HPN 2021 October by IPN Communications LTD

HOSPITAL PROFESSIONAL NEWS IRELAND

HPN October 2021 Issue 89 HOSPITALPROFESSIONALNEWS.IE

Ireland’s Dedicated Hospital Professional Publication

IN THIS ISSUE: NEWS: Hospital Pharmacists key to Medicines Access Page 6 REPORT: Falsified Medicines Directive Use and Learn Page 12 CPD: Multiple Sclerosis Page 19 FEATURE: Model of Care for Osteoarthritis Page 24 WOMEN’S HEALTH SPECIAL FOCUS: Cervical Cancer Page 32

Legal Category: POM S1A. Marketing Authorisation Holder: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium. For further information please contact: Pfizer Healthcare Ireland, 9 Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24 or Medical Information on 1800 633 363 or at medical.information@pfizer.com

▼ T 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. Please see summary of product characteristics for more information.

PP-BIO-IRL-0149

September 2021

This Publication is for Healthcare Professionals Only

WOMEN’S HEALTH SPECIAL FOCUS: Menopause Page 62 CLINICAL: Preventable Deaths in Blood Clotting (VTE) Page 76

ASCO 2021 UPDATE

SECOND-LINE MONOTHERAPY

AFTER AT LEAST 5 YEARS OF FOLLOW UP, KEYTRUDA MONOTHERAPY CONTINUED TO SHOW IMPROVED OS, ORR & DOR COMPARED WITH INVESTIGATORS CHOICE OF CHEMOTHERAPY IN PATIENTS WITH ADVANCED UROTHELIAL CARCINOMA1,3 Kaplan-Meier Estimates of Overall Survival with KEYTRUDA vs. Chemotherapy (N=542)3 100

KEYTRUDA 200mg Q3W

Overall survival (%)

10.1

(HR=0.71; 95%CI, 0.59-0.86; P=0.0003)

months

(95%CI, 8.0-12.3)

7.2

months

SELECTED SAFETY INFORMATION4

with KEYTRUDA

• Grade 3-5 treatment-related adverse events,16.9% (Keytruda) versus 50.2% (chemotherapy)

22%

Chemotherapy

MEDIAN OS

5-YEAR OVERALL RESPONSE RATE3

VS. 11.0

(95%CI, 6.1-8.1)

with Chemotherapy

FLEXIBLE DOSING2

0 0

KEYTRUDA

270

195

148

116

Chemotherapy

272

173

109

• 200 mg every 3 weeks or • 400 mg every 6 weeks administered as an intravenous infusion over 30 minutes

Months

No. at risk

• Treatment-related adverse events, 62% (Keytruda) versus 90.6% (chemotherapy)

Adapted from Bellmunt J et al. Poster presented at American Society of Clinical Oncology (ASCO) 20213 Intention to treat population and median follow up of 62.9 months3

reactions and other causes should be excluded. Cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving pembrolizumab. If SJS or TEN is confirmed, pembrolizumab should be permanently discontinued. 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, myelitis, vasculitis, cholangitis sclerosing and gastritis. Refer to SmPC for information on management of significant immune-related adverse reactions. Complications of allogeneic Haematopoietic Stem Cell Transplant (HSCT): Allogeneic HSCT after treatment with pembrolizumab: Cases of graft-versushost-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. 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. 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, thrombocytopenia, neutropenia, lymphopenia, hyponatraemia, hypokalaemia, hypocalcaemia, insomnia, neuropathy peripheral, lethargy, dry eye, cardiac arrhythmia (including atrial fibrillation), hypertension, hyperthyroidism, thyroiditis, insomnia, dizziness, dysgeusia, pneumonitis, colitis, dry mouth, severe skin reactions, vitiligo, dry skin, alopecia, eczema, dermatitis acneiform, erythema, dermatitis, 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. Combination with chemotherapy: Very Common: pneumonia, anaemia, neutropenia, thrombocytopenia, hypothyroidism, hyponatraemia, hypokalaemia, decreased appetite, insomnia, dizziness, neuropathy peripheral, headache, dyspnoea, cough, alopecia, nausea, diarrhoea, vomiting, abdominal pain, constipation, rash, pruritus, musculoskeletal pain, arthralgia, pyrexia, fatigue, asthenia, oedema, blood creatinine increased. Common: febrile neutropenia, leukopenia, lymphopenia, infusion related reaction, hyperthyroidism, hypocalcaemia, dysgeusia, lethargy, dry eye, cardiac arrhythmia (including atrial fibrillation), vasculitis, hypertension, pneumonitis, colitis, dry mouth, gastritis, hepatitis, severe skin reactions, dry skin, erythema, dermatitis, myositis, pain in extremity, arthritis, acute kidney injury, influenza-like illness, chills, hypercalcaemia, ALT increase, AST increased, blood alkaline phosphatase increased, blood bilirubin 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, neutropenia, leukopenia, thrombocytopenia, 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, gastritis, 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 2021. © Merck Sharp & Dohme B.V. 2021. All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin 18, D18 X5K7 or from www. medicines.ie. PSUSA-202009-II-097 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) 1. Bellmunt J, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med 2017; 376;11:101526. 2. Keytruda Summary of Product Characteristics available at www.medicines.ie, accessed April 2021. 3. Bellmunt J et al. Five-year follow-up from phase III KEYNOTE-045 trial: Pembrolizumab versus investigator’s choice (paclitaxel, docetaxel, or vinflunine) in recurrent, advanced urothelial cancer. Poster (4532) presented ASCO 2021; virtual. 4. Necchi A et al. Threeyear follow-up from the phase III KEYNOTE-045 trial: Pembrolizumab versus investigator’s choice (paclitaxel, docetaxel, or vinflunine) in recurrent, advanced urothelial cancer. Poster (919P) presented ESMO) 2019; Barcelona, Spain Red Oak North, South County Business Park, Leopardstown, Dublin D18 X5K7, Ireland.

IE-KEY-00376

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 and paediatric patients aged 3 years and older with relapsed or refractory classical Hodgkin lymphoma (cHL) who have failed autologous stem cell transplant (ASCT) or following at least two prior therapies when ASCT is not a treatment option. 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. KEYTRUDA as monotherapy is indicated for the first line treatment of metastatic microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer in adults. KEYTRUDA, in combination with platinum and fluoropyrimidine based chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic carcinoma of the oesophagus or HER-2 negative gastroesophageal junction adenocarcinoma in adults whose tumours express PD-L1 with a CPS ≥ 10. 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 in adults 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 monotherapy in paediatric patients aged 3 years and older with cHL is 2 mg/kg bodyweight (up to a maximum of 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 are limited in patients ≥ 75 years for pembrolizumab monotherapy in patients with resected Stage III melanoma and MSI-H or dMMR CRC; for pembrolizumab in combination with axitinib in patients with advanced RCC; for chemotherapy combination in patients with metastatic NSCLC and oesophageal carcinoma; for pembrolizumab (with or without chemotherapy) in patients receiving first line treatment for metastatic or unresectable recurrent HNSCC. 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 except in paediatric patients with cHL. 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 and patients should be monitored for these endocrinopathies. Refer to SmPC for information on management of immune-related endocrinopathies. Immune-related skin adverse reactions: Patients should be monitored for suspected severe skin

Date of Preparation: July 2021

Keytruda is also indicated as monotherapy 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) ≥ 102

October Issue Issue 89

Contents

Foreword

Medicines.ie recognised for Innovation Award P6

Editor As Hospital Professional News was going to print, the Irish Hospital Consultants Association (IHCA) stated that it is critical Budget 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.

Stop blaming the pandemic for rising waiting lists say Hospital Consultants P7 7

Looking ahead to a gloomy and dark winter P11

With the number of people on hospital waiting lists now at 907,617, the IHCA said Budget 2022 has to put in practice the political commitments made to the public and to healthcare professionals.

FMD Use and Learn gears up to end, what next? P12 Over 152,000 Wait for Care P14 Largest intake of 2021 StAR MD Programme P16

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.

Budget 2022: Critical moment for mental health services P74 REGULARS

Women’s Health Focus: Cervical Cancer P32

Analysis in the Association’s Pre-Budget 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.

Women’s Health Focus: Polycystic Ovary Syndrome P48 Women’s Health Focus: Stress Urinary Incontinence P52 16

Clinical R&D: P81 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

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.

DESIGN DIRECTOR Ian Stoddart Design HOSPITALPROFESSIONALNEWS.IE

@HospitalProNews HospitalProfessionalNews

In other news this issue, Covid-19 vaccine hesitancy has dropped by 36 points over the past 10 months, 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. You can read more about this on page 8. Our special focus this month looks at Women’s Health and we have a fantastic range of clinically authored articles covering this field. Ranging from Prenatal Screening for Congenital Heart Disease in Ireland on page 35 to Polycystic Ovary Syndrome on page 48. Hospital pharmacist Cathy Naylor gives an in-depth overview of Diabetic Keotacidosis in our second Continuing Professional Development module of the issue. Diabetic ketoacidosis (DKA) is a serious, life threatening emergency in patients with diabetes mellitus. DKA continues to be a common cause of hospital admission in type 1 diabetes mellitus (T1DM) and is the leading cause of mortality in young people with T1DM. Turn to page 67 to read the full article. I hope you enjoy the issue.

HOSPITAL PROFESSIONAL NEWS IRELAND Ireland’s Dedicated Hospital Professional Publication

HOSPITALPROFESSIONALNEWS.IE | HPN • OCTOBER - 2021

4 News

Ensuring Security of Supply for Medicines Legislative reforms aligned with current off-patent market conditions are the precondition for a coherent policy to improve the secure supply of essential medicines, says Medicines for Europe, which represents the generic, biosimilar and valueadded medicines industries across Europe. The EU structured dialogue on medicines manufacturing is a critical first step to align stakeholders on workable reforms. “As the biggest supplier of prescription medicines, our industry is committed to improving security of supply in Europe,” says the organisation.

For security of supply, legislative reform should cover: 1. Up-to-date European regulation based on interconnected digital tools to improve the predictability of supply and demand on the EU market. 2. Alignment of Member States on security of supply based on EU solidarity – notably on what are critical products, to reward companies for investments in supply chain resilience, notably by introducing smart multi criteria tenders, and to prevent distortive national stockpiling requirements. 3. Restore European leadership in manufacturing by adapting state aid rules to enable

the generic medicines and API industry to participate in national Recovery and Resilience plans for green and digital technology investments. Speaking at the EU Structured Dialogue, Medicines for Europe President, Christoph Stoller (TEVA) outlined, “Pharmaceutical and industrial policy, must be an enabler for robust supply chains and support our industry efforts to mitigate and address the root causes of supply chain vulnerabilities, while ultimately supporting more investments in European manufacturing. The urgency is to agree and implement smart regulatory and economic policies! In the off patent sector, the race to the lowest price has

reached its limit. And rather than punishing companies via penalties or by implementing distortive national requirements such as stockpiling, we should think win win.” Medicines for Europe Vice President Rebecca Guntern (Sandoz) said, “We need to jointly design a coherent policy to ensure security of supply for essential medicines, which is better aligned with the prevailing market conditions for off-patent medicines. Medicine manufacturing costs cannot be compressed indefinitely. We need policies that enable a meaningful digital framework, promote flexible regulatory systems and phase out unhelpful and short-sighted costcontainment measures.”

Medicines.ie Recognised for Innovation Medicines.ie, a website owned by the Irish Pharmaceutical Healthcare Association, has been recognised for innovation by the Pharma Industry Awards. The website, Ireland’s most accessible source of accurate and reliable medicines information, placed second in the ‘Innovation of the Year’ category. Medicines.ie is an online resource that provides patient information leaflets, a summary of product characteristics (SmPCs) and educational materials (risk management materials) for most medicines on the Irish market. The platform’s content is easily searchable and the functionality is intuitive. It is available on desktop, on mobile and on tablet. IPHA plans to add new features that enhance the user experience for people working in healthcare and medicine, and for the public. From early next year, pictures of each medicine pack will be displayed beside each medicine. There are plans for a new homepage, with product updates and key trends and statistics.

The Sleepy Surgeon Dale Whelehan, PhD researcher in Behaviour Science, School of Medicine

New research from the School of Medicine at Trinity investigating the effect of sleep deprivation on surgical performance has found that surgeons were already sleep deprived before their on-call shifts and were even more sleepdeprived afterwards, and crucially, that sleep deprivation impacted surgical performance. The research focussed on the effects of being ‘on-call’; a

frequent state for surgeons. The Trinity study recruited surgical trainees and consultants in the Dublin region and explored subjective and objective metrics around sleep and performance using ‘on-call’ as a particular influencer for increased fatigue. Participants were wired up using electroencephalogram (EEG) and a validated modified Multiple Sleep Latency Test testing was

OCTOBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

used to objectively measure sleep on the morning of their on-call shift. Several other validated tests for subjective sleep and fatigue measurement were also recorded. ‘Sleep latency’ refers to the time it takes to go from being fully awake to sleeping and is often an indicator of sleepiness. The surgeons in the study had early onset sleep latency before on-call, which was exacerbated further in post-call settings The study, led by Dale Whelehan, PhD researcher in Behaviour Science at the School of Medicine is unique as it is the first to attempt to control for a series of confounding variables such as experience, quality and quantity of sleep, the influence of caffeine and circadian rhythm influences.

The research found that the current models of surgical on-call were not conducive to optimising sleep for surgeons. However, there are challenges associated with making changes to ensure better sleep. For example, there may be loss of continuity of patient care, loss of trainee exposure, and reduced service delivery. Nevertheless, patient safety is of utmost importance to healthcare workers. Speaking on the impact of the study’s findings and future recommendations, Dale Whelehan, PhD researcher in Behaviour Science at the School of Medicine and lead researcher said, “The current situation needs urgent attention. Policy makers must ensure appropriate work-life balance legislation is in place with appropriate resourcing, institutions must enforce this legislation and healthcare staff must professionally and personally internalise and adhere to recommended guidelines.”

News

Pandemic Not to Blame for Waiting Lists The Irish Hospital Consultants Association (IHCA) has called for Government and the HSE to expedite the publication of plans to tackle Ireland’s escalating acute hospital waiting lists.

Consultant Histopathologist and IHCA Vice President, Professor Rob Landers

The call came ahead of the latest National Treatment Purchase Fund (NTPF) hospital waiting lists which are expected soon, following a 2-month delay due to the cyberattack impacting reporting. Consultant Histopathologist and IHCA Vice President, Professor Rob Landers, said that waiting lists have been deteriorating progressively over the past decade - despite HSE claims that the service was resourced to bring these lists down before the Covid-19 pandemic struck. According to the latest available information online (from May 2021), there were over 885,000 people on some form of NTPF waiting list to be treated or seen by a consultant. The number of people waiting for inpatient and day-case hospital treatment has grown by more than 31,000 in the past decade – an increase of 69%. More worryingly, in May 2021 there were 20,820 patients on these lists waiting longer than a year for hospital care; which the IHCA says is more than a 100-fold increase in such ‘long waiters’ since May 2012 – when there were just 199 patients waiting longer than 12 months for treatment. In addition, over the past seven years due to insufficient consultant staffing and vacancies, a further 286,000 people are

waiting on public hospital outpatient lists to be assessed by a consultant, an increase of 84%. Consultants now fear that the next NTPF figures, expected to be published this month, could show significant increases across all waiting lists – anticipating the overall number of people waiting to be around 900,000 - taking Ireland’s health system ‘over the cliff edge’ and tumbling into another healthcare crisis. Commenting further on the waiting lists in a video released today, Prof. Landers said, “Over the last decade, the situation has progressively deteriorated to a point where we are now in an absolute crisis. The Government and health service must stop hiding behind the pandemic and cyberattack as the main reasons for our growing waiting lists.”

