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HPN July/August 2016

Issue 29

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HOSPITAL PROFESSIONAL NEWS IRELAND

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Ireland’s Dedicated Hospital Professional Publication

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Gemcitabine Edited.pdf

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ONCOLOGY

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ONCOLOGY

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IN THIS ISSUE:

Gemcitabine 38 mg/ml Ethanol Free

Gemcitabine 38 mg/ml TRUSTED GENERICS: TOTAL CARE Store below 25˚C. Do not refrigerate. Do not freeze.

Ethanol Free

Store below 25˚C. Do not refrigerate. Do not freeze.

Locally advanced or metastatic TRUSTED GENERICS: TOTAL CARE bladder cancer

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C

C

M

M

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Y

Y

Y

C CM

C MC

C MC

M MY

M YM

M YM

Y CY

Y YC

Y YC

CM CMY

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MY K

YM K

YM K

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Locally advanced or metastatic Locally advanced or metastatic adenocarcinoma of the pancreas bladder cancer First line treatment of locally Locally advanced or metastatic advanced or metastatic NSCLC adenocarcinoma of the pancreas Locally advanced or First line treatment of locally metastatic epithelial ovarian advanced or metastatic NSCLC carcinoma Locally advanced or Unresectable locally recurrent metastatic epithelial ovarian or metastatic breast cancer carcinoma Unresectable locally recurrent or metastatic breast cancer Gemcitabine Kabi 200 mg/5.26ml .26 ml Gemcitabine Kabi 1000 mg/26.3ml 26.3 ml 200 mg/5.26ml .26 ml 52.6 ml 2000 mg/52.6ml 1000 mg/26.3ml 26.3 ml 2000 mg/52.6ml 52.6 ml

Prescribing Information Consult the Summary of Product Characteristics for full information. Additional information is available on request. Gemcitabine 38 mg/ml concentrate for solution for infusion. Active ingredients: gemcitabine hydrochloride, equivalent to 38 mg gemcitabine/ml.Excipients include sodium hydroxide and propylene glycol. Indications: Locally advanced or metastatic bladder cancer in combination with cisplatin. Locally advanced or metastatic adenocarcinoma of the pancreas. Consult SPC for additional indications for use. First line treatment in locally advanced or metastatic non-small cell lung cancer (NSCLC) in combination with cisplatin. Gemcitabine monotherapy considered in elderly or performance status 2 patients. Locally advanced or metastatic epithelial ovarian carcinoma, in combination with carboplatin, in relapsed disease following a recurrence-free interval of at least 6 months after platinum-based, first-line therapy. In combination with paclitaxel, in unresectable, locally recurrent or metastatic breast cancer who have relapsed following adjuvant/neoadjuvant chemotherapy. Prior chemotherapy should have included an anthracycline unless clinically contraindicated. Dosage and administration: Dosage reduction with each cycle or within a cycle may be applied based upon the grade of toxicity experienced by the patient. Bladder cancer, combination use: 1,000 mg/m2, given by 30-minute infusion. Dose on days 1, 8 and 15 of each 28-day cycle in combination with cisplatin. Cisplatin dose 70 mg/m2 on day 1 following gemcitabine or Day 2 of each 28-day cycle. This 4-week cycle is then repeated. Pancreatic cancer: 1,000 mg/m2, given by 30-minute intravenous infusion. Repeat once weekly for up to 7 weeks followed by a week of rest. Subsequent cycles of injections once weekly for 3 consecutive weeks out of every 4 weeks. See SPC for dosages in other indications. NSCLC monotherapy: 1,000 mg/m2, given by 30-minute intravenous infusion. Repeat once weekly for 3 weeks, followed by a 1-week rest period. This 4-week cycle is then repeated. NSCLC combination use: 1,250 mg/m2 body surface area given as a 30-minute intravenous infusion on Day 1 and 8 of the treatment cycle (21 days). Cisplatin has been used at doses between 75 - 100 mg/m2 once every 3 weeks. Breast cancer, combination use: Paclitaxel (175 mg/m2) administered on Day 1 over approximately 3 hours as an intravenous infusion, followed by gemcitabine (1,250 mg/m2) as a 30-minute intravenous infusion on Days 1 and 8 of each 21-Day cycle. Patients should have an absolute granulocyte count of at least 1,500 (x 106/l) prior to initiation of gemcitabine + paclitaxel combination. Ovarian cancer, combination use: Gemcitabine 1000 mg/m2 administered on Days 1 and 8 of each 21-day cycle as a 30-minute intravenous infusion. After gemcitabine, carboplatin will be given on Day 1 consistent with a target AUC of 4.0 mg/ml·min. Dose modification due to haematological toxicity dependant on platelet and granulocyte counts – see SPC for detail. Use with caution in renal or hepatic impairment; not recommended in children under 18yrs. Contraindications: Hypersensitivity to the active substance or excipients, breast-feeding. Special Warnings and precautions (See SPC for full details) for use: Prolongation of infusion time and increased dosing frequency increases toxicity. Haematological toxicity.: Suppression of bone marrow function as manifested by leucopaenia, thrombocytopaenia and anaemia. Patients should be monitored prior to each dose for platelet, leucocyte and granulocyte counts. Suspension or modification of therapy when drug-induced bone marrow depression is detected. Peripheral blood counts may continue to deteriorate after gemcitabine has stopped. In patients with impaired bone marrow function, treatment should be started with caution. The risk of cumulative bone-marrow suppression considered when given together with other chemotherapy., Hepatic and renal impairment.Concomitant radiotherapy given together or ≤ 7 days apart - toxicity reported. Live vaccinations not recommended. Posterior reversible encephalopathy syndrome. Caution in patients with a history of cardiovascular events. Capillary leak syndrome reported when receiving gemcitabine as single agent or in combination with other chemotherapeutic agents. Pulmonary oedema, interstitial pneumonitis or adult respiratory distress syndrome (ARDS) have been reported - consider discontinuation of therapy. Renal: Haemolytic Uraemic Syndrome. Fertility: Men advised not to father a child during and up to 6 months after treatment. Interactions: Consult SPC for detailed information on interactions. Fertility, pregnancy, lactation: not recommended, see SPC. Undesirable effects: Very common: Leucopaenia, thrombocytopaenia, anaemia, dyspnoea, vomiting, nausea, elevation of liver transaminases (AST and ALT) and alkaline phosphatise, allergic skin rash frequently associated with pruritus, alopecia, haematuria, mild proteinuria, influenza-like symptoms, oedema/peripheral oedema. Common: Febrile neutropaenia, anorexia, headache, insomnia, somnolence, cough, rhinitis, diarrhoea, stomatitis and ulceration of the mouth, constipation, increased bilirubin, itching, sweating, back pain, myalgia, fever, asthenia, chills. Consult SPC for additional adverse reactions. Legal classification: POM. PA number: PA 1422/003/005. Marketing Authorisation Holder: Fresenius Kabi Oncology Plc., Lion Court, Farnham Road, Bordon, Hampshire, GU350NF United Kingdom. Adverse events should be reported via HPRA Pharmacovigilance, Earlsfort Terrace, IRL – Dublin 2; Tel: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie. Date of Preparation: June 2016.

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CPD: m3.62/gm 0001 llm Management of m6.25/gm 0002 llm Lung Cancer Page 27 REPORT: Antimicrobial Insights Page 34 CLINICAL: Remnant cholesterol in the news Page 43


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HPN July/August 2016 Issue 29

Contents

Foreword

TCD and Our Lady's Hospice & Care Service forge link P6

Editor

Kelly Jo Eastwood

Championing non-invasive heart treatment for patients P8 6

Biologics and Biosimilars – Where are we now? P14 The burden of Psoriasis P24

The HSE said it is extending the clinical eligibility to Directly Acting Antivirals (DAAs) as part of the next phase of a plan to eliminate Hepatitis C in Ireland by 2026. Some ¤30 million has been made available for the plan, which has been welcomed by Minister for Health Simon Harris. Health Minister Harris said, “I’m delighted that the HSE has extended the national Hepatitis C treatment programme using the ¤30 million in Government funding provided for in the 2016 HSE National Service Plan. It builds on the significant progress made in 2015 under the programme. In particular, the HSE is confident that all State-infected people will have commenced treatment by the end of next year, following through on the Government decision of last year.

Antimicrobial insights during Stewardship day P34 34

New President for Consultants Association P37

Turn to page 12 for further details on the goals of eliminating Hepatitis C across Ireland the rest of the world.

Regulars CPD: Lung Cancer P27 37

Feature: Crohn's Disease P40

Antimicrobial resistance is now recognised as a global threat to human health. To this end, the inaugural AMS Insight Antimicrobial Stewardship Study Day, which took place in the Royal College of Physician’s in Dublin, organised by the multidisciplinary Antimicrobial Stewardship Team (AST) from St. James Hospital, Dublin brought together healthcare professionals from various fields to look at the issue in greater detail. The idea for the meeting came from the recognition of continuing education as a pillar of an effective antimicrobial stewardship programme. It provided an opportunity for attendees to hear about and discuss the many challenges posed by the threat of antimicrobial resistance, and the development and implementation of effective hospital based antimicrobial stewardship programmes to counter this threat. Senior Antimicrobial Pharmacist Marie Tierney covers the event for Hospital Professional News on pages 34-35.

Feature: COPD P47 Event Gallery P52 Clinical R&D P54

Good news this month within the field of Hepatitis C as it was revealed that anti-viral drugs that can cure Hepatitis C are to be provided to an additional 1,500 people with the disease. The drugs, which can cure 90% of cases, have already been used to treat 700 people with severe Hepatitis C.

43

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

More recently, as Hospital Professional News was going to press, the Irish Pharmaceutical Healthcare Authority announced a new level of transparency in the relationship between the pharmaceutical industry and the medical community and healthcare organisations, which commenced last month (June). As IPHA CEO Mr Oliver O’Connor points out, this news will have a hugely positive impact on the lives of patients. “Interactions between the pharmaceutical industry and healthcare professionals have a profound and positive influence on the quality of patient treatment and the value of future research,” he says.

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

COMMERCIAL MANAGER Ingrid Lyons Ingrid@ipnirishpharmacynews.ie + 353 1 669 0562 + 353 87 777 0480

“They have delivered numerous innovative medicines and changed the way many diseases impact on our lives. This new level of transparency is designed to assure the public that they can trust their HCPs to recommend treatment or administer appropriate care based solely on clinical evidence. Along with the research based pharmaceutical industry across Europe, Ireland, as represented by IPHA, has today entered this new era of transparency.”

MANAGING DIRECTOR Natalie Maginnis n-maginnis@btconnect.com

CONTRIBUTORS

Paul Mulholland | Maire Tierney Dr Deirdre Kelly | Dr Brian Kirby Professor John Crown Professor JJ Gilmartin Dr Bob Rutherford Dr Suzanne McCormack Dr Anne Marie Tobin

Turn to page 45 for the full story.

EDITOR Kelly Jo Eastwood kjeastwood@hotmail.com 00447876548989 ACCOUNTS Rachel Wilson cs.ipn@btconnect.com

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

HOSPITAL PROFESSIONAL NEWS IRELAND Ireland’s Dedicated Hospital Professional Publication HPN • July/August 2016


4 News

Clinical trials regulation consultation The European Commission has opened four separate public consultations, each examining a distinct issue, or set of issues, related to implementation of EU Regulation 536/2014 ("the Clinical Trials Regulation"). 1. Consultation on risk proportionate approaches to clinical trial regulation The first consultation seeks stakeholder opinions on how best to apply the "risk proportionate" approach to regulation of clinical trials envisaged in Regulation 536/2014. Regulation 536/2014 provides for less stringent rules or adaptations with regards to monitoring, traceability of the Investigational Medicinal Product (IMP) and content of the Trial Master File (TMF), to those clinical trials which pose only a minimal additional risk to subject safety (as defined in Article 2(3) of the Regulation) compared to normal clinical practice. The consultation covers such issues as how identification of risk levels should be conducted and the application of risk proportionate approaches to safety report. The deadline for response is 31 August 2016. 2. Public consultation on "Summary of Clinical Trial Results for Laypersons" A second consultation interrogates the application of Article 37 of the Clinical trial Regulation (EU) No 536/2014 which requires that sponsors provide a summary of clinical trial results in the EU Portal and Database, in a format understandable to laypersons. The consultation seeks stakeholder opinion on the

recommendations formed by an expert group on what primary elements should be covered in a lay summary, and other guidelines such as format, language and a recommended template. The deadline for response is 31 August 2016. 3. Definition of Investigational Medicinal Products (IMPs) and use of Auxiliary Medicinal Products (AMPs) A third consultation examines the definition of "Investigational

Medicinal Product" with a particular focus given to how common understanding about the term and concept of "Auxiliary Medicinal Products" can be established. Different types of AMP are explored, such as rescue medication and challenge agents. The deadline for response is 31 August 2016. 4. Public consultation on the revision of "Ethical Considerations for Clinical Trials on Medicinal products conducted with Minors"

A fourth consultation is now published exploring aspects of change that Regulation (EU) No 536/2014 ushers in in respect to the participation of children in clinical trials. This includes greater emphasis on understanding informed consent as a continual process, new recommendations in respect to consent in emergency situations and the provision of age appropriate information. The deadline for response is 31 August 2016.

HSE to expand hepatitis C treatment programme Anti-viral drugs that can cure Hepatitis C are to be provided to an additional 1,500 people with the disease, the HSE has announced. The drugs, which can cure 90% of cases, have already been used to treat 700 people with severe Hepatitis C. The HSE said it is extending the clinical eligibility to Directly Acting Antivirals (DAAs) as part of the next phase of a plan to eliminate Hepatitis C in Ireland by 2026. Some ¤30 million has been made available for the plan, which has been welcomed by Minister for Health Simon Harris. July/August 2016 • HPN

Health Minister Harris said, “I’m delighted that the HSE has extended the national Hepatitis C treatment programme using the ¤30 million in Government funding provided for in the 2016 HSE National Service Plan. It builds on the significant progress made in 2015 under the programme. In particular, the HSE is confident that all State-infected people will have commenced treatment by the end of next year, following through on the Government decision of last year. “The new direct-acting anti-viral drugs that the programme covers give over 90% of those treated

the chance to be cured of this serious illness which can persist for decades before manifesting itself. Expanding the programme will enable more people to get that chance at a cure, improving their lives immeasurably, while also helping free up scarce resources in our hospitals.” Before the development of the new treatments, as little as 50% of Hepatitis C cases could be cleared with the available drugs, and the rate was lower in patients with cirrhosis. An estimated 20,000 to 50,000 people in Ireland are chronically infected with hepatitis C, more than half of

whom are not aware of their infection. Some 14,500 people have been tested and clinically diagnosed with hepatitis C since it became a notifiable disease in 2004. However, research has found that the disease could affect up to twice that number with 700-800 cases being notified each year. Most people with hepatitis C have no discernible symptoms, with just non-specific signs such as general fatigue. People can live for decades with the virus before health complications arise.


5

Second Annual Report of the National Healthcare Quality Reporting System Minister for Health Simon Harris has welcomed the publication of the second annual report of the National Healthcare Quality Reporting system (NHQRS). The Minister said, “I am very impressed with this report which is an excellent source of information which I know will lead to many improvements in outcomes for patients. It’s very encouraging to see the improvements in many areas already just one year after the first NHQRS report for example in the areas of rates of immunisation, improved uptake of cancer screening and improved survival rates for patients with breast and colorectal cancer. “I know that many areas of our health service perform very well but it is unfortunately true to say that good performance receives far less attention than when things go wrong. Reports like this one help us see the bigger picture and take a broader and longer term

Health Minister Simon Harris

view of what is really happening in our health service Of course not everything is where we want it to be, but the first step in dealing with a problem is to know it exists. I will be encouraging the new allparty Committee on the Future of Healthcare to use this information to help inform their discussions. I’m also glad to see that more

information on patient experience will form part of future NHQRS reports.” The report focuses on a range of outcomes that are important to patients and that reflect the broad range of health services provided in Ireland. It builds on last year’s report and includes a number of additional indicators.

It also presents health information related to immunisation uptake, cancer screening and survival, management of chronic diseases including asthma, chronic obstructive pulmonary disease (COPD), diabetes, stroke and heart failure. Information is also included on healthcare associated infection rates and antibiotic usage. The report highlights information gaps where new information streams are required such as patient experience data. However, there are areas identified where further room for improvement exists. In particular, considerable variation can be seen between counties in rates of hospitalisation for common chronic diseases such as chronic obstructive pulmonary disease, asthma, diabetes and heart failure.

EAHP make 5 recommendations The European Association of Hospital Pharmacists (EAHP) has advised the European Heads of Medicines Agencies to work together to improve the information available about medicines shortages, assign responsibilities and learn from replicable actions on shortages taken by medicines regulators in other parts of the globe.

EAHP described real life case studies, shared the results of surveys of its membership on the topic and made 5 key recommendations to the network:

The Heads of Medicines Agencies (HMA) is a network of both human and veterinary medicines agencies of the European Economic Area. The network provides a forum for the co-ordination and the exchange of views and proposals on issues concerning the European regulatory system and the role of the national authorities within that system.

This should be patient-centred, focusing on the experience at the end of the supply chain. When a patient cannot receive the medicine they need and have been prescribed within a reasonable timeframe, this is a shortage.

The HMA recently adopted a Multi-Annual Work Plan to 2020, in which "availability of appropriately authorised medicines" is the second described business priority of the network. It was in this context that EAHP was invited to speak about the experiences of medicines shortages in the hospital sector.

Information on confirmed shortages should be publicly available. Patients and healthcare professionals need to know how long a shortage is likely to last, and what alternatives might be available in the interim.

1. A common definition for a medicine shortage is needed to ensure all medicines agencies and stakeholders in Europe are speaking the same language on the problem.

2. Information systems for medicines shortages across Europe should operate to common standards

3. Improve reporting requirements It is questionable the extent to

which current EU requirements for manufacturers to report likely disruptions to supply (Art. 81 of Directive 2001/83/EC) is meeting its purpose. Experience of legislation in the USA (FDASIA 2012) has shown clarifying these requirements can improve management of problems and better enable contingencies to be put in place. 4. Monitor and analyse the shortage situation at the European and international level Many shortages can be said to have cause at the international level, for example as a result of globalisation of production, demand spikes, or parallel trade. If common European standards for shortages information systems can be put in place, then a European level system for monitoring, oversight and cooperation can be put in place. 5. Assign responsibilities As well as an "information gap", EAHP identifies a "responsibility gap" at the European level on the topic of medicines shortages. EAHP has suggested the remit of the European Medicines Agency

to be active in this area be enhanced. Experience of the Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012 suggests assignment of responsibility helps to alleviate inertia. A pan-European health threat merits an EU response. Commenting on the meeting, Aida Batista, EAHP Director of Professional Development and policy lead on medicines shortages, said,"At the meeting, I detected a strong desire from European medicines regulators to cooperate and take action on medicines shortages. I believe the recommendations we provided offer a sensible, realistic and achievable way forward by which the process of amelioration on shortages can begin. Once we have improved information and assigned responsibilities we can really start to pinpoint more precisely causes and solutions. I thank the Heads of Medicines Agencies for their invitation to engage, and congratulate them on making availability of medicines one of their key priorities to 2020."

HPN • July/August 2016


6 News

Trinity College Dublin and Our Lady's Hospice & Care Service Forge Academic Link Trinity College Dublin (TCD) and Our Lady’s Hospice & Care Services have signed a Memorandum of Understanding (MOU) formalising an academic link between the Hospice and TCD.

programmes. Our Palliative Meds Info service, providing drug therapy advice to health professionals nationwide has, particularly, benefitted from TCD’s academic support in developing education programmes.”

Speaking at the signing, Professor Linda Hogan, Vice-Provost and Chief Academic Officer of Trinity College Dublin said, “Trinity College is delighted to officially recognise Our Lady’s Hospice & Care Services as an affiliated clinical teaching centre for students of its School of Pharmacy and Pharmaceutical aSciences.

This MOU complements agreements the School has in place with St James’s and Tallaght Hospitals.

“This collaboration includes undertaking and disseminating of research and clinical audits, and the provision of clinical teaching, including clinical placements and visits. Our Lady’s Hospice & Care Services staff associated with the education and training of students will be formally affiliated with the School, will be awarded with the appropriate academic/clinical titles and will be provided access to TCD’s library facilities. We hope that, in the future, there may be opportunities to consider joint funding for the provision of staff between the two institutions.” Chief Executive of Our Lady’s Hospice & Care Services, Ms Audrey Houlihan added, “We are delighted to be a recognised education partner of Trinity College. This formalises a relationship that has existed for over a decade with the School of Pharmacy and Pharmaceutical Sciences.

Back row (L-R): Eimear O’Dwyer, Chief Pharmacist at Our Lady’s Hospice & Care Services, Professor Anne Marie Healy, Head of School of Pharmacy and Pharmaceutical Sciences. Front Row (L-R): Professor Linda Hogan, Vice-Provost and Chief Academic Officer of Trinity College Dublin, Ms Audrey Houlihan, Chief Executive of Our Lady’s Hospice & Care Services

We believe this formal commitment to teaching, research and clinical links provides a wonderful opportunity for our staff and Trinity students and promotes excellence in patient care. We hope that future multidisciplinary education programmes at OLH&CS will also benefit from this affiliation. It will encourage greater opportunity for research projects across the organisations and will provide additional opportunities for the education of pharmacists in the care specialties offered at OLH&CS and for the professional development of pharmacy staff. “This agreement also facilitates academic support for OLH&CS’ education

July/August 2016 • HPN

Eimear O’Dwyer, Chief Pharmacist at Our Lady’s Hospice & Care Services, Professor Martin Henman (Practice of Pharmacy, Trinity College Dublin), Professor Anne Marie Healy, Head of School of Pharmacy and Pharmaceutical Sciences

Eimear O’Dwyer, Chief Pharmacist at Our Lady’s Hospice & Care Services said, “In return for our clinical support, this link with TCD will support our staff to participate in regular audits, research and Continuing Professional Development (CPD). We will also be in a position to engage in wider reaching internal and external research in the disciplines of Palliative Medicine, Rheumatology and Gerontology. As well as playing a role as an educator, our pharmacy department has a longstanding record of being progressive and innovative with its history of a fruitful affiliation with St James’ Hospital for many years. This has led to our current stand-alone service with a strong patient-centred focus. Our ‘Palliative Meds Info’ service is now a well-established and widely used resource for health professionals on all aspects of drug therapy that are used in palliative care. For the future, we are interested in further developing our clinical services across the organisation. We are constantly exploring opportunities to develop practices in line with the evidence base, including improved systems facilitating self-administration by patients.” Explaining the meaning of this relationship for TCD, Professor Anne Marie Healy, Head of School of Pharmacy and Pharmaceutical Sciences, said, “Palliative care impacts upon us all and it is growing in importance. Palliative care will continue to evolve as a discipline and as a service and the School is excited to be entering this partnership with Our Lady’s and is concerned to ensure that all of our students, undergraduate and postgraduate, have the opportunity to learn with and from the best and that we, as a School, can contribute in some way to improving patients’ quality of life through palliative care.”


BE THE

ONE WHO CAN CHANGE WHAT’S POSSIBLE FOR HCV GT1 ADULT PATIENTS1

HARVONI® – Make cure a reality for the majority of your GT1 patients1–4 In clinical trials of compensated hepatitis C (HCV) patients: • Upto 99% Cure 1-4 •

94–97% of treatment-naïve, non-cirrhotic patients cured with 8 wks*1,4

99% of treatment-naïve patients cured with 12 wks2

94–99% of treatment-experienced patients cured with 12–24 wks 3

• 8 weeks may be considered for treatment-naïve, non-cirrhotic patients1 •

One pill once a day1

• Small number of clinically relevant DDIs1** Compensated cirrhosis, decompensated cirrhosis and post-transplant patients may require the addition of RBV 1

Albert Einstein used with permission of the HUJ/GreenLight.

*97% relates to the SVR for patients with a viral load of less than 6 million IU/ml

HARVONI is indicated for the treatment of chronic hepatitis C infection in adults1 ®

PRESCRIBING INFORMATION Consult the Summary of Product Characteristics before prescribing.

90mg ledipasvir/400mg sofosbuvir film coated tablets. HARVONI® Indications: For the treatment of chronic hepatitis C (CHC) in adults. Dosage & Administration: Adults: One tablet, taken orally, once daily with or without food. Genotype 1, 4, 5 or 6; without cirrhosis: 12 weeks of treatment with Harvoni is recommended. 8 weeks may be considered in previously untreated genotype 1-infected patients. Harvoni + ribavirin for 12 weeks or Harvoni (without ribavirin) for 24 weeks should be considered for previously treated patients with uncertain subsequent retreatment options. Genotype 1, 4, 5 or 6; with compensated cirrhosis: Harvoni + ribavirin for 12 weeks or Harvoni (without ribavirin) for 24 weeks of treatment with is recommended. Harvoni (without ribavirin) for 12 weeks may be considered for patients deemed at low risk for clinical disease progression and who have subsequent retreatment options. Genotype 1, 4, 5 or 6; post liver transplant without cirrhosis or with compensated cirrhosis: Harvoni + ribavirin for 12 weeks. Harvoni (without ribavirin) for 12 weeks (in patients without cirrhosis) or 24 weeks (in patients with cirrhosis) may be considered for patients who are ineligible for or intolerant to ribavirin. Genotype 1, 4, 5 or 6; with decompensated cirrhosis: Harvoni + ribavirin for 12 weeks. Harvoni (without ribavirin) for 24 weeks may be considered in patients who are ineligible for or intolerant to ribavirin. Genotype 3 with compensated cirrhosis and/or prior treatment failure: 24 weeks treatment with Harvoni in combination with ribavirin is recommended. Please refer to the SmPC for recommended dose & treatment duration for combination therapy. When used in combination with ribavirin, refer also to the SmPC of ribavirin. Refer to the individual SmPCs for additional information regarding dose modifications & discontinuations. Renal impairment: Mild or moderate renal impairment: no dose adjustment required. Severe renal impairment or end stage renal disease (ESRD) requiring haemodialysis: not recommended. Refer to the SmPC for ribavirin for patients with creatinine clearance (CrCl) < 50 mL/min. Hepatic impairment: Mild, moderate or severe hepatic impairment: no dose adjustment required. Safety and efficacy of Harvoni have been established in patients with decompensated cirrhosis. Children and adolescents: The safety and efficacy of Harvoni in children & adolescents aged <18 years have not yet been established. Elderly: No dose adjustment is warranted for elderly patients. Contraindications: Hypersensitivity to the active substance or to any excipients. Use with potent P-gp inducers (in the intestine; rifampicin, rifabutin, St. John’s wort [Hypericum perforatum], carbamazepine, phenobarbital and phenytoin) will significantly decrease ledipasvir & sofosbuvir plasma concentrations and could result in loss of efficacy of Harvoni. When Harvoni is used in combination with ribavirin, contraindications applicable to that agent is applicable to combination therapies. Refer to the ribavirin SmPC for a list of contraindications. Warnings and Precautions: Harvoni should not be administered concomitantly with other medicinal products containing sofosbuvir. The clinical data to support the use of Harvoni in HCV genotype 2, 3 and 6 patients are limited. A conservative 24 weeks of therapy is advised in all treatment-experienced genotype 3 patients and those treatment-naïve genotype 3 patients with cirrhosis. Severe bradycardia and heart block: Cases of severe bradycardia and heart block have been observed when Harvoni is used with concomitant amiodarone with or without other drugs that lower heart rate. The  mechanism is not established. Should concomitant use of amiodarone be considered necessary, it is recommended that patients are closely monitored when initiating Harvoni. All  patients receiving Harvoni in combination with amiodarone with or without other drugs that lower heart rate should be warned of the symptoms

**Drug-drug interaction

Cure defined as SVR12

1. HARVONI® SmPC available at https://www.medicines.org.uk/emc/medicine/29471 (Accessed June 2016) 2. Afdhal N et al. N Engl J Med 2014;370:1889–1898. 3. Afdhal N et al. N Engl J Med 2014;370:1483–1493. 4. Kowdley KV et al. N Engl J Med 2014;370:1879–1888. 5. Gilead Data On File – SOFUK1601 (February 2016)

of bradycardia and heart block and should be advised to seek medical advice urgently should they experience them. Patients who are identified as being high risk of bradyarrhythmia should be continuously monitored for 48 hours in an appropriate clinical setting. Due to the long half-life of amiodarone, appropriate monitoring should also be carried out for patients who have discontinued amiodarone within the past few months and are to be initiated with Harvoni. Treatment of patients with prior exposure to HCV directacting antivirals: There are no data to support the effectiveness of retreatment of patients who have failed Harvoni with a subsequent regimen that contains an NS5A inhibitor. Consideration should be given to longer treatment for patients with uncertain subsequent retreatment options. Patients with decompensated cirrhosis and/or who are awaiting liver transplant or post-liver transplant: The efficacy of Harvoni in genotype 5 and 6 with decompensated cirrhosis and/ or who are awaiting liver transplant or post-liver transplant has not been investigated. Treatment with Harvoni should be guided by an assessment of the potential benefits and risks for the individual patient. Use with moderate P-gp inducers: Medicinal products that are moderate P-glycoprotein (P-gp) inducers in the intestine (e.g. oxcarbazepin) decrease ledipasvir and sofosbuvir plasma concentration leading to reduced therapeutic effect of Harvoni. Co-administration is not recommended. Use with certain HIV antiretroviral regimens: Harvoni has been shown to increase tenofovir exposure, especially when used together with an HIV regimen containing tenofovir disoproxil fumarate and a pharmacokinetic enhancer (ritonavir or cobicistat). The safety of tenofovir disoproxil fumarate in this setting has not been established. The potential risks and benefits associated with co-administration of Harvoni with the fixed-dose combination tablet containing elvitegravir/cobicistat/ emtricitabine/tenofovir disoproxil fumarate or tenofovir disoproxil fumarate given in conjunction with a boosted HIV protease inhibitor (e.g. atazanavir or darunavir) should be considered, particularly in patients at increased risk of renal dysfunction. Patients receiving Harvoni concomitantly with elvitegravir/cobicistat/emtricitabine/ tenofovir disoproxil fumarate or with tenofovir disoproxil fumarate and a boosted HIV protease inhibitor should be monitored for tenofovir-associated adverse reactions. Refer to the SmPCs of the aforementioned agents for recommendations on renal monitoring. Use with HMG-CoA reductase inhibitors: Co-administration of Harvoni and HMG-CoA reductase inhibitors (statins) can significantly increase the concentration of the statin, which increases the risk of myopathy and rhabdomyolysis. HCV/HBV co-infection: There are no data available. Excipients: Harvoni contains sunset yellow FCF aluminium lake (E110), which may cause allergic reactions. It also contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take Harvoni. Interactions: Harvoni should not be administered concomitantly with other medicinal products containing sofosbuvir. Ledipasvir is an in vitro inhibitor of drug transporter P-gp and breast cancer resistance protein (BCRP) and may increase intestinal absorption of co-administered substrates for these transporters. Ledipasvir may be a weak inducer of metabolising enzymes such as CYP3A4, CYP2C and UGT1A1. Compounds that are substrates of these enzymes may have decreased plasma concentrations when co-administered with Harvoni. In vitro ledipasvir inhibits intestinal CYP3A4 and UGT1A1. Medicinal products that have a narrow therapeutic range and which are metabolised by these isoenzymes should be used with caution and carefully monitored. Ledipasvir and sofosbuvir are substrates of drug transporter P-gp and BCRP while GS-331007 is not. Refer to the Contraindication & Warnings & Precautions for P-gp inducers (in the intestine). Co-administration with medicinal products that inhibit P-gp and/or BCRP may increase ledipasvir and sofosbuvir plasma

concentrations without increasing GS-331007 plasma concentration; Harvoni may be co-administered with P-gp and/or BCRP inhibitors. Refer to SPC for full information regarding interactions. Pregnancy & lactation: When Harvoni is used in combination with ribavirin; extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Significant teratogenic and/or embryocidal effects have been demonstrated in all animal species exposed to ribavirin. Women of childbearing potential or their male partners must use an effective form of contraception during treatment and for a period of time after the treatment has concluded as recommended in the SmPC for ribavirin. Refer to the SmPC for ribavirin for additional information. There are no or limited amount of data (<300 pregnancy outcomes) from the use of ledipasvir, sofosbuvir or Harvoni in pregnant women. As a precautionary measure, it is preferable to avoid the use of Harvoni during pregnancy. Harvoni should not be used during breast-feeding. See also the SmPC for ribavirin for pregnancy and breast-feeding. Side effects: When Harvoni was studied with ribavirin, the most frequent adverse drug reactions to Harvoni in combination with ribavirin were consistent with the known safety profile of ribavirin, without increasing the frequency or severity of the expected adverse drug reactions. The following adverse drug reactions have been identified with Harvoni. Frequencies are defined as follows: Very commonly reported adverse events (≥1/10): headache and fatigue. Description of selected adverse reactions; Cardiac arrhythmias: Cases of severe bradycardia and heart block have been observed when Harvoni is used with concomitant amiodarone and/or other drugs that lower heart rate. Legal Category: POM. Package Quantities: Bottle of 28 film-coated tablets. Price: UK NHS Price - £12,993.33; Eire Price - €TBA Marketing Authorisation Number: EU/1/14/958/001 Further information is available from the local representative of the marketing authorisation holder: Gilead Sciences Ltd, 280 High Holborn, London, WC1V 7EE, UK. Telephone: +44 (0) 8000 113700, For Ireland: +353 214 825 999. E-mail: ukmedinfo@gilead.com. Harvoni is a trademark. Date of PI preparation: April 2016: HAR/UK/15-11/MM/1992(2)

▼ This medicinal product is currently subject to additional monitoring. Reporting suspected adverse reactions after

authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse reactions to Harvoni should be reported to Gilead via email to safety_FC@gilead.com or by telephone +44 (0) 1223 897500. Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Suspected adverse reactions should be reported to the HPRA Pharmacovigilance using a Yellow Card obtained either from the HPRA, or electronically via the website at www.hpra.ie. Adverse reactions can also be reported to the HPRA by calling +353 1 6764971.

