HPN 2021 November

HOSPITAL PROFESSIONAL NEWS IRELAND

HPN November 2021 Issue 90 HOSPITALPROFESSIONALNEWS.IE

Ireland’s Dedicated Hospital Professional Publication

IN THIS ISSUE:

CONFRONT R/R CLL

NEWS: Historic Mental Health Deficit Cleared Page 4 REPORT: Is Hospital Pharmacy Facing the Perfect Storm?

Page 8 FEATURE: Future of Digital Diabetes Page 19

VENCLYXTO® in combination with rituximab is NOW AVAILABLE for the treatment of adult patients with CLL who have received at least one prior therapy1

INDICATIONS1: VENCLYXTO® in combination with obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL) (see section 5.1) †. VENCLYXTO® in combination with rituximab is indicated for the treatment of adult patients with CLL who have received at least one prior therapy*. VENCLYXTO® monotherapy is indicated for the treatment of CLL in the presence of 17p deletion or TP53 mutation in adult patients who are unsuitable for or have failed a B cell receptor pathway inhibitor or in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B cell receptor pathway inhibitor*. VENCLYXTO® in combination with a hypomethylating agent is indicated for the treatment of adult patients with newly diagnosed acute myeloid leukaemia (AML) who are ineligible for intensive chemotherapy †.

Full Summary of Product Characteristics is available at www.medicines.ie. ▼ 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 via HPRA Pharmacovigilance; Website: www.hpra.ie. Suspected adverse events should also be reported to AbbVie Limited on 01-4287900.

LEGAL CATEGORY: POM (S1A). MARKETING AUTHORISATION NUMBERS/PRESENTATIONS: 10mg film-coated tablet, 14 tablets, EU/1/16/1138/002; 50mg filmcoated tablet, 7 tablets, EU/1/16/1138/004; 100mg film-coated tablet, 7 tablets, EU/1/16/1138/005;100mg film-coated tablet, 14 tablets, EU/1/16/1138/006; 100mg film-coated tablet, 112 tablets, EU/1/16/1138/007. MARKETING AUTHORISATION HOLDER: AbbVie Deutschland GmbH & Co. KG, Knollstrasse, 67061 Ludwigshafen, Germany. Further information is available from AbbVie Limited, 14 Riverwalk, Citywest Business Campus, Dublin 24, Ireland. † Indications are not reimbursed. * Indications are reimbursed. R/R, Relapsed/Refractory.

References: 1. VENCLYXTO® Summary of Product Characteristics, available at www.medicines.ie.

IE-VNCLY-210025 Date of Preparation: July 2021

This Publication is for Healthcare Professionals Only

PERSPECTIVES: The Role of Hospitals in Protecting the Environment Page 28 CPD: Management and Treatment of Lung Cancer Page 39 MEN’S HEALTH SPECIAL FOCUS: Testicular Tumours Page 46 MEN’S HEALTH SPECIAL FOCUS: Obesity Page 61

Therapeutic Indications1

CRESEMBA® is indicated in adults for the treatment of:1 Invasive Aspergillosis

Mucormycosis in patients for whom amphotericin B is inappropriate

Consideration should be given to official guidance on the appropriate use of antifungal agents.1 Early targeted therapy (pre-emptive or diagnostic-driven therapy) may be instituted pending confirmation of the disease from specific diagnostic tests. However, once these results become available, antifungal therapy should be adjusted accordingly.1 Formulations and strengths1

IV

200 mg powder for concentrate for solution for infusion

Oral

100 mg hard capsules

References 1. CRESEMBA Summary of Product Characteristics. 2021 Abbreviated prescribing information CRESEMBA™ [isavuconazole] 200 mg powder for concentrate

for solution for infusion and 100 mg hard capsules. Please refer to the Summary of Product Characteristics (SmPC) before prescribing CRESEMBA. Presentation: Each vial of CRESEMBA powder for concentrate for solution for infusion contains 200 mg isavuconazole.

Each CRESEMBA hard capsule contains 100 mg isavuconazole.

Indications: Indicated in adults for the treatment of invasive aspergillosis; mucormycosis in patients for whom amphotericin B is inappropriate. Administration & dosage: Early targeted therapy (pre-emptive or diagnosticdriven therapy) may be instituted pending confirmation of the disease from specific diagnostic tests. However, once these results become available, antifungal therapy should be adjusted accordingly. Loading dose (IV): 200 mg CRESEMBA every 8 hours for the first 48 hours followed by a maintenance dose of 200 mg once daily 12 to24 hours after the last loading dose. The infusion must be administered via an infusion set with an in-line filter with a microporous membrane made of polyethersulfone (PES) and with a pore size of 0.2 μm to 1.2 μm. Switching between intravenous and oral administration is appropriate when clinically indicated. Loading dose (ORAL): two capsules (equivalent to 200 mg of isavuconazole) every 8 hours for the first 48 hours (6 administrations in total) followed by a maintenance dose of two capsules (equivalent to 200 mg of isavuconazole) once daily, starting 12 to 24 hours after the last loading dose. Duration of therapy according to clinical response. The safety and efficacy of CRESEMBA in children aged below 18 years have

not been established. Contra-indications: Hypersensitivity to the active substance or to any of the excipients; co-administration with ketoconazole, high-dose ritonavir, strong and moderate CYP3A4/5 inducers; patients with familial short QT syndrome. Warnings and precautions: Caution in patients hypersensitive to azole antifungal agents or taking medicinal products known to decrease the QT interval. CRESEMBA infusion should be stopped if infusion-related reactions or severe cutaneous adverse reactions occur. Monitoring of hepatic enzymes should be considered as clinically indicated.

Treatment with isavuconazole is not recommended in patients with severe hepatic impairment (Child-Pugh Class C), unless the potential benefit outweighs the risks. Hepatitis has been reported.

Drug interactions: Isavuconazole is a substrate of cytochrome P450 isoenzyme CYP3A4/5; inducers and strong inhibitors of this enzyme may change its plasma levels. Isavuconazole is a moderate inhibitor of CYP3A4/5, a mild inducer of CYP2B6, and a mild inhibitor of P-glycoprotein (P-gp), organic cation transporter 2 (OCT2), and uridine diphosphate-glucuronosyltransferases (UGT) and in vitro, inhibitor of BCRP. Coadministration of CRESEMBA with drugs that are substrates for these enzymes or transporters may change their plasma levels. Monitoring the plasma levels or biological effects of these drugs and appropriate dose adjustment may be required.

See SmPC for interaction tables and further information. Pregnancy and lactation: Not be used except in severe or potentially lifethreatening fungal infections, if the anticipated benefits outweigh the possible risks to the foetus. Discontinue breastfeeding during treatment. Side-effects: Common (incidence ≥1/100 to <1/10):

neutropenia, thrombocytopenia, pancytopenia, leukopenia, anaemia, hypokalaemia, decreased appetite, delirium, headache, somnolence, thrombophlebitis, dyspnoea, acute respiratory failure, vomiting, diarrhoea, nausea, abdominal pain, elevated liver chemistry tests, rash, pruritus, renal failure, chest pain, fatigue, injection site reaction.

Uncommon (incidence ≥1/1,000 to <1/100): hypersensitivity, hypomagnesaemia, hypoglycaemia, hypoalbuminaemia, malnutrition, depression, insomnia, convulsion, syncope, dizziness, paraesthesia, encephalopathy, presyncope, neuropathy peripheral, dysgeusia, vertigo, atrial fibrillation, tachycardia, bradycardia, palpitations, atrial flutter, electrocardiogram QT shortened, supraventricular tachycardia, ventricular extrasystoles, supraventricular extrasystoles, circulatory collapse, hypotension, bronchospasm, tachypnoea, haemoptysis, epistaxis, dyspepsia, constipation, abdominal distension, hepatomegaly, hepatitis petechiae, alopecia, drug eruption, dermatitis, back pain, oedema peripheral, malaise, asthenia.

Legal Category: S1A. Marketing Authorisation Number (s): EU/1/15/1036/001 (IV); EU/1/15/1036/002 (oral). Marketing Authorisation Holder: Basilea Pharmaceutica Deutschland GmbH, Marie-Curie-Strasse 8, 79539 Lörrach, Germany. Local Representative: Pfizer Healthcare Ireland, Pfizer Building 9, Riverwalk, National Digital Park, Citywest Business Campus, Dublin, 24, Ireland.

Last revised: 01/2021.

Ref: CM 5_0

For further information on this medicine please contact: Pfizer Medical Information on 1800 633 363 or at EUMEDINFO@pfizer.com.

For queries regarding product availability please contact: Pfizer Healthcare Ireland, Pfizer Building 9, Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24 + 353 1 467 6500.

Pfizer Healthcare Ireland, 9 Riverwalk, National Digital Park, CityWest Business Campus, Dublin 24, Ireland.

Legal category: S1A. Further information available at www.medicines.ie

PP-CRB-IRL-0130 Date of Preparation October 2021

3

November Issue Issue 90

Contents

Foreword

Mater Private Network has become the first electrophysiology centre P4

Editor Our exclusive report for this issue looks closer at pharmacy recruitment levels. Hospitals are struggling to recruit pharmacists. Yet, pharmacist numbers in Ireland have never been higher.

Health solutions are ‘hiding in plain sight’ P6 Is Hospital Pharmacy facing a recruitment crisis? P8

The apparent incongruity begs several questions. Does a pharmacist manpower shortage exist? What are the factors influencing the pharmacist workforce? And what, if anything, is being done to ensure pharmacists are attracted to and remain in the profession?

4

More is needed to secure future of cancer services P16

Tim Delaney, Head of Pharmacy at Tallaght University Hospital, and Adjunct Associate Professor at the School of Pharmacy and Pharmaceutical Sciences at Trinity College Dublin (TCD) believes the sector is facing a “perfect storm.”

Tallaght University Hospital acknowledge their Heroes P24 The role of hospital professionals in today’s environmental challenge P28

9

It is fair to say Covid-19 has forced Ireland’s digital hand and on page 18, Professor Derek O’Keeffe discusses the future of digital technology in the treatment and management of diabetes. “We are experiencing a Cambrian explosion of digital health tools in medicine and diabetes care is a great example of their impact. This is thanks to Moore’s Law,” he reflects.

IPHA presents latest Ipsos study findings on Covid-19 vaccination P32 REGULARS

CPD: Lung Cancer P39

24

Environmental issues are not always something to consider when we are talking about hospital and medical related topics. However on page 28, Dr Blaithin Moriarty and colleagues highlight the vital role that not only individuals, but organisations, can play in helping to ease the burden.

Men’s Health Focus: Erectile Dysfunction P50 Men’s Health Focus: Renal Cancer P54 Men’s Health Focus: Tinnitus P64 Clinical R&D: P80

28

Hospital Professional News is a publication for Hospital Professionals and Professional educational bodies only. Subscription rate for Hospital Professional News ¤60 plus vat per year.

DIGITAL MARKETING & EDITORIAL EXECUTIVE Carla Fulton carla@hospitalprofessionalnews.ie

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.

IPN Communications Ltd 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.

CPD Lead Sibongile Swan Mude swan@ipn.ie

PUBLISHER IPN Communications Ireland Ltd Clifton House, Lower Fitzwilliam Street, Dublin 2 (01) 669 0562 GROUP DIRECTOR Natalie Maginnis n-maginnis@btconnect.com EDITORIAL editorial@hospitalprofessionalnews.ie ACCOUNTS Rachel Wilson cs.ipn@btconnect.com

Turn to page 8 to read the full report.

CONTRIBUTORS Professor Derek O’Keeffe Dr Blathain Moriarty Theresa Lowery-Lenhan Mr Greg Nason Professor Kilian Walsh Richard Walsh Dr Werd Al-Najim Ms Rand Al-Najim Ms Emma Cashman Professor Brendan Kelly Paweł Zapolnik Antoni Pyrkosz Professor Aidan McCormick Dr Jarush Naidoo DESIGN DIRECTOR Ian Stoddart Design HOSPITALPROFESSIONALNEWS.IE

@HospitalProNews HospitalProfessionalNews

“The summer of 2021 will be remembered for a variety of difficult reasons. As the world was still tight in the grip of a global pandemic, an onslaught of environmental disasters struck. The healthcare sector must recognise its roll in contributing to carbon emissions and commit to taking decisive action to reduce these,” they note.

Our Special Focus for November is on Men’s Health and we have a wealth of clinically contributed articles giving an overview of conditions such as Bladder Cancer (page 51), Male Obesity (page 61) and the lesser known field of Hunter Syndrome (page 72).

Make sure you look out for next month’s bumper December issue, which carries our annual Professional Top 100 – the leading figures in Ireland’s hospital and healthcare arena who are making a notable difference. We will also have our End of Year Reviews and more exclusively written clinical content.

Meantime, I hope you enjoy our November issue.

HOSPITAL PROFESSIONAL NEWS IRELAND Ireland’s Dedicated Hospital Professional Publication

HOSPITALPROFESSIONALNEWS.IE | HPN • NOVEMBER - 2021

4 News Changes to Access to Training for non-EU Doctors Welcomed The Medical Council has welcomed the announcement by the Minister for Health, that greater access to higher specialist training will be available for non-EU/EEA doctors working in Ireland making it easier for these doctors to progress their careers, which will in time help fill vacant consultant posts and ultimately benefit patients.

progression in other jurisdictions, to the detriment of Irish hospitals and healthcare facilities.

Medical Council CEO, Mr Leo Kearns said, “This decision is greatly welcomed, and one long sought by the Medical Council.

“Although this is a very welcome announcement, medical workforce planning is vitally important to the provision of safe healthcare and much work remains to make sure we make Ireland an attractive and healthy place for doctors to work”, concluded Mr Kearns.

“The data gathered by the Medical Council through the annual Medical Workforce Intelligence Reports in recent years has shown that large numbers of non-EU doctors are withdrawing from the medical register in Ireland in order to access further training and career

“Research conducted by the Medical Council showed that 127 non-EU doctors left Ireland in 2019 citing reasons such as limited career progression, poor quality of training available to them and no flexible training opportunities.

This change in policy announced by the Minister for Health, Stephen Donnelly TD, regarding the application of EU/EEA Community

Preference to postgraduate medical training programmes, by the Postgraduate Medical Training Bodies, making it easier for non-EU citizens to progress their careers is a very welcomed development.

Medical Council President, Dr Suzanne Crowe, said “This announcement will bring great hope for the future for many families around Ireland. For too long I have seen excellent colleagues work for years in the same or similar roles with little or no chance of career progression due to lack of training opportunities for them in Ireland because they came from outside the EU to work in Ireland.”

“Not only will these excellent doctors, many of whom are raising

their families here, benefit from this decision but so too will the patients of Ireland.”

“As we continue to employ and welcome doctors from outside the EU we must work towards making Ireland a place that they wish to settle in long term and contribute to the development of our health service while addressing the many other issues which must be tackled to ensure that the Irish health service becomes one that is an attractive place to work in which we can retain all of our doctors currently working here.

This announcement is one which will greatly help.”

“I want to congratulate all those who advocated and fought so long for this change,” concluded Dr Crowe.

First for Mater Private Network Mater Private Network has become the first electrophysiology centre in the UK and Ireland, and one of the first ten hospitals in the world, to implement the new SPI digital platform for quantifying the efficiencies inside the Cath Lab. Led by Professor Gabor Szeplaki and his team, this new technology is designed to reduce variability in surgical processes and enhance team performance through synchronised workflows, real-life learning and real-time analytics.

SPI digital platform enables the hospital team to deliver consistent high quality of care and improved efficiency, to reduce risk and improve patient outcomes.

Historic Mental Health Funding Deficit Cleared Minister for Mental Health, Mary Butler, TD, has confirmed that a historic deficit in mental health funding has been cleared in the funding allocation of 2021. These deficits have accumulated over a number of years due to pressures with unfunded increased pay costs and other increased costs for provision of existing levels of service.

Minister Butler stated, “Since coming into post I was acutely aware of this deficit creating an unstable basis for the continued development of services, where deficits had grown to ¤53 million by the end of 2020. From 2012,

considerable development funding has been allocated to mental health to enhance service provision, however this has not been matched with funding for existing services, despite rising costs in this area. It was therefore a priority for me to stabilise as well as improve the overall mental health funding position."

“A one off opportunity presented this year to reduce this deficit to zero. This was done through allocations provided by the Department of Health, HSE Corporate and a small amount of reconfigured historical development funds which were

NOVEMBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

previously unspent due to ongoing difficulties with recruitment, where this also allowed for better alignment of historic funding with more modern models of care”.

The full clearance of this deficit has been called for over recent years by various advocacy organisations in the mental health sector. It will, on a separate basis, enable the HSE to allocate ¤49 million to new developments in mental health, including ¤23 million in development funding from Budget 2021 and ¤26 million in historical development funding. Over 400 new mental health staff are at

various stages of recruitment as part of these developments, including the various national mental health clinical programmes, along with initiatives relating to counselling, Advanced Nurse Practitioners as well as mental health services for people experiencing homelessness.

Minister Butler concluded, “This represents a final settlement of the existing deficit and any cost increases for an existing level of service from 2022 and beyond will be considered as part of the normal annual Estimates process in future budgets.”

News

5

Hospital Pharmacy Role in Antimicrobial Stewardship The European Centre for Disease Prevention and Control (ECDC) offers an e-learning course on antimicrobial resistance, focusing on antimicrobial stewardship as an approach to address healthcare-associated infections (HAI) resulting from multi-drug resistance organisms in acute care settings. The course is self-paced and takes approximately 2 hours to complete.

to antimicrobial resistance and how antimicrobial stewardship can be used as an intervention to address the burden. Health care professionals with responsibility for prevention and control of HAIs working at national or local level within the EU/EEA member states are the target audience for the course.

After completing this course, the participants will be able to understand the challenges related

• understand the challenges related to antibiotic prescription, burden of anti-microbial

The objectives of this course are:

resistance (AMR) and the principles of antibiotic stewardship; • identify guidelines for treatment of specific conditions and formularies both at the national and local level; • understand the implementation of antibiotic policies; • understand measurement of drug usage and the prescribing indicators in relation to structure, process and outcomes;

• identify drug usage over time and interpret prescribing surveillance data; • understand the elements and performance measurement for an antimicrobial stewardship program (AMS); • identify interventions to improve antibiotic prescribing practices for hospitalised patients and measure intervention effect, barriers, and possible solutions.

Register and benefit from the early bird registration rate (until end of November 2021) From 23 and 25 March 2022, the European Association of Hospital Pharmacists (EAHP) will host its 26th annual congress for the hospital pharmacy profession. The event will bring together hospital pharmacists from all over the world to Vienna, Austria.

The programme is centred around the theme "Hospital pharmacists – changing roles in a changing world".

The keynotes of EAHP’s congress will provide participants with insights on the latest developments in the fields of artificial intelligence, digitalisation and pharmacy prescribing.

Visit the following link to access the current programme schedule (subject to changes) and the 2nd announcement with detailed information on the keynotes and sections: www.eahp.eu/congresses

New Technology at Tallaght Another first for Tallaght University Hospital was marked recently, as they launched Electronic Vital Signs for patients, the first model IV hospital in the country to adopt vital signs automation.

Taking the vital signs i.e. temperature, oxygen saturation, heart rate/pulse and blood pressure of patients is a vitally important part of their care.

Hospitals use the National Early Warning Score (NEWS) which is a guide that determines the degree of illness of a patient and determines how often their vital signs need to be checked.

A change in the NEWS can indicate early detection of infection or sepsis, and an increase of the score prompts medical review. Previous studies have shown that staff can make errors when manually calculating

Professor Martin Curley, Director of Digital Transformation, HSE with Professor Catherine Wall, Consultant Nephrologist and Director of Quality Safety & Risk Management, Elsamma Philip, Clinical Nurse Manager on Osborne Ward, Mary Hickey, Process Improvement Manager and Lucy Nugent, CEO Tallaght University Hospital

the EWS, this can lead to delayed or inappropriate escalation of patient care.

Commenting on the rollout in TUH Professor Catherine Wall, Consultant Nephrologist and

Director of Quality Safety & Risk Management said, “Our hospital is always busy with staff required to continuously make decisions about patient care. We are open to any innovative use of technology that will benefit our patients. The

introduction of this technology is another major step in the rollout of the electronic patient record in TUH and an aid to help staff with patient rounds, reducing repetitive data entry and possible errors that may be made.”

HOSPITALPROFESSIONALNEWS.IE | HPN • NOVEMBER - 2021

first three years of the plan.

2.2.1 ICU Bed Capacity Requirements

6 News

Between February 2020 and January 2021 over 1,100 critically ill adult Covid patients were admitted to ICUs and HDUs in Ireland.34 Increased ICU bed capacity is paramount in meeting surges in demand from Covid-19 and is an important indicator of a health system’s capacity to respond to such crises. Pre-Covid, the variation in ICU capacity across 17 European countries ranged from 34 ICU beds per 100,000 people in Germany to a low of just 5 ICU beds per 100,000 people in Ireland - less than half the EU average (Figure 8).35

Budget 2022: Health Solutions 'Hiding in Plain Sight'

Figure 8: Number of ICU Beds in EU per 100,000 population before Covid-19 crisis, latest year available The Irish Hospital Consultants Association (IHCA) has said that it is critical their Budget for 2022 retains the additional funding for Covid allocated this year, and that the Government ensures the redeployment of funds goes towards addressing the severe deficits in bed capacity, hospital facilities and Consultant staffing across our acute public hospital services.

Number of intensive care beds per 100 000 population 40 33.9 35 28.9 30 25 17.4

20

16.3

15

15.0

12.9

11.8

11.2

10

10.5

10.1

9.7

8.6

8.5

7.8

6.7

5

5.4

5.3

5.0

0

With the number of people on hospital waiting lists now at 907,617, with over 290,000* people waiting longer than a year to be assessed and treated by a Source: Health at a Glance: Europe 2020; Data referHealth to adults only in Belgium and Ireland; totoalladults ages only in Germany, England hospital consultant, the IHCA Source: at a Glance: Europe 2020; Data refer in Belgium and Figure 8:Data Number of ICU Beds in Ireland; to all ages inunits Germany, England and Spain. Data in France exclude beds in said Budget 2022 has to put in and Spain. in France exclude beds in constant monitoring and paediatric ICUs. EU per 100,000 population before constant monitoring units and paediatric ICUs. practice the political commitments Covid-19 latest year made to the public and to OECD datacrisis, also shows thatavailable 65% of ICU beds in Ireland were occupied by Covid-19 patients at the height of healthcare professionals.

36

These beds must be delivered under the anticipated, revised National Development Plan by 2030; with half of the additional

Denmark.

address this inequity.

honour its promises to the public

the Government must provide adequate investment under 8 Budget 2022 and in the years to come. Analysis shows that Ireland currently has one of the lowest levels of acute hospital funding compared to our Northern European neighbours, with ¤1.588 billion per annum less funding for our hospitals in 2019 than other nations; spending ¤316.80

business as usual with growing numbers of patients awaiting care, month after month.

“The solutions are ‘hiding in plain sight’. The Government must embrace them and implement them, so that our public health service becomes a more attractive place to work and is fit for purpose for the patients of today and in the years to come.”

Figure 15: Specialist medical practitioners per 1,000 population in EU in 2019 (or nearest year)

Figure 15: Specialist medical practitioners per 1,000 population in EU in 2019 (or nearest year)

2

3.39

3.24

3.17

2.89

2.74

2.64

2.63

2.62

2.6

2.55

2.54

2.26

2.1

2.09

3

2.09

4

2.49

5

3.54

5.04

6

2

As part of its submission, the Association says that 6,000 additional public hospital beds and 4,500 community step-down and rehab beds are required in order to alleviate pressure on the system.

The low number of consultant posts in Ireland is preventing patients from receiving timely access to care, with 652,344 outpatients, including over 85,000 children, awaiting appointment to be assessed by a hospital consultant specialist.

1.96

Bed capacity commitments must be delivered

and retention crisis will continue to impact on achieving health targets unless action is taken to urgently fill the one in five vacant permanent posts and expand consultant numbers further.

1.95

The Association has called on the Department of Health to bring forward the long-awaited waiting list reduction plan and to provide realistic yet ambitious targets and timescales for the reduction of Ireland’s shocking waiting lists.

for any future increases in

1.94

Analysis in the Association’s PreBudget Submission suggests it may take over a decade to clear the backlog of deferred care built up during the pandemic and bring our unacceptable waiting lists under control.

consultants contracted since

Covid-19 Despite thecases.

HSE/DOH commissioned 2009 Prospectus Report recommending that the number of ICU beds and healthcare professionals.

Matching ambition with Commitments to end the Ending the consultant should be doubled from 289 to 579 beds by 2020, a 2019 HSE report found that there were theninequity only 249 investment and address the deficits must be recruitment crisis 2021 confirm that there ICU beds pre-Covid – 40 fewer than 10 years previously.38 Updates in mid-August delivered on, otherwise Sláintecare To fund the provision of Consultants also say the persistent 39more than risks amounting to little are now around 300 acute ICU beds open, a rise of around 45 since the start of the pandemic. capacity, facilities and staffing, hospital consultant recruitment

1.81

While public hospitals attempted to catch up after the postponement of planned care in 2020, the targets for 2021 outlined in the HSE’s National Service Plan were still 194,000 short of 2019 levels. Consultants say the lack of robust targets, coupled with underinvestment in capacity and severe shortages in consultant staffing to meet targets, means that hospital waiting lists will only continue to grow.

of the new plan.

In response to this pressure on hospitals androot ICUcause beds, capacity measures were introduced 2012 as the forsurge the The Association has set out 19 37 There is also a need to more exodus of Ireland’s medical talent equivalent to 70 ICU beds and provided an ICU/HDU bed capacity of up to key 350recommendations beds on 1 December 2020. in total for than double current critical to other countries and the inability Budget 2022. care capacity over 640 ICU did not ‘breach’ the 350 figure at a national Although peaktoICU occupancy level during the third wave in to attract Irish specialists working beds in order to avoid delays in abroad back home. The Minister IHCA President, Professor AlanAt a January 2021, many hospitals critically ill Covid patients.

ICU admission, cancellation of experienced overwhelming surges locally of for Health has previously stated his Irvine said: “It really is now or essential surgery, and to cater minimum, this additional ICU surge capacity needs to be opened and staffed on a permanent basis. unambiguous commitment to fully never. The Government must act to

1.77

In its submission, the IHCA says that there were almost 363,000 less outpatient hospital appointments last year compared with 2019, and that inpatient/day case activity in 2020 was down 255,000 appointments.

the first wave of the pandemic in 2020 (Figure 9, Appendix 1). This is second only to Italy (78%), according to a study on the impact in eight selected EU countries. The share of ICU beds occupied by Covid patients in per head less than the average The IHCA points to the ongoing public hospital beds urgently Ireland was double thatthree in Denmark (33%) and more than five times Austria (12%). and ¤593.83inper head less than needed within the first years pay discrimination imposed on the percentage

1.48

Targets should be realistic but ambitious

1 0

Source: Eurostat, 2021

Source: Eurostat, 2021

Comparing consultant staffing in Ireland with the UK and Australia confirms we have 27% fewer Consultants on a population basis compared with the UK and a third (32%) fewer compared with

NOVEMBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

Launching Launching Launching

Ondansetron 2mg/ml Ondansetron Ondansetron2mg/ml 2mg/ml Solution for injection Solutionfor forinjection injection Solution 4mg/2ml 4mg/2ml 4mg/2ml 8mg/4ml 8mg/4ml 8mg/4ml

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Additional dose after of 0.1mg/kg a maximum of 4mg eithersurgery prior to, at, orgeneral after induction of anaesthesia. solution for injection contains ondansetron hydrochloride dihydratesolution equivalent to 2mg ondansetron.

Indications: slow intravenous (not less than 30 seconds) a dose of 0.1mg/kg to a maximum of a4mg.

Nodose data by in information is available upon request.

Ondansetron Kabi 2mg/ml for injection.

Active ingredients: 1ml treatment of PONVinjection after surgery in paediatric patients at having surgery under up general anaesthesia single PRESCRIBING INFORMATION: Consult the Summary of Product Characteristics for further information.

Additional seconds) at a dose of 0.1mg/kg up to a maximum of 4mg either prior to, at, or after induction of anaesthesia.

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Ondansetron Kabi 2mg/ml solution for injection.

Active ingredients: 1ml treatment of PONV after surgery in paediatric patients having surgery under general anaesthesia a single dose and treatment of PONV. Renal impairment – No<2alteration of daily dosingexperience frequencyinofprevention route of by prevention and treatment of post-operative and vomiting Paediatric population -and management of treatment Adults – prevention and treatment of nauseanausea and vomiting induced(PONV). by cytotoxic chemotherapy radiotherapy, of postoperative vomiting in children years of age.

Older dosage people –orLimited solutionchemotherapy-induced for injection ondansetron hydrochloride dihydrate equivalent to 2mg Indications: intravenous injection (not less than 30 –seconds) at with a dose of 0.1mg/kg uporto a maximum of 4mg.

No data administration patients moderate or severe impairment of hepatic nausea and vomiting (CINV) inand children aged ≥6 months, and ondansetron. for prevention and treatment prevention andcontains treatment of post-operative nausea vomiting (PONV).

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Older or people Limited experience infunction, prevention PONV in children aged ≥1ofmonth.

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Contraindications: tosevere any– component of hepatic the preparation, chemotherapy-induced nausea and vomiting (CINV) children ≥6 months, and prevention andinjection treatment administration required.

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Paediatric population - management of or and treatment ofdaily PONV. Renal impairment – No alteration daily dosage dosing frequency of route of concomitant use withdose apomorphine.

Special warnings and of precautions use: Hypersensitivity reactions intravenous infusionofaged after dilution.

Chemotherapy radiotherapy induced nausea vomiting (CINV and RINV): of PONV in children ≥1 month.

Posology andand method of administration: Forand intravenous (iv) injection maximum total of 8mg.

Contraindications: Hypersensitivity to for any or component of the preparation, chemotherapy-induced nausea vomiting (CINV) in children ≥6 months, and for and prevention and treatment required. impairment – Inwarnings patients with moderate or 5HT3 severe impairment of hepatic function, reported in patients whoHepatic have exhibited hypersensitivity toand other selective receptor antagonists.

Clinicians Adults – Selection of dose regimen should be determined byaged the severity of the emetogenic challenge.

Emetogenic intravenous infusion afterand dilution.

Chemotherapy and radiotherapy induced nausea vomiting (CINV and RINV): administration concomitant use with apomorphine.

Special precautions for use: Hypersensitivity reactions should pay to respiratory events as precursorsHypersensitivity of other hypersensitivity; treat such events symptomatically. and radiotherapy: Give either by iv orof administration.

Recommended dose is or 8mg maximum of PONVchemotherapy in children aged month.

Posology and method administration: intravenous (iv)iv injection total daily who dose of 8mg.

Contraindications: anyreceptor component of the preparation, Adults – Selection of ≥1 dose regimen should be determined byoral the severity of theFor emetogenic challenge.

Emetogenic reported in attention patients have exhibited hypersensitivity to selectiveto5HT3 antagonists.

Clinicians administered a slow iv injection in not less than immediately before treatment.

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Chemotherapy andby radiotherapy nausea and vomiting (CINV and or RINV): use withtoQT apomorphine.

Special warnings precautions treat for use: Hypersensitivity ondansetron in patients with congenital long QT syndrome. with caution toofpatients who have or may recommended protect prolonged emesis after first 24 Emetogenic hours.or Highly administered as a regimen slow iv to injection not lessdelayed than immediately beforethe treatment.

Oral rectal reported Ondansetron prolongs interval in a dose dependent manner; post-marketing cases Torsade de Pointes.

Avoid Adults –treatment Selection of dose should beinagainst determined by 30 theorseconds severity of the emetogenic challenge. in patients whoQThave exhibited hypersensitivity toAdminister other selective 5HT3 receptor antagonists.

Clinicians develop ofwith QTccongenital including patients with of electrolyte abnormalities, congestive heart failure, emetogenic chemotherapy: be administered asora single 8mg iv doseemesis immediately chemotherapy.

Doses should treatmentandrecommended protect against prolonged after before the first hours.

Highly ondansetron in patients long syndrome.

Administer with caution patients who have or may chemotherapy radiotherapy:toMay Give either by ivdelayed oralor administration.

Recommended iv 24dose is 8mg pay prolongation attention to respiratory events asQT precursors hypersensitivity; treattosuch events symptomatically. bradyarrhythmias or QT patients other medicinal products thatabnormalities, lead to cases QT prolongation or electrolyte of greater 8mg up May to ainmaximum 16mgas may only 8mg beimmediately given by iv infusion 50 to 100ml saline Ondansetron emetogenic chemotherapy: benot administered a seconds single iv dose immediately beforeinchemotherapy.

Doses develop prolongation ofinterval QTc taking including patients with electrolyte congestive heart failure, administered as athan slow iv and injection lessofthan 30 beforediluted treatment.

Oral or of rectal prolongs in a dose dependent manner; post-marketing of Torsade de Pointes.

Avoid or other compatible and infused overmay not 15 minutes.

A single dose greater than 16mg must ondansetron abnormalities.

Correct hypokalaemia and prior use. of greater than 8mg infusion and up tofluid a maximum of 16mg onlythan be given by iv infusion diluted in 50 100ml of saline bradyarrhythmias or patients taking other medicinal products that tolead to IfQTconcomitant prolongation or electrolyte treatment recommended to protect against delayed or less prolonged emesis after the first 24 tohours.

Highly in patients with congenital longhypomagnesaemia QT syndrome.

Administer with caution to patientstreatment who have with or may ondansetron and otherofhypokalaemia serotonergic drugs is clinically oftreatment theheart patient is not be given due toinfusion dosebedependent increase of not QT-prolongation risk. ForAmanagement of highly or other compatible fluid and infused less than 15 minutes. single dosechemotherapy. greater thanemetogenic 16mg must develop abnormalities.

Correct andpatients hypomagnesaemia priorappropriate to use. If observation concomitant with emetogenic chemotherapy: May administered as over a single 8mg iv dose immediately before Doses prolongation QTc including with warranted, electrolyte abnormalities, congestive failure, advised; post-marketing reports of serotonin concomitant use. Monitor patients with signs of subchemotherapy a dose of 8mg may be administered by slow iv injection in not than 30 seconds followed by two ondansetron notthan be given due to to dose dependent QT-prolongation Forless management emetogenic and or other serotonergic drugs ismedicinal clinicallywith warranted, appropriate observation of the is of greater 8mg and up a maximum ofincrease 16mg mayofonly be given by ivrisk. infusion diluted in 50oftohighly 100ml of saline bradyarrhythmias patients taking other syndrome products that lead to QT prolongation orpatient electrolyte acute intestinal obstruction following administration; increases Monitor large bowel transit further iv dosesa of 8mgoffour hours apart, or by a constant infusion of 1mg/hour up to 24seconds hours. Efficacy may be advised; dose 8mgand mayinfused be administered by slow lessfordose than 30 followed by two post-marketing reports of serotonin syndromeondansetron with concomitant patients withtime. signsPatients of sub-with or otherchemotherapy compatible infusion fluid over not less thaniv15injection minutes.inAnot single greater than 16mg must abnormalities.

Correct hypokalaemia and hypomagnesaemia prior touse.use.

If concomitant treatment enhanced by addition a single dose of sodiumofphosphate 20mg to chemotherapy. with adenotonsillar surgery should be monitored carefully following ondansetron administration; may mask occult further iv doses of 8mgoffour hoursivapart, or dexamethasone by a constant infusion 1mg/hour for up prior to 24 hours.

Efficacy mayOral be acute intestinal obstruction following administration; ondansetron increases large bowel transit time.

Patients not be given due to dose dependent increase of QT-prolongation risk. For management of highly emetogenic ondansetron and other serotonergic drugs is clinically warranted, appropriate observation of the patient is or rectal treatment to of protect against delayed prolonged20mg emesis after the first 24 hours. bleeding.

Paediatricsurgery patientsshould receiving ondansetron with hepatotoxic chemotherapy agents should monitored enhanced by additionisofrecommended a single iv dose dexamethasone sodiumorphosphate prior to chemotherapy.

Oral with adenotonsillar be monitored carefully following ondansetron administration; maybemask occult chemotherapy a dose of 8mg may be administered by slow iv injection in not less than 30 seconds followed by two advised; post-marketing reports of serotonin syndrome with concomitant use. Monitor patients with signs of subclosely forPaediatric impaired patients hepatic function. calculating for CINV in paediatric patients a mg/kg basis and Paediatric populationis– CINV in childrentoaged ≥ 6 months adolescents: Dose can be calculated body24surface or rectal treatment recommended protect againstand delayed or prolonged emesis after theonfirst hours. bleeding. receivingWhen ondansetron withdose hepatotoxic chemotherapy agents on should be monitored further iv doses of 8mg four hours apart, or by a constant infusion of 1mg/hour for up to 24 hours. Efficacy may be acute intestinal obstruction following administration; ondansetron increases large bowel transit time. Patients area (BSA)population or weight.– Weight-based dosing results in higher total daily Dose dosescan compared to BSA-based dosing. closely administering three hepatic doses atfunction.

4 hourlyWhen intervals, total daily will be thanpatients if one single dose ofbasis 5mg/m Paediatric CINV in children aged ≥ 6 months and adolescents: be calculated on body surface for impaired calculating dosedose for CINV in higher paediatric on a mg/kg and2 enhanced by addition of a single iv dose of dexamethasone sodium phosphate 20mg prior to chemotherapy.

Oral with adenotonsillar surgery should be monitored carefully following ondansetron administration; may mask occult Ondansetron diluted in 5%dosing dextrose or 0.9% sodium chloride or other compatible infusion fluid and administering followed by anthree oral dose given.

Comparative of these two be dosing regimens has not been investigated. area (BSA) orshould weight.beWeight-based results in higher total daily doses compared to BSA-based dosing. dosesisat 4 hourly intervals,efficacy total daily dose will higher than if one single dose of 5mg/m2 or rectal treatment is recommended to than protect againstDosing delayed prolonged emesis after the firstchemotherapy 24 hours. bleeding.

Paediatric patients receiving ondansetron with hepatotoxic chemotherapy agents should or beflushing, monitored infused intravenously not less 15 minutes. by or BSA: Administer immediately before effects: Veryiscommon (≥1/10): Headache. to <1/10): Sensation of warmth Ondansetron should beover diluted in 5% dextrose or 0.9% sodium chloride or other compatible infusion fluid and Undesirable followed by an oral dose given. Comparative efficacyCommon of these(≥1/100 two dosing regimens has not been investigated.

Paediatric population CINVofin children months adolescents: Dose canimmediately betwelve calculated on body surface for impaired function.

WhenHeadache. calculating dose(≥1/1000 for(≥1/100 CINVtoin paediatric patients on a mg/kg basis and as a single iv –dose 5mg/m constipation, local hepatic ivVery injection site(≥1/10): reactions.

Uncommon Seizures, toaged maximum 8mg. and Oral dosing canAdminister commence hours later and may be closely infused intravenously over not 2less than≥156 minutes.

Dosing

by BSA: before chemotherapy Undesirable effects: common Common to<1/100): <1/10): Sensation ofmovement warmth ordisorders, flushing, area (BSA) weight.

Weight-based results in higher totalasdaily doses compared BSA-based dosing. three doses ator4 hourly intervals, total daily dose will be than if one singleasymptomatic dose of 5mg/m2 arrythmias, with without ST segment depression, bradycardia, hypotension, hiccups, continued foriv up to 5ofdays (see2dosing SmPC).

Total daily dose divided doses, includes oral and doses) must as a orsingle dose 5mg/m constipation,chest localpain iv injection site reactions.

Uncommon (≥1/1000 to higher <1/100): Seizures, movement disorders, to maximum 8mg.

Oral(given dosing can commence twelve to hours lateriv and may be administering Ondansetron should be to diluted in(see 5%SmPC). dextrose ordaily 0.9%dose sodium chloride or other fluid by in anchest oral pain dose is given.

Comparative efficacy of these two dosing regimens has not been investigated. increases liver function tests.

Rare ST (≥1/10,000 todepression, <1/1000): Immediate hypersensitivity reactions sometimes not exceed adult dose of 32mg.

Dosing by bodyweight: Administer immediately before chemotherapy as a and single arrythmias, with or without segment bradycardia, hypotension, hiccups, asymptomatic continued for up 5 days Total (given as divided doses,compatible includes oralinfusion and iv doses) must followed infusediv intravenously not than 158mg. minutes.

Dosingivby BSA:may Administer before chemotherapy Very common (≥1/10): Headache.

Common (≥1/100 to hypersensitivity <1/10): transient Sensationreactions of warmth or flushing, severe, anaphylaxis, duringto rapid iv Immediate administration, visual disturbances dose of 0.15mg/kg not exceeding further doses be givenimmediately in 4-hourly intervals.

Oral dosing can Undesirable increasesincluding ineffects: liver function tests. dizziness Rare (≥1/10,000 <1/1000): sometimes not exceed adultover dose ofless 32mg.

Dosing byTwo bodyweight: Administer immediately before chemotherapy as a single 2 as a single iv of dose of 5mg/m local ivanaphylaxis, injection site reactions.

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Website: www.fresenius-kabi.com/ie/ Email: FK-enquiries.ireland@fresenius-kabi.com

Ref: IE-IVF-2100006

Date of Prep: August 2021 Ref: IE-IVF-2100006

8

Report

A ‘Perfect Storm’ The past 18 months have had an unforgettable impact on our health service. The pandemic has brought with it innumerable challenges for healthcare workers, including hospital and community pharmacists.

An even more shifting, unsteady landscape has emerged within healthcare. Niamh Cahill reports.

“a sense of optimism and of the possibility for change to practicing community pharmacists”.

Against this backdrop, hospitals are struggling to recruit pharmacists and community pharmacies are crying out for locums. Yet, pharmacist numbers in Ireland have never been higher.

On top of that, according to Delaney, “many hospitals are struggling to recruit pharmacists and there are large numbers of vacancies”.

The apparent incongruity begs several questions. Does a pharmacist manpower shortage exist? What are the factors influencing the pharmacist workforce? And what, if anything, is being done to ensure pharmacists are attracted to and remain in the profession?

Tim Delaney, Head of Pharmacy at Tallaght University Hospital, and Adjunct Associate Professor at the School of Pharmacy and Pharmaceutical Sciences at Trinity College Dublin (TCD) believes the sector is facing a “perfect storm”.

“One of the big drivers of movement out of retail is dissatisfaction with hours of work, high pressure workloads and lack of breaks; people eating sandwiches off the desk to keep lunchtime services going, for example,” he said.

An IPU paper published in January 2019 found low job satisfaction levels among community pharmacists, with a rating of 5.4 out of 10.

It concluded that community pharmacy was at a crossroads and underlined the need to return

Pharmacy Numbers at an all time High Last year 320 pharmacists were added to the professional register, bringing the total number in 2020 to an all-time high of 6,767, up from 6,506 in 2019 and 6,246 in 2018.

“It doesn't help when a potential recruit working in the UK is now being charged a large fee to register under the third country route [in place since Brexit]. Why come home and have all that cost added, when you get paid just as well in UK and having lower living costs?”

Despite this, shortages persist and more pharmacists are needed in both community and hospital pharmacy.

Crisis in Leadership

According to Delaney, the UK has for many years been “a critical source of pharmacists for Ireland”.

Furthermore, he believes a “crisis in leadership” is impacting the profession, created by the Pharmacy Act 2007, which transformed the PSI into a regulator, leaving the profession without a leadership body.

Ways in which the profession could be used and transformed within healthcare are also being ignored, he said, while manpower planning is non-existent.

“There is no sign Government understands what is possible if the profession is utilised better. Government does not see pharmacy in the way UK does,” he warned.

“There is no enthusiasm in the HSE for real transformation of hospital pharmacy including the development of an advanced practice framework.”

As an example, he referenced a deal agreed between the Department of Public Expenditure and Reform (DPER) and the Hospital Pharmacists Association of Ireland (HPAI) in October last year, which has since “stagnated”.

“It doesn't help when a potential recruit working in the UK is now being charged a large fee to register under the third country route [in place since Brexit]. Why come home and have all that cost added, when you get paid just as well in UK and having lower living costs?”

Tim Delaney

NOVEMBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

What’s more, there is a fear that Brexit could lead to a fall in pharmacist numbers here long-term.

He cited a 2018 analysis of pharmacist workforce capacity in Ireland over the past 15 years, published by McMahon, Bermingham, and Griffin of UCC School of Pharmacy, which illustrated our reliance on overseas-trained pharmacists.

It found that the workforce is “highly dependent on new registrants applying via the EU mutual recognition route, predominantly from the UK”.

It revealed that pharmacist numbers increased by 90 per cent over the last 15 years and that 57 per cent of new registrants qualified via the EU route, mainly through the UK. PSI registrants via the national route were 27-56 per cent of total additions annually, it found, while Ireland’s output of pharmacy graduates is 40 per cent lower than the UK. Brexit has been anything but smooth While the supply of drugs and medicines here has remained largely unaffected, the same cannot be said for the movement of pharmacists between both jurisdictions.

New barriers are already having an impact here. This is evidenced in data from the Pharmaceutical Society of Ireland (PSI).

The PSI has processed just 29 UK (including Northern Ireland) Third Country Qualification Recognition (TCQR) applications processed to date in 2021.

But a spokesman for the PSI qualified the figure with the proviso that due “to time of conferral of qualifications, both in Ireland and the UK, the upcoming end of year registration period is the busiest time of application for new graduates to the PSI”.

A look at the number of UK qualified pharmacists registered with the PSI in recent years tells its own story.

In 2018 the figure was 127, in 2019 it rose to 164. But in 2020, during the pandemic, the number fell to 106.

The fees applicable to UK based graduates to practice as pharmacists in Ireland since Brexit are being criticised as a deterrent to recruitment here.

“Brexit will certainly pose problems for pharmacy workforce numbers in Ireland when you consider the large numbers coming onto the

9 “We closed a campaign for senior pharmacists in April for which we had eight vacancies. We got just three eligible applicants, two of which were internal. It makes the prospect of any service development extremely challenging” Colm Devine

warned that “any interruption to mutual recognition of pharmacists between the EU and UK, as a result of Brexit, would significantly affect the capacity of pharmacy services in Ireland.

Review of Capacity register here, that trained in the UK,” according to Delaney.

“I have heard from pharmacies near border areas that this has already proven to be a deterrent to pharmacists living and qualifying in Northern Ireland, who might otherwise have considered working in this jurisdiction. Reducing that fee to a more nominal level might be a practical start.”

The 2018 workforce capacity analysis, mentioned earlier

“In order to meet global trends of the increasing number of patients needing access to pharmacy related services and diversification of pharmacist roles, ongoing review of capacity in pharmacy is essential.”

A PSI spokesman said a review is underway into the entire TCQR process “with the intention of introducing a new system of recognition that would be a more effective and efficient route for all third country applicants seeking to practice in Ireland”.

The pandemic and Covid-related work has to date delayed the review’s progress, however, the spokesman added.

The PSI operates three routes for first time pharmacist registration. The route through which a pharmacist can apply to the register is based on where their pharmacy qualification was awarded.

Pharmacists from Non EU/EEA countries must pay an application fee of ¤1,500 and another ¤540 registration fee under the TCQR process.

The same rules apply to pharmacists from Great Britain and Northern Ireland. But the fee does not apply in certain circumstance.

These include if a UK professional qualification was recognised in Ireland before 31 December 2020, if an Irish professional qualification was recognised in the UK before the same date and if an application was in the process of being recognised at the end of the 31 December transition period deadline last year.

After this date, however, there is no exemption, it is understood, and the fee applies.

“The current streamlined process for recognition of UK

qualifications obtained prior to the Brexit date is facilitated by a legislative amendment made to the PSI’s registration rules. The PSI Council put this streamlined approach in place on the basis that the UK qualification would have been previously recognised under the Professional Qualifications Directive to and this would have removed the requirement for the steps involved in qualification recognition,” a spokesman explained.

They added that the PSI “continuously monitors the education and training requirements for pharmacists in the UK, and divergence from the existing EU-aligned programmes may require the Council to reassess the route of recognition”.

Kerry based pharmacist Dr Jack Shanahan said Brexit would have a long term impact on pharmacist manpower in Ireland.

Factors at Play “But in the short term, we already have a shortage of manpower in community pharmacy. Brexit is exacerbating it, but it’s not the major factor.”

Indeed, Brexit is but one factor.

Many others are at play.

Colm Devine, Chief Pharmacist at

HOSPITALPROFESSIONALNEWS.IE | HPN • NOVEMBER - 2021

10 Report “I experienced first-hand the difficulty getting locum and part-time pharmacist cover. This was one of my considerations in pursuing a career change” Michael McCarthy

businesses across the country, with many permanent vacancies going unfilled and a scarcity of locum cover.”

Letterkenny Hospital, told IPN that it is becoming increasingly difficult to fill pharmacist vacancies within hospitals.

“We closed a campaign for senior pharmacists in April for which we had eight vacancies.

We got just three eligible applicants, two of which were internal. It makes the prospect of any service development extremely challenging.

“I had hoped there would be interest from across Northern Ireland but the PSI's third country registration process, courtesy of Brexit, requires a gouging ¤2,000 upfront to get registered here now. As if recruitment wasn’t hard enough already.

“The other thing we could really do with is structured training posts like we see in the hospitals in Dublin and Cork and of course right across Northern Ireland.”

Others have blamed poor entry level salaries for HSE pharmacists on recruitment problems. The entry level salary scale for a qualified pharmacist is ¤34,000. Meanwhile, inadequate support and postgraduate training schemes at some hospitals have been attributed to poor take up.

Elsewhere, in Scotland, Wales, England, and more recently in Northern Ireland, it has been reported that GP recruitment of pharmacists has resulted in a shortage of pharmacists in community pharmacies.

This is a problem not experienced in the Republic, as there are few if any GP pharmacist roles.

Although, such a role has been examined here as part of drug safety initiatives and is supported by many GPs. Squeeze on Manpower Secretary General of the IPU, which represents community pharmacists, Darragh O’Loughlin, said it is aware of a “squeeze on pharmacist manpower at the moment that is affecting pharmacy

Work was underway to help retain community pharmacists but since the emergence of Covid-19 it remains suspended, O’Loughlin said.

“In the hope of staunching the outflow of pharmacists from community pharmacy into other career options and recognising the need to attract and retain good people in community pharmacy, since 2018 the IPU has been engaged in a forum with the Department of Health, HSE, PSI, IIoP, Appel and the Schools of Pharmacy, which was established to identify and agree measures to improve the attractiveness of community pharmacy as a career.

“This work is informed by previous IPU research into the pharmacists’ perspectives of community pharmacy and the primary satisfiers and dissatisfiers of working in community pharmacy.

“However, as a result of the Covid-19 public health emergency and need to focus resources on the pandemic response the work of the forum has been in abeyance. We are working to reconvene the forum so that we can again renew our efforts to enhance the attractiveness of community pharmacy as a career.”

So what are the factors affecting pharmacist recruitment here?

Two years ago, according to Shanahan, locums for community pharmacy were very difficult to source at reasonable rates.

Last year, because of the pandemic and lockdown, locums were largely unneeded as few pharmacists took time off.

This year, with restrictions eased, the situation changed once again and locums were in high demand.

Despite extremely high rates on offer, some pharmacists still couldn’t source a locum, however, he said.

Shanahan believes community pharmacy had changed enormously in recent years, moving from being a drug focused to a patient focused profession.

“Each patient requires more work.

NOVEMBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

Every prescription requires extra time to look after because you’re giving a more holistic, patient approach. That takes time and effort.”

The profession has become overburdened and overly-bureaucratic, factors which are steering pharmacy graduates in other directions, he said. In addition, others are leaving the profession.

“A lot of our time is wasted trying to contact suppliers about drug shortages or trying to contact prescribers about prescription issues. This is got worse due to Covid as GPs are a lot busier on the phone now than they were before.

“The reality is we don’t have enough community pharmacists coming into the profession at the moment.”

Pharmacist Michael McCarthy completed a survey on this subject in 2019 along with pharmacist James Vaughan as part of a Masters course in health economics at NUIG. Pharmacist Recruitment Survey McCarthy currently works as a health economics and outcomes research consultant at MAP BioPharma Limited. But he used to be a full-time supervising community pharmacist.

He now locums in community pharmacy to “stay in touch” with developments.

“Until Sept 2019, I was a supervising pharmacist in a pharmacy in Cork. I experienced first-hand the difficulty getting locum and part-time pharmacist cover. This was one of my considerations in pursuing a career change,” he said.

“On my course in NUIG, four of the 16 or so students were also pharmacists who had decided to change career path. And anecdotally, I knew of many other pharmacists who had left community pharmacy in recent years. This was the inspiration for the survey that myself and James carried out.”

The research yielded responses from 1,570 pharmacists and was distributed to around 6,000 pharmacists.

Titled “A Survey of Pharmacist Career Paths”, it concluded that while pharmacy as a career is evolving the community pharmacy sector was not.

“Current issues with workforce shortages need to be addressed as a matter of urgency. With uncertainty surrounding Brexit also on the horizons, innovation needs to be swift and effective. The

sector needs to be revitalised and has to become a more challenging, stimulating and progressive career choice. Higher wages alone are insufficient to attract pharmacists to community pharmacy,” the authors warned.

For McCarthy, the onerous administrative burden from the PSI and HSE were other factors in his decision to switch career.

“There is also a distinct lack of development in community pharmacy in Ireland. The role of the pharmacist hasn't really been allowed to grow or expand. The opportunity for career progression is important to me and career progression plateaus very early in community pharmacy. As a supervising pharmacist, the difficulty arranging locum cover was another constant struggle. It is also a very isolated profession in a lot of cases. Most pharmacies only have a single pharmacist on duty at any time. A lot of these issues are connected.”

He believes that minimising paperwork and the overall administrative burden would help to make the career more attractive, as well as expanding the services offered at pharmacies.

Double Edged Sword for Pharmacy The pandemic has been a “double edged sword” for community pharmacy, he argued.

On the one hand, it led to the electronic transfer of prescriptions from GPs to pharmacies and the suspension of end of month reimbursement claims using paper.

The Covid-19 vaccination programme by pharmacists, which has seen 250,000 vaccines administered by pharmacists, has also demonstrated the convenience of pharmacies, McCarthy added.

But, he warned that the crisis had turned Government attention away from the challenges facing community pharmacy.

Indeed, many pharmacists believe there is distinct lack of leadership within the Department of Health on pharmacy issues, without any attention being paid to the future of pharmacy in Ireland.

For many years there has been no chief pharmacist post at the Department, for example.

Shanahan questioned the focus on pharmacy manpower planning, saying there is little evidence any such work is taking place.

“There is no individual in the Department of Health charged with looking at community pharmacy for example,” he said.

Value Added Medicines 11

Value Added Medicines in Ireland Medicines for Ireland have published a new report, “Value Added Medicines Report: Discussion document on the contribution of Value Added Medicines in Ireland”, which has been produced in conjunction with sister organisation, Medicines for Europe.

harness these benefits, potentially saving costs and increasing patient care. Says the report, “We need a shift in mindset – from one that focuses purely on cost to an outlook that is centred around better outcomes for patients that takes a holistic look at the whole patient journey. Perhaps even more importantly, we need a new and simplified regulatory pathway for VAMs in Ireland.

David Delaney, Chairperson, Medicines for Ireland

The report outlines a range of value and savings that VAMs can important national and European bring to the State.” policy recommendations that illustrate the important role that Proven Effectiveness “That’s why all of us at Medicines Value Added Medicines (VAMs) for Ireland and within the Value Value Added Medicines (VAMs) play in a wide range of benefits Added Medicines Committee, are medicines based on known for patients and Healthcare welcome the opportunity to engage molecules that address healthcare Professionals – from ensuring with key stakeholders on this needs and deliver improvements better adherence and compliance, important topic, and to begin the for patients, healthcare to keeping healthcare costs down Value Added Medicines (VAMs) are around medicines based on known and molecules that discussions what a fit-forprofessionals payers. by reducing the need for patients regulatory framework for VAMs are developed through address healthcare needs purpose and deliver improvements for patients, healthcare to be moved to expensive next VAMs may look like for Ireland. continuous innovation on line therapies. professionals and payers. VAMs areclear developed through continuous innovation on wellWhat’s is that we need a well-established molecules, system that rewards innovation applying different strategies, all The current Irish environment, and established molecules, applying different strategies, all of which proved effective during with appropriate incentives, whilst of which proved effective during structure of reimbursement, does recognising the potential long-term the Covid-19 pandemic. not the Irish pandemic government to theallow Covid-19 (Fig 1).

p

w

v

VAM development strategy Repositioning

p

Covid-19 application A new indication was found for dexamethasone in the treatment of Covid-19. The drug reduced mortality in hospitalised patients by a third.