“The Government and health service must stop hiding behind the pandemic and cyberattack as the main reasons for our growing waiting lists” Within his own specialty of Histopathology, Prof Landers said that long wait times are nothing new. He noted that patients have been presenting with more advanced symptoms for the past number of years, which is a particular concern for those who come in for cancer

resections (removal of tumours) at a later stage of progression of the disease. Growing waiting lists are not simply a result of Covid-19 but demonstrate the impact of years of consultant shortages and underinvestment in capacity across public hospitals.

Early bird registration before 1 December 2021! Abstract/GPI submission are open! It is a great pleasure that hospital pharmacists across Ireland are now invited to the 2022 European Association of Hospital Pharmacists (EAHP) Annual Congress. While these unprecedented times have turned all healthcare professionals worlds upside down, the pharmacy profession has prevailed and hospital pharmacists have never ceased to proactively adapt to a changing world in order to continuously serve their patients best interests. Fortunately, EAHP has proved to be resilient during this period and continued to work hard for the upcoming EAHP 2022 Congress undaunted by the challenges the Association has had to face. “We are very much looking forward to welcoming you in Vienna, from 23 to 25 March 2022 when spring will, hopefully, be already shining its heart-warming light on the Danube Valley,” says the Association. WHAT TO EXPECT • Live panel discussions by hospital pharmacy and healthcare experts • Opening and Closing Ceremonies • Social events and networking opportunities • Access to session presentations after the Congress • Poster Walk Sessions • Visit the many exhibitors. Interact with them, meet the expert sessions and much more!

HOSPITALPROFESSIONALNEWS.IE | HPN • OCTOBER - 2021

6 News

Patients are directly affected and increasingly faced with avoidable accessibility and affordability issues. Besides the constraints faced by public health budgets, there are other barriers to treatment access. These include the growing problem of medicines shortages , delayed market access for new treatments in some European regions or increased out of pocket costs for patients. The European Association of Hospital Pharmacists (EAHP's) Position Paper on Access to Medicines advocates for affordable medicines of good quality that are provided in a timely manner to patients. To achieve this goal barriers to treatment access need to be broken down and the uptake of enablers that promote and safeguard the access of patients to both new life-saving medicines and older, essential medicines must be increased.

Hospital Pharmacy - Meeting the Needs of Patients Hospital pharmacists across the world are working every day for their patients to ensure that they receive the medication they need to improve their health and to prevent and cure diseases. However, sometimes the medicine that is suited for an individual patient is not accessible. Growing healthcare expenditure has become a problem for many European countries. Innovative drugs, in particular, place an additional strain on already tight hospital budgets. Patients are directly affected and increasingly faced with avoidable accessibility and affordability issues. Besides the constraints faced by public health budgets, there are other barriers to treatment access. These include the growing problem of medicines shortages and delayed market access for new treatments in some European regions or increased out of pocket costs for patients. The European Association of Hospital Pharmacists (EAHP's)

Barriers to treatment access

• • • •

Enablers to treatment access

Lack of purposeful procurement practices National pricing and reimbursement policy choices jeopardising patients' adequate access Medicine shortages Unavailability in certain markets, leading to inequity between Member States

• • • •

Health Technology Assessments (HTAs), including common reports at EU level Collaboration and best practice sharing on pricing and reimbursement Increasing the use of prevention measures Fostering innovation and research

• calls on hospital managers and pharmacoeconomics and the Position Paper on Access to its members to work together Medicines advocates for affordable assessment of drug effectiveness to increase the uptake of risk medicines of good quality that be leveraged and well utilised assessments are providedaninequilibrium a timely manner To achieve between the barriers the enablers to treatment access, EAHP: in hospitals; and, within and value-based evaluation to patients. To achieve this goal approaches. Additionally, • urges increased investment to barriers to treatment access need the implementation of the support the development of • broken recommends thatthe theuptake expertise offorthcoming the hospitalHTA pharmacist in pharmacoeconomics and the assessment of to be down and Regulation innovative proposals Additionally, and the drugthat effectiveness be leveraged and well utilised within value-based evaluation approaches. of enablers promote and should be used for the expansion encouragement of practicethethe implementation of the forthcoming HTA Regulation should for the expansion of healthcare safeguard access of patients of healthcare professional inputbe usedbased research projects input in HTAs at bothinEuropean and national level. to both professional new life-saving medicines HTAs at both European and to investigate new fields of and• older, essential medicines supports the view of EURIPID and strongly recommends that this tool infectious is not applied on control its ownsuch but in national level. disease must beconjunction increased. with other policy measures, including transparency; as immunotherapy and to • supports the view of EURIPID • callsanonequilibrium hospital managers the uptake of risk assessments the cost-effectiveness To achieve between and its members to work together to increaseoptimise and strongly recommends that in hospitals; and, of systems for surveillance on the barriers and the enablers to this tool is not applied on its antibiotic resistance. of • urges increased anduse theand encouragement treatment access, EAHP:investment to support the development of innovative proposals in conjunction practice-based research projectsown to but investigate new with fields of infectious disease control such as other policy measures,of including • recommends that the and expertise immunotherapy to optimise the cost-effectiveness systems for surveillance on antibiotic use and transparency; of theresistance. hospital pharmacist in

New Head of Pharmacology The Department of Pharmacology at University College Cork have announced Professor Christian Waeber as our new Head of Department, taking over the reins from Professor David Kerins who had a challenging year as Interim head of department during Covid. Prior to his appointment Professor Waeber joined University College Cork (UCC) in 2013 where he is now Professor of Pharmacology, a joint appointment between the School of Pharmacy and the Department of Pharmacology. Early in his career, Professor Waeber worked as a Ph.D. student at Novartis Basel. Professor Waeber then joined as a post-

doctoral fellow the laboratory of Joel Bockaert, at the “Centre CNRS-INSERM de PharmacologieEndocrinologie” in Montpellier. In 1993, Prof Waeber joined Harvard Medical School to characterize the pharmacological profile of 5-HT1like receptors inhibiting neurogenic inflammation, a research carried out in collaboration with Michael Moskowitz. His current research at UCC is focused on characterizing the role of the adaptive immune system is stroke recovery. Professor Waeber is looking forward to the challenge this new role presents, and all of us at the Department of Pharmacology wish him every success in his new role.

Pharma Managers Series – HSE Briefing Date: 4th November, 2021 We’re delighted to welcome HSE CEO, Paul Reid back to the PMI to give our 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.

OCTOBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

OPEN

A NEW

DIMENSION

Unlocking hope

≥5x

OF COMBINATION EFFICACY

Meaningful response

increase in rate of MRD negativity2

Remarkable PFS benefit

DVd complete response (CR) or better vs Vd2

>79%

RRR* in disease progression or death vs Vd of patients with 1PL of therapy2

Transform the treatment of multiple myeloma

DARZALEX® in combination with Velcade® (bortezomib) + dexamethasone is indicated for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. See DARZALEX® SmPC for full indication, including its use as a monotherapy.1 * Recorded Response Rates DARZALEX® 20 mg/ml Concentrate for Solution for Infusion and 1,800 mg Solution for Injection PRESCRIBING INFORMATION. ACTIVE INGREDIENT(S): Daratumumab. Please refer to Summary of Product Characteristics (SmPC) before prescribing. INDICATION(S): Newly diagnosed multiple myeloma: in combination with lenalidomide/dexamethasone or bortezomib/melphalan/ prednisone in adults, ineligible for autologous stem cell transplant; in combination with bortezomib, thalidomide and dexamethasone in adults, eligible for autologous stem cell transplant. Relapsed/Refractory multiple myeloma: Monotherapy for adults whose prior therapy included a proteasome inhibitor and an immunomodulatory agent and who have demonstrated disease progression on last therapy. In combination with lenalidomide/dexamethasone or bortezomib/ dexamethasone in adults who have received ≥ one prior therapy. DOSAGE & ADMINISTRATION: Administration by healthcare professional where resuscitation facilities are available, intravenous (IV) infusion or subcutaneous (SC) injection. For SC injection, resuscitation facilities required only for first dose. Adults: Recommended IV dose: 16 mg/kg body weight. Dilute with sodium chloride 0.9% solution for injection and administer by IV infusion using incremental escalation of infusion rate, only if previous infusion well-tolerated. SC dose: inject 15 mL (1,800 mg) Darzalex solution for SC injection into the subcutaneous tissue of the abdomen approximately 7.5 cm to the right or left of the navel over approximately 3 5 minutes according to dosing schedule. Patients > 120 kg, flat-dose 1,800 mg SC, efficacy not established. SC injection: no dose adjustments based on body weight recommended. Darzalex solution for SC injection should never be injected into areas where the skin is red, bruised, tender, hard or areas where there are scars, rotate injection site. During treatment with Darzalex SC injection, do not administer other medicinal products for subcutaneous use at the same site as Darzalex. Check the vial labels to ensure that the appropriate formulation (IV or SC formulation) and dose is being given as prescribed. For dose and schedule of medicinal products administered with DARZALEX, refer to SmPC 4.2 and the corresponding SmPC for other products. Administer pre and post injection medicinal products to reduce the risk of infusion related reactions (IRRs). Recommended concomitant medications for management of infusion/injection-related reactions (IRRs): administer pre- IV infusion/ SC Injection medicinal products to all patients 1-3 hours prior to every infusion (corticosteroid, antipyretics and antihistamine). For SC injections, pre-medications can be given orally from the first dose. When dexamethasone is background regimen specific corticosteroid, this dose will serve as pre medication on infusion days. If dexamethasone given on infusion day, do not take additional background regimen specific corticosteroids (e.g. prednisone). Post- IV infusion/SC injection medicinal products should be administered to reduce the risk of delayed IRRs: administer oral corticosteroid. SC injections: if the patient experiences no major IRRs after the first three SC injections, post-injection corticosteroids (excluding any background regimen corticosteroids) may be discontinued. Consider short/long acting bronchodilators and inhaled corticosteroids in patients with history of chronic obstructive pulmonary disorder. IV Infusion: Any grade/severity IRRs, interrupt Darzalex immediately and manage symptoms. Re-starting Darzalex IV infusion: reduce infusion rate (refer to SmPC); Grade 4 IRRs (or third occurrence of Grade 3) – permanently discontinue. For haematological toxicity dose delay may be required to allow recovery of blood cell counts. No dose reductions of Darzalex recommended. Consider anti viral prophylaxis for prevention of herpes zoster virus reactivation. Children: No data available. Elderly/Renal impairment/Hepatic impairment: No dose adjustments. CONTRAINDICATIONS: Hypersensitivity to active substance or excipients. SPECIAL WARNINGS & PRECAUTIONS: IRRs: can cause serious IRRs including anaphylactic reactions. Majority occurred following first IV infusion/SC injection. IV infusion: monitor for IRRs throughout the IV infusion, continue monitoring post-IV infusion until symptoms resolve. For SC injection, median time to onset of IRRs was 3.7 hours following injection, monitor IRRs especially in the first and second SC injection. IV infusion: interrupt Darzalex for any severity IRRs. Institute medical management/supportive treatment as needed. For both IV and SC

Darzalex if an anaphylactic reaction or life threatening (Grade 4) IRR occurs, initiate appropriate emergency resuscitation immediately and discontinue Darzalex immediately and permanently. Neutropenia/Thrombocytopenia: Darzalex may increase neutropenia and thrombocytopenia induced by background therapy; monitor for infections & periodic complete blood cell counts (refer to relevant SmPCs); consider supportive care. Indirect Antiglobulin Test (Indirect Coombs Test): Daratumumab binds to CD38; may mask detection of antibodies to minor antigens; ABO and Rh blood typing not impacted. Interference may occur up to 6 months post-treatment. Type and screen patients prior to starting daratumumab; consider phenotyping; red blood cell genotyping not affected by daratumumab. Inform blood transfusion centres when appropriate. If emergency transfusion required, give non-cross-matched ABO/RhD-compatible RBCs. Hepatitis B virus (HBV) reactivation: Fatal cases reported in patients treated with Darzalex. Perform HBV screening before initiation of treatment. Suspend treatment in patients who develop reactivation of HBV while on Darzalex. Patient’s with body weight >120 kg receiving SC injection, potential for reduced efficacy. IV infusion contains sodium. SC injection contains sorbitol. SIDE EFFECTS: Very common: IRRs, pneumonia, bronchitis, upper respiratory tract infection, anaemia, neutropenia, thrombocytopenia, lymphopenia, leukopenia, decreased appetite, peripheral sensory neuropathy, paraesthesia, headache, hypertension, cough, dyspnoea, nausea, diarrhoea, constipation, vomiting, back pain, muscle spasms, fatigue, pyrexia, oedema peripheral, asthenia. SC only: insomnia, arthralgia. Common: urinary tract infection, influenza, sepsis, cytomegalovirus infection, hyperglycaemia, hypocalcaemia, dehydration, atrial fibrillation, pulmonary oedema, pancreatitis, chills. SC only: dizziness, musculoskeletal chest pain, rash, pruritus, injection site erythema/reactions. Other side effects: HBV reactivation (uncommon), anaphylactic reaction (rare). Refer to SmPC for other side effects. LEGAL CATEGORY: Prescription only medicine. PRESENTATIONS, PACK SIZES, MARKETING AUTHORISATION NUMBER(S): 5 ml vial (100mg daratumumab), X1, EU/1/16/1101/001; 20 ml vial (400mg daratumumab), X1, EU/1/16/1101/002; 15 ml vial (1,800 mg daratumumab), X1 EU/1/16/1101/004. MARKETING AUTHORISATION HOLDER: Janssen-Cilag International NV Turnhoutseweg 30, B-2340 Beerse, Belgium. FURTHER INFORMATION IS AVAILABLE FROM: Janssen Sciences Ireland UC, Barnahely, Ringaskiddy, IRL – Co. Cork P43 FA46. Prescribing information last revised: December 2020. Adverse events should be reported.  This medicinal product is subject to additional monitoring and it is therefore important to report any suspected adverse events related to this medicinal product. Healthcare professionals are asked to report any suspected adverse events via: HPRA Pharmacovigilance, Website: www.hpra.ie. Adverse events should also be reported to, Janssen Sciences Ireland UC on 1800 709 122 or at dsafety@its.jnj.com. References: 1. Darzalex® SmPC. Available at www.medicines.ie/medicines/darzalex-1-800-mg-solutionfor-injection-34971/patient-info. 2. Weisel K et al, Castor Four Year Update. Ash 2019, Poster 3192. Date of Preparation: May 2021 | CP-233416 | Janssen Sciences Ireland UC 2021

8 News

Vaccine Hesitancy Drops Covid-19 vaccine hesitancy has dropped by 36 points over the past 10 months, 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. Last October, when IPHA began tracking public appetite for Covid-19 vaccines, 12% of people said they would not get vaccinated for the disease. In the same month, 33% said they were unsure. By this month, the proportion of people who said they will not get vaccinated for Covid-19 had dropped to 5%. Just 4% are unsure.