© 2016 Gilead Sciences, Inc. All rights reserved. Date of preparation: June 2016 HAR/UK/14-11/MI/1033(7)


8 Profile

Championing the cause of non-invasive heart treatment for patients Dr Kathleen (Kate) McGarry is President of the Irish Heart Foundation. In taking up this new appointment earlier this year, Dr McGarry set out to help deliver the organisation’s life-changing and life-saving services to more people affected by heart disease and stroke in Ireland. Here, she talks to Hospital Professional News about her background, and the current and future challenges facing our cardiology services.

Dr McGarry joined the Irish Heart Foundation (IHF) with a wealth of experience and as a champion of non-invasive treatment for heart patients. She is a consultant in General Internal Medicine (GIM) with a specialty interest in non-invasive Cardiology and a renowned figure in the northeast where she was a consultant physician in Our Lady's Hospital, Navan from 1983 until 2014. Dr McGarry’s early training in Cardiology included Registrar posts in The Hammersmith and Great Ormond Street Hospitals in London and a subsequent Clinical Fellowship year in the University Hospital in Edmonton, Alberta in Canada. In 1983 she returned to Ireland and commenced practice as a Consultant Physician with a sub-specialty interest in non-invasive Cardiology in Our Lady's Hospital, Navan. She retired from public practice in 2014 and is currently practising part-time in the Cardiology Outreach Clinic of the Mater Private Hospital in Navan. She continues, “I have been July/August 2016 • HPN

associated with the IHF for many years and served before on its Board. I also served a term as the Chairperson of its Council on Women and Cardiovascular Disease. “I have authored more than 30 publications in peer-reviewed journals, many of which are in the Cardiology area. I have been an elected Council member of the Royal College of Physicians in Ireland for 25 years and have served a term as its VicePresident.” During Dr McGarry’s career as aforementioned, one of her key responsibilities has been in developing Cardiology services in Navan. She explains, “Our Lady's Hospital Navan (OLHN) was always, and still is, a busy acute general hospital. Its Medical department has a new fully equipped coronary care unit (CCU) which treats approximately 200 patients with acute myocardial infarcts each year. “I was responsible for setting-up and developing a dedicated noninvasive cardiology service and in planning the new CCU. Much of the sophisticated equipment

in the unit was purchased with the assistance of the local Navan fund-raising committee. I also established close working links with the Cardiology Department in the Mater Hospital in Dublin which has served our patients very well over the last 15 years.

“2016 marks the 50th anniversary of the founding of the IHF and both its first President (Professor Risteard Mulcahy) and another founding member (Professor Conor Ward) are aware and pleased it has reached this important milestone,” continues Dr McGarry.

“It is worth recording that in the recently published Department of Health report on National Healthcare Quality, the in-hospital mortality within 30 days after acute myocardial infarction in OLHN was the lowest in the country. This is a recognised outcome measure of acute care quality and reflects well on the hospital in Navan.”

“The IHF is at the forefront in educating the public about cardiovascular diseases and about how to manage risk through lifestyle changes. It is currently lobbying the Government on the National Obesity Plan and the National Physical Activity Plan. The IHF employs specialized nurses to provide advice and support and education to the public on the ground across the country and also through the expanded Freephone Helpline launched this year. In addition the IHF actively supports and funds research by clinical units and individual research professionals.

Approximately 10,000 people die each year from cardiovascular disease (CVD) - including coronary heart disease (CHD), stroke and other circulatory diseases. CVD is the most common cause of death in Ireland, accounting for 32% of all deaths. The largest number of these deaths relate to CHD mainly heart attack - at 5,000. Furthermore, each year, approximately 10,000 Irish people have a stroke and around 2,000 die – more deaths than breast cancer, prostate cancer and bowel cancer combined. An estimated 30,000 people are living in the community with disabilities as a result of a stroke. This makes stroke the third biggest cause of death in Ireland and the biggest cause of acquired disability. The vision of the IHF is that every person living in Ireland will live a long, active and healthy life free from heart, stroke and blood vessel disease.

“Every hour someone in Ireland suffers from a stroke. Every day, hundreds of Irish people are diagnosed with heart disease. The lives of these people are often cut tragically short. Many are left disabled and up to 10,000 die each year which makes cardiovascular disease Ireland’s biggest killer. “But some 80% of premature heart disease and stroke is preventable. At the Irish Heart Foundation we empower people in Ireland to make their health last longer and we do this through key programme areas in care and patient support, community prevention, research and advocacy. “This year marks our 50th year and our key aims include the launch


10 Profile of a new national full-time mobile service delivering free blood pressure checks by Irish Heart Foundation nurses nationwide. More than 60% of adults over 45 years have high blood pressure in Ireland, placing them at greater risk of stroke or heart attack - and half of them do not know it. This community prevention programme provides vital risk factor detection and it will now be made available all year-round for the first time. Preventing and managing hypertension is at the core of the IHF’s service delivery to reduce premature mortality and disability. “Additionally, at the Foundation we have just launched a new freephone number for our nurseled helpline and we will continue with plans to promote and build this lifeline to support patients and their families, post-cardiac and stroke events. We will also continue to roll-out stroke support groups around the country with two new clubs being launched this autumn. In the area of stroke, we are currently developing a position paper on the national development of thrombectomy services and a new stroke manifesto. “Childhood obesity is a significant issue on the Foundation’s agenda and the inclusion of a sugar sweetened drinks tax in the Programme for Government is a highly positive step and a vindication of the Irish Heart Foundation’s stance on the issue and immense effort. One of our key aims for the rest of 2016 is to continue to campaign for regulation to prevent food marketing to children including a ban on unhealthy food ads on TV before 9pm and specific regulation of online marketing. “This will build on the launch of our recent report ‘Who’s Feeding the Kids Online?’ which exposed the hidden tactics being used to target children online and how little parents know about the efforts being made to influence their children.” So what of the future? For Dr McGarry, hospital professionals and allied healthcare peers should be taking full advantage of the new and current management and treatment plans available. She says, “There have been many significant advances and new developments in the management of cardiovascular diseases in

recent years. Some are related to new drugs and others to innovations in technology and new procedures with the ability now to deliver more targeted care by less invasive treatment modalities. “The management of some forms of valvular heart disease and of atrial fibrillation are examples of this new approach. The burden of chronic heart failure has increased due to the expanding elderly population and the management of this condition is now one of the major challenges for cardiology professionals in 2016 and beyond. “There has been a great improvement in Stroke management in Irish hospitals in the last decade. In 2008 only one hospital had a fully resourced Stroke unit. Today in 2016, 21 hospitals have such a dedicated unit. “Medical consultants are just one important component of the expert stroke multidisciplinary team,” Dr McGarry adds. “The in-hospital mortality for both haemmorhagic and ischaemic strokes has significantly reduced in the past decade and this is a vindication of the development of such above dedicated units. There is much more to do to bring our rates down to the European average and the IHF is a major advocate for further resources to tackle this growing problem which is related to an aging population. “New treatment strategies including new drugs and advances in endovascular and minimally invasive laparoscopic interventions bring new opportunities for cardiologists, radiologists and surgeons to improve outcomes for many patients with cardiovascular diseases including stroke. In Ireland we are fortunate to have consultants who have this "cutting edge" expertise who have returned from major world-renowned centres to practise here. “Atrial Fibrillation is a major risk factor in stroke and is also associated with ill health and cardiovascular complications as a stand-alone disease entity. Its importance in this regard has only recently been understood and acknowledged. It is a growing problem in all adult age groups. It requires careful monitoring and proactive treatment. Cardiologists and surgeons are very involved in its management. A combination of

drugs and ablation therapies are considered in each case.” What does Dr McGarry foresee as being the biggest challenges for cardiology healthcare professionals in Ireland during the rest of 2016? She reflects, “There are increasing pressures on health care services with increasing age and longevity, major but costly improvements in technology and medical treatment. These changes are leading to increased numbers of patients in hospital, the lack of available beds for acute admissions is in turn putting pressure on the Emergency departments and waiting times for cardiology and cardiothoracic interventions. We are also seeing alarming increases in childhood obesity which is storing up potential medical problems such as diabetes and hypertension. “To both improve patient care and reduce inpatient stay the IHF have been advocating for Early supported discharge (ESD). This is an intensive approach to rehabilitation in the community used internationally but not generally available in Ireland. Only 10% of Irish stroke survivors were able to avail of ESD, compared to 30% in the UK despite conclusive evidence on their effectiveness in improving outcomes and reducing overall health service costs. “More than 3,000 people a year could benefit from ESD programmes that would reduce hospital bed days by 24,000, resulting in annual net savings of from ¤2 to ¤7 million. Implementing ESD would require a substantial increase in the resourcing of community therapists (physiotherapists, occupational therapists, and speech and language therapists), community nurses and other community care above current levels in Ireland. However, savings from the reduced cost of acute bed days could fund this increase in resourcing. “Obesity and food poverty are having very negative impacts on Irish children’s health. One in four girls and one in five boys are overweight or obese[i], with children from disadvantaged areas are more likely to be obese. “One of the driving forces behind higher rates of obesity and ill-health in the worst off communities is food poverty.

We therefore need to create an environment which supports children to eat healthy diets. Regulation and legislation is needed to effect major changes for children’s lives. The IHF believes that the introduction of a tax on sugar-sweetened drinks would have a small but significant impact on obesity rates. By applying a portion of the revenue generated to a Children’s Future Health Fund, the introduction of the tax could have a highly significant impact across children’s lives.” Dr McGarry adds that the IHF is calling on Government to: 1. End junk food marketing to children. Ban junk food ads on TV before 9pm and regulate digital junk food marketing. 2. Pull the plug on vending machines in schools and move towards only healthy food sold in schools 3. Set up Children’s Future Health Fund, with the money raised by a tax on sugar-sweetened drinks. “The fund would pay for programmes to combat childhood obesity and food poverty. These measures should improve future cardiovascular health and so mitigate the increasing burden on the health service,” she concludes. Key Points • Active clinical practice in the Mater Private Cardiology Clinic in Navan • Cardiology training undertaken in the Hammersmith and Great Ormond Street hospitals in London • Cardiology Fellow in Edmonton University Hospital in Canada before returning to Ireland in 1983. • Responsible for developing Cardiology services in Navan. • Over 30 peer-reviewed publications related to cardiovascular disease including a major collaborative study which identified a unique gene in a large Irish family with hypertrophic cardiomyopathy. • Chairperson on the Irish Heart Foundation's (IHF) Council on Women's heart disease for a number of years • Served on the Board of the IHF from 2009 until 2014.

Death of Irish Heart Foundation Founder The team at Hospital Professional News were saddened to learn of the death of Professor Risteard Mulcahy, as we were going to press. Professor Mulcahy, one of Ireland’s first anti-smoking advocates was founder and president of the Irish Heart Foundation. He was also an environmentalist, keep fit enthusiast, a researcher, historian and author of a number of books. Professor Mulcahy died aged 94 on Friday, July 1st. Sincere condolences to his family and friends at this time.

July/August 2016 • HPN


NOW LICENSED

NEW ONCE-DAILY LIXIANA® ANOTHER STEP AHEAD.

.

(edoxaban)

Only LIXIANA combines: ®

Proven efficacy comparable to well-controlled warfarin1,2 Superior reduction in clinically relevant bleeding vs. well-controlled warfarin1,2 Once-daily dosing across both NVAF and VTE indications3 Indicated for: 3 Prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation (NVAF) with one or more risk factors, such as congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischaemic attack (TIA) Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults LIXIANA▼ (edoxaban) 60 mg/30 mg/15 mg film coated tablets ▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. See summary of product characteristics prior to prescribing for full list of adverse events. Presentation: 60 mg (yellow) / 30 mg (pink) / 15 mg (orange) edoxaban film coated tablets (as tosilate). Indications: Prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation (NVAF) with one or more risk factors, such as congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke or transient ischaemic attack (TIA) and treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults. Posology and method of administration: NVAF - The recommended dose is 60 mg edoxaban once daily with or without food. Therapy with edoxaban in NVAF patients should be continued long term. VTE - The recommended dose is 60 mg edoxaban once daily following initial use of parenteral anticoagulant for at least 5 days with or without food. Duration of therapy (at least 3 months) should be based on risk profile of the patient. For NVAF and VTE the recommended dose is 30 mg edoxaban once daily in patients with one or more of the following clinical factors: moderate or severe renal impairment (creatinine clearance (CrCl) 15–50 ml/min), low body weight ≤60 kg and/or concomitant use of the following P-glycoprotein (P-gp) inhibitors: ciclosporin, dronedarone, erythromycin, or ketoconazole. The 15 mg dose of edoxaban is not indicated as monotherapy, and should only be used during a switch from edoxaban to VKA (see SmPC for full details). If a dose of edoxaban is missed, the dose should be taken immediately and then continued once daily on the following day. Contraindications: Hypersensitivity to the active substance or to any of the excipients; clinically significant active bleeding. Hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Lesion or condition, if considered to be a significant risk for major bleeding. This may include current or recent gastrointestinal (GI) 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. Uncontrolled severe hypertension. Concomitant treatment with any other anticoagulants e.g. UFH, low molecular weight heparins, heparin derivatives (fondaparinux, etc.), VKA or NOACs except under specific circumstances of switching oral anticoagulant therapy or when UFH is given at doses necessary to maintain an open central venous or arterial catheter. Pregnancy and breastfeeding. Special warnings and precautions for use: Haemorrhagic risk: Use with caution in patients with increased risk of bleeding such as elderly on ASA and should be discontinued if severe haemorrhage occurs. The anticoagulant effect of edoxaban cannot be reliably monitored with standard laboratory testing. A specific anticoagulant reversal agent for edoxaban is not available. Haemodialysis does not significantly clear edoxaban. Renal impairment: Renal function should be assessed prior to initiation of edoxaban and afterwards when clinically indicated. Not recommended in patients with end stage renal disease or on dialysis. Renal function and NVAF: A trend towards decreasing efficacy with increasing creatinine clearance was observed for edoxaban compared to well-managed warfarin. Edoxaban should only be used in patients with NVAF and high creatinine clearance after a careful benefit risk evaluation. Hepatic impairment: Not recommended in patients with severe hepatic impairment and should be used with caution in patients with mild or

www.lixiana.ie

moderate hepatic impairment. Edoxaban should be used with caution in patients with elevated liver enzymes (ALT/ AST > 2 x ULN) or total bilirubin ≥1.5 x ULN. Surgery or other interventions: discontinue edoxaban at least 24 hours before the procedure. If the procedure cannot be delayed, the increased risk of bleeding should be weighed against the urgency of the procedure. Edoxaban should be restarted as soon as haemostasis is achieved. Prosthetic heart valves and moderate to severe mitral stenosis: Not recommended. Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy: Not recommended. Patients with active cancer: Not recommended. Drug interactions: The P-gp inhibitors ciclosporin, dronedarone, erythromycin, or ketoconazole result in increased concentration of edoxaban and a dose reduction of 30 mg is required. Edoxaban should be used with caution with concomitant P-gp inducers (e.g. phenytoin, carbamazepine, phenobarbitol or St John’s Wort). Concomitant high dose ASA (325 mg) or chronic NSAIDs is not recommended. There is very limited experience with dual antiplatelet therapy or fibrinolytic agents. Pregnancy: Not recommended. Breastfeeding: discontinue breastfeeding or edoxaban therapy. Undesirable effects: Common: anaemia, epistaxis, lower GI haemorrhage, upper GI haemorrhage, oral/pharyngeal haemorrhage, nausea, blood bilirubin increased, gamma GT increased, cutaneous soft tissue haemorrhage, rash, pruritus, macroscopic haematuria/urethral haemorrhage, vaginal haemorrhage, puncture site haemorrhage, liver function test abnormal. Uncommon: hypersensitivity, intracranial haemorrhage (ICH), intraocular haemorrhage, other haemorrhage, haemoptysis, surgical site haemorrhage. Rare: anaphylactic reaction, allergic oedema, subarachnoid haemorrhage, pericardial haemorrhage, retroperitoneal haemorrhage, intramuscular haemorrhage (no compartment syndrome), intra-articular haemorrhage, subdural haemorrhage, procedural haemorrhage. Legal category: POM. Package quantities: 60 mg/30 mg – 28 tablets. 15 mg – 10 tablets. Marketing Authorisation (MA) number: EU/1/15/993/001-16. MA holder: Daiichi Sankyo Europe GmbH, Zielstattstrasse 48, 81379 Munich, Germany. Additional Information: Available on request from Daiichi Sankyo Ireland Ltd. Telephone: (01) 489 3000. Fax: (01) 489 3033. Email: medinfo@daiichi-sankyo.ie. Date of preparation: July 2015. ▼ This medicine is subject to additional monitoring. Adverse events and product complaints should be reported. To report an adverse event or a product complaint about a Daiichi Sankyo medicine, please call Daiichi Sankyo Ireland Ltd. on (01) 489 3000. Healthcare professionals are also asked to report any suspected adverse reactions to Daiichi Sankyo medicines to HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: (01) 676 4971; Fax: (01) 676 2517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

References: 1. Giugliano RP et al. NEJM 2013;369(22):2093–2104. 2. The Hokusai-VTE Investigators. NEJM 2013;369(15):1406–1415. 3. LIXIANA®, Summary of Product Characteristics, www.medicines.ie, September 2015. Date of item: July 2015. EDX/15/0169


12 News

Working together to eliminate viral hepatitis HPN Editor Kelly Eastwood chats to the Managing Director of MSD, Louise Houson on their initiatives to elimate viral hepatitis Hepatitis C is a major cause of liver disease worldwide; the WHO estimates that approximately 3% of the world's population (180 million) is infected. A significant challenge is that many of those who are infected do not show symptoms for a long period and consequently diagnosis is often delayed. As a result, hepatitis C is often described as the ‘silent’ epidemic. Many organisations are working tirelessly to eliminate this global threat, such as the World Hepatitis Alliance, alongside global pharmaceutical companies such as MSD. Managing Director of MSD Louise Houson told Hospital Professional News, “MSD is committed to building on its strong legacy in the field of viral hepatitis by continuing to discover, develop and deliver medicines and vaccines to help prevent and treat viral hepatitis. “Elimination of viral hepatitis is feasible and achievable but only if governments, organisations and healthcare professionals work together,” she added. “Reducing mortality rates will not only mean a reduction in the personal cost of viral hepatitis, but will also mean reduced financial costs, with health systems no longer having to deal with significant numbers of people suffering from the results of untreated viral hepatitis. “MSD's long standing commitment in hepatitis C virus spans three decades. It represents an important contribution for people living with hepatitis C and the healthcare professionals who treat them.”

Hepatitis C in the News In most recent news, it has been revealed testing for hepatitis C virus (HCV) core antigen could eventually replace the current two-step procedure for diagnosing chronic hepatitis C infection in lower- and middle-income countries, speeding up access to treatment and improving retention in care, a systematic review designed to inform World Health Organisation hepatitis C testing guidelines has found. Chronic hepatitis C infection is currently diagnosed by antibody testing followed by a confirmatory nucleic acid test to detect HCV RNA, which indicates active viral infection. The second step is essential because between 15 and 50% of people with HCV antibodies will have spontaneously cleared HCV infection during the first six months after exposure and will not have chronic infection. Nucleic acid testing must be done by a laboratory equipped to carry out molecular testing. Nucleic acid testing is costly and inaccessible in many places. As a result an unknown proportion of people who test positive for HCV receive no confirmatory testing and are lost to follow-up, resulting in lack of monitoring and treatment. The two-step diagnostic process is seen as a major obstacle to diagnosis and treatment of hepatitis C on the scale needed to achieve ambitious targets for reducing the burden of the disease and eliminating hepatitis C as a public health problem. The Work of the World Hepatitis Alliance The World Hepatitis Alliance provides global leadership and supports action that will halt the

Louise Houson, MSD

death toll and improve the lives of people living with or affected by chronic viral hepatitis. Through better awareness, prevention, care, support and access to treatment, their ultimate goal is to work with members, Governments and other key partners to eradicate these diseases from the planet. Whilst they have accomplished a great deal in their history, there is still a lot of work to do. The strategy of the World Health Alliance is structured around four key goals, each of which consists of numerous minor goals. However, the essential components of what they do include raising global awareness of viral hepatitis and helping to ensure that every country has

a robust and detailed viral hepatitis strategy in place or in development. By doing so, they ensure real improvements to the lives of viral hepatitis patients. An important part of this work is increasing the influence of members in order to make their impact more widespread. This year sees the first ever World Health Organisation’s Global Strategy for Viral Hepatitis, which sets a goal of eliminating viral hepatitis as a public health threat by 2030. Let's join together on World Hepatitis Day (28 July) to make the elimination of viral hepatitis our next greatest achievement.

Save the Date – World Hepatitis Summit 2017 Following the success of last year’s event in Scotland, the World Hepatitis Alliance has announced that the second World Hepatitis Summit is currently in production. Designed to provide a focus for efforts to implement the first ever Global Health Sector Strategy on Viral Hepatitis, the World Hepatitis Summit 2017 is a joint project between the World Hepatitis Alliance, World Health Organisation and Brazilian Government and will be taking place 29 – 31 March 2017 at the World Trade Centre in São Paulo, Brazil. Bringing together civil society, patients, policy-makers, public health scientists, global funders and industry, the Summit will provide the opportunity for the hepatitis community to share ideas, experience and best practice in addressing the many challenges of viral hepatitis. WHA members will also be invited to the pre-Summit, which will be taking place immediately before the main Summit: 27 – 28 March 2017. These two days, exclusively for WHA members, will include the World Hepatitis Alliance’s AGM and a number of workshops and events designed to strengthen the global patient voice and to help improve the skills of its members. Pease do save these dates to your diary and for any questions, please contact summit@worldhepatitisalliance.org

July/August 2016 • HPN


NOhep Our Next Greatest Achievement

Join the NOhep campaign to help make the elimination of Hepatitis C our next greatest achievement

#NOhep

NOhep is an independent initiative led by the World Hepatitis Alliance. All content and design has been developed solely by NOhep with no influence or support from MSD or any other commercial organisation.

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NOhep.org


14 Feature

Biologics and Biosimilars – Where are we Now? The Irish Platform for Patients’ Organisations, Science and Industry recently held a breakfast seminar in the Royal College of Physicians, Dublin, to look at the issues of biologics and biosimilars more closely.

Professor Laurence Egan, NUI Galway

Speakers at the event included Joan O’Callaghan from the HPRA; Professor Laurence Egan of NUI Galway and Professor Bjorn Moum from Oslo University Hospital Ulleval, Norway alongside Professor Michael Barry from NCPE and John Church, Arthritis Ireland. Dr Derick Mitchell is the Chief Executive at IPPOSI. He says, “As more originator biologic medicines approach the end of their patent, and an increasing number of biosimilars reach the stage of approval, the issue of their safe and effective use is topical, as well as controversial,” he says.

Professor Michael Barry, NCPE

“Although biosimilars have the promise of reduced drug expenditure, where these savings will re-appear is a legitimate question. Informed patients and patient representatives are crucial to addressing their introduction and possible adoption. “The IPPOSI breakfast meeting on Biologics and Biosimilars aimed to provide more clarity on what patients and prescribers should expect from this shift in the treatment paradigm. The meeting was attended by a wide range of stakeholders, with representatives from patient organisations, the scientific and medical communities, industry, as well as Government agencies and Departments. “A survey of patients and patient organisations uncovered reasonable levels of awareness & understanding of biologic medicines, but there were low levels of awareness and little

July/August 2016 • HPN

understanding of biosimilars among patients. “The survey also highlights how patients prioritise safety over effectiveness, how there is a clear need for understandable, patient focused information and critically, the importance of patient involvement in decision making regarding switching.” Joan O’Callaghan from the Health Products Regulatory Authority (HPRA) was there to provide the regulatory perspective and she gave a brief overview of the biosimilar approval process. She explained to attendees that manufacturers

of biosimilars must prove that their agent has similar quality, efficacy and safety to the originator drug, with no clinically meaningful differences between the two. Concerns remain around interchangeability, substitution, and switching with regard to biologics and biosimilars. Ms O’Callaghan explained that there is a wide variation in international policies with regard to these matters. While Ireland’s generic substitution policy, as defined under the Health Act of 2013, excludes biosimilars, the HPRA is cognisant of issues

with regard to interchangeability and switching, and has recently issued guidance on this topic. The HPRA issued guidance in relation to use of biosimilars in 2015 and Hospital Professional News featured an article at the time, authored by Ms O’Callaghan. The HPRA position on interchangeability and switching is that if it is planned to change the medicine a patients receives from an originator to a biosimilar medicine or vice versa, the treating physician should be involved, she explained. This should involve a discussion


Real world patients remain on Stelara over the long term versus any other 1st line anti TNF1-3 Newly published PSOLAR data demonstrates greater drug persistency* over 4 years for Stelara compared to any other anti-TNF therapy2 Persistence of Therapy in Biologic-Naïve Patients2

Proportion of patients continuing therapy

1.0

Stelara® 0.8

0.6 Infliximab† 0.4

Etanercept‡ Adalimumab‡

0.2 0.0

0

12

Adapted from Menter A et al. 2015

24

36 48 Time on therapy (months)

60

72

84

• A higher proportion of patients stayed on Stelara® over the

long term versus any other 1st line anti TNF.2

• Fewer patients discontinued Stelara® vs. adalimumab, etanercept and infliximab.2 • Higher drug persistency was observed for Stelara® compared to the other biologics based

on statistically significant differences in time to stop/switch for each biologic vs Stelara®.2

* Drug Persistence Reflects various factors including: Primary or Secondary Drug Effectiveness, Drug Safety, AE Profile, Tolerability.1 Persistency was assessed by Kaplan-Meier analysis for time to therapy stop/switch seperately for Stelara®, infliximab, adalimumab and etanercept Study Limitations: Data in the overall population were adjusted for possible differences amongst groups. Data were not adjusted for variability such as socioeconomic factors (e.g. access to medication), setting of administration (self- versus physician-administered), geographic region, and clinical characteristics.