Finding new indications for existing molecules

Reformulation

Changing the dose or mode of administration of an established medicine

Combination Pooling sets of wellestablished molecules to simplify therapy regimes or combining an existing medicine with an innovative device (which can include a digital component)

Novel treatment regimes and administration routes allowed atrisk patients to minimise the time spent in hospitals, where they would have been at increased risk of contracting Covid-19.

Digital VAMS empowered patients to better manage their therapies, enabling treatment continuity even when hospitals did not have sufficient capacity and resources to accommodate all patients.

The Report in Brief The Covid-19 pandemic has demonstrated that traditional pharmaceutical innovation, taking several years from the discovery of a drug target to the delivery of a novel therapy, does not move fast enough to address urgent unmet medical needs during a crisis.

In this setting, repurposing has been key to the discovery of new therapeutic strategies.

In the RECOVERY trial, dexamethasone was shown to be effective in combatting severe forms of Covid-19, demonstrating how off-patent molecules have enormous potential to deliver benefits to patients worldwide if enough resources are deployed for their evaluation. While the potential of repurposing as a strategy for innovation has been demonstrated in the context of an acute crisis, the power of this approach extends far beyond emergencies.

The importance of repurposing has been recognised in both the Pharmaceutical Strategy for Europe and Europe’s Beating Cancer Plan, which were published by the European Commission in 2020 and 2021 respectively.

The initiatives promoted by the European Commission allocate resources and lay out a strategy to identify promising candidate molecules to be tested in new indications. Once a candidate is identified, pre-clinical and clinical testing are required to confirm its therapeutic potential. Collaboration among stakeholders is crucial to ensure that appropriate clinical evidence is generated to validate the most promising candidates.

Figure 1 - VAM development strategies and use cases for VAMs during the Covid-19 pandemic

Figure 1 - VAM development strategies and use cases for VAMs during the Covid-19 pandemic HOSPITALPROFESSIONALNEWS.IE | HPN • NOVEMBER - 2021

12 Value Added Medicines Engaging Patients

a vulnerable category of patients.

Enabling continuous innovation is Digital VAMs can be a valuable most important in areas of unmet tool to enable patients to better need Continuous innovation understand their treatment has the potential to provide and become confident in the solutions in areas of unmet need management of their therapy. The where traditional approaches to combination of known molecules innovation have failed. with a digital component can One such area is neurology, where support better therapy adherence many patients receive treatments through improved feedback that are generally considered Unfortunately, the current and education of patients with suboptimal and cures are rare. regulatory framework often makes respiratory diseases. For example, this process cumbersome, costly, smart inhalers detect if a dose As the “Value of Treatment for and complex. In addition, and has been correctly administered Brain Disorders” report highlights, especially where the medicines are and can track therapy adherence there is a need for cost-effective off-patent, the costs associated patterns, to inform better strategies that can provide timely with indication change or addition prescription choices by clinicians improvements patients. Thanksit While the clinical evaluation ofand a identify novel patients indication is an essential step inforrepurposing, and the uncertainty around patent that would to their shorter development protection does not encourage need further training on inhaler use alone is not sufficient to maximise the societal benefit of timelines this continuous innovation and better affordability repurposing. technique. compared to originators, VAMs While the clinical evaluation of a novel indication is an essential step in repurposing, it alone is not sufficient to maximise the societal benefit of this continuous innovation strategy. To fully benefit patients and healthcare systems, the new indication needs to be added to the label of the repurposed medicine.

strategy. To fully benefit patients and healthcare systems, the new indication needs to

can provide important solutions for This is especially the case where Reformulation delivers therapies affected by brain existing chemical entities can be be added to the label of the that repurposed medicine Unfortunately, the disorders current can keep at-risk patients (Fig 2).patients worldwide. Therefore, their value repurposed for novel indications out of harm’s way In healthcare regulatory framework often makes this process cumbersome, costly, and complex. should be recognised, taking intoIn for rare diseases where options systems worldwide, during the account also the hidden costs with for are already.

The dexamethasone addition, and especially whereCovid-19 the medicines are off-patent, the costs associated pandemic, reducing society that are associated with case well exemplifies the regulatory patient hospital visits became indication that change or additionaand the uncertainty around neurological patent protection conditions,does such not inefficiencies are associated key priority due to the risk of as the inability of patients be with adding a new indication on the infections.

Through encourage repurposing. This acquiring is especially the case whereemployed. existing chemical to entities label of well-established molecules. reformulation, VAMs allowed can bethis repurposed for novel indications for rare diseases options are already.

Indeed, drug is presently fragile non-Covid patients needing where What Truly Matters? employed to save the lives of complex therapies to significantly Covid-19 patients through off-label Currently, the US is leading the reduce their visits to healthcare use in most European countries. way ininefficiencies terms of VAM sales and are The dexamethasone case well exemplifies the regulatory that facilities. the number of available VAMs Regulatory frameworks and associated with adding a new indication on the label of well-established molecules.

This is exemplified by the change on the market. This is primarily rembursement bodies need to flex in guidelines into thesave UK which led thanks to the establishment of a Indeed, this drug is presently employed the lives of Covid-19 patients through with the changing environment to a preference for administration favourable regulatory environment and the potential formost optimising off-label use in Europeanofcountries. the VAM Abraxane, instead of that enables the streamlined older medicines in the treatment of the corresponding taxanes, to development of VAMs within the patients. Manufacturers wanting to oncology patients, despite the dedicated 505(b)2 pathway. invest in the development of VAMs premium associated with the Regulatory frameworks and price rembursement bodies need to flex with the changing encounter significant hurdles.

Dedicated regulatory procedures use of an improved formulation. environment the potential for optimising older medicines in smoother the treatment of To fully exploit theand untapped also enable knockThanks to its improved safety potential of innovation on offpatent on processes at later stages of patients. Manufacturers wanting to invest in the development of VAMs encounter profile, this VAM reduced the molecules, change is needed at VAM development, providing a country and European longer hospital stays in clear pathway for companies significant hurdleslevel.

(Fig 3). Toneed fullyforexploit the untapped potential of innovation on off-

patent molecules, change is needed at country and European level.

Lack of official evaluation of the scientific evidence

Lack of data collection systems

Liability issues

Reimbursement issues

Supply issues

Patients' concerns

Figure 2 - Registering new indications of known molecules is instrumental in solving multiple issues that are associated with off-label prescribing.

NOVEMBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

to invest, for payers to assess the value of continued innovation and for patients and healthcare professionals to gain access to improved treatment options. Overall, this results into a structured, predictable development path.

To unlock the benefits that can be delivered by VAMs, the EU should create an ecosystem that enables and fosters off-patent innovation.

VAMs should be recognised as a separate group of medicines in EU legislation, linking approval procedures, innovation frameworks and reimbursement processes to create an ecosystem that delivers better health to patients, solutions for healthcare systems and fair returns on R&D investments.

“Medicines for Ireland believes that policies need to be pursued to facilitate investment into off-patent innovation.

Ireland can benefit greatly from changes in the area of Value Added Medicines.

As a country, we can learn from the work at EU level, including the Pharmaceutical Strategy for Europe, and recognise the value of this type of reform.

As an industry, we welcome clear guidance and policy to allow the off-patent industry innovate for the benefit of patients, healthcare professionals and healthcare systems” – David Delaney, Chair, Medicines for Ireland

Figure 2 - Registering new indications of known molecules is instrumental in solving multiple issues that are associated with off-label prescribing

Pelgraz® PFI Patient Support App The Pelgraz® PFI App is designed to support patients self-administering Pelgraz® PFI at home How severe is your

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Pre-Filled Injector One Dose for ANC Recovery

Confidence, Convenience, Compliance ABBREVIATED PRESCRIBING INFORMATION Please refer to the Summary of Product Characteristics (SmPC) before prescribing Pelgraz▼(pegfilgrastim) 6 mg solution for injection in pre-filled syringe or prefilled injector. Presentation: Each pre-filled syringe or pre-filled injector contains 6 mg of pegfilgrastim* in 0.6 mL solution for injection. The concentration is 10 mg/mL based on protein only**. *Produced in Escherichia coli cells by recombinant DNA technology followed by conjugation with polyethylene glycol (PEG). ** The concentration is 20 mg/mL if the PEG moiety is included. Indications: Reduction in the duration of neutropenia and the incidence of febrile neutropenia in adult patients treated with cytotoxic chemotherapy for malignancy (with the exception of chronic myeloid leukaemia and myelodysplastic syndromes). Dosage and Administration: Pelgraz therapy should be initiated and supervised by physicians experienced in oncology and/or haematology.

Posology: One 6 mg dose (a single pre-filled syringe or pre-filled injector) of Pelgraz is recommended for each chemotherapy cycle, given at least 24 hours after cytotoxic chemotherapy. Safety and efficacy of Pelgraz in children and adolescents has not yet been established and no recommendation on a posology can be made. No dose change is recommended in patients with renal impairment, including those with end-stage renal disease. Method of administration: Pelgraz is for subcutaneous use. The injections should be given subcutaneously into the thigh, abdomen or upper arm. See SmPC for instructions on handling of the medicinal product before administration.

Contraindications: Hypersensitivity to pegfilgrastim or any of the excipients in Pelgraz.

Warnings and precautions: To improve the traceability of biological medicinal products, the trade name of the administered product should be clearly recorded. The long-term effects of pegfilgrastim have not been established in acute myeloid leukaemia (AML); therefore, it should be used with caution in this patient population. Granulocytecolony stimulating factor (G-CSF) can promote growth of myeloid cells in vitro and similar effects may be seen on some non-myeloid cells in vitro. The safety and efficacy of pegfilgrastim have not been investigated in patients with myelodysplastic syndrome, chronic myelogenous leukaemia, and in patients with secondary AML; therefore, it should not be used in such patients. Particular care should be taken to distinguish the diagnosis of blast transformation of chronic myeloid leukaemia from AML. The safety and efficacy of pegfilgrastim administration in de novo AML patients aged < 55 years with cytogenetics t(15;17) have not been established. The safety and efficacy of pegfilgrastim have not been investigated in patients receiving high dose chemotherapy. This medicinal product should not be used to increase the dose of cytotoxic chemotherapy beyond established dose regimens. Pulmonary adverse reactions, in particular interstitial pneumonia, have been reported after G-CSF administration. Patients with a recent history of pulmonary infiltrates or pneumonia may be at higher risk. The onset of pulmonary signs such as cough, fever, and dyspnoea in association with radiological signs of pulmonary infiltrates, and deterioration in pulmonary function along with increased neutrophil count may be preliminary signs of adult respiratory distress syndrome (ARDS). In such circumstances pegfilgrastim should be discontinued at the discretion of the physician and the appropriate treatment given. Glomerulonephritis has been reported in patients receiving filgrastim and pegfilgrastim. Generally, glomerulonephritis resolved after dose reduction

or withdrawal of filgrastim and pegfilgrastim. Urinalysis monitoring is recommended.

Capillary leak syndrome has been reported after G-CSF administration and is characterised by hypotension, hypoalbuminaemia, oedema and haemoconcentration. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. Generally asymptomatic cases of splenomegaly and cases of splenic rupture, including some fatal cases, have been reported following administration of pegfilgrastim. Spleen size should be carefully monitored (e.g. clinical examination, ultrasound). A diagnosis of splenic rupture should be considered in patients reporting left upper abdominal pain or shoulder tip pain. Treatment with pegfilgrastim alone does not preclude thrombocytopenia and anaemia because full dose myelosuppressive chemotherapy is maintained on the prescribed schedule. Regular monitoring of platelet count and haematocrit is recommended. Special care should be taken when administering single or combination chemotherapeutic medicinal products which are known to cause severe thrombocytopenia. Pegfilgrastim in conjunction with chemotherapy and/or radiotherapy has been associated with development of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML) in breast and lung cancer patients. Patients treated in these settings should be monitored for signs and symptoms of MDS/AML. Sickle cell crises have been associated with the use of pegfilgrastim in patients with sickle cell trait or sickle cell disease. Therefore, use caution when prescribing pegfilgrastim in patients with sickle cell trait or sickle cell disease, monitor appropriate clinical parameters and laboratory status and be attentive to the possible association of this medicinal product with splenic enlargement and vasoocclusive crisis. White blood cell (WBC) counts of 100 × 109/L or greater have been observed in less than 1% of patients receiving pegfilgrastim. No adverse reactions directly attributable to this degree of leukocytosis have been reported.

Such elevation in WBCs is transient, typically seen 24 to 48 hours after administration and is consistent with the pharmacodynamic effects of this medicinal product. Consistent with the clinical effects and the potential for leukocytosis, a WBC count should be performed at regular intervals during therapy. If leukocyte counts exceed 50 × 109/L after the expected nadir, this medicinal product should be discontinued immediately. Hypersensitivity, including anaphylactic reactions, have been reported with pegfilgrastim. Permanently discontinue pegfilgrastim in patients with clinically significant hypersensitivity. Do not administer pegfilgrastim to patients with a history of hypersensitivity to pegfilgrastim or filgrastim. If a serious allergic reaction occurs, appropriate therapy should be administered, with close patient follow-up over several days. Stevens-Johnson syndrome (SJS), which can be life-threatening or fatal, has been reported rarely in association with pegfilgrastim treatment. If the patient has developed SJS with the use of pegfilgrastim, treatment must not be restarted at any time. As with all therapeutic proteins, there is a potential for immunogenicity. Rates of generation of antibodies against pegfilgrastim is generally low.

Binding antibodies do occur as expected with all biologics; however, they have not been associated with neutralising activity at present. Aortitis has been reported after filgrastim or pegfilgrastim administration in healthy subjects and in cancer patients. The symptoms experienced included fever, abdominal pain, malaise, back pain and increased inflammatory markers (e.g. C-reactive protein and WBC count). In most cases aortitis was Associated member of:

Oncology & Haematology

www.accord-healthcare.ie

exhauste

th y Thursday 11 Jul

Fatigue

Chemotherapy sess Pelgraz dose

Feeling weary or

injection is due

diagnosed by CT scan and generally resolved after withdrawal of filgrastim or pegfilgrastim. The safety and efficacy of Pelgraz for the mobilisation of blood progenitor cells in patients or healthy donors has not been adequately evaluated. Increased haematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone-imaging findings. This should be considered when interpreting bone-imaging results. The additive effect of concomitantly administered products containing sorbitol (or fructose) and dietary intake of sorbitol (or fructose) should be taken into account. Pelgraz contains less than 1 mmol sodium (23 mg) per 6 mg dose, that is to say essentially ‘sodium-free’. The needle cover contains dry natural rubber (a derivative of latex), which may cause allergic reactions. Pregnancy and Lactation: Pegfilgrastim is not recommended during pregnancy and in women of childbearing potential not using contraception. A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from pegfilgrastim therapy taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman. Adverse Events include: Adverse events which could be considered serious include: Common: Thrombocytopenia. Uncommon: Myelodysplastic syndrome, acute myeloid leukaemia, sickle cell anaemia with crisis, capillary leak syndrome, glomerulonephritis, hypersensitivity reactions (including angioedema, dyspnoea, anaphylaxis), splenic rupture (including some fatal cases), Sweet’s syndrome (acute febrile neutrophilic dermatosis), pulmonary adverse reactions including interstitial pneumonia, pulmonary oedema and pulmonary fibrosis have been reported.

Uncommonly cases have resulted in respiratory failure or ARDS which may be fatal. Rare: Aortitis, pulmonary haemorrhage, Stevens-Johnson syndrome. Other Very Common adverse events: Headache, nausea, bone pain. Other Common adverse events: Leukocytosis, musculoskeletal pain (myalgia, arthralgia, pain in extremity, back pain, musculoskeletal pain, neck pain), injection site pain, non-cardiac chest pain. See SmPC for details of other adverse events. Shelf Life: 3 years. Store in a refrigerator (2∞C – 8∞C).

Pelgraz may be exposed to room temperature (not above 25°C ± 2°C) for a maximum single period of up to 72 hours. Pelgraz left at room temperature for more than 72 hours should be discarded. Do not freeze. Accidental exposure to freezing temperatures for a single period of less than 24 hours does not adversely affect the stability of Pelgraz. Keep the container in the outer carton in order to protect from light. Pack Size: One prefilled syringe or prefilled syringe injector with one alcohol swab, in a blistered packaging.

Marketing Authorisation Numbers: Pre-filled syringe: EU/1/18/1313/001, Prefilled injector: EU/1/18/1313/002. Marketing Authorisation Holder (MAH): Accord Healthcare S.L.U, World Trade Center, Moll de Barcelona, s/n, Edifici Est, 6a planta, Barcelona, 08039 Spain. Legal Category: POM. Full prescribing information including the SmPC is available on request from Accord Healthcare Ireland Ltd, Euro House, Little Island, Co. Cork, Tel: 021-4619040 or www.accord-healthcare.ie/products. Adverse reactions can be reported to Medical Information at Accord Healthcare Ltd. via E-mail: medinfo@accord-healthcare.com or Tel: +44(0)1271385257.

Date of Generation of API: May 2021. IE-01426

Adverse events should be reported. Reporting forms and information can be found on the HPRA website (www.hpra.ie), or by e-mailing medsafety@hpra.ie. Adverse events should also be reported to Medical Information via email; medinfo@accord-healthcare.com or tel:0044 (0) 1271 385257

July 2021. IE-01663

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14 News Better Managed Hypertension Crucial The number of adults aged 30-79 years with hypertension or high blood pressure has increased from 650 million to 1.28 billion in the last thirty years, according to the first comprehensive global analysis of trends in hypertension prevalence, detection, treatment and control, led by Imperial College London and the World Health Organization (WHO), and published in The Lancet. Nearly half these people did not know they had high blood pressure.

The UK was one of the top ten countries with the lowest prevalence of high blood pressure among women in 2019 at 23% while in Ireland this figure was 26.6” In Ireland the prevalence of high blood pressure among men in 2019 was 38.2%

The study, conducted by a global network of physicians and researchers, covered the period 1990-2019. It used blood pressure measurement and treatment data from over 100 million people aged 30-79 years in 184 countries, together covering 99% of the global population, which makes it the most comprehensive review of global trends in hypertension to date.

By analysing this massive amount of data, the researchers found that there was little change in the overall rate of hypertension in the world from 1990 to 2019, but the burden has shifted from wealthy nations to low- and middle-income countries. The rate of hypertension has decreased in wealthy countries – which now typically have some of the lowest rates – but has increased in many low- or middle-income countries.

As a result, Canada, Peru and Switzerland had among the lowest prevalence of hypertension in the world in 2019, while some of the highest rates were seen in the Dominican Republic, Jamaica and Paraguay for women and Hungary, Paraguay and Poland for men.

confirms the rising burden of high blood pressure around the world.

Although there has been a relative improvement in Ireland, we still have an increasing prevalence of hypertension, and a lack of awareness of the importance of diagnosing and treating high blood pressure.

Although the percent of people who have hypertension has changed little since 1990, the number of people with hypertension doubled to 1.28 billion. This was primarily due to population growth and ageing.

In 2019, over one billion people with hypertension (82% of all people with hypertension in the world) lived in low- and middle-income countries.

“The need to better manage hypertension is crucial in preventing adverse outcomes such as stroke, heart failure, kidney failure and dementia . By increasing and improving access to blood pressure measurement, identifying and adequately treating high blood pressure as well as managing comorbidities such as diabetes and pre-existing heart disease, promoting healthier diets and regular physical activity, and more strictly controlling tobacco products, we can save lives and improve people’s lives.”

Commenting Dr Angie Brown, Medical Director of the Irish Heart Foundation said, “This large study

Pharma Managers Series – HSE Briefing Date: 4th November, 2021 The Pharmaceutical Managers’ Institute is delighted to welcome HSE CEO, Paul Reid back to the PMI to give members an update on where the HSE, the rollout of the vaccination programme and the impact of the pandemic on the healthcare budget.

This event is proudly sponsored by AXIS Consulting.

Visit www.thepmi.com for more details.

New Rheumatology Appointment A graduate of medicine from UCC in 2010 Dr Cronin returned to Cork following 5 years at the Rheumatic Diseases Unit, Western General Hospital, Edinburgh where he completed specialist training and held post as acting Consultant Rheumatologist. Dr Cronin also held the position as Clinical Tutor Associate and Honorary Clinic Research Fellow at the Institute of Genetics and Molecular Medicine at the University of Edinburgh.

In 2013, Dr Cronin completed a Master's degree in Sports and Exercise Medicine at UCC before

NOVEMBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

undertaking full time clinical research at APC Microbiome Ireland and the Department of Medicine. Dr Cronin was awarded a PhD in 2018 for his thesis entitled "Physical Activity for Health: The Impact of exercise on the human gut microbiota and pro-flammatory cytokines". He has published widely in the areas of the gut microbiome, bone health and exercise medicine.

He is a Fellow of the Faculty of Sport and Exercise Medicine and an invited member of the Royal Osteoporosis Soceity's Bone Research Academy. In 2019

Owen was awarded a Research and Education Young Investigator award for his work from the Americal Society of Bone and Mineral Research. He currently sits on the editorial board of the journal Rheumatology Advances and Practice.

Dr Cronin is proficient in all areas of general adult Rheumatology including the use of ultrasound for the assessment of temporal arteritis. He has achieved certification from Glasgow Caledonian University in the use of Ultrasound for synovitis assessment.

16 News Budget 2022: ¤45m to Secure Future of Cancer Services Dr Shirley Potter, Consultant plastic and reconstructive surgeon

“We are seeing some really shocking cancer cases now that you used to see only very rarely….

It will take years for these to filter through the system…”

Investment of ¤45 million is urgently needed in Budget 2022 to rebuild pandemic-hit cancer services so they can cope with an expected upcoming surge in demand, the Irish Cancer Society has said.

In its 2022 Pre-Budget Submission the Society highlights that the pandemic and cyberattack exposed Ireland’s fragile and underfunded health system.

Relentless competition with other types of urgent care for theatre space, beds and other resources has caused delays to providing vital cancer care for patients at the earliest opportunity.

why we need this investment now for more capacity and resources to deal with this situation.”

Within the ¤45m figure is a proposed ¤15m to deal with existing services backlogs and an anticipated surge in demand.

The Irish Cancer Society is also asking the Government to make funding available towards the ¤3 billion transitional fund called for in the Sláintecare report to deliver a system of universal healthcare based on need and not the ability to pay.

The calls come amid warnings from doctors and healthcare professionals about an oncoming tide of later stage cancer cases that will emerge because people put off seeking medical advice during the pandemic, as well as ongoing delays accessing tests and treatment.

Consultant Plastic and Reconstructive Surgeon Dr Shirley Potter says she now sees

“shocking” cases of advanced cancers which used to be rare as they were picked up earlier.

She says, “Access for surgical procedures has been extremely challenging: even before Covid the pressures on the system were not acceptable, and when you add in the pandemic on top of that it has made things even worse.

“Patients who had delayed access to healthcare because of the pandemic are now needing bigger, more complicated procedures. We are seeing some really shocking cancer cases now that you used to see only very rarely.

“It will take years for these to filter through the system and while urgent surgeries are being done, the more of them we’re seeing it’s having a bigger knock-on effect with elective cases pushed further and further down the line, which is

Consultant Medical Oncologist Professor Seamus O’Reilly added, “The Covid pandemic has been a challenging time for patients, families and healthcare workers including administrative and civil service staff – its legacy on each of these groups has and will be significant, compromising the advances in care and outcomes witnessed in the past two decades in Ireland.

“While the pandemic has demonstrated the significant human capital in Irish healthcare it has also magnified inequalities and exposed vulnerabilities – resourcing is needed to regain lost ground and also to develop 21st Century infection control and patient dignity-appropriate infrastructure.”

The charity’s Pre-Budget Submission also calls for more funding to increase capacity for diagnostic services including colonoscopies and endoscopies to help ease current severe backlogs, along with a proposed ¤25m allocation to abolish all inpatient charges, and support for crucial clinical trials as well as a range of important cancer prevention measures.

Novel Therapeutic Strategy for Acute Myeloid Leukemia A new type of targeting chaperon protein HSP70 inhibitor QL47 was recently discovered by a team led by Prof. LIU Qingsong from the Hefei Institutes of Physical Science (HFIPS) of the Chinese Academy of Sciences to treat FLT3-ITD-positive acute myeloid leukemia (AML). Their findings have been published on Signal Transduction and Targeted Therapy.

Approximately, 25% of AMLs carry FLT3-ITD (internal tandem

duplication) oncogenic mutations, and FLT3 kinase inhibitors have already achieved great success in the clinic for FLT3-ITD-positive AML. However, after prolonged treatment, drug-acquired resistance is observed in patients treated with FLT3 kinase inhibitor.

Further study proved that QL47 irreversibly bound to the heat shock protein HSP70 and inhibited its refolding activity, which in turn led to the degradation of FLT3-ITD and inhibited proliferation of the FLT3ITD positive AML cells.

In this research, the researchers found that compound QL47 had potent anti-proliferative activity against FLT3-ITD positive AML cell lines and induces FLT3-ITD protein degradation.

“It is inducible HSP70 instead of constitutive expressed HSC70 that is important for FLT3 protein stabilization and FLT3-ITDpositive cell viability,” said Dr. HU.

NOVEMBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

The evaluation of QL47 in primary patient cells and in vivo tumor models showed that QL47 induced the degradation of FLT3ITD protein and cell apoptosis in primary patient cells. In mice bone marrow engraftment model, QL47 significantly extends the animal survivals.

“Targeting the chaperone protein HSP70 could potentially provide a novel strategy for FLT3-ITDpositive AML treatment,” said HU.

TOGETHER. LONGER. Superior 5-year Overall Survival vs. DA 3+71 In patients with AML-MRC and t-AML1 Who were fit for IC¹ Regardless of their HSCT eligibility1,2 Similar safety profile with prolonged myelosuppression vs. DA 3+73

For more data and a wealth of educational resources, visit www.vyxeos.co.uk or scan the QR code

6

5

4

In AML-MRC and t-AML, consider Vyxeos Liposomal first

Prescribing Information Vyxeos® Liposomal 44mg/100mg powder for concentrate for solution for infusion (daunorubicin and cytarabine) Please refer to the Summary of Product Characteristics before prescribing.

Presentation: Purple lyophilised cake of powder for concentrate for solution for infusion. Each vial contains 44 mg of daunorubicin and 100 mg of cytarabine. After reconstitution the solution contains 2.2 mg/mL daunorubicin and 5 mg/mL cytarabine encapsulated in liposomes in a fixed combination in a 1:5 molar ratio. Indication: For the treatment of adults with newly diagnosed, therapy-related acute myeloid leukaemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). Dosage and administration: FOR INTRAVENOUS USE ONLY. An in-line membrane filter may be used provided the minimum pore diameter of the filter is greater than or equal to 15 μm. It must not be administered via an intramuscular, intrathecal, or subcutaneous route. Refer to the full SmPC for detailed information on preparation of solution for infusion. Treatment should be initiated and monitored under the supervision of a physician experienced in the use of chemotherapeutic medicines. Recommended dosing schedule for induction of remission: 44 mg/100 mg/m2, administered intravenously over 90 minutes on days 1, 3, and 5 as the first course of induction therapy; then on days 1 and 3 as subsequent course of induction therapy, if needed. Recommended dosing schedule for consolidation: The first consolidation cycle should be administered 5 to 8 weeks after the start of the last induction. The recommended dosing schedule is 29 mg/65 mg/m2, administered intravenously over 90 minutes on days 1 and 3 as subsequent courses of consolidation therapy, if needed. Dose adjustments during treatment may be required in hypersensitivity symptoms and cardiotoxicity. Assessment of cardiac function prior to start of treatment is recommended. Renal impairment: Dose adjustment is not required for patients with mild (creatinine clearance [CrCL] 60 - 89 mL/min by Cockcroft Gault equation [C-G]) or moderate (CrCL 30 - 59 mL/min) renal impairment. There is no experience in patients with severe renal impairment (CrCL 15 - 29 mL/min) or endstage renal disease. It should only be used in patients with severe renal impairment if the benefits outweigh the risks. Hepatic impairment: Dose adjustment is not required for patients with a bilirubin ≤50 μmol/L. There is no experience in patients with hepatic impairment resulting in a bilirubin level >50 μmol/L. It should only be used in patients with severe hepatic impairment if the benefits outweigh the risks. Elderly population (≥65 years): No dose adjustment is required. Paediatric population: The safety and efficacy in children aged 0–18 years has not yet been established. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Warnings, precautions and interactions: Do not substitute or interchange with other daunorubicin and/or cytarabine-containing products. Severe myelosuppression and serious or fatal haemorrhagic events have been reported. Due to the long plasma half-life of Vyxeos liposomal, time to recovery of ANC and platelets may be prolonged and require additional monitoring. Prophylactic anti-infectives may be administered during the period of profound neutropenia until ANC returns to ≥500/μL. If myelosuppressive complications occur, appropriate supportive measures should be used. Blood counts should be regularly monitored until recovery. As cardiotoxicity is a known risk, prior therapy with anthracyclines, pre-existing cardiac disease, previous radiotherapy of the mediastinum, or concomitant use of cardiotoxic products may increase the risk. Hepatotoxic medicinal products may impair liver function and increase toxicity. Evaluation of hepatic and renal function is recommended prior to administration and periodically during treatment.

Blood uric acid levels should be monitored and appropriate therapy initiated if hyperuricemia develops. Each vial contains 100 mg of copper gluconate. It should only be used in patients with a history of Wilson’s disease or other copper-related disorder if the benefits outweigh the risks. To avoid local tissue necrosis care should be taken to ensure that there is no extravasation of Vyxeos liposomal during administration. Administration of live or live-attenuated vaccines should be avoided. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished.

The absorption of oral accompanying medicinal products may be considerably influenced by gastrointestinal mucositis and/ or diarrhoea frequently occurring in association with intensive chemotherapy. Effect on ability to drive and use machines; Minor influence, fatigue and dizziness reported, caution is advised. Pregnancy, lactation and fertility: There are no data on use in pregnant women. It should not be used during pregnancy unless the benefit of treatment outweighs the risk. It is not known if Vyxeos liposomal is excreted in human milk therefore mothers should be advised to discontinue breastfeeding during therapy. Patients should be advised to avoid becoming pregnant while receiving Vyxeos liposomal.

Male patients and women of childbearing potential must use an effective method of contraception during treatment and for 6 months following the last dose. Male fertility may be compromised by treatment. Undesirable effects: Please refer to the full SmPC for the complete list of undesirable effects. The most frequently occurring adverse reactions were hypersensitivity, febrile neutropenia, oedema, diarrhoea/colitis, mucositis, fatigue, musculoskeletal pain, abdominal pain, decreased appetite, cough, headache, chills, arrhythmia, pyrexia, sleep disorders, and hypotension. The most serious and frequently occurring ADRs were infection, cardiotoxicity and haemorrhage. Overdose: There is no specific antidote for overdose and treatment should be symptomatic. Storage and Handling: Store in a refrigerator (2°C - 8°C). Shelf life of unopened vials: 2 years. Keep vial in the original carton to protect from light and store in an upright position. Vyxeos liposomal is a cytotoxic medicinal product intended for single use only. Any unused medicinal product or waste material should be disposed of in accordance with local requirements for cytotoxic agents. Legal category: POM. Marketing authorisation number: EU/1/18/1308/001. Package quantity and Cost: 1 × 50 mL vial. UK: £4581 per vial. IE: Price on Application. Marketing Further information is available from the Marketing Authorisation Holder: Jazz Pharmaceuticals Ireland, 5th Floor, Waterloo Exchange, Waterloo Road, Dublin D04 E5W7, Ireland. Date of preparation: February 2021.

Job Code: UK-VYX-2100042. Vyxeos® is a registered trade mark.

Adverse events should be reported. Healthcare professionals are asked to report any suspected adverse reactions. For the UK, reporting forms and information can be found at: www.mhra.gov.uk/yellowcard For Ireland, reporting forms and information can be found at: www.hpra.ie Adverse events should also be reported by email: AEreporting@jazzpharma.com References: 1. Lancet JE, et al. E-poster EP556. EHA25 Virtual Congress 2020. 2. Lin TL, et al. E-poster EP562. EHA25 Virtual Congress 2020. 3. Lancet JE, et al. J Clin Oncol 2018;36(26):2684–2692. 4. National Institute for Health and Care Excellence. Technology Appraisal Guidance [TA552]. December 2018. 5. Scottish Medicines Consortium. SMC2130.

March 2019. 6. Health Service Executive. Regimen code 00613a. February 2021 Abbreviations: AML-MRC, acute myeloid leukaemia with myelodysplasia-related changes; DA, daunorubicin/cytarabine; HSCT, haematopoietic stem-cell transplantation; HSE, Health Service Executive; IC, intensive chemotherapy; NICE, National Institute for Health and Care Excellence; SMC, Scottish Medicines Consortium; t-AML, therapy-related AML

August 2021 | IE-VYX-2100019

18 News

Becton Dickinson (BD) Tackle Epic Charity Cycle The Mizen Head to Malin Head challenge is well known among cyclists, usually taking several days to complete.

However, Peter Ferguson from BD decided to attempt to complete it in just 24 hours. Peter, who lives in Northern Ireland, has family members with Type 1 diabetes and he currently works for medical device company, Becton Dickinson (BD), where he is the diabetes care account manager for the UK and Ireland.

Currently, 97% of its insulin pens that are distributed worldwide are manufactured in Ireland. Last year was the 50th anniversary of when BD started manufacturing in Ireland, while this year is the 100year anniversary of the discovery of insulin. Peter wanted to undertake some sort of challenge to mark these two events. He also wanted to do it for health reasons.

“This time 18 months ago, I was 17 stone. I was driving around Ireland for my job, eating the wrong things and doing no exercise and then lockdown happened. I started worrying that I would get Type 2 diabetes. I decided to use that four to five hours that I would have

Peter Ferguson, BD

been spending in a car and do a bit of exercise and within about six months, I had lost most of the weight,” he explains.

Peter is an ex-professional rugby referee, so he had been fit previously. However, he had never cycled seriously before. This did not stop him from deciding to do a charity cycle for BD’s nominated UK charity, which involved cycling 30 miles every day over a onemonth period. He had always wanted to do something with Diabetes Ireland so he decided to set himself a new charity challenge.

While he would have liked to cycle around Europe, this was not possible as a result of the pandemic, so he decided to do the Mizen to Malin Head cycle, but with a twist – he hoped to complete it in 24 hours. He reached out to work colleagues in Ireland to see if anyone else would like to take part and in the end, 12 cyclists decided to give it a go.

Members of the Mizen to Malin challenge team

Including the support team, almost 30 people were involved. “We completely overengineered what was going to happen on the cycle and what was going to happen with the support team. We had to consider details like how long we were going to stop for, what type of clothes to bring and what we were going to eat. As long as there is food in the body, it will keep going. The problem a lot of people have is that they just don’t eat enough,” he notes.

However, the one thing you cannot engineer is the weather. At the last minute, due to a change in the direction of the wind, the team decided to cycle from Malin to Mizen Head instead. Peter says he didn’t really struggle with the lack of sleep, but the hardest thing for him was the cold.

“It got down to one degree and I personally wasn’t prepared for it. I was prepared for everything else, but that cold really saps your energy. It didn’t really start to get warm for us until about 10am

the next morning as it was quite a misty and damp morning,” he recalls. While the cyclists fell just outside the 24 hours altogether, when just cycling time was taken into account (excluding food stops etc), they managed complete the cycle in 21.5 hours – a huge achievement.

“In the few days after the cycle, I was living on adrenaline, but as the week wore on I became more tired, but it wasn’t a physical tiredness it was an emotional tiredness. Some of the emotions that came out after the race were unbelievable. I was delighted that people were happy afterwards,” he says. At the time of going to press, the cyclists had already raised over ¤25,000 for Diabetes Ireland.

If you would like to donate, visit: https://www.justgiving. com/team/ bddiabetesirelandcycle *This article first appeared in Diabetes Ireland Autumn 2021 issue.

Diabetes Ireland CEO, Kieran O’Leary, pictured with Peter in Mizen Head

Peter Ferguson (left) and other members of the Mizen to Malin challenge team pictured at Malin Head celebrating their achievement

Diabetes Ireland CEO, Kieran O’Leary, pictured with Peter in Mizen Head

NOVEMBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

Diabetes 19

Digital Diabetes – The Future Is Now “It has significantly changed my life for the better” is what the final patient of my diabetes clinic said to me last week, when I asked her about her new continuous glucose monitor (CGM).

We are experiencing a Cambrian explosion of digital health tools in medicine and diabetes care is a great example of their impact.

This is thanks to Moore’s Law, which states that the transistor density of integrated circuits doubles approximately every two years. This corresponds to smaller, more powerful computer chips which continuously push the boundaries of what’s possible with technology. We see this in our shops with better phones and TVs and now in our clinics with better patient outcomes.

In a very short period of time, primarily since the release of the iPhone (2007), we have seen the emergence of the Internet of Things (IoT) and personal health sensor ecosystems that can be harvested by a smartphone, analysed in the cloud and make suggestions to improve your health (e.g. step-counts, glucose etc.). Furthermore COVID19 has resulted in 10 years of digital transformation in medicine happening in one year (e.g. video consults, remote monitoring etc.)

Diabetes is a global health emergency affecting approximately 10% of the planets population. It is a chronic metabolic disease which results in glucose dysregulation and it’s management is multifaceted involving diet, exercise and usually medications (pills and insulin therapy). Several studies have shown that keeping blood glucose levels in the normal range reduces medical complications (e.g. nerve, eye, kidney and cardiovascular disease). It requires multidisciplinary team input (e.g. physicians, nurses, dieticians, podiatrists, psychologists, ophthalmologists etc.) and its ongoing management can often be burdensome for patients. Indeed my patients have described the extra mental load, as trying to live your life like everyone else but also having to be constantly tapping to keep a balloon in the air (like the party game). This is because so many things can affect your blood sugar levels from day to day including diet, exercise, stress,

illness etc. Technology offers tools to help lighten the load by providing the patient with the right information at the right time, such as smartphone apps to calculate the carbohydrate content of different meals. Indeed for people with diabetes, having to calculate the required insulin doses based on the current blood sugar, the macronutrients of the meal to be eaten in addition to the above mentioned variables is like a math Olympiad several times a day. This in addition to physically having prick your finger, draw blood and measure with a glucometer four times a day, forever.

In the real world, patients will never get their insulin / glucose matched 100% all of the time and can feel upset by this but I reassure them using a golf analogy, that it’s impossible to get a hole in one every time. Using traditional methods, they might get on the fairway but by using diabetes technology, the results will get them on the putting green, every time.

Therefore technology such as intermittently scanned continuous glucose monitors can help remove some of this management burden by simply wearing a 2 euro sized device on your upper arm (e.g.

Abbott Libre) for 2 weeks and not having to prick your fingers.

Instead the glucose data is sampled every 5 minutes and stored on the device which can be read by waving your mobile phone over the sensor, every 8 hours. This data is then stored on the cloud for review by you and your clinician to see your unique glucose variation and to then make more informed management decisions to improve this. If more nuance is needed then matchbox sized real time continuous glucose monitors can be worn on the abdomen (e.g. Dexcom G6) and then not only can glucose data be seen instantly on your smartphone (and stored in cloud) but also alarms can be set to alert you when you are going low/high.

On the software side, clinicians now use Ambulatory Glucose Profiles (AGP) reports to analyse this new glucose big data in a structured way.

Written Professor Derek O’Keeffe MD PhD FRCPI, Consultant Endocrinologist UHG, Professor of Medical Device Technology NUIG

These pager sized devices allow very flexible, micro dosing of insulin throughout the day, so that a tailored programme can be developed for each specific patient. Next generation diabetes technology research is exploring the use of artificial intelligence algorithms coupled with glucose big data to predict when patients will have sentinel events (e.g. hypoglycaemia) many hours ahead of what we can do now. In addition the closed loop insulin pumps will soon be a full artificial (bionic) pancreas, meaning it will

be able to match insulin/glucose requirements in real time day and night, taking into account all the variables to ensure normal glucose patterns at all times.

Of course the rapidly changing landscape of diabetes technology requires clinicians to stay up to date and so NUI Galway is now offering a stand-alone diabetes module, as well as a diploma and masters in Diabetes. http://www.nuigalway.ie/courses/ taught-postgraduate-courses/ diabetes-medicine-msc-pdip.html

Another important technology to improve glucose Time in Range (TIR) is an insulin pump (which is often paired with a CGM).

HOSPITALPROFESSIONALNEWS.IE | HPN • NOVEMBER - 2021

For the treatment of diabetes mellitus in adults, adolescents and children from the age of 6 years1 Prescribing Information: Toujeo ® (insulin glargine 300 units/ml) Please refer to Summary of Product Characteristics (SmPC) before prescribing.

Presentation: Toujeo SoloStar and DoubleStar pre-filled pens. Each ml contains 300 units of insulin glargine. SoloStar pen contains 1.5ml (450 units) of solution for injection. DoubleStar pen contains 3ml (900 units) of solution for injection.

Indication: Treatment of diabetes mellitus in adults, adolescents and children from the age of 6 years. Dosage and ® Administration: Toujeo is administered subcutaneously, by injection into the abdominal wall, the deltoid or the thigh, once daily, at any time of the day, preferably at the same time every day. Injection sites must be rotated within a given injection area from one injection to the next in order to reduce the risk of lipodystrophy and cutaneous amyloidosis. The dose regimen (dose and timing) should be adjusted according to individual response. Do not administer intravenously. In type 1 diabetes mellitus, Toujeo must be combined with short-/rapid-acting insulin to cover mealtime insulin requirements.

In patients with type 2 diabetes mellitus, recommended daily starting dose is 0.2 units/kg followed by individual dose adjustments. Toujeo can also be given together with other anti-hyperglycaemic medicinal products. Switch between insulin glargine 100 units/ml and Toujeo: Insulin glargine 100 units/ml and Toujeo are not bioequivalent and are not directly interchangeable. When switching from insulin glargine 100 units/ml to Toujeo, this can be done on a unit to unit basis, but a higher Toujeo dose (approximately 10-18%) may be needed to achieve target ranges for plasma glucose levels. When switching from Toujeo to insulin glargine 100 units/ml, the dose should be reduced (approximately by 20%).

Switching from other basal insulins to Toujeo: A change of dose and/or timing of the basal insulin and concomitant anti hyperglycaemic treatment may be required. Dose adjustments may also be required if the patient’s weight or lifestyle changes, the timing of insulin dose is changed or other circumstances arise that increase susceptibility to hypo- or hyperglycaemia. Toujeo must not be mixed or diluted with any other insulin or other medicinal products. Close metabolic monitoring is recommended during a switch and in the initial weeks thereafter. SoloStar 1-80 units per single injection in steps of 1 unit and DoubleStar 2-160 units in steps of 2 units. When changing from Toujeo SoloStar to Toujeo DoubleStar, if the patient’s previous dose was an odd number then the dose must be increased or decreased by 1 unit. Toujeo DoubleStar prefilled pen is recommended for patients requiring at least 20 units per day. Special Populations: Insulin requirements may be diminished in the elderly or patients with renal or hepatic impairment. Paediatric: When switching basal insulin to Toujeo, dose reduction of basal and bolus insulin needs to be considered on an individual basis, in order to minimise the risk of hypoglycaemia. The safety and efficacy of Toujeo in children and adolescents below 6 years of age have not been established. Contraindications: Hypersensitivity to insulin glargine or any excipients.

Precautions and Warnings: Traceability: In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Toujeo is not the insulin of choice for treatment of diabetic ketoacidosis. Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden change

References: 1. Toujeo® Summary of Product Characteristics Date of preparation: August 2020 | MAT-IE-2000822 (v1.0)

in the injection site to an unaffected area has been reported to result in hypoglycaemia. Blood glucose monitoring is recommended after the change in the injection site, and dose adjustment of antidiabetic medications may be considered.

Hypoglycaemia: In case of insufficient glucose control or a tendency to hyper/hypoglycaemic episodes, the patient’s adherence to the prescribed treatment regimen, injection sites and proper injection technique and all other relevant factors must be reviewed before dose adjustment is considered. Particular caution should be exercised, and intensified blood glucose monitoring is advisable for patients in whom hypoglycaemic episodes might be of clinical relevance and in those where dose adjustments may be required. Warning signs of hypoglycaemia may be changed, less pronounced or absent in certain risk groups, potentially resulting in severe hypoglycaemia and loss of consciousness. Risk groups include patients in whom glycaemic control is markedly improved, hypoglycaemia develops gradually, an autonomic neuropathy is present, or who are elderly. The prolonged effect of subcutaneous insulin glargine may delay recovery from hypoglycaemia. Intercurrent illness: Requires intensified metabolic monitoring and often it is necessary to adjust the insulin dose. Insulin antibodies: administration may cause insulin antibodies to form. Use with pioglitazone: Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for development of cardiac heart failure. If the combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs. Medication errors: Insulin labels must always be checked before each injection to avoid errors between Toujeo and other insulins. Patients must be instructed to never use a syringe to remove Toujeo from the SoloStar or DoubleStar pre-filled pen, A new sterile needle must be attached before each injection. Needles must not be re-used. Pregnancy and lactation: There is no data from exposed pregnancies in controlled clinical trials. However, there is a large amount of data on use of insulin glargine 100 units/ml in pregnant women indicating no specific adverse effects on pregnancy and no specific malformative nor feto/neonatal toxicity. The use of Toujeo may be considered during pregnancy, if clinically needed. Careful monitoring of glucose control is essential. It is unknown if insulin glargine is excreted in breast milk. Interactions: Substances that affect glucose metabolism may require adjustment of insulin glargine. Adverse Reactions: Very common: Hypoglycaemia. Prolonged or severe hypoglycaemia may be life-threatening. Common: Lipohypertrophy, injection site reactions, including redness, pain, itching, hives, swelling, or inflammation. Legal Category: POM. Marketing Authorisation Number: SoloStar 3 Pen pack: EU/1/00/133/034, DoubleStar EU/1/00/133/038. Marketing Authorisation Holder: Sanofi Aventis Deutschland GmbH, D-65926 Frankfurt am Main, Germany. Further information is available from: Medical Information, Sanofi 18 Riverwalk, Citywest Business Campus, Dublin 24 or contact IEmedinfo@sanofi.com. Date of preparation: July 2020.

Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie; email: medsafety@hpra.ie Adverse events should also be reported to Sanofi Ireland Ltd. Tel: 01 403 5600.

Alternatively, send via email to IEPharmacovigilance@sanofi.com

Diabetes 21

Budget 2022: Actions Identified for Diabetes Care Diabetes Ireland has launched its Pre-budget submission and is proposing eight immediate actions which will improve the quality of life for over 225,000 people living with diabetes and reduce the long-term costs of preventable diabetes complications.

Speaking at the launch, Professor Hilary Hoey, Chairperson of Diabetes Ireland said, “The submission is focused on a range of deliverable actions that are person-centred, cost effective and builds on existing HSE commitments to tackle chronic conditions including diabetes.”

With an average of 12-13,000 new diagnoses of diabetes annually, the prevalence of diabetes is increasing at an alarming rate. However, without a National Diabetes Register clinicians are unable to accurately measure clinical outcomes, track prevalence rates at a geographical level or enhance diabetes services where there is most need.

This has resulted in inequity of care based on a person’s postal address. A Slaintecare project was paused as a result of Covid 19 and an immediate action the government can take is to restart this project immediately. We are also concerned that the funding for diabetes posts outlined in the HSE’s Winter Plan 2021 will not be made available so we are seeking confirmation that the funding will be made available and that the posts are filled urgently.

Diabetes Ireland is also seeking the removal of the age restriction

Cormac Devlin TD, Chair of the Cross Parliamentary Group on Diabetes & Diabetes Ireland Chairperson, Professor Hilary Hoey

on the Flash Glucose Monitoring system, the Freestyle Libre.

“This has been a major issue for the past 3 years, and we are simply looking for adults to be able to access the technology based on clinical need. There is a substantial body of clinical evidence demonstrating that the technology improves clinical outcomes for people with diabetes who intensively use insulin as it allows users to see a more comprehensive profile of their blood glucose levels and make more informed diabetes management decisions on a daily basis” added Prof Hoey.

Cormac Devlin TD, Chair of the Cross Parliamentary Group on Diabetes, added, “With more than 225,000 people living with diabetes in Ireland and numbers increasing every year, these actions, identified by both people with diabetes and diabetes healthcare professionals, can easily be delivered and we are calling on the Minister for Health to allocate appropriate funding for them in the upcoming budget.

“In February 2021, the HSE Medicines Management Programme (MMP) completed an evaluation to identify preferred blood glucose test strips for adults with type 1 and type 2 diabetes

mellitus, as part of the MMP’s remit to support safe, effective, and cost-effective prescribing and launched new guidelines for healthcare professionals.

Diabetes Ireland estimates that

around ¤8-10m will be saved this year alone with similar or higher savings in future years. Our Cross Parliamentary Group is looking for these savings to be ringfenced for diabetes care.”

Type Diabetes and Physical Activity Physical activity (PA) is known to reduce cardiovascular disease risk (CVD) among patients with type 1 diabetes. Guidelines recommend that adults with type 1 diabetes should engage in at least 150 minutes of moderateto-vigorous-intensity PA per day.

Accurate information on activity levels is limited however with possibly inaccurate self-reporting measures being employed rather than objective data collection via electronic devices.

Researchers from Trinity College Dublin at Tallaght University Hospital have studied how well patients with type 1 diabetes in Ireland comply with PA guidelines, and what the barriers

to compliance are. The study examined PA among a broad range of participants with type 1 diabetes and looked at the association between PA and CVD risk factors.

The findings suggest that patients overestimate their activity levels using self-reported measures, with only one third of patients actually meeting the PA guidelines when activity levels were measured using an accelerometer. The fear of developing exercise-induced hypoglycaemia was the strongest barrier to exercise for patients with Type 1 diabetes.

The research team assessed adherence to PA guidelines using both objective and subjective measures. Physical activity was

measured objectively over seven days in 72 participants using an Actigraph accelerometer, and subjectively using the International Physical Activity Questionnaire (IPAQ). Perceived barriers to activity were assessed using the Barriers to Physical Activity in Diabetes scale. Researchers also determined the influence of physical activity on HbA1c (a common measure of diabetes control) as well as risk factors for cardiovascular disease.

• Exercise was positively correlated with body mass index (BMI), waist circumference, body fat and HbA1c (blood glucose levels), highlighting the importance of PA among this group.

Key Findings:

• Diabetes-specific barriers do exist, specifically fear of hypoglycaemia, which result in poor uptake of exercise among this group.

• The majority of participants with type 1 diabetes failed to meet PA recommendations.

• Overestimation in PA is a serious concern, as it almost certainly results in individuals not getting sufficient exercise and therefore not realizing the associated improvements in CVD risk factors.

HOSPITALPROFESSIONALNEWS.IE | HPN • NOVEMBER - 2021

MORE PATIENTS CAN DO IT WITH THEIR PHONES1

Digital health tools that work together for seamless diabetes management

Healthcare providers have secure, online access to glucose insights2

Caregivers can remotely monitor their loved ones4 People with diabetes can conveniently check their glucose using their phone1,3

For more information visit www.FreeStyleDiabetes.ie Images are for illustrative purposes only. Not actual patient or data.

1. The FreeStyle LibreLink app is only compatible with certain mobile devices and operating systems. Please check the website for more information about device compatibility before using the app. Use of FreeStyle LibreLink requires registration with LibreView. 2. The LibreView website is only compatible with certain operating systems and browsers. Please check www.LibreView.com for additional information. 3. The FreeStyle LibreLink app and the FreeStyle Libre reader have similar but not identical features. Finger pricks are required if readings do not match symptoms or expectations. The FreeStyle Libre sensor communicates with the FreeStyle Libre reader that started it or the FreeStyle LibreLink app that started it. A sensor started by the FreeStyle Libre reader will also communicate with the FreeStyle LibreLink app. 4. The LibreLinkUp app is only compatible with certain mobile device and operating systems. Please check www.LibreLinkUp.com for more information about device compatibility before using the app. Use of LibreLinkUp and FreeStyle LibreLink requires registration with LibreView. The LibreLinkUp mobile app is not intended to be a primary glucose monitor: home users must consult their primary device(s) and consult a healthcare professional before making any medical interpretation and therapy adjustments from the information provided by the app. © 2021 Abbott. FreeStyle, Libre, and related brand marks are marks of Abbott. ADC-37632 v1.0 04/21.

Diabetes 23

Ground-Breaking Diabetes Research at EASD 2021 As Hospital Professional News was going to print, the European Association for the Study of Diabetes annual congress was taking place. This was the 57th Annual Meeting of EASD and was held virtually.

The age at diagnosis of type 1 diabetes has decreased substantially across successive generations, study findings presented at the event show.

Kathleen Gillespie, from the University of Bristol in the UK, and team used data from the Bart’s Oxford family study to investigate changes in age at onset among 264 child and parent pairs who all had type 1 diabetes. The study has been registering people with diabetes diagnosed before age 21 years, and their families, since 1985.

The researchers found that the children with diabetes were significantly younger than their parents when they were diagnosed, at a median of 9.5 versus 21.3 years, and a mean difference of 13.5 years.

However, to address the fact that “by definition parents are going to be older than their children,” the investigators repeated the analysis for 137 child and parent pairs with diabetes who were all diagnosed before the age of 21 years.

In this case, the median age at diagnosis was still lower among the children than their parents, at 9.0 and 13.0 years, respectively.

Furthermore, 70% of children were younger than their parents when they were diagnosed, 3% were the same age, and 27% were older.

Gillespie also reported that the data reflects previously observed trends showing a difference in risk among children depending on whether their mother or father has diabetes.

Precision Medicine - The Future?

Precision medicine is the practice of treating each patient with the best possible therapy. This presentation by Dr Miriam S. Udler from the Massachusetts General Hospital discussed how management of diabetes has already made great strides towards Precision Medicine over the past few years, shifting from a onesize-fits-all treatment approach to more nuanced algorithms for type 2 and autoimmune diabetes that take into account patient co-morbidities and biomarker levels. Nevertheless, management of all forms of diabetes still

focuses primarily on treating hyperglycaemia – a final endpoint of disease – rather than on treating the causal mechanisms underlying it. As a result of focusing on the symptom rather than the cause of disease, we are rarely able to “cure” diabetes in patients, and in fact usually see worsening betacell deterioration over time despite our best efforts.

“Providers are already striving to deliver Precision Medicine using existing professional society-based management algorithms,” says Dr. Udler who continued, “The debate is not whether Precision Medicine is the future of diabetes medicine, but rather how management can continue to improve and become more individualized in a practical, cost-effective manner.”

In particular, the causal pathways leading to type 2 diabetes are not well-understood, especially at the individual patient level.

Recent research efforts describing potential clinical and genetic subtypes of type 2 diabetes provide key insights into disease pathways. Elucidation of these pathways causing diabetes opens the opportunity for development of novel therapeutics that modify or prevent disease rather than simply providing stopgaps for hyperglycaemia. At the individual patient level, additional research is needed to determine whether placing patients into subcategories or using biomarkers to direct treatment choices offers practical clinical benefit.

The answer to these questions may ultimately depend on the landscape of therapies available.

Dr. Udler concluded, “It is becoming clear across all areas of medicine that the future of patient care is targeting underlying mechanisms of disease rather than correcting symptoms.

Unravelling the causal pathways of diabetes and connecting such pathways back to individual patients will likely be necessary to realise the full potential of Precision Medicine.”

Improving Diabetes Control Dr John Dennis, Senior Independent Research Fellow at the University of Exeter Medical School, focused on how clinicians can match people with type 2 diabetes to the right drug for them to improve control of blood sugar and help avoid damaging side-effects, simply by factoring in characteristics such as BMI and kidney function into prescribing decisions.

Metformin is the first line of drug treatment in type 2 diabetes, but many patients will eventually need additional drugs on top of metformin to lower their blood sugar levels. Currently, clinicians have to make prescribing decisions on these additional drug options based on limited available guidance. This means which drugs are prescribed to which patients varies enormously, both within and between countries.

Dr Dennis presented research, led by the University of Exeter, which uses big data to show that a ‘precision medicine’ approach using a person's specific clinical or biomarker characteristics, can

optimise choice of treatment. He demonstrated how this approach is more useful to clinicians than recent attempts to subclassify people with type 2 diabetes into subtypes. Uniquely, the Exeter approach is based on clinical blood tests that doctors measure routinely in their patients. This means it can be integrated into clinical practice at very low cost.

“This Exeter-led research is important as it provides the first concrete evidence that personalised or ‘precision’ medicine approaches in diabetes can be based on simple patient characteristics available to any doctor, rather than expensive genetics or other technology,” stated Dr Dennis. “We are using big data on millions of patients to develop our precision medicine approach, and big data is also making it possible to systematically test how useful the approach is for clinicians and patients.”