In the 18 to 34-year-old cohort, 86% either intend to get vaccinated for Covid-19 or have already received a vaccine for the disease. Last October, 19% of people in that age cohort said they would refuse a Covid-19 vaccine against 7% this month. A further 32% of the 18 to 34-yearolds said they were unsure about Covid-19 vaccination last October compared with 8% this month.

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 5% of people will take a COVID-19 vaccine. But when combined with the cohort that has received at least one Covid-19 vaccine dose, or 86% of the sample*, that number rises to 91%.

In the 18 to 24-year-old cohort, 10% said they were unsure about getting a Covid-19 vaccine against 15% last month. In the same age cohort, 4% said they would refuse to get vaccinated for the disease – the same proportion as last month.

The industry urged continued uptake of Covid-19 vaccines across the eligible population. 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 rid the world of smallpox, driven polio to the brink of eradication, and virtually eliminated measles, diphtheria and rubella in many parts of the world.

New Appointment at Mater Private Network Mater Private Network has strengthened its multi-disciplinary team of consultants and specialists with the appointment of Dr Daniel Cagney as Clinical Director of Radiation Oncology. Joining from Dana-Farber Brigham and Women’s Cancer Center in Boston, USA, Dr Daniel Cagney has returned home to Ireland to take up the role at Mater Private Network having held several strategic positions at the world-leading cancer treatment and research facility over the past 6 years. These roles included Consultant Radiation Oncologist, Director of Stereotactic Radiation and Director of MRI Guided Radiation Program. Sharing his insights and expertise across treatment centres in Dublin and Limerick, Dr Cagney will spearhead the further development of radiation oncology services at Mater Private Network. With a specialist interest in the field of stereotactic radiation, Dr Daniel Cagney previously identified an unreported pattern of intracranial failure in neuro-oncology and initiated the first trial of its kind to assess the safety and efficacy of combination stereotactic radiation and nanoparticles for patients with centrally located NSCLC and pancreatic cancer. Commenting on his appointment Dr Cagney said, “I am incredibly excited to work with the whole team in Mater Private Network. Our multidisciplinary group of doctors, nurses, therapists, physicists, and support staff deliver holistic, personalised care daily. I am humbled to join this group and will strive to continue to innovate and deliver patient-centric care.”

Progress Despite Challenge Tallaght University Hospital, with its mission of People Caring for People to Live Better Lives, has published its 2020 Annual Report. The report outlines what was achieved by the staff, management and board of the Hospital in a year of significant and unprecedented pressure on the Hospital. Despite the challenges the Hospital maintained and delivered on the Hospital’s strategy with

tremendous progress made on implementation across six priority strategy areas. With a clear focus on future development the Hospital has announced plans to recruit an additional 300 staff including Nursing, Medical, Health & Social Care Professionals and Administrative staff. The plan is to recruit the additional staff over the next 12-18 months to support expansion and enhancement of services across the Hospital.

OCTOBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

Commenting on the publication of the report and jobs announcement Chief Executive Lucy Nugent said: “Despite COVID-19 there was incredible progress made during the year with the completion of several capital projects. The challenges that COVID presented also meant we accelerated our digital enabled care programme with technology used to aid communication, diagnosis and treatment. I could not be more

proud of my colleagues across the TUH Campus ensuring services were adapted, maintained and restarted as soon as it was safe to do so. 2021 has already presented a new set of challenges but I am confident that the indomitable TUH team spirit will continue to shine through and I look forward to welcoming new members to the team as we continue to grow and expand our services.”

News

Hospital Doctors Looking Ahead to ‘Winter of Gloom’ The Health Information and Quality Authority (HIQA) has published an overview report of the monitoring and regulation of healthcare services in 2020. According to the organisation, while the Irish hospital system adapted swiftly to cope with the Covid-19 pandemic, recurring underlying issues of concern relating to non-compliance with national standards were evident. These issues included poor physical infrastructure, capacity issues and workforce challenges, which often hindered these very significant efforts. Throughout 2020, HIQA focused its healthcare monitoring resources on known areas of risk, with a particular focus on the management of Covid-19 across public acute hospitals, and rehabilitation and community inpatient services. These areas included infection prevention and control, governance and risk management, and medication safety. HIQA also continued to advance its newer role in regulating medical exposure to ionising radiation. Extreme Pressure While HIQA has seen progress and improvement in achieving compliance with standards across various areas monitored, the many challenges since the onset of Covid-19 in early 2020 has put extreme pressure on every service. HIQA has noticed that despite an increase in both temporary and longer term investment in services in response to the pandemic, some healthcare services continue to be proportionately less resourced than others. In many hospitals, ongoing

challenges posed by poor physical infrastructure and constrained service capacity continued to be identified by HIQA. These issues have been worsened by the Covid-19 pandemic. HIQA’s Director of Regulation, Mary Dunnion said, “The Covid-19 pandemic required HIQA to change our inspection plans in 2020 to focus on the challenges posed by the pandemic. In most instances, we found an effective approach to adapt to this unprecedented crisis in hospitals. However, hospitals’ efforts were made more difficult due to underlying historic problems with infrastructure, limited bed capacity and unequal or limited access to specialist workforce input and advice - problems that HIQA’s prior monitoring work against national standards has consistently highlighted.” HIQA’s Head of Healthcare, Sean Egan said, “The pandemic has further reiterated that a high performing, fit for purpose healthcare service that is compliant with national standards is required to meet Ireland’s needs now and into the future. HIQA remains committed to supporting continual and sustainable improvement across the healthcare services that we have a remit for monitoring or regulating. We intend to enhance our approach to future monitoring against national standards, to further support recovery and reform of services as we emerge from the pandemic. “In doing so, HIQA will continue to work closely and openly with all stakeholders and interested parties to advance the quality and safety of care for people who use healthcare services in Ireland.”

Dr Ina Kelly, Irish Medical Organisation

Confirmed View The report confirms the longstanding view of the Irish Medical Organisation that the health services in Ireland are operating at dangerous levels of capacity and there is a crisis in medical manpower. Dr Ina Kelly, President of the IMO warned that Doctors are now looking ahead to the Winter with a sense of despair and foreboding. The problems identified by HIQA are not a result of the pandemic – these problems beset our services long before Covid which has only served to expose the system deficits which have led to ever increasing waiting lists, inadequate access to timely care, increasing pressures on doctors seeking to provide care in General Practice, in the community and in our acute settings. The health service will continue to fail to meet the realistic expectations and demands of the Irish public unless significant and long-term action is taken to address: • Government policy which has left the health services understaffed and which has increased the length of waiting lists for patients – we urgently need 2,000 medical specialists across our acute hospital and psychiatry services. We also need up to 1,660 additional GPs along with a sustainable career pathway for General Practice.

HIQA’s Director of Regulation, Mary Dunnion

• The shortage of hospital beds we urgently need a further 5,000 beds. adhering to the minimum requirements of the Health Capacity Review are clearly insufficient.

• The lack of support in General Practice as there are too few GPs to meet patient demand which is growing exponentially particularly as patients cannot access hospital care in a timely manner. Dr Kelly said that the HIQA report (Healthcare Overview Report 2020) would be a damning indictment in normal times; “the report details the long-term damage caused by under investment and poor policy decisions. Tragically these problems have been ongoing for so long that public has learnt to accept the unacceptable when it comes to waiting lists and access to timely care. This is not something we can or should accept and as Government now considers measures for the budget, we need to see a significant ramping up of sustainable investment in our services that will deliver timely patient care in a system that is well resourced and properly staffed.” “People must understand that this level of structural failure in the health services is neither necessary nor acceptable and must be addressed. Doctors around the country are naturally very concerned about the level of demand for care and what the winter will bring. We cannot continue to treat and react to healthcare spending in a crisis mode and must make significant, sustainable investment now and for the years ahead. We have seen how dependent our nation is on a properly functioning health service – if we do not address this now when will we?”

HOSPITALPROFESSIONALNEWS.IE | HPN • OCTOBER - 2021

10 Report

FMD Use and Learn Due for Closure What does this mean for Hospital Pharmacists? The Safety Features Oversight Group1 continues to oversee progress with FMD implementation in Ireland. FMD has been in a ‘use and learn’ phase for pharmacies, hospitals and wholesalers in this country since February 2019 due, in part, to the impact of Covid-19 and Brexit. When will use and learn end in Ireland? The Safety Features Oversight Group, following consultation with all relevant stakeholders, has now agreed a plan for ending use and learn on a phased basis concluding at the end of Q1 2022 (see table 1 for details). What prerequisites must be met to end use and learn? The following prerequisites have been defined by the Safety Features Oversight Group to ensure that end-users and marketing authorisation holders (MAHs) are ready for the end of use and learn, minimising disruption for them and for patients: • Alert rate at 0.05% or lower, i.e., alerts generated by pharmacies, hospitals and wholesalers (‘end-users’), as a % of the total number of end-user scans2;

• All end-users scanning packs in accordance with their obligations under the Commission Delegated Regulation on Safety Features (EU) 2016/161 as amended; • Avoidable alerts minimised by addressing issues with scanners, software, MAH data and procedural errors; • Clear instructions available for all parties on what to do if there is an alert, including clear responsibilities for deciding if packs may be supplied or not, i.e., alert handling guidance in place; • Fast efficient process for communication between parties; • Clarity on impact of Brexit on supply chain/alerts; • Capacity of end-users to deal with alerts in face of challenges of Covid-19; • European Medicines Verification System has the capacity to cope with Covid-19 vaccines and treatments. Efforts are continuing on several fronts to achieve each of these prerequisites and IMVO is working closely with all relevant stakeholders to support them. The

Safety Features Oversight Group will monitor progress against each prerequisite on a regular basis to ensure that everything is in place to move to the next phase of the plan, including targeted communications with each group on details of what is involved for them. What is the advice for pharmacies, hospitals, wholesalers and MAHs while we are still in use and learn? 1. Pharmacies, hospitals and wholesalers are expected to comply with their obligations under the Commission Delegated Regulation (EU) 2016/161 to scan packs and verify safety features during use and learn. o If an alert or any other unexpected message is flagged when a pack is scanned, the pack should still be supplied to the patient in line with your existing procedures, unless you have overriding concerns that a falsified medicine is involved. o If you have grounds for believing that a pack has been interfered with or could be falsified, please report this to the HPRA, by email to qualitydefects@hpra.ie or using

the HPRA’s online reporting system https://www.hpra.ie/ homepage/about-us/reportan-issue (select the online form ‘Medicine Quality Issue / Defect’). 2. If you have any queries about your FMD obligations, please contact the PSI (Retail Pharmacy Businesses), HSE FMD project team (public hospitals), HPRA (wholesalers, MAHs, manufacturers, parallel importers, parallel distributors) or IMVO. 3. Parallel importers and parallel distributors should continue to comply with the guidance issued to them by the HPRA on 7th February 2020. 4. MAHs should continue to investigate the alerts they receive and ensure that any necessary preventative actions related to alerts that result from data upload or other issues pertaining to the MAH’s activities are put in place in a timely manner. As previously advised, MAHs are not required to carry out a documented investigation of A7/ A24 alerts (pack already decommissioned) and A68 alerts (batch ID mismatch) except in the following circumstances: o Where they know they have caused the alert(s) themselves due to, for example, repeating decommissioning transactions when the packs are under their control; or o Where an end-user (pharmacy, hospital or wholesaler) contacts them about such an alert; or o Where the HPRA or IMVO contacts them about such an alert. 5. Please contact IMVO if you have any other queries or need support on any matter. Queries specifically related to FMD software should be sent to your FMD software provider. [1] Comprising Irish Medicines Verification Organisation (IMVO), Department of Health, Health Products Regulatory Authority (HPRA), Pharmaceutical Society of Ireland (PSI), Health Service Executive (HSE) and Private Hospitals Association (PHA). [2] The following are excluded when calculating the % alert rate as they have no impact on Irish end-users – alerts generated by MAH transactions and alerts from intermarket transactions (IMTs), i.e. alerts on Irish packs generated by end-users in other markets.

OCTOBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

▼

500,000 PATIENTS TREATED. 5 YEARS OF EVIDENCE. 4

THIS IS

PREVENTION ABBREVIATED PRESCRIBING INFORMATION ▼ Aimovig® (erenumab) 70 mg and 140 mg solution for injection in pre-filled pen Important note: Before prescribing, consult full prescribing information. Presentation: Aimovig 70 mg solution for injection in pre-filled pen. Each pre-filled pen contains 70 mg erenumab. Aimovig 140 mg solution for injection in pre-filled pen. Each pre-filled pen contains 140 mg erenumab. Indications: Aimovig is indicated for prophylaxis of migraine in adults who have at least 4 migraine days per month. Dosage and administration: Adults: The recommended dose of Aimovig is 70 mg administered subcutaneously every 4 weeks. Some patients may benefit from a dosage of 140 mg once every 4 weeks. Each 140 mg dose is given either as one subcutaneous injection of 140 mg or as two subcutaneous injections of 70 mg. Aimovig is intended for patient self-administration in the abdomen, thigh, or, if someone else is giving the injection, also into the outer area of the upper arm. Administration should be performed by an individual who has been trained to administer the product. The needle cover of Aimovig prefilled pen contains dry natural rubber, which may cause allergic reactions in individuals sensitive to latex. Special populations: Paediatric patients: The safety and effectiveness of Aimovig has not been studied in paediatric patients. Elderly (aged 65 years and over): The safety and effectiveness of Aimovig has not been studied in elderly patients. No dose adjustment is necessary as the pharmacokinetics of erenumab are not affected by age. Renal impairment: No dose adjustment is necessary in patients with mild to moderate renal impairment. Hepatic impairment: No studies have been performed in patients with hepatic impairment. Hepatic clearance is not a major clearance pathway for erenumab. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Warnings and precautions: Hypersensitivity reactions: Serious hypersensitivity reactions, including rash, angioedema, and anaphylactic reactions, have been reported with erenumab in post-marketing experience. These reactions may occur within minutes, although some may occur more than one week after treatment. In that context, patients should be warned about the symptoms associated with hypersensitivity reactions. If a serious or severe hypersensitivity reaction occurs, initiate appropriate therapy and do not continue treatment with erenumab. Constipation: Constipation is a common undesirable effect of Aimovig and is usually mild or moderate in intensity. In a majority of the cases, the onset was reported after the first dose of Aimovig; however patients have also experienced constipation later on in the treatment. In most cases constipation resolved within three months. In the post marketing setting, constipation with serious complications has been reported with erenumab. In some of these cases hospitalisation was required, including cases where surgery was necessary. History of constipation or the concurrent use of medicinal products associated with decreased gastrointestinal motility may increase the risk for more severe constipation and the potential for constipation related

1,2

complications. Patients should be warned about the risk of constipation and advised to seek medical attention in case constipation does not resolve or worsens. Patients should seek medical attention immediately if they develop severe constipation. Constipation should be managed promptly as clinically appropriate. For severe constipation, discontinuation of treatment should be considered. 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. Latex sensitive individuals: The removable cap of the Aimovig pre-filled pen contains dry natural rubber latex, which may cause Allergic reactions in individuals sensitive to latex Pregnancy, lactation, fertility: Pregnancy: There are a limited amount of data from the use of erenumab in pregnant women. As a precautionary measure it is preferable to avoid the use of Aimovig during pregnancy. Lactation: It is not known whether erenumab is present in human milk. The use of Aimovig could be considered during breastfeeding only if clinically needed. Fertility: There is no data available on the impact of Aimovig on male and female fertility. Animal studies showed no impact on female and male fertility. Adverse drug reactions: Common (≥1/100 to <1/10): Hypersensitivity reactions including anaphylaxis, angioedema, rash, swelling/ oedema and urticaria. Injection site reactions, constipation, muscle spasm, pruritus. Interactions: No effect on exposure of co-administered medicinal products is expected based on the metabolic pathway of monoclonal antibodies. No interactions with oral contraceptives (ethinyl estradiol and norgestimate) or sumatriptan were observed in studies with healthy volunteers. Legal Category: POM. Marketing Authorisation Holder: Novartis Europharm Ltd, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland. Marketing Authorisation Numbers: EU/1/18/1293/001 006. Date of last revision of Abbreviated Prescribing Information: September 2020. Full prescribing information is available upon request from: Novartis Ireland Limited, Vista Building, Elm Park Business Campus, Merrion Road, Dublin 4, Ireland, Tel: + 353 1 220 4100 or at www.medicines.ie. Detailed information on this product is also available on the website of the European Medicines Agency http://www.ema.europa.eu. ▼ This medicinal product is subject to additional monitoring. Reporting suspected adverse reactions of the medicinal product is important to Novartis and the HPRA. It allows continued monitoring of the benefit/risk profile of the medicinal product. All suspected adverse reactions should be reported via HPRA Pharmacovigilance, website: www.hpra.ie. Adverse events could also be reported to Novartis preferably via www.report.novartis.com or by email: drugsafety.dublin@novartis.com or by calling 01 2080 612.