STELARA® solution for injection PRESCRIBING INFORMATION ACTIVE INGREDIENT(S): Ustekinumab. Please refer to Summary of Product Characteristics (SmPC) before prescribing. INDICATION(S): Plaque psoriasis adults: Treatment of moderate to severe plaque psoriasis in adults who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapies including ciclosporin, methotrexate or PUVA. Plaque psoriasis paediatrics: Moderate to severe plaque psoriasis in adolescent patients from the age of 12 years and older, who are inadequaely controlled by, or are intolerant to, other systemic therapies or phototherapies. Psoriatic arthritis: Alone or in combination with methotrexate for the treatment of active psoriatic arthritis in adult patients when the response to previous non-biological diseasemodifying anti-rheumatic drug (DMARD) therapy has been inadequate. DOSAGE & ADMINISTRATION: Under the guidance and supervision of a physician experienced in diagnosis and treatment of psoriasis or psoriatic arthritis. Subcutaneous injection. Avoid areas with psoriasis. Self-injecting patients or caregivers ensure appropriate training Physicians are required to follow-up and monitor patients. Plaque psoriasis, adults & elderly: Patients <100kg, 45 mg at week 0 followed by a 45 mg dose at week 4, then every 12 weeks. Patients >100 kg, 90 mg at week 0 followed by a 90 mg dose at week 4, then every 12 weeks (45 mg was less effective in these patients). Plaque psoriasis paediatrics (12 years and older): Patients <60 kg, 0.75 mg/kg at week 0, followed by 0.75 mg/kg at week 4 then every 12 weeks thereafter. Patients ≥60-<100kg, 45 mg at week 0 followed by 45 mg at week 4, then every 12 weeks. Patients >100 kg, 90mg at week 0, followed by 90mg at week 4, then every 12 weeks. Psoriatic arthritis, adults & elderly: 45 mg at week 0 followed by a 45 mg dose at week 4, then every 12 weeks. Alternatively, 90 mg may be used in patients with a body weight >100 kg. Consider discontinuation if no response after 28 weeks. Children <12 years: Not recommended. Renal & Hepatic impairment: Not studied. CONTRAINDICATIONS: Hypersensitivity to product; clinically important, active infection. SPECIAL WARNINGS & PRECAUTIONS: Infections: Potential to increase risk of infections and reactivate latent infections. Caution in patients with a chronic infection or history of recurrent infection, particularly TB. Patients should be evaluated for tuberculosis prior to initiation of STELARA. Consider anti-tuberculosis therapy prior

to initiation of STELARA in patients with past history of latent or active tuberculosis. Patients should seek medical advice if signs or symptoms suggestive of an infection occur. If a serious infection develops, they should be closely monitored and STELARA should not be administered until infection resolves. Malignancies: Potential to increase the risk of malignancy. No studies in patients with a history of malignancy or in patients who develop malignancy while receiving STELARA. Monitor all patients, in particular those older than 60, patients with a medical history of prolonged immunosuppressant therapy or those with a history of PUVA treatment for non-melanoma skin cancer. Concomitant immunosuppressive therapy: Caution, including when changing immunosuppressive biologic agents. Hypersensitivity reactions: Serious hypersensitivity reactions (anaphylaxis and angioedema) reported, in some cases several days after treatment. If these occur appropriate therapy should be instituted and, STELARA discontinued immediately. Latex sensitivity: Needle cover contains natural rubber (latex), may cause allergic reactions. Immunotherapy: Not known whether STELARA affects allergy immunotherapy. Serious skin conditions: Exfoliative dermatitis has been reported following treatment. Discontinue STELARA if a drug reaction is suspected. SIDE EFFECTS: Common: dental infections, upper respiratory tract infection, nasopharyngitis, dizziness, headache, oropharyngeal pain, diarrhoea, nausea, pruritus, back pain, myalgia, arthralgia, fatigue, injection site erythema, injection site pain, antibodies to ustekinumab. Other side effects include: cellulitis, serious hypersensitivity reactions (including anaphylaxis, angioedema), skin exfoliation, exfoliative dermatitis. Studies show adverse events reported in ≥12 year olds with plaque psoriasis were similar to those seen in previous studies in adults with plaque psoriasis. Refer to SmPC for other side effects. FERTILITY: The effect of ustekinumab has not been evaluated. PREGNANCY: Should be avoided. Women of childbearing potential: Use effective contraception during treatment and for at least 15 weeks posttreatment. LACTATION: Limited data in humans. INTERACTIONS: In vitro, STELARA had no effect on CYP450 activities. Vaccinations: Live vaccines should not be given concurrently with STELARA, and should be witheld for at least 15 weeks after last dose of STELARA. STELARA can resume at least 2 weeks after such vaccinations. No data on secondary transmission of infection by live vaccines

in patients receiving STELARA. Concomitant immunosuppressive therapy: Psoriasis: The safety and efficacy of STELARA in combination with other immunosuppressants, including biologics, or phototherapy have not been evaluated. Refer to SmPC for full details of interactions. LEGAL CATEGORY: Prescription Only Medicine. PRESENTATIONS, PACK SIZES, MARKETING AUTHORISATION NUMBER: 45 mg: 1 x vial. EU/1/08/494/001, 45mg: 1 x 0.5ml prefilled syringe. EU/1/08/494/003. 90mg: 1 x 1.0ml pre-filled syringe. EU/1/08/494/004. 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 2015 Adverse events should be reported. Healthcare professionals are asked to report any suspected adverse events via: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website: 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: 06/2015 References: 1. Warren RB et al. J Inv Dermatol. Accepted article: June 2015; doi: 10.1038/jid.2015.208. 2. Menter et al. P1705: Presented at the AAD annual meeting 2015. 3. Gniadecki R et al. Br J Dermatol. 2015 Jan; 172(1): 244-252. 4. Kimball AB et al. JEADV 2013; 37: 1535-1545. Date of preparation: April 2016 | PHIR/STE/0416/0002


16 Feature between the prescriber/ patient and also the prescriber/ dispensing pharmacist. The Authority also urges ongoing engagement between prescribers, dispensers, and those with responsibility for procurement. O’Callaghan said there should also be meaningful stakeholder engagement in order to ensure both the optimal use of resources as well as ensuring the best patient outcomes. Switching back and forth is not recommended due to the paucity of data on the impact of this. The Authority is currently involved in a Regulatory Science Ireland project on biosimilars, working adjacently with University College Cork and the Irish Pharmaceutical and Healthcare Association (IPHA). Ms O’Callaghan explained that this is focused on identifying practical considerations for health professionals; a prescriber survey has already been carried out to determine the knowledge, behaviours, and attitudes towards biologic medicines, particularly biosimilars. The goal is to develop appropriate training material and online resources for both prescribers and patients. Introducing Biosimilars in the Irish Hospital Setting Professor Laurence Egan from NUI Galway discussed concerns regarding indication extrapolations for biosimilars, particularly within autoimmune conditions such as rheumatoid arthritis, psoriasis and inflammatory bowel disease (IBD). A biosimilar of the anti-tumour necrosis factor (TNF) infliximab was approved by the European Medicines Agency in 2013, and Professor Egan outlined concerns, formally stated by the European Crohn’s and Colitis Organisation in a position statement, and echoed by his own hospital, regarding extrapolation for biosimilar infliximab, with no published data on its use in IBD. Galway University Hospital (GUH) carried out a study in 2014 which investigated whether the biosimilar infliximab could provide advantages for patients

July/August 2016 • HPN

and/or the hospital. This looked at switching existing rheumatoid arthritis (RA) patients who were already on infliximab to the biosimilar, as well as newlypresenting patients starting biologic therapy. The study also aimed to explore the cost implications of adopting the biosimilar infliximab for patients at GUH. It was supported by a detailed policy on Biosimilar Medicines drawn up by the hospital. All 40 RA patients agreed to switch to the biosimilar, and while consultants were not confident of its use in IBD, it was agreed to start new infliximab patients on the biosimilar for a trial period. “No new problems arose and they have continued on it since,” explained Professor Egan. No IBD patients switched from the originator drug. He said patients were given additional information, such as leaflets. The study was broadly successful, although there were too few patients involved to detect any significant differences in efficacy or safety. Biosimilar infliximab has been subsequently adopted by several other Irish hospitals, and at least one private health insurer has approved reimbursement for infliximab biosimilar. Professor Egan concluded by stating that infliximab biosimilar usage continues to grow, and was successfully introduced at GUH albeit with a different approach for RA and IBD patients, based on the available clinical data. He emphasised the key role and autonomy of the prescribing consultants and the crucial requirement of a defined policy on biosimilar adoption. The International Perspective – Norway Professor Bjorn Moum of Oslo University Hospital Ulleval discussed the Norwegian experience with biosimilars. He echoed Professor Egan by saying that biosimilar use has increased in Norway, and with this the resulting economic impact has been felt. The first biosimilar was approved in February 2014, and at that time the professor penned an editorial explaining his scepticism towards biosimilars, as well as

urging their conservative use, and only under close monitoring. This scepticism is mirrored throughout Europe, with the positions of the respective medical societies being quite similar. Professor Moum explained that societies are generally quite neutral regarding switching but have broadly negative views on indication extrapolation. Various patient advocacy groups have also published their positions, and are broadly neutral or positive regarding biosimilars but again have concerns when it comes to extrapolation. “My experience with my patients is that they have been more sceptical than my colleagues, about starting, but especially about extrapolation and switching from a stable treatment.” He said the policy is to inform all patients in advance that they plan to switch therapies at their next visit. While most accept this, some initially refuse to do so, and he added that new patients are also quite sceptical. Professor Moum advised that a comprehensive discussion should take place between the prescriber and the patient. He continued by saying that while efficacy does appear to be similar between biosimilars and originator medicines, concerns remain about safety due to lack of clinical data. He is involved in a study being carried out in Norway, which has the goal of determining the safety and efficacy of switching from the originator infliximab to the biosimilar, compared with continuation of treatment with the originator. The NOR SWITCH study involves patients with RA, spondyloarthritis, psoriatic arthritis, Crohn’s disease, ulcerative colitis, and chronic plaque psoriasis. All new IBD patients were given the infliximab biosimilar from May 2014, and in September 2015 all patients were switched from the originator to the biosimilar, he explained. Switching was carried out for medical reasons, such as loss of response or adverse effects, but if patients were stable on their biologic therapy they remained

on it. The results of this study will be delivered at a major European gastroenterology meeting this autumn. Professor Moum said that the gastroenterology unit at his hospital gives more than 300 infusions of biologics each month, and this had increased more than 50% in the past two years. There are capacity issues, as well as cost implications for this. Switching to biosimilars had resulted in significant cost savings at the hospital, but he raised the question of who benefits from these savings; Professor Moum’s department successfully negotiated that some of the savings be used to improve the IBD service by funding additional staff at the unit, such as an additional consultant and an IBD specialist nurse. Although the Infliximab biosimilar (Remsima) market share is steadily increasing in Norway, there has been no concomitant fall in the use of other anti TNF therapies, as would have been expected, the professor explained. Instead, the use of biologics is increasing, and this is for a variety of reasons. Patients are being prescribed biologics much earlier in their disease course than before in a bid to reverse the disease course and prevent complications; patients are also being given intensified doses, as well as combinations of different biologics in more difficult patients. In Norway, patients are not being prevented access to biologics for economic reasons, although this is happening in other countries. Professor Moum posed the question: If switching to a cheaper biosimilar results in more patients on biologics, who will take on these costs? These include not only the cost of the therapy, but also the associated costs such equipment, facilities, and staff. The concern is also there that if manufacturers of originator therapies are forced to reduce their price dramatically, this may affect funding for further innovative therapies. “Biosimilars are here to stay. So far they appear safe and can save great resources but the future is complex with more biosimilars expected.


INTUNIV is a different non-stimulant: – It has a unique mechanism of action in ADHD1 – It provides significant improvement in core ADHD symptoms within 3 weeks2 – INTUNIV provides up to 24 hour control,2 with a flexible once-daily morning or evening dosing regimen 3 Find out more about what makes INTUNIV different at www.fullattention.ie

INTUNIV is a non-stimulant indicated as part of a treatment programme for attention deficit/ hyperactivity disorder (ADHD) in paediatric patients (children and adolescents 6-17 years old inclusive).1 INTUNIV is not indicated in all individuals with ADHD and the decision to use INTUNIV must be based on a thorough assessment of the severity and chronicity of the child’s symptoms in relation to the child’s age.1 Please consult the INTUNIV Summary of Product Characteristics (SPC) before prescribing, particularly in relation to hypotension, bradycardia, syncope, sedation, somnolence and switching Intuniv® (guanfacine hydrochloride) Prescribing Information: Consult the Summary of Product Characteristics (SmPC) before prescribing. Presentation: Prolonged-release tablets, 1 mg, 2 mg, 3 mg and 4 mg; each tablet contains guanfacine hydrochloride equivalent to 1 mg, 2 mg, 3 mg and 4 mg respectively. Indication: Treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents 6 - 17 years old for whom stimulants are not suitable, not tolerated or have been shown to be ineffective. Use as a part of a comprehensive ADHD treatment programme. Dosage and administration: Oral, take once daily morning or evening, with or without food, but not with high fat meals. Do not crush, chew or break before swallowing. Do not take with grapefruit juice. Initiate treatment under the supervision of an appropriate specialist in childhood and/or adolescent behavioural disorders. Pre-treatment screening: Baseline evaluation to identify patients at increased risk of somnolence and sedation, hypotension and bradycardia, QT-prolongation arrhythmia and weight increase/ risk of obesity. Posology: Careful dose titration and monitoring is necessary at the start of treatment since clinical improvement and risks for several clinically significant adverse reactions are dose and exposure related. Recommended starting dose is 1 mg of guanfacine which may be adjusted in increments of not more than 1 mg per week. Dose should be individualised according to the patient’s response and tolerability. Recommended maintenance dose range is 0.05-0.12 mg/kg/day. For dose adjustments, dose titration and discontinuation plus monitoring requirements, refer to the Intuniv SmPC. Renal and hepatic impairment: Dose reduction may be required in patients with different degrees of hepatic impairment, and in patients with severe renal impairment (GFR 29-15 ml/min) and end stage renal disease (GFR<15 ml/ min or requiring dialysis). Children under 6 years: Intuniv should not be used because efficacy and

safety in this patient population has not been studied. Patients treated with CYP3A4/5 inhibitors/ inducers: Patients on moderate/strong CYP3A4/5 inhibitors: a dose reduction is recommended. Patients on strong CYP3A4 inducers: a dose increase within the recommended range is recommended. See SmPC for further details. Contraindications: Hypersensitivity to the active substance or any of the excipients. Warnings and precautions: Intuniv can cause syncope, hypotension and bradycardia. Caution is advised when treating patients with a history of hypotension, heart block, bradycardia, or cardiovascular disease, who have a history of syncope or a condition that may predispose them to syncope. Caution also advised with patients treated concomitantly with antihypertensives or other medicinal products that can reduce blood pressure or heart rate or increase the risk of syncope. Patients should be advised to drink plenty of fluid. Prescribe with caution in patients with a known history of QT prolongation, risk factors for torsade de pointes or patients taking medicinal products that prolong the QT interval. These patients should receive further cardiac evaluation based on clinical judgement. Intuniv may cause somnolence and sedation predominantly at the start of treatment and could typically last for 2-3 weeks and longer in some cases, therefore it is recommended that patients are monitored closely during dose titration and stabilisation. Patients with emergent suicidal ideation or behaviour during treatment for ADHD should be evaluated immediately by their physician. Children and adolescents treated with Intuniv may show an increase in their BMI, therefore, monitoring of height, weight and BMI should be done prior to initiation of therapy and then every 3 months for the first year. Six monthly monitoring should follow thereafter with more frequent monitoring following any dose adjustment. Intuniv contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or

from other formulations of guanfacine. Very common adverse reactions include somnolence, headache, sedation, abdominal pain and fatigue. Common adverse reactions include decreased appetite, depression, anxiety, affect lability, insomnia, middle insomnia, nightmare, syncope/loss of consciousness, dizziness, lethargy, bradycardia, hypotension, orthostatic hypotension, asthma, vomiting, diarrhoea, nausea, dyspepsia, constipation, abdominal/stomach discomfort, dry mouth, rash, enuresis, irritability, change in blood pressure and weight increased.

glucose-galactose malabsorption should not take Intuniv. Interaction with other medicinal products and other forms of interaction: All drug-drug interaction studies have been performed in adults. However, the outcome is expected to be similar in the indicated paediatric age range. QT-Prolonging medicinal products: Intuniv causes a decrease in heart rate, therefore the concomitant use of Intuniv with QT prolonging medicinal products is generally not recommended. CYP3A4 and CYP3A5 inhibitors: See SmPC for further details. Valproic acid: Co-administration can result in increased concentrations of valproic acid. Adjustments in the dose of valproic acid and Intuniv may be indicated when co-administered. Antihypertensive medicinal products: Caution when administered concomitantly due to the potential for hypotension and syncope. CNS depressant medicinal products: Caution when administered concomitantly due to the potential for sedation and somnolence. Effects on ability to drive and use machines: May cause drowsiness and somnolence. Side effects: Very common (≥1/10 patients): somnolence, headache, abdominal pain, fatigue; Common (≥1/100, <1/10 patients): decreased appetite, depression, anxiety, affect lability, insomnia, middle insomnia, nightmare, sedation, dizziness, lethargy, bradycardia, hypotension, orthostatic hypotension, vomiting, diarrhoea, nausea, constipation, abdominal/stomach discomfort, dry mouth, rash, enuresis, irritability, blood pressure decreased, weight increased. See the Intuniv Summary of Product Characteristics for full details of Undesirable Effects. Package quantity and price for the UK: 28 tablet pack: 1 mg: £56.00; 2 mg: £58.52; 3 mg: £65.52; 4 mg: £76.16. Pharmaceutical precautions: None. Legal category: POM. Date of preparation: September 2015. Marketing authorisation number and holder: EU/1/15/1040/001-009. Shire Pharmaceuticals Ireland Limited, 5 Riverwalk, Citywest Business Campus, Dublin 24, IRELAND. Tel: 0800

055 6614. Email: medinfouk@shire.com. Further information is available on request. INTUNIV is a registered trade name. References: 1. Intuniv Summary of Product Characteristics. Shire Pharmaceuticals Ireland Limited. 2. Biederman J et al. Pediatrics 2008; 121: 1: e73-e84. 3. Newcorn JH et al. J Am Acad Child Adolesc Psychiatry 2013; 52(9): 921-930. This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. UK: Adverse events should be reported. Reporting forms and information can be found at: www.mhra.gov.uk/ yellowcard. Ireland: Adverse events should be reported to the Pharmacovigilance Unit at the Health Products Regulatory Authority (HPRA) at: http://www.hpra.ie. UK and Ireland: Adverse events should also be reported to Shire Pharmaceuticals Ltd. on +44 (0)1256 894000 or faxed on +44 (0) 1256 894715 or emailed to: globalpharmacovigilance@shire.com Date of preparation: June 2016 IRE/C-APROM/INT/16/0006 ©Shire 2016


18 Feature We can’t keep doing what we are doing or people will lose out. It might not be rheumatology patients but someone will lose out as we will not be able to afford everything. The biosimilars do afford us a chance to impact on an unsustainable situation ‘Biogenerics’ are also coming, as well as ‘biobetters’ and ‘biosuperiors’, and eventually the second generation biologics,” he concluded. Patient Benefits – Panel Discussion A wide-ranging and interactive panel discussion, chaired by IPPOSI Chief Executive Derick Mitchell, took place following the presentations. The three speakers were joined by Professor Michael Barry from the National Centre for Pharmacoeconomics and John Church, CEO of Arthritis Ireland. Mr Church spoke about the potential impact of biosimilars from the patient perspective. He believed this would be limited, citing the current failure rates of available biologics. Although the increased use of biosimilars may have a cost impact, this will not immediately benefit the patient, he said. “We are talking about biosimilars but you could actually have ‘biopatients’ – no two patients are the same. You might have two females with RA, the same age, etc. but neither may respond to anti-TNFs, or one may respond positively and the other not. So it’s not going to close the gap on unmet needs.” Asked if patients were actually more sceptical than doctors in this area, John Church responded with, “my interpretation of the survey results are that safety is number one over efficacy, because ultimately the patient fully trusts the doctor as long as it is safe. We openly encourage patients to actively communicate with the doctor on that, and Arthritis Ireland has produced twenty drug specific patient information leaflets to be sent out to clinics. I’m not sure any other patient organisation is doing that”, he added.

July/August 2016 • HPN

Drugs with new and different modes of action are required, he said, referencing the significant investment Arthritis Ireland are making in terms of research into personalised medicine as it becomes clear that anti-TNF therapies are not suitable for everyone. He also echoed previous statements that any savings achieved by the use of biosimilars should stay within the particular disease area, and be used to improve the service by hiring more clinicians and nurse specialists, with the ultimate goal of decreasing waiting lists. Professor Barry followed by saying the “volume of biologics is going up and up and up”; therefore the real issue is sustainability. “We can’t keep doing what we are doing or people will lose out. It might not be rheumatology patients but someone will lose out as we will not be able to afford everything. The biosimilars do afford us a chance to impact on an unsustainable situation.” In response to a question by Dr Mitchell on where the cost savings would be reappropriated, Prof Barry stated that he is a firm believer in “incentives” and agreed that at least some of these savings should be put back into patient care. Professor Egan commented that both clinicians and patients have attempted to limit the “excessive” use of biologics, citing concerns about safety, uncertainty about the long term impact of biologics on the natural history of disease, as well as a “moral or ethical perspective where we need to be sure we are prescribing these medications cost effectively”. He admitted the “expense is hard to justify”, but emphasised the impact of improved quality of life for patients.

“It’s being able to remain in work, it’s avoiding complicated surgeries, potentially avoiding patients going on long term sick leave and requiring welfare. The pricing and value for money when it comes to patients is very, very complex.” When asked how could some of the non-clinical impacts be appropriately incorporated into drug assessments, Professor Barry acknowledged that there has been a “sophistication” in relation to the case put forward by industry when medicines are being assessed for reimbursement. “It does include a quality of life, a wide range of costs and benefits. I think it’s fair to say that all those aspects are taken into consideration when you are doing the value for money. You could argue that about ten years ago that wasn’t happening but it certainly is now.” He added, however, that anti-TNFs had been made available in Ireland before the routine assessment of therapies commenced, and suggested that perhaps it is time to assess them again, alongside the biosimilars. The key role of the patient voice was asserted throughout the discussion, and Professor Barry stated that he reads many patient submissions that now accompany requests for reimbursement, and is impressed by their content. “Through collaboration with patient groups such as yourselves (IPPOSI), patients do know what’s coming next, they know what assessments we are going to do and we value their input. Very often, the patients have more insight into it than the prescribers.” Ms O’Callaghan reiterated the importance of pharmacovigilance in relation to the biosimilars; she said that the establishment of Irish patient registries would be an ideal way to achieve close monitoring and reassure when it comes to the biosimilars. “If there is an Irish registry it will give more assurance to prescribers and to patients as well, knowing that the safety of these products is being

closely watched. As well as that, pharmaceutical companies would have to submit updated safety data to the regulator once the product is authorised because there would be a re-evaluation of the benefit/risk profile of the medicine every so often.” Ms O’Callaghan added that when the infliximab biosimilar was approved by the European Medciines Agency in 2013, their advice was for safety data to be included in patient registries. The HPRA endorses that approach, she emphasised. Asked if we have learned anything for the introduction of the next biosimilars, Professor Egan said that “based on our experience with biosimilar infliximab so far, I would say it has been positive for both IBD patients and for physicians as well”. Bjorn Moum agreed. “I think we have learned a lot from the first monoclonal biosimilars and the next ones will come onto the market faster, as the amount of reluctance will be less. However he clarified that “At the moment, it is all about costs. For the future, we need to take into account the global costs, not just the medical ones. In IBD, two thirds of costs are indirect (sick leave, disability etc.)” Key Points  Awareness and understanding about biosimilars is low among patients 
  Patients have limited access to appropriate information on these treatments  Biosimilars may provide benefit in terms of cost savings  Concerns remain about switching and interchangeability 
  Close follow-up is required if a patient is prescribed a biosimilar 
  Hope that use of biosimilars does not impede innovative drug development
  Patient experience must inform value assessments


Date of Preparation: May 2016. NA-059-03

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20 Clinical Synopsis

ASCO 2016 Meeting Updates Written by D Kelly, M Higgins J McCaffrey ‘Every year, thousands of oncologist and millions of patients all over the world await the news coming from this meeting-new breakthroughs, new therapies, new promises of cure, hope. ASCO is harnessing the collective wisdom of oncologists around the world to put patients at the centre of research and care’- Joe Biden ASCO 2016 The annual ASCO meeting, with over 5,000 research submissions and over 34,000 attendees, concentrates the most recent advances in global cancer research .There has been huge optimism over the last few years with breakthroughs in immunotherapy demonstrating durable activity across certain cancer types. Priority remains on continuing to refine treatment combinations and identify effective biomarkers to enhance clinical efficacy. Local Management of Breast Cancer Updated results from the ACOSOG ZOO11 trial were presented. This trial looked at patients with early stage (T1-T2) breast cancer, with clinically node negative disease at presentation. Patients underwent standard breast conserving surgery. Those with less than 2 lymph nodes positive at surgery were then randomised to receive axillary lymph node dissection (ALND) versus no further surgery. Patients then proceeded to planned whole breast radiation and adjuvant systematic therapy. At 10 years of follow up there was no difference in locoregional recurrence or disease free survival (DFS) between the two arms.1 This study confirmed that there is no role for ALND for patients with positive sentinel lymph node at surgery who receive adjuvant radiation and systemic therapy. This result remains practice informing by limiting surgical interventions to only those that will produce clinically meaningful outcomes. Two other prospective studies with different designs (MFO7- 01 and TBCRC 013)2,3 reviewed whether there was a role of mastectomy in stage IV breast cancer. In the US 5% of patients present with de novo metastatic breast cancer. The TBCRC 013 trial did not show a benefit for surgical intervention. At present the mainstay of treatment for women with stage IV breast cancer remains systemic therapy. Surgical intervention should only be considered for palliation. Oestrogen Receptor + Breast Cancer The plenary breast cancer session examined extended Aromatase Inhibitor (AI) therapy in post menopause early stage estragon receptor positive(ER+) breast cancer ( CTCG MA.17R).4 This was a Phase III study of 1918 July/August 2016 • HPN

patients. The majority (70%) had received 5 years of tamoxifen followed by 5 years of letrozole. They were then randomised to an additional 5 year of letrozole versus placebo. Extended letrozole significantly reduced the disease free survival relative to placebo however the absolute advantage was small and there was no difference in overall survival (OS). The primary advantage of the extended AI therapy was a reduced incidence of contralateral breast cancers. There was a 5% increased risk of bone fractures and new osteoporosis in group with extended AI therapy. Of note only 62% were adherent to the extended therapy regimen.4 Overall it appears the benefits of extended AI are small. Patients selection is necessary with an individualized approach based on baseline tumour risk factors, tolerance, bone health and the presence of contralateral breast tissue. HER 2 + Breast Cancer In Her 2 + breast cancer incredible responses to targeted therapy have improved long term survival outcomes for patients. The Cleopatra Study in first line metastatic Her 2 + breast cancer established that pertuzumab added to a taxane and trastuzumab improved OS by an additional 15.7 months.5 The Pherexa Trial examined the role of pertuzumab in 2nd line Her 2 + breast cancer. Patients who have received pervious paclitaxel and trastuzumab were randomised to chemotherapy and trastuzumab with pertuzumab versus chemotherapy and trastuzumab. There was no difference in progression free survival (PFS) between the two arms6 and trastuzumab emtansine (TDM-1) remains the standard of care in this setting. The Kristine Trial (Abstract 500) was a phase III study of over 400 patients with early stage Her 2 + breast cancers. Patients were included if their primary tumours were over 2cm and 62% of patients had ER + disease. Patients were randomised to wither neoadjuvant TDM1 and Pertuzumab or docetaxel, carboplatin, trastuzumab (TCH) and pertuzumab. The primary endpoint was rate of pathological complete response (pCR). pCR rates were higher in the TCH and pertuzumab arm (56% versus 44% ,p0.015) .Toxicity was increased TCH and pertuzumab 29% versus 5% with TDM1 + pertuzumab.7 This study is helpful in aiding patients selection based on goals of treatment and the need to balance efficacy versus toxicity. Developmental Therapeutics Ground-breaking work continues to be

advanced in the field of immunotherapy .A phase 2 study looking at PD-1 blockade in mismatch repair (MMR) deficient cancers reported on 55 patients with metastatic or locally advanced MMR deficient colorectal cancer.8 They had received at least two prior lines therapy and proceeded to pembrolizumab 10mg/kg q2w.The overall response rate (ORR) in MMR deficient colorectal cancer was 57% versus 0% in MMR proficient colorectal cancer. The investigators also found that mutational load was a good predictor of response to PD-1 blockade.8 This study is practice changing as it shows that MMR deficient colorectal cancers have high and durable responses to anti PD1 therapy (where available). Unprecedented response rates were seen in first line advanced non-small cell lung cancer (NSCLA) with ORR 39-47% with the combination nivolumab 3mg/kg q2 /w and low dose ipilimumab(1mg/kg q 6-12w).9 Head and Neck Cancer Particularly exciting work has revealed new standards for recurrent and metastatic head and neck cancer. The Checkmate 141 Trial randomised over 300 patients with recurrent refractory metastatic Head and Neck squamous cell carcinoma (HNSCC) who had received previous platinum therapy. They proceeded to nivolumab versus standard second line chemotherapy. The one year OS to the nivolumab arm was 36% versus 16% in the standard of care arm (p0.01).10 This represents a new treatment paradigm for this patient cohort. The Keynote 055 Study was a single arm phase II trial of recurrent HNSCC refractory to platinum and cetuximab. Patients received pembrolizumab 200mg q3w.The ORR was 18%.The represents a new standard of care in platinum refractory patients and FDA approval is pending.11 Lung Cancer An intriguing area of development is a novel agent rovalpituzumab tesirine (Rova-T).This is a conjugate drug antibody to delta-like protein 3 (DLL3 which is overexpressed in up to 80% of small cell lung cancer (SCLC).A combined phase 1 and 2 study demonstrated ORR of 20-40%.This result is unprecedented in this patients group and represents a new target with promising level of activity .A phase III trial is currently underway.12 The Phase III J-ALEX study compared first line alectinib to crizotinib for the treatment of ALK-translocated non small cell lung cancer with much improved disease free


Taking life further in CLL

IMBRUVICA is indicated1 • As a single agent for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia • For the treatment of adult patients with: - chronic lymphocytic leukaemia who have received at least one prior therapy - relapsed or refractory mantle cell lymphoma - Waldenström’s macroglobulinaemia who have received at least one prior therapy, or in first-line treatment for patients unsuitable for chemo-immunotherapy

IMBRUVICA® 140 mg Hard Capsules PRESCRIBING INFORMATION ACTIVE INGREDIENT: Ibrutinib. Please refer to Summary of Product Characteristics (SmPC) before prescribing. INDICATIONS: Treatment of adult patients with: relapsed or refractory mantle cell lymphoma (MCL); chronic lymphocytic leukaemia (CLL) who are previously untreated or have received ≥ one prior therapy; Waldenström’s macroglobulinaemia (WM) who have received ≥ one prior therapy, or in first line in patients unsuitable for chemo-immunotherapy. DOSAGE & ADMINISTRATION: Adults: Orally, once daily, swallowed whole with water. MCL - 4 capsules. CLL & WM - 3 capsules. Concomitant moderate/ strong CYP3A4 inhibitors – reduce to 1 capsule (or, with strong inhibitors, withhold IMBRUVICA for up to 7 days). Withhold IMBRUVICA therapy for any new onset/worsening grade ≥ 3 nonhaematological toxicity, grade ≥ 3 neutropenia with infection/ fever, or grade 4 haematological toxicities. Re-initiate when toxicities resolved to grade 1 or baseline. If toxicities recur, reduce dose by 1-2 capsules. Discontinue IMBRUVICA if toxicities persist/recur following two dose reductions. Children: Safety/ efficacy not established ≤ 18 years old. Elderly: No dose adjustment required. Renal impairment: Mild/moderate - no dose adjustment. Severe – no data; consider benefit/risk and monitor closely. No data with dialysis. Hepatic impairment: Mild (Child-Pugh class A) – 2 capsules daily; moderate (ChildPugh class B) – 1 capsule daily; severe (Child-Pugh class C) – not recommended. Monitor for toxicities. Severe cardiac disease: No clinical data. CONTRAINDICATIONS: Hypersensitivity to active substance/excipients. St. John’s Wort preparations. SPECIAL WARNINGS & PRECAUTIONS: Bleeding-related events: Minor and major haemorrhagic events reported; caution with anticoagulant therapy – do not use concomitantly with warfarin or other vitamin K antagonists, avoid fish oil and vitamin E preparations. Withhold IMBRUVICA ≥ 3 to 7 days pre-/post-surgery. Leukostasis: Cases reported; consider temporary withhold of IMBRUVICA; monitor closely, give supportive care. Infections: Infections seen, some resulting in hospitalisation and death; monitor for fever, neutropenia and infections and give anti-infective therapy. Cytopenias: Treatment-emergent grade 3/4 cytopenias reported; monitor complete blood counts monthly. Atrial fibrillation/ flutter: reported particularly in patients with cardiac risk factors/ acute infections/previous history of atrial fibrillation; periodic clinical monitoring; consider ECG if arrhythmic symptoms or new onset dyspnoea develop; consider alternative to IMBRUVICA when pre-existing atrial fibrillation requiring anticoagulant

therapy or high risk of thromboembolic disease; where no suitable alternatives to IMBRUVICA, consider tightly controlled treatment with anticoagulants. Tumour lysis syndrome: cases reported. Monitor at risk patients closely, take precautions. Non-melanoma skin cancer: cases reported; monitor patients. Effects on the QT interval: mild decrease in QTcF interval seen; use clinical judgment before prescribing for patients at risk from further shortening QTc duration. Drug-drug interactions: Strong/ moderate CYP3A4 inhibitors may increase ibrutinib exposure; CYP3A4 inducers may decrease ibrutinib exposure. Avoid where possible, if not monitor closely for toxicities/lack of efficacy. SIDE EFFECTS: Very common: Pneumonia, upper respiratory tract infection, urinary tract infection, sinusitis, skin infection, neutropenia, thrombocytopenia, anaemia, dizziness, headache, haemorrhage, bruising, diarrhoea, vomiting, stomatitis, nausea, constipation, rash, arthralgia, musculoskeletal pain, pyrexia, oedema peripheral, muscle spasms. Common: Sepsis, nonmelanoma skin cancer, basal cell carcinoma, squamous cell carcinoma, febrile neutropenia, leukocytosis, lymphocytosis, dehydration, hyperuricaemia, vision blurred, atrial fibrillation, subdural haematoma, epistaxis, petechiae, hypertension, dry mouth, erythema. Other side effects: Leukostasis syndrome, tumour lysis syndrome, hepatic failure, angioedema. Refer to SmPC for other side effects. PREGNANCY: Women of childbearing potential must use highly effective contraceptive measures during and for 3 months after stopping treatment; if using hormonal contraceptives, add barrier method. Not to be used during pregnancy. LACTATION: Discontinue breast-feeding during treatment. INTERACTIONS: CYP3A4 inhibitors: Strong: Avoid where possible or reduce dose (or withhold IMBRUVICA for ≤ 7 days) and monitor closely; e.g. ketoconazole, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, nefazadone, cobicistat. Moderate: Avoid where possible or reduce dose and monitor closely; e.g. diltiazem, voriconazole, erythromycin, amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, fluconazole, fosamprenavir, imatinib, verapamil, amiodarone, dronedarone. Avoid grapefruit and Seville oranges. Mild: No dose adjustment required; monitor closely. CYP3A inducers: Strong/moderate: Avoid or monitor closely for lack of efficacy; e.g. carbamazepine, rifampicin, phenytoin. Mild: may be used; monitor for lack of efficacy. Medicines that increase stomach pH (e.g. proton pump inhibitors) may decrease ibrutinib exposure. Potential interactions: Oral narrow therapeutic range P-gp

or breast cancer resistance protein (BCRP) substrates (e.g. digoxin, methotrexate) should be taken ≥ 6 h before/after IMBRUVICA. Ibrutinib may inhibit BCRP in the liver and so increase exposure of drugs undergoing BCRP-mediated hepatic efflux (e.g. rosuvastatin). Ibrutinib may inhibit intestinal CYP3A4 and thus increase exposure of some CYP3A4 substrates sensitive to gut CYP3A metabolism; caution with narrow therapeutic range oral CYP3A4 substrates (e.g. dihydroergotamine, ergotamine, fentanyl, cyclosporine, sirolimus, tacrolimus). Ibrutinib is a weak CYP2B6 inducer and may affect expression of other enzymes and transporters regulated via the constitutive androstane receptor (CAR),(e.g. CYP2C9, CYP2C19, UGT1A1, MRP2). Exposure to substrates of CYP2B6 (e.g. efavirenz, bupropion) and co -regulated enzymes may be reduced with ibrutinib. Refer to SmPC for full details of interactions. LEGAL CATEGORY: Prescription only medicine PRESENTATIONS

PACK SIZES

MARKETING AUTHORISATION NUMBER(S)

Bottles

90 capsules

EU/1/14/945/001

Bottles

120 capsules

EU/1/14/945/002

MARKETING AUTHORISATION HOLDER: Janssen-Cilag International NV, Turnhoutseweg 30, B-2340 Beerse, Belgium FURTHER INFORMATION IS AVAILABLE FROM: JanssenCilag Limited, 50-100 Holmers Farm Way, High Wycombe, Buckinghamshire, HP12 4EG UK. Prescribing information last revised: May 2016 Reference: 1. Imbruvica® Summary of Product Characteristics. Janssen Cilag International May 2016. Date of preparation: June 2016. PHIR/IBR/0616/0003 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 Limited on +44 1494 567447 or at dsafety@its.jnj.com

IMBRUVICA® is co-developed with Pharmacyclics. Janssen-Cilag Limited is the marketing authorisation holder and responsible editor of this document.