Dr. Dennis concluded, “Using a person’s specific characteristics to match them to their most effective medication for them will be a major advance in type 2 diabetes care. Recent progress in precision medicine means has there is now clear potential to move away from the current one-size-fitsall approach to type 2 diabetes treatment in the near future.”

The December issue of Hospital Professional News will give a further insight into some of the presentations which took place.

HOSPITALPROFESSIONALNEWS.IE | HPN • NOVEMBER - 2021

24 News

Tallaght Recognise their Heroes Service Excellence – Damien O’Connor, Facility Officer, Trinity Education Centre

Tallaght University Hospital (TUH) recently held their 4th annual Hero Awards where individual staff and teams are recognised for the incredible difference they have made to patients, their families and to their colleagues.

Chief Executive of TUH Lucy Nugent said, “The Covid-19 Pandemic has presented us all both professionally and personally with enormous challenges. No one could ever have envisaged the changes we would have undergone in providing care to our patients or how our own lives would alter.

Every single person working across the Hospital has had to adapt and this has been done with incredible spirit, compassion and dedication, always putting the patient and their families first. I would like to congratulate all of the award recipients and thank them for the incredible energy and commitment they bring to the Hospital.”

Also commenting on the awards, Director of HR at TUH, Sharon Larkin added, “In addition to the Covid Pandemic this year our staff also faced the challenges brought by the cyber-attack.

Today, in addition to the Hero Awards, we presented a specially commissioned medal on behalf of the Hospital Management team and Medical Board. This medal is a symbolic gesture to recognise the incredible TUH team effort that staff across every service and discipline have made to our patients and one another during the most challenging of times. It is a symbol for us all to have to remember what we have achieved and overcome in the last 18 months.”

2021 TUH HERO AWARD CATEGORIES AND WINNERS Patient Experience – Dr Marianne Foley, Junior Doctor This category is open to our community to nominate an individual/team who for that patient demonstrated the finer ideals of caring through extraordinary service to a patient and / or their family, ‘an exceptional patient experience.’ Dr Foley was nominated by the daughter of a one of our patients in her submission she said ‘Marianne has been absolutely outstanding in her care and dedication to my Dad. Her communication and regular updates to both my Dad and us, his family has been amazing and we would be lost without her assistance. She shows such

This award is for a staff member who provides an outstanding service to patients or staff within our Hospital.

“Damian treats all of his colleagues with the same respect regardless of grade or job role. He is always there to help just when you need him and will always go above and beyond for everything and everyone who asks for assistance with the most brilliant smile on his face.”

Dr Marianne Foley, Junior Doctor

Ann Creaven, Outpatient Department Manager

compassion towards Dad and makes him feel important not just another ‘random patient.”

Unsung Hero – Ann Creaven, Outpatient Department Manager

People Caring for People – Susan Graydon & Audrey Francis, Patient Food Services, Catering Department

This award is for a staff member who demonstrates exceptional service to the organisation. Ann was an extremely popular nominee for this award by a number of colleagues.

This category is for a staff member who exemplifies the core values of TUH. This year the award is being presented jointly to Susan and Audrey who were nominated by other colleagues following the sudden illness and death of a colleague. Our colleague suddenly became ill while at work, in the nomination their colleagues said: “Susan and Audrey could not have done a better job supporting, caring and watching over our colleague when they became ill suddenly at work. They followed this care and compassion through to the family and friends of their colleague demonstrating how people care for one another at TUH.”

“Ann at all times embodies the spirit of the Hospital, while her core responsibility is to the Out Patients Department she will always help and assist anyone. She has extraordinary vision for planning the outpatient clinics. During the last year, like so many staff she stepped up and was involved in the co-ordination of the COVID Vaccination clinics and led on the restoration of the iPMS database which is so essential to the running of the Hospital following the cyberattack on the healthcare system.”

Mentoring Award – Nicola Lowry, Senior Enhanced Nurse, Lane Ward This category is for a staff member who demonstrates outstanding teaching skills and serves as a role model and mentor to their colleagues.

“Nicola is an incredible nurse demonstrating empathy, compassion, skill and knowledge in her work whilst also having the time and patience to guide and teach. Nicola works hard in her role as a nurse, educator and role model. She is approachable, kind, intelligent and so very modest!”

Maria McArdle CNM2 Discharge Planning Teamwork Award Maria McArdle CNM2 Discharge Planning This award is for a valued team player that will always ask how they can help.

Susan Graydon & Audrey Francis, Patient Food Services, Catering Department

NOVEMBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

Damien O’Connor, Facility Officer, Trinity Education Centre

“Maria liaises closely with the Social Workers and is always keenly aware of the relevant issues with our complex and

25 together in a number of days and put in place a process to safely and efficiently vaccinate TUH and CHO7 staff. All the staff involved in the Clinic made themselves available with a great generosity of spirt working long hours and at weekends.”

CEO Awards There were two further awards nominated by the Chief Executive on behalf of herself and the management team recognising individuals that go above and beyond, often behind the scenes that may not be evident to all staff.

The first recipient for this award is the ICT Department. When people think of a hospital the first people apart from the patients are the medical / clinical staff that deliver care to the patient. In order to do this we need our technology to work and the ICT team in the last 18 months have demonstrated incredible innovation, commitment and energy.

The arrival of Covid-19 and the subsequent cyber-attack on our systems presented enormous challenges to the Hospital and how it could continue with patient care during some extremely challenging times.

delayed patients. She always has time to listen and work with the multi-disciplinary team to resolve complex issues. She takes that extra step with Management and Doctors where Social Workers may not be in a position to liaise directly. She is respectful and extremely diligent in her work and has excellent communication skills”

Team of the Year – Covid-19 Vaccination Team This category is for a new or established team that demonstrate excellence in teamwork. The Covid-19 vaccination team is a team involving over 70 staff from many different disciplines and departments across the Hospital,

the team received a number of nominations from colleagues across the Hospital.

During the constant - and sometimes seemingly never ending challenges we have faced in the last 18 months - this team have has responded to every challenge with energy and commitment in finding and implementing a solution embodying the Hospital’s CARE values of Collaborate, Achieve, Respect and Equity. They have done this whilst also ensuring that the new service areas such as the Vartry Renal Unit and the Reeves Day Surgery Centre were ready to open and deal with the day to day ICT requirements of a very busy hospital.

“The TUH Vaccination Team are the most wonderful group of professionals, who with very short notice implemented a wide ranging vaccination programme for both staff and patients. The team came

The second recipient was, Mr John O’Byrne, Acting Head of the Pharmacy Department, John is a long standing valued member of the Pharmacy team but also in the wider hospital team.

Improvement in Heart Failure waiting lists The Minister for Health Stephen Donnelly TD has welcomed the news that a new service, funded

by Sláintecare, providing heart failure diagnostics and care in the community, has reduced waiting lists from 6 weeks to six months.

Galway University Hospital is running the community-based service with Primary Care Centres in Tuam, Gort, Claremorris and

Galway City. The service allows patients to receive care closer to home in a Primary Care Centre.

GPs can refer their patients with suspected Heart Failure directly to the service for tests and diagnosis, making it easier for patients to access routine care related to their heart condition.

• Over 1,000 patients have received diagnostic tests through the service;

Recent results from the service show that:

• 55% had appointments in 2 weeks or less.

• 88% of patients of the service have come through a GP referral; • 89% of patients received tests within 6 weeks of referral;

• This is compared to common wait-times of up to 33 weeks for the hospital service.

Minister Donnelly said, “Sláintecare is transforming our health and social care services for both patients and healthcare workers across the country. I am delighted to see that both patients and GPs are delighted with the service with 95% of patients saying they were satisfied or very satisfied with the service.”

HOSPITALPROFESSIONALNEWS.IE | HPN • NOVEMBER - 2021

ZINFORO® (ceftaroline fosamil)

A smart choice to treat patients when there’s no time to wait ZINFORO® is indicated for the treatment of CAP and cSSTI in adults, children and neonates from birth1

Extended Gram-negative and Gram-positive pathogen coverage*

Rapid, proven efficacy in the treatment of patients with CAP and cSSTI

Simple dosing and a flexible 5–60 minute infusion time for most patients†

Including Streptococcus pneumoniae and MRSA in CAP and cSSTI respectively1–3

High clinical cure rates and rapid response at Day 4 in CAP and Day 3 in cSSTI2–5

No dosage adjustment required for those with hepatic or mild renal impairment; dosage adjustment required for patients with moderate or severe impairment (CrCI ≤50 mL/min).

Infusion time of less than 60 minutes not suitable for high dose, neonates < 2months and may not be suitable for supranormal renal clearance

Consideration should be given to the official guidance on the appropriate use of antibacterial agents. Organisms that are resistant to ZINFORO® can occur at variable rates between countries and between healthcare facilities within countries. If ZINFORO® is commenced before susceptibility test results are available, then local information on the risk of encountering resistant organisms should be taken into consideration. *Efficacy has been demonstrated in CAP clinical studies against the following pathogens that were susceptible to ZINFORO® in vitro: Streptococcus pneumoniae, Staphylococcus aureus (methicillin-susceptible strains only), Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae and Klebsiella pneumoniae. Efficacy has been demonstrated in cSSTI clinical studies against the following pathogens that were susceptible to ZINFORO® in vitro: Staphylococcus aureus (including methicillin-resistant strains), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus anginosus group, Streptococcus dysgalactiae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca and Morganella morganii.1 † Infusion times of < 60 minutes are based on PK/PD (pharmacokinetic/pharmacodynamics) analyses only. Applies only for standard dose regimens in adults and children from 2 months of age, including patients with renal impairment.

Abbreviations: CAP: community acquired pneumonia; cSSTI: complicated skin and soft-tissue infections; MRSA: methicillin-resistant Staphylococcus aureus.

References: 1. ZINFORO® (ceftaroline fosamil) Summary of Product Characteristics. Pfizer Jan 2021; 2. File TM, et al. Clin Infect Dis 2010;51:1395–405; 3. Corey G, et al. Clin Infect Dis 2010;51:641–50; 4. Friedland D, et al. Antimicrob Agents Chemother 2012;56:2231–6; 5. Eckburg P, et al. Infect Dis Clin Pract 2012;20:254–60.

ABBREVIATED PRESCRIBING INFORMATION ZINFORO® 600mg (ceftaroline fosamil) POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION Prescribing Information: Please refer to the Summary of Product Characteristics (SmPC) before prescribing Zinforo. Indications: Zinforo is indicated for treatment of complicated skin and soft tissue infections (cSSTI) and community-acquired pneumonia (CAP) in neonates, infants, children, adolescents and adults.

Consideration should be given to official guidance on the appropriate use of antibacterial agents. Presentation: 600mg ceftaroline fosamil powder for concentrate for solution for infusion containing 600mg ceftaroline fosamil. After reconstitution, 1ml of solution contains 30mg of ceftaroline fosamil. Dosage and administration: Zinforo is administered by intravenous infusion over 5 to 60 mins for standard dose or 120 minutes for high dose (for cSSTI caused by S. aureus with MIC of 2 or 4 mg/L to ceftaroline) in infusion volumes of 50mL, 100mL or 250mL. Please consult SmPC for further information. Infusion volumes for paediatric patients will vary according to weight of child. The infusion solution concentration should not exceed 12mg/ml ceftaroline fosamil. The recommended intravenous dose for adults and adolescents aged from 12 to < 18 years with bodyweight ≥ 33kg with creatinine clearance (CrCL) > 50mL/min is 600mg every 12 hours over 5 to 60 minutes. Based on pharmacokinetic (PK) and pharmacodynamic (PD) analyses the recommended dose for treatment of cSSTI due to S. aureus for which ceftaroline MIC is 2 or 4 mg/L is 600 mg every 8 hours using 2-hour infusions. The recommended dose in children ≥ 2 years to < 12 years and adolescents aged from ≥ 12 years to < 18 years with bodyweight < 33kg with CrCL > 50mL/min is 12mg/kg every 8 hours over 5 to 60 minutes. The dose administered should not exceed 400mg. For infants aged ≥ 2 months to < 2 years with CrCL > 50mL/min, the recommended dose is 8mg/kg every 8 hours over 5 to 60 minutes. For neonates from birth to < 2 months CrCL > 50mL/min, the recommended dose is 6mg/kg every 8 hours over 60 minutes. The dose recommendations are applicable to treatment of S.aureus for which the ceftaroline MIC is ≤ 1 mg/L. Duration of treatment for cSSTI is 5-14 days and for CAP is 5-7 days. Special populations: Elderly: No dose adjustment required with CrCL values > 50mL/min. Renal impairment: The dose should be adjusted when creatinine clearance is ≤ 50 ml/min. The recommended durations of treatment are the same as for patients with CrCL > 50mL/min. The recommended dose for adults and adolescents aged from 12 to < 18 years with bodyweight ≥ 33kg for cSSTI and CAP with CrCL > 30 to ≤ 50 is 400mg every 12 hours over 5 to 60 minutes. For CrCL ≥ 15 to ≤ 30, the recommended dose is 300mg every 12 hours over 5 to 60 minutes. For end-stage renal disease (ESRD) including haemodialysis, the recommended dose is 200mg every 12 hours over 5 to 60 minutes. Please consult SmPC for further information. Based on PK and PD analyses the recommended dose for treatment of cSSTI due to S. aureus for which the ceftaroline MIC is 2 or 4 mg/L is the dose recommended by renal function category administered every 8 hours using 2 hour infusions. Please consult SmPC for further information. The recommended dose for children aged from 2 to < 12 years and adolescents aged from 12 to < 18 years with bodyweight < 33kg with CrCL > 30 to ≤ 50 is 8mg/kg every 8 hours over 5 to 60 minutes. The dose admininstered should not exceed 300mg. For CrCL ≥ 15 to ≤ 30, for children aged from 2 to < 12 years and adolescents aged from 12 to < 18 years with bodyweight < 33kg, the recommended dose is 6mg/kg every 8 hours over 5 to 60 minutes. The dose administered should not exceed 200mg.

For CrCL > 30 to ≤ 50, for children and adolescents aged from > 2 to < 18 years the recommended dose is 10mg/kg every 8 hours over 120 minutes.

The dose administered should not exceed 400mg.For CrCL ≥ 15 to ≤ 30, for children and adolescents aged from > 2 to < 18 years the recommended dose is 8mg/kg every 8 hours over 120 minutes. The dose administered should not exceed 300mg. The dose recommendations are applicable to treatment of S. aureus for which the ceftaroline MIC is ≤ 1 mg/L. For ESRD, there is insufficient information to recommend dosage adjustments in adolescents aged from 12 to < 18 years with bodyweight < 33kg and in children aged from 2 to 12 years. There is insufficient information to recommend dosage adjustments in children aged from 2 months to < 2 years with moderate or severe renal impairment or ESRD. Hepatic impairment: No dose adjustment necessary. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Hypersensitivity to the cephalosporin class of antibacterials. Immediate and severe hypersensitivity (e.g. anaphylactic reaction) to any other type of beta-lactam antibacterial agent (e.g. penicillins or carbapenems). Warnings and precautions: Hypersensitivity reactions: Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalised exanthematous pustulosis (AGEP) have been reported in association with beta-lactam antibiotics (including cephalosporins) treatment. Patients who have a history of hypersensitivity to cephalosporins, penicillins or other beta-lactam antibacterials may also be hypersensitive to ceftaroline fosamil.

Zinforo should be used with caution in patients with a history of non-severe hypersensitivity reactions to any other beta- lactam antibiotics (e.g. penicillins or carbapenems). If a severe allergic reaction or SCAR with Zinforo occurs, discontinue use and take appropriate measures. Clostridium difficile-associated diarrhoea: Antibacterial-associated colitis and pseudomembranous colitis have been reported and may range from mild to life threatening. Therefore, it is important to consider this diagnosis in patients with diarrhoea during or subsequent to the administration of ceftaroline fosamil. In such circumstance, consider discontinuation of therapy and use supportive measures together with the administration of specific treatment for Clostridium difficile.

Non-susceptible organisms: Superinfections may occur during or following treatment with Zinforo. Patients with pre-existing seizure disorder: Use with caution in this patient population. Direct antiglobulin test (Coombs test) seroconversion and potential risk of haemolytic anaemia: A positive direct antiglobulin test (DAGT) may occur during treatment with cephalosporins and the possibility that haemolytic anaemia may occur cannot be ruled out. Patients experiencing anaemia during or after treatment with Zinforo should be investigated for this possibility. Limitations of clinical data: No experience with ceftaroline in treatment of CAP in the following patient groups: the immunocompromised, patients with severe sepsis/septic shock, severe underlying lung disease (e.g. cystic fibrosis, see section 5.2), those with PORT Risk Class V, and/or CAP requiring ventilation at presentation, CAP due to methicillin-resistant S. aureus or patients requiring intensive care. Caution advised when treating such patients. No experience with ceftaroline in treatment of cSSTI in the following patient groups: the immunocompromised, patients with severe sepsis/septic shock, necrotizing fasciitis, perirectal abscess and patients with third degree and extensive burns. Limited experience in treating patients with diabetic foot infections. Caution advised when treating such patients. Limited data on use of ceftaroline to treat cSSTI caused by S. aureus with an MIC of > 1mg/mL.

The recommended dosages of Zinforo for the treatment of cSSTI caused by S. aureus with ceftaroline MIC of 2 or 4 mg/L are based on PK-PD modelling and simulation.

Zinforo should not be used to treat cSSTI due to S. aureus for which ceftaroline MIC is > 4mg/mL. Limitations of clinical data: No experience with ceftaroline in treatment of CAP in the following patient groups: the immunocompromised, patients with severe sepsis/septic shock, severe underlying lung disease (e.g. cystic fibrosis, see section 5.2), those with PORT Risk Class V, and/or CAP requiring ventilation at presentation, CAP due to methicillin-resistant S. aureus or patients requiring intensive care. Caution advised when treating such patients. No experience with ceftaroline in treatment of cSSTI in the following patient groups: the immunocompromised, patients with severe sepsis/septic shock, necrotizing fasciitis, perirectal abscess and patients with third degree and extensive burns. Limited experience in treating patients with diabetic foot infections. Caution advised when treating such patients. Limited data on use of ceftaroline to treat cSSTI caused by S. aureus with an MIC of > 1mg/mL. The recommended dosages of Zinforo for the treatment of cSSTI caused by S. aureus with ceftaroline MIC of 2 or 4 mg/L are based on PK-PD modelling and simulation. Zinforo should not be used to treat cSSTI due to S. aureus for which ceftaroline MIC is > 4mg/ mL.Drug interactions: Co -administered CYP450 inducers or inhibitors are unlikely to influence the pharmacokinetics of ceftaroline. Interactions with substrates or inhibitors (e.g. probenecid) of renal uptake transporters (OCT2, OAT1 and OAT3) would not be expected. Pregnancy and lactation: Avoid using during pregnancy unless the clinical condition of the woman requires treatment.

Unknown whether ceftaroline fosamil or ceftaroline is excreted in human milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Zinforo therapy taking into account the benefit of therapy for the woman. Ability to drive and use machines: Dizziness may occur. Undesirable events: Consult SmPC for full list of side effects. Very Common: Coombs direct test positive. Common: Rash, pruritus, headache, dizziness, phlebitis, diarrhoea, nausea, vomiting, abdominal pain, increased transaminases, pyrexia, infusion site reactions (erythema, phlebitis, pain). Uncommon: Clostridium difficile colitis, anaemia, leucopenia, neutropenia, thrombocytopenia, prothrombin time (PT) prolonged, activated partial thromboplastin time (aPTT) prolonged, international normalised ratio (INR) increased, anaphylaxis, hypersensitivity (e.g.urticaria, lip and face swelling), encephalopathy, blood creatinine increased.

Rare: Agranulocytosis, Eosinophilia. Paediatric safety profile was similar to that observed in adults. Legal category: S1A. Marketing Authorisation number: ZINFORO 600 mg powder for concentrate for solution for infusion (20 mL vial), supplied in packs of 10 vials. EU/1/12/785/001. Marketing Authorisation Holder: Pfizer Ireland Pharmaceuticals, Operations Support Group, Ringaskiddy, County Cork, Ireland.Distributed by: Pfizer Healthcare Ireland, 9 Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24 For further information on this medicine please contact: Pfizer Medical Information on 1800 633 363 or at medical.information@pfizer.com.

For queries regarding product availability please contact: Pfizer Healthcare Ireland, Pfizer Building 9, Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24 +35314676500.

Last revised: January 2021

Ref: ZI 9_0

PP-ZFO-IRL-0063 Date of Prep: September 2021

P. aeruginosa

ESBL-producing Enterobacterales

Carbapenem-resistant Enterobacterales

Ceftazidime- and carbapenem-resistant strains, AmpC-producing strains

Extended-spectrum β-lactamases and AmpC-producing strains

KPC and OXA-48

ZAVICEFTA has in vitro activity against pathogens producing AmpC, ESBM, KPC and OXA-48 enzymes.1 ZAVICEFTA’s range of in vitro activity against β-lactamases does not necessarily predict clinical success.1 ZAVICEFTA has no in vitro activity against pathogens producing class B metallo-β-lactamases and is not able to inhibit many class D enzymes.1

Therapeutic Indications1 ZAVICEFTA is indicated for the treatment of adult and paediatric patients aged 3 months and older with the following infections:1*

Complicated urinary tract infection (cUTI), including pyelonephritis

Complicated intra-abdominal infection (cIAI)

ZAVICEFTA is also indicated for the treatment of adult patients with bacteraemia that occurs in association with, or is suspected to be associated with, cUTI, cIAI or HAP/VAP

ABBREVIATED PRESCRIBING INFORMATION ZAVICEFTA® (ceftazidime and avibactam) 2g/0.5g powder for concentrate for solution for infusion. Prescribing Information: Please refer to the Summary of Product Characteristics (SmPC) before prescribing Zavicefta. Indications: Zavicefta is indicated in adults and paediatric patients aged 3 months and older for treatment of complicated intra-abdominal infection (cIAI), complicated urinary tract infection (cUTI), including pyelonephritis and hospital-acquired pneumonia (HAP), including ventilator associated pneumonia (VAP). Treatment of adult patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above. Also indicated for the treatment of infections due to aerobic Gram-negative organisms in adult patients and paediatric patients aged 3 months and older with limited treatment options. Consideration should be given to official guidance on the appropriate use of antibacterial agents. Presentation: 2g ceftazidime (as ceftazidime pentahydrate) and 0.5g avibactam (as avibactam sodium) powder for concentrate for solution for infusion. After reconstitution, 1mL of solution contains 167.3mg of ceftazidime and 41.8mg of avibactam. Dosage and administration: Zavicefta is administered by intravenous infusion over 120 minutes in an appropriate infusion volume(see section 6.6 of SPC). The recommended intravenous dose for adult patients with estimated creatinine clearance (CrCL) ≥ 51mL/min is 2g ceftazidime and 0.5g avibactam every 8 hours, for a duration of 5 to 14 days for complicated IAI, 5-10 days for complicated UTI including pyelonephritis and 7-14 days for Hospitalacquired pneumonia, including VAP. For infections due to aerobic Gram-negative organisms in patients with limited treatment options, duration of treatment should be guided by the severity of infection, pathogen and patient’s clinical and bacteriological progress. Duration of treatment for patients with bacteraemia that occurs in association with, or is suspected to be associated with, any of the infections listed above should be in accordance with the site of infection. Recommended dose for paediatric patients with estimated CrCL1 > 50 mL/min/1.73 m2: age group 6 months to <18 years CrCL 50 mg/kg/12.5 mg/kg to a maximum of 2 g/0.5 g, every 8 hours. Age group 3 months to <6 months CrCL 40 mg/kg/10 mg/kg, every 8 hours. Recommended treatment duration for paediatric patients: 5 to 14 days for complicated IAI, 5-14 days for complicated UTI including pyelonephritis and 7-14 days for Hospital-acquired pneumonia, including VAP. For infections due to aerobic Gram-negative organisms in patients with limited treatment options, duration of treatment should be guided by the severity of infection, pathogen and patient’s clinical and bacteriological progress. There is limited experience with the use of Zavicefta in paediatric patients 3 months to < 6 months (see section 5.2 of SPC). Special populations: Elderly: No dose adjustment required. Renal impairment: Mild (estimated CrCL ≥ 51 - ≤ 80mL/min): No dose adjustment. CrCL 31-50mL/ min (estimated): 1g ceftazidime and 0.25g avibactam, every 8 hours. CrCL 16-30mL/ min (estimated): 0.75g ceftazidime and 0.1875g avibactam, every 12 hours. CrCL 6-15mL/ min (estimated): 0.75g ceftazidime and 0.1875g avibactam, every 24 hours. ESRD including on haemodialysis: 0.75g ceftazidime and 0.1875g avibactam, every 48 hours. Dosage in paediatric patients aged 2 years to <18 years CrCL 31- 50mL/min (estimated): 25 mg/ kg/6.25 mg/kg to a maximum of 1 g/0.25 g, every 8 hours. CrCL 16-30mL/ min (estimated): 18.75 mg/kg/4.75 mg/kg to a maximum of 0.75 g/0.1875 g, every 12 hours.

CrCL 6-15mL/ min (estimated): 18.75 mg/kg/4.75 mg/kg to a maximum of 0.75 g/0.1875 g, every 24 hours. ESRD including on haemodialysis: 18.75 mg/kg/4.75 mg/kg to a maximum of 0.75 g/0.1875 g, every 48 hours. Dosage in paediatric patients <2 years of age with estimated CrCL ≤ 50 mL/min/1.73 m2 age group 3 to < 6 months CrCL 31-50mL/min (estimated): 20 mg/kg/5 mg/kg, every 8 hours. Age group 6 months to < 2 years CrCL 31-50mL/min (estimated): 25 mg/kg/6.25 mg/kg, every 8 hours. Age group 3 to < 6 months CrCL 16-30mL/min (estimated): 15 mg/kg/3.75 mg/kg, every 12 hours. Age group 6 months to < 2 years CrCL 16-30mL/min (estimated): 18.75 mg/ kg/4.7 mg/kg, every 12 hours. There is insufficient information to recommend a dosage regimen for paediatric patients < 2 years of age that have a CrCL < 16 mL/min/1.73 m2. Hepatic impairment: No dose adjustment required. Paediatric population: <3 months: The safety and efficacy of Zavicefta in paediatric patients < 3 months old have not been established. No data are available. Contraindications: Hypersensitivity to the active substances, any of the excipients or to any cephalosporin antibacterial agent.

Severe hypersensitivity (e.g. anaphylactic reaction, severe skin reaction) to any other type of β-lactam antibacterial agent (e.g. penicillins, monobactams or carbapenems).

Warnings and precautions: Hypersensitivity reactions: Treatment with Zavicefta must be discontinued immediately and adequate emergency measures must be initiated.

Before beginning treatment, it should be established whether the patient has a history of hypersensitivity reactions to ceftazidime, to other cephalosporins or to any other type of β-lactam antibacterial agent. Caution should be used if ceftazidime/avibactam is given to patients with a history of non-severe hypersensitivity to penicillins, monobactams or carbapenems. Clostridium difficile-associated diarrhoea: Discontinuation of Zavicefta and the administration of specific treatment for Clostridioides difficile should be considered in patients who present with diarrhoea during or subsequent to the administration of Zavicefta. Medicinal products that inhibit peristalsis should not be given. Renal References 1. ZAVICEFTA. Summary of Product Characteristics, 2021.

2. Tumbarello M, et al. Clin Infect Dis 2012;55:943–50.

3. Castón JJ, et al. Int J Infect Dis 2017;59:118–23.

4. van Duin D, et al. Clin Infect Dis 2018;66:163–71.

5. Sousa A, et al. J Antimicrob Chemother 2018;73:3170–5.

6. Temkin E, et al. Antimicrob Agents Chemother 2017;61:e01964-16.

7. Shields RK, et al. Antimicrob Agents Chemother 2017;61:e00883-17.

8. Tumbarello M, et al. Clin Infect Dis 2019;68:355-64.

Hospital-acquired pneumonia, including ventilator-associated pneumonia (HAP/VAP)

Infections due to aerobic Gramnegative organisms in patients with limited treatment options.†

* Consideration should be given to official guidance on the appropriate use of antibacterial agents.1 †

Data support the use of ZAVICEFTA in adult patients with limited treatment options for the treatment of bacteraemia (both primary and secondary), cSSTI, BJI, meningitis due to KPC and OXA-48 resistance mechanisms, and MD R Pseudomonas.2–8

impairment: Dose should be reduced according to the degree of renal impairment. Neurological sequelae, including tremor, myoclonus, non-convulsive status epilepticus, convulsion, encephalopathy and coma have occasionally been reported with ceftazidime when the dose has not been reduced in patients with renal impairment. Close monitoring of estimated creatinine clearance is advised. Nephrotoxicity: Concurrent treatment with high doses of cephalosporins and nephrotoxic medicinal products such as aminoglycosides or potent diuretics (e.g. furosemide) may adversely affect renal function. Direct antiglobulin test (DAGT or Coombs test) seroconversion and potential risk of haemolytic anaemia: Ceftazidime/avibactam use may cause development of a positive direct antiglobulin test, which may interfere with the cross-matching of blood and/or may cause drug induced immune haemolytic anaemia. Patients experiencing anaemia during or after treatment with Zavicefta should be investigated for this possibility.

Spectrum of activity: Ceftazidime has little or no activity against the majority of Gram-positive organisms and anaerobes. Additional antibacterial agents should be used when these pathogens are known or suspected to be contributing to the infectious process. The inhibitory spectrum of avibactam includes many of the enzymes that inactivate ceftazidime, including Ambler class A β lactamases and class C β-lactamases. Avibactam does not inhibit class B enzymes (metallo-β-lactamases) and is not able to inhibit many of the class D enzymes. Non-susceptible organisms: Prolonged use may result in the overgrowth of nonsusceptible organisms (e.g. enterococci, fungi), which may require interruption of treatment or other appropriate measures. Interference with laboratory tests: Ceftazidime may interfere with copper reduction methods (Benedict’s, Fehling’s, Clinitest) for detection of glycosuria leading to false positive results. Ceftazidime does not interfere with enzyme-based tests for glycosuria. Controlled sodium diet: Consideration should be given to patients who are on a controlled sodium diet. Zavicefta is considered high in sodium. Paediatric population: There is a potential risk of overdosing, particularly for paediatric patients aged from 3 to less than 12 months of age. Care should be taken when calculating the volume of administration of the dose (see sections 4.9 and 6.6).

Drug interactions: Co-administration with probenecid may affect elimination of avibactam and is therefore not recommended. Avibactam and ceftazidime do not inhibit the major renal or hepatic transporters in the clinically relevant exposure range, therefore the interaction potential via these mechanisms is considered to be low. No interaction between ceftazidime and avibactam, or between ceftazidime/avibactam and metronidazole have been demonstrated. Concurrent treatment with high doses cephalosporins and aminoglycosides or potent diuretics (e.g. furosemide) may adversely affect renal function. Chloramphenicol should be avoided, due to the possibility of antagonism in vivo.

Pregnancy and lactation: Zavicefta should only be used during pregnancy if the potential benefit outweighs the possible risk. Ceftazidime is excreted in human milk in small quantities. A risk to newborns/infants cannot be excluded. A decision must be made whether to discontinue breast feeding Ability to drive and use machines: Undesirable effects may occur (e.g. dizziness). Undesirable events: Very common: Coombs direct test positive. Common: Candidiasis (including vulvovaginal candidiasis and oral candidiasis), eosinophilia, thrombocytosis, thrombocytopenia, headache, dizziness, diarrhoea, abdominal pain, nausea, vomiting, alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, gamma-glutamyltransferase increased, blood lactate dehydrogenase increased, rash maculopapular, urticaria, pruritus, infusion site thrombosis, infusion site phlebitis, pyrexia. Uncommon: Clostridium difficile colitis, pseudomembranous colitis, neutropenia, leukopenia, lymphocytosis, paraesthesia, dysgeusia, blood creatinine and urea increased, acute kidney injury. Very rare: Tubulointerstitial nephritis. Unknown: Agranulocytosis, haemolytic anaemia, anaphylactic reaction, jaundice, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, angioedema, jaundice, drug reaction with eosinophilia and systemic symptoms (DRESS). Refer to SmPC for further information on side effects. Overdose: Overdose with ceftazidime/avibactam can lead to neurological sequelae including encephalopathy,convulsions and coma. Legal Category: S1A. Marketing Authorisation Number: EU/1/16/1109/001 - 2g/0.5g powder for concentrate for solution for infusion, 20 mL vial. Marketing Authorisation Holder: Pfizer Ireland Pharmaceuticals, Operations Support Group, Ringaskiddy, County Cork, Ireland. For full prescribing information see Summary of Product Characteristics. Last revised: February 2021. Ref: ZV 5_1 For further information on this medicine please contact: Pfizer Medical Information on 1800 633 363 or at EUMEDINFO@pfizer.com. For queries regarding product availability please contact: Pfizer Healthcare Ireland, Pfizer Building 9, Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24 + 353 1 467 6500.

Legal category: S1A. Further information available at www.medicines.ie Pfizer Healthcare Ireland, 9 Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24, Ireland.

PP-ZVA-IRL-0185 – Date of Preparation October 2021

28 Perspectives

The Environmental Challenge: The Role Hospital Professionals can Play Written by Dr Moriarty

NOVEMBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

The summer of 2021 will be remembered for a variety of difficult reasons. As the world was still tight in the grip of a global pandemic, an onslaught of environmental disasters struck. Particularly over the last 12 months, increasingly frequent extreme weather events shattered many communities with the resultant loss of life and displacement of thousands.

Hurricane Ida devastated much of the east coast of the USA causing unprecedented flooding. We saw

flooding destroy homes livelihood and even causing loss of life in Germany and Belgium.

Throughout Europe and North America temperatures soared causing an unprecedented heatwave and subsequent raging wildfires with the resultant loss of valuable homes, farmland, animals and crops not to mention the loss of endangered wildlife and vegetation. July set the record of the hottest month ever recorded.1 This followed an already record setting extremely cold winter.2 Over the past 50 years alone there has been a fivefold increase in the number of recorded weather-related disasters; the frequency and severity of which

29 are predicted to rise.3 With this pattern likely to continue extreme weather events will continue to decimate communities, leaving hundreds of thousands displaced and vulnerable.

The link between these extreme weather events and global warming is not a direct one, however scientists do agree that global warming is the cause behind the increasing severity and frequency of these events.

Furthermore, the theory of extreme event attribution looks at the patterns of extreme weather events and can link them to climate change.4 In 2015 world leaders met in Paris and agreed to curb the effects of global warming by limiting temperature rises to less than 2oC but with a preferable target of less than 1.5oC; however, global temperatures have already risen by 1.1-1.3oC.5

Current predictions, which include the policy agreed upon in the Paris Agreement 2015, show that by 2100 the world is likely to be 2.7oC warmer compared to pre-industrial times6. Even with our best efforts, it is likely that the target set out in 2015 will not be met. With the Intergovernmental Panel on Climate change due to meet this coming November, climate activists will anxiously be awaiting further reform and commitments by governments to stem the effects seen so far.

Carbon emissions account for a significant proportion of the factors attributed to climate change. The need to reduce these emissions has long been recognised as necessary by governments who continue to pledge carbon reductions. In Ireland we have pledged to be net carbon zero by 2050. It is now nearing the end of 2021 and we have yet to see any significant reduction in carbon emissions in Ireland, in fact Irelands greenhouse gas emissions increased by 10% between 1990 and 2019.7 The World Health Organisation has predicted that climate change will result in approximately 250,000 extra deaths between 2030 and 2050 as a result of heat exposure leading to subsequent malnutrition and vulnerability to diseases such as Malaria8. It is likely that this will have the greatest impact in countries where health systems are already under-developed.

Climate health inequality is not only subject to global variances but also generational inequality, the impact of global warming will be experience most by our younger and future generations. The United Nations Intergovernmental Panel on Climate Change highlights the disproportionate affect this has on children, calling for immediate action.9 The healthcare sector must recognise its roll in contributing to carbon emissions and commit to taking decisive action to reduce these. A recent study from the Lancet calculated the impact healthcare has on climate change at between 1 and 5% of the total burden; accounting for 4.4% of total greenhouse gas emissions.10 As the impact of these numbers are coming to the fore, sustainable healthcare is becoming a necessity.

At the Dermatology Department in St. Vincent’s University Hospital, we looked at the introduction of sustainable measures by providing same day surgery to patients attending outpatient skin cancer assessment clinics over a six-month period. Of the 299

patients enrolled, 75% opted to have surgery on the same day as their clinic appointment. Issues regarding anticoagulation and patient availability were factors in patients being offered surgery on an alternative day.

Not only did this intervention reduce the number of outpatient appointments it also led to a significant reduction in CO2 emissions. The total carbon saving resulting from the intervention was 55%; a carbon saving of 2.93 tonnes, or the equivalent saving of over 300 gallons of oil.11 Studies like this highlight the critical role individual health departments have in implementing change and policy. What may seem like small scale change to a department can contribute to the larger global effort to reduce carbon emissions. Consideration should also be given to the volume of non-recyclable plastic that is used within our health Service and measures that can be introduced to reduce this.

The Health Sustainability Office has recognised environmental sustainability as one of the five pillars of a sustainable health service, firmly placing its importance in the future development of our health care system.12 Defining the role of the individual in what is now a well-established global crises is extremely challenging, however no raindrop blames itself for the flood and small changes made by the individual can certainly being about a positive, often dramatic collective change. Although the world is becoming a far smaller place with ever increasing access to news and statistics; this can become overwhelming and alienating to those it is trying to motivate most. How is one individual going to change the course of a global warming crisis that has been ongoing since the industrial revolution?

The only answer is through individual change, which collectively makes all the difference. Change doesn’t have to be dramatic or life altering but simple everyday changes at home or in the work environment can make a significant difference to the fight against global warming. Over the past eighteen months we have seen how individual actions can supress a global pandemic, this demonstrates our global capacity for change and our ever increasing adaptability. In the Dermatology Department at St. Vincent’s we will continue and strive to implement innovative, creative and worthwhile change as our contribution to create a more sustainable future for all.

References 1. National Oceanic and Atmospheric Administration. Its official: july was the hottest month on record. [homepage on the Internet]. United States of America: National Oceanic and Atmospheric Administration; 2021 cited 2021 14/09/2021].

Available from: https://www.noaa. gov/news/its-official-july-2021-wasearths-hottest-month-on-record.

2. Zheng, F., Yuan, Y., Ding, Y. et al., 2021. The 2020/21 extremely cold winter in China influenced by the synergistic effect of La Niña and warm Arctic. Adv. Atmos. Sci. (2021).

3. World Meteorological Organisation.

Weather-related disasters increase over the past 50 years, causing more damage but fewer deaths. [homepage on the Internet]. The United States of America: World Meteorological Organisation; 2021 [updated 31/08/2021; cited 2021 14/9]. Available from: https://public. wmo.int/en/media/press-release/ weather-related-disasters-increaseover-past-50-years-causing-moredamage-fewer.

4. Bellprat O, Guemas V, Doblas-Reyes F, Donat MG. Towards reliable extreme weather and climate event attribution. Nature communications.

2019; 10(1):1-7.

5. The United Nations, 2015. The Paris Agreement. 1st ed. Paris: The United Nations.

6. Climate Action Tracker. The Climate Action Tracker. [homepage on the Internet]. The United States of America: New Climate Institute; 2021 cited 2021 24/08]. Available from: https://climateactiontracker.org/ about/.

7. Department of Transport, Tourism and Sport. Transport Trends 2019: An overview of Irelands Transport Sector. Ireland: Department of Transport,Tourism and Sport; 2019 8. World Health Organisation. Climate Change and Health. [homepage on the Internet]. World Health Organisation; 2018 cited 2021 10/08]. Available from: https://www. who.int/news-room/fact-sheets/ detail/climate-change-and-health.

9.

Schachtel A, Boos MD. Pediatric dermatology and climate change: An argument for the pediatric subspecialist as public health advocate. Pediatric dermatology.

2019; 36(4):564-566.

10. Lenzen M, Malik A, Li M, Fry J, Weisz H, Pichler P, et al. The environmental footprint of health care: a global assessment. The Lancet Planetary Health. 2020; 4(7):e271-e279.

11. Fleming, S., Drumm, Ciara., Lynch S., O' Donnell C., Lally, A., and Moriarty, B. The enviromental impact of skin cancer surgery. The 10th World Congress of Melanoma ed.

Italy: The European Association of Dermato Oncology; 2021.

12. Health Service Executive.

Sustainability Strategy for Health 2017--2019. [homepage on the Internet]. Ireland: National Health Sustainability Office; 2017 cited 2021 08/06]. Available from: https:// www.hse.ie/eng/about/who/ healthbusinessservices/nationalhealth-sustainability-office/files/ sustainability-strategy-for-health.pdf.

HOSPITALPROFESSIONALNEWS.IE | HPN • NOVEMBER - 2021

30 News

New National Clinical Guideline Recently, on World Sepsis Day, the Minister for Health, Stephen Donnelly TD, welcomed the publication of a new and fully updated National Clinical Guideline to help healthcare professionals recognise and treat sepsis and septic shock patients.

This initiative was led by a group from the Health Service Executive’s (HSE) National Clinical Programme on Sepsis and supported by the department’s Clinical Effectiveness Unit. The guideline was quality assured by the National Clinical Effectiveness Committee (NCEC).

The clinical guideline is based

on best research evidence and developed in line with international best practice.

Sepsis is a potentially lifethreatening complication of most common infections that can affect anyone, and which is frequently under-diagnosed at the early stages when it is potentially reversible. Prompt identification and treatment are vital.

Welcoming the publication of the guideline, the Chief Medical Officer, Dr Tony Holohan said, “Sepsis is a global public health crisis and a leading cause of preventable mortality, with

20% of all deaths worldwide associated with sepsis. Vigilance and rapid response saves lives and protects quality of life in survivors. It is gratifying that we have seen a 26.5% reduction in age-adjusted mortality in Ireland since 2011 and I commend the HSE National Sepsis Programme on this achievement.

“I greatly welcome this latest National Clinical Guideline, which was developed by a multi-disciplinary Guideline Development Group, led by Dr Vida Hamilton and supported by the HSE National Sepsis Programme. It takes the

best international clinical evidence and provides updated recommendations for the recognition and care of adult and maternity patients with sepsis and septic shock in Ireland.

“It has been quality assured by the National Clinical Effectiveness Committee in line with international best practice and has undergone public consultation and international expert review.

I would like to acknowledge the work of all involved to make these guidelines available for patient care to further improve the management of sepsis and septic shock in Ireland.”

Understanding Multiple Sclerosis Ava Battles, Chief Executive, MS Ireland, John Lee, Teacher, Donahies Community School, Simone Feresin, Patient Journey Partner, Roche Products Ireland

its members ahead of the launch of Understanding MS@Work, a dedicated online employment resource for those living with MS and their employers.

Nine out of 10 people (90%) living with multiple sclerosis (MS) in Ireland say that the Covid-19 pandemic has helped, or could help, steer conversations with

their employer about how working from home could benefit them in the long-term1. That’s according to new research which was carried out by MS Ireland among

The research found that 80% of people with MS say the way they work has changed as a result of the pandemic, while almost twothirds (64%) of those surveyed say that working from home has benefitted them over the past 18 months1. Although the majority of respondents (85%) say that their employer knows they are

living with MS, more than one-fifth (21%) of respondents cited ‘lack of understanding / empathy’ as the issue that most impacts their working life1.

MS is the most common disabling neurological disease of young adults in Ireland, and affects the motor, sensory and cognitive functioning of the body2.

Symptoms of MS include impaired mobility and vision, severe fatigue and cognitive difficulties2 which can have a huge impact on an individual’s work and family life2.

Understanding MS@Work, which is supported by Roche Products (Ireland) Ltd., aims to encourage and enable people living with MS to have beneficial conversations with their employers about their working environment.

References upon request

Women in Vision Conference

The conference brought together a community of academic and clinical medicine experts to share research and ideas that addresses key topics in all aspects of the field of eye care.

Miss Julie Silvestri, Consultant Ophthalmic Surgeon Clinical Director at Belfast Health and Social Care Trust; Dr Sarah Atkinson, Lecturer in Stratified Medicine (Vision) at the School of Biomedical Sciences, Ulster University; and Dr Joan Ní Gabhann-Dromgoole, Lecturer in Immunology and Ophthalmology at the RCSI School of Pharmacy and Biomolecular Sciences.

and Eye Research committee was established in 2019 to address the gender disparity experienced by women in science, by providing a platform that recognises and supports excellence in eye care and research. We are delighted to host a conference focused on the latest scientific discoveries that is also uniquely aimed to support and promote the visibility of women at all stages of their careers."

Organised by the RCSI School of Pharmacy and Biomolecular Sciences, the conference was addressed by speakers including

Opening the conference, Professor Hannah McGee, Deputy Vice Chancellor for Academic Affairs at RCSI, said, "The Women in Vision

The conference recognised the life and legacy of Dr Kathleen Lynn, pioneering doctor, socialist and public-health campaigner.

The inaugural Women in Vision and Eye Research (WVER) Ireland conference took place at RCSI University of Medicine and Health Science last month (October).

NOVEMBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

Professor Louis Collum, Ophthalmologist at the Royal Victoria Eye and Ear Hospital (RVEEH), delivered a keynote address exploring her contribution to ophthalmology and healthcare.

MYLOTARGTM is indicated for combination therapy with daunorubicin (DNR) and cytarabine (AraC) for the treatment of patients age 15 years and above with previously untreated, de novo CD33-positive acute myeloid leukaemia (AML), except acute promyelocytic leukaemia (APL)1,2

▼

Add MYLOTARG™ to

REINFORCE YOUR

AML TREATMENT

FOR LONGER REMISSION COMPARED WITH STANDARD OF CARE CHEMOTHERAPY1,2 MYLOTARG™ significantly extends EFS and RFS* for patients with previously untreated de novo AML compared with the standard of care, chemotherapy with DNR and AraC1,2

▼ MYLOTARG® (gemtuzumab ozogamicin) PRESCRIBING INFORMATION Please refer to the Summary of Product Characteristics (SmPC) before prescribing MYLOTARG 5 mg powder for concentrate for solution for infusion.

Presentation: Each vial contains 5 mg gemtuzumab ozogamicin. After reconstitution the concentrated solution contains 1 mg/ mL gemtuzumab ozogamicin. Gemtuzumab ozogamicin is an antibody-drug conjugate composed of the CD33-directed recombinant monoclonal antibody humanized hP67.6; recombinant humanised immunoglobulin [Ig] G4, kappa antibody covalently linked to the cytotoxic agent N-acetyl gamma calicheamicin.

Indications: MYLOTARG is indicated for combination therapy with daunorubicin (DNR) and cytarabine (AraC) for the treatment of patients aged 15 years and above with previously untreated, de novo CD33-positive acute myeloid leukaemia (AML), except acute promyelocytic leukaemia (APL). Dosage: Administer under the supervision of a physician experienced in the use of cancer therapy and in an environment where full resuscitation facilities are immediately available.

MYLOTARG should be used only in patients eligible to receive intensive induction chemotherapy. The recommended induction dose of MYLOTARG is 3 mg/m2/dose (up to a maximum of one 5 mg vial) infused over a 2 hour period on Days 1, 4, and 7 in combination with DNR 60 mg/m2/day infused over 30 minutes on Day 1 to Day 3, and AraC 200 mg/m2/day by continuous infusion on Day 1 to Day 7. If a second induction is required, DNR should be infused at a dose of 35 mg/m2/ day on Day 1 to Day 2 and AraC at a dose of 1 g/ m2/every 12 hours on Day 1 to Day 3. MYLOTARG should not be administered during a second induction. For patients experiencing a complete remission (CR) following induction, defined as fewer than 5% blasts in a normocellular marrow and an absolute neutrophil count (ANC) of more than 1.0 × 109 cells/L with a platelet count of 100 × 109/L or more in the peripheral blood in the absence of transfusion, up to 2 consolidation courses of intravenous DNR (60 mg/m 2 for 1 day [first course] or 2 days [second course]) in combination with intravenous AraC (1 g/m2 every 12 hours, infused over 2 hours on Day 1 to Day 4) with intravenous MYLOTARG (3 mg/m 2/dose infused over 2 hours up to a maximum dose of one 5 mg vial on Day 1) are recommended. Dose modification of MYLOTARG may be required based on individual safety and tolerability.

Management of some adverse drug reactions may require dosing interruptions and/or dose reductions, or permanent discontinuation of MYLOTARG. See SmPC for dose modification guidelines for haematological and non haematological toxicities. Special populations: Hepatic impairment: No adjustment of the starting dose is required in patients with hepatic impairment defined by total bilirubin ≤ 2 × upper limit of normal (ULN) and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 × ULN. Postpone MYLOTARG until recovery of total bilirubin to ≤ 2 × ULN and AST and ALT to ≤ 2.5 × ULN prior to each dose. Renal impairment MYLOTARG has not been studied in patients with severe renal impairment. Paediatric population: The safety and efficacy of MYLOTARG in patients less than 15 years has not been established. Contra-indications: Hypersensitivity to the active substance or to any of the excipients.

Special warnings and precautions for use: In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Premedication with a corticosteroid, antihistamine and acetaminophen (or paracetamol) is recommended 1 hour prior to MYLOTARG dosing due to the potential for infusion related reactions. In patients with hyperleukocytic AML, leukoreduction should be considered with hydroxyurea or leukapheresis to reduce the peripheral WBC count to below 30,000/mm3 prior to administration of MYLOTARG to reduce the risk of inducing tumour lysis syndrome.

Appropriate measures to help prevent the development of tumour lysis-related hyperuricaemia, such as hydration, a d m i n i s t rat i o n o f a nt i hy p e r u r i ce m i c s (e.g., allopurinol) or other agents for treatment of hyperuricaemia (e.g., rasburicase) must be taken.

Hepatotoxicity: Hepatotoxicity, including severe, life-threatening, and sometimes fatal hepatic failure and VOD/SOS have been reported in patients treated with MYLOTARG. Adult patients who received MYLOTARG as monotherapy, either before or after a haematopoietic stem cell transplant (HSCT), and patients with moderate or severe hepatic impairment are at increased risk for developing VOD. Signs and symptoms of VOD/SOS should be monitored closely in all patients. For patients who develop abnormal liver tests, more frequent monitoring of liver tests and clinical signs and symptoms of hepatotoxicity is recommended. For patients who proceed to HSCT, close monitoring of

References 1. Pfizer MYLOTARG™ (gemtuzumab ozogamicin) Summary of Product Characteristics.

2. Pfizer Cytarabine Summary of Product Characteristics.

PP-MYL-IRL-0053 Date of preparation December 2020

liver tests is recommended during the post-HSCT period, as appropriate. Management of signs or symptoms of hepatic toxicity may require a dose interruption, or discontinuation of MYLOTARG (see section 4.2). In patients who experience VOD/SOS, MYLOTARG should be discontinued and patients treated according to standard medical practice.

Myelosuppression/cytopenias: Neutropenia, thrombocytopenia, anaemia, leukopenia, febrile neutropenia, lymphopenia, and pancytopenia, some life-threatening and some with complications, were reported. Blood counts should be monitored prior to dosing and signs of myelosuppression should be monitored during treatment. Infusion related reactions: Infusion should be interrupted immediately for patients who develop evidence of severe reactions, especially dyspnoea, bronchospasm, or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinuation of treatment should be strongly considered for patients who develop signs or symptoms of anaphylaxis, including severe respiratory symptoms or clinically significant hypotension. The efficacy of MYLOTARG has been shown in AML patients with favourable- and intermediate-risk cytogenetics, with uncertainty regarding the size of the effect in patients with adverse cytogenetics (see smPC section 5.1).

For patients being treated with MYLOTARG in combination with daunorubicin and cytarabine for newly diagnosed de novo AML, when cytogenetics testing results become available it should be considered whether the potential benefit of continuing treatment with MYLOTARG outweighs the risks for the individual patient (see smPC section 5.1) Fertility, pregnancy and lactation: Women of childbearing potential receiving this medicinal product, or treated male partners should use effective contraception during therapy and for at least 7 months or 4 months after completing therapy for females and males, respectively. There are no or limited amount of data from the use of MYLOTARG in pregnant women. Non-clinical studies have shown reproductive toxicity.

MYLOTARG must not be used during pregnancy unless the potential benefit to the mother outweighs the potential risks. The potential hazard to the foetus of MYLOTARG treatment must be explained to pregnant women, patients becoming pregnant while receiving treatment, or treated male partners of pregnant women. Because of the potential for adverse reactions in breast-fed children, women must not breast-feed during treatment with MYLOTARG and for at least 1 month after the final dose. Based on non-clinical findings,

male and female fertility may be compromised by treatment with MYLOTARG. Driving and operating machinery: MYLOTARG may cause fatigue and patients should exercise caution when driving or using machines. Undesirable effects: The overall safety profile of MYLOTARG is based on data from patients with acute myeloid leukaemia from the combination therapy study ALFA-0701, monotherapy studies, and from post-marketing experience. In the combination therapy study, safety data consisting of selected treatment emergent adverse events (TEAEs) considered most important for understanding the safety profile of MYLOTARG consisted of all grades haemorrhages, all grades VOD, and severe infections. The most common adverse reactions (> 30%) in the combination therapy study were haemorrhage and infection. In patients who received MYLOTARG in the combination therapy study ALFA-0701, clinically relevant serious adverse reactions were hepatoxicity including VOD/SOS (3.8%), haemorrhage (9.9%), severe infection (41.2%), and tumour lysis syndrome (1.5%). See relevant SmPC (Table 5) for full details on specific comprehensive list of AEs for combination therapy.

Instructions for reconstitution and dilution: Use appropriate aseptic technique for the reconstitution and dilution procedures. Following reconstitution and dilution, the solution should be protected from light and should be used immediately. If the product cannot be used immediately, the diluted solution may be stored up to 18 hours in a refrigerator (2°C–8°C) from the time of initial vial puncture with not more than 6 hours at room temperature (below 25°C).

Legal Category: S1A. Marketing Authorisation Number: EU/1/18/1277/001 – 5mg 1 vial. The Marketing Authorisation Holder: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium. For further information on this medicine please contact: Pfizer Medical Information on 1800 633 363 or at EUMEDINFO@pfizer.com.

For queries regarding product availability please contact: Pfizer Healthcare Ireland, Pfizer Building 9, Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24 + 353 1 4676500. ▼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.

Last revised: 11/2020 Ref: ML 4_0

*RFS is a secondary endpoint. Only EFS and RFS achieved significance in the ALFA-0701 study.1 AML, acute myeloid leukaemia; APL, acute promyelocytic leukaemia; AraC, Cytarabine; DNR, Daunorubicin; EFS, event-free survival; RFS, relapse-free survival.

32 News IPHA Presents Latest Ipsos Survey Bernard Mallee, Director of Communications and Advocacy at IPHA. Pic Fergal Phillips

Young people are still less likely to get vaccinated for Covid-19 compared with the population overall, according to the latest research carried out by Ipsos MRBI for the Irish Pharmaceutical Healthcare Association (IPHA), the representative organisation for the originator biopharmaceutical industry.

The research shows that vaccine hesitancy is at 13% in the 18 to 34-year-old age group. That figure is composed of 8% who said they would refuse a Covid-19 vaccine and 5% who said they were unsure. In the population overall, Covid-19 vaccine hesitancy is 9%, with 6% saying they would not get vaccinated for the disease while 3% are unsure.

Last October, when IPHA began tracking public appetite for Covid-19 vaccines, 12% of people said they would not get

vaccinated for Covid-19 and 33% said they were unsure. That means Covid-19 hesitancy in the population overall has dropped by 36 points in 11 months.

Overall, 91% of people either intend to get vaccinated for Covid-19 or have already received a vaccine for the disease, according to the research. The results show that 2% of people will take a vaccine but, when combined with the cohort that has received at least one vaccine dose, or 88% of the sample*, that number rises to 91%. Just 6% of people would refuse a vaccine – a proportion that has remained relatively stable since the start of the year.

The industry paid tribute to the Government, the HSE, vaccinators and everyone involved in setting up and delivering Covid-19 vaccination

infrastructure. Ireland having the highest vaccination rate in the EU attests to their efforts.

Bernard Mallee, Director of Communications and Advocacy at IPHA, said, “Vaccination is the difference. It is reducing serious illness, hospitalisations and deaths caused by Covid-19. Even though vaccine hesitancy is more prevalent in younger people than the overall population, Ireland’s vaccination rate in the community is still among the highest in Europe. There should be no room for complacency, though. It is vital that we engage with people of all ages in continuing to build trust in science and in facts, and in maximising vaccinations across the eligible population. We have clear evidence of the real-time effectiveness of vaccination for Covid-19. Strong public health messaging on safety – whether

during trials or in the community – helps to build public confidence.