References: 1. Aimovig SmPC available at medicines.ie 2. Tepper S, et al. Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebocontrolled phase 2 trial. Lancet Neurol 2017; 16: 425-434. 3. Ashina M, et al. Eur J Neurol. 2021 in Press Long-term efficacy and safety of erenumab in migraine prevention: Results from a 5-year, open-label treatment phase of a randomized clinical trial - PubMed (nih.gov). 4. Novartis data on file, February 2021. *Image used is not an actual Aimovig® patient IE148433 | August 2021

12 News

Ireland’s Health ‘Disconnect’ Dr Nina Byrnes and Mary Maguire, Personalised Healthcare Lead, Roche Products (Ireland) Ltd. at the launch of the FutureProofing Personalised Health Index

in Ireland. By focusing on creating wider understanding of the power of civic participation we can improve on our willingness to share data for research and improved care. Roche is committed to collaborating with patients, stakeholders and experts from multidiscipline areas on a unified approach to address the data infrastructure challenges and improve access to life-changing research, clinical trials and medical advancements, to deliver truly personalised care.” The FutureProofing Personalised Health Index report outlines the following recommendations for Ireland to address the deficiencies highlighted by the Index and improve its approach to personalised healthcare:

“Other countries were found to be far ahead in terms of sharing medical data seamlessly across their health systems and embedding this data in research to further benefit patients and citizens overall. This is something we in Ireland need to prioritise” Ireland lags significantly behind on the delivery of personalised healthcare and was found to display a sharp disconnect between policy and implementation of this form of care. That’s according to the FutureProofing Personalised Health Index which ranked Ireland as 19th out of 34 other countries.1 The Irish public’s willingness to share data for medical research and care improvements was found to be low with a score of 4 out of 10.3 A panel of Irish healthcare and policy experts was brought together by Roche Ireland to interrogate the Index findings and develop a report with their recommendations for improving Ireland’s approach to personalised healthcare. The experts ultimately found that the deficiencies are due to a lack of infrastructure and delays in implementing data sharing policies, meaning Ireland is losing out on opportunities in research, clinical trials and advancements in genomic testing – to the detriment of patients and the Irish healthcare system. Ireland ranked 22nd out of 34 countries for ‘Health Services’ which includes the planning, organisation

and delivery of services that will drive personalised healthcare.2 Commenting on the launch of the report, panel member Dr Nina Byrnes, GP, Medical Director Generation Health Medical Clinics, Media Medical Expert said, “The Index revealed significant scope for improvement in Ireland before fully integrated implementation of personalised healthcare can be achieved here. Other countries were found to be far ahead in terms of sharing medical data seamlessly across their health systems and embedding this data in research to further benefit patients and citizens overall. This is something we in Ireland need to prioritise. For example, telemedicine has advanced significantly here but for it to reach its full capability we need to utilise technology to capture medical data and share via unique patient identifiers, making it accessible to healthcare professionals and the research community across our health system.” Personalised healthcare means delivering care tailored to the specific individual, putting the patient firmly at the centre, and moving away from a ‘one-size-fits-

OCTOBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

all’ approach to care. It promises efficiencies for the patient but also the healthcare system, as resources including diagnostics, data and analytics are used in a more effective manner.

1. The roll out of the national electronic health record (EHR) system is pivotal; it will enable an efficient healthcare delivery system and pave the way for digital health

The Personalised Health Index analysed the health systems of 34 international countries to evaluate how healthcare is progressing towards a more personalised, digital and data-driven standard. Led by an independent panel of global experts in partnership with Roche, the Index measured a country’s performance based on four equally weighted ‘Vital Signs’: Policy Context; Health Information; Personalised Technologies; and Health Services.

2. Significant investment will be required, however Sláintecare, the cross-party plan for the future of healthcare, is the most suitable form of delivery of personalised care and could provide necessary funding for the upgrading of data and IT systems

The experts found that while Ireland ranked below average across most of the Index measures, there were areas where advancements and improvements have been made since the Index data was collated, most recently due to the Covid-19 pandemic. Specifically, the use of telemedicine has grown exponentially out of necessity since the beginning of the public health crisis, while the introduction of electronic prescriptions has proven hugely beneficial and efficient for medical practitioners, pharmacists and patients alike. Additionally, the panelists agreed that the pandemic may have made the wider public more aware of the merits of clinical research and thus more willing to share their health data. Mary Maguire, Personalised Healthcare Lead, Roche Products (Ireland) Ltd said, “The Index serves to highlight the shortcomings that will need to be addressed if personalised healthcare is to become a reality

3. The development of an Interdepartmental strategy, aligning academia, medical schools, clinical research and primary/secondary/tertiary care towards the common goal of enabling personalised healthcare could overcome bureaucracy and put the patient first 4. A formalised national policy for genomic testing, as well as an appropriately funded genome resource. This will maximise the benefits of pre-existing and forthcoming targeted therapies and enable the use of data in ground-breaking clinical research 5. A coherent and extensive public awareness campaign to educate the broader public on the value of sharing data for the betterment of medical care and clinical research. To learn more and read the expert’s analysis and further insights into the Personalised Health Index results for Ireland visit www.futureproofinghealthcare. com/en/personalised-healthindex-ireland. References on request

When it comes to your patients’ psoriasis treatment goals

What means everything to the patient? The potential for nothing left on their skin.* High skin clearance matters to patients: Patients who achieve and maintain high levels of skin clearance (PASI 9099 or PASI 100) have significantly better HRQoL than those with lower levels of skin clearance (PASI 75-89). 2

* Nothing on the skin: Defined as 75% achievement of PASI90 at Week 16 and ≥50% achievement of PASI 100 at Week 52 in UltIMMa-1 and UltIMMa-2.1

Sustaining high skin clearance or complete skin clearance is associated with incremental and durable benefits in HRQoL and mental health of psoriasis patients. 2

PRESCRIBING INFORMATION (PI) SKYRIZI®▼ (risankizumab) 75 mg solution for injection in pre-filled syringe. Refer to Summary of Product Characteristics (SmPC) for full information before prescribing. PRESENTATION: Each pre-filled syringe contains 75 mg risankizumab in 0.83 ml solution. INDICATION: For treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy. DOSAGE AND ADMINISTRATION: Intended for use under guidance and supervision of a physician experienced in diagnosis and treatment of psoriasis. Dosage: The recommended dose of Skyrizi is 150 mg (two 75 mg injections) by subcutaneous injection at weeks 0, 4, and every 12 weeks thereafter. Consider discontinuation of treatment in patients showing no response after 16 weeks of treatment. Some patients with initial partial response may subsequently improve with continued treatment beyond 16 weeks. Special Populations: Elderly: No dose adjustment required. Renal or hepatic impairment: No dose adjustment required. Paediatric Population: No data available. Overweight patients: No dose adjustment required. CONTRAINDICATIONS: Hypersensitivity to any of the active substances or excipients. Clinically important active infections (e.g. active tuberculosis). SPECIAL WARNINGS AND PRECAUTIONS: See SmPC for full details. In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Skyrizi may increase the risk of infections. In patients with a chronic infection or history of recurrent infections, or known risk factors for infection, Skyrizi should be used with caution. Treatment with Skyrizi should not be initiated in patients with any clinically important active infection until the infection resolves or is adequately treated. Patients should be evaluated for tuberculosis infection prior to initiating treatment. Anti-TB therapy should be considered prior to initiating Skyrizi in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Completion of all appropriate immunisations should be considered prior to initiating therapy. If a patient has received live vaccination (viral or bacterial), it is recommended to wait at least 4 weeks prior to starting treatment with Skyrizi. Patients treated with Skyrizi should not receive live vaccines during treatment and for at least 21 weeks after treatment. If a serious hypersensivity reaction occurs, administration of Skyrizi should be discontinued immediately and appropriate therapy initiated. Skyrizi contains 68.0 mg sorbitol and less than 1 mmol sodium (23 mg) per 150 mg dose. INTERACTIONS: The safety and efficacy of Skyrizi in combination with immunosuppressants, including biologics or phototherapy have not been evaluated. PREGNANCY AND LACTATION: Women of Childbearing potential: An effective method of contraception during treatment

and for at least 21 weeks after treatment should be used. Pregnancy: Limited data available. It is preferable to avoid the use of Skyrizi during pregnancy as a precautionary measure. Lactation: It is not known whether Skyrizi is excreted in breast milk. Human IgGs are known to be excreted in breast milk during the first few days after birth, which decreases to low concentrations soon afterwards; consequently, a risk to the breast-fed infant cannot be excluded during this short period. A decision should be made whether to discontinue/abstain from Skyrizi therapy, taking into account the benefit of breast-feeding to the child and the benefit of Skyrizi therapy to the woman. Fertility: The effect of Skyrizi on human fertility has not been evaluated. ADVERSE REACTIONS: See SmPC for full details on adverse reactions. Very common adverse reactions (≥1/10): Upper respiratory infections. Common adverse reactions (≥1/100 to <1/10): Tinea infections, headache, pruritus, fatigue and injection site reactions. ▼ 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 CLASSIFICATION: POM (S1A). MARKETING AUTHORISATION NUMBERS/PRESENTATIONS: EU/1/19/1361/001: Skyrizi 75 mg solution for injection in pre-filled syringe (Pack of 2 pre-filled syringes). Further information is available from: AbbVie Ltd., 14 Riverwalk, Citywest Business Campus, Dublin 24. DATE OF REVISION: March 2020. PI/1361/002 HRQoL, Health-Related Quality of Life; PASI, Psoriasis Area Severity Index. REFERENCES: 1. Gordon KB, et al. Lancet 2018; 392: 650-661. 2. Ryan C et al. Poster presented at the 27th European Academy of Dermatology & Venerology (EADV) Congress 2018; September 12–16; Paris, France. Skyrizi® Summary of Product Characteristics, available on www.medicines.ie. Date of preparation: September 2020 | IE-RISN-190074

14 News ¤300,000 in Professor Kieran Taaffe Research Bursaries Dr Sulaiman has recently been appointed as a consultant physician to Beaumont hospital, having worked for many years in New York University, NYC, the United States. He has an international reputation in the area of profiling the microbiome of the upper and lower airways, in addition to acknowledged expertise in the diagnosis and management of obstructive sleep apnea.

The Charitable Infirmary Charitable Trust (CICT), Ireland’s oldest charity, has awarded two medical research bursaries to teams at Beaumont Hospital to fund scientific and medical research and simultaneously support education and development through pursuit of MD or PhD qualifications. Each award is for two years and has an annual value of up to ¤75,000. Following an open competition, the Medical Group of CICT awarded the bursaries to: Dr Christina Campbell, Respiratory Department,

Beaumont Hospital and Dr Olufemi Olumide Aoko, Hepatology Unit, Beaumont Hospital. Dr Campbell is a specialist trainee in Pulmonary Medicine in Beaumont hospital. She will evaluate susceptibility to obstructive sleep apnea in a post SARS-CoV-2 infection population. She hopes to establish the relationship between this condition and the upper airway microenvironment utilizing state-of-the-art next-generation sequencing. She will be working directly under the supervision of the chief investigator for this study, Dr Imran Sulaiman.

Dr Aoko is a specialist trainee in Hepatology. He will study the impact of bariatric endoscopy on non-alcoholic fatty liver disease (NAFLD). This is a novel clinical approach to treating the most common cause of liver disease in Ireland and internationally. He will specifically evaluate the impact of this novel technique on metabolic and histologic parameters in obese patients with NAFLD. He will be working directly under the supervision of the Chief investigator for this study, Dr John Ryan, Consultant Hepatologist, Beaumont Hospital. Dr Ryan has recently been appointed as a consultant physician to Beaumont Hospital, having worked for many years in the Royal Free hospital London and Oxford University, United Kingdom. He has an international reputation in the area of non-alcoholic fatty liver disease (NAFLD) and has pioneered new diagnostic and therapeutic interventions in this area. Commenting on the awards, Michael Patten, Chairman of the CICT said, “The CICT goes back

to the foundation in 1718 of the Charitable Infirmary (better known as Jervis St Hospital), the first voluntary hospital in the British Isles. Today the Trust continues its focus on serving Dublin by supporting medical excellence at Beaumont Hospital and giving financial aid to Dublin charities serving the poor and underprivileged. “These new bursaries are designed to promote talent development and scientific/ medical research and discovery at Beaumont and are open to all the caring professions based on the hospital campus. We were delighted with the sheer quality of applications for these inaugural bursaries which bodes well for medical discovery at Beaumont. We wish the recipients well in the coming years and will track their progress with great interest”, Mr Patten concluded. The Bursaries are named in honour of Professor Kieran Taaffe, a long serving and inspirational member of the CICT Managing Committee, who was a passionate advocate of education and research. Staff at Beaumont Hospital are welcome to apply to become members of the Trust at any time. Since 1987, the Trust has donated over ¤5 million to research and teaching projects at Beaumont Hospital and at its medical school, the Royal College of Surgeons of Ireland (RCSI) and to Dublin charities.

