmedinfo@lilly.com or Eli Lilly and Company (Ireland) Limited Hyde House, 65 Adelaide Road, Dublin 2, Republic of Ireland. Telephone: Dublin (01) 661 4377 E-mail: ukmedinfo@lilly.com. ALIMTAÂŽ (pemetrexed disodium) is a registered trademark of Eli Lilly and Company. Reference: 1. Paz-Ares LG et al. PARAMOUNT: Final Overall Survival Results. Phase III Study of Maintenance Pemetrexed plus Best Supportive Care (BSC) versus Placebo plus BSC Immediately Following Induction with Pemetrexed plus Cisplatin for Advanced Nonsquamous NSCLC. Presented at American Society of Clinical Oncology Annual Meeting, June 1-5 2012, Chicago, IL (oral presentation slide set). Adverse events and product complaints should be reported. To report an adverse event or a product complaint about a Lilly medicine, please call Lilly on: 01 664 0446. Adverse events and product complaints may also be reported to the Irish Medicines Board. Reporting forms and information can be found at www.imb.ie then click â&#x20AC;&#x153;Online Reportingâ&#x20AC;?. 0,(34 I 1\UL

Doing Now What Patients Need Next

We take cancer personally

Patients are at the heart of everything we do at Roche. They motivate and inspire us to produce innovative medicines and therapeutic solutions that will continue to transform the lives of people with cancer around the globe. Weâ&#x20AC;&#x2122;ve come a long way, but thereâ&#x20AC;&#x2122;s still a long way to go. Fortunately, no one takes cancer more personally than we do.

P06/11/13

ONCOLOGY

NEW

RADIATION ONCOLOGY TREATMENT CENTRES FOR CORK AND GALWAY

Two new state-of-the-art radiation oncology treatment centres are being built, in Cork and Galway. When complete, they will play their part in an “excellent national network of facilities,” Dr. Jerome Coffey, newly appointed interim Director of the HSE National Cancer Control Programme tells Maureen Browne.

he HSE National Cancer Control Programme (NCCP) has started work on the provision of two new state-of-the-art radiation oncology treatment centres in Cork and Galway, which will signiﬁcantly increase treatment capacity for patients from in those regions, according to Dr. Jerome Coffey, newly appointed interim Director of the NCCP. “We have made progress with the big infrastructure projects in Cork and Galway. To build the new radiation oncology unit in Cork necessitated the transfer of a staff carpark and building a new adult mental health unit, which was handed over in December 2014. The

project team takes over the site of the old mental health unit for preparatory work early in 2015 and we should go to tender for construction and equipping of the new radiation oncology unit later in the year, with a view to commissioning the new equipment in 2017 or 2018. Construction will take 12 to 18 months and will provide ﬁve new linear accelerators in comparison with the current four units. Galway has three machines and this will be increased to a minimum of four in the new facility, with one-two shelled bunkers for future expansion of treatment capacity. “Cancer incidence is increasing and we need to get the new centres operational before demand for radiation

therapy exceeds current capacity in the system. When the Galway and Cork centres are opened, with the existing centres in the St. Luke’s Radiation Oncology Network in Dublin, we will have an excellent national network of facilities with state-of-the-art technology for treatment planning and delivery.”

TALKING STRATEGY Dr. Coffey says that the NCCP has completed an internal report on the implementation of the National Cancer Strategy, published in 2006, and it is planned to invite the minister to launch this. “We are also looking at refreshing the cancer strategy in 2015. During 2014, as in previous years we have contin-

THE CLINICAL CARE JOURNAL | 15

ONCOLOGY

Beyond that, we are working on survivorship as a relatively new theme, in partnership with the Irish Cancer Society.

ued to centralise surgical oncology in the designated cancer centres. Moving beyond the more common solid tumours we recently participated in the inaugural meeting of the Irish Sarcoma Group. Initiated by Dr. Charles Gillham, my colleague in the St. Luke’s Network, this international meeting brought together clinical staff from Ireland, the UK, Germany and Italy to discuss the optimal approach to the management of rare soft tissue and bone sarcomas. “The NCCP is working with the NET (neuro-endocrine tumour) Patient Network (http://netpatientnetwork. ie) on co-ordination of care for these patients with rare tumours. These patients receive routine care in Ireland but a signiﬁcant proportion goes to Uppsala in Sweden for peptide receptor radionuclide therapy. St. Vincent’s has been designated by the NCCP as the national centre for neuro-endocrine tumours under the leadership of consultant gastroenterologist Professor Dermot O’Toole. “The NCCP has put considerable work into community oncology, working with the Irish College of General Practitioners on electronic referrals for cases of suspected cancer to the nearest cancer centre for diagnostics. “Beyond that, we are working on survivorship as a relatively new theme, in partnership with the Irish Cancer Society. Internationally the deﬁnition of survivorship varies. We are focusing on patients post-completion of treatment, providing a care plan summary, sending it to their GP and then providing support and education on the management of treatment side effects and lifestyle issues. “The National Cancer Screening Service transitioned from the NCCP to the Health and Wellness Directorate in early 2014. We continue to work closely together. Screening data, including the number of cancers diagnosed, are shared so that we can see how both the diagnostic and treatment elements of the pathway are functioning. We are a year into this new relation-

16 | THE CLINICAL CARE JOURNAL

ship and it is working very well. “The NCCP runs a number of audit, quality and risk forums on an annual basis. This year’s breast cancer forum meeting took place in Limerick for pathologists, radiologists, surgeons, medical and radiation oncologists and specialist nurses, with a similar meeting for prostate cancer in Farmleigh in November. “We work with the HSE MET Unit on manpower planning and that fed into our service plan funding priorities for next year. We have funding for a second paediatric radiation oncologist for the country, who will be based jointly in the St. Luke’s Radiation Oncology Network and Our Lady’s Children’s Hospital in Crumlin, Dublin. We have also got approval to appoint a clinical lead for hereditary cancers to develop further the existing cancer genetics service. The new clinical lead will be based in St. James’s Hospital, with four sessions per week dedicated to the NCCP. Other funded priorities in 2015 are the appointment of an additional urooncologist and two medical ocologists.”

DATA AND GUIDELINES Dr. Coffey says that the NCCP was

also working on a medical oncology cancer information service. “Data collection and reporting are still relatively manual and labour-intensive processes. With 26 medical oncology day wards delivering systemic anti-cancer therapies across the country, we are looking at data on cancer drug management. Similarly we are looking at clinical protocols for these drugs and have started to make these accessible online. “Finally, we have done a lot of work on guidelines for cancer diagnosis and treatment. The NCCP worked with senior clinicians from all cancer centres and provided research methodology and administrative support. The ﬁrst two of these guidelines, on breast and prostate cancer, are being launched shortly, in co-operation with the National Clinical Effectiveness Committee in the Department of Health.”

Prior to his appointment as interim Director, DR JEROME COFFEY was radiation oncology advisor to the NCCP. This post has now been filled by DR JOE MARTIN, Consultant Radiation Oncologist at Galway University Hospital.

HerceptinÂŽ Subcutaneous

Less waiting time More free time Administer the standard of care in just 2 - 5 minutes compared to between .5 - 2 hours with Herceptin IV1-4 3URYHQ FRPSDUDEOH HIÂżFDF\ DQG VDIHW\ WR , 9 +HUFHSWLQ1, 2, 5 6LPSOH UHDG\ WR XVH formulation, frees up clinic resources6

ABRIDGED PRESCRIBING INFORMATION (Early & Metastatic Breast Cancer Indication Only) (For full prescribing information, refer to the Summary of Product Characteristics [SmPC] HERCEPTINÂŽ (trastuzumab) 600mg solution for injection Indications: Metastatic Breast Cancer (MBC): Treatment of patients with HER2 positive MBC: (i) as monotherapy following at least 2 chemotherapy regimens for MBC. Prior chemotherapy to include at least an anthracycline and a taxane, unless unsuitable for treatments. Hormone receptor positive patients must also have failed hormonal therapy, unless unsuitable for treatments. (ii) in combination with paclitaxel for patients who have not received chemotherapy for MBC and where anthracyclines not suitable. (iii) in combination with docetaxel for patients who have not received chemotherapy for MBC. (iv) in combination with an aromatase inhibitor for the treatment of postmenopausal patients with hormone-receptor positive MBC, not previously treated with Herceptin. Early Breast Cancer (EBC): Treatment of patients with HER2 positive EBC (i) following surgery, chemotherapy (neoadjuvant or adjuvant) and radiotherapy (if applicable) (ii) following adjuvant chemotherapy with doxorubicin and cyclophosphamide, in combination with paclitaxel or docetaxel. (iii) in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin. (iv) in combination with neoadjuvant chemotherapy followed by adjuvant Herceptin therapy for locally advanced (including inflammatory) disease or tumours >2cm diameter. Herceptin should only be used in MBC or EBC patients whose tumours have either HER2 overexpression or HER2 gene amplification as determined by an accurate and validated assay. Dosage and Administration: HER2 testing mandatory prior to Herceptin therapy. Only physicians experienced in cytotoxic chemotherapy should initiate Herceptin: The injection should be administered by a healthcare professional only. Herceptin subcutaneous (SC) formulation is not intended for intravenous (IV) administration and should be administered via a SC injection only. Check product labels to ensure correct formulation administered. Limited information available on switching from one formulation to another. In order to prevent medication error it is important to the check the vial labels to ensure that the drug been prepared and administered is Herceptin (trastuzumab) and not Kadcyla (trastuzumab emtansine). Not recommended in patients <18 years of age. Dedicated PK studies in older people and those with renal or hepatic impairment have not been carried out. Refer to SmPC for dose reduction and missed doses. Treat MBC patients until disease progression. Treat EBC patients for 1 year or until disease progression; whichever occurs first, extending treatment beyond one year in EBC is not recommended. Recommended dose is 600mg irrespective of the patientâ&#x20AC;&#x2122;s body weight. No loading dose is required. This dose should be administered subcutaneously over 2-5 minutes every three weeks, refer to SmPC. Patients should be observed for six hours after the first injection and for two hours after subsequent injections for signs or symptoms of administration-related reactions. Refer to SmPC for chemotherapy combination dosing. Contraindications: Hypersensitivity to trastuzumab, murine proteins, hyaluronidase or any excipients. Severe dyspnoea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy. Warnings and Precautions: In order to improve traceability, the trade name of the administered product should be clearly recorded (or stated) in the patients file. HER2 testing in a specialised laboratory mandatory to ensure adequate validation of test. No trial data available on re-treatment of patients with previous exposure to Herceptin in the adjuvant setting. Heart failure observed in patients receiving monotherapy or in combination with paclitaxel or docetaxel, particularly following anthracycline-containing regimens: may be moderate to severe, has been fatal. All candidates for treatment (especially those with prior anthracycline and cyclophosamide exposure) should undergo baseline cardiac assessment including history and physical examination, ECG, echocardiogram, and/or MUGA scan or magnetic resonance imaging. A careful risk-benefit assessment should be made. In all patients cardiac assessments should be repeated every 3 months during treatment and every 6 months following discontinuation until 24 months from the last dose. Anthracycline therapy should be avoided for up to 27 weeks after last dose of Herceptin. Formal cardiological assessment should be considered in patients with cardiovascular concerns following baseline screening. For patients who develop cardiac dysfunction monitoring should take place every 6-8 weeks. Consider discontinuing treatment in patients with asymptomatic decreased LVEF function if no clinical benefit seen. Caution in treating patients with symptomatic heart failure, history of hypertension, Coronary artery disease, and in EBC patients with LVEF of 55% or less. If LVEF drops 10 ejection fraction points from baseline and to below 50% treatment should be suspended, repeat LVEF assessment within 3 weeks. If LVEF does not improve or further declines, consider discontinuation, refer to SmPC. All such patients should be reviewed by cardiologist and followed up. If symptomatic cardiac failure develops during therapy, treat with standard medications. Most patients in the pivotal trials who experienced heart failure improved with standard medication, refer to SmPC. MBC: Herceptin and anthracyclines should not be given concurrently in the metastatic breast cancer setting.

Increased risk of cardiotoxicity in patients who previously received anthracycline therapy. EBC: For EBC patients, cardiac assessment, as performed at baseline, should be repeated every 3 months during treatment and every 6 months following discontinuation of treatment for duration of 24 months from the last dose. Further monitoring is recommended for patients receiving anthracycline containing chemotherapy and should occur yearly up to 5 years from the last dose or longer if a continuous decrease of LVEF is observed. In EBC, no data on patients with existing or a history of documented CHF (New York Heart Association Class greater than or equal II), history of MI, LVEF of <55%, other cardiomyopathy, hemodynamic effective pericardial effusion, cardiac arrhythmia requiring medical treatment, angina pectoris requiring medical treatment, clinically significant cardiac valvular disease, poorly controlled hypertension. Therefore treatment not recommended. Herceptin and anthracyclines should not be given concurrently in the adjuvant treatment setting. In EBC adjuvant patients, the incidence of symptomatic and asymptomatic cardiac events increased when Herceptin (IV formulation) was administered after anthracycline-containing chemotherapy compared to administration with a non-anthracycline regimen of docetaxel and carboplatin and was more marked when Herceptin was administered concurrently with taxanes than when administered sequentially to taxanes. Most symptomatic cardiac events occurred within the first 18 months, regardless of the regimen used, refer to SmPC for further details. In patients eligible for neoadjuvantadjuvant treatment, low dose anthracycline regimens (maximum cumulative doses: doxorubicin 180 mg/m2 or epirubicin 360 mg/m2) can be administered concurrently with chemotherapy naĂŻve Herceptin patients. If patients have been treated concurrently with low dose anthracyclines and Herceptin in the neoadjuvant setting, no additional cytotoxic chemotherapy should be given after surgery. Experience of concurrent administration of anthracycline regimens is low, refer to SmPC for details. Neoadjuvantadjuvant treatment is not recommended for patients older than 65 years of age refer to SmPC. Administration-related reactions (ARRs) are known to occur with Herceptin SC formulation. Pre-medication may reduce risk, refer to SmPC. Serious ARRs were not reported in the clinical trial however ARRs have been associated with the IV formulation. ARRs can be treated with an analgesic/antipyretic, or antihistamine. In rare cases, ARRs have resulted in fatal outcome. Patients experiencing dyspnoea at rest due to complications of advanced malignancy and co-morbidities may be at increased risk of fatal ARR and pulmonary events, therefore these patients should not be treated with Herceptin. Refer to SmPC for delayed (including fatal) ARR and pulmonary events. Severe pulmonary events have been reported with use of the IV formulation, occasionally fatal. Cases of interstitial lung disease reported: risk factors include prior or concomitant therapy with other anti-neoplastic therapies known to be associated with it such as taxanes, gemcitabine, vinorelbine and radiation therapy. Exercise caution for pneumonitis, especially in patients treated concomitantly with taxanes. Drug Interactions: No formal drug interaction studies have been performed. Effect of Herceptin on the pharmacokinetics of other antineoplastic agents: Pharmacokinetic data (PK) from studies BO15935 and M77004 in women with HER2 positive MBC suggest that exposure to paclitaxel and doxorubicin is not altered by Herceptin IV loading or maintenance dose, refer to SmPC. However Herceptin may elevate the overall exposure of one doxorubicin metabolite (7-deoxy-13 dihydro-doxorubicinone, D7D). The bioactivity of D7D and the clinical impact of the elevation of this metabolite is unclear. Study JP16003 in HER2 positive Japanese MBC patients suggest administration of Herceptin has no effect on the single dose PK of docetaxel. Study JP19959, a substudy of BO18255 performed in male and female Japanese patients with advanced gastric cancer studied the PK of capecitabine and cisplatin administered with or without Herceptin. Exposure to the bioactive metabolite 5 â&#x20AC;&#x201C;FU of capecitabine was not affected by the concurrent use of cisplatin plus Herceptin. However, higher concentrations and a longer half-life of capecitabine were demonstrated when combined with Herceptin. The PK of cisplatin was not affected by concurrent use of capecitabine or by concurrent use of capecitabine plus Herceptin, refer to SmPC. Effect of antineoplastic agents on Herceptin pharmacokinetics: Study JPI6003 in Japanese HER2 positive MBC patients found no evidence of a PK effect on Herceptin with concurrent administration of docetaxel. Comparison of PK results from phase II & III clinical trials in HER2 positive MBC patients indicate that individual and mean Herceptin trough serum concentrations varied within and across studies however no clear effect of the concomitant administration of paclitaxel on the pharmacokinetics of Herceptin, refer to SmPC for further details. The administration of anastrozole did not appear to influence the pharmacokinetics of trastuzumab. Fertility, Pregnancy and Lactation: Avoid during pregnancy unless potential benefit for mother outweighs risk to foetus. Do not breastfeed during and for 7 months after last treatment. Cases of foetal renal growth and and/ or function impairment in association with oligohydramnios (some associated with fatal pulmonary hypoplasia of the foetus) reported in pregnant women in the post-marketing setting. Use effective contraception during and for at least 7 months after treatment has

concluded. Advise women who become pregnant of potential foetal harm and manage with a multidisciplinary team. Side Effects and Adverse Reactions: Most serious and/or common adverse reactions (reported for IV and SC formulations) are cardiac dysfunction, ARRs, haematotoxicity (especially neutropenia), infections and pulmonary events. The safety profile of Herceptin SC formulation from the pivotal trial in EBC was overall similar to the known safety profile of the IV formulation. Adverse events reported more frequently for the SC formulation: serious adverse events which included postoperative wounds infections, ARRs, hypertension. The following adverse reactions have been reported with Herceptin IV monotherapy or in combination with chemotherapy in trials and in the post marketing setting: Very Common (â&#x2030;Ľ1/10): infection, febrile neutropenia, anaemia, neutropenia, leukopenia, hypertension, hypotension, dyspepsia, constipation, alopecia, mucosal inflammation, infusion related reactions, tremor, dizziness, headache, increased/decreased BP, irregular heart beat, palpitation, cardiac flutter, decreased ejection fraction, wheezing, dyspnoea (14%), diarrhoea, vomiting, nausea, lip swelling, hot flush, conjunctivitis, increased lacrimation, abdominal pain, erythema, rash, facial swelling, alopecia, nail disorder, arthralgia, muscle tightness, myalgia, asthenia, chest pain, chills, fatigue, cough, epistaxis, rhinorrhoea, influenza-like symptoms, IRR, pain and pyrexia. Common (â&#x2030;Ľ1/100 - <1/10): pneumonia, neutropenic sepsis, cystitis, herpes zoster, influenza, nasopharyngitis, sinusitis, skin infection, rhinitis, upper respiratory tract infection, urinary tract infection, erysipelas, cellulitis, thrombocytopenia, hypersensitivity, weight decreased/weight loss, anorexia, anxiety, depression, insomnia, abnormal thinking, peripheral neuropathy, paraesthesia, hypertonia, somnolence, dysgeusia, ataxia, dry eye, congestive cardiac failure (2%), supraventricular tachyarrhythmia, cardiomyopathy, hypotension, vasodilation, asthma, lung disorder, pharyngitis, pancreatitis, dyspepsia, haemorrhoids, constipation, dry mouth, hepatitis, liver tenderness, hepatocellular injury, acne, dry skin, ecchymosis, hyperhydrosis, maculopapular rash, pruritus, onychoclasis, dermatitis, arthritis, back pain, bone pain, muscle spasms, neck pain, pain in extremity, renal disorder, breast inflammation/mastitis, peripheral oedema, malaise, oedema and contusion. Serious or potentially serious: Severe infections, heart failure (New York Association [NYHA] class II-IV, hypertension, immunogenicity, pneumonitis, acute pulmonary oedema, renal failure and febrile neutropenia. Refer to SmPC for full listings of adverse events. See SmPC section 4.8 for instructions on reporting adverse events. Legal Category: Limited to sale and supply on prescription only. Presentation and Marketing Authorisation Number: EU/1/00/145/002 Pack of one 6mL vial containing 5mL of solution Marketing Authorisation Holder: Roche Registration Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom. Herceptin is a registered trade mark. Full prescribing 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: 26th August 2014. References: 1. Ismael G, et al. Lancet Oncol. 2012; 13(9):869â&#x20AC;&#x201C;878. 2. Jackisch C, et al. Oral presentation at the 8th European Breast Cancer Conference, Vienna, Austria 2012 (Abstract 1BA). 3. Pivot X, et al. Poster presentation at the 37th ESMO, Vienna, Austria 2012 (Poster 272P). 4. Herceptin SC SmPC, July 2014. 5. Jackisch C, et al. Poster presentation at the 37th ESMO, Vienna, Austria 2012 (Poster 271P). 6. Pivot X, et al. Poster presentation at the 13th St Gallen Breast Cancer Conference, St Gallen, Switzerland 2013 (Poster 207).

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The recommended dose is 10mg daily for HR+,HER2 - negative advanced breast cancer1 • In postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor.1

Break out from the cycle of conventional treatment for advanced breast cancer

AFINITOR enhances and extends the benefit of endocrine therapy in HR-positive, HER2-negative postmenopausal women1 ABBREVIATED PRESCRIBING INFORMATION Refer to the Summary of Product Characteristics (SmPC) before prescribing. Afinitor 2.5 mg Tablets. Afinitor 5 mg Tablets. Afinitor 10 mg Tablets. Presentation: tablets containing 2.5mg, 5 mg or 10 mg of everolimus Indications: adult patients with advanced renal cell carcinoma (RCC), whose disease has progressed on or after treatment with VEGF-targeted therapy. Treatment of unresectable or metastatic, well- or moderately- differentiated neuroendocrine tumours of pancreatic origin in adults with progressive disease. Afinitor is indicated for the treatment of hormone receptor-positive, HER2/neu negative advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor. Dosage: Adults: one 10 mg dose once daily at the same time every day, with or without food. Dose adjustment may be required due to side-effects or when used with moderate CYP3A4 or PgP inhibitors or strong CYP3A4 inducers. Children: Afinitor is not recommended for use in children or adolescents. Patients with hepatic impairment: Mild hepatic impairment (Child-Pugh A) – the recommended dose is 7.5 mg daily. Moderate hepatic impairment (Child-Pugh B) – the recommended dose is 5 mg daily. Severe hepatic impairment (Child-Pugh C)–Afinitor is only recommended if the desired benefit outweighs the risk. In this case, a dose of 2.5 mg daily must not be exceeded. Contraindications: Hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients. Warnings/Precautions: Non-infectious pneumonitis: Cases have been described in patients taking Afinitor, some of these have been severe and on rare occasions, a fatal outcome was observed. In case of shortness of breath, pleural effusion, cough or dyspnoea not due to infection or malignancy, radiologic assessment for pneumonitis is indicated. In some cases, management of pneumonitis may require dose adjustment and/or interruption, or discontinuation of Afinitor and/or addition of corticosteroid therapy. Infections: Afinitor is immunosuppressive. Localised and systemic infections have been described in patients taking Afinitor, some of these have been severe (e.g. leading to sepsis, respiratory or hepatic failure) and occasionally fatal. In case of fevers and chills, signs of a potential bacterial or invasive fungal infection should be looked for and appropriate treatment promptly instituted; Treat pre-existing invasive fungal infections prior to starting treatment with Afinitor; If a diagnosis of invasive systemic fungal infection is made, discontinue Afinitor and treat with appropriate antifungal therapy. Hypersensitivity reactions: manifested by symptoms including but not limited to, anaphylaxis, dyspnoea, flushing, chest pain or angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus (see section 4.3). Oral ulceration: Mouth ulcers, stomatitis and oral mucositis have been seen in patients treated with Afinitor (see section 4.8), topical treatments are recommended, but alcohol- or peroxide- containing mouthwashes should be avoided. Anti-fungal agents should not be used unless fungal infection has been diagnosed (see section 4.5) Laboratory tests and monitoring: Renal function, blood glucose, and complete blood counts are recommended prior to initiation and periodically during treatment. Blood Lipids: Dyslipidaemia (including hypercholesterolaemia and hypertriglyceridaemia) has been reported. Monitoring of blood cholesterol and triglycerides prior to the start of Afinitor therapy and periodically thereafter, as well as management with appropriate medical therapy, is recommended. Hepatic Impairment: Not recommended in patients with severe hepatic impairment (Child-Pugh class C) Vaccination: Avoid use of live vaccines Fertility: The potential for everolimus to cause infertility in male and female patients is unknown, however, secondary amenorrhoea and associated LH/ FSH imbalance has been observed in female patients. Pregnancy: should not be given to pregnant women unless the

potential benefit outweighs the potential risk to the foetus. The potential risk for humans is unknown. Women of childbearing potential: Use effective contraception methods while receiving Afinitor, and for up to 8 weeks after ending treatment Breast-feeding: Women taking Afinitor should not breast feed Interactions: Patients taking concomitant ACE inhibitor (e.g. ramipril) therapy may be at increased risk for angioedema (see section 4.4 of the SmPC) , avoid concurrent treatment with strong CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir, clarithromycin, telithromycin) and strong PgP inhibitors caution with moderate inhibitors of CYP3A4 and/or PgP (e.g. erythromycin, verapamil, diltiazem, fluconazole, ciclosporin, amprenavir, fosamprenavir, aprepitant) avoid concurrent treatment with strong inducers of CYP3A4 or PgP (e.g. rifampicin, rifabutin) St. John’s Wort (Hypericum perforatum), carbamazepine, phenobarbital, phenytoin, efavirenz, nevirapine, dexamethasone, prednisone, prednisolone avoid grapefruit juice, grapefruit and other foods affecting CYP3A4 or PgP. Co-administration of everolimus and exemestane increased exemestane Cmin and C2h by 45% and 64%, respectively. However, the corresponding oestradiol levels at steady state (4 weeks) were not different between the two treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive advanced breast cancer receiving the combination. The increase in exemestane levels is unlikely to have an impact on efficacy or safety. Adverse reactions: Very common (≥10%): Infections, decreased appetite, stomatitis, rash, fatigue, asthenia, diarrhoea, nausea, vomiting, peripheral oedema, epistaxis, pneumonitis, pruritus, anaemia, dysgeusia, headache, hyperglycaemia, hypercholesterolaemia, Common (≥1 to <10%): Thrombocytopenia, neutropenia, leukopenia, lymphopenia, proteinuria, blood creatinine increased, dry mouth, dry skin, cough, dyspnoea, abdominal pain, mucosal inflammation, oral pain, dyspepsia, dysphagia, pyrexia, dry skin, nail disorders, mild alopecia, acne, erythema, onychoclasis, skin exfoliation, skin lesion, proteinuria, blood creatinine increased, hypertriglyceridaemia; hypophosphataemia, hyperlipidaemia, hypokalaemia, dehydration, hypocalcaemia; insomnia, creatinine increased, eyelid oedema, hypertension, haemorrhage, dehydration, chest pain, haemoptysis, diabetes mellitus, pulmonary embolism Uncommon (<1%): Pancytopenia, conjunctivitis, menstruation irregular, flushing, deep vein thrombosis, non- cardiac chest pain, increased daytime urination, acute renal failure, haemoptysis, pulmonary embolism, ageusia, congestive cardiac failure, haemorrhages, Cases of Hepatitis B reactivation have been observed in clinical studies and post-marketing reports. Legal Category: POM Product Authorisation Numbers: EU/1/09/538/001-003 EU/1/09/538/004-007 Pack Sizes: 30 Tablets Date of Revision of Text: July 2014 Full prescribing information is available on request from: Novartis Ireland Ltd, Beech Hill Office Campus, Clonskeagh, Dublin 4 or at www.medicines.ie Tel: 01 260 1255 Fax: 01 260 1263 Afinitor® is a registered Trade Mark IE02/AFI14-CNF037 Date of preparation August 2014 References: 1. AFINITOR Summary of Product Characteristics November 2013

CANCER | RESEARCH

EXERCISE

SLOWS TUMOUR GROWTH, IMPROVES CHEMOTHERAPY IN MOUSE CANCERS

ne way many cancers grow resistant to treatment is by generating a web of blood vessels that are so jumbled they fail to provide adequate oxygen to the tumor. With oxygen starvation, the tumor gains a sort of cloaking device that protects it from the toxic effects of chemotherapy drugs and radiation, which are designed to seek out well-oxygenated tissue. Researchers have long tested various approaches to improving blood flow to the tumor in the hopes of restoring potency to treatments. Not much has shown promise, until researchers investigated exercise. In a study published in the March 16, 2015, issue of the Journal of the National Cancer Institute, researchers led by Duke Cancer Institute (DCI) scientists studied the impact of exercise in models of breast cancer in mice. They found that exercise stimulated significant improvements in the number and function of blood vessels around the tumors, improving oxygen flow to the cancer site. When treated with chemotherapy, the tumors shrank markedly better than they did in sedentary animals. “We set about to see whether exercise would affect the tumor perfusion, and could not have guessed that it would be as effective as it was,” said co-senior author Mark W. Dewhirst, DVM, Ph.D, the Gustavo S. Montana Professor of Radiation Oncology and vice director for Basic Science at DCI. The researchers used two different models of breast cancer cells and implanted them in mice, then randomly assigned the animals to either exercise (running on a wheel) or remaining sedentary. Among the animals that exercised,

Ultimately, however, the team is optimistic that exercise will become an important component of cancer therapy in the clinic.

tumour growth was significantly slower than growth in the sedentary mice, and tumour cell death was 1.5 times higher. The density of small blood vessels was approximately 60 percent higher in exercised mice compared to the controls, and oxygen transport improved, leading to less oxygen starvation of the cancer tissue. The vasculature in the tumours also looked and behaved more normally. Based on the observed effects of exercise on tumour physiology, the researchers next tested whether exercise would improve the efficacy of the chemotherapy drug cyclophosphamide. Animals were randomized to one of four groups: sedentary, exercise alone, cyclophosphamide alone, or exercise in combination with cyclophosphamide. The rate of tumour growth was significantly slower in mice treated with exercise and cyclophosphamide compared to all other groups. Tumour growth was also delayed in both the exercise alone and cyclophosphamide alone groups, but there was no difference in tumour growth rate between those two groups, suggesting that exercise showed similar effect as chemotherapy in this experiment. “We were truly amazed by these findings,” Dewhirst said. “I have spent the better part of the last 30 years trying to figure out how to eliminate hypoxia in tumors, and have looked at a lot of different approaches -- drugs, hyperthermia and metabolic manipulations. None has worked very well, and in some cases,

made things worse. So these findings with exercise are quite encouraging.” Dewhirst said future research would examine the effect of exercise on slowergrowing tumours that are more typical of human breast cancers, and move to other animal models. Ultimately, however, the team is optimistic that exercise will become an important component of cancer therapy in the clinic. “There is a growing body of work showing that exercise is a safe and tolerable therapy associated with improvements in many outcomes such as fitness, quality of life, and reductions in symptoms such as fatigue in a number of cancer types, including breast cancer,” said co-lead author Lee Jones, Ph.D., member and director of the Cardio-Oncology Research Program at Memorial Sloan Kettering Cancer Institute. “On the basis of these findings in mice, we are now designing studies to test whether exercise can inhibit tumor growth / risk of recurrence in humans. Such research will prove very exciting.”

In addition to DEWHIRST AND JONES, study authors include graduate student ALLISON S. BETOF, CHRISTOPHER D. LASCOLA, DOUGLAS WEITZEL, CHELSEA LANDON, PETER M. SCARBROUGH, AND GAYATHRI R. DEVI. The research team received grant support from the Department of Defense (BC093532) and the National Cancer Institute (CA40355). Citations Journal of the National Cancer Institute; BC093532; CA40355

THE CLINICAL CARE JOURNAL | 19

RESEARCH | CANCER

CUTTING EDGE MEDICINE FOR

OVARIAN CANCER

ersonalised medicine is getting closer to reality for women with late-stage ovarian cancer. An experimental immunotherapy is in the works that can target an individual woman’s tumor and extend the time period between initial treatment and the cancer’s return. “This is cutting edge medicine for ovarian cancer,” said Jonathan Oh, MD, a gynecologic oncologist at Texas Oncology, P.A., in Dallas, who presented the results of a preliminary study on the vaccine at the Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer on March 28 in Chicago, in the United States. The phase II study included 31 women with stage III or IV ovarian cancer. Twenty received immunotherapy and 11 did not. The cancer in those who did not receive the immunotherapy returned in a median of 14.5 months. Those who did receive the immunotherapy had not reached the median time to recurrence and the majority were well beyond 14.5 months. In 2015, an estimated 21,290 women will be diagnosed with ovarian cancer in the United States and 14,180 will die, according to the American Cancer Society.

20 | THE CLINICAL CARE JOURNAL

Because symptoms are often not noticeable in the early stages, most women are diagnosed in later stages when treatment is less effective, and prognosis worse. The United States National Cancer Institute states that about 80 per cent of women treated for ovarian cancer relapse after their first treatment. “This immunotherapy may keep the cancer away longer,” Dr. Oh said. The immunotherapy is called “bifunctional” because it works by targeting a biochemical pathway in cancer cells and by helping to stimulate the patient’s immune response to fight cancer. During the initial surgery to remove the tumor, sample cells are taken to develop the personalised immunotherapy. After the initial surgery followed by standard of care chemotherapy, women received either one injection per month for anywhere between four and 12 months or were randomized to standard of care. “This was a preliminary study with promising results that may give women with advanced ovarian cancer an option for a maintenance regimen,” Dr. Oh said. “Additionally, the vaccine is very well tolerated.” “The results from this clinical trial suggest that using a patient’s immune system to fight advanced ovarian cancer

may be a promising avenue to improve outcomes in what has continued to be the most aggressive gynecologic cancer,” said Krishnansu S. Tewari, MD, a gynecologic oncologist, professor and director of research at the University of California, Irvine Medical Center, Orange, CA.

The immunotherapy was developed by Gradalis, Inc., which sponsored the clinical trial. DR. OH is a shareholder in Gradalis. Dr. Tewari was not involved in the trial and has no relationship with Gradalis. The Society of Gynecologic Oncology (SGO) is the premier medical specialty society in the United States for health care professionals trained in the comprehensive management of gynecologic cancers. The SGO contributes to the advancement of women’s cancer care by encouraging research, providing education, raising standards of practice, advocating for patients and members and collaborating with other domestic and international organizations. SGO’s 2,000 members provide multidisciplinary cancer treatment including chemotherapy, radiation therapy, surgery and supportive care. They practise in a variety of settings, including academic institutions and hospitals, major regional cancer centers and private practice.

IN MULTIPLE MYELOMA EMPOWERED RESPONSE RIGHT FROM THE

LICENSED IN: FRONT LINE ASCT MULTIPLE MYELOMA1 FRONT LINE NON-ASCT MULTIPLE MYELOMA1 RELAPSED/ REFRACTORY MULTIPLE MYELOMA1

AVAILABLE IN SC AND IV1 VELCADE® 3.5 mg POWDER FOR SOLUTION FOR INJECTION PRESCRIBING INFORMATION. ACTIVE INGREDIENT: Bortezomib Please refer to Summary of Product Characteristics (SmPC) before prescribing. INDICATIONS: Adults only. Monotherapy or with pegylated liposomal doxorubicin or dexamethasone: progressive multiple myeloma in patients who have had at least 1 prior therapy and already undergone/are not suitable for haematopoietic stem cell transplant. With melphalan & prednisone: for previously untreated multiple myeloma in patients not eligible for high-dose chemotherapy with haematopoietic stem cell transplant. With dexamethasone, or with dexamethasone and thalidomide: for induction treatment of previously untreated multiple myeloma in patients eligible for high-dose chemotherapy with haematopoietic stem cell transplant. DOSAGE & ADMINISTRATION: Adults and Elderly: Administer as 3-5 second IV bolus or SC in thighs/abdomen. At least 72 hours between consecutive doses. Recommended dose 1.3mg/m2 body surface area. Posology modifications required for VELCADE-related toxicity, refer to SmPC. Treatment of progressive multiple myeloma (after at least 1 prior therapy) VELCADE treatment cycle: twice weekly for 2 weeks in 21-days treatment cycle. Two cycles of VELCADE recommended following confirmation of complete response. Responding patients without complete remission should receive total of 8 cycles. Monotherapy: as above. Combination with pegylated liposomal doxorubicin: 30 mg/m² pegylated liposomal doxorubicin (1h IV infusion) on day 4 of VELCADE treatment cycle. Combination with dexamethasone: 20 mg oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 of VELCADE treatment cycle. Previously untreated multiple myeloma patients not eligible for haematopoietic stem cell transplant Combination with oral melphalan (9mg/m2) and prednisone (60mg/m2): 9 x 6-weeks treatment cycles (see SmPC for details of posology and toxicity related modifications). Previously untreated multiple myeloma patients eligible for haematopoietic stem cell transplant (induction therapy) Combination with oral dexamethasone (40mg): 4 x 21-days treatment cycles (see SmPC for details of posology and toxicity related modifications). Combination with oral dexamethasone (40mg) and thalidomide (50mg): 4 x 28-days treatment cycles. At least partial responders: 2 additional cycles. See SmPC for details of posology and toxicity related modifications; for other medicinal products, see appropriate SmPCs. Children: Not applicable. Hepatic Impairment: mild - no dose adjustment; moderate or severe - start on reduced dose of 0.7 mg/m2 per injection for first cycle, then possible increase to 1.0 mg/m2 or reduction to 0.5 mg/m2 based on tolerability. Renal Impairment: See precautions. CONTRAINDICATIONS: Hypersensitivity to active substance, boron or any excipients. Acute diffuse infiltrative pulmonary and pericardial disease. SPECIAL WARNINGS & PRECAUTIONS: Do not administer intrathecally. Monitor complete blood counts. GI toxicity very common; monitor closely. Herpes zoster virus reactivation: consider anti-viral prophylaxis. Very rarely John Cunningham virus infection resulting in Progressive Multifocal Leukoencephalopathy (PML) and death; monitor regularly for PML symptoms, discontinue if diagnosed. Peripheral neuropathy common; requires careful monitoring, neurological evaluation and possible dose/schedule modification, or change to SC route. Special care if risk factors for seizures. Caution when history of syncope with medicinal products linked with hypotension, or dehydration due to recurrent diarrhoea/vomiting. Discontinue treatment if Posterior Reversible Encephalopathy Syndrome (PRES) occurs. Development/exacerbation of congestive heart failure/QT prolongation; monitor closely if cardiac risk factors. Renal impairment common; monitor closely. Rarely acute diffuse infiltrative pulmonary disease of unknown aetiology e.g. pneumonitis, interstitial pneumonia, lung infiltration and acute respiratory distress syndrome (ARDS); baseline chest radiograph recommended. If new/worsening pulmonary symptoms perform prompt diagnostic evaluation and treat appropriately; consider benefit/risk ratio before continuing. Immunocomplex-mediated reactions e.g. serum sickness, polyarthritis with rash, proliferative glomerulonephritis: discontinue if severe. Bortezomib exposure increased in moderate/severe hepatic impairment; reduce doses, closely monitor. Patients with high pre-treatment tumour burden at risk of tumour lysis syndrome; monitor closely. Concomitant CYP3A4-inhibitors: monitor closely. Caution with CYP3A4 or CYP2C19 substrates. SIDE EFFECTS: Very common: thrombocytopenia, neutropenia, anaemia, decreased appetite, neuropathies, peripheral sensory neuropathy, dysaesthesia, neuralgia, nausea, vomiting, diarrhoea, constipation, musculoskeletal pain, fatigue, pyrexia, asthenia. Common: herpes zoster (inc disseminated & ophthalmic), pneumonia, herpes simplex, fungal infection, leukopenia, lymphopenia, dehydration, hypokalaemia, hyponatraemia, blood glucose abnormal, hypocalcaemia, enzyme abnormality, mood disorders & disturbances, anxiety disorder, sleep disorders & disturbances, motor neuropathy, loss of consciousness (inc syncope), dizziness, dysgeusia, lethargy, headache, eye swelling, vision abnormal, conjunctivitis, vertigo, hypotension, orthostatic hypotension, hypertension, dyspnoea, epistaxis, upper/lower respiratory tract infection, cough, gastrointestinal haemorrhage (inc mucosal), dyspepsia, stomatitis, abdominal distension, oropharyngeal pain, abdominal pain (inc gastrointestinal and splenic pain), oral disorder, flatulence, hepatic enzyme abnormality, rash, pruritus, erythema, dry skin, muscle spasms, pain in extremity, muscular weakness, renal impairment, oedema (inc peripheral), chills, pain, malaise, weight decreased. Other side effects include: cardiac failure, tumour lysis syndrome, pulmonary hypertension, Posterior Reversible Encephalopathy Syndrome, acute diffuse infiltrative pulmonary disorders, autonomic neuropathy, sepsis, herpes virus infection, meningitis, meningoencephalitis herpetic, Epstein-Barr virus infection, neoplasm malignant, leukaemia plasmacytic, mycosis fungoides, neoplasm benign, lymphadenopathy, pancytopenia, febrile neutropenia, thrombocytopenic purpura, hypersensitivity, anaphylactic shock, type III immune complex mediated reaction, Cushing’s syndrome, mental disorder, suicidal ideation, psychotic disorder, haemorrhage intracranial, peripheral sensory motor neuropathy, encephalopathy, neurotoxicity, cerebral haemorrhage, seizure disorders, paralysis, coma, eye haemorrhage, optic neuropathy, different degrees of visual impairment, hearing impaired, cardiac tamponade, cardio-pulmonary arrest, cardiac fibrillation, arrhythmia, tachycardia, angina pectoris, pericarditis, cardiomyopathy, ventricular dysfunction, atrial flutter, myocardial infarction, atrioventricular block, cardiovascular disorder (inc cardiogenic shock), torsade de pointes, angina unstable, cardiac valve disorders, sinus arrest, cerebrovascular accident, deep vein thrombosis, thrombophlebitis, phlebitis, vasculitis, peripheral embolism, pulmonary embolism, pulmonary alveolar haemorrhage, bronchospasm, wheezing, respiratory failure, acute respiratory distress syndrome, apnoea, haemoptysis, respiratory alkalosis, throat tightness, pancreatitis, haematemesis, gastro-intestinal obstruction, enteritis, colitis, megacolon, peritonitis, gastrointestinal ulceration & perforation, hepatotoxicity, hepatitis, cholestatis, hepatic failure, hepatic haemorrhage, acute febrile neutrophilic dermatosis, toxic skin eruption, toxic epidermal necrolysis, Stevens Johnson syndrome, purpura, erythema multiforme, myopathies, rhabdomyolysis, renal failure, urinary retention, oliguria, death, multi-organ failure, ECG abnormality. Refer to SmPC for other side effects. PREGNANCY: No clinical data available for bortezomib. Thalidomide contraindicated during pregnancy and in women of childbearing potential unless all conditions of thalidomide pregnancy prevention programme met. Male and female patients of childbearing potential must use effective contraceptive measures during treatment and for 3 months following. LACTATION: Not recommended. INTERACTIONS: Closely monitor when bortezomib is combined with potent CYP3A4-inhibitors (e.g. ketoconazole, ritonavir). Concomitant use of bortezomib with strong CYP3A4 inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital and St. John’s Wort) not recommended. Hypo/hyperglycaemia reported in diabetic patients receiving oral hypoglycaemics. LEGAL CATEGORY: Prescription Only Medicine. PRESENTATIONS, PACK SIZES, MARKETING AUTHORISATION NUMBERS: 1 vial per pack. EU/1/04/274/001. 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: February 2014. Reporting suspected adverse reactions 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 the online reporting option accessible from the IMB homepage. A downloadable report form is also accessible from the IMB website, which may be completed manually and submitted to the IMB via ‘freepost’., in addition to the traditional post-paid ‘yellow card’ option Alternatively the traditional post-paid ‘yellow card’ may also continue to be used. FREEPOST, Pharmacovigilance Section, Irish Medicines Board, Kevin O’Malley House, Earlsfort Centre, Earlsfort Terrace, Dublin 2. Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.imb.ie e-mail: imbpharmacovigilance@imb.ie Adverse events should also be reported to Janssen-Cilag Ltd on +44 (0)1494 567447. Reference: 1. Velcade Summary of Product Charateristics SmPC. Date of Preparation: November 2014. PHIR/VEL/0114/0003a.

Now Approved For patients with HER2-positive metastatic breast cancer (mBC)

Evolving therapy, improving outcomes Kadcyla®W (trastuzumab emtansine): The first antibody-drug conjugate (ADC) for patients with HER2-positive mBC1 Indication1 Kadcyla, as a single agent, is indicated for the treatment of adult patients with HER2-positive, unresectable locally advanced or metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have either: t Received prior therapy for locally advanced or metastatic disease, or t Developed disease recurrence during or within six months of completing adjuvant therapy.

ABRIGED PRESCRIBING INFORMATION (For full prescribing information refer to the Summary of Product Characteristics [SmPC]) KADCYLA®W(trastuzumab emtansine) 100 mg powder for concentrate for solution for infusion, 160 mg powder for concentrate for solution for infusion. Indications: Treatment as a single agent of adult patients with HER2-positive, unresectable locally advanced or metastatic breast cancer who previously received trastuzumab and a taxane, separately or in combination. Patients should have received prior therapy for locally advanced or metastatic disease, or developed disease recurrence during or within six months of completing adjuvant therapy. Dosage and Administration: Kadcyla should only be prescribed by a physician and administered under the supervision of a HCP who is experienced in the treatment of cancer patients. Patients should have HER2-positive tumour status, scored as 3 + by immunohistochemistry or a ratio of ≥ 2.0 by in situ hybridization. To prevent medication errors check vial labels to ensure the medicinal product being prepared and administered is Kadcyla (trastuzumab emtansine) and not Herceptin (trastuzumab). Kadcyla should be administered by a healthcare professional at a dose of 3.6 mg/kg as an intravenous (IV) infusion every 3 weeks (21 day cycle) until disease progression or unacceptable toxicity. Kadcyla should not be mixed with glucose. Use of 0.22 micron in-line polyethersulfone (PES) filter is required for the infusion when the concentrate for infusion is diluted with sodium chloride 9 mg/ml (0.9%) soln for infusion. Initial dose should be administered as 90 minute IV infusion, followed by 90 minutes of observation for infusion-related reactions (IRR’s). If well tolerated, subsequent doses may be administered as 30 minute infusion, followed by 30 minutes of observation. If a dose is missed, it should be administered as soon as possible, adjust the dosing schedule to maintain a 3-week interval between doses. Dose Modification: management of symptomatic adverse event may require temporary interruption, dose reduction or treatment discontinuation. First dose reduction 3mg/kg, second dose reduction 2.5 mgs/kg, if there is a requirement for further dose reduction, discontinue treatment. Kadcyla dose should not be re-escalated after a dose reduction is made. Refer to SmPC for information on dose modification guidelines for increased transaminases (AST/ALT), hyperbilirubinemia, thrombocytopenia, peripheral neuropathy and left ventricular dysfunction. No dose adjustment requirement in elderly. No dose adjustment to the starting dose in needed in patients with mild or moderate renal impairment, patients with severe renal impairment should be monitored carefully. Safety and efficacy has not been studied in patients with hepatic impairment no specific dose reductions can be made. Safety and efficacy has not been established in children and adolescents. Refer to SmPC for further details. Contraindications: Hypersensitivity to active substance or any excipients. Warning and Precautions: In order to improve traceability the trade name of the administered product should be clearly recorded in the patient file. Cases of interstitial lung disease (ILD), including pneumonitis some leading to respiratory distress syndrome or a fatal outcome have been reported, patients with dyspnoea due to complications of advanced malignancy and co morbidities may be at increased risk of pulmonary events. Discontinue treatment in patients diagnosed with ILD and pneumonitis refer to SmPC for further details. Hepatotoxicity in the form of asymptomatic increases in serum transaminases has been reported, transaminase elevations were generally transient with peak elevation after day 8, cumulative effect observed, improvements to grade 1 or normal within 30 days of last dose of Kadcyla in majority of cases. Liver function should be monitored prior to initiation of treatment and each dose. Patients with baseline elevation of ALT may be predisposed to liver injury with a higher risk of a Grade 3-5 hepatic event or liver function test increase refer to SmPC for dose modifications. Serious hepatobiliary disorders including nodular regenerative hyperplasia (NRH) some with a fatal outcome have been observed. Diagnosis of NRH can only be confirmed by histopathology. Consider NRH in patients with clinical symptoms of portal hypertension and cirrhosis- like patterns confirmed by CT scan of liver but with normal transaminases and no other manifestations of cirrhosis. Discontinue treatment with Kadcyla in patient diagnosed with NRH. Discontinue Kadcyla in patients with serum transaminases >3 × ULN and concomitant bilirubin >2 × ULN, refer to SmPC for further details. Left ventricular ejection fraction (LVEF) < 40% has been observed in patients treated with Kadcyla. Risk factors for a cardiac event include advancing age (>50 yrs), low baseline LVEF values (<55%), low LVEF prior to or following paclitaxel in the adjuvant setting, prior or concomitant use of antihypertensives, previous treatment with anthracyclines and high BMI (> 25 kg/m2 ). Baseline cardiac function testing should be performed and every 3 months during treatment. Kadcyla dose should be delayed or treatment discontinued as necessary in cases of LVEF. See SmPC for further details. Do not administer Kadcyla in patients who had Herceptin permanently discontinued due to infusion related reactions. Observe closely for IRR’s, symptoms reported: flushing, chills, pyrexia, dyspnoea, hypotension, wheezing, bronchospasm, and tachycardia. Reactions resolved over several hours to a day after the infusion was terminated. Treatment should be interrupted in patients with a severe IRR and terminated in the event of a life threatening IRR, refer to SmPC. Do not administer Kadcyla in patients who had Herceptin permanently discontinued for hypersensitivity reactions. Observe closely for hypersensitivity/allergic reaction. Discontinue Kadcyla in event of true hypersensitivity reaction refer to SmPC. Patients with thrombocytopenia and patients on anti-coagulant treatment should be monitored closely. Monitor platelet counts prior to each dose. Cases of bleeding events with a fatal outcome have been observed. Kadcyla has not been studied in patients with platelet count of (≤ 100,000/mm3) prior to initiation of therapy. Refer to SmPC for dose modifications. Peripheral neuropathy has been reported. Treatment with Kadcyla should be temporarily discontinued in patients experiencing G3/4 peripheral neuropathy until symptoms resolve or improve refer to SmPC. Patients should be clinically monitored for signs/symptoms of neurotoxicity. This medicinal product contains less than 1mmol sodium (23mgs) per

dose. Drug Interactions: No formal interaction studies have been performed. In vitro metabolism studies suggest that concomitant use of strong CYP3A4 and CYP3A5 inhibitors should be avoided (e.g ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelﬁnavir, ritonavir, saquinavir, telithromycin, and voriconazole). If concomitant use of CYP3A4 inhibitors is unavoidable, consider a delay in administration of Kadcyla until the CYP3A4 inhibitor has cleared from circulation approximately 3 elimination half-lives of the inhibitors. If Kadcyla treatment cannot be delayed, patients should be closely monitored. Fertility, pregnancy and Lactation: Women of childbearing potential should use effective contraception during Kadcyla treatment and for 6 months following the ﬁnal dose. Animal studies indicate Kadcyla is teratogenic and potentially embryotoxic. The use of Kadcyla in pregnant and breast feeding women is not advised. Women should be informed of the possibility of harm to the foetus before they become pregnant. Women who become pregnant must immediately contact their doctor, close monitoring by the multidisciplinary team is recommended. Women may breast feed 6 months after concluding treatment. No reproductive and developmental toxicology studies with Kadcyla, refer to SmPC. Side effects and Adverse reactions: The most common serious adverse drug reactions seen in clinical trials with Kadcyla were pyrexia, thrombocytopenia, vomiting, abdominal pain, nausea, constipation, diarrhoea, dyspnoea and pneumonitis. Common ADR’s (≥25%) with Kadcyla were haemorrhage (including epistaxis), increased transaminases, fatigue, musculoskeletal pain, and headache. NCI-CTCAE G3/4 ADR’s (>2%) were thrombocytopenia, fatigue, increased transaminases, anemia, hypokalaemia, musculoskeletal pain and neutropenia. Very common reaction( ≥ 1/10): urinary tract infection, thrombocytopenia, anemia, hypokalaemia, insomnia, peripheral neuropathy, headache, dizziness, haemorrhage, epistaxis, cough, dyspnea, stomatitis, diarrhoea, vomiting, nausea, constipation, dry mouth, abdominal pain, rash, musculoskeletal pain, arthralgia, myalgia, fatigue, pyrexia, asthenia, chills, transaminases increased. Common reactions (≥1/100 to <1/10): neutropenia, leucopoenia, drug hypersensitivity, dysgeusia, memory impairment, dry eye, conjunctivitis, vision blurred, lacrimation increased, left ventricular dysfunction, hypertension, dyspepsia, gingival bleeding, pruritus, alopecia, nail disorder, palmar-plantar erythrodysaesthesia syndrome, urticaria, peripheral oedema, blood alkaline phosphatase increased, infusion related reactions. Laboratory abnormalities: Both hepatic and haematological abnormalities were observed refer to SmPC for further details. Serious or potentially serious: Pneumonitis (ILD), hepatotoxicity, hepatic failure, nodular regenerative hyperplasia, portal hypertension, Legal Category: POM. Presentations and Marketing Authorisation Numbers: EU/1/13/885/001 for 100mg/5 ml (pack size of ): EU/1/13/885/002 for 160mg/8ml (pack size of). Marketing Authorisation Holder: Roche Registration Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom Kadcyla® 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: 11th December 2013.

This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you become aware of. In the event of a suspected adverse event, please report it to:

Alternatively, suspected adverse reactions should be reported to:

The Drug Surveillance Centre Roche Products (Ireland) Limited Telephone: (01) 4690700 Fax: (01) 4690793 Email: ireland.drug_surveillance_centre@roche.com

The Pharmacovigilance Section The Irish Medicines Board Telephone: (01) 6764971 Fax: (01) 6762517 Website: www.imb.ie Email: imbpharmacovigilance@imb.ie

Reference: 1. Kadcyla Summary of Product Characteristics, dated 15th November 2013 (http://www.medicines.ie). Date of Item: June 2014. P38/05/14.