“The EU and the US have agreed to step up efforts to get more of the world vaccinated for Covid-19. They are boosting their dose-sharing commitments, pledging support for stronger vaccines delivery, investing in regional vaccines production and guarding against supply chain disruptions. These steps are important in the move towards more equitable global Covid-19 vaccines distribution.

Waiving intellectual property rights for Covid-19 vaccines and treatments, even temporarily, would not boost supply. Rather, it would disincentivise the discovery of new vaccines and treatments for unmet medical needs, including for Covid-19 variants.”

With the exception of clean, safe drinking water, vaccination is among the most successful and cost-effective public health interventions ever. The World Health Organisation estimates that vaccines save up to three million lives every year.

We have vaccines to prevent more than 20 life-threatening diseases, helping people of all ages live longer, healthier lives. Vaccines administered in Ireland already help to prevent 13 diseases including measles, meningitis and whooping cough.

Vaccines have ridded the world of smallpox, driven polio to the brink of eradication, and virtually eliminated measles, diphtheria and rubella in many parts of the world.

Raising Awareness of Arthritis A new campaign from Arthritis Ireland, aims to raise awareness of a form of inflammatory arthritis that can take up to eight years to diagnose in Ireland.

Ankylosing spondylitis mainly affects the spine, but can also cause pain and/or swelling in the shoulders, hips, knees, heels, chest/ribs and small joints of the hands and feet. While back pain is very common in the general population, only a small percentage of people will have inflammatory arthritis of the spine.

Eight times All-Ireland winner, Michael Fennelly, and novelist, Amanda Geard, are supporting Back in Action, the new campaign.

Former Kilkenny hurler and current Offaly manager, Michael Fennelly, was just 20 when he was diagnosed with AS and he has been living with the painful condition for the past 16 years.

He initially found himself needing extra physiotherapy to ease his joints before training sessions and games. Over time, the

NOVEMBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

stiffness and pain caused by AS in Fennelly’s back and neck began to create major difficulties, given the massive physical demands of the game.

Arthritis Ireland chief executive, Gráinne O’Leary, said, “Ankylosing spondylitis can have an enormous physical and emotional impact on people, which can disrupt every aspect of life. Symptoms of AS frequently begin in younger people, as early as the teenage years or 20s, so runs counter to

the expectation that arthritis is an older person’s disease. Part of the complexity of the condition is that it can take years to diagnose.

In fact, Irish data highlights an eight-year-delay in diagnosing axial spondyloarthritis.

“The situation is exacerbated by low levels of awareness of the condition, which is why campaigns such as this are important. As always, we encourage anyone who has concerns about their health, or is experiencing persistent pain or stiffness to seek medical advice.”

NOW BVBM FOR 20MG ADALIMUMAB

AW

ARDED

BVBM

AMGEVITA® AND ME CITRATE FREE HOW AND WHEN IS IT GIVEN?

AMGEVITA® is injected under the skin (a subcutaneous in a specially designed pen called SureClick® or using a pre

AW

ARDED

VITA® AND ME ®

Amgevita®

awarded best value biosimilar medicine value biologic medicine inAwarded a citrate best free formulation of adalimumab a citrate free formulation of by theinMedicines Management Programme

adalimumab and is the only BVBM awarded for 20mg adalimumab.

WHEN IS IT GIVEN?

jected under the skin (a subcutaneous injection) with ned pen called SureClick® or using pre-filledPre-fi syringe.

AMGEVITA® 40mga SureClick® lled pen

You should inject in the tummy, or the tops of your legs ( see diagram below.

The medicine travels into your bloodstream to work on t that are inflamed and causing your symptoms.

AMGEVITA® 20mg Pre-filled syringe

t in the tummy, or the tops of your legs (thighs), Your doctor, pharmacist or nurse will show ow. you or your parent/carer how to give the avels into your bloodstream toIt’s work on the areas injection. important the injection is given d and causing your symptoms. correctly for it to work.

YouAMGEVITA may have the injection in hospital or ® 40mg Pre-filled syringe at home. You can give it to yourself or your armacist or nurse will show parent/carer can do this for you. Usually, the ent/carer how to give the injection is given every 2 weeks, but your portant the injection is given doctor may change toCharacteristics best suit(SmPC) what Further information is available on request or in the Summary ofthis Product at www.medicines.ie. o work. works for you. he injection in hospital or You need to follow Adult the advice of yourPaediatric n give it to yourself or your • Rheumatoid arthritis Polyarticular juvenile idiopathic healthcare team and ask to speak to •them arthritis (JIA) • Ankylosing spondylitis (AS) n do this for you. Usually, the (from 2 years of age) • Axial spondyloarthritis without if you are not feeling well.

• Enthesitis-related arthritis radiographic evidence of AS n every 2 weeks, but your (from 6 years of age) • Psoriatic A arthritis • Crohn’s disease nge this to best suit what For full and detailed instructions on how to • Crohn’s disease (from 6 years of age) • Ulcerative colitis • Ulcerative Colitis administer your AMGEVITA®, please read the (from 6 years of age) • Psoriasis Plaque psoriasis • Hidradenitis suppurativa instructions provided in the product •carton. (from 4 years of age) ow the advice of your • Uveitis • Adolescent hidradenitis C B suppurativa (acne inversa) and ask to speak to them (from 12 years of age) • Uveitis (from 2 years of age) eling well. ©2021 Amgen Inc. All rights reserved.

IE-AMB-0821-00003. Date of preparation: August 2021.

Legal Category: POM. Marketing Authorisation Numbers:

EU/1/16/1164/001 – 1 pack: AMGEVITA® 20 mg solution for injection in pre-filled syringe EU/1/16/1164/003 – 2 pack: AMGEVITA® 40 mg solution for injection in pre-filled syringe EU/1/16/1164/007 – 2 pack: AMGEVITA® 40 mg solution for injection in pre-filled pen

Marketing Authorisation Holders: Amgen Europe B.V., Minervum 7061, NL-4817 ZK Breda, The Netherlands. ▼This medicinal product is subject to additional monitoring. Adverse reactions /events should be reported to the Health Products Regulatory Authority (HPRA) using the available methods via www.hpra.ie. Adverse reactions/events should also be reported to Amgen Limited on +44 (0) 1223 436441 or Freephone 1800 535 160.

Further information is available on request or in the Summary of Product Characteristics (SmPC) at www.medicines.ie.

References: 1. BVBM Amgevita Product Information Sheet. https://www.hse.ie/eng/about/who/cspd/ncps/ medicines-management/best-valuebiologicalmedicines/bvb-medicine-amgevita-productinformationsheetpdf Accessed Aug 2021.

2. Medicines Management Programme Best-Value Biological Medicines: Adalimumab 20 mg solution for injection. https://www.hse.ie/eng/about/who/cspd/ncps/medicines-management/bestvaluemedicines/best-value-biological-medicines/mmp-report-bvbmedicine-adalimumab-20mgmarch-2021.pdf Accessed Aug 2021.

ailed instructions on how to

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34 News NUI Galway awards Gold Medals Dr Rosemary James with her NUI Galway CKI Gold Medal for Civic Engagement gold medals are also awarded for contributions to civic engagement.

Dr James, a junior doctor and global health academic with the World Health Organisation, said she was honoured to have been given the award.

A junior doctor and a speech and language therapist have been awarded gold medals by NUI Galway for civic engagement.

Dr Rosemary James, a graduate of Medicine in 2021, was honoured by the School of Medicine for her outstanding community outreach and volunteering, as well as research in global health.

Lisa O'Neill, a graduate of Speech and Language Therapy in 2021, was honoured by the School of Health Sciences for raising awareness around mental health, volunteering, fundraising and providing peer support to first year students during the pandemic.

NUI Galway's College of Medicine, Nursing and Health Sciences has been honouring student excellence with the award of gold medals for more than 100 years. In partnership with the Community Knowledge Initiative specific

“I believe that it is important as medical graduates that we are aware of the vulnerabilities certain populations are subject to and act to advocate for, study, and improve their health and wellbeing wherever possible,” Dr James said.

“I look forward to continuing to engage with vulnerable communities as I progress onto my postgraduate training - taking with me the knowledge and skills I owe to NUI Galway and the inspiring people I have met along the way.”

Ms O'Neill, a Speech and Language Therapy graduate, said: “One of my main aims as a volunteer is to contribute to raising awareness about and funds for mental health.

“The volunteering opportunities I have been involved in so far have allowed me to work as part of a group to achieve the common goal of creating communities that support people when they are most in need. I envisage a world that is more just and accepting, and where

people's differences are celebrated.

Volunteering is one way in which I actively contribute to making this vision a reality.”

The CKI Gold Medal can be awarded to graduates and students for activities including volunteering, service learning, collaborative research and actions for the public good which benefit both the wider community and the University.

Dr Maureen Kelly, Senior Lecturer in General Practice and Vice Dean for Civic Engagement, College of Medicine, Nursing and Health Sciences, said: “Within healthcare, civic engagement is fundamentally aligned with working with the public, patients and communities to promote and improve community health status.

Speech and Language Therapist Lisa O'Neill with her NUI Galway CKI Gold Medal for Civic Engagement

“Rosemary and Lisa are very deserving of their award. It is testament to their longstanding partnership with community, reflecting the principles and values of civic engagement that we espouse in NUI Galway.”

Dr Lorraine McIlrath, director of the Community Knowledge Initiative at NUI Galway, said: “The CKI was established to promote student commitment to positive social change within community and Dr Rosemary James and Lisa O'Neill are wonderful ambassadors for civic engagement and inspire others to take action. I congratulate them.”

Clinical Research Facility Galway ¤3m Funding

Some ¤3million funding has been announced for the Clinical Research Facility Galway - a Health Research Board (HRB) centre supporting clinical trials to improve health and care.

The investment is part of a EUR22million fund from the HRB for clinical research facilities located at hospital sites and supported by universities.

NOVEMBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

Professor Fidelma Dunne and Professor Andrew Smyth at the Clinical Research Facility Galway

Hospitals, said, "The HRB-CFRG aims to improve patient care and population health through the delivery of clinical trials by providing the necessary infrastructure, physical space, facilities, expertise, specialist training and culture.

The Clinical Research Facility Galway is a joint initiative of NUI Galway and Saolta University Health Care Group for the promotion of clinical research and conduct of clinical trials, bringing together clinicians, researchers and academics to focus on studies aimed at understanding diseases and translating the knowledge gained into advances in patient care.

“This infrastructure funding support from the HRB puts us on the map globally in terms of the ability to manage and execute all stages of clinical trials from conception to conclusion.”

Professor Andrew Smyth, Director of the HRB Clinical Research Facility Galway and Consultant Nephrologist at Galway University

The overall HRB funding package will keep Ireland at the forefront of clinical research and trials internationally while also increasing opportunities for patient participation and benefit.

The Clinical Research Facility Galway currently supports 107 clinical trials and investigations.

OYAVAS®: THE NEW BEVACIZUMAB BIOSIMILAR FROM CLONMEL HEALTHCARE1 SIMPLY CONVINCING – with similar efficacy, safety and quality to the reference product*2 SIMPLY RELIABLE – with European production supported by over 20 years of biosimilars experience† SIMPLY DEDICATED – with a continuously expanding oncology portfolio ABBREVIATED PRESCRIBING INFORMATION Oyavas 25 mg/ml concentrate for solution for infusion. Each ml contains 25 mg of bevacizumab. Each 4 ml vial contains 100 mg of bevacizumab.

Each 16 ml vial contains 400 mg of bevacizumab. Presentation: Glass vial. Indications: 1) Oyavas in combination with fluoropyrimidine based chemotherapy is indicated for treatment of adult patients with metastatic carcinoma of the colon or rectum. 2) Oyavas in combination with paclitaxel is indicated for first line treatment of adult patients with metastatic breast cancer. 3) Oyavas in combination with capecitabine is indicated for first line treatment of adult patients with metastatic breast cancer in whom treatment with other chemotherapy options including taxanes or anthracyclines is not considered appropriate. Patients who have received taxane and anthracycline containing regimens in the adjuvant setting within the last 12 months should be excluded from treatment with Oyavas in combination with capecitabine. 4) Oyavas in addition to platinum-based chemotherapy is indicated for first line treatment of adult patients with unresectable advanced, metastatic or recurrent non-small cell lung cancer other than predominantly squamous cell histology. 5) Oyavas in combination with erlotinib, is indicated for first line treatment of adult patients with unresectable advanced, metastatic or recurrent non squamous non-small cell lung cancer with Epidermal Growth Factor Receptor (EGFR) activating mutations. 6) Oyavas in combination with interferon alfa 2a is indicated for first line treatment of adult patients with advanced and/or metastatic renal cell cancer. 7) Oyavas in combination with carboplatin and paclitaxel is indicated for the front line treatment of adult patients with advanced (International Federation of Gynecology and Obstetrics (FIGO) stages III B, III C and IV) epithelial ovarian, fallopian tube, or primary peritoneal cancer. 8) Oyavas in combination with carboplatin and gemcitabine or in combination with carboplatin and paclitaxel is indicated for treatment of adult patients with first recurrence of platinum sensitive epithelial ovarian, fallopian tube or primary peritoneal cancer who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents. 9) Oyavas in combination with topotecan or pegylated liposomal doxorubicin is indicated for the treatment of adult patients with platinum resistant recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who received no more than two prior chemotherapy regimens and who have not received prior therapy with bevacizumab or other VEGF inhibitors or VEGF receptor-targeted agents. 10) Oyavas in combination with paclitaxel and cisplatin or, alternatively, paclitaxel and topotecan in patients who cannot receive platinum therapy, is indicated for the treatment of adult patients with persistent, recurrent, or metastatic carcinoma of the cervix.

Dosage: Refer to Summary of Product Characteristics. Method of administration: Oyavas is for intravenous use. The initial dose should be delivered over 90 minutes as an intravenous infusion. If the first infusion is well tolerated, the second infusion may be administered over 60 minutes. If the 60 minute infusion is well tolerated, all subsequent infusions may be administered over 30 minutes.

Contraindications: Hypersensitivity to the active substance or excipients, hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies, pregnancy. Warnings and precautions: GI perforations and fistulae, GI vaginal fistulae, non-GI fistulae, wound healing complications, hypertension, posterior reversible encephalopathy syndrome, proteinuria, arterial thromboembolism, venous thromboembolism, haemorrhage, pulmonary haemorrhage/haemoptysis, aneurysms and artery dissections, congestive heart failure, neutropenia and infections, hypersensitivity reactions/infusion reactions, osteonecrosis of the jaw. Oyavas is not formulated for intravitreal use. Eye disorders, systemic effects following intravitreal use, female fertility impairment. Interactions: Refer to Summary of Product Characteristics. Fertility, pregnancy and lactation: Women of childbearing potential have to use effective contraception during (and up to 6 months after) treatment. Oyavas is contraindicated in pregnancy. Women must discontinue breast-feeding during therapy and not breast-feed for at least six months following the last dose of bevacizumab.

Repeat dose toxicity studies in animals have shown that bevacizumab may have an adverse effect on female fertility. Long term effects of the treatment with bevacizumab on fertility are unknown. Driving and operation of machinery: Bevacizumab has no or negligible influence on the ability to drive and use machines. However, somnolence and syncope have been reported with bevacizumab use. If patients are experiencing symptoms that affect their vision or concentration, or their ability to react, they should be advised not to drive and use machines until symptoms abate. Undesirable effects: Very common: Febrile neutropenia, leukopenia, neutropenia, thrombocytopenia, anorexia, hypomagnesaemia, hyponatraemia, peripheral sensory neuropathy, dysarthria, headache, dysgeusia, eye disorder, lacrimation increased, hypertension, thromboembolism (venous), dyspnoea, rhinitis, epistaxis, cough, rectal haemorrhage, stomatitis, constipation, diarrhoea, nausea, vomiting, abdominal pain, wound healing complications, exfoliative dermatitis, dry skin, skin discolouration, arthralgia, myalgia, proteinuria, ovarian failure, asthenia, fatigue, pyrexia, pain, mucosal inflammation, weight decreased.

A copy of the SmPC is available upon request or go to www.clonmel-health.ie Pack size: 1 vial of 4 ml or 16 ml. Marketing authorisation holder: STADA Arzneimittel AG, Stadastrasse 2-18, 61118 Bad Vilbel, Germany. Marketing authorisation number: EU/1/20/1510/001-002. Medicinal product subject to medical prescription. Date last revised: May 2021. *Avastin® (bevacizumab) † STADA founded Bioceuticals Arzneimittel AG in 2000 1. Oyavas® SmPC (Apr. 2021). 2. Oyavas® EPAR Public Assessment Report. Available at: https://www.ema.europa.eu/en/documents/ assessment-report/oyavas-epar-public-assessment-report_en.pdf. Last accessed Apr. 2021. 2021/ADV/OYA/027H.

oyavas.ie

36

ERECTILE DYSFUNCTION

Developments in Erectile Dysfunction A Mediterranean diet is associated with improvements in erectile dysfunction, according to research presented at ESC Congress 2021.1 Men with hypertension are twice as likely to have erectile dysfunction as their peers with normal blood pressure.2 Erectile dysfunction is primarily considered a disorder of the small arteries, which lose the ability to dilate and augment flow. Declining testosterone levels in middle age contribute to its onset. Previous research has shown that fitness is linked with improved survival in men with hypertension,3 while the Mediterranean diet lowers blood pressure4 and prevents heart attacks and strokes5 in individuals at high cardiovascular risk.

This study assessed adherence to the Mediterranean diet in middle aged men with high blood pressure and erectile dysfunction.

This dietary pattern emphasises fruit, vegetables, whole grains and olive oil, modest consumption of dairy products, and limiting red meat. The researchers then examined whether dietary habits were linked with fitness, testosterone levels, blood flow, arterial stiffness, and erectile performance.

The study included 250 men with high blood pressure and erectile dysfunction. The average age was 56 years. Mediterranean diet consumption was assessed by questionnaire and participants received a score of 0 to 55, with higher values indicating greater adherence.6 Exercise capacity was assessed with a treadmill test and testosterone was measured in blood samples taken before 09:00 am.

Regarding vascular health, echocardiography was performed

to assess coronary flow reserve, which indicates the ability to increase blood flow when needed. Values of 2 or higher are considered normal and point to better vascular function. The researchers examined arterial stiffness using two measures: augmentation index and central pulse pressure. Higher values indicate stiffer arteries, which are associated with a higher risk of adverse heart events in men with erectile dysfunction.7 Severity of erectile dysfunction was assessed using the Sexual Health Inventory for Men (SHIM) which uses five questions about erectile ability to allocate a score of 0 to 25, with higher values correlating to better erectile performance.8 The researchers found that men with a higher Mediterranean diet score (above 29) also had higher coronary flow reserve and testosterone, better erectile performance (SHIM score above 14), and lower arterial stiffness.

When the relationships were analysed according to fitness, the researchers found that patients with greater exercise capacity (above 10 METs)9 had higher coronary flow reserve, testosterone, Mediterranean diet score (above 25) and SHIM score (above 12), and lower arterial stiffness.

Study author Dr. Athanasios Angelis of the University of Athens, Greece said: “In our study, consuming a Mediterranean diet was linked with better exercise capacity, healthier arteries and blood flow, higher testosterone levels, and better erectile performance. While we did not examine mechanisms, it seems plausible that this dietary pattern may improve

NOVEMBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

fitness and erectile performance by enhancing function of the blood vessels and limiting the fall in testosterone that occurs in midlife.”

He concluded: “The findings suggest that the Mediterranean diet could play a role in maintaining several parameters of vascular health and quality of life and in middle aged men with hypertension and erectile dysfunction.”

References 1 Abstract title: Exercise capacity benefit in relation to endogenous testosterone, coronary and central vascular physiology, and the Mediterranean regime in hypertensive males with erectile dysfunction.

2 Doumas M, Douma S. Sexual dysfunction in essential hypertension: myth or reality? J Clin Hypertens (Greenwich). 2006;8:269–274.

3 Kokkinos P, Manolis A, Pittaras A, et al. Exercise capacity and mortality in hypertensive men with and without additional risk factors. Hypertension.

2009;53:494–499.

4 Domenech M, Roman P, Lapetra J, et al. Mediterranean diet reduces

24-hour ambulatory blood pressure, blood glucose, and lipids: oneyear randomized, clinical trial.

Hypertension. 2014;64:69–76.

5 Estruch R, Ros E, Salas-Salvado J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368:1279–1290.

6 Panagiotakos DB, Pitsavos C, Stefanadis C. Dietary patterns: a Mediterranean diet score and its relation to clinical and biological markers of cardiovascular disease risk. Nutr Metab Cardiovasc Dis. 2006;16:559–568.

7 Vlachopoulos C, Ioakeimidis N, Aznaouridis K, et al. Prediction of cardiovascular events with aortic stiffness in patients with erectile dysfunction. Hypertension.

2014;64:672–678.

8 Cappelleri JC, Rosen RC. The Sexual Health Inventory for Men (SHIM): a 5-year review of research and clinical experience. Int J Impot Res. Jul-Aug 2005;17:307–319.

9 One metabolic equivalent of task (MET) is the rate of energy expenditure, or oxygen use, while sitting quietly (1 kcal/kg/hour or 3.5 mL/kg/min).

3 in 1 solution

Helping to Combat Cardiovascular Disease1

NEW The 1st Statin, ACEi & CCB

combination in Ireland2

Controlling High Cholesterol and Hypertension in unison1 Lipertance® (Atorvastatin,perindopril,amlodipine): Abbreviated Prescribing Information: Please refer to the Summary of Product Characteristics before prescribing. COMPOSITION*: Lipertance 10mg/5mg/5mg, 20mg/5mg/5mg, 20mg/10mg/5mg, 20mg/10mg/10mg, 40mg/10mg/10mg film-coated tablets contain 10 mg atorvastatin (ator)/5 mg perindopril arginine (per)/5 mg amlodipine (amlo), 20mg ator/5 mg per/5 mg amlo, 20mg ator/10 mg per/5 mg amlo, 20mg ator/10 mg per/10 mg amlo, 40mg ator/10 mg per/10 mg amlo. Contains lactose as excipient. INDICATIONS*: Substitution therapy for treatment of essential hypertension and/or stable coronary artery disease, in association with primary hypercholesterolaemia or mixed hyperlipidaemia, in adult patients adequately controlled with atorvastatin, perindopril and amlodipine given concurrently at the same dose level. DOSAGE AND ADMINISTRATION*: One tablet once daily before a meal in the morning. Lipertance is not suitable for initial therapy. If a change of posology is required, the dose could be modified or individual titration with free combination may be considered. Co-administration: with elbasvir/grazoprevir or letermovir, the dose of atorvastatin should not exceed 20 mg/day. Lipertance not recommended when letermovir co-administered with ciclosporin. Elderly and patients with renal failure: frequent monitoring of creatinine and potassium. Clcr < 60 ml/min: not suitable. Hepatic impairment: should be used with caution. Lipertance is contraindicated in patients with active liver disease. Children and adolescents: should not be used. CONTRAINDICATIONS*: Hypersensitivity to the active substances or to any other ACE inhibitor or dihydropyridine derivatives or statin or to any of the excipients, active liver disease or unexplained persistent elevations of serum transaminases exceeding 3 times the upper limit of normal, during pregnancy, while breast-feeding and in women of child-bearing potential not using appropriate contraceptive measures (see section PREGNANCY* and BREASTFEEDING*), concomitant use with the hepatitis C antivirals glecaprevir/pibrentasvir, severe hypotension, shock (including cardiogenic shock), obstruction of the outflow tract of the left ventricle (e.g., hypertrophic obstructive cardiomyopathy and high grade aortic stenosis), haemodynamically unstable heart failure after acute myocardial infarction, history of angioedema (Quincke’s oedema) associated with previous ACE inhibitor therapy, hereditary or idiopathic angioedema, concomitant use with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73m²) (see section INTERACTIONS*), concomitant use with sacubitril/valsartan (see WARNING* and INTERACTIONS*), extracorporeal treatments leading to contact of blood with negatively charged surfaces (see INTERACTIONS*), significant bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney (see WARNINGS*). WARNINGS*: Special warnings and precaution for use: Liver effects: liver function tests should be performed periodically and in case of transaminase levels increased, the patient should be monitored until resolution. Stop treatment if jaundice or marked elevations of hepatic enzymes (serum transaminases exceeding 3 times the upper limit of normal) and in patients with active liver disease. Use with caution in patients with hepatic impairment, who consume alcohol and/or have history of liver disease. Skeletal muscle effects: stop treatment if elevation of CK levels > 10 x ULN or muscular symptoms with elevation of CK level > 5 x ULN occur, or if rhabdomyolysis is suspected. Caution should be exercice when Lipertance is used with certain medicinal products that may increase the plasma concentration of atorvastatin and then the risk of rhabdomyolysis such as potent inhibitors of CYP3A4 or transport proteins (e.g ciclosporine, ketoconazole, letermovir, ritonavir…). Increased risk of myopathy with concomitant use of gemfibrozil and other fibric acid derivatives, antivirals for the treatment of hepatitis C, erythromycin, niacin and ezetimibe. Co-administration with systemic fusidic acid or within 7 days of stopping the treatment is not recommended. If use essential, Lipertance should be discontinued during fusidic acid treatment. Interstitial lung disease: if suspected, treatment should be discontinued. Diabetes Mellitus: In diabetic patients, glycaemic control should be closely monitored during first month of treatment. Patients with cardiac failure: use with caution. Hypotension: monitor blood pressure, renal function and potassium in patients at high risk of symptomatic hypotension (volume depleted or who have severe renin-dependent hypertension) or with symptomatic heart failure (with our without renal insufficiency), or with ischaemic heart or cerebrovascular disease. A transient hypotensive response is not a contraindication to further doses once the blood pressure has increased after volume expansion. Aortic and mitral valve stenosis/hypertrophic cardiomyopathy: use with caution and see CONTRAINDICATIONS. Kidney transplantation: no experience in case of recent transplantation.

Renovascular hypertension: Increased risk of hypotension and renal insufficiency in patient with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney. Diuretics may be a contributory factor. Loss of renal function may occur (minor changes in serum creatinine) even in patients with unilateral renal artery stenosis. Renal impairment: monitor potassium and creatinine; individual dose titration with the monocomponents recommended if Clcr < 60 ml/min. In patients with renal artery stenosis, blood urea and creatinine may increase; with renovascular hypertension, risk of severe hypotension and renal insufficiency. Amlodipine may be used at normal doses in patients with renal failure. Amlodipine is not dialysable. Haemodialysis patients: use with caution.

Hypersensitivity/Angioedema: stop treatment and monitor until complete resolution of symptoms. Angioedema associated with laryngeal oedema may be fatal. Combination with sacubitril/valsartan (contraindicated due to the increased risk of angioedema). Sacubitril/ valsartan must not be initiated until 36 hours after taking the last dose of perindopril therapy. Perindopril therapy must not be started until 36 hours after the last dose of sacubitril/valsartan. Concomitant use of other NEP inhibitors (e.g. racecadotril) and ACE inhibitors may also increase the risk of angioedema. Concomitant use of mTOR inhibitors: Increased risk for angioedema. Anaphylactoid reactions during low-density lipoproteins (LDL) apheresis: rarely, patients have experienced life-threatening anaphylactoid reactions, temporarily withhold treatment prior to exams. Anaphylactoid reactions during desensitisation: temporarily withhold treatment prior to exams. These reactions reappeared upon inadvertent rechallenge. Neutropenia/agranulocytosis/thrombocytopenia/anaemia: extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treated with allopurinol or procainamide, periodic monitor of white blood cell counts advised. Race: perindopril may be less effective and cause a higher rate of angioedema than in non-black. Cough: resolves after discontinuation. Surgery/Anaesthesia: stop treatment one day prior to surgery. Hyperkaliemia: frequent monitoring of blood potassium if renal insufficiency, worsening of renal function, age (>70 years), diabetes mellitus, dehydration, acute cardiac decompensation, metabolic acidosis, and concomitant use of potassium-sparing diuretics and potassium salts or supplements. Combination with lithium. not recommended Dual blockade of the renin-angiotensin-aldosterone system (RAAS): concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS is therefore not recommended. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy. Primary aldosteronism: Use not recommended in patients with primary hyperaldosteronism (not responding to drugs acting through inhibition of reninangiotensin system). Galactose intolerance/glucose- galactose malabsorption/total lactase deficiency: should not be taken. Sodium: ‘sodium-free’. INTERACTIONS*: Contraindicated: Aliskiren (in diabetic and impaired renal patients), Extracorporeal treatments, Sacubitril/valsartan, Glecaprevir/pibrentasvir. Not recommended: CYP3A4 inhibitors, aliskiren, concomitant therapy with ACE inhibitor and angiotensin-receptor blocker, estramustine, lithium, Co-trimoxazole (trimethoprim/sulfamethoxazole), potassium- sparing diuretics (e.g. triamterene, amiloride, eplerenone, spironolactone), potassium salts, dantrolene (infusion), grapefruit or grapefruit juice. Precautions: CYP3A4 inducers, digoxin, ezetimibe, fusidic acid, gemfibrozil / fibric acid derivatives, transport inhibitors, warfarin, antidiabetic agents (insulins, oral hypoglycaemic agents), baclofen, non-steroidal anti- inflammatory medicinal products (NSAIDs) (including aspirin ≥ 3 g/day), racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus), colchicine, colestipol, oral contraceptives, gliptins (linagliptin, saxagliptin, sitagliptin, vildagliptin), sympathomimetics, tricyclicantidepressants/antipsychotics/anesthetics, gold, digoxin, atorvastatin, warfarin or ciclosporine, tacrolimus, antihypertensive agents and vasodilators. PREGNANCY AND BREASTFEEDING*: Lipertance is contraindicated during pregnancy and lactation. FERTILITY*: Reversible biochemical changes of spermatozoa in some patients treated by calcium channel blockers. DRIVE AND USE MACHINES*: May be impaired if dizziness, headache, fatigue, weariness or nausea. Caution is recommended especially at the start of treatment. UNDESIRABLE EFFECTS*: Very common: Oedema. Common: nasopharyngitis, hypersensitivity, hyperglycaemia, somnolence, dizziness, headache, dysgeusia, paraesthesia, vertigo, visual impairment, diplopia, tinnitus, palpitations, hypotension (and effects related to hypotension), flushing, pharyngolaryngeal pain, epistaxis , cough , dyspnoea, nausea, vomiting, abdominal pain upper and lower, dyspepsia, diarrhoea, constipation, change of bowel habit, flatulence, rash, pruritus, joint swelling, ankle swelling, pain in extremity, arthralgia, muscle spasms, myalgia, back pain, asthenia, fatigue, liver function test abnormal, blood creatine kinase increased. Uncommon: Rhinitis, eosinophilia, hypoglycaemia, hyponatraemia, hyperkalaemia reversible on discontinuation, anorexia, insomnia, mood altered (including anxiety), sleep disorder, depression, nightmares, tremor, syncope, hypoaesthesia, amnesia, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), vision blurred, tachycardia, vasculitis, bronchospasm, dry mouth, pancreatitis, eructation, hepatitis either cytolytic or cholestatic, urticaria, purpura, skin discolouration, hyperhidrosis, exanthema, alopecia, angioedema, pemphigoid, photosensitivity reactions, neck pain, muscle fatigue, micturition disorder, nocturia, pollakiuria, renal failure, erectile dysfunction, gynecomastia, chest pain, pain, malaise, oedema peripheral, pyrexia, blood urea increased, blood creatinine increased, weight increase, white blood cells urine positive, weight decrease, fall. Rare: Thrombocytopenia, confusional state, neuropathy peripheral, cholestasis, psoriasis aggravation, stevens-johnson syndrome, toxic epidermal necrolysis, erythema multiforme, myopathy, myositis, rhabdomyolysis, muscle rupture, tendinopathy sometimes complicated by rupture, hepatic enzymes increased, blood bilirubin increased. Very rare: Leucopenia/neutropenia, agranulocytosis or pancytopenia, haemolytic anaemia in patients with a congenital deficiency of g-6pdh, haemoglobin decreased and haematocrit decreased, anaphylaxis, hypertonia, hearing loss, myocardial infarction secondary to excessive hypotension in high-risk patients, angina pectoris, stroke possible secondary to excessive hypotension in high-risk patients, eosinophilic pneumonia, gastritis, gingival hyperplasia, jaundice, hepatic failure, exfoliative dermatitis, lupus-like syndrome, renal failure acute. Not known: immune-mediated necrotizing myopathy, extrapyramidal disorder (extrapyramidal syndrome), Raynaud’s phenomenon. Syndrome of inappropriate antidiuretic hormone secretion (SIADH) can be considered as a very rare complication associated with ACE inhibitor therapy. OVERDOSE*. PROPERTIES*: Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase. Perindopril is an inhibitor of the enzyme that converts angiotensin I into angiotensin II (Angiotensin Converting Enzyme ACE). Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle. PRESENTATION*: Box of 30 film-coated tablets for Lipertance 10mg/5mg/5mg, 20mg/5mg/5mg, 20mg/10mg/5mg, 20mg/10mg/10mg, 40mg/10mg/10mg.

FOR BOTH LIPERTANCE AND LIPERCOSYL: MARKETING AUTHORISATION HOLDER Les Laboratoires Servier, 50 rue Carnot, 92284 Suresnes cedex France. www.servier.com. Marketing Authorisation number: PA0568/028/001-005 (LPT) PA0568/032/001-006 (LPC). Legal Classification for Supply: Lipertance and Lipercosyl POM. Further information available from: Servier Laboratories (Ireland) Ltd. Second Floor, 19 Lr. George’s Street, Dun Laoghaire, Co. Dublin A96 ER84, Ireland. Tel (01) 6638110, www.servier.ie. *For complete information, please refer to the Summary of Product Characteristics available on medicines.ie.

Date of last revision of text: June 2021 (Date of last approved SmPC: August 2021). 2122 C1 LPT.LPC Press ad CBU. Date of Preparation September 2021 1. Lipertance SmPC, August 2021 2. IMS Data, C11A Monthly Sales, June 2021. ACEi = Angiotensin-converting-enzyme inhibitors; CCB= Calcium channel blocker.

▼ The Next Line Is Clear¹

LORVIQUA as monotherapy is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) whose disease has progressed after: •

lectinib or ceritinib as the first ALK tyrosine kinase a inhibitor (TKI) therapy; or

•

crizotinib and at least one other ALK TKI.1

References: 1. Lorviqua® Summary of Product Characteristics.

PRESCRIBING INFORMATION ▼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. Refer to section 4.8 of the SPC for how to report adverse reactions.

Lorviqua®▼ 25 mg and 100 mg film-coated tablets IE Prescribing Information: Before prescribing Lorviqua (lorlatinib) please refer to the full Summary of Product Characteristics (SmPC). Presentation: Each 25 mg film-coated tablet contains 25 mg lorlatinib; Each 100 mg film-coated tablet contains 100 mg lorlatinib. Indications: Lorviqua as monotherapy is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK) positive advanced non small cell lung cancer (NSCLC) whose disease has progressed after alectinib or ceritinib as the first ALK tyrosine kinase inhibitor (TKI) therapy, or crizotinib and at least one other ALK TKI. Dosage and Administration: Treatment should be initiated and supervised by a physician experienced in the use of anticancer medicinal products. The recommended dose is 100 mg lorlatinib taken orally once daily. Treatment is recommended as long as the patient is deriving clinical benefit from therapy without unacceptable toxicity. If a dose is missed, then it should be taken as soon as the patient remembers unless it is less than 4 hours before the next dose. Patients should not take 2 doses at the same time to make up for a missed dose. To manage adverse reaction, dose interruption or dose reduction see SmPC section 4.2. Concurrent use of lorlatinib with medicinal products that are strong CYP3A4/5 inhibitors and grapefruit juice products may increase lorlatinib plasma concentrations, see SmPC section 4.2 for further information. Special populations: Elderly (≥ 65 years): There are limited data on this population, no dose recommendation can be made for patients aged 65 years and older (see section 5.2). Renal impairment: See SmPC section 4.2. No dose adjustment is required for patients with mild or moderate renal impairment. A reduced dose of lorlatinib is recommended in patients with severe renal impairment (absolute eGFR < 30 mL/min), e.g. a once daily starting dose of 75 mg taken orally (see SmPC section 5.2). No information is available for patients on renal dialysis. Hepatic impairment: See SmPC section 4.2. No dose adjustment is required for patients with mild hepatic impairment. No information is available for lorlatinib in patients with moderate or severe hepatic impairment. Therefore, lorlatinib is not recommended in patients with moderate to severe hepatic impairment (see section 5.2). Paediatric population: The safety and efficacy of lorlatinib in children and adolescents < 18 years of age have not been established. Method of administration: Lorlatinib is for oral use. Patients should be encouraged to take their dose of lorlatinib at approximately the same time each day with or without food (see SmPC section 5.2). The tablets should be swallowed whole (tablets should not be chewed, crushed or split prior to swallowing). No tablet should be ingested if it is broken, cracked, or otherwise not intact.

Contra-indications: Hypersensitivity to the active substance or to any of the excipients. Concomitant use of strong CYP3A4/5 inducers (see SmPC sections 4.4 and 4.5). Special Warnings and Precautions: Hyperlipidaemia: The use of lorlatinib has been associated with increases in serum cholesterol and triglycerides (see SmPC section 4.8). Serum cholesterol and triglycerides should be monitored before initiation of lorlatinib; 2, 4 and 8 weeks after initiating lorlatinib and regularly thereafter. Initiate or increase the dose of lipid lowering medicinal products, if indicated (see SmPC section 4.2). Central nervous system (CNS) effects: CNS effects have been observed in patients receiving lorlatinib, including psychotic effects and changes in cognitive function, mood, mental status or speech (see SmPC section 4.8). Dose modification or discontinuation may be required for those patients who develop CNS effects (see SmPC section 4.2).

Atrioventricular block: Lorlatinib was studied in a population of patients that excluded those with second degree or third degree AV block (unless paced) or any AV block with PR interval > 220 msec. PR interval

prolongation and AV block have been reported in patients receiving lorlatinib (see SmpC section 5.2). Monitor electrocardiogram (ECG) prior to initiating lorlatinib and monthly thereafter, particularly in patients with predisposing conditions to the occurrence of clinically significant cardiac events. Dose modification may be required for those patients who develop AV block (see SmPC section 4.2). Left ventricular ejection fraction decrease: Left ventricular ejection fraction (LVEF) decrease has been reported in patients receiving lorlatinib who had baseline and at least one follow-up LVEF assessment. In patients with cardiac risk factors and those with conditions that can affect LVEF, cardiac monitoring, including LVEF assessment at baseline and during treatment, should be considered. In patients who develop relevant cardiac signs/symptoms during treatment, cardiac monitoring, including LVEF assessment, should be considered.

Lipase and amylase increase: Elevations of lipase and/or amylase have occurred in patients receiving lorlatinib (see SmPC section 4.8). Risk of pancreatitis should be considered in patients receiving lorlatinib due to concomitant hypertriglyceridemia and/or a potential intrinsic mechanism.

Patients should be monitored for lipase and amylase elevations prior to the start of lorlatinib treatment and regularly thereafter as clinically indicated (see SmPC section 4.2). Interstitial lung disease/Pneumonitis: Severe or life threatening pulmonary adverse reactions consistent with ILD/pneumonitis have occurred with lorlatinib (see SmPC section 4.8). Any patient who presents with worsening of respiratory symptoms indicative of ILD/ pneumonitis (e.g. dyspnoea, cough and fever) should be promptly evaluated for ILD/pneumonitis. Lorlatinib should be withheld and/or permanently discontinued based on severity (see SmPC section 4.2).

Hypertension: Hypertension has been reported in patients receiving lorlatinib (see SmPC section 4.8). Blood pressure should be controlled prior to initiation of lorlatinib. Blood pressure should be monitored after 2 weeks and at least monthly thereafter during treatment with lorlatinib.

Lorlatinib should be withheld and resumed at a reduced dose or permanently discontinued based on severity (see SmPC section 4.2).

Hyperglycaemia: Hyperglycaemia has occurred in patients receiving lorlatinib (see SmPC section 4.8). Fasting serum glucose should be assessed prior to initiation of lorlatinib and monitored periodically thereafter according to national guidelines. Lorlatinib should be withheld and resumed at a reduced dose or permanently discontinued based on severity (see SmPC section 4.2). Interactions: Concomitant use of a strong CYP3A4/5 inducer is contraindicated (see SmPC sections 4.3 and 4.5). No clinically meaningful changes in liver function tests were seen in healthy subjects after receiving a combination of lorlatinib with the moderate CYP3A4/5 inducer modafinil (see section 4.5). Concurrent administration of lorlatinib with CYP3A4/5 substrates with narrow therapeutic indices, including but not limited to alfentanil, ciclosporin, dihydroergotamine, ergotamine, fentanyl, hormonal contraceptives, pimozide, quinidine, sirolimus and tacrolimus, should be avoided since the concentration of these medicinal products may be reduced by lorlatinib (see SmPC section 4.5). Lorlatinib is a weak inducer of CYP2B6, no dose adjustment is necessary when lorlatinib is used in combination with medicinal products that are mainly metabolised by CYP2B6 (see SmPC section 4.5). Lorlatinib is a weak inducer of CYP2C9, no dose adjustment is required for medicinal products that are mainly metabolised by CYP2C9. Patients should be monitored in case of concomitant treatment with medicinal products with narrow therapeutic indices metabolised by CYP2C9 (e.g. coumarin anticoagulants) (see SmPC section 4.5). Lorlatinib is a weak inducer of UGT, no dose adjustment is required for medicinal products that are mainly metabolised by UGT. Patients should be monitored in case of concomitant treatment with medicinal products with narrow therapeutic indices metabolised by UGT (see SmPC Section 4.5). Lorlatinib is a moderate inducer of P gp. Medicinal products that are P gp substrates with narrow therapeutic indices (e.g. digoxin, dabigatran etexilate) should be used with caution in combination with lorlatinib due to the likelihood of reduced

PP-LQA-IRL-0068

Preparation Date: September 2021

plasma concentrations of these substrates. Lorlatinib should be used with caution in combination with substrates of BCRP, OATP1B1, OATP1B3, OCT1, MATE1 and OAT3 as clinically relevant changes in the plasma exposure of these substrates cannot be ruled out (see SmPC section 4.5).

Fertility, pregnancy and Breast-feeding: Fertility: Male fertility may be compromised during treatment with lorlatinib (see SmPC section 5.3). Men should seek advice on effective fertility preservation before treatment. It is not known whether lorlatinib affects female fertility. Pregnancy: Lorlatinib is not recommended during pregnancy or for women of childbearing potential not using contraception. Women of childbearing potential should be advised to avoid becoming pregnant while receiving lorlatinib. A highly effective non hormonal method of contraception is required for female patients during treatment because lorlatinib can render hormonal contraceptives ineffective (see SmPC sections 4.5 and 4.6). If a hormonal method of contraception is unavoidable, then a condom must be used in combination with the hormonal method. Effective contraception must be continued for at least 35 days after completing therapy (see SmPC section 4.6). During treatment and for at least 14 weeks after the final dose, male patients with female partners of childbearing potential must use effective contraception, including a condom, and male patients with pregnant partners must use condoms (see SmPC section 4.6).

Breast-feeding: Lorlatinib should not be used during breast feeding. Breast feeding should be discontinued during treatment and for 7 days after the final dose. Lactose intolerance: This medicinal product contains lactose as an excipient. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose galactose malabsorption should not take this medicinal product. Effects on ability to drive and use machines: Lorlatinib has moderate influence on the ability to drive and use machines. Caution should be exercised when driving or operating machines as patients may experience CNS effects (see SmPC section 4.8).

Undesirable Effects: See SmPC section 4.8. The overall safety profile of lorlatinib is presented from data from 295 adults treated with lorlatinib 100 mg once daily with advanced NSCLC from Study A (Phase II 1001 (n=275), Phase I (n=17), Japanese Cohort (n=3)). The most common (≥2%) Grade ≥3 adverse reactions of lorlatinib were Anaemia, Hypercholesterolaemia, Hypertriglyceridaemia, Cognitive effects, Peripheral neuropathy, Oedema, Weight increased, Lipase increased, Amylase increased. Commonly reported adverse events (≥ 1/100 to < 1/10) were Hyperglycaemia, Psychotic effects, Mental status changes, Speech effects, Pneumonitis. Dose reductions due to adverse reactions occurred in 23.4% of patients receiving lorlatinib. Very common (≥ 1/10) adverse reactions in patients receiving lorlatinib in this study were Anaemia, Hypertension, Hypercholesterolaemia, Hypertriglyceridaemia, Mood effects, Cognitive effects, Peripheral neuropathy, Headache, Vision disorder, Diarrhoea, Nausea, Constipation, rash, Arthralgia, Myalgia, Oedema, Fatigue, Weight increased, Lipase increased, Amylase increased.

Common (≥ 1/100 to < 1/10) adverse effects were Speech effects, Pneumonitis. Legal Category: S1A. Package quantities and Marketing Authorisation Numbers: Lorviqua 25 mg film-coated tablets EU/1/19/1355/003, 90 tablets. Lorviqua 100 mg film-coated tablets EU/1/19/1355/002, 30 tablets. For further information on this medicine please contact: Pfizer Medical Information on 1800 633 363 or at EUMEDINFO@pfizer.com For queries regarding product availability please contact: Pfizer Healthcare Ireland, Pfizer Building 9, Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24 + 353 1 4676500. Marketing Authorisation Holder: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium.

Date of Preparation: 07/2021 Ref: LQ 5_0

CPD 81: LUNG CANCER Continuing Professional Development

AUTHOR: Dr Jarushka Naidoo and Dr David McMahon

CPD

Dr Jarushka Naidoo MB BCH MHS is a Consultant Medical Oncologist at Beaumont Hospital and The Royal College of Surgeons in Ireland. She is Lung Cancer Lead at Cancer Trials Ireland and Adjunct Assistant Professor of Oncology, at Johns Hopkins University USA. Her specialty interests are in thoracic oncology, melanoma, immunotherapy and clinical trials.

60 Second Summary

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

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?

Lung cancer is the single largest contributor to cancerrelated death in Ireland. The majority of patients with lung cancer have non-small cell lung cancer (NSCLC) histology (80-85%), while a minority represent small-cell lung cancer.

The discovery of the Anaplastic Lymphoma Kinase (ALK) rearrangement is one of the major success stories of personalized medicine in NSCLC. ALK rearrangements have also been identified in other cancer types including oesophageal, renal cell, serous ovarian and several haematologic malignancies, but it is in NSCLC that progress in ALK targeting has been greatest.

Its role as an oncogenic driver in other cancers is less clearly understood.

The first targeted agent for this rare subtype of NSCLC to be clinically developed, was Crizotinib. The phase III PROFILE 1014 trial conducted in 2011 established Crizotinib as a new standard of care for ALK-rearranged NSCLC, by demonstrating a benefit in survival outcomes compared with chemotherapy in patients with ALK-rearranged NSCLC. The side effect profile of each of the ALK inhibitors are distinct, and provide critical information to tailor treatment choice. Class side effects of ALK-TKIs include peripheral oedema and GI disturbance.

Unfortunately, most ‘oncogene-addicted’ tumours will ‘acquire resistance’ to targeted therapies over time through a number of mechanisms, leading to progressive disease.

39

Dr David McMahon MB, BCH, BAO (Hons) LRCPI is a Specialist Registrar in the Medical Oncology at Beaumont Hospital. He graduated from RCSI in 2015. He is a member of Cancer Trials Ireland. His subspecialty interest is in thoracic oncology.

3. PLAN - If I have identified a

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. 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.

ALK–rearranged lung cancer: new treatments, better outcomes Lung cancer is the single largest contributor to cancer-related death in Ireland. The majority of patients with lung cancer have non-small cell lung cancer (NSCLC) histology (80-85%), while a minority represent smallcell lung cancer. Historically, histological subtyping alone in NSCLC has guided prognosis

and treatment selection for patients with this cancer type.

However, in the last 10 years, it is now a widely accepted standard of care to perform a panel of genomic tests. These tests identify therapeutically actionable cancer-causing genes (oncogenes), which can guide selection of more focused

and often more successful ‘targeted therapies.’ Broadly, the development and use of targeted therapies in cancer has been referred to as either “precision” or “personalized” oncology, as patients receive treatments that are tailored towards the specific genomic features of their cancer type. Genomic testing in

: The40breakdown of oncogenic mutations in Non-Small cell Lung Cance CPD 81: LUNG CANCER

Figure 1: The breakdown of oncogenic mutations in Non-Small cell lung Cancer NSCLC has led to the discovery of >10 oncogenes that can be therapeutically targeted (Figure 1), and thus led to significant benefits in patient quality and quantity of life.

quoted for patients with NSCLCs that do not harbor an oncogenic driver mutation.

The oncogenic ‘ALKrearrangement’ occurs in approximately 4-8% of NSCLC. Echinoderm microtubuleassociated protein-like 4 (EML4)-ALK fusion is the most prevalent rearrangement, but ALK gene alterations including mutations, deletions and other rearrangements are also well described. Wild-type (ie ‘normal’) ALK protein is a transmembrane tyrosine kinase, however this oncogenic rearrangement leads to the uncontrolled growth of cancer cells.

and several haematologic malignancies, but it is in NSCLC that progress in ALK targeting has been greatest. Its role as an oncogenic driver in other cancers is less clearly understood.

2 ALK inhibitors approved for use in Ireland ALK-rearranged NSCLC: A subset of NSCLC with rapidly expanding treatment options

nhibitor nib (Xalkori®, Pfizer) The discovery of the Anaplastic Lymphoma Kinase (ALK) rearrangement is one of the major success stories of personalized medicine in NSCLC. Due to a number of successful clinical trials that led to approvals for >5 different ALK-targeting agents, patients with ALK-rearranged NSCLC now have a median survival of approximately 5-7 years. This is substantially longer, compared with the median survival of 12-18 months which is

ALK-rearranged NSCLC is associated with certain clinical characteristics, in that patients with this subset of NSCLC are more likely to be young, of asian ethinicity, and either never smokers, or have a distant history of light smoking.

ALK-rearranged NSCLC can also exhibit a unique biological behaviour, with a predisposition for intracranial spread.

Generation 1st

nib (Alcensa®, Roche) nib (Alunbrig®, Takeda)

2nd

nib (Lorbrena®, Pfizer)

3rd

ALK rearrangements have also been identified in other cancer types including oesophageal, renal cell, serous ovarian

All patients with newly diagnosed non-squamous NSCLC should have their cancers tested for the presence of an ALK rearrangement along with

other genomic alterations, to inform potential targeted treatment. ALK-rearrangements may be tested for using nextgeneration sequencing, FISH (fluorescent in-situ hybridization) or immunohistochemical testing, however FISH is the accepted gold standard. If an ALK rearrangement is detected, several ALK-TKI treatment options may be appropriate treatment options.

Targeted therapy for ALKrearranged NSCLC The first targeted agent for this rare subtype of NSCLC to be clinically developed, was Crizotinib. The phase III PROFILE 1014 trial conducted in 2011 established Crizotinib as a new standard of care for ALK-rearranged NSCLC, by

41

Figure 2 ALK inhibitors approved for use in Ireland ALK Inhibitor Crizotinib (Xalkori®, Pfizer)

Generation 1st

Alectinib (Alcensa®, Roche) Brigatinib (Alunbrig®, Takeda)

2nd

Lorlatinib (Lorbrena®, Pfizer)

3rd

Figure 2 ALK inhibitors approved for use in Ireland

demonstrating a benefit in survival outcomes compared with chemotherapy in patients with ALK-rearranged NSCLC. Specifically, this trial showed a median progression-free survival (PFS) benefit of 7.7 months for Crizotinib vs 3.0 months for chemotherapy.

Second generation TKIs are more potent inhibitors of ALK. The development of 2nd generation ALK inhibitors, Alectinib, Ceritinib and Brigatinib, have brought further promise. Late phase clinical trials have elucidated that these agents confer a benefit in PFS compared with Crizotinib.

Specifically, these studies include the ALEX trial (Alectinib versus Crizotinib in previously untreated ALK-rearranged NSCLC) and the ALTA-1L trial (Brigatinib versus Crizotinib in previously untreated ALK-rearranged NSCLC). These newer drugs also demonstrate superior intracranial disease control than that seen with Crizotinib. Ceritinib was demonstrated in the ASCEND-4 trial to have a superior PFS than platinum-based chemotherapy with pemetrexed (an anti-folate chemotherapeutic agent).

As mentioned earlier, ALKrearranged NSCLC has a predilection for intracranial spread, making drugs which effectively cross the blood-brain barrier a focus of recent research.

The most promising approved drug with regards to intracranial disease control is Lorlatinib, a 3rd generation TKI. Lorlatinib has an 82% intracranial response rate, compared to 23% with Crizotinib, in those with measurable disease at baseline. Impressively, Lorlatinib demonstrated that 71%

of patients with brain metastases had a complete intracranial response - no visible disease in this area on subsequent imaging.

Encouragingly, the 12-month PFS was 78% in the Lorlatinib arm compared to 39% in the Crizotinib arm.

What are the side effects of targeted therapy?

The side effect profile of each of the ALK inhibitors are distinct, and provide critical information to tailor treatment choice.

Class side effects of ALK-TKIs include peripheral oedema, ECG changes (QT prolongation and bradycardia) and GI disturbance. Serious adverse events are rare. Side effects of Lorlatinib include but are not limited to: hypercholesterolemia, hypertriglyceridemia, oedema, weight gain, peripheral neuropathy, cognitive affects and hypertension. Indeed, 72% of patients had grade 3 or higher toxicity (although no deaths were reported) in the registration trial of Lorlatinib referenced above.

Only 7% of patients experienced side effects requiring cessation of treatment. Cognitive effects were mainly grade 1 and respond to treatment interruption, and mainly consisted of inattention and memory impairment.

In contrast, there are side effects of particular interest with each ALK inhibitor. For example, Crizotinib requires careful monitoring of LFTs and can cause flashing lights, floaters or other mild visual phenomena that are mild and short-lived, but is otherwise well tolerated.

Alectinib is known to cause anaemia, arthralgia and myalgia,

and Brigatinib can lead to rises in CK, amylase and lipase, as well as a classic interstitial lung toxicity. Ceritinib causes GI disturbance, with diarrhea, nausea and vomiting. As a result of their slightly different side effect profiles, the choice of ALK inhibitor is individualized, while also taking into account patient preference, licensing and burden of intracranial disease.

and for monitoring of therapy on a monthly basis thereafter.

It is also important to note, despite side effects being significantly higher in the Lorlatinib arm when compared head-to-head with Crizotinib, quality of life, as measured by validated patient reported outcome scores, was improved in the Lorlatinib arm, presumably due to a reduction in cancer related symptoms.

Acquired resistance to targeted therapy

The management of side effects of ALK-inhibitors often consists of dose interruption or dose reduction. Use of statins for hypercholesterolemia and hypertriglyceridemia is common, as is the use of diuretics for fluid retention. It is important given the average life expectancy of patients is 5-7 years to treat this subset of lung cancer patients as we would patients with any other chronic disease.

The overall health of patients is monitored, with optimization of chronic disease management for any co-existing illnesses. The NCCP protocols for these agents give clear guidance for when to consider introducing lipidlowering therapy for example.

The NCCP protocols also outline baseline evaluations required prior to initiation of therapy (ECG, biochemical evaluation, haematological evaluation etc)

Importantly, if severe side effects do develop, amelioration of this adverse events is possible with cessation of therapy.

Future efforts in drug development seek not only to maximize the efficacy of anti-cancer therapies, but also minimize side effect profiles.

While direct targeting of the defective protein often leads to tumour shrinkage and control, unfortunately, most ‘oncogeneaddicted’ tumours will ‘acquire resistance’ to targeted therapies over time through a number of mechanisms, leading to progressive disease. Acquired resistance in ALK-rearranged NSCLC may be due to development of secondary ALK mutations, activation of ‘bypass’ signaling pathways, development of alternative mutations e.g. cMET/HER2, epigenetic changes or transformation to different subtypes e.g. small cell transformation. The most common secondary mutations to develop after initial treatment with an ALK-TKI include L1196M and G1269A. These alterations can be identified via conventional tumour biopsy of a progressing area, or assessment by ‘liquid biopsy,’ a test that detects circulating tumour DNA in the blood. This also has the ability to account for heterogeneity of tumour cell clones – and is both quicker and less invasive. It also allows for repeated assessment over time which can be correlated with radiological and clinical response.

42

CPD 81: LUNG CANCER treatment with 2-3 ALK inhibitors before requiring treatment with chemotherapy. Chemotherapy is rarely associated with the longer duration of response seen with ALK inhibition, and is also less likely to achieve intracranial disease control. There is always also a role for radiotherapy as an option in patients with a limited number of areas of progressive cancer (‘oligoprogressive disease’) or areas causing clinically meaningful symptoms e.g., pain or mass effect, throughout the treatment course of patients with this disease.