@JanssenIE © Pharmacyclics LLC 2016

Destination survival

© Janssen-Cilag Limited 2016


22 Clinical Synopsis survival and improved tolerability. If these findings are confirmed in the ongoing global ALEX study it is anticipated that alectinib will become the preferred first treatment in this subgroup of lung cancer patients.13 Gastrointestinal Cancer Review of colorectal cancer databases and studies have revealed that right and left sided colorectal tumours appear to be distinct cancers with different biological targets, responses to treatment and prognosis .OS outcomes for stage IV right sided tumours are inferior to left sided tumours (HR 1.25 ).14 There is a 10 month additional improved OS for patients with Stage IV CRC with left sided tumours. Right sided tumours have a higher frequency of BRAF mutations15 and appear to benefit more from Bevacizumab with minimal benefit from cetuximab. Cetuximab appears to add more than bevacizumab in kras wild type patients with metastatic colorectal cancer in the first line setting with left sided primaries.16 Within resected pancreatic cancer, the new standard of care is adjuvant gemcitabine with capecitabine 1660mg/m2/d 21 days of 28 day cycle based on the ECPAC -4 trial of over 700 patients. This regimen was well tolerated and demonstrated an additional OS advantage of 2.5 months versus gemcitabine alone (HR 0.82).17 Genitourinary Cancer Advanced urothelial cancer has been challenging to treat however two studies of atezolizumab have provided positive data. In patients who were cisplatin ineligible, first line Atezolizumab produced a 12 month os of 57%.18 In patients who had receive previous platinum therapy, atezolizumab elicited a 12 month OS of 35%.It was well tolerated and compared favourably to alternative therapies in this space. This has led to the FDA accelerating approval of atezolizumab in post platinum bladder cancer patients.19 Melanoma Patients with unresectable Braf mutated stage IIIc/IV melanoma with low or normal LDH, less than 3 sites of disease and a good performance status should be considered for up front Braf-Mek inhibition. This is based on a phase III study of over 400 patients, randomised to dabrafenib and trametinib versus dabrafenib alone, which demonstrated an improved three year OS for the combination arm 44% versus 32%. It was well tolerated with over half the patients who had durable responses remain on combination treatment represent. It also represents a very active therapy in patients with CNS involvement.20 Updated Checkmate 067 data was presented. This was a trial of over 900 patients with unresectable metastatic July/August 2016 â&#x20AC;˘ HPN

melanoma randomised to nivolumab and ipilimumab combination versus nivolumab versus ipilimumab. ORR were 57.6% for the combination, 43.7% for nivolumab monotherapy and 19% for ipilimumab monotherapy however PFS at 12 and 18 months is similar between combination versus nivolumab. It appears there may not be a substantial advantage in adding ipilimumab to nivolumab in terms of improving the rates of complete responses. Of note, the combination therapy is associated with increased incidence (55%) of grade 3-4 adverse events which appear to also have increased likelihood of involving multiple organs.21

breakthroughs to the clinic and continue to provide our patients with the most up-todate care possible.

A phase II survival analysis in patients with advanced melanoma who discontinued treatment with nivolumab plus ipilimumab due to toxicity showed similar one year OS rates between patients who discontinued versus those who continued therapy.22 Patients who get immune related adverse events may not need to continue treatment as if they are going to benefit, they will get the clinical response whether the drug is restarted or not and there is little value in reposing patients to potential further toxicity.

6. J Clin Oncol 33, 2015 (suppl; abstr 507)

At this time the 12 month OS for combination therapy is identical to that of nivolumab.23 Sequential treatment may be approached similar efficacy and the stander of care remains both anti PDL-1 monotherapy or combination immunotherapy.

15. J Clin Oncol 34, 2016 (suppl; abstr 3506)

These are only some of the incredible advances presented at the ASCO 2016 meeting. All of which, are due to the generous and inspiring role patients play in engaging with clinical trials. It is their steadfast resolve and courage that calls us to be innovative in our quest for improved outcomes, to be meticulous in our research and maintain integrity in the face of challenges. It is now our responsibility as healthcare practitioners to translate theses

20. J Clin Oncol 33, 2015 (suppl; abstr 102)

References 1. J Clin Oncol 28:18s, 2010 (suppl; abstr CRA506) 2. J Clin Oncol 34, 2016 (suppl; abstr 1005) 3. J Clin Oncol 34, 2016 (suppl; abstr 1006) 4. J Clin Oncol 34, 2016 (suppl; abstr 1005). 5. Sandra M. Swain, M.D., JosĂŠ Baselga, M.D., Sung-Bae Kim, M.D et al. Pertuzumab, Trastuzumab, and Docetaxel in HER2-Positive Metastatic Breast Cancer. N Engl J Med 2015; 372:724-734February 19, 2015DOI: 10.1056/NEJMoa1413513 7. J Clin Oncol 34, 2016 (suppl; abstr 500) 8. J Clin Oncol 34, 2016 (suppl 4S; abstr 195) 9. J Clin Oncol 34, 2016 (suppl; abstr 3001) 10. J Clin Oncol 34, 2016 (suppl; abstr 6009) 11. J Clin Oncol 33, 2015 (suppl; abstr TPS3094) 12. J Clin Oncol 34, 2016 (suppl; abstr LBA8505) 13. J Clin Oncol 34, 2016 (suppl; abstr 9008) 14. J Clin Oncol 34, 2016 (suppl; abstr 3505 16. J Clin Oncol 34, 2016 (suppl; abstr 3504) 17. J Clin Oncol 34, 2016 (suppl; abstr LBA4006) 18. J Clin Oncol 34, 2016 (suppl; abstr LBA4500 19. J Clin Oncol 34, 2016 (suppl 2S; abstr 355) 21. J Clin Oncol 33, 2015 (suppl; abstr LBA1) 22. J Clin Oncol 34, 2016 (suppl; abstr 9518) 23. J Clin Oncol 34, 2016 (suppl; abstr 9517)

ASCO Vice President Joe Biden's Moonshot address


STILL EXPLORING

34.7 median OS1

MO N T H S

94.9%

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

reduction in the risk of

48% radiographic progression3 WITH

of median follow up

YEARS

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

4+

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 post-dose). Swallow whole with water. Take with recommended dose of prednisone or prednisolone of 10 mg daily. Medical castration with LHRH analogue should be continued during treatment in patients not surgically castrated. Children: No relevant use. Hypokalaemia: In patients with pre-existing, or who develop hypokalaemia during treatment with Zytiga, consider maintaining potassium level at ≥4.0 mM. Patients who develop Grade ≥ 3 toxicities (hypertension, hypokalaemia, oedema and other nonmineralocorticoid 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 pre-treatment. Caution in patients whose medical conditions might be compromised by hypertension, hypokalaemia or fluid retention e.g. heart failure, severe or unstable angina pectoris, recent myocardial infarction or ventricular arrhythmia, severe renal impairment. Monitor blood pressure, serum potassium and fluid retention and other signs and symptoms of congestive heart failure before treatment, then every two weeks for 3 months, and monthly thereafter. QT prolongation observed in patients experiencing hypokalaemia with Zytiga treatment. Consider discontinuation if there is a clinically significant decrease in cardiac function. Hepatotoxicity & hepatic impairment: Measure serum transaminases pre-treatment and every two weeks for first three months, then monthly. If symptoms/signs suggest hepatotoxicity, immediately measure serum transaminases. If ALT or AST > 5x ULN, stop treatment and monitor liver function. Restart treatment after liver function returns to baseline; use reduced dose (see dosage and administration). No clinical data in patients with active or symptomatic viral hepatitis. Rare reports of acute liver failure and hepatitis fulminant, some fatal. Corticosteroid withdrawal: Monitor for adrenocortical insufficiency if prednisone or prednisolone is withdrawn. Monitor for mineralocorticoid excess if Zytiga continued after corticosteroids withdrawn. Bone density: Decreased bone density may be accentuated by Zytiga plus glucocorticoid. Prior use of ketoconazole: Lower response rates may occur in patients previously treated with ketoconazole for prostate cancer. Hyperglycaemia: Use of glucocorticoids could increase hyperglycaemia, measure blood sugar frequently in patients with diabetes. Use with chemotherapy: Safety and efficacy of concomitant use of Zytiga with cytotoxic chemotherapy not established. Intolerance to excipients: Not to be taken by patients with galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption. Take sodium content into account for those on controlled sodium diet. Potential risks: Anaemia and sexual dysfunction may occur in men with metastatic castration resistant prostate cancer including those taking Zytiga. Skeletal muscle effects: Cases of

myopathy reported. Some patients had rhabdomyolysis with renal failure. Caution is recommended in patients concomitantly treated with drugs known to be associated with myopathy/rhabdomyolysis. SIDE EFFECTS: Very common: urinary tract infection, hypokalaemia, hypertension, diarrhoea, peripheral oedema. Common: sepsis, hypertriglyceridaemia, cardiac failure (including congestive heart failure, left ventricular dysfunction and decreased ejection fraction), angina pectoris, arrhythmia, atrial fibrillation, tachycardia, dyspepsia, increased alanine aminotransferase, increased aspartate aminotransferase, rash, haematuria, fractures (includes all fractures with the exception of pathological fracture). Other side effects: adrenal insufficiency, myocardial infarction, QT prolongation, hepatitis fulminant, acute hepatic failure, myopathy, rhabdomyolysis. Refer to SmPC for other side effects. FERTILITY/ PREGNANCY/ LACTATION: Not for use in women. Not known whether abiraterone or its metabolites are present in semen. A condom is required if the patient is engaged in sexual activity with a pregnant woman. If the patient is engaged in sexual activity with a woman of childbearing potential, a condom is required along with another effective contraceptive method. Studies have shown that abiraterone affected fertility in male and female rats, but these effects were fully reversible. INTERACTIONS: Caution with drugs activated by or metabolised by CYP2D6 particularly when there is a narrow therapeutic index e.g. metoprolol, propranolol, desipramine, venlafaxine, haloperidol, risperidone, propafenone, 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). Caution with medicines known to prolong QT interval or induce Torsade de pointes e.g. quinidine, disopyramide, amiodarone, sotalol, dofetilide, ibutilide, antiarrhythmic medicinal products, methadone, moxifloxacin and antipsychotics. Use of Zytiga with spironolactone is not recommended. Refer to SmPC for full details of interactions. LEGAL CATEGORY: Prescription only medicine. PRESENTATIONS, PACK SIZES & MARKETING AUTHORISATION NUMBERS: Bottle, 120 tablets, EU/1/11/714/001. MARKETING AUTHORISATION HOLDER: JANSSENCILAG INTERNATIONAL NV, Turnhoutseweg 30, B-2340 Beerse, Belgium. FURTHER INFORMATION IS AVAILABLE FROM: Janssen-Cilag Limited, 50-100 Holmers Farm Way, High Wycombe, Buckinghamshire, HP12 4EG, UK. Prescribing information last revised: May 2016 Adverse events should be reported. Healthcare professionals are asked to report any suspected adverse events via: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website: www.hpra.ie, E-mail: medsafety@hpra.ie. Adverse events should also be reported to Janssen-Cilag Limited on +44 1494 567447 or at dsafety@its.jnj.com. © Janssen-Cilag Limited 2016 References: 1. Ryan CJ, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo controlled phase 3 study. Lancet Oncol 2015; 16: 152–60. 2. Fizazi, K., et al (2015). ASCO GU 2015 (abstract 169). 3. Rathkopf, DE et al. Updated Interim Efficacy Analysis and Long-term Safety of Abiraterone Acetate in Metastatic Castration-resistant Prostate Cancer Patients Without Prior Chemotherapy (COU-AA-302). Eur Urol (2014), http://dx.doi.org/10.1016/j. eururo.2014.02.056. Date of Preparation: June 2016 | PHIR/ZYT/1014/0004(4)


24 Meeting Report

Living with Psoriasis Last year the Irish Skin Foundation (ISF) and Novartis Ireland in conjunction with the National University of Ireland, Galway supported a report entitled, “The Burden of Psoriasis, which estimated that there are over 73,000 people living with psoriasis in Ireland. Psoriasis is a chronic, systemic inflammatory skin condition,characterised by an increase in the rate in which skin cells are produced and shed from the skin, appearing as red and scaly patches. In Ireland,6,167 new cases are diagnosed annually. The report also estimates there are about 9,000 people in Ireland with severe psoriasis. This represents a significant number of people who are heavily impacted by the disease. Those with severe psoriasis experience poorer quality of life and are more likely to have co-morbidities such as psoriatic arthritis, cardiovascular disease and depression, compared to those with the mild form of the disease. Regarding treatment, Health Promotion Nurse Manager with the ISF, Ms Michelle Dolan told the Hospital Pharmacy News that that treatment for people with mild to moderate psoriasis usually begins with topical agents, such as tar preparations, topical corticosteroids or vitamin based drugs. Topical corticosteroids are available in four strengths (mildly potent, moderately potent, potent, and very potent). These can be effective, but strong steroids preparations can have significant side effects including thinning of the skin, and rebound flaring of psoriasis. The potency of the steroid prescribed is based on several factors including body site and size of affected area e.g. for the face or body folds, mild or moderately potent preparations arecommonly prescribed. They are most effective when used alongside other topical treatments, as directed by the doctor, and usually not recommended for long term use. Vitamin D analogue (calcipotriol) preparations are also one of the July/August 2016 • HPN

Michelle Dolan, Irish Skin Foundation

(etanercept), while others block interleukin 12/23 (ustekinumab) or neutralize interleukin (IL) 17A (secukinumab). A number of biologic agents have been licensed for the treatment of psoriasis including: tumour necrosis factor inhibitors (e.g. adalimumab, etanercept and infliximab), the interleukin (IL) 12/23 compound ustekinumab, and the IL 17A antagonist, secukinumab.

most common treatments for mild to moderate psoriasis. They work by slowing the production of skin cells and also have an anti-inflammatory effect. Combination therapy is also often employed, according to Ms Dolan. “Different topical treatments may be prescribed to be used in sequence, for example a topical steroid may be used in addition to a tar preparation or a vitamin D analogue, with one applied in the morning and one applied in the evening,” Ms Dolan said.“Or there are other products that contain two topicals combined, for example corticosteroid/tar mixtures. Depending on what treatment is prescribed, topical preparations work by either slowing down the accelerated rate at which the skin cells are produced, or by reducing the inflammation associated with psoriasis. They form an important element of treatment, but it is also very important to think of emollients and soap substitutes as well, which aren’t necessarily prescribed but form an important backdrop to treatment.” Ms Dolan said that phototherapy is another treatment option for the condition using artificial ultraviolet light, either ultraviolet A (UVA) or ultraviolet B (UVB) wavelengths of light, delivered in hospital Dermatology Day Care Centres. Phototherapy has been specifically designed to treat certain skin conditions, including psoriasis, and may help to improve or clear skin lesions

by slowing down the rapid rate at which skin cells develop in psoriasis Ultraviolet B (UVB) can be an effective treatment for guttate or plaque psoriasis, that has not responded to topical treatment. Each session only takes a few seconds or minutes (depending on skin type and other factors) but the patient may need to go to hospital three times a week, for six to eight weeks. PUVA is an acronym for Psoralen plus ultraviolet A. UVA must be combined with a light sensitizing medication such as psoralen (in tablet or bath form), to be effective. Commercial sunbeds are not recommended to treat psoriasis, as they contain more harmful wavelengths than those provided in dermatological settings. Even so long-term use of this treatment is not encouraged. Ms Dolan said that if necessary (when psoriasis has not been responsive to topical or UV light treatment), patients would then move onto systemic treatment, which includes a range of options depending on the suitability of a particular patient. One of the major developments over the past two decades that hastransformed the treatment of psoriasis has been the advent of biologics. Biologic treatments reduce inflammation by targeting overactive cells in the immune system. Some biologic agents target tumour necrosis factor (TNF): anti-TNF monoclonal antibodies (adalimumab and infliximab) and sTNF receptors

The development of such agents has “revolutionised” the treatment of psoriasis, according to Ms Dolan. In terms of treatment goals, current European guidelines define treatment success for moderate to severe psoriasis as achieving a Psoriasis Area and Severity Index(PASI) 75 response (i.e. a 75 per cent improvement (clearance) from baseline, as per the PASI criteria). According to the ISF report, this clinical endpoint may, however, be out of date. The report states that the majority of patients with psoriasis now achieve PASI 90 responses in randomised trials of the latestgeneration biologic agents. Over the past 20 years, because of genetic and immunological techniques, significant advances have been made with respect to understanding the pathogenesis of psoriasis. This better understanding has facilitated vast improvements in the treatments available for psoriasis, with newer medicines providing high levels of skin clearance. This signifies a significant leap forward in the evolution of medicines that areavailable to treat psoriasis, as for the majority of patients, attaining a PASI 90 response had not been a realistic therapeutic option. For example the report refers to a published trial of methotrexate, a drug which was first used to treat psoriasis fifty years ago only 9.1 per cent of patients had reached a stage where they had experienced a 90 per cent reduction in the extent of disease, after 12 weeks of treatment. The first-generation of biologic treatments increased


THE AIM IS CLEAR TARGET IL-17A

Introducing Cosentyx® • The first and only fully human IL-17A inhibitor

Cosentyx 300mg: • Demonstrated superior efficacy against both ustekinumab and etanercept2,3

approved in Ireland for

• 8/10 psoriasis patients achieved clear or almost clear skin at week 162

the treatment of moderate to

• Sustained efficacy up to 3 years4

severe plaque psoriasis

• Rapid and sustained relief from joint and skin symptoms of PsA5-7

and psoriatic arthritis

1

t

ABBREVIATED PRESCRIBING INFORMATION. t COSENTYX 150 mg solution for injection in pre-filled pen. 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: COSENTYX 150 mg solution for injection in pre-filled pen. Therapeutic Indications: The treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy; the treatment of active ankylosing spondylitis in adults who have responded inadequately to conventional therapy; the treatment, alone or in combination with methotrexate (MTX), of active psoriatic arthritis in adult patients when the response to previous disease modifying anti rheumatic drug (DMARD) therapy has been inadequate. Dosage & Method of Administration: Plaque Psoriasis: Recommended dose in adults is 300 mg given as two subcutaneous injections of 150 mg. Dosing at Weeks 0, 1, 2 and 3, followed by monthly maintenance dosing starting at Week 4. Ankylosing Spondylitis: The recommended dose is 150 mg by subcutaneous injection with initial dosing at Weeks 0, 1, 2 and 3, followed by monthly maintenance dosing starting at Week 4. Psoriatic Arthritis: For patients with concomitant moderate to severe plaque psoriasis or who are anti TNFa inadequate responders, the recommended dose is 300 mg by subcutaneous injection with initial dosing at Weeks 0, 1, 2 and 3, followed by monthly maintenance dosing starting at Week 4. Each 300 mg dose is given as two subcutaneous injections of 150 mg. For all other patients, the recommended dose is 150 mg by subcutaneous injection with initial dosing at Weeks 0, 1, 2 and 3, followed by monthly maintenance dosing starting at Week 4. For all of the above indications, available data suggest that a clinical response is usually achieved within 16 weeks of treatment. Consideration should be given to discontinuing treatment in patients who have shown no response up to 16 weeks of treatment. Some patients with initially partial response may subsequently improve with continued treatment beyond 16 weeks. The safety and efficacy in children below the age of 18 years have not yet been established. Contraindications: Severe hypersensitivity reactions to the active substance or to any of the excipients. Clinically important, active infection (e.g. active tuberculosis). Warnings/Precautions: Infections: Cosentyx has the potential to increase the risk of infections. Infections observed in clinical studies are mainly mild or moderate upper respiratory tract infections such as nasopharyngitis not requiring treatment discontinuation. Non serious mucocutaneous candida infections more frequently reported for secukinumab than placebo in psoriasis clinical studies. Caution in patients with a chronic infection or a history of recurrent infection. Instruct patients to seek medical advice if signs or symptoms suggestive of an infection occur. If a patient develops a serious infection, close monitoring and discontinue treatment until the infection resolves. Should not be given to patients with active tuberculosis. Anti tuberculosis therapy should be considered prior to initiation in patients with latent tuberculosis. Crohn’s disease: Caution should be exercised when prescribing to patients with Crohn’s disease as exacerbations of Crohn’s disease, in some cases serious, were observed in clinical studies. Close monitoring of patients with Crohn’s disease treated with Cosentyx. Hypersensitivity reactions: In clinical studies, rare cases of anaphylactic reactions have been observed in patients receiving Cosentyx. If an anaphylactic or other serious allergic reactions occur, administration should be discontinued immediately and appropriate therapy initiated. Latex-sensitive individuals: The removable cap of the Cosentyx pre filled pen contains a derivative of natural rubber latex. Vaccinations: Live vaccines should not be given concurrently with Cosentyx. Patients may receive concurrent inactivated or non live vaccinations. Concomitant immunosuppressive therapy: Use in combination with immunosuppressants, including biologics, or phototherapy have not been evaluated. Interactions: Live vaccines should not be given concurrently with Cosentyx. No interaction studies have been performed in humans. A clinically relevant effect on CYP450 substrates with a narrow therapeutic index, where the dose is individually adjusted (e.g. warfarin) cannot be excluded. Therapeutic monitoring should be considered on initiation in patients treated with these types of medicinal products. No interaction seen when administered concomitantly with methotrexate (MTX) and/or corticosteroids. Fertility, Pregnancy and Lactation: Women of childbearing potential should use an effective method of contraception during treatment and for at least 20 weeks after treatment. It is preferable to avoid the use of Cosentyx in pregnancy as there are no adequate data from the use of secukinumab in pregnant women. It is not known whether secukinumab is excreted in human milk. A decision on whether to discontinue breast feeding during treatment and up to 20 weeks after treatment or to discontinue therapy with Cosentyx must be made taking into account the benefit of breast feeding to the child and the benefit of Cosentyx therapy to the woman. The effect of secukinumab on human fertility has not been evaluated. Undesirable Effects: Very common (≥1/10); Upper respiratory tract infections. Common (≥1/100 to <1/10); Oral herpes, rhinorrhoea, diarrhoea, urticaria. Uncommon (≥1/1,000 to <1/100); Oral candidiasis, tinea pedis, otitis externa, neutropenia, conjunctivitis. Rare (≥1/10,000 to <1/1,000); Anaphylactic reactions. Please see Summary of Product Characteristics for further information on undesirable effects. Legal Category: POM. Marketing Authorisation Holder: Novartis Europharm Ltd, Frimley Business Park, Camberley, GU167SR, United Kingdom. Marketing Authorisation Numbers: EU/1/14/980/004-005. Date of Revision of Abbreviated Prescribing Information: November 2015. Full prescribing information is available upon request from: Novartis Ireland Limited, Vista Building, Elm Park Business Park, Elm Park, Dublin 4. Tel: 01-2204100 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. Cosentyx Summary of Product Characteristics, April 2016. 2. Thaci D. et al. JAAD 2015:73 (3) 400-409. 3. Langley RG. et al. N Eng J Med 2014: 371 (4) 326-338. 4. Bissonnette R. et al. Secukinumab maintains high levels of efficacy through three years of treatment. Abstract presented at EADV 2015; 7th-11th October: Copenhagen, Denmark. 5. Kavanaugh A. et al. Ann Rheum Dis 2015;74(S2):345-6. Poster THU0411 at European League Against Rheumatology (EULAR), 10 June, 2015, Rome, Italy. 6. Kavanaugh A. et al. Arthritis Rheum 2015;67(S10):2573: Oral presentation 2146 at the American College of Rheumatology (ACR), 9 November 2015, San Francisco, USA. 7. Novartis Data on File 2015. FUTURE 2 52 week Clinical Study Report. Date of Preparation: April 2016. IE02/COS15-CNF034b


26 Meeting Report

this figure to 21 per cent. As newer, more targeted treatments are developed, the numbers achieving such high levels of skin clearance have continued to increase. Results from clinical trials for treatments which target the Interleukin (IL)-12 and 23 pathways, show more than 50 per cent of people achieving a PASI 90 response or greater after 12 weeks. Results from clinical trials for treatments which target the IL-17 pathway, show more than 70 per cent of people achieving a PASI 90 response. In addition to this, studies report that the complete visible clearance of psoriasis (as per the PASI criteria) is now becoming a realistic therapeutic outcome. A recent study reports that 24.1 per cent of patients achieved PASI 100 (completely clear skin) after 12 weeks, efficacy, which increased close to 40 per cent after 52 week. New biologic treatments are constantly coming on-stream. Earlier this year the FDA approved ixekizumab for the treatment of psoriasis. The FDA approval of ixekizumab was July/August 2016 • HPN

based on findings from a large Phase 3 trial programme of more than 3,800 patients with moderate-to-severe plaque psoriasis from 21 countries. This number includes patients who began the trial on ixekizumab or placebo, or active comparator ( etanercept). The programme included three double-blind, multicentre Phase 3 studies—UNCOVER-1, UNCOVER-2 and UNCOVER-3— which demonstrated the safety and efficacy of ixekizumab in patients with moderate-tosevere plaque psoriasis. All three studies evaluated the safety and efficacy of ixekizumab (80 mg every two weeks, following a 160-mg starting dose) compared to placebo after 12 weeks. UNCOVER-2 and UNCOVER-3 included an additional comparator arm in which patients received U.S.-approved etanercept (50 mg twice a week) for 12 weeks. UNCOVER-1 and UNCOVER-2 also evaluated response rates with ixekizumab during the maintenance period through 60 weeks.

In these studies, the co-primary efficacy endpoints at 12 weeks were a 75 percent improvement in the composite PASI score and static Physician's Global Assessment (sPGA) 0 or 1 and at least a 2-point improvement from baseline. PASI measures the extent and severity of psoriasis by assessing average redness, thickness and scaliness of skin lesions (each graded on a zero to four scale), weighted by the body surface area of involved skin, while the sPGA is the physician's assessment of severity of a patient's psoriasis lesions overall at a specific point in time and is a required measure the FDA uses to evaluate effectiveness. In all three studies, at 12 weeks, 87 to 90 percent of patients treated with ixekizumab saw a significant improvement of their psoriasis plaques (PASI 75). In addition, 81 to 83 percent of patients treated with ixekizumab achieved sPGA 0 or 1. The majority of patients treated with ixekizumab, 68 to 71 percent, achieved virtually clear skin (PASI 90) and 35 to 42 percent of

patients saw complete resolution of their psoriasis plaques (PASI 100, sPGA 0). Among those patients treated with placebo, 7 percent or fewer achieved PASI 75, 7 percent or fewer achieved sPGA 0 or 1, 3 percent or fewer achieved PASI 90 and 1 percent or fewer achieved PASI 100 and sPGA 0. In UNCOVER-1 and UNCOVER-2, of patients who responded to ixekizumab (sPGA 0 or 1 and at least a 2-point improvement from baseline) at 12 weeks, 75 percent consistently maintained that response at the 60-week endpoint. This is just one recent development in the area. New treatment options for psoriasis were also a subject of discussion at a recent meeting of the Irish Association of Dermatologists earlier this year. The development of biologics and targeted therapies will continue to offer hope for patients living with the condition and also for the clinicians who treat them.


CPD 23: Lung Cancer Continuing Professional Development

CPD

27

Dr Robert Smyth MRCPI Respiratory Specialist Registrar And Dr Ross Morgan MD FRCPI FCCP Consultant Respiratory Physician, Beaumont Hospital Honorary Senior Lecturer RCSI

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

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

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

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

60 Second Summary While lung cancer was a rare disease at the start of the 20th century, today it represents one of the most common cancers worldwide. Lung cancer is the second most commonly diagnosed cancer in Ireland, with over 2,300 cases per year. It is also our leading cause of cancer mortality, accounting for 20% of all cancer deaths. Encouragingly however, notable achievements have been made in lung cancer care in the last number of years. Firstly rapid access services have achieved efficiencies and improvements in lung cancer detection and staging. Lung cancer has rapidly become a leading model for personalised cancer medicine with a detailed understanding of its molecular pathogenesis and consequently the development of precise, targeted molecular and immuno-therapies improving survival, with 5 new drugs approved by the FDA in the last year alone. Improvements in the delivery of lung cancer care have been achieved through earlier diagnosis, with online referrals, rapid access to diagnostic and minimally invasive staging procedures, such as Endobronchial Ultrasound (EBUS) for accurate assessment of mediastinal lymph nodes, and the provision of coordinated care by a multidisciplinary team (MDT) of specialists who care for a significant number of patients with lung cancer on a regular basis. The standard therapy for patients with early stage lung cancer is surgical resection, which offers the best chance of cure. Many patients presenting with small tumours have significant co-morbidities however, particularly co-existing COPD that may have previously deemed them inoperable.

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

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

Management and Treatment of Lung Cancer While lung cancer was a rare disease at the start of the 20th century, today it represents one of the most common cancers worldwide. Lung cancer is the second most commonly diagnosed cancer in Ireland, with over 2,300 cases per year. It is also our leading cause of cancer mortality, accounting for 20% of all cancer deaths. While the high incidence and mortality of this disease has thankfully declined somewhat in recent years in men, they are worryingly increasing in women. This new trend is attributable to societal changes in cigarette smoking over the past 30 years and underlines the importance of providing concerted action to address smoking cessation and prevention efforts to women in particular. Other risk factors for lung cancer include exposure to radon gas (particularly relevant in Ireland), asbestos, diesel exhaust and air pollution, COPD, pulmonary fibrosis, and immune suppression. These risk factors are common in patients seen in a respiratory practice, and so respiratory physicians have a unique opportunity in recognising and facilitating the early diagnosis of this disease. While lung cancer kills more Irish people every year than breast and colon cancer

combined it rather perversely receives far less attention, possibly due to its strong association with high deprivation indices and social stigma. Slow improvements in 5-year survival figures for patients with lung cancer in Ireland have been achieved over the last decade according to the most recent data from the National Cancer Registry but still remain only just above 13%. By comparison, the survival for bowel cancer in Ireland, a disease that affects patients with a similar age profile is almost 60%. Encouragingly however, notable achievements have been made in lung cancer care in the last number of years. Firstly rapid access services have achieved efficiencies and improvements in lung cancer detection and staging. Lung cancer has rapidly become a leading model for personalised cancer medicine with a detailed understanding of its molecular pathogenesis and consequently the development of precise, targeted molecular and immuno-therapies improving survival, with 5 new drugs approved by the FDA in the last year alone. Lung cancer screening using low-dose CT has shown to be effective in reducing lung

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


28

CPD 23: Lung Cancer

cancer mortality with ongoing efforts worldwide to improve its affordability. Academically, thoracic oncology is now a distinct assembly of the European Respiratory & the American Thoracic Society, with high quality research regularly published in major peer review journals. Closer to home, attendance rates and output at the British Thoracic Oncology Group (BTOG) annual meeting in Dublin increase year on year. Lung cancer therefore is a rapidly evolving, increasingly specialized area and there are reasons for optimism for lung cancer specialists and patients alike. ORGANISATION OF CARE Improvements in the delivery of lung cancer care have been achieved through earlier diagnosis, with online referrals, rapid access to diagnostic and minimally invasive staging procedures, such as Endobronchial

Ultrasound (EBUS) for accurate assessment of mediastinal lymph nodes, and the provision of coordinated care by a multidisciplinary team (MDT) of specialists who care for a significant number of patients with lung cancer on a regular basis. Modern multidisciplinary management leads to more efficient use of scarce resources, better quality of life and improved survival. Respiratory physicians have an important role in this team leadership, as they are most frequently involved with patients from their initial diagnosis and staging through treatment and restaging. They are subsequently often involved with complications, the palliation of symptoms and end-of-life care. There are also societal efforts for a greater involvement of respiratory physicians in lung cancer research, given the rapid advances in the understanding of its tumour biology.