CANCER | RESEARCH

USING

FIREFLIES MECHANISM TO STUDY

TUMOUR RESPONSE

he mechanism that makes fireflies glow through a process called bioluminescence can be used to study tumor response to therapy as well, researchers have found. Led by Barjor Gimi, PhD of Dartmouth-Hitchcock’s Norris Cotton Cancer Centre and Ralph Mason, PhD from The University of Texas Southwestern Medical Centre at Dallas, United States, with first author Li Liu, PhD, the team published the findings in their paper “Dynamic bioluminescence and fluorescence imaging of the effects of the antivascular agent Combretastatin-A4P (CA4P) on brain tumor xenografts,” in Cancer Letters. “By using a model of multiple tumours in the same animal, we established a platform for more efficient studies requiring fewer animals,” explained Gimi. “Another benefit of the multiple tumours-same animal model is that it provides more consistency in interpreting results.” Bioluminescence has a major role in small animal research, and the technique has been widely applied in tumor models. The multiple tumor approach can also be used for high throughput screening of a vast range of anti-cancer drug therapies. In this study, investigators used dy-

namic bioluminescence imaging to study the effects of a tumor vascular disrupting agent, provided by OXiGENE, known as CA4P on subcutaneous 9L rat brain tumor xenografts in mice. A single dose of CA4P induced rapid, temporary tumor vascular shutdown, as revealed by a rapid and reproducible decrease of light emission. The vasculature showed distinct recovery within 24 hours post therapy, and multiple tumours behaved similarly. “The beauty of using bioluminescence is that it is relatively inexpensive, has no background signal, and has been validated against other imaging modalities,” said Gimi.

Looking forward, the collaborators intend to pursue further investigation using combinatorial approaches where all the tumours in a single animal are subject to the same systemic vascular disrupting agent, followed by a second, local, and tailored treatment. Barjor Gimi is an Associate Professor of Radiology and of Medicine at Dartmouth’s Geisel School of Medicine. His work in cancer is facilitated by Dartmouth-Hitchcock’s Norris Cotton Cancer Centre where he is a member of the Cancer Imaging and Radiobiology Research Program.

“Dynamic bioluminescence and fluorescence imaging of the effects of the antivascular agent Combretastatin-A4P (CA4P) on brain tumor xenografts,” was supported in part by funds from NIHR01 CA140674 and U24 CA126608, and facilitated by the Southwestern Small Animal Imaging and Live Cell Imaging Resources of the Harold C. Simmons Cancer Centre through an NCI Cancer Centre Support Grant, 1P30 CA142543. The Caliper IVIS Spectrum was purchased under NIH 1S10RR024757. Norris Cotton Cancer Centre combines advanced cancer research at Dartmouth and the Geisel School of Medicine with patient-centreed cancer care provided at Dartmouth-Hitchcock Medical Centre in Lebanon, NH, at Dartmouth-Hitchcock regional locations in Manchester, Nashua, and Keene, NH, and St. Johnsbury, VT, and at 12 partner hospitals throughout New Hampshire and Vermont. It is one of 41 centres nationwide to earn the National Cancer Institute’s “Comprehensive Cancer Centre” designation. Learn more about Norris Cotton Cancer Centre research, programs, and clinical trials online at cancer.dartmouth.edu. NIHR01 CA140674; U24 CA126608; 1P30 CA142543; NIH 1S10RR024757; Cancer Letters.

THE CLINICAL CARE JOURNAL | 23

RESEARCH | CANCER

INVESTIGATORS DISCOVER MECHANISM RESPONSIBLE FOR

TUMOUR INVASION IN GLIOBLASTOMA

neuro-oncology research team at Dartmouth’s Norris Cotton Cancer Center, led by the Director Mark A. Israel, MD with first author Gilbert J. Rahme, PhD has identified the transcription factor Id4 as a suppressor of tumor cell invasion in glioblastoma. Their paper, “Id4 suppresses MMP2mediated invasion of glioblastomaderived cells by direct inactivation of Twist1 function,” was recently published in Oncogene. A key finding was the mechanism by which Id4 silences matrix metalloproteinase 2 (MMP2), determined to be inhibition of the protein Twist1 that is required for MMP2 expression. “This finding suggests a novel therapeutic target to decrease invasion of tumor cells in patients and may also provide a novel biomarker that could help predict survival of patients with glioblastoma,” explained Israel. Glioblastoma is the most lethal form of primary brain tumor and leads to death in patients by invading the brain tissue in a process that allows single cells to move through normal brain tissue, which makes complete surgical removal of the tumor impossible. Israel and his team sought to understand the mechanisms that drive tumor invasion of normal tissue in glioblastoma. Using data from The Cancer Genome Atlas (TCGA), the Dartmouth team demonstrated that Id4 expression correlates with survival of glioblastoma patients and inversely correlates with MMP2 expression. The data suggests that the upregulation of MMP2 resulting from decreased Id4 expression in glioblastoma multiforme (GBM) may

24 | THE CLINICAL CARE JOURNAL

This finding suggests a novel therapeutic target to decrease invasion of tumor cells in patients and may also provide a novel biomarker that could help predict survival of patients with glioblastoma

contribute to the morbidity and mortality of GBM patients. This study used Dartmouth’s Shared Resources including Microscopy and Molecular Biology. “Using the core facilities greatly facilitated the conduct of the work saving time and reducing cost,” Rahme said. All 14 of Dartmouth’s Shared Resources are available to outside investigators by arrangement. “Conventional drugs targeting the enzymes encoded by MMP genes have not been successful in the clinic due to adverse side effects,” said Rahme. “We believe that proteins in the pathway that controls the expression of MMP2 are likely to be better therapeutic targets. Targeting Twist1 might silence MMP2 and decrease tumor invasion, which will help patients with GBM. Furthermore, the expression of Id4 may serve as a tumor biomarker that can predict the degree of tumor inﬁltration.” Looking forward, the therapeutic targets revealed in this study to be actors in tumour invasion need to be further characterized as drug targets and, if possible, therapeutically inhibited. Their pursuit of Id4 as a biomarker for patients with GBM continues in hopes of making

useful predictions of tumor invasion and survival. Israel is the Preston T. and Virginia R. Kelsey Distinguished Chair in Cancer and Professor of Pediatrics and of Genetics at Dartmouth’s Geisel School of Medicine. He is the Director of Norris Cotton Cancer Center at Geisel and the Dartmouth-Hitchcock Medical Center. Rahme is a graduate student in the Genetics Department at Geisel. This study was supported by a Hitchcock foundation grant for Rahme. Israel’s work was supported by the Jordan and Kyra Memorial Foundation, and the Theodora B. Betz Foundation. Norris Cotton Cancer Center combines advanced cancer research at Dartmouth and the Geisel School of Medicine with patient-centered cancer care provided at Dartmouth-Hitchcock Medical Center in Lebanon, NH, at Dartmouth-Hitchcock regional locations in Manchester, Nashua, and Keene, NH, and St. Johnsbury, VT, and at 12 partner hospitals throughout New Hampshire and Vermont. It is one of 41 centers nationwide to earn the National Cancer Institute’s “Comprehensive Cancer Center” designation.

STRENGTHEN HER

PROTECTION Indication: PERJETA® is indicated for use in combination with trastuzumab and docetaxel for the treatment of adult patients with HER2-positive metastatic or locally recurrent unresectable breast cancer, who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease.

ABRIDGED PRESCRIBING INFORMATION (For full prescribing information refer to the summary of product characteristics [SmPC]) PERJETA®▼ (pertuzumab) 420 mg, 30mgs/ml concentrate for solution for infusion Indications: In combination with trastuzumab and docetaxel for the treatment of adult patients with HER2-positive metastatic or locally recurrent unresectable breast cancer, who have not received previous anti-HER2 therapy or chemotherapy for their metastatic disease. Dosage and Administration: Please refer to Perjeta Summary of Product Characteristics (SmPC) for full guidance. Perjeta is for use in adults only. Treatment should be initiated under the supervision of a physician experienced in the administration of anti-cancer agents. Perjeta should be administered by a health care professional prepared to manage anaphylaxis and in an environment with full resuscitation facilities immediately available. Administer as an intravenous (IV) infusion (not as an IV push or bolus) through a dedicated line. Patients treated with Perjeta must have HER2-positive tumour status, defined as a score of 3+ by immunohistochemistry (IHC) and/or a ratio of >2.0 by in situ hybridisation (ISH) assessed by a validated test, refer to SmPC for further details. The recommended initial loading dose is 840 mg administered as a 60 minute intravenous infusion, followed every 3 weeks thereafter by a maintenance dose of 420mg administered over a period of 30-60 minutes. When administered with Perjeta the recommended initial loading dose of trastuzumab is 8mg/kg body weight administered as an intravenous infusion followed every 3 weeks thereafter by a maintenance dose of 6mg/kg bodyweight. When administered with Perjeta the recommended initial dose of docetaxel is 75mg/m2, administered thereafter on a 3-weekly schedule. The dose of docetaxel may be escalated to 100mg/m2 on subsequent cycles if the initial dose is well tolerated. The medicinal products should be administered sequentially. Perjeta and trastuzumab can be given in any order. When the patient is receiving docetaxel, the docetaxel should be administered after Perjeta and trastuzumab. An observation period of 30-60 mins is recommended after each Perjeta infusion before commencement of any subsequent infusion with trastuzumab or docetaxel. If a patient develops an infusion related reaction interrupting or slowing the infusion may help control symptoms; resume when symptoms abate. Treatments include oxygen, beta agonists, antihistamines, rapid i.v fluids and antipyretics may also help alleviate symptoms. Discontinue if patient experienced (NCI-CTCAE) grade 4 reaction (anaphylaxis), bronchospasm or acute respiratory distress syndrome, refer to SmPC for further details. Not recommended in patients <18 years of age. Dose adjustments are not needed in patients with mild or moderate renal failure. No data in severe renal impairment or hepatic impairment. Administer until disease progression or unmanageable toxicity. Refer to SmPC for guidelines on missed doses. Dose modifications: Dose reduction not recommended. Patients may continue treatment during periods of reversible chemotherapy-induced myelosuppression but should be monitored for complications of neutropenia, for docetaxel dose modifications refer to docetaxel SmPC. Dose reduction not recommended for trastuzumab, refer to trastuzumab SmPC. If trastuzumab is discontinued, Perjeta treatment should be discontinued. If docetaxel is discontinued, continue treatment with Perjeta until disease progression or unmanageable toxicity. Left ventricular dysfunction: Perjeta and trastuzumab should be withheld for at least 3 weeks if signs and symptoms suggestive of congestive heart failure, a drop in left ventricular ejection fraction (LVEF) to less than 40% or a LVEF of 40-45% associated with a fall of ≥10% points below pre-treatment values. Treatment with Perjeta and trastuzumab may be resumed if LVEF has recovered to >45% or 40-45% associated with <10% points below pre-treatment values. Repeat LVEF assessment within 3 weeks. If LVEF does not improve or further declines consider discontinuation of Perjeta and trastuzumab, refer to SmPC for further details. Contraindications: Severe hypersensitivity reactions (NCI-CTCAE Grade 4) to pertuzumab or to any of the excipients. Warning and Precautions: Please refer to the Perjeta SmPC for further information. Perjeta has not been studied in patients with: a pre-treatment LVEF value of <50%; a prior history of congestive heart failure (CHF); LVEF declines to <50% during prior trastuzumab adjuvant therapy; or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to >360mg/m2 of doxorubicin or its equivalent. Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of LVEF declines. Assess LVEF prior to initiation of Perjeta and at regular intervals (e.g. every three months) during treatment. If LVEF is <40% or 40-45% associated with ≥10% points below the pretreatment value, Perjeta and trastuzumab should be withheld and a repeat LVEF assessment performed within approximately 3 weeks. If the LVEF has not improved, or has declined further, discontinuation of Perjeta and trastuzumab should be strongly considered. Perjeta has been associated with infusion and hypersensitivity reactions. Close observation of the patient during and for 60 minutes after the first infusion and during and for 30-60 minutes after subsequent infusions is recommended following the administration of Perjeta. If an infusion-reaction occurs, the infusion should be slowed down or interrupted and appropriate medical therapies should be administered. Patients should be evaluated and carefully monitored until complete resolution of signs and symptoms. Permanent discontinuation should be strongly considered for any patient who experiences a severe (NCI-CTCAE Grade 4) infusion reaction. Patients treated with Perjeta, trastuzumab and docetaxel are at increased risk of febrile neutropenia compared with patients treated with placebo, trastuzumab and docetaxel, especially during the first 3 cycles of treatment. Higher incidences of febrile neutropenia in Perjeta treated patients may be associated with the higher incidence of mucositis and diarrhoea in these patients. Symptomatic treatment for mucositis and diarrhoea should be considered. Drug Interactions: No formal interactions studies have been performed. No pharmacokinetic interactions were observed between Perjeta and trastuzumab, or between Perjeta and docetaxel in the pivotal trial. No evidence of effects of Perjeta on the PK of docetaxel, gemcitabine, erlotinib and capecitabine. Fertility, Pregnancy and Lactation: Avoid during pregnancy unless potential benefit outweighs risk. Women of childbearing potential should use effective contraception while receiving Perjeta and for 6 months following the last dose of Perjeta. A decision should be made to discontinue breast- feeding or to discontinue treatment taking into account the benefit of nursing for the child and the benefit of Perjeta therapy for the woman. Side-effects and adverse reactions: Please refer to the Perjeta SmPC for

further information. In the pivotal clinical trial Perjeta was given in combination with docetaxel and trastuzumab, it is therefore, difficult to ascertain the causal relationship of an adverse event to a particular medicinal product. The safety of Perjeta in phase I and II studies was generally consistent with that observed in the pivotal trial, though the incidence and most common ADRs varied depending on whether Perjeta was administered as monotherapy or with concomitant antineoplastic agents. Very common reactions: Upper respiratory tract infection, nasopharyngitis, febrile neutropenia*, neutropenia, leucopenia, anaemia, hypersensitivity/anaphylactic reaction, infusion related reaction/ cytokine release syndrome, decreased appetite, insomnia, peripheral neuropathy, peripheral sensory neuropathy, headache, dizziness, dysgeusia, lacrimation increased, dyspnoea, cough, diarrhoea, vomiting, stomatitis, nausea, constipation, dyspepsia, alopecia, rash, nail disorder, pruritus, dry skin, myalgia, arthralgia, mucositis/mucosal inflammation, pain, oedema, pyrexia, fatigue, asthenia. Common reactions: paronychia, left ventricular dysfunction (including congestive heart failure), pleural effusion, chills. *Denotes events with a fatal outcome. Laboratory abnormalities: In the pivotal trial, the incidence of NCI-CTCAE (version 3) Grade 3-4 neutropenia was balanced in the two treatment groups. Serious or Potentially Serious: Left venticular dysfunction, anaphylaxis, febrile neutropenia and interstitial lung disease. Legal Category: Limited to sale and supply on prescription only. Presentation and Market marketing authorisation number: EU/1/13/813/001 for 420mg/14ml (pack size of one). Marketing Authorisation Holder: Roche Registration Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, United Kingdom. Perjeta is a registered trade mark. Further information is available from Roche Products (Ireland) Limited, 3004 Lake Drive, Citywest, Naas Rd, Dublin 24. Telephone (01) 4690700. Fax (01) 4690791. Date of Preparation: November 2013.

Alternatively, suspected adverse reactions should be reported to:

The Drug Surveillance Centre Roche Products (Ireland) Limited Telephone: (01) 4690700 Fax: (01) 4690793 Email: ireland.drug_surveillance_centre@roche.com

The Pharmacovigilance Section The Irish Medicines Board Telephone: (01) 6764971 Fax: (01) 6762517 Website: www.imb.ie Email: imbpharmacovigilance@imb.ie

References: 1. Perjeta Summary of Product Characteristics dated 13th September 2013 (http://www.medicines.ie). 2. Scheuer W et al. Cancer Res 2009, 69:9330-9336. 3. Baselga J. Ann Oncol. 2010;21(suppl 7); vii36-vii40. Enhanced Safety Reporting for Potential Perjeta-Exposed Pregnancies Perjeta should be avoided during pregnancy. There is limited amount of data from the use of Perjeta in pregnant women and the safe use of Perjeta during pregnancy and lactation has not been established. Verify pregnancy status prior to the initiation of PERJETA. Women of child bearing potential should use effective contraception while receiving Perjeta and for 6 months following the last dose of Perjeta. Monitor patients who become pregnant during PERJETA therapy or within 6 months following the last dose of PERJETA closely for oligohydramnios. If PERJETA is used during pregnancy or if a patient becomes pregnant while being treated with PERJETA or within 6 months following the last dose of PERJETA, immediately report exposure to the local Roche Adverse Event Line at Tel: (01) 4690700, Fax: (01) 4690793, Email: ireland.drug_surveillance_centre@roche.com, Out of Hours: (01) 2910943. Additional information will be requested during a PERJETA-exposed pregnancy and the first year of the infant’s life. This will enable Roche/ Genentech to better understand the safety of PERJETA and to provide appropriate information to Health Authorities, Healthcare Providers and patients.

Date of Item: June 2014 P37/05/14

WITH XGEVA® YOU CAN GIVE YOUR PATIENTS BETTER PROTECTION FROM SREs† vs ZOLEDRONIC ACID1,2

PRECISE. PROVEN. PRACTICAL. XGEVA® T (denosumab) Brief Prescribing Information Please refer to the Summary of Product Characteristics (SmPC) before prescribing XGEVA®. Pharmaceutical Form: 1.7 ml solution for injection presented as a single use vial containing 120 mg of denosumab. Contains sorbitol (E420). Indication: Prevention of skeletal related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with bone metastases from solid tumours. Dosage and Administration: Single subcutaneous injection of XGEVA® 120 mg given once every 4 weeks. No dosage adjustment is required in patients with renal impairment or in elderly patients (age ≥ 65). Patients must be supplemented daily with at least 500 mg calcium and 400 IU vitamin D unless hypercalcaemia is present. Not recommended in paediatric patients (under 18 years of age). Contraindications: Severe, untreated hypocalcaemia or hypersensitivity to the active substance or to any of the excipients. Special Warnings and Precautions: Pre-existing hypocalcaemia must be corrected prior to initiating therapy with XGEVA®. Hypocalcaemia can occur at any time during therapy. Monitoring of calcium should be conducted prior to initial dose, within two weeks of initial dose and if suspected symptoms of hypocalcaemia occur. Severe symptomatic hypocalcaemia has been reported. Consider additional monitoring of calcium level in patients with risk factors for hypocalcaemia or if otherwise indicated based on clinical condition of the patient. Patients with severe renal impairment (creatinine clearance < 30 ml/min) or receiving dialysis are at greater risk of developing hypocalcaemia; this risk and accompanying elevations in parathyroid hormone increases with increasing degree of renal impairment. Regular monitoring of calcium levels in these patients is especially important. If hypocalcaemia occurs while receiving XGEVA®, additional calcium supplementation and additional monitoring may be necessary. Osteonecrosis of the jaw (ONJ) has occurred commonly in patients treated with XGEVA®. In clinical trials, the incidence of ONJ was higher with longer duration of exposure. For information on known risk factors for ONJ, please refer to the SmPC. In patients with risk factors for ONJ, an individual beneﬁt:risk assessment should be performed before initiating therapy with XGEVA®. A dental examination with appropriate preventive dentistry is recommended. XGEVA® should not be initiated in patients with an active dental or jaw condition requiring surgery or in patients who have not recovered following oral surgery. Patients should be encouraged to maintain good oral hygiene practices and receive routine dental check-ups during treatment with XGEVA®. Patients should avoid invasive dental procedures if possible while on treatment. For patients who develop ONJ while on XGEVA® therapy dental surgery may exacerbate the condition. The management plan of individual patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Atypical femoral fracture (AFF) has been reported in patients receiving XGEVA®. Discontinuation of XGEVA® therapy in patients suspected to have AFF should be considered pending evaluation of the patient based on an individual beneﬁt risk assessment. Patients being

treated with XGEVA® should not be treated concomitantly with other denosumab containing medicinal products (for osteoporosis indications) or with bisphosphonates. Patients with rare hereditary problems of fructose intolerance should not use XGEVA®. Interactions: No interaction studies have been performed. Pregnancy and lactation: There are no adequate data on the use of XGEVA® in pregnant women. Not recommended for use in pregnant women or women of childbearing potential not using contraception. It is unknown whether XGEVA® is excreted in human milk. A risk/benefit decision should be made in patients who are breast-feeding. No data are available on the effect of XGEVA® on human fertility. Undesirable Effects: Adverse reactions in patients receiving XGEVA® to prevent the occurrence of skeletal related events: very common (≥ 1/10) dyspnoea, diarrhoea and musculoskeletal pain; common (≥ 1/100 to < 1/10) hypocalcaemia, hypophosphataemia, tooth extraction, hyperhidrosis and osteonecrosis of the jaw; rare (≥ 1/10,000 to < 1/1000) drug hypersensitivity, anaphylactic reaction, atypical femoral fracture. In 3 phase III clinical trials, ONJ was confirmed in 1.8% of patients treated with XGEVA® and 1.3% of patients treated with zoledronic acid (primary treatment phase). Among subjects with confirmed ONJ, most (81% in both treatment groups) had a history of tooth extraction, poor oral hygiene, and/ or use of a dental appliance. Hypocalcaemia was reported in 9.6% of patients treated with XGEVA® and 5.0% of patients treated with zoledronic acid. Neutralizing antibodies have not been observed in clinical studies. In the postmarketing setting, severe symptomatic hypocalcaemia (including fatal cases), hypersensitivity (including rare events of anaphylactic reaction) and musculoskeletal pain (including severe cases) have been reported. Please consult the SmPC for a full description of undesirable effects. Pharmaceutical Precautions: Do not mix with other medicinal products. Store at 2°C to 8°C (in a refrigerator). XGEVA® may be stored at room temperature (up to 25°C) for a maximum single period of up to 30 days in its original container. Once removed from the refrigerator, XGEVA® must be used within this 30 day period. Do not freeze. Keep vial in outer carton to protect from light. XGEVA® solution should be inspected visually before administration. Do not inject the solution if it is cloudy or discoloured. Legal Category: POM. Presentation, Basic Costs and Marketing Authorisation Number: XGEVA®120 mg: Pack of 1, EU/1/11/703/001. Price in Republic of Ireland is available on request. Marketing Authorisation Holder: Amgen Europe B.V., Minervum 7061, NL-4817 ZK Breda, The Netherlands. Further information is available from Amgen Limited, 240 Cambridge Science Park, Milton Road, Cambridge, CB4 0WD. XGEVA® is a registered trademark of Amgen Inc. Date of PI preparation: August 2014 (Ref: DMOIRL-AMG-111-2014-P). This medicinal product is subject to additional monitoring. Adverse events should be reported directly to HPRA Pharmacovigilance, Earlsfort Terrace, IRL-Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, website: www.hpra.ie, e-mail: medsafety@hpra.ie. Adverse events should also be reported to Amgen Limited on +44 (0)1223 436712

References: 1. XGEVA®. Summary of Product Characteristics 2. Litpon et al. Eur J Cancer 2012;48 (16) 3082-3092. † XGEVA is indicated for the prevention of skeletal related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with bone metastases from solid tumours. #

The integrated analysis was a pre-speciﬁed analysis of 3 head to head studies (breast cancer, prostate cancer and other solid tumours including 3% multiple myeloma). XGEVA is not licensed in multiple myeloma.

LUNG CANCER

IRREVERSIBLE INHIBITOR IDENTIFIED FOR

KRAS GENE MUTATION INVOLVED IN LUNG, COLON, AND PANCREATIC CANCERS

ancer researchers in UT Southwestern Medical Center in Dallas, Texas, US have found a molecule that selectively and irreversibly interferes with the activity of a mutated cancer gene common in 30 percent of tumours. The molecule, SML-8-73-1 (SML), interferes with the KRAS gene, or Kirsten rat sarcoma viral oncogene homolog. The gene produces proteins called K-Ras that inﬂuence when cells divide. Mutations in K-Ras can result in normal cells dividing uncontrollably and turning cancerous. These mutations are particularly found in cancers of the lung, pancreas, and colon. In addition, people who have the mutated gene are less responsive to therapy. Researchers have unsuccessfully tried to develop a drug to inhibit K-Ras for some 30 years. “RAS proteins including KRAS have not been ‘druggable’ for many decades despite a lot of effort from academia and industry,” said senior author Dr. Kenneth Westover, Assistant Professor of Radiation Oncology and Biochemistry, and a member of UT Southwestern’s Harold C. Simmons Cancer Center. “We are exploring irreversible inhibitors as a solution, which we believe may pave the way for the development of KRAS-targeted compounds with therapeutic potential and perhaps compounds that target other RAS family proteins involved in cancer,” Dr. Westover said. Dr. Westover works as both a clinician as a member of the Lung Radiation Oncology Team at the Simmons Cancer Center, and as a researcher. The Westover laboratory investigates the molecular basis of cancer with an eye toward developing compounds that perturb cancer biology, and therefore have potential to become therapies. Dr. Westover’s lab has been particularly targeting KRAS because this gene is the most commonly mutated oncogene in cancer. Building on previous work, Dr.

Westover and fellow investigators used a technique called X-ray crystallography to determine what happens when SML is added to KRAS carrying the G12C mutation, a hallmark of tobacco-associated lung cancer and present in 25,000 of the new cases of lung cancer in the U.S. annually. Researchers found that SML irreversibly binds to mutated KRAS, making the KRAS G12C inactive. SML competes with molecules that KRAS naturally binds to, called GTP and GDP, and is not removable, even when GTP and GDP are present at very high levels. This attribute is what makes SML an irreversible inhibitor – neither GDP nor GTP are able to knock it off and take its place. The researchers then used a technique called mass spectrometry to determine that SML is not only irreversible, but selective – binding only to KRAS and not the roughly 100 other

members of the RAS protein family that have very similar structures. “We believe SML may be the ﬁrst irreversible and selective inhibitor of KRAS,” said Dr. Westover, who was recruited to UT Southwestern with funds from the state-funded Cancer Research and Prevention Institute of Texas. “As a next step, we are improving the SML compound to facilitate studies involving living cancer cells, and eventually animals and humans.” Other UT Southwestern researchers involved include DR. ZHE CHEN, Assistant Professor of Biophysics, and postdoctoral researchers DR. JOHN HUNTER, first author, DR. DEEPAK GURBANI, and DR. MARTIN CARRASCO, in Radiation Oncology and Biochemistry. The research, published online in the journal Proceedings of the National Academy of Sciences, was supported by funds from the Cancer Research and Prevention Institute of Texas, and The Welch Foundation.

THE CLINICAL CARE JOURNAL | 27

New indication

When their prostate cancer progresses to mCRPC (metastatic castrate-resistant prostate cancer), take direct control and help keep life the way it is now for longer.1,2 XTANDI is now indicated for the treatment of adult men with mCRPC who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy, in whom chemotherapy is not yet clinically indicated.1 Its novel mechanism of action3 offers significant improvements in overall survival vs. placebo.2 XTANDI pushes the time to chemotherapy from months to years; maintaining quality of life for significantly longer vs. placebo. With dosing that’s simple and convenient, XTANDI is a generally well-tolerated treatment.1,2 Treat what really matters in mCRPC, treat with XTANDI.

Xtandi (enzalutamide) 40mg soft capsules. Prescribing Information: Please read the Summary of Product Characteristics (SPC) before prescribing. Presentation: Xtandi 40 mg soft capsules each containing 40 mg of enzalutamide. Indication: Xtandi is indicated for the treatment of adult men with metastatic castration resistant prostate cancer who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated. It is also indicated for treatment of adult men with metastatic castrationresistant prostate cancer whose disease has progressed on or after docetaxel therapy. Posology and administration: The recommended dose is 160 mg enzalutamide (four 40 mg capsules) as a single oral daily dose. Medical castration with an LHRH analogue should be continued during treatment of patients not surgically castrated. For further details please refer to the SPC. Contra-indications: Hypersensitivity to the active substance or to any of the excipients. Women who are, or who may become, pregnant. Precautions and warnings: Caution should be used in administering Xtandi to patients with a history of seizures or other predisposing factors. The risk of seizure may be increased in patients receiving concomitant medicinal products that lower the seizure threshold. Caution is required in patients with severe renal impairment as enzalutamide has not been studied in this patient population. Caution is required in patients with moderate hepatic impairment. Xtandi contains sorbitol (E420). Patients with rare hereditary problems of fructose intolerance should not take this medicinal product. Interactions: Strong inhibitors (e.g. gemfibrozil) or inducers (e.g. rifampicin) of CYP2C8 are to be avoided or used with caution during enzalutamide treatment. If patients must be co-administered a strong CYP2C8 inhibitor, the dose of enzalutamide should be reduced to 80 mg once daily CYP3A4 plays a minor role in the metabolism of enzalutamide. No dose adjustment is necessary when Xtandi is co-administered with inhibitors or inducers of CYP3A4. Enzalutamide is a potent enzyme inducer and increases the synthesis of many enzymes and transporters; therefore, interaction with many common medicinal products that are substrates of enzymes or transporters is expected. Enzymes that may be induced include CYP3A4 in the liver and gut, CYP2C9, CYP2C19, CYP1A2 and uridine 5’-diphospho-glucuronosyltransferase (UGTs - glucuronide conjugating enzymes). The transport protein P-gp may also be induced, and probably other transporters as well, e.g. multidrug resistance-associated protein 2 (MRP2), breast cancer resistant protein (BCRP) and the organic anion transporting polypeptide 1B1 (OATP1B1). In vivo studies have shown that enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. The full induction potential of enzalutamide may not occur until approximately 1 month after the start of treatment, when steady-state plasma concentrations of enzalutamide are reached, although some induction effects may be apparent earlier. Patients taking medicinal products that are substrates of CYP3A4, CYP2C9, CYP2C19, CYP1A2 or UGT1A1 should be evaluated for possible loss of pharmacological effects (or increase in effects in cases where active metabolites are formed) during the first month of enzalutamide treatment, and dose adjustment should be considered as appropriate. If their therapeutic effect is of large importance to the patient, and dose adjustments are not easily performed based on monitoring of efficacy or plasma concentrations, these medicinal products are to be avoided or used with caution. In consideration of the long half-life of enzalutamide (5.8 days), effects on enzymes may persist for one month or longer after stopping enzalutamide. A gradual dose reduction of the concomitant medicinal product may be necessary when stopping enzalutamide treatment. In vitro data indicate that enzalutamide may be an inhibitor of the efflux transporter P-gp. The effect of enzalutamide on P-gp substrates has not been evaluated in vivo; however, under conditions of clinical use, enzalutamide may be an inducer of P-gp via activation of the nuclear pregnane receptor (PXR). Medicinal products with a narrow therapeutic range that are substrates for P-gp (e.g. colchicine, dabigatran etexilate, digoxin) should be used with caution when administered concomitantly with Xtandi and may require dose adjustment to maintain optimal plasma concentrations. The safety and efficacy of concomitant use of Xtandi with cytotoxic chemotherapy has not been established. Fertility, Pregnancy and lactation: Enzalutamide is not for use in women. Enzalutamide is contraindicated in women who are, or who may become, pregnant. If the patient engages in sexual intercourse with a woman of childbearing potential, a condom and another form of birth control must be used during and for 3 months after treatment. Undesirable effects: Very Common (≥ 1/10): Asthenia, fatigue, headache, hot flush; hypertension. Common (≥ 1/100 to < 1/10):, anxiety, memory impairment, amnesia, dry skin, pruritus, fractures, falls, gynaecomastia, disturbance in attention, restless leg syndrome; Uncommon (≥ 1/1,000 to < 1/100): cognitive disorders, neutropenia, leucopenia, *seizure, visual hallucinations. (*In the phase 3 clinical, 7 patients (0.4%) experienced a seizure out of 1671 patients treated with a daily dose of 160 mg enzalutamide, whereas one patient (<0.1%) receiving placebo experienced a seizure). Please refer to SPC for further details of other side effects. Legal category: POM/S1A. Marketing Authorisation numbers: EU/1/13/846/001. Marketing Authorisation holder: Astellas Pharma Europe B.V. Sylviusweg 62,2333 BE Leiden,The Netherlands. Further information is available from; Astellas Pharma Co. Ltd., 5 Waterside, Citywest Business Campus, Dublin 24. Ph:+353 1467 1555. Summary of Product Characteristics with full prescribing information available upon request. Reporting suspected adverse events after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinial product. Healthcare professionals are asked to report any suspected adverse events via HPRA Pharmacovigilnce, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6764971 Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie. Job number: XTD14051IE Date of preparation of API: Dec 2014 XTD 14052IE Date of preparation: December 2014

References: 1. XTANDI Summary of Product Characteristics, 2014. 2. Beer TM et al. N Engl J Med 2014; 371: 424-33. 3. Tran C et al. Science 2009; 324(5928): 787–790.

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Reporting of 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 requested to report n suspected adverse events to: Health Products Regulatory Authority (Formerly IMB) Earlsfort Terrace IRL – Dublin 2 Tel: + 353 1 6764971 Fax: +353 1 6762517 E – mail: medsafety@hpra.ie Astellas Pharma Co., Ltd Tel: + 353 1467 1555 E- mail: Irishdrugsafety@astellas.com

BREAST CANCER

ASPIRIN &CANCER

In our study of almost 3,000 women with a breast cancer diagnosis, we found that regular pre-diagnostic aspirin use was associated with a 20 per cent lower risk of presenting with lymph node metastasis and a reduced risk of breast cancerspeciﬁc mortality, write Dr Thomas Ian Barron and Prof Kathleen Bennett.

cetylsalicylic acid was ﬁrst marketed as “Aspirin” by Bayer in 1899 for the treatment of pain or fever (1) and salicylate-containing plants, such as willow bark, have been referenced in pharmacopoeia for similar indications for more than 2,000 years.(1) More recently, in the 1970s, aspirin was also shown to have antiplatelet action and today it is commonly used for the prevention of cardiovascular disease.(2) Similarly, interest in the use of aspirin for the prevention and treatment of cancer also began in the 1970s,(3) however, despite considerable progress in understanding its potential

THE CLINICAL CARE JOURNAL | 29

In mHRPC after docetaxel . . .

SURVIVAL IN A DIFFERENT LIGHT Introducing JEVTANA®, a next generation taxane for the treatment of second-line mHRPC

Please read section 6.6 of the Jevtana Summary of Product Characteristics (SPC) before mixing and diluting. Jevtana requires TWO dilutions prior to administration.

Precautions and Warnings: Patients should be observed

For full information on Adverse Events please consult the Jevtana Summary of Product Characteristics.

IE.CAB.14.03.02

Date of preparation: April 2014

IE.CAB.14.04.01

BREAST CANCER

REFERENCES The next steps for our research will be to identify the molecular mechanisms underlying the inhibition of breast cancer metastasis by aspirin.

role as an anti-cancer agent, questions still remain about its possible benefit in patients with, or at risk of, developing cancer and its mechanism of action. Two recent meta-analyses of data from randomized trials of aspirin for cardiovascular disease prevention (4,5) have provided evidence to suggest that daily aspirin use is associated with up to a 21 per cent reduction in the risk of dying from any cancer. The short term effects of daily aspirin (<300 mg) use in the 51 randomised controlled trials, found that allocation to aspirin reduced deaths from cancer, particularly from five years of daily use onwards, and the effect was strongest for gastrointestinal cancers (4,5). Dose stratification did not appear to influence the observed risk estimates. In addition, aspirin significantly reduced the risk of incident cancer in women and men by about 25 per cent. Results such as these have fuelled interest in defining a therapeutic role for aspirin in cancer, and the United States’ National Cancer Institute has highlighted, identifying aspirin’s molecular mechanisms as a key question that will drive progress towards this. Several mechanisms have been proposed to explain reductions in cancer mortality associated with aspirin use.(6–8) One of these is that aspirin inhibits the development of lymphatic and distant metastases by reducing a tumor cell’s ability to invade local vasculature or survive while in circulation. We examined this

question in a recent Health Research Board funded study using linked cancer and prescribing data from the National Cancer Registry Ireland (NCRI) and the Health Services Executive Primary Care Reimbursement Services (HSEPCRS).(9) In our study of almost 3,000 women with a breast cancer diagnosis, we found that regular pre-diagnostic aspirin use was associated with a 20 per cent lower risk of presenting with lymph node metastasis, and a reduced risk of breast cancer-specific mortality. These analyses were adjusted for factors that may influence nodal status, including participation in screening mammography. Our results are supported by those from a meta-analysis of the effects of daily aspirin use on cancer metastasis from five large-scale randomized trials, that found allocation to aspirin was associated with a significant 36 per cent reduction in the risk of presenting with distant metastasis. (10) Together, these findings provide some insight into aspirin’s potential mechanism of action in breast cancer. The next steps for our research will be to identify the molecular mechanisms underlying the inhibition of breast cancer metastasis by aspirin, research that is targeted at the population level. In addition, to identify the types of breast cancer patients who would benefit most from taking aspirin, or most at risk of adverse effects of aspirin, the optimal dose and duration of treatment.

This work is being carried out as part of the BREAST PREDICT Collaborative Cancer Research Centre funded by the Irish Cancer Society. www.breastpredict.com DR THOMAS IAN BARRON, Trinity Centre for Health Sciences, St James’s Hospital, Dublin.

PROF KATHLEEN BENNETT, Trinity Centre for Health Sciences, St James’s Hospital, Dublin.

1. Jeffreys D. Aspirin: The Extraordinary Story of a Wonder Drug by Jeffreys, Diarmuid (2005) Paperback. Bloomsbury Publishing PLC; 1111. 2. Elwood PC, Cochrane AL, Burr ML, Sweetnam PM, Williams G, Welsby E, et al. A randomized controlled trial of acetyl salicylic acid in the secondary prevention of mortality from myocardial infarction. Br Med J. 1974;1:436–40. 3. Gasic GJ, Gasic TB, Murphy S. Antimetastatic effect of aspirin. Lancet. 1972;2:932–3. 4. Rothwell PM, Price JF, Fowkes FGR, Zanchetti A, Roncaglioni MC, Tognoni G, et al. Short-term effects of daily aspirin on cancer incidence, mortality, and nonvascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet. 2012;379:1602–12. 5. Rothwell PM, Fowkes FGR, Belch JFF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on longterm risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet. 2011;377:31–41. 6. Thun MJ, Jacobs EJ, Patrono C. The role of aspirin in cancer prevention. Nat Rev Clin Oncol. 2012;9:259–67. 7. Dovizio M, Bruno A, Tacconelli S, Patrignani P. Mode of action of aspirin as a chemopreventive agent. Recent Results Cancer Res. 2013;191:39–65. 8. Alfonso L, Ai G, Spitale RC, Bhat GJ. Molecular targets of aspirin and cancer prevention. Br J Cancer. 2014;111:61–7. 9. Barron TI, Flahavan EM, Sharp L, Bennett K, Visvanathan K. Recent Prediagnostic Aspirin Use, Lymph Node Involvement, and 5-Year Mortality in Women with Stage I-III Breast Cancer: A Nationwide Population-Based Cohort Study. Cancer Research. 2014;74:4065–77. 10. Rothwell PM, Wilson M, Price JF, Belch JFF, Meade TW, Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet. 2012;379:1591–601.

THE CLINICAL CARE JOURNAL | 31

RESEARCH | PROSTATE CANCER

FAVOURABLE

15-YEAR SURVIVAL OUTCOMES FOR OLDER PROSTATE CANCER PATIENTS WITH LOW-RISK DISEASE

esults from a populationbased study from investigators at Rutgers Cancer Institute of New Jersey, United States, show favourable survival outcomes among patients with low-risk prostate cancer treated with conservative management initially. revious research by the study’s lead author Grace Lu-Yao, PhD, MPH, cancer epidemiologist at the Cancer Institute of New Jersey and professor of medicine at Rutgers Robert Wood Johnson Medical School, and colleagues examined 10-year outcomes for this population (JAMA, Vol. 302, No. 11). The 2009 research showed men diagnosed with prostate cancer beginning in the early 1990s had significantly improved survival compared with patients whose cancers were diagnosed in prior decades. Given the protracted nature of the disease and increasing longevity among elderly men, 10-year follow-up may not be sufficient to make informed treatment decisions. Dr. Lu-Yao notes this new study, which extends data examination by an additional five years, “helps provide a more complete picture of potential outcomes for patients who have a life expectancy greater than 10 years.” The new research, which appeared in the online edition of European Urology (doi: 10.1016/j.eururo.2015.03.021), examined 33,137 Medicare patients aged 65 or older who were diagnosed with early-stage (T1 or T2) prostate cancer from 1992 through 2009 and received conservative management (no surgery, radiotherapy, cryotherapy or androgen deprivation therapy) within the first six months of diagnosis. The researchers utilised information from the Surveillance, Epidemiology and

32 | THE CLINICAL CARE JOURNAL

The information provided by this long-term study will help facilitate treatment decisions.

End Results (SEER) cancer registries and Medicare claims. All SEER registries hold the highest level of certiﬁcation of data quality. Investigators found that men aged 64 to 74 with a Gleason score (a grading system that indicates how likely a tumour will spread) of between ﬁve and seven had a lower risk (5.7 per cent) of dying from prostate cancer over a 15-year period as compared to men 75 and older, whose risk was 10.1 per cent. For men with the highest level Gleason scores (between eight and 10), 15-year prostate cancer mortality rates were 22 per cent for men aged 65 to 74 and 27 per cent for men 75 and older. The authors also note mortality rates remained relatively stable from six to 16 years following diagnosis. The work also examined if these men had comorbid diseases and found that those who did have other health problems had a lower risk of dying from prostate cancer due to deaths from competing health issues. “The proportion of men diagnosed with localized prostate cancer who choose to have conservative management is relatively small but, is on the rise. The information provided by this long-term study will help facilitate treatment deci-

sions,” says Lu-Yao. “Our study, which includes data from the PSA testing era, is a more current representation of outlook survival for this population.” Lu-Yao indicates the study could help change the conversation between patient and physician. “In weighing whether treatment beneﬁts outweigh the risks, radical prostatectomy – for instance – is typically not recommended for older men with low-grade disease. But many elderly patients are treated with radiotherapy or hormonal therapy even if their cancer is indolent, so that they can feel like they are doing something,” she says. “By having additional data available to support conservative management, doctors can further educate their patients about survival outcomes and possibly help avoid treatments that may put the patient at risk.” The authors note strengths of the study include the fact it is population based and broadly representative instead of focused on speciﬁc geographic areas or institutions. Lu-Yao also notes the study provided information on more than 10,000 men aged 75 or older – a population which is often omitted from studies. But they also caution that because the men in the study were older than 65, the data may not apply to younger patients. Other authors on the study include: Peter C. Albertsen, University of Connecticut; Dirk F. Moore and Yong Lin, both Cancer Institute and School of Public Health; and Robert S. DiPaola and Siu-Long Yao, both Cancer Institute and Robert Wood Johnson Medical School.

The work was supported by funding from the National Cancer Institute (NCI) (R01 CA116399) and the Rutgers Cancer Institute of New Jersey core grant (NCI CA-7272010). European Urology, Mar-2015

EXPLORING 34.7 median OS

MONTHS

4.4

MONTHS

extension of life1

in the risk of 48% reduction radiographic progression WITH

4+ YEARS

ZYTIGA® ▼ 250 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 (4 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 postdose). 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 (2 tablets) 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 pretreatment. 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 i-mpairment. 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. 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. 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

of median follow up ZYTIGA maintains a favourable safety proﬁle and is generally well-tolerated1

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, 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, flecanide, codeine, oxycodone and tramadol. Avoid strong inducers of CYP3A4 (e.g. phenytoin, carbamazepine, rifampicin, rifabutin, rifapentine, phenobarbital, St John’s wort). Zytiga is a CYP2C8 inhibitor (in vitro data). Examples of medicinal products metabolised by CYP2C8 incl paclitaxel, repaglinide. No clinical data are available on the use of Zytiga with CYP2C8 substrates. May increase concentrations of drugs eliminated by OATP1B1. Food (see Dosage & Administration). LEGAL CATEGORY: Prescription only medicine. PRESENTATIONS, PACK SIZES & MARKETING AUTHORISATION NUMBERS: One bottle containing 120 tablets. EU/1/11/714/001. 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 Adverse events should be reported. This medicinal product is subject to additional monitoring and it is therefore important to report any suspected adverse events related to this medicinal product. 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: www.hpra.ie, E-mail: medsafety@ hpra.ie. Adverse events should also be reported to Janssen-Cilag Ltd on +44 1494 567447. Prescribing information last revised: July 2014 References: 1. Ryan C et al. ESMO 2014; Final Overall Survival Analysis of COU-AA-302, a Randomized Phase 3 Study of Abiraterone Acetate in Metastatic Castration-Resistant Prostate Cancer Patients Without Prior Chemotherapy, Abstract 7530 (oral presentation), September 2014, Madrid, Spain. 2. 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 (COU-AA-302). Eur Urol (2014), http://dx.doi.org/10.1016/j. eururo.2014.02.056. Date of Preparation: October 2014 | PHIR/ZYT/1014/0004

For patients with hypercholesterolemia not at LDL-C goal on statin monotherapy1

Legal Category: POM Marketing Authorisation Holder: MSD Limited, Hertford Road, Hoddesdon, Hertfordshire EN11 9BU, UK Date of Review: September 2013. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin 18 or from www.medicines.ie ÂŠ Merck Sharp & Dohme Ireland (Human Health) Limited, 2015. All rights reserved. Date of Preparation: January 2015

Red Oak North, South County Business Park, Leopardstown, Dublin 18, Ireland

CARD-1130559-0006

Reference: 1. Ezetrol SPC

CARDIOLOGY

SIGNIFICANT IMPROVEMENTS IN

ACS SERVICES The HSE National Clinical Programme for Acute Coronary Syndrome has provided a real boost to the standard of care for cardiac patients, writes Maureen Browne.

here have been very significant improvements in the services for acute coronary syndrome in Ireland since the establishment of the HSE National Clinical Programme. The HSE says that the Acute Coronary Syndrome Programme was endeavouring to standardise 21st century treatment of acute coronary syndromes nationally to reduce mortality and morbidityv from heart attack – to save up to 30 lives per year and reduce incidence of related strokes. The aim of the programme was to ensure that all patients with ACS nationally are managed according to clear protocols in a timely and efficient manner. Approximately 10,000 people die each year in Ireland from cardiovascular disease, including coronary heart disease, stroke and other circulatory diseases. The HSE says that all cath lab centres have been reviewed and six 24/7 and one 9/5 primary percutaneous coronary intervention (PPCI) centres have been designated and are in operation. There has been an increase in the percentage of STEMI patients who received PPCI from 67 per cent in the period October 2011 to Sept 2012, to 82 per cent in the period July 2012 to June 2013. A national Optimal Reperfusion Service (ORS) was started in 2013. A data set and a methodology for data collection for STEMI data were established and data is being collected in five PPCI and two PCI centres.

IMPROVING AND STANDARDISING An important part of the programme was to improve and standardise the care of ACS patients by ensuring that ambulances were equipped and paramedics trained to recognise a major heart attack (STEMI) and to transport these patients to the best place in line with the ORS protocol. The Optimal Reperfusion Service protocol stipulated that the best place to take a STEMI patient for appropriate care was a primary PCI centre hospital if it

was within transport time limits. If a STEMI patient could not be transferred to a PPCI centre within 90 minutes then the protocol provided for transfer to the nearest emergency department to allow thrombolysis. In the pre-hospital services all ambulances have been equipped with 12-lead ECG machines and trained personnel in STEMI recognition. An ambulance freephone service had been established, enabling ambulance crew to speak directly with PPCI centres and the Air Medical Service, and Coast Guard Helicopters have been involved in transporting STEMI patients for PPCI. Primary PCI centre hospitals are designated based on having available catheter laboratories plus a requisite number of cardiologists trained in PPCI. The HSE says that other non PPCI centre hospitals were clear on how best to treat all ACS patients and arrange timely transfer of ACS patients that needed further investigation to PPCI centre hospitals.

First response to collapse – by ambulance, uniformed coresponders and community responders – has been improved throughout Ireland

As well as immediate transport of STEMI patients to a primary PCI centre, the ACS programme is also recommending the transfer of thrombolysed STEMI patients as soon as possible to a primary PCI centre to ensure that angiography can be performed in a timely manner.

Approximately 10,000 people die each year in Ireland from cardiovascular disease, including coronary heart disease, stroke and other circulatory diseases.

In some cases a rescue angioplasty (PCI) was required in a PPCI centre when the thrombolysis failed.

ESTABLISHED IN ALL AREAS The HSE also says that the ACS programme aimed to increase (from 30 per cent to 80 per cent) the percentage of STEMI patients in Ireland getting PPCI by ensuring patients were being taken to the right place, standardising treatment and putting in place processes to ensure prompt investigation of all ACS patients. Systems were in place to measure the performance of the ACS programme. Cardiac rehabilitation programmes have been established in all areas “so that every ACS patient has the opportunity to be part of a cardiac rehabilitation programme. “First response to collapse – by ambulance, uniformed co-responders and community responders – has been improved throughout Ireland,” says the HSE. It says that there was clear evidence that good cardiac rehabilitation programmes that involved exercise programmes and lifestyle changes reduced the number of recurrent heart attacks and other ACS events. Established and resourced cardiac rehabilitation programmes are an important part of the ACS programme – this includes programmes to assist smokers to stop smoking.

THE CLINICAL CARE JOURNAL | 35

Multaq 400mg ﬁlm-coated tablets

SAIE.DRO.14.09.0095 Date of Preparation September 2014

Multaq is indicated for the maintenance of sinus rhythm after successful cardioversion in adult clinically stable patients with paroxysmal or persistent atrial ﬁbrillation.

Further information is available from Sanofi, 18 Riverwalk, Citywest Business Campus, Dublin 24. Tel. (01) 4035600 or contact iemedinfo@sanofi.com. Legal Category: POM MA Holder: Sanofi-aventis groupe, 54 Rue la Boetie, F-75008, Paris, France.

CARDIOLOGY | RESEARCH

TWO DIFFERENT CAROTID ARTERY STENTING PROCEDURES SHOW

LITTLE

DIFFERENCE

IN EFFECTIVENESS

se of either proximal embolic protection devices (P-EPDs) or distal filter embolic protection devices (F-EPDs) during elective carotid artery stenting results in low rates of in-hospital stroke and death, according to a new study from researchers at the Perelman School of Medicine at the University of Pennsylvania. The study, published in JACC: Cardiovascular Interventions, found that although P-EPDs have been theorised to be more effective than F-EPDs at preventing stroke during carotid artery stenting, this first comparative effectiveness study revealed no statistically significant difference between the two devices. During carotid artery stenting, the placement of small mesh-like tubes via catheters to open the artery and stabilise the plaque, there is a risk of releasing small amounts of debris into the brain’s circulation. To prevent this problem, two types of EPDs were developed: FEPDs have a small filter to catch debris; while P-EPDs stop blood flow to the brain in the carotid artery being stented, then debris-containing blood is removed before normal blood flow resumes.

“These study results challenge the notion that proximal EPDs are significantly superior to distal EPDs, or that they can serve as a ‘magic bullet’ for stroke prevention during carotid artery stenting,” said first author Jay Giri, MD, MPH, assistant professor of clinical medicine at Penn. “Even for patients who had recent symptoms of stroke or mini-stroke — who have been thought to get more benefit from proximal EPD — this study showed no statistical difference in device effectiveness.” The research team examined 10,246 consecutive elective carotid artery stenting procedures performed with embolic protection between January 2009 and March 2013 in the CARE (Carotid Artery Revascularization and Endarterectomy) Registry. P-EPDs were used in 590 (5.8 percent) of the cases, and the rest were F-EPDs. The differences in in-hospital stroke or death between P-EPDs (1.5 percent) and F-EPDs (2.4 percent) were not statistically significant, and the 30-day adverse events rates were similar for both P-EPDs (2.7 percent) and F-EPDs (4.0 percent).

The research team examined 10,246 consecutive elective carotid artery stenting procedures performed with embolic protection between January 2009 and March 2013.

“There is certainly no signal of harm with use of proximal EPDs, and our study cannot rule out a small beneﬁt of these devices. The choice of EPD type in a given case really comes down to physician discretion,” added Giri. Given the overall results of this study, the research team has concluded that although a large controlled trial randomising patients to these two devices might be useful, its feasibility is unlikely due to the scope necessary.