Conclusions and Future Directions

Treatment beyond ALK Inhibitors Interestingly, patients with ALK-rearranged NSCLC typically have a poor response to immunotherapy. This is thought to be due to an immunesuppressive microenvironment in ALK-rearranged NSCLC which leads to immune evasion. As a result of known poor response

to immunotherapy in oncogeneaddicted NSCLC, these patients are now routinely excluded from first-line trials of immunotherapy in NSCLC. There is biological rationale for overcoming this immune refractory tumour microenvironment in ALKrearranged NSCLC in the future, but for now the treatment paradigm of ALK-rearranged NSCLC is firmly established, with

TKIs and chemotherapy playing the largest role.

These cancers respond similarly to other subtypes of NSCLC when treated with chemotherapy, which remains an option in later lines of therapy or in rare cases where patients may be unsuitable for treatment with ALK-TKIs. It is common for patients with an ALK rearrangement to undergo

ALK-rearranged lung cancer is an example of how bench to bedside (and back again) research has led to several new treatment options, that have translated into tangible benefits in survival for patients. The story of target oncogene identification, drug development, clinical trials and real-world efficacy and tolerability is the foundation for personalized medicine. Long may lung cancer reign, as the poster-child of this approach in oncology.

References on request

Beating Cancer: Reclaim Lost Momentum to Deliver Measurable Advances February 2020 marked a unique turning point in the fight against cancer. Cancer stakeholders – including oncology experts, patients and industry – stepped up collaboration on cancer policy at EU level. It was a key moment: the European Commission had just opened a consultation that promised a new era in cancer care. Optimism was in the air.

Then COVID-19 struck. Within weeks, the world had changed.

People with cancer found their appointments cancelled or moved online. Treatment and clinical trials were disrupted. Screening was paused.

However, at the policy level, momentum never stopped. An intensive one-year consultation period led to the publication of Europe’s Beating Cancer Plan – an impressive achievement under challenging circumstances.

We applauded the Plan, while stressing the importance of measuring progress.

This year’s European Health Forum Gastein (EHFG) offered an opportunity to reflect on

the impact of the COVID-19 pandemic and the opportunities of the new Beating Cancer Plan. At a session organised by the EFPIA Oncology Platform, the European Cancer Patient Coalition and European Cancer Organisation there was a strong sense that the Plan provides a platform on which to build back to a “new better” the cancer care system. Cancer care could – to borrow the theme of this year’s EHFG – rise like a Phoenix in the post-pandemic world.

Building a Data-driven Cancer Service However, the event also heard some worrying data that made us sit up and take notice. There have been 100 million missed screening tests in the EU during the pandemic. This means that 1 million people may be walking around unaware that they have cancer.

There is also deep concern that the advances in patient outcomes gained in the decade before the pandemic could be lost. Not only could the pace of progress slow,

but there is also a real risk of going backwards.

Despite this well-founded fear, we remain optimistic that Europe has an unprecedented opportunity for progress. If we unite and act now in unison, we can create a future that is far better than anything that has gone before. We can revert the current trend that sees cancer becoming the leading cause of death in the EU by 2035.

At the heart of this will be data and the ability to use them.

Europe’s Beating Cancer Plan includes an inequalities registry, designed to bridge the gap between Member States. The OECD has been appointed to explore this, and we look forward to engaging on this key topic.

But we also see the need to go further. The Plan cannot be a success unless we demonstrate progress. A public-facing measurement system displaying key indicators would empower patients and policymakers with the information required to drive change. We trust in plans but what gets measured gets done.

We need a jointly agreed set of indicators, defined by an expert group with input from all stakeholders. This does not take years to be developed – it can be built from existing indicators and introduced as swiftly as possible.

Tracking key indicators is not to name, shame or blame. It is to have an up-to-date picture of progress on the core areas of cancer, to learn what works and what doesn’t, and provide an early warning system in case implementation is in danger of drifting off course. It is for citizens to understand and be involved.

Seizing the Moment – Together Europe has never had a better chance than this to get cancer services right. Key policymaking institutions are on board while experts, patients and industry are ready to play their part. But cancer cannot wait – and neither can we. Now is the moment to ensure that the Beating Cancer Plan is a success.

Flexible scheduling for your second-line non-small cell lung cancer patients*1-3 Every 3 weeks: Fixed dose 1200 mg IV (1 vial)

2

OR

Every 4 weeks: Fixed dose 1680 mg IV (2 x 840 mg vials)3

Once prepared, TECENTRIQ remains stable for up to 30 days at 2-8°C. However, to avoid the risk of contamination, immediate use is always recommended.2,3 Please see Summary of Product Characteristics for further details.2,3 *A study examined the exposure-response relationship between TECENTRIQ’s efficacy and safety in patients with non-small cell lung cancer using data from pooled Phase I and III studies in non-small cell lung cancer and urothelial carcinoma. Population pharmacokineticsimulated exposures for the 1680mg Q4W were compared with the previously approved 1200mg Q3W. The results from the study support the interchangeable use of 1200mg Q3W and 1680mg Q4W dosing regimens for atezolizumab, as they are anticipated to demonstrate comparable efficacy and safety profiles while offering patients greater flexibility and convenience in their treatment.1

TECENTRIQ as monotherapy is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) after prior chemotherapy.

Patients with EGFR mutant or ALK-positive NSCLC should have received targeted therapies before receiving TECENTRIQ.2,3 2L, 2nd line. References: 1. Morrissey, K.M et al.

Cancer Chemother Pharmacol 2019; 84: 1257–1267. 2. TECENTRIQ 1,200 mg concentrate for solution for infusion Summary of Product Characteristics 06 May 2021 available on www.medicines.ie. 3. TECENTRIQ 840 mg concentrate for solution for infusion Summary of Product Characteristics 06 May 2021, available on www.medicines.ie. Date of item: July 2021. M-IE-00000762. ABRIDGED PRESCRIBING INFORMATION (API). For full prescribing information refer to the Summary of Product Characteristics [SmPC]. Tecentriq® (atezolizumab)

▼ 1,200 mg concentrate for solution for infusion (One 20 ml vial of concentrate contains 1,200 mg atezolizumab) and 840 mg concentrate for solution for ▼

This medicinal product is subject to additional monitoring. This will allow quick identification of new infusion (One 14 ml vial of concentrate contains 840mg of atezolizumab). safety information. Healthcare professionals are asked to report any suspected adverse reactions. See box below for details on how to report. Therapeutic Indications: Tecentriq 1,200mg and 840mg: As monotherapy for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma (UC) after prior platinum-containing chemotherapy, or who are considered cisplatin ineligible and whose tumours have a PD-L1 expression ≥ 5%. As monotherapy for the first-line (1L) treatment of adult patients with metastatic nonsmall cell lung cancer (NSCLC) whose tumours have a PD-L1 expression ≥ 50% tumour cells (TC) or ≥ 10% tumour-infiltrating immune cells (IC) and who do not have EGFR mutant or ALK-positive NSCLC. As monotherapy for the treatment of adult patients with locally advanced or metastatic NSCLC after prior chemotherapy. Patients with EGFR mutant or ALKpositive NSCLC should also have received targeted therapies before receiving Tecentriq. Tecentriq 1,200mg: In combination with bevacizumab, paclitaxel and carboplatin for the 1L treatment of adult patients with metastatic non-squamous NSCLC. In combination with bevacizumab, paclitaxel and carboplatin, for patients with EGFR mutant or ALK-positive NSCLC, is indicated only after failure of appropriate targeted therapies. In combination with nab-paclitaxel and carboplatin, for the 1L treatment of adult patients with metastatic NSCLC who do not have EGFR mutant or ALK-positive NSCLC. In combination with carboplatin and etoposide, for the 1L treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC). In combination with bevacizumab, is indicated for the treatment of adult patients with advanced or unresectable hepatocellular carcinoma (HCC) who have not received prior systemic therapy. Tecentriq 840mg: In combination with nab-paclitaxel for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumours have PD-L1 expression ≥ 1% and who have not received prior chemotherapy for metastatic disease. Posology and Method of Administration: The initial dose must be administered over 60 minutes and if well tolerated, subsequent infusions may be administered over 30 minutes. It must not be administered as an intravenous push or bolus. For instructions on dilution and handling, refer to SmPC. For combination therapies refer to the full prescribing information for the combination products. Recommended to treat patients until loss of clinical benefit or unmanageable toxicity for (2L) NSCLC, 2L UC and HCC; or until disease progression or unmanageable toxicity for 1L NSCLC, 1L UC, 1L ES-SCLC and TNBC. Atypical responses (i.e., an initial disease progression followed by tumour shrinkage) have been observed with continued Tecentriq treatment after disease progression. Treatment beyond disease progression may be considered at the discretion of the physician, for 1L NSCLC (Tecentriq in combination therapy) and 1L ES-SCLC. Administer Tecentriq as soon as possible if a planned dose is missed and adjust administration schedule to maintain a regular schedule. Dose reduction is not recommended. Dose delay or discontinuation may be required based on individual safety and tolerability, refer to SmPC. The safety and efficacy of Tecentriq in children and adolescents (< 18 years) has not been established, and no posology recommendation can be made. PD-L1 testing: Tecentriq monotherapy: Patients with 1L (cisplatin ineligible) UC and 1L NSCLC should be selected for Tecentriq treatment based on the tumour expression of PD-L1 by a validated test (1L (cisplatin ineligible) UC: PD-L1 ≥ 5%, 1L NSCLC: PD-L1 ≥ 50% TC or >10% IC). Tecentriq in combination therapy: Patients with previously untreated TNBC should be selected for treatment based on the tumour expression of PD-L1 ≥1% confirmed by a validated test. Refer to 1,200mg SmPC (1L UC and 1L NSCLC). Refer to 840mg SmPC (UC, TNBC or NSCLC). UC, 1L NSCLC and 2L NSCLC: Tecentriq monotherapy: 1,200mg administered intravenously every three weeks, or 840mg administered intravenously every 2 weeks, or 1,680 mg administered intravenously every 4 weeks. 1L NSCLC: Tecentriq in combination with bevacizumab, paclitaxel, and carboplatin: Induction phase recommended dose of Tecentriq is 1,200 mg administered by intravenous infusion, followed by bevacizumab, paclitaxel, and then carboplatin every 3 weeks for 4 or 6 cycles; followed by a maintenance phase without chemotherapy in which 1,200 mg Tecentriq followed by bevacizumab, is administered by intravenous infusion every 3 weeks. Tecentriq in combination with nab-paclitaxel and carboplatin: Induction phase recommended dose of Tecentriq is 1,200 mg administered by intravenous infusion, followed by nab-paclitaxel and carboplatin every three weeks for 4 or 6 cycles. For each 21-day cycle, Tecentriq, nab-paclitaxel, and carboplatin are administered on day 1. Nab-paclitaxel is administered on days 8 and 15. The induction phase is followed by a maintenance phase without chemotherapy in which 1,200 mg Tecentriq is administered by intravenous infusion every three weeks. ES-SCLC: Tecentriq in combination with carboplatin and etoposide: Induction phase recommended dose of Tecentriq is 1,200 mg

administered by intravenous infusion followed by carboplatin, and then etoposide administered by intravenous infusion on day 1. Etoposide is also administered by intravenous infusion on days 2 and 3. This regimen is administered every three weeks for four cycles; followed by a maintenance phase without chemotherapy in which 1,200 mg Tecentriq is administered by intravenous infusion every three weeks. TNBC: Tecentriq in combination with nab-paclitaxel: The recommended dose of Tecentriq is 840 mg administered by intravenous infusion, followed by 100mg/m2 nab-paclitaxel. For each 28-day cycle, Tecentriq is administered on days 1 and 15, and nab-paclitaxel is administered on days 1, 8, and 15. HCC: Tecentriq in combination with bevacizumab: The recommended dose of Tecentriq is 1,200 mg followed by bevacizumab 15 mg/kg of body weight, administered by intravenous infusion every three weeks. Contraindications: Hypersensitivity to Tecentriq or to any of the excipients listed in the SmPCs. Special Warnings and Precautions for Use: Refer to Tecentriq 1,200mg and 840 mg SmPCs for full description of Special Warnings and Precautions. Tecentriq is associated with immune-related adverse reactions. For suspected immune-related adverse reactions, thorough evaluation should be performed to confirm aetiology or exclude other causes. Based on the severity of the adverse reaction, Tecentriq should be withheld and corticosteroids administered. Upon improvement to Grade ≤ 1, corticosteroids should be tapered over ≥ 1 month. Permanently discontinue treatment with Tecentriq for any recurrent Grade 3 immune-related adverse reactions, and for any Grade 4, except for endocrinopathies that are controlled with replacement hormones. Immune-related pneumonitis: Monitor patients for signs and symptoms of pneumonitis and causes other than immune-related pneumonitis should be ruled out. Treatment with Tecentriq must be permanently discontinued for Grade 3 or 4 pneumonitis. Immune-related colitis: Monitor patients for signs and symptoms of colitis. Treatment with Tecentriq must be permanently discontinued for Grade 4 (life threatening; urgent intervention indicated) diarrhoea or colitis. Immune-related hepatitis: Monitor patients for signs and symptoms of hepatitis, transaminase and bilirubin elevation. In patients without HCC, treatment with Tecentriq must be permanently discontinued for Grade 3 or Grade 4 events (ALT or AST>5.0 x ULN or blood bilirubin>3xULN). In patients with HCC, treatment with Tecentriq must be permanently discontinued if ALT or AST increases to > 10 x ULN or total bilirubin increases > 3 x ULN. Immune-related endocrinopathies: Monitor patients for clinical signs and symptoms of endocrinopathies. Thyroid function should be monitored prior to and periodically during treatment with Tecentriq. Treatment with Tecentriq should be permanently discontinued for Grade 4 hypophysitis. Immune-related meningoencephalitis: Monitor patients for clinical signs and symptoms of meningitis or encephalitis.

Treatment with Tecentriq must be permanently discontinued for any grade of meningitis or encephalitis. Immune-related neuropathies: Monitor patients for symptoms of motor and sensory neuropathy. Treatment with Tecentriq must be permanently discontinued for any grade of myasthenic syndrome/myasthenia gravis or Guillain-Barré syndrome. Immunerelated pancreatitis: Monitor patients closely for signs and symptoms suggestive of acute pancreatitis. Treatment with Tecentriq should be permanently discontinued for Grade 4, or any grade of recurrent pancreatitis. Immune-related myocarditis: Monitor patients for signs and symptoms of myocarditis. Treatment with Tecentriq must be permanently discontinued for Grade 3 or 4 myocarditis. Immune-related nephritis: Monitor patients for changes in renal function. Treatment with Tecentriq must be permanently discontinued for Grade 3 or 4 nephritis. Immune-related myositis: Monitor patients for signs and symptoms of myositis. Treatment with Tecentriq should be permanently discontinued for Grade 4 or 3 recurrent myositis. Infusion-related reactions (IRRs): Severe IRRs have been observed. Tecentriq must be permanently discontinued for grade 3 or 4 IRRs. Immune-related severe cutaneous adverse reactions (SCARs): (SCARs), including cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in patients receiving Tecentriq.

Monitor patients for suspected severe skin reactions and other causes should be excluded. For suspected SCARs, refer patients to a specialist for further diagnosis and management.

Based on the severity of the adverse reaction, Tecentriq should be withheld for Grade 3 skin reactions and treatment with systemic corticosteroids at a dose of 1-2 mg/kg/day of prednisone or equivalent should be started. Treatment may be resumed if the event improves to ≤ Grade 1 within 12 weeks, and corticosteroids have been reduced to ≤ 10 mg prednisone or equivalent per day. Treatment with Tecentriq should be permanently discontinued for Grade 4 skin reactions, and corticosteroids should be administered. Tecentriq should be withheld for patients with suspected SJS or TEN. For confirmed SJS or TEN, Tecentriq should be permanently discontinued. Caution should be used when considering the use of Tecentriq in a patient who has previously experienced a severe or life-threatening skin adverse reaction on prior treatment with other immune-stimulatory anticancer agents. Tecentriq in combination with bevacizumab, paclitaxel and carboplatin in metastatic NSCLC: Carefully consider the combined risks of the four-drug regimen of Tecentriq, bevacizumab, paclitaxel, and carboplatin before initiating treatment, refer to SmPC. Tecentriq in combination with nab-paclitaxel in metastatic TNBC: Neutropenia and peripheral neuropathies occurring during treatment with Tecentriq and nab-paclitaxel may be reversible with interruptions of nab-paclitaxel. Consult the nab-paclitaxel SmPC for specific precautions and contraindications.

Tecentriq in combination with bevacizumab in HCC: Severe gastrointestinal haemorrhage, including fatal events, were reported. Screening for and subsequent treatment of oesophageal varices should be performed as per clinical practice prior to starting treatment. Bevacizumab should be permanently discontinued in patients who experience Grade 3 or 4 bleeding with the combination treatment. Diabetes mellitus can occur. Monitor blood glucose levels prior to and periodically during treatment. Please refer to the bevacizumab SmPC. Tecentriq as monotherapy for 1L treatment in metastatic NSCLC: The delayed onset of Tecentriq effect should be considered before initiating 1L treatment as monotherapy in patients with NSCLC. A higher number of deaths within 2.5 months after randomisation followed by a long-term survival benefit was observed with Tecentriq compared with chemotherapy. No specific factor(s) associated with early deaths could be identified, refer to SmPC. Special Populations: Patients excluded from clinical trials included; baseline performance status ≥ 2, history of autoimmune disease and pneumonitis, active brain metastasis, HIV, hepatitis B or C infection (for non-HCC patients), significant cardiovascular disease and patients with inadequate hematologic and end–organ function, patients who were administered a live attenuated vaccine within 28 days prior to enrolment, systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medicinal products within 2 weeks prior to study entry; therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Use Tecentriq with caution in these populations, refer to SmPC for full list of specific precautions. Interactions: No formal pharmacokinetic drug interaction studies have been performed. Since Tecentriq is cleared from the circulation through catabolism, no metabolic drug-drug interactions are expected. The use of systemic corticosteroids or immunosuppressants should be avoided before starting Tecentriq. However systemic corticosteroids or other immunosuppressants can be used to treat immune-related adverse events after starting Tecentriq, refer to SmPC. Fertility, Pregnancy and Lactation: The effect of Tecentriq on fertility and pregnancy is unknown. Women of childbearing potential must use effective contraception methods during and for 5 months after treatment with Tecentriq. Tecentriq should not be used during pregnancy, unless the clinical condition of the woman requires treatment. It is not known whether Tecentriq is excreted in human milk. A risk t o newborns/infants cannot be excluded. Effects on ability to drive and use machines: Tecentriq has minor influence on the ability to drive and use machines. Advise patients experiencing fatigue not to drive and use machines until symptoms abate Undesirable Effects: Tecentriq monotherapy: Very common (≥ 1/10): cough, decreased appetite, headache, dyspnoea, musculoskeletal pain, nausea, vomiting, diarrhoea, urinary tract infections, rash, pruritus, arthralgia, back pain, pyrexia, fatigue, asthenia. Common (≥1/100 to <1/10): thrombocytopenia, hypothyroidism, hyperthyroidism, hypokalaemia, hyponatremia, hyperglycaemia, hypotension, pneumonitis, hypoxia, nasal congestion, nasopharyngitis, abdominal pain, colitis, dysphagia, oropharyngeal pain, infusion–related reaction, AST increased, ALT increased, hepatitis, dry skin, blood creatinine increased, influenza like illness, chills. Tecentriq in combination therapy: Very common (≥ 1/10): anaemia, thrombocytopenia, neutropenia, hypothyroidism, lung infection, leukopenia, decreased appetite, peripheral neuropathy, dyspnoea, nausea, diarrhoea, back pain, constipation, rash, pruritus, alopecia, arthralgia, pyrexia, oedema peripheral, headache, hypertension, fatigue, musculoskeletal pain, vomiting, cough, asthenia. Common (≥1/100 to <1/10): hypokalaemia, hyponatremia, dysgeusia, dysphonia, stomatitis, sepsis, infusion-related reaction, hypomagnesaemia, dizziness, lymphopenia, hyperthyroidism, syncope, AST increased, ALT increased, proteinuria, blood creatinine increased, blood alkaline phosphatase increased. Immunogenicity: 13.1%-54.1% of patients developed treatment-emergent anti-drug antibodies (ADAs), refer to SmPC for details.

Tecentriq in combination with bevacizumab, paclitaxel and carboplatin: Other clinically significant adverse events which were observed more frequently in the Tecentriq, bevacizumab, paclitaxel, and carboplatin arm were epistaxis, haemoptysis, cerebrovascular accident, including fatal events. Refer to SmPC for full listings of adverse events. Refer to SmPC section 4.8 for instructions on reporting of suspected adverse events. Legal Category: Product subject to medical prescription which may not be renewed (A). Presentation(s) and Marketing Authorization Number(s): 1,200 mg of atezolizumab in 20 mL, pack of one vial (EU/1/17/1220/001); 840 mg atezolizumab in 14 ml, pack of one vial (EU/1/17/1220/002). Marketing Authorisation Holder: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany. Tecentriq is a registered trademark. Further information is available from Roche Products (Ireland) Limited, 3004 Lake Drive, Citywest, Naas Road, Dublin 24. Telephone: (01) 4690700. Date of API Preparation: July 2021.

▼

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.

In the event of a suspected adverse reaction, Or alternatively, report to: The Drug Surveillance Centre HPRA Pharmacovigilance Roche Products (Ireland) Limited Website: www.hpra.ie Telephone: (01) 4690700 Email: ireland.drug_surveillance_centre@roche.com Tecentriq® Summary of Product Characteristics [SmPC] is available on www.medicines.ie. API M-IE-M-IE-00000725 based on Tecentriq 840mg and 1,200mg SmPCs dated 06 May 2021

46

TESTICULAR CANCER

Primary Chemotherapy in a 47-Year-Old Patient with Giant Ulcerative and Necrotizing Nonseminomatous Testicular Germ Cell Tumor Written by Stock S.a  Marcon J.b  Chaloupka M.b  Becker A.b  Kunz W.G.c  Ormanns S.d Pichler T.e  Mumm F.H.A.a,e  Holch J.W.a,e,f  Lindner L.H.a a

Department of Medicine III, University Hospital, LMU Munich, Munich, Germany

b c

Department of Radiology, University Hospital, LMU Munich, Munich, Germany

d e

Department of Urology, University Hospital, LMU Munich, Munich, Germany Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany

Comprehensive Cancer Center Munich, University Hospital, LMU Munich, Munich, Germany

German Cancer Consortium (DKTK), Partner Site Munich and German Cancer Research Centre (DKFZ), Heidelberg, Germany

f

Introduction Testicular cancer is a rare disease.

Notably, cure rates are >90% for all stages due to consistent use of appropriate therapy concepts.1 International recommendations and guidelines define the use of chemotherapy, surgery and radiation as well as the type and duration of its use depending on histology, tumor stage and risk factors.1 Classification of germ cell tumors is performed by histological criteria and tumor markers.1 Germ cell tumors are defined as seminomatous or nonseminomatous. Mixed tumors and cases with alpha-fetoprotein (AFP) elevation are considered as nonseminomatous. The prognostic classification of the International Germ Cell Cancer Collaborative Group (IGCCCG 1997) define three prognosis groups for nonseminomatous tumors by clinical and laboratory criteria.2 Mostly, the disease is diagnosed at an early (local) stage.1

1

Painless enlargement, swelling or circumscribed hardening of the testicles are early symptoms.

Primary orchiectomy is the standard treatment. Depending on the stage, prognostic classification and further risk factors, patients with nonseminomatous tumors are managed with surveillance or treated with 1–4 cycles of chemotherapy after primary orchiectomy. Stage I nonseminomatous germ cell tumors with risk factors (e.g., vascular or lymphatic invasion) are usually treated with 1 cycle of cisplatin, etoposide and bleomycin (PEB). Cases with advancedstage tumor and elevated tumor markers usually receive 3–4 cycles of PEB or cisplatin, etoposide and ifosfamide (PEI) depending on the prognosis group. Patients with initially advanced or acute life-threatening disease receive chemotherapy first and undergo delayed orchiectomy afterward.3

We report the case of a 47-yearold male patient diagnosed with a giant nonseminomatous testicular tumor in the left scrotum and multiple lymph node metastases.

Due to the tumor size and patient’s poor general condition, he received 4 cycles of primary chemotherapy followed by tumor resection.

Case Presentation A 47-year-old man was transferred to our university hospital in March 2020 because of an ulcerating testicular tumor. For about 3 years, the patient had noted a progredient testicular mass without consulting with a doctor.

Some days before hospitalization, the patient noticed ulcerating scrotal wounds and fever. He had also noticed a swelling, redness and strong pain in the left leg for about 3 weeks. The patient had no preexisting conditions, long-term medication or history of infections or cancer.

Initial computed tomography (CT) scanning showed an ∼22 × 18 cm ulcerating testicular mass with para-aortic, iliac and inguinal lymph node metastases on both sides (Fig. 1a–c). Moreover, an extensive thrombosis of the deep leg veins of the left upper and partially lower leg with an increase in circumference as well as subcutaneous and perifascial edema was detected.

No parenchymatous distant metastases were found. Antibiotic treatment and anticoagulant therapy with the low-molecularweight heparin tinzaparin were initiated. On March 7, 2020, the

Fig 1: Initial computed tomography (CT) scan showing the germ cell tumor in the coronal plane (a) and axial planes (b, c). CT angiography showing pulmonary artery embolization in the axial plane (d).

NOVEMBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

patient developed a hemorrhagic shock due to tumor bleeding and was transferred to the intensive care unit (ICU). CT angiography showed bilateral acute pulmonary embolism with right heart strain and pulmonary infarction in the right middle lobe (Fig. 1d).

Anticoagulation was switched to a heparin syringe pump despite the bleeding tumor as the pulmonary embolism severity index (PESI) was high with a 30-day mortality >10%.

After administration of volume and blood products, the patient stabilized and was transferred to the Department of Hematology and Oncology. Heparinization was later switched back to tinzaparin.

Imaging was completed with magnetic resonance imaging of the head, showing no brain metastases. Additionally, bone metastases could be excluded by single-photon emission computed tomography.

Psycho-oncological support was offered to the patient. During the first consultation, the patient reported psychosocial distress.

The predominant topics were the psychosocial circumstances preceding hospitalization – for example, having „no time for self-care“ because of financial responsibilities, caring for his family and a demanding job.

Aspects of embarrassment were addressed by the patient.

However, in view of the lifethreatening situation, he was not willing to be more specific.

It seemed that a more in-depth conversation about this emotion might have been too demanding.

In this case, the patient benefited from the therapist’s containment. After 2–3 consultations, he was willing to involve friends for further social support. Notably, the patient showed high compliance during medical treatment, which may be interpreted as a kind of compensation for the delayed consultation.

A combined force against LUTS and BPH

49% of men with LUTS report bladder and prostate symptoms1 VESOMNI treats the symptoms of both the bladder and prostate2 Abbreviated Prescribing Information - Vesomni 6 mg/0.4 mg modified release tablets. Please read the Summary of Product Characteristics (SPC) before prescribing. Presentation: Each tablet contains a layer of 6 mg solifenacin succinate, corresponding to 4.5 mg solifenacin free base and a layer of 0.4 mg tamsulosin hydrochloride, corresponding to 0.37 mg of tamsulosin free base. Indication: Treatment of moderate to severe storage symptoms (urgency, increased micturition frequency) and voiding symptoms associated with benign prostatic hyperplasia (BPH) in men who are not adequately responding to treatment with monotherapy. Posology and method of administration: Adult males, including older people: One Vesomni tablet (6 mg/0.4 mg) once daily taken orally with or without food. The maximum daily dose is one Vesomni tablet. The tablet must be swallowed whole, intact without biting or chewing. Do not crush the tablet. Special populations (see also contraindications below): Renal impairment: Severe renal impairment (creatinine clearance ≤ 30 mL/min): Treat with caution, maximum daily dose in these patients is one Vesomni tablet.

Hepatic impairment: Moderate hepatic impairment (Child-Pugh score of 7-9): Treat with caution, maximum daily dose in these patients is one Vesomni tablet. In patients with severe hepatic impairment (Child-Pugh score > 9), the use of Vesomni is contraindicated. Concomitant treatment with moderate and strong inhibitors of CYP450 3A4: e.g. verapamil, ketoconazole, ritonavir, nelfinavir, itraconazole: Treat with caution, maximum daily dose should be limited to one Vesomni tablet.

Paediatric population: There is no relevant indication for use of Vesomni in children and adolescents.

Contraindications: Patients with hypersensitivy to the active substance(s) or to any of the excipients (see SPC). Patients undergoing haemodialysis. Patients with severe hepatic impairment. Patients with severe renal impairment who are also treated with a strong cytochrome P450 (CYP)3A4 inhibitor e.g. ketoconazole. Patients with moderate hepatic impairment who are also treated with a strong CYP3A4 inhibitor e.g. ketoconazole. Patients with severe gastrointestinal conditions (including toxic megacolon), myasthenia gravis or narrow-angle glaucoma and patients at risk for these conditions.

Patients with a history of orthostatic hypotension. Special Warnings and Precautions for Use: Vesomni should be used with caution in patients with: severe renal impairment; risk of urinary retention; gastrointestinal obstructive disorders; risk of decreased gastrointestinal motility; hiatus hernia/ gastroesophageal reflux and/or who are concurrently taking medicinal products (such as bisphosphonates) that can cause or exacerbate oesophagitis; autonomic neuropathy. The patient should be examined in order to exclude the presence of other conditions, which can cause similar symptoms to benign prostatic hyperplasia. Other causes of frequent urination (heart failure or renal disease) should be assessed before treatment with Vesomni is initiated. If a urinary tract infection is present, appropriate antibacterial therapy should be started. QT prolongation and Torsade de Pointes have been observed in patients with risk factors, such as pre-existing long QT syndrome and hypokalaemia, who are treated with solifenacin succinate. Angioedema with airway obstruction has been reported in some patients on solifenacin succinate and tamsulosin. If angioedema occurs, Vesomni should be discontinued and not restarted. Appropriate therapy and/or measures should be taken. Anaphylactic reaction has been reported in some patients treated with solifenacin succinate. In patients who develop anaphylactic reactions, Vesomni should be discontinued and appropriate therapy and/or measures should be taken. As with other alpha1-adrenoceptor antagonists, a reduction in blood pressure can occur in individual cases during treatment with tamsulosin, as a result of which, rarely, syncope can occur. Patients starting treatment with Vesomni should be cautioned to sit or lie down at the first signs of orthostatic hypotension (dizziness, weakness) until the symptoms have disappeared. The ‘Intraoperative Floppy Iris Syndrome’ (IFIS, a variant of small pupil syndrome) has been observed during cataract and glaucoma surgery in some patients on or previously treated with tamsulosin hydrochloride. IFIS may increase the risk of eye complications during and after the operation. Therefore, the initiation of therapy with Vesomni in patients for whom cataract or glaucoma surgery is scheduled is not recommended. Discontinuing treatment with Vesomni 1-2 weeks prior to cataract or glaucoma surgery is anecdotally considered helpful, but the benefit of treatment discontinuation has not been established. During pre-operative assessment, surgeons and ophthalmic teams should consider whether patients scheduled for cataract or glaucoma surgery are being or have been treated with Vesomni in order to ensure that appropriate measures will be in place to manage IFIS during surgery. Vesomni should be used with caution in combination with moderate and strong inhibitors of CYP3A4 and it should not be used in combination with strong inhibitors of CYP3A4, e.g., ketoconazole, in patients who are of the CYP2D6 poor metaboliser phenotype or who are using strong inhibitors of CYP2D6, e.g., paroxetine.

Interactions: Pharmacological interactions: Concomitant medication with other anticholinergic medicinal products may result in more pronounced therapeutic and undesirable effects. Allow approximately one week after stopping treatment with Vesomni before commencing any anticholinergic therapy. The therapeutic effect of solifenacin may be reduced by concomitant administration of cholinergic receptor agonists. Pharmacokinetic interactions: Pharmacokinetic interactions involving the potential for other medicinal products to affect Vesomni exposures: Interactions with CYP3A4 and CYP2D6 inhibitors: See Contraindications, Posology and administration and Special warnings and precautions above. Concomitant administration may lead to increased exposure to both solifenacin (ketoconazole 400 mg/day resulted in a 1.5-fold increase in Cmax and a 2.8-fold increase in AUC). and tamsulosin (ketoconazole 400 mg/day resulted in a 2.2-fold increase in Cmax and a 2.8-fold increase in AUC). Vesomni should be used with caution in combination with strong CYP3A4 inhibitors. Vesomni should not be given together with strong CYP3A4 inhibitors in patients who are also CYP2D6 poor metabolizer phenotype or who are using strong CYP2D6 inhibitors. See SPC for details of the effects of other CYP3A4 and CYP2D6 inhibitors. Inducers: Inducers of CYP3A4 (e.g. rifampicin) may decrease the plasma concentrations of solifenacin and tamsulosin. Information available for the individual active substances: Solifenacin can reduce the effect of medicinal products that stimulate the motility of the gastrointestinal tract, such as metoclopramide and cisapride. Solifenacin did not affect the pharmacokinetics of digoxin, or the pharmacokinetics or effect on prothrombin time of R- or S-warfarin. Co-administration of tamsulosin and other alpha1-adrenoreceptor antagonists could lead to hypotensive effects. Diclofenac and warfarin may increase the elimination rate of tamsulosin. No interactions have been seen when tamsulosin was given concurrently with atenolol, enalapril or theophylline. Fertility, pregnancy and lactation: The effect of Vesomni on fertility has not been established. Ejaculation disorders have been observed in short and long term clinical studies with tamsulosin. Events of ejaculation disorder, retrograde ejaculation and ejaculation failure have been reported in the post authorization phase.

Vesomni is not indicated for use in women. Driving and use of machines: No studies have been performed, however patients should be informed about the possible occurrence of dizziness, blurred vision, fatigue and uncommonly somnolence, which may negatively affect the ability to drive or use machines. Undesirable Effects: Summary of the safety profile: Vesomni may cause anticholinergic undesirable effects of, in general, mild to moderate severity. The most frequently reported adverse reactions during the clinical studies performed for the development of Vesomni were dry mouth (9.5%), followed by constipation (3.2%) and dyspepsia (including abdominal pain; 2.4%). Other common undesirable effects are dizziness (including vertigo; 1.4%), vision blurred (1.2%), fatigue (1.2%), and ejaculation disorder (including retrograde ejaculation; 1.5%). Acute urinary retention (0.3%, uncommon) is the most serious adverse drug reaction that has been observed during treatment with Vesomni in clinical studies. List of adverse reactions: the ‘Vesomni frequency’ below reflects adverse drug reactions that have been observed during the double-blind clinical studies performed for the development of Vesomni (based on reports of treatment-related adverse events, which have been reported by at least two patients and occurred with a frequency higher than for placebo in the double-blind studies). The ‘solifenacin frequency’ and ‘tamsulosin frequency’ below reflect adverse drug reactions (ADRs) previously reported with one of the individual components (as presented in the Summary of Product Characteristics (SmPCs) of solifenacin 5 and 10 mg and tamsulosin 0.4 mg respectively that may also occur when receiving Vesomni (some of these have not been observed during the clinical development program of Vesomni). The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data). The adverse events are grouped by MedDRA system organ class preferred term (PT). Vesomni frequency: Nervous system disorders: Common: dizziness Eye disorders: Common: vision blurred Gastrointestinal disorders: Common: dry mouth, dyspepsia, constipation Skin and subcutaneous tissue disorders: Uncommon: pruritus Renal and urinary disorders: Uncommon: Urinary retention*** Reproductive system and breast disorders: Common: ejaculation disorders including retrograde ejaculation and ejaculation failure General disorders and administration site conditions: Common: fatigue Solifenacin 5mg & 10mg frequency#: Infections and infestations: Uncommon: urinary tract infection, cystitis Immune system disorders: Not known: anaphylactic reaction* Metabolism and nutrition disorders: Not known: decreased appetite*, hyperkalemia* Psychiatric disorders: Very rare: hallucination*, confusional state* Not known:

References: 1. Sexton CC, et al. BJU Int 2009; 103(Suppl 3): 12-23. 2. VESOMNI Summary of Product Characteristics.

Date of preparation: July 2019 Job code: VESOM_2019_0003_IE

delirium* Nervous system disorders: Uncommon: somnolence, dysgeusia Rare: dizziness*, headache* Eye disorders: Common: vision blurred Uncommon: dry eyes Not known: glaucoma* Cardiac disorders: Not known: palpitations*, Torsade de Pointes*, electrocardiogram QT prolongation*, atrial fibrillation*, tachycardia* Respiratory, thoracic and mediastinal disorders: Uncommon: nasal dryness Not known: dysphonia* Gastrointestinal disorders: Very common: dry mouth Common: dyspepsia, constipation, nausea, abdominal pain Uncommon: gastro-oesophageal reflux disease, dry throat Rare: vomiting*, colonic obstruction, faecal impaction, Not known: ileus*, abdominal discomfort* Hepatobiliary disorders: Not known: liver disorder*, liver function test abnormal* Skin and subcutaneous tissue disorders: Uncommon: dry skin Rare: pruritus*, rash* Very rare: urticaria*, angioedema*, erythema multiforme* Not known: exfoliative dermatitis* Musculoskeletal and connective tissue disorders: Not known: muscular weakness* Renal and urinary disorders: Uncommon: difficulty in micturition Rare: urinary retention***Not known: renal impairment* General disorders and administration site conditions: Uncommon: fatigue, perhiperal oedema Tamsulosin 0.4mg frequency#: Nervous system disorders: Common: dizziness Uncommon: headache Rare: syncope Eye disorders: Not known: vision blurred*, Intraoperative Floppy Iris Syndrome (IFIS)**, visual impairment* Cardiac disorders: Uncommon: palpitations Not known: atrial fibrillation*, arrhythmia*, tachycardia* Vascular disorders: Uncommon: orthostatic hypotension Respiratory, thoracic and mediastinal disorders: Uncommon: rhinitis Not known: dyspnoea*, epistaxis* Gastrointestinal disorders: Uncommon: constipation, nausea, diarrhea, vomiting Skin and subcutaneous tissue disorders: Uncommon: pruritus, rash, urticaria Rare: angioedema Very Rare: Stevens-Johnson syndrome Not known: erythema multiforme*, exfoliative dermatitis* Reproductive system and breast disorders: Common: ejaculation disorders including retrograde ejaculation and ejaculation failure Very rare: priapism General disorders and administration site conditions: Uncommon: asthenia. #: The ADRs from solifenacin and tamsulosin included are the ADRs listed in the summary of product characteristics of both products. *: from post-marketing reporting. Because these spontaneously reported events are from the worldwide post-marketing experience, the frequency of events and the role of solifenacin or tamsulosin and their causation cannot be reliably determined. **: from post-marketing reporting, observed during cataract and glaucoma surgery. ***: see Special warnings and precautions for use. Long-term safety of Vesomni: The profile of undesirable effects seen with treatment up to 1 year was similar to that observed in the 12-week studies. The product is well-tolerated and no specific adverse reactions have been associated with long-term use.

Description of selected adverse reactions: For urinary retention see Special warnings and precautions for use. Older people: The therapeutic indication of Vesomni, moderate to severe storage symptoms (urgency, increased micturition frequency) and voiding symptoms associated with BPH, is a disease affecting elderly men. The clinical development of Vesomni has been performed in patients 45 to 91 years of age, with an average age of 65 years. Adverse reactions in the elderly population were similar to the younger population. Reporting of suspected adverse reactions: see below. Overdose: Overdosage with the combination of solifenacin and tamsulosin can potentially result in severe anticholinergic effects plus acute hypotension. Refer to SPC for details of treatment of overdose. Legal Category: Prescription Only Medicine (SIB). Nature and contents of container: Aluminium blister packs containing 30 tablets. Product Authorisation Number: PA1241/016/001. Marketing Authorisation holder: Astellas Pharma Co. Ltd. Further information is available from: Astellas Pharma Co. Ltd, 5 Waterside, Citywest Business Campus, Naas Road, Dublin 24. Phone: +3531 467 1555. Summary of Product Characteristics with full prescribing information available upon request. Job number: VESOM_2019_0001_IE Date of preparation of API: 24 May 2019 Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: HPRA Pharmacovigilance Astellas Pharma Co. Ltd Earlsfort Terrace, IRL - Dublin 2 Tel: + 353 1 467 1555 Tel: +353 1 6764971 E-mail: Irishdrugsafety@astellas.com Fax: +353 1 6762517 Website: www.hpra.ie E-mail: medsafety@hpra.ie.

48

Initial assessment of serum tumor markers revealed high levels of lactate dehydrogenase (LDH), beta-human chorionic gonadotropin and AFP (Table 1). Additional assessment of serum hormones revealed low levels of luteinizing hormone, follicle-stimulating hormone and testosterone, revealing a hypogonadotropic hypogonadism in which negative feedback may have been involved (Table 1). Due to the detected serum hormone levels, we considered a Leydig cell tumor as the most probable differential diagnosis.

Histomorphological investigation of a tumor sample obtained by inguinal lymph node biopsy predominantly showed scar-like fibrosclerosis and subtotally necrotic infiltrates of a small cell neoplasia. The morphology and immunophenotype were consistent with lymph node metastasis of a clinically suspected germ cell neoplasia, most likely a classic seminoma. Immunohistochemical stainings of the sparse vital tumor cells showed a distinct and strong expression of SALL4, podoplanin and OCT4, but no expression of PLAP or CD45. CAL1 was focally, though most probably aberrantly, expressed. CD30 expression was not detected. Although histopathology suggested a

Table 1: Time course of tumor marker and hormone levels in serum

TESTICULAR CANCER

pure classic seminoma as the most probable differential diagnosis, the tumor was considered as nonseminoma due to a strongly increased AFP level >10,000 ng/mL. According to the IGCCCG prognostic classification, the patient had a high-risk profile due to AFP being >10,000 ng/mL and LDH >10× the upper limit of normal.2 After an interdisciplinary evaluation, primary preoperative chemotherapy with 4 cycles of PEB was determined as the therapeutic approach. Initially, 3 cycles of cisplatin (20 mg/m2) on days 1–5, etoposide (100 mg/ m2) on days 1–5, and bleomycin (30 mg) on days 1, 8 and 15 were performed with repetition after 21 days. Upon restaging after 1 cycle in mid-March 2020, with a decrease in size of the primary bulk (∼20 × 16 cm), 2 more cycles of PEB were applied.

Chemotherapy was well tolerated besides a temporary hearing impairment after the 2nd cycle.

Audiometry in mid-April 2020 revealed an inner ear deterioration in the high frequency range on both sides of about 20 dB compared to a previous audiogram in March 2020 (CTCAE grade 1; CTCAE v5.0). Another control audiometry showed no further change of the hearing threshold.

The patient reported a continuous improvement of his symptoms with no affection of his daily life.

Due to chemotherapy-associated hematotoxicity, a blood transfusion was performed after the 3rd

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Fig 2: Photographs of the ulcerative testicular mass in April 2020 cycle. Tumor marker monitoring revealed a significant reduction in LDH, beta-human chorionic gonadotropin and AFP (Table 1). A pulmonary function test before the 4th cycle showed a deterioration of the diffusion capacity of the lung for carbon monoxide (DLCO) with 41% of the predicted value.

The patient was asymptomatic, and no intervention was indicated (CTCAE grade 1; CTCAE v5.0).

As there was a contraindication for bleomycin, the 4th cycle was performed without bleomycin as PEI with cisplatin (20 mg/ m2), etoposide (75 mg/m2) and ifosfamide (1,200 mg/m2) each on days 1–5. The 4th cycle was well tolerated.

Throughout the systemic treatment, the patient received multiple surgical wound controls and local debridement. A macroscopically visible tumor decay and reduction without evidence of superinfection was observed (Fig. 2). The patient had multiple episodes of fever and elevated infection parameters

in serum during his prolonged hospitalization. Antibiotic therapy was applied almost continuously according to the sensitivity of the microorganisms depending on the antibiogram. No ICU stay or surgery was necessary during the application of chemotherapy.

On June 10, 2020, positron emission tomography and CT imaging after 4 cycles of chemotherapy showed a decreasing scrotal mass (∼9.5 × 9.5 cm) with still existing contact to the penis root (Fig. 3). The lymph node metastases had shrunk significantly. No new hematogenic or lymphogenic lesions were detected.

Furthermore, an entrapment of the left iliac vessels by a lymph node metastasis with consecutively unchanged thrombosis of the left external iliac vein was still present. After a repeated interdisciplinary evaluation, the

50mgs once daily

50mgs once daily

Her 10th shopping trip since the day she started BETMIGA1

Prescribing Information: Please read the Summary of Product Characteristics (SPC) before prescribing. Presentation: Prolonged-release tablet, containing mirabegron 25mg/50mg. Indication: Symptomatic treatment of urgency, increased micturition frequency and/or urgency incontinence as may occur in adult patients with overactive bladder (OAB) syndrome. Posology and method of administration: The recommended dose is 50 mg once daily. A lower dose of 25mg is recommended for specific patient populations (renal and hepatic impairment) as well as in specific patient populations in combination with strong CYP3A inhibitors such as itraconazole, ketoconazole, ritonavir and clarithromycin.

Renal impairment: End stage renal disease (GFR < 15 mL/min/1.73 m2 or patients requiring haemodialysis): Not recommended. Severe renal impairment (GFR 15 to 29 mL/min/1.73 m2): Reduce dose to 25 mg. Severe renal impairment and concomitant strong CYP3A inhibitors: Not recommended. Moderate renal impairment (GFR 30 to 59 mL/min/1.73 m2): 50 mg. Moderate renal impairment and concomitant strong CYP3A inhibitors: Reduce dose to 25 mg. Mild renal impairment (GFR 60 to 89 mL/min/1.73 m2): 50 mg. Mild renal impairment and concomitant strong CYP3A inhibitors: Reduce dose to 25 mg. Hepatic impairment: Severe hepatic impairment (Child-Pugh Class C): Not recommended. Moderate hepatic impairment (Child-Pugh B): Reduce dose to 25 mg. Moderate hepatic impairment and concomitant strong CYP3A inhibitors: Not recommended. Mild hepatic impairment (Child-Pugh A): 50 mg. Mild hepatic impairment and concomitant strong CYP3A inhibitors: Reduce dose to 25 mg. The tablet is to be taken once daily, with liquids, swallowed whole and is not to be chewed, divided, or crushed. It may be taken with or without food Contraindications: Hypersensitivity to the active substance or to any of the excipients (see the SPC for a list of excipients). Severe uncontrolled hypertension defined as systolic blood pressure ≥180 mm Hg and/or diastolic blood pressure ≥110 mm Hg. Special warnings and precautions for use: Renal impairment: Betmiga has not been studied in patients with end stage renal disease (GFR < 15 mL/min/1.73 m2 or patients requiring haemodialysis) and, therefore, it is not recommended for use in this patient population. Data are limited in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m2); based on a pharmacokinetic study a dose reduction to 25 mg is recommended in this population.

This medicinal product is not recommended for use in patients with severe renal impairment (GFR 15 to 29 mL/min/1.73 m2) concomitantly receiving strong CYP3A inhibitors. Hepatic impairment: Betmiga has not been studied in patients with severe hepatic impairment (Child-Pugh Class C) and, therefore, it is not recommended for use in this patient population. This medicinal product is not recommended for use in patients with moderate hepatic impairment (Child-Pugh B) concomitantly receiving

Date of preparation: June 2019

strong CYP3A inhibitors. Hypertension: Mirabegron can increase blood pressure. Blood pressure should be measured at baseline and periodically during treatment with mirabegron, especially in hypertensive patients. Data are limited in patients with stage 2 hypertension (systolic blood pressure ≥ 160 mm Hg or diastolic blood pressure ≥ 100 mm Hg). Patients with congenital or acquired QT prolongation: Betmiga, at therapeutic doses, has not demonstrated clinically relevant QT prolongation in clinical studies. However, since patients with a known history of QT prolongation or patients who are taking medicinal products known to prolong the QT interval were not included in these studies, the effects of mirabegron in these patients is unknown. Caution should be exercised when administering mirabegron in these patients. Patients with bladder outlet obstruction and patients taking antimuscarinic medicinal products for OAB: Urinary retention in patients with bladder outlet obstruction (BOO) and in patients taking antimuscarinic medicinal products for the treatment of OAB has been reported in postmarketing experience in patients taking mirabegron. A controlled clinical safety study in patients with BOO did not demonstrate increased urinary retention in patients treated with Betmiga; however, Betmiga should be administered with caution to patients with clinically significant BOO. Betmiga should also be administered with caution to patients taking antimuscarinic medicinal products for the treatment of OAB. Interactions: Pharmacokinetic interactions: Mirabegron is a substrate for CYP3A4, CYP2D6, butyrylcholinesterase, uridine diphosphoglucuronosyltransferases (UGT), the efflux transporter P-glycoprotein (P-gp) and the influx organic cation transporters (OCT) OCT1, OCT2, and OCT3. Pharmacokinetic interactions involving the potential for other medicinal products to affect mirabegron exposures: Increases in mirabegron exposure due to drug-drug interactions may be associated with increases in pulse rate. Strong CYP3A inhibitors See Posology and administration above for dose adjustments recommended during concomitant use of strong CYP3A inhibitors in patients with renal or hepatic impairment. Mirabegron exposure (AUC) was increased 1.8-fold in the presence of the strong inhibitor of CYP3A/P-gp ketoconazole. CYP2D6 inhibitors: No dose adjustment is needed for mirabegron when administered with CYP2D6 inhibitors (or in patients who are CYP2D6 poor metabolisers). Inducers: Inducers of CYP3A (such as rifampicin) or P-gp may decrease the plasma concentrations of mirabegron. No dose adjustment of mirabegron is required as this effect is not expected to be clinically relevant.

Pharmacokinetic interactions involving the potential for mirabegron to affect exposures to other medicinal products: Inhibition of CYP2D6: Moderate and time dependent inhibition of CYP2D6 by mirabegron may result in clinically relevant drug interactions. CYP2D6 activity recovers within 15 days after discontinuation of mirabegron. Caution is advised if mirabegron is co-administered with medicinal

products metabolized by CYP2D6 with a narrow therapeutic index such as thioridazine, Type 1C antiarrhythmics (e.g.flecainide, propafenone) and tricyclic antidepressants (e.g., imipramine, desipramine). Caution is also advised if mirabegron is co-administered with CYP2D6 substrates that are individually dose titrated. Inhibition of P-gp: Mirabegron is a weak inhibitor of P-gp. For patients who are initiating a combination of Betmiga and digoxin, the lowest dose for digoxin should be prescribed initially. Serum digoxin concentrations should be monitored and used for titration of the digoxin dose to obtain the desired clinical effect. The potential for inhibition of P-gp by mirabegron should be considered when Betmiga is combined with sensitive P-gp substrates e.g. dabigatran. Fertility, pregnancy and lactation: The effect of mirabegron on human fertility has not been established.

Betmiga is not recommended during pregnancy and in women of child-bearing potential not using contraception. Mirabegron should not be administered during breast feeding. Refer to SPC for full guidance. Driving and use of machines: Betmiga has no or negligible influence on the ability to drive and use machines.

Undesirable effects: Summary of the Safety Profile: the safety of Betmiga was evaluated in 8433 patients with OAB, of which 5648 received at least one dose of mirabegron in the phase 2/3 clinical program, and 622 patients received Betmiga for at least 1 year (365 days). In the three 12-week phase 3 double blind, placebo controlled studies, 88% of the patients completed treatment with this medicinal product, and 4% of the patients discontinued due to adverse events. Most adverse reactions were mild to moderate in severity. The most common adverse reactions reported for patients treated with Betmiga 50 mg during the three 12-week phase 3 double blind, placebo controlled studies are tachycardia and urinary tract infections.

The frequency of tachycardia was 1.2% in patients receiving Betmiga 50 mg.

Tachycardia led to discontinuation in 0.1% patients receiving Betmiga 50 mg. The frequency of urinary tract infections was 2.9% in patients receiving Betmiga 50 mg.

Urinary tract infections led to discontinuation in none of the patients receiving Betmiga 50 mg. Serious adverse reactions included atrial fibrillation (0.2%). Adverse reactions observed during the 1-year (long term) active controlled (muscarinic antagonist) study were similar in type and severity to those observed in the three 12-week phase 3 double blind, placebo controlled studies. The following adverse reactions were observed with mirabegron in the three 12-week phase 3 double blind, placebo controlled studies. The frequency of adverse reactions is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be established from the available data) Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The adverse events

References: 1. Freeman R, et al. Current Medical Research and Opinion 2017. https://doi.org/10.1080/03007995.2017.1419170.

are grouped by MedDRA system organ class. Infections and infestations: Common: urinary tract infection Uncommon: vaginal infection, cystitis Psychiatric disorders: Not known: Insomnia*, confusional state* Nervous system disorders: Common: headache* dizziness* Eye disorders: Rare: eyelid oedema Cardiac disorders: Common: tachycardia Uncommon: palpitation, atrial fibrillation Vascular disorders: Very rare: Hypertensive crisis* Gastrointestinal disorders: Common: nausea*, constipation*, diarrhoea* Uncommon: dyspepsia, gastritis Rare: lip oedema Skin and subcutaneous tissue disorders: Uncommon: urticaria, rash, rash macular, rash papular, pruritus Rare: leukocytoclastic vasculitis, purpura, angioedema* Musculoskeletal and connective tissue disorders: Uncommon: joint swelling Renal and urinary disorders: Rare: urinary retention* Reproductive system and breast disorders: Uncommon: vulvovaginal pruritus Investigations Uncommon: blood pressure increased, GGT increased, AST increased, ALT increased (*observed during post-marketing experience). Reporting of suspected adverse reactions: see below. Legal category: POM (S1B) Marketing Authorisation number: EU/1/12/809/003 - 25mg EU/1/12/809/010 - 50mg. Marketing Authorisation holder: Astellas Pharma Europe B.V. Sylviusweg 62, 2333 BE Leiden, The Netherlands. Further information is available from: Astellas Pharma Co., Ltd, 5 Waterside, Citywest Business Campus, Dublin 24. Phone: +3531 467 1555. Summary of Product Characteristics with full prescribing information available upon request. Job number: BET_2019_0002_IE Date of preparation of API: 27 May 2019.

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: HPRA Pharmacovigilance Astellas Pharma Co. Ltd Earlsfort Terrace, IRL - Dublin 2 Tel: + 353 1 467 1555 Tel: +353 1 6764971 E-mail: Irishdrugsafety@astellas.com Fax: +353 1 6762517 Website: www.hpra.ie E-mail: medsafety@hpra.ie.

Approval code: BET_2019_0004_IE

50

TESTICULAR CANCER

Discussion extent of tumor resection was defined. On July 7, 2020, radical inguinal orchidectomy, inguinal left-sided lymphadenectomy and partial resection of affected scrotal tissue were performed. It was possible to preserve the right testicle in its testicular layers.

Furthermore, it was possible to separate the entire penis from the left-sided testicular tumor so that all compartments could be preserved. Macroscopic analysis of the removed tumor revealed a size of ∼10 × 10 × 6 cm. Upon histomorphological examination of the resected specimen, no more vital tumor cells were found. The findings were well compatible with a testicular tumor with complete tumor regression after primary chemotherapy, so that no further statements about the entity and composition could be made. Furthermore, two analyzed inguinal lymph nodes showed a complete regression, since histomorphological examination detected totally necrotic tissue. Therefore, the response to preoperative treatment was classified as a complete pathological response.

Postoperative tumor classification (UICC 8th edition 2017) was ypT0, ypN0 (0/2 lymph nodes), L0, V0, Pn0 with an R0 situation. A standardized follow-up schedule without further adjuvant treatment was determined and performed.

Standard therapy of germ cell tumors is primary orchiectomy, followed by surveillance, radiotherapy or chemotherapy depending on the stage, histology and further risk factors. After orchiectomy, standard therapy for patients with nonseminomatous tumors in an advanced stage (stage ≥II) is 3–4 cycles of PEB depending on risk classification.

An alternative chemotherapy regime is PEI, having a similar effect with more myelotoxicity.4 Recently, more intensive chemotherapy strategies have been investigated for patients with intermediate and poor prognoses.

If chemotherapy is intensified as a primary high-dose (HD) chemotherapy, 3–4 sequential cycles of HD-PEI plus stem cell support should be performed.5 It was shown that patients with a poor prognosis had survival rates of >70% when treated with HDPEI as primary therapy.5 General use of primary HD chemotherapy, however, is currently still not the standard. HD chemotherapy was not an option in this case due to a necrotic, superinfected and bleeding tumor bulk. For patients initially ineligible for surgery because of an advanced and acutely life-threatening disease, primary chemotherapy is the favored therapy.6, 7 In this case, hospitalization occurred due to fever, thrombosis of deep leg veins, bilateral acute

pulmonary embolism and tumor bleeding leading to ICU treatment. Because of the patient’s poor general condition and acute life-threatening disease, primary orchiectomy was not an option. After 4 cycles of chemotherapy, orchiectomy and inguinal lymphadenectomy were performed. Notably, during chemotherapy, macroscopically visible necrosis was managed by local wound control and debridement without the need for surgical intervention (e.g., due to wound infection or bleeding).