New findings from OCTAVE trial The ongoing OCTAVE study has published its first results on vaccine effectiveness in people with impaired immune systems. The study found that a significant proportion of people with immunosuppression have a low or undetectable antibody response after two doses of the covid vaccine. The study is important because it is one of the largest studies in the world so far into covid vaccine efficacy in immunosuppressed patients. It looked at both antibody response and T cell response to the covid vaccine. The OCTAVE trial includes over 2,500 people from across the UK,

recruited between February and August 2021, with conditions that affect the immune system (or have treatments that do). Conditions include arthritis, inflammatory bowel disease, end stage kidney disease, solid tumour cancers, blood cancer, and people who’ve had a stem cell transplant. This includes 139 cancer patients (solid tumour patients and blood cancer patients) and 160 people who’ve had a stem cell transplant. The blood cancer patients had acute myeloid leukaemia or myeloma. The results released today are only based on 455 people from the trial, for whom all the necessary blood test results are available.

OCTOBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

This includes 18 blood cancer patients (acute myeloid leukaemia or myeloma) and 42 people who’ve had a stem cell transplant. Everyone’s antibody response to the covid vaccine was measured 4 weeks after their second vaccine dose. Where possible, people’s antibody response was also measured in between their first and second dose, and before their first dose. Most people had either the Pfizer or AstraZeneca jab. These results were compared against 93 healthy individuals. Read about the findings here: These are only the first set of results to come out of OCTAVE. The study is ongoing and will

publish more data in the future. We are cautious about drawing conclusions from this very small sample, but the results do confirm that even when blood cancer and stem cell transplant patients do produce antibodies after vaccination, the quantity of antibodies is lower. It’s positive to see a good T cell response, although we don’t know what this means alongside a poorer antibody response. This study reinforces the need to find alternative methods to protect people with blood cancer from covid, through extra vaccinations or alternative preventative methods such as antibody treatments.

Launching Launching

Flucloxacillin Powder Powder for solution for injection/infusion injection/infusion

Launching 500mg 500mg

1000mg 1000mg

2000mg 2000mg

Flucloxacillin Powder for solution for injection/infusion 500mg

1000mg

2000mg

PRESCRIBING INFORMATION: Consult the in in patients receiving beta-lactam antibiotics, PRESCRIBING the Summary Summary of of Product ProductCharacteristics Characteristicsfor forfurther furtherinformation. information.Additional Additional occasionally occasionallyfatal fatalhypersensitivity hypersensitivityreactions reactionshave havebeen beenreported reported patients receiving beta-lactam antibiotics, information is available upon request. Flucloxacillin to to oral therapy. Reactions more likely to occur in patients information Flucloxacillin 500mg, 500mg, 1000mg 1000mg and and 2000mg 2000mgpowder powderfor forsolution solutionfor for occurrence occurrencemore morefrequent frequentwith withparenteral parenteralcompared compared oral therapy. Reactions more likely to occur in patients injection/infusion. Active ingredients: occurs discontinue flucloxacillin andand institute injection/infusion. ingredients: As As flucloxacillin flucloxacillin sodium, sodium, each each 10mL 10mL vial vial contains contains500mg 500mgflucloxacillin flucloxacillin with withhistory historyofofbeta-lactam beta-lactamhypersensitivity. hypersensitivity.If Ifallergic allergicreaction reaction occurs discontinue flucloxacillin institute (25.5mg sodium approximately), 20mL vial erythema associated with pustula occurring at treatment initiation maymay (25.5mg vial contains contains 1000mg 1000mgflucloxacillin flucloxacillin(51mg (51mgsodium sodiumapproximately), approximately),50mL 50mLvial vial appropriate appropriatetherapy. therapy.Feverish Feverishgeneralized generalized erythema associated with pustula occurring at treatment initiation contains 2000mg flucloxacillin (102mg sodium approximately). Indications: For the treatment of the following be a symptom of acute generalised exanthematous pustulosis (AGEP); in case of AGEP diagnosis discontinue contains sodium approximately). Indications: For the treatment of the following be a symptom of acute generalised exanthematous pustulosis (AGEP); in case of AGEP diagnosis discontinue infections due to beta-lactamase producing staphylococci and other sensitive Gram-positive organisms such as flucloxacillin and subsequent administration is contraindicated. Use with caution in patients with evidence of of infections due to beta-lactamase producing staphylococci and other sensitive Gram-positive organisms such as flucloxacillin and subsequent administration is contraindicated. Use with caution in patients with evidence streptococci –– skin skin and and soft ofof age and those with serious underlying disease; hepatic events maymay be be streptococci soft tissue tissue infections infections (like (likeabscesses, abscesses,cellulitis, cellulitis,infected infectedburns, burns,impetigo), impetigo),upper upperrespiratory respiratory hepatic hepaticdysfunction, dysfunction,patients patients≥50 ≥50years years age and those with serious underlying disease; hepatic events tract infections infections (like (like pharyngitis, deaths have been reported. Flucloxacillin solutions reconstituted withwith tract pharyngitis, tonsillitis, tonsillitis, sinusitis), sinusitis), lower lower respiratory respiratory tract tract infections infections (like (like pneumonia, pneumonia, severe severeand andininextremely extremelyrare rarecircumstances circumstances deaths have been reported. Flucloxacillin solutions reconstituted bronchopneumonia, pulmonary pulmonary abscess), iv iv administration. Adjust dose in renal impairment. Special bronchopneumonia, abscess), bone bone and and joint jointinfections infections(like (likeosteomyelitis osteomyelitisand andarthritis), arthritis),endocarditis. endocarditis. local localanesthetics anesthetics(lidocaine) (lidocaine)should shouldnotnotbebegiven givenbyby administration. Adjust dose in renal impairment. Special Prophylaxis in cardiovascular surgery (valve prostheses, artery prostheses) and orthopedic surgery (arthroplasty, caution essential in newborns due to risk of hyperbilirubinaemia and potential for high serum levels of of Prophylaxis in cardiovascular surgery (valve prostheses, artery prostheses) and orthopedic surgery (arthroplasty, caution essential in newborns due to risk of hyperbilirubinaemia and potential for high serum levels osteosynthesis and arthrotomy). Consideration should be given to official guidance on appropriate use of flucloxacillin due to reduced rate of renal excretion. Regular monitoring of blood count, hepatic and renal function osteosynthesis and arthrotomy). Consideration should be given to official guidance on appropriate use of flucloxacillin due to reduced rate of renal excretion. Regular monitoring of blood count, hepatic and renal function antibacterial agents. agents. Posology colitis cancan occur; if this develops discontinue antibacterial Posology and and method method of of administration: administration: Parenteral Parenteral therapy therapy isis indicated indicatedififoral oralroute route recommended recommendedduring duringprolonged prolongedtreatment. treatment.Pseudomembranous Pseudomembranous colitis occur; if this develops discontinue impracticable or or unsuitable unsuitable as result in in overgrowth of of nonimpracticable as in in the the case case of of severe severe diarrhoea diarrhoeaor orvomiting vomitingand andparticularly particularlyfor forurgent urgenttreatment treatment flucloxacillin flucloxacillinand andinitiate initiateappropriate appropriatetherapy. therapy.Prolonged Prolongeduseusemay mayoccasionally occasionally result overgrowth nonof severe severe infection. infection. Routes Routes of concomitantly with paracetamol duedue to increased riskrisk of high of of administration: administration: 500mg 500mg vial vial -- Intramuscular Intramuscular(im), (im),intravenous intravenous(iv), (iv),intrapleural intrapleuraland and susceptible susceptibleorganisms. organisms.Caution Cautionwhen whenadministered administered concomitantly with paracetamol to increased of high intraarticular. 1000mg vial and 2000mg vial – intramuscular and intravenous routes only. Intravenous injection/ anion gap metabolic acidosis (HAGMA). High risk of HAGMA particularly in patients with severe renal impairment, intraarticular. 1000mg vial and 2000mg vial – intramuscular and intravenous routes only. Intravenous injection/ anion gap metabolic acidosis (HAGMA). High risk of HAGMA particularly in patients with severe renal impairment, infusion should should be be administered administered slowly. daily doses of of paracetamol used. Following co-administration close infusion slowly. Dosage Dosage depends dependson onage, age,weight weightand andrenal renalfunction functionasaswell wellasasthe theseverity severity sepsis sepsisorormalnutrition malnutritionespecially especiallyif ifmaximum maximum daily doses paracetamol used. Following co-administration close and nature nature of of the the infection. infection. Adults testing forfor urinary 5-oxoproline). If If and Adults and and adolescents adolescents≥≥1212years years––Total Totaldaily dailydosage dosageofof1g1gtoto4g, 4g,administered administeredininthree three monitoring monitoringrecommended recommendedtotodetect detectthetheappearance appearanceof ofHAGMA HAGMA(including (including testing urinary 5-oxoproline). to four four divided divided doses, doses, by to to ensure no no HAGMA signals. Particular to by iv iv or or im im injection. injection. Severe Severe infections: infections:up uptoto8g 8gper perday dayadministered administeredininfour fourinfusions infusions(over (over flucloxacillin flucloxacillinisiscontinued continuedafter afterparacetamol paracetamolcessation, cessation,it itis isadvisable advisable ensure HAGMA signals. Particular 20 to to 30 30 min). min). No No single single bolus frequency of of these disorders 20 bolus injection injection or or infusion infusion should shouldexceed exceed2g. 2g.Maximum Maximumdose doseofof12g 12gper perday dayshould shouldnot notbebe caution cautionwith withdrug-induced drug-inducedliver liverinjury injuryin inpatients patientswith withHLA-B*5701 HLA-B*5701haplotype; haplotype; frequency these disorders exceeded. In In surgical surgical prophylaxis: of of exposure to to flucloxacillin. Hypokalaemia exceeded. prophylaxis: 2g 2g iv iv (bolus (bolus or or infusion) infusion) upon uponinduction inductionofofanesthesia, anesthesia,totobeberepeated repeatedevery every6h6h increasing increasingininHIV-infected HIV-infectedpatients patientswho whomay maybebeat atincreased increasedriskrisk exposure flucloxacillin. Hypokalaemia for 24h in vascular and orthopedic surgery, and for 48h in cardiac or coronary surgery. Methicillin-susceptible (potentially life threatening) can occur especially at high doses and may be resistant to potassium for 24h in vascular and orthopedic surgery, and for 48h in cardiac or coronary surgery. Methicillin-susceptible (potentially life threatening) can occur especially at high doses and may be resistant to potassium Staphylococcus aureus. aureus. Endocarditis: potassium levels during high dose flucloxacillin therapy. Attention warranted Staphylococcus Endocarditis: 2g 2g every every 6h, 6h, increasing increasingto to2g 2gevery every4h 4hininpatients patientsweighing weighing>85kg. >85kg.Children Children supplementation. supplementation.Regularly Regularlymeasure measure potassium levels during high dose flucloxacillin therapy. Attention warranted under 12 years of age – In mild to moderate infections: 25 to 50mg/kg/24 hours administered in three to four when combining flucloxacillin with hypokalaemia inducing diuretics or when other risk factors for development of under 12 years of age – In mild to moderate infections: 25 to 50mg/kg/24 hours administered in three to four when combining flucloxacillin with hypokalaemia inducing diuretics or when other risk factors for development of equally divided doses by im or iv injection. Severe infections: Up to 100mg/kg/24 hours in three to four divided hypokalaemia present. Contains sodium, consider in patients on a sodium controlled diet. Undesirable effects: equally divided doses by im or iv injection. Severe infections: Up to 100mg/kg/24 hours in three to four divided hypokalaemia present. Contains sodium, consider in patients on a sodium controlled diet. Undesirable effects: doses. No single bolus injection or infusion should exceed 33mg/kg. Methicillin-susceptible Staphylococcus Common (>1/100 to <1/10): Minor gastrointestinal disturbances. Uncommon (>1/1000 to <1/100): Rash, urticaria, doses. No single bolus injection or infusion should exceed 33mg/kg. Methicillin-susceptible Staphylococcus Common (>1/100 to <1/10): Minor gastrointestinal disturbances. Uncommon (>1/1000 to <1/100): Rash, urticaria, aureus. Endocarditis: 200mg/kg/24 hours in three to four divided doses. Premature infants, neonates, sucklings purpura. Very rare (<1/10,000): Neutropenia (including agranulocytosis), thrombocytopenia, eosinophilia, aureus. Endocarditis: 200mg/kg/24 hours in three to four divided doses. Premature infants, neonates, sucklings purpura. Very rare (<1/10,000): Neutropenia (including agranulocytosis), thrombocytopenia, eosinophilia, and infants – Risk of kernicterus; only use in premature infants and neonates after rigorous risk-benefit haemolytic anaemia, anaphylactic shock, angioneurotic oedema, high anion gap metabolic acidosis, and infants – Risk of kernicterus; only use in premature infants and neonates after rigorous risk-benefit haemolytic anaemia, anaphylactic shock, angioneurotic oedema, high anion gap metabolic acidosis, assessment. Treatment is generally with 25mg to 50mg/kg/24 hours divided into three or four equal doses. pseudomembranous colitis, neurological disorders with convulsions possible with high dose iv injection in assessment. Treatment is generally with 25mg to 50mg/kg/24 hours divided into three or four equal doses. pseudomembranous colitis, neurological disorders with convulsions possible with high dose iv injection in Maximum daily dose 100mg/kg/24 hours. Abnormal renal function – Renal excretion slowed in patients with renal patients with renal failure, hepatitis, cholestatic jaundice, changes in liver function laboratory test results, Maximum daily dose 100mg/kg/24 hours. Abnormal renal function – Renal excretion slowed in patients with renal patients with renal failure, hepatitis, cholestatic jaundice, changes in liver function laboratory test results, insufficiency. In severe renal insufficiency (creatinine clearance <10ml/min) consider dose reduction or extension erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, arthralgia, myalgia, interstitial insufficiency. In severe renal insufficiency (creatinine clearance <10ml/min) consider dose reduction or extension erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, arthralgia, myalgia, interstitial of dose interval. Maximum recommended dose in adults is 1g every 8 to 12 hours. In anuric patients maximum nephritis, fever sometimes develops more than 48 hours after start of treatment. Frequency not known: Acute of dose interval. Maximum recommended dose in adults is 1g every 8 to 12 hours. In anuric patients maximum nephritis, fever sometimes develops more than 48 hours after start of treatment. Frequency not known: Acute dosage is 1g every 12 h. Flucloxacillin not significantly removed by dialysis hence no supplementary dosages need generalized exanthematous pustulosis, phlebitis. Legal Category: POM Marketing Authorisation Numbers: dosage is 1g every 12 h. Flucloxacillin not significantly removed by dialysis hence no supplementary dosages need generalized exanthematous pustulosis, phlebitis. Legal Category: POM Marketing Authorisation Numbers: be administered either during or at end of dialysis period. Hepatic impairment – Dose reduction not necessary. PA2059/069/001, PA2059/069/002, PA2059/069/003. Marketing Authorisation Holder: Fresenius Kabi Deutschland be administered either during or at end of dialysis period. Hepatic impairment – Dose reduction not necessary. PA2059/069/001, PA2059/069/002, PA2059/069/003. Marketing Authorisation Holder: Fresenius Kabi Deutschland Intrapleural and intraarticular – Usual dose is 250mg to 500mg once daily. Contraindications: Hypersensitivity to GmbH, Else-Kroener Strasse 1, Bad Homburg v.d.H 61352, Germany Further Information: See the SmPC for further Intrapleural and intraarticular – Usual dosenot is 250mg once Contraindications: Hypersensitivity GmbH,Adverse Else-Kroener Bad Homburg v.d.H 61352, Germany Further Information: Seesuspected the SmPC adverse for further the active substance or excipients, should be giventoto500mg patients withdaily. history of hypersensitivity to beta-lactamto details. eventsStrasse should1,be reported. Healthcare professionals are asked to report any the active substance or excipients, should not be given to patients with history of hypersensitivity beta-lactam details. Adverse should be reported. Healthcare report any adverse antibiotics, patients with previous history of flucloxacillin-associated jaundice/hepatic dysfunction.toNot suitable reactions via HPRAevents Pharmacovigilance, Earlsfort Terrace, professionals IRL - Dublin 2,are Tel:asked +353 to 1 6764971, Fax:suspected +353 1 6762517. antibiotics, patients with previous history of flucloxacillin-associated jaundice/hepatic dysfunction. Not suitable reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517. for ocular or subconjunctival administration or intrathecal injection. Special warnings and precautions for use: Website: www.hpra.ie, E-mail: medsafety@hpra.ie. Adverse events should also be reported to Fresenius Kabi Limited for ocular or subconjunctival administration or intrathecal injection. Special warnings and precautions for use: Website: www.hpra.ie, E-mail: medsafety@hpra.ie. Adverse events should also be reported to Fresenius Kabi Limited Before initiating therapy with flucloxacillin check patient history concerning previous hypersensitivity reactions via email Pharmacovigilance.GB@Fresenius-Kabi.com. Date of Preparation: August 2021 IE-IVF-2100004 Before initiating therapy with flucloxacillin patientand history concerning is previous hypersensitivity reactions to beta-lactams. Cross sensitivity betweencheck penicillins cephalosporins well documented. Serious and via email Pharmacovigilance.GB@Fresenius-Kabi.com. Date of Preparation: August 2021 IE-IVF-2100004 to beta-lactams. Cross sensitivity between penicillins and cephalosporins is well documented. Serious and