The other Penn co-authors include DANIEL J. MCCORMICK, DO, FACC, FSCAI, BENJAMIN JACKSON, MD, and PREETHI RAMCHAND, MD. Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $4.9 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 17 years, according to U.S. News & World Report’s survey of research-oriented medical schools. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $409 million awarded in the 2014 fiscal year JACC: Cardiovascular Interventions, Apr-2015

THE CLINICAL CARE JOURNAL | 37

For patients with hypercholesterolemia not at LDL-C goal on statin monotherapy1

Red Oak North, South County Business Park, Leopardstown, Dublin 18, Ireland

CARD-1130559-0006

Reference: 1. Ezetrol SPC

CARDIOLOGY | RESEARCH

ANCIENT HERBAL THERAPY

CAN PREVENT - AND REVERSE CARDIAC HYPERTROPHY IN MICE

natural compound derived from the bark of the magnolia tree, can protect the heart from hypertrophy, a thickening of cardiac muscle often caused by chronic high blood pressure that can lead to heart failure, researchers report in the April 14 issue of the online journal Nature Communications. When injected into mice, honokiol (hoh-NOH’-kee-ohl) reduced the excess growth of individual cardiac muscle cells, decreased ventricular wall thickness and prevented the accumulation of interstitial fibrosis, a stiffening of cardiac muscle cells that reduces their ability to contract. It also protected heart muscle cells from the damage caused by oxidative stress, which can damage DNA. The researchers, based at the University of Chicago Medicine, also describe how this ancient remedy, widely used in Asia for centuries, protects the heart. They found the compound activates SIRT3, a protective protein associated with delayed aging, stress resistance and metabolic regulation. “Honokiol, by increasing SIRT3 levels, effectively blocked both the induction and progression of cardiac hypertrophy in mice,” said study author Mahesh Gupta, PhD, director of the Cardiac Cell Biology Research Program at the University of Chicago. “It even mitigated pre-existing cardiac hypertrophy. This has the potential to play a significant role in the prevention and treatment of heart failure.” “To the best of our knowledge, this is the first report to describe a pharmacologic activator of SIRT3” he added. “Until now, caloric restriction combined with endurance exercise has been the only way to boost SIRT3 levels. Very few

The researchers, based at the University of Chicago Medicine, also describe how this ancient remedy, widely used in Asia for centuries, protects the heart.

people have been able to follow such a rigorous regimen.” One of a family of sirtuin proteins, SIRT3 is primarily active in the mitochondria, the cell’s main source of energy. It plays a central role there in energy metabolism and in preventing acetylation, a process that can alter the function of proteins. In the absence of SIRT3, mitochondrial proteins become hyperacetylated, which can impair function. Human studies show that sedentary patients over 60 years old have nearly 40 per cent less SIRT3. Mice that lack the gene for SIRT3 have 40 per cent lower levels of ATP, a primary source of energy, than those with the gene. The researchers tested multiple compounds in search of one that could activate SIRT3. They found that honokiol reduced mitochondrial protein acetylation. When they tested it in the heart muscle cells from mice, they found

that a small amount of honokiol nearly doubled SIRT3 levels within 24 hours. Additional studies showed that honokiol, acting through SIRT3, could reduce or prevent hypertrophic growth in cardiac muscle cells, prevent mice from developing full blown hypertrophy and even reduce existing damage from established hypertrophy. It also blocked the production of fibroblasts—cells that interfere with heart muscle performance—and reduced production of myofibroblasts, cells that speed wound healing but can impair heart function. The researchers did not detect any appreciable toxicity. To confirm the mechanism, the researchers performed the same experiments on mice that lacked the SIRT3 gene. In those studies, honokiol had no effect. They also determined that honokiol binds directly to SIRT3. The combination appears to increase SIRT3’s activity. The results, the authors wrote, suggest pharmacological activation of SIRT3 by honokiol could be “a potential therapeutic strategy to prevent adverse cardiac remodeling and other diseases associated with abnormal cellular growth and organ fibrosis.” “Although we feel this is extremely promising,” Gupta said, “there is still much work to be done.” Honokiol is available as an herbal remedy but the purity of such preparations is undetermined. “We treated the mice with injections into the peritoneal cavity,” Gupta emphasized, “rather than by mouth, which is how this compound has traditionally been administered. We are testing to see if oral use will have a similar effect.” Despite those caveats, “we are tremendously excited,” Gupta said. “We are working to design a clinical trial involving patients with cardiac hypertrophy and potentially other metabolic diseases, such as type 2 diabetes.” The National Institutes of Health, the Rabinowitch-Davis Foundation and the Margolis Foundation funded this study. Additional authors were VINODKUMAR PILLAI, SADHANA SAMANT, NAGALINGAM SUNDARESAN, HARIHARASUNDARAM RAGHURAMAN and GENE KIM of the University of Chicago; MICHAEL BONNER and JACK ARBISER of the Atlanta VA Medical Center; DOUGLAS I. WALKER and DEAN JONES of the Emory University School of Medicine; and DAVID GIUS of Northwestern University - Nature Communications, April 14, 2015

THE CLINICAL CARE JOURNAL | 39

Could you recognise Gaucher disease? Type 1 Gaucher disease has a variable age of onset, severity and symptom progression.1, 2 Patients with Gaucher disease may have some or all of the following signs and symptoms.1, 2

ORGAN

HAEMATOLOGICAL

Abnormal liver function

Thrombocytopenia (<100 x 109/L) Anaemia (<12g/dL for men, <11g/dL for women)

Splenomegaly Hepatomegaly

OTHER Bruising

SKELETAL

Fatigue

Chronic bone or joint pain

Growth retardation

Bone crises (causing debilitation for several days)

Other non-speciﬁc signs Some haematological markers are increased in individuals with Gaucher disease: 1 Normal patient levels

Typical Gaucher patient levels at diagnosis

Median: 20 (range 4-76)3

Median: 9,501 (range 70-77,500)4

Median: 68.9 (range 32.8-107.9)4

Median: 259.5 (range 1 to 650)4

Median: 4.6 (range 0.28-9.84)4

Median: 11 (range 1 to 47)4

Median: 33 (range 10-72)5

Median: 948 (range 237-2285)5

Median: 12-300 (range 12-150)4

Median: 682.5 (range 68-3230)4

Chitotriosidase (nmol/mL/h) Angiotensin-coverting enzyme (ACE) (IU/L) Tartrate-resistant acid phosphatase (TRAP) (IU/L) Chemokine CCL18 (ng/mL) Ferritin (ng/mL)

Elevated levels of these biomarkers may help to indicate Gaucher disease, but they are not speciﬁc and should not be used for a deﬁnitive diagnosis.4 Patients may also show low vitamin B12 and low serum cholesterol (low density lipoprotein (LDL) and high density lipoprotein (HDL)).1 1. Mistry PK, et al. Consensus Conference: A reappraisal of Gaucher disease – diagnosis and disease management algorithms. Am J Hematol 2011;86(1):110-115. 2. Connock M, et al. The clinical effectiveness and cost-effectiveness of enzyme replacement therapy for Gaucher’s disease: a systematic review. Health Technol Assess. 2006;10(24):iii-iv, ix-136. 3. Hollak CE, et al. Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease. J Clin Invest 1994;93(3):1288-1292. 4. Stirnemann J, et al. Bone events and evolution of biologic markers in Gaucher disease before and during treatment. Arthritis Res Ther 2010;12(4):R156. 5. Boot RG, et al. Marked elevation of the chemokine CCL18/PARC in Gaucher disease: a novel surrogate marker for assessing therapeutic intervention. Blood. 2004 Jan 1;103(1):33-9. Epub 2003 Sep 11.

5 Riverwalk, Citywest Business Campus, Dublin 24 Tel: +353 14297700 | www.shire.com

Date of preparation: January 2013 IRE/HG/GCB/13/0002

COPD

MANY BENEFITS FOR

COPD PATIENTS Treating Chronic Obstructive Pulmonary Disease (COPD) depends on early diagnosis and pulmonary rehabilitation and 12 new Outreach Centres are believed to have brought down the average length of hospital stay, according to Prof Tim McDonnell, National Clinical Lead, National Clinical Programme for COPD and Consultant Respiratory Physician at St Vincent’s University Hospital and St Michael’s Hospital, Dublin. Maureen Browne reports. Continued on page 43

THE CLINICAL CARE JOURNAL | 41

A LAMA for the treatment of COPD1

Improvement in early morning, daily and night-time COPD symptoms.2 Twice daily administration2

Eklira Genuair 322 micrograms inhalation powder Abbreviated Prescribing Information. Please consult the Summary of Product Characteristics (SPC) for the full prescribing information. Presentation: Inhalation powder in a white inhaler with an integral dose indicator and a green dosage button. Each delivered dose contains 375 μg aclidinium bromide equivalent to 322 μg of aclidinium. Also, contains lactose. Use: Maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Dosage: For inhalation use. Recommended dose is one inhalation of 322 μg aclidinium twice daily. Patients should be instructed on how to administer the product correctly. No dose adjustments are required for elderly patients, or those with renal or hepatic impairment. No relevant use in children and adolescents. Contraindications: Hypersensitivity to aclidinium bromide, atropine or its derivatives, including ipratropium, oxitropium or tiotropium, or to any of the excipients. Warnings and Precautions: Do not use in asthma. Stop use if paradoxical bronchospasm occurs and consider other treatments. Do not use for the relief of acute episodes of bronchospasm. Use with caution in patients with myocardial infarction in the previous 6 months, unstable angina, newly diagnosed arrhythmia within the previous 3 months, or hospitalisation within the previous 12 months for heart failure functional classes III and IV. Dry mouth, observed with anticholinergic treatment, may be associated with dental caries in the long term. Use with caution in patients with symptomatic prostatic hyperplasia or bladder-neck obstruction or with narrow-angle glaucoma. Do not use in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. Interactions: Do not administer with other anticholinergic-containing medicinal products. No other interactions expected. Please consult the SPC for more details. Fertility, pregnancy and lactation: No data on use in pregnancy. Consider risk-benefit before using during lactation. Unlikely to affect fertility at the recommended dose. Side-effects: Common (1-10%): Sinusitis, nasopharyngitis, headache, cough, diarrhoea. Uncommon (0.1- 1%): Blurred vision, tachycardia, dysphonia, dry mouth, rash, pruritus, urinary retention. Rare (0.01-0.1%): hypersensitivity. Not known: angioedema. Pack sizes: Carton containing 1 inhaler with 60 unit doses. Legal category: POM Marketing Authorisation Number: EU/1/12/778/002. Marketing Authorisation holder: Almirall, S.A., Ronda General Mitre 151, ES-08022, Barcelona, Spain. Marketed by: A. Menarini Pharmaceuticals Ireland Ltd., Castlecourt, Monkstown Farm, Monkstown, Glenageary, Co. Dublin. Further information is available on request to A. Menarini Pharmaceuticals Ireland Ltd. or may be found in the SPC. Last updated: May 2014. References: 1. Kerwin EM, D’Urzo AD, Gelb AF, et al. Efficacy and safety of a 12-week treatment with twice-daily aclidinium bromide in COPD patients (ACCORD COPD I). COPD. 2012;9(2):90-101. 2. Eklira® Genuair® Summary of Product Characteristics, last updated May 2014. 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 to: IMB Pharmacovigilance, Earlsfort Centre, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.imb.ie, e-mail: imbpharmacovigilance@imb.ie Adverse events should also be reported to A. Menarini Pharmaceuticals Ireland Ltd. Phone no: 01 284 6744. Abbreviated prescribing information is up to date at time of printing; updated prescribing information will be available at www.medicines.ie Date of Item: September 2014 14Eklira006d

COPD

ew Outreach Centres, opened as part of the work of the HSE National Clinical Programme for Chronic Obstructive Pulmonary Disease (COPD), have been associated with a drop in the length of hospital stay. This has come down from an average length of stay of 9.1 days in 2009 to 7.6 days in 2013, according to Prof Tim McDonnell, National Clinical Lead, National Clinical Programme for COPD and Consultant Respiratory Physician at St. Vincent’s University Hospital and St. Michael’s Hospital, Dublin. “This has many obvious benefits for patients and has also resulted in significant savings in bed days and reduced the stress on the system generally over the last year,” Prof McDonnell says. “We want to maintain this, as it works well for patients and for the healthcare system. There are many significant hospitals who do not have outreach centres yet. The Mater Hospital in Dublin and Sligo General Hospitals have made strong business cases for the outreach centres, but the resources have not been available to date.”

Patients do not need to be admitted to hospital when they have an exacerbation generally.

The 12 COPD Outreach Centres that were planned by the programme are now up and running, with some extending their scope to provide other services such as rehabilitation and case management. They are run by a senior respiratory physiotherapist and a clinical nurse specialist. The COPD programme facilitates patients with exacerbations of COPD, where they can be treated in the community by outreach teams from the hospital. Therefore patients do not need to be admitted to hospital when they have an exacerbation generally – however, there are some instances where the patient will have to be admitted. The programme enables patients to be discharged earlier through the work of the outreach programme, where the patient continues to be managed by the team in the com-

munity. The outreach centres also offer pulmonary rehabilitation for patients.

REHABILITATION Pulmonary rehabilitation is a comprehensive programme for patients with respiratory disability, built around a structured exercise programme in conjunction with a dedicated education and self-management programme. Prof McDonnell says pulmonary rehabilitation is now available in about 31 different areas – 26 acute hospitals and 15 centres in the community. “This is great for patients, as they really beneﬁt from pulmonary rehabilitation – it allows a patient to gain a better quality of life and helps them to self-manage their condition better. It is important that the rehabilitation is delivered in appropriate places and we have some fantastic initiatives underway. These initiatives need continued support as they make a real difference to the patient.” Prof McDonnell emphasised the importance of an early diagnosis of COPD. “The problem in getting early diagnosis is mainly related to the fact that GPs are handicapped in making a diagnosis, because access to spirometry services is frequently very poor. We have had a programme in spirometry training developed for use by practice nurses, accredited by DIT. Some of the challenges faced to date include getting the practice nurses freed up time-wise to undertake the training course, and the ongoing need for the skill to be used to ensure competence over time.” The National Clinical Programme is always looking for solutions to enable more spirometry testing, for example the possibility of lab testing, outreach testing (by hospital labs – a pilot programme has been undertaken, which proved successful), and outreach centres providing testing (respiratory nurses and physiotherapist testing) are all being worked through to see what can work best for all concerned. “In addition to spirometry, a clinical assessment can be done with advice on airway clearance and inhaler technique. The data is then reviewed by a respiratory consultant who can advise the GPs on the best care plan for the patient. Patients are diagnosed and treated in the primary care sites, which avoids their having to travel and negotiate their way through a hospital. It promotes the more appropriate and convenient care of patients, the workload of the hospital is reduced and GPs are helped to manage chronic disease with support from the hospital consultant team.”

Pulmonary rehabilitation is now available in about 31 different areas – 26 acute hospitals and 15 centres in the community.

ONE IN FOUR? Extrapolating from Canadian ﬁgures, approximately one in four people in Ireland are likely to be diagnosed and treated with COPD by age 80. COPD is a major cause of morbidity and mortality in Ireland with approximately 1,500 deaths and 12,000 admissions a year from the disease. In 2009, Ireland had the highest rate of admission for COPD in the OECD. “There are 180,000 patients over the age of 40 provided with an inhaler under the medical card system in any one year. They might not be taking it all the year around and a minority might be asthmatic, but we have to remember this is just the medical card population. There is a huge population of people in this age category who have at least obstructive lung disease and more probably COPD, and hospitals cannot deal with these quantities of patients alone. The patient may be attending their GPs with some co-morbidities and the challenge is to support GPs to look after the patient in the community, which is better for the patient as well. “I think it would be enormously costeffective to get support to enable these patients to be looked after in primary care with support from the hospital team,” concluded Prof McDonnell.

PROF TIM MCDONNELL, National Clinical Lead, National Clinical Programme for COPD and Consultant Respiratory Physician at St Vincent’s University Hospital and St Michael’s Hospital, Dublin. For more information on the work of the National Clinical Programme for COPD visit www.hse.ie/COPD

THE CLINICAL CARE JOURNAL | 43

A maintenance bronchodilator treatment for patients with COPD who are breathless1

Anoro Ellipta 55/22mcg: G 69;8?.< 5>70 />7,=287 =;8>01 '1 ,869*;.- @2=1 =28=;892>61,2 G %1. <26952,2=B 8/ *7 27=>2=2?. 271*5.;3 G (*< 0.7.;*55B @.55 =85.;*=.- 27 ,5272,*5 =;2*5<1

Visit Anoro.ie for more information

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Adverse events should be reported. For the UK, reporting forms and information can be found at www.mhra.gov.uk/yellowcard. For Ireland, adverse events should be reported directly to the IMB; Pharmacovigilance Section, Irish Medicines Board, Kevin Oâ&#x20AC;&#x2122;Malley House, Earlsfort Centre, Earlsfort Terrace, Dublin 2, Tel: +353 1 6764971. Adverse events should also be reported to GlaxoSmithKline on_ 0800 221 441 in the UK or 1800 244 255 in Ireland. References: 78;8 5529=* $>66*;B 8/ ";8->,= 1*;*,=.;2<=2,< ?*25*+5. /;86 @@@ 6.-2,27.< 2. ,,.<<.- *B .,;*6.; .= *5 *7,.= #.<92; .- ">+52<1.- 87527. 1==9 -A -82 8;0 $

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ANORO ELLIPTA was developed in collaboration with

COPD | RESEARCH

THE FUTURE DIRECTIONS OF

COPD RESEARCH The American Thoracic Society (ATS) and the European Respiratory Society (ERS) have published a statement describing the state of current evidence on the diagnosis, assessment, and management of chronic obstructive pulmonary disease (COPD), identifying gaps in knowledge and making recommendations for the directions of future research.

“A

lthough much progress has been made in the assessment and treatment of patients with COPD, a range of important questions remain,” said Kevin C. Wilson, MD, Senior Director of Documents and Medical Affairs at the ATS and co-chair of the committee that produced the statement. “In our review of the evidence, we aimed to identify these knowledge gaps and highlight questions that will have the greatest impact on improving patient outcomes if addressed by future research.” ERS Guidelines Director, Professor Guy Brusselle, commented: “The World Health Organization (WHO) predicts that COPD will become the third leading cause of death worldwide by 2030. It is therefore a critical time for us to act with improving the management of people with the condition. This document provides us with a valuable point of reference for identifying the most effective types of research in the ﬁeld of COPD. By identifying the right questions to ask, we aim to improve the diagnosis, assessment, and treatment of people with COPD.” The ATS/ERS Research Statement highlights the types of research that leading clinicians and researchers believe will have the greatest impact on outcomes, including studies that determine the impact of COPDrelated clinical practice guidelines on outcomes in patients with COPD. The statement appears in the April 1 issue of the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine and in the April issue of the European Respiratory

Our recommendations on what’s needed in COPD research, from leading experts in the field, should help in the fight to alleviate some of the burden of this debilitating disease

Society’s European Respiratory Journal. Recommendations include: • Using patient-centred outcomes in clinical research • Finding high-quality surrogate outcomes that reliably predict patient-centred outcomes • Research examining the role of CT scanning in COPD patients • Studies assessing the accuracy and utility of COPD screening tools currently used for diagnosis and guiding treatment • Examination of the relationship between phenotypic traits and patient outcomes • Studies on the relationships between COPD and comorbidities • Research on the effects of quitting smoking on COPD disease activity and on approaches to help patients quit smoking • Studies measuring the effects of pharmacological treatments in different COPD subtypes and of different pharmacological treatment approaches and combinations • Studies comparing the effectiveness of home-based, hospital-based, and community-based pulmonary rehabilitation programs • Research on the effectiveness

of long-term oxygen therapy and long-term noninvasive mechanical ventilation for COPD patients. “COPD is a major contributor to morbidity, mortality, and resource use around the world,” said Dr. Wilson. “Our recommendations on what’s needed in COPD research, from leading experts in the ﬁeld, should help in the ﬁght to alleviate some of the burden of this debilitating disease.”

ABOUT With an impact factor of 11.986, the American Journal of Respiratory Research and Critical Care Medicine (AJRRCM) is a peer-reviewed journal published by the American Thoracic Society. It aims to publish the most innovative science and the highest quality reviews, practice guidelines, and statements in the pulmonary, critical care, and sleep-related fields. Founded in 1905, the American Thoracic Society is the world’s leading medical association dedicated to advancing pulmonary, critical care and sleep medicine. The Society’s 15,000 members prevent and fight respiratory disease around the globe American Journal of Respiratory and Critical Care Medicine.

THE CLINICAL CARE JOURNAL | 45

THE FIRST ONCE-DAILY DUAL BRONCHODILATOR Â®

Â®

ULTIBRO BREEZHALER

START A NEW CHAPTER IN COPD

2-4

85mcg indacterol maleate/43mcg glycopyrronium bromide inhalation powder

Once-daily ULTIBRO BREEZHALER is indicated as maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD).1 Ultibro Breezhaler W5IJT NFEJDJOBM QSPEVDU JT TVCKFDU UP BEEJUJPOBM NPOJUPSJOH 5IJT XJMM BMMPX RVJDL JEFOUJÃ DBUJPO PG OFX TBGFUZ JOGPSNBUJPO )FBMUIDBSF QSPGFTTJPOBMT BSF BTLFE UP SFQPSU BOZ TVTQFDUFE BEWFSTF SFBDUJPOT 4FF TFDUJPO PG UIF 4N1$ GPS IPX UP SFQPSU BEWFSTF SFBDUJPOT "##3&7*"5&% 13&4$3*#*/( */'03."5*0/ 1MFBTF SFGFS UP 4VNNBSZ PG 1SPEVDU $IBSBDUFSJTUJDT 4N1$ CFGPSF QSFTDSJCJOH 1SFTFOUBUJPO 6MUJCSP #SFF[IBMFS NDH NDH JOIBMBUJPO QPXEFS IBSE DBQTVMFT DPOUBJOJOH JOEBDBUFSPM NBMFBUF BOE HMZDPQZSPOJVN CSPNJEF SFTQFDUJWFMZ BOE TFQBSBUF 6MUJCSP #SFF[IBMFS JOIBMFS Indications: A maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Dosage and administration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Ã U PVUXFJHIT UIF QPUFOUJBM SJTL /P SFMFWBOU VTF JO UIF QBFEJBUSJD QPQVMBUJPO Contraindications: Hypersensitivity to UIF BDUJWF TVCTUBODFT PS UP BOZ PG UIF FYDJQJFOUT Warnings/Precautions: /PU UP CF BENJOJTUFSFE DPODPNJUBOUMZ XJUI NFEJDJOBM QSPEVDUT DPOUBJOJOH PUIFS -"#" T PS -"." T Asthma: x6-5*#30 #3&&;)"-&3 4)06-% /05 #& 64&% '03 53&"5.&/5 0' "45)." 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Patients with severe renal impairment: x4IPVME POMZ CF VTFE JO QBUJFOUT XJUI TFWFSF SFOBM JNQBJSNFOU JODMVEJOH UIPTF XJUI FOE TUBHF SFOBM EJTFBTF SFRVJSJOH EJBMZTJT JG UIF FYQFDUFE CFOFÃ U PVUXFJHIT UIF QPUFOUJBM SJTL 5IFTF QBUJFOUT TIPVME CF NPOJUPSFE DMPTFMZ GPS QPUFOUJBM BEWFSTF SFBDUJPOT Cardiovascular effects: x5P CF VTFE XJUI DBVUJPO JO QBUJFOUT XJUI DBSEJPWBTDVMBS EJTPSEFST DPSPOBSZ BSUFSZ EJTFBTF BDVUF NZPDBSEJBM JOGBSDUJPO DBSEJBD BSSIZUINJBT IZQFSUFOTJPO JO QBUJFOUT XJUI LOPXO PS TVTQFDUFE QSPMPOHBUJPO PG UIF 25 JOUFSWBM PS QBUJFOUT USFBUFE XJUI NFEJDJOBM QSPEVDUT BGGFDUJOH UIF 25 JOUFSWBM BOE JO QBUJFOUT XJUI VOTUBCMF JTDIBFNJD IFBSU EJTFBTF MFGU WFOUSJDVMBS GBJMVSF IJTUPSZ PG NZPDBSEJBM JOGBSDUJPO BSSIZUINJB FYDMVEJOH DISPOJD TUBCMF BUSJBM Ã CSJMMBUJPO B IJTUPSZ PG MPOH 25 TZOESPNF PS XIPTF 25D 'SJEFSJDJB NFUIPE XBT QSPMPOHFE x-"#" T NBZ QSPEVDF B DMJOJDBMMZ TJHOJÃ DBOU DBSEJPWBTDVMBS FGGFDU JO TPNF QBUJFOUT BT NFBTVSFE CZ JODSFBTFT JO QVMTF SBUF CMPPE QSFTTVSF BOE PS TZNQUPNT &$( DIBOHFT *O DBTF TVDI FGGFDUT PDDVS USFBUNFOU NBZ OFFE UP CF EJTDPOUJOVFE Hypokalaemia: x -"#" T NBZ QSPEVDF TJHOJÃ DBOU IZQPLBMBFNJB JO TPNF QBUJFOUT XIJDI IBT UIF QPUFOUJBM UP QSPEVDF DBSEJPWBTDVMBS FGGFDUT *O QBUJFOUT XJUI TFWFSF $01% IZQPLBMBFNJB NBZ CF QPUFOUJBUFE CZ IZQPYJB BOE DPODPNJUBOU USFBUNFOU XIJDI NBZ JODSFBTF UIF TVTDFQUJCJMJUZ UP DBSEJBD BSSIZUINJBT Hyperglycaemia: x*OIBMBUJPO PG IJHI EPTFT PG -"#" T NBZ QSPEVDF JODSFBTFT JO QMBTNB HMVDPTF 6QPO JOJUJBUJPO PG USFBUNFOU XJUI 6MUJCSP #SFF[IBMFS QMBTNB HMVDPTF TIPVME CF NPOJUPSFE NPSF DMPTFMZ JO EJBCFUJD QBUJFOUT x 6MUJCSP #SFF[IBMFS IBT OPU CFFO JOWFTUJHBUFE JO QBUJFOUT GPS XIPN EJBCFUFT mellitus is not well controlled. General disorders: x5P CF VTFE XJUI DBVUJPO JO QBUJFOUT XJUI DPOWVMTJWF EJTPSEFST PS UIZSPUPYJDPTJT BOE JO QBUJFOUT XIP BSF VOVTVBMMZ SFTQPOTJWF UP -"#" T Excipients: x 1BUJFOUT XJUI SBSF IFSFEJUBSZ QSPCMFNT PG HBMBDUPTF JOUPMFSBODF UIF -BQQ MBDUBTF EFÃ DJFODZ PS HMVDPTF HBMBDUPTF NBMBCTPSQUJPO TIPVME OPU UBLF UIJT NFEJDJOF Pregnancy and Lactation: x6MUJCSP #SFF[IBMFS TIPVME POMZ CF VTFE EVSJOH QSFHOBODZ JG UIF FYQFDUFE CFOFÃ U UP UIF QBUJFOU KVTUJÃ FT UIF QPUFOUJBM SJTL UP UIF GPFUVT x/PU LOPXO XIFUIFS JOEBDBUFSPM HMZDPQZSSPOJVN BOE UIFJS NFUBCPMJUFT BSF FYDSFUFE JO IVNBO NJML 6TF PG 6MUJCSP #SFF[IBMFS CZ CSFBTU GFFEJOH XPNFO TIPVME POMZ CF DPOTJEFSFE JG UIF FYQFDUFE CFOFÃ U UP UIF XPNBO JT HSFBUFS UIBO BOZ QPTTJCMF SJTL UP UIF JOGBOU Interactions: xConcomitant use is not SFDPNNFOEFE XJUI CFUB BESFOFSHJD CMPDLFST BOUJDIPMJOFSHJDT PS TZNQBUIPNJNFUJD BHFOUT x$PODPNJUBOU IZQPLBMBFNJD USFBUNFOU XJUI NFUIZMYBOUIJOF EFSJWBUJWFT TUFSPJET PS OPO QPUBTTJVN TQBSJOH EJVSFUJDT NBZ QPUFOUJBUF UIF QPTTJCMF IZQPLBMBFNJD FGGFDU PG CFUB BESFOFSHJD BHPOJTUT UIFSFGPSF VTF XJUI DBVUJPO x*OIJCJUJPO PG UIF LFZ DPOUSJCVUPST PG JOEBDBUFSPM DMFBSBODF $:1 " BOE 1 HQ EPFT OPU SBJTF BOZ TBGFUZ DPODFSOT HJWFO UIF TBGFUZ FYQFSJFODF PG USFBUNFOU XJUI JOEBDBUFSPM x/P DMJOJDBMMZ SFMFWBOU ESVH JOUFSBDUJPO JT FYQFDUFE XIFO HMZDPQZSSPOJVN JT DP BENJOJTUFSFE XJUI DJNFUJEJOF PS PUIFS JOIJCJUPST PG UIF PSHBOJD DBUJPO USBOTQPSU Adverse reactions: x7FSZ DPNNPO VQQFS SFTQJSBUPSZ USBDU JOGFDUJPO x$PNNPO OBTPQIBSZOHJUJT VSJOBSZ USBDU JOGFDUJPO TJOVTJUJT SIJOJUJT EJ[[JOFTT IFBEBDIF DPVHI PSPQIBSZOHFBM QBJO JODMVEJOH UISPBU JSSJUBUJPO EZTQFQTJB EFOUBM DBSJFT HBTUSPFOUFSJUJT NVTDVMPTLFMFUBM QBJO QZSFYJB DIFTU QBJO x6ODPNNPO IZQFSTFOTJUJWJUZ EJBCFUFT NFMMJUVT BOE IZQFSHMZDBFNJB JOTPNOJB QBSBFTUIFTJB HMBVDPNB JTDIBFNJD IFBSU EJTFBTF BUSJBM Ã CSJMMBUJPO UBDIZDBSEJB QBMQJUBUJPOT QBSBEPYJDBM CSPODIPTQBTN FQJTUBYJT ESZ NPVUI QSVSJUVT SBTI NVTDMF TQBTN NZBMHJB QBJO JO FYUSFNJUZ CMBEEFS PCTUSVDUJPO BOE VSJOBSZ SFUFOUJPO QFSJQIFSBM PFEFNB BOE GBUJHVF x1MFBTF SFGFS UP 4N1$ GPS B GVMM MJTU PG BEWFSTF FWFOUT GPS 6MUJCSP #SFF[IBMFS Legal Category: 10. 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IE02/ULT14-CNF098b

COPD | RESEARCH

OUTCOMES OF

LUNG

TRANSPLANTATIONS NEED-BASED ALLOCATION SYSTEM Since implementation of a medical need-based allocation system of donor lungs in 2005, double-lung transplantation has been associated with better graft survivals than singlelung transplantation in patients with idiopathic pulmonary ﬁbrosis (IPF); at ﬁve years, there has been no survival difference between single- and double-lung transplant recipients in patients with chronic obstructive pulmonary disease (COPD), according to a study in the March 3, 2015 issue of JAMA.

efore 2005, lung transplant allocation in the United States was based on accumulated time on the lung transplant waiting list after matching for ABO blood type. In response to increasing wait times, the U.S. Department of Health and Human Services mandated the development of an allocation system based on medical need instead of waiting time. The resulting system—the Lung Allocation Score (LAS) organ allocation algorithm—was implemented in May 2005. A patient’s LAS is based on risk factors associated with either wait list or post-transplantation mortality. The use of the LAS has brought with it a change in the demographics of single- and doublelung transplant recipients; what effect this may have on post-transplantation outcomes has not been assessed, according to background information in the article. Hari R. Mallidi, M.D., of the Baylor College of Medicine, Houston, and colleagues reviewed data from the United Network for Organ Sharing thoracic registry to summarise the contemporary demographics and outcomes in adults with IPF or COPD who underwent single- or double lung transplantation in the United States between

The interaction between diagnosis (COPD or IPF) and treatment type (singleand double-lung transplantation) was significant

May 2005 and December 2012. Since May 2005, the researchers identiﬁed 4,134 patients with IPF (of whom 2,010 underwent single-lung and 2,124 underwent double-lung transplantation) and 3,174 patients with COPD, of whom 1,299 underwent single-lung and 1,875 underwent double-lung transplantation. The median follow-up time was 23.5 months. Of the patients with IPF, 33.4 per cent died and 2.8 percent underwent retransplantation; of the patients with COPD, 34.0 per cent died and 1.9 percent underwent retransplantation. Further analysis indicated that doublelung transplants were associated with better graft survival in patients with

IPF (adjusted median survival, 65.2 months vs 50.4 months) but not in patients with COPD (adjusted median survival, 67.7 months vs 64.0 months). “The interaction between diagnosis (COPD or IPF) and treatment type (single- and double-lung transplantation) was significant, supporting the finding that the benefit of double-lung transplantation may differ by diagnosis. Likewise, prognostic models designed to account for the time varying effect of double-lung transplantation (compared with single-lung transplantation) showed that double-lung transplantation was significantly associated with graft survival among patients with IPF but not among patients with COPD,” the authors write. Other variables associated with graft failure included age, excessively high or low body mass index, worse functional status, poor 6-minute walk test performance, pulmonary hypertension (in patients with COPD), and donor age. Variables associated with graft survival included undergoing transplantation at a high-performing centre, undergoing transplantation at a moderate- or high volume transplant centre, receiving a locally allocated organ, and donorrecipient race match (in patients with IPF). (doi:10.1001/jama.2015.1175

THE CLINICAL CARE JOURNAL | 47

A LAMA for the treatment of COPD1

Improvement in early morning, daily and night-time COPD symptoms.2 Twice daily administration2

COPD | RESEARCH

FAMILIAL TRANSMISSION OF

CHRONIC OBSTRUCTIVE PULMONARY DISEASE IN ADOPTEES

he novel ﬁndings of a new study published in the BMJ implicate genetic or early life factors in the familial transmission of COPD. Family history of COPD signals a potential genetic susceptibility to the disease according to the researchers at the Center for Primary Health Care Research, Lund University, Malmö, Sweden and Stanford Prevention Research Centre, Stanford University School of Medicine, Stanford, California, USA. Familial clustering of chronic obstructive pulmonary disease (COPD) is well established, but the familial risk of COPD has not been determined among adoptees. The aim of this study was to determine whether the familial transmission of COPD was related to disease in biological and/or adoptive parents. It was a historic cohort study with 80,214 participants of whom half were female. The Swedish Multi-Generation Register was used to follow all Swedish-born adoptees born in 1932–2004 (n=80 214) between 1 January 1964 and 31 December 2010 for COPD (n=1978). The risk of COPD was estimated in adoptees with at least one biological parent with COPD but no adoptive parent with COPD (n=162) compared with adoptees without a biological or adoptive parent with COPD. The risk of COPD was also determined in adoptees with at least one adoptive parent but no biological parent with COPD (n=110), and in adoptees with both affected biological and adoptive parents (n=162). The results revealed that adoptees with COPD in at least one biological parent but no adoptive parent were more likely to have COPD than adoptees without a biological or adoptive parent with COPD (standardised incidence ratio, SIR=1.98 (95% CI 1.69 to 2.31)). The familial SIR for adoptees with both a biological parent and an adoptive parent with COPD was 1.68 (95% CI 1.39 to 2.00). Adoptees with at least one adoptive parent with COPD

but no biological parent with COPD were not at an increased risk of COPD (SIR=1.12 (95% CI 0.92 to 1.35)). The reearchers concluded that the familial transmission of COPD is associated with COPD in biological but not adoptive parents, suggesting that genetic or early life factors are important in the familial transmission of COPD. The researchers said that the study included only adoptees born in Sweden. They therefore could not generalise this study to populations of non-European origin. “However, the Swedish population is, for instance, genetically closely related to British and German people. Results from Swedish nationwide family studies such as this

study are therefore likely to be valid for many individuals of Caucasian origin in Europe and the USA, they concluded. The Swedish Multi-Generation Register consists of data on more than nine million individuals born from 1932 onwards and links all adoptees born in Sweden since 1932 to their biological and adoptive parents. In previous studies of coronary heart disease, venous thromboembolism, breast cancer, prostate cancer and colorectal cancer in adoptees, it was possible to link Swedish-born adoptees to their biological and adoptive parents. BMJ Open 2015;5:e007310 doi:10.1136/ bmjopen-2014-007310 Respiratory medicine.

STRENGTHS AND LIMITATIONS OF THE STUDY: • The researchers stated that to the best of their knowledge, this was the ﬁrst nationwide study of adoptees to determine whether the familial transmission of chronic obstructive pulmonary disease (COPD) was related to disease in biological and/or adoptive parents. • The present study designs allowed them to determine whether the familial transmission of COPD among adoptees was related to COPD in biological and/ or adoptive parents. • A limitation was the lack of smoking data, though the familial risks were adjusted for socioeconomic factors, which were related to lifestyle factors such as smoking. • This was a register-based study which did not allow the researchers to determine how COPD was diagnosed. • Unknown confounders might lead to overestimation or underestimation of the familial risks. • The researchers said that the study included only adoptees born in Sweden. They therefore could not generalise this study to populations of non-European origin. “However, the Swedish population is, for instance, genetically closely related to British and German people. Results from Swedish nationwide family studies such as this study are therefore likely to be valid for many individuals of Caucasian origin in Europe and the USA, they concluded. The Swedish Multi-Generation Register consists of data on more than nine million individuals born from 1932 onwards and links all adoptees born in Sweden since 1932 to their biological and adoptive parents. In previous studies of coronary heart disease, venous thromboembolism, breast cancer, prostate cancer and colorectal cancer in adoptees, it was possible to link Swedish-born adoptees to their biological and adoptive parents.

THE CLINICAL CARE JOURNAL | 49

Proven clinical efﬁcacy in pancreatic exocrine insufﬁciency1,2,3

In good hands pancreatin

PRESCRIBING INFORMATION Creon 10000 Gastro-resistant Capsules, Creon 25000 Gastro-resistant Capsules, Creon 40000 Gastro-resistant Capsules, Creon for Children 5000 Gastro-resistant Granules. Refer to Summary of Product Characteristics for full information. Presentation: Creon 10000 Capsules: containing gastro-resistant granules with 150 mg pancreatin equivalent to lipase 10,000 PhEur units, amylase 8,000 PhEur units and protease 600 PhEur units. Creon 25000 Capsules: containing gastro-resistant granules with 300 mg pancreatin equivalent to lipase 25,000 PhEur units, amylase 18,000 PhEur units and protease 1,000 PhEur units. Creon 40000 Capsules: containing gastro-resistant granules with 400 mg pancreatin equivalent to lipase 40,000 PhEur units, amylase 25,000 PhEur units and protease 1,600 PhEur units. Creon for Children 5000: Gastro-resistant granules. Each 100 mg of gastroresistant granules (equivalent to one measuring spoonful) contains 60.12 mg pancreatin, containing the pancreatic enzymes lipase 5,000 PhEur units, amylase 3,600 PhEur units and protease 200 PhEur units. Produced from porcine pancreatic tissue. Indication: Pancreatic exocrine insufﬁciency Dosage and Administration: Creon Capsules: Initially one or two capsules of Creon swallowed whole with meals. Dose adjustments, if required, should be done slowly, with careful monitoring of response and symptomatology. Only use Creon 40000 if * 40,000 units of lipase is required per meal or snack. Creon for Children 5000: Initially 100 mg (5,000 lipase units) using measuring spoon supplied, to be taken with each feed or meal without chewing. Any dose increases should be made slowly, with careful monitoring of response and symptomatology. Daily dose for most patients should remain below 2500 units of lipase per kilogram per meal (10,000 units per kilogram per day). Higher doses should be used with caution and only if quantitative measures demonstrate substantially improved absorption with such treatment. This applies particularly to young children. Ensure patient is adequately hydrated at all times. Capsules: The capsules can be swallowed whole, or for ease of administration they may be opened and the granules taken with acidic ﬂuid [pH<5.5] or acidic soft food [pH<5.5] e.g. apple sauce, yoghurt or fruit juice with a pH less than 5.5 (apple, orange or pineapple juice). Granules: In weaned infants, granules should be taken as described above but without chewing, directly before the meal. In young infants, granules should be mixed with a small amount of infant formula, expressed breast milk or fruit puree and given from a spoon directly before the feed. All forms: If the granules are mixed with food, IRECRE120235b. Date of Preparation: March 2014.

take immediately, do not store the mixture. To protect the enteric coating, do not crush or chew the granules or mix with food or fluid with pH>5.5. Care should be taken that no product is retained in the mouth. Contraindications, Warnings etc: Contraindications: Hypersensitivity to the active substance or to any of the excipients. Warnings and Precautions: Strictures of the ileo-caecum and large bowel (fibrosing colonopathy) have been reported in patients with cystic fibrosis taking high doses of pancreatin preparations. As a precaution, unusual abdominal symptoms or changes in abdominal symptoms should be medically assessed to exclude the possibility of fibrosing colonopathy, especially if the patient is taking in excess of 10000 units of lipase/kg/day. Creon is sourced from pancreatic tissue from swine used for food consumption. Although the risk that Creon will transmit an infectious agent to humans has been reduced by the testing and inactivation of certain viruses during manufacturing, there is a theoretical risk for transmission of viral disease, including diseases caused by novel or unidentified viruses. Interaction with other medicinal products and other forms of interaction: No interaction studies have been performed. Fertility, Pregnancy and Lactation: The potential risk of Creon in pregnancy and lactation is unknown. Do not use unless clearly necessary, but if required should be used in doses providing adequate nutritional status. Ability to Drive and Operate Machinery: No or negligible effect. Side Effects: Very common: abdominal pain. Common: nausea, vomiting, constipation, distension, diarrhoea. Uncommon: rash. Frequency not known: strictures of the ileo-caecum and large bowel (fibrosing colonopathy), pruritus, urticarial, hypersensitivity (anaphylactic reactions). Frequency, type and severity of adverse reactions were similar in children with cystic fibrosis as compared to adults. In case of overdose, stop Creon and ensure adequate rehydration. Hyperuricosuria and hyperuricaemia may occur with very high doses. M.A No.: Creon 10000 Capsules 108/25/1, Creon 25000 Capsules 108/25/2, Creon 40000 Capsules 108/25/5, Creon for Children 108/25/4. Supplied in Ireland by/Further information from: Abbott Laboratories Ireland Ltd, 4051 Kingswood Drive, Citywest Business Campus, Dublin 24, Ireland. Legal Category: POM Date of Last Review: January 2014 PI/25/1,2,4,5/004 References: 1. Stern RC. et al. Am J Gastroenterol 2000; 95: 1932-1938. 2. Colombo C. et al. Pancreas 2009; 38: 693-699. 3. Safdi M. et al. Pancreas 2006; 33: 156-162.

CYSTIC FIBROSIS

PROVIDING CF PATIENTS WITH

QUALITY OF LIFE

The HSE National Clinical Programme on Cystic Fibrosis aims to provide those with CF the right kind of care at the right time and place, according to Prof Charles Gallagher, National Lead of the programme and Consultant Respiratory Physician at St. Vincent’s University Hospital and University College Dublin. Maureen Browne reports.

he goal of the HSE National Clinical Programme on Cystic Fibrosis is to provide people with CF with the best health and quality of life, according to Prof Charles Gallagher, National Lead of the HSE National Clinical Programme on Cystic Fibrosis and Consultant Respiratory Physician at St. Vincent’s University Hospital and University College Dublin. “To do this we have, as a community, to provide people with CF with the care they need at the time they need it and where they need it. Treating people with cystic fibrosis is a moving target and the treatment changes with time and is different from patient to patient.” Prof Gallagher says that the HSE National Clinical Programme on Cystic Fibrosis has six priorities. They are standardisation of the model of care, establishing the standards of care, getting data on the experience of patients and others, collecting patient data using standardised methods, standardisation of the annual assessment of patients, and the accreditation of CF centres. One of the key documents regarding cystic fibrosis care in Ireland is the Pollock Report, an external report carried out by a UK healthcare specialist and published in 2005. The Pollock Report found gaping holes in the resourcing of CF care and these findings were backed subsequently by a HSE review. “From these two reports considerable progress has been made in the treatment of cystic fibrosis patients and a very strongly connected network of CF

centres has been strengthened,” says Prof Gallagher. “We have approximately 1,250 people with CF in Ireland. The latest figures (2013) show that 53 per cent of CF patients are adults and 47 per cent are children, so we now have more adults than children with CF – which is great, as it means people are living longer and doing better. “Dealing with cystic fibrosis is like dealing with leukaemia for life. CF patients have the disease from the day they are born to the day they die. They are doing better than they did 20 or 30 years ago but cystic fibrosis is very demanding on patients and their families and they need very rapid access to hospitals when they become ill. “We have designated paediatric and adult CF centres in five cities, as was recommended in the Pollock Report, and they all include a component of home-based treatment. The good

news is that they are linked and work well together. Some patients also receive some of their care at other sites.”

CHANGING TRENDS Prof Gallagher says that while we have moved on with the provision of services in the last decade, health care needs of patients have also increased. “Thankfully, survival figures are improving. In Ireland and internationally the vast majority of people with CF reach adult life. Most are working or studying or involved in some occupation. Many have families and with time my goal is that cystic fibrosis will become a disease of the elderly. It is definitely improving all the time, but as it improves healthcare needs become even greater. For now, 22 per cent of all people with cystic fibrosis are over the age of 30 and that is great news but we also know too that as people are living longer healthcare needs change. So in childhood it

Women do less well than men, especially beyond the age of 20 years. For example, the Irish registry now shows that 57 per cent of CF patients are male and 43 per cent are female.

THE CLINICAL CARE JOURNAL | 51

CYSTIC FIBROSIS

The latest figures (2013) show that 53 per cent of CF patients are adults and 47 per cent are children, so we now have more adults than children with CF – which is great, as it means people are living longer and doing better.

is mainly an outpatient disease and in children many, but not all, infections can be treated at home. “However, the severity and complexity of CF becomes greater as patients reach adulthood; therefore for adults many infections need to be treated in hospital and successful treatment of acute infections takes longer in adults. Patients see the CF team in dedicated centres. A core part of CF care is the team approach, which involves doctors, dieticians, nurses, pharmacists, physiotherapists, psychologists, secretarial/administrative staff, social workers and other healthcare professionals. It also involves an increasingly greater involvement by the diabetes, gastroenterology and herpetology teams and other groups. “Patients come into our units for outpatient visits a minimum of four times a year and will be seen by the team. It is a speciﬁc model of care that involves a team approach. People are living longer with better quality of life, but unfortu-

52 | THE CLINICAL CARE JOURNAL

nately we still see deaths every year and a small group of people still die in their 20s. “Our goal is to provide people with CF with the best quality of life and the best healthcare at the time they need it and where they need it. People with CF are prone to acute infections or exacerbations and we know that prompt and appropriate treatment improves the short and long-term outcome for patients. When they get an exacerbation we need to treat them very quickly and the faster they get treatment the better their lung function will be maintained,” Prof. Gallagher says.

patients the care of their CF is dominated by outpatient and day care treatment but when they become acutely sick they may need to come into hospital. “The experiences of our patients and their families are a key part of all we do. Patient data is really very important. We need to have very accurate patient data on an ongoing basis. As demographics change we want an annual review process, which is a linchpin of CF care internationally; this annual assessment of the patient is a the key part of patient care.” For reasons that are not clear, there is deﬁnitely a gender divide in CF. “Women do less well than men, especially beyond the age of 20 years. For example, the Irish registry now shows that 57 per cent of CF patients are male and 43 per cent are female. “I have set up a cystic ﬁbrosis clinical working group nationally under the auspices of the HSE. It has a very broad representation of very committed people from all over the country. They include representatives of all health care providers involved in CF care, a specialist in public health, HSE representatives, and representation from Cystic Fibrosis Ireland and from the Cystic Fibrosis Registry, which collates all the data on people with CF.”

TREATMENT PATTERNS “The average person with CF, when stable, spends at least two hours every day of every year taking treatment even if they are well. We are now seeing complications in adult life that we did not see 25 years ago when patients were not living so long. The nature of CF care has changed signiﬁcantly in recent years. For most

PROF CHARLES GALLAGHER is National Lead of the programme and Consultant Respiratory Physician at St. Vincent’s University Hospital and University College Dublin

A new perspective on life with MS 61%

begins with a reduction in relapse rates vs interferon beta-1a IM at 1 year, in licenced subgroups of patients with highly active relapsing remitting MS not responding to interferon treatment1* • Superior efﬁcacy compared to placebo in a 2-year study2†

ABBREVIATED PRESCRIBING INFORMATION ź GILENYA 0.5MG Hard Capsules. This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 of the SmPC for how to report adverse reactions. Please refer to the Summary of Product Characteristics (SmPC) before prescribing. Presentation: GILENYA 0.5 mg hard capsules. Therapeutic indications: Gilenya is indicated as single disease modifying therapy in highly active relapsing remitting multiple sclerosis for the following adult patient groups: Patients with high disease activity despite treatment with at least one disease modifying therapy. These patients may be defined as those who have failed to respond to a full and adequate course (normally at least one year of treatment) of at least one disease modifying therapy Patients should have had at least 1 relapse in the previous year while on therapy, and have at least 9 T2-hyperintense lesions in cranial MRI or at least 1 Gadolinium-enhancing lesion. A “non-responder” could also be defined as a patient with an unchanged or increased relapse rate or ongoing severe relapses, as compared to the previous year. Or patients with rapidly evolving severe relapsing remitting multiple sclerosis defined by 2 or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI. Dosage: Adults: One 0.5 mg capsule to be taken orally once daily. Use with caution in patients aged 65 years and over. Safety and efficacy of GILENYA in children up to 18 years has not been established. See SmPC for full details on Posology and Method of Administration. Contraindications: Known immunodeficiency syndrome. Patients with increased risk for opportunistic infections, including immunocompromised patients (including those currently receiving immunosuppressive therapies or those immunocompromised by prior therapies). Severe active infections, active chronic infections (hepatitis, tuberculosis). Known active malignancies, except for patients with cutaneous basal cell carcinoma. Severe liver impairment (Child-Pugh class C). Hypersensitivity to the active substance or to any of the excipients. Warnings/Precautions: Bradyarrhythmia: Initiation of treatment results in a transient decrease in heart rate which may be associated with atrioventricular conduction delays, including isolated reports of transient, spontaneously resolving complete AV block. All patients should have an ECG and blood pressure measurement performed prior to and 6 hours after the first dose of GILENYA. Same recommendation applies after an interruption of one day or more during the first 2 weeks of treatment, or for more than 7 days during week 3 and 4 of treatment; or after an interruption for more than 2 weeks after the first month of treatment. If the treatment interruption is of shorter duration than the above, the treatment should be continued with the next dose as planned. Monitor all patients for 6 hours for bradycardia, with hourly heart rate and blood pressure measurement. Continuous (real time) ECG monitoring during this 6 hour period is recommended. In the event of bradyarrhythmia-related symptoms, initiate appropriate clinical management and observe until symptoms resolve. If pharmacological intervention is required, overnight monitoring should be instituted and the first-dose monitoring should be repeated after the second dose of GILENYA. If the heart rate at 6 hours is the lowest since the first dose was administered, monitoring should be extended by at least 2 hours and until heart rate increases again. Additionally, if after 6 hours, the heart rate is <45 bpm, or the ECG shows new onset second degree or higher grade AV block or a QTc interval *500 msec, or occurrence at any time of third degree AV block extended monitoring (at least overnight), should be performed. The same precautions apply if GILENYA is discontinued for more than 2 weeks.See Summary of Product Characteristics for further information. Infections: Before initiating treatment with Gilenya, a recent complete blood count (CBC) (i.e. within 6 months) should be available. Assessments of CBC are also recommended periodically during treatment, at month 3 and at least yearly thereafter, and in case of signs of infection. Reduction of the lymphocyte count to 20-30% of baseline values occurs with GILENYA. Perform a complete blood count (CBC) at baseline and periodically during treatment, and in case of signs of infection, stop GILENYA until recovery if absolute lymphocyte count <0.2x109/L is confirmed. Consider VZV vaccination of patients without a history of chickenpox or VZV antibody negative patients prior to commencing GILENYA. GILENYA may increase the risk of infections. Employ effective diagnostic and therapeutic strategies in patients with symptoms of infection while on GILENYA and for 2 months after discontinuation. Macular oedema: Macular oedema with or without visual symptoms has been reported in patients taking GILENYA. Perform an ophthalmological evaluation 3 to 4 months after GILENYA initiation. Evaluate the fundus, including the macula in patients reporting visual disturbances. Perform ophthalmological evaluation prior to initiating therapy and periodically thereafter in patients with diabetes mellitus or a history of uveitis. Discontinue GILENYA if a patient develops macular oedema. Liver function: Do not use GILENYA in patients with severe pre-existing hepatic injury (Child-Pugh class C). Delay GILENYA initiation in patients with active viral hepatitis until resolution. Recent transaminase and bilirubin levels should be available before initiation of GILENYA. Monitor liver transaminases at months 1, 3, 6, 9 and 12 and periodically thereafter. Patients with symptoms of hepatic dysfunction should have liver enzymes checked and discontinue GILENYA if significant liver injury is confirmed. Resume GILENYA only if

This medicinal product is subject to additional monitoring. This will allow quick identiﬁcation of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 of the SmPC for how to report adverse reactions.

another cause of liver injury is determined and if the benefits of therapy outweigh the risks. Exercise caution with GILENYA use in patients with a history of significant liver disease. Blood pressure effects: GILENYA can cause a mild increase in blood pressure. Monitor blood pressure regularly during GILENYA treatment. Respiratory effects: Use GILENYA with caution in patients with severe respiratory disease, pulmonary fibrosis and chronic obstructive pulmonary disease due to minor reductions in values for forced expiratory volume (FEV1) and diffusion capacity for carbon monoxide (DLCO). Prior immunosuppressant treatment: No washout is necessary when switching patients from interferon or glatiramer acetate to GILENYA assuming any immune effects (e.g. neutropenia) have resolved. Exercise caution when switching patients from natalizumab to GILENYA owing to the long half-life of natalizumab and concomitant immune effects. Stopping therapy: GILENYA is cleared from the circulation in 6 weeks. Caution is indicated with the use of immunosuppressants soon after the discontinuation of GILENYA due to possible additive effects on the immune system. Interaction with other medicinal products and other forms of interaction: Anti-neoplastic, immunosuppressive or immune-modulating therapies should not be co-administered due to the risk of additive immune system effects. Exercise caution when switching patients from long-acting therapies with immune effects, e.g. natalizumab or mitoxantrone. No increased rate of infection was seen with concomitant treatment of relapses with a short course of corticosteroids. Vaccination may be less effective during and for up to 2 months after GILENYA treatment. Avoid use of live attenuated vaccines due to infection risk. GILENYA should not be initiated in patients receiving beta blockers, or class Ia and III antiarrhythmics, heart rate lowering calcium channel blockers (e.g. verapamil or diltiazem), digoxin, anticholinesteratic agents or pilocarpine. Caution is indicated with substances that may inhibit CYP3A4. Co-administration of fingolimod with ketoconazole increases fingolimod exposure. No interaction has been observed with oral contraceptives when co-administered with fingolimod. The combination of fingolimod with potent CYP450 inducers should be used with caution. Concomitant administration with St John’s wort is not recommended (see section 4.5 of the Summary of Product Characteristics). Fertility, pregnancy and lactation: There is potential for serious risk to the foetus with GILENYA. A negative pregnancy test is required before initiation of GILENYA. Female patients must use effective contraception during treatment with GILENYA and for 2 months after discontinuation. Discontinue GILENYA if a patient becomes pregnant. Fingolimod is excreted into breast milk. Women receiving GILENYA should not breast feed. Fingolimod is not associated with a risk of reduced fertility. Undesirable effects: Very common (*1/10); Influenza viral infections, headache, cough, diarrhoea, increased alanine transaminase (ALT), back pain. Common (*1/100 to <1/10); herpes viral infections, bronchitis, sinusitis, gastroenteritis, tinea infections, lymphopenia, leucopenia, depression, dizziness, paraesthesia, migraine, blurred vision, eye pain, bradycardia, atrioventricular block, hypertension, dyspnoea, eczema, alopecia, pruritus, asthenia, increased gamma-glutamyl transferase (GGT), increased hepatic enzymes, abnormal liver function test, increased blood triglycerides, decreased weight. Uncommon (*1/1,000 to <1/100); pneumonia, depressed mood, macular oedema, decreased neutrophil count. Please see Summary of Product Characteristics for further information on undesirable effects. Marketing Authorisation Holder: Novartis Europharm Ltd, Wimblehurst Rd, Horsham, W Sussex, RH12 5AB, UK. Marketing Authorisation Numbers: EU/1/11/677/001-005. Date of last revision of Abbreviated Prescribing Information: July 2014. Full prescribing information is available upon request from: Novartis Ireland Limited, Beech House, Beech Hill Office Campus, Clonskeagh, Dublin 4. Tel: 01-2601255, Fax: 01-2601263 or at www. medicines.ie Detailed information on this product is also available on the website of the European Medicines Agency http://www.ema.europa.eu.