Nowadays, cases with very large tumor sizes are rare. In most cases, patients notice early symptoms. Screening for testicular cancer is usually performed by self-examination or examination by an experienced physician.

A general screening for early detection of testicular tumors in asymptomatic young males is not recommended, as the incidence is low and even patients with advanced cancer have favorable outcomes.8 In case of a suspected testicular tumor, specific follow-up tests are required for diagnostic confirmation. Physicians should inform patients with clinical risk factors for testicular cancer (e.g., undescended testes, testicular intraepithelial neoplasia, history of testicular cancer and hereditary disposition). In this case, the patient had noticed symptoms about 3 years before he was finally hospitalized due to the life-threatening emergency. An analysis of 168 patients with nonseminomatous germ cell tumor revealed a median primary tumor size of 3.2 cm.9 Cases with tumor sizes >10 cm were rare.9 Here, testicular cancer was diagnosed with a size of ∼22 × 18 cm (measured by CT). Primary tumor size is associated with clinical stage, pathological stage and laterality.9

Sociocultural norms as well as deficits of knowledge and awareness may lead to a lack of health-related knowledge, causing an unnecessary delay of medical consultation at an early stage.10 It was reported that young men have little knowledge about their risk for testicular cancer, early testicular cancer signs and performance of a self-examination.10 This highlights the need to increase awareness and education programs tailored to the target group, such as mass media campaigns. Psychological issues also play an important role for long-term survivors, especially as testicular cancer occurs at a young age. Here, mainly repression and embarrassment were the reasons leading to the late medical consultation.

Perception of masculinity, sexual relationships and attractiveness plus fertility and sexual function is highly associated with the testes, especially by young men.11 Sexuality-related concerns may lead to elevated distress levels (e.g., anxiety and depression), fear of the future and loss of control.12 Patients in a long-term relationship mostly receive more social support, have a higher self-esteem and overall better mental health than singles.13 However, therapyassociated sexuality and fertility problems may cause psychological stress to young couples with incomplete family planning.13 Here, the patient was single and childless; however, sperm analysis and cryopreservation were declined. The quality of life of long-term survivors is influenced by individual health, sexual relationships and work problems.14 Sociocultural differences in sexuality, masculinity and fertility have a direct impact on quality of life.14 Therefore, psycho-oncological support should routinely address these issues during follow-up care, when patients may have more resources to talk about more complex issues and emotions such as embarrassment. Even more so because high levels of distress, mainly anxiety and fear of cancer recurrence, are reported for testicular cancer survivors.14, 15 Conclusion

Fig 3: Computed tomography scan showing the germ cell tumor in the coronal plane (a) and in the axial plane (c), as well as positron emission tomography-computed tomography showing the germ cell tumor in the coronal plane (b) and the axial plane (d), after 4 cycles of systemic chemotherapy in June 2020.

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This case of a giant nonseminomatous testicular tumor successfully treated with primary chemotherapy without major complications is remarkable. Psychological aspects and sociocultural norms play an important role in testicular cancer discovery and throughout treatment. For improved management of these patients, psychologically supportive intervention and a biopsychosocial approach have to play a role.

References available on request

BLADDER CANCER

51

The Emerging Role of Robotic Cystectomy for Bladder Cancer Written by Mr Greg Nason, MSc, FRCS Urol, FEBU - Consultant Urologist 1. Mater Misericordiae University Hospital 2. Our Lady’s Hospital, Navan Mr Greg Nason is a Consultant Urologist at the Mater Misericordiae University Hospital and Our Lady’s Hospital Navan with a special interest in pelvic oncology and robotic surgery. Following higher surgical training in Ireland, Mr Nason completed a two-year accredited Society of Urologic Oncology (SUO) fellowship at the University of Toronto.

Mr Nason then pursued a further year of dedicated robotic pelvic oncology at the Royal Surrey, one of the highest volume robotic centres for prostate and bladder cancer in the UK.

Bladder cancer is the 13th most common malignancy in Ireland with approximately 500 new cases diagnosed per year.1 Most patients present with haematuria (blood in the urine). Haematuria can be classified as visible haematuria (previously described as frank or macroscopic- blood that you see) or non-visible haematuria (previously described as microscopic- blood that is only detected on a urine dipstick or microscopy). The diagnostic yield for detecting a malignancy in a patient presenting with visible and non-visible haematuria is 13% and 3%, respectively, hence the requirement for investigation.2 The most common risk factors are age and smoking. Other rarer risk factors include occupational exposure to certain aromatic amines and polycyclic aromatic hydrocarbons.

There is no formal screening program for bladder cancer although development of

haematuria clinics is one priority of the Model of Care for Urology.3 In an ideal setting, haematuria should be investigated in a one stop haematuria clinic. In the UK, patients referred via a haematuria pathway require a diagnosis within 14 days through a suspected cancer 2-week rule.4 There are guidelines for the investigation of haematuria and it is risk stratified based upon age, smoking history and symptoms.

Patients diagnosed with a bladder tumor require a transurethral resection of the bladder tumor under anaesthetic (general or spinal anaesthetic). This a diagnostic and therapeutic procedure. Bladder cancer is then largely classified based upon depth of invasive of the bladder wall as muscle invasive (MIBC) or non-muscle invasive bladder cancer (NMIBC) based.

The majority (80%) of patients are diagnosed with NMIBC.

At a haematuria clinic- patients would have a dedicated history and clinical examination by a urologist or urology nurse specialist. A urine sample would be sent for microscopy and cytology. The upper urinary tract (kidneys and ureters) would be assessed with a renal ultrasound or CT urogram while the lower urinary tract (bladder and urethra) is directly visualized with a flexible cystoscopy under local anaesthetic.

NMIBC is risk stratified into low, intermediate, high and very high risk based with respect to risk of recurrence and more concerning progression to MIBC.5 Tumors are risk stratified according to size, multifocality, presence of concomitant carcinoma in situ, histological grade and depth of invasion. High risk patients have a 40% risk of progression to MIBC at 5 years. Based on risk, patients with NMIBC can be offered adjuvant intravesical chemotherapy (Mitomycin, Epirubicin, Gemcitabine) or immunotherapy (BCG) regimens ranging from one immediate postoperative instillation for low-risk tumours to 3-year induction and maintenance schedules of BCG for high-risk tumours. All patients with NMIBC undergo surveillance cystoscopies and upper tract imaging at regular intervals based upon their risk. Due to the intravesical regimens, long term surveillance schedules and repeat requirements for transurethral resections for recurrent disease, bladder cancer is recognized as the most expensive cancer.6 MIBC is aggressive and requires radical treatment. Despite this, the 5 year overall survival rate is approximately 50%.7 However,

untreated patients do very poorly with symptomatic local progression, development of metastases and mortality. Fewer than 15% survive longer than 2 years if untreated.8 The current standard of care for the treatment of MIBC is radical cystectomy.7 Bladder sparing approaches are an alternative for patients with MIBC who are too comorbid to undergo or who refuse a radical cystectomy. The guidelines regarding MIBC from the urological societies [European Association of Urology (EAU), American Urological Association (AUA), American Society of Clinical Oncology (ASCO), American Society of Radiation Oncology (ASTRO), Society of Urologic Oncology (SUO) and National Comprehensive Cancer Network (NCCN)] recommend radical cystectomy and pelvic lymph node dissection as the gold standard treatment for patients with MIBC. There is also evidence supporting the use of cisplatin-based neoadjuvant chemotherapy.

Radical cystectomy is a complex operation with both an exenterative portion (removal of the bladder and extended pelvic lymph nodes) and a reconstructive portion (using a segment of bowel as an ileal conduit or a neobladder). Traditionally this

HOSPITALPROFESSIONALNEWS.IE | HPN • NOVEMBER - 2021

52

has been performed as an open operation and the length of stay for an open radical cystectomy in Ireland is 14.7 days.3 A radical cystectomy can also be performed via minimally invasive surgery and the optimal approach is currently debated.9 To date there have been three randomised control trials (RCT) comparing robotic to open radical cystectomy. Robotic cystectomy may widen the scope of cystectomy as its less of a physiological insult to an already comorbid cohort of patients.

The CORAL trial was a three arm RCT comparing open, laparoscopic and robotic radical cystectomy.10 With over 5 years of follow-up, 60 patients were randomized with primary end points of recurrence free survival (RFS), cancer specific survival (CSS) and overall survival (OS).

The authors concluded robotic and laparoscopic radical cystectomy achieved equivalent oncological outcomes to the gold standard of open radical cystectomy. The 5-year RFS was 60%, 58%, and 71%; 5-year CSS was 64%, 68%, and 69%; and 5-year OS was 55%, 65%, and 61% for open, robotic, and laparoscopic

BLADDER CANCER

radical cystectomy, respectively.

There was no significant survival differences noted based on surgical modality.

Opponents of robotic (and laparoscopic) cystectomy have questioned whether the quality of an MIS approach can mirror that of an open operation. To address this concern, surgical margin status and nodal yield have been scrutinized as surrogates of surgical technique.

No difference was noted in positive margins between the CORAL groups: 10% (open), 15% (robotic), 5% (laparoscopic).

Mean nodal yield was 18.8, 16.3, and 15.5, respectively, with the difference only reaching statistical significance between the open and laparoscopic arms.

Another larger RCT comparing open versus robotic cystectomy was the RAZOR trial which reported in the Lancet in 2018.11 That landmark paper demonstrated that robotic cystectomy was non-inferior to open cystectomy for 2-year progression free survival (PFS).

To date, a robotic approach has not been shown to have a considerable impact

on oncological outcomes, complication rates and quality of life outcomes compared to open cystectomy. The benefits lie in a significantly shorter length of stay, blood loss and associated transfusion rates. The current standard of care in Ireland is an open radical cystectomy however robotic cystectomy programs are currently being established.

There is less awareness in the community and amongst health professionals surrounding bladder cancer compared with the other urological malignancies.

Patients with haematuria warrants specialist investigation to outrule bladder cancer which can be fatal if untreated.

References 1. https://www.ncri.ie/sites/ncri/ files/factsheets/Factsheet%20 bladder.pdf (Accessed 6th September 2021) 3. Rogers E, Lonergan P. Urology: a model of care for Ireland update. 2018. Available from www.rcsi.ie (Accessed 6th September 2021) 4. https://www.baus.org. uk/_userfiles/pages/files/ Publications/BAUS%20 Cancer%20Guidelines%20 Summary.pdf (Accessed 6th September 2021)

5. Babjuk M, Burger M, Compérat EM, Gontero P, Mostafid AH, Palou J, van Rhijn BWG, Rouprêt M, Shariat SF, Sylvester R, Zigeuner R, Capoun O, Cohen D, Escrig JLD, Hernández V, Peyronnet B, Seisen T, Soukup V. European Association of Urology Guidelines on Nonmuscle-invasive Bladder Cancer (TaT1 and Carcinoma In Situ) - 2019 Update. Eur Urol. 2019 Nov;76(5):639-657.

6. Williams SB, Howard LE, Foster ML, Klaassen Z, Sieluk J, De Hoedt AM, Freedland SJ. Estimated Costs and Long-term Outcomes of Patients With High-Risk Non-Muscle-Invasive Bladder Cancer Treated With Bacillus Calmette-Guérin in the Veterans Affairs Health System. JAMA Netw Open.

2021 Mar 1;4(3):e213800.

7. Alfred Witjes J, Lebret T, Compérat EM, Cowan NC, De Santis M, Bruins HM, Hernández V, Espinós EL, Dunn J, Rouanne M, Neuzillet Y, Veskimäe E, van der Heijden AG, Gakis G, Ribal MJ. Updated 2016 EAU Guidelines on Muscle-invasive and Metastatic Bladder Cancer. Eur Urol. 2017 Mar;71(3):462-475.

8. Martini A, Sfakianos JP, Renström-Koskela L, Mortezavi A, Falagario UG, Egevad L, Hosseini A, Mehrazin R, Galsky MD, Steineck G, Wiklund NP. The natural history of untreated muscle-invasive bladder cancer. BJU Int. 2020 Feb;125(2):270-275.

9. Nason GJ, Ajib K, Tan GH, Kulkarni GS. Radical cystectomy-what is the optimal surgical approach?

Transl Androl Urol. 2020 Oct;9(5):2308-2312.

10. Khan MS, Omar K, Ahmed K, et al. Long-term Oncological Outcomes from an Early Phase Randomised Controlled Threearm Trial of Open, Robotic, and Laparoscopic Radical Cystectomy (CORAL). Eur Urol 2020;77:110-8.

11. Parekh DJ, Reis IM, Castle EP, et al. Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3, non-inferiority trial.

Lancet 2018;391:2525-36.

NOVEMBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

(pembrolizumab) Injection 25mg/ml KEYTRUDA®: HELPING TO REDEFINE OVERALL SURVIVAL EXPECTATIONS for more patients with mNSCLC1-4 PD-L1 <1% or unknown

PD-L1 1-49%

PD-L1 >50%

NONSQUAMOUS

√

√

√

1st line Combination** Therapy3

SQUAMOUS

√

√

√

1st line*** Monotherapy4

NON-SQUAMOUS AND SQUAMOUS

X

X

√

Line

Histology

1st line Combination* Therapy2

* KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of metastatic non-squamous NSCLC in adults whose tumours have no EGFR or ALK positive mutations. ** KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of metastatic squamous NSCLC in adults. *** KEYTRUDA, as monotherapy, is indicated for the first-line treatment of metastatic non-small cell lung carcinoma (NSCLC) in adults whose tumours express PD-L1 with a≥ 50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations. skin adverse reaction on prior treatment with other immune- stimulatory anticancer agents. Other clinically significant immune-related adverse reactions: The following additional clinically significant, immune-related adverse reactions, have been reported in clinical studies or in post-marketing experience: uveitis, arthritis, myositis, myocarditis, pancreatitis, Guillain-Barré syndrome, myasthenic syndrome, haemolytic anaemia, sarcoidosis, encephalitis and myelitis. For Grades 3 or 4 myocarditis, encephalitis or Guillain Barré syndrome, pembrolizumab should be permanently discontinued. Refer to SmPC for information on management of significant immune-related adverse reactions. Solid organ transplant rejection has been reported in the post-marketing setting in patients treated with PD-1 inhibitors. The benefit of treatment with pembrolizumab versus the risk of possible organ rejection should be considered in these patients. Complications of allogeneic Haematopoietic Stem Cell Transplant (HSCT): Allogeneic HSCT after treatment with pembrolizumab: Cases of graft-versus-host-disease (GVHD) and hepatic veno-occlusive disease (VOD) have been observed in patients with classical Hodgkin lymphoma undergoing allogeneic HSCT after previous exposure to pembrolizumab. Until further data become available, careful consideration to the potential benefits of HSCT and the possible increased risk of transplant-related complications should be made case by case. Allogeneic HSCT prior to treatment with pembrolizumab: In patients with a history of allogeneic HSCT, acute GVHD, including fatal GVHD, has been reported after treatment with pembrolizumab. Patients who experienced GVHD after their transplant procedure may be at an increased risk for GVHD after treatment with pembrolizumab. Consider the benefit of treatment with pembrolizumab versus the risk of possible GVHD in patients with a history of allogeneic HSCT. Infusion-related reactions: For Grades 3 or 4infusion reactions including hypersensitivity and anaphylaxis, stop infusion and permanently discontinue pembrolizumab. With Grades 1 or 2 infusion reactions, infusion may continue with close monitoring. Premedication with antipyretic and antihistamine may be considered. Overdose: There is no information on overdose with pembrolizumab. In case of overdose, monitor closely for signs or symptoms of adverse reactions and treat appropriately. INTERACTIONS No formal pharmacokinetic drug interaction studies have been conducted with pembrolizumab. No metabolic drug-drug interactions are expected. The use of systemic corticosteroids or immunosuppressants before starting pembrolizumab should be avoided because of their potential interference with the pharmacodynamic activity and efficacy of pembrolizumab. Corticosteroids can be used as premedication, when pembrolizumab is used in combination with chemotherapy, as antiemetic prophylaxis and/or to alleviate chemotherapy-related adverse reactions. FERTILITY, PREGNANCY AND LACTATION Women of childbearing potential Women of childbearing potential should use effective contraception during treatment with pembrolizumab and for at least 4 months after the last dose of pembrolizumab. Pregnancy No data on use in pregnant women. Do not use during pregnancy unless the clinical condition of the woman requires treatment with pembrolizumab.

Breast-feeding It is unknown whether pembrolizumab is secreted in human milk. A risk to newborns/ infants cannot be excluded.

Fertility No clinical data available. SIDE EFFECTS Refer to SmPC for complete information on side effects. Pembrolizumab is most commonly associated with immune-related adverse reactions. Most of these reactions resolved with appropriate medical treatment or withdrawal of pembrolizumab. The most serious adverse reactions were immune-and infusion-related adverse reactions. Monotherapy: Very Common: anaemia, hypothyroidism, decreased appetite, headache, dyspnea, cough, abdominal pain, nausea, vomiting, constipation, musculoskeletal pain, arthralgia, asthenia, oedema, pyrexia, diarrhoea, rash, pruritus, fatigue. Common: pneumonia, thrombocytopaenia, lymphopaenia, hyponatraemia, hypokalaemia, hypocalcaemia, insomnia, neuropathy peripheral, lethargy, dry eye, cardiac arrhythmia (including atrial fibrillation), hypertension, hyperthyroidism, insomnia, dizziness, dysgeusia, pneumonitis, colitis, dry mouth, severe skin reactions, vitiligo, dry skin, alopecia, eczema, dermatitis acneiform, erythema, myositis, pain in extremity, arthritis, influenza like illness, chills, AST and ALT increases, hypercalcaemia, increase in blood alkaline phosphatase, blood bilirubin increased, blood creatinine increased, infusion related reaction. Frequency not known: solid organ transplant rejection. Combination with chemotherapy: Very Common: anaemia, neutropaenia, thrombocytopaenia, hypokalaemia, decreased appetite, dizziness, neuropathy peripheral, dysgeusia, headache, dyspnoea, cough, abdominal pain, alopecia, diarrhoea, nausea, vomiting, constipation, rash, pruritus, musculoskeletal pain, arthralgia, pyrexia, fatigue, asthenia, oedema, blood creatinine increased. Common: pneumonia, febrile neutropaenia, leukopaenia, lymphopaenia, infusion related reaction, hypothyroidism, hyperthyroidism, hyponatraemia, hypocalcaemia, insomnia, lethargy, dry eye, cardiac arrhythmia (including atrial fibrillation), hypertension, pneumonitis, colitis, dry mouth, severe skin reactions, erythema, dry skin, myositis, pain in extremity, arthritis, nephritis, acute kidney injury, chills, influenza-like illness, hypercalcaemia, ALT increase, AST increased, blood alkaline phosphatase increased. Combination with axitinib: Very Common: hyperthyroidism, hypothyroidism, decreased appetite, headache, dysgeusia, hypertension, dyspnoea, cough, dysphonia, diarrhoea, abdominal pain, nausea, vomiting, constipation, palmar-plantar erythrodysaesthesia syndrome, rash, pruritus, musculoskeletal pain, arthralgia, pain in extremity, fatigue, asthenia, pyrexia, alanine aminotransferase increased, aspartate aminotransferase increased, blood creatinine increased. Common: pneumonia, anaemia, neutropaenia, leukopaenia, thrombocytopaenia, infusion related reaction, hypophysitis, thyroiditis, adrenal insufficiency, hypokalaemia, hyponatraemia, hypocalcaemia, insomnia, dizziness, lethargy, neuropathy peripheral, dry eye, cardiac arrhythmia (including atrial fibrillation), pneumonitis, colitis, dry mouth, hepatitis, severe skin reactions, dermatitis acneiform, dermatitis, dry skin, alopecia, eczema, erythema, myositis, arthritis, tenosynovitis, acute kidney injury, nephritis, oedema, influenza like illness, chills, blood alkaline phosphatase increased, hypercalcaemia, blood bilirubin increased. PACKAGE QUANTITIES KEYTRUDA 25 mg/mL: 4 mL of concentrate in a 10 mL Type I clear glass vial. Legal Category: POM. Marketing Authorisation numbers: EU/1/15/1024/002. Marketing Authorisation holder: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands. Date of revision: June 2020. © Merck Sharp & Dohme B.V. 2020. All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin D18 X5K7 or from www.medicines.ie. Date of Preparation: November 2020. PSUSA. Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie.

Adverse events should also be reported to MSD (Tel: 01-2998700) References 1. Keytruda Summary of Product Characteristics, July 2020, available at www.medicines.ie.

2. Gandhi L, et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med. 2018;378:2078-2092.

3. Paz-Ares L, et al. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med. 2018;379:2040–2051.

4. Reck, M et al. Pembrolizumab versus chemotherapy for PDL1 positive-non-small cell lung cancer, N Eng J Med 2016, 375(19)1823-1833.

ALK=anaplastic lymphoma kinase; EGFR=epidermal growth factor receptor; mNSCLC=metastatic non–small cell lung carcinoma; PDL1=programmed death ligand 1.

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

IE-KEY-00332

KEYTRUDA® (pembrolizumab) ABRIDGED PRODUCT INFORMATION Refer to Summary of Product Characteristics before prescribing. PRESENTATION KEYTRUDA 25 mg/mL: One vial of 4 mL of concentrate contains 100 mg of pembrolizumab. INDICATIONS KEYTRUDA as monotherapy is indicated for the treatment of advanced (unresectable or metastatic) melanoma in adults. KEYTRUDA as monotherapy is indicated for the adjuvant treatment of adults with Stage III melanoma and lymph node involvement who have undergone complete resection. KEYTRUDA as monotherapy is indicated for the first-line treatment of metastatic non-small cell lung carcinoma (NSCLC) in adults whose tumours express PD-L1 with a ≥50% tumour proportion score (TPS) with no EGFR or ALK positive tumour mutations. KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of metastatic non-squamous NSCLC in adults whose tumours have no EGFR or ALK positive mutations. KEYTRUDA, in combination with carboplatin and either paclitaxel or nab-paclitaxel, is indicated for the first-line treatment of metastatic squamous NSCLC in adults. KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic NSCLC in adults whose tumours express PD-L1 with a ≥1% TPS and who have received at least one prior chemotherapy regimen. Patients with EGFR or ALK positive tumour mutations should also have received targeted therapy before receiving KEYTRUDA. KEYTRUDA as monotherapy is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL) who have failed autologous stem cell transplant (ASCT) and brentuximab vedotin (BV), or who are transplant-ineligible and have failed BV. KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who have received prior platinum-containing chemotherapy. KEYTRUDA as monotherapy is indicated for the treatment of locally advanced or metastatic urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy and whose tumours express PD L1 with a combined positive score (CPS) ≥ 10. KEYTRUDA as monotherapy or in combination with platinum and 5-fluorouracil (5-FU) chemotherapy, is indicated for the first-line treatment of metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) in adults whose tumours express PD-L1 with a CPS ≥ 1. KEYTRUDA as monotherapy is indicated for the treatment of recurrent or metastatic HNSCC in adults whose tumours express PD-L1 with a ≥ 50% TPS and progressing on or after platinum-containing chemotherapy. KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of advanced renal cell carcinoma (RCC) in adults. DOSAGE AND ADMINISTRATION See SmPC for full details. Therapy must be initiated and supervised by specialist physicians experienced in the treatment of cancer. The recommended dose of KEYTRUDA as monotherapy is either 200 mg every 3 weeks or 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes. The recommended dose of KEYTRUDA as part of combination therapy is 200 mg every 3 weeks administered as an intravenous infusion over 30 minutes. KEYTRUDA must not be administered as an intravenous push or bolus injection. When administering KEYTRUDA as part of a combination with intravenous chemotherapy, KEYTRUDA should be administered first. Treat patients until disease progression or unacceptable toxicity. Atypical responses (i.e., an initial transient increase in tumour size or small new lesions within the first few months followed by tumour shrinkage) have been observed. Recommended to continue treatment for clinically stable patients with initial evidence of disease progression until disease progression is confirmed. For the adjuvant treatment of melanoma, KEYTRUDA should be administered until disease recurrence, unacceptable toxicity, or for a duration of up to one year. KEYTRUDA, as monotherapy or as combination therapy, should be permanently discontinued (a) For Grade 4 toxicity except for: endocrinopathies that are controlled with replacement hormones; or haematological toxicity, only in patients with cHL in which KEYTRUDA should be withheld until adverse reactions recover to Grade 0-1; (b) If corticosteroid dosing cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks; (c) If a treatment-related toxicity does not resolve to Grade 0-1 within 12 weeks after last dose of KEYTRUDA; (d) If any event occurs a second time at Grade ≥ 3 severity. Patients must be given the Patient Alert Card and be informed about the risks of KEYTRUDA. Special populations. Elderly: No dose adjustment necessary. Data from patients ≥ 65 years are too limited to draw conclusions on cHL population. Data from pembrolizumab monotherapy in patients with resected Stage III melanoma, from pembrolizumab in combination with axitinib in patients with advanced RCC, and from chemotherapy combination in patients with metastatic NSCLC, and from pembrolizumab (with or without chemotherapy) in patients receiving first line treatment for metastatic or unresectable recurrent HNSCC ≥ 75 years are limited. Renal impairment: No dose adjustment needed for mild or moderate renal impairment. No studies in severe renal impairment. Hepatic impairment: No dose adjustment needed for mild hepatic impairment. No studies in moderate or severe hepatic impairment. Paediatric population: Safety and efficacy in children below 18 years of age not established. CONTRAINDICATIONS Hypersensitivity to the active substance or to any excipients. PRECAUTIONS AND WARNINGS Assessment of PD-L1 status When assessing the PD-L1 status of the tumour, it is important that a well-validated and robust methodology is chosen to minimise false negative or false positive determinations. Immune-related adverse reactions Immune-related adverse reactions, including severe and fatal cases, have occurred in patients receiving pembrolizumab. Most immune-related adverse reactions occurring during treatment with pembrolizumab were reversible and managed with interruptions of pembrolizumab, administration of corticosteroids and/or supportive care. Immune-related adverse reactions have also occurred after the last dose of pembrolizumab. Immune-related adverse reactions affecting more than one body system can occur simultaneously. See SmPC for full details. Immune-related pneumonitis: Patients should be monitored for signs and symptoms of pneumonitis.. Suspected pneumonitis should be confirmed with radiographic imaging and other causes excluded. Refer to SmPC for information on management of immune-related pneumonitis. Immune-related colitis: Patients should be monitored for signs and symptoms of colitis, and other causes excluded. Consider the potential risk of gastrointestinal perforation. Refer to SmPC for information on management of immune-related colitis. Immune-related hepatitis: Patients should be monitored for changes in liver function (at the start of treatment, periodically during treatment and as indicated based on clinical evaluation) and symptoms of hepatitis, and other causes excluded. Refer to SmPC for information on management of Immune-related hepatitis. Immune-related nephritis: Patients should be monitored for changes in renal function, and other causes of renal dysfunction excluded. Refer to SmPC for information on management of immune-related nephritis. Immune-related endocrinopathies: Severe endocrinopathies, including adrenal insufficiency, hypophysitis, type 1 diabetes mellitus, diabetic ketoacidosis, hypothyroidism, and hyperthyroidism have been observed with pembrolizumab treatment. Long-term hormone replacement therapy may be necessary in cases of immune-related endocrinopathies. Hypophysitis has been reported in patients receiving pembrolizumab. Patients should be monitored for signs and symptoms of adrenal insufficiency and hypophysitis (including hypopituitarism) and other causes excluded. Patients should be monitored for hyperglycaemia or other signs and symptoms of diabetes. Thyroid disorders, including hypothyroidism, hyperthyroidism and thyroiditis, have been reported in patients receiving pembrolizumab and can occur at any time during treatment. Hypothyroidism is more frequently reported in patients with HNSCC with prior radiation therapy.

Patients should be monitored for changes in thyroid function (at the start of treatment, periodically during treatment and as indicated based on clinical evaluation) and clinical signs and symptoms of thyroid disorders. Refer to SmPC for information on management of immune-related endocrinopathies. Immune-related skin adverse reactions: Patients should be monitored for suspected severe skin reactions and other causes should be excluded. Based on the severity of the adverse reaction, pembrolizumab should be withheld for Grade 3 skin reactions until recovery to Grade ≤ 1or permanently discontinued for Grade 4 skin reactions, and corticosteroids should be administered. Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving pembrolizumab. For suspected SJS or TEN, pembrolizumab should be withheld and the patient should be referred to a specialised unit for assessment and treatment. If SJS or TEN is confirmed, pembrolizumab should be permanently discontinued. Caution should be used when considering the use of pembrolizumab in a patient who has previously experienced a severe or life-threatening

54

RENAL CANCER

A Urological Update on the Diagnosis and Surgical Management of Renal Cancer Written by Professor Kilian Walsh FRCSI Urol (Consultant Urological Surgeon) and Richard Walsh (UCD Medical Student)

Professor Kilian Walsh FRCSI Urol (Consultant Urological Surgeon)

Richard Walsh (UCD Medical Student)

The classical presentation of Renal Cancer taught to Medical students 30 to 40 years ago was of weight loss, haematuria and loin pain, however with the advent and availability of modern radiological imaging there has been a significant stage migration in the presentation of the disease, as presently it is far more common for Renal tumours to be identified incidentally while undergoing

radiological imaging for non-urological conditions than present with that classic historical triad as described.

that are identified more frequently with increasingly sophisticated imaging techniques being so widely available.

Although this has led to earlier detection of the disease and potentially a greater opportunity for curative surgical treatment, it has also created the dilemma of how to manage potentially clinically insignificant small renal masses

However without doubt the most important symptom or sign for detection of Renal Cancer is Haematuria either Visible(Macroscopic)or Non visible (microscopic) which is why it is advised that both are investigated by a Urologist when a patient presents to their GP with either or is detected in their surgery by dipstick.3 Further Investigations by a Urologist should include a cystoscopy and upper tract imaging potentially within the environment of a dedicated Haematuria Clinic which have become more widely available in recent years.1

Partial Nephrectomy

If a renal mass is identified, the preferred Radiological imaging modality for clarification is a CTIVU (Triple phase CT).

This CT with IV Contrast and a delayed phase will allow the radiologist give a Housefield Score to the lesion and as renal tumours are vascular tumours associated with angiogenesis (new blood vessel formation) and therefore give a characteristic blush on a CTIVU an experienced radiologist can identify with a high degree CTIVU of Large Renal Tumour

NOVEMBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

of certainty whether the lesion is malignant or not. This is extremely useful and beneficial for the patient as in the majority of renal cancer cases a biopsy is un-necessary, however where there is some doubt a percutaneous tru-cut biopsy can be arranged to confirm the diagnosis with Histological conformation if necessary. A biopsy of the kidney does carry the risk of a significant retroperitoneal bleed and therefore it is preferable to rely on the Radiologists report for a diagnosis of cancer where possible. A CT IVU will also identify whether there is Vascular (Usually renal vein involvement )of the tumour or associated tumourthrombus which can extend from the renal vein into the Inferior Vena Cava and as far as the Right Atrium in some cases.2 As renal cancer can metastasize to the Lungs it is also recommended to perform a CT Thorax to out rule pulmonary Mets, the presence or absence of skeletal and liver Mets should also be commented upon by the radiologist in any report also. So that the patient can be given an accurate assessment of the benefits of a surgical or oncological approach to their treatment.

If surgery is contemplated Pre-operative bloods should include Haemoglobin as patients can either be anaemic from severe haematuria or occasionally

CALQUENCE CONFIDENCE

A selective BTKi1

CALQUENCE now reimbursed in the following indications:

• Calquence as monotherapy for the treatment of previously untreated Chronic Lymphoytic Leukaemia (CLL) in the presence of 17p deletion or TP53 mutation in adult patients unsuitable for chemoimmunotherapy.* • Calquence as monotherapy for the treatment of adult patients with CLL who have received at least one prior therapy. *Please see the below prescribing information or SmPC for full detail on licensed indications.

ABRIDGED PRESCRIBING INFORMATION CALQUENCE® 100mg HARD CAPSULES  (acalabrutinib)

Consult Summary of Product Characteristics (SmPC) before prescribing. Indication: Calquence as monotherapy or in combination with obinutuzumab is indicated for the treatment of adult patients with previously untreated chronic lymphocytic leukaemia (CLL). Calquence as monotherapy is indicated for treatment of adult patients with CLL who have received at least one prior therapy. Presentation: Each hard capsule contains 100mg of acalabrutinib. Dosage and Administration: Treatment should be initiated and supervised by a physician experienced in the use of anticancer medicinal products. The capsules should be swallowed whole with water at approximately the same time each day, with or without food and should not be chewed, dissolved or opened. Recommended dose is 100mg acalabrutinib twice daily. Refer to obinutuzumab prescribing information for recommended obinutuzumab dosing information. The dose interval is 12 hours approximately and treatment should be continued until disease progression or unacceptable toxicity. Refer to SmPC for recommended dose modifications of Calquence for Grade ≥ 3 adverse reactions and interactions with CYP3A inhibitors or inducers and gastric acid reducing agents. Elderly: No dose adjustment required for patients (aged ≥ 65 years). Renal impairment: No dose adjustment needed in patients with mild to moderate renal impairment (greater than 30mL/min creatinine clearance). Maintain hydration and monitor serum creatinine levels periodically. Only use in patients with severe renal impairment (<30mL/min creatinine clearance) if benefit outweighs risk. Monitor closely for signs of toxicity. Hepatic impairment: No dose adjustment recommended in patients with mild or moderate hepatic impairment (Child-Pugh A, ChildPugh B, or total bilirubin between 1.5-3 times the upper limit of normal [ULN] and any AST). Patients with moderate hepatic impairment should be closely monitored for signs of toxicity. Calquence is not recommended in patients with severe hepatic impairment (Child-Pugh C or total bilirubin >3 times ULN and any AST). Severe cardiac disease: Patients with severe cardiovascular disease were excluded from studies. Paediatric population: The safety and efficacy of Calquence in children and adolescents aged 0 to 18 years have not been established. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Warnings and Precautions: Haemorrhage: Major haemorrhagic events including central nervous system and gastrointestinal haemorrhage, some with fatal outcomes, have occurred in patients with haematological malignancies treated with Calquence monotherapy and in combination with obinutuzumab. Patients receiving antithrombotic agents may be at increased risk of haemorrhage. Exercise caution with antithrombotic agents and consider additional monitoring for signs of bleeding when concomitant use is medically necessary. Warfarin or other vitamin K antagonists should not be administered concomitantly with Calquence. Consider benefit-risk of withholding Calquence for at least 3 days pre- and post-surgery. Infections: Serious infections (bacterial, viral or fungal) including fatal events have occurred in patients with haematological malignancies treated with Calquence monotherapy and in combination with obinutuzumab. These infections predominantly occurred in the absence of Grade 3 or 4 neutropenia. Infections due to hepatitis B virus (HBV) and herpes zoster virus (HZV) reactivation, aspergillosis and progressive multifocal leukoencephalopathy (PML) have also occurred. Viral reactivation cases of hepatitis B have been reported and therefore HBV status should be established before initiating treatment with Calquence. A liver disease expert should be consulted before initiation of treatment if patients have a positive Hepatitis B serology and the patient should be monitored and managed to prevent hepatitis B reactivation. Progressive multifocal leukoencephalopathy (PML): Cases of PML including fatal ones have been reported following use of Calquence within the context of a prior or concomitant immunosuppressive therapy. Consider PML in differential diagnosis where there are new or worsening neurological, cognitive or behavioural signs or symptoms. If PML is suspected, appropriate diagnostic evaluations should be undertaken and treatment with Calquence should be stopped until PML is excluded. Prophylaxis should be considered in patients who are at increased risk for opportunistic infections. Monitor for signs and symptoms of infection.

Cytopenias: Treatment-emergent Grade 3 or 4 cytopenias, including neutropenia, anaemia and thrombocytopenia, occurred in patients with haematological malignancies treated with Calquence monotherapy and in combination with obinutuzumab. Monitor complete blood counts as medically indicated (refer to section 4.8 of the SmPC). Second primary malignancies: Skin and non-skin cancers, occurred in patients with haematological malignancies treated with Calquence monotherapy and in combination with obinutuzumab. Monitor for appearance of skin cancers and advise protection from sun exposure. Atrial fibrillation/flutter: Atrial fibrillation/flutter occurred in patients with haematological malignancies treated with Calquence monotherapy and in combination with obinutuzumab. Monitor for symptoms (e.g. palpitations, dizziness, syncope, chest pain, dyspnoea) and obtain ECG as medically

indicated (see section 4.5 and 4.2 of the SmPC). If atrial fibrillation is developed on therapy with Calquence, a thorough assessment of risk for thromboembolic disease should be undertaken. Patients at high risk for thromboembolic disease, tightly controlled treatment with anticoagulants and alternative treatment options should be considered. Drug Interactions: Concomitant use with strong CYP3A/P-gp inhibitors should be avoided. If strong CYP3A/P-gp inhibitors (e.g. ketoconazole, conivaptan, clarithromycin, indinavir, itraconazole, ritinovair, telaprevir, posaconazole, voriconazole) are used shortterm, treatment with Calquence should be interrupted. CYP3A inducers may decrease acalabrutinib plasma concentrations. Concomitant use of strong inducers (e.g. phenytoin, rifampicin, carbamazepine) should be avoided. Concomitant use of St. John’s wort should be avoided. If treatment with a gastric acid reducing agent is required, consider using an antacid (e.g. calcium carbonate) or H2-receptor antagonist (e.g. ranitidine or famotidine). Due to the long-lasting effect of proton pump inhibitors, separation of doses with proton pump inhibitors may not eliminate the interaction with Calquence and therefore concomitant use should be avoided. Exercise caution if co-administering acalabrutinib with CYP3A4 substrates with narrow therapeutic range administered orally (e.g. cyclosporine, ergotamine, pimozide). Co-administration with CYP1A2 substrates (e.g. theophylline, caffeine) may decrease their exposure. Acalabrutinib may increase exposure to co-administered BCRP substrates (e.g. methotrexate) by inhibition of intestinal BCRP. To minimise the potential of an interaction in the gastrointestinal tract, oral narrow therapeutic range BCRP substrates such as methotrexate should be taken at least 6 hours before or after acalabrutinib. ACP-5862 (active metabolite of acalabrutinib) may increase exposure to co-administered MATE1 substrates (e.g. metformin) by inhibition of MATE1. Patients should be monitored for signs of changed tolerability as a result of increased exposure of the concomitant medication whilst taking Calquence. Pregnancy and Lactation: Women of childbearing potential should be advised to avoid becoming pregnant whilst receiving Calquence. Calquence should not be used during pregnancy unless the clinical condition of the woman requires treatment with acalabrutinib.

A risk to the breast-fed child cannot be excluded therefore breast-feeding mothers are advised not to breast-feed during treatment with Calquence and for 2 days after receiving the last dose. Ability to Drive and Use Machines: Fatigue and dizziness have been reported and patients who experience these symptoms should be advised not to drive or use machines until symptoms abate. Undesirable Events: Consult SmPC for full list of side effects. For monotherapy: Very common (≥ 1/10): Upper respiratory tract infection, sinusitis, second primary malignancy (SPM); neutropenia, anaemia, headache, dizziness, bruising, contusion, petechiae, haemorrhage/haematoma, diarrhoea, nausea, constipation, vomiting, abdominal pain, rash, musculoskeletal pain, arthralgia, fatigue, haemoglobin decreased, absolute neutrophil count decreased, platelets decreased. Common (> 1/100 to < 1/10): Nonmelanoma skin malignancy, SPM excluding non-melanoma skin, Pneumonia, urinary tract infection, nasopharyngitis, bronchitis, herpes viral infections, non-melanoma skin malignancy, SPM excluding non-melanoma skin, thrombocytopenia, atrial fibrillation/flutter, ecchymoses, gastrointestinal haemorrhage, intracranial haemorrhage, epistaxis, asthenia. Uncommon (≥ 1/1,000 to < 1/100): Aspergillus infections, hepatitis B reactivation, lymphocytosis, tumour lysis syndrome. For combination therapy: Very common (≥ 1/10): Upper respiratory tract infection, sinusitis, nasopharyngitis, urinary tract infection, pneumonia, SPM, neutropenia, thrombocytopenia, anaemia, headache, dizziness, bruising, contusion, petechiae, haemorrhage/haematoma, diarrhoea, nausea, constipation, vomiting, abdominal pain, rash, musculoskeletal pain, arthralgia, fatigue, absolute neutrophil count decreased, platelets decreased, haemoglobin decreased. Common (> 1/100 to < 1/10): Bronchitis, herpes viral infections, non-melanoma skin malignancy, SPM excluding non-melanoma skin, atrial fibrillation/flutter, ecchymoses, gastrointestinal haemorrhage, epistaxis, asthenia. Uncommon (≥ 1/1,000 to < 1/100): Progressive multifocal leukoencephalopathy, hepatitis B reactivation, lymphocytosis, tumour lysis syndrome, intracranial haemorrhage. Legal Category: Product subject to medical prescription which may not be renewed (A) Marketing Authorisation Number: EU/1/20/1479/001, EU/1/20/1479/002 Marketing Authorisation Holder: AstraZeneca AB, SE-151 85 Södertälje, Sweden. Further product information available on request from: AstraZeneca Pharmaceuticals (Ireland) DAC, Block B, Liffey Valley Office Campus, Dublin 22. Tel: +353 1 609 7100. CALQUENCE is a trade mark of the AstraZeneca group of companies. Date of API Preparation: 11/2020.

Veeva ID: IE-2229 This medicinal product is subject to additional monitoring.

Adverse events should be reported directly to: HPRA Pharmacovigilance, Website: www.hpra.ie Adverse events should also be reported to AstraZeneca Patient Safety on Freephone 1800 800 899

1. CALQUENCE 100mg Hard Capsules Summary of Product Characteristics. June 2021.

BTki = Bruton tyrosine kinase inhibitor

IE-2943 Date of preparation: October 2021

56

hyperaemic due to excessive erythropoietin production, a serum creatinine and e GFR to check overall renal function and Liver Function tests that may be altered in some para-neoplastic events associated with renal cancer.3 After identification of a renal tumour and appropriate blood and radiological work up the treatment depends on the size of the mass, the presence of metastatic or locally extensive disease and the patients renal function and overall health status.

Staging of renal tumours with the TNM classification classifies organ confined tumours as T1 and T2.

T1 are less than 7 cm in size and further sub classified as T1a if less than 4cm and T1b if between 4 and 7 cm.

This distinction is important as in a patient with normal renal function a tumour of less than 4 cm may be considered suitable for a partial Nephrectomy rather than complete removal of the kidney and its surrounding structures i.e. a radical nephrectomy. In a partial Nephrectomy where patients have a tumour of less than 4 cm the tumour and a margin of renal parenchyma of at least 2mm are removed from the kidney and the

RENAL CANCER

remaining defect is oversewn with sutures and surgical bolsters to reduce the risk of bleeding and urinary leakage post operatively.

This procedure can be performed either open, laparoscopically or with a DA Vinci Robot depending on the location of the tumour within the Kidney and the Surgeons preference and training.

Partial Nephrectomy is usually performed for tumours of 3 to 4 cm, however can be performed in larger tumours when the patient has limited renal function in an attempt to preserve as much functioning renal tissue as possible. i.e. in a single functioning kidney, or patients with limited renal function secondary to nephrological or systemic disease such as Diabetes therefore attempting to reduce the requirement for dialysis post operatively.8 When tumours of less than 3 cm are identified the surgeon will choose between a partial nephrectomy, active surveillance of the tumour by following the patient with serial scans on a 6 monthly basis to determine the rate of growth of the tumour or if the patient is elderly or has co-morbidity making surgery a high risk sometimes a percutaneous ablation of

the mass performed by an Interventional radiologist whom will percutaneously pass a probe into the kidney and then utilise an energy source such as Micro-Wave, Radio-Frequency, Cryotherapy or Electroporation and ablate and significantly reduce the size of a small renal lesion.

While the energy source can destroy the cancer and the surrounding tissue creating a cavity or defect within the Kidney, follow up can be problematic as it can be difficult to determine if recurrence occurs. It is therefore a selective procedure to be utilised in appropriate patients.4 When the CTIVU suggests that the Tumour is greater than 7cm i.e. T3 disease, and the patient is suitable for surgery then a Radical Nephrectomy( removing the kidney, the surrounding gerotas fascia and encapsulated Fat is recommended, this can be performed Laparoscopically or Open depending on the surgeons preference.

The classical Radical Nephrectomy as described by Whitmore included removal of the Adrenal, Gerota’s, and all Lymph Nodes however in a lower pole mass or when the tumour is not directly adjacent to the adrenal its removal is now left to the discretion of the operating surgeon.

When the CTIVU suggests Vascular Involvement with extension into the renal vein or beyond) the majority of Surgeons would suggest that an open surgical approach is favourable to allow adequate vascular control of the Inferior Vena Cava and safe removal of the thrombus in its full extent. However some experienced laparoscopic Surgeons would attempt to remove a thrombus confined to the renal vein with the aid of a Laparoscopic Satinsky.

The Involvement of a Vascular Surgeon may be necessary if the Thrombus is large, extends into the IVC or is adherent to the wall of the IVC and their assistance can help reduce potential bleeding complications. Occasionally if the thrombus were to extend to the Right Atrium involvement of a Cardio-Thoracic Surgeon and the use of Cardiac Bypass may be required for full surgical Resection of the Kidney and its associated thrombus.5 Despite the introduction of Haematuria Clinics and Improved Imaging , some patients will still present with Metastatic disease and in a young and otherwise fit patient the question arises as to whether removal of the primary cancer i.e.

Nephrectomy will improve the patients overall prognosis.

Two Large Randomised trials at the turn of the Century performed by EORTC and SWOG suggested a benefit for surgery and patients were routinely offered a nephrectomy on the basis of improving systemic symptoms if they were present and improving cancer specific survival.11 However since the advent of newer biological agents

Renal Vena Cava Involvment

NOVEMBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

57

Laparoscopic Nephrectomy

such as Tyrosine Kinase Inhibitors and Anti VEGF agents which can help stabilise the progression of the disease a recent Randomised trial called the Carmina Trial suggested that selection for surgery in the presence of high volume metastatic disease and poor performance status should be limited and that use of the disease modifying agents available to Oncologist’s may be more favourable than a combination of surgery and those agents post operatively. On occasions a difference of opinion can occur, but will be clarified by a robust Multi-Disciplinary process and discussion.6 The utilisation of Nomograms such as the Fox- Chase can be useful in balancing the decision making in elderly or unhealthy patients when contemplating surgery versus risk of the disease.7

Tumours quoted as 80-85%. And hence the drive for early detection.

Nowadays recovery from Laparoscopic Nephrectomy can result in as little as a 48-72 hour in hospital stay for a patient.

With Renal Tumours , annual follow up is important and a variety of Algorithms are available to put in place an appropriate follow up regimen in order that recurrence can be identified early and treated appropriately.

If patients are unfortunate enough to suffer a recurrence a number of biological agents that actively target the growth pattern of renal cancer are available to Oncologist’s and they have proven to be beneficial in altering the progression of the disease.

These agents can often be administered orally rather than by IV and therefore the patient can be monitored on an out patient basis rather than requiring long periods of hospitalisation.8

With so many different potential clinical presentation’s of renal cancer depending upon size of tumour and presence of metastatic disease and such an array of treatment options and decisions, it is paramount the each patient is discussed at an MDT meeting so that a Surgical, Radiological and Oncological opinion can be given to reflect the complexity of each given situation.

The Modern management of renal cancer requires an institution to have the necessary skills to provide Laparoscopic, and Open Surgical techniques, Interventional Radiological and Oncological Support and an ability to offer a comprehensive treatment plan for a patient presenting with this disease.

The prognosis for organ Confined disease remains excellent with 5 year Survival for T1 and T2

Modern Units should be adequately resourced to full-fill these needs to the population

they serve and although renal cancer may not have as high a profile as some other cancers it remains a tumour with a potentially poor outcome if not detected and treated early, that can be transformed by good diagnostics and appropriate treatment options and interventions being available.

It will require ongoing investment in adequately resourced Urology Units to help improve the outcomes for this disease.

References 1. Renal Mass and Localized Renal Cancer: AUA Guideline Campbell S, Uzzo RG, Allaf ME, Bass EB, Cadeddu JA, Chang A, Clark PE, Davis BJ, Derweesh IH, Giambarresi L, Gervais DA, Hu SL, Lane BR, Leibovich BC, Pierorazio PM.J Urol. 2017 Sep;198(3):520-529. doi: 10.1016/j.juro.2017.04.100.

Epub 2017 May 4.PMID: 28479239 2. Renal cancer at unenhanced CT: imaging features, detection rates, and outcomes O'Connor SD, Silverman SG, Cochon LR, Khorasani RK.Abdom Radiol (NY). 2018 Jul;43(7):1756-1763. doi: 10.1007/s00261-017-13760.PMID: 29128991 3. Kidney Cancer: Hancock SB, Georgiades CS.Cancer J. 2016 Nov/Dec;22(6):387-392.

4. Achieving the "trifecta" with open versus minimally invasive

partial nephrectomy Ghavimi S, Saarela O, Pouliot F, Rendon RA, Finelli A, Kapoor A, Moore RB, Breau RH, Lavallee L, Lacombe L, Fairey A, Jewett M, Liu Z, Tanguay S, Black PC.World J Urol. 2021 May;39(5):1569-1575.

5. Systematic Review of Surgical Management of Nonmetastatic Renal Cell Carcinoma with Vena Caval Thrombus Lardas M, Stewart F, Scrimgeour D, Hofmann F, Marconi L, Dabestani S, Bex A, Volpe A, Canfield SE, Staehler M, Hora M, Powles T, Merseburger AS, Kuczyk MA, Bensalah K, Mulders PF, Ljungberg B, Lam TB.Eur Urol. 2016 Aug;70(2):265-80.

6. Cytoreductive Nephrectomy in Metastatic Renal Cell Cancer: Not All That It's Cut Out to Be: Lara PN Jr, Evans CP.JAMA Oncol. 2019 Feb 1;5(2):171172.

7. Collaborative Review: Factors Influencing Treatment Decisions for Patients with a Localized Solid Renal Mass Chandrasekar T, Boorjian SA, Capitanio U, Gershman B, Mir MC, Kutikov A.Eur Urol. 2021 Feb 5:S03022838(21) 8. Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†Escudier B, Porta C, Schmidinger M, RiouxLeclercq N, Bex A, Khoo V, Grünwald V, Gillessen S, Horwich A; ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo. org.Ann Oncol. 2019 May 1;30(5):706-720.

HOSPITALPROFESSIONALNEWS.IE | HPN • NOVEMBER - 2021

Strength of Balance Introducing JYSELECA – a preferential JAK1 inhibitor for moderate to severe RA1

Indicated for the treatment of moderate to severe active rheumatoid arthritis in adults who have responded inadequately to, or are intolerant to one or more disease modifying anti-rheumatic drugs.1 May be used as monotherapy or in combination with methotrexate.1 Refer to Summary of Product Characteristics (SmPC) before prescribing, and for full prescribing information.

JYSELECA®

filgotinib 100 mg or 200 mg film-coated tablets.

Indication: Jyseleca is indicated for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have responded inadequately to, or who are intolerant to one or more disease modifying anti-rheumatic drugs (DMARDs). Jyseleca may be used as monotherapy or in combination with methotrexate (MTX). Dosage: Adults: 200 mg once daily. Taken orally with/ without food. It is recommended that tablets are swallowed whole. Laboratory Monitoring: Refer to the SmPC for information regarding laboratory monitoring and dose initiation or interruption. Elderly: A starting dose of 100 mg once daily is recommended for patients aged 75 years and older as clinical experience is limited. Renal impairment: No dose adjustment required in patients with estimated creatinine clearance (CrCl) ≥ 60 mL/min. A dose of 100 mg of filgotinib once daily is recommended for patients with moderate or severe renal impairment (CrCl 15 to < 60 mL/min). Not recommended in patients with CrCl < 15 mL/min.

Hepatic impairment: Mild moderate hepatic impairment: no dose adjustment required. Severe hepatic impairment: not recommended. Children (< 18 years): Safety and efficacy not yet established. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Active tuberculosis (TB) or active serious infections. Pregnancy. Warnings/Precautions: See SmPC for full

information. Immunosuppression: Combination use, with immunosuppressants e.g. azathioprine, ciclosporin, tacrolimus, or biologic DMARDs (bDMARDs) or other Janus kinase (JAK) inhibitors is not recommended as a risk of additive immunosuppression cannot be excluded. Infections: Infections, including serious infections such as; pneumonia and opportunistic infections e.g. tuberculosis (TB), oesophageal candidiasis, and cryptococcosis have been reported. In some cases, treatment should be temporarily interrupted. There is a higher incidence of serious infections in the elderly aged 75 years and older, caution should be used when treating this population. Treatment should be interrupted if a patient develops a serious infection until the infection is controlled. Patients should be closely monitored for the development of signs and symptoms of infections during and after filgotinib treatment. Tuberculosis: Patients should be screened for TB before initiating filgotinib, and filgotinib should not be administered to patients with active TB. Viral reactivation: Cases of herpes virus reactivation (e.g., herpes zoster), were reported in clinical studies (see SmPC). If a patient develops herpes zoster, filgotinib treatment should be temporarily interrupted until the episode resolves. Screening for viral hepatitis and monitoring for reactivation should be performed. Malignancy: Immunomodulatory medicinal products may increase the risk of malignancies. Malignancies were observed in clinical studies (see SmPC). Fertility: In animal studies, decreased fertility, impaired spermatogenesis, and histopathological effects on male reproductive organs were observed (see SmPC). The potential effect of filgotinib on sperm production

JYSELECA, GALAPAGOS and the JYSELECA and GALAPAGOS logos are registered trademarks of Galapagos NV. © 2021 Galapagos NV. All rights reserved.

JYSELECA is now reimbursed and will be dispensed under the High Tech Arrangement effective March 1st 2021

JYSELECA 200 mg offers a balance of sustained efficacy from Week 2 to Week 52,2 with acceptable tolerability and low rates* of JAK inhibitor-associated adverse events1,3† ACR20 response seen by Week 2 in 37% of JYSELECA patients (n=475) vs. 15% of those in the placebo group (n=475; p<0.001)2

By Week 52, 44% of JYSELECA patients had achieved ACR70 response (n=475)2 Similar observed rates of serious infections, VTEs and Herpes Zoster vs. adalimumab2,3 * Based on AE rates observed as ‘Uncommon’ (<1% and ≥0.1%) or of lower frequency in the JYSELECA clinical trials.1,3 † JAK inhibitor-associated adverse events defined as VTEs, Herpes Zoster reactivation and serious infections.4

Visit strengthofbalance.co.uk to learn more and male fertility in humans is currently unknown. Haematological abnormalities: Do not start therapy, or temporarily stop, if Absolute Neutrophil Count (ANC) <1 × 109 cells/L, ALC <0.5 × 109 cells/L or haemoglobin <8 g/dL Temporarily stop therapy if these values are observed during routine patient management.

Vaccinations: Use of live vaccines during, or immediately prior to, filgotinib treatment is not recommended. Lipids: Treatment with filgotinib was associated with dose dependent increases in lipid parameters, including total cholesterol, and high-density lipoprotein (HDL) levels, while low density lipoprotein (LDL) levels were slightly increased (see SmPC). Cardiovascular risk: Rheumatoid arthritis patients have an increased risk for cardiovascular disorders. Patients should have risk factors (e.g., hypertension, hyperlipidaemia) managed as part of usual standard of care. Venous thromboembolism: Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving JAK inhibitors including filgotinib. Caution should be used in patients with risk factors for DVT/PE, such as older age, obesity, a medical history of DVT/PE, or patients undergoing surgery, and prolonged immobilisation. Lactose content: Contains lactose; patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take filgotinib. Interactions: Co-administration with sensitive OATP1B1 or OATP1B3 substrates (e.g., valsartan, statins) is not recommended. See SmPC for full list. Pregnancy/Lactation: Filgotinib is contraindicated in pregnancy.

Filgotinib should not be used during breast-feeding. Women of childbearing

potential must use effective contraception during and for at least 1 week after cessation of treatment. Driving/Using machinery: No or negligible influence, however dizziness has been reported. Side effects: See SmPC for full information.