Fresenius Kabi Limited Fresenius Kabi Limited Fresenius Kabi Ireland Fresenius Kabi Ireland Unit 3B Fingal Bay, Balbriggan, Unit 3B Fingal Bay, Balbriggan, Co. Dublin, Ireland Co. Dublin, Ireland

Website: www.fresenius-kabi.com/ie/ Website: www.fresenius-kabi.com/ie/ Email: FK-enquiries.ireland@fresenius-kabi.com Email: FK-enquiries.ireland@fresenius-kabi.com Phone: +353 (0)1 841 3030 Phone: +353 (0)1 841 3030

Date of Prep: August 2021 Date of Prep: August 2021 Ref: IE-IVF-2100007 Ref: IE-IVF-2100007

16 News Over 152,000 Wait for Care Professor Alan Irvine, President, IHCA

Some of the longest waiting lists across the whole region are for routine, planned care particularly in Orthopaedics, ENT (Otolaryngology), Urology, General Surgery, Ophthalmology, Gynaecology and Dermatology. Patients are waiting to see a consultant and then receive treatment for procedures such as hip or knee replacements, tonsillectomies, prostate biopsies, and cataract surgery, while others face similar waits for critical gynaecological assessments and skin biopsy for possible cancers.

The Irish Hospital Consultants Association (IHCA) has warned that the ongoing shortage of hospital consultants across a large number of specialties in the Saolta University Health Care Group* is restricting patients from accessing timely, high-quality medical and surgical care and is contributing massively to growing waiting lists where now more than 152,000 people in the region are waiting for hospital treatment or an outpatient appointment with a consultant.

The hospitals concerned and the respective increase in outpatient waiting lists alone include: In total, between the period of July 2015 and July 2021, there have been an additional 53,466 people added to outpatient waiting lists, an increase of 72% with a total of 127,750 across the Saolta Group now waiting to be assessed by a hospital consultant, according to the latest available figures from the National Treatment Purchase Fund.**

The hospitals that have seen the greatest growth in outpatient waiting lists are Roscommon University Hospital, which has seen its list increase 3-fold (+4,307, 199%) since July 2015, and Mayo University Hospital, where there has been an additional 9,473 people added over the same period, an increase of 162%. Of the 17,222 currently waiting for inpatient or day case treatment across the Saolta Group, 5,915 are waiting more than 12 months, a third of the total number. This is two-and-a-half times (+161%) the 2,266 patients waiting for the same length of time in July 2015. A further 7,689 people are currently awaiting a gastrointestinal (GI) endoscopy in Saolta hospitals - more than a 4-fold increase (+5,942) since 2015.

These waiting lists are likely to worsen in the coming months as more people who have put off seeking care during the pandemic enter the system, and as a result of the ongoing impact of the cyber-attack on the HSE. Commenting on the waiting lists, IHCA President Professor Irvine said, "The severe shortage of consultants in our public hospitals is the main contributor to the unacceptable delays in providing care to patients at our regional hospitals. These growing waiting lists demonstrate the impact of years of consultant shortages and underinvestment in capacity across public hospitals in the region. "Covid-19 and, more recently, the cyberattack have unmasked deep fundamental deficiencies in our health system which we always knew were there, but which have now been exposed in a way previously unseen. "We have a chronic recruitment and retention crisis with 1 in 5 permanent hospital consultant posts across the country and in the Saolta Group either vacant or filled on a temporary basis. "Meeting the healthcare needs of the 152,000 people in the West and North-West regions currently waiting to be assessed or treated by a consultant will only be possible by urgently filling vacant permanent hospital consultant posts and expanding the regions hospital beds, operating theatre and other essential hospital facilities. The success of the ongoing consultant contract discussions will be critical to the survival of our public health service for years to come.”

World Psoriasis Day 2021 World Psoriasis Day takes place in October annually. Each year, IFPA sets a specific theme for the upcoming World Psoriasis Day. This theme inspires members’ activities and shines a spotlight on a specific psoriasis-related issue. Several Core Communication Messages accompany the theme to explain its relevance. The theme for World Psoriasis Day 2021 is “United”. IFPA and its members in 56 countries are

organizing awareness-raising and advocacy campaigns to join forces, celebrate our collective victories, and rally support for policy changes that will support people living with psoriasis. Psoriasis is a chronic, systemic, inflammatory skin disorder in which there is an increase in the rate at which skin cells are produced and shed from the skin. Psoriasis affects at least 73,000 people in Ireland.

OCTOBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

Psoriasis may seem only skin deep, but it begins inside the body within the immune system. The red, scaly, flaky, and itchy patches occur when the skin cells grow too quickly as a result of inflammation caused by the body’s immune system. Triggers for this abnormal immune reaction can include physical injuries or infections (in particular, a streptococcal throat infection), certain medicines, and emotional

stress. Psoriasis varies in severity from person to person and can vary in severity in the same person at different times. Occasionally psoriasis can disappear without treatment but more usually, it is a chronic disease that requires treatment. Patches (also called plaques or lesions) can occur on various parts of the body, including the scalp, elbows, and or knees.

CONFRONT R/R CLL

VENCLYXTO® + rituximab provides superior PFS to bendamustine + rituximab with a

2-YEAR FIXED TREATMENT DURATION*2

VENCLYXTO® in combination with rituximab is NOW AVAILABLE for the treatment of adult patients with CLL who have received at least one prior therapy1 * 81% risk reduction of progression or death with VEN+R vs BR (HR=0.19;95% CI:0.15-0.26, P<0.0001) at 5 year median follow up. as appropriate. Immunisation: Live vaccines should not be administered during treatment and thereafter until B-cell recovery as the 2-year fixed treatment following 5-week dose titration period.2 PFS = Progression-Free Survival, R/R = relapsed/refractory safety and efficacy has not yet been established. CYP3A inducers: Co-administration of CYP3A4 inducers may lead to decreased VENCLYXTO®▼ (venetoclax) 10 mg/50 mg/100 mg film-coated tablets. PRESCRIBING INFORMATION. PRESENTATION: Venclyxto exposure and consequently a risk for lack of efficacy. Concomitant use of Venclyxto with strong or moderate CYP3A4 inducers Each film-coated tablet contains 10mg, 50mg or 100mg of venetoclax. Please refer to the Summary of Product Characteristics (SmPC) should be avoided. Women of childbearing potential: Women of childbearing potential must use a highly effective method of before prescribing. INDICATION: Venclyxto in combination with obinutuzumab is indicated for the treatment of adult patients with contraception while taking Venclyxto. INTERACTIONS: See SmPC for full details. Venetoclax is predominantly metabolised by CYP3A. previously untreated chronic lymphocytic leukaemia (CLL) (see section 5.1)†. Venclyxto in combination with rituximab is indicated for the CYP3A inhibitors: Concomitant use of Venclyxto with strong CYP3A inhibitors at initiation and during the dose titration phase is treatment of adult patients with CLL who have received at least one prior therapy*. Venclyxto monotherapy is indicated for the treatment contraindicated due to increased risk for TLS. At initiation and during the dose-titration phase, concomitant use with moderate CYP3A 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 inhibitors should be avoided. Alternative treatments should be considered. If a moderate CYP3A inhibitor must be used, the doses must inhibitor or in the absence of 17p deletion or TP53 mutation in adult patients who have failed both chemoimmunotherapy and a B cell be reduced and patients should be monitored more closely. Refer to SmPC for full details. Grapefruit, Seville oranges and starfruit receptor pathway inhibitor*. DOSAGE AND ADMINISTRATION: Oral. Treatment to be initiated and monitored by a physician should be avoided during treatment. P-gp and BCRP inhibitors: Concomitant use of Venclyxto with P-gp and BCRP inhibitors at initiation experienced in the use of anticancer medicinal products. See SmPC for full posology. Posology: Dose-titration schedule: the starting and during the dose titration phase should be avoided; if a P-gp and BCRP inhibitor must be used, patients should be monitored closely dose is 20 mg of venetoclax, once daily for 7 days. The dose must be gradually increased over a period of 5 weeks up to the daily dose for signs of toxicities. CYP3A inducers: Concomitant use of Venclyxto with strong or moderate CYP3A inducers should be avoided. of 400 mg. Post-titration dose for venetoclax in combination with rituximab: the recommended dose of venetoclax in Alternative treatments with less CYP3A induction should be considered. Preparations containing St. John’s wort are contraindicated combination with rituximab is 400 mg once daily. Administer Rituximab after the patient has completed the dose-titration schedule and during treatment with venetoclax. Bile acid sequestrants: Co-administration of bile acid sequestrants with Venclyxto is not has received the recommended daily dose of 400 mg venetoclax for 7 days. Venetoclax is taken for 24 months from Cycle 1 Day 1 of recommended as this may reduce the absorption of venetoclax. If a bile acid sequestrant is to be co-administered with Venclyxto, the rituximab. Venetoclax in combination with obinutuzumab: Venetoclax is given for a total of 12 cycles, each cycle consisting of 28 SmPC for the bile acid sequestrant should be followed to reduce the risk for an interaction, and Venclyxto should be administered at days: 6 cycles in combination with obinutuzumab, followed by 6 cycles of venetoclax as a single agent. Administer obinutuzumab 100 least 4-6 hours after the sequestrant. Warfarin: It is recommended that the international normalised ratio be monitored closely in mg on Cycle 1 Day 1, followed by 900 mg which may be administered on Day 1 or Day 2. Administer 1000 mg on Days 8 and 15 of Cycle patients receiving warfarin. Substrates of P-gp, BCRP, and OATP1B1; Co-administration of narrow therapeutic index P-gp, or BCRP 1 and on Day 1 of each subsequent 28-day cycle, for a total of 6 cycles. Start the 5-week venetoclax dose-titration schedule (see Table 1) substrates with Venclyxto should be avoided. If a narrow therapeutic index P-gp or BCRP substrate must be used, it should be used with on Cycle 1 Day 22 and continue through Cycle 2 Day 28. After completing the dose-titration schedule, the recommended dose of caution. For an orally administered P-gp or BCRP substrate sensitive to inhibition in the gastrointestinal tract its administration should venetoclax is 400 mg once daily from Cycle 3 Day 1 of obinutuzumab to the last day of Cycle 12. Post-titration dose for venetoclax be separated from Venclyxto administration as much as possible to minimise a potential interaction. If a statin is used concomitantly monotherapy: the recommended dose of venetoclax is 400 mg once daily. Treatment should be continued until disease progression with Venclyxto, close monitoring of statin related toxicity is recommended. FERTILITY PREGNANCY AND LACTATION: Women of or no longer tolerated by the patient. Patients should swallow the tablets whole with water at approximately the same time each day. childbearing potential/Contraception in females: Women should avoid becoming pregnant while taking Venclyxto and for at least 30 The tablets should be taken with a meal. Prevention of tumour lysis syndrome (TLS): Prior to initiating Venclyxto, tumour burden days after ending treatment. Pregnancy: Venclyxto is not recommended during pregnancy and in women of childbearing potential not assessment, including radiographic evaluation must be performed for all patients. The following prophylaxis measures should be using highly effective contraception. Breast-feeding: Breast-feeding should be discontinued during treatment with Venclyxto. Fertility: followed to minimise the risk of TLS and more intensive measures should be employed as overall risk increases; adequate hydration, Before starting treatment, counselling on sperm storage may be considered in some male patients. SIDE EFFECTS: See SmPC for full administration of anti-hyperuricaemic agents if necessary, blood chemistry monitoring and correction of abnormalities. Monitoring details on side effects. Very common side effects (≥1/10): Pneumonia, upper respiratory tract infection, neutropenia, anaemia, should be increased for patients at high risk of TLS. Temporary hospitalisation and close monitoring may be required in some patients, lymphopenia, hyperphosphataemia, hyperkalaemia, hypocalcaemia, diarrhoea, vomiting, nausea, constipation and fatigue. Common especially those at greater risk of TLS. Dose modifications for TLS or other toxicities may need to be considered during treatment. See side effects (≥1/100 to <1/10): Sepsis, urinary tract infection, febrile neutropenia, tumour lysis syndrome, hyperuricaemia and blood SmPC for full details of prophylaxis measures. Special Populations: Elderly: No dose adjustment required. Renal impairment: No creatinine increased. Tumour lysis syndrome (TLS): TLS is an important identified risk when initiating Venclyxto. dose adjustment required in patients with mild or moderate renal impairment. Patients with reduced renal function may require more ▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new intensive prophylaxis to reduce the risk of TLS and closer monitoring. Safety in patients with severe renal impairment or on dialysis has not been established, and a recommended dose for these patients has not been determined. Hepatic impairment: No dose adjustment safety information. Healthcare professionals are asked to report any suspected adverse reactions via HPRA is recommended in patients with mild or moderate hepatic impairment. Patients with moderate hepatic impairment should be Pharmacovigilance; Website: www.hpra.ie. Suspected adverse events should also be reported to AbbVie Limited monitored more closely for signs of toxicity. A dose reduction of at least 50% throughout treatment is recommended for patients with on 01-4287900. severe hepatic impairment. These patients should be monitored more closely for signs of toxicity. Paediatric Population: The safety and efficacy of Venclyxto in children aged less than 18 years has not been established. CONTRAINDICATIONS: Hypersensitivity to any of the active substances or excipients. Concomitant use of strong CYP3A inhibitors at initiation and during the dose-titration phase Preparations containing St. John’s wort. SPECIAL WARNINGS AND PRECAUTIONS: Tumour lysis syndrome (TLS): Patients with high tumour burden (any lymph node with a diameter ≥5 cm) or those with a high absolute lymphocyte count (≥25 x 109/L), are at greater risk of TLS when initiating Venclyxto. Reduced renal function (CrCL < 80mL/min) further increases the risk. Patients should be assessed for risk and should receive appropriate prophylaxis for TLS, including hydration and anti-hyperuricaemics. Blood chemistries should be monitored and abnormalities managed promptly. Dosing should be interrupted if needed. More intensive measures should be employed as overall risk increases. Neutropenia and infections: Grade 3 or 4 neutropenia has been reported. Complete blood counts should be monitored throughout the treatment period. Dose interruptions or reductions are recommended for patients with severe neutropenia. Serious infections, including sepsis with fatal outcome, have been reported. Monitoring of any signs and symptoms of infection is required. Suspected infections are to receive prompt treatment, including antimicrobials and dose interruption or reduction

LEGAL CATEGORY: POM (S1A). MARKETING AUTHORISATION NUMBERS/PRESENTATIONS: 10mg film-coated tablet, 14 tablets, EU/1/16/1138/002; 50mg film-coated 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 fromAbbVie Limited,14 Riverwalk,Citywest Business Campus,Dublin 24,Ireland.†This indication is not reimbursed. * Indications are reimbursed. DATE OF REVISION: June 2020. PI/1138/008. References: 1. VENCLYXTO® Summary of Product Characteristics, available at www.medicines.ie. 2. Kater AP, Kipps TJ, Eichhorst B, et al. Five-year analysis of MURANO study demonstrates enduring undetectable minimal residual disease (uMRD) in a subset of relapsed/refractory chronic lymphocytic leukemia patients following fixed-duration venetoclax-rituximab therapy. Oral presentation (125) presented at: 62nd American Society of Hematology Annual Meeting and Exposition; December 5-8, 2020; Virtual meeting IE-VNCLY-210002 Date of Preparation: January 2021

▼

For adults. Not actual patients.