References: 1. Havrdová E. et al. Clinical outcomes in subgroups of patients with highly action relapsing-remitting multiple sclerosis treated with Fingolimod (FTY720): Results from the FREEDOMS and TRANSFORMS phase III studies. Poster presented at ECTRIMS, Amsterdam, October 2011. 2. Kappos et al, N Engl J Med. 2010 Feb 4; 362(5):387-401. *TRANSFORMS: A 1-year, randomised, double-blind, double-dummy, active (interferon beta-1a IM)-controlled study of 1292 people with RRMS. Patients received either a daily 0.5 mg dose of GILENYA or interferon beta-1a IM at a weekly dose of 30 μg. †

FREEDOMS: A 2-year, randomised, double-blind, placebo-controlled study of 1272 people with RRMS. Patients received either a 0.5mg daily dose or matching placebo. IE02/GIL14-CNF004a Date of Preparation: August 2014

The NEW licensed treatment for Chronic Spontaneous Urticaria (CSU)

• 71% reduction in itch after 12 weeks’ treatment with Xolair® 300mg1 • Rapid itch reduction after 1st dose1 • Simple dosing schedule2

FEEL THE DIFFERENCE XOLAIR 150 mg solution for injection. ABBREVIATED PRESCRIBING INFORMATION for Chronic Spontaneous Urticaria. Xolair is also indicated for severe allergic asthma so for full details please refer to Summary of Product Characteristics (SmPC) before prescribing. Presentation: XOLAIR (omalizumab) solution for injection. XOLAIR 150mg solution for injection - each pre-filled syringe of 1ml solution contains 150mg of omalizumab. Indications: Xolair is indicated as add-on therapy for the treatment of chronic spontaneous urticaria in adult and adolescent (12 years and above) patients with inadequate response to H1 antihistamine treatment. Dosage and Administration: Treatment should be initiated by physicians experienced in the diagnosis and treatment of chronic spontaneous urticaria. Xolair is intended to be administered subcutaneously in the deltoid region of the arm by a healthcare professional. Alternatively, the injections can be administered in the thigh if there is any reason precluding administration in the deltoid region. The recommended dose is 300 mg every four weeks. Prescribers are advised to periodically reassess the need for continued therapy. Clinical trial experience of long-term treatment beyond 6 months in this indication is limited. Contraindications: Hypersensitivity to omalizumab or to any of the excipients. Precautions/Warnings: X Not indicated for the treatment of acute asthma exacerbations, acute bronchospasm or status asthmaticus. X Xolair has not been studied in patients with hyperimmunoglobulin E syndrome or allergic bronchopulmonary aspergillosis or for the prevention of anaphylactic reactions, including those provoked by food allergy, atopic dermatitis or allergic rhinitis. X Caution is warranted in patients with autoimmune diseases, immune complex-mediated conditions or pre-existing renal or hepatic impairment. X Abrupt discontinuation of systemic or inhaled corticosteroids after initiation of Xolair therapy is not recommended, however gradual discontinuation of omalizumab should be considered in all severe cases of any of the listed immune system disorders. X Type I local or systemic allergic reactions, including anaphylaxis and anaphylactic shock may occur when taking omalizumab, also with onset after long duration of treatment (most occurred within 2 hours after the first and subsequent injections). Medications for treating anaphylactic reactions should always be available for immediate use following administration of Xolair. Prompt medical attention should be sought if allergic reactions occur. X Serum sickness and serum sickness-like reactions, which are delayed allergic type III reactions, may occur when taking omalizumab, with onset typically 1-5 days after the first or subsequent injections, also after long duration of treatment. Symptoms suggestive of serum sickness include arthritis/arthralgias, rash (urticaria or other forms), fever and lymphadenopathy. X Patients with severe asthma may present with or develop systemic hypereosinopihilic syndrome or Churg-Strauss syndrome, both of which are usually treated with systemic corticosteroids. X Patients on therapy with anti-asthma agents, including omalizumab, may present or develop systemic eosinophilia and vasculitis, particularly upon reduction of oral corticosteroid therapy. In these patients, physicians should be alert to the development of marked eosinophilia, vasculitic rash, worsening pulmonary symptoms, paranasal sinus abnormalities, cardiac complications, and/or neuropathy. X Caution is warranted in patients at high risk of helminth infection, in particular when travelling to areas where helminthic infections are endemic. X There is a potential risk for hypersensitivity reactions for latex-sensitive individuals as the removable needle cap of the pre-filled syringe contains a derivative of natural rubber latex. • Xolair should not be used during pregnancy unless clearly necessary and should not be used during breast-feeding. Interactions: There is little potential for drug-drug interactions. In clinical studies, Xolair was used in conjunction with antihistamines and leukotriene receptor antagonists and there was no evidence that the safety of omalizumab was altered when used with these medicinal products relative to its known safety profile in allergic asthma. Adverse Reactions: X Common: Sinusitis, headache, arthralgia, injection site reaction, upper respiratory tract. For a full list of adverse events please refer to the SmPC. Legal Category: Prescription-only. Pack Size: Xolair is supplied in packs of one pre-filled syringe containing 1ml solution for injection (150mg). Marketing Authorisation Number: EU/1/05/319/008. Marketing Authorisation Holder: Novartis Europharm Limited, Wimblehurst Road, Horsham, West Sussex, RH12 5AB, United Kingdom. Full prescribing information is available upon request from: Novartis Ireland Limited, Beech House, Beech Hill Office Campus, Clonskeagh, Dublin 4, Tel # +353 1 2601255 or at www.medicines.ie Date of Revision of API Text: August 2014. References. 1. Maurer M, et al. N Engl J Med 2013; 368; 924-35. 2. Xolair SmPC 2014. Date of Preparation: October 2014. IE02/XSU14-CNF024

DERMATOLOGY

IMPROVING ACCESS TO

DERMATOLOGY SERVICES The aim of the National Clinical Programme for Dermatology is to signiﬁcantly reduce the waiting lists for dermatology services and introduce standardised care, according to Dr. Anne Marie Tobin, Consultant Dermatologist at Tallaght Hospital, Dublin and National Clinical Lead for the HSE National Clinical Programme on Dermatology. Maureen Browne reports.

r. Anne Marie Tobin, Consultant Dermatologist at Tallaght Hospital in Dublin, took up the post of National Clinical Lead for the HSE National Clinical Programme on Dermatology in January of this year. She succeeds Prof. Louise Barnes, who stepped down as clinical lead in 2013 to take up the post of Clinical Director of the SaMS Directorate in St. James’s Hospital, Dublin. Dr. Tobin sees the main challenge ahead as to improve access for patients to dermatology services nationally, and to promote and standardise clinical care in dermatology throughout the country. “We will be working on this in conjunction with Dr. Colm Henry, National Clinical Advisor & Group Lead – Acute Hospitals Division and we will be driving the agenda to ensure that there is timely access to dermatology care for patients, no matter where in the country they live,” says Dr Tobin. “I am planning to re-establish the Dermatology Clinical Advisory Group and I want to re-engage with primary care and develop the treatment pathways for the four common skin conditions – psoriasis, eczema, acne and skin cancers. The Clinical Advisory Group will help to develop the pathways for these conditions to improve the interface for dermatology patients between primary and secondary care.”

MORBIDITY The four main skin conditions are responsible for a considerable amount of morbidity in Ireland. Skin cancer is the most common malignancy any patient will have, particularly in our fair-skinned population. At least 20 per cent of children under the age of six suffer from eczema, with one in 12 adults suffering from the condition. This can have a huge impact on families and individual patients. Psoriasis affects up to four per cent of the population. Psoriasis is also

associated with signiﬁcant co-morbidities, such as higher rates of cardiovascular disease and metabolic syndrome. Good access to a well-resourced dermatology department is extremely important for patients. Where acne is concerned, timely access to appropriate treatment is very important, as apart from the clinical aspect of the condition it can also cause signiﬁcant psychological problems for teenagers. “I want to carry out a mapping process to establish the infrastructure, services and resources which we have, so that we can develop a plan for the future,” says Dr. Tobin. “We will look at existing units, the equipment which they have – for example access to phototherapy is poor

outside Dublin – and I hope we can then draw up a strategic plan for the development of dermatology services throughout the country.” The programme also aims to work with the NCCP to help with the roll-out of the melanoma referral process to GPs. The ofﬁcial melanoma referral form will facilitate the management of skin cancer services nationally. The aim of the National Clinical Programme for Dermatology is to “signiﬁcantly reduce the waiting lists for dermatology services and introduce standardised care.” DR ANNE MARIE TOBIN is Consultant Dermatologist at Tallaght Hospital in Dublin.

THE CLINICAL CARE JOURNAL | 55

Duac is indicated for mild to moderate acne vulgaris, particularly inﬂammatory lesions1

Duac Safety Information1 • Duac Once Daily Gel is contraindicated for patients with known hypersensitivity to clindamycin, linomycin, benzoyl peroxide, or any of the excipients in the formulation. • Treatment with Duac should not exceed more than 12 weeks of continuous use. • Duac is not recommended for use in children under 12 years of age.

Duac Once Daily 10mg/g + 50mg/g Gel (clindamycin and anhydrous benzoyl peroxide) Abbreviated prescribing information (Please refer to SmPC before prescribing). Presentations: 1g of gel contains 10mg clindamycin as clindamycin phosphate and 50mg anhydrous benzoyl peroxide as hydrous benzoyl peroxide. Therapeutic Indications: Topical treatment of mild to moderate acne vulgaris, particularly inflammatory lesions, in adults and adolescents aged 12 years and above. Dosage and administration: Adults and adolescents: Apply once daily in the evening, to the entire affected area. Excessive application will not improve efficacy, but may increase the risk of skin irritation. Frequency of application should be reduced or temporarily interrupted if excessive dryness or peeling occurs. An effect of the treatment may be seen in 2-5 weeks. Treatment should not exceed more than 12 weeks of continuous use. Children under 12 years: Safety and efficacy has not been established and therefore not recommended. Elderly: No specific recommendations. After washing gently with a mild cleanser and fully drying, apply a thin film of gel. If the gel does not rub into the skin easily, too much is being applied. Hands should be washed after application. Contraindications: Known hypersensitivity to clindamycin, lincomycin, benzoyl peroxide or any of the excipients in the formulation. Warnings and Precautions: Avoid contact with mouth, eyes, lips, other mucous membranes and areas of irritated or broken skin. Apply with caution to sensitive areas of skin. In case of accidental contact, rinse well with water. Use with caution in patients with a history of regional enteritis, ulcerative colitis, a history of antibiotic-associated colitis or in atopic patients. At first, an increase in peeling and reddening will occur in most patients. Depending upon the severity of these side effects, patients can

• Skin and subcutaneous tissue disorders at the site of application: very common (t1/10) undesirable effects include erythema, peeling, and dryness (generally reported as ‘mild’ in severity) • Please refer to the Duac SPC on www.medicines.ie for full information on contraindications, special warnings and precautions for use, and undesirable effects

use a non-comedogenic moisturiser, temporarily reduce the frequency of application or temporarily discontinue use however; efficacy has not been established for less than once daily dosing frequencies. Caution with concomitant topical acne therapy because a possible cumulative irritancy may occur. Discontinue if severe local irritancy occurs. Exposure to sun or sunlamps should be avoided or minimised. If this is not possible, patients should be advised to use a sunscreen and wear protective clothing. Do not use if a patient has sunburn. If prolonged or significant diarrhoea occurs or the patient suffers from abdominal cramps, treatment should be discontinued immediately, as the symptoms may indicate antibiotic-associated colitis. Diagnostic and treatment options for colitis should be considered. May bleach hair or coloured fabrics. Avoid contact with hair, fabrics, furniture or carpeting. Patients with a recent history of systemic or topical clindamycin or erythromycin use are more likely to have pre-existing anti-microbial resistance. Cross-resistance may occur with other antibiotics such as lincomycin and erythromycin when using antibiotic monotherapy. Drug Interactions: Caution with concomitant topical antibiotics, medicated or abrasive soaps and cleansers, soaps and cosmetics that have a strong drying effect, and products with high concentrations of alcohol and/or astringents, as a cumulative irritant effect may occur. Do not use in combination with erythromycin-containing products. Caution with concomitant use of neuromuscular blocking agents as clindamycin may enhance the action of these. Avoid concomitant use of tretinoin, isotretinoin and tazarotene as their efficacy may be reduced and irritation may increase. If combination treatment is required, the products should be applied at different times of the day (e.g. one in the morning and the other in the evening). Simultaneous use with topical sulphonamide-containing products may cause skin and facial

1. Duac® 5% Summary of Product Characteristics, available from www.medicines.ie, last accessed November 2014

hair to temporarily change colour (yellow/orange). Pregnancy and Lactation: Safety in human pregnancy, lactation and fertility is not established. Balance risks against beneﬁts. Should not be applied to the breast area if used during breast-feeding. Undesirable effects: Very Common: Erythema, peeling, dryness; Common: skin burning sensation; Uncommon: paraesthesia, dermatitis, pruritus, erythematous rash, worsening of acne. For less frequent undesirable effects, please see SmPC. Legal Category: POM. PA Holder: GlaxoSmithKline (Ireland) Ltd, Stonemasons Way, Rathfarnham, Dublin 16, Trading as Stiefel. PA Number: PA 1077/120/001. Further information available from: GlaxoSmithKline (Ireland) Limited, Stonemasons Way, Rathfarnham, Dublin 16. Telephone: 01 4955000. Code: IE/CBP/0007/14. Date of preparation: November 2014

Adverse events should be reported directly to the HPRA; Freepost, Pharmacovigilance Section, Health Products Regulatory Authority, Earlsfort Terrace, Dublin 2, Tel: +353 1 676 4971, medsafety@hpra. ie. Adverse events should also be reported to Glaxo SmithKline on 1800 244 255. Date of preparation: November 2014. IE/CBP/0021e/11(1)a(1)

DERMATOLOGY | RESEARCH

PERSONALISED

MELANOMA VACCINES

MARSHAL

POWERFUL

IMMUNE RESPONSE Personalised melanoma vaccines can be used to marshal a powerful immune response against unique mutations in patients’ tumours, according to early data in a ﬁrst-in-people clinical trial at Washington University School of Medicine in St. Louis, United States.

he tailor-made vaccines, given to three patients with advanced melanoma, appeared to increase the number and diversity of cancer-fighting T cells responding to the tumours. The finding is a boost to cancer immunotherapy, a treatment strategy that unleashes the immune system to seek out and destroy cancer. The research is reported April 2 in Science Express, in a special issue devoted to cancer immunology and immunotherapy. In a new approach, the cancer vaccines were developed by first sequencing the genomes of patients’ tumours and samples of the patients’ healthy tis-

sues to identify mutated proteins called neoantigens unique to the tumour cells. Then, using computer algorithms and laboratory tests, the researchers were able to predict and test which of those neoantigens would be most likely to provoke a potent immune response and would be useful to include in a vaccine. The vaccines were given to melanoma patients who had had surgery to remove their tumours but whose cancer cells had spread to the lymph nodes, an indicator the deadly skin cancer is likely to recur. These clinical ﬁndings set the stage for a phase I vaccine trial, approved by the Food and Drug Administration as part of an investigational new drug applica-

tion. The trial will enrol six patients. Data on the immune response seen in the ﬁrst three patients is reported in the paper. If additional testing in more patients indicates the vaccines are effective, they may one day be given to patients after surgery to stimulate the immune system to attack lingering cancer cells and prevent a recurrence. “This proof-of-principle study shows that these custom-designed vaccines can elicit a very strong immune response,” said senior author Gerald Linette, MD, PhD, a Washington University medical oncologist leading the clinical trial at Siteman Cancer Center and Barnes-Jewish Hospital. “The tumor

THE CLINICAL CARE JOURNAL | 57

Further information is available on request from GlaxoSmithKline (Ireland) Ltd., Stonemasons Way, Rathfarnham, Dublin 16, Ireland. Tel: 01-4955000 PA1077/6/1, PA 1077/5/1, PA 1077/1/1 Medicinal Product subject to medical prescription. Date of preparation March 2014. IE/DERM/0004/13b Adverse events should be reported directly to the IMB; Pharmacovigilance Section, Irish Medicines Board, Kevin Oâ&#x20AC;&#x2122;Malley House, Earlsfort Centre, Earlsfort Terrace, Dublin 2. Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.imb.ie, e-mail: imbpharmacovigilance@imb.ie Adverse events should also be reported to GlaxoSmithKline on Free phone 1800 244 255, Fax 01 4938839 or e-mail ireland.drugsurveillance@gsk.com.

IE/DERM/0004/13b Date of Preparation March 2014

Betnovate and Dermovate are contraindicated in children under one year of age. Use of Eumovate with occlusive covering is contraindicated in children under one year of age

DERMATOLOGY | RESEARCH

Our results are preliminary, but we think the vaccines have therapeutic potential based on the breadth and remarkable diversity of the T-cell response.

antigens we inserted into the vaccines provoked a broad response among the immune system’s killer T cells responsible for destroying tumors. Our results are preliminary, but we think the vaccines have therapeutic potential based on the breadth and remarkable diversity of the T-cell response.” It’s too early to say whether the vaccines will be effective in the long term, the researchers cautioned. The study was designed to evaluate safety and immune response; however, none of the patients has experienced adverse side effects. Earlier attempts at vaccines have focused on targeting normal proteins commonly expressed at high levels in particular cancers. Those same proteins also are found in healthy cells, making it difﬁcult to stimulate a potent immune response. The new approach investigated by the Washington University team merges cancer genomics with cancer immunotherapy. “This is about as personalized as vaccines can get,” said co-author Elaine Mardis, PhD, co-director of the McDonnell Genome Institute at Washington University, where the cancer genome sequencing, analysis and neoantigen prediction were performed. “The approach we describe is fundamentally different from conventional mutation discovery, which focuses on identifying mutated genes that drive cancer development. Instead, we’re looking for a unique set of mutated proteins in a patient’s tumor that would be most likely to be recognized by the immune system as foreign.” Melanomas are notorious for having high numbers of genetic mutations caused by exposure to ultraviolet light. Biopsy samples of melanomas typically carry 500 or more mutated genes. Using prediction algorithms, the researchers narrowed their search

for vaccine candidates by identifying neoantigens that not only were expressed in a patient’s tumour but also were likely to be seen by that patient’s immune system as “non-self.” Biochemical validation of neoantigen peptide expression on the cancer cells’ surfaces was performed in collaboration with William Hildebrand’s group at the University of Oklahoma Health Sciences Center and provided critical assurance that the vaccine would elicit the most effective T cells to combat the melanoma. “You can think of a neoantigen as a flag on each cancer cell,” said first author Beatriz Carreno, PhD, associate professor of medicine. “Each patient’s melanoma can have hundreds of different flags. As part of validating candidate vaccine neoantigens, we were able to identify the flags on the patients’ cancer cells. Then we created customized vaccines to a select group of flags on each patient’s tumor.” Carreno and her colleagues selected a set of seven unique neoantigens for each vaccine and used specialised immune cells called dendritic cells, derived from the patients, to carry those neoantigens to the immune system. Dendritic cells play an important role in waking up the immune system, reminding T cells to attack the cancer. After the vaccine infusions, the

patients’ blood was drawn every week for about four months. By analysing the blood samples, the researchers could see that each patient mounted an immune response to speciﬁc neoantigens in their vaccines. The vaccines also stimulated diverse clones of battle-ready T cells against neoantigens, suggesting this approach also could be used to activate a range of T cells and target them to mutations in other cancers with high mutation rates, such as lung cancer, bladder cancer and certain colorectal cancers. “Our team has developed a new strategy for personalized cancer immunotherapy,” Linette said. “Many researchers have hypothesized that it would be possible to use neoantigens to broadly activate the human immune system, but we didn’t know that for sure until now. We still have much more work to do, but this is an important ﬁrst step and opens the door to personalized immune-based cancer treatments.” CARRENO BM, MAGRINI V, BECKERHAPAK M, KAABINEJADIAN S, HUNDAL J, PETTI AA, LY A, LIE W-R, HILDEBRAND WH, MARDIS ER AND LINETTE GP. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cell - Science Express, April 2, 2015.

THE CLINICAL CARE JOURNAL | 59

See your success in the eyes of your patients

LUCENTIS: Defining the standard of care in DME* • The FIRST licensed intravitreal Anti-VEGF therapy that can improve vision for DME patients*1 • Improved vision for DME* patients: Sustained Visual Acuity gains for 3 years with decreasing injection frequency2-5

• Flexible dosing regimen for personalised treatment1 • More than double the percentage of patients treated with LUCENTIS versus laser achieved VA levels legally required for driving (53% vs 23.6%)1,6-9

• More than 2.2 million patient years of treatment exposure10 Lucentis© 10mg/ml solution for injection. ABBREVIATED PRESCRIBING INFORMATION. Please refer to the Summary of Product Characteristics (SmPC) before prescribing. Presentation: A pre-filled syringe containing 0.165 ml, equivalent to 1.65 mg ranibizumab. The extractable volume of one pre-filled syringe is 0.1 ml. This provides a usable amount to deliver a single dose of 0.05 ml containing 0.5 mg ranibizumab. Indications: The treatment of neovascular (wet) age-related macular degeneration (AMD). The treatment of visual impairment due to diabetic macular oedema (DME). The treatment of visual impairment due to macular oedema secondary to retinal vein occlusion (branch RVO or central RVO). The treatment of visual impairment due to choroidal neovascularization (CNV) secondary to pathologic myopia (PM). Administration and Dosage: Pre-filled syringe for intravitreal use only. Lucentis must be administered by a qualified ophthalmologist experienced in intravitreal injections under aseptic conditions. Broad-spectrum topical microbicide and anaesthetic should be administered prior to the injection. Patients should be monitored monthly for visual acuity. The pre-filled syringe contains more than the recommended dose of 0.5 mg. The extractable volume of the pre-filled syringe (0.1 ml) is not to be used in total. The excess volume should be expelled prior to injection. Injecting the entire volume of the pre-filled syringe could result in overdose. To expel the air bubble along with the excess medicinal product, slowly push the plunger until the edge below the dome of the rubber stopper is aligned with the black dosing line on the syringe (equivalent to 0.05 ml, i.e., 0.5 mg ranibizumab). Each pre-filled syringe should only be used for the treatment of a single eye. The interval between two doses injected into the same eye should be at least four weeks. Treatment is initiated with one injection per month and continued until maximum visual acuity is achieved and/or there are no signs of disease activity i.e. no change in visual acuity and in other signs and symptoms of the disease under continued treatment. In patients with wet AMD, DME and RVO, initially, three or more consecutive, monthly injections may be needed. Thereafter, monitoring and treatment intervals should be determined by the physician and should be based on disease activity, as assessed by visual acuity and/or anatomical parameters. If, in the physician’s opinion, visual and anatomic parameters indicate that the patient is not benefiting from continued treatment, Lucentis should be discontinued. Monitoring for disease activity may include clinical examination, functional testing or imaging techniques (e.g. optical coherence tomography or fluorescein angiography). If patients are being treated according to a treat-and-extend regimen, once maximum visual acuity is achieved and/or there are no signs of disease activity, the treatment intervals can be extended stepwise until signs of disease activity or visual impairment recur. The treatment interval should be extended by no more than two weeks at a time for wet AMD and may be extended by up to one month at a time for DME. For RVO, treatment intervals may also be gradually extended, however there are insufficient data to conclude on the length of these intervals. If disease activity recurs, the treatment interval should be shortened accordingly. In the treatment of visual impairment due to CNV secondary to PM, many patients may only need one or two injections during the first year, while some patients may need more frequent treatment. Lucentis and laser photocoagulation in DME or in BRVO. Lucentis has been used concomitantly with laser photocoagulation in clinical studies. When given on the same day, Lucentis should be administered at least 30 minutes after laser photocoagulation. Lucentis can be administered in patients who have received previous laser photocoagulation. CNV secondary to PM Treatment is initiated with a single injection, further treatment is recommended if monitoring reveals signs of disease activity. The frequency of monitoring should be determined by the treating physician. Before * Visual impairment due to diabetic macular edema

treatment, evaluate the patient’s medical history for hypersensitivity. Paediatric population: Not recommended for use in children and adolescents due to a lack of data. Elderly: No dose adjustment is required. Consult SmPC for full administration details before using Lucentis. There is limited experience in patients older than 75 years with DME. Contraindications: Hypersensitivity to the active substance or excipients. Patients with active or suspected ocular or periocular infections. Patients with active severe intraocular inflammation. Warnings and Precautions: Lucentis is for intravitreal injection only. Intravitreous injections have been associated with endophthalmitis, intraocular inflammation, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract. Monitor during week following injection for infections. Patients should be instructed to report symptoms suggestive of any of the above without delay. Transient increases in intraocular pressure (IOP) have been seen within 1 hour of injection. Sustained IOP increases have also been identified. Both intraocular pressure and perfusion of the optic nerve head should be monitored and managed appropriately. Concurrent use in both eyes has not been studied. Limited data on bilateral use of Lucentis (including same-day administration) do not suggest an increased risk of systemic adverse events compared with unilateral treatment. There is a potential for immunogenicity and patients should report an increase in severity of intraocular inflammation. Since there is a potential for an increased systemic exposure in subjects with DME, an increased risk for developing hypersensitivity in this patient population cannot be excluded. Lucentis should not be administered concurrently with other antiVEGF agents (systemic or ocular). Withhold dose and do not resume treatment earlier than the next scheduled treatment in the event of the following: a decrease in BCVA of ≥30 letters compared with the last assessment of visual acuity; an intraocular pressure of ≥30 mmHg; a retinal break; a subretinal haemorrhage involving the centre of the fovea, or if the size of the haemorrhage is ≥50% of the total lesion area; performed or planned intraocular surgery within the previous or next 28 days. Discontinue treatment in cases of rhegmatogenous retinal detachment or stage 3 or 4 macular holes. There is only limited experience in the treatment of subjects with DME due to type 1 diabetes. Lucentis has not been studied in patients who have previously received intravitreal injections, in patients with active systemic infections, proliferative diabetic retinopathy or in patients with concurrent eye conditions such as retinal detachment or macular hole. There is also no experience of treatment with Lucentis in diabetic patients with an HbA1c over 12% and uncontrolled hypertension. Systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events have been reported following intravitreal injection of VEGF inhibitors. There are limited data on safety in the treatment of DME and macular oedema due to RVO patients with prior history of stroke or transient ischaemic attacks. Since there is a potential risk of arterial thromboembolic events following intravitreal use of VEGF inhibitors caution should be exercised when treating such patients. There is limited experience with treatment of patients with prior episodes of RVO and of patients with ischaemic branch RVO (BRVO) and central RVO (CRVO). In patients with RVO presenting with clinical signs of irreversible ischaemic visual function loss, treatment is not recommended. Ranibizumab should not be used during pregnancy unless the expected benefit outweighs the potential risk to the foetus. Women of child-bearing potential should use effective contraception during treatment. For women who wish to become pregnant and have been treated with ranibizumab, it is recommended to wait at least 3 months after the last dose of ranibizumab before conceiving a child. Breastfeeding is not recommended during treatment. The treatment procedure may induce temporary visual disturbances and patients who experience these signs must not drive or

use machines until these disturbances subside. Interactions: No formal interaction studies have been performed. Adjunctive use of verteporfin photodynamic therapy (PDT) and Lucentis in an open study showed a low incidence of intraocular inflammation following initial combination treatment. In clinical studies for the treatment of visual impairment due to DME, the outcome with regard to visual acuity or central retinal subfield thickness (CSFT) in patients treated with Lucentis was not affected by concomitant treatment with thiazolidinediones. Adverse Reactions: Serious adverse events related to the injection procedure included endophthalmitis, rhegmatogenous retinal detachment, retinal tear and iatrogenic traumatic cataract. Other serious ocular events included intraocular inflammation and increased intraocular pressure. Very Common: Intraocular pressure increased, headache, vitritis, vitreous detachment, retinal haemorrhage, visual disturbance, eye pain, vitreous floaters, conjunctival haemorrhage, eye irritation, foreign body sensation in eyes, lacrimation increased, blepharitis, dry eye, ocular hyperaemia, eye pruritus, arthralgia, nasopharyngitis. Common: Anaemia, retinal degeneration, retinal disorder, retinal detachment, retinal tear, detachment of the retinal pigment epithelium, retinal pigment epithelium tear, visual acuity reduced, vitreous haemorrhage, vitreous disorder, uveitis, iritis, iridocyclitis, cataract, cataract subcapsular, posterior capsule opacification, punctate keratitis, corneal abrasion, anterior chamber flare, vision blurred, injection site haemorrhage, eye haemorrhage, conjunctivitis, conjunctivitis allergic, eye discharge, photopsia, photophobia, ocular discomfort, eyelid oedema, eyelid pain, conjunctival hyperaemia, influenza, cough, nausea, allergic reactions (rash, urticaria, pruritus, erythema), hypersensitivity, anxiety, urinary tract infection (observed only in DME population). Uncommon: Blindness, endophthalmitis, hypopyon, hyphaema, keratopathy, iris adhesion, corneal deposits, corneal oedema, corneal striae, injection site pain, injection site irritation, abnormal sensation in eye, eyelid irritation. Product-class-related adverse reactions: There is a theoretical risk of arterial thromboembolic events including stroke and myocardial infarction, following intravitreal use of VEGF inhibitors. Please refer to SmPC for full listing of all undesirable effects. Pack Size: Lucentis is supplied in packs containing 1 pre-filled syringe. Legal Category: POM. Marketing Authorisation Number: EU/1/06/374/003. Marketing Authorisation Holder: Novartis Europharm Limited, Frimley, Camberley, Surrey GU16 7SR, United Kingdom. Full prescribing information, including SmPC, is available upon request from Novartis Ireland Limited, Beech House, Beech Hill Office Campus, Clonskeagh, Dublin 4. Telephone: (01) 260 1255. Date of API Revision: September 2014. References. 1. Lucentis Summary of Product Characteristics, September 2014. 2. Mitchell P et al. The RESTORE extension study. Oral presentation at ARVO 2012, Florida, USA. May 2012;#4667. 3. Elman MJ et al. Ophthalmology. June 2010; 117 (6): 1064-1077.e35. 4. Elman MJ et al. Ophthalmology. April 2011; 118(4): 609-14. 5. Elman MJ et al. Ophthalmology. 2012; 119 (11): 2312-8. 6. Official Journal of the European Union, Commission Directive 2009/113/EC of 25 August 2009 amending Directive 2006/126/EC of the European Parliament and of the Council on Driving Licences. 7. Optometry Northern Ireland, Department of the Environment (Northern Ireland) Consultation on proposals for implementing the 3rd Directive on Driving Licences. 8. Visual Standards, Vision Requirements for Driving Safety with emphasis on individual assessment. Report prepared for the International Council of Ophthalmology at the 30th World Ophthalmology Congress, San Paulo, Brazil, February 2006. 9. Data on File, Novartis. 10. Data on file. Novartis Pharma AG, Basel, Switzerland. Date of Preparation: September 2014. IE02/LUC13-CNF005a.

DIABETES | RESEARCH

“OPEN” STEM CELL CHROMOSOMES REVEAL NEW POSSIBILITIES FOR DIABETES

tem cells hold great promise for treating a number of diseases, in part because they have the unique ability to differentiate, specialising into any one of the hundreds of cell types that comprise the human body. Harnessing this potential, though, is difficult. In some cases, it takes up to seven carefully orchestrated steps of adding certain growth factors at specific times to coax stem cells into the desired cell type. Even then, cells of the intestine, liver and pancreas are notoriously difficult to produce from stem cells. Writing in Cell Stem Cell April 2, 2015 researchers at University of California, San Diego School of Medicine, United States, have discovered why. It turns out that the chromosomes in laboratory stem cells open slowly over time, in the same sequence that occurs during embryonic development. It isn’t until certain chromosomal regions have acquired the “open” state that they are able to respond to added growth factors and become liver or pancreatic cells. This new understanding, say researchers, will help spur advancements in stem

cell research and the development of new cell therapies for diseases of the liver and pancreas, such as type 1 diabetes. “Our ability to generate liver and pancreatic cells from stem cells has fallen behind the advances we’ve made for other cell types,” said Maike Sander, MD, professor of pediatrics and cellular and molecular medicine and director of the Pediatric Diabetes Research Center at UC San Diego. “So we haven’t yet been able to do things like test new drugs on stem cell-derived liver and pancreatic cells. What we have learned is that if we want to make specific cells from stem cells, we need ways to predict how those cells and their chromosomes will respond to the growth factors.” Sander led the study, together with cosenior author Bing Ren, PhD, professor of cellular and molecular medicine at UC San Diego and Ludwig Cancer Research member. Sander, Ren and their teams first made maps of chromosomal modifications over time, as embryonic stem cells differentiated through several different developmental intermediates on their way to becoming pancreatic and liver cells. Then,

This new understanding, say researchers, will help spur advancements in stem cell research and the development of new cell therapies for diseases of the liver and pancreas, such as type 1 diabetes

in analyzing these maps, they discovered links between the accessibility (openness) of certain regions of the chromosome and what they call developmental competence – the ability of the cell to respond to triggers like added growth factors. “We’re also ﬁnding that these chromosomal regions that need to open before a stem cell can fully differentiate are linked to regions where there are variations in certain disease states,” Sander says. In other words, if a person were to inherit a genetic variation in one of these chromosomal regions and his or her chromosome didn’t open up at exactly the right time, he or she could hypothetically be more susceptible to a disease affecting that cell type. Sander’s team is now working to further investigate what role, if any, these chromosomal regions and their variations play in diabetes.

Co-authors of this study also include ALLEN WANG, RUIYU XIE, THOMAS HARPER, NISHA A. PATEL, KAYLA MUTH, JEFFREY PALMER, JINZHAO WANG, and DIETER K. LAM, UC San Diego; FENG YUE, The Pennsylvania State University; YAN LI, YUNJIANG QIU, Ludwig Cancer Research; and JEFFREY C. RAUM, DORIS A. STOFFERS, University of Pennsylvania. This research was funded, in part, by the National Institutes of Health (grants U01DK089567, U01-DK072473, U01-ES017166, U01-DK089540 and T32-DK7494-27), California Institute for Regenerative Medicine (grants RB5-07236 and TG201154, Bridges to Stem Cells Program), Helmsley Charitable Trust and JDRF - Cell Stem Cell.

THE CLINICAL CARE JOURNAL | 61

RESEARCH | DIABETES

CONTROL SWITCH MAY BE KEY TO DIABETES AND MANY OTHER DISEASES

esearchers at the University of California, San Diego School of Medicine in the United States, have discovered a control switch for the unfolded protein response (UPR), a cellular stress relief mechanism drawing major scientiﬁc interest because of its role in diabetes, cancer, inﬂammatory disorders and several neural degenerative disorders, including Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS), otherwise known as Lou Gehrig’s disease. The normal function of the UPR pathway is to protect cells from stress but it can also trigger their death if the stress is not resolved. The researchers’ discovery of a control switch that acts on the UPR pathway, published March 25, 2015 in the online edition of EMBO Reports, opens new drug development avenues for treating a wide variety of diseases by modulating the UPR pathway to prevent excessive cell death. “Our paper reports that two highly conserved pathways – the UPR and the nonsense-mediated RNA decay pathway – intersect with each other at a pivotal point in cell stress,” said Miles Wilkinson, PhD, senior author and professor in the Department of Reproductive Medicine and a member of the UC San Diego Institute for Genomic Medicine. “In essence, we’ve shown that the nonsensemediated RNA decay pathway, typically referred to as ‘NMD,’ keeps the UPR in check to avoid the potentially dangerous consequences if the UPR pathway were allowed to mount an inadvertent response to innocuous stress.” In cells, like people, too much stress can cause bad things to happen. In the case of cells, one such bad consequence is the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER), the cell’s protein-making factory. To carry out their many biological functions, proteins must be precisely folded in the correct shape. The body’s answer to excessive cell stress and accompanying mis-

62 | THE CLINICAL CARE JOURNAL

Because of the important role of UPR in regulating cell life/death decisions, it is critical that mechanisms are in place to prevent unnecessary UPR activation in response to innocuous or low-level stimuli.

shapen proteins is the unfolded protein response. The UPR kicks in and restores normal ER-folding capacity by adjusting certain cellular processes. If this fails, the UPR instructs the cell to self-destruct, a process known as programmed cell death or apoptosis. Wilkinson describes the UPR pathway as a double-edged sword. “In a large number of diseases, ranging from cancer to ALS, major stress occurs in the affected cells, leading the UPR pathway to be triggered,” he said. “And that’s meant to be helpful. But if the stress isn’t relieved in a timely fashion, it triggers cell death. A limited amount of cell death is normal, but if too many cells die, especially critical cells, then it’s a problem. Chronic UPR activation and excessive cell death has been implicated in brain disorders like Alzheimer’s and Parkinson’s disease.” In their study, Wilkinson, with ﬁrst author Rachid Karam, PhD, and colleagues found that the NMD pathway plays a critical role in shaping the activities of UPR. Speciﬁcally, they discovered that NMD prevents inappropriate activation of the UPR and also promotes its timely termination to protect cells from pro-

longed ER stress. “Because of the important role of UPR in regulating cell life/ death decisions, it is critical that mechanisms are in place to prevent unnecessary UPR activation in response to innocuous or low-level stimuli,” said Wilkinson. “In this report we demonstrate that the NMD pathway serves in this capacity by raising the threshold for triggering UPR and also promoting its shut off at the appropriate time.” He added that NMD doesn’t deter the UPR if an important stress comes along where more action is needed. “Although NMD normally represses the UPR, our paper and previous work have shown that it gets out of the way if there’s a real problem,” Wilkinson noted. Previous studies from the Wilkinson group and others have established that NMD has two broad roles. First, it is a quality control mechanism used by cells to eliminate faulty messenger RNA (mRNA) – molecules that are essential for transcribing genetic information into the construction of proteins critical for life. Second, NMD degrades a speciﬁc group of normal mRNAs. The latest study shows that NMD suppresses inappropriate UPR activities by driving the rapid decay of several normal mRNAs encoding proteins critical for the UPR. “We demonstrate that NMD directly targets the mRNAs encoding several UPR components, including the highly conserved UPR sensor, IRE1alpha, whose NMD-dependent degradation partly underpins this process,” said Wilkinson. “Our work not only sheds light on UPR regulation, but demonstrates the physiological relevance of NMD’s ability to regulate normal mRNAs.”

Co-authors include CHIH-HONG LOU, HEIKE KROEGER, JONATHAN H. LIN, all at UC San Diego; LULU HUANG, formerly of UC San Diego and now at ISIS Pharmaceuticals. Funding for this research came, in part, from NIH grant (RO1 GM111838) – EMBO Reports.

RESEARCH | DIABETES

GUT IMMUNE SYSTEM IDENTIFIED AS A NEW AND EFFECTIVE TARGET IN TREATING

DIABETES

commonly-used drug to treat inflammatory bowel disease, such as Crohn’s disease, has been shown to lower blood sugar levels in obese mice, potentially identifying the gut immune system as a new and effective target in treating diabetes in humans. “These results are novel and important because we have identified the immune system that lives in the gut as a new player in the control of blood sugar. This opens up the entire field of bowel immunology to the study of obesity and its complications such as high blood sugar,” says Dan Winer, Scientist, Diabetes Research Group in the Toronto General Research Institute (TGRI), whose laboratory spearheaded this work, along with his twin brother Shawn Winer, and who are both co-senior authors on this paper. Their research is published in an article entitled, “Regulation of Obesity-Related Insulin Resistance with Gut Anti-inflammatory Agents,” in the prestigious journal, Cell Metabolism, online April 7, 2015. Being overweight, especially around the abdomen or waistline, increases the chances of developing type 2 diabetes. The question many scientists are trying to answer is: why does obesity contribute to insulin resistance? In their previous work, the Winers demonstrated that immune cells inside abdominal fat cause the release of ‘pro-inflammatory’ chemicals, which make the body less sensitive to insulin. Insulin resistance is known as a major trigger for type 2 diabetes. In this research, the focus shifted from the fat to the gut, where the Winers found that mice fed a high-fat, high-calorie diet had larger amounts of pro-inflammatory immune cells and less of the regulating cells which help end an immune response, than in normal mice. The researchers found this same result in 14 humans, seven of whom were obese.

64 | THE CLINICAL CARE JOURNAL

By using this drug, we found that we could prevent type 2 diabetes in mice.t

The high-fat diet induces inflammatory changes in the immune cells in the bowel, upsetting the immune balance, which in turn sets off a chemical cascade, damaging the bowel wall, allowing bacterial products to leak into the blood stream. This leakage is what contributes to insulin resistance, when the cells can no longer respond to and use insulin effectively to stabilise blood sugar. “If we could block the pro-inflammatory immune cells at the very beginning of this process, we could treat the disease more effectively,” reasons Shawn Winer, who is a gastrointestinal pathology fellow in the Laboratory Medicine Program at University Health Network (UHN). “By refocusing on the bowel, we open up many more therapeutic options as we already have a number of approved drugs available to treat an inflamed bowel.” The researchers then targeted the bowel inflammation found in the obese mice with 5-ASA, or mesalamine, a commonly used drug to treat inflammatory bowel disease. They found that the drug reversed insulin resistance and lowered blood sugar significantly in the mice to near normal levels. “By using this drug, we found that we could prevent type 2 diabetes in mice,” says Dan Winer, who is also an endocrine pathologist at UHN and an Assistant Professor in Laboratory Medicine and Pathobiology at the University of Toronto. “If this works in humans, it could change the whole field of diabetes prevention and

treatment.” He also points out that some medications targeting the bowel act locally in the gut, with minimal side effects and absorption in the rest of the body. More than two million Canadians have diabetes. Currently, those with diabetes lower their glucose through diet, exercise, anti-diabetic tablets or insulin injections and must regularly monitor blood glucose levels. High glucose levels result in damage to eyes, nerves and kidneys and increase the risk of heart attack, stroke, blindness, erectile dysfunction, foot problems and amputations. Many laboratories around the world are in a race to ﬁnd alternative and effective ways to lower glucose levels because of the severe complications which can result from high sugar levels. The current ﬁndings of this paper point to changes in the bowel which can be targeted by new classes of potentially effective, minimal side-effect therapies for insulin resistance, a precursor to type 2 diabetes. Other researchers involved in the study include co-first authors HELEN LUCK, who is a graduate student in Immunology at the University of Toronto, and SUE TSAI, who is postdoctoral researcher and winner of the esteemed Banting Fellowship from Canadian Institutes of Health Research. Additional collaborators include JASON CHUNG, XAVIER CLEMENTE-CASARES, MAGAR GHAZARIAN, XAVIER REVELO, HELENA LEI, CYNTHIA LUK, SALLY YU SHI, ANURADHA SURENDRA, JULIA COPELAND, JENNIFER AHN, DAVID PRESCOTT, BRITTANY RASMUSSEN, MELISSA HIU YEN CHNG, EDGAR ENGLEMAN, STEPHEN GIRARDIN, TONY LAM, KENNETH CROITORU, SHANNON DUNN, DANA PHILPOTT, DAVID GUTTMAN, and MINNA WOO. The work was funded by the Canadian Institutes of Health Research, the Canadian Diabetes Association, and the Banting and Best Diabetes Centre at the University of genomic medicine - Cell Metabolism.

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The only once-weekly GLP-1 for type 2 diabetes Introducing the BYDUREON® Pen Now easier to use† and an ideal choice for your patients’ first injectable BYDUREON® (exenatide) 2MG POWDER AND SOLVENT FOR PROLONGED-RELEASE SUSPENSION FOR INJECTION Consult Summary of Product Characteristics before prescribing. Use: Treatment of type 2 diabetes mellitus in combination with metformin, sulphonylurea, thiazolidinedione, or combinations of metformin and sulphonylurea or metformin and thiazolidinedione, in adults who have not achieved adequate glycaemic control on maximally tolerated doses of these oral therapies. Presentation: Powder and solvent for prolonged-release suspension for injection containing 2mg exenatide. Dosage and administration: Adults: The recommended dose is 2mg exenatide once weekly, on the same day each week, at any time of day, with or without meals. Administer as subcutaneous injection in the thigh, abdomen, or back of the upper arm immediately after suspension of powder in the solvent. If dose is missed, administer as soon as practical, then resume once weekly dosing schedule. Two injections should not be given on the same day. Bydureon is for self-administration, appropriate training is recommended. Patients switching from exenatide twice daily to Bydureon may experience transient elevations in blood glucose concentrations, which generally improve within first two weeks after therapy initiation. When Bydureon is added to existing metformin and/or thiazolidinedione, the current dose of these oral therapies can be continued. Increased risk of hypoglycaemia when Bydureon is added to sulphonylurea. Consider reduction in dose of sulphonylurea to reduce the risk of hypoglycaemia. Blood glucose selfmonitoring may be necessary to adjust the dose of sulphonylurea. If a different antidiabetic treatment is started after the discontinuation of Bydureon, consideration should be given to the prolonged release of Bydureon. Elderly: No dose adjustment required. >75 years: Very limited clinical experience. Consideration should be given to the patient’s renal function. Renal or hepatic impairment: No dose adjustment required for patients with mild renal impairment (creatinine clearance 50-80 ml/min) or hepatic impairment. Very limited experience in moderate renal impairment (creatinine clearance 30 50ml/min). Not recommended in patients with moderate renal impairment, severe renal impairment (creatinine clearance <30 ml/min) or end-stage renal disease. Children and adolescents: <18 years old: Safety and efficacy not established. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Warnings and precautions: Not to be used in patients with type 1 diabetes mellitus or for diabetic ketoacidosis. Must not be administered by intravenous or intramuscular injection. Renal impairment: Rare, spontaneously reported events of altered renal function with exenatide, including increase serum creatinine, renal impairment, worsened chronic renal failure and acute renal failure, sometimes requiring haemodialysis. Some occurred in patients experiencing events that may affect hydration and/or receiving medicinal products known to affect renal function/hydration status, including angiotensin converting enzyme inhibitors, angiotensin-II antagonists, non-steroidal anti-inflammatory medicinal products and diuretics. Reversibility observed with supportive treatment and discontinuation of potentially causative medicinal products, including exenatide. Severe gastrointestinal disease: Not recommended. Acute pancreatitis: Use of GLP-1 receptor agonists has been associated with a risk of developing acute pancreatitis. Rare, spontaneously reported events of acute pancreatitis. Resolution of pancreatitis has been observed with supportive treatment, but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. Inform patients of the characteristic

symptom of acute pancreatitis: persistent, severe abdominal pain. If pancreatitis suspected, discontinue use; if acute pancreatitis is confirmed, Bydureon should not be restarted. Caution should be exercised in patients with a history of pancreatitis. Concomitant medicinal products: Concurrent use of Bydureon with insulin, meglitinides, alpha-glucosidase inhibitors, dipeptidyl peptidase-4 inhibitors or other GLP-1 receptor agonists have not been studied. The concurrent use of Bydureon and exenatide twice daily has not been studied and is not recommended. Weight loss: Rapid weight loss at a rate of >1.5kg per week has been reported with exenatide, which may have harmful consequences. Discontinuation of treatment: The effect of Bydureon may continue as plasma levels of exenatide decline over 10 weeks. Choice of other medicinal products and dose selection should be considered accordingly until exenatide levels decline. Drug interactions:. No dose adjustment required for medicinal products sensitive to delayed gastric emptying. Warfarin and cumarol derivatives: Increased INR (International normalised ratio) reported during concomitant use of warfarin and exenatide. INR should be monitored during initiation of Bydureon. HMG CoA reductase inhibitors: Concomitant use with exenatide was not associated with consistent changes in lipid profiles. Lipid profiles should be monitored as appropriate. Pregnancy and lactation: Women of childbearing potential should use contraception during treatment with Bydureon. Discontinue at least 3 months before trying to get pregnant. Avoid use during pregnancy and breast-feeding. Undesirable Effects: Consult SmPC for full list of side effects. Very common (≥1/10): Hypoglycaemia (with sulphonylurea), constipation, diarrhoea, nausea, vomiting, injection site pruritus. Common (≥1/100 to <1/10): Decreased appetite, dizziness, headache, abdominal distention, abdominal pain, dyspepsia, eructation, flatulence, gastroesophageal reflux disease, fatigue, injection site erythema, injection site rash, somnolence. Uncommon (≥ 1/1000 to < 1/100): Intestinal obstruction. Not known (cannot be estimated from available data): Anaphylactic reaction, acute pancreatitis, angioneurotic oedema, macular and papular rash, altered renal function (including acute renal failure, worsened chronic renal failure, renal impairment, increased serum creatinine). Also, not observed with Bydureon but reported with exenatide: Rare (≥1/10,000 to <1/1000): Dehydration (generally associated with nausea, vomiting and/or diarrhoea), INR ratio increased with concomitant warfarin use (some reports associated with bleeding). Patients may develop anti-exenatide antibodies following treatment with Bydureon. These patients tend to have more injection site reactions (e.g. skin redness, itching). Small subcutaneous injection site nodules observed very frequently, consistent with the known properties of PLGA polymer microsphere formulations. Legal Category: POM. Marketing authorisation number: EU/1/11/696/001 (single dose kit) and EU/1/11/696/003 (pre-filled pen). Further product information available on request from: Freephone 1800 800 899 or contact AstraZeneca UK Limited, Horizon Place, 600 Capability Green, Luton, Bedfordshire, LU1 3LU, United Kingdom. Bydureon is a trademark of the AstraZeneca group of companies. Date of API preparation: 12/2014. References: 1. Buse JB, Drucker DJ, Taylor K, et al. Exenatide once weekly produces sustained glycaemic control and weight loss over 52 weeks. Diab Care 2010;33:1255–61. 2. Bydureon® Summary of Product Characteristics available at www.medicines.ie Date of preparation: January 2015. Approval ID: 638,412.011 †vs Bydureon Single Dose Tray

* BYDUREON is not indicated for the management of obesity, and weight loss was a secondary endpoint in clinical trials.

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DIABETES | RESEARCH

INCREASE IN

INFLAMMATION LINKED TO HIGH TRAFFIC POLLUTION FOR PEOPLE ON INSULIN

two-year epidemiological study of Puerto Rican adults with type 2 diabetes in the greater Boston area who were using insulin and lived next to roads with heavy traffic had markedly increased C-reactive protein, a marker of inflammation, compared to those living in lower traffic areas. Individuals taking oral diabetes medications did not experience increases in CRP concentration. The study, published online in Environmental Pollution, builds on the research team’s previous work suggesting that oral diabetes medications may provide a protective effect against inflammation for people with type 2 diabetes. “C-reactive protein (CRP) concentration increased 75-200% over the two-year period for those 10% of study participants living in the highest traffic areas who were using insulin when compared to those living in lower traffic areas. In contrast, CRP concentration did not increase for the 22% of people taking metformin and/or other oral diabetes medications who were also living in the high traffic areas,” said Christine Rioux, Ph.D., M.S., first and corresponding author, research assistant professor in the department of public health and community medicine at Tufts University School of Medicine. Prior studies of the adverse health effects of traffic or air pollution have not considered the role that type of medication may play in relation to inflammation for people with diabetes. In a crosssectional study published in 2011, this research team reported that medication type appeared to modify the relationship between traffic exposure and CRP concentration. Of the 356 participants in the new study, approximately 20% lived within 100 metres of one or more roads with more than 20,000 vehicles/day. Another 20% lived within 100 to 200 meters of

It’s important to know who is most vulnerable to the adverse effects of traffic pollution exposure for purposes of education and policy.

roads with more than 20,000 vehicles/ day. Approximately 70% of the 356 participants in the study lived in Boston neighbourhoods, including the South End, Dorchester, Roxbury and Jamaica Plain. CRP was measured at the beginning of the study and again two years later, using a high sensitivity test. Study participants are part of a larger cohort of Puerto Ricans living in the Boston, MA area who were found to have a high prevalence (40%) of type 2 diabetes. Of 356 study participants, 91 (26%) used insulin, 197 (55%) used only oral diabetes medication and 68 (19%) reported using no diabetes medication. “It’s important to know who is most vulnerable to the adverse effects of trafﬁc pollution exposure for purposes of education and policy. People who live near busy roads and spend most of their time in these areas have been shown in many studies to have higher levels of inﬂammation, a risk factor for many cardiovascular and metabolic diseases. People on insulin

appear to be even more susceptible to increases in inflammation when living in high traffic areas. People can reduce their exposure to traffic pollution by keeping windows closed during the heaviest traffic periods of the day, using air conditioners in the summer months, and avoiding heavy exercise near busy roads, especially during peak traffic times,” said Rioux. “This study is important because many people who live near highways may have diabetes and other serious chronic conditions. It’s interesting to see that treatments for diabetes may interact with the risks associated with exposure to air pollution. While this is an intriguing finding, it is not clear why oral diabetes medications, unlike insulin, appear to be protective and it warrants additional research,” said last author Mkaya Mwamburi, M.D., Ph.D., M.A., director of the Center for Global Public Health and associate professor in the department of public health and community medicine, both at Tufts University School of Medicine.

This analysis is part of the Boston Puerto Rican Health Study at the Center for Population Health and Health Disparities, a longitudinal cohort study on stress, nutrition, aging and chronic health conditions conducted by researchers at the University of Massachusetts at Lowell, Northeastern University, and Tufts University, led by co-author KATHERINE TUCKER, Ph.D., professor of nutritional epidemiology at the University of Massachusetts, Lowell. DOUG BRUGGE, Ph.D., M.S., professor in the department of public health and community medicine at Tufts University School of Medicine is an additional co-author. Rioux, C.L., Tucker K. L., Brugge, D., and Mwamburi, M. (2015, March 24). Medication type modifies inflammatory response to traffic exposure in a population with type 2 diabetes. Environmental Pollution, 202, 58-65. doi:10.1016/j.envpol.2015.03.012

THE CLINICAL CARE JOURNAL | 67

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OLDER PEOPLE

STATISTICS REVEAL

KEY GERIATRIC CARE TRENDS

An increase in daycare treatment rates for the elderly and an increase in dedicated elderly care wards are among the many statistics that illustrate the state of play in geriatric care in Ireland, according to Dr Diarmuid O’Shea, Clinical Lead for the National Clinical Programme for Older People (NCPOP) and Consultant Geriatrician at St. Vincent’s University Hospital, Dublin. Maureen Browne reports.

he number of elderly people treated on a day-care basis has increased, the length of hospital inpatient stay for the majority of older people has decreased, and a new survey is expected to show that the percentage of acute hospitals admitting people over the age of 65 years acutely with a dedicated elderly care ward has more than doubled, according to Dr. Diarmuid O’Shea, Clinical lead for the National Clinical Programme for Older People (NCPOP) and Consultant Geriatrician at St. Vincent’s University Hospital, Dublin. “The acute sector has responded to the increased presentations of older people due to demographic trends and the high prevalence of chronic disease by increasing the number of people treated on a day-case basis and by decreasing the length of hospital inpatient stay for the majority of older people,” he says. “The national average length of stay (ALoS) for patients aged 65 years and over decreased from 10.8 days in 2010 to 9.7 days in 2013. There has also been a substantial increase in the number of day cases for this age cohort of patients (over 65 years), from 278,222 in 2010 to 308,732 in 2013, an increase of 11 per cent. This has enabled the services to respond to demographic trends without a corresponding increase in admissions and bed days for the over 65s.”