Common (≥1/100 to <1/10): nausea, upper respiratory tract infection, urinary tract infection and dizziness. Uncommon (≥1/1000 to <1/100): herpes zoster, pneumonia, neutropenia and blood creatine phosphokinase increase. Serious side effects: See SmPC for full information Legal category: POM Pack: 30 film-coated tablets/ bottle Price: Ireland: POA Marketing authorisation number(s): Ireland & United Kingdom (Northern Ireland): EU/1/20/1480/001, EU/1/20/1480/003 Further information: Gilead Sciences Ltd, 280 High Holborn, London, WC1V 7EE, Great Britain & Northern Ireland: +44 (0) 8000 113700; Ireland: +353 214825999. ukmedinfo@gilead.com.

Jyseleca® is a trade mark. Date of Preparation: July 2021 UK-RA-JY-202107-00014 Additional monitoring required Adverse events should be reported.

For Ireland, reporting forms and information can be found at www.hpra.ie and can be reported to HPRA on +353 1 6764971.

Adverse events should also be reported to Gilead to safety_FC@gilead.com or +44 (0) 1223 897500.

References: 1. JYSELECA SPC. Available at: www.medicines.ie. Last accessed: August 2021. 2. Combe B, et al. Ann Rheum Dis 2021;doi:10.1136/annrheumdis-2020-219214. 3. Genovese MC, et al.

Poster presented virtually at the European League Against Rheumatism (EULAR) 2020 E-Congress, June 3–6, 2020. 4. Angelini J, et al. Biomolecules 2020;10(7):E1002. doi: 10.3390/biom10071002.

Date of preparation: August 2021 Job code: UK-RA-JY-202107-00017

60

NEWS

Startling New Statistics on Men’s Heart Health Men are nearly three times more likely than women to die young from heart disease and stroke A new survey has found that more than one in four men do not consider the health of their heart a priority, even though male deaths account for almost three quarters of premature cardiovascular deaths in Ireland.

Data from the Central Statistics Office (CSO) shows that almost 30% of all premature deaths (younger than 65) in 2018 were from cardiovascular conditions such as heart attacks and strokes and the vast majority (73%) of those affected were men.

However, an Ipsos MRBI poll, conducted on behalf of the Irish Heart Foundation, revealed that 28% of men do not consider the health of their heart a priority.

To help combat this the Irish Heart Foundation has launched a ‘Reboot Your Life’ campaign which aims to encourage men to review their lifestyles and make vital, sustainable changes to improve their heart health.

CSO data shows that 999 men died of a heart attack in 2020, compared to 642 women. In the same year, in the 45 to 54 age group, 217 men died of heart disease and stroke compared to only 75 women.

“One in four men in Ireland die from heart disease and stroke and men are nearly three times more likely than women to die young from these issues – but the good news is that 80% of those deaths are preventable through healthy lifestyles,” said Janis Morrissey,

the Irish Heart Foundation’s Director of Health Promotion.

“The proportion of men who are living with overweight (43%) and obesity (25%) is higher than for women (31% and 22% respectively) and men’s diets are generally less healthy.

“The older you get, the higher your risk – and so we are encouraging men, particularly men in their 40s and 50s, to take stock of and Reboot their lifestyles by identifying what simple changes they can make now to benefit their heart health into the future.”

The campaign is being supported by the HSE as part of their delivery on Healthy Ireland, the national framework to support health and wellbeing in Ireland.

“We are delighted to support this campaign by the Irish Heart Foundation, which encourages men to Reboot their lives this September by making sustainable lifestyle changes,” said Fergal Fox, Head of Stakeholder Engagement and Communications with HSE Health and Wellbeing.

“Women tend to be more proactive in engaging with their health. In fact, men are typically 33 per cent less likely to engage with their GP before they experience heart issues.

“That is why this campaign is so important – it encourages men to take action now before that crisis point happens.”

Men all over Ireland can sign up to Reboot their lives and find lots of helpful tips and information by visiting www.irishheart.ie

Lipertance Launched in Ireland Servier Laboratories (Ireland) Ltd is delighted to announce that Lipertance, the combination of atorvastatin, perindopril and amlodipine1, will be available for prescription from November 2021 and is listed as a PCRS reimbursable product.

Lipertance® is the first Statin + ACEi + Calcium Channel blocker combination available in Ireland2.

Servier continue to add to their range of Single Pill Combination solutions for the management of patients with cardiovascular disease3. The arrival of Lipertance, in particular, offers greater intensification of blood pressure (BP) control for patients on a statin1. It follows the recent launch (Feb 2021) of , Lipercosyl the statin/ACEi combination of atorvastatin and perindopril4.

Like Lipercosyl®, Lipertance® controls high cholesterol and hypertension in unison1, helping patients with these cardiovascular risk factors to meet their target blood pressure5 and low-density lipoprotein cholesterol (LDL-C)6

and thereby helping to avoid cardiovascular outcomes1.

Atorvastatin has been shown to reduce concentrations of LDL-C by up to 49%7. Perindopril and amlodipine reduce BP by up to 33.7/17.1mmHg helping patients reach lower targets8. Perindopril and amlodipine’s antihypertensive effect is sustained for at least 24 hours and atorvastatin is a longacting statin, ensuring true 24hr control from a single daily dose1, 9.

Furthermore, it has been demonstrated in the large ASCOT study (n=19,259 patients) that a combination of statin with amlodipine +/- perindopril yields a 53% relative risk reduction in fatal coronary events and non-fatal MI p<0.00011.

Prescribing the 3 agents in a Single-Pill Combination offers patients better efficacy, tolerability and adherence10-13. Lipertance is taken one tablet daily in the morning before breakfast.1 Lipertance® is indicated for the treatment of essential hypertension

NOVEMBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

and/or stable coronary artery disease, in association with primary hypercholesterolaemia or mixed hyperlipidaemia, as substitution therapy in adult patients adequately controlled with atorvastatin, perindopril and amlodipine given concurrently at the same dose level as in the combination.1

Should you require any further information, please contact Servier on 01 6638110, or refer to the full Summary of Product Characteristics on www.medicines.ie References on request

OBESITY

61

A Short Guide to Nutrition and Exercise Therapy for the Management of Obesity in Men Written by Dr Werd Al-Najim, Clinical Nutritionist, School of Medicine, University College Dublin; and ProHealth365 Nutrition and Physiotherapy and Ms Rand Al-Najim, Chartered Physiotherapist, ProHealth365 Nutrition and Physiotherapy

Globally, obesity rates are on the rise. In Ireland, at least 6 out of 10 men live with overweight or obesity, and COVID-19 exacerbated the crisis. During the first COVID-19 lockdown in Ireland, 3 out of 10 men reported that they had gained weight during this period, and only 40% of them were trying to lose it. Compared to women, men's engagement in weight loss services is low and estimated to be only around 11-18% of participants. Possible reasons highlighted in research include men not viewing their weight as a health risk, perceiving diets as feminine and weight loss facilities as feminised places, as well as the association of dieting with unpalatable foods, small portions, and restrictions. Meanwhile, the inclusion of physical activity in weight loss services can facilitate the attendance of men.

A high percentage of men attend weight loss clinics to seek help for weight-related comorbidities rather than weight loss. In our services, typical comments we have heard from male patients are "I don't have a weight problem as I have always been large", "I am just a big man", and "I have my father's genes". This article aims to guide healthcare professionals to address the weight issue with male patients in a non-stigmatising way as early as possible. Men should not wait until they are diagnosed with an obesity complication before taking action.

The World Health Organisation (WHO) defines pre-obesity (overweight) and obesity as medical conditions marked by an excessive accumulation of body fat that presents a risk to health.

Additionally, obesity is a chronic relapsing disease, which in turn acts as a gateway to a range of other non-communicable diseases, such as diabetes, cardiovascular disease, and cancer; please see figure 1 (page 62).

While the prevention of obesity is ideal for decreasing the development of these diseases, there is already a large percentage of the population living with overweight and obesity, so disease management needs to be addressed as early as possible.

According to the Healthy Ireland Summary Report (2019), the most common actions taken to lose weight are performing more exercise (56%), eating fewer calories (54%) and eating/ drinking fewer sugar-sweetened foods/drinks (49%). These are all significant lifestyle changes that will improve general health and result in some weight loss but may not effectively prevent the development of complications or reverse them if they already exist in patients with BMI above 25kg/m2.

Therefore, a more structured and supervised treatment is required.

Clinical Assessment Appropriate clinical assessment is fundamental in weight management programmes.

Obesity is not a cosmetic issue; it is a disease that requires a structured and thorough evaluation. Our colleagues in Canada have created a system called the 5 A’s that can facilitate a non-judgmental, blame-free discussion with patients living with excess weight. The 5 A’s stand for Ask, Assess, Advise, Agree, and Assist. Weight for many patients is a sensitive issue, and many patients are embarrassed or fear blame and stigma. Therefore, it is necessary for conversations about weight to be non-judgemental, explore readiness for change, use motivational interviewing techniques, and ensure that the consultation environment is weight friendly.

The collection of weight history can provide a lot of information on the drivers of weight gain, risk factors for complications, and indications of successful

Dr Werd Al-Najim, Clinical Nutritionist, School of Medicine, University College Dublin; and ProHealth365 Nutrition and Physiotherapy

Ms Rand Al-Najim, Chartered Physiotherapist, ProHealth365 Nutrition and Physiotherapy

treatments and response rates.

Weight history should include:

be evaluated and discussed with the patient to choose the most appropriate one.

1 - a history of weight from as early as the patient can remember, 2 - events related to weight gain such as trauma, abuse, or use of certain medications, 3 - any significant changes to the environment, such as immigration or leaving the parents' house, 4 - information on current eating behaviour, eating disorders, and lifestyle, 5 - information on previous weight loss experiences and amount of weight loss each time.

The assessment of obesity should not only rely on the Body Mass Index (BMI) of patients.

Instead, clinical assessments should include using the King's College Obesity Staging System tool to assess the severity of the disease. As a result, all the available treatment options can

Several treatment options are available in Ireland; these include intensive lifestyle treatment combining nutritional and exercise therapy, pharmacotherapy, and bariatric surgery. Patients need to understand the pros and cons of each treatment, the amount of weight loss to be expected, and the lifetime commitment. All weight loss treatments require life-long follow-ups.

Nutritional therapy Large research studies such as the Look AHEAD Trial that was a randomised controlled trial comparing Intensive Lifestyle Intervention to Diabetes Support and Education in 5145 patients with overweight and obesity suggests that a realistic weight loss expectation with an intensive lifestyle approach is around 8.6%.

However, weight loss maintenance is even more challenging, and half of the patients will only be able to

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maintain a 5% of weight loss past the first year. Obesity is a brainrelated disorder where the signals of hunger and fullness regulated by the hypothalamus are disrupted.

Therefore, successful treatments need to focus on controlling these symptoms. Simply reducing the calories and enforcing dietary restrictions will cause more hunger, less fullness, and increased cravings, thereby producing unsustainable weight loss plans, diet fatigue, stress, and long-term health damage.

It is typical for patients to think that they can lose weight independently without the help of healthcare professionals. As a result, many patients will try to mimic the same diet as their friend's or relative's or follow unhealthy dietary restriction practices. While sometimes they can be successful in losing weight, they may be at a high risk of macro and micronutrient deficiencies.

The following 10 points should be considered to ensure patients receive optimal nutritional therapy for weight loss: 1

- Create a small sustainable calorie deficit of around 500kcal/day.

2

- Ensure adequate intake of protein to prevent the loss of lean body mass. Research suggests a minimum intake of 1g per 1kg of body weight per day.

3

- The dose of high-quality protein in each meal should not be less than 25-30g.

4

- Supplementation with leucine, the most potent branched-chain amino acid for stimulation of protein synthesis, is recommended, especially for older patients.

5

advisable as co-ingestion of carbohydrates has been shown to exert negative effects on muscle protein turnover.

10 - Measuring fluid intake is essential to prevent dehydration, especially for older adults and during hot weather.

6

- Many patients like to follow a restricted eating pattern such as intermittent fasting.

A thorough evaluation of their nutrients intake and the consumption pattern is needed, especially for protein.

Once the above points are addressed with the patient, they will feel more in control of their food choices, make sustainable changes and realise the importance of supervision and support.

7

- Ensure the consumption of adequate amounts of essential mono and poly-unsaturated fatty acids. Research supports the role of fats in boosting the feeling of fullness by exaggerating the release of appetite-suppressing gut hormones.

Exercise therapy

8

- Overcrowding the meal with colourful vegetables rather than restricting portion size.

9

- Fruits are healthy, but patients need to be reminded that they are still a source of calories.

For most patients, three portions of fruits a day are sufficient to provide adequate fibre, fluids, and nutrients.

- While sufficient protein intake is paramount to optimising the muscle protein synthetic response, a diet relatively low in carbohydrates is also

It is well-known that the lack of physical activity has negative impacts on mental and physical health. Still, the reality is that many find it challenging even to meet the minimum requirements for physical activity (PA).

Sedentary occupations, busy lifestyles, advancements in technology, electronics, and machinery have all led to the development of time-saving options. Modern means of transport, computers, and indoor entertainment are now more attractive alternatives to energyconsuming activities such as commuting by foot and other

Figure 1. Obesity affects every system in the human body and increases the risk of a wide variety of conditions

Cardiovascular System:

Respiratory System:

• Coronary heart disease • Hypertension • Varicose veins • Pulmonary embolism • Cor pulmonale • Congestive heart failure

Mental Health:

• Obstructive sleep apnoea • Hypoventilation syndrome • Asthma • Increased risk of infections

Nervous System:

Integumentary System:

Gastrointestinal System:

• Stretch marks • Skin pigmentation • Cellulitis • Acanthosis nigricans • Psoriasis • Pressure ulcers

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• Metabolic syndrome • Type 2 diabetes • Dyslipidemia • Infertility

Musculoskeletal System: • Stroke • Dementia • Alzheimer’s disease • Polyneuropathy • Decreased concentration

• Reduced quality of life • Negative body image • Depression • Low self esteem • Binge eating disorder

Endocrine System:

• Non-alcoholic fatty liver disease • Colon cancer • Hernia • Gallstones • Gastroesophageal reflux disease

• Gout • Poor mobility • Osteoarthritis • Back pain • Osteoporosis • Fibromyalgia • Soft tissue complaints

Genitourinary System: • Urinary incontinence • Kidney stones • Hypogonadism • Colorectal cancer • Prostate cancer • Sexual dysfunction

affects every system in the human body and increases the risk of a wide variety of conditions.

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never assume that all patients attending a weight loss clinic follow an inactive lifestyle, 3 - Assessment of muscular strength, cardiorespiratory fitness, balance, coordination, flexibility, and mobility, 4 - Creation of individualised programs targeting physical activity, cardiovascular training and strengthening exercises, 5 - Regular re-evaluation.

Images courtesy of World Obesity outdoor activities. More than 25% of adults are at risk of chronic disease or an exacerbation of their current illness due to insufficient PA. Despite the controversy of exercise as a single intervention for weight reduction, increased physical activity attenuates the risks related to overweight and obesity. Furthermore, when exercise is combined with dietary interventions, the benefits are further maximised.

Aerobic and/or resistance exercises can be effective tools in reducing body weight, especially if performed at high intensities. While success rates vary between individuals, the emphasis on exercise in subjects with obesity should not solely be from a weight management perspective. Instead, we should emphasise the numerous health benefits obtained from structured exercise and general PA, such as improved body composition, cardiorespiratory fitness, mobility, strength, coordination, enhanced blood glucose levels, reduced risk of falls, fractures, and chronic diseases. In addition, the mental health benefits of exercise and improved cognitive functioning should also be emphasised as depression, anxiety, lack of concentration, low self-esteem, and reduced productivity are very common challenges they face on a daily basis.

Sarcopenic obesity, the loss of muscle mass combined with preserved or even increased fat mass, is a significant concern. It leads to severe health deterioration by rapidly reducing independence and quality of life and increasing morbidity and mortality. Patients often report difficulties performing basic daily activities such as walking a short distance, waiting

Multidisciplinary approach in line for a few minutes, turning in bed, and sitting/standing up unsupported. Regardless of weight loss, increasing general PA and incorporating a structured exercise routine can reverse many of these health challenges and dramatically improve quality of life as the patient will be able to do more with less effort.

We need to shift away from recommending increased PA for weight loss and focus more on health gains. Research suggests that the general advice of a weekly minimum of 150 minutes of moderate PA or 75 minutes of vigorous activity, combined with resistance training, is only to maintain general health but is not sufficient to induce significant weight loss. A minimum of 300 minutes of PA per week is required to lose weight and maintain it in the long term. Practically, such a high activity level is not only time consuming but is also challenging to achieve for people living with obesity. This is because patients with obesity are at an increased risk of health limitations such as hip/knee/foot arthritis, lower back pain, cardiovascular disease, gout, sleep apnoea, and asthma, to name a few. Thus, only the minority will be able to meet the exercise intensities or durations recommended for effective weight loss or maintenance.

Physiotherapists are experts in movement. While their involvement in the multidisciplinary treatment approach of obesity is still evolving, physiotherapists are trained to deal with the physical and psychological aspects of health issues. Moreover, physiotherapists are likely to have the most contact time with these patients as they see them regularly and sometimes multiple

times per week. This allows for opportunities to discuss barriers to PA, challenges along the way and find suitable alternatives when needed.

Some of the most common barriers to PA include pain, lack of space for home training, feeling embarrassed to exercise in public (e.g., gym or outdoors), feeling intimidated to train with or in front of other people, acute or chronic injuries, and not knowing how to exercise (type of exercise, frequency, duration, or intensity).

An obesity-trained physiotherapist can help direct these patients through supervised individual or small group training and provide them with a concrete plan of action that targets the different aspects of physical fitness, including aerobic endurance, strength, flexibility, coordination, and balance.

"I'm too heavy to exercise", "I have a bad back I can't go for a walk", "my knee is way overdue for replacement, so I can't exercise", "people will laugh at me if they see me training", "you can't expect me to exercise at this age" are sadly all common remarks we hear in the clinic from patients living with obesity. Our role as healthcare professionals is to empower patients and reassure them that they won't be harming themselves through supervised graded exercises. We need to emphasise the benefits and remind them that they are not alone by offering ongoing support and encouragement.

An exercise therapy plan may comprise of: 1 - Assessment of the individual's medical history to take health limitations into consideration, 2 - Evaluation of current physical activity level. We should

Obesity is a complex disease requiring a multidisciplinary approach. Obesity trained dieticians, endocrinologists, GPs, physiotherapists, psychologists, and bariatric surgeons form the cornerstone for gold standard obesity care. As a team, the goal needs to be improved health by applying personalised treatment methods within a friendly, safe, non-stigmatising professional environment.

GPs play a vital role in the management of obesity as they are the gatekeepers to the health system. Their role in addressing the problem and encouraging patients to seek professional help by referring them to appropriate resources and weight loss clinics is a crucial first step. In fact, research shows that when a GP advises and encourages patients to seek professional help with diet and exercise, patients are much more likely to comply with the treatment.

It is also advisable that GPs start collecting weight charts for their patients. It is never too late to do so; while the prospective collection is ideal for young patients, retrospective weight history for older patients is as important.

This chart should include the weight at birth (if possible), weight during childhood, teenage life, and throughout adulthood life with emphasis on special life events such as the start of university, marriage, separation, trauma, abuse, etc. This chart should be discussed with the patient as soon as the GP identifies a trend in weight gain. Patients should then be referred to specialised weight management clinics to design a suitable personalised long-term weight management programme, and that should include life-long follow-ups.

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Tinnitus: Ringing in the Ears and What to Do about it Written by Ms Emma Cashman MB BAO BCh BMedSci FRCSI Consultant ENT Surgeon, Beacon Hospital

Introduction Tinnitus, or the conscious perception of a meaningless sound without an external acoustic stimulation, is a prevalent phenomenon. An estimated 15% of the population experiences chronic tinnitus which denotes tinnitus symptoms persisting for longer than six months. However, only a subset of the population experiences tinnitus that is bothersome enough to disrupt or disturb sleep, concentration and/or mood. The perception of tinnitus can be described with respect to its loudness, pitch, spectral quality and laterization. People with tinnitus often report that they hear multiple sounds. Whilst the word tinnitus is derived from the Latin word tinnire meaning ‘to ring’, or ‘a ringing’ tinnitus can present as a whole host of sounds such as a pulsatile, buzzing or clicking sound. For example, a tinnitus sufferer might hear a high-pitched sound along with a low-pitched hum. The high-pitched sound will be noticeable in most situations if it is above the frequency range of typical ambient sound. By contrast the hum might be masked by ambient sound and therefore be noticeable only in very quiet environments.

Who experiences tinnitus?

It is estimated that over 80% of the general population will experience transient tinnitus over a lifetime. After exposure to loud sounds such as concerts or parties many people when in a quiet environment perceive some hearing loss accompanied by tinnitus, and in most cases, it disappears completely by the next morning. Tinnitus is most prevalent between 40-70 years of age and the severity of tinnitus tends to increase with age with a

peak prevalence observed in the 60-69 cohort. The primary catalyst for tinnitus is hearing loss and age-related hearing loss tends to accelerate after the age of 60.

The prevalence of tinnitus in the hearing-impaired population is estimated to be as high as 70%.

Males are more likely to experience tinnitus over a lifetime and this disparity is most likely attributable to males being more represented in loud professions such as manufacturing, construction and military service. Men are also more likely to participate in high hearing risk behavior such as hunting and motorsport.

Causes of tinnitus Tinnitus may be due to various underlying pathologies and it can be classified in a variety of different ways. In general, pulsatile tinnitus, unilateral tinnitus and tinnitus associated with other unilateral otological symptoms represent potentially more serious underlying disease than bilateral tinnitus. Otological disorders are the most common cause of subjective tinnitus including noise induced hearing loss, presbycusis, otosclerosis, impacted cerumen and idiopathic sudden sensorineural hearing loss. For many years hearing loss has been understood to be the most common cause of tinnitus. Population based data indicates that excessive noise exposure represents the second most common cause of tinnitus. However, about 40% of patients cannot identify any cause associated with tinnitus onset. Infectious causes include otitis media and sequelae of Lyme disease, meningitis and other infections or inflammatory processes that effect hearing.

Tinnitus is also the side effect of some oral medications such as salicylates, nonsteroidal anti-inflammatory drugs, aminoglycoside antibiotics, loop diuretics, and chemotherapy agents (e.g. platins and vincristine) Temporomandibular-joint dysfunction and other dental disorders can cause tinnitus but in the vast majority of cases

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no underlying physical cause is identified. Unilateral tinnitus may suggest the presence of a tumor typically a vestibular schwannoma/ acoustic neuroma.

More recent studies have focused on abnormalities in neural activity in the auditory pathway and demonstrated that deprivation of auditory input can cause a harmful plasticity effect that could lead to the onset of tinnitus.

Management of tinnitus There is currently no scientifically proven cure for most cases of chronic tinnitus, in particular the vast majority of cases caused by sensorineural hearing loss. There are however excellent tools to help patients manage their condition and treatments that reduce the perceived intensity, omnipresence and burden of tinnitus. Patients presenting with intrusive tinnitus may benefit from sound therapy to facilitate habituation in the first instance. Broadly, sound therapy refers to the enrichment of the sound environment. The intent of sound therapy is to reduce the perceptual contrast between the internal noise (tinnitus) and external noise (environmental sound).

A candle in a dark room is a popular analogy to describe the role of sound therapy in reducing tinnitus intrusiveness. The lack of other visual stimuli makes the candle more prominent and therefore harder to ignore. When lights are turned on the candle is less noticeable and thus easier to ignore. In addition to sound enrichment avoidance of silence is recommended to facilitate habituation to tinnitus. Sound enrichment can be accomplished with non-medical or medical devices. Ear level medical devices for sound enrichment include sound generators and tinnitus treatment -specific devices.

Because over half of patients

with chronic tinnitus have some measurable degree of hearing loss amplification is an appropriate intervention. Hearing aids improve audibility, reducing the strain to hear. They amplify ambient sound, reducing exposure to excessively quiet environments and provide natural sound therapy.

Many studies have supported the efficacy of CBT for treating tinnitus. CBT for tinnitus focuses on reducing the distress and handicap induced by tinnitus. The goal of CBT is not to reduce the acoustic features of the condition such as loudness or pitch, but to help patients who face specific difficulties in everyday situations by constructing more positive and realistic thoughts about their situation. More recently neuromodulation devices such as Lenire, which aims at alternating nerve activity through a targeted delivery of a stimulus have emerged as a potential option in tinnitus management. A recent clinical trial showed that over 80% of participants who used Lenire as directed achieved an improvement in their tinnitus handicap inventory score after 12 weeks of treatment.

Conclusion Although there seems to be a virtual gap in understanding the pathophysiology of tinnitus and the possible treatments for the same the treatment options have increased on a time axis. Currently individuals suffering from tinnitus are showing improvement with sound therapy, CBT along with other medical therapies. Within the last decade, neuroscientific research has contributed to a better understanding of the pathophysiological mechanisms that underlie the development and progression of tinnitus which will hopefully lead to more efficient treatment options for the many patients who currently still suffer from tinnitus.

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Pharmacy Management of Prostate Cancer Interview with Theresa Lowry Lehnen (GPN, RNP, PhD).

Clinical Nurse Specialist and Associate Lecturer at Institute of Technology Carlow.

Member of the Irish General Practice Nurses Educational Association (IGPNEA).

About 3,890 men are diagnosed with prostate cancer each year in Ireland. This means that 1 in 7 men will be diagnosed with prostate cancer during their lifetime.

Prostate cancer can be treated with active surveillance, external beam radiotherapy, hormone therapy, brachytherapy, surgery, chemotherapy and watchful waiting. In 2018, 1,276,106 new cases of prostate cancer were registered worldwide, representing 7.1% of all cancers in men and 358,989 deaths representing 3.8% of all male cancer deaths.1 3,890 men are diagnosed with prostate cancer each year in Ireland indicating that 1 in 7 men in Ireland will be diagnosed with prostate cancer during their lifetime.1, 2 We recently spoke to Theresa Lowry Lehnen (GPN, RNP, PhD) Clinical Nurse Specialist and Associate Lecturer at Institute of Technology Carlow to find out more about current advances in this field.

The prostate is part of the male reproductive system, which includes the penis, prostate, seminal vesicles, and testicles.

The prostate gland is located just below the bladder and in front of the rectum. It surrounds the urethra and produces fluid that makes up a part of semen.5 The prostate gland is a conglomerate of tubular or saclike glands that secrete fluids into the urethra and ejaculatory ducts. The secretory ducts and glands are lined with a

moist, folded mucous membrane.

Beneath the mucous membrane lies connective tissue composed of a thick network of elastic fibres and blood vessels. The interstitial tissue surrounding the secretory ducts and glands contains muscle, elastic fibres, and collagen fibres that give the prostate gland support and firmness. The capsule enclosing the prostate is also composed of interstitial tissue.1, 6 Theresa, who is a member of the Irish General Practice Nurses Educational Association says, “Prostate cancer incidence rates are highly variable worldwide and the variations in incidence is likely to be attributed to PSA testing.

In Europe, prostate cancer is the most frequently diagnosed cancer among men, accounting for 24% of all new cancers in 2018, with around 450,000 new prostate cancer cases detected in 2018.3 Prostate cancer incidence increases with age.”

Risk factors So what are the most common risk factors for prostate cancer?

Theresa reflects that increasing age is one of them.

She adds, “It usually affects men over the age of 50 and almost two in every three prostate cancers are diagnosed in men over the age of 65. In Ireland, the majority of cases are detected in men aged 65-to-84 years, with 37 per cent detected in men under 65 years of age. Genetic factors play a role.

Family history is associated with

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an increased risk and men with a father or brother diagnosed with prostate cancer at age 50 years have an approximately two-fold increased risk of prostate cancer.1 “Risk is higher in males with a relative who developed prostate cancer at a younger age and in males who have more than one relative with the disease. Two genes, BRCA1 (breast cancer type 1) and BRCA2 (breast cancer type 2), have been linked to prostate cancer. Like women, men can have mutations in the BRCA1 and BRCA2 genes.”

The function of the BRCA genes is to repair cell damage and keep breast, ovarian, and other cells growing normally. “Men carrying mutations in BRCA2 gene have an increased risk of developing prostate cancer, and mutations in either gene can significantly reduce survival,7 she adds.

“Studies have revealed an association between hereditary susceptibility to prostate cancer and sequence variations in the RNASEL gene (ribonuclease L), which plays a role in maintaining immunity against viral infections.

“A common RNASEL variant involves a mutation resulting in decreased activity of the encoded ribonuclease L protein, reducing the immune defence against viruses. Men who inherit this mutation have a significant increased risk of developing prostate cancer.7 It is estimated that about 20% of patients with prostate cancer report a family history, which may develop not only because of shared genes, but also for a similar pattern of exposure to certain environmental carcinogens and common lifestyle habits.9 “Afro-Caribbean men have the highest incidence of prostate cancer of any group (231.9 per 100,000) while Asian men have the lowest risk. Obesity and physical inactivity has been associated with higher-grade prostate cancers and studies have shown increased risk associated with various dietary intakes, including high levels of high-saturated fats and red meats and reduced intake of fish, fruit and vegetables.1, 2, 9 Research is ongoing into the links between diet and prostate cancer and

there is some evidence that a diet high in calcium is also linked to an increased risk of developing prostate cancer.8 “Although there are no studies that can sufficiently demonstrate the direct correlation between diet and nutrition with risk or prevention of prostate cancer development, many preclinical studies that look at links between certain eating behaviours and cancer suggest there may be a connection,”9 says Theresa.

Unknown Factors The aetiology of prostate cancer is the subject of numerous studies and remains largely unknown compared to other common cancers.

She continues, “While the exact causes of prostate cancer are not fully understood many cases do appear to be related to aberrant cell signalling that involves male androgen hormones, particularly testosterone and its metabolites.

“Within certain tissues, testosterone may be converted into one of two active compounds, oestradiol or dihydrotestosterone.

Oestradiol promotes the growth of prostate cancer cells and dihydrotestosterone inhibits apoptosis of those cells.

Testosterone plays a central role in maintaining prostate cells and stimulating apoptosis when abnormal cells arise. However, the mechanism by which testosterone and its active derivatives contribute to the development of prostate cancer is not entirely understood.7 “During the process of malignant transformation, cells gradually evolve from the benign to malignant phenotype. High-grade prostatic intraepithelial neoplasia (PIN) is the histological entity widely considered to be the most likely precursor of invasive prostatic cancer. It is characterised by cellular proliferation within pre-existing ducts and glands with cytological changes.2 “Although other prostate lesions may be associated with even higher rates of carcinoma, PIN has been identified as the most likely progenitor of the majority of prostatic adenocarcinomas.”9

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Symptoms and Diagnosis When the prostate gland becomes cancerous, it can put pressure on the urethra, causing dysuria, a burning sensation and frequency of micturition. It can also cause hesitancy, a weak and intermittent flow, nocturia, haematuria and impotence or sexual dysfunction.

Theresa continues, “Other symptoms include swollen lymph nodes in the groin and pain in the pelvis, hips, back, or ribs. More advanced stage of the disease may present with urinary retention and back pain, as the axis skeleton is the most common site of bony metastatic disease. Prostate cancer should not be confused with benign prostate hyperplasia, which has similar symptoms and often occurs in older men but is not a type of cancer.”7 Prostate cancers usually grow very slowly, and symptoms may not occur for some time. She adds, “If the prostate is enlarged, a preliminary diagnosis can be made by rectal examination or transrectal ultrasound (TRUS).

A PSA blood test for prostatespecific antigen is used to detect prostate tumours in their earliest stages in high-risk individuals.

“Although originally introduced as a tumour marker for the detection of cancer recurrence, PSA testing became widely adopted as a screening tool for prostate cancer. However, it is not prostate cancer-specific and other prostate conditions, such

as benign prostatic hyperplasia (BPH) or prostatitis, can also affect PSA levels.2 If prostate cancer is suspected a biopsy is done to confirm the diagnosis. When detected early, prostate cancer is treatable. A large majority of prostate cancers are diagnosed either before they have spread or when they have spread only locally. Survival rates in these cases are very high.”7

If diagnosed with early prostate cancer, N0 signifies that the cancer has not spread outside the prostate.

Staging Systems

If diagnosed with early prostate cancer M0 signifies that the cancer has not spread outside the prostate.

The TNM staging system refers to the size of the tumour (T), if the cancer has spread to the lymph nodes (N) and if the cancer has spread to other parts of the body- metastasis (M).1 Tumour (T) –Size of the tumour T1 The tumour is within the prostate gland. It is too small to be felt during a rectal exam.

T2 The tumour is still within your prostate gland. It is large enough to be felt during a rectal exam.

T3 The tumour can be felt throughout the prostate, and may have broken through the outer layer of the prostate.

T4 The tumour has spread to organs outside the prostate gland.

Node (N) – Are the lymph nodes affected?

N Cancer is present in the lymph nodes.

N0 No cancer in the lymph nodes.

N1 Cancer has spread to 1 or more of the lymph nodes.

Metastasis (M) – has it spread outside the prostate?

M The cancer has spread to lymph nodes and/or other organs, commonly bones M0 The cancer has not spread.

The Gleason Score The Gleason Score is a grading system used to determine the aggressiveness of prostate cancer and can be used to choose appropriate treatment options.

“The Gleason Score ranges from 1-5 and describes how much the cancer looks like healthy or abnormal tissue,” she notes.

“Most cancers score a grade 3 or higher. Since prostate tumours are often made up of cancerous cells that have different grades, two grades are assigned for each patient. A primary grade is given to describe the cells that make up the largest area of the tumour and a secondary grade is given to describe the cells of the next largest area. If the Gleason Score is written as 3+4=7, it means most of the tumour is grade 3 and the next largest section of the tumour is grade 4. If the cancer is almost entirely made up of cells with the same score, the grade for that

area is counted twice to calculate the total Gleason Score. Typical Gleason Scores range from 6-10.

The higher the Gleason Score, the more likely that the cancer will grow and spread quickly. Scores of 6 or less describe cancer cells that look similar to normal cells and suggest that the cancer is likely to grow slowly. A score of 7 suggests an intermediate risk for aggressive cancer. Scoring a 7 means that the largest section of the tumour (primary score) scored a 3 or 4. Tumours with a primary score of 3 and a secondary score of 4 have a reasonably good outlook, whereas cancers with a primary Gleason Score of 4 and a secondary score of 3, are more likely to grow and spread. Scores of 8 or higher describe cancers that are likely to spread more rapidly and these cancers are often referred to as high grade or poorly differentiated.”10 Treatment Options Treatment options for patients with prostate cancer depend on the stage and grade of the cancer and include active surveillance, watchful waiting, hormone therapy, radical prostatectomy, external beam radiotherapy, and brachytherapy.1 “Active surveillance is used to monitor the cancer closely. This involves a prostate-specific antigen (PSA) blood test every three months and a digital rectal exam (DRE) every six months for the first year followed by a PSA blood test every 6 months and a DRE at least once a year. Prostate biopsies and imaging tests may also be done every 1 to 3 years.12 Because prostate cancers usually progress slowly, a “watchful waiting” approach rather than immediate treatment may be recommended.

“This is especially true for patients who are elderly or in otherwise poor health. In patients with intermediate or high-risk localised prostate cancer with a real prospect of long-term disease control and those with locally-advanced disease, radical prostatectomy or radical radiotherapy should be offered.2 “Hormone therapy is the primary treatment for metastatic prostate cancer, but is also used for patients with locally-advanced, non-metastatic disease. In

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PROSTATE CANCER

patients with localised prostate cancer, the choice of treatment depends on whether the disease is low, intermediate, or high risk.2 Hormone therapy also called androgen suppression or androgen deprivation therapy (ADT) attacks androgens that stimulate the growth of prostate cancer. A form of hormone therapy involves drugs called LHRH analogs, or LHRH agonists such as buserelin, goserelin, leuprorelin acetate or triptorelin that chemically block the production of androgens. Side effects of hormone therapy include reduced libido, sexual dysfunction, osteoporosis, gynaecomastia and hot flushes.2, 7 “Brachytherapy is a form of radiation therapy used to treat prostate cancer. Prostate brachytherapy involves placing radioactive seeds in the prostate gland which destroys the cancer cells while causing less damage to healthy tissue nearby. Prostate brachytherapy procedures vary based on the type. High dose rate (HDR) brachytherapy is a temporary type of prostate brachytherapy that involves placing radioactive sources in the prostate gland and delivering a high dose of radiation over a few minutes before the sources are removed. Treatment may involve several sessions. Low dose rate (LDR) brachytherapy is permanent and involves placing radioactive seeds in the prostate gland permanently, where they slowly release radiation over several months. Brachytherapy may be the only treatment used for early-stage prostate cancer that is less likely to spread beyond the prostate.

For larger prostate cancers or those that have a greater chance of spreading beyond the prostate, brachytherapy may be used along with other treatments, such as external beam radiation therapy (EBRT) or hormone therapy.1, 11 “In external beam radiation therapy, beams of radiation are focused on the prostate gland from a machine outside the body. This type of radiation can be used to try to cure earlier stage cancers, or to help relieve symptoms such as bone pain if the cancer has spread to a specific area of bone.”1 Surgery is usually only carried out if the cancer has not spread from the prostate, Theresa explains.

“A radical prostatectomy may be considered if examination of the pelvic lymph nodes reveals that

they are not cancerous. Surgical risks can include impotence and urinary incontinence.7 Transurethral resection of the prostate (TURP) can be used to relieve symptoms but does not remove all of the cancer. TURP is often used in men who cannot have a radical prostatectomy because of advanced age or illness or in men who have a noncancerous enlargement of the prostate.

“In men who are unable to have traditional surgery, cryosurgery may also be used. In this procedure, a metal probe is inserted into the cancerous regions of the prostate; liquid nitrogen is then used to freeze the probe, killing the surrounding cells. If the cancer has spread from the prostate, radiation therapy may be used. Bi lateral orchidectomy should be offered to all patients with metastatic prostate cancer as an alternative to continuous LHRH agonist treatment. Removal of the testicles cuts off the supply of testosterone to the tumour, which the prostate cancer needs in order to continue growing. It can delay or stop the tumour growth and eliminates the need for other hormone therapy. If surgery or hormone therapy fails, chemotherapy may be used.

While chemotherapy can slow the growth of the tumour, it is not very effective in treating prostate cancer.”7

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Prognosis and Outlook The outlook for prostate cancer is generally good because, unlike many other types of cancer, it usually progresses very slowly. If treated early, prostate cancer can often be cured. She concludes, “The survival rate is over 90% and many men die with prostate cancer, rather than as a result of having it. Prostate cancer has one of the highest survival rates of any type of cancer. 92% of all prostate cancers are found when they are in the early stage, and almost 100% of men who have local or regional prostate cancer will survive more than five years after diagnosis. For most with local or regional prostate cancer, the relative 10-year survival rate is 98% and the relative 15-year survival rate is 96%.

Once prostate cancer has spread beyond the prostate, however, survival rates fall and about 7% have more advanced prostate cancer at the time of diagnosis.

For men with prostate cancer that has spread to other parts of the body, the 5-year survival rate is 30%.13, 14 “Prostate cancer presents a number of challenges for primary care clinicians. Many men with prostate cancer are asymptomatic until the tumour has progressed, and common symptoms have significant crossover with benign conditions affecting the prostate.

PSA-based testing of prostate cancer is very common but remains controversial. The value

of screening remains uncertain because the PSA test does not distinguish between benign and malignant disease, and there has been no proof that early treatment leads to increased cure rates.

Digital rectal examination alone is insufficient for screening as its positive predictive value is only 11%–26%. Current diagnostic tests have limitations in terms of significant false positive and false negative rates however research is ongoing into improved methods for diagnosing prostate cancer.

Nanotechnology has shown initial success in prostate cancer disease diagnosis, imaging and treatment.

A number of new tests and testing strategies are being trialled to improve the diagnosis of clinically significant prostate cancer and blood-based biomarkers for prostate cancer are also being extensively investigated.15, 16 Because the value of PSA-based testing of prostate cancer remains unclear, more genetic testing– based detection strategies are needed to identify individuals at high risk of prostate cancer and novel drugs need to be evaluated to substantially improve the clinical care of patients with prostate cancer. Continued clinical and translational research in prostate cancer is important and could be key to the treatment and management of prostate cancer through leading improvements in prostate cancer imaging and diagnosis.16 References available on request

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MENTAL HEALTH

Managing Men’s Mental Health Written by Professor Brendan Kelly, Professor of Psychiatry, Trinity College Dublin Photo: Ruth Medjber

changing our lifestyles as best we can, watching our diets, getting more exercise, reaching out to family and friends, and finding activities that absorb us, like running, gardening, reading or knitting. Reflective pursuits such as mindfulness, meditation and yoga can be especially beneficial.

For many people, these activities will help them through the difficult times that we have all faced over the past two years.

Over the past two years, the Covid-19 pandemic has brought added attention to mental health and mental illness. Both the pandemic itself and the public health restrictions it necessitated have had a significant impact on psychological wellbeing.

This article focuses on men’s psychological wellbeing and mental health, as well as common mental illnesses, such as depression, and suicide. These were important issues before the pandemic, but the past two years have brought added challenges that require us to pay increased attention to mental health.

The difference between unhappiness, stress and mental illness It is useful to start by noting the difference between the understandable stresses of life on the one hand, and mental illness on the other. Pharmacists who are familiar with their customers will often identify when a customer is stressed, unhappy, or distressed.

During the pandemic, virtually everybody’s wellbeing came under pressure at various points, as family members fell ill, tests results were awaited, or public health restrictions were tightened. Most people were stressed, upset or anxious for periods of time. Many sought informal support from family, friends and professionals with whom they were familiar: GPs, counsellors, pharmacists and others.

Many of these problems are largely understandable, especially during a pandemic. Most of these issues are best addressed by

These stressful experiences in our day-to-day lives are, however, different to mental illness. Mental illness occurs when our distress exceeds our personal and family resources, when we are disabled to a significant degree by our symptoms, and when we need to reach beyond our immediate circle for assistance and support.

Depression is one example of a mental illness that commonly exceeds our usual ability to cope, and requires additional treatment.

Features of depression Depression is one of the most common mental illnesses among both men and women. The symptoms of depression vary significantly between individuals.

The symptoms and signs depend on the person’s general character, their life situation, any stresses triggering their depression, and various other factors.

are of rapid onset or unusually severe. Everybody is different, but this is the most common picture of depression: low mood, hopelessness, and various physical disturbances, such as loss of appetite, poor sleep, and diminished libido.

Women are diagnosed with depression more often than men. There are likely to be many reasons for this, but it is relevant that men are less likely to seek help for depression, stress and substance misuse. The reasons for this include prevailing perceptions of social norms for men, reluctance to talk openly, and a tendency for men to downplay symptoms. It is useful to bear these factors in mind if you feel that someone is depressed and might be reluctant to confide. This is particularly important owing to one of the most concerning consequences of depression: self-harm and suicide.

Self-harm and suicide in men Deliberate self-harm is the intentional infliction of non-fatal harm on oneself. It includes methods such as self-cutting and overdosing. Suicide is intentional self-killing and it features in every society for which there is recorded history. Non-fatal deliberate self-harm is more common among women compared to men, but completed suicide is more common among men.

For most people, key symptoms of depression include low mood or feeling down; loss of interest and enjoyment in usual activities; reduced energy, with fatigability and diminished activity; notable tiredness after slight effort; reduced concentration and attention; diminished selfconfidence and self-esteem; thoughts of guilt and unworthiness; bleak, pessimistic views about the future; feelings of helplessness and hopelessness; ideas or acts of self-harm; disturbed sleep, and changes to appetite.

Risk factors for non-fatal selfharm, in addition to female gender, include younger age, poor social support, major life events, poverty, being unemployed, being divorced, mental illness and previous deliberate selfharm. Risk factors for suicide, in addition to male gender, include poor social support, major life events, chronic painful illness, family history of suicide, and previous deliberate self-harm.

Suicide is also associated with major depression (long-term risk of suicide: 10-15%), bipolar affective disorder (10-20%), schizophrenia (10%) and alcohol dependence syndrome (15%). For both deliberate self-harm and suicide, availability of means is significant (e.g. availability of tablets to take overdoses).

For a diagnosis of depression, rather than stress or unhappiness, these symptoms should, for the most part, be present for two weeks, but shorter periods are reasonable if the symptoms

How common is suicide, and what are the rates in men and women?

The 2019 Annual Report of the HSE National Office for Suicide Prevention (NOSP) indicates that there were 421 completed suicides

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in Ireland in 2019, yielding a rate of 8.6 per 100,000 population per year. The 2019 data are, however, provisional and subject to change.

Official data for 2016, including late registrations, indicate that there were 506 suicides in 2016, yielding a rate of 10.7 per 100,000 population per year.

The NOSP report points out that “it is not easy to compare suicide rates among European counterparts because of the variations in registration and reporting systems in different jurisdictions. Nevertheless, Eurostat provides comparisons using standardised death rates”.

In 2017, “the overall rate of suicide in Ireland was the 9th lowest rate of 33 countries”. However, “the rate of suicide of age 15-19 year olds in Ireland was the 13th highest rate of 31 countries”.

The ratio of male to female suicide in Ireland is 3:1, according to the provisional 2019 data, with 317 male suicides compared to 104 female suicides. Official data for 2016 also show a substantial male excess, with 403 male suicides compared to 103 female suicides.

Men who are at particular risk likely include those who have experienced trauma, employment problems, marital breakdown, financial problems, substance misuse or mental illness.

Treating depression Individuals with depression commonly require assistance and support in order to deal with their symptoms, enter recovery, and maintain wellness into the future.

In the first instance, it is important that the individual with depression is able to talk openly about their symptoms, without fear of criticism or judgment.

It is also important that any issues relating to alcohol or other drugs are identified at the outset and, if possible, resolved: treatment of depression is rendered extremely difficult in the presence of alcohol or drug misuse. These problems occur in both men and women, but are more common among men.

Treatment of depression is based on a bio-psycho-social approach to management; i.e. there are “biological” treatments (such as medication), psychological treatments, and social interventions.

Cognitive-behaviour therapy (CBT) focuses on the use of cognitive

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strategies (i.e. strategies related to thinking patterns and habits) and behavioural strategies (i.e. strategies related to actions and behavioural habits), in an effort to re-frame depressive thoughts, enhance coping strategies, reduce symptoms, and promote recovery. CBT is effective in the management of depression, generalised anxiety disorder, panic disorder, social phobia and posttraumatic stress disorder.

Biological treatments for depression include administration of medications and treatment of co-existing medical or substance-related disorders. Most guidelines now recommend newer antidepressants (such as selectiveserotonin re-uptake inhibitors) as first-line treatments for depression, ahead of older ones (such as tricyclic antidepressants). Newer agents are safer and have fewer side effects, although adverse effects can occur and should be discussed beforehand.

Approximately two-thirds of patients with moderate or severe depression respond to the first antidepressant prescribed. In these patients, the medication should be continued for six to nine months after recovery from a single depressive episode. For individuals who have experienced multiple depressive episodes, there is evidence to support continuation of treatment for up to two years.

If there is no or insufficient response to the first antidepressant prescribed after several weeks, it is recommended to either increase the dose, switch to a different antidepressant, or engage in a broader reconsideration of options. In

the event of poor response after a second antidepressant, alternative treatment strategies may be required, possibly involving specialist mental health services.

For everyone with depression, a consideration of the social environment and social reengagement is an essential step on the road to recovery. Self-help groups and organisations such as Aware (www.aware.ie) are very helpful. For men, in particular, Men’s Sheds offer psychological support and social outlets, and can be accessed through the Irish Men’s Sheds Association (https://menssheds.ie).

Alcohol and other substance misuse in men Alcohol and other substance misuse are substantial problems among both men and women, but are more common among men. The Healthy Ireland Survey 2018 found that “male drinkers (54%) are more likely than female drinkers (19%) to binge drink on a typical occasion”. In addition, “out of men who drink, 67% of those aged 15-24 and 64% of those aged 25-34 binge drink on a typical occasion”.

This problem is not confined to alcohol: men are also more likely than women to enter specialised treatment for cannabis, cocaine, heroin and amphetamine misuse.

Therefore, while alcohol and substance misuse present problems for both men and women, they likely make a particular contribution to the higher rate of suicide among men.

Treatment for alcohol misuse or dependence is provided through local addiction services which can be accessed following referral

by a GP, psychiatrist or other health professional, as well as through self-referral in certain circumstances. Abstinence is the usual and most sensible goal of treatment. The precise supports offered depend on the stage of the person’s addiction, their readiness for change, their general life circumstances, and their previous experiences of treatment.

For acute detoxification from alcohol, hospital admission is considered if there is a high risk of delirium tremens or seizures, or if the person is otherwise vulnerable (e.g. a child, cognitively impaired, or severely lacking social support).

For many people, however, detoxification is just as effective if it occurs as an outpatient, using reducing doses of a medication such as chlordiazepoxide (for symptoms of acute alcohol withdrawal), appropriate medical supervision, and psycho-social or family support.

Treatments for drugs other than alcohol depend on the drug in question, but often include CBT, motivational interviewing and selfhelp groups, as well as specialist clinics and residential care. The precise strategies vary according to the substance in question, the person’s history, and the social and family circumstances in which the problem developed and is sustained.

Conclusion: minding men’s mental health Men experience a broad range of mental health problems ranging from stress and unhappiness to severe depression and schizophrenia. This article highlights some of the more common issues: depression, suicide and substance misuse.

Taking a broader perspective, it is useful to remember that maintaining good mental health involves not only preventing and treating mental illness and substance misuse, but also taking positive steps towards wellness. Exercise, diet and social connection all matter. Men experience particular difficulty speaking about emotional and psychological problems, and seeking assistance when needed.

This is a pity and it highlights the need for pro-active strategies to improve men’s mental health.

Brendan Kelly is Professor of Psychiatry at Trinity College Dublin and author of “The Science of Happiness: The Six Principles of a Happy Life and the Seven Strategies For Achieving It” (Gill Books, 2021).

Sources and Further Reading Castle D, Coghill D (editors).

Comprehensive Men’s Mental Health. Cambridge: Cambridge University Press, 2021.

Healthy Ireland. Healthy Ireland Survey 2018. Dublin: Government Publications, 2018. (https://assets. gov.ie/41139/80328fcb555d4ed0a c6c4b2ddcd7b677.pdf).

HSE National Office for Suicide Prevention. Annual Report 2019.

Dublin: HSE National Office for Suicide Prevention, 2020. (https://www.hse.ie/eng/services/ list/4/mental-health-services/ connecting-for-life/publications/ nosp-annual-report-2019.pdf).

Kelly BD. Mental Health in Ireland: The Complete Guide for Patients, Families, Health Care Professionals and Everyone Who Wants to Be Well. Dublin: The Liffey Press, 2017.

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HUNTER SYNDROME

Gene Therapy for Mucopolysaccharidosis Type II—A Review of the Current Possibilities Written by Paweł Zapolnik1,* and Antoni Pyrkosz2 1 Students’ Scientific Association of Clinical Genetics, Department of Clinical Genetics, Medical College, University of Rzeszów, 35-959 Rzeszów, Poland - 2 Department of Clinical Genetics, Medical College, University of Rzeszów, 35-959 Rzeszów, Poland; antoni.pyrkosz@gmail.com * Correspondence: pawel.zapolnik@onet.pl

Mucopolysaccharidosis type II (MPS II, OMIM #309900), also called Hunter syndrome, is a rare monogenic disease belonging to the group of lysosomal storage disorders (LSDs). The estimated incidence of MPS II is 0.3–0.7/100,000 births.1 The condition occurs more often in the countries of East Asia than in Europe.2 It is inherited in an X-linked recessive way as the only form among mucopolysaccharidoses.

Almost exclusively males are affected, but there have also been reports of affected females, mainly due to non-random inactivation of the X chromosome.3–9 Charles A. Hunter first described this entity in 1917 in two brothers.10 MPS II is caused by a mutation in the IDS gene, located at Xq28 (OMIM *300823), which encodes iduronate 2-sulphatase.

This enzyme is responsible for catalysing the hydrolysis of sulphate groups from dermatan sulphate (DS) and heparan sulphate (HS) molecules. Enzyme deficiency or decreased activity results in the accumulation of glycosaminoglycans (GAGs) in various tissues and organs, leading to dysfunction.11,12 Dermatan sulphate and heparan sulphate accumulated in cells disrupt cellular processes such as endocytosis, ion balance, and cell movement. In addition, heparan sulphate promotes the accumulation of GM2 and GM3 gangliosides in the brain, due to which microglial cells are stimulated, and an inflammatory reaction occurs in the central nervous system (CNS).13 On the other hand, studies on model organisms (Danio rerio, Mus musculus) indicate that a mutation in the IDS gene may also affect the developmental process differently by influencing the signalling pathway of the fibroblast growth factor (FGF).14

Another factor contributing to the development of inflammation is the presence of incompletely degraded GAGs, which may structurally resemble lipopolysaccharide, an endotoxin of Gram-negative bacteria that activates the Toll-like receptor 4 (TLR4). This process leads to the secretion of proinflammatory cytokines and the activation of the STAT1/STAT3 protein pathway, increasing the concentration of tumour necrosis factor α (TNF-α) and inflammation in the affected tissues.15 The animal models, mainly mouse models, of mucopolysaccharidosis type II significantly contributed to understanding the pathophysiology and the application of therapy in this disease, including gene therapy.13 The first preclinical attempts of gene therapy were carried out in the 1990s [16]. It was also when the first clinical trials began, which resulted in the further development of Hunter syndrome treatment.

1.2. Clinical Features Despite its heterogeneity, the disease is usually classified into two main forms: attenuated (without central nervous system involvement) and severe (with central nervous system involvement). Both conditions show signs of many organs’ dysfunction, such as hepatosplenomegaly, coarse facial features, skeletal system abnormalities (dysostosis multiplex), joint stiffness, short stature, carpal tunnel syndrome, heart valve disease, hypertension and other cardiac abnormalities, communicating hydrocephalus and hearing loss. In addition, patients with MPS II also suffer from frequent respiratory infections and decreased exercise tolerance.

The severe form of the disease, which accounts for about 60% of cases, is characterized by the child’s normal development until

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about 2–4 years of age when cognitive functions deteriorate and the process of acquiring new skills is inhibited. Attention difficulties are also common in school-age patients with the severe form of Hunter syndrome.

An additional manifestation of CNS damage is frequent epileptic seizures. Patients with deletions, recombination, frameshift mutations, or splicing abnormalities are more likely to develop a severe phenotype. In the case of missense mutations, some may lead to a severe phenotype but most likely predisposed to the attenuated form. Due to the heterogeneity, in many cases, it is difficult to determine the exact genotype/phenotype correlation and predict the nature of development in a particular patient.13,17 1.3. Diagnosis and Management For the final diagnosis of the disease, biochemical and molecular tests are performed. First, the level of glycosaminoglycans in a 24-h urine collection is determined and then the activity of the iduronate 2-sulphatase enzyme, e.g., in peripheral blood lymphocytes, skin fibroblasts or chorionic cells (as prenatal diagnosis) is assessed.11,13 Sanger sequencing is usually performed to detect mutations in the IDS, but the development of Next Generation Sequencing (NGS) has paved the way to use gene panels to detect the mutation quickly and exclude other lysosomal storage disorders.11,18,19 Patients with mucopolysaccharidosis type II, as a disease with a heterogeneous clinical picture, require multidisciplinary care. Historically, before the pathophysiology of the disease was known, management was limited to symptomatic treatment and palliative therapy.

In studies conducted on

fibroblasts collected from patients with mucopolysaccharidosis type I (MPS I) and mucopolysaccharidosis type II, normal levels of GAGs were observed. Researchers discovered the phenomenon, so-called crosscorrection, i.e., enzyme secretion by some cells and its uptake by others via the mannose-6phosphate receptor.20,21 The discovery of this phenomenon contributed to the acceleration of studies on therapeutic agents. Currently, the mainstay of treatment is enzyme replacement therapy (ERT) using human recombinant iduronate 2-sulphatase administered intravenously.1 Thanks to ERT, it is possible to reduce the concentration of GAGs in the urine, reduce the size of the liver and spleen, and improve physical tolerance and stabilize the bone and cardiac abnormalities.

Unfortunately, the enzyme itself cannot cross the blood–brain barrier (BBB). Attempts are made to administer the enzyme intrathecally or intraventricularly.

These studies were successfully performed in the MPS II mouse model. Higuchi et al.22 showed a reduced concentration of GAGs in the brain tissue of mice and other organs, such as the heart, lungs, kidneys, testes, and liver.