The National Cancer Control Programme (NCCP) was established in 2007 to manage, organise and deliver cancer services in Ireland. Lung cancer has been a key area of focus of the NCCP, which supports Rapid Access Diagnostic Clinics in each of the eight designated cancer centres. These clinics are run by Respiratory physicians who are referred patients with abnormal chest imaging or haemoptysis. The Rapid Access clinic serves as a conduit to the lung cancer MDT and the four designated surgical lung cancer centres in Cork University Hospital, Galway University Hospital, and St Jamesâ&#x20AC;&#x2122;s and the Mater hospitals in Dublin. The work of lung cancer specialist nurse coordinators in each centre has facilitated this integration and enhanced the patientâ&#x20AC;&#x2122;s journey through the service. In 2015 over 3,000 new patients were seen at Rapid Access Lung Cancer Clinics in Ireland

with a case find rate of almost 30%. The NCCP role also includes collection and reporting of Key Performance Indicators (KPIs) across a number of areas including; Access to care, Multidisciplinary working, Time to Diagnosis and Time to treatment. An annual Irish National Lung Cancer Quality and Audit meeting has been held since 2013 and provides a forum for the purpose of clinical audit, sharing of good practice and problem solving into the future. A key challenge will be continuing to provide prompt access to cancer services and diagnostics and advocacy for more resources for service improvement and research. EARLY STAGE LUNG CANCER The standard therapy for patients with early stage lung cancer is surgical resection, which offers the best chance of

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


29 been developed. Blocking programmed cell death protein 1 (PD-1) and its ligand (PDL1) restores anti-tumour T-cell activity. Phase II & Phase III studies of previously treated patients randomised to Nivolumab or Pembrolizumab have shown improved survival and more favourable toxicity profiles. Further studies investigating their use in earlier stages of NSCLC and extending their use to other thoracic malignancies such as mesothelioma and thymic carcinoma are in the pipeline. SCREENING

cure. Many patients presenting with small tumours have significant co-morbidities however, particularly coexisting COPD that may have previously deemed them inoperable. Advances in surgical techniques including less invasive procedures e.g. Video-assisted thoracoscopic (VATS)-lobectomy and sub-anatomic resection for smaller tumours, together with the increasing evidence for efficacy of stereotactic radiotherapy (SBRT) have broadened the therapeutic options available to the MDT when planning treatment. ADVANCED LUNG CANCER TARGETED THERAPIES: Up until recently the role of the pathologist in lung cancer management was only to differentiate small cell from non-small cell lung cancer (NSCLC). Platinum-doublet based chemotherapy was the standard of care for advanced disease and the treatment for all forms of NSCLC was the same. However with the advent of newer therapies, more accurate histological classification was necessary via immuno-histochemical staining. This diagnostic landscape changed markedly

in 2004 with the discovery of the sensitizing mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase (TK) domain. This was the first driver mutation identified in lung cancer for which a targeted therapeutic drug, gefitinib (a first generation TK inhibitor) was available. Driver mutations are mutations in genes that encode signalling proteins crucial for cell proliferation and drive tumour formation. Subsequently, these somatic mutations were identified as occurring predominantly in adenocarcinomas of the lung and more frequently in non-smokers. Tyrosine kinase inhibition has been to shown to improve survival in lung cancer patients harbouring an EGFR mutation compared to conventional chemotherapy and newer generation TKI’s can now also target evolving resistance patterns providing patients with prolonged disease control.

arrangements constitute about 5% of all non-small cell lung cancers and have also been shown to occur predominantly in lung adenocarcinomas. Crizotinib, the first in class oral inhibitor of ALK and ROS-1 is associated with superior response rates and significant improvements in quality of life compared to chemotherapy in patients harbouring these re-arrangements.

Rarer driver mutations have also been identified; a transforming echinoderm microtubule-associated protein like (EML) 4-anaplastic lymphoma kinase (ALK) gene fusion and more recently ROS1 rearrangements. The ALK re-

Immunotherapy has also recently emerged as an exciting avenue for targeted lung cancer treatment after many years of failure. Antibodies directed against negative immunologic regulators (checkpoints) have

The understanding of the impact of the molecular classification of lung cancer and the advent of targeted therapies has further enhanced the role of the pathologist in lung cancer management. As a result of a more precise classification of a patient’s lung cancer, there have been significant improvements in outcomes in selected patients, and mutational analysis of lung tumours prior to consideration of systemic therapy has now become standard in clinical practice.

The majority of new lung cancer diagnoses present later in the course of disease leading to poor outcomes. In 2011, the National Lung Screening Trial in the U.S. demonstrated a significant reduction in lung cancer mortality of 20% among a high risk group undergoing screening with low-dose CT scan of the thorax annually for 3 years compared to chest x-ray. Lung cancer screening with low-dose CT in high-risk individuals now has a grade B recommendation by the U.S. Preventative Services Task Force. Many questions remain regarding widespread implementation of lung cancer screening programs; while there will likely be a big impact on stage at detection – so called ‘stage shift’, significant concerns exist regarding health care costs (modeled recently across the Medicare population in the United States at $9.3 billion over the first 5 years) as well as the high rates of false positive findings once nodules were detected. The NELSON study the largest European lung cancer screening trial used volume doubling time (VDT) of nodules as a management strategy. This resulted in a higher positive predictive value (40.6% vs 3.6%) and a substantially lower false positive result (59.4% vs 96.4%) than in NLST, with final cost analysis eagerly awaited.

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


30

CPD 23: Lung Cancer

TOBACCO CONTROL Over 90% of lung cancer in Ireland may be attributed to smoking tobacco and thus is theoretically preventable. The prevalence of smoking in Ireland remains around 19.5%, with peak prevalence of 27.3% in the 25-34 year old age group. In Ireland the incidence of lung cancer in women has been rising steadily over past three decades and is projected to increase by 141% in this group between 2010 and 2030. There is no doubt that continued efforts to curb tobacco dependence will have the largest impact in improving outcomes and should remain a priority in any multidisciplinary approach to management of lung cancer. CONCLUSION Lung Cancer continues to result in high mortality with profound effects on the quality of life of patients and their families. Modern multidisciplinary care, advances in diagnostics and therapies, together with targeted treatments for advanced lung cancer are evolving rapidly. Screening of high-risk individuals with low-dose CT scan will emerge further in the coming years and will become more costeffective. So there is cause for optimism for this disease and greater advocacy and research on our part will only help to further advance our drive for better outcomes. Over a third of Irish adults who are currently experiencing three or more symptoms of lung cancer are unconcerned about being diagnosed with the disease, according to the Irish Cancer Society who launched new research around attitudes to lung cancer among the Irish public at the start of this year. The research, which was commissioned by the Irish Cancer Society and carried out by Coyne Research, surveyed over 1,000 adults..

This latest report reveals a number of barriers when it comes to the early detection of lung cancer which in turn can impact on survival rates and may be behind why the majority of lung cancer cases in Ireland continue to be diagnosed at a late stage. This includes a lack of awareness around the severity of the disease with just over a half of Irish adults unable to identify lung cancer as the leading cancer killer and a third of the public with three or more symptoms unconcerned about being diagnosed with lung cancer. Despite this ambivalence to lung cancer, the disease continues to increase with 2,312 people diagnosed in Ireland in 2012. While the incidence in men is decreasing every year by one per cent, lung cancer in women continues to increase at a significant rate of two per cent each year. For the first time, lung cancer has now moved from 3rd place to 2nd place ahead of colorectal cancer when it comes to the most common cancers in Irish women*. The majority of lung cancer patients are also diagnosed at a later stage when there may be fewer

treatment options available. Between 2004 to 2008, 64 per cent of lung cancer patients were diagnosed at an advanced stage (stage three or stage four lung cancer)**. Lung cancer is also the leading cause of cancer death in both men and women comprising 18% of cancer deaths in women and 23% of cancer deaths in men during the period 2011-2012*. Kevin O’Hagan, Cancer Prevention Manager at the Irish Cancer Society said, “Lung health needs to be taken seriously – we need Irish people to start talking about it and to consider it important enough to take action. Lung cancer can be treated once it is diagnosed at an early stage but unfortunately too many people don’t go to their doctor at a time when it would be most beneficial for them. We need doctors and pharmacists to keep lung cancer front of mind and to encourage their patients to maintain good lung health. When it comes to lung cancer, awareness and early detection are the key to survival.” The Irish Cancer Society, developed an Online Lung Health Checker to help the public find out if their lungs are in a healthy condition. The

Online Lung Health Checker also provides users with a printable letter which they can bring along to their doctor to help explain any symptoms. O’Hagan continued: “We are inviting members of the public to take our Online Lung Health Checker which is available on our website and to encourage friends and family to do the same. “This will help you consider your lung health and to examine symptoms you may be experiencing. We want Irish people to take action and this is a simple way to do so.” The Irish Cancer Society is reminding the public to get to know the signs and symptoms of lung cancer and to act quickly. With early detection, patients can have more effective treatment options and potential cures available to them. All patients can now be fast tracked through to early diagnosis and treatment through the Lung Cancer Rapid Access Clinics which are in operation in all eight of the designated cancer centres. This has resulted in a steady improvement in lung cancer survival from 10 per cent to 15 per cent over the last 15 years.

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


Feature 31

Current and emerging medications for psoriasis Psoriasis is a complex immune-mediated disease that affects approximately 120 million people globally and requires chronic management.1 The condition manifests itself in the skin, joints, or both, and exhibits associated comorbidities that increase risk for early death, including metabolic syndrome, cardiovascular disease, psoriatic arthritis, depression, anxiety, non-alcoholic fatty liver disease, Crohn's disease, and lymphoma.2 


(IL)-23-T helper cell 17 (Th17) axis, among other immune reactions in the cells of the skin, have all been shown to be involved in the pathogenesis of psoriasis.2,8 


Physicians should encourage lifestyle changes to reduce modifiable cardiovascular risk factors, such as smoking, which has been shown to independently increase risk of onset and exacerbation of psoriasis. Excessive alcohol intake has been reported in up to one-third of patients with psoriasis, likely due to psychologic distress. Excess alcohol ingestion is also a risk factor for cardiovascular disease.3 As emerging research illustrates its increasing complexity, psoriasis is now considered a systemic inflammatory disorder.2 


This article discusses established therapies for psoriasis and their indications for use, as well as emerging treatments that hold promise for the future.


Clinically, there are 5 types of psoriasis: plaque psoriasis, guttate or eruptive psoriasis, inverse psoriasis, pustular psoriasis, and erythrodermic psoriasis. Plaque psoriasis is the most common form, with monomorphic, welldemarcated erythematous plaques under a silvery scale, typically on the scalp and extensor surfaces. Guttate psoriasis exhibits teardrop shaped lesions with scale. Inverse psoriasis is found in the intertriginous or flexural areas. Pustular psoriasis can present as either palmoplantar pustulosis or as the serious generalised pustular psoriasis. Any form can evolve into erythrodermic psoriasis, a rare and serious complication of the disease with significant risk of mortality. Psoriasis can affect the skin, nails, scalp, and joints to different degrees in each patient.2,4 
 The prevalence of psoriasis within certain populations ranges from less than 1% to more than 10%, depending on ethnic and geographic factors, with a 2% prevalence rate in Europe and North America.5 Family studies have shown a genetic predisposition for the disease, with the literature illustrating certain susceptibility alleles in immunerelated genes.6,7 Dysregulation between the innate and adaptive immune systems, tumour necrosis factor (TNF)-α, and the interleukin

Management varies according to severity and effect on quality of life and should be tailored to each individual patient. There are many therapeutic options available, ranging from topical agents, to phototherapy and systemic and biologic agents.1,2 


Mild disease
 For mild disease, which affects 70% to 80% of patients with psoriasis, first-line management remains topical treatments. Glucocorticoids and vitamin D derivatives, or their combination, are typically sufficient for mild psoriasis. Topical calcineurin inhibitors (tacrolimus or pimecrolimus) are reserved for difficult anatomic sites, such as the face and intertriginous areas, which are more prone to the adverse effects of the other topical agents.2 For the scalp, combinations of corticosteroids and vitamin D3 analogues are most effective, though very potent corticosteroids alone are more effective than vitamin D3 derivatives.9 
 Moderate-to-severe disease 
 There is no single definition in the literature of what constitutes moderate-to-severe psoriasis. The Psoriasis Area and Severity Index (PASI), percentage of BSA affected, and the Dermatological Life Quality Index provide physicians with some metrics to differentiate mild disease from moderate-orsevere psoriasis. However, these guidelines and their numeric cut-offs are cumbersome to calculate and use in daily practice and may not take into account the full clinical and subjective picture of disease burden. For example, although predominant psoriatic nail involvement may not constitute a significant percentage of BSA, it can negatively affect quality of life and be difficult to treat topically.2,10 Patients with moderate-to-severe psoriasis are often treated with a combination of phototherapy and topical or systemic therapy. Narrow-band UV-B (311 nm and 313 nm) is the more widely

used phototherapy, whereas photochemotherapy, such as PUVA (320-400 nm), is used less frequently. Although phototherapy is effective, it is time consuming, as it is performed 2 to 5 times per week in a clinical environment. Therefore, phototherapy is mainly used for acute disease control rather than chronic management.2,11 
 PUVA increases the risk of skin cancers, especially after 200 treatments, which also limits its chronic use.11 Absolute contraindications to phototherapy include genetic defects that increase light sensitivity or risk of skin cancer, lupus erythematosus, and pregnancy or lactation (for pregnancy, the contraindication applies to oral PUVA only). Phototherapy was developed based on the observation that exposure to sunlight helped reduce the symptoms of many skin diseases. Phototherapy has been shown to inhibit keratinocyte proliferation, induce apoptosis in cells of the immune system, and inhibit Th1 and Th17 proliferation, as well as stimulation of the Th2 system.2,12 Conventional systemic therapies. Conventional systemic therapies used for psoriasis treatment include acitretin, methotrexate, and cyclosporine, which have been used for more than 10 years.2,13 
 Acitretin is an oral retinoid and is teratogenic, limiting its use in women of childbearing age. Dosing starts at 10 mg/d to 25 mg/d and is increased according to the patient's ability to tolerate its side effects. However, in the case of generalised pustular psoriasis, it should be started at a high dose and titrated down if a lower dose is effective. Its adverse effects include increases in xerosis and

triglyceride level and abnormal liver function tests. Acitretin is also classified as Pregnancy Category X and inappropriate for use in women of childbearing age or men who wish to conceive; in rare cases, the drug has been associated with decreased night vision, skeletal hyperostosis, or pseudotumor cerebri.13,14 Acitretin is more effective when used in combination with topical vitamin D3 derivatives such as calcipotriene, or phototherapy or biologics. Among the drawbacks of acitretin are that it has a slow onset of action and may only thin psoriatic plaques, rather than effectively eliminating them, when used alone. It is not as effective a monotherapy as methotrexate or cyclosporine at tolerable doses,2,14 but acitretin is helpful in treating specific subtypes of psoriasis, such as generalised, palmoplantar, pustular, and hyperkeratotic psoriasis.14 One advantage of acitretin is that it has less potential for end-organ toxicity than methotrexate or cyclosporine.10 
 Secukinumab is a fully human monoclonal antibody that inhibits IL-17A and has been approved for the treatment of moderate to severe plaque psoriasis, psoriatic arthritis and ankylosing spondylitis. 1a IL-17A is a key mediator in the inflammatory pathway that causes the skin and joint symptoms seen in these diseases.1a By inhibiting this interleukin with Secukinumab, psoriasis trials have shown rapid onset of action and significant improvements in PASI scoring with 79% of patients achieving clear or almost clear skin by week 16 (PASI 90) and 44.3% achieving PASI 100.2 70% of patients receiving Secukinumab said that their psoriasis had little or no effect on their quality of life after 52 weeks on treatment (DLQI 0/1).3a The

HPN • July/August 2016


32 Feature recommended dose for patients with plaque psoriasis is 300 mg of secukinumab by subcutaneous injection with initial dosing at Weeks 0, 1, 2 and 3, followed by monthly maintenance dosing starting at Week 4. Each 300 mg dose is given as two subcutaneous injections of 150 mg.1a Methotrexate inhibits DNA replication by disrupting cellular folic acid metabolism and is the oldest systemic therapy for moderate-to-severe psoriasis. Although it is cytostatic, it also leads to reduced T-cell gene expression, increases endogenous levels of adenosine, and decreases antibody responses, which are direct anti-inflammatory effects. Methotrexate is available in 2.5-mg tablets, prescribed as 7.5 mg to 25 mg taken once weekly. Subcutaneous methotrexate, also dosed once weekly, exhibits improved bioavailability, efficacy, and tolerability in patient studies of rheumatoid arthritis.13 Cumulative use of methotrexate increases risk of liver toxicity, but folate supplementation can reduce that risk,15 as well as the risks of bone marrow suppression and gastrointestinal side effects.10 A multi-centre, randomised controlled trial found that 40% of subjects achieved a 75% reduction in PASI scores (PASI 75) at 24 weeks.13,16
 The most common side effects of methotrexate include nausea, diarrhoea, fatigue, and headaches. Additionally, liver function tests should be performed every 4 to 12 weeks, as hepatotoxicity may manifest early as elevated transaminases. 
 Methotrexate is an abortifacient and classified as Pregnancy Category X; it is also contraindicated during lactation. The drug should be discontinued in both men and women at least 3 months prior to attempting to conceive. 
 Methotrexate can be combined with other systemic medications or phototherapy for additive or synergistic responses. Combinations allow for lower doses of the individual drugs and improved overall efficacy.13 
 Cyclosporine is an oral calcineurin inhibitor that lowers the production of IL-2 and other proinflammatory cytokines that activate T cells. It is used in many immunemediated disease states, including moderate-to-severe psoriasis. It is typically dosed at 2.5 mg/kg/d to 5.5 mg/kg/d.13 Cyclosporine is fast acting and is therefore considered a first-line treatment for types of pustular psoriasis and erythrodermic psoriasis as a rescue drug. A dose of approximately

July/August 2016 • HPN

5 mg/kg/d has shown a reliable average PASI 75 rate of 70%.13,18 
 Once a course of cyclosporine is complete, management is switched to a therapy with fewer long-term adverse effects. Long-term use and high doses of cyclosporine are associated with renal damage, hypertension, hypertriglyceridemia, electrolyte abnormalities, and increased risk of squamous and basal cell carcinomas. Therefore, it is used intermittently for no longer than 12 weeks at a time and is effective for management of flares. Baseline laboratory and blood pressure tests are necessary prior to its use. While on the medication, weekly blood pressure measurements and monthly comprehensive metabolic panels with lipids, magnesium, and potassium are necessary. 
 Cyclosporine has many relative contraindications and is metabolised through the cytochrome P450 liver system; thus, it is important to be aware of a patient's medical history, diagnoses, and current medications and potential interactions prior to its use.2,10,13 Because cyclosporine can only be used temporarily, it is often combined with or titrated down while also using overlapping therapy, such as methotrexate, acitretin, or biologic agents.13
 Biologic agents. The biologic agents are a newer class of medications available to patients with moderate-to-severe psoriasis and are effective long-term treatment options. They have increased safety, efficacy, and tolerability when compared with the classical agents, especially because they show no cumulative toxicity or significant interactions with other drugs. As a result, they are no longer reserved as second-line treatments, but their cost may delay their use until after conventional therapies have been exhausted.2 
 The risks of biologics include a small increase in opportunistic infections, so they should not be used in immunocompromised individuals or those with active infections. Patients should be tested for latent tuberculosis prior to use. Common side effects include flu-like symptoms and injection site reactions. Cost, the severity of disease, and the medical history of the individual patient should determine their use.2,10 
 TNF-α inhibitors approved for use in moderate-to-severe psoriasis and psoriatic arthritis include etanercept, adalimumab, and infliximab. Given their mechanism of immunosuppression, they share a heightened risk of causing

infection (including sepsis and tuberculosis), autoimmune disorders (eg, lupus), and lymphoma.2 Etanercept reaches a PASI 75 in a majority of patients at 24 weeks when dosed at 50 mg twice weekly and then reduced to 50 mg/wk after 12 weeks. The twice-weekly dosing can be maintained if the patient's improvement is inadequate after 24 weeks.10 Adalimumab and infliximab have shown effective control of plaque psoriasis and rapid onset of action, respectively. A loading dose of 80 mg of adalimumab is followed 1 week later by 40-mg injections every other week. For infliximab, 3 intravenous induction infusions (5 mg/kg) are given at weeks 0, 2, and 6, with infusions thereafter every 8 weeks. Adalimumab and infliximab have shown greater efficacy than methotrexate with regard to PASI score improvement.10,19,20 Furthermore, infliximab has the greatest short-term efficacy and most rapid onset of action, followed closely by adalimumab and ustekinumab, making it an ideal medication for treatment of erythrodermic psoriasis.21 
 Alefacept carries the risk of CD4 T lymphocyte depletion, so CD4 counts must be regularly checked; alefacept should be discontinued when the count is less than 250 CD4 T cells/uL. Like cyclosporine, alefacept is prescribed for intermittent 12-week courses, leading to a 50% to 75% reduction in PASI scores in approximately 25% of patients, an effect that may last for more than 12 months. Each course can be repeated twice a year. As long as CD4 counts are regularly supervised, alefacept has shown few adverse effects10,22 and is often combined with phototherapy regimens for increased efficacy.23 
 Ustekinumab is a human monoclonal antibody that blocks IL-12 and IL-23 and has been approved for the treatment of psoriasis and psoriatic arthritis. By blocking these interleukins, ustekinumab interrupts the development of Th17 lymphocytes involved in the psoriasis inflammatory process. Trials have shown no significant risks due to its method of immunosuppression, but long-term data are lacking.10,24 After 2 initial doses of 45 mg at weeks 0 and 4, health care providers give patients an injection of the same dose once every 12 weeks for those weighing 100 kg or less. Patients weighing more than 100 kg are given 90-mg injections every 12 weeks. In 67% to 81% of patients who have a prolonged response, PASI 75 was reached, and many achieved a reduction in PASI scores of 50% by week 2.10,25,26 


Small molecule therapies Otezla (apremilast) is a small, oral phosphodiesterase-4 (PDE4) inhibitor effective for the treatment of psoriasis and psoriatic arthritis;2 it showed a minimum 75% reduction in PASI scores in approximately 30% of subjects dosed at 30 mg twice daily after 16 weeks. PDE4 is active in the immune cells and keratinocytes and increases the production of inflammatory cytokines, so its inhibition improves inflammation in psoriasis. Patients in apremilast trials may have had side effects of nausea, vomiting, diarrhoea, headaches, and upper respiratory tract infections, but no significant laboratory changes are seen in those taking apremilast, so no monitoring is necessary.13,28 One interesting side effect seen in 10% of subjects treated with apremilast was a decrease of 5% to 10% in body weight at baseline, the cause of which remains unknown.29 
 JAK molecules are proteins within cells that transmit signals from extracellular cytokines to the cellular nucleus. By inhibiting JAK, cytokine effects on the cell are reduced. Pregnancy
 Due to hormonal changes, most women have symptomatic improvement of their psoriatic symptoms during pregnancy. For those women who do require therapy during pregnancy, topical agents such as corticosteroids are preferred. UV-B phototherapy is safe to use in pregnant women with moderate-to-severe disease.12,32 Although more data are necessary, biologic agents are the favoured systemic medications for pregnant patients whose disease is not well-controlled with topical agents or phototherapy, including bath PUVA.32 Cyclosporine is classified as a Pregnancy Category C agent, so its potential benefits may warrant its use. As more patients are diagnosed with chronic diseases, it is wise to understand psoriasis in their context and to be able to identify the nuances of treating psoriasis in patients with many co-morbid conditions. The list of medications used to treat psoriasis continues to grow, with several other drugs having recently completed phase 3 clinical trials, providing hope and more options for patients with this serious cutaneous disease. References: 1. Cosentyx Summary of Product Characteristics. April 2016. 2. Thaçi D et al. J Am Acad Dermatol 2015; 73(3): 400-409. 3. Blauvelt A et al. Presentation A2302E1 at AAD 2015. Further references available on request


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

www.versatis.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 2015. IRE/V15 0001a.


34 Antimicrobial Meeting

AMS Insight Antimicrobial Stewardship Study Day – Lessons Learned! Author: Marie Tierney, Antimicrobial Pharmacist

Antimicrobial resistance is now recognised as a global threat to human health. Antimicrobial resistance is driven by antimicrobial use and antimicrobial stewardship programs in hospitals aim to promote the appropriate use of antimicrobials. Prescribing is now becoming recognised as a behaviour, and given that up to 50% of antimicrobial use is considered to be inappropriate, innovations in organisational and behaviour change are increasingly studied and harnessed to influence prescribing behaviour. The inaugural AMS Insight Antimicrobial Stewardship Study Day, which took place in the Royal College of Physician’s in Dublin on Monday 13th June, was a resounding success. Over one hundred doctors, nurses, pharmacists and scientists attended the meeting, organised by the multidisciplinary Antimicrobial Stewardship Committee from St. James’s Hospital, Dublin. The idea for the meeting came from the recognition of continuing education as one of the pillars of an effective antimicrobial stewardship programme. It provided an opportunity for attendees to hear about and discuss the many challenges posed by the threat of antimicrobial resistance, and the development and implementation of effective hospital based antimicrobial stewardship programmes to counter this threat. A panel of expert Irish and UK speakers shared their experience in developing initiatives to provide safe and effective high quality care to patients. Lessons Learned from London The opening speaker was Mark Gilchrist, a consultant pharmacist in Infectious Diseases at Imperial College Healthcare Trust, London and a Fellow of the Royal Pharmaceutical Society. Mark shared his experience of lessons learned from fifteen years of Antimicrobial Stewardship in Imperial. His talk was peppered with practical and useful hints and tips. The foundation of an effective hospital is visibility and accessibility of members of the Antimicrobial Stewardship Team at the point of prescribing on hospital wards. Equally important is engagement and support from senior hospital managers and senior clinicians. July/August 2016 • HPN

The development and ongoing update of robust evidence based user friendly antimicrobial prescribing guidelines is a pillar of antimicrobial stewardship programmes. Mark outlined how the Imperial antimicrobial prescribing guidelines have evolved from a pocket guide and ward based posters to a Smartphone app, similar to many Irish hospitals. He emphasised the importance of continuous ongoing monitoring for unintended consequences following any changes in practice. In the case of the antimicrobial guidelines staff requested the reinstatement of the poster guidelines, which were removed from the wards following launch of the app. Effective communication is critical and Mark gets his message across by embedding important content in the body of e-mail messages, as he has learned that most people are too busy to open attachments. Lessons Learned from the Irish OPAT Programme – IV antibiotics in the community Dr. Susan Clarke, Infectious Diseases Consultant, St. James’s Hospital and National Lead, Outpatient Parenteral Antimicrobial Therapy (OPAT) Programme updated participants on the IV Antibiotics at Home initiative. Since its introduction the programme has freed up hospital beds by providing a nurse or self administered service which allows patients to complete a course of IV antibiotics at home. Each month an average of one hundred and fifty patients are discharged home on IV antibiotics, equivalent to a small hospital. Oversight and screening by a Medical Microbiologist of Infectious Diseases Consultant is a critical step in ensuring that the principles of antimicrobial stewardship are embedded in the prescribing of OPAT. This helps to ensure that the patient, the infection being treated and the antibiotic used to treat the infection are all suitable for home administered antibiotics. Lessons Learned from Irish Hospitals In four short and lively interactive presentations antimicrobial pharmacists and microbiologists shared findings from antimicrobial stewardship audits in their hospitals. • Dr. Roisin Connolly spoke about efforts to improve adherence

to antibiotics used to prevent surgical site infections in Limerick University Hospitals. Roisin’s take home message was the need to interact and engage with consultants, as key decision makers. • Elmarie Cottrell’s audit examined adherence to the Start Smart, Then Focus Antibiotic Care Bundle in St. James’s Hospital. The lesson learned was the importance of feeding back data to change antimicrobial prescribing patterns. • Marie Tierney described antibiotic use in patients at the end of life in Galway University Hospitals. The key learning point was that further research is needed to understand the factors contributing to intensive antimicrobial use at end of life, and to determine if such use is appropriate. • Dr. Robert Cunney shared his experience of the “Start Smart” antimicrobial quality improvement programme at TSCUH, a recent finalist at the HSE Excellence Awards. Involving prescribers in the initiative and creating healthy competition were key to success in Temple St. Lessons Learned from Health Information and Quality Authority (HIQA) Sean Egan, Acting Head of Healthcare Regulation at HIQA, manages the regulatory output of the HIQA Healthcare Regulation Team. This team regulates healthcare services provided or funded by the Health Service Executive. Recent monitoring against the National Standards for the Prevention and Control of Healthcare Associated Infection, has included a national quality assurance review of antimicrobial stewardship programmes across Irish public acute hospitals. The publication of the HIQA report is expected in the next few weeks and will be widely published. HIQA’s role is to promote safety and quality in healthcare. As part of its remit HIQA is planning regulatory work in medication safety, with details to follow later this year. Lessons Learned from Ireland Dr. Robert Cunney, Consultant Microbiologist, Temple St. Children’s University Hospital (TSCUH) and Clinical Lead for the

RCPI/HSE Clinical Programme for Healthcare Associated Infection and Antimicrobial Resistance (HCAI/AMR) spoke about the past, present and future of antimicrobial stewardship in Ireland. The three key areas in the HCAI/AMR programme are antimicrobial stewardship, hand hygiene and prevention of device related infection. It is important that antimicrobial stewardship is viewed in the broader perspective of infection prevention and control. The key challenge for antimicrobial stewardship programmes is translating research findings into day to day practice in healthcare. Rob is leading on expanding the “Start Smart” quality improvement project through a national antimicrobial stewardship improvement collaborative, whereby through shared learning several hospitals are working with each other on a common project, to rapidly test and implement changes that lead to lasting improvement. The public awareness campaign “undertheweather.ie” about avoiding unnecessary antibiotic use for colds and flu has been a huge success. Rob attributed the success to the shift from a negative message to a positive focus, telling people what they can do instead of what they can’t do. We’ve come a long way on the antimicrobial stewardship journey in Ireland. However, many gaps exist especially outside hospitals. Lessons Learned from Behaviour Change Techniques Professor Alison Holmes, Imperial College Healthcare Trust, London, is a leading clinician and researcher in Infectious Diseases in the UK and internationally, with a particular interest in antibiotic use, antimicrobial resistance and public health. Alison is Director of the National Institute for Health Research Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance. In a rousing and broad ranging talk Alison described research based innovations in behaviour change and organisational development to address healthcare associated infections and antimicrobial stewardship. Key ingredients include organisational to individual focus, broadening stakeholder engagement, implementing change, getting the message right, and quantifying clinical outcomes.