BEST PRACTICE The Model of Care for Older People in Acute Hospitals, launched and published by the HSE and Department of Health in 2012, clearly deﬁnes requirements for older persons in the acute hospital setting. It describes the core acute hospital services for the older person as a minimum of a dedicated elderly care ward, a rehabilitation ward and a day hospital on

the acute hospital site. The overall aim is to implement best practice in acute care of the older person nationally through the establishment of a specialist geriatric service (SGS) in each acute hospital, to include: • Geriatric specialist wards, rehabilitation and day hospital facilities • Comprehensive geriatric assessment • Liaison with primary care services and discharge planning. “The implementation of the acute specialist geriatric service model has complemented the development of acute medical units as part of the Acute Medicine Programme,” says Dr. O’Shea. “The appointment of geriatricians to work in those units facilitates the identiﬁcation of the older person with complex needs. Links with the inpatient geriatric services facilitate referral to the appropriate diagnostic, treatment, rehabilitation and support services. Referral may be to community services, outpatients or day hospital as appropriate to meet the needs of the patient “The NCPOP is now in the process of completing the Specialist Geriatric Service Model of Care for Mental Health Services which should be published in early 2015. “Society and Government need to continue to support the development of services for older people with policy and funding. It requires focused reconﬁguration of acute hospital and community services. It also requires society to make it unacceptable that these services are not available when we are older and require access to this type of care and support.” An example of this can be seen in the need for care of people over 80 years of age coming into acute hospitals. In one area in Ireland they make up 3 per cent of the population in the catchment area, but 13 per cent of the attendances

at the emergency department and 25 per cent of the actual bed occupancy of that hospital in a year. While these ﬁgures will vary from region to region, they demonstrate why each local region should be required to do this type of analysis, and to know their own demographics well. “A survey carried out in 2011 by the NCPOP identiﬁed that only 30 per cent of acute hospitals admitting people over the age of 65 years who were acutely ill had a dedicated elderly care ward. A repeat survey is currently being completed, and based on a number of hospital visits this year the programme anticipates that this penetration rate has increased to approximately 70 per cent, with the majority having improved dedicated multidisciplinary input. We have, however, a lot more progress to make.”

The NCPOP is now in the process of completing the Specialist Geriatric Service Model of Care for Mental Health Services, which should be published in early 2015.

BETTER OUTCOMES Dr O’Shea says that evidence published recently in a Cochrane review clearly demonstrated that admitting an appropriately clinically identiﬁed older person to a specialist geriatric ward, with gerontologically attuned nursing staff and

THE CLINICAL CARE JOURNAL | 69

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Interactions $EVRUSWLRQ RI FDOFLXP DQG RU YLWDPLQ ' PD\ EH DIIHFWHG E\ WHWUDF\FOLQHV WDNH KRXUV EHIRUH RU WR KRXUV DIWHU &DOFLFKHZ SUHSDUDWLRQ OHYRWK\UR[LQH WDNH IRXU KRXUV EHIRUH RU DIWHU WKLD]LGH GLXUHWLFV FDUGLDF JO\FRVLGHV Calcichew-D3 Forte Chewable Tablets: ELVSKRVSKRQDWHV RU VRGLXP รธXRULGH WDNH KRXUV EHIRUH FRUWLFRVWHURLGV LRQ H[FKDQJH UHVLQV FKROHVW\UDPLQH OD[DWLYHV SDUDIรทQ RLO GR QRW WDNH ZLWKLQ KRXUV RI HDWLQJ IRRGV KLJK LQ R[DOLF DFLG H J VSLQDFK DQG UKXEDUE RU SK\WLF DFLG H J ZKROH FHUHDOV TXLQRORQH DQWLELRWLFV WDNH WZR KRXUV EHIRUH RU DIWHU Calcichew-D3 Forte Double Strength 1000 mg/800 IU Chewable Tablets: %LVSKRVSKRQDWHV WDNH KRXU EHIRUH LURQ ]LQF RU VWURQWLXP UDQHODWH GR QRW WDNH ZLWKLQ KRXUV 4XLQRORQH DQWLELRWLFV WDNH WZR KRXUV EHIRUH RU VL[ KRXUV DIWHU Fertility, Pregnancy & Lactation: Calcichew-D3 Forte Chewable Tablets: &DQ EH XVHG GXULQJ SUHJQDQF\ LQ FDVH RI FDOFLXP DQG YLWDPLQ ' GHรทFLHQF\ 'DLO\ LQWDNH LQ SUHJQDQF\ VKRXOG QRW H[FHHG PJ FDOFLXP DQG ,8 FROHFDOFLIHURO PLFURJUDPV YLWDPLQ '3 $YRLG RYHUGRVH DV SHUPDQHQW K\SHUFDOFDHPLD DIIHFWV GHYHORSLQJ IRHWXV &DOFLFKHZ '3 )RUWH 'RXEOH 6WUHQJWK PJ ,8 &KHZDEOH 7DEOHWV QRW VXLWDEOH GXULQJ SUHJQDQF\ Calcichew-D3 Forte Chewable Tablets/ Calcichew-D3 Forte Double Strength 1000 mg/800 IU Chewable Tablets: can be used during breast-feeding. Calcium and vitamin D3 SDVV LQWR EUHDVW PLON VR FRQVLGHU WKLV ZKHQ JLYLQJ DGGLWLRQDO YLWDPLQ ' WR WKH FKLOG Undesirable Effects: 8QFRPPRQ ! รด +\SHUFDOFDHPLD K\SHUFDOFLXULD Refer to the SmPC for details and full side HIIHFW SURรทOH DQG LQWHUDFWLRQV /HJDO &ODVVLรทFDWLRQ 3KDUPDF\ SURGXFW Marketing Authorisation Holder: 7DNHGD 8. /WG %XLOGLQJ *ORU\ 3DUN *ORU\ 3DUN $YHQXH :RREXUQ *UHHQ %XFNV +3 ') 7HO )D[ )XUWKHU LQIRUPDWLRQ LV DYDLODEOH RQ UHTXHVW RU LQ WKH 6P3& Marketing Authorisation Number: 3$ DQG 3$ PI Approval Code: ,5( &$/ Date of Revision: October 2014. Adverse Events should be reported to the Pharmacovigilance Unit at the Health Products Regulatory Authority (medsafety@hpra.ie). Information about Adverse Event reporting can be found on the HPRA website (www.hpra.ie). Adverse Events should also be reported to Takeda UK Ltd on 1800 937 970. References 1. Calcichew-D3 )RUWH 'RXEOH 6WUHQJWK FDOFLXP FDUERQDWH FROHFDOFLIHURO 6XPPDU\ RI 3URGXFW &KDUDFWHULVWLFV $YDLODEOH DW ZZZ PHGLFLQHV LH $FFHVVHG 2FWREHU ,5( &$/ P

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OLDER PEOPLE

health and social care professionals who got a comprehensive geriatric assessment (CGA), were more likely to be alive and at home six months later. “CGA is a multidimensional interdisciplinary diagnostic process focused on determining a frail elderly person’s medical, psychological and functional capability in order to develop a co-ordinated and integrated plan for treatment and long-term follow-up. In the context of inpatient treatment and dedicated services, CGA is associated with better outcomes for frail elderly patients, i.e. health improvement and reduction in disability, and a signiﬁcant increase in being alive and living at home on follow-up (Cochrane 2011). For every six frail elderly receiving specialist in-patient care, one additional person can be expected to be alive and living at home at six months.

There is actually a surprising lack of social, economic and health information on older people in Ireland.

“This is timely evidence. You would not consider admitting a patient with a myocardial infarct to anything other than a coronary care unit, and similarly for a patient with a stroke. In all these scenarios, outcomes including lower mortality rates, less disability and better long-term outcomes have been demonstrated. We now have similar evidence for the management of the frail older person and should act accordingly.” As we are all living longer, we are challenged to ensure that these years gained will be healthy years. “We need to work into our daily lives attitudes and behaviours that maximise our health and delay the onset of disabling illness. In essence, we should aim to spend a longer time living healthily and a shorter time dying!”

EFFECTIVE PLANNING Between 2006 and 2021, Ireland’s population is predicted to increase from 4.2 million to 5.1 million, those over 65 years will increase from 11 per cent to 15.1 per cent, while those over 85 will increase from 1.2 to 2.1 per cent, an

absolute increase of nearly 50,000 people. Planning effectively for population ageing and the predicted growth will have positive consequences for the health and wellbeing of Irish people. Paramount in this will be a continued emphasis on healthcare promotion and prevention. “This challenge does not start at the age of 65; it starts when we are much younger. The worrying rates of childhood obesity will impact on life expectancy for some and quality of life for others in the years ahead. If you are overweight at 40, your life expectancy is three years less; if you are obese at 40, it is seven years less and if you are obese and smoke at the age of 40, it is 14 years less. Obesity is associated with increased risk of certain cancers, high blood pressure, high cholesterol, arthritis, diabetes and dementia. All of these illnesses, and more, lead to disability and altered quality of life. Our own personal challenge is that in knowing we will live longer, we must ensure that these years gained are healthy years. “Those over the age of 80 years requiring healthcare tend to be frail with multiple co-morbidities, have longer stays in hospital and require more services when they go home. It is important that there is a structured programme of acute hospital care that patients have access to, and timely access to support services in the community on discharge. “The undoubted challenge is that this frail older group require a different combination of services than younger people. Substantial service reconﬁguration and investment, particularly in the community sector, are required to meet this growing need. There is a danger that in the current economic climate delivering ongoing better quality care to a large group of people with the same or less resource might potentially overwhelm the service. “Four major factors drive the need

for care in the community for the older person, be that care at home, hospital or in a nursing home – they are population growth, life expectancy, disability trends and household composition” Between 1968 and 2009, the number of public nursing home beds has fallen from 13,600 to 8,250, while the number of private nursing home beds has increased from 6,900 in 1997 to 20,500 in 2009. Dr O’Shea says: “There is actually a surprising lack of social, economic and health information on older people in Ireland. Real opportunity exists to understand the characteristics and needs of our ageing population. We also need to further explore service care models and develop new technologies and treatments to enable independent living. The Irish Longitudinal on Ageing (TILDA) conducted by Trinity College, is a resource for us to exploit all these opportunities and needs in the years to come. “We have a great opportunity to plan and get this type of care right. A meeting is planned for May 26th 2015, ‘Transforming Care of Older People in Ireland’, to be held in conjunction with the RCPI and HSE. One of the keynote speakers is Professor David Oliver, who led the King’s Fund review on ‘Making our health and care systems ﬁt for an ageing population’. He will speak on the title ‘Making health and care services ﬁt for an ageing population: how we need to change’. This talk and the meeting will give us further impetus to drive these important changes forward.”

DR DIARMUID O’SHEA is Clinical Lead for the National Clinical Programme for Older People (NCPOP) and Consultant Geriatrician at St. Vincent’s University Hospital, Dublin.

THE CLINICAL CARE JOURNAL | 71

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ELDERLY CARE | RESEARCH

CHANGES IN A

BLOOD-BASED MOLECULAR PATHWAY IDENTIFIED IN

ALZHEIMER’S DISEASE

y the time most people receive a diagnosis of Alzheimer’s disease — based on clinical signs of mental decline — their brains have already suffered a decade or more of damage. But although the mechanisms that spur the destruction of neurons in Alzheimer’s disease are not yet fully understood, two welldocumented signs of the condition are accumulation of the amyloid-Ɯ peptide (the main component of plaques found in Alzheimer’s patient brains) and chronic inflammation. New research from Rockefeller University, United States, published March 16 in the Proceedings of the National Academy of Sciences, identifies a bridge between the two. That bridge, a molecular cascade known as the contact system, may provide opportunities for early diagnosis of the disease through simple blood tests. “People have been looking for a long time for markers for Alzheimer’s disease,” says Sidney Strickland, head of the Patricia and John Rosenwald Laboratory of Neurobiology and Genetics. But current diagnostic tests for pre-symptomatic Alzheimer’s leave much to be desired. Evaluating the level of amyloid-Ɯ in the cerebral spinal fluid, for instance, requires an invasive spinal tap procedure. “Finding a blood biomarker that would let us know through a simple test whether someone is on their way to developing the disease would be a significant advance,” says first author Daria Zamolodchikov, a postdoctoral associate in the Strickland lab.

Finding a blood biomarker that would let us know through a simple test whether someone is on their way to developing the disease would be a significant advance.

The new study grew from the lab’s ongoing work that looks at how the vascular system is involved in Alzheimer’s disease. It has been shown that amyloid-Ɯ can activate a protein in plasma called factor XII, the first step in a pathway known as the contact system. When activated, this system leads to the release of a small peptide called bradykinin, a molecule known to promote potentially damaging inflammation. Although some studies have found these molecules in the cerebral spinal fluid and brain tissue of Alzheimer’s patients, no one had studied them in Alzheimer’s patient plasma. Using plasma from people with and without diagnosed Alzheimer’s disease, the researchers measured the activation levels of the contact system. They found increased activation of this system in the plasma of Alzheimer’s patients, potentially implicating it in the inflammatory

pathology of the disease. Moreover, in a subset of patients whose amyloid-Ɯ levels in the cerebral spinal fluid were known, the researchers demonstrated a positive correlation between activation of the contact system and changes in cerebral spinal fluid amyloid-Ɯ levels, which as mentioned above are correlated with the development of Alzheimer’s. The researchers found similar activation of the contact system in mouse models of Alzheimer’s, which are genetically modified to overproduce amyloid-Ɯ. They then conducted a follow-up experiment with healthy mice. “We went one step further and took completely normal wild-type mice and injected them with amyloid-Ɯ. We found that on its own, injection with amyloid-Ɯ can activate this system. It’s a proof of principle in a complex environment,” says Zamolodchikov. These findings will need to be supported by studies in larger patient populations and longitudinal studies, but they could eventually open the door to diagnosis of pre-symptomatic Alzheimer’s based on blood levels of these molecules. The contact system may also offer a new approach to therapies for Alzheimer’s disease, since inhibition of the pathway could blunt some of the inflammatory aspects of the disease. One concern is that the contact system is also involved in blood clotting and inhibition might carry a risk of bleeding. However, people with a defect in this system do not have hemophilia. Thus, inhibition of this pathway might slow progression of the disease without increasing the risk of hemorrhage - Proceedings of the National Academy of Sciences.

THE CLINICAL CARE JOURNAL | 73

HCAI & AMR

PATIENTS SHOULD EXPECT

HIGH-QUALITY

HEALTHCARE IN A SAFE ENVIRONMENT

Antimicrobial stewardship, hand hygiene and the prevention of infections associated with medical devices are key priorities for Irish healthcare, according to Dr. Fidelma Fitzpatrick, National Clinical Lead for the National Clinical Programme for the Prevention of Healthcare-Associated Infection and Antimicrobial Resistance, Consultant Microbiologist at Beaumont Hospital and Senior Lecturer at the Royal College of Surgeons in Ireland. Maureen Browne reports.

he National Clinical Programme for the Prevention of Healthcare-Associated Infection (HCAI) and Antimicrobial Resistance (AMR) has concentrated on three main areas – antimicrobial stewardship, hand hygiene and the prevention of infections associated with medical devices such as intravascular (IV) lines and urinary catheters, according to Dr. Fidelma Fitzpatrick, National Clinical Lead for the Programme, Consultant Microbiologist at Beaumont Hospital and Senior Lecturer at the Royal College of Surgeons in Ireland. This is the only national clinical programme with a multidisciplinary expert clinical advisory group and includes representation from patient groups, the acute and non-acute healthcare sectors, and the Department of Health, Department of Agriculture and HIQA. The national programme works as part of the Quality and Patient Safety Division of the HSE, led by Dr. Philip Crowley. Following four years heading up the programme, Dr. Fitzpatrick moved on at the end of 2014 to be succeeded by Dr. Robert Cunney, Consultant Microbiologist, Temple Street University Hospital and Health Protection Surveillance Centre. Dr. Fitzpatrick says that during her time as clinical lead, the programme had overseen the development of a variety of guidelines, educational tools, HCAI indicators and information for healthcare staff, patients and the public.

74 | THE CLINICAL CARE JOURNAL

HIGH-QUALITY HEALTHCARE The clinical programme’s overarching principle is that every patient should expect to receive high-quality healthcare in a safe environment without acquiring a preventable HCAI or multidrug-resistant organism. “HCAI is not an inevitable consequence of contact with healthcare. In fact, 70 per cent of infections are preventable, speciﬁcally those associated with medical devices such as IV lines and urinary catheters,” she says. “Our patients are rightly at the centre of our work on the programme and we have consulted widely with patients and patients’ organisations on the programme work. Every time you care for your patients and perform hand hygiene, use antimicrobials wisely and ensure good practice with regard to IV line and urinary catheter insertion and maintenance reliably, you can prevent a HCAI. “We have developed a ﬁve-year national strategy for HCAI and AMR prevention, which has guided our work over the last number of years. After reviewing the approaches taken by other countries with respect to HCAI and AMR prevention, the programme’s focus on ‘getting back to basics’ was established. The aim was to facilitate healthcare staff focus on three areas every time they care for patients, irrespective of the healthcare setting.

These are: 1. Hand hygiene as outlined by the World Health Organisation’s ‘ﬁve moments’ 2. Use antimicrobials appropriately (antimicrobial stewardship) 3. Prevent medical infections associated with medical devices such as intravenous lines 4. and urinary catheters. “When I took over as clinical lead, I was lucky that I could build on preexisting national and local work in this area, led by the national committee and subcommittees, RCPI policy group and the HSE. As programme lead, in conjunction with colleagues in the Department of Health, the HSE and the SARI (Strategy for the Control of AMR in Ireland) national committee, I oversaw the transition of governance of the functions of the SARI national committee to the RCPI and the HSE and agreed terms of reference for the multidisciplinary clinical advisory group of the programme, which is based at RCPI. “At an early stage, we recommended national and regional programme governance structures for HCAI and AMR prevention, with regional committees in each HSE region reporting into the regional director of operations and directly linked with regional quality and patient safety departments. These governance structures will need to be reﬁned now, as new HSE governance structures emerge to ensure that

Rapidly effective X Rapidly bactericidal against MRSA1 X Proven efficacy vs. standard therapies2,3

Simple approach X Once daily, 30-minute infusion or a 2-minute IV injection4 X No loading dose4 X No routine drug level monitoring4

Efficacy with tolerability

ABBREVIATED PRESCRIBING INFORMATION - IRELAND. Refer to the Summary of Product Characteristics (SmPC) before prescribing. Cubicin® 350mg powder for solution for injection or infusion. Cubicin® 500mg powder for solution for injection or infusion. Presentations: Single-use vials containing 350mg or 500mg daptomycin powder for solution for injection or infusion. A pale yellow to light brown lyophilised powder. One ml provides 50mg of daptomycin after reconstitution with 7ml (350mg strength vial) or 10ml (500mg strength vial) sodium chloride 0.9% solution. Please refer to SmPC for full details regarding reconstitution and dilution of vials. Indications: Cubicin is indicated for the treatment of the following infections in adults: Complicated skin and soft-tissue infections (cSSTI) . Right-sided infective endocarditis (RIE) due to Staphylococcus aureus. (It is recommended that the decision to use daptomycin should take into account the antibacterial susceptibility of the organism and should be based on expert advice). Treatment of Staphylococcus aureus bacteraemia (SAB) when associated with RIE or with cSSTI. Daptomycin is active against Gram positive bacteria only. In mixed infections where Gram negative and/or certain types of anaerobic bacteria are suspected, Cubicin should be co-administered with appropriate antibacterial agent(s). Dosage and Administration: Method of Administration: Cubicin is given by intravenous infusion and administered over a 30-minute period (see Section 6.6 of the SPC) or by intravenous injection and administered over a 2-minute period. Cubicin should only be reconstituted with sodium chloride (0.9%). See section 6.6 for full details regarding the methods of administration for Cubicin. cSSTI without concurrent SAB: the dosage is 4 mg/kg administered once every 24 hours for 7-14 days or until the infection is resolved. cSSTI with concurrent Staphylococcus aureus bacteraemia: Cubicin 6 mg/kg is administered once every 24 hours. The duration of therapy may need to be longer than 14 days in accordance with the perceived risk of complications in the individual patient. - Known or suspected RIE due to Staphylococcus aureus: Cubicin 6 mg/kg is administered once every 24 hours. The duration of therapy should be in accordance with available official recommendations. Caution in patients >65 years. Severe renal impairment/dialysis: for patients with RIE or cSSTI with SAB with a creatinine clearance ≥30 ml/min the dose recommended is 6mg/kg once daily and dosing in patients with creatinine clearance <30 ml/min the dose should be adjusted to 6mg/kg once every 48 hours. For patients with cSSTI without bacteraemia with creatinine clearance of ≥30 ml/min the recommended dose is 4mg/kg once daily and patients <30ml/min the dose should be adjusted to 4mg/kg every 48 hours. Whenever possible, administer following the completion of dialysis. See SmPC for more details. Severe hepatic impairment: No dose adjustment in mild to moderate hepatic impairment. Refer to SPC for more information on renal and hepatic impairment. Contraindications: Hypersensitivity to the active substance or any excipients. Precautions/Warnings: Anaphylaxis/hypersensitivity reactions have been reported with Cubicin. If an allergic reaction occurs, discontinue use and institute appropriate therapy. Cubicin is not effective in pneumonia. The efficacy of Cubicin in patients with prosthetic valve infections or with left-sided infective endocarditis due to S. aureus has not been demonstrated. Patients with deep seated infections should promptly receive required surgical interventions as appropriate. There is insufficient evidence to be able to draw any conclusions regarding the possible clinical efficacy of Cubicin against infections due to enterococci, including Enterococcus faecalis and Enterococcus faecium. The use of antimicrobials may promote the overgrowth of non-susceptible micro-organisms. If superinfection occurs during therapy, appropriate measures should be taken. Clostridium difficile-associated diarrhoea (CDAD) has been reported with Cubicin. If CDAD is suspected or confirmed, Cubicin may need to be discontinued and appropriate treatment instituted as clinically indicated. False prolongation of prothrombin time (PT) and elevation of INR have been observed when certain recombinant thromboplartin reagents are utilised for the assay (see section 4.5). Creatine phosphokinase (CPK) and myopathy: CPK levels should be measured at baseline and at least once weekly during therapy. CPK should be measured more frequently than once weekly in patients who are at higher risk of developing myopathy. These patients include those with any degree of renal insufficiency (creatinine clearance <80 ml/min; see also section 4.2 of the SmPC) and patients taking other medications known to be associated with myopathy (e.g. HMG-CoA reductase inhibitors, fibrates and ciclosporin). Patients should be reviewed regularly for signs or symptoms of myopathy. Patients developing unexplained muscle pain, tenderness, weakness or cramps should have CPK levels monitored every 2 days. Cubicin should be discontinued in the presence of unexplained muscle symptoms if CPK levels reach >5 times upper limit of normal. Peripheral neuropathy: Patients developing signs or symptoms should be investigated and consideration given to discontinuing treatment. Eosinophilic pneumonia: Eosinophilic pneumonia has been reported in patients receiving Cubicin. In most reported cases, patients developed fever, dyspnoea with hypoxic respiratory insufficiency and diffuse pulmonary infiltrates after more than two weeks of treatment and improved when Cubicin was discontinued and steroid therapy was initiated. Recurrence upon re-exposure has been reported. Patients who develop these signs and symptoms should undergo prompt medical evaluation, Cubicin should be discontinued immediately and treatment with systemic steroids initiated when appropriate. For more information see section 4.4 and 4.8 of the SPC. Renal impairment: Severe renal impairment may increase the risk of myopathy. Dose adjustment is needed in patients with creatinine clearance (CL/cr) <30 ml/min- (see section 4.2 and 5.2). Caution is advised before commencing and during therapy in these patientsand renal function should be closely monitored in all such patients. Regular monitoring of renal function is advised during concomitant administration of potentially nephrotoxic agents. Caution is recommended in very obese patients. Pregnancy and Lactation: Cubicin should not be administered in pregnancy unless the potential benefit outweighs the possible risk. Breastfeeding should be discontinued during treatment with Cubicin. Children and adolescents (<18 years old): Due to the lack of data on safety and efficacy Cubicin is not recommended for use in children and adolescents. Interactions: No CYP450 related drug interactions are expected. In vitro studies indicate that daptomycin does not inhibit or induce the activities of clinically significant human CYP isoforms (1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4). Interaction studies for Cubicin performed were performed with aztreonam, tobramycin, warfarin and probenecid. Daptomycin had no pharmacokinetic effect on warfarin or probenecid, nor did these medicinal products alter the pharmacokinetics of daptomycin. The pharmacokinetics of daptomycin were not significantly altered by aztreonam. The interaction between daptomycin and tobramycin with an approved dose of Cubicin is unknown and caution when co-administered is warranted. Anticoagulant activity in patients receiving Cubicin and warfarin should be monitored for several days after therapy is iniated It is recommended that other medications associated with myopathy should if possible be temporarily discontinued during treatment with Cubicin unless the benefits of concomitant administration outweigh the risk (See SPC for more information). Caution is advised when Cubicin is co-administered with any other medicinal product known to reduce renal filtration. If unexplained abnormalities or PT/INR are observed in patients taking daptomycin, consideration should be given to a possible in vitro interaction with the laboratory test. Incompatibilities: glucose-containing solutions. Medicinal products other than those listed in the SmPC. Adverse Reactions: Clinical trials: Common (≥1% to <10%): fungal infections, urinary tract infections, candida infections, anaemia, anxiety, insomnia, dizziness, headache, hypertension, hypotension, gastrointestinal and abdominal pain, nausea, vomiting, constipation, diarrhoea, flatulence, bloating and distension, rash, pruritis, infusion site reactions, pyrexia, asthenia, limb pain, increased CPK and abnormal liver function tests (increased ALT, AST and ALP.) Uncommon (≥0.1% to <1%): Fungaemia, thrombocythaemia, eosinophilia, INR increased, decreased appetite, hyperglycaemia, paraesthesia, taste disorder, tremor, vertigo, supraventricular tachycardia, extrasystole, flushes, urticaria, dyspepsia, glossitis, myositis, muscular weakness, muscle pain, arthralgia, vaginitis, renal impairment, including renal insufficiency and renal failure, fatigue, pain, electrolyte imbalance , increased serum creatinine, increased myoglobin, serum lactic dehydrogenase (LDH) increased. Rare (≥0.01% <0.1%): PT prolonged, jaundice. Postmarketing reports: clostridium difficile associated diarrhoea, hypersensitivity, anaphylaxis, infusion reactions, rhabdomyolysis, peripheral neuropathy, eosinophilic pneumonia, angioedema, drug rash with eosinophilia and systemic symptoms (DRESS), cough. Pack Size: Single use vials in packs of one or five vials containing: Cubicin 350 mg powder for solution for injection or infusion, Cubicin 500 mg powder for solution for injection or infusion. Legal Category: POM. Product Authorisation Numbers: EU/1/05/328/001-004. Product Authorisation Holder: Novartis Europharm Limited, Wimblehurst Road, Horsham, West Sussex, RH12 5AB, United Kingdom. Date of Revision of API Text: February 2012. Full prescribing information, including SmPC is available on request from: Novartis Ireland Limited, Beech House, Beech Hill Office Campus, Clonskeagh, Dublin 4 or at www.medicines.ie References 1. LaPlante KL, Rybak MJ. Antimicrob Agents Chemother 2004;48(12):4665-4672. 2. Arbeit RD et al. CID 2004;38:1673–1681. 3. Fowler VG et al. N Engl J Med 2006;355:653–665. 4. CUBICIN® Summary of Product Characteristics. Date of Preparation: October 2012. NO1012716

HCAI & AMR

HCAI and AMR prevention is coordinated across all healthcare sectors.” The programme works across the entire healthcare spectrum – patients, primary care, long-term care and hospitals. The ICGP lead is Dr. Nuala O’Connor.

INFORMATION Over the years, the programme has initiated a major public engagement, with the HSE public information campaign on antibiotics and public education evenings in the RCPI to educate people on the importance of antibiotics. A mobile app for antibiotic prescribing in primary care has been developed (www.antibioticprescribing.ie) and GP education on antibiotics and AMR have been run through the ICGP by Dr. O’Connor. Says Dr. Fitzpatrick: “Making information on HCAI and AMR accessible for our patients and the public is a key programme focus. We have developed new sections on both HSE and RCPI websites to reflect the ongoing work of the programme, developed new sections on the HSE website on HCAI, antibiotics and hand hygiene and have contributed to relevant HCAI and AMR sections of the HSE A-Z website for the public. “In 2014, we shifted the emphasis for our antibiotic campaign, promoting ‘how to care for’ information, rather than ‘don’t use antibiotics’, which is a positive approach aimed at promoting learning and empowerment for the patient, rather than scolding poor health knowledge and behaviour. A new self-care website (www.undertheweather.ie), outlining how to get well at home without antibiotics, was launched. The website is positioned to ensure that people, particularly mums and young families, are supported to look after themselves at home if they have a cold or flu, and to reinforce the message that you do not need an antibiotic to recover from flu or a range of day-to-day illnesses. “Parallel with the three-work stream, we have tried to improve and use information on HCAI and AMR in order to drive improvements in conjunction with colleagues in the Health Protection Surveillance Centre. We have had a number of national prevalence surveys of HCAI in hospitals and long-term care facilities that have provided valuable information on where to target infection prevention and antimicrobial stewardship efforts. Every month, we now have monthly measurements of certain hospital infections in addition to quarterly information

76 | THE CLINICAL CARE JOURNAL

HCAI is not an inevitable consequence of contact with healthcare. In fact, 70 per cent of infections are preventable, specifically those associated with medical devices such as IV lines and urinary catheters.

on AMR in bloodstream infection and biannual measurements of antibiotics consumption from hospitals and the community. For example, in the ﬁrst quarter of 2014 there were very good signs that GPs were focusing on more targeted, rather than broad spectrum, antibiotics.” The programme has a multidisciplinary advisory group. “You can’t control infection on your own, you have to work with the team,” Dr. Fitzpatrick emphasises. “Everyone has a role – patients, the public, doctors, nurses and managers.” She said that preventing AMR spread was important, especially before AMR bacteria such as carbapenem

resistant enterobacteriacae (CRE) becomes ﬁrmly established in more Irish hospitals and in the community.

COLLECTING DATA Recent information shows that the proportion of S. aureus isolates that are MRSA have decreased from 42 per cent in 2006 to 21 per cent in 2014. The number of reported MRSA bloodstream infections have decreased steadily over the last seven years from 592 in 2006 to 222 in 2013, representing a reduction of 62.5 per cent. Dr. Fitzpatrick says that in the ﬁrst quarter of 2014, additional information

HCAI & AMR

was collected on the origin of S. aureus isolates causing bloodstream infection. Over half of the isolates were associated with healthcare, over a third of patients had been on recent antibiotics and a signiﬁcant proportion were associated with IV lines. The information showed that 18 per cent of MRSA infections were device-associated (12 per cent central lines, 3 per cent peripheral lines), and 31 per cent of meticillinsusceptible S. aureus bloodstream infections were device-associated (13 per cent central lines, 6 per cent peripheral lines and 6 per cent dialysis catheter). She says that 54 per cent of ﬂuro-

quinolone-resistant E. coli bloodstream infections and 46 per cent of fluroquinolone-susceptible E. coli bloodstream infections were classified as healthcare-associated in the first quarter of 2014. Nearly one in five (18 per cent) of fluroquinolone-resistant E. coli bloodstream infections were device-associated – 13 per cent associated with a urinary catheter. “A progressive increase in bloodstream infection due to multidrug-resistant K. pneumoniae (MDR- KP) between 2010 and 2013 led to this pathogen becoming notifiable and a national surveillance programme commenced on January 1, 2014. In the first seven months of surveillance,

265 patients with MDRKP colonisation and infection have been reported by 31 of 40 microbiology laboratories. Three quarters of the patients were aged >57 years. MDRKP have been reported predominantly from hospital inpatients, but also from outpatients, GP patients and residents of long-term care facilities.” Dr. Fitzpatrick says that Ireland remains the only EU country with a VRE proportion in excess of 25 per cent – in the first quarter of 2014, the proportion of E. faecium bloodstream infections that were vancomycin-resistant (i.e. VRE) increased to 45.9 per cent. “Interestingly, the majority of VRE and vancomycin-susceptible enterococci (VSE) are healthcareassociated (all of the VRE and 68 per cent of the VSE infections were classified as healthcare-associated in the first quarter of 2014). Figures from the first quarter of 2014 indicate that 42 per cent of VRE were device-associated: 16 per cent were associated with central line (CVC) infections, 16 per cent with CVC-PICC lines and 11 per cent with a dialysis catheter.” She says that bacteria, as natural survivors, would always have the capability to develop AMR. “However, as prescribers and medical leaders, we can all play a part in AMR prevention and control. We should use antimicrobials wisely and according to guidelines: prescribing antimicrobials according to your hospital guidelines, using the framework of the ‘start smart and then focus’ antimicrobial care bundle will help ensure that antimicrobials are used wisely. Antimicrobials are life-saving drugs, however, as with any medication, can lead to unwanted effects and cause adverse outcomes such as C. difficile infection. “Good hand hygiene and aseptic technique practices, especially when inserting and manipulating IV lines; using good infection prevention and control practices when caring for our patients, especially good hand hygiene, will help prevent the spread of AMR pathogens to other patients in that ward/unit.”

DR. FIDELMA FITZPATRICK paid tribute to the work of the two chairs of the clinical advisory group, Dr. Olive Murphy and Dr. Niamh O’Sullivan, for giving of their time so freely and expertly guiding the work of the National Clinical Programme, and to the ICGP lead Dr. Nuala O’Connor.

THE CLINICAL CARE JOURNAL | 77

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NATIONAL RENAL OFFICE

MORE PATIENTS TREATED

AT MORE CENTRES AT A LOWER COST An integrated clinical network of haemodialysis facilities is improving capacity, geographic spread and travel time for patients, according to Dr Liam Plant, National Clinical Director of the HSE National Renal Ofﬁce and Consultant Renal Physician at Cork University Hospital. Maureen Browne reports.

he HSE National Renal Ofﬁce (NRO) is facilitating the development of an integrated clinical network of haemodialysis facilities around the country. It is also working in conjunction with the National Organ Donation and Transplantation Ofﬁce (NODTO) towards increasing the number of patients with a functioning kidney transplant, and is increasing the number of patients availing of dialysis therapies in their own homes, according to Dr Liam Plant, National Clinical Director of the NRO and Consultant Renal Physician at Cork University Hospital. “We are treating more patients at more centres at a lower cost than in the past,” he says. “We are working with the NODTO to optimise the long-term function of kidney transplants and to increase the numbers availing of living donor transplants.

“We are establishing an integrated clinical network of haemodialysis facilities around the country, which is securing adequate capacity for patients to receive dialysis over a broader geographic spread and reducing their travel times to and from treatment. “These units will provide patients with easier access to treatment and reduce pressure on busy acute hospital facilities. “In addition, there are now more than 50 renal patients receiving home haemodialysis, as opposed to centre-based haemodialysis, which has reduced annual patient travel by 435,000km, taken 7,800 day cases out of the acute hospital sector and reduced treatment cost by 1.85 million. “We work in partnership with the National Organ Donor and Transplant Ofﬁce, under the direction of Prof Jim Egan, in the ongoing expansion of access to kidney transplantation and we will continue to support developments to ensure that as many patients as possible secure a kidney

THE CLINICAL CARE JOURNAL | 79

NATIONAL RENAL OFFICE

transplant. We have not yet achieved the desired number of transplants each year, but we will progress towards this by maintaining deceased donor transplant activity and increasing living donor transplant activity. “I welcome the establishment of the seven new hospital groups, which will help co-ordinate renal services delivery across the country to a common standard of equity of access and excellence in facility conﬁguration, range of services and clinical outcomes. For a number of years, we have been working towards the creation of integrated clinical networks of directly provided and contracted haemodialysis units based upon lead renal units within each of the hospital group catchment areas. One of these is due to be commissioned early in 2015 in Drogheda. This should reduce the travel time for haemodialysis treatments for patients from Louth, north Meath and north Dublin and allow Beaumont Hospital to discontinue the overnight treatment shifts currently in place and move towards commissioning its new on-site haemodialysis unit. “In the Dublin North East Hospitals Group, Beaumont Hospital should continue to increase its transplantation activity and act as the lead renal unit of an integrated network of four haemodialysis sites – at Beaumont Hospital, FMC Northern Cross, Cavan General Hospital and Beacon Drogheda. This should allow much better matching of treatment sites to the location of patients’ homes. The patients under the clinical care of the Mater Hospital (in the Dublin East Hospitals Group) will also be availing of

the facilities at Northern Cross and in Drogheda. “On the south side of Dublin, the current contracted haemodialysis unit in the Beacon Hospital will be replaced by two new units, both provided by the Beacon Renal Group – at Beacon South Quarter and at Tallaght Cross. These units will be integrated with St. Vincent’s University Hospital and AMNCH. We also hope to complete the tendering for, and commissioning of, two additional contracted units in the midlands and in Wexford.”

ADEQUATE CAPACITY Dr Plant says that the contracted units now deliver about a quarter of total annual haemodialysis treatments. “We currently deliver over 260,000 day case treatments per year, accounting for about 20 per cent of all day case attendances in acute public hospitals. “We are comfortable that this strategy is securing adequate capacity for patients to receive dialysis in a broader geographic spread, which reduces their travel time. In Ireland, the average patient lives 29km from a haemodialysis centre and travels over 9,000km per year to and from dialysis. Our 2012 audit showed that in that year, haemodialysis patients travelled a staggering 13.2 million kilometres in total to access their treatment.” Dr Plant says that one of the things about which he was most pleased was that renal home therapies, particularly home haemodialysis therapy, were continuing to expand. “More than 60 patients have been trained on home haemodialysis with more than 50 continuing on therapy (the others have been fortunate enough

to have been transplanted). There were ﬁve training centres for home haemodialysis around the country – two in Dublin, one in Cork, one in Waterford and one in Galway, and we hope to open one in Limerick in 2015. “It is, in many ways, the ‘best’ dialysis treatment for suitable patients; it is much preferred by patients and is considerably less costly than centre-based treatment. The National Home Haemodialysis Programme operates to exactly the same standards wherever the supervising units, and its practices and policies are co-ordinated by a truly national group of nurses, technicians and doctors. “We are hoping to complete a national tender for home peritoneal dialysis services, which should standardise the quality and delivery of care throughout the country. In 2014, we completed a three-year exercise of re-equipping all the HSE haemodialysis units around the country with state-of-the-art equipment and consumables, also achieving a very substantial reduction in unit costs. We are now treating more patients at more centres at less cost.”

Chronic kidney disease afflicts 20 per cent of Irish citizens aged under 45 years and acute kidney injury, which afflicts 20 per cent of hospitalised patients.

HARD WORK AND DEDICATION The HSE National Service Plan for 2015 makes provision for three additional consultant nephrologists. “One post will hopefully expand the number of paediatric nephrologists, so we are looking forward to enhancing services for the children of Ireland with kidney disease. The other posts will be allocated to balance the access of patients to consultant nephrologists more evenly between hospital groups.” Dr Plant paid tribute to the hard work, patient-focused dedication and innovative problem-solving skills exhibited by members of the multi-disciplinary teams

THE CLINICAL CARE JOURNAL | 81

NATIONAL RENAL OFFICE

in renal units throughout the country. He hopes that future service plans may focus on expanding/developing new staff roles, particularly in posts such as renal dieticians, renal nurse specialists/advanced nurse practitioners. He also says that another exciting development has been the continued deployment of a common IT platform (the Kidney Disease Clinical Patient Management System), which is now deployed in practically all acute hospitals that look after renal patients. AMNCH, St. James’s and the Mater are due to be linked in during the spring of 2015. “That is a very powerful tool for checking quality and outcomes. In 2014, for the first time, we will use it to carry out our biannual census of activities in the renal units. It assists us greatly in patient management, activity monitoring and data collection on processes and outcomes. We are finally close to a point from which we can establish a National Renal Registry, as exists in almost all other European countries. “Some renal units now have bi-directional data-flow to and from individual haemodialysis machines. When this is fully operational, we anticipate a substantial reduction in the time that nurses will spend recording data, allowing them to focus more on the nursing care of their patients.”

CLOSE WORKING RELATIONSHIPS The NRO enjoys and values an ongoing close working relationship with the Irish Kidney Association (IKA), especially with Mr Mark Murphy, its CEO. The IKA and the NRO led the Irish participation in an international inventory of services for patients with chronic kidney disease, the Kidney Health For Life (KH4L) Alliance, in which 18 countries participated. A prominent ﬁnding was that Ireland

82 | THE CLINICAL CARE JOURNAL

There are now more than 50 renal patients receiving home haemodialysis, which has reduced annual patient travel by 435,000km, taken 7,800 day cases out of the acute hospital sector and reduced treatment cost by 1.85 million.

employs the lowest number of (wholetime equivalent) consultant nephrologists per capita of any of the 18 participating countries, but did seem to perform comparatively better than others in terms of strategic planning of renal services. “Over the last year, renal services have struggled with much the same challenges as in the past, particularly in the care of patients with end stage kidney disease. Our strategy remains to try to ensure that as many patients as possible can be transplanted, to try and ensure there is a nationally dispersed integrated clinical network of renal units so that patients can avail of therapies in their own homes, or close to their own homes. Over the last six years, we have been pleased by the fact that the numbers of patients with functioning kidney transplants has gone up (533 – a 32 per cent increase) by more than the numbers of those on dialysis (284 – a 19 per cent increase). “At the beginning of 2014, the total number of patients on haemodialysis in Ireland was the same as it had been at the end of 2010, largely because more patients are being transplanted and have easier access to renal home therapies. Hopefully we can maintain this trajectory. “Like all other disciplines, we are adapting to circumstances that follow from the introduction of the European Working Time Directive for NCHDs

and the legacy of a recruitment hiatus for other healthcare professionals of the multi-disciplinary team. We would be of the view that the continued strategic expansion of consultant nephrologists, renal dieticians and, especially, renal nurse specialist/advanced renal nurse practitioner posts is necessary to improve services and outcomes. This will be leveraged by enhanced strategic/operational planning, enhanced procurement practices and smart use of the IT resources already mentioned. “Finally, we look forward in 2015 to working with others within the developing integrated care programmes to contribute the particular knowledge, skill sets and care pathway designs that we can contribute to enhance generic patient care, particularly in the areas of nonspecialist prevention, detection and early management of chronic kidney disease (which afﬂicts 20 per cent of Irish citizens aged >45 years) and acute kidney injury (which afﬂicts 20 per cent of hospitalised patients).”

DR LIAM PLANT is National Clinical Director of the HSE National Renal Office and Consultant Renal Physician at Cork University Hospital

NOW AVAILABLE FOR MAINTENANCE TREATMENT OF SCHIZOPHRENIA

New once-monthly Abilify Maintena® (aripiprazole) reduces the risk of relapse for your patients* Recurring relapse in schizophrenia can lead to clinical deterioration and decreased functioning.1 Abilify Maintena® can significantly reduce the risk of relapse during long-term treatment2,3* and maintain personal and social functioning.4†

* In a 38-week study with dosing under controlled trial conditions, the relapse rate with Abilify Maintena® was comparable to that of oral aripiprazole (7.1% vs 7.8%, respectively).2 In a 52-week study, Abilify Maintena® significantly delayed the time to relapse vs placebo (P<0.0001).3 † In a 52-week study, Abilify Maintena® achieved improvements in personal and social functioning vs placebo as measured by the Personal and Social Performance (PSP) Scale during stabilization treatment, and maintained these over the course of the double-blind treatment phase.4 ABILIFY MAINTENA® (aripiprazole) PRESCRIBING INFORMATION - SCHIZOPHRENIA 400 mg powder and solvent for prolonged-release suspension for injection (IM) once monthly Please refer to the full Summary of Product Characteristics (SmPC) before prescribing, particularly in relation to side effects, interactions, precautions and contraindications. INDICATIONS: Maintenance treatment of schizophrenia in adult patients stabilised on oral aripiprazole. DOSAGE: For patients who have never taken aripiprazole, tolerability with oral aripiprazole must occur prior to initiation. The recommended starting and maintenance dose is 400 mg (2 ml, IM). Titration of the dose of this medicinal product is not required. To reconstitute, add 1.9 ml of solvent to the 400 mg powder for injection. The reconstituted suspension should be administered once monthly as a single injection (no sooner than 26 days after the previous injection) into the gluteal muscle. After the first injection, treatment with 10 mg to 20 mg oral aripiprazole should be continued for 14 days to maintain therapeutic levels. Consider reducing the dose to 300 mg if there are adverse reactions. Missed doses: Administer the injection as soon as possible and then resume monthly injection schedule; if the second or third dose is missed by > 7 days, then concomitant oral aripiprazole should be restarted for 14 days. If the fourth or subsequent doses (after attainment of steady state) are missed by > 14 days, then concomitant oral aripiprazole should be restarted for 14 days. Remember to rotate sites between the two gluteal muscles. Dosage reductions are needed in patients who are taking concomitant strong CYP3A4 inhibitors and/or strong CYP2D6 inhibitors for more than 14 days. For patients taking 400 mg of Abilify Maintena® and either concomitant strong CYP2D6 inhibitors or strong CYP3A4 inhibitors, reduce dose to 300 mg: for patients taking both strong CYP2D6 and strong CYP3A4 inhibitors reduce dose to 200 mg. Avoid use with CYP3A4 inducers. Upon discontinuation of the CYP2D6 or CYP3A4 inhibitor, the dosage of Abilify Maintena® should be increased to the dose prior to the initiation of the concomitant therapy. Refer to SmPC for instructions for use with missed doses, interactions, reconstitution and injection procedure. Elderly (>65 years): Safety and efficacy not established. Children and adolescents (<18 years): Not recommended, Safety and efficacy not established. Renal impairment: No dosage adjustment required. Hepatic impairment: No dose adjustment in mild or moderate hepatic impairment. In severely impaired hepatic function data available are insufficient to establish recommendations, and the oral formulation should be preferred. CONTRAINDICATIONS: Hypersensitivity to active substance or any of the excipients. WARNINGS AND PRECAUTIONS: Clinical improvement may take several days to some weeks: monitor patient throughout this period. Closely supervise high risk patients for risk of suicide until individual patient response is established. Caution in patients with a history of cardiovascular disorders (myocardial infarction or ischaemic heart disease, heart failure or a family history of QT prolongation), cerebrovascular disease and treatment with anti-hypertensive medicinal products. All risk factors for venous thromboembolism (VTE) should be identified before and during treatment and preventive measures taken. Reduce dose or discontinue if signs of tardive dyskinesia appear. Discontinue if patient develops signs and symptoms indicative of neuroleptic malignant syndrome. Caution in patients with a history of seizure or conditions associated with seizure, and in patients with diabetes. Caution in older people with dementia-related psychosis as there is an increased risk of death compared to placebo (Abilify Maintena® is not indicated for this treatment group). Caution in those at risk of aspiration pneumonia. Monitor for hypersensitivity, weight gain and pathological gambling. Caution; Do not drive or operate machinery until individual response to this medicinal product is established. FERTILITY, PREGNANCY AND LACTATION: Do not use during pregnancy unless potential benefit clearly outweighs potential risk to the foetus. Neonates exposed to antipsychotics (including aripiprazole) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration. Agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in neonates have been reported. Newborns should be monitored carefully. Breastfeeding is not recommended. DRUG INTERACTIONS: Increased hypotensive effect with certain antihypertensives. Caution is advised when combining with alcohol or other CNS medication with overlapping side effects such as sedation; and medicines known to cause QT prolongation or electrolyte imbalance. Cases of serotonin syndrome have been reported in patients taking aripiprazole. Reduce aripiprazole dose with concomitant use of potent CYP3A4 inhibitors e.g. ketoconazole, itraconazole, HIV Protease inhibitors or strong CYP2D6 inhibitors e.g. quinidine, fluoxetine, paroxetine. Concomitant use with CYP3A4 inducers (e.g. carbamazepine, St. John’s Wort, rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz and nevirapine) should be avoided because blood aripiprazole levels may be below effective levels. Refer to SmPC for dose adjustments. UNDESIRABLE EFFECTS: Adverse drug reactions were reported during clinical trials and/or post-marketing use of aripiprazole. Frequency of adverse reactions reported during post-marketing use cannot be determined as they are derived from spontaneous reports: Common (≥1/100 to <1/10): weight increased, weight decreased, diabetes mellitus, agitation, anxiety, restlessness, insomnia, extrapyramidal disorder, akathisia, tremor, dyskinesia, sedation, somnolence, dizziness, headache, dry mouth, musculoskeletal stiffness, erectile

dysfunction, injection site pain, injection site induration, fatigue, blood creatinine phosphokinase increased. Uncommon (≥1/1000 to <1/100): neutropenia, anaemia, thrombocytopenia, neutrophil count decreased, white blood cell count decreased, hypersensitivity, blood prolactin decreased, hyperglycaemia, hypercholesterolaemia, hyperinsulinaemia, hyperlipidaemia, hypertriglyceridaemia, appetite disorder, suicidal ideation, psychotic disorder, hallucination, delusion, hypersexuality, panic reaction, depression, affect lability, apathy, dysphoria, sleep disorder, bruxism, libido decreased, mood altered, dystonia, tardive dyskinesia, parkinsonism, movement disorder, psychomotor hyperactivity, restless legs syndrome, cogwheel rigidity, hypertonia, bradykinesia, drooling, dysgeusia, parosmia, oculogyric crisis, vision blurred, eye pain, ventricular extrasystoles, bradycardia, tachycardia, electrocardiogram t wave amplitude decreased, electrocardiogram abnormal, electrocardiogram t wave inversion, hypertension, orthostatic hypotension, blood pressure increased, cough, gastrooesophageal reflux disease, dyspepsia, vomiting, diarrhoea, nausea, abdominal pain upper, abdominal discomfort, constipation, frequent bowel movement, salivary hypersecretion, liver function test abnormal, hepatic enzyme increased, alanine aminotransferase increased, gamma-glutamyl transferase increased, blood bilirubin increased, aspartate aminotransferase increased, alopecia, acne, rosacea, eczema, skin induration, muscle rigidity, muscle spasms, muscle twitching, muscle tightness, myalgia, pain in extremity, arthralgia, back pain, joint range of motion decreased, nuchal rigidity, trismus, nephrolithiasis, glycosuria, galactorrhoea, gynaecomastia, breast tenderness, vulvovaginal dryness, pyrexia, asthenia, gait disturbance, chest discomfort, injection site reaction, injection site erythema, injection site swelling, injection site discomfort, injection site pruritus, thirst, sluggishness, blood glucose increased, blood glucose decreased, glycosylated haemoglobin increased, waist circumference increased, blood cholesterol decreased, blood triglycerides decreased. Not known (cannot be estimated from available data, for a complete list refer to the SmPC): anaphylactic reaction, angioedema, diabetic hyperosmolar coma, diabetic ketoacidosis, hyponatremia, completed suicide, suicide attempt, neuroleptic malignant syndrome, grand mal convulsion, serotonin syndrome, sudden unexplained death, cardiac arrest, Torsades de pointes, ventricular arrhythmias, QT prolongation, venous thromboembolism, aspiration pneumonia, pancreatitis, hepatic failure, jaundice, hepatitis, rhabdomyolysis, urinary retention, drug withdrawal syndrome neonatal. Injection site pain (incidence 5.1 %), has a median onset on day 2 after the injection and a median duration of 4 days. Leukopenia: Neutropenia has been reported in the clinical program with Abilify Maintena® and typically starts around day 16 after first injection, and lasts a median of 18 days. Prescribers should consult the SmPC for a detailed description of selected adverse reactions. OVERDOSAGE: Treatment should be symptomatic and supportive: adequate airway maintenance, cardiovascular monitoring and close medical supervision. Care must be taken to avoid inadvertent injection into a blood vessel. LEGAL CATEGORY: POM. AUTHORISATION NUMBERS: Prolonged-release suspension for injection: Single pack vial of 400 mg powder, 2ml vial of solvent and syringes, (EU/1/13/882/002). MARKETING AUTHORISATION HOLDER: Otsuka Pharmaceutical Europe Ltd, Gallions – 1st Floor, Wexham Springs, Framewood Road, Wrexham SL3 6PJ, UK. FURTHER INFORMATION FROM: Lundbeck Ireland Ltd, 7 Riverwalk, Citywest Business Campus, Dublin 24, Ireland. Tel.: 01 4689800. www.abilifymaintena.ie DATE OF P.I. PREPARATION: July 2014. Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie Adverse events should also be reported to Lundbeck (Ireland) Ltd on 01 4689800 or by email to safetyluireland@lundbeck.com REFERENCES: 1. Lieberman JA, Perkins D, Belger A, et al. The early stages of schizophrenia: speculations on pathogenesis, pathophysiology, and therapeutic approaches. Biol Psychiatry. 2001;50:884-897. 2. Fleischhacker WW, Sanchez R, Perry PP, et al. Aripiprazole once-monthly for the treatment of schizophrenia: a double-blind, randomized, non-inferiority study vs. oral aripiprazole. Poster presented at the 166th Annual Meeting of the American Psychiatric Association; 18-22 May, 2013; San Francisco, CA, USA. 3. Kane JM, Sanchez R, Perry PP, et al. Aripiprazole intramuscular depot as maintenance treatment in patients with schizophrenia: a 52-week, multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2012;73(5):617-624. 4. Carson WH, Perry P, Sanchez R, et al. Effects of a long-acting injectable formulation of aripiprazole on secondary efficacy outcomes in maintenance treatment of schizophrenia. Poster presented at the 52nd Annual Meeting of the New Clinical Drug Evaluation Unit (NCDEU); May-June, 2012; Phoenix, AZ, USA. ABM 3/7/14

MENTAL HEALTH

MARRYING THE

STRATEGIC OPERATIONAL WITH THE

Dr. Margo Wrigley, HSE National Clinical Adviser Group Lead for Mental Health sees her role as marrying the strategic work with the operational work “ensuring the reports and documents on the development of the mental health are implemented.” Maureen Browne reports.

r. Margo Wrigley, HSE National Clinical Adviser Group Lead for Mental Health sees her role as marrying the strategic work with the operational work “ensuring the reports and documents on the development of the mental health are implemented.” This is a shared post between two HSE Divisions – the Clinical Strategy & Programmes Division

and the Mental Health Division. The HSE is now organised into ﬁve operational divisions – Mental Health, Acute Hospitals, Health & Wellbeing, Social Care and Primary Care. The Clinical Strategies and Programmes Directorate, which is responsible for the Clinical Programmes (CPs) works closely with each of the relevant Divisions and similar posts to Dr. Wrigley’s have been created for each of the Divisions. Dr. Orla O’Reilly is the National

Clinical Adviser Group Lead for Health & Wellbeing while Dr. Colm Henry is the National Clinical Adviser Group Lead for Acute Hospitals. Dr Siobhan Kennelly has been appointed National Clinical Group Lead for Social Care and will take up this role shortly. Dr. Wrigley, who took up her post in April 2014 has one day a week clinical commitment, which she feels is very important to keep in touch with the front line real-

THE CLINICAL CARE JOURNAL | 85

MENTAL HEALTH

ity and the challenges it encounters. She is responsible for three Mental Health Clinical Programmes. They include the Assessment and Management of Self Harm in Emergency Departments (EDs), Early Intervention for Psychosis and Eating Disorders. All three are joint initiatives between the HSE and the College of Psychiatrists of Ireland. The Assessment and Management of Self Harm in EDs CP started in early December and the other two CPs are in train. “It is known that many people present to EDs. following episodes of self harm. Data shows that there were about 11,000 presentations to ED last year, which was a slight reduction on the previous year. About 20 per cent are repeat presentations with a number who leave the ED before being assessed. The thrust of this work is to provide a proactive response to people who come into the ED either feeling suicidal or following an episode of self harm. The new way of working now allows for people to be seen by a clinical nurse specialist who is trained in assessment and management of people who have self harmed or have suicidal ideas. This is complementary to the service provided by liaison psychiatry during the day and at night there is a consultant psychiatrist and NCHD service available. “As part of the resourcing of the programme 35 clinical nurse specialist posts were agreed. Twenty four of these have been recruited and deployed to the Model 4 and Model 3 hospitals. Training has been provided for these nurses and it continues to be provided on an ongoing basis. An integral part of the Programme includes the collection of data in terms of the number of people seen, (whether following an episode of self harm or because they are suicidal) how quickly they are seen, what the assessment outcome is and what follow up people are linked into.” Dr Wrigley said that one of the advantages of having the nurses post protected for these functions was that instead of just giving people advice on where to go and making an appointment for them, there was active follow up within 24 hours in the form of a phone call to encourage them to attend the appropriate service. The follow up support could include a support group, their GP, or the local community mental health team. “We hope to see some reduction in the number of repeat attendances as there is a strong association between repeating selfharm and completing suicides. Self-harm increases the risk of suicide 40 fold. ” The other two Clinical Programmes

86 | THE CLINICAL CARE JOURNAL

are Early Intervention for Psychosis and Eating Disorders. The College of Psychiatrists of Ireland has produced a draft Early Intervention for Psychosis strategy. This is at present being externally reviewed and once the review is completed and the strategy is published, work will being on its implementation. “The HSE’s Clinical Strategy and Programmes Division and the College of Psychiatrists of Ireland are in the process of recruiting a Clinical Lead to develop a strategy for Eating Disorders. The strategy should be comprehensive, dealing with the full range of eating disorders (from mild to severe)” Dr Wrigley said. Quite a lot of training has already taken place for the second two Clinical Programmes. A survey was conducted and as a result supervision for all forms of training and investigating what other training particularly in eating disorders in adolescents may be required. Once the strategy is published, it will then be possible to have this Programme up and running fully.