SLOW DOWN SPMS WITH ACTIVE DISEASE.1

IT’S TIME FOR MAYZENT® MAYZENT® is the first and only oral treatment specifically indicated for SPMS with active disease1,2*† Mayzent ▼ (Siponimod) 0.25mg and 2mg film-coated tablets ▼ 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.Important note: Before prescribing, consult Summary of Product Characteristics (SmPC). Presentation: Tablets: 0.25 mg film-coated tablets corresponding to 0.25 mg siponimod. 2 mg filmcoated tablets corresponding to 2 mg siponimod. ♦Excipient with known effect: Each tablet of 0.25 mg contains 59.1 mg lactose (as monohydrate) and 0.092 mg soya lecithin. Each tablet of 2 mg contains 57.3 mg lactose (as monohydrate) and 0.092 mg soya lecithin. Indications: Treatment of adult patients with secondary progressive multiple sclerosis (SPMS) with active disease evidenced by relapses or imaging features of inflammatory activity. Dosage and administration (D&A): Treatment with Mayzent should be initiated and supervised by a physician experienced in the management of multiple sclerosis. CYP2C9 genotype should be determined before initiation of treatment. Mayzent should not be used in patients with a CYP2C9*3*3 genotype. Treatment initiation with a titration pack that lasts for 5 days. Once daily intake in the morning. On day 1 and 2: 0.25 mg. On day 3: 0.5 mg. On day 4: 0.75 mg. On day 5: 1.25 mg. Maintenance dose starts on day 6. Adults: Maintenance dose: 2 mg once daily. Maintenance dose for CYP2C9 *2*3 or *1*3 genotype: 1 mg once daily. No dose adjustments are needed in patients with renal impairment. Caution should be exercised when initiating treatment in patients with mild or moderate hepatic impairment (see section CI). Mayzent should be used with caution in the elderly patients (65 years or above) due to insufficient data on safety and efficacy. ♦Missed dose and re-initiation: If a dose is missed on one day in the first 6 days of treatment or if 4 or more consecutive daily doses are missed during maintenance therapy, the same initial dose titration and monitoring recommendations should apply. Contraindications (CI): Hypersensitivity to the active substance, or to peanut, soya or any of the excipients listed. ♦Immunodeficiency syndrome. ♦History of progressive multifocal leukoencephalopathy (PML) or cryptococcal meningitis (CM). ♦Active malignancies. ♦Severe liver impairment (Child Pugh class C). ♦Patients who in the previous 6 months had a myocardial infarction (MI), unstable angina pectoris, stroke/transient ischaemic attack (TIA), decompensated heart failure (requiring inpatient treatment), or New York Heart Association (NYHA) class III/IV heart failure. ♦Patients with a history of second degree Mobitz type II atrioventricular (AV) block, third degree AV block, sino atrial heart block or sick sinus syndrome, if they do not wear a pacemaker. ♦Patients homozygous for CYP2C9*3 (CYP2C9*3*3) genotype (poor metaboliser). ♦During pregnancy and in women of childbearing potential not using effective contraception. Warnings and precautions (W&P): ♦Infections: Before initiating treatment with Mayzent, a recent complete blood count (CBC) (i.e. within last 6 months or after discontinuation of prior therapy) should be available. Assessments of CBC are also recommended periodically during treatment. Absolute lymphocyte counts <0.2 x 109/l, if confirmed, should lead to dose reduction to 1 mg. Confirmed absolute lymphocyte counts <0.2 x 109/l in such a patient (already receiving 1 mg) should lead to interruption of Mayzent until the level reaches 0.6 x 109/l when re initiation of Mayzent can be considered. In patients with severe active infection, wait for resolution before initiating treatment. Patients should be instructed to report symptoms of infection to their physician promptly. Effective diagnostic and therapeutic strategies should be used in patients with symptoms of infection while on therapy and up to 3 to 4 weeks after discontinuation. Consider discontinuing therapy if a serious infection develops. Vigilance is advised for clinical symptoms or magnetic resonance imaging (MRI) findings suggestive of PML or for clinical symptoms of CM and, if suspected, Mayzent treatment should be suspended until PML or CM can be excluded. If diagnosed, appropriate treatment should be initiated. Patients without a healthcare professional confirmed history of varicella or without vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV prior to treatment initiation. ♦Vaccination: VZV vaccination is recommended in antibody-negative patients and initiation of treatment should be postponed for 1 month to allow the full effect of vaccination to occur. Concomitant use is not recommended with live attenuated vaccines and for 4 weeks after stopping Mayzent therapy. Vaccines may be less effective if administered during Mayzent treatment. Treatment discontinuation 1 week prior to planned vaccination until 4 weeks after is recommended. ♦Anti-neoplastic, immune-modulating or immunosuppressive therapies (including corticosteroids): Caution is required when used concomitantly with Mayzent and in the weeks after administration of any of these medicinal products is stopped. ♦Macular edema: Siponimod therapy should not be initiated in patients with macular oedema until resolution. An ophthalmic examination is recommended 3 to 4 months after Mayzent therapy initiation in all patients. In patients with history of diabetes mellitus, uveitis or underlying/co-existing retinal disease Mayzent should be used with caution due to potential increase of risk of macular oedema and an opthalmic examination is recommended prior to and regularly during therapy. Discontinuing therapy is recommended if macular edema develops. After resolution, reinitiation of treatment after discontinuation should be based on the potential benefits and risks for the individual patient. ♦Bradyarrhythmia and Treatment initiation with certain pre existing cardiac conditions: See section CI. ♦Patients with the following cardiac conditions should be observed for a period of 6 hours after the first dose of Mayzent for signs and symptoms of bradycardia: sinus bradycardia (heart rate <55 bpm), history of first- or second- degree (Mobitz type I) AV block, history of myocardial infarction, or history of heart failure (patients with NYHA class I and II). In these patients, it is recommended that an electrocardiogram (ECG) is obtained prior to dosing and at the end of the observation period. If post dose bradyarrhythmia or conduction related symptoms occur or if ECG 6 hours post dose shows new onset second degree or higher AV block or QTc ≥500 msec, appropriate management should be initiated and observation continued until the symptoms/findings have resolved. If pharmacological treatment is required, monitoring should be continued overnight and 6 hour monitoring should be repeated after the second dose. ♦Due to the risk of serious cardiac rhythm disturbances or significant bradycardia Mayzent should not be used in patients with: history of symptomatic bradycardia or recurrent syncope, uncontrolled hypertension, or severe untreated sleep apnoea. In such patients, treatment with siponimod should be considered only if the anticipated benefits outweigh the potential risks, and advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy. ♦Mayzent should not be used in patients with significant QT prolongation (QTc >500 msec) or who were treated with QT prolonging medicinal products with known arrhythmogenic properties. ♦Mayzent should not be used in patients with arrhythmias requiring treatment with class Ia (e.g. quinidine, procainamide) or class III (e.g. amiodarone, sotalol) antiarrhythmic medicinal products (risk of torsades de pointes). ♦Mayzent should not be used in patients receiving concurrent therapy with heart-rate-lowering calcium channel blockers (such as verapamil or diltiazem) or other substances that may decrease heart rate (e.g. ivabradine or digoxin) (risk of severe bradycardia and heart block). ♦If concomitant treatment with one of the above substances is being considered during initiation of treatment with Mayzent, advice from a cardiologist should be sought regarding the switch to a nonheart-rate-lowering medicinal product or appropriate monitoring for treatment initiation. ♦At treatment initiation, use with caution in patients receiving

stable dose of beta-blocker if resting heart rate is ≤50 bpm. In this case, beta-blocker should be interrupted until the baseline heart rate is >50 bpm. Mayzent treatment can then be started and treatment with beta blocker can be re-initiated after up-titration to Mayzent maintenance dose. ♦Initiation of Mayzent treatment results in a transient decrease in heart rate and has been associated with transient atrioventricular conduction delays; therefore a titration scheme to reach the maintenance dose on day 6 is applied. After the first dose, the heart rate decrease starts within one hour and the day 1 decline is maximal at approximately 3 to 4 hours. With continued up titration, further heart rate decreases are seen on subsequent days, with maximal decrease reached on day 5 to 6. The highest daily post-dose decrease in absolute hourly mean heart rate is observed on day 1, post-dose declines on the following days are less pronounced. Heart rate returns to placebo levels within 10 days after treatment initiation. ♦Liver function: Recent (i.e. within last 6 months) transaminase and bilirubin levels should be available before initiation of treatment with Mayzent. A liver function test is recommended in patients who develop symptoms suggestive of hepatic dysfunction during treatment and therapy should be discontinued if significant liver injury is confirmed. After resolution, reinitiation of treatment should be based on the potential benefits and risks for the individual patient. Caution should be exercised in patients with a history of significant liver disease. See section CI. ♦Cutaneous neoplasms: Mayzent should not be used in patients receiving concomitant phototherapy with UV-B radiation or PUVA photochemotherapy. Skin examination is recommended for all patients at treatment initiation, and then every 6 to12 months taking into consideration clinical judgement. Patients should be advised to promptly report any suspicious skin lesions to their physician. Caution is required against exposure to sunlight without protection in patients treated with Mayzent. ♦Unexpected neurological signs: Vigilance is warranted for any unexpected neurological or psychiatric symptoms/signs or accelerated neurological deterioration (posterior reversible encephalopathy syndrome). ♦Prior treatment with immunosuppressive or immune modulating therapies: Caution is required when switching patients from other disease modifying therapies (the half-life and mode of action of the other therapy must be considered). A CBC is recommended prior to initiating Mayzent to ensure that immune effects of the previous therapy (i.e. cytopenia) have resolved. Initiating treatment with Mayzent after alemtuzumab is not recommended. ♦Blood pressure: Special care is indicated if patients with uncontrolled hypertension are treated with Mayzent. Blood pressure should be regularly monitored during treatment. ♦Pharmacogenomics: See section CI for patients with CYP2C9*3*3 genotype (approximately 0.3 to 0.4% of population). See section D&A for CYP2C9 *2*3 or *1*3 genotype. ♦Women of childbearing potential: See section CI. Before initiation of treatment, women of childbearing potential must be informed of the risk to the foetus, must have a negative pregnancy test and must use effective contraception during treatment and for at least 10 days after treatment discontinuation.♦Stopping therapy: Patients should be observed for relevant signs of possible severe exacerbation or return of high disease activity upon Mayzent discontinuation and appropriate treatment should be instituted as required. In vast majority of SPMS patients, lymphocyte counts return to the normal range within 10 days of stopping therapy. However, residual pharmacodynamic effects, such as lowering effects on peripheral lymphocyte count, may persist for up to 3 to 4 weeks after the last dose. ♦Interference with haematological testing: Peripheral blood lymphocyte counts cannot be utilised to evaluate the lymphocyte subset status of a patient treated with Mayzent. ♦Excipients: Peanut or soya: see section CI. Lactose: patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose galactose malabsorption should not take Mayzent. Interactions: ♦Anti-neoplastic, immune-modulating or immunosuppressive therapies (including corticosteroids): See section W&P.♦Anti-arrhythmic drugs, QT prolonging drugs, drugs that may decrease heart rate: See section W&P.♦Betablockers: See section W&P. ♦Vaccination: see W&P. ♦CYP2C9 and CYP3A4 inhibitors: Concomitant use with Mayzent is not recommended with moderate CYP2C9 inhibitors and moderate or strong CYP3A4 inhibitors (can consist of a moderate CYP2C9/CYP3A4 dual inhibitor e.g. fluconazole or a moderate CYP2C9 inhibitor in combination with a separate moderate or strong CYP3A4 inhibitor).♦CYP2C9 and CYP3A4 inducers: Caution is required with strong CYP3A4/moderate CYP2C9 inducers (e.g. carbamazepine) in all patients and with moderate inducers of CYP3A4 (e.g. modafinil) in patients with CYP2C9*1*3 and*2*3 genotype (a reduction in siponimod exposure is expected). Fertility, Pregnancy and Lactation: Pregnancy, women of childbearing potential, contraception in females: see section CI. Before initiation of treatment in women of childbearing potential a negative pregnancy test result must be available and counselling should be provided regarding serious risk to the foetus. Women of childbearing potential must use effective contraception during treatment with Mayzent and for at least 10 days after stopping treatment. Mayzent should be stopped at least 10 days before a pregnancy is planned. If a woman becomes pregnant while on treatment, Mayzent must be discontinued. Medical advice should be given regarding the risk of harmful effects to the foetus associated with treatment and ultrasonography examinations should be performed. Embryotoxicity, fetotoxicity and teratogenicity were demonstrated in animal studies. Breast-feeding: Mayzent should not be used during breast feeding (no data in human lactation are available and siponimod is excreted into animal milk). Fertility: The effect of siponimod on human fertility has not been evaluated. Siponimod had no effect on male reproductive organs in rats and monkeys or on fertility parameters in rats. Driving and using machines: Mayzent has no or negligible influence on the ability to drive and use machines. However, dizziness may occasionally occur when initiating therapy. Therefore, patients should not drive or use machines during the first day of treatment initiation with Mayzent. Undesirable effects: Very common (≥10%): Headache, hypertension, liver function test increased. Common (≥1 to <10%): Herpes zoster, melanocytic naevus, Basal cell carcinoma, lymphopenia, dizziness, seizure, tremor, macular oedema, bradycardia, atrioventricular block (first & second degree), nausea, diarrhoea, pain in extremity, oedema peripheral, asthenia, pulmonary function test decreased. Please see Summary of Product Characteristics for further information on undesirable effects. Frequency not known: In the extension part of the phase 3 study, a case of cryptococcal meningitis has been reported. Marketing Authorisation Holder: Novartis Europharm Ltd, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland. Marketing Authorisation Numbers, Mayzent 0.25 mg film coated tablets: EU/1/19/1414/001 002. Marketing Authorisation Numbers, Mayzent 2 mg film coated tablets: EU/1/19/1414/003. Prescribing information last revised: Feb 2021. ▼ This medicinal product is subject to additional monitoring. Reporting suspected adverse reactions of the medicinal product is important to Novartis and the HPRA. It allows continued monitoring of the benefit/risk profile of the medicinal product. All suspected adverse reactions should be reported via HPRA Pharmacovigilance, website www.hpra.ie. Adverse events could also be reported to Novartis preferably via www.report.novartis.com or by email: drugsafety.dublin@novartis.com or by calling 01 2080 612.