35

1

2

3

4

Key messages from Alison’s talk included the importance of: • Getting the message right by using unambiguous language. The term “drug resistance” is much more easily understood by the general public than antimicrobial resistance. The term “antimicrobial resistance” is easily confused leading to erroneous media reporting about people being resistant to superbugs. • Becoming part of the peer group at ward level and influencing the decision making of clinical leaders • Cross specialty engagement with nursing, the largest group of healthcare professionals • Integrating rather than competing with medication safety Conclusion The AMS Insight Antimicrobial Stewardship Day was a chance to hear from leading experts in antimicrobial stewardship in Ireland and the UK about recent research and developments locally and internationally. It provided a welcome opportunity to meet and network with colleagues in other hospitals, and to showcase and learn about the work done in other hospitals. A key message from the day was the importance

of creating positive interactive relationships with prescribers and patients to influence behaviour. Recurring themes included: • The importance of using effective communication tools to engage with staff using techniques proven to change behaviour in the management of infection and appropriate prescribing of antimicrobials • The need for those leading on the delivery of antimicrobial stewardship programmes to be visible and accessible to frontline staff, to be embedded in Infection and Prevention and Control Programmes and to integrate with Medication Safety to drive high quality safe care for patients The biggest lesson learned was that policies and guidelines are not enough, by themselves, unless prescribing is also recognised as a behaviour that can be influenced by using the science of behaviour change techniques, and the challenge of translating that science into sustainable changes in prescribing behaviour. The day shone a light on the evolving journey of antimicrobial stewardship - to reflect on where we’ve come from, where we are now and where we might be heading in the future.

5 Thanks to Dr. Alida Fe Talento, Consultant Microbiologist, Chair of the Organising Committee, for kindly reviewing the article. Dr. Talento would like to acknowledge the contribution of fellow members of the organising committee to the study day – Professor Colm

Bergin, Consultant, Infectious Diseases Physician, Elmarie Cottrell, Antimicrobial Pharmacist, Gerry Hughes, Antimicrobial Pharmacist, and Dr. Geraldine Moloney, Research Fellow, Trinity College Dublin.

Captions 1. Elmarie Cottrell, Gerry Hughes, Dr Susan Clarke, Mr. Mark Gilchrist, Professor Colm Bergin, Dr Rob Cunney, Professor Alison Holmes, Dr Alida Fe Talento and Geraldine Moloney 2. Eoin Bradley MSD, Dr Anna-Rose Prior, Dr Alida Fe Talento, Gerry Hughes, Marie Tierney, Geraldine Moloney, Elmarie Cottrell andNatasha Friess MSD 3. Marie Tierney and Susan Knowles 4. Dr Breda Lynch, Connie Merrick MSD, Andre Oliveira MSD, Geraldine Moloney, Anne Barry and Roisin Connolly 5. Professor Alison Holmes, Gerry Hughes, Mr Mark Gilchrist, Mr Sean Egan, Dr Alida Fe Talento and Dr Una Geary

HPN • July/August 2016


36 News

Variations in health evident from NHQRS Report Older women have lower uptake rates for cervical cancer screening while cervical screening uptake remains below target in many areas, according to the new report of the National Healthcare Quality Reporting system (NHQRS). While the report also found that in general cancer screening rates are improving while national hospitalisation rates for heart failure and diabetes are decreasing and are below the OECD average. Excluding non-melanoma skin cancer, cervical cancer is the 8th most common cancer (www.ncri. ie. accessed May 12th 2016), diagnosed among women in Ireland and its incidence has increased between 2001 and 2011. The majority of cases of cervical cancer are due to sexual exposure to human papilloma virus (HPV). CervicalCheck is the national cervical screening programme in Ireland and provides free cervical smear tests to women aged 25-60 years. The target for coverage is 80% of the eligible population. The report also shows room for improvement, in particular, considerable variation can be seen between counties in rates of hospitalisation for common chronic diseases such as chronic obstructive pulmonary disease, asthma, diabetes and heart failure. “Identifying this variation is a first step to addressing the reasons why this variation exists and to improving it,” said Health Minister Simon Harris. This is the second National Healthcare Quality Reporting System (NHQRS) annual report. It focuses on a range of outcomes that are important to patients and that refl¬ect the broad range of health services provided in Ireland. Presenting the information in this way is an important first step in understanding performance, quality and safety of health services. It is an essential part of the Department of Health’s commitment to transparency and the use of public information. The report highlights a range of outcomes that are important to

July/August 2016 • HPN

patients and that reflect the broad range of health services provided in Ireland. It builds on last year’s report and includes a number of additional indicators. It also presents health information related to immunisation uptake, cancer screening and survival, management of chronic diseases including asthma, chronic obstructive pulmonary disease (COPD), diabetes, stroke and heart failure. Information is also included on healthcare associated infection rates and antibiotic usage. The report highlights information gaps where new information streams are required such as patient experience data. Minister for Health Simon Harris says, “This second annual report makes available measures of health service performance and outcomes of care for Irish health services. The report analyses information that is readily available to inform questions of performance and quality which can then further inform the development of policy, priorities and specific service plans” said Dr Tony Holohan, Chief Medical Officer. The Minister added, “The report makes clear that many areas of our health services are performing well. Immunisation rates have improved and cancer screening rates continue to improve. A continuing downward trend for hospitalisation for heart failure and for diabetes can be observed. It also shows that survival rates for breast and colorectal cancer are improving. A further positive is the continuing downward trend of the last decade in deaths following admission to hospital with a heart attack or a stroke. “There are areas identified where further room for improvement exists. In particular, considerable variation can be seen between counties in rates of hospitalisation for common chronic diseases such as chronic obstructive pulmonary disease, asthma, diabetes and heart failure. Identifying this variation is a first step to addressing the reasons why this variation exists and to improving it.”

Areas needing improvement • Older women have lower uptake rates for cervical cancer screening. Cervical screening uptake remains below target in many areas. • National Chronic Obstructive Pulmonary Disease (COPD) hospitalisation rates are the highest of all the OECD countries that report this indicator. • There is considerable variation by county in rates of hospitalisation for COPD, asthma, diabetes and heart failure • In-hospital mortality for patients admitted with a heart attack or stroke varies between individual hospitals with a small number of hospitals having rates that are statistically significantly higher than the national average. • The proportion of cases undergoing hip fracture surgery within the recommended two days of admission varies between individual hospitals. • The rate of caesarean sections varies between individual hospitals. Area that are performing well • Immunisation rates have improved in the last few years.

• Cancer screening rates are improving. • National hospitalisation rates for heart failure and diabetes are decreasing and are below the OECD average. • Survival rates for patients with breast and colorectal cancer are improving and at a rate higher than other European countries in the OECD. • Centralisation of breast cancer surgery to the designated cancer centres has been achieved. • 78% of rectal cancer surgery has been centralised to the designated cancer centres. • In-hospital mortality following admission with a heart attack or stroke decreased substantially between 2006 and 2015. • Over 80% of stroke patients are admitted to hospitals with a designated stroke unit. • The proportion of patients undergoing hip fracture surgery within the recommended time of two days in Ireland is improving and is higher than the OECD average. • The national rates of MRSA and C. difficile infections have improved in recent years.


37

New IHCA President cites capacity deficits which are jeopardising patient care The Irish Hospital Consultants Association (IHCA) has announced that Dr Tom Ryan, Consultant in Intensive Care and Anesthesia, St James’s Hospital, Dublin, was elected President of the Association at the June IHCA National Council meeting. Dr Ryan takes over the Presidency from Dr Gerard Crotty, who had completed his two year term. Dr Ryan has been a Consultant in Intensive Care and Anesthesia since 1997. He began his training in Ireland, followed by subspecialty training at the University of Washington in the US. He undertook additional Intensive Care and Anesthesia training at the Mayo Clinic in Minnesota and was a consultant in the Cleveland Clinic, before returning to Ireland to his position in St. James’s Hospital. Commenting, after being elected the 16th IHCA President, Dr Ryan said he was enthusiastic about the real opportunities that exist for the State, after so many years of austerity, to address the fundamental constraints which are severely restricting delivery of timely high quality safe care to patients. Dr Ryan highlighted the

critical lack of physical capacity and other resource constraints, which have been compounded by a damaging medical brain drain in recent years. The newly appointed IHCA President said that consultants, who attempt to deliver safe care for their patients, are continuously aware of the mismatch between the available physical and human resources and the actual needs of their patients. “The urgency for investment cannot be overstated in view of the inexorable increase in demand for acute medical care. Investment must be accompanied by improved clinical governance to ensure that new investment improves quality of care and patient safety,” he said. “As a Consultant in Intensive Care, I am very concerned that the lack of intensive care unit (ICU) beds is putting patients’ lives at risk. The reduction in ICU beds in recent years contrasts sharply with the recommendations of the HSE commissioned Prospectus Report. Prospectus recommended in 2009 that the number of ICU beds increase by 45% immediately and double by 2020. These recommendations have not been acted upon.

Dr Tom Ryan, IHCA President

“In the last decade a total of 1,500 acute hospital beds have been closed. The unacceptable consequences of the resultant inadequate capacity, is that hundreds of patients are being treated on trolleys every day. 75,000 patients were awaiting essential surgery at the end of May and the cancellation of surgical appointments is a regular occurrence because of the shortage of acute hospital beds” he added.

Minister Simon Harris to end the discrimination against new entrant consultants and honour the 2008 Consultant Contract; actions that are necessary to restore trust and our international competiveness in recruiting consultants. Dr Ryan will be joined by two new Vice Presidential appointments to the IHCA, in Dr Oisín O’Connell, Consultant in Respiratory Medicine, Mater Hospital and Dr Roy Browne, Consultant Psychiatrist, Phoenix Care Centre.

The IHCA President said there is a real opportunity for the State and

Phage treatment kills bacteria in CF lung An international team of scientists involving RCSI Researchers have published the first preclinical study demonstrating viral phage efficacy against bacterial infections in lung epithelia. The research team involved microbiologists from the University of Wroclaw, Poland, led by Prof Zuzanna Drulis-Kawa, geneticists from the Laboratory of Gene Technology, KU Leuven, Belgium, led by Prof Rob Lavigne, and CF researchers from the RCSI Department of Molecular Medicine and the National Children's Research Centre led by Prof Brian Harvey (pictured). The team developed and tested a virus-derived phage (KTN4) against the most common bacterial infection (Psudomonas aeruginosa) in CF lung epithelia. The lytic virus was shown to have a very strong

bactericidal effect with broad spectrum of activity against clinical isolates of P. aeruginosa strains, especially from cystic fibrosis patients. Prof Harvey whose team at RCSI carried out the functional studies in normal and CF lung epithelia said this study provides evidence that bacteriophages such as KTN4 have potential to efficiently fight the most common CF lung infections. What this study adds to the field

The rise in antibiotic resistance genes among microbial pathogens poses an alarming threat to the efficacy of current antimicrobial therapy to treat severe bacterial infections in CF and in sepsis. Antibiotic resistance is reaching a crisis situation in some bacterial pathogens where few therapeutic alternatives remain and panresistant strains are becoming more prevalent. Moreover, there is a dearth of new antibiotics in the developmental pipeline.

Chronic bacterial infections are the underlying cause of lung destruction (bronchiectasis) and morbidity in cystic fibrosis. CF lung disease involves chronic and virulent infection by Pseudomonas pathogens which produce a cycle of acute inflammatory responses necessitating repeated and longterm antibiotic treatments.

Non-antibiotic therapies to treat bacterial infections are now under serious consideration and one possible option is the therapeutic use of viral phage particles that can target specific bacterial pathogens. Phage therapy can be likened to a ‘guided missile' approach to lyse and kill selected bacteria in contrast to the ‘big hammer' effect of antibiotics

which also wipe out beneficial gut bacteria leaving a niche for antibiotic resistant ‘superbugs'. A drawback in the application of phage therapy has been the lack of rigorous pre-clinical evaluation of phage efficacy in human disease models of infection such as CF. The study focused on preclinical approaches to assess bacteriophage efficacy against Pseudomonas biofilms and infections in CF lung epithelia. The significant bacterial killing effects observed in the study indicate that giant KTN4 phage is a suitable candidate for in vivo phage therapy evaluation for lung infection applications. The breakthrough was published last month in the Nature publication Scientific Reports.

HPN • July/August 2016


38 News

Calls for guidelines for Pregnant women Researchers at University College Cork (UCC) have reported that high Vitamin D status is associated with lower risk of pregnancy complications such as pre-eclampsia and small-forgestational age (SGA) birth. The findings, published at the end of June in the American Journal of Clinical Nutrition, come from analysis of vitamin D status in the SCOPE (Screening for Pregnancy Endpoints) Ireland study. The project aims to develop screening tests to predict and prevent the major complications of late pregnancy, such as pre-eclampsia, SGA and spontaneous preterm birth. Professor Mairead Kiely, who leads the Maternal and Child Nutrition research programme at INFANT, and is co-Director of the Cork Centre for Vitamin D and Nutrition Research noted that, “The data highlights the need to conduct nutrition research in vulnerable populations such as children, pregnant and breastfeeding women to develop life-stage specific recommendations for nutrient intakes. Currently in

Professor Mairead Kealy

Ireland, there are no pregnancyspecific guidelines for vitamin D intake. This is true of many countries as few research studies are carried out in women during pregnancy. Through the ECfunded ODIN project on vitamin D and Human Health, co-ordinated by our group at UCC, we are following up the results of this analysis in SCOPE with a vitamin D intervention study in pregnant women which will be completed before the end of the year. This data will provide the evidence to make pregnancy-specific recommendations for vitamin D to prevent deficiency and protect mothers and their babies.” The study surveyed 1,786 mothers who attended Cork University Maternity Hospital and was designed to explore whether or not there was a connection between vitamin D status in early pregnancy and any major pregnancy

complications. The study showed that 17% of the pregnant women were at high risk of vitamin D deficiency, compared with 12% of non-pregnant women of the same age. It also reported a lower risk of pregnancy complications among women with high vitamin D status. Professor Louise Kenny, Director of the INFANT Centre, explained that the research “is about helping

mothers and their babies: our goal here is to look at the data and what we can learn to help mums have safe pregnancies and deliver healthy babies. Nutrition is a large part of that. This study is an example of collaboration at work between clinicians and scientists to improve maternal and infant health, which is at the core of what we are doing at INFANT.”

11th annual Pfizer Health Index focuses on family health in Ireland The Pfizer Health Index has shown that 55% of patients view budgetary health cuts as having impacted us the deepest with 86% ranking health as a top priority for investment in the future. These findings were found in the 11th annual Pfizer Health Index launched at the Science Gallery in Dublin. The Index launch was addressed by a number of experts in the area including Dr Nina Byrnes, GP, Dr Cliodhna FoleyNolan, Director, Human Health & Nutrition, safefood and Dr John Sharry, Family Psychotherapist. The research also highlighted that since the financial recovery has started, Irish adults have become more optimistic about their health with 65% rating health as 8 or higher out of 10.

Dr John Sharry, Family Psychotherapist; Dr Cliodhna Foley-Nolan, Director, Human Health & Nutrition, safefood; Paul Reid, Managing Director, Pfizer Ireland and Dr Nina Byrnes, GP at the Science Gallery in Dublin

New cancer drug to be made available The HSE is to make a new cancer drug available free to patients with melanoma. Pembrolizumab should be included in the State drugs scheme for the treatment of melanoma, the HSE drugs group has recommended at their latest meeting held last month (June). The decision comes three months after the drug was approved on cost effectiveness grounds by the National Centre for Pharmacoeconomics. Oncologists had warned patients would die as a result of the delay in making the decision. Minister for Health Simon Harris had asked for a report on the HSE deliberations on new cancer drugs. Pembrolizumab, which costs almost ¤70,000 per patient per year, will be made available to about 130 patients, according to its manufacturer, MSD.

July/August 2016 • HPN


Awards Hospital Professional

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Celebrating innovation and best practice

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40 Feature

ECCO-EFCCA Patient Guidelines on Crohn’s Disease (CD) We take a brief overview of the ECCO-EFCCA latest guidelines on Crohn’s Disease diagnosis, treatment and management

Crohn’s Disease (CD) is a disease that affects the small and the large bowel, and less often other parts of the gastrointestinal tract. It may also affect various organs and tissues outside the gut, most commonly the skin, the joints, and the eyes. CD most commonly affects the end of the small bowel and the large bowel. However, CD may affect any part of the entire gastrointestinal tract, starting from the mouth and ending at the anus. The inflammation of the bowel is usually ‘discontinuous’ and areas of inflammation (‘patches of diseased bowel’) alternate with normal bowel parts (‘skip lesions’). Depending on the severity of the inflammation the innermost lining of the bowel wall (‘mucosa’) may appear red (‘erythematous’) and swollen (‘oedematous’) with ulcers of various size and form (aphthous, superficial, deep, longitudinal) and the mucosa may appear as ‘cobblestone’. These lesions affect the entire thickness of the bowel wall and may lead to complications, such as stenosis of the lumen and/or penetration resulting in formation of abscesses (diffusion of the contents of the intestinal lumen in the abdominal cavity) or fistulae (tracts which communicate and drain the contents of the bowel lumen to the skin, or to adjacent organs, such as the bladder, or to other loops of the bowel). In addition, in a significant proportion of patients CD may involve various parts of the body outside the gut, most commonly the skin, the joints and the eyes. These extra-intestinal manifestations may appear before the development of the typical bowel symptoms of CD (see later) and sometimes are more troublesome and more difficult to treat than the bowel symptoms. Because CD is a polymorphic disease, the lesions in the gut must be mapped by appropriate diagnostic tests and graded for severity at the time of diagnosis.

July/August 2016 • HPN

In addition, because CD is a lifelong disease without a definitive cure at the moment, therapy aims to relieve the inflammation in the gut and extra-intestinal sites (if present), preserve the function of the bowel, prevent the complications, and offer patients a normal quality of personal, professional and social life without disability. Therapeutic interventions include cessation of smoking, dietetic interventions, and a variety of medicines that are used alone or in combination according to the location and severity of disease. Diagnosis of Crohn’s Disease (CD) Symptoms of CD can be diverse. They often include abdominal pain, weight loss and diarrhoea for more than four weeks. If these symptoms occur especially in young patients, a doctor should consider the possibility of CD. General symptoms of feelings

of discomfort, fatigue, loss of appetite, or fever are common. Symptoms can start suddenly, and sometimes CD may be mistaken for acute appendicitis. Symptoms may also be similar to irritable bowel syndrome (IBS). Most patients experience abdominal pain and weight loss before diagnosis. Blood and mucus in stools is seen less frequently than in UC patients. Symptoms related to CD outside the bowel, most commonly in the joints, can be seen before bowel symptoms. Diagnostic tests CD varies between patients depending on the patient’s age at onset, the location of the disease in the bowel and how the disease behaves. There is no single test for the diagnosis of CD. The diagnosis is established by a combination of assessment of clinical symptoms, blood tests, findings in imaging, endoscopy,

and histological assessment of bowel biopsies (to be explained in glossary). Genetic tests are not recommended for a routine diagnosis of CD at the moment. Smoking, family history of IBD and appendectomy in earlier life are all risk factors for CD. Bacterial or viral infection of the stomach or intestine increases the risk of developing CD. Studies of NSAIDs as a risk factor have less consistent findings. Non-gut-related (extra-intestinal) symptoms of CD There are many symptoms that can occur with CD and not all them involve the intestines directly. As previously mentioned, CD may also affect various organs and tissues outside the gut. Anaemia and thrombocytosis (when the body produces too many thrombocytes or platelets) are the most common findings of


Introducing Entyvio: the rst and only gut-selective biologic for patients with moderately to severely active ulcerative 1 colitis (UC) or Crohn’s disease (CD)

TREAT WITH PRECISION The first and only gut-selective biologic 1 Achieved remission at Week 52 in: 42% of UC patients vs 16% for placebo in patients responding at Week 6 (P<0.001) 39% of CD patients vs 22% for placebo in patients responding at Week 6 (P<0.001) Targeted mechanism of action 1 different from anti-TNFα therapies

One dose for all patients1 : 300-mg IV infusion

References: 1. Entyvio Summary of Product Characteristics. Takeda Pharmaceuticals Ireland Ltd. www.medicines.ie ITEM CODE: IRE/VED/14/0008c(1) DATE OF PREPARATION: October 2015

© 2015 Takeda Pharmaceuticals International GmbH Entyvio® ▼ (vedolizumab) PRESCRIBING INFORMATION Refer to the Summary of Product Characteristics (SmPC) before prescribing. Presentation: 300 mg powder for concentrate for solution for infusion. Indication: Adult patients with moderately to severely active ulcerative colitis(UC)/Crohn’s disease (CD) who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a tumour necrosis factor-alpha (TNFα) antagonist. Dosage & Administration: Treatment should be initiated and supervised by a specialist healthcare professional experienced in diagnosis and treatment of ulcerative colitis or Crohn’s disease. Patients should be monitored during and after infusion in a setting equipped to manage anaphylaxis. Ulcerative colitis: Recommended dose regimen 300mg administered by intravenous infusion over approximately 30 minutes at 0, 2, 6 weeks and 8 weeks thereafter. Reconsider treatment if no evidence of therapeutic benefit at week 10. If patients experience a decrease in response, they may benefit from increased dosage frequency to 300mg every 4 weeks. Corticosteroids may be reduced/discontinued in patients who respond to treatment with Entyvio. If therapy is interrupted and needs to be restarted, Entyvio dosing every 4 weeks may be considered. Crohn’s disease: Recommended dose regimen is 300mg administered by intravenous infusion over approximately 30 minutes at 0, 2, 6 weeks and 8 weeks thereafter. Patients who have not shown evidence of therapeutic benefit may benefit from a dose at week 10. Continue therapy every 8 weeks from week 14 in responding patients. Therapy should be discontinued if no evidence of therapeutic benefit is observed at week 14. If therapy is interrupted and needs to be restarted, Entyvio dosing every 4 weeks may be considered. Paediatric populations: No data available in children aged 0-17 years. Not recommended. Elderly patients: No dosage adjustment required. Renal or hepatic impairment: Entyvio has not been studied in these populations. No dose recommendation can be given. Contraindications: Hypersensitivity to Entyvio or any of the excipients. Active infections such as tuberculosis (TB), sepsis, cytomegalovirus, listeriosis and opportunistic infections such as Progressive Multifocal Leukoencephalopathy (PML). Warnings and Precautions: Patients should be observed continuously during infusions for signs/symptoms of hypersensitivity reactions. Patients should continue to be observed for two hours following infusion completion for the first two infusions and one hour for subsequent infusions. Infusion-related reactions (IRR): Hypersensitivity reactions have been reported, the majority were of mild to moderate severity. Discontinue treatment if anaphylaxis or other serious allergic reactions occur and institute appropriate treatment. In mild to moderate IRR, slow or interrupt infusion. Consideration for pre-treatment with antihistamine, hydrocortisone and/or paracetamol should be given prior to next infusion, for patients with history of mild/moderate IRR to Entyvio. Infections: Not recommended in patients with active, severe infections until infections are controlled. Consider withholding in patients who develop severe infection while on treatment with Entyvio. Before initiating treatment, patients must be screened for TB. If latent TB is diagnosed, anti-tuberculosis appropriate treatment must be initiated prior to Entyvio treatment.

Progressive Multifocal Leukocephalopathy (PML): No cases were observed in Entyvio clinical trials, but John Cunningham (JC) virus infection resulting in PML and death has occurred in patients treated with other integrin receptor antagonists and systemic immunosuppressive agents. A risk of PML cannot be ruled out. Monitor patients for any new or worsening neurological signs/symptoms. Malignancy: Underlying increased risk of malignancy in UC and CD. Immunomodulatory products may increase risk. Prior and concurrent use of biological products: No clinical data available for Entyvio use in patients previously treated with natalizumab or rituximab. Patients previously exposed to natalizumab should wait at least 12 weeks prior to initiating Entyvio therapy. Entyvio not recommended for concomitant use with biologic immunosuppressants as no clinical data available. Live and oral vaccines: Patients may continue to receive non-live vaccines. Patients recommended to be up-to-date with all appropriate immunisations prior to initiating Entyvio. Live vaccines may be administered concurrently only if benefit clearly outweighs risk. Interactions: No interaction studies performed. Concomitant administration of corticosteroids, immunomodulators (azathioprine, 6-mercaptopurine, and methotrexate) and aminosalicylates did not have a clinically meaningful effect on Entyvio pharmacokinetics. Fertility, pregnancy and lactation: Women of child-bearing potential should use adequate contraception and continue for at least 18 weeks after last Entyvio treatment. Since maternal antibodies are excreted in breast milk, decision whether to discontinue breast-feeding or discontinue/abstain from Entyvio should be made according to relative benefit to child of breast-feeding or to mother of Entyvio. Undesirable Effects: Very Common (≥ 1/10): nasopharyngitis, headache, arthralgia. Common (≥1/100, <1/10): bronchitis, gastroenteritis, URTI, influenza, sinusitis, pharyngitis, paraesthesia, hypertension, oropharyngeal pain, nasal congestion, cough, anal abscess, anal fissure, nausea, dyspepsia, constipation, abdominal distension, flatulence, haemorrhoids, rash, pruritis, eczema, erythema, night sweats, acne, muscle spasm, back pain, muscular weakness, fatigue, pain in extremities, pyrexia. Other serious undesirable effects (≥1/1000 to <1/100): respiratory tract infection, infusion site reaction, infusion-related reaction. Refer to the SmPC for details on full side effect profile and interactions. Legal Classification: POM. Marketing Authorisation Number: EU/1/14/923/001; 300mg powder for concentrate for solution for infusion. Further information is available from Takeda UK Ltd. Building 3, Glory Park, Glory Park Avenue, Wooburn Green, Buckinghamshire, HP10 0DF. Tel: 01628 537900 Fax: 01628 526617. PI Approval Code: IRE/VED/15/0014 Date of revision: September 2015. 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.


42 Feature CD in the blood. CRP and ESR show whether inflammation is present; CRP broadly correlates with disease activity, whereas ESR is less accurate. Faecal calprotectin correlates well with disease activity in the intestines. None of these tests, however, is specific enough to diagnose CD or differentiate it from UC. Colonoscopy and biopsies is the first line procedure to diagnose inflammation in the colon. In most colonoscopies, biopsies can also be taken from the small bowel. Endoscopic signs of CD include discontinuous, patchy inflammation, anal lesions, and cobblestone-like appearance of the intestinal wall. The severity of CD in the colon can be assessed well in colonoscopy, but in case of CD located in the end of the small bowel, ileoscopy in combination with imaging techniques is more efficient for diagnosis. Imaging techniques alone like ultrasonography, CT scan or MRI cannot definitely diagnose CD. Prediction of disease course Clinical factors at diagnosis and/or endoscopic findings may predict the course of CD. This should be taken into account when deciding on what treatment to use. Studies suggest that the following factors predict a more severe disease within five years after diagnosis: - perianal lesions, - disease in the end of the small bowel and beginning of the colon, - young age at diagnosis, and/or - the need to treat the first flare with steroids. There is increasing evidence that early intensive therapy with immunomodulators and/or biologics may induce mucosal healing and early continuous remission without steroids. Early intensive therapy should, however, only be considered in severe cases due to the risks of immunosuppressive therapy. Medical Management of Active Crohnâ&#x20AC;&#x2122;s Disease including Alternative Therapies The presence of active inflammation caused by CD should be confirmed before a medical treatment is started or changed. The CD treatment plan should take into account disease activity, location, and behaviour, and the plan should always be discussed with the patient. Sometimes, especially in severe cases, treatment decisions may have to be made without knowing the full distribution of the disease. Doctors may not always be able to judge disease activity, and

July/August 2016 â&#x20AC;˘ HPN

objective markers (e.g. biopsies, faecal calprotectin) of disease activity should be obtained by various examinations before starting or changing therapy. When deciding on a suitable therapy, a balance between drug potency and potential side effects, previous response to treatment, and potential complications or symptoms outside the bowel should be taken into account. Moderately active CD Moderately active CD, which is located in the end of the small bowel and beginning of the colon, should be treated with budesonide or systemic corticosteroids like prednisolone or methyl-prednisolone. An antiTNF treatment should be used for patients who have not responded to steroids in the past or do not tolerate them. For patients with a disease that relapses rarely, starting steroids again together with an immunosuppressant may be suitable. In patients who do not respond to steroids and/ or anti-TNF, vedolizumab is a suitable option. Budesonide and prednisolone are suitable initial therapies for moderately active CD. Prednisolone is very effective and less expensive, but usually causes more side effects than budesonide. Corticosteroid exposure should, however, be minimised in CD treatment, because it is not effective in maintaining remission. Steroid therapy can be effectively minimised by starting anti-TNF therapy early. Certain patient groups, such as those who are dependent on steroids or do not respond to them, may benefit more from anti-TNF. In patients at early stages of the disease, a combination of infliximab and azathioprine has been found to be more effective than infliximab alone in reaching and maintaining remission. Severely active CD Severely active CD, which is located in the end of the small bowel and beginning of the colon, should at first be treated with systemic corticosteroids. An antiTNF treatment is suitable for those who have relapsed. In patients who do not respond to steroids and/or anti-TNF, vedolizumab is a suitable option. For some patients who have a rarely relapsing disease, starting steroids again with an immunosuppressant may be suitable. Surgery should be discussed with patients who do not respond to medical treatment. Although prednisolone or

intravenous hydrocortisone is still used as initial treatment of severe CD in the end of the small bowel, in recent years the threshold for starting antiTNF therapy has been lowered in patients with a poor prognosis. According to studies, continuous treatment with the anti-TNF agents infliximab or adalimumab reduces the risk of surgery and hospitalisation in CD. Anti-TNF therapy is frequently used for patients who do not respond to initial therapy and who are not candidates for surgery. The threshold for surgery is lower in CD located in the end of the small bowel and beginning of the colon than for disease elsewhere, especially if disease is localised at the small bowel, as extensive or repeated loss of small bowel may cause malnutrition. Some experts prefer surgery to anti-TNF therapy for disease in this location, whereas others prefer surgery if medical therapy does not work fast enough or causes intolerable side effects. Colonic CD Active CD in the colon should be treated with systemic corticosteroids. For those who have relapsed, thiopurines, a treatment with anti-TNF, or vedolizumab are suitable options. In patients who do not respond to first anti-TNF treatment, vedolizumab may be suitable. Active, severe CD in the colon is more easily and earlier confirmed than CD in the small bowel. This may be why CD in the colon seems to respond better to antiTNF therapy than CD in the small bowel. Systemic corticosteroids, such as prednisolone, are effective, but budesonide has no effect in treating CD in the colon. If patients do not respond or lose response to anti-TNF or vedolizumab therapy, surgery is usually discussed. Surgery should however always be discussed, when initiating or changing an immunosuppressive therapy. Extensive CD Extensive CD in the small bowel should at first be treated with systemic corticosteroids. Early treatment with anti-TNF should also be evaluated. For patients with a severe disease who have relapsed, an anti-TNF based treatment is suitable. The consequences of continuous intestinal inflammation, such as poor nutrition, development of intestinal strictures and obstruction are greater in extensive compared

to localized small bowel CD. Therefore, treatment with steroids in combination with early start of immunomodulators is considered appropriate in these patients. Immunosuppressive therapy Early treatment with immunosuppressants seems to suit best for patients who have signs and symptoms that suggest a poor outcome. Early treatment with anti-TNF should be started in patients who have very active disease and signs and symptoms that suggest a poor outcome. Several studies have shown that anti-TNF is more effective when it is started early in the disease, especially in those with certain risk factors for a poor outcome. Such risk factors include extensive disease, young age at diagnosis, initial need for steroid therapy and perianal disease. All anti-TNF treatments that are available at the moment seem to be equally efficient in treating CD inside the intestine. They also have similar side effects. The choice of treatment depends on what is available, how the medicine is delivered, what the patient prefers and cost. Primary lack of response to an anti-TNF based treatment should be determined within 12 weeks. After 12 weeks of insufficient response it is unlikely that a positive therapeutic effect will occur and patients should be switched to a new therapeutic regimen that may be able to induce remission. There is a risk of serious infections when a patient is treated with immunosuppressants, including anti-TNF. This risk should be taken into account.

All immunosuppressants including steroids, thiopurines, methotrexate and anti-TNF decrease the activity and competence of the immune system. This may increase the risk to acquire various infections that may cause severe and even lethal diseases. Co-therapy with more than one immunosuppressant increases the risk of infections significantly. Therefore, long-term co-immunosuppressive therapy should be avoided whenever possible. On the other hand, co-immunosuppressive therapy has been demonstrated to be more potent and may be needed especially in severe disease.