The thrust of this work is to provide a proactive response to people who come into the ED either feeling suicidal or following an episode of self harm.

Dr Wrigley went on to say that “The Clinical Lead for the Self Harm and Eating Disorders Clinical Programme will be advertised shortly and in due course the Clinical Lead for the Psychosis Clinical Programme will also be advertised. Each programme is implemented by the local Mental Health Area and our work is to support and oversee this implementation. “Part of the reason that I and my colleagues are working not just in the Clinical Strategy and Programmes Division but also in the relevant Operational Divisions, is to ensure that there is joined up thinking and support for programme initiatives being implemented on the ground.” Dr Wrigley is also a member of the National Management Team of the Mental Health Division. Her speciﬁc role includes strategic design of aspects

of services and advising on their implementation. For example “we are looking at developing mental health services for persons with Intellectual Disabilities in line with that recommended in ‘A Vision for Change’. Currently I am collating information on the extent of community based weekend daytime cover for existing vulnerable patients. This is with a view to developing a plan on how at least 50% of Mental Health Areas in the country would have this available. This is a commitment the Division has made in this year’s Service Plan. Another example is that ‘A Vision for Change’ recommended that acute mental health units should have a ‘high observation’ area. I carried out a review of these last year and found quite a number don’t have that so the National Mental Health Division has committed in the Service Plan to operating an additional ﬁve ‘high observation’ areas in such units this year. Dr Wrigley went on to say that “Working with colleagues in the other Divisions is also immensely useful. For instance, there is a potential interface and governance gap between Acute Hospital Groups and the Mental Health Services. Mental Health Services are part of the Community Health Organisation structure. Within Mental Health we have services based in acute hospitals such as our acute units and we also provide services within acute hospitals such as liaison psychiatry services, a psychiatry on call service, and of course now the Self Harm Clinical Programme. There is a need for a clear governance structure between the acute hospitals and the Mental Health Services to ensure that services are integrated and work across the divisions in a safe way. Currently Colm Henry and I are developing a draft structure which we will then submit for consideration and implementation. A Data Design and Optimisation Group has been set up which is co-chaired by the Head of Performance and Dr Wrigley. Dr Wrigley will be involved in the data design. This complements data that is already being collected on activity within the Division. This project allows for this data collection to be extended to cover the collection of Psychiatry of Old Age liaison activity data within the acute hospitals setting. Although only ten month in post she believes that this role allows for the provision of better integration across divisions.

DR. MARGO WRIGLEY, HSE National Clinical Adviser Group Lead for Mental Health

COGNITION IS RELEVANTâ&#x20AC;Ś

DEPRESSION IS MORE THAN JUST Re-thinking MOOD *

depression

BRI 1/9/14

LUNDBECK: EVOLVING ANTIDEPRESSANT THERAPY * American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-V). 2013.

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SCHIZOPHRENIA GENOMICS

The great leap forward:

PROGRESS IN SCHIZOPHRENIA GENOMICS Prof. Aiden Corvin describes an international scientiﬁc collaboration involving almost 37,000 patients in which he and colleagues in TCD participated, which has resulted in a landmark in schizophrenia research.

chizophrenia is remarkably challenging as it forces patients to confront their perception, and very understanding of the world around them. Since the 19th century, the syndrome has been deﬁned and crystalized through the work of key researchers and their descriptions of symptoms such as hallucinations, delusions and disor-

ganized thinking, and the course of the illness process. This work has heavily influenced modern diagnostic classification of a disorder that has a lifetime risk of around 1%; a disorder associated with substantial morbidity and mortality, including a shocking twenty-year reduction in average life expectancy. In the 1950s the chance discovery of the therapeutic efficacy of blockade

of the type 2 dopaminergic receptor heralded optimism. But this has faded across the decades with the failure of antipsychotic drugs to treat functionally disabling negative and cognitive symptoms and a dearth of novel therapeutic targets. Although much has been learned about schizophrenia, the pathophysiology involved remains a mystery hindering our ability to improve patient care.

THE CLINICAL CARE JOURNAL | 89

SCHIZOPHRENIA GENOMICS

A recently published Nature paper by the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC-SCZ) represents a landmark in schizophrenia research (2014). Schizophrenia is substantially a heritable disorder and for many years researchers have been interested in identifying the genes involved to inform understanding of disease biology. In the last few years the technology has matured sufficiently to make it possible to systematically investigate genetic variation across the genome for involvement in disease. These genome-wide association studies (GWAS), typically testing millions of genetic markers across the genome, have prompted unprecedented collaboration in an effort to detect statistically robust findings. The PGC-SCZ study represents the culmination (for now) of this work involving the participation of almost 37,000 patients and 302 investigators across four continents. At the clinic one cannot help but be struck by how heterogeneous this patient population is, in terms of symptomatology, treatment response and illness course. Researchers have long questioned how well the clinical syndrome maps to underlying biology and whether this involves one, or many different disease processes. The GWAS data provides some answers. Genetic variants that are common in the human population, although individually making a small contribution, collectively explain at least a quarter of the variance in genetic risk. This gives the syndrome cohesion, in that the same molecular processes are contributing in most cases. But this work, and other recent studies, suggest that for some individuals rare genetic mutations may have a much larger effect on risk, essentially representing discrete rare disease processes within the syndrome similar to what we observe in epilepsy or hyperlipidaemia. A second related question, with ‘realworld’ implications is the validity of the diagnostic distinctions between schizophrenia and other psychiatric disorders. Data from the earlier International Schizophrenia Consortium had shown that there is substantial molecular overlap between schizophrenia and bipolar disorder (Purcell, Wray et al. 2009). This has since been confirmed, with the overlap extending to recurrent depressive disorder, but also, to a lesser extent to autistic spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) (Lee, Ripke et al. 2013). In the PGCSCZ study a subset of the risk genes reported are already known to be involved

90 | THE CLINICAL CARE JOURNAL

in more severe genomic syndromes such as ASD and intellectual disability (ID). This suggests that fundamental neurodevelopmental processes are likely to underpin schizophrenia and other psychiatric disorders with the clinical presentation being a consequence of the severity of the molecular pathology involved, timing, chance and the influence of environment. Defining these molecular processes may have far-reaching ramifications in defining which patients are likely to most benefit from therapeutics advances, but also in planning future care delivery where this could be based on disease mechanisms rather than age and the traditional clinical service divisions (e.g. child, adult or learning disability in psychiatry). Assumptions held about the nature of the pathophysiolog§y involved were challenged by a third finding of the study. We tested across 56 cell lines or tissue samples to see where risk genes are being expressed. This confirmed enriched expression in brain, specifically in neurons rather than glia, supporting neuronal pathology. More surprisingly enrichment was also seen in tissues with important immune functions, particularly B-lymphocyte lineages involved in acquired immunity supporting older epidemiological data suggesting a role for immune dysregulation in schizophrenia. Digging deeper, the study provides an almost five-fold increase in the number of genomic regions known to be involved in schizophrenia. Specifically, 128 statistically independent genetic associations implicating at least 108 conservatively defined association loci were identified. Of these, 25 had been previously reported, but 83 are novel or had not previously received robust support. Of the 108 loci, 75% included protein- coding genes and a further 8% were within 20kb of a gene. The list of risk genes, while far from complete, begins to provide some insight into the molecular etiology of the disorder. The DRD2 gene, target of all current antipsychotic drugs makes the list. So too do genes implicated in glutamatergic neurotransmission and synaptic plasticity mechanisms (e.g. GRM3, GRIN2A, SRR, GRIA1). Less expected were associations detected at the genes CACNA1C, CACNA1I and CACNB2, extend the findings from earlier GWAS analyses implicating voltage-gated calcium channel subunits in schizophrenia and other psychiatric disorders. Based on what we know now, the implicated loci do not suggest a single overarching molecular disease process. Rather these findings represent a springboard to test

new hypotheses and potentially many molecular targets for treatment. This study represents a new beginning reinvigorating schizophrenia research. Much remains to be done. In only a small fraction of cases (<10%) could the association signal be attributed to known protein changing variants. From what we know of other common disorders, this is likely to be because most common associated variants exert their effects by influencing regulation of gene expression rather than by altering protein structure directly. In 40% of cases the association signal intersected a single gene, making this the most likely target for functional follow-up, but in almost 10% of cases the signal mapped to a region containing five or more genes where more mapping will be required. In addition to resolving these individual loci, many (if not most) pieces of the puzzle are still missing: the confirmed loci explain less than 4% of the total variance in schizophrenia susceptibility. But we now have a framework, where gaps can be filled through larger more powerful GWAS analyses and investigation of other classes of genetic variation, in particular rare mutations (McCarthy, Gillis et al. 2014). The hope is that in time, we will be able to stratify patients based on molecular etiology, to predict risk, guide prevention strategies and achieve personalized care.

REFERENCES •

•

(2014). “Biological insights from 108 schizophrenia-associated genetic loci.” Nature 511(7510): 421-427. Lee, S. H., et al. (2013). “Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs.” Nat Genet 45(9): 984-994. McCarthy, S. E., et al. (2014). “De novo mutations in schizophrenia implicate chromatin remodeling and support a genetic overlap with autism and intellectual disability.” Mol Psychiatry 19(6): 652-6 Purcell, S. M., et al. (2009). “Common polygenic variation contributes to risk of schizophrenia and bipolar disorder.” Nature 460(7256): 748-752.

PROFESSOR AIDEN CORVIN, Department of Psychiatry, Trinity College Dublin, Trinity Centre for Health Sciences, St James’s Hospital, Dublin. Email: acorvin@tcd.ie

BRI 5/12/14

References 1. World Health Organization Depression Factsheet no.369. Available at: http://www.who.int/mediacentre/factsheets/fs369/en/ Last accessed November 2014 2. Conradi HJ, Ormel J, de Jonge P. Presence of individual (residual) symptoms during depressive episodes and periods of remission: a 3-year prospective study. Psychol Med. 2011;41(6):1165–74 3. Greer TL, Kurian BT, Trivedi MH. Deﬁning and measuring functional recovery from depression. CNS Drugs. 2010; 24(4):267–284 4. Impact of Depression at Work European Audit. European Depression Association 2012. Available at: http://www. europeandepressionday.com/idea.html Last accessed November 2014 5. J. Olesen, et al. The economic cost of brain disorders in Europe. Eur J Neurology. 2012; 19:155–162 6. Making Mental Health Count. OECD 2014. Available at: http://www.oecd.org/els/health-systems/Focus-on-Health-Making-MentalHealth-Count.pdf Last accessed: November 2014 7. Rush AJ, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006; 163(11):1905–17

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NXT

Getting pregnant may be in her plans one day. Just not today.

A highly reliable, compliance-free, 3 year contraceptive option 1,2 No pills to remember or forget

Implanon NXT® (See SPC before Prescribing) Etonogestrel Presentation: Preloaded applicator with a radiopaque non-biodegradable implant containing 68mg of etonogestrel. USES: Contraception. DOSAGE AND ADMINISTRATION: One implant should be inserted subdermally after pregnancy has been excluded. Each implant will last for up to 3 years. Implanon NXT should only be inserted or removed by HCPs familiar with the insertion and removal technique. Insertion, removal and replacement instructions must be strictly followed. CONTRAINDICATIONS: Active venous thromboembolic disorder, known or suspected sex-steroid sensitive malignancies, presence or history of liver tumours, presence/history of severe hepatic disease with current abnormal liver function tests, undiagnosed vaginal bleeding, hypersensitivity to ingredients. PRECAUTIONS AND WARNINGS: Risk of having breast cancer diagnosed in users of progestogen-only preparations is possibly similar to the slightly increased risk associated with combined OCs. This may be due to earlier diagnosis, the biological effects of the OC, or a combination of both. Some epidemiology studies have associated combined OC use with an increased incidence of VTE, DVT and PE. It is unclear whether etonogestrel carries the same risk. Remove implant in the event of a thrombosis and prior to long-term immobilisation. Caution patients with a history of thromboembolic disorders. Abnormal liver function. Hypertension. Diabetes. Chloasma. HCPs may need to consider earlier replacement of the implant in heavier women. Ectopic pregnancy should be ruled out if a women presents with abdominal pain and amenorrhoea. History during pregnancy or previous use of sex steroids: jaundice and/or pruritis related to cholestasis, gallstone formation, porphyria, SLE, HUS, Sydenham’s chorea, herpes gestationis, otosclerosis, (hereditary) angioedema, anaphylactic reactions. Expulsion may occur if the implant is not inserted correctly or as a consequence of local inflammation. In rare cases the implant may migrate from the insertion site. PREGNANCY AND LACTATION: Not indicated during pregnancy. Exclude pregnancy prior to insertion. Implanon NXT may be used during lactation, growth and development of the child should be carefully followed. INTERACTIONS: Possible interactions with phenytoin, phenobarbital, primidone,

carbamazepine, rifampicin, oxcarbazepine, topiramate, felbamate, ritonavir, nelfinavir, nevirapine, griseofulvin and St John’s Wort. Implanon NXT may also interfere with the metabolism of other drugs - consult their prescribing information for details. UNDESIRABLE EFFECTS: Very Common: Vaginal Infection, headache, acne, irregular bleeding, weight increase, breast tenderness and pain. Common: Alopecia, dizziness, depressed mood, affect lability, nervousness, nausea, flatulence, libido decreased, increased appetite, abdominal pain, ovarian cyst, painful menstruation, flu-like illness, pain, fatigue, weight decrease, insertion site pain or reaction and hot flushes. Other less common and rarely reported side effects are listed in the SPC. OVERDOSE: Remove previous implant before inserting a new one. There are no data on overdose with etonogestrel. LEGAL CATEGORY: Prescription Medicine PRODUCT AUTHORISATION NUMBER: PA 61/28/1. PRODUCT AUTHORISATION HOLDER: Organon Ireland Limited, P.O. Box 2857, Drynam Road, Swords, Co. Dublin, Ireland. DATE OF REVISION OF PRESCRIBING INFORMATION: August 2012 Further information is available on request from: MSD, Red Oak North, South County Business, Park, Leopardstown, Dublin 18 or from www.medicines.ie. © Merck Sharp & Dohme Limited 2012. All rights reserved. Date of preparation: September 2014. References 1. Otero Flores JB et al. Int J Gynecol and Obstet 2005;90:228-33. 2. Implanon NXT Summary of Product Characteristics February 2011.

Red Oak North, South County Business Park, Leopardstown, Dublin 18, Ireland

www.talkoptions.ie

WOMN-1131190-0000

Discreet subdermal method 2

OBSTETRICS & GYNAECOLOGY

NEW GUIDELINES FOR OBSTETRICS AND GYNAECOLOGY TREATMENT Over 30 guidelines produced by the HSE National Clinical Programme for Obstetrics and Gynaecology are having a positive impact – and more guidelines are on the way, according to Prof Michael Turner, National Clinical Lead. Maureen Browne reports.

he HSE National Clinical Programme for Obstetrics and Gynaecology has now produced over 30 national guidelines for the care and treatment of women in the specialty and a further 20 have been commissioned, according to Prof Michael Turner, National Clinical Lead. Prof Turner, who is also Consultant Obstetrician at the Coombe Women’s and Infants University Hospital and Professor of Obstetrics and Gynaecology at UCD, says that one of the challenges was trying to ﬁnd the resources to fully implement these guidelines in all 19 units throughout the country. “These guidelines are having an impact, and are being used to drive improvements in clinical practice. For example, we know that the screening of obese women for gestational diabetes has increased. I think the best example of how improvements can be achieved is the whole area of misdiagnosis in miscarriage. We have gone from a situation where the HSE reported three years ago that there had been 18 cases over ﬁve years, to the current position where no cases have been reported in the three years since that report came out.

One of the challenges was trying to find the resources to fully implement these guidelines in all 19 units throughout the country.

Prof Turner believes that there is no room for further cuts in staffing levels in maternity services and that there is an urgent need to increase consultant staffing.

“This is very important clinically for women and their families, but it also means that savings have been achieved in terms of obstetric negligence claims with the State Claims Agency. I think it is an example of how clinical guidelines can produce rich dividends – not only clinically but also ﬁnancially.”

STERLING WORK Prof Turner says that sterling work has been done on developing the IMEWS guideline, which has been endorsed by the National Clinical Effectiveness Committee. As part of its quality development work, the programme produced Phase 1 of a quality report with 30 clinically based indicators. This has been implemented in all 19 units since July 2014. Phase 2 of this report, which is now being developed, will provide benchmarks that will allow each hospital to benchmark its key performance indicators against its own results for the previous year and against each of the 19 units. There is also a workstream in multidisciplinary obstetric emergency training, and Prof Turner and his team held their ﬁrst national conference in Dublin in September. “We are trying to standardise the management of obstetrics nationally. We have identiﬁed ten core subjects and they will be the subject of national guidelines. An educational resource pack will be distributed to all the hospitals and to relevant professional bodies,” he says. Prof Turner believes that there is no

room for further cuts in stafﬁng levels in maternity services and that there is an urgent need to increase consultant stafﬁng. “There is a national review of maternity services underway which is being conducted by the Department of Health and the HSE and we are hoping to contribute to that review.” The National Clinical Programme for Obstetrics and Gynaecology was set up in 2010 as a joint initiative between the HSE Clinical Strategy and Programmes Division and the Institute of Obstetricians and Gynaecologists, RCPI. Its overarching aim is to “improve choices in women’s healthcare”. The programme takes direction and guidance from the Clinical Advisory Group of Obstetricians and Gynaecologists from the institute. This group is chaired by Prof Robbie Harrison and meets at least four times each year. The programme also established a multi-disciplinary national working party to ascertain the views of, and gain consensus from, the range of healthcare providers associated with maternity services including midwifery, obstetrics, gynaecology, anaesthesia and allied health professionals.

PROF MICHAEL TURNER, National Clinical Lead. For more information on the work of the National Clinical Programme for Obstetrics and Gynaecology visit www.hse.ie/obsandgynae

THE CLINICAL CARE JOURNAL | 93

CONVENIENCE

r The only once-monthly* contraceptive in Ireland1,2 r Unlike combined pills NuvaRing does not require daily administration1

RING *In a given 1-month period, NuvaRing must be inserted, removed after 3 weeks, and a new ring must be inserted no more than 7 days later.1

EFFICACY COMPARABLE WITH THAT OF THE COMBINED PILL1

EASE OF USE3

r 99% effective at preventing pregnancy when used as directed1

r More than 95% of women rarely or never had a problem inserting or removing NuvaRing3

Actual NuvaRing user.

The unique delivery system of NuvaRing1,2,† valvular heart disease, atrial fibrillation, dyslipoproteinaemia and systemic lupus erythematosus. Symptoms of ATE In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC. Symptoms of a cerebrovascular accident can include: - sudden numbness or weakness of the face, arm or leg, especially on one side of the body; - sudden trouble walking, dizziness, loss of balance or coordination; - sudden confusion, trouble speaking or understanding; - sudden trouble seeing in one or both eyes; - sudden, severe or prolonged headache with no known cause; - loss of consciousness or fainting with or without seizure. Temporary symptoms suggest the event is a transient ischaemic attack (TIA). Symptoms of a myocardial infarction (MI) can include: - pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone; - discomfort radiating to the back, jaw, throat, arm, stomach; - feeling of being full, having indigestion or choking; - sweating, nausea, vomiting or dizziness; - extreme weakness, anxiety, or shortness of breath; - rapid or irregular heartbeats. Medical examination/consultation Prior to the initiation or reinstitution of Nuvaring use a complete medical history (including family history) should be taken and pregnancy must be ruled out. Blood pressure should be measured and a physical examination should be performed, guided by the contraindications and warnings. It is important to draw a woman’s attention to the information on venous and arterial thrombosis, including the risk of Nuvaring compared with other CHCs, the symptoms of VTE and ATE, the known risk factors and what to do in the event of a suspected thrombosis. The woman should also be instructed to carefully read the user leaflet and to adhere to the advice given. The frequency and nature of examinations should be based on established practice guidelines and be adapted to the individual woman. Women should be advised that hormonal contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases. Remove ring in event of a thrombosis and before long-term immobilisation. Council patients on symptoms of thrombosis. Increased risk of cervical cancer in long term COC users has been reported, but this may be confounded by other factors. Abnormal liver function or liver tumors. Increased risk of pancreatitis in women with hypertriglyceridemia taking hormonal contraceptives. Hypertension. Diabetes. Crohn’s disease/ulcerative colitis. Chloasma. History during pregnancy/previous use of sex steroids: jaundice and/or pruritis related to cholestasis, gallstone formation, porphyria, SLE, HUS, Sydenham’s chorea, herpes gestationis, otosclerosis. Remove ring if there is increased frequency/severity of migraine. Increased risk of thromboembolism in the puerperium. May not be suitable for women with a prolapse or severe constipation. Consider incorrect positioning in case of cystitis. Occasional vaginitis. Very rarely it has been reported that the ring adhered to vaginal tissue, necessitating removal by a healthcare provider.If ring accidentally expelled follow SPC instructions. Interactions: Possible interactions with phenytoin, phenobarbital, primidone, carbamazepine, rifampicin, oxcarbazepine, topiramate, felbamate, ritonavir, griseofulvin, penicillins, tetracyclines, ciclosporin, lamotrigine and St John’s Wort. Use of antimycotic ovules may increase the chance of ring disconnection. Pregnancy and Lactation: Not recommended. The increased risk of VTE during the postpartum period should be considered when re-starting NuvaRing. Common Undesirable effects: Vaginal infection, depression, decreased libido, headache, migraine, abdominal pain, nausea, acne, pelvic pain, breast tenderness, genital pruritis, female dysmenorrhoea, vaginal discharge, weight increased, discomfort, device expulsion. See SPC for full details of other uncommon side effects. Overdose: No reports of serious effects from overdose. Legal Category: Prescription Medicine. Product Authorisation Number: PA 1286/53/1. Product Authorisation holder: Merck Sharp & Dohme Ireland (Human Health) Limited, Red Oak North, South County Business Park, Leopardstown, Dublin 18, Ireland. 1Mid-point range of 5-7 per 10,000 WY, based on a relative risk for CHCs containing levonorgestrel versus non-use of approximately 2.3 to 3.6. Date of review: June 2014. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin 18 or from www.medicines.ie. © Merck Sharp & Dohme Ireland (Human Health) Limited, 2014. All rights reserved. Date of preparation: September 2014. † The only vaginal contraceptive ring in Ireland References: 1. Nuvaring Summary of Product Characteristics August 2010 2. MIMS Ireland, Dec 2011 3. Novák A, de la Loge C, Abetz L, van der Meulen EA. The combined contraceptive vaginal ring, NuvaRing: an international study of user acceptability. Contraception. 2003;67(3):187-194.

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Red Oak North, South County Business Park, Leopardstown, Dublin 18, Ireland

WOMN-1131277-0000

Nuvaring 0.120 mg/0.015mg per 24 hours vaginal delivery system® (See SPC before Prescribing) Etonogestrel and ethinylestradiol Presentation: Vaginal ring. Uses: Contraception. The decision to prescribe NuvaRing should take into consideration the individual woman’s current risk factors, particularly those for venous thromboembolism (VTE), and how the risk of VTE with NuvaRing compares with other CHCs. Dosage and Administration: A ring should be inserted into the vagina and left in for 3 weeks. Strictly follow insertion instructions. Contraindications: Presence/risk of venous thromboembolism (deep vein thrombosis, pulmonary embolism)., APCresistance (including Factor V Leiden), antithrombin-III-deficiency, protein C deficiency, protein S deficiency, major surgery with prolonged immobilisation,arterial thromboembolism (e.g. myocardial infarction) or prodromal conditions (eg. angina rectoris), cerebrovascular disease (transient ischaemic attack, TIA), hyperhomocysteinaemia, antiphospholipid-antibodies (anticardiolipinantibodies, lupus anticoagulant), history of migraine with focal neurological symptoms, diabetes mellitus with vascular symptoms, severe hypertension, severe dyslipoproteinaemia,. pancreatitis or history thereof if associated with severe hypertriglyceridemia,presence/history of severe hepatic disease if liver function values abnormal, presence/history of liver tumors , known/suspected sex-hormone dependent tumors undiagnosed vaginal bleeding, hypersensitivity to any ingredients. Precautions and Warnings: No epidemiology data available on vaginal administration but the warnings for combined HCs (CHCs) are considered applicable. Risk of breast cancer possibly similar to that associated with COCs. This may be due to earlier diagnosis in COC users, the biological effects of the COC, or a combination of both.. Use of any combined hormonal contraceptive (CHC), including NuvaRing, carries an increased risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) compared with no use. The use of any combined hormonal contraceptive (CHC) increases the risk of venous thromboembolism (VTE) compared with no use. Products that contain levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. Other products such as NuvaRing may have up to twice this level of risk. The decision to use any product other than one with the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with NuvaRing, how her current risk factors influence this risk, and that her VTE risk is highest in the first ever year of use. There is also some evidence that the risk is increased when a CHC is re-started after a break in use of 4 weeks or more. In women who do not use a CHC and are not pregnant about 2 out of 10,000 will develop a VTE over the period of one year. However, in any individual woman, the risk may be far higher, depending on her underlying risk factors (see below). It is estimated that out of 10,000 women who use a low dose CHC that contains levonorgestrel, about 61 will develop a VTE in one year. Inconsistent results on the risk of VTE with NuvaRing compared with CHCs that contain levonorgestrel have been found (with relative risk estimates ranging from no increase, RR=0.96, to an almost 2-fold increase, RR=1.90). This corresponds to between about 6 and 12 VTEs in a year out of 10,000 women who use NuvaRing. In both cases, the number of VTEs per year is fewer than the number expected in women during pregnancy or in the postpartum period. VTE may be fatal in 1-2 % of the cases. Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal, or retinal veins and arteries.Risk factors for VTE The risk for venous thromboembolic complications in CHC users increases with obesity, positive family history, other medical conditions associated with VTE (cancer, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease ((Crohn’s disease or ulcerativce colitis)) sickle cell disease) and increasing age (particularly above 35 years of age). Also prolonged immobilisation, major surgery, any surgery to the legs or pelvis, or major trauma where discontinuation is advisable. There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in the onset or progression of venous thrombosis. The increased risk of thromboembolism in pregnancy, and particularly the 6-week period of the puerperium, must be considered. Symptoms of VTE (deep vein thrombosis and pulmonary embolism) In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC. Symptoms of deep vein thrombosis (DVT) can include: - unilateral swelling of the leg and/or foot or along a vein in the leg; - pain or tenderness in the leg which may be felt only when standing or walking; - increased warmth in the affected leg; red or discoloured skin on the leg. Symptoms of pulmonary embolism (PE) can include: - sudden onset of unexplained shortness of breath or rapid breathing; - sudden coughing which may be associated with haemoptysis; - sharp chest pain; - severe light headedness or dizziness; - rapid or irregular heartbeat. Some of these symptoms (e.g. “shortness of breath”, “coughing”) are non-specific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections). Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of an extremity. If the occlusion occurs in the eye symptoms can range from painless blurring of vision which can progress to loss of vision. Sometimes loss of vision can occur almost immediately. Risk of arterial thromboembolism (ATE) Epidemiological studies have associated the use of CHCs with an increased risk for arterial thromboembolism (myocardial infarction) or for cerebrovascular accident (e.g., transient ischaemic attack, stroke). Arterial thromboembolic events may be fatal. Risk factors for ATE The risk of arterial thromboembolic complications or of a cerebrovascular accident in CHC users increases with increasing age, smoking, hypertension, obesity, positive family history, migraine. Other medical conditions associated with adverse vascular events, include diabetes mellitus, hyperhomocysteinaemia,

PAEDIATRICS & NEONATOLOGY

NEW NATIONAL MODEL OF CARE FOR

PAEDIATRICS & NEONATOLOGY The new national model of care for paediatrics and neonatology is being developed following a major summit of paediatric healthcare personnel, according to Prof. Alf Nicholson, who with Prof. John Murphy, is Joint National Clinical Lead for the Programme. Maureen Browne reports.

new National Model of Care for Paediatrics and Neonatology in Ireland is being developed by the HSE National Clinical Programme for Paediatrics and Neonatology. The programme is a joint initiative between the HSE and the RCPI.

The model of care is being developed following a major summit of paediatric healthcare personnel in Dublin in January 2014, according to Prof Alf Nicholson, who with Prof John Murphy is Joint National Clinical Lead for the programme. Prof Nicholson heads up the paediatrics section and Prof Murphy leads the

neonatology element of the programme. Ireland has a population of 4.6 million and just over 1m of these are children under the age of 16. These children make up 23 percent of the population. Ireland has the highest birth rate in the EU and about 75,000 paediatric inpatient admissions and 245,000 paediatric emergency

THE CLINICAL CARE JOURNAL | 95

FOR HEALTHCARE PROFESSIONAL USE ONLY

SMA H.A. is a nutritionally complete infant milk that has been shown to reduce the 1 risk of developing allergy to cows’ milk proteins . It should be used for babies with a family history of allergy and from the first formula feed. There is no need for a prescription. IMPORTANT: SMA H.A. Infant Milk should NOT be used if a baby has already been diagnosed with allergy to cows’ milk proteins or is suspected of already having an allergy to cows’ milk protein. SMA H.A. Infant Milk should be used as the first formula feed, before babies have been exposed to intact cows’ milk proteins. * Medical indications include: Hypoglycaemia, jaundice, dehydration or excessive weight loss Von Berg. A et al. J Allergy Clin Immunol 2003; 111 (3):533-40 Health Service Executive, Infant Feeding Policy for Maternity and Neonatal Services (2012). National Breastfeeding Strategic Implementation Monitoring Committee, Health Promotion HSE. IMPORTANT NOTICE: Breast milk is best for babies and breastfeeding should continue for as long as possible. Infant milks should only be used on the advice of a doctor, midwife, health visitor, public health nurse, dietitian or pharmacist, or other professionals responsible for maternal and child care.

PAEDIATRICS & NEONATOLOGY

department attendances per year. “The new model of care will cover many aspects, for example: where children should be treated, who should ideally treat them; the integration between local, regional and tertiary care; the environment in which children should be treated, how to improve in-patient and out-patient ﬂow, and the workforce,” says Prof Nicholson, who is Professor of Paediatrics at the RCSI and Consultant Paediatrician at the Children’s University Hospital, Temple Street, Dublin. “When we started, we could have gone abroad to look at systems in different countries, but instead we concentrated on what was going on at home and meeting professionals working in the ﬁeld in Ireland – nurses, doctors, health and social care professionals and those working in the community and primary care setting. We asked them what they thought of the service and how they felt it could be improved. Then we pulled all the views together and got a crystal-clear understanding of how the service has developed and where it should go from here. We have visited and re-visited every paediatric department in the country and visited all the tertiary specialities seeking their views. “Following this, a consultative summit was held in January 2015 in the Royal College of Physicians. It was a consultative meeting of colleagues from all over the country which looked at

When we started, we could have gone abroad to look at systems in different countries, but instead we concentrated on what was going on at home and meeting professionals working in the field in Ireland.

the ‘big ticket’ issues and the best way to tackle these,” Prof Nicholson says. “We had views from consultant paediatricians, paediatric nurses, neonatal nurses, public health nurses, health and social care professionals and hospital managers and we are now getting further feedback from general practice to try and reach a consensus on how we should develop the services.” Presentations to the meeting were made by Prof Murphy and Prof Nicholson, by Eilish Hardiman, CEO of the new Children’s Hospital, Dr. Kevin Kelleher and Dr Phil Jennings, who leads out for the

HSE on the child health model and Dr. Michael Capra, Consultant Oncologist in Crumlin, who spoke on the evolution of shared care tertiary services. “The presentations were followed by roundtable discussions on the major items.” Prof Nicholson says that the new model of care document is being developed incrementally in three volumes. The ﬁrst volume is care of the newborn, the second volume highlights the vision and mission, disability services and care of children in the community, and the third volume relates to tertiary services.

FOCUS The January summit debate focused on a number of important areas on which the programme is working at present. “We are thinking about where children should be treated, the care of the well and the sick newborn, and how to co-ordinate and categorise paediatric units and how to evaluate performance outcomes. There are three categories of children requiring treatment: illness in previously well children, illness in children with a background complex disease and illness in a child with a previously underlying condition. We want to deﬁne where these children should be treated, which involves organising primary and secondary care, informing the public of how the optimum service is organised, supporting GPs and developing closer links between primary and secondary care. Then we

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need to deﬁne how secondary care should be developed locally and in regional hospitals. It is all about clinical standards for how children should be treated.” Prof Nicholson goes on to say that “the programme is working on strategies to prevent children coming unnecessarily to EDs to be seen by emergency staff rather than having a co-ordinated review by their GP and a rapid response OPD appointment. This involves organisational training, new skills mix and out of hours care”. Ireland must generate and develop a modern paediatric workforce, which is one of the drivers for change, he says: we are talking about more consultant-delivered care, increased consultant numbers, more advanced nurse practitioners, clinical nurse specialists and public health nurses and integrating secondary and GP care. We must link community and in-patient workforces together to achieve a modern future-proofed workforce. “It is clear that primary, local, regional and tertiary services must be integrated so that a child, say with a heart murmur who may live in Donegal, can get access to appropriate care locally from their GP or local paediatric service, and then if necessary access tertiary care in an outreach clinic or in Dublin.” It is generally agreed that generalists will have a central role in the future development of paediatric services. They will be involved with some special area of interest. The majority of new consultant paediatric appointments will be generalists with a special interest. “We have got additional funding in this year’s service plan for new clinical specialists, including two consultant paediatricians with a special interest in endocrinology to further develop our diabetic services for children, and an additional six

The first volume is care of the newborn, the second volume highlights the vision and mission, disability services and care of children in the community, and the third volume relates to tertiary services.

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There are three categories of children requiring treatment: illness in previously well children, illness in children with a background complex disease and illness in a child with a previously underlying condition.

radiographers to provide a national ultrasound hip screening service,” Prof Nicholson says. “There is already an ultrasound screening service and we hope to provide an ultrasound screening service on a national basis if there are risk factors for developmental dysplasia of the hip.”

EFFECTIVE PROCESSES A child can access paediatric services up to and including the eve of a patient’s 16th birthday, and Prof Nicholson says it is very important to have processes in place to effectively transition the young adolescent to the adult service. The programme is working on a number of strategies, which include the improving inpatient and outpatient ﬂow, and improving access to emergency care for children. The programme is very supportive of a national charter for children, and is important to the programme that families are involved more in the solutions to tackling lengthy OPD waiting times, congested OPDs, cancellation of surgery and fragmentation of services. The programme also aims to ensure further development of the neonatal retrieval and retro-transfer service for the national paediatric transport service. “One of the biggest changes in the last 20 years has been the increase in allergic disease, type 1 diabetes and mental health and psychosomatic illness in children, particularly in adolescents. There is far less vaccine-preventable illness and much greater survival from complex diseases such as complex congenital heart disease, chronic renal disease and childhood cancer,” says Prof Nicholson. There is an agreed child protection plan, but a disability service plan is also required. Hospital accommodation is also very important and the programme would like to see full audiovisual separation of children and adults in emergency departments. Children should also have adequate play areas and a school service while in hospital. “We would like to see a national triage system. The Emergency Nurses Group has done excellent work in developing this and it is already in use

in some places but we want to introduce it to every emergency department that sees children in Ireland. We want to have a trained paediatric nurse on each shift, complete audio and visual separation for children and adults, rapid access to generalist paediatric clinics to reduce congestion and the development of paediatric assessment units. “The programme is currently working on the lengthy waiting times in OPDs, rapid response clinics by generalist paediatricians and improved triage and standardised referral letters. The data suggests that there are a number of appointments made for children who do not turn up for their appointment. This is causing issues as the waiting lists are long and each appointment made must be for someone who is going to turn up. The programme is looking at processes that will improve this situation and reduce the rate of non-attendance to OPD to less than ten per cent nationally. “The changes to a 24-hour/seven-day a week neonatal transport system has been dramatic, with the numbers transported in the ﬁrst 12 months since its introduction doubling from 300 to 600 children. Paediatric transport has just started and so far is working very well also.” Prof Nicholson concludes that “it is likely that the new model of care (MOC) will be agreed prior to the new Children’s Hospital building being complete. However, the MOC will ensure that the highest quality services are available to all children in all hospitals where children are seen. This is an incredibly exciting time to be involved in paediatric health care, as we are poised to develop a service and a model for other countries to follow.”

PROF. ALF NICHOLSON is Joint National Clinical Lead for the new national model of care for paediatrics and neonatology. For more information on the National Clinical Programme for Paediatrics and Neonatology please visit: www.hse.ie/paeds

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OPHTHALMOLOGY

A NEW STRATEGY FOR EYE CARE IN IRELAND

The HSE National Clinical Programme for Ophthalmology’s new model of care aims to provide care for patients with chronic eye disease as close to home in the community as appropriate, according to Mr. Paul Moriarty, Clinical Lead for the Programme. Maureen Browne reports.

he HSE National Clinical Programme for Ophthalmology has developed a model of care, which is currently ready to go for consultation with relevant stakeholders prior to publication as the strategy for eye care in Ireland. “Our aim is to have a virtual department of ophthalmology in each region that would include a regional surgical centre and satellite clinics which could work on a cooperative basis so

that patients are treated at the appropriate level of complexity,” says Mr. Paul Moriarty, Clinical Lead for the Ophthalmology Programme. “This will mean a shift of people and assets to the community, but I think it is the only way. “I am currently in contact with the new hospital group CEOs to build awareness of the programme and the implications for a regionalised service where patients will move seamlessly between the surgical centres and satellite clinics within each group.”

REVIEW GROUP The Primary Care Division of the HSE has established a Primary Eye Care Services Review Group under the chairmanship of Mr. Brian Murphy. This group is examining the current provision of service within primary care and will be making recommendations in a report due in April 2015. It has a wide group of hospital and community stakeholders including eye doctors, orthoptists, administrators and nurses. “The next challenge is to integrate

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the community-based service with the new hospital groups and the community healthcare organisations. Each hospital group will have a dedicated integration service. This will assist in the integration of hospital and community services into a single eye care domain.” The model of care document looks at the ﬁve groups in ophthalmology that account for the majority of patients within the service: age-related macular degeneration, cataract, glaucoma, diabetic retinopathy and children’s services. The philosophy behind the clinical programme is to provide care for patients with chronic eye disease as close to home in the community as appropriate. “At present, ophthalmic services are delivered in hospitals and we would prefer to see it more community based. To have all these services delivered in hospital reduces the time surgeons take to carry out surgery.” Mr. Moriarty says that diabetes had its own national clinical programme and that was going very well. “The initial retinopathy screening programme is up and running and the treatment programme that spun off from the screening is operational with funding provided for it in the system.”

SCREENING CHILDREN Together with the Primary Care Review Group, the clinical programme is currently focusing on children’s vision screening and new ways to follow up with children who fail school screening tests, according to Mr. Moriarty. “Children’s screening is normally done by school nurses in junior infants because we need to catch problems as early as possible. Those that fail this screening are usually seen within the community setting or sent to the hospital eye clinic. However, with the rising birth rate, our capacity is struggling to meet demand. Therefore we are looking at teams of orthoptists and optometrists who would triage children who fail the primary screening and then only those who needed to go to the medical clinics would be reviewed there. The 2015 HSE Service Plan ring fences 1 million to implement the recommendations of the review group. “Once the recommendations from the review group are implemented we should have a more appropriate and timely referral pathway for children who fail vision screening. “As far as the demand for cataracts is concerned, unfortunately we are constrained in relation to access to theatre time to deliver the service. However, we have made recommendations that we

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would have one or two purely service units in excess of the teaching hospital supply. We have a model of care in Sligo, where the consultant surgeon goes to Letterkenny on a regular basis. The surgical service is also supported by community ophthalmic physicians and optometrists who do a signiﬁcant part of the pre- and post-op care for these patients. We would like to bring that model nationwide to get the numbers under control. “The number of patients with acute macular degeneration has risen from approximately 600 treatments a year in 2008 to 14,000 treatments currently and rising. There is no additional budget available to treat these patients, which means that existing treatment pathways have been squeezed in order to provide this care. We will need a national strategy and programme similar to what has been delivered in the UK. “On the glaucoma side we are looking at a shared community/hospital programme; most stable patients with this disease would be reviewed in the community.

COMMUNITY-BASED CARE “Our aim is to have a virtual department of ophthalmology in each region with a regional surgical centre and satellite clinics which could work on a cooperative basis so that patients are treated at the appropriate level of complexity,” says Mr Moriarty. “We will have to look at the physical space available in the community and make recommendations as to where the clinics should be. Each region will require a local integration programme which will match community and hospital services to give a balanced delivery of care.

I am currently in contact with the new hospital group CEOs to build awareness of the programme and the implications for a regionalised service where patients will move seamlessly between the surgical centres and satellite clinics.

“Locally integrated delivery of care is dependent on a system that facilitates free ﬂow of information between community and hospital. Such a system is in use in Sligo, linking the unit in Letterkenny with the hospital centre in Sligo. The unit in Letterkenny can send images on to Sligo for a second opinion. The North West has been very forward-thinking in how they have integrated the various sites. “My vision for the future is of integrated areas with a surgical centre and satellite units. The Irish College of Ophthalmologists is in parallel developing the curriculum for medical ophthalmologists whom we would see as largely running the satellite units.”

MR. PAUL MORIARTY is Clinical Lead for the HSE National Clinical Programme for Ophthalmology’s new model of care.

PALLIATIVE CARE

PALLIATIVE CARE IS THE RESPONSIBILITY OF ALL HEALTHCARE STAFF Palliative care is a core skill and competence, and the HSE/RCPI National Clinical Programme for Palliative Care aims to enhance patients’ quality of life, according to Dr. Karen Ryan, National Clinical Lead of the Programme and Consultant Palliative Care Physician to the Mater University Hospital and St. Francis Hospice. Maureen Browne reports.

he objective of the joint HSE/RCPI National Clinical Programme for Palliative Care is to enhance patients’ quality of life and allow them to easily access an appropriate level of palliative care regardless of their diagnosis and care setting, according to Dr. Karen Ryan, National Clinical Lead of the programme and Consultant Palliative Care Physician to the Mater University Hospital and St. Francis Hospice, Dublin. “The National Clinical Programme for Palliative Care considers that palliative care is the responsibility of all healthcare staff in the health service. It is a core skill

and competence but there has perhaps been a tendency up to now to think of palliative care solely in the context of specialist palliative care,” says Dr Ryan. “You need to regard palliative care as the responsibility of both specialist and generalist, working in partnership. We are talking about a whole systems change so we have taken the WHO health strengthening approach, which has six building blocks. It recommends activities to be done along each of these building blocks: ensuring efﬁciency, quality and accessibility of health system delivery; ensuring competency and availability of the health workforce; using health information

systems to produce and utilise accurate and timely information; ensuring safe, effective use of medications; developing health ﬁnancing systems that are ﬁt for purpose; and supporting effective leadership and governance. Details of all of our work-streams, which focus on the building blocks, can be found on the Palliative Care Clinical Programme webpage, together with outputs produced to date (www.hse.ie/palliativecareprogramme).”

ACCESS TO SERVICES Dr. Ryan says that in relation to service delivery, the National Clinical Programme for Palliative Care began with

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considering the issue of access. She says that “there is now agreement across all specialist palliative care services that services will be provided in accordance with need and not diagnosis. National referral criteria and eligibility criteria for accessing palliative care have been developed and will be published in 2015. In this way, we are moving away from the idea that palliative care is only for people with cancer and motor neurone disease. “When one looks at need rather than diagnosis as the basis for service provision, it follows, therefore, that we need to provide best practice guidance that will help people appropriately assess need. As a result, the programme has developed a needs assessment guidance document, which is accompanied by supporting resources. Dr Ryan says that “the document looks at how you best engage with persons and their families in order to try and identify if they have palliative care needs. The approach is holistic, looking at psychosocial, emotional and spiritual as well as physical needs and the guidance identiﬁes key trigger points for consideration of needs assessment.”

PROGRAMMES AND FRAMEWORKS The programme is also rolling out a Palliative Care Needs Assessment educational programme to develop champions in this area. “Lorna Peelo-Kilroe, Nursing Lead to the National Clinical Programme for Palliative Care and Dr. Aisling O’Gorman, Regional Representative for Dublin North East and Consultant in Palliative Care, are leading this. They are delivering workshops to provide training for over 80 champions. These champions will bring their training back to their own workplaces and roll out further educational sessions. The training programme is supplemented by an online module available on the All Ireland Institute of

There is now agreement across all specialist palliative care services that services will be provided in accordance with need and not diagnosis.

Hospice and Palliative Care website.” A National Palliative Care Competence Framework has been developed in collaboration between the clinical programme, the Irish Hospice Foundation, the All Ireland Institute of Hospice & Palliative Care and the Irish Association of Palliative Care supported by the HSE Ofﬁce of the Nursing and Midwifery Services Director and professional bodies. “We come back to the idea of palliative care as everybody’s business. Traditionally, there was a lack of clarity about what skills staff should have in order to provide high-quality palliative care in all settings. Therefore we set out to describe the competences that the HSE and the RCPI expect their members to have. The Palliative Care Competence Framework describes core competences that are common to all health care professionals and discipline-

The approach is holistic, looking at psychosocial, emotional and spiritual as well as physical needs and the guidance identifies key trigger points for consideration of needs assessment.

speciﬁc competences, at three ascending levels of practice. The framework can be used as a learning tool for self assessment, or used by line managers to help work-based assessment. We hope the next stage will involve the educational bodies and the universities using it to inform their curricula and CPD programmes.” Two national clinical guidelines: Pharmacological Management of Cancer Pain in Adults and Management of Constipation in Adults Receiving Palliative Care are due to be launched in the ﬁrst part of 2015. The programme has also developed a National Rapid Discharge Planning Pathway, which sits under the framework of the integrated discharge guidance developed by the HSE. Dr Ryan says that “this pathway aims to provide best practice in discharge planning from hospitals. If people

become ill very quickly and wish to die at home you have to move quickly to get them home as soon as possible.”

WORKBOOKS From a quality perspective, the programme has developed a number of quality assessment and improvement workbooks for specialist palliative care services that may be preparing for inspection by HIQA and subsequently licensing. The workbooks align with the content of the National Standards for Safer Better Healthcare and were developed with the support of the HSE Quality and Patient Safety Division. Palliative care services also feature as an essential element within the acute hospitals workbooks, which also helps to promote good practices. The programme has also tried to encourage innovation through the establishment of best practice projects. The Irish Hospice Foundation is supporting a joint initiative between the National Clinical Programmes for Emergency Medicine and the National Clinical Programme for Palliative Care. Dr Ryan says that “the initiative aims to develop a model of palliative care in hospital emergency departments. Dr. Eoin Tiernan and Prof John Ryan of St. Vincent’s University Hospital Dublin are currently leading a study that will help inform practice.”

DR. KAREN RYAN is National Clinical Lead of the Programme and Consultant Palliative Care Physician to the Mater University Hospital and St. Francis Hospice, Dublin. For more information on the work of the National Clinical Programme for Palliative Care visit www.hse.ie/ palliativecareprogramme

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PAIN MANAGEMENT | RESEARCH

PATIENT SATISFACTION WITH

PAIN MANAGEMENT RELIES MOST ON COORDINATION OF CARE The main driver of patient experience depends less on the individual provider than on the overall coordination among the clinic, the primary care physician and all others who participate in delivery of care, researchers at Stanford, California have reported.

he results, in a scientific poster at the 31st Annual Meeting of the American Academy of Pain Medicine, describe the wisdom of moving away from episodic care and toward long-term, overall outcome in ways that matter to the patient. Patient satisfaction, and more broadly patient experience, is an emerging metric demonstrating healthcare quality to policy makers and insurance payers but is an assessment on which pain medicine, as a specialty, has historically underperformed. This is unfortunate, because patient satisfaction is of particular importance to those who suffer with chronic pain, the study’s lead author said. “Patients with chronic pain also often have significant emotional distress, raising the bar for providing complete, satisfactory care,” said Ming-Chih Kao, M.D., Ph.D., clinical assistant professor within the Stanford University School of Medicine in Palo Alto, Calif. “Dissatisfied patients may have reduced compliance, may switch providers unnecessarily and may seek care that is not indicated, which in turn may cause more frustration and distress for the patient.” Kao went on to say that the pain provider remains an important contributor; however, improvement efforts that look too narrowly at the individual provider in improving patient satisfaction may be counter-productive because they divert attention and resources away from more important aspects of patient experience. The research team surveyed the field of patient experience assessments and created the Survey To Enhance Patient Experience (STEPx) system to fully characterize patient experience. For this study, the STEPx contained 20 items to measure patient experience in seven “touch points,” which are domains,

plus one free-text item. It is designed to survey the end-to-end patient experience in a pain clinic by examining some core concepts of patient satisfaction but is worded to maximize actionable results. The team administered the STEPx post-visit over three weeks at an academic multidisciplinary pain centre to 628 patients, 123 (20 per cent) of whom completed the questionnaire. Factor analysis and multi-dimensional scaling were performed. On touch-point-level factor analysis, the three following factors were revealed: care coordination and outcomes represented 32 per cent of variance, patientfacing staff and provider constituted 22 per cent of variance, and outcomes and provider accounted for 15 per cent. Notably, going deeper into an item-level analysis of the ﬁrst factor found that scheduling and communications constituted 45 per cent of the variance. But the most surprising ﬁnding to the researchers came when the relationships between touch-points were analysed, and the satisfaction with care coordination had the highest correlation with all the others (average r 0.74). The satisfaction with outcomes was strongly correlated only with care coordination and had relatively weak correlations with other touch-points. In the future, Kao said, STEPx as-

“In part, based on these findings, we have expanded our staff support specifically for greater care coordination of complex cases.”

sessments will be dynamically generated based on the care actually received. This is possible because of the platform’s integration with the Collaborative Health Outcomes Information Registry (CHOIR) platform, a learning health system created through the National Institutes of Health. More information on the CHOIR platform is at http://choir. stanford.edu. Future studies will focus on measuring the impact of touch-point interventions. Changes to practice are already taking place within Stanford’s Pain Management Center, Kao said. “In part, based on these ﬁndings, we have expanded our staff support speciﬁcally for greater care coordination of complex cases.”

Poster 191 – Stanford Patient Experience Questionnaire (SPEQ): Care Coordination as a Core Touch Point of Patient Satisfaction in the Chronic Pain Population. The American Academy of Pain Medicine is the premier medical association for pain physicians and their treatment teams with over 2,500 members. Now in its 32nd year, the Academy’s mission is to optimise the health of patients in pain and eliminate pain as a major public health problem by advancing the practice and specialty of pain medicine through education, training, advocacy and research. Information is available on the Academy’s website at www.painmed.org. - 31st Annual Meeting of the American Academy of Pain Medicine.