In addition, they demonstrated an improvement in short-term memory and learning skills, and in brain autopsy, a reduction in cell vacuolization and the expression of the lysosomal marker protein LAMP2. Similar research results were obtained by Sohn et al.23 They additionally showed a correlation between the concentration of HS in the cerebrospinal fluid (CSF) and the GAGs levels in the brain. At a later stage, clinical trials were carried out in MPS II patients with the administration of the enzyme via

73 the intrathecal or intraventricular route, along with the standard intravenous drug administration.24 In a study conducted by Muenzer’s group25, the enzyme administered intrathecally in increasing doses made it possible to reduce the concentration of GAGs in CSF by 80–90%. Another clinical trial was conducted by the group of Seo et al.26 in Japan (JMACCT CTR JMA-IIA00350) on a group of six patients with severe MPS II. They were administered idursulfase beta into the brain’s lateral ventricle via a CSF reservoir system implanted under the scalp.

The drug was administered in escalating doses from 1 to 30 mg every four weeks from 0 to 24 weeks and then 30 mg to 100 weeks of the study.

At the same time, during the study, patients continued to receive the enzyme intravenously. The authors assessed Int. J. Mol.the Sci.developmental 2021, 22, 5490 age based on the Kyoto Scale of Psychological Development 2001 (KSPD). Patients receiving intraventricular idursulfase beta had stabilized CNS function decline compared to patients receiving the enzyme intravenously only. In addition, HS level in CSF at week 100 was significantly reduced compared to the baseline.

Anti-idursulfase antibodies were not detected in cerebrospinal fluid during the trial.

Apart from a few side effects (pyrexia, vomiting, and upper respiratory tract infection), the therapy was generally well tolerated. Thanks to this study,

intraventricularly administered idursulfase beta was approved in Japan as Hunterase®.26 The results of these studies are promising, but the procedure is more invasive than intravenous injection and still requires repeated administration of the enzyme. Another way to bypass the difficulties associated with the blood–brain barrier is to create a system that allows the drug to pass through the barrier.

enzyme to cross the blood–brain barrier.30 The results of using AGT182 have not been published yet.24

a single transplant procedure, is a strong argument for A clinical trial is currently underway the use of HSCT. However, using an enzyme conjugated to complications associated with an antibody binding site to the transferrin receptor (DNL-310, immunosuppressive therapy and Denali Therapeutics). There are graft versus host disease (GvHD) 16 patients with Hunter syndrome necessitate careful consideration between the ages of 2 and 18 of this method. An alternative to For this purpose, two solutions in the study, and recruitment the above therapeutic methods is are tried: receptor-mediated is still open (ClinicalTrials.gov the constantly developing gene transcytosis and the use of Identifier: NCT04251026).31 therapy. Mucopolysaccharidosis 24,27 The first option uses a carriers.

Another possibility to overcome type II is a monogenic disease natural process by which proteins the BBB is using a carrier that with relatively well-known enter the central nervous system. will deliver the enzyme to the pathomechanisms, making it The enzyme is conjugated with cell through the surface heparan a good candidate as a target an antibody against a specific sulphate receptor. Such a system for gene therapy. In addition, it receptor and can defeat the BBB using a recombinant enzyme allows avoiding the characteristic by transcytosis via epithelial and a guanidinylated neomycin difficulties of ERT and HSCT. cells. Clinical trials have been molecule, which has a high conducted using iduronate A comparison of the three main affinity for heparan sulphate 4 of 14 2-sulphatase combined with an treatments in MPS II is shown proteoglycans, has so far been anti-human transferrin receptor used in a mouse model of in Table 1. A more detailed antibody (JBrain Cargo®, JR-141, mucopolysaccharidosis type I discussion of the current 28 JCR Pharmaceuticals) and an (MPS I). Still, no trials have been possibilities of gene therapy in anti-insulin receptor antibody carried out on II models.32 An is provided in the next part Another method of causal treatment is MPS hematopoietic stemMPS cell IItransplantation (HSCT).

(AGT-182, ArmaGen Technologies). additional limitation of ERT is the of the review.

The first outcomes of studies with can cross the blood–brain barrier and settle in the central Peripheral blood monocytes enzyme immunogenicity, against JR-141 showed a positive result in cells [34]. This property, combined Challenges Perspective nervous system as microglial with aand single transplant which antibodies in the IgG class reducing the concentration of HS are produced, even in about 50% procedure, a strong argument for the use of HSCT. However, complications associated Gene therapy for and DS in the is cerebrospinal fluid, of treated patients.11,33 type II has urine, immunosuppressive and plasma. The positive therapy and graft versus host diseasemucopolysaccharidosis with (GvHD) necessitate careful made tremendous progress since results of clinical trials conducted Another method of causal consideration of this method. the first studies on cell lines in the in Japan with pabinafusp alfa treatment is hematopoietic stem An29 alternative to the above developing 1990s. However, there are stillgene a enabled the approval (JR-141) celltherapeutic transplantationmethods (HSCT). is the constantly limitations that researchers , a system based on of Izcargo®Mucopolysaccharidosis Peripheral blood monocytes can therapy. type II is a monogenic diseasefew with relatively well-known dealing with this topic must face.

10 mL it a cross J-Brain Cargo® containing blood–brain pathomechanisms, making goodthe candidate asbarrier a target for gene therapy. In addition, it First, many animal models differ of pabinafusp alfa administered and settle in the central nervous 34 allows avoiding the characteristic difficulties of ERT and HSCT. A comparison of theinthree from the in vivo conditions the system as microglial cells. intravenously. It is the first agent human body.

This property, combined with detailed on the treatments market that allowed the II is shown main in MPS in Table 1. A more discussion of the current

possibilities of gene therapy in MPS II is provided in the next part of the review.

Table 1. Comparison of enzyme replacement therapy, gene therapy, and hematopoietic stem cell transplantation.

Features

Gene Therapy

Enzyme Replacement Therapy (ERT)

Hematopoietic Stem Cell Transplantation (HSCT)

The essence of the method

Delivery of the correct gene to cells by vector

Administration of the correct enzyme into the organism

Transplantation of donor cells with the correct gene

Number of therapeutic interventions

Single

Multiple

Single

The main advantages of the method

Stable gene expression, single application with a long-standing effect, improvement in the central nervous system (CNS) and other organs

Relatively safe route of administration (intravenous), the only Food and Drug Administration (FDA)-approved method so far

The ability to deliver the enzyme to the brain via monocytes, a single application

The main disadvantages of the method

The risk of developing an immune response against the vector and elements of the transgene, the risk of mutagenesis in the case of viral vectors

The need for multiple administration of the enzyme, the inability of the enzyme to cross the blood–brain barrier, the risk of developing neutralizing antibodies against the enzyme

Conditioning before HSCT, immunosuppression, the risk of graft vs. host disease (GvHD), limited gene expression in the central nervous system

2. Gene Therapy 2.1. The Basics

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HUNTER SYNDROME

The beneficial effects of the applied therapies in the mouse model, especially on the central nervous system, may not necessarily be reproduced in human studies due to the therapeutic threshold, which differs between species.

safety. The use of retroviral and lentiviral vectors is likely to be abandoned in the near future due to their random integration into the genome and the risk of mutagenesis. AAVs seem to be the most optimal vectors. Combined with the precise genome editing method, they are currently the best form of gene therapy and the only one so far used in human clinical trials.

Another limitation is the risk of generating an immune response that mainly affects viruses but also elements of genome editing systems. AAVs seem to be the most optimal viral vector so far. However, neutralizing antibodies have been reported, and they lead the way to reduce the effectiveness of the entire therapy.85 Additionally, cells that have already received the transgene can be eliminated by lymphocytes CD8+.

Therefore, it is worth considering the use of immunosuppression in order to increase the effectiveness of subsequent gene therapy attempts.48,55 A solution to this problem could be non-viral vectors, but so far, they have not been widely used in model organisms in MPS II, so further studies are needed to assess their efficacy and

It is possible that in the next few years, new clinical studies will be opened, and this process would be significantly accelerated by the positive results of phase I/ II trials with RGX-121 and SB913. It is also worth mentioning additional therapy that may play a role in improving organ functions and quality of life in patients with Hunter syndrome soon. The process of autophagy, which is disturbed in lysosomal storage disorders, may become a potential therapeutic target. Maeda et al.86 analysed the morphology of central nervous system cells in the MPS II mouse model.

They showed an increased number of autophagy vesicles in an electron microscope and

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an increased concentration of the autophagy impairment markers—p62 protein and subunit c of mitochondrial ATP synthetase (SCMAS). The authors administered chloroquine orally at a dose of 10 mg/day for 25 weeks to improve the function of neurons. After this period, the vacuolization in neurons was significantly reduced compared to untreated individuals. Chloroquine can inhibit autophagy. Its use in MPS II patients may slow down neurodegenerative processes in the CNS. Researchers also tried to use verapamil and rapamycin (drugs that promote autophagy), but the study had to be discontinued due to serious adverse effects in mice.86 Conclusions Mucopolysaccharidosis type II, as a monogenic disease with relatively well-known pathophysiology, is an optimal example of the possibility of applying gene therapy. Over the past two decades, this technology has been advanced enough to open up clinical trials using the most promising methods— genome editing and adeno-

associated viral vectors. Thus far, it has not been possible to come up with an ideal therapeutic agent.

Additionally, gene therapy has some limitations: the immunogenicity of vectors and transgenic elements and the relatively high cost of developing this technology. However, comparing gene therapy to the current standard of treatment for Hunter syndrome—enzyme replacement therapy is essential.

A single administration of a vector that will deliver the IDS gene to target cells and maintain a high expression level far exceeds the need for repeated intravenous administration of the enzyme. ERT applied intravenously is a heavy burden on the healthcare system and partially improves somatic symptoms without improving central nervous system function.

In conclusion, the further development of molecular engineering techniques and the ongoing clinical trials in humans will likely contribute to the broader use of gene therapy.

References available upon request

News 75

Ultra-short Course Treatment for Hepatitis C Ultra-short treatment courses tailored to a person's pretreatment viral load deliver lower cure rates than 8-week treatment courses, but failure of ultra-short treatment does not prevent subsequent cure of hepatitis C with a second course of treatment, the STOPHCV1 study has found.

Shortening hepatitis C treatment courses may have advantages for people who have adherence difficulties. There is some evidence that treatment courses as short as four to six weeks may cure some people with hepatitis C, but it is unclear what criteria should be used to select people for shorter treatment courses.

Shorter-course treatment carries a higher potential risk of failure, and it is unclear if this leads to resistance that compromises the effectiveness of re-treatment.

To address these questions, the STOPHCV1 study investigated whether people with mild liver disease could be cured of hepatitis C after four to seven weeks of direct-acting antiviral treatment or successfully re-treated if ultrashort course treatment failed.

Participants were randomised to receive either short-course treatment, the duration determined by baseline viral load, or an eight-week course of treatment.

The regimen was chosen by the treating physician based on genotype and local availability.

Participants in both arms were also randomised to receive ribavirin or no ribavirin. People who did not achieve a sustained virologic response after the first treatment course received a second course of treatment with 12 weeks of sofosbuvir/ledipasvir.

The study recruited participants with F0 or F1 fibrosis and hepatitis C viral load below 10 million IU/ ml at 14 hospitals in the United Kingdom. The study recruited people with genotype 1a/1b/4 infection and people co-infected with HIV were eligible to join the study. Recruitment took place between May 2016 and May 2018.

The pre-specified duration of treatment based on baseline viral load ranged from 28 days for viral loads of 50,000 IU/ml or below, to 49 days for viral loads above 8.8 million IU/ml. Fifty-eight per cent of the study population randomised

to short-course treatment were treated for between 28-34 days (4-5 weeks), 30% for 35-42 days (5-6 weeks) and 12% for 42-49 days (6-7 weeks). The duration of treatment based on viral load was increased on the recommendation of the study’s Data Monitoring Committee halfway through the recruitment period. This increased the treatment duration at all viral loads by three to four days.

The primary outcome of the study was sustained virologic response after ultra-short-course and retreatment course. There was no significant difference between study arms; all participants achieved a sustained virologic response after first-line treatment and re-treatment apart from five participants who were lost to follow-up.

After first-line treatment there was a significant difference in outcome.

Whereas 91% of those in the fixed-duration study arm achieved a sustained virologic response, only 48% in the ultra-short course arm did so (p<0.0001). After adjustment in the duration of

treatment in the ultra-short-course arm halfway through the study, sustained virologic response rates improved significantly in this study arm, from 36% to 72% (p<0.0001).

Inclusion of ribavirin in the regimen did not significantly affect treatment outcome.

In the first treatment course, five participants in the fixed-duration arm and 16 in the ultra-shortcourse arm never achieved an undetectable viral load. Six in the fixed-duration arm and 35 in the ultra-short course arm experienced viral rebound after having an undetectable viral load.

Fourteen participants whose firstline treatment failed developed resistance to at least one drug in their regimen. There was no difference in resistance emergence after failure between study arms but people who received ribavirin were significantly less likely to develop resistance (p=0.01).

Serious adverse events occurred in 5% of study participants and did not differ between study arms. Serious adverse events

did not occur more frequently in ribavirin recipients.

The study investigators conclude that “a high proportion of patients can be cured with […] approximately 60% of the licensed duration of first-line therapy of agents used in the trial.” But they also note that cure rates with the ultra-short-course regimen were not high enough to justify using it in people able to adhere to an eight-week treatment course.

They also say that the strategy needs to be tested using pangenotypic regimens to assess whether failure of a first-line regimen that does not contain a protease inhibitor permits successful re-treatment in all cases.

References Cooke GS et al. Strategic treatment optimization for HCV (STOPHCV1): a randomised controlled trial of ultrashort duration therapy for chronic hepatitis C. Wellcome Open Research, 6: 93, published online 29 July 2021

HOSPITALPROFESSIONALNEWS.IE | HPN • NOVEMBER - 2021

76 News Milestone for Children’s Hospital NPHDB hands over the new facility to Children’s Health Ireland for commissioning of services The construction of the 4,600m2 Paediatric Outpatient and Emergency Care Unit, CHI at Tallaght was completed by the National Paediatric Hospital Development Board on the 9 September and handed over to Children’s Health Ireland (CHI).

This new state of the art paediatric facility will open for services in the middle of November following a period of operational commissioning, equipping and familiarisation of staff who will work there.

The completion of this new facility in CHI at Tallaght marks a significant milestone in the children’s hospital project and the expansion of services being delivered to children, young people and their families.

It follows the successful completion of a similar facility in CHI at Connolly in Blanchardstown in July 2019. Since services in CHI at Connolly opened, it has contributed to a 65% reduction in waiting lists for general paediatric services. To date 18,078 outpatient appointments have taken place there and more than 16,807 children and young people have been treated in the Urgent Care Centre.

Deep Concern at Significant Decline in Transplantation and Organ Donation Rates Patient groups involved in the Irish Donor Network (IDN) have expressed their deep concern about the marked decline in the rates of organ donation and transplantation in Ireland between 2019 and 2020, a period that includes the onset of the Covid-19 pandemic.

The IDN further expressed deep concern that Ireland is struggling in respect of organ donation and transplantation compared with other EU28 countries*, slipping from 14th place in 2019 to 18th place in 2020 in respect of transplantation and being in 17th place for organ donation.

The IDN comprises nine patient groups concerned with organ donation and transplants in Ireland including, for example: Cystic Fibrosis Ireland; COPD Support Ireland; Cystinosis Ireland; the Irish Lung Fibrosis Association; the Irish Thoracic Society; the Irish Heart and Lung Transplant Association; and the Alpha-1 Foundation Ireland.

The network is calling on Government to undertake a range of measures to revive organ donation and transplantation in Ireland including: developing an ambitious plan to bring Ireland into the Top 10 EU countries

for transplantation and organ donation; increasing investment in facilities and staffing; and enacting the Human Tissue Bill to introduce soft opt-out organ donation.

Ireland Struggling The stark figures showing the marked decline are revealed in the recently published annual Council of Europe Report Newsletter Transplant 20201. Both reports from 2020 and 2019 reveal that Ireland has been struggling to keep up with many of our EU neighbours in respect of organ donation and transplant rates, even before Covid-19 severely disrupted services.

IDN analysis of the figures (Annex 1) shows: BOX BELOW • There was a 32.1% decline in solid organ transplantation2 in Ireland in 2020 compared with 2019 • There was a 27.1% decline in deceased organ donations in Ireland in 2020 compared with 2019 • Ireland slipped to 18th place in 2020 in respect of our overall rate of all organ transplants compared with 14th place in 2019

NOVEMBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

• In 2020, Ireland was only 17th out of the EU28 countries in respect of the deceased organ donation rate, marginally up from 18th position in 2019

• Develop an ambitious and detailed plan to raise Ireland to the top 10 countries in the EU for transplantation and organ donation by 2025

• The most impacted transplant programmes in Ireland in 20203 are:

• Urgently enact the Human Tissue Bill and soft opt-out organ donation to make more organs available for transplantation in Ireland, as per the commitments of the current and previous Programmes for Government

o All lung transplants down 58.2% in 2020 compared with 2019 o All heart transplants down 42% in 2020 compared with 2019 o All liver transplants down 44.9% in 2020 compared with 2019 o All kidney transplants, from both living and deceased donors, are down 21.3% compared with 2019 • Pancreas transplants in Ireland bucked the overall trend and actually increased from 2019 to 2020, though the actual numbers of transplants involved are smaller (2 transplants in 2019 compared with 5 in 2020)

• Accelerate the full return of all transplant facilities used for COVID-19 (and those impacted

by COVID-19) for their original transplant purpose • Significantly increase investment in organ donation and transplantation, including an immediate organ donation and transplant 'revitalisation fund' • Increase investment in both preand post-transplant clinical care staff to address remaining gaps in services

Range of Measures Proposed

• Allocate additional resources to ensure the change to soft optout is effective

In order to begin to address the current situation, the IDN is urgently calling on Government to undertake the following range of measures:

• Undertake a review of the impact of COVID-19 from an organ donation and transplant perspective to ensure we learn lessons for future pandemics

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Special precautions warnings: Avoid taking inincases of: severe liver disease; diabetes or impaired kidney function; have haemophilia, risk of bleeding; cases of: severe liver disease; diabetes or impaired kidney function; have haemophilia, risk of bleeding; allergic sulphonamides (e.g. used to to treat certain infections); develop skinskin rash; notice anyany musculoskelallergictoto sulphonamides (e.g. used treat certain infections); develop rash; notice musculoskeletal etc.

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78 News

Indications that Asthma ‘Not under Control’ The Asthma Society of Ireland has revealed data-based research, commissioned to establish the level of Oral Corticosteroid (OCS) usage by people with asthma in Ireland, covering the period from November 2018 to October 2020.

The research revealed that from the estimated 380,000 people with asthma in Ireland, almost 27% (101,997) filled a prescription for Oral Corticosteroids from a retail pharmacy in 2020, with 82,500 people with asthma collecting up to two OCS prescriptions over a 12-month period – an indication that they may not have their asthma under control. This research was supported by AstraZeneca.

Oral Corticosteroid is a medical term for steroid tablets. They are an anti-inflammatory medicine prescribed for a wide range of conditions, including asthma and COPD. They are typically prescribed for two purposes in asthma - short courses are commonly used to treat asthma attacks or they can be

prescribed as ongoing daily maintenance therapy for patients with severe asthma.

2018 to 2020 by 31% compared to 10% among adults during the same period.

Oral Corticosteroids can be associated with significant harmful side effects as a result of long-term use. Research now indicates that even occasional short courses of OCS can be associated with increased health risks.

Of particular concern from the findings, 18.46% of all people with asthma prescribed steroid tablets are using the medication three or more times per year, leaving them at significant risk of immediate side effects as well as cumulative health risks associated with OCS use into the future.

The continual need to prescribe steroid tablets for a patient with mild to moderate asthma should signify that they need a review by their GP. The person with asthma may not be taking their “controller” inhaler every day or they may not be using it properly.

The data also revealed, while the total number of people requiring steroid tablets for their asthma increased by 5,728 in 2019 from the previous year, the numbers decreased in 2020 by over 25,000 - a drop of 21%.

Reassuringly, the figures indicate Oral Corticosteroid use amongst children fell by almost a third from

Despite the overall drop in OCS usage, there has been an alarming increase in Oral Corticosteroid use among a small but vulnerable group of people (4,212) whose numbers have increased between 2019 and 2020 by a staggering 26%. These are patients who have collected OCS prescriptions three months or more in a row and are being prescribed consistent dosages over those months. The Asthma Society is particularly concerned about this group of patients. Independent of dose, prolonged use of steroid tablets has proven to be problematic for severe asthma patients - experts

claiming that they ‘could not find a well-founded threshold for side-effects of OCS or a dosing window for a “safe” long-term use’.

Dr Marcus Butler, Respiratory Consultant at St Vincent's University Hospital and Medical Director at the Asthma Society of Ireland remarks, “Due to the Covid-19 pandemic, people have been isolating at home, wearing masks and washing hands more frequently and we are therefore seeing a drop in steroid tablet use in 2020 amongst asthma patients, which is heartening. Unfortunately, prolonged use of OCS medication has severe health implications. In the short term, side effects can include sleep disturbance, mood changes, appetite increase and hyperglycaemia while depression, diabetes, hypertension, and adrenal suppression are more of an issue in the longer term. It’s important to remember that OCS is the last tool we should reach for in our toolbox and a focus on improving better asthma control and management are preferred.”

New Hospital Plans for Bon Secours Bon Secours Health System (BSHS), the country’s largest private hospital operator, has appointed Reddy Architecture & Urbanism in partnership with HOK International to design its new 150-bed hospital on the outskirts of Limerick City.

Reddy Architecture & Urbanism is an award-winning international architect and design firm providing comprehensive services from their office in Ireland and the UK including significant Irish developments such as Cork University Maternity Hospital.

Bon Secours Health System announces the appointment of award-winning Architects for New Limerick Hospital

NOVEMBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

HOK International design buildings and spaces that respond to the needs of people and the environment, with their partnering medical planners, designers, healthcare professionals and strategic consultants helping healthcare institutions navigate complex requirements to provide flexible and sustainable care environments. Recent hospital projects include the Royal Papworth Hospital in Cambridge, UK, and the David H. Koch Center in New York City.

Research 79

Greater Understanding in Dermatitis JAMA Dermatology has published 24-week results from the Phase 3b Heads Up study evaluating the efficacy and safety of upadacitinib (30 mg, once daily) versus dupilumab (300 mg, every other week) – both as monotherapy treatments – in adults with moderate to severe atopic dermatitis who were candidates for systemic therapy.

The publication showed upadacitinib (30 mg, once daily) achieved superiority compared to dupilumab for the primary endpoint, the proportion of patients with at least a 75 percent improvement in the Eczema Severity Index (EASI 75) at week 16.1 Of those treated with upadacitinib, 71 percent achieved EASI 75 at week 16 compared to 61 percent of those treated with dupilumab.1 Additionally, upadacitinib demonstrated statistically significant greater efficacy across all ranked secondary endpoints compared to dupilumab through week 16, including early reduction in itch and rates of skin clearance improvement.1 Professor Brian Kirby, Consultant Dermatologist at St Vincent’s University Hospital, who was an investigator in this study, said that "it was welcome that an Irish centre had the opportunity to participate in one of the first head-to-head Studies in Atopic Dermatitis. Not only does this study greatly add to our understanding of this disease and its treatment, but Irish patients got the benefit of access to treatments they would not have otherwise had.”

Results for select ranked secondary endpoints include: • After one week of treatment, the upadacitinib 30 mg treatment group had a 31 percent reduction in itch (as measured

by Worst Pruritus Numerical Rating Scale [NRS]) compared to 9 percent in the dupilumab group (p<0.001).1 • After two weeks of treatment, 44 percent receiving upadacitinib achieved EASI 75 versus 18 percent receiving dupilumab (p<0.001).1 • At 16 weeks, 28 percent of people treated with upadacitinib achieved clear skin (EASI 100; p<0.001) and 61 percent achieved almost clear skin (EASI 90; p<0.001), compared to 8 percent and 39 percent,

Professor Brian Kirby, Consultant Dermatologist at St Vincent’s University Hospital

“Not only does this study greatly add to our understanding of this disease and its treatment, but Irish patients got the benefit of access to treatments they would not have otherwise had”

respectively, of those treated with dupilumab.1 The recommended dose of upadacitinib for Atopic Dermatitis is 15 mg or 30 mg once daily based on individual patient presentation.4 • A dose of 30 mg once daily may be appropriate for patients with high disease burden.4 • A dose of 30 mg once daily may be appropriate for patients with an inadequate response to 15 mg once daily.4 • The lowest effective dose for maintenance should be considered.4 • For patients ≥ 65 years of age, the recommended dose is 15 mg once daily.4 The safety profile of upadacitinib in Heads Up was consistent with what was observed in the Phase 3 pivotal studies, Measure Up 1, Measure Up 2 and AD Up.1-3 Through week 16, the most common adverse events were acne (15.8%) for the upadacitinib group and conjunctivitis (8.4%) for the dupilumab group.1 Serious adverse events occurred in 2.9 percent of those receiving upadacitinib and 1.2 percent

of those receiving dupilumab.1 Serious infections were numerically higher in upadacitinib group, although at generally low levels (1.1 percent in those who received upadacitinib and 0.6 percent in those who received dupilumab).1 One treatment-emergent death due to bronchopneumonia associated with influenza A occurred in a patient who received upadacitinib.1 No malignancies were reported in the upadacitinib group; one non-melanoma skin cancer was reported in the dupilumab group.1 No major adverse cardiac events or venous thromboembolic events were reported in either treatment group.1 In the placebo-controlled atopic dermatitis clinical trials, the most commonly reported adverse reactions of patients with upadacitinib 15 mg or 30 mg were upper respiratory tract infection, acne, herpes simplex, headache, CPK increased, cough, folliculitis, abdominal pain, nausea, neutropenia, pyrexia, and influenza.1 About Heads Up1 Heads Up is a Phase 3b multicentre, randomised, doubleblind, double-dummy, active comparator-controlled study in

adults with moderate to severe atopic dermatitis. Patients were randomized to receive upadacitinib (30 mg, once daily, orally administered) or dupilumab (300 mg, every other week, subcutaneous injection) for 24 weeks. Patients who received dupilumab received an initial dose of 600 mg at the baseline visit followed by 300 mg every other week. All patients received placebo of the other treatment as part of the Heads Up doubledummy study design.

The primary endpoint was the proportion of patients achieving EASI 75 at week 16. Ranked secondary endpoints were percent change from baseline in Worst Pruritus NRS (weekly average) at weeks 1, 4 and 16; proportion of patients achieving EASI 100 and EASI 90 at week 16; proportion of patients achieving EASI 75 at week 2; and Worst Pruritus NRS (weekly average) improvement ≥4 at week 16. Additional endpoints at week 24 included EASI 75, EASI 90, EASI 100 and improvement from baseline Worst Pruritus NRS (weekly average). More information on this trial can be found at www. clinicaltrials.gov (NCT03738397).

References available on request

HOSPITALPROFESSIONALNEWS.IE | HPN • NOVEMBER - 2021

80 Clinical R&D WEST ESTABLISHES NEW GLOBAL FINANCE CENTER IN DUBLIN CREATING 60 JOBS

programme. The plant doubled its workforce to meet this new demand over the past year.

West Pharmaceutical Services, Inc. (NYSE: WST), a global leader in innovative solutions for injectable drug administration, has created 60 new jobs in Dublin as part of establishing a new global finance shared service model here.

Led by Site Director Tom Clarke, West’s Dublin facility has 20 years of operations and sustained growth including high volume, complex device manufacturing.

With almost 100 years of experience and a reputation for leadership in quality, West is internationally recognised for its excellence in the manufacturing of pharmaceutical packaging and medical devices. It is a leading manufacturer of delivery systems for injectable drugs and healthcare products.

The new shared service model centralises West’s key finance activities in Dublin and Exton, Pennsylvania, to drive efficiency and support increasing company growth. The new center in Dublin includes various accounting and finance activities and will create greater scale and value for West’s global business and operations. West now employs over a thousand team members across Ireland, including its manufacturing facilities in Waterford and Dublin.

Bernard J. Birkett, West Senior Vice President & Chief Financial Officer, said the new finance service center in Dublin will ultimately support the company’s overall mission to improve patient lives: “This new finance support model enables our overall business strategy of responding and transforming to meet the changing needs of the market to deliver high quality components and service to our customers that will ultimately improve more patient lives—and that’s what matters most.”

Tánaiste and Minister for Enterprise, Trade and Employment Leo Varadkar said: “I’m really pleased to see West adding 60 new highly skilled jobs to its operations here in Ireland. Our pharma industry continues to grow from strength to strength and companies like West are an important part of that story.

The company employs over a thousand people here and this new Global Finance Centre is a further testament to our attractive business environment, robust regulatory framework and skilled labour force. I wish the team at West all the best with this new chapter.”

DASSIET NEW PRODUCT LINE UCAST the materials company Dassiet is launching UCAST – a product line targeted towards hospitals and health centres, making fracture treatment faster and safer both for the patient and nursing staff.

Thermoplastic UCAST cast takes only about 5 minutes to apply, while a traditional cast can take up to 30 minutes to prepare.

UCAST splints are made of completely non-allergenic and non-toxic materials, and the medical staff does not need to protect themselves for casting.

The splint is light-weight, breathable and unobtrusive to the patient.

The UCAST splint is made of the wood composite material called Woodcast, which has already been used in hospitals in Finland and around the world for more than 10 years. Woodcast is also used in the field of veterinary medicine, including institutions such as the Veterinary Teaching Hospital in Helsinki. The material

This is West’s latest expansion of its Irish operations and follows the company’s scaling up of its Waterford plant’s working schedules late last year in response to a big surge in customer demand as a result of the COVID-19 pandemic. The Waterford plant is now supplying millions of rubber vial stoppers to a dozen global customers to package vaccine doses as part of the COVID-19 vaccine NOVEMBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

is in widespread use in the medical field due to its safety and ease of use. UCAST, developed by casting professionals, will be a big step forward in trauma treatment. It is a breathable and non-toxic cast that removes the need to measure, cut and clean up during fracture treatment.

UCAST also helps hospitals to fight against climate change, as the splint is completely biodegradable, and the fabric can be recycled.

Michael Lindroos, COO at Dassiet, is responsible for the product development and has created UCAST in cooperation with physicians, researchers and other casters.

“I have carried out the duties of a casting specialist since 1999. Patients’ wellbeing and proper treatment have always been my top priorities, which is why I have spent the past years developing UCAST to make the daily lives of my colleagues and the patient easier. UCAST consists of only two materials: thermoplastic Woodcast splint and padded fabric. Our innovative fabric completely replaces the stockinettes, paddings, bandages and tapes needed during casting.

Units using UCAST spend less time on the procedure, which in turn can reduce the waiting time for patients. UCAST is an effective, fast and safe cast, which is something that I always wanted when I was working in a hospital”, Lindroos comments.

In addition to launching UCAST, Dassiet continues product and material development. Recently, the company acquired a leading US company OrthoPets, that produces animal orthoses.

Improving veterinary treatment is one of the main focuses of the company. Furthermore, Dassiet offers various industries an opportunity to replace plastic parts with durable and ecological wood composite and biopolymer options.

The first products available in the UCAST product line include a wrist splint and a short thumb splint. Additional products for the treatment of upper and lower limbs will become available soon.

Additional information on UCAST products can be read at www. ucastmedical.com DR THORSTEN GIESECKE APPOINTED GENERAL MANAGER, COMMERCIAL BUSINESS, JANSSEN SCIENCES IRELAND UC Janssen, the pharmaceutical companies of Johnson & Johnson, has appointed Dr Thorsten Giesecke as General Manager, Commercial Business, Janssen Sciences Ireland UC, which is responsible for commercialising six areas of medicines where the need is high including: oncology, immunology, neuroscience, infectious diseases and vaccines, pulmonary hypertension and cardiovascular and metabolism.

Thorsten joins Janssen from the Company’s headquarters in New Jersey where he worked as Director of Global Commercial Strategy for early assets in oncology and prior to that as lead of the EMEA regional haematology strategy for multiple myeloma.

Thorsten, who has relocated to Ireland from the US, is a performance and purpose-driven leader with an impressive

Clinical R&D 81 Dr Thorsten Giesecke as General Manager, Commercial Business, Janssen Sciences Ireland UC

track record of building and leading high performing teams, together with solid experience in Global/Regional Strategic leadership roles.

In these roles, Thorsten has spearheaded several strategic projects including ensuring a transformational pipeline in prostate cancer through earlier and better commercial input, improving the global patient advocacy interaction, assessing the dynamic impact of new market entrants on cancer epidemiology, and developing biomarker strategies.

He has also driven the digital agenda in EMEA, introducing and implementing a digital customer experience at scientific conferences across the region.

Thorsten first joined Janssen Germany in 2006 as Medical Development Manager and assumed roles of increasing responsibility before being appointed as Business Unit Director for therapy areas including neuroscience and metabolics.

Originally from Germany, Thorsten began his career as an anaesthesiologist and scientist at University Hospitals in Germany and the US. He is a board-certified anaesthesiologist and pain therapist and holds an MD and a PhD from the University of Cologne.

Commenting on his appointment, Thorsten said, “I am delighted to be joining the Irish team and to be taking on the role of General Manager with responsibility for the Janssen commercial business at such an important time, and I believe we have a huge opportunity ahead of us. As we emerge from this pandemic, a new era of partnership between the

government, the health service and industry will be vital to achieving the best for Irish patients. I am fully committed to building on the remarkable work that has already been done here to improve care and ensure timely access to innovative treatments as we continue to make a real difference to the lives of people, health systems and society as a whole.”

With a passion for putting patients first, Thorsten brings his vast international experience to support the teams at Janssen working to address some of Ireland’s most pressing health challenges including the COVID-19 pandemic and tackling cancer with precision medicines and cuttingedge technologies in cell and gene therapy.

Janssen is part of the Johnson & Johnson family of companies in Ireland which employs over 5,000 people at 10 sites in Ireland across manufacturing, R&D and business operations, representing all three sectors of the company – Pharmaceutical, Medical Devices and Consumer Health. Many of Janssen’s innovative medicines are manufactured for global export from Irish sites.

SANOFI ANNOUNCES POSITIVE PHASE 1/2 STUDY INTERIM RESULTS FOR ITS FIRST MRNABASED VACCINE CANDIDATE Positive interim results from a Phase 1/2 study1 of Sanofi's mRNA-based COVID-19 vaccine candidate confirm the potential of recently-acquired Translate Bio's messenger RNA (mRNA) and lipid nanoparticle (LNP) platform and support Sanofi's mRNA strategy.

The initial data from Phase 1/2 showed neutralizing antibody

seroconversion (defined as 4-fold increase vs baseline) in 91% to 100% of study participants, two weeks after a second injection, across all 3 dosages tested.

No safety concern has been observed and the tolerability profile is comparable to that of other unmodified mRNA COVID-19 vaccines. Further data from this first study of Sanofi's mRNA platform will be presented at a later date.

"We are happy to see those positive initial results. We have made an impressive move just 9 months after the worldwide proof of concept of mRNA vaccines and only 17 since we started this first mRNA vaccine project", says Jean-Francois Toussaint, Global Head of Research and Development, Sanofi Pasteur.

"These results will clearly help inform the path forward for our mRNA development programs.

Today, we have a promising mRNA platform, which we're taking to the next level in development, including moving to modified mRNA, and against other diseases, including flu."

Targeting 2022 initiation of its clinical studies for an influenza vaccine with modified mRNA, Sanofi launched a Phase 1 clinical trial in June 2021 evaluating an mRNA-based investigational vaccine against seasonal influenza. The trial will evaluate the safety and immunogenicity of a monovalent flu vaccine candidate coding for the hemagglutinin protein of the A/H3N2 strain of the influenza virus across two formulations (MRT5400 and MRT5401) with different lipid nanoparticles.

At the same time, Sanofi continues its efforts in the fight against the COVID-19 pandemic with its adjuvanted recombinant protein candidate vaccine, developed in partnership with GSK. In parallel to its ongoing Phase 32 efficacy and safety study, Sanofi has expanded its development program to include a study of the vaccine as a potentially broadly protective booster to address evolving public health needs. Recently published preclinical data3 indicated the candidate has the potential to strongly boost immune responses following primary vaccination across multiple vaccine technology platforms and against a broad spectrum of variants of concern.

The booster studies4 began this summer in the U.S., Australia, France, and the UK. First results are expected by the end of Q4 2021.

Sanofi also keeps its commitment to making a strong contribution to current global public health priorities, with the supply of half a billion doses of authorized

vaccines. Sanofi is the only company leveraging its worldwide manufacturing capacity and expertise for the supply of three different authorized COVID-19 vaccines from BioNTech / Pfizer, Moderna, and Johnson & Johnson.

Manufacturing teams on three industrial sites of the company in France, Germany and the U.S. are mobilized, with 30 million doses released so far.

FDA ACCELERATED APPROVAL FOR TIVDAK™ (TISOTUMAB VEDOTIN-TFTV) Genmab A/S (Nasdaq: GMAB) and Seagen Inc. (Nasdaq: SGEN) have announced that the U.S. Food and Drug Administration (FDA) has granted accelerated approval to TIVDAKTM (tisotumab vedotintftv), the first and only approved antibody-drug conjugate (ADC) for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. TIVDAK is approved under the FDA's Accelerated Approval Program based on tumor response and the durability of the response.

Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.1 In the innovaTV 204 clinical trial, TIVDAK was evaluated in 101 patients with recurrent or metastatic cervical cancer who had received no more than two prior systemic regimens in the recurrent or metastatic setting, including at least one prior platinum-based chemotherapy regimen. Results from the trial showed a 24 percent confirmed objective response rate (ORR) (95% CI; 15.9-33.3), as assessed by an independent review committee (IRC) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. The median duration of response (DOR) was 8.3 months (95% CI; 4.2 to not reached).

The prescribing information for TIVDAK includes a BOXED WARNING for ocular toxicity, and Warnings for peripheral neuropathy, hemorrhage, pneumonitis, and embryo-fetal toxicity. The most common (≥25%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased (52%), fatigue (50%), lymphocytes decreased (42%), nausea (41%), peripheral neuropathy (39%), alopecia (39%), epistaxis (39%), conjunctival adverse reactions (37%), hemorrhage (32%), leukocytes decreased (30%), creatinine increased (29%), dry eye (29%), prothrombin international normalized ratio increased (26%), activated partial thromboplastin time prolonged

HOSPITALPROFESSIONALNEWS.IE | HPN • NOVEMBER - 2021

82 Clinical R&D (26%), diarrhea (25%), and rash (25%). Please see Important Safety Information below.1 The Biologics License Application (BLA) for TIVDAK was submitted in February 2021 and accepted with Priority Review in April 2021.

The submission was based on the results of the innovaTV 204 trial.

The FDA's Accelerated Approval Program allows for approval of a medicine based on a surrogate endpoint that is reasonably likely to predict clinical benefit, if the medicine fills an unmet medical need for a serious condition. A global, randomized phase 3 clinical trial (innovaTV 301) is underway and is also intended to support global registrations.

MS IRELAND AND NOVARTIS LAUNCH MS PODCAST MS Explored – The Podcast, a new series created by MS Ireland in partnership with Novartis Ireland was launched recently, providing support and advice to the 9,000 people in Ireland currently living with Multiple Sclerosis (MS).

The podcast series has been developed in response to the increased demand for information

and support witnessed by MS Ireland throughout the pandemic and the distinct need for easily accessible resources.

Hosted by Aoife Kirwan, Information, Advocacy and Research Officer, at MS Ireland, MS Explored – The Podcast explores a range of topics from diagnosis through to managing family and work pressures.

Listeners will hear from top healthcare experts as well as individuals who have been diagnosed with the condition as they share their first-hand experiences.

MS Explored – The Podcast featured leading healthcare professionals including: • Dr Eddie Murphy - Clinical Psychologist & Mental Health Expert at RTE’s Operation Transformation • Dr Lisa Costello, Consultant Neurologist at Beaumont Hospital • Dr Maria Gaughan, MS Fellow • Sinead Jordan, Clinical Nurse Specialist

• Sinead Brady, Career Psychologist Audrey Derveloy, General Manager and Country President, Novartis Ireland speaking about the podcast launch said, “We are delighted to be launching MS Explored – The Podcast today in partnership with MS Ireland. We believe that the series will serve to provide support and advice to those living with MS whenever they need it. Access to resources such as this is critical for people navigating their way through living with a condition like MS, and we hope that the series addresses key areas of concern for the MS community.”

Three episodes were released weekly beginning Tuesday, 21st September 2021 and each covered an important topic relating to the life of someone living with MS and potential challenges.

• Episode 1: MS the journey A diagnosis of MS can be overwhelming, and the treatment journey is different for every person with MS. In the first episode of MS Explored – The Podcast, host Aoife Kirwan is joined by Consultant Neurologist, Dr. Lisa Costello and Laura Lee who was diagnosed with MS ten years ago, to break down a diagnosis of MS, discuss what the future might look like and how to best manage the condition.

• Episode 2: Family life & MS Having MS doesn’t just affect the person living with it, it can hugely impact the lives of families and loved ones too. In this episode of MS Explored – The Podcast, Aoife Kirwan is joined by Sharon Henvey who is living with MS, MS Fellow Dr. Maria Gaughan, MS Nurse Specialist, Sinead Jordan and Clinical Psychologist Dr. Eddie Murphy to explore the challenges faced by people living with MS and how they can communicate their diagnosis to loved ones.

• Episode 3: Work and education Living with MS can have a big impact on work-life and/or the education journey. In this episode of MS Explored – The Podcast, Aoife Kirwan is joined by Lauren McAuley and Keith Byrne who are both living with MS, and by Career Psychologist Sinead Brady to discuss the supports and

Aoife Kirwan, Information, Advocacy and Research Officer, at MS Ireland, MS Explored

NOVEMBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

resources that are available to people living with MS, as well as tips on how and when to talk to your employer about your diagnosis.

Dr Lisa Costello, Consultant Neurologist at Beaumont Hospital and MS Explored – The Podcast contributor commented, “It is great to have such a useful resource for people living with MS that we can guide them to for support on many important areas. It is not always possible for us to support across every element of life with MS as part of the treatment pathway and so we welcome resources such as this as they can provide great comfort to people at all stages of their MS journey whether they have just been diagnosed or are at a different juncture.”

Listen, rate, and subscribe and find more information about MS at MS-Society.ie To join the conversation, use the hashtag #MSExplored.

UPM BIOMEDICALS AND PERKINELMER COLLABORATE TO OFFER HIGH THROUGHPUT 3D CELL SCREENING SOLUTION UPM Biomedicals is pleased to announce that it has entered into an agreement with PerkinElmer Health Sciences, Inc., for the life science leader, to act as a distributor of the UPM GrowDex® and GrowDase™ range of products. This new collaboration will offer researchers a complete solution for high throughput screening (HTS) of 3D cell cultures in early drug discovery, bringing together PerkinElmer's cell imaging and automation solutions and knowledge with UPM's animal-free 3D reagent offerings and expertise.

Automated HTS is frequently used to assess the therapeutic potential for hundreds of candidate drugs in parallel, and the rise of 3D cell culture approaches has created a need for new high quality reagents suitable for HTS applications such as cancer drug screening.

UPM's nanofibrillar cellulose GrowDex hydrogels create an environment that resembles the conditions inside the human body, and can be effectively handled at room temperature, making them well suited for scale up and automation without compromising performance. Combined with GrowDase – which enables effective one-step recovery of cells for downstream processing applications – this provides an ideal solution for high throughput 3D cell culture applications, offering more reproducible and reliable results to help predict how drugs will work in vivo.

Clinical R&D 83 NEW, LATE-BREAKING DATA AT EADV

Also, at 16 weeks, key secondary endpoint data included:

Positive results from a Phase 2a study evaluating the safety and efficacy of amlitelimab, a human monoclonal antibody targeting key immune system regulator OX40-Ligand, were presented as a late-breaker today at the European Academy of Dermatology and Venerology (EADV) 2021 Virtual Congress. In the study, amlitelimab showed significant improvements in signs and symptoms of moderate-to-severe atopic dermatitis with a well-tolerated safety profile in adults whose disease cannot be adequately controlled with topical medications or for whom topical medications are not a recommended treatment approach.

• 44% of patients treated with amlitelimab-LD and 37% of patients treated with amlitelimab-HD achieved a score of 0 (clear) or 1 (almost clear) on the validated Investigator's Global Assessment (vIGA) scale compared with 8% with placebo (p<0.001 both LD and HD). The vIGA is a 5-point scale ranging from 0 (clear) to 4 (severe) that measures the overall severity of skin lesions.

In this Phase 2a double-blind, placebo-controlled study, participants were randomized to either intravenous amlitelimablow dose (LD) (n=29), intravenous amlitelimab-high dose (HD) (n=30) or placebo (n=29) and were treated every four weeks over a 12-week period. Eligible patients included adults with moderateto-severe atopic dermatitis whose disease is inadequately controlled with topical therapies such as corticosteroids, or where such therapies were not advisable.

• 33% of amlitelimab-LD and 30% of amlitelimab-HD patients achieved 90% or greater skin improvement (EASI-790 compared to 13% with placebo.

Co-primary endpoints included percent change in EASI from baseline, and incidence of treatment-emergent adverse events (TEAEs), at week 16.

At week 16, the data demonstrated that when dosed every four weeks: • Patients treated with amlitelimab-LD showed 80% improvement in average EASI from baseline, and patients treated with amlitelimab-HD showed 70% improvement in average EASI from baseline, compared to 49% for the placebo group (p=0.009 and p=0.072, respectively). The difference between amlitelimabLD and placebo was nominally statistically significant.

• The onset of response versus placebo was seen as early as Week 2 for both amlitelimab groups. No meaningful difference in responses was seen for the amlitelimab-LD and amlitelimab-HD groups.

• The overall rate of TEAEs was 35% for amlitelimab-LD, 17% for amlitelimab-HD and 31% for placebo. One serious adverse event was reported in the amlitelimab-LD group (infected atheroma) deemed related by the investigator at week 16; the event was resolved, and the patient was able to complete the study. No hypersensitivity reactions were reported.

• 59% of amlitelimab-LD and 52% of amlitelimab-HD patients achieved 75% or greater skin improvement (EASI-75) compared to 25% with placebo.

• A 60% improvement in the amlitelimab-LD group and a 59% improvement in the amlitelimab-HD group compared with 37% improvement in the placebo group in mean percent change from baseline in SCORing Atopic Dermatitis (SCORAD), a combined measure of area and severity of atopic dermatitis on the skin as well as patient-reported symptoms of itch and sleeplessness, (p=0.011 and p=0.016, respectively).

• At Week 36, 68% of patients who achieved a vIGA score of 0 or 1 at Week 16 maintained their response — 24 weeks after their last dose.

Amlitelimab is a fully human nondepleting monoclonal antibody that binds to OX40-Ligand, a key immune regulator, and has the potential to be a first-inclass treatment for a range of immune-mediated diseases and inflammatory disorders, including moderate-to-severe atopic dermatitis. By targeting OX40-Ligand, amlitelimab aims to restore immune homeostasis between pro-inflammatory and anti-inflammatory T cells.

Amlitelimab is being studied in patients with moderate-to-severe atopic dermatitis with suboptimal response to topical therapies.

The potential for long-lasting treatment responses in atopic dermatitis patients may help reduce the burden of frequent dosing, and further investigation will be conducted in a future Phase 2b study. Amlitelimab is currently under clinical investigation, and its safety and efficacy have not been evaluated by any regulatory authority.

In April 2021, Sanofi finalized the acquisition of Kymab, a clinical-stage biopharmaceutical company developing fully human monoclonal antibodies with a focus on immune-mediated diseases and immuno-oncology therapeutics, adding amlitelimab to the company's dynamic pipeline.

GENMAB AND SEAGEN ANNOUNCE FDA ACCELERATED APPROVAL FOR TIVDAK™ Genmab A/S (Nasdaq: GMAB) and Seagen Inc. (Nasdaq: SGEN) have announced that the U.S. Food and Drug Administration (FDA) has granted accelerated approval to TIVDAKTM (tisotumab vedotintftv), the first and only approved antibody-drug conjugate (ADC) for the treatment of adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. TIVDAK is approved under the FDA's Accelerated Approval Program based on tumor response and the durability of the response.

Continued approval may be contingent upon verification and description of clinical benefit in confirmatory trials.1 "Once recurrent or metastatic cervical cancer progresses, there is a need for more options for these patients," said Robert L. Coleman, M.D., Chief Scientific Officer, US Oncology Research and lead investigator of the innovaTV 204 clinical trial. "This is an important development for patients with recurrent or metastatic cervical cancer."

In the innovaTV 204 clinical trial, TIVDAK was evaluated in 101 patients with recurrent or metastatic cervical cancer who had received no more than two prior systemic regimens in the recurrent or metastatic setting, including at least one prior platinum-based chemotherapy regimen. Results from the trial showed a 24 percent confirmed objective response rate (ORR) (95% CI; 15.9-33.3), as assessed by an independent review committee (IRC) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria.

The median duration of response (DOR) was 8.3 months (95% CI; 4.2 to not reached).

The prescribing information for TIVDAK includes a BOXED WARNING for ocular toxicity, and Warnings for peripheral neuropathy, hemorrhage, pneumonitis, and embryo-fetal toxicity. The most common (≥25%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased (52%), fatigue (50%), lymphocytes

decreased (42%), nausea (41%), peripheral neuropathy (39%), alopecia (39%), epistaxis (39%), conjunctival adverse reactions (37%), hemorrhage (32%), leukocytes decreased (30%), creatinine increased (29%), dry eye (29%), prothrombin international normalized ratio increased (26%), activated partial thromboplastin time prolonged (26%), diarrhea (25%), and rash (25%). Please see Important Safety Information below.1 "We are thrilled to see this new treatment approved by the FDA. We are grateful to have another option for this devastating disease," said Tamika Felder, Founder, Cervivor.

"TIVDAK's approval as a monotherapy in the U.S. is an important milestone for women with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy, as they are in need of a new treatment option and we look forward to making it available to them," said Jan van de Winkel, Ph.D., Chief Executive Officer, Genmab. "The journey towards the approval of TIVDAK started nearly two decades ago with innovative research by scientists at Genmab and Seagen and reflects on our purpose of making an impact in the lives of cancer patients and their families. Today's announcement marks Genmab's evolution into a fully integrated biotechnology company and we would like to thank patients, caregivers, investigators and our collaborators for their participation in our clinical studies."

"We are pleased with the accelerated approval of TIVDAK, Seagen's third FDA-approved antibody-drug conjugate, and fourth approved medicine. Our mission at Seagen is to develop medicines that make a difference for people impacted by cancer," said Roger Dansey, M.D., Chief Medical Officer, Seagen.

The Biologics License Application (BLA) for TIVDAK was submitted in February 2021 and accepted with Priority Review in April 2021.

The submission was based on the results of the innovaTV 204 trial.

The FDA's Accelerated Approval Program allows for approval of a medicine based on a surrogate endpoint that is reasonably likely to predict clinical benefit, if the medicine fills an unmet medical need for a serious condition. A global, randomized phase 3 clinical trial (innovaTV 301) is underway and is also intended to support global registrations.

HOSPITALPROFESSIONALNEWS.IE | HPN • NOVEMBER - 2021

Therapeutic Indications1

CRESEMBA® is indicated in adults for the treatment of:1 Invasive Aspergillosis

Mucormycosis in patients for whom amphotericin B is inappropriate

Consideration should be given to official guidance on the appropriate use of antifungal agents.1 Early targeted therapy (pre-emptive or diagnostic-driven therapy) may be instituted pending confirmation of the disease from specific diagnostic tests. However, once these results become available, antifungal therapy should be adjusted accordingly.1 Formulations and strengths1

IV

200 mg powder for concentrate for solution for infusion

Oral

100 mg hard capsules

References 1. CRESEMBA Summary of Product Characteristics. 2021 Abbreviated prescribing information CRESEMBA™ [isavuconazole] 200 mg powder for concentrate

for solution for infusion and 100 mg hard capsules. Please refer to the Summary of Product Characteristics (SmPC) before prescribing CRESEMBA. Presentation: Each vial of CRESEMBA powder for concentrate for solution for infusion contains 200 mg isavuconazole.

Each CRESEMBA hard capsule contains 100 mg isavuconazole.

Indications: Indicated in adults for the treatment of invasive aspergillosis; mucormycosis in patients for whom amphotericin B is inappropriate. Administration & dosage: Early targeted therapy (pre-emptive or diagnosticdriven therapy) may be instituted pending confirmation of the disease from specific diagnostic tests. However, once these results become available, antifungal therapy should be adjusted accordingly. Loading dose (IV): 200 mg CRESEMBA every 8 hours for the first 48 hours followed by a maintenance dose of 200 mg once daily 12 to24 hours after the last loading dose. The infusion must be administered via an infusion set with an in-line filter with a microporous membrane made of polyethersulfone (PES) and with a pore size of 0.2 μm to 1.2 μm. Switching between intravenous and oral administration is appropriate when clinically indicated. Loading dose (ORAL): two capsules (equivalent to 200 mg of isavuconazole) every 8 hours for the first 48 hours (6 administrations in total) followed by a maintenance dose of two capsules (equivalent to 200 mg of isavuconazole) once daily, starting 12 to 24 hours after the last loading dose. Duration of therapy according to clinical response. The safety and efficacy of CRESEMBA in children aged below 18 years have

not been established. Contra-indications: Hypersensitivity to the active substance or to any of the excipients; co-administration with ketoconazole, high-dose ritonavir, strong and moderate CYP3A4/5 inducers; patients with familial short QT syndrome. Warnings and precautions: Caution in patients hypersensitive to azole antifungal agents or taking medicinal products known to decrease the QT interval. CRESEMBA infusion should be stopped if infusion-related reactions or severe cutaneous adverse reactions occur. Monitoring of hepatic enzymes should be considered as clinically indicated.

Treatment with isavuconazole is not recommended in patients with severe hepatic impairment (Child-Pugh Class C), unless the potential benefit outweighs the risks. Hepatitis has been reported.

Drug interactions: Isavuconazole is a substrate of cytochrome P450 isoenzyme CYP3A4/5; inducers and strong inhibitors of this enzyme may change its plasma levels. Isavuconazole is a moderate inhibitor of CYP3A4/5, a mild inducer of CYP2B6, and a mild inhibitor of P-glycoprotein (P-gp), organic cation transporter 2 (OCT2), and uridine diphosphate-glucuronosyltransferases (UGT) and in vitro, inhibitor of BCRP. Coadministration of CRESEMBA with drugs that are substrates for these enzymes or transporters may change their plasma levels. Monitoring the plasma levels or biological effects of these drugs and appropriate dose adjustment may be required.

See SmPC for interaction tables and further information. Pregnancy and lactation: Not be used except in severe or potentially lifethreatening fungal infections, if the anticipated benefits outweigh the possible risks to the foetus. Discontinue breastfeeding during treatment. Side-effects: Common (incidence ≥1/100 to <1/10):

neutropenia, thrombocytopenia, pancytopenia, leukopenia, anaemia, hypokalaemia, decreased appetite, delirium, headache, somnolence, thrombophlebitis, dyspnoea, acute respiratory failure, vomiting, diarrhoea, nausea, abdominal pain, elevated liver chemistry tests, rash, pruritus, renal failure, chest pain, fatigue, injection site reaction.

Uncommon (incidence ≥1/1,000 to <1/100): hypersensitivity, hypomagnesaemia, hypoglycaemia, hypoalbuminaemia, malnutrition, depression, insomnia, convulsion, syncope, dizziness, paraesthesia, encephalopathy, presyncope, neuropathy peripheral, dysgeusia, vertigo, atrial fibrillation, tachycardia, bradycardia, palpitations, atrial flutter, electrocardiogram QT shortened, supraventricular tachycardia, ventricular extrasystoles, supraventricular extrasystoles, circulatory collapse, hypotension, bronchospasm, tachypnoea, haemoptysis, epistaxis, dyspepsia, constipation, abdominal distension, hepatomegaly, hepatitis petechiae, alopecia, drug eruption, dermatitis, back pain, oedema peripheral, malaise, asthenia.

Legal Category: S1A. Marketing Authorisation Number (s): EU/1/15/1036/001 (IV); EU/1/15/1036/002 (oral). Marketing Authorisation Holder: Basilea Pharmaceutica Deutschland GmbH, Marie-Curie-Strasse 8, 79539 Lörrach, Germany. Local Representative: Pfizer Healthcare Ireland, Pfizer Building 9, Riverwalk, National Digital Park, Citywest Business Campus, Dublin, 24, Ireland.

Last revised: 01/2021.

Ref: CM 5_0

For further information on this medicine please contact: Pfizer Medical Information on 1800 633 363 or at EUMEDINFO@pfizer.com.

For queries regarding product availability please contact: Pfizer Healthcare Ireland, Pfizer Building 9, Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24 + 353 1 467 6500.

Pfizer Healthcare Ireland, 9 Riverwalk, National Digital Park, CityWest Business Campus, Dublin 24, Ireland.

Legal category: S1A. Further information available at www.medicines.ie

PP-CRB-IRL-0130 Date of Preparation October 2021