Feature 43

Remnant cholesterol back in the news Written by Professor Jean Charles Fruchart, Professor Michel Hermans & Professor Pierre Amarenco Despite emphasis on low-density lipoprotein cholesterol (LDL-C) as the primary lipid target, reinforced by publication of the Sixth Joint Task Force European Guidelines for Cardiovascular Disease Prevention in Clinical Practice this month,1 it is increasingly clear that individuals with well controlled LDL-C levels are still at high residual risk of cardiovascular events. A proportion of this risk is undoubtedly lipid-related, given that the INTERHEART study showed that dyslipidaemia was one of the top nine factors associated with risk for myocardial infarction.2 The question remains: what other lipid measures should be taken into account for assessment of residual cardiovascular risk? What is remnant cholesterol? Remnant cholesterol is one contender. By definition, remnant cholesterol represents the cholesterol content of a subset of triglyceride-rich lipoproteins called remnants, i.e. chylomicron remnants, very lowdensity lipoprotein (VLDL), and intermediate-density lipoprotein (IDL) in the nonfasting state, and VLDL and IDL in the fasting state.3 There are difficulties in specific measurement, and therefore it has been suggested that a simple formula for calculation may be preferable, i.e. remnant cholesterol = total cholesterol – LDL-C – highdensity lipoprotein cholesterol (HDL-C).3 Although this may not be as precise as direct measurement, such an approach had practical advantages given that these parameters are measured in the nonfasting state. What is the evidence for remnant cholesterol as causal for heart disease? There is accumulating evidence to support remnant cholesterol as a contributor to residual cardiovascular risk; it is beyond the scope of this editorial to review the studies individually, instead the reader is referred to a comprehensive review.3 Perhaps some of the strongest support comes from elegant Mendelian randomization studies which show that genetic variants that only influence remnant cholesterol

levels were causal for ischaemic heart disease risk, increasing this risk by 2.8-fold per 1 mmol/L (39 mg/dL) higher remnant cholesterol levels. Incidentally, there were also variants that increased both remnant cholesterol and HDL-C; however, variants which solely affect HDL-C were not causally associated with ischaemic heart disease risk, thus reinforcing that it is remnant cholesterol which contributes to cardiovascular risk.4 Added to this, this month’s Landmark study adds to the evidence-base for a causal role for remnant cholesterol in ischaemic heart disease.5 In a combined cohort analysis from the Jackson Heart and Framingham Offspring Cohort Studies involving both black and white subjects without prior cardiovascular disease, Joshi and co-workers showed that each 1 standard deviation increase in remnant cholesterol levels increased the risk of coronary heart disease by 23%. While this association was slightly attenuated by adjustment for HDL-C, it remained statistically significant. Moreover, this month’s Focus report of a large genetic study from Iceland adds to this, showing that non-HDL-C, which incorporates both LDL-C and remnant cholesterol, confers risk for coronary artery disease beyond LDL-C.6 This therefore provides further argument for the causality of remnant cholesterol in ischaemic heart disease. Indeed, the Sixth Joint Task Force has recognized that remnant cholesterol is causally related to atherosclerosis.1 The main hurdle before recommendations for management can be made relate to the absence of “hard” cardiovascular outcome prospective clinical trials focused on this parameter. The most common cause of elevated remnant cholesterol (and triglycerides, a surrogate for remnant cholesterol) is obesity. Given the ongoing obesity pandemic, particularly in the Middle East where more than 50% of individuals in some countries are overweight or obese,7 this argues for urgent action for treatments that are effective in lowering remnant cholesterol (and its surrogate, triglycerides). A number of promising novel agents

Professor Jean Charles Fruchart

are in development and we await the results of advanced trials with interest. As with all clinical development, it is important that the agent is efficacious in reducing remnant cholesterol levels, largely free of side effects, and shows definitively that the treatment reduces the risk of cardiovascular disease in statin-treated patients. Watch this space for further news. Prof. Jean-Charles Fruchart, Pasteur Institute, Lille, France, President of R3i Prof. Michel Hermans, Clin. Universitaires Saint-Luc, Brussels, Belgium, General Secretary Prof. Pierre Amarenco, University Paris-VII, Paris, France, Member The R3i is a worldwide, academic, multidisciplinary non-profit organisation, aims to successfully address the excessively high risk of macro- and micro-vascular complications in patients with atherogenic dyslipidemia, characterised by elevated triglycerides and low levels of high-density lipoprotein (HDL) cholesterol and unaddressed by current standards of care. The R3i is led by a Board of Trustees and an International Steering Committee (ISC) of 43 officers and members from the disciplines of cardiology, diabetology, lipidology, endocrinology, epidemiology, nutrition, ophthalmology, nephrology and basic science. The legal body of the R3i is a foundation established in Switzerland. National organisations are in the process of being established in more than 40 countries worldwide, including Ireland. Irish Residual Risk Reduction Initiative (R3i) committee co-chairs are Dr Maeve Durkan, Consultant in Diabetes and Endocrinology, Portiuncula Hospital and Dr Vincent Maher, Consultant Cardiologist, AMNCH, and also to Prof Gerald Tomkin, Consultant in Diabetes & Endocrinology, Blackrock Clinic and Associate Professor of Endocrinology, TCD.

References 1. Piepoli MF, Hoes AW, Agewall S et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J 2016; DOI: http://dx.doi.org/10.1093/eurheartj/ ehw106 ehw106 First published online: 23 May 2016. 2. Yusuf S, Hawken S, Ounpuu S et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet;364:937-52. 3. Varbo A, Benn M, Nordestgaard BG. Remnant cholesterol as a cause of ischemic heart disease: Evidence, definition, measurement, atherogenicity, high risk patients, and present and future treatment. Pharmacol Ther 2014;141:358-67. 4. Varbo A, Benn M, Tybjaerg-Hansen A et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol. 2013;61:427–36. 5. Joshi PH, Khokhar AA, Massaro JM et al, on behalf of the Lipoprotein Investigators Collaborative (LIC) Study Group. Remnant lipoprotein cholesterol and incident coronary heart disease: the Jackson Heart and Framingham Offspring Cohort Studies. Am Heart Assoc J 2016;5:e002765. 6. Helgadottir A, Gretarsdottir S, Thorleifsson G et al. Variants with large effects on blood lipids and the role of cholesterol and triglycerides in coronary disease. Nat Genet 2016 May 2. doi: 10.1038/ng.3561. [Epub ahead of print]. 7. Ng M, Fleming T, Robinson M et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014;384:766-81.

HPN • July/August 2016


44 News

New breast cancer trial for Ireland Cancer Trials Ireland has announced that it has opened a cancer trial to test a new treatment for patients with advanced breast cancer which has not responded to currently available treatments. The trial will test for the first time the use of the new drug copanlisib in combination with trastuzumab to treat advanced HER2-positive (HER2+) breast cancer which has progressed or recurred in patients during or following standard anti-HER2 treatment. It is expected that up 34 patients will take part in the trial which will be conducted over the next 2-3 years in Beaumont Hospital in Dublin, St Vincent’s University Hospital in Dublin, St. James’s Hospital in Dublin, University Hospital Galway and Cork University Hospital at a cost of approximately 750,000 euro.

The trial is being led by Professor Bryan Hennessy, Clinical Lead, Cancer Trials Ireland, and Consultant Oncologist, Beaumont Hospital. It builds on Professor Hennessy’s previous laboratory research, funded by the Health Research Board (HRB) and the Irish Cancer Society, which identified the exciting potential of the new drug copanlisib in breast cancer. The trial is sponsored by Cancer Trials Ireland and supported by Bayer HealthCare AG. HER2+ breast cancer is a type of breast cancer that over-produces Human Epidermal growth factor Receptor 2 (HER2), a protein that stimulates the growth of cancer cells. Current treatments that specifically target HER2, such as trastuzumab, are effective at helping to slow or even stop the

growth of breast cancer cells. However, resistance to HER2targeted treatments can develop, meaning that current treatments can become ineffective. Professor Hennessy said that copanlisib could help to reverse the resistance of some HER2+ breast cancers to trastuzumab (a commonly used anti-HER2 treatment) and lead to a new therapy for advanced HER2+ breast cancer. Professor Hennessy said, “It is known that HER2+ breast cancer can become resistant to current HER2 therapy. We are now learning how this happens. The switching on of a pathway called the PI3K pathway in cancer cells is often responsible. One of the possible ways this happens is through mutations (changes) that occur in a gene called PIK3CA.

Research studies that we have carried out at the laboratory level have suggested that blocking the abnormal activity of the PI3K pathway in cancer cells, may help to reverse the resistance of some HER2+ breast cancers to HER2 treatments including trastuzumab”, he said. “Copanlisib blocks the abnormal activity in the PI3K pathway and it is currently being tested in a variety of cancers. By combining copanlisib and trastuzumab, this trial hopes copanlisib will block the abnormal activity of the PI3K pathway and allow trastuzumab to work effectively.” To find out more about the trial and their suitability, patients should ask their doctor or healthcare professional. Information on other cancer trials is available at www.cancertrials.ie.

New Hybrid Cardiac Catheterisation Laboratory Minister for Health, Mr Simon Harris TD and Minister for Health Ms. Michelle O’Neill MLA have officially opened the new Hybrid Cardiac Catheterisation Laboratory (HCCL) at Our Lady’s Children’s Hospital Crumlin. The Hybrid Cardiac Catheterisation Laboratory is the only paediatric interventional cardiology service on the island of Ireland. OLCHC as the National Centre for Paediatric Cardiology and Cardio-Thoracic Surgery is the Republic of Ireland’s (ROI) partner in the Congenital Heart Disease (CHD) All Island Network, treating approximately 600 patients per year. The project was funded in totality by the Health Service Executive at a cost of ¤5.6million. This new Hybrid Cardiac Catheterisation Laboratory at Our Lady’s Children’s Hospital Crumlin has the most advanced paediatric interventional cardiology equipment in Europe. This Unit has been designed to create the infrastructure and technology to deliver cardiac catheterisation procedures to the Children of Ireland, to international standards. In addition, the design enables a group of children to proceed directly from cardiac catheterisation to cardiac surgery without having to change facilities. This was not available to OLCHC previously.

Minister for Health Simon Harris, TD and Minister for Health Michelle O’Neill, MLA officially opened the Laboratory

TCS Partners with the Royal College of Physicians of Ireland Tata Consultancy Services a leading global IT services, consulting and business solutions organization, has announced it is working with the Royal College of Physicians of Ireland (RCPI) to deploy iON Cloud solutions to transform how doctors interact with each other. The partnership will enable the postgraduate medical training college to create an online community which helps doctors share expertise and access online courses throughout their careers. The new tool called The Physician Network is a resource based on the TCS iON Digital Learning July/August 2016 • HPN

Platform to enable virtual ‘common-interest communities’ and facilitate best practice knowledge-sharing. Doctors will be able to collaborate from any location around the world, using the mobile-optimized solution to share insights and learnings with other medical professionals. RCPI’s assessment process has also been digitised, removing the need for paper-based examinations and delivering significant cost and time efficiencies, helping make the organization an international leader in supporting the professional development of its membership,

comprised of doctors based in 84 countries around the world. The TCS iON Digital Platform enables the College’s digital strategy to be reimagined as a fully integrated service bringing real value to physicians worldwide. Mr. Leo Kearns, CEO, RCPI said, “The world of higher education is changing and the solutions TCS is innovating help to put RCPI at the forefront of an emerging trend that sees technology being used to support doctors in the delivery of care and in their own professional development throughout their careers.

“Our network of doctors is our greatest asset which is why we are committed to their professional development, through both online courses and through collaborative knowledge exchange, so that new ideas and techniques and discoveries can be readily shared and adopted globally. TCS has worked closely with RCPI to determine our needs and to ensure that the technology we deploy enables us to equip our members for the medical world of today and tomorrow.”


45

Disclosure of payments to Healthcare Organisations and Professionals New levels of transparency between the pharmaceutical industry, medical community and healthcare organisations A new level of transparency in the relationship between the pharmaceutical industry and the medical community and healthcare organisations commenced last month (June) as details of transfers of value are made publicly available by the industry for the first time. The initiative is part of a voluntary Europe-wide initiative of the European Federation of Pharmaceutical Industries and Associations (EFPIA) and is designed to enhance the transparency surrounding relationships between the pharmaceutical industry and healthcare organisations and professionals. As a result, the Irish Pharmaceutical Healthcare Association (IPHA) changed its mandatory Code of Practice to require disclosure of transfers of value.

IPHA will publish details of payments or ‘transfers of value’ (ToV) totalling ¤24.1 million in 2015 made by its member companies to Healthcare Organisations (HCOs) and Healthcare Professionals (HCPs). ToV data relate to  Research and development funding including clinical trials support  Donations and grants to HCOs (e.g. medical equipment, education and staff etc.)  Contributions to the cost of events (e.g. medical conferences and educational events) for HCOs and HCPs: sponsorship, registration fees and travel and accommodation costs

 Fees and related expenses for services and consultancy for HCPs and HCOs (e.g. participation in advisory boards etc.) The total value for R&D was ¤8.5 million, for transfers to HCOs ¤9.5 million, and for HCPs ¤6.1 million. Details of transfers of value made in 2015 by each member company of IPHA – and some nonmember companies voluntarily participating - will be available in an IPHA central report at www. transferofvalue.ie from 4pm today. Subsequent reports will be published within six months of year end and will be publicly available for three years from date of initial publication. In order to comply with personal rights under data protection law, consent must be obtained

by companies from HCPs for publication of the individual data. In the absence of consent, an aggregate value of transfers of value to non-consenting HCPs is disclosed. Individuals may grant or withdraw their consent at any time and any change arising will be reflected in the relevant return by each company throughout the year. Such consent is not required from HCOs. Commenting on the publication of the ToV data, IPHA CEO Oliver O’Connor said, “Interactions between the pharmaceutical industry and healthcare professionals have a profound and positive influence on the quality of patient treatment and the value of future research. They have delivered numerous innovative medicines and changed the way many diseases impact on our lives. This new level of transparency is designed to assure the public that they can trust their HCPs to recommend treatment or administer appropriate care based solely on clinical evidence. Along with the research based pharmaceutical industry across Europe, Ireland, as represented by IPHA, has today entered this new era of transparency. The commencement of disclosure, which will from now on be an annual event, is a clear demonstration of the pharmaceutical industry is committed to working with healthcare professionals and organisations to drive innovation that benefits patients”.

Doctor emigration remains a challenge for Irish Health Service Foreign trained doctors experience slower career progression than doctors trained in Ireland and half of them plan to move on to a new country, as reported in two papers from RCSI (Royal College of Surgeons in Ireland) and Trinity College Dublin (TCD), which were published in BMC Human Resources for Health. The study which surveyed 366 foreign doctors registered to practice medicine in Ireland, funded by the Health Research

Board and enabled by the Medical Council, shows that international recruitment is not an effective long-term strategy for addressing shortages of doctors, with only around one third of foreign doctors planning to remain in Ireland. In a third paper, the RCSI health workforce research group, in collaboration with a senior researcher from Dublin City University, reports that the longer the time that Irish-trained doctors spend abroad, the less likely

they are to return to Ireland. A survey of 388 Irish trained health professionals working abroad - 307 doctors and 81 nurses/ midwives, most of whom had left Ireland between 2008 and 2014, showed that the proportion of doctors who planned to remain abroad permanently had risen from 10% at the time they left Ireland to 34%, at the time of the 2014 survey.

consistent pattern of findings from these studies. The same problems in how we manage our medical workforce, whether it is the doctors we train or those we recruit from overseas, are leading to large numbers leaving for more attractive jobs and increasingly to make their long-term careers abroad. The UK, Australia, Canada, US and New Zealand are the most popular destination countries.”

According to Professor Ruairí Brugha of the RCSI, "there is a HPN • July/August 2016


46 News

All public hospitals now receiving electronic referrals GPs across the country can now refer patients into every acute hospital electronically following the completion of phase one of the HSE National eReferral Programme. Over 10,550 ereferrals were received in hospitals in May, up significantly from the 2,289 received in August 2015 when the new process was initiated.

Mr Richard Corbridge, Chief Information Officer, HSE

Congratulating all those involved and pointing to the benefits for patients, HSE Director General Mr Tony O Brien today (Monday July 4th) said that “this project is allowing for rapid and secure electronic referrals for patients from their GPs to the appropriate Consultant and Hospital. It happens in real time with the GP receiving acknowledgement from the hospital of the referral, while the patient is there with them.” Speaking at Tallaght Hospital, Mr O Brien stressed that this new process has enabled patient data to be securely communicated between primary and secondary care, meaning the process is streamlined and standardised. Using the e referral solution, a GP can submit a referral electronically, directly from their practice management system to the hospital in question using

the HIQA approved referral form and immediately receive an acknowledgement confirming receipt. The system also enables the hospital to send a response message to the GP once the patient has been triaged. According to Mr David Slevin, CEO Tallaght Hospital, “This is an example of the many innovations adopted by our hospital where we

are focused on providing a better service for our patients. This project illustrates how primary care and acute care can work together to improve the overall service for patients.” E referral is one of the strategic programmes of the HSE’s Chief Information Office. Mr Richard Corbridge, Chief Information Officer, HSE concluded, “This is a

great achievement for the project, where patients can be referred for care to the acute setting through electronic communication. We are looking forward to the next phases of the project, and want to thank the GP community and the hospital groups for their commitment and energy which has helped us reach this milestone today.”

Commitment to all-island Congenital Heart Disease Network Health Ministers Simon Harris TD and Michelle O’Neill MLA have committed to a ¤57 million investment in the all-island Congenital Heart Disease Service. The Ministers made the announcement at the opening of the new Hybrid Cardiac Catheterisation Laboratory at Our Lady’s Children’s Hospital Crumlin (OLCHC) Dublin. The joint opening of the Lab provided a unique platform to confirm both Ministers’ commitment to the further development of the all-island Congenital Heart Disease Network which was established in March 2015. This is the first clinical network of its kind, bringing benefit to patients across the island of Ireland. July/August 2016 • HPN

The investment by both Health Departments will realise the implementation plan put forward by the all-island Congenital Heart Disease Network Board. The plan envisages completing the phased implementation of the transfer of all urgent surgical cases from the north to OLCHC between now and the end of 2017 and all elective surgical cases by the end of 2018. In the interim OLCHC will continue to provide emergency surgical treatment for patients from Northern Ireland under the current service level agreement with the Belfast Trust. Minister Harris said, “Being here today, in the midst of so many people whose sole purpose is to support and reassure children with congenital heart disease and their families is both humbling

and uplifting. It is very clear that the staff in Crumlin, the staff who are here from the Clark Clinic in Belfast, and the Network Board have put the best interests of these children at the centre of every decision, and I am delighted to publicly confirm my support for the continued implementation of the Network. The investment announced today, combined with the detailed planning by the Network Board over the past year, will help to realise our vision of a world-class all-island Network service. This unique collaboration is the first formally established all-island Network for clinical care and I look forward to working with Minister O’Neill and her Department to identify further opportunities for collaboration into the future, so that patients – children and adults alike – can

benefit from safe, high quality services with equally high quality outcomes.” Both Ministers thanked Dr Len O’Hagan and his colleagues on the all island Congenital Heart Disease Network Board who have developed the Vision Statement and produced the Business Case and Implementation Plan to support the case for investment. They also paid tribute to the patient representative organisations for their role in supporting heart patients and families across the island of Ireland, and to the excellent treatment and care provided by the clinical, nursing and administrative staff of the Network.


Feature 47

The Challenge of COPD Key Points

Figure 1

Chronic Obstructive Pulmonary Disease (COPD) affects over 10% of the population over 40 years of age. COPD is largely preventable and easily diagnosed by spirometry with bronchodilator challenge. COPD is underdiagnosed in primary and secondary care and late diagnosis is common leading to unnecessary disability. The new GOLD guidelines include symptoms and exacerbation risk as essential components in assessment. The precise grading stratifies appropriate therapy especially in reducing exacerbation frequency. All susceptible people in the community should have ready access to spirometry either in primary care or through their local Lung Function Laboratory. All patients with COPD should have access to pulmonary rehabilitation if appropriate for their disease stage. These two latter recommendations need appropriate resourcing through the Chronic Disease Programme. COPD as a disorder causes significant morbidity and mortality. In Ireland it is the third most common cause of acute hospital admissions. Its prevalence in Ireland is unknown but extrapolating from the BOLD study of 2007, it is at least 11% of the population over the age of 40. All population studies in which post-bronchodilator spirometry was performed have found that the under-diagnosis of COPD is alarmingly high averaging approximately 80% in most areas. In addition there is some misdiagnosis in the smoking asthmatic group. These estimates of COPD under-diagnosis are substantially higher than those reported for hypertension, hypercholesterolaemia or diabetes mellitus. Perhaps a more alarming statistic, however, is that around 50% of patients are only diagnosed when

they have severe, or very severe, disease, i.e. when their FEV1 is < 50% predicted. Why do patients present so late? On the patient’s side, the disease is very insidious and patients gradually do less activity in tandem with their diminishing lung function. As we can see from Fletcher and Peto’s iconic graphic (Figure 1) the window between symptom recognition and disability is quite narrow. There is also a perception that persistent cough and sputum and the odd episode of bronchitis is normal for a smoker. Smokers are less likely to consult because of cough than non-smokers. A lot of people are also ashamed that their disease is self-inflicted and some patients may be worried about their fitness to work. Health professionals also contribute to the under-diagnosis of COPD. There is a lack of awareness that as little as 10 pack years of smoking can cause COPD and patients are frequently under the age of 40. Diagnosis also requires spirometry which requires owning a spirometer, technical training, maintenance and annual calibration of the measuring device and training and retraining in interpretation of the result. There is also no national screening programme for COPD despite the disease causing a massive financial and societal burden and there being an inexpensive, safe, and highly-sensitive screening test. Indeed, a recent paper examining UK primary and secondary care over 20 years showed many missed opportunities where the diagnosis of COPD should have been considered. These opportunities included lower respiratory infections in smokers, referral for chest x-ray for chest symptoms and even hospitalisation for respiratory infections.

Recent estimates put the percentage of those > 40 years of age who smoke and do have COPD but remain undiagnosed at 20% and that those diagnosed with asthma >40 years who actually have COPD at about one in three. PREVENTION COPD can be potentially prevented at all levels, primary to tertiary. Primary care studies suggest the need to undertake spirometry on five people to identify one with COPD. If a screening questionnaire is incorporated then 1:2 will be positive. Spirometry, as a diagnostic test, fulfils the criteria of being a reliable, simple, non-invasive, safe and inexpensive procedure to detect airflow obstruction. It is well established that simple brief advice from a health professional increases the chances of smoking cessation. Every consultation with a smoker should establish smoking status and willingness to quit. CAN WE MAKE A DIFFERENCE? Yes we can! The influential prospective Lung Health Study underpins this

assertion. 6,000 subjects with mild to moderate COPD (mean FEV1 78% predicted) were studied from over 70,000 current smokers aged 35-59 and offered a structured smoking cessation programme. Around 25% of the larger group quit and remained abstinent over five years follow-up. Those who quit showed a mean annual decline of 34ml/year compared to an annual loss of 63 mls in the persistent smokers. 11 years after LHS entry 93% of the quitters were still abstinent. Separate analysis showed that symptoms such as cough, wheeze, etc., improved dramatically over a very short interval after quitting. Again from Fletcher and Peto we can see that smokers quitting by age of 45 will have enough preserved lung function to survive without significant disability (Figure 1). Since the first GOLD initiative the past decade has seen greater interest and much better treatment for the individual patient. The emphasis on symptoms and exacerbation rate in the most recent GOLD iteration are welcome. In that timeframe, pulmonary rehabilitation has come of age and should now be available to the majority of our patients with COPD. HPN • July/August 2016


48 Feature Diagnosis and Assessment of Severity Once having achieved a diagnosis of COPD with demonstration of post-bronchodilator obstructed spirometry (FEV1:FVC ratio <70%), it is important to characterise the severity of disease for that individual patient. Patients who exacerbate more suffer a more rapid decline in FEV1, QoL and have a higher mortality. The most recent GOLD guidelines stress the importance of assessing symptoms as well as future risk of exacerbations (Table 1) not just measuring spirometry. The GOLD organisation has devised a treatment algorithm based on these clinical parameters which splits patients into four groups of increasing severity A-D (Figure 2). TABLE 1 1.

FEV1 % predicted - GOLD 1 >80%, GOLD 2 50-80%, GOLD 3 30-50%, GOLD 4 <30%

Figure 2

Treatment 1. Sustained smoking cessation and reducing other exposures 2. Symptom improvement (shortness of breath and wheeze) 3. Exacerbation reduction 1 Smoking Cessation • Counselling and ongoing support alone can achieve 5% long-term quit rates. • Nicotine replacement therapy doubles long-term quit rates. • Buproprion can achieve up to 15% long-term quit rates.

2. Exacerbation frequency - low frequency ≤1 exac. Per year, high frequency ≥2 exac per year

• Varenicline in controlled trials for COPD patients over one year has achieved 20% quit rates, but little is known about its efficacy in real-world clinical practice.

3. CAT score (COPD Assessment Test)

2. Symptom Control

4. Modified Medical Research Council dyspnoea score (mMRC score Table 2)

First of all we need to understand the mechanisms of shortness of breath in COPD patients.

Figure 2

a. Dynamic Hyperinflation

The graphic is read first of all on the x-axis to determine symptom score and then vertically to assess risk of future exacerbations,

COPD tends to affect expiration more than inspiration. As oxygen demand increases with exercise, patients do not have time to expel the previous breath before they have to breathe in again. As a result the end residual volume increases leading to progressive discomfort, worsening diaphragm function and decreasing tidal volumes.

e.g. patients with low symptoms, GOLD stage 1 FEV1 and < 2 exacerbations per year are in class A; patients with high symptoms and either GOLD stage 3 or 4 FEV1 and/or ≥ 2 exacerbations per year are in class D TABLE 2 mMRC score 0 Normal exercise capacity 1 SOB walking fast or on inclines 2 Not able to keep up with peers walking on the flat 3 Maximum walking distance not > 100m 4 Housebound due to SOB July/August 2016 • HPN

b. The Legs Muscle deconditioning results in the premature onset of anaerobic metabolism. The resultant lactic acid production stimulates the brainstem to increase the respiratory rate which results in worsening dynamic hyperinflation and more breathlessness. c. Emphysema This leads to reduction in the gas exchange surface in the lungs with reduced O2 uptake and reduced ability to eliminate CO2 from the bloodstream.

d. High BMI Obesity leads to worsening of shortness of breath due to increased load, particularly on inclines and adds a restrictive defect and splinting of diaphragm. Weight loss, if obese, therefore is crucial to symptom reduction. Bronchodilators (see Table 3) Bronchodilators are more correctly termed deflators as by increasing airway calibre they improve lung emptying and reduction in dynamic hyperinflation. In the last few years, a number of new ultra-long acting bronchodilators have been introduced which have led to

Table 3

better symptom control and better lung function. Long acting anti-muscarinic agents (LAMAs) are usually first-line therapy. Long acting beta2-agonists (LABAs) can also be used first-line or added in if symptom control is not adequate. The recommended inhaled treatment for patients in GOLD group A+B are bronchodilators. Pulmonary Rehabilitation The spiral of disability is illustrated below in Figure 3. As the patient with COPD adapts to their increasing breathlessness, inactivity leads to muscle deconditioning, more inactivity and further breathlessness.


WITH ULTIBRO BREEZHALER EXACERBATION PREVENTION IS IN YOUR HANDS1 ®

®

Only ULTIBRO has demonstrated consistent superiority vs. Salmeterol/Fluticasone* across exacerbation outcomes1† ®

ULTIBRO® BREEZHALER® is indicated as a maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD).2 * Fluticasone/salmeterol 500/50 mg BID. † Patients had at least one moderate or severe exacerbation in the previous 12 months. Ultibro Breezhaler ▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 of the SmPC for how to report adverse reactions. ABBREVIATED PRESCRIBING INFORMATION Please refer to Summary of Product Characteristics (SmPC) before prescribing. Presentation: Ultibro® Breezhaler® 85mcg / 43mcg inhalation powder hard capsules containing indacaterol maleate and glycopyrronium bromide respectively and separate Ultibro® Breezhaler® inhaler.Indications: A maintenance bronchodilator treatment to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). Dosage and administration: Recommended dose is the inhalation of the content of one capsule once daily, administered at the same time of the day each day, using the Ultibro® Breezhaler® inhaler. Capsules must not be swallowed. No dose adjustment required in elderly patients, for patients with mild and moderate hepatic impairment or for patients with mild to moderate renal impairment. No data available for use in patients with severe hepatic impairment and should only be used in patients with severe renal impairment or end-stage renal disease requiring dialysis if the expected benefit outweighs the potential risk. No relevant use in the paediatric population. Contraindications: Hypersensitivity to the active substances or to any of the excipients. Warnings/Precautions: Not to be administered concomitantly with medicinal products containing other LABA’s or LAMA’s. Asthma: ♦ULTIBRO® BREEZHALER® SHOULD NOT BE USED FOR TREATMENT OF ASTHMA. Acute use: ♦Not indicated for treatment of acute episodes of bronchospasm. Hypersensitivity: ♦Immediate hypersensitivity reactions have been reported after administration of indacaterol or glycopyrronium. If signs suggesting allergic reactions occur (in particular, angioedema, difficulties in breathing or swallowing, swelling of the tongue, lips and face, urticaria or skin rash), treatment should be discontinued immediately and alternative therapy instituted. Paradoxical bronchospasm: ♦If paradoxical bronchospasm occurs, Ultibro® Breezhaler® should be discontinued immediately and alternative therapy instituted. Anticholinergic effects related to glycopyrronium: ♦To be used with caution in patients with narrow-angle glaucoma and in patients with urinary retention. Patients with severe renal impairment: ♦Should only be used in patients with severe renal impairment, including those with end-stage renal disease requiring dialysis, if the expected benefit outweighs the potential risk. These patients should be monitored closely for potential adverse reactions. Cardiovascular effects: ♦To be used with caution in patients with cardiovascular disorders (coronary artery disease, acute myocardial infarction, cardiac arrhythmias, hypertension), in patients with known or suspected prolongation of the QT interval or patients treated with medicinal products affecting the QT interval and in patients with unstable ischaemic heart disease, left ventricular failure, history of myocardial infarction, arrhythmia (excluding chronic stable atrial fibrillation), a history of long QT syndrome or whose QTc (Fridericia method) was prolonged. ♦LABA’s may produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, blood pressure, and/or symptoms, ECG changes. In case such effects occur, treatment may need to be discontinued. Hypokalaemia: ♦ LABA’s may produce significant hypokalaemia in some patients, which has the potential to produce cardiovascular effects. In patients with severe COPD, hypokalaemia may be potentiated by hypoxia and concomitant treatment which may increase the susceptibility to cardiac arrhythmias. Hyperglycaemia: ♦Inhalation of high doses of LABA’s may produce increases in plasma glucose. Upon initiation of treatment with Ultibro® Breezhaler® plasma glucose should be monitored more closely in diabetic patients. ♦ Ultibro® Breezhaler® has not been investigated in patients for whom diabetes mellitus is not well controlled. General disorders: ♦To be used with caution in patients with convulsive disorders or thyrotoxicosis, and in patients who are unusually responsive to LABA’s. Excipients: ♦ Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. Pregnancy and Lactation: ♦Ultibro® Breezhaler® should only be used during pregnancy if the expected benefit to the patient justifies the potential risk to the foetus. ♦Not known whether indacaterol, glycopyrronium and their metabolites are excreted in human milk. Use of Ultibro® Breezhaler® by breast-feeding women should only be considered if the expected benefit to the woman is greater than any possible risk to the infant. Interactions: ♦Concomitant use is not recommended with beta adrenergic blockers, anticholinergics or sympathomimetic agents. ♦Concomitant hypokalaemic treatment with methylxanthine derivatives, steroids, or non-potassium-sparing diuretics may potentiate the possible hypokalaemic effect of beta2adrenergic agonists, therefore use with caution. ♦Inhibition of the key contributors of indacaterol clearance, CYP3A4 and P-gp, does not raise any safety concerns given the safety experience of treatment with indacaterol. ♦No clinically relevant drug interaction is expected when glycopyrronium is co administered with cimetidine or other inhibitors of the organic cation transport. Adverse reactions: ♦Very common: upper respiratory tract infection. ♦Common: nasopharyngitis, urinary tract infection, sinusitis, rhinitis, dizziness, headache, cough, oropharyngeal pain including throat irritation, dyspepsia, dental caries, gastroenteritis, musculoskeletal pain, pyrexia, chest pain. ♦Uncommon: hypersensitivity, angioedema, diabetes mellitus and hyperglycaemia, insomnia, paraesthesia, glaucoma, ischaemic heart disease, atrial fibrillation, tachycardia, palpitations, paradoxical bronchospasm, epistaxis, dry mouth, pruritus / rash, muscle spasm, myalgia, pain in extremity, bladder obstruction and urinary retention, peripheral oedema and fatigue. ♦Please refer to SmPC for a full list of adverse events for Ultibro® Breezhaler®. Legal Category: POM Pack sizes: Cartons containing 10 capsules (1x10 capsule blister strips) and one Ultibro® Breezhaler® inhaler or 30 capsules (3x10 capsule blister strips) and one Ultibro® Breezhaler® inhaler. Marketing Authorisation Holder: Novartis Europharm Limited, Frimley Business Park, Camberley GU16 7SR, United Kingdom. Marketing Authorisation Numbers: EU/1/13/862/007 & 003. Full prescribing information is available on request from Novartis Ireland Ltd, Vista Building, Elm Park Business Park, Dublin 4. Tel: 01 2601255 or at www.medicines.ie Date of Revision of API Text: 9th February 2016 References: 1. Wedzicha JA, Banerji D, Chapman KR, et al. Indacaterol–glycopyrronium versus salmeterol–fluticasone for COPD. N Engl J Med. DOI: 10.1056/NEJMoa1516385. 2. Ultibro® Breezhaler®. Summary of Product Characteristics.Accessed on www.medicines.ie, May 2016.