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PAIN MANAGEMENT | RESEARCH

STUDY FIRST TO USE

MARKOVIAN MODELS FOR TRACING

POSTOPERATIVE PAIN TRAJECTORIES Markovian models show promise for describing postoperative pain states and, eventually, may help guide clinical decisions, a new study found.

n a surgical inpatient population, patients early in their postoperative recovery period carry roughly the same probability of transitioning from one pain state to another, regardless of the timing of the assessment, according to preliminary results presented at the 31st Annual Meeting of the American Academy of Pain Medicine. “Pain trajectories help us to understand why different patients will hurt for different lengths of time after injury or surgery,” said Patrick Tighe, M.D., who led the team of investigators from the University of Florida in Gainesville, Fla. “Different analgesics each have different pharmacokinetic proﬁles, and so a better understanding of pain trajectories could help us better match analgesics to patients.“ The use of Markovian models is new in this context. Markovian models and their derivatives have been applied to a range of problems in ﬁnancial markets, weather patterns, board game development, DNA sequencing and speech recognition. The models use sequential data to help explain how systems that continually change do so in a probabilistic manner, Tighe explained. The behaviour of a probabilistic system cannot be predicted exactly, but the probability of certain behaviours is known. Thus, these methods require certain assumptions about a system. With institutional review board approval through the University of Florida and funding through a grant from the National Institutes of Health, the investigators set out to test whether Markovian

Pain trajectories help us to understand why different patients will hurt for different lengths of time after injury or surgery.

models could be used to predict pain trajectories. First, they examined the first five clinically recorded postoperative pain intensity ratings from a mixed surgical cohort of 26,090 patients. They then measured the probability that a patient would transition from a given pain intensity rating to a subsequent pain intensity rating between each of the first four transition steps. What they found was that the clinically measured pain states were stable, in terms of the probable distribution over the first five assessments following surgery. Thus, if the initial pain rating was 0, which was the most common rating for all ages and both sexes (range 30.7 percent – 74.6 percent), the sequential transition matrices demonstrated a high probability of transition to 0 for all; indeed, the highest probability was observed for 0 to 0 and 10 to 10. All pain states had a high probability of transitioning to 0 as well as to the same pain state. “This was a bit surprising, given that we had hoped to see an increase in the probability that patients would transition from higher to lower pain states with each sequential transition,” Tighe said. The potential for Markovian models to assist medical decision making has been

described before. In a scientific journal article, Sonnenberg and Beck wrote, “Markov models are useful when a decision problem involves risk that is continuous over time, when the timing of events is important, and when important events may happen more than once. Representing such clinical settings with conventional decision trees is difficult and may require unrealistic simplifying assumptions. Markov models assume that a patient is always in one of a finite number of discrete health states, called Markov states (Med Decis Making 1993;13(4):322-38).” Tighe said the current results must be validated in other contexts and institutions, then stratified to specific patient populations. Further, these preliminary explorations must be further matured into decision process models that balance short-term gains with long-term outcomes. “We still have a ways to go,” he said.

Poster 204 – Is Acute Pain Medicine Ready for Markov? Preliminary Testing of Sequential Postoperative Pain Intensity Transition Matrix Stabilities - 31st Annual Meeting of the American Academy of Pain Medicine.

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PALEXIA® - A PROPOSED NEW CLASS MOR-NRI1

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Now available in Oral Solution PALEXIA SR®, PALEXIA® Film-coated Tablets and PALEXIA Oral Solution® Prescribing Information Refer to the Summary of Product Characteristics (SmPC) before prescribing. Presentation: Palexia SR: 50 mg (white), 100 mg (pale yellow), 150 mg (pale pink), 200 mg (pale orange) and 250 mg (brownish red) prolonged-release tablets contain 50 mg, 100 mg, 150 mg, 200 mg and 250 mg of tapentadol (as hydrochloride) respectively. Palexia Film-coated Tablets: 50 mg (white), 75 mg (pale yellow) and 100 mg (pale pink) film-coated tablets contain 50 mg, 75 mg and 100 mg of tapentadol (as hydrochloride) respectively. Palexia Oral Solution: 20 mg/ml oral solution containing 20 mg tapentadol (as hydrochloride) in 1 ml solution. Indication: Palexia SR is indicated for the management of severe chronic pain in adults, which can be adequately managed only with opioid analgesics. Palexia Film-coated Tablets and Palexia Oral Solution are indicated for the relief of moderate to severe acute pain in adults, which can be adequately managed only with opioid analgesics. Dosage and method of administration: Individualise according to severity of pain, the previous treatment experience and the ability to monitor the patient. Can be taken with or without food. Palexia SR and Palexia Film-coated Tablets: Swallowed whole with sufficient liquid. Palexia SR should not be divided or chewed. Palexia Oral Solution: Can be taken undiluted or diluted in water or non-alcoholic drinks. Palexia SR dosage: Initial dose 50 mg twice a day. Switching from other opioids may require higher initial doses. Titrate in increments of 50 mg twice a day every 3 days for adequate pain control. Total daily doses greater than 500 mg not recommended. Palexia Filmcoated Tablets and Oral Solution dosage: Initial dose 50 mg every 4 to 6 hours. On the first day of dosing, an additional dose may be taken 1 hour after the initial dose, if no pain control. The first day’s dose should not exceed 700 mg. Maximum maintenance daily dose of up to 600 mg. Duration of treatment: Palexia Film-coated Tablets and Oral Solution: The possibility of switching to Palexia SR should be considered if longer term treatment is required, and pain relief is achieved with Palexia Film-coated Tablets or Oral Solution in the absence of intolerable adverse events. Discontinuation of treatment: Taper dose gradually to prevent withdrawal symptoms. Renal/hepatic impairment: Not recommended in patients with severe cases. Caution and dose adjustments with moderate hepatic impairment. Elderly: May need dose adjustments. Children below 18 years: Not recommended. Contraindications: Hypersensitivity to ingredients, suspected or having paralytic ileus, acute intoxication with alcohol, hypnotics, centrally acting analgesics or psychotropics. Not for use when mu-opioid receptor agonists are contraindicated (e.g. significant respiratory depression, acute or severe bronchial asthma or hypercapnia). Special warnings and precautions: At risk patients may require monitoring due to misuse, abuse, addiction or diversion. At high doses or in mu-opioid receptor agonist sensitive patients, dose-related respiratory depression may occur. Caution and monitoring required with impaired respiratory function. Should not use in patients susceptible to intracranial effects of carbon dioxide retention (e.g. increased intracranial pressure, impaired consciousness or coma). Use with caution with head injury, brain tumours, moderate hepatic impairment, biliary tract disease including acute pancreatitis. Not recommended if history of or at risk of seizures or with severe renal or hepatic impairment. Care should be taken when combining with mixed mu-opioid agonists/antagonists (e.g. pentazocine, nalbuphine) or partial mu-opioid agonists (e.g. buprenorphine). Should not use with hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption. Interactions: Use with benzodiazepines, barbiturates and opioid analgesics, antitussive drugs and substitutive treatments may enhance the risk of respiratory depression. Central nervous system (CNS) depressants (e.g. benzodiazepines, antipsychotics, H1-antihistamines, opioids, alcohol) can enhance the sedative effect and impair vigilance. Consider dose reduction with respiratory or CNS depressant agents. In isolated cases, there have been reports of serotonin syndrome in a temporal connection with the therapeutic use of tapentadol in combination with serotoninergic medicinal products (e.g. serotonin re-uptake inhibitors). Use with strong inhibitors of uridine diphosphate transferase isoenzymes (involved in glucuronidation) may increase systemic exposure of Palexia/Palexia SR. Caution if concomitant administration of strong enzyme inducing drugs (e.g. rifampicin, phenobarbital, St John’s Wort) starts or stops as this may lead to decreased efficacy or risk for adverse events, respectively. Avoid use in patients who have taken monoamine oxidase inhibitors (MAOIs) within the last 14 days, due to cardiovascular events. Pregnancy and lactation: Use in pregnancy only if the potential benefit justifies the potential risk to the foetus. Not recommended during and immediately before labour and delivery. Do not use during breast feeding. Driving and using machines: May have major effect on ability to drive and use machines, especially at the beginning or change in treatment, in connection with alcohol or tranquilisers. Undesirable effects: Very common (*1/10): dizziness, somnolence, headache, nausea. Palexia SR only: constipation. Palexia Film-coated Tablets and Oral Solution only: vomiting. Common (*1/100, <1/10): decreased appetite, anxiety, sleep disorder, tremor, flushing, diarrhoea, dyspepsia, pruritus, hyperhidrosis, rash, asthenia, fatigue, feeling of body temperature change. Palexia SR only: depressed mood, nervousness, restlessness, disturbance in attention, involuntary muscle contractions, dyspnoea, vomiting, mucosal dryness, oedema. Palexia Film-coated Tablets and Oral Solution only: confusional state, hallucinations, dry mouth, muscle spasms, constipation, abnormal dreams. Other important undesirable effects: palpitations, heart rate increased (uncommon *1/1000, <1/100), convulsion (rare *1/10,000, <1/1000). Palexia SR only: drug hypersensitivity including angioedema, anaphylaxis and anaphylactic shock (uncommon *1/1000, <1/100), heart rate decreased (uncommon *1/1000, <1/100), respiratory depression (rare *1/10,000, <1/1000). Palexia Film-coated Tablets and Oral Solution only: respiratory depression (uncommon *1/1000, <1/100), hypersensitivity including angioedema, anaphylaxis and anaphylactic shock (rare *1/10,000, <1/1000), heart rate decreased (rare *1/10,000, <1/1000). No evidence of increased risk of suicidal ideation or suicide with Palexia/Palexia SR. Additional information is available on request. Overdose: Seek specialist treatment (see SmPC). Legal classification: POM, CD (Schedule II). Marketing Authorisation numbers and pack sizes: Palexia SR: 50 mg: PA 1189/7/4, 28 and 56 packs; 100 mg: PA 1189/7/5, 56 pack; 150 mg: PA 1189/7/6, 56 pack; 200 mg: PA 1189/7/7, 56 pack and 250 mg: PA 1189/7/8, 56 pack. Palexia Film-coated Tablets: 50 mg: PA 1189/7/1, 28 and 56 packs; 75 mg: PA 1189/7/2, 28 and 56 packs; 100 mg: PA 1189/7/3, 28 packs. Palexia Oral Solution: 20 mg/mL: PA 1189/7/11, 200 ml bottle. Marketing Authorisation Holder: Grünenthal Ltd, Regus Lakeside House, 1 Furzeground Way, Stockley Park East, Uxbridge, Middlesex, UB11 1BD, UK. IRE/P14 0003. Date of Preparation: March 2014. References: 1. Kress HG. European Journal of Pain 2010; 14 (8): 781-3. Date of Preparation: November 2014. IRE/P14 0022.

PAIN MANAGEMENT | RESEARCH

EARLY IMPROVEMENTS

DISSIPATE PAST 90 DAYS IN STUDY OF

PLATELETRICH PLASMA Early gains in pain relief, behavioral markers and function were not sustained in patients treated with platelet-rich plasma (PRP) injection for facet joint arthropathy, according to new research made available at the 31st Annual Meeting of the American Academy of Pain Medicine.

he study caps two years of investigation based on research showing PRP could promote progressive improvement and even repair for painful conditions such as elbow tendonitis and “tennis elbow.” The research team from Stony Brook, N.Y., investigated whether PRP might also prove an effective alternative to corticosteroid injection or radiofrequency ablation for cervical and lumbar facet arthropathy. Arthropathy is a collective term for joint disease that can encompass many types of speciﬁc and non-speciﬁc pathologies or injuries and affects all age groups. “It was our hope, based on other indications, that we might actually heal a joint,” or observe long-term (up to a year) improvement, said Marco Palmieri, D.O., the lead study author, who specialises in interventional techniques in the Chronic Pain Division of the Center For Pain Management At Stony Brook. “Unfortunately, we haven’t seen that in our results.” Palmieri stressed, however, that the treatment has promise, and further work should focus on identifying proper treat-

The study caps two years of investigation based on research showing PRP could promote progressive improvement and even repair for painful conditions such as elbow tendonitis and “tennis elbow.”

ment protocols and subgroups that might beneﬁt most from the therapy. The researchers examined pain and functional outcomes for 24 PRP patients, extracted from medical records with institutional review board approval. They found that pain intensity levels decreased in months one and three compared to baseline (p<0.01) but returned to baseline in months six and 12. Similarly, measures of function and disability decreased in the ﬁrst month (both p<0.01) but returned to baseline afterward. Behavioural markers measured by PROMIS tools, developed through the National Institutes of Health, found less anger, anxiety, pain interference and pain

behaviour in the ﬁrst month (all p<0.03). The patients also reported higher physical function and satisfaction with social roles (p<0.03) in the ﬁrst and third months. Palmieri said part of the follow-up research would entail determining the optimal intervals between injections and other particulars that have not been clearly delineated to date. Poster 127 – Pain, Functional, and Behavioral Outcomes in Patients Undergoing Platelet Rich Plasma (PRP) Injection for Cervical and Lumbar Facet Arthropathy available on the Academy’s website at www.painmed.org - 31st Annual Meeting of the American Academy of Pain Medicine.

THE CLINICAL CARE JOURNAL | 111

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PRIMARY CARE

MANAGING CHRONIC DISEASE IN THE COMMUNITY Transferring the management of chronic disease from hospitals to the community is an aim of the Minister for Health and a proposed new model of primary care. Maureen Browne reports.

ealth Minister Dr. Leo Varadkar has taken a major step forward towards the Holy Grail of a new model of primary care that would see the management of a significant amount of chronic disease transferred from hospitals to the community. It has long been acknowledged that the future development of the highly successful HSE National Clinical Care Programmes is dependent on achieving this new model of care, whereby up to 95 per cent of patients would be treated in the community. The transfer of a significant amount of chronic disease management from hospital to the community, including some complex cases, would be more patient-friendly and free up the hospitals to deal with more acute patients, which is a basic tenet of the programmes in line with good medical practice. It could also significantly reduce current unacceptable waiting lists and reduce overall costs. However, with GPs under-resourced, over-burdened with work and having to deal with totally unacceptable waiting lists for patient referral and treatment, this has looked like an increasingly difficult strategy to implement. The first public indication of progress on this front was the announcement at the end of February that the IMO, the HSE and the Department of Health had signed a memorandum of understanding to start negotiations on a new GP contract. Ostensibly, the main focus of the new contact will be free GP care for the under-sixes and the over 70s, with the door remaining open to the further extension of universal GP care. However, Health Minister Dr. Leo

Varadkar has made it plain that his ambitions are to go much further than that. Welcoming the agreement of the IMO to enter negotiations he said: “At the centre of the new contract, we would like to see a new model of primary care which involves management of chronic diseases by the GP who you know, rather than in hospital clinics. We would also like to see a focus on disease prevention and early intervention, alongside the traditional ‘diagnose and treat’ model. “We fully appreciate that this new vision for general practice will take time to negotiate, will have to be done with the agreement of GPs, and will have to be properly resourced. But I believe the new contract will be a great beneﬁt for patients and for GPs alike. I want to encourage everyone to seize this great opportunity for general practice.”

GREAT OPPORTUNITY Not only will it be a great opportunity for general practice, it will be a great opportunity for the health services, if it can be achieved – and that is still a big “if.” The memorandum of understanding will allow substantive discussions to start on a new overall GP contract to replace the 1971 and 1989 contracts. These discussions are scheduled to start no later than March 31st 2015, with a 12 month timeframe for the negotiations. The negotiations can be expected to be difﬁcult, both in terms of free GP care for the young and the older, but more so on the movement of chronic disease care and management. This will require the full implementation of the long-promised new primary care infrastructure, with integrated multi-disciplinary primary care teams including general practitioners, nurses, physiotherapists, occupational therapists, dental services, community

However, Health Minister Dr. Leo Varadkar has made it plain that his ambitions are to go much further than that.

metal health services, child and adolescent mental health services, early intervention teams and doctor-on-call services working in primary care centres. The Government’s Primary Care Strategy argues that in a developed primary care system, up to 95 per cent of people’s day-to-day health and social care needs can be met in the primary care setting, thereby avoiding the need for them to go to hospital. However, this is predicated on a network of primary care centres throughout the country. These centres, if fully operational, would be able to deliver the kind of reform needed – provided the resources are in place to deliver this. And these resources are what the minister and the HSE will need to deliver if they are to reach the Holy Grail and achieve the visions of all those who have signed up to, and work tirelessly for, the HSE National Clinical Programmes.

DR LEO VARADKAR, Health Minister.

THE CLINICAL CARE JOURNAL | 113

REHABILITATION MEDICINE

REHABILITATION MEDICINE A new Model of Care for Rehabilitation Medicine will feature a tertiary rehabilitation centre with six regional in-patient units in a blueprint that will attempt to address an “overwhelming” demand for rehabilitation services, according to Dr Jacinta Morgan, National Clinical Lead. Maureen Browne reports.

tertiary rehabilitation centre with six regional in-patient units that will be coterminous with the catchment area of the new hospital groups is proposed in the Model of Care for Rehabilitation Medicine, Dr Jacinta Morgan has indicated. Dr Morgan is the National Clinical Lead for the National Clinical Programme for Rehabilitation (a joint initiative between the HSE and the RCPI) and is also a full-time Consultant in Rehabilitation Medicine at the National Rehabilitation (NRH) and Beaumont Hospitals. Since its establishment in late 2010, with the current Clinical Strategy and Programmes Division’s National Director Dr Aine Carroll as its ﬁrst national clinical lead, the National Clinical Programme for Rehabilitation Medicine has been concerned with shaping future specialist rehabilitation services for adults with disability resulting from neurological injury and limb absence across acute, post-acute and primary care settings. The programme’s overall objective is to extend access to specialist rehabilitation services for people with acquired disability so that their ability can be maximised and dependency reduced. There is an overwhelming demand for rehabilitation services, particularly for people who have sustained severe brain injuries. “Emergency trauma and medical care is now more responsive and protocolised, and more people are surviving catastrophic injuries with complex neurological, vascular and orthopaedic sequelae,” says Dr Morgan. “These injuries are always life changing for the patient and their extended family. Those who are developing the framework for managing trauma in Ireland have recognised the crucial role of rehabilitation services in ensuring the best functional outcome for all severely injured patients. I also

represent RCPI on the Major Trauma Audit and Governance Committee, which manages Ireland’s TARN database.” Dr Morgan says it is vital to ensure rapid access to specialist rehabilitation in all hospitals admitting patients after major trauma and neurological injury. This involves patients having access to a centre equipped to treat patients with complex rehabilitation needs, developing regional specialist inpatient and outpatient rehabilitation units and reconﬁguring community-based rehabilitation services. The desired outcomes are reduced length of stay, prevention of unnecessary re-admissions and successful, sustained discharge to home. “We are advocating a model of care where our patients are managed by specialist rehabilitation clinicians who are connected and supported by the governance structures of a managed clinical rehabilitation network (MCRN). The National Rehabilitation Hospital has been the national hub for specialist rehabilitation for many years and will link formally with new rehabilitation teams in regional centres within each hospital group area. We are studying the geographical spread of the new community healthcare organisations (CHOs) and how our community partners in the HSE and voluntary agencies can continue to deliver and expand their existing services within the new structures,” says Dr Morgan.

DEVELOPMENT Dr Morgan is keen that uniform standards of service delivery can be realised in due course across the national, regional and community components of the network. The new model of care (which will be published early in 2015) will deliver, in line with the 2012 Neurorehabilitation Strategy, a blueprint for future provision of specialist rehabilitation services in Ireland. The illness management models

and pathways contained within the document have been developed, taking note of existing best practice within Ireland and beyond, after an extensive collaborative process involving interdisciplinary working groups. External consultation is currently underway with HSE divisions, Department of Health and voluntary health agencies before its launch in early 2015.

It is vital to ensure rapid access to specialist rehabilitation in all hospitals admitting patients after major trauma and neurological injury.

Once the model of care is agreed and formally launched, Dr Morgan and Programme Manager Ms Edina O’Driscoll wish to see the development of clear referral protocols and pathways at the interface between specialist and non-specialist rehabilitation services, and community disability services. They also believe it is important that statutory and non-statutory services should work collaboratively to improve outcomes and experience for service users. Another challenge for the National Clinical Programme for Rehabilitation is to inﬂuence policy development that could result in appropriate discharge options for those under the age of 65, other than nursing homes. “We would like to help develop more structured community-based rehabilita-

THE CLINICAL CARE JOURNAL | 115

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REHABILITATION MEDICINE

We would like to help develop more structured communitybased rehabilitation teams that could support people during gradual step-down from tertiary centres and regional units.

tion teams that could support people during gradual step-down from tertiary centres and regional units so that they can be supported in reintegrating within their local communities,” Dr Morgan says. The programme is also in discussion with colleagues in the National Clinical Programme for Paediatrics to enable the secure future development of specialist neurorehabilitation services for children. Since the establishment of the National

Clinical Programme for Rehabilitation, an additional ﬁve consultants in rehabilitation medicine posts have been approved and four have been ﬁlled. In the past year, 79 per cent of patients who have been admitted to a new ten-bedded Early Access Rehabilitation Unit in the NRH came from acute hospitals and 99 per cent went home with minimal or no community support necessary. The programme is engaged in a number of other important workstreams including: (i) the publication of Standards and Guidelines for the Procurement of Prosthetics, Orthotics and Specialist Footwear (2012), (ii) liaison with the National Disability Unit in developing an implementation plan for the National Policy and Strategy for the Provision of Neuro-Rehabilitation Services in Ireland 2011-2015 and (iii) development of standards of care for specialist in-patient and community rehabilitation services. Dr Morgan emphasises the importance of ongoing education of healthcare professionals within the rehabilitation clinical community and, more broadly, among those who interface with rehabilitation

services. “The programme is strongly team-focused and has started to describe the generic and specialist competencies for staff working in rehabilitative care spanning acute, post-acute and community settings. Effective and realistic goal setting, with patient and family engagement, is the cornerstone of the rehabilitation process. We are keen to contribute to education and support for primary care practitioners through the development of online resources on the management of disabling neurological conditions and limb absence,” Dr Morgan says.

DR JACINTA MORGAN, National Clinical Lead.

MS EDINA O’DRISCOLL, Programme Manager

For more information on the work of the programme visit www.hse.ie/ rehabilitationmedicineprogramme

THE CLINICAL CARE JOURNAL | 117

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References: 1. Conaghan P et al. Rheumatology 2013 Jul;52(7):1303-12. 2. Kneer W et al. J Pain Res 2013;6:743-7. 3. Rother M, Conaghan PG. J Rheumatology 2013;40:1742-48. 4. Data on file: Cantab Study Report: Caliper Lifesciences In vivo Bio-distribution Study. 5. Sivan et al. Langmuir 2010;26(2):1107-1116. 6. CNT Collaboration. Lancet 2013;383(9894):769-779. 7. McKenzie S, Torkington A. Aust Fam Physician. 2010 Sep;39(9):622-5. A Medical Device. Manufactured according to ISO 13485. Conforms to EU Medical Device Directive 93/42 EEC.

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ORTHOPAEDICS/RHEUMATOLOGY

PATIENTS SATISFIED WITH NEW

WAITING LIST REDUCTION INITIATIVE Around 50,000 patients have been removed from national orthopaedic and rheumatology secondary care waiting lists and patients have scored their experiences very highly, according to Prof Oliver FitzGerald, National Clinical Lead of the HSE National Clinical Programme for Rheumatology. Maureen Browne reports.

THE CLINICAL CARE JOURNAL | 119

I T I S1 HR RT

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LO SPONDY

THE ENBREL WAY ACROSS ALL STAGES OF axSpA

axSpA, Axial SpondyloArthritis * Enbrel is licensed for the treatment of adults with severe non-radiographic axial spondyloarthritis with objective signs of inflammation as indicated by elevated CRP and/or MRI evidence who have had an inadequate response to nonsteroidal anti-inflammatory drugs and for the treatment of adults with severe active ankylosing spondylitis who have had an inadequate response to conventional therapy.1

ABBREVIATED PRESCRIBING INFORMATION Enbrel® etanercept Before prescribing Enbrel® please refer to full Summary of Product Characteristics (SmPC). Presentation: Enbrel Pre-filled Syringe: Enbrel 25 mg and 50 mg solution for injection in pre-filled syringe. Each pre-filled syringe contains either 25 mg or 50 mg etanercept. Enbrel Pre-filled Pen (MYCLIC®): Enbrel 50 mg solution for injection in pre-filled pen. Each pre-filled pen contains 50 mg etanercept. Enbrel Powder: Enbrel 25 mg powder and solvent for solution for injection. Each vial contains 25 mg etanercept and each pre-filled syringe contains 1 ml water for injections. Enbrel Paediatric: Enbrel 10 mg powder and solvent for solution for injection for paediatric use. Each vial contains 10 mg etanercept and each pre-filled syringe contains 1 ml water for injections. Uses: Adults: Moderate to severe active rheumatoid arthritis (RA), in combination with methotrexate, when response to disease-modifying anti-rheumatic drugs DMARDs, including methotrexate (unless contraindicated), has been inadequate. Enbrel can be given as monotherapy in the case of intolerance to methotrexate or when continued treatment with methotrexate is inappropriate. Severe, active and progressive RA without prior methotrexate treatment. Enbrel alone or with methotrexate has been shown to reduce the rate of progression of joint damage measured by X-ray and to improve physical function. Patients with moderate to severe plaque psoriasis (PP) who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapy including ciclosporine, methotrexate or PUVA. Active and progressive psoriatic arthritis (PsA) when response to DMARDs has been inadequate. Enbrel has been shown to improve physical function in PsA patients, and to reduce the progression rate of peripheral joint damage as measured by X-ray in patients with polyarticular symmetrical subtypes of PsA. Severe active ankylosing spondylitis (AS) when response to conventional therapy has been inadequate. Non-radiographic axial spondyloarthritis (nr-axSpA).Treatment of adults with severe non-radiographic axial spondyloarthritis with objective signs of inflammation as indicated by elevated C-reactive protein (CRP) and/or magnetic resonance imaging (MRI) evidence, who have had an inadequate response to nonsteroidal anti-inflammatory drugs (NSAIDs).Children aged 2-17 years: Juvenile idiopathic arthritis (JIA). Polyarthritis (rheumatoid factor positive or negative) and extended oligoarthritis from the age of 2 years when inadequate response to, or intolerant of methotrexate. Psoriatic arthritis from the age of 12 years when inadequate response to, or intolerant of methotrexate. Enthesitis-related arthritis from the age of 12 years when inadequate response to, or intolerant of, conventional therapy. Children aged 6-17 years: Chronic severe psoriasis when inadequately controlled by, or intolerant to, other systemic therapies or phototherapies. Dosage: By subcutaneous injection. Adults: RA – 25 mg twice weekly or 50 mg once weekly PP - 25 mg twice weekly or 50 mg once weekly for up to 24 weeks, or 50 mg twice weekly for up to 12 weeks followed by 25 mg twice weekly or 50 mg once weekly for a further 12 weeks if needed. Continuous therapy may be appropriate for some adult patients. Discontinue if no response after 12 weeks. For re-treatment: 25 mg twice weekly or 50 mg once weekly for up to 24 weeks. AS, nr-axSpA and PsA – 25 mg twice weekly or 50 mg once weekly. Children aged 2-17 years: JIA – 0.4 mg/kg (maximum per dose 25 mg) twice weekly with an interval of 3 – 4 days or 0.8 mg/kg (maximum per dose 50 mg) once weekly. Discontinuation of treatment should be considered in patients who show no response after 4 months. Children aged 6-17 years: Plaque psoriasis in children aged 6-17 years – 0.8 mg/kg (maximum per dose 50 mg) once weekly for up to 24 weeks. Discontinue if no response after 12 weeks. For re-treatment: 0.8 mg/kg (maximum per dose 50 mg) once weekly for up to 24 weeks. Contra-indications: Hypersensitivity to any of the ingredients, sepsis or risk of sepsis, active infections. Warnings and Precautions: Enbrel should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of RA, JIA, PsA, AS, PP or Paediatric PP. Patients treated with Enbrel should be given the Patient Alert Card. Use carefully in patients predisposed to, or with history of, infection due to underlying diseases other than RA (e.g. advanced or poorly controlled diabetes) or with history of blood dyscrasias, preexisting or predisposition to demyelinating disease or congestive heart failure. Cases of active tuberculosis have been reported, therefore all patients should be evaluated for both active and inactive TB prior to being treated with Enbrel. If active TB is diagnosed, Enbrel should not be initiated. Caution should be used when administering Enbrel to patients previously infected with hepatitis B and there have been reports of worsening hepatitis C in patients receiving Enbrel. Use with caution in patients with a history of hepatitis C. Whether treatment with Enbrel might influence the development and course of active and/or chronic infections is unknown. Concurrent administration of Enbrel and anakinra has been associated with increased risk of serious infections and neutropenia, and is therefore not recommended. In clinical studies, concurrent administration of abatacept and Enbrel resulted in increased incidences of serious adverse events, and is therefore not recommended. Use caution when considering combination therapy with DMARDs other than methotrexate . Reports of various malignancies have been received in the post-marketing period, therefore with current knowledge, a possible risk for the development of lymphomas, leukaemia or other haematopoietic or solid malignancies in patients treated with a TNF-antagonist cannot be excluded. Malignancies, some fatal, have been reported among children, adolescents and young adults (up to 22 years of age) treated with TNFantagonists (initiation of therapy ≤ 18 years of age) in the post marketing setting. Melanoma and non-melanoma skin cancer (NMSC) have been reported in patients treated with TNF-antagonists, including Enbrel. Post-marketing cases of Merkel cell carcinoma have been reported very infrequently in patients treated with Enbrel. Periodic skin examination is recommended for all patients, particularly those with

risk factors for skin cancer. Enbrel has not been studied in combination with other systemic therapies or phototherapy for the treatment of psoriasis. Monitor closely if patient develops new infection during treatment. Discontinue treatment if serious infection or allergic reaction develops or if blood dyscrasias are confirmed. Caution should be used in patients who have moderate to severe alcoholic hepatitis and Enbrel should not be used in patients for the treatment of alcoholic hepatitis. Discontinue temporarily if significantly exposed to varicella virus. Live vaccines should not be given concurrently with Enbrel. Paediatric patients should have received all vaccines recommended in current immunization guidelines prior to starting Enbrel. Treatment with Enbrel may result in the formation of autoantibodies. Enbrel is not recommended for use in patients with Wegener’s granulomatosis. There have been reports of hypoglycaemia in Enbrel patients receiving medication for diabetes, necessitating a reduction in anti-diabetic medication in some of these patients. There have been reports of Inflammatory Bowel Disease (IBD) and uveitis in JIA patients being treated with Enbrel. Caution should be exercised when treating the elderly and with particular attention to occurrence of infections. Pregnancy & Lactation: Enbrel is not recommended in pregnant or breast-feeding women. Undesirable Effects: Adults: The most commonly reported adverse reactions are injection site reactions, infections, allergic reactions, development of autoantibodies, itching, and fever. See SmPC for less commonly reported side effects. TNFantagonists, such as Enbrel, affect the immune system and their use may affect the body’s defences against infection and cancer. Serious infections affect fewer than 1 in 100 patients treated with Enbrel. Reports have included fatal and life-threatening infections and sepsis. Various malignancies have also been reported with use of Enbrel, including cancers of the breast, lung, skin and lymphatic system (lymphoma). Serious infections and other adverse events such as uncommon reports of: thrombocytopenia, systemic vasculitis, uveitis and scleritis, interstitial lung disease, rare reports of tuberculosis, opportunistic infections, anaemia, leucopoenia, neutropenia, pancytopenia, seizures, worsening of heart failure, autoimmune hepatitis, Steven Johnson’s syndrome and very rare reports of : anaphylaxis, toxic epidermal necrolysis and aplastic anaemia have been reported. Reactivation of hepatitis B (a liver infection) and worsening of symptoms of dermatomyositis have also been reported. Central and peripheral demyelinating events have been seen rarely and very rarely, respectively, with Enbrel use. There have been rare reports of lupus, lupus-related conditions, and vasculitis. Rate of new malignancies was similar to that expected for the population studied. Fatalities associated with serious infections, pancytopenia, aplastic anaemia and interstitial lung disease have also been reported. Paediatrics: Generally as for adults, except the following were more common: headaches, nausea, vomiting and abdominal pain. In addition the following were reported as severe events: varicella, appendicitis, gastroenteritis, depression/ personality disorder, cutaneous ulcer, oesophagitis/gastritis, group A streptococcal septic shock, type I diabetes mellitus and soft tissue and post operative wound infection. There have been post-marketing reports of IBD and uveitis in JIA patients, including cases indicating a positive re-challenge. See section 4.8 of the SmPC for how to report adverse reactions. Package Quantities: Enbrel Pre-filled Syringe: Each carton contains 4 pre-filled syringes containing either 25 mg or 50 mg of Enbrel and 4 alcohol swabs. Enbrel Pre-filled Pen (MYCLIC): Each carton contains 4 pre-filled pens containing 50 mg of Enbrel and 4 alcohol swabs. Enbrel Powder: Each carton contains 4 vials of Enbrel 25 mg powder, 4 pre-filled syringes of water for injections, 4 needles, 4 vial adaptors and 8 alcohol swabs. Enbrel Paediatric (10 mg): Each carton contains 4 vials of Enbrel 10 mg powder, 4 prefilled syringes of water for injections, 4 needles, 4 vial adaptors and 8 alcohol swabs. European Marketing Authorisation Numbers: Enbrel Pre-filled Syringe 25 mg: EU/1/99/126/013 Enbrel Pre-filled Syringe 50 mg: EU/1/99/126/017 Enbrel Pre-filled Pen (MYCLIC) 50 mg: EU/1/99/126/020 Enbrel Powder 25 mg: EU/1/99/126/003 Enbrel Paediatric 10 mg: EU/1/99/126/022. Legal Category: S1A. European Marketing Authorisation Holder: Pfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK. For full prescribing information see the Summary of Product Characteristics. For further information on this medicine please contact: Pfizer Medical Information on 1800 633 363 or at EUMEDINFO@pfizer. com. 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. API Reference Number: EN 8_0. Pfleet number: 2013-0003980. Date of Prescribing Information: July 2014 References: 1. Enbrel (etanercept) SmPC. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/ human/000262/WC500027361.pdf. Last accessed June 2014. 2. Dougados M et al. Arthritis Rheum. 2014 Accepted Article doi: 10.1002/art.38721. 3. Maksymowych WP et al. Poster presented at: EULAR Annual Meeting; Paris, France, June 11-14, 2014. Poster FRI0260. 4. Song IH et al. Ann Rheum Dis. 2011;70(4):590-596. 5. Song IH et al. Paper presented at: ACR/ ARHP Annual Meeting; San Diego CA, USA, October 26-30, 2013. Abstract 1526. 6. Song IH et al. Ann Rheum Dis. 2013;72(6):823-825. 7. Pavelka K et al. Clin Exp Rheum. 2009;27:964-969. 8. Baraliakos X et al. Arthritis Res Ther. 2013;15(3):R67. 9. Dougados M et al. Ann Rheum Dis. 2011;70:799-804. Date of preparation: September 2014. ENB/2014/093/1

ORTHOPAEDICS/RHEUMATOLOGY

total of approximately 50,000 patients have been removed from the national orthopaedic and rheumatology secondary care waiting lists by an initiative whereby 24 musculo-skeletal (MSK) physiotherapists have been appointed to centres around the country to assess, triage and treat patients on the rheumatology and orthopaedic waiting lists. Prof Oliver FitzGerald, National Clinical Lead of the HSE National Clinical Programme for Rheumatology and Consultant Rheumatologist at St. Vincent’s University Hospital, Dublin, says. “Patients are very, very satisﬁed with the assessments and have scored their experiences as very high and as extremely high in terms of the quality of the service they have received. Following assessment, about 80 per cent of these patients are referred for physiotherapy in the community or the hospital and do not need to see a consultant rheumatologist or consultant orthopaedic surgeon.

Following assessment, about 80 per cent of these patients are referred for physiotherapy in the community or the hospital and do not need to see a consultant rheumatologist or consultant orthopaedic surgeon.

cal programmes to be successful. We are looking at trying to quantify the amount of work disability that is occurring in patients with MSK pain and trying to devise the treatment programme required to keep them in the workplace or get them back into the workplace. “We also want to commence a pilot study of that treatment programme in a group of patients with a view to a much larger clinical trial subsequently where we would hopefully prove that this intervention keeps people at work and gets them back to work.

ANTI-TNF PRODUCTS

The other area which we have been successful in getting over the line is the web-based high-tech prescription authorisation form.

“This continues to be one of the major success stories of the clinical programmes and we would like to build further on it. We would benefit from additional MSK physiotherapists. In some areas it is difficult to reduce the waiting lists due to insufficient staff numbers.” Building on the success of the MSK physiotherapy initiative, the Rheumatology Programme has also been awarded a grant from the Royal College of Physicians/HSE/Health Research Board. “We put in an application together with Prof Pamela Gallagher from Dublin City University and Dr. Deirdre Desmond from NUI Maynooth for financial support for programme-related research to improve the quality of care. We were one of two HSE national clini-

“The other area which we have been successful in getting over the line is the web-based high-tech prescription authorisation form,” says Prof FitzGerald. When a consultant is prescribing one of the expensive anti-TNF products, at present he or she will fill out a high-tech prescription form in four copies, one of which is sent to the HSE Primary Care Reimbursement Service (PCRS). The data is supposed to be collated within the PCRS, but given the volume coming through very little data is in fact captured other than that approximately 125 million is the total spend on anti-TNF products. “We were asked to see if we could better understand the use of these medications and in conjunction with the PCRS we have developed a web-based high-tech authorisation form which can be filled out on line in the rheumatology clinic. This means it will be immediately quantified and we will begin to understand much more about the use of anti-TNF products such as who is prescribing them, for what condition, in what doses as well as other information. “As the form includes clinical outcome measures, we will be able to tell the effect of the medication on whatever disease is being treated. This initiative is going live in the Dublin North East Hospital Network and we plan to roll it

out to all the hospital networks by end of Q2 2015. As these prescriptions have to be renewed every six months we hope to collect good data by the end of 2015.” Prof FitzGerald says that they were putting together a proposal for submission to the HSE in 2015 to do with treating patients with inﬂammatory arthritis in the most effective manner by treating to target. “The current

This continues to be one of the major success stories of the clinical programmes.

standard is that we should be trying to treat these diseases to speciﬁc levels of disease activity or targets which are agreed by the patient. For most patients, the target would be a disease remission but because of other health reasons some patients may wish to target a minimal disease activity state. “Then by reviewing the patient regularly and measuring patients’ response to treatment intervention, you can escalate treatment until you reach that agreed target. I think it is possible for most patients with inﬂammatory arthritis to achieve their target with resultant better health outcomes and cost savings. Treating to target would be nurse-driven but we would need to employ more nurses to implement it. Discussions related to this initiative will begin in early 2015 with presentation of the business plan.” PROF OLIVER FITZGERALD is National Clinical Lead of the HSE National Clinical Programme for Rheumatology.

THE CLINICAL CARE JOURNAL | 121

IN DMARD-IR AND TNF-IR RA PATIENTS, WHEN COMBINATION WITH MTX IS NOT AN OPTION...

THINK ROACTEMRA1

RoACTEMRA, in combination with methotrexate (MTX), is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients who have either responded inadequately to, or who were intolerant to, previous therapy with one or more disease-modifying anti-rheumatic drugs (DMARDs) or tumour necrosis factor (TNF) antagonists. In these patients, RoACTEMRA can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate. RoACTEMRA 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 methotrexate.2 ABRIDGED PRESCRIBING INFORMATION (For full prescribing information, refer to the Summary of Product Characteristics [SmPC]). RoActemra® (Tocilizumab) 20mg/ml Concentrate for Solution for Infusion Indications: (i) In combination with methotrexate (MTX), for the treatment of adult patients with moderate to severe active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more DMARDs or TNF antagonists. In these patients, RoActemra can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate. RoActemra 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 methotrexate. (ii) As monotherapy (in case of intolerance to MTX or where treatment with MTX is inappropriate) or in combination with MTX, for the treatment of active systemic juvenile idiopathic arthritis (sJIA) in patients * 2 years of age, who have responded inadequately to previous therapy with NSAIDs and systemic corticosteroids. (iii) In combination with MTX, for the treatment of juvenile idiopathic polyarthritis (rheumatoid factor positive or negative and extended oligoarthritis) in patients * 2 years of age, who have responded inadequately to previous therapy with MTX. In these patients RoActemra can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate. Dosage and Administration: Treatment should be initiated by healthcare professionals experienced in the diagnosis and treatment of RA, sJIA or pJIA and all patients should be given the Patient Alert Card. RA Patients: Recommended posology is 8mg/kg diluted to a final volume of 100ml, given once every 4 weeks by iv infusion over 1 hour. For patients weighing > 100kg, doses > 800mg per infusion are not recommended. No data on doses above 1.2g. Dose adjustments: Dose modification, interruption or in some cases discontinuation of RoActemra recommended in the event of raised liver enzymes, low absolute neutrophil count (ANC) or low platelet count (see SmPC for details). In patients not previously treated with RoActemra, initiation not recommended in patients with an ANC below 2 x 109/l. Closely monitor renal function in patients with moderate to severe renal impairment as RoActemra has not been studied in these patients. No data in patients with hepatic impairment. sJIA Patients: No data in patients < 2 years of age. Posology: In patients >2 years of age - 8mg/kg diluted to a final volume of 100ml for patients * 30kg or 12mg/kg diluted to a final volume of 50ml for patients < 30kg once every 2 weeks by iv infusion over 1 hour. Check patient’s weight at each visit – refer to SmPC. In the event of raised liver enzymes, low ANC or low platelet count, interrupt/discontinue RoActemra dose or modify/stop concomitant MTX and other medications where appropriate - see SmPC for details. Reduction of RoActemra dose due to laboratory abnormalities not studied in sJIA patients. Clinical improvement is generally seen within 6 weeks of starting RoActemra; reconsider continued therapy if no improvement is seen in this timeframe. pJIA Patients: No data in patients < 2 years of age. Posology: In patients >2 years of age - 8mg/kg diluted to a final volume of 100ml for patients * 30 kg or 10 mg/kg diluted to a final volume of 50ml for patients < 30kg once every 4 weeks by iv infusion over 1 hour. Check patient’s weight at each visit – refer to SmPC. In the event of raised liver enzymes, low ANC or low platelet count, interrupt/discontinue RoActemra dose or modify/stop concomitant MTX and other medications where appropriate - see SmPC for details. Reduction of RoActemra dose due to laboratory abnormalities not studied in pJIA patients. Clinical improvement is generally seen within 12 weeks of starting RoActemra; reconsider continued therapy if no improvement is seen in this timeframe. Contraindications: Hypersensitivity to any component of the product; active, severe infections. Warnings and Precautions: Serious (sometimes fatal) infections reported in patients receiving immunosuppressive agents including RoActemra. Do not initiate in patients with active infection. If serious infection develops interrupt therapy until infection controlled. Caution in patients with history of recurring/chronic infections, or other underlying conditions (e.g. diverticulitis, diabetes and interstitial lung disease) which may predispose patients to infection. Vigilance for the timely detection of serious infection recommended. Advise all patients and parents/guardians of sJIA and pJIA patients to contact their healthcare professional immediately when symptoms suggestive of an infection appear. Screen for latent TB prior to starting therapy. Treat latent TB with standard anti-mycobacterial therapy before initiating RoActemra. Risk of false negative tuberculin skin and interferon-gamma TB blood test results, especially in severely ill/immunocompromised patients. Advise patients to seek medical attention if sign/symptoms (e.g. persistent cough, wasting/weight loss, low grade fever) suggestive of TB infection occur during or after treatment with RoActemra. Viral reactivation (e.g. hepatitis B) reported with biologic therapies for RA. Patients screening positive for hepatitis excluded from clinical trials. Events of diverticular perforations as complications of diverticulitis reported uncommonly with RoActemra in RA patients. Exercise caution in patients with a history of intestinal ulceration or diverticulitis. Evaluate patients with symptoms of complicated diverticulitis promptly. Serious hypersensitivity reactions reported - may be more severe and potentially fatal in patients who have experienced hypersensitivity reactions during previous infusions 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 with RoActemra. If an anaphylactic reaction or other serious hypersensitivity/serious infusion related reaction occurs, stop administration of RoActemra immediately and discontinue therapy permanently. Use with caution in patients with active hepatic disease or hepatic impairment. Not recommended in patients with baseline ALT or AST > 5 x ULN; use with caution in patients with ALT or AST > 1.5 x ULN. Monitor ALT and AST levels for RA, sJIA and pJIA patients according to SmPC – other liver function tests including bilirubin should be considered where indicated. If raised, follow dosage recommendations in SmPC for RA, sJIA and pJIA patients. Risk of neutropenia may be increased in patients previously treated with a TNF antagonist. Continued therapy not recommended in patients who develop an ANC < 0.5 x 109/l or platelet count < 50 x 103/μl. In patients not previously treated with RoActemra, initiation not recommended 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. If reduced, follow dosage recommendations in SmPC for RA, sJIA and pJIA patients. Elevations in lipid parameters seen - refer to SmPC. Assess lipid parameters according to SmPC if elevated; manage patients according to local guidelines for hyperlipidaemia. Potential for central demyelination with RoActemra currently unknown; physicians should be vigilant for symptoms of new onset disease. Immunomodulatory medicines may increase malignancy risk in RA patients. Do not give live and live attenuated vaccines concurrently with RoActemra as safety not established. In a randomized open-label study, adult RA patients treated with RoActemra and MTX were able to mount an effective response to the 23-valent pneumococcal polysaccharide and tetanus toxoid vaccines. – refer to SmPC for further details on immunisations. RA patients should have CV risk factors managed as part of usual standard of care. Not recommended for use with other biological agents. Macrophage activation syndrome (MAS) is a serious life-threatening disorder that may develop in sJIA patients – RoActemra has not been studied in patients during an active MAS episode. Advise patients experiencing dizziness not to drive or use machines until dizziness resolved. Product contains 26.55mg sodium per 1200mg. Drug Interactions: Interaction studies only performed in adults. In RA patients, levels of simvastatin (CYP3A4) were decreased by 57% one week following a single dose of tocilizumab to levels similar to or slightly higher than those observed in healthy subjects. Monitor patients taking medicines which are individually adjusted and metabolised via CYP450 3A4, 1A2 or 2C9 when starting or stopping RoActemra, as doses may need to be increased to maintain therapeutic effect. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy. Refer to SmPC for further details on the effects of RoActemra on cytochrome CYP450 and drug interactions generally. Fertility, Pregnancy and Lactation: Women of childbearing potential should use effective contraception during and up to 3 months after treatment. No adequate data from use in pregnant women. Animal study showed an 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). Side Effects and Adverse Reactions: RA: Most commonly reported ADRs (occurring in >5% patients treated with tocilizumab monotherapy or with DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALTs. ADRs occurring in patients with RA receiving tocilizumab as monotherapy or in combination with MTX or other DMARDs in the clinical trial doubleblind controlled periods: Very Common (* 1/10): upper respiratory tract infections and 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. sJIA: In general, the ADRs were similar to those seen in RA patients. Infections – Serious infections of varicella and otitis media reported, in addition to infections for RA. Infusion reactions – Hypersensitivity reactions requiring treatment discontinuation occurred in < 1% of patients. Other events occurring within 24 hours of infusion in 16% of patients included, but were not limited to rash, urticaria (considered serious), diarrhoea, epigastric discomfort, arthralgia and headache. IgG – decreased levels during therapy. Other – decreases in neutrophil and platelet counts, hepatic transaminase elevations, lipid parameter increases and anti-tocilizumab antibodies observed. Serious or Potentially Serious: serious infections, active tuberculosis, invasive pulmonary infections, interstitial lung disease (including pneumonitis and pulmonary fibrosis), gastrointestinal perforations (as complications of diverticulitis), serious hypersensitivity reactions. pJIA: In general, the ADRs were similar to those seen in RA and sJIA patients. Nasopharyngitis, headache, nausea, and decreased neutrophil count were more frequently reported in the pJIA population and increased cholesterol was less frequently reported in pJIA than RA. Infections – The incidence of infections leading to dose interruptions was numerically higher in patients weighing <30 kg, the rate of serious infections was also higher in these patients. Infusion reactions – 20.2% experienced an event within 24 hours of infusion. No clinically significant hypersensitivity reactions associated with tocilizumab and requiring treatment discontinuation were reported. Refer to SmPC for a complete listing of adverse events for RA, sJIA and pJIA. See SmPC section 4.8 for instructions on the reporting of Suspected Adverse Reactions. Legal Category: Product subject to medical prescription which may not be renewed (A). Presentations and 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). 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: March 2014. Copyright © 2014 by Roche Products (Ireland) Ltd. All rights reserved. References: 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. 2. SmPC. RoACTEMRA (tocilizumab) Summary of Product Characteristics, 23 January 2014. Date of Item: September 2014. IE/RACTE/0814/0019.

RHEUMATOLOGY | RESEARCH

SHARED SYMPTOMS OF

CHIKUNGUNYA VIRUS

AND RHEUMATOID ARTHRITIS MAY CLOUD DIAGNOSIS A mosquito-borne virus that has spread to the Caribbean and Central and South America and has caused isolated infections in Florida often causes joint pain and swelling similar to that seen in patients with rheumatoid arthritis.

esearchers at Washington University School of Medicine in St. Louis, United States also found that blood tests of patients with the Chikungunya virus and those with rheumatoid arthritis can produce similar results. This may lead some patients with the virus to be misdiagnosed. The findings, reported in the January2015 issue of Arthritis and Rheumatology, underscore the need for doctors to obtain detailed travel and medical histories from patients being evaluated for rheumatoid arthritis. Such details could help distinguish between the two conditions. “For now, good travel histories of pa-

tients are among the best diagnostic tools for physicians,” said senior author Wayne Yokoyama, MD, the Sam and Audrey Loew Levin Professor of Medicine. “Recent travel to the Caribbean, Central and South America, Africa, India or other areas where the virus is prevalent should raise suspicions of Chikungunya infection. In addition, the disease typically starts with high fever and abrupt onset of severe pain in the joints, which are not usually seen with rheumatoid arthritis.” The global spread of the Chickungunya virus suggests that the disease is likely to be a diagnostic challenge in the years ahead. It is not yet know if rheumatoid arthritis treatment which suppresses the immune

THE CLINICAL CARE JOURNAL | 123

123_CLINICAL CARE_Research_Rheumatology1.indd 123

22/05/2015 15:24

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

For the short-term treatment of1

30-60mg once daily

Rheumatoid Arthritis

90mg

Acute Gouty Arthritis

once daily

Ankylosing Spondylitis

Postoperative Moderate Dental Surgery Pain

90mg

once daily, maximum 3 days.

120mg

once daily, maximum 8 days.

90mg once daily

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

Interactions: Effect of etoricoxib on other drugs: Lithium: NSAIDs decrease lithium renal excretion and therefore increase lithium plasma levels. If necessary monitor blood lithium closely and adjust lithium dosage. Methotrexate: Monitor for methotrexate-related toxicity when administered concomitantly. Oral contraceptives: Etoricoxib has shown to increase concentration of ethinyl estradiol when coadministered with oral contraceptives; this can increase the incidence of adverse events associated oral contraceptives. Hormone Replacement Therapy: Evidence of increases in estrogenic concentration in concomitant use; consider when selecting post-menopausal hormone therapy for use with etoricoxib. Prednisone/prednisolone: No clinically important effects. Digoxin: Monitor patients at high risk for digoxin toxicity when administered concomitantly due to possible increase of digoxin Cmax. Drugs metabolised by sulfotransferases: Etoricoxib inhibits human sulfotransferase. Care when concomitantly administering with other drugs primarily metabolised by human sulfotransferases (e.g. oral salbutamol, minoxidil). Drugs metabolised by CYP isoenzymes: Not expected to inhibit cytochrome P450 enzymes. Effect of other drugs on Etoricoxib: Etoricoxib is metabolised by CYP enzymes. Ketoconazole: 400mg o.d. for 11 days did not have clinically important effect on single dose PK of 60 mg etoricoxib. Voriconazole (oral) and Miconazole (oral gel): Co-administration of either with etoricoxib caused slight increased exposure of etoricoxib but not clinically significant. Rifampicin: Coadministration produced decrease in etoricoxib concentrations. Etoricoxib doses higher than those studied are not recommended. Antacids: Does not affect PK of etoricoxib. Pregnancy and lactation: Not recommended. If woman becomes pregnant during treatment, etoricoxib must be discontinued. Do not use during breast feeding. Not recommended when attempting to conceive. Driving and using machines: Patients who experience dizziness, vertigo or somnolence when on treatment should refrain from driving or operating machinery. Undesirable effects: Very common (≥1/10): Abdominal pain. Common (≥1/100, <1/10): Alveolar osteitis, oedema/fluid retention, dizziness, headache, palpitations, arrhythmia, hypertension, bronchospasm, constipation, flatulence, gastritis, heartburn/acid reflux, diarrhoea, dyspepsia/epigastric discomfort, nausea, vomiting, oesophagitis, oral ulcer, ALT increase, AST increased, ecchymosis, asthenia/fatigue, flu-like disease. Other important undesirable effects: Upper respiratory infection, leukopenia, hypersensitivity, atrial fibrillation, tachycardia, congestive heart failure, , angina pectoris, myocardial infarction, cerebrovascular accident, transient ischaemic attack, hypertensive crisis, vasculitis, gastroduodenal ulcer, peptic ulcers including gastrointestinal perforation and bleeding, pancreatitis, hepatitis, hepatic failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, angioedema/ anaphylactic/ anaphylactoid reactions including shock. Consult the SmPC for full details. Overdose: Remove unabsorbed material from GI tract, clinical monitoring, institute supportive therapy, if required. Not dialyzable by haemodialysis; not known whether dialyzable by peritoneal dialysis. Legal classification: POM. Marketing Authorisation numbers and pack sizes: Arcoxia 30 mg filmcoated tablets: PA1286/7/1 28 pack, 60 mg film-coated tablets: PA1286/7/2 28 pack, 90 mg film-coated tablets: PA1286/7/3 5 and 28 pack, 120 mg film-coated tablets: PA1286/7/4 7 and 28 pack. Marketing Authorisation Holder: Merck Sharp & Dohme Ireland (Human Health) Limited, Red Oak North, South County Business Park, Leopardstown, Dublin 18. Date of preparation: July 2014. IRE/A14 0004. Additional information is available on request. References: 1. Arcoxia SmPC, www.medicines.ie. a Doses greater than those recommended for each indication have either not demonstrated additional efficacy or have not been studied. Due to cardiovascular risks, the shortest duration possible and the lowest effective daily dose of ARCOXIA should be used. b The recommended dose for osteoarthritis is 30 mg once daily. An increased dose of 60 mg once daily may increase efficacy. The dose for osteoarthritis should not exceed 60 mg daily. Date of Preparation: November 2014 IRE/A14 0012a

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

RHEUMATOLOGY | RESEARCH

system, approach will help or harm patients with Chikungunya virus. The virus is spread by infected mosquitoes and was ﬁrst identiﬁed 60 years ago in eastern Africa. Since then, it has spread to many parts of the world. In 2014, more than 2,000 people in the United States developed the infection after travelling abroad, mostly to the Caribbean. That same year, the Centers for Disease Control and Prevention reported 11 cases of Chikungunya infection among people living in Florida who had not travelled outside the United States, suggesting that mosquitoes in that state were spreading the virus. In most patients, the infection causes a fever, rash and severe joint pain in the hands, feet, knees, neck and elbows. The fever and rash typically subside in seven to 10 days, but symptoms of arthritis may persist for 12-15 months in up to 60 per cent of patients. Some patients’ symptoms persist for up to three years. For the study, lead author Jonathan Miner, MD, PhD, a rheumatology fellow, studied 10 St. Louis-area residents who travelled in June 2014 to Haiti, where they were infected

The global spread of the Chickungunya virus suggests that the disease is likely to be a diagnostic challenge in the years ahead.

with Chikungunya virus. The patients were evaluated seven to 10 weeks after the onset of symptoms. During that time, eight patients developed persistent arthritis, several with joint pain so severe they had difﬁculty walking. “All eight patients with Chikungunya-related arthritis met the American College of Rheumatology’s criteria for a diagnosis of rheumatoid arthritis,” Miner said. “Their recent travel to Haiti led us to suspect they had Chikungunya virus infections.” As a comparison, the study also included healthy subjects and patients newly diagnosed with rheumatoid arthritis who had not yet received treatment. Laboratory tests that measured levels

of specialised immune cells in the blood showed additional similarities between Chikungunya virus infection and rheumatoid arthritis, including elevated levels of specialised T cells, which suggest, despite the persistence of symptoms, that the immune system has recognized and is ﬁghting the virus. These studies were performed on state-of-the-art instruments in the university’s newly established Center for Human Immunology and Immunotherapy Programs. To positively identify Chikungunya virus, the researchers performed highly specialised tests of the immune system, with results that showed antibodies against the Chikungunya virus in patients’ blood. Such testing is only available at the CDC and in research laboratories. According to Yokoyama, a Howard Hughes Medical Institute investigator, the similarities between Chikungunya virus infection and rheumatoid arthritis suggest that learning more about the virus may help scientists better understand

rheumatoid arthritis, which affects about one in every 100 people worldwide. Said co-author Deborah Lenschow, MD, PhD, associate professor of medicine and of pathology and immunology: “We’re anticipating that Chikungunya virus will spread broadly in the United States, so it’s important to develop better tools for diagnosis, prevention and treatment.” The researchers also have established a Chikungunya registry at chikv.dom. wustl.edu to build a database of cases for studying the virus in more detail.