Date of Preparation: May 2016 IE02/ULT16-CNF057e


50 Feature Figure 3

Results from a major study, the head-to-head FLAME study, comparing the efficacy of oncedaily Ultibro® Breezhaler® (indacaterol/glycopyrronium bromide) 110/50 mcg to twice-daily Seretide® (salmeterol/fluticasone [SFC]) 50/500 mcg in reducing chronic obstructive pulmonary disease (COPD) exacerbations has shown positive results. In addition to meeting the primary endpoint (non-inferiority), findings demonstrated the superiority of Ultibro® Breezhaler® over the widely used inhaled corticosteroid (ICS)/LABA* combination on exacerbation outcomes. The published FLAME results are anticipated to impact the future management and treatment of COPD patients.

Figure 4

If patients still remain breathless, despite optimal bronchodilator therapy, with poor walking distance pulmonary rehabilitation (PR) should be instituted. PR is the single most effective treatment for breathlessness and improving walking distance in COPD patients. It is usually conducted in a secondary care environment over eight weeks. Patients undergo progressively more intense aerobic exercise during the programme which effects a change in skeletal muscle, with up-regulation of their oxidative capacity and resultant diminished lactic acid production. See Figure 4. 3. Exacerbation Reduction Vaccination Patients should receive yearly flu vaccination and PneumoVax once under the age of 65 and once over the age of 65.

Inhaled Therapy

Oral Anti-inflammatories

There is strong evidence from the TORCH study that if a patient has two or more exacerbations a year and an FEV1 <60% predicted, combined salmeterol and fluticasone will reduce their exacerbation frequency by 25%. The UPLIFT study demonstrated that tiotropium (LAMA) reduces annual exacerbations in a similar patient group by 16%.

Patients who continue to exacerbate can be considered for Roflumilast 500mcg daily which has been shown to reduce exacerbations in COPD patients with an FEV1 <50% predicted. Azithromycin 250mg daily has also been shown to reduce exacerbations in COPD patients. It is a very well tolerated drug but there are concerns about potential cardiac toxicity. Daily Exercise Walking 2,000 steps a day, or being active > 2 hours a week, helps maintain fitness and reduces the risk of exacerbations. Written by: Dr Bob Rutherford, Consultant Respiratory Physician, Galway University Hospitals; Professor J J Gilmartin, Consultant Respiratory Physician, Galway University Hospitals and COPD Support Ireland.

July/August 2016 • HPN

Results confirmed that Ultibro® Breezhaler® 110/50 mcg met its primary endpoint (noninferiority) and furthermore demonstrated superiority to SFC 50/500 mcg on the rate of all COPD exacerbations (mild/moderate/severe) over one year of treatment in COPD patients with a history of at least one exacerbation in the previous year. Against further secondary endpoints, Ultibro Breezhaler was also superior compared to SFC in reducing or improving the following: - Rate and time to first moderate or severe COPD exacerbation - Time to first COPD exacerbation (mild/ moderate/severe) - Time to first severe COPD exacerbation - Lung function (trough FEV1) -

Health-related quality of life (St. George’s Respiratory Questionnaire)


An initial maintenance therapy for patients with COPD who are breathless on exertion

Don’t wait - prescribe Anoro Ellipta instead of tiotropium. Give your patients the immediate results they need.1-3

Visit www.anoro.ie to find out more Anoro is contraindicated for patients who are hypersensitive to the active substances or to any of the excipients. Anoro should not be used in patients with asthma4 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. Anoro® (umeclidinium bromide/vilanterol [as trifenatate]) Prescribing information (Please consult the full Summary of Product Characteristics (SmPC) before prescribing) Anoro® 55/22mcg (umeclidinium bromide/vilanterol [as trifenatate]) inhalation powder. Each single inhalation of umeclidinium bromide (UMEC) 62.5 micrograms (mcg) and vilanterol (VI) 25  mcg provides a delivered dose of UMEC 55  mcg and VI 22 mcg. Indications: COPD: Maintenance bronchodilator treatment to relieve symptoms in adult patients with COPD. Dosage and administration: Inhalation only. COPD: One inhalation once daily of Anoro. Contraindications: Hypersensitivity to the active substances or to any of the excipients (lactose monohydrate and magnesium stearate). Precautions: Anoro should not be used in patients with asthma. Treatment with Anoro should be discontinued in the event of paradoxical bronchospasm and alternative therapy initiated if necessary. Cardiovascular effects may be seen after the administration of muscarinic receptor antagonists and sympathomimetics therefore Anoro should be used with caution in patients with severe cardiovascular disease. Anoro should be used with caution in patients with urinary retention, narrow angle glaucoma, convulsive disorders, thyrotoxicosis, hypokalaemia, hyperglycaemia and severe hepatic impairment. No dosage adjustment is required in renal or mild to moderate hepatic impairment. Acute symptoms: Anoro is not indicated for acute episodes of bronchospasm. Warn patients to seek medical advice if short-acting inhaled bronchodilator use increases, a re-evaluation of the patient and of the COPD treatment regimen should be undertaken. Interactions with other medicinal products: Interaction studies have only been performed in adults. Avoid ß-blockers. Caution is advised when co-administering with strong CYP3A4 inhibitors (e.g. ketoconazole, clarithromycin, itraconazole, ritonavir, telithromycin). Anoro should not be used in conjunction with other long-acting ß2-adrenergic agonists or medicinal products

containing long-acting muscarinic antagonists. Caution is advised with concomitant use with methylxanthine derivatives, steroids or non-potassium-sparing diuretics as it may potentiate possible hypokalaemic effect of ß2-adrenergic agonists. Fertility, pregnancy, and breast-feeding: No available data. Balance risks against benefits. Side effects: Common: Urinary tract infection, sinusitis, nasopharyngitis, pharyngitis, upper respiratory tract infection, headache, cough, oropharyngeal pain, constipation and dry mouth. Uncommon: Hypersenstivity reactions including rash; trenor, dysgeusia, atrial fibrillation, supraventricular tachycardia, rhythm idioventricular, tachycardia, supraventricular extrasystoles and palpitaations. Rare: Anaphylaxis, angioedema and urticaria. Marketing authorisation (MA) Holder: Glaxo Group Ltd, 980 Great West Road, Brentford, Middlesex TW8 9GS, UK. MA Nr: 55/22 mcg 1x30  doses [EU/1/14/898/002]. Legal category: POM S1B. Last date of revision: October 2015. Job Ref: IE/UCV/0063/15. Further information available on request from GlaxoSmithKline, 12 Riverwalk, Citywest Business Campus, Dublin 24, Tel: 01-4955000. Adverse events should be reported to the Health Products Regulatory Authority (HPRA) using an Adverse Reaction Report Form obtained either from the HPRA or electronically via the website at www.hpra.ie. Adverse reactions can also be reported to the HPRA by calling (01) 6764971. Adverse events should also be reported to GlaxoSmithKline on 1800 244 255. References: 1. Donohue JF et al. Respir Med 2013; 107: 1538–1546. 2. Singh S et al. A comparison of shuttle walking test endpoints in exercise studies in patients with COPD. Presented at BTS Winter Meeting 2015; London, UK. Poster no: P144. 3. Maleki-Yazdi MR et al. Respir Med 2014; 105: 1752-1760. 4. Anoro Ellipta Summary of Product Characteristics. Available from: www.medicines.ie. Accessed: December 2015. ANORO ELLIPTA was developed in collaboration with

IE/UCV/0074/15

Date of Preparation: December 2015

©2015 GSK group of companies. All Rights Reserved.


52 Event Gallery

Cancer cookbook launched at UCC A cookbook for cancer patients experiencing difficulties in chewing or swallowing their food is available free of charge to cancer patients throughout Ireland. The book, ‘Eating Well with swallowing difficulties in cancer,’ was launched by University College Cork (UCC) and Breakthrough Cancer Research. The recipes contained within the cookbook are simple, nourishing and enjoyable, more importantly, all of the recipes are easy to chew, swallow and were created specifically for patients who are losing weight. 10,000 copies of the book are available free of charge to cancer patients through their hospitals, and an e-book is also available from www. breakthroughcancerresearch.ie. Difficulties chewing and swallowing food affect many cancer patients suffering from cancer of the mouth, throat, neck, oesophagus, and stomach and eating frequently becomes an enormous challenge for these patients. Critically, weight loss during a cancer patient’s treatment can not only have a serious negative impact on their quality of life, but directly impacts on their tolerance to chemotherapy, radiation therapy, and surgery. The team behind the cookbook include Dr Aoife Ryan, Ms Fiona Dwyer and Ms Ruth Elliot from UCC with input from Dr Derek Power, Consultant Medical Oncologist, Cork and Mercy University Hospitals and Ms Anne O’Connor and Ms Jane Healy, lecturers in the Culinary Arts in CIT. Dr Aoife Ryan comments that: “If you’ve ever watched someone you love suffer from cancer then you know that one of the side effects of cancer is weight loss.

Fiona Dwyer, UCC; Jane Healy, Culinary Arts Lecturer, CIT; Dr Aoife Ryan, Dietitian and Lecturer, Nutritional Sciences, UCC and Dr Derek Power, Consultant Medical Oncologist at Mercy and Cork University Hospitals

Dr Derek Power comments that, “Maintaining patient weight during cancer treatment is a huge challenge, and eating nourishing meals, and eating often, is important no matter what weight they are. Research has shown that patients who lose a lot of muscle are susceptible to more toxic side-effects to their chemotherapy, and regrettably their treatments often have to be reduced or stopped earlier than planned.

“As a cancer specialist patients ask me daily how they can stop losing weight, and what they can eat when they can’t swallow food easily - unfortunately doctors do not really have any medications that safely stimulate appetite or cause weight gain at present, so it is our hope that this cookbook will assist cancer patients in the challenging task of meeting their nutritional requirements as they battle cancer.”

RCSI welcomes Erasmus+ students from East Tennessee State University RCSI School of Pharmacy were pleased to welcome their first students participating in the Erasmus+ International Credit Mobility programme. Leona Holland, Kendra Rice, Dustin Wood and Brandie LeBlanc joined the team for three months from the Bill Gatton College of Pharmacy (BGCOP), East Tennessee State University (ETSU). While in Ireland they undertook a series of rotations across a variety of pharmacy settings, including research, hospital and community placements. This is the first year Erasmus+ has included Partner Countries from outside Europe in their exchange activities, under the International Credit Mobility Programme.

Dr Helena Kelly (RCSI), Leona Holland (BGCOP), Dustin Wood (BGCOP), Kendra Rice (BGCOP), Brandie LeBlanc (BGCOP) and Dr. Gráinne Cousins (RCSI)

July/August 2016 • HPN


53

First of its kind Irish Heart Failure resource The Heart Failure Patient Toolkit was officially launched at the 2nd Heart Failure Patient Organisation Capacity Building Academy, which took place on the 23rd and 24th of June at the Croí Heart and Stroke Centre in Galway. Representatives from Heart Failure patient organisations from all over World attended to discuss the issues that need to be addressed for those living with Heart Failure, which include education and self-care support.

Attendees launch the Heart Failure toolkit at the Croí Heart Failure Academy in Galway last week

The toolkit, which was created to address some of these issues, is a new heart failure patient resource developed by the Heart Failure Patient Alliance, a partnership between the heart and stroke charity Croí, the West of Ireland Cardiac Foundation and The Heartbeat Trust, a national Heart Failure charity and supported by Novartis Pharmaceuticals.

to help educate and inform people living with heart failure, their families and carers. The Heart Failure Patient Alliance’s ambition for this toolkit, is to encourage people living with heart failure in Ireland to take a more active role in the management of their condition, which will lead to better symptom control and reduce the likelihood of patients being hospitalised. Professor Ken McDonald, from the Heartbeat Trust said, “There are 90,000 people living in Ireland with Heart Failure, however, until now, there has not be a comprehensive multimedia resource for these people and their families. We are delighted that Ireland has been acknowledged as a centre of excellence to develop these materials and that they will also be available to people with living with heart failure across Europe”

The toolkit consists of a series of booklets supported by a comprehensive online resource

¤2m investment to bring new product to market Irish biotech company, Metabolomic Diagnostics, has secured an additional ¤2 million in venture funding to help complete PrePsia, its new screening test for first time pregnant mothers. This latest funding round is supported by existing investors, SOSventures, Enterprise Equity and Enterprise Ireland as well as with a number of other private investors. Affecting almost 7.5 million pregnancies per year, pre-eclampsia is the single greatest cause of premature births and is still responsible for the deaths of more than 75,000 mothers and half a million babies during pregnancy. The PrePsia blood test will be able to detect the risk of pre-eclampsia early on in the pregnancy and ultimately save the lives of women and their babies through personalised medical interventions. While the condition begins in early pregnancy, it does not typically manifest until the second half of the pregnancy.

The investment is being used by Metabolomic Diagnostics to commercialise the metabolomic biomarkers technology invented by Professor Louise Kenny, Director at the INFANT Research Centre. The company’s technology takes the form of a blood test that is ‘spun’ in the laboratory before a unique algorithm is applied to detect patterns that represent a high likelihood of a pregnant woman developing pre-eclampsia.

diagnostics entrepreneur. Over the years Dr Walsh has been responsible for making several high profile investments in research, medicines, and devices.

“Securing this new funding will allow Metabolomic Diagnostics to complete PrePsia in our laboratory and assign CE Marking to bring the company to first revenues in 2017”, said Charles Garvey, CEO Metabolomic Diagnostics. The company has also announced that Dr Jim Walsh has joined their board. Dr Walsh currently serves as Executive Director of Trinity Biotech (NASDAQ: TRIB) and is Ireland’s leading

Cognitive Computing Research for Children with Cochlear Implants Trinity College Dublin, The National Centre for Cochlear Implants at Beaumont Hospital and IBM have launched a research project using cognitive computing to help predict speech perception in children with cochlear implants. It will improve device tuning and speed, but most critically it will improve overall patient outcomes in children with severe to profound hearing loss. To obtain a high level of speech perception, the software within the cochlear implant must be customised and adjusted for each individual child. This is a complex and time consuming rehabilitation programme managed by audiological scientists over numerous sessions in order to obtain optimal access to speech and environmental sounds for the patient. The project aims to use predictive modelling to help detect the subtle signs of vital changes

in a patient's sound and speech perception to enable earlier proactive intervention. IBM data scientists and multidisciplinary teams at the Trinity Centre for Bioengineering at Trinity College Dublin and The National Centre for Cochlear Implants at Beaumont Hospital will use cognitive computing to gain new insights into speech perception in cochlear implants recipients. In addition, by analysing the diverse data from healthcare management systems, researchers can use machine based learning to aid the personalised approach to patient care and help to optimise the clinical decision-making processes while reducing costs. “Combining our neural engineering research with cognitive computing will help us to gain new insights from our electrophysiology data

of speech perception in cochlear implant patients and be a powerful complement in the development with our clinical colleagues of more personalised rehabilitation plans,” says Professor Richard Reilly, Professor of Neural Engineering at Trinity College Dublin. The cognitive algorithms that the IBM data scientists will develop are based on machine learning that has drawn heavily on knowledge of neuroscience, statistics and applied mathematics. Professor Reilly added “the focus of our research at Trinity College Dublin is on clinical neural engineering based on signal processing of neuroimaging and physiological data for specific clinical problems. This collaboration with IBM helps to develop new understanding of how the brain processes audio information in cochlear implant recipients.”

HPN • July/August 2016


54 Clinical R&D DURVALUMAB MONOTHERAPY DEMONSTRATES EFFICACY IN UROTHELIAL BLADDER CANCER AstraZeneca and its global biologics research and development arm, MedImmune, announced efficacy and safety data for durvalumab, a selective programmed-death ligand-1 (PD-L1) antibody, in patients with advanced urothelial bladder cancer (UBC). Preliminary results of the Phase I/ II trial, presented at the American Society of Clinical Oncology (ASCO) Annual Meeting, showed an objective response rate (ORR) of 31% in all evaluable patients (95% confidence interval (CI): 18%-47%) and 46% (95% CI: 28%-66%) in patients with PDL1-high-expressing* tumours. Disease control rate (DCR), defined as confirmed complete or partial response or stable disease for 12 or more weeks, was 48% (95% CI: 32%-64%) in all evaluable patients, and 57% (95% CI: 37%-76%) in patients with PD-L1high-expressing tumours. Median duration of response had not yet been reached. Durvalumab 10mg/kg was administered every two weeks intravenously for up to 12 months, and demonstrated a manageable safety profile among all patients (n=61). The most common adverse events reported in 5% or more of patients were all grade 1 or 2: fatigue (13%), diarrhoea (10%), decreased appetite (8%), arthralgia (7%), asthenia (7%), nausea (7%) and pyrexia (7%). Three patients experienced treatment-related Grade 3 adverse events (1 acute kidney injury, 1 infusion-related reaction and 1 tumour flare). Dr Christophe Massard, Head of Early Clinical Trials at the Institut Gustave Roussy, Villejuif, France, said: “These positive preliminary data continue to support durvalumab’s clinical efficacy and safety profile for the treatment of bladder cancer, and confirm durvalumab as a potential breakthrough therapy for a patient population with enormous unmet need.” *PD-L1-high expression is defined as 25% or more PD-L1 staining in tumour cells (TCs) or immune cells (ICs) as assessed through use of the Ventana SP263 diagnostic assay. In 2016, durvalumab received Breakthrough Therapy Designation by the U.S. Food and Drug Administration as a potential treatment for patients with PD-L1 positive inoperable or metastatic UBC. July/August 2016 • HPN

OLAPARIB: INTERIM ANALYSIS REPORTS UPDATED DATA FOR OVERALL SURVIVAL IN PATIENTS WITH PLATINUM SENSITIVE OVARIAN CANCER AstraZeneca recently presented results from a third interim analysis of Study 19 reporting updated data for overall survival (OS) for patients with ovarian cancer treated with olaparib maintenance therapy following platinum-based chemotherapy. This was a secondary endpoint of the trial. These results support the previously reported benefits of olaparib in progression-free survival (PFS) compared to placebo, the primary endpoint of the trial. A 27% reduction in risk of death compared to placebo was seen in the overall trial population (HR 0·73, 95% CI 0·55–0·96, nominal p=0.02483; median OS 29·8 vs 27·8 months), with greater reduction in the risk of death of 38% compared to placebo observed in patients with BRCA1/2 mutations (BRCAm) (HR 0·62, 95% CI 0·41–0·94, nominal p=0.02480; 34·9 vs 30·2 months). As this was the third analysis of survival, the nominal p-values did not meet the criterion for statistical significance and therefore the treatment effect observed for OS can only be considered descriptive. A number of patients continue to benefit from olaparib maintenance therapy, with 15% of BRCAm patients receiving olaparib for over five years. The update from Study 19, presented this month at the American Society of Clinical Oncology (ASCO) congress in Chicago, is based on a 77% data maturity conducted after more than five years total follow-up, with an additional three years of follow-up since the previous analysis. Two interim analyses of OS from Study 19 have previously been conducted, at 38% data maturity (HR 0·94, 95% CI 0·63–1·39, p=0·75) and 58% data maturity (HR 0·88, 95% CI 0·64–1·21, p=0·44) in the overall trial population. Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: “These results are a testament to the value of olaparib’s mode of action and the potential significance of targeting the DNA damage response (DDR) pathway, reinforcing our commitment to explore the full potential of DDR targeted treatments across a range of cancers.”

FASLODEX MET PRIMARY ENDPOINT IN FIRST LINE TREATMENT OF ADVANCED BREAST CANCER AstraZeneca recently announced positive results from the Phase III FALCON trial comparing Faslodex 500mg (fulvestrant) to Arimidex 1mg (anastrozole) for the treatment of locally advanced or metastatic breast cancer, in postmenopausal women who have not had prior hormonal treatment for hormone-receptor-positive (HR+) breast cancer. Faslodex 500mg demonstrated superiority compared with Arimidex 1mg in FALCON, and met its primary endpoint of extended progression-free survival. The trial showed an adverse event profile generally consistent with current knowledge of the safety profile of the medicines. Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: “The FALCON results bring us closer to offering more and earlier treatment options to postmenopausal women with HR+ locally-advanced or metastatic breast cancer; the potential to delay disease progression is important for these patients as there is currently no cure. Faslodex has over 10 years of clinical evidence and we are committed to exploring its potential along with the rest of our outstanding oncology portfolio.” A full evaluation of the data is ongoing and the results are expected to be presented at a medical meeting in 2016. Aromatase inhibitors (such as Arimidex) are the current standard of care in first-line treatment for postmenopausal women with advanced HR+ breast cancer. Faslodex 500mg is approved for the treatment of postmenopausal women with oestrogenreceptor (ER)-positive locally-advanced or metastatic breast cancer whose cancer has progressed following anti-oestrogen therapy. Most recently, on 2 March 2016, the US Food and Drug Administration approved Faslodex 500mg, in combination with palbociclib, for the treatment of women with hormone-receptor-positive, human-epidermal-growth-factor receptor 2-negative (HER2-) advanced or metastatic breast cancer (MBC), whose cancer has progressed after endocrine therapy.

SANOFI ANNOUNCES POSITIVE PHASE 3 RESULTS FOR INVESTIGATIONAL TITRATABLE FIXED-RATIO COMBINATION OF INSULIN GLARGINE AND LIXISENATIDE Sanofi has announced the presentation of the results of the pivotal Phase 3 LixiLan-O and LixiLan-L clinical trials with the investigational titratable fixed-ratio combination of basal insulin glargine 100 Units/mL and GLP-1 receptor agonist lixisenatide in adults with type 2 diabetes. Both studies met their primary endpoints, demonstrating statistically superior reduction of HbA1c (average blood glucose over the previous three months) with the titratable fixed-ratio combination versus comparators (lixisenatide and insulin glargine 100 Units/mL, respectively).The most frequent adverse events were nausea, vomiting and diarrhea. Full results were presented on June 12 at the American Diabetes Association 76th Scientific Sessions in New Orleans, LA, U.S. Top-line results were previously reported in Q3 of 2015. The results of the LixiLan-O and LixiLan-L studies have been included in regulatory submissions to the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA), with regulatory decisions anticipated in August 2016 (FDA) and Q1 -2017 (EMA). The presentation abstracts are titled: •Clinical Impact of Titratable Fixed-Ratio Combination of Insulin Glargine/Lixisenatide vs. Each Component Alone in Type 2 Diabetes Inadequately Controlled on Oral Agents: LixiLan-O Trial (NCT02058147) (Rosenstock, J et al. Oral presentation 186-O, American Diabetes Association 76th Scientific Sessions, New Orleans, LA, U.S. at 8:45am on June 12, 2016). •Efficacy and Safety of the Insulin Glargine/Lixisenatide Fixed-Ratio Combination vs. Insulin Glargine in Patients with T2DM: the LixiLan-L Trial (NCT02058160) (Aroda, V et al. Oral presentation 238-O, American Diabetes Association 76th Scientific Sessions, New Orleans, LA, U.S. at 2:30pm on June 12, 2016). The proprietary name for the titratable fixed-ratio combination is under consideration. Its safety and efficacy have not been evaluated by any regulatory authority.


55 OSIMERTINIB SHOWS CLINICAL ACTIVITY IN PATIENTS WITH LEPTOMENINGEAL DISEASE FROM LUNG CANCER AstraZeneca recently announced clinical and safety data for Osimertinib in patients with leptomeningeal (LM) disease, a complication of epidermal growth factor receptor (EGFR) mutation-positive advanced nonsmall cell lung cancer (NSCLC), where cancer cells spread to the cerebrospinal fluid (CSF). LM is a devastating disease associated with advanced lung cancer. The updated BLOOM Phase I trial results, presented at the American Society of Clinical Oncology (ASCO) annual meeting, showed that irrespective of T790M status of patients, osimertinib led to a change in MRI signal intensity indicative of a reduction in central nervous system (CNS) lesions. Data from 21 patients treated with osimertinib 160mg once daily showed intracranial radiological improvement in seven patients, neurological function improvement in five patients, and clearance of tumour cells from the CSF at two consecutive visits in two patients. None of the 21 patients treated with osimertinib received concomitant radiotherapy or intrathecal chemotherapy. Fifteen patients remained on treatment at data cut-off (10 March 2016), of whom seven had been on treatment for more than nine months. Further data from the BLOOM study showed that osimertinib crossed the blood-brain barrier. In six of nine patients, a greater than 50% decrease in EGFR mutation level was observed in the CSF up to cycle 9, day 1 of treatment, with a sustained reduction observed in five. These results support previously reported preclinical data demonstrating that osimertinib crosses the blood-brain barrier. Dr James CH Yang, from the National Taiwan University Hospital and National Taiwan University Cancer Centre, Taipei, said: “Leptomeningeal disease carries a devastating prognosis, so the safety, tolerability and activity profile seen with osimertinib is encouraging. In the BLOOM study, we saw a decrease in central nervous system lesions in patients with

leptomeningeal disease, with accompanying neurological improvement. The results build on previous findings with osimertinib in preclinical and clinical studies and provide evidence of the potential of osimertinib in difficult-to-treat patients who have central nervous system metastases.” In leptomeningeal disease, cancer cells spread to the membranes surrounding the brain and spinal cord. The disease is currently treated with systemic or intrathecal chemotherapy, wholebrain radiation therapy or EGFR tyrosine kinase inhibitors (TKIs), with median overall survival of 4.5-11 months. However, most currently-available EGFR-TKIs have limited ability to cross the blood-brain barrier to effectively treat or prevent brain metastases.

NEW DATA ANALYSIS HIGHLIGHTS THE BENEFITS OF ONCE-DAILY LIXIANA® (EDOXABAN) OVER WARFARIN IN ELDERLY PATIENTS WITH NON-VALVULAR ATRIAL FIBRILLATION Daiichi Sankyo Europe GmbH (hereafter, Daiichi Sankyo) has announced results of a prespecified analysis of the ENGAGE AF-TIMI 48 trial, which showed that age had a greater influence on major bleeding than on thromboembolic risk in patients with atrial fibrillation. Given the higher rates of bleeding and death with increasing age, treatment of elderly patients with once-daily LIXIANA® (edoxaban) provided an even greater absolute reduction in major bleeding events over warfarin, compared to treatment with edoxaban versus warfarin in younger patients. The data were published in the Journal of the American Heart Association (JAHA). The results of the “Efficacy and Safety of edoxaban in Elderly Patients with Atrial Fibrillation” data analysis showed that the effect of the high dose edoxaban regimen (60mg/30mg once daily) on efficacy and safety outcomes was consistent throughout the pre-specified age groups (pinteraction>0.05). Furthermore, in patients considered at high risk (age ≥75), edoxaban, compared to warfarin,

significantly reduced major bleeding (4.8%/year with warfarin compared to 4.0%/year with edoxaban, Hazard Ratio [HR]=0.83, 95% Confidence Interval (CI):0.70-0.99) and intracranial haemorrhage (1.2%/year with warfarin compared to 0.5%/ year with edoxaban, HR=0.40, 95% CI: 0.26-0.62). In addition, the primary net clinical outcome (stroke, systemic embolic events, major bleeding, or death from any cause) was improved in the elderly, in the edoxaban treatment group versus warfarin (HR=0.88 [95% CI: 0.79-0.97]). The ENGAGE AF-TIMI 48 trial enrolled 21,105 patients – the median age was 72 years (interquartile range, 64 to 78) and 8,474 (40.2%) were ≥75 years.1 Patients were stratified into three pre-specified age groups: <65 (n=5,497), 65 to 74 (n=7,134), and ≥75 (n=8,474) (‘elderly’).1 Patients were randomised in a 1:1:1 ratio to a higher-dose edoxaban regimen (60 mg once daily), a lower-dose edoxaban regimen (30 mg once daily), or to warfarin titrated to achieve a target international normalized ratio of 2.0 to 3.0.1

JANSSEN’S SINGLE-AGENT DARZALEX® (DARATUMUMAB) APPROVED BY EUROPEAN COMMISSION FOR TREATMENT OF MULTIPLE MYELOMA (MM) Janssen-Cilag International NV (“Janssen”) has announced that the European Commission (EC) has granted conditional approval to DARZALEX® (daratumumab) for monotherapy of adult patients with relapsed and refractory multiple myeloma (MM), whose prior therapy included a proteasome inhibitor (PI) and an immunomodulatory agent and who have demonstrated disease progression on the last therapy. Daratumumab was approved under an accelerated assessment, a process reserved for medicinal products expected to be of major public health interest, particularly from the point of view of therapeutic innovation.

so, daratumumab triggers the patient’s own immune system to attack the cancer cells, resulting in rapid tumour cell death through multiple immunemediated mechanisms of action and through immunomodulatory effects, in addition to direct tumour cell death via apoptosis (programmed cell death). The approval of daratumumab was based on data from the Phase 2 MMY2002 (SIRIUS) study, published in The Lancet; the Phase 1/2 GEN501 study, published in The New England Journal of Medicine; and data from three additional supportive studies. Findings from a combined efficacy analysis of the GEN501 and MMY2002 (SIRIUS) trials demonstrated that after a mean follow-up of 14.8 months, the estimated median OS for single-agent daratumumab (16 mg/kg) in these heavily pretreated patients was 20 months (95 percent CI, 15-not estimable). The overall response rate (ORR) for the combined analysis was 31 percent, and 83 percent of patients achieved stable disease or better.12 Daratumumab demonstrated a tolerable and clinically manageable safety profile as a monotherapy in heavily pre-treated patients. The most common adverse events (AEs) in the Phase 2 MMY2002 (SIRIUS) trial, which occurred in more than 20 percent of patients, were fatigue, anaemia, nausea, thrombocytopenia, back pain, neutropenia and cough.10 The most common adverse events (AEs) in the Phase 1/2 GEN501 trial were fatigue, allergic rhinitis, and pyrexia (fever). The marketing authorisation approval follows a positive opinion from the European Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued on 01 April 2016.13 This approval allows for the marketing of daratumumab in all 28 member states and the three European Economic Area countries of the European Union.

Daratumumab is the first CD38directed monoclonal antibody (mAb) approved in Europe. It works by binding to CD38, a signalling molecule highly expressed on the surface of multiple myeloma cells regardless of stage of disease. In doing HPN • July/August 2016


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