This work was supported by The Foundation for Barnes-Jewish Hospital and the Howard Hughes Medical Institute. MINER JJ, AW-YEANG H-X, FOX JM, TAFFNER S, MALKOVA ON, OH ST, KIM AHJ, DIAMOND MS, LENSCHOW DJ, YOKOYAMA WM. Chikungunya viral arthritis in the United States: A mimic of seronegative rheumatoid arthritis. Arthritis & Rheumatology, DOI 10.1002/art.39027.

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Versatis® is indicated for the symptomatic relief of neuropathic pain associated with Post-Herpetic Neuralgia (PHN) in adults1

Versatis® provides: Proven efﬁcacy3,4,5 Superior tolerability1,3* Easy to use1,6

tis.ie

Abbreviated Prescribing Information for Versatis® 5% medicated plaster Refer to the Summary of Product Characteristics for full details before prescribing. Presentation: Versatis is a medicated plaster (10cm x 14cm) containing 700 mg (5% w/w) of lidocaine (50 mg per gram adhesive base). Indication: Symptomatic relief of neuropathic pain associated with previous herpes zoster infection (post-herpetic neuralgia, PHN) in adults. Dosage and method of administration: Adults and elderly patients: Cover the painful area with the plaster once daily for up to 12 hours within a 24 hour period, followed by at least a 12 hour plaster free interval. Not more than three plasters should be used at the same time. Plasters may be cut to size. Apply the plaster to intact, dry, non-irritated skin (after healing of the shingles). Remove hairs in affected area with scissors (do not shave). Remove the plaster from sachet and its surface liner before applying immediately to the skin. Re-evaluate treatment after 2 to 4 weeks. Reassess treatment regularly to adjust dosing or plaster-free period as required. Long-term use showed that the number of plasters used decreased over time. Renal/hepatic impairment: Use with caution in patients with severe impairment. Children below 18 years: Safety and efficacy not established. Contra-indications: Hypersensitivity to active substance, any excipients, or local anaesthetics of amide type (e.g. bupivacaine, etidocaine, mepivacaine and prilocaine). Do not apply to inflamed or injured skin (e.g. active herpes zoster lesions, atopic dermatitis or wounds). Special warnings and precautions: The plaster should not be applied to mucous membranes or the eyes. Plasters contain propylene glycol which may cause skin irritation, methyl parahydroxybenzoate and propyl parahydroxybenzoate which may cause allergic reactions. Use with caution in patients with severe cardiac impairment, severe renal impairment or severe hepatic impairment. In rats, metabolites of lidocaine have been shown to be genotoxic, carcinogenic and mutagenic, with unknown clinical significance. Consider long term treatment only if there is a therapeutic benefit for the patient. Interactions: No clinically relevant interactions have been observed in clinical studies. Absorption of lidocaine from the skin is low. Use with caution in patients receiving Class I antiarrhythmic drugs (e.g. tocainide, mexiletine) or other local anaesthetics due to the risk of additive systemic effects. Pregnancy and lactation: Not for use during pregnancy unless clearly necessary. Lidocaine is excreted in breast milk. No clinical data regarding fertility. Undesirable effects: Very common (*10%): administration site reactions (e.g. burning, dermatitis, erythema, pruritus, rash, skin irritation and vesicles). Uncommon (*0.1% to <1%): skin injury, skin lesion. Very rare (<0.01%): anaphylaxis, hypersensitivity, open wound. Systemic adverse reactions are unlikely. Overdose: Unlikely. If suspected, remove plasters, provide supportive treatment. Legal classification: POM. Marketing Authorisation number: PA 1189/009/001. Pack size: 30 plasters. Marketing Authorisation Holder: Grünenthal Ltd, Regus Lakeside House, 1 Furzeground Way, Stockley Park East, Uxbridge, Middlesex, UB11 1BD, UK. Additional information is available upon request. Date of preparation: July 2013. Reference: IRE/V13 0006. References: 1. Versatis® Summary of Product Characteristics. 2. Binder A et al. Clin Drug Invest 2009; 29 (6); 393-408 3. Baron R et al. 5% lidocaine medicated plaster versus pregabalin in post-herpetic neuralgia and diabetic polyneuropathy: an open-label, non-inferiority two-stage RCT study. Curr Med Res Opin. 2009; 25(7):1663-76. 4. Rehm S et al. Post-herpetic neuralgia: 5% lidocaine medicated plaster, pregabalin, or combination of both? A randomised, open, clinical effectiveness study. Curr Med Res Opin. 2010; 26:1607-19. 5. Sabatowski R et al. Safety and Efficacy Outcomes of Long-Term Treatment up to 4 Years with 5% Lidocaine Medicated Plaster in Patients with Post-Herpetic Neuralgia. Curr Med Res Opin. 2012;28:1-10. 6. Davies PS, Galer BS. Review of lidocaine patch 5% studies in the treatment of postherpetic neuralgia. Drugs 2004;64:937–47. *(compared to Pregabalin). Date of preparation: November 2014. IRE/V14 0013.

RHEUMATOLOGY | RESEARCH

MODIFIABLE RISK FACTORS FOR

POOR RA OUTCOMES A study by Hospital for Special Surgery (HSS) researchers ﬁnds that body mass index (BMI) plays a role in rheumatoid arthritis (RA) patients’ ability to achieve a sustained remission. Looking at patients who had received an RA diagnosis within the past 12 months, investigators found that those who were signiﬁcantly underweight or overweight/obese were the least likely to remain in remission.

he study, titled, “Very Low or High Body Mass Index Negatively Affects Patients’ Ability to Achieve Sustained Remission in Early RA in a Multicenter Canadian Cohort,” was presented at the American College of Rheumatology annual meeting on November 16, 2014, in Boston. Researchers set out to determine if early RA patients with a very low BMI (<18.5) or high BMI (> 25) were able to achieve a sustained remission. Patients were grouped by BMI categories and symptoms were measured prospectively over three years in patients participating in the CATCH (Canadian Early Arthritis Cohort) study using the Disease Activity Score for RA (DAS28). The DAS28, which measures the number of swollen and tender joints, as well as inflammation markers in the blood and the patients’ own assessment of their disease, is used to determine the severity of RA and can indicate if a patient is in remission. In the study, sustained remission was defined as having low disease activity at two consecutive doctor visits three to six months apart. A total of 944 patients were categorised into six groups based on World Health Organization BMI classifications. Researchers analysed data for eligible patients with a measured BMI and at least two consecutively measured DAS28 scores over three years. Only two per cent of patients were underweight and 65 per cent were either

The other area which we have been successful in getting over the line is the web-based hightech prescription authorisation form.

overweight or obese. Patients with a higher BMI were older, more often female and had worse function. Those with a very low or high BMI had more inflammation, and those with a low or normal BMI were more often smokers. “What’s striking is that if you look at the BMI classifications, all the patients in the underweight or overweight categories were much less likely to achieve sustained remission compared to those with a normal BMI,” said Susan Goodman, M.D., a rheumatologist at HSS. “Patients who were severely obese had an even lower chance of achieving sustained remission. Individuals in the highest BMI categories also had more inflammation and more pain.” When looking at other contributing factors, the researchers found that early use of methotrexate, non smoker status and responding to treatment within the first six months increased

the chances of achieving a sustained remission, independent of BMI. “It is important to identify possible factors we can modify to help patients with this disease,” said Vivian Bykerk, M.D., principal investigator and director of the Inflammatory Arthritis Center at HSS. “We also saw that those who smoked were less able to achieve sustained remission.” “Our findings represent the first study to present evidence that BMI should be considered among the modifiable risk factors for poor RA outcomes,” said Dr. Goodman. “There are many things patients can do to manage the disease. Along with timely diagnosis and treatment, weight control and other good practices can result in better outcomes.” Dr. Bykerk and her team at Hospital for Special Surgery have initiated an American Early Arthritis Cohort (CATCHU.S.) study and have begun to enroll patients. The study will be expanded to include a multicenter cohort at eight additional U.S. sites to expand this collaboration. The centers will enroll patients with early inflammatory arthritis thought to be RA to compile information on outcomes and determine best practices.

Founded in 1863, Hospital for Special Surgery (HSS) is a world leader in orthopedics, rheumatology and rehabilitation. It is located in New York City and online at www.hss.edu - American College of Rheumatology Annual Meeting.

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monthly

Help put everyday life back in their hands Efficacy still going strong five years on

The GO studies Five-year data confirm good persistence, sustained efficacy and predictable tolerability with Simponi in RA, AS and PsA1-4

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 (all TNF-blocking agents including Simponi) and Merkel cell carcinoma (other TNF-blocking agents) 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) and discontinued in the event of worsening symptoms of heart failure. 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, leucopaenia, neutropaenia, aplastic anaemia, and thrombocytopaenia in patients receiving TNF-blockers. Cytopaenias 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: 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. 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, viral infections, bronchitis, sinusitis, superficial fungal infections, anaemia, allergic reactions, autoantibody positive, dizziness, headache, hypertension, dyspepsia, gastrointestinal and abdominal pain, nausea, alanine aminotransferase increased, aspartate aminotransferase increased, pruritus, rash, pyrexia, asthenia and injection site reaction, were reported. Serious, including fatal adverse events have been reported including septic shock, lymphoma, leukaemia, melanoma, Merkel cell carcinoma*, hepatosplenic T-cell lymphoma*, leucopaenia, 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, but not observed in clinical studies with golimumab Package quantities: 1 50 mg pre-filled pen containing 50 mg of golimumab in 0.5 ml solution for injection or 1 50 mg pre-filled syringe containing 50 mg of golimumab in 0.5 ml solution for injection or 1 100 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 © Merck Sharp & Dohme Ireland (Human Health) Limited, 2013. All rights reserved. Date of Revision of Text: October 2013. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin 18 or from www.medicines.ie. Date of preparation: December 2013. References: 1. Keystone E et al. Presented at EULAR 2013 Congress, Madrid, Spain, June 12-15, 2013. Abstract AB0267. 2. Han C et al. Presented at EULAR 2013 Congress, Madrid, Spain, June 12-15, 2013. Abstract THU0513. 3. Kavanaugh A et al. Presented at EULAR 2013 Congress, Madrid, Spain, June 12-15, 2013. Abstract AT0270. 4. Deodhar A et al. Presented at EULAR 2013 Congress, Madrid, Spain, June 12-15, 2013. Abstract THU0352.

Red Oak North, South County Business Park, Leopardstown, Dublin 18, Ireland

RHEU-1105420-0000

Simponi 50 mg, 100 mg Solution for Injection in pre-filled pen Simponi 50 mg Solution for Injection in pre-filled syringe (golimumab) Prescribing Information [Refer to full SPC text before prescribing Simponi (golimumab)] 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 treatment of severe, active AS in adults who have responded inadequately to conventional therapy. 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. 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 or UC. 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: 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). 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) and patients with renal and hepatic impairment: Simponi is not recommended in these populations. 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. 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 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

RHEUMATOLOGY | RESEARCH

DOES A

WINDOW OF OPPORTUNITY EXIST WHEN

RHEUMATOID ARTHRITIS IS MORE SUSCEPTIBLE TO TREATMENT?

The association between symptom duration and Rheumatoid Arthritis persistence is not linear, suggesting the presence of a conﬁned period in which RA is more susceptible to treatment, according to the results of a study on the Leiden Early Arthritis Clinic and ESPOIR cohorts.

rolonged symptom or disease duration at treatment initiation is associated with unfavourable outcomes in rheumatoid arthritis (RA). It is unknown whether this relation is linear, referring to a common ‘theearlier-the-better principle’, or whether a transient time frame in which the disease

is more susceptible to treatment exists, referring to a ‘window of opportunity.’ To elucidate this, the study evaluated the shape of the associations of symptom duration with persistence of RA. During the last two decades, many studies have observed that the time to intervention is associated with the efﬁcacy of this intervention. The

concept of this window was first hypothesised in the early 1990s “The duration of the window is unknown. In 1991, the window was supposed to endure two years and at present it is considered to be the first three months. However, these suggestions are based on expert opinion rather than on scientific data. Although the cut-off

THE CLINICAL CARE JOURNAL | 129

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* in combination with methotrexate ORENCIAÂŽ (abatacept) PRESCRIBING INFORMATION. See Summary of Product Characteristics before prescribing. PRESENTATION: 250 mg powder for concentrate for solution for IV infusion containing 250 mg abatacept per vial. Each ml contains 25 mg of abatacept, after reconstitution; 125 mg pre-ďŹ lled syringe for SC injection. Each pre-ďŹ lled syringe contains 125 mg of abatacept in 1 ml. INDICATION: Rheumatoid arthritis (IV infusion and SC pre-ďŹ lled syringe): Treatment of moderate to severe active rheumatoid arthritis (RA), in combination with methotrexate, in adult patients who have responded inadequately to previous therapy with one or more disease-modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX) or a Tumour Necrosis Factor (TNF) -alpha inhibitor. A reduction in the progression of joint damage and improvement of physical function have been demonstrated during combination treatment with abatacept and methotrexate. See SmPC. Polyarticular Juvenile Idiopathic Arthritis (pJIA) {IV infusion only}: Orencia 250 mg powder for concentrate for solution for infusion is indicated for treatment of moderate to severe active pJIA in paediatric patients 6 years of age and older who have had an insufďŹ cient response to other DMARDs including at least one TNF inhibitor. DOSAGE and ADMINISTRATION: Treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of RA. Orencia 250 mg powder for concentrate for solution for IV infusion Adults and elderly: Patients weighing < 60 kg: 500 mg (2 vials). Patients weighing â&#x2030;Ľ 60 kg to â&#x2030;¤ 100 kg: 750 mg (3 vials). Patients weighing > 100 kg: 1000 mg (4 vials). Treatment of pJIA: Paediatric patients, 6 to 17 years of age, weighing less than 75 kg: 10 mg/kg. Paediatric patients weighing 75 kg or more: to be administered adult dosage, not exceeding a maximum dose of 1,000 mg. See SmPC for details of reconstitution and administration as a 30 minute IV infusion. After initial administration, Orencia should be given at 2 and 4 weeks, then every 4 weeks thereafter. Children: Use in children below 6 years of age is not recommended. Orencia 125 mg solution for injection (SC pre-ďŹ lled syringe) Adults and elderly: Orencia SC may be initiated with or without an intravenous (IV) loading dose. Orencia SC should be administered weekly at a dose of 125 mg by subcutaneous injection regardless of weight. If a single IV infusion is given to initiate treatment (IV loading dose before SC administration), the ďŹ rst 125 mg abatacept SC should be administered within a day of the IV infusion, followed by the weekly 125 mg abatacept SC injections.Patients transitioning from Orencia IV therapy to SC administration should administer the ďŹ rst subcutaneous dose instead of the next scheduled intravenous dose. Children: Administration in children below 18 years of age is not recommended. The continuation of treatment with abatacept should be re-assessed if patients do not respond within 6 months. CONTRAINDICATIONS: Hypersensitivity to the active substance or excipients. Severe and uncontrolled infections such as sepsis and opportunistic infections. WARNINGS AND PRECAUTIONS: Allergic Reactions: Caution in patients with a history of allergic reactions. Anaphylaxis or anaphylactoid reactions can occur after the ďŹ rst infusion and can be life threatening. Orencia IV or SC should be discontinued permanently if a patient develops serious allergic or anaphylactic reaction. Infections: Caution should be exercised when considering the use in patients with a history of frequent infections, or underlying conditions which may predispose to infection. Treatment with Orencia should not be initiated with patients with active infections until infections are controlled. Screening for tuberculosis and hepatitis B should be performed prior to therapy. Any patient who develops a new infection should be closely monitored and Orencia should be discontinued if a patient develops a serious infection. Monitor patients for signs of infection when transitioning from TNF-antagonist to Orencia. Co-administration of Orencia with biologic immunosuppressive or immunomodulatory agents could potentiate the effects of abatacept on the immune system. Treatment with immunosuppressive therapy may be associated with progressive multifocal leukoencephalopathy (PML). Orencia treatment should be discontinued if neurological symptoms suggestive of PML occur, and appropriate diagnostic measures initiated. Malignancies: The potential role of Orencia in the development of malignancies is unknown, see SmPC. Elderly: Caution should be used when treating elderly patients due to a higher incidence of infections and malignancies in this patient group. Autoimmune processes: Theoretical risk of deterioration in autoimmune disease. Immunisation: Live vaccines should not be given simultaneously or within 3 months of discontinuation of Orencia. See SmPC. DRUG INTERACTIONS: Concomitant therapy of Orencia with a TNF-inhibitor is not recommended. No major safety issues were identiďŹ ed with the use of Orencia in combination with sulfasalazine, hydroxychloroquin or leďŹ&#x201A;unomide. PREGNANCY AND LACTATION: Do not use in pregnancy unless clearly necessary. Women should use contraception and not breast-feed during treatment and for up to 14 weeks after last dose treatment. UNDESIRABLE EFFECTS: In adult placebo-controlled trials the following adverse drug reactions were reported. Very Common (â&#x2030;Ľ 1/10): upper respiratory tract infection including tracheitis, nasopharyngitis. Common (t 1/100 to < 1/10): Lower respiratory tract infection (including bronchitis), urinary tract infection, herpes infections (including herpes simplex, oral herpes and herpes zoster), rhinitis, pneumonia, inďŹ&#x201A;uenza, leukopenia, headache, dizziness, paraesthesia, conjunctivitis, hypertension, ďŹ&#x201A;ushing, blood pressure increased, cough, abdominal pain, diarrhoea, nausea, dyspepsia, mouth ulceration, aphthous stomatitis, vomiting, liver function test abnormal (including transaminases increased), rash (including dermatitis), alopecia, pruritus, pain in extremity, fatigue, asthenia, local injection site reactions*, systemic injection reactions* (e.g. pruritus, throat tightness, dyspnea) (*Orencia SC). Uncommon (â&#x2030;Ľ 1/1,000 to < 1/100): Tooth infection, onychomycosis, sepsis, musculoskeletal infections, skin abscess, pyelonephritis, pelvic inďŹ&#x201A;ammatory disease, basal cell and squamous cell carcinoma, skin papilloma, thrombocytopenia, hypersensitivity, depression, anxiety, sleep disorder (including insomnia), migraine, dry eye, visual acuity reduced, vertigo, palpitations, tachycardia, bradycardia, hypotension, hot ďŹ&#x201A;ush, vasculitis, blood pressure decreased, bronchospasm, wheezing, dyspnea, gastritis, increased tendency to bruise, dry skin, urticaria, psoriasis, erythema, hyperhidosis, arthralgia, amenorrhea, menorrhagia, inďŹ&#x201A;uenza like illness, weight increased. Rare (â&#x2030;Ľ 1/10,000 to < 1/1,000): Tuberculosis,bacteraemia, gastrointestinal infection, lymphoma, lung neoplasm malignant, throat tightness.See SmPC for further details. LEGAL CATEGORY: POM. MARKETING AUTHORISATION NUMBER : Orencia 250 mg concentrate for solution for infusion - EU/1/07/389/001, 1 vial pack; Orencia 125 mg solution for Injection- EU/1/07/389/008, 4 pre-ďŹ lled syringes with needle guard. MARKETING AUTHORISATION HOLDER: Bristol-Myers Squibb Pharma EEIG, Uxbridge Business Park, Sanderson Road, Uxbridge, Middlesex UB8 1DH, UK. FURTHER INFORMATION FROM: Bristol-Myers Squibb Pharmaceuticals, Watery Lane, Swords, Co. Dublin. Tel: 1-800-749-749 or medical.information@bms.com. DATE OF PREPARATION: September 2014. Job No: 427IE14PR06813-01

Reporting of suspect adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the beneďŹ t/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Freeport, HPRA Pharmacovigilance, Earlsfort Terrace, IRL- Dublin 2; Tel: +353 1 6764971; Fax: +353 1 676 25 17. Website: www.hpra.ie, medsafety@hpra.ie. Adverse reactions should also be reported to Bristol-Myers Squibb Medical Information on 1 800 749 749 or medical.information@bms.com. Reference: 1. Fleischmann R et al. ACR/ARHP Annual ScientiďŹ c Meeting, October 25-30, 2013, San Diego, California, Poster 424.

427IE14PR08634-01 Date of Approval: October 2014 IROC-143915- 01

RHEUMATOLOGY | RESEARCH

of three months or 12 weeks is often referred to, we did not ﬁnd literature with data supporting this time-point. Several studies compared patients with symptoms for < or >3 months, but a rationale for this categorisation was not provided and it is unknown whether results would have been even stronger when another cut-off was chosen,” wrote the authors. Patients with 1987 RA treated with disease modifying antirheumatic drugs (DMARDs) in the Leiden Early Arthritis Clinic (EAC, n=738) and Evaluation et Suivi de POlyarthrites Indifférenciées Récentes (ESPOIR) (n=533) were studied. Cox proportional hazards regression models using natural cubic splines were performed; the log-HR on DMARDfree sustained remission (the opposite of RA persistence) during 5-year follow-up was plotted against symptom duration. Discrimination was measured using time-dependent receiver operator characteristic curves. Subanalyses were performed stratiﬁed for the DMARDs used (methotrexate or other conventional DMARDs) and for anticitrullinated peptide antibody (ACPA). The results showed that 11.5% (85/738) and 5.4% (29/533) of EAC and ESPOIR RA patients achieved DMARD-free sustained remission. In both cohorts and all analyses, the curves depicting the log-HRs on remission in relation to symptom duration were not linear. The symptom dura-

This study is the first providing strongly suggestive evidence that a confined period in which RA is more susceptible to treatment exists.

tion with optimal discriminative ability was 14.9 weeks (95% CI 12.3 to 16.0; area under the curve (AUC) 0.61) in the EAC and 19.1 weeks (95% CI 12.3 to 28.0; AUC 0.59) in ESPOIR. For ACPA-positive RA, this was 11.4 weeks (95% CI 7.7 to 79.0; AUC 0.56) and for ACPA-negative RA 15.0 weeks (95% CI 9.7 to 48.7; AUC 0.56). “ In the present data, the steepness of the curve plotting the log-HR against symptom duration diminished around 15–20 weeks after symptom onset,” commented the researchers. It cannot be concluded that the window ‘is closed’ after this period, but the data of the present cohorts clearly showed that the hazard on remission was less after this period, and so possibly it ‘starts to close’ at this point in time. In other words, we do not suggest that DMARD treatment after a certain window is futile, but that initiating a DMARD in this particular window might yield a better outcome. In case a patient is identiﬁed after this period has passed, DMARD therapy should certainly

not be withheld,” wrote the researchers. “ This study is the ﬁrst providing strongly suggestive evidence that a conﬁned period in which RA is more susceptible to treatment exists. Further proof might be obtained by performing clinical trials in patients with symptoms of very recent onset randomising for direct or delayed treatment. However, given the present knowledge this may be considered unethical,” they concluded. The study was carried out by researchers at the Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands, the Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands, the Department of Rheumatology, Nîmes University Hospital, EA 2415, Montpellier I University, Nîmes, France and Université Pierre et Marie Curie Curie—Paris 6, GRC08, Institut Pierre Louis d’Epidémiologie et Santé Publiqu, Paris, France. - Ann Rheum Dis 2015;74:806-812 doi:10.1136/annrheumdis-2014-206047.

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STROKE

STROKE DEATHS IN IRELAND FALL New data has revealed that stroke deaths have declined by 7.5 per cent, with 450 fewer deaths in the ﬁrst three years of the HSE National Clinical Programme for Stroke, according to Prof Peter Kelly, Joint Clinical Lead of the programme and Consultant Neurologist at the Mater Hospital, Dublin. Maureen Browne reports.

here has been a 7.5 per cent reduction in deaths from stroke in Ireland in the ﬁrst three years of the HSE National Clinical Programme for Stroke, according to Prof Peter Kelly, Joint Clinical Lead of the Programme and Consultant Neurologist at the Mater Hospital, Dublin. “Overall, we estimate that there are approximately 450 fewer deaths in the three-year period. There has also been a reduction of 7.5 per cent in nursing home discharges for stroke in 2013 compared to 2009. That is 200 nursing home discharges saved in 2013,” says Prof Kelly. The average length of stay for stroke

132 | THE CLINICAL CARE JOURNAL

has dropped by two days in acute hospitals. It dropped by one day in 2011 and by a second day in 2012. When the programme started in 2010 the median length of stay was 11 days. It dropped by one day in 2012 and by an additional day in 2013 and has remained at that in 2014, with a resultant saving of thousands of bed days. Prof Kelly said he wanted to emphasise that credit for all the work and the outputs, in terms of the clinical programme, should go to the clinicians on the ground and the management staff. “Our Project Manager Carmel Brennan, Una Cunningham, who has led on supported discharge, Dr Breda Smith,

who has been in charge of atrial ﬁbrillation screening and several others have done wonderful work. The percentage of stroke patients who made it into a stroke unit was less than 3 per cent in 2008 and it was up to 64 per cent in 2013, so the metrics are improving all the time. “According to the stroke register, the percentage of patients with ischaemic stroke who receive thrombolysis was hitting 11.3 per cent in 2013 – the second highest rate in the developed world, exceeded only by the UK. A paper presented at the 2014 Stroke Conference showed that the national rate in the US was ﬁve per cent, so we are more than double that.”

STROKE

COLLECTING DATA Statistics are coming from HIPE and the National Stroke Register, which was set up in 2011 and are considered the foundation stone data sets of the programme. It provides data from 28 hospitals, and according to Prof Kelly is being used increasingly in 25 of the 28 hospitals. “Prof Emer Shelly is now chair of the Stroke Register Group and she and the Project Manager, Paul Marsden, are running it wisely and effectively. In 2013 there were almost 4,000 patients entered on the stroke register by clinical staff around the country. The register is a real success story. There is still more work to be done as we are not getting all the patients, but considering we had no register and zero patients in 2010 and we now have 4,000, it should be sustainable. I think it is excellent progress. “A signiﬁcant amount of work has also been done on governance of the programme. The two highlights of the last year were renewed membership of our clinical advisory group, and very strong governance arrangements for the programme have been developed within the acute hospital sector of the HSE. “The programme hopes to repeat the stroke audit in 2015 as it will enable a greater understanding of the strengths and contributions which have underpinned that progress while recognising the residual areas which will require further work. “In order to do this, we need to conduct a very detailed audit of hospital stroke services around the country. This is being done in partnership between the National Clinical Programme, the Irish Heart Foundation, the HSE and the Department of Health. A project manager and a research fellow have been appointed to carry out the work and we have been setting up the arrangements for the steering group. We have developed an audit tool based on the UK audit tools for sentential audit, so we will have comparable data with the UK.

The aim is to discharge patients from hospital early to targeted rehabilitation programmes delivered in their home environment.

There has also been a reduction of 7.5 per cent in nursing home discharges for stroke in 2013 compared to 2009. That is 200 nursing home discharges saved in 2013.

Our goal is to measure, in particular, the structures for the organisation, but also the journey of the individual patient. We will take samples from individual hospitals so that we can validate the data from the stroke register,” he says.

OTHER PROJECTS “Telemedicine, which has been developed for a couple of years and is operating between the Mater, Cavan and St. James’s, is a national initiative and a roll-out schedule is underway in several other hospitals in Ireland East and the West/North West Hospital Groups. I expect the next phase of the roll-out to be operational early in 2015. It was always envisaged that it would have other uses and we might use it for intensive care to link up ICUs and also for neurology and possibly rheumatology. “Other projects which were very active in 2014 were the atrial ﬁbrillation project and supporting early discharge. Prof Joe Harbison, the joint National Clinical Lead, and Dr Breda Smith, who is a public health doctor, based in Galway, are leading the trial atrial ﬁbrillation initiative. This project involves a partnership approach with GPs in the west of Ireland to screen

patients for undetected atrial ﬁbrillation and therefore for stroke prevention. This has resulted in thousands of patients being very successfully screened. “The pilot programme on early supported discharge has also been very successful. This was started initially in north Dublin city and has been further rolled out to Tallaght and Galway. The aim is to discharge patients from hospital early to targeted rehabilitation programmes delivered in their home environment. It was estimated from the ﬁrst year of data from the north Dublin programme that this initiative contributed to, and was associated with, about a 25-30 per cent reduction in the length of stay of patients. The programme is looking forward to the year ahead where it can continue to contribute to the healthcare system and continue to improve services for patients,” Prof Kelly concludes.

PROF PETER KELLY is Joint Clinical Lead of the programme and Consultant Neurologist at the Mater Hospital, Dublin. For more information on the work of the programme visit www.hse.ie/strokeprogramme

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Prescribing Information (SPAF and DVT/PE- Ireland) PRADAXA® (dabigatran etexilate) Capsules containing 110 mg or 150 mg dabigatran etexilate (as mesilate) Action: Direct thrombin inhibitor Indications: Prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation with one or more risk factors (SPAF), such as prior stroke, or transient ischaemic attack; Age ≥ 75 years; heart failure (NYHA Class ≥II); diabetes mellitus; hypertension. Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults (DVT/PE). Dose and Administration: Renal function should be assessed by calculating CrCL prior to initiation to exclude patients with severe renal impairment (CrCL < 30 mL/min). SPAF: Recommended daily dose 300 mg taken as one 150 mg capsule twice daily. Therapy should be continued long term. DVT/PE: Recommended daily dose 300 mg taken as one 150 mg capsule twice daily following treatment with parenteral anticoagulant for at least 5 days. Duration of treatment should be individualised after careful assessment of the treatment benefit against risk for bleeding. Short duration of therapy (at least three months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation) and longer durations should be based on permanent risk factors or idiopathic DVT or PE. In case of intolerability to dabigatran, patients should be instructed to immediately consult their doctor. For patients aged 80 years or above, or those receiving concomitant verapamil, the recommended daily dose is Pradaxa 220 mg taken as 110 mg twice daily. Pradaxa and verapamil should be taken at the same time. For the following patient groups, the daily dose of 300 mg or 220 mg should be selected based on an individual assessment of the thromboembolic risk and risk of bleeding: aged 75 – 80 years; with moderate renal impairment (CrCL 30-50 mL/min); with gastritis, oesophagitis or gastroesophageal reflux; other risk of increased bleeding. Close clinical surveillance is recommended in patients with renal impairment. Use is contraindicated in patients with severe renal impairment (CrCL < 30 mL/min). In all patients assess renal function by calculating CrCL prior to initiation to exclude patients with severe renal impairment. Renal function should also be assessed when a decline in renal function is suspected. Additionally in patients > 75 years or with mild to moderate renal impairment, renal function should also be assessed at least once a year or more frequently as needed in certain clinical situations when it is suspected that the renal function could decline or deteriorate. Patients with an increased risk of bleeding: closely monitor clinically looking for signs of bleeding or anaemia. A coagulation test may help identify increased risk patients. No dose adjustment required but close clinical surveillance in patients < 50 kg. Not recommended if liver enzymes > 2 Upper Limit of Normal (ULN). If switching from Pradaxa to parenteral anticoagulant wait 12 hours after the last dose of Pradaxa; if switching from parenteral anticoagulant to Pradaxa discontinue the parenteral anticoagulant and start Pradaxa 0-2 hours prior to the time that the next dose of the alternate therapy would be due, or at the time of discontinuation in case of continuous treatment; if switching from Pradaxa to VKA adjust the starting time of the VKA based on CrCL; if switching from VKA to Pradaxa stop VKA and give Pradaxa once INR <2.0. Cardioversion patients can stay on Pradaxa whilst being cardioverted. No relevant use of Pradaxa in the paediatric population in the SPAF indication. In DVT/PE indication safety and efficacy of Pradaxa in ages less than 18 years have not been established. Pradaxa can be taken with or without food. Pradaxa should be swallowed as a whole with a glass of water, to facilitate delivery to the stomach. Patients should be instructed not to open the capsule as this may increase the risk of bleeding. Contraindications: Hypersensitivity to any component; severe renal impairment (CrCL < 30 mL/min); active clinically significant bleeding; lesion or condition, if considered a significant risk factor for major bleeding. This may include current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent intracranial haemorrhage, known or suspected oesophageal varices, arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities; concomitant treatment with any other anticoagulants e.g. unfractionated heparin (UFH), low molecular weight heparins (enoxaparin, dalteparin etc), heparin derivatives (fondaparinux etc), oral anticoagulants (warfarin, rivaroxaban, apixaban etc) except under specific circumstances of switching anticoagulant therapy or when UFH is given at doses necessary to maintain an open central venous or arterial catheter; hepatic impairment or liver disease expected to have any impact on survival; concomitant systemic ketoconazole, cyclosporine, itraconazole, dronedarone; prosthetic heart valves requiring anticoagulant treatment. Warnings and Precautions: Not recommended if liver enzymes > 2 ULN. Haemorrhagic risk: Close clinical surveillance (signs of bleeding or anaemia) is recommended throughout the treatment period, especially when haemorrhagic risk is increased or risk factors combined. Factors which may increase haemorrhagic risk: age ≥ 75 years; moderate renal impairment (CrCL 30 – 50 mL/min); P-glycoprotein inhibitor co-medication; body weight < 50 kg; acetylsalicylic acid (aspirin); NSAID; clopidogrel; selective serotonin re-uptake inhibitors (SSRIs) or selective serotonin norepinephrine re-uptake inhibitors (SNRIs); other drugs which may impair haemostasis; diseases/procedures associated with a risk of bleeding such as coagulation disorders, thrombocytopenia or functional platelet defects, recent biopsy, major trauma, bacterial endocarditis, oesophagitis, gastritis or gastroesophageal reflux. Concomitant use of ticagrelor. The measurement of dabigatran related anticoagulation may be helpful to avoid excessive high exposure to dabigatran in the presence of additional risk factors. Patients who develop acute renal failure must discontinue Pradaxa. If severe bleeding occurs, discontinue treatment and investigate the source of the bleeding. Avoid or use with caution medicinal products which may increase the risk of haemorrhage. The use of fibrinolytic medicinal products for the treatment of acute ischaemic stroke may be considered if the patient presents with a dTT, ECT or aPTT not exceeding the ULN according to the local reference range. Avoid concomitant administration with P-gp inducers. Patients on dabigatran etexilate who undergo surgery or invasive procedures are at increased risk for bleeding therefore surgical interventions may require the temporary discontinuation of dabigatran etexilate; prescribers should consult the Summary of Product Characteristics for further information. Procedures such as spinal anaesthesia may require complete haemostatic function. The risk of spinal or epidural haematoma may be increased in cases of traumatic or repeated puncture and by the prolonged use of epidural catheters. After removal of a catheter, an interval of at least 2 hours should elapse before the administration of the first dose of dabigatran etexilate; these patients require frequent observation for neurological signs and symptoms of spinal or epidural haematoma. Treat with caution patients at high surgical mortality risk and with intrinsic risk factors for thromboembolic events. Myocardial infarction. Efficacy and safety have not been established for DVT/PE patients with active cancer. Contains Sunset Yellow (E110) which may cause allergic reactions. Interactions: Anticoagulants and antiplatelet aggregation medicinal products; P-gp inhibitors e.g. amiodarone, quinidine, verapamil, clarithromycin, ticagrelor co-administration (close clinical surveillance); verapamil co-administration - reduce Pradaxa dose to 220 mg (see above) close clinical monitoring is recommended; caution when co-administered with posaconazole; not recommended for concomitant treatment tacrolimus, protease inhibitors including ritonavir and its combinations with other protease inhibitors; avoid with P-gp inducers e.g. rifampicin, St John’s wort, carbamazepine, phenytoin; SSRIs or SNRIs. Dabigatran etexilate and dabigatran are not metabolised by cytochrome CYP450 system, therefore related medicinal product interactions not expected. Pantoprazole and other proton-pump inhibitors (PPI) were co-administered with Pradaxa in clinical trials and concomitant PPI treatment did not appear to reduce the efficacy of Pradaxa. Ranitidine administration together with Pradaxa had no clinically relevant effect on the extent of absorption of dabigatran. Fertility, pregnancy and lactation: Avoid pregnancy during treatment. Do not use in pregnancy unless clearly necessary. Discontinue breast-feeding during treatment. Undesirable effects: Most commonly reported adverse reactions are bleedings occurring in total in approximately 16.5 % in patients with atrial fibrillation treated for the prevention of stroke and SEE and 14.4 % in patients treated for DVT/PE. Bleeding occurred in 19.4% of patients in DVT/PE prevention trial RE-MEDY and in 10.5% of patients in DVT/PE prevention trial RE-SONATE. Common (≥ 1/100 to <1/10): epistaxis; gastrointestinal haemorrhage; dyspepsia; skin haemorrhage; genitourological haemorrhage, including haematuria. Additional common adverse events seen with Stroke and SEE prevention in patients with atrial fibrillation: anaemia; abdominal pain; diarrhoea; nausea. Additional common adverse event seen in patients with DVT/PE treatment and DVT/PE prevention: rectal haemorrhage. Prescribers should consult the Summary of Product Characteristics for further information on side effects. Pack sizes: 110 mg 60 capsules 150 mg 10 and 60 capsules Legal category POM MA numbers: 110 mg EU/1/08/442/007 (60 capsules); 150 mg EU/1/08/442/009 (10 capsules), EU/1/08/442/011 (60 capsules) Marketing Authorisation Holder: Boehringer Ingelheim International GmbH, Binger Str. 173, 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 Hyde Building, The Park, Carrickmines, Dublin 18. Prepared in June 2014.

Pradaxa® is now also approved for the treatment and secondary prevention of DVT§ and PE†

References: 1. Boehringer Ingelheim. Pradaxa® 150mg hard capsules Summary of Product Characteristics. 2. Connolly S, Ezekowitz MD, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med 2009; 361:1139–1151. 3. Connolly S, Ezekowitz MD, et al. Newly identiﬁed events in the RE-LY trial. N Engl J Med 2010; 363:1875–1876. 4. Granger GB, Alexander JH, et al. Apixaban versus Warfarin in Patients with Atrial Fibrillation N Engl J Med 2011; 365:981–992. 5. Patel MR, Mahaffrey KW, et al. Supplementary appendix to Rivaroxaban versus warfarin in nonvalvular atrial ﬁbrillation. N Engl J Med 2011; 365:883–891. IRE/PRA-141827 Date of Preparation: September 2014

*NOAC - Novel Oral Anticoagulant ^RRR - Relative Risk Reduction § DVT - Deep Vein Thrombosis † PE - Pulmonary Embolism

25% RRR^ of ischaemic stroke with Pradaxa 150mg BID versus warfarin1

THE 2 FACES OF STROKE PRADAXA速 150mg BID IS THE ONLY NOAC* TO REDUCE ISCHAEMIC AND HAEMORRHAGIC STROKE Vs WARFARIN1-5

CLINICAL LEADS

CLINICAL

LEADS

The clinicians heading up the HSE Clinical Programmes are:

EFFECTIVENESS OF SERVICE

DR MARGO WRIGLEY

Dr Aine Carroll, the HSE’s National

National Clinical Lead HSE

Director of Clinical Strategy &

National Programme for

Programmes explains the restructuring

Mental Health

and realignment of clinical programmes.

DR AINE CARROLL HSE

PROF MICHAEL TURNER National Director HSE National

National Director Of Clinical

Programme for Obstetrics

Strategy & Programmes

and Gynaecology

PROF PAT MANNING National Clinical Lead HSE

PROF ALF NICHOLSON PROF JOHN MURPHY

National Asthma Programme

Joint National Clinical Leads

PICTURED: Dr Aine Carroll

HSE National Programme For

PROF KIERAN DALY

Paediatrics & Neonatology -

National Clinical Lead HSE National

Prof Nicholson (Paediatrics)

Acute Coronary Syndrome Programme

Prof Murphy (Neonatology)

DR JEROME KELLY

MR PAUL MORIARTY

Director HSE National Cancer

National Clinical Lead HSE

Care Programme

National Programme For Ophthalmology

PROF TIM MCDONNELL National Clinical Lead HSE

DR KAREN RYAN

National COPD Programme

National Clinical Lead HSE

PICTURED: DR KAREN RYAN

National Programme For

PROF CHARLES GALLAGHER

Palliative Care

National Clinical Lead HSE National Cystic Fibrosis Programme

VACANT National Director, HSE

DR ANN MARIE TOBIN

National Programme for

National Clinical Lead HSE National

Primary Care

Dermatology Programme

DR DIARMAID O’SHEA National Clinical Lead HSE National

DR JACINTA MORGAN

PICTURED: Prof Pat Manning

National Clinical Lead, HSE National Programme for Rehabilitation

Programme For Older People

DR FIDELMA FITZPATRICK National Clinical Lead HSE

PROF OLIVER FITZGERALD National Clinical Lead HSE National Programme On Rheumatology

National Programme For HAIs

DR LIAM PLANT

PROF PETER KELLY DR JOE HARBISON

National Clinical Director HSE

Joint National Clinical Leads

National Renal Ofﬁce

HSE Stroke Programme.

136 | THE CLINICAL CARE JOURNAL

PICTURED: DR DIARMAID O’SHEA

After more than 50 years of combined oral contraceptives…

Zoely—the pill made from an innovative combination of hormones is here.1,2 ®

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 of the SPC for how to report adverse reactions. Abbreviated Prescribing Information (Refer to Summary of Product Characteristics before prescribing) Zoely 2.5 mg/1.5 mg filmcoated tablets nomegestrol acetate and estradiol. PRESENTATION: One blister containing 1 strip of 28 tablets (24 white filmcoated tablets, each tablet containing 2.5 milligram nomegestrol acetate and 1.5 milligram estradiol (as hemihydrate) and 4 yellow placebo film-coated tablets). Three blisters per pack. USES: Contraception. The decision to prescribe Zoely should take into consideration the individual woman’s current risk factors, particularly those for venous thromboembolism (VTE), and how the risk of VTE with Zoely compares with other CHCs. DOSAGE: One tablet daily at about the same time. There is no pill-free week between strips. CONTRAINDICATIONS: Presence or risk of venous thrombosis (deep venous thrombosis, pulmonary embolism), APCresistance (including Factor V Leiden), antithrombin-III-deficiency, protein C deficiency, protein S deficiency, major surgery with prolonged immobilisation, arterial thrombosis (e.g. myocardial infarction) or prodromal conditions (e.g. angina pectoris), cerebrovascular disease (e.g. transient ischaemic attack, TIA), hyperhomocysteinaemia, antiphospholipid-antibodies (anticardiolipin-antibodies, lupus anticoagulant), history of migraine with focal neurological symptoms, diabetes mellitus with vascular symptoms, severe hypertension, sever dyslipoproteinaemia, pancreatitis associated with severe hypertriglyceridaemia, severe hepatic disease with current abnormal liver function tests, liver tumor, known or suspected sex-steroid sensitive malignancies, undiagnosed vaginal bleeding, hypersensitivity to any ingredients. PRECAUTIONS AND WARNINGS: All data below are based upon epidemiological data obtained with CHCs containing ethinylestradiol. Zoely contains 17β-estradiol. As no epidemiological data are yet available with estradiol containing-CHCs, the warnings are considered applicable to the use of Zoely. The use of any combined hormonal contraceptive (CHC) increases the risk of venous thromboembolism (VTE) compared with no use. Products that contain levonorgestrel, norgestimate or norethisterone are associated with the lowest risk of VTE. It is not yet known how the risk with Zoely compares with these lower risk products. The decision to use any product other than one known to have the lowest VTE risk should be taken only after a discussion with the woman to ensure she understands the risk of VTE with CHCs, how her current risk factors influence this risk, and that her VTE risk is highest in the first ever year of use. There is also some evidence that the risk is increased when a CHC is re-started after a break in use of 4 weeks or more. In women who do not use a CHC and are not pregnant about 2 out of 10,000 will develop a VTE over the period of one year. However, in any individual woman, the risk may be far higher, depending on her underlying risk factors (see below). Epidemiological studies in women who use low dose (<50 μg ethinylestradiol) combined hormonal contraceptives have found that out of 10,000 women between 6 and 12 will develop a VTE in one year. It is estimated that out of 10,000 women who use a levonorgestrel-containing CHC about 61 will develop a VTE in one year. It is not yet known how the risk of VTE with CHCs that contain nomegestrol acetate in combination with estradiol compares with the risk with low dose levonorgestrel-containing CHCs. The number of VTEs per year with low dose CHCs is fewer than the number expected in women during pregnancy or in the postpartum period. VTE may be fatal in 1-2 % of cases. Extremely rarely, thrombosis has been reported to occur in CHC users in other blood vessels, e.g. hepatic, mesenteric, renal, retinal veins and arteries. Discontinue in the event of a thrombosis. Risk factors for VTE The risk for venous thromboembolic complications in CHC users increases with obesity, positive family history, other medical conditions associated with VTE (cancer, systemic lupus erythematosus, haemolytic uraemic syndrome, chronic inflammatory bowel disease ((Crohn’s disease or ulcerativce colitis)) sickle cell disease) and increasing age (particularly above 35 years of age). Also prolonged immobilisation, major surgery, any surgery to the legs or pelvis, or major trauma where discontinuation is advisable. There is no consensus about the possible role of varicose veins and superficial thrombophlebitis in the onset or progression of venous thrombosis. The increased risk of thromboembolism in pregnancy, and particularly the 6-week period of the puerperium, must be considered. Symptoms of VTE (deep vein thrombosis and pulmonary embolism) In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC. Symptoms of deep vein thrombosis (DVT) can include: - unilateral swelling of the leg and/or foot or along a vein in the leg; - pain or tenderness in the leg which may be felt only when standing or walking; - increased warmth in the affected leg; red or discoloured skin on the leg. Symptoms of pulmonary embolism (PE) can include: - sudden onset of unexplained shortness of breath or rapid breathing; sudden coughing which may be associated with haemoptysis; - sharp chest pain; - severe light headedness or dizziness; - rapid or irregular heartbeat. Some of these symptoms (e.g. “shortness of breath”, “coughing”) are non-specific and might be misinterpreted as more common or less severe events (e.g. respiratory tract infections). Other signs of vascular occlusion can include: sudden pain, swelling and slight blue discoloration of an extremity. If the occlusion occurs in the eye symptoms can range from painless blurring of vision which can progress to loss of vision. Sometimes loss of vision can occur almost immediately. Risk of arterial thromboembolism (ATE) Epidemiological studies have associated the use of CHCs with an increased risk for arterial thromboembolism (myocardial infarction) or for cerebrovascular accident (e.g., transient ischaemic attack, stroke). Arterial thromboembolic events may be fatal. Risk factors for ATE The risk of arterial thromboembolic complications or of a cerebrovascular accident in CHC users increases with increasing age, smoking, hypertension, obesity, positive family history, migraine. Other medical conditions associated with adverse vascular events, include diabetes mellitus, hyperhomocysteinaemia,

valvular heart disease, atrial fibrillation, dyslipoproteinaemia and systemic lupus erythematosus. Symptoms of ATE In the event of symptoms women should be advised to seek urgent medical attention and to inform the healthcare professional that she is taking a CHC. Symptoms of a cerebrovascular accident can include: - sudden numbness or weakness of the face, arm or leg, especially on one side of the body; - sudden trouble walking, dizziness, loss of balance or coordination; - sudden confusion, trouble speaking or understanding; - sudden trouble seeing in one or both eyes; - sudden, severe or prolonged headache with no known cause; loss of consciousness or fainting with or without seizure. Temporary symptoms suggest the event is a transient ischaemic attack (TIA). Symptoms of a myocardial infarction (MI) can include: - pain, discomfort, pressure, heaviness, sensation of squeezing or fullness in the chest, arm, or below the breastbone; - discomfort radiating to the back, jaw, throat, arm, stomach; - feeling of being full, having indigestion or choking; - sweating, nausea, vomiting or dizziness; - extreme weakness, anxiety, or shortness of breath; - rapid or irregular heartbeats. Consider stopping if there is an increase in frequency or severity of migraine. An increased risk of cervical cancer in long-term users of COCs has been reported however, the risk in users of Zoely is not available. Epidemiological studies reported that there is a slightly increased risk of having breast cancer diagnosed. Women with hypertriglyceridaemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs. If a sustained clinically significant hypertension develops suspend use. The following conditions have been reported to occur or deteriorate with both pregnancy and COC use, but the evidence of an association with COC use is inconclusive: jaundice and/or pruritus related to cholestasis; gallstone formation; porphyria; systemic lupus erythematosus; haemolytic uraemic syndrome; Sydenham’s chorea; herpes gestationis; otosclerosis-related hearing loss. In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema. Worsening of depression, Crohn’s disease and ulcerative colitis have been associated with COC use. Chloasma may occasionally occur. Monitor patients with diabetes. Zoely contains less than 65mg lactose, and therefore should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption. Medical examination/consultation Prior to the initiation or reinstitution of Zoely use a complete medical history (including family history) should be taken and pregnancy must be ruled out. Blood pressure should be measured and a physical examination should be performed, guided by the contraindications and warnings. It is important to draw a woman’s attention to the information on venous and arterial thrombosis, including the risk of Zoely compared with other CHCs, the symptoms of VTE and ATE, the known risk factors and what to do in the event of a suspected thrombosis. The woman should also be instructed to carefully read the user leaflet and to adhere to the advice given. The frequency and nature of examinations should be based on established practice guidelines and be adapted to the individual woman. Women should be advised that hormonal contraceptives do not protect against HIV infections (AIDS) and other sexually transmitted diseases. USE IN PREGNANCY AND LACTATION: Not recommended during pregnancy. The increased risk of VTE during the postpartum period should be considered when re-starting Zoely. Not recommended during breastfeeding. INTERACTIONS: Interactions may lead to breakthrough bleeding and contraceptive failure. This may be seen with enzyme inducers such as phenytoin and phenobarbital, primidone, carbamazepine, rifampicin, oxcarbazepine, topiramate, felbamate, ritonavir, nelfinavir, nevirapine, efavirenz, griseofulvin, bosentan, and products containing St John’s Wort. Reduced absorption of etonogestrel may be seen with medical charcoal. Hormonal contraceptives may interfere with metabolism of other drugs, and therefore increase or decrease their plasma or tissue concentrations. UNDESIRED EFFECTS: Refer to SmPC for full details. Very Common: acne and abnormal withdrawal bleeding. Common: headache, migraine, weight gain, nausea, decreased libido, depression, depressed mood, mood altered, metrorrhagia, menorrhagia, breast pain, pelvic pain. Breast discharge may also occur. OVERDOSE: No serious effects have been reported. Symptoms may include nausea, vomiting and in young girls, slight vaginal bleeding. Treatment should be symptomatic. Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie. Adverse events should also be reported to MSD (Tel: 01-2998700) LEGAL CATEGORY: Prescription Only Medicine. MARKETING AUTHORISATION NUMBER: EU/1/11/690/002 MARKETING AUTHORISATION HOLDER: Teva B.V., Swensweg 5, 2031 GA Haarlem, Netherlands Date of review: September 2014. 1. Mid-point of range of 5-7 per 10,000 WY, based on a relative risk for CHCs containing levonorgestrel versus non-use of approximately 2.3 to 3.6. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin 18 or from www.medicines.ie. Date of Preparation: September 2014. 1. Dhont M. History of oral contraception. Eur J Contracept Reprod Health Care. 2010;15(S2):S12-S18. 2. Mansour D et al. The Eur J Contracept Reprod Health Care. 2011;16;6:430-443.

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Zoely