CDP=confirmed disability progression; CI=confidence interval; Gd+=gadolinium-enhancing; HR=hazard ratio; MOA=mechanism of action; SPMS=secondary progressive multiple sclerosis. * EXPAND was a randomized, double-blind, placebo-controlled, Phase III study with a broad range of 1651 patients with SPMS over 24 months, followed by an optional open-label extension.2 † In a subgroup analysis in EXPAND, SPMS with active disease was defined as patients with relapse in the 2 years prior to the study and/or presence of T1 Gd+ lesions at baseline.1 References: 1. MAYZENT [Summary of Product Characteristics]. Novartis Ireland, available from Novartis Ireland Limited, Vista Building, Elm Park Business Campus Merrion Road, Dublin 4. 2. Kappos L, Bar-Or A, Cree BAC, et al; for the EXPAND Clinical Investigators. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet. 2018;391(10127):1263-1273.

August 2021 | IE_145831

CPD 80: MULTIPLE SCLEROSIS Continuing Professional Development

CPD 60 Second Summary MS as a chronic, heterogeneous disease with a pathogenesis that derives from the complexities of both the immune and central nervous system lends its self to evidence based treatment guidelines and consensus statements to guide therapeutic decisions. This is even more the case in view of the rapidly increasing number of available compounds and therapeutic strategies that are now available for the different stages of the disease. Guidelines and consensus statements aim to provide orientation to the less specialized health care professional, inform patients and help in defining common standards of care and harmonizing treatment policies, often with implications for reimbursement. With such a wide range of implications, including important financial interests, the value and acceptance of guidelines depends on the transparency of the development process and the scientific and professional authority and recognition of those involved, particularly when it comes to “softer” recommendations that are not derived from unequivocal evidence. An explicit goal of multiple sclerosis (MS) therapy is the “best possible disease control”, including the “best possible quality of life” of the patient, with the option to use highly effective therapeutics early or as early as possible in response to disease activity. Presently, two treatment approaches dominate the selection of optimal therapy for (highly) active MS. Both strategies are based on evaluating the individual patient’s risk of further MS progression and considering the risk versus efficacy of the specific diseasemodifying therapies.

AUTHOR: Heinz Wiendl, Ralf Gold & Frauke Zipp for the Multiple Sclerosis Therapy Consensus Group

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?

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.

Multiple sclerosis therapy consensus group (MSTCG): answers to the discussion questions Question 1: when should disease-modifying immunotherapy be initiated? Before or after the onset of disability? Already with CIS (e.g., isolated optic neuritis)? An explicit goal of multiple sclerosis (MS) therapy is the “best possible disease control”, including the “best possible quality of life” of the patient, with the option to use highly effective therapeutics early or as early as possible in response to disease activity. Specifically, the appropriate disease-modifying therapy (DMT) is selected based on the individual patient, and incorporates a situation and prognostic analysis that includes disease activity, disease severity, balancing therapy safety and risks, and considering the patient’s age, gender, and living situation. From the perspective of the MSTCG (Multiple Sclerosis Therapy Consensus Group) and supported by several large observational and registry studies, modern MS therapy can and should prevent the accumulation of disability and, thus, possible neurodegeneration. The MSTCG recommends classifying MS as mild/moderate or active/highly active (see Fig.

1). The classification is based on i) relapse frequency, ii) MRI findings (lesion load, lesion localization), and iii) regression of relapse(s), disease activity, and disease severity (measured by clinical as well as radiological parameters); also, the patient’s age and comorbidities have to be considered. Activity is determined based on clinical relapses (severity of clinical symptoms/duration/tendency to regress) and/or MRI activity (contrast-enhancing lesions; new or enlarged T2 lesions). Progression is determined by an annual or more frequent examination, including a careful clinical assessment. In addition to the EDSS, standardized instruments for assessing clinical function in patients with MS include the Multiple Sclerosis Functional Composite (MSFC), the Brief International Cognitive Assessment for MS (BICAMS), the 6- and 2-min walk tests, or the timed 25-ft walk test. Notably, the MS classifications are not categorical and rigid: they require continuous review and close follow-up. It is generally agreed that DMTs have a better effect early in the course of MS. Recent registry data indicate that later initiation

of DMT leads to more extensive disability in the longer term.1,2,3 In addition to preventing acute episodes of the disease, prophylactic therapy may reduce the risk of long-term neurologic deterioration or secondary progression.4 The long-term therapeutic benefits strongly depend on how early DMT is started. Due to the great heterogeneity of the clinical MS course, the further individual patient’s course is extremely difficult to predict. Although the term “benign MS” has been abandoned eventually, there may be courses that do not lead to any (significant) disability after 30 years – even without therapy. While in overall analyses up to 15–20% of patients may not accumulate measurable disability in the longer term, there are no reliable or accepted predictors for a course without substantial disability. Hence, DMT in MS must be started as early as possible after diagnosis to avoid further/future disability. In individual cases, a waitand-see approach with regular neurological and imaging checks may also be considered in patients with very low lesion burden and complete remission of mild clinical symptoms.

CPD 80: MULTIPLE SCLEROSIS

In the context of a clinically isolated syndrome (CIS) suggestive of central nervous system demyelination, defined as a monofocal or multifocal clinical event, e.g., optic neuritis or a spinal cord, brain stem, or hemispheric syndrome, the MSTCG takes a proactive position on the management of these patients. Currently, three licensed medical treatments are available for CIS patients (Interferon-b-1a i.m., Interferonb-1a s.c., Interferon-b-1b s.c.). (Interestingly, in the USA, siponimod is a recently approved additional option). Furthermore, it is of utmost importance that in this early phase of the disease, the affected patients become aware of and compliant to the need to monitor the situation to ensure the best possible treatment and management in the long term to prevent disease activity and neurodegeneration. This includes clinical and MRI follow-up and patient education in this specific phase of the disease. In persons with isolated optic neuritis without further evidence of CNS pathology on MRI, there is the possibility of no further progression to MS. Hence, here disease monitoring without treatment can be an option to consider in discussion with the patient.5 In patients with further evidence of CNS lesions

or oligoclonal bands that do not fulfill the MRI criteria for a full MS diagnosis, medical therapy needs to be clearly favored and advised over a pure monitoring approach. Any decision-making is a joint process requiring a responsible choice by the affected patient. In case of no immediate medical treatment, disease monitoring will be continued to uphold the opportunity for an effective early therapeutic intervention. Generally, under exclusion of other differential diagnostic causes, CIS patients (regardless of whether the criteria for DIT and DIS are met) must be offered immunotherapy. The choice of immunotherapy should be based on predictive parameters; primarily i) MRI findings (number and localization of lesions) but also ii) extent of relapse regression, iii) multifocal presentation, and iv) CSF-specific OCB or chronic inflammatory CSF changes. For CIS patients with a high lesion burden and/or infratentorial lesions on diagnostic MRI, immunotherapy should be actively recommended given the presumed unfavorable prognosis. Here, depending on the individual circumstances, high-efficacy therapy can be considered already for initial treatment. Importantly, the treatment of CIS should not be unnecessarily

delayed and should not follow an escalation approach in the individual (highly-active) case. Last but not least, already CIS can be considered as MS in several colleagues’ opinions. The latest revision of the McDonald criteria allows the diagnosis of MS in many cases previously considered as CIS.6, 7 Question 2: which diseasemodifying therapy should be selected when? Should a less potent and low-risk therapy initially be selected for all patients, or should some patients immediately receive a high-efficacy therapy with a higher risk profile and requiring more complex monitoring? To be considered in this context: escalation in three stages versus individually adjusted escalation Presently, two treatment approaches dominate the selection of optimal therapy for (highly) active MS. Both strategies are based on evaluating the individual patient’s risk of further MS progression and considering the risk versus efficacy of the specific disease-modifying therapies. According to the escalation approach, lowerefficacy therapies with a known and relatively safe risk profile are selected for initial treatment.

Figure 1

If – despite sufficiently long and regular treatment – disease activity persists/recurs, treatment is escalated to a more potent therapy option. In the alternative approach, treatment is initiated with a high-efficacy diseasemodifying therapy already at the time of diagnosis; for example, with alemtuzumab, cladribine, natalizumab, ocrelizumab, ofatumumab, or S1P receptor modulators (fingolimod, ozanimod, ponesimod). Limiting current treatment recommendations to the escalation approach is insufficient regarding the current data situation and diminishes the possibilities to start treatment with a higher-efficacy medication. The DGN guideline attempts to grade disease-modifying therapies according to potency and thus divides medications into three groups. In the view of the MSTCG, this is scientifically unsound as any minimal differences in the percentage of relapse reduction cannot be formally compared between the drugs due to different study collectives. Problematically, this

scientifically not well-founded approach ultimately results in a “three-part division” of the therapy algorithm – consisting of first a low-potent, then a medium-potent, and finally a highpotent therapy. This stepwise escalation, which is described as the preferential approach, does not correspond to established consensus recommendations, new study findings, or European/ international therapy concepts – according to which not only the time of therapy (earliest possible) but also the potency of the therapy influences the long-term outcome. Thus the meanwhile more proactive therapy concepts and the freedom of therapy are ultimately restricted with a threepart escalation. Choosing the first DMT in MS patients is challenging. The choice must occur on an individual patient level and take into account several factors: clinical symptoms, MRI activity, the efficacy of the therapeutic agent, side effects of the therapeutic agent, handling, route of administration, and the

patient’s life circumstances and family situation.8, 9 A general rule applies: the more potent the DMT, the higher the potential risk of severe side effects. The escalation regimen, in which therapy is always started with a less effective drug and switched to a high-efficacy DMT if disease activity persists, was initially advocated when only a few DMTs were available. With the availability of multiple highefficacy DMTs, including depleting therapies, the hit-hard-andearly concept was postulated, recommending the use of high-efficacy DMT at disease onset, in analogy to, for example, rheumatology. Controlled trials that might demonstrate the superiority of one of these therapeutic approaches have now been initiated, but results will not be available for several years. Retrospective registry studies already suggest that in patients with disease activity, early use of high-efficacy DMT compared to lower-efficacy DMT may delay subsequent disability progression or transition to

SPMS.2, 4 The underlying reason may be in concordance with delaying therapy initiation early in the disease: persistent clinical or subclinical disease activity under less effective therapy may cause irreversible neurological deficits and allow the activation of signaling pathways associated with progressive disease that could have been otherwise prevented. High-efficacy therapies are not suitable for every patient and require an individual risk-benefit assessment. Depleting or immune reconstitution therapies (IRTs), including autologous hematopoietic stem cell transplantation, have a special position in this regard. They cause profound changes in the immune system. Thus, on the one hand, they show a higher risk of severe side effects and notably increased risk of infection in the first months after a therapy pulse. On the other hand, a proportion of patients profit from disease stabilization and therapeutic effects persisting years beyond

the end of therapy, inducing long-lasting therapy-free disease stability.10,11,12 Substance-specific risk reduction strategies need to be applied. In comparison, conventional immunotherapies require continuous therapy with cumulative risks over time, counting towards the individual risk-benefit balance. Considering the disease course in the long term, there is an advantage of using high-efficacy versus lower-efficacy DMTs from the beginning. This treatment strategy is supported by registry data, although prospective studies are lacking. Due to a likely increased risk for severe side effects and in consideration of individual life circumstances, the use of high-efficacy DMTs at the beginning of the disease should be decided individually, following the neurologist’s recommendations and the patient’s wishes. Different therapy concepts exist within the group of highefficacy DMTs. I) Sustained therapy: efficacy relatively

CPD 80: MULTIPLE SCLEROSIS

immediate with application and accompanied by reversibility after discontinuation: natalizumab and S1P receptor modulators (as well as ocrelizumab and ofatumumab with limitation due to the mechanism of action), versus II) pulsed therapy: efficacy due to immune depletion and repopulation significantly beyond the half-life of the drug, possibly also permanent therapy-free disease stability: alemtuzumab and cladribine (and possibly ocrelizumab, with severe limitation due to mechanism of action).

IRTs (alemtuzumab, cladribine, and within limitation maybe also ocrelizumab) are special cases, in the sense that disease stability without further or follow-up treatment is part of the therapeutic concept. Available data indicate that about 50% of patients can be stable for many years after alemtuzumab without a need for follow-up treatment, including the possibility of treating recurrent disease activity again with CD52 depletion (with the prospect of achieving re-stabilization).

Although the DGN guideline mentions chronic/continuous versus pulsed therapy approaches, it clearly prefers the chronic therapy approach. This is justified by pointing towards the lack of long-term data for pulsed therapies, which, however, is not correct. Ultimately, education about both therapy concepts must be provided, especially since the patient must be informed about the possibility of disease stabilization without continuous therapy.10

Only a few controlled studies currently exist for the discontinuation of B-cell depleting drugs. However, a reversible mechanism of action, and therefore ultimately a return of disease activity, can be expected due to the B-cell dominance of the depletion principle. Established prognostic or diagnostic markers (such as the dynamics of depleting vs. repopulating immune cell types) that would indicate durable remission for a specified group do not exist for MS. Hence, also IRTs require established guidelines for monitoring and appropriate action plans for recurring disease activity.

Question 3: when should the immunotherapy be terminated? Should the therapy generally be terminated after a few5 years, or is long-term and sometimes permanent therapy feasible? To be considered in this context: the problem of disease reactivation/rebound The scientific data on this clinically highly relevant question is scarce. The only available data result from retrospective observational studies mostly on older injectable MS therapeutics and comprising relatively small cohorts. A prospective paper from the Global MS Database describes that while relapse rates remain stable after discontinuation of injectable MS therapies, disease progression is significantly accelerated.13 These results are consistent with smaller retrospective observations. So if treatment is well tolerated and safe, patients should be motivated to continue. Special consideration must be given to agents inhibiting leukocyte migration (natalizumab and the S1P receptor modulators fingolimod, ozanimod, ponesimod, siponimod). Here, discontinuation without a concept for follow-up treatment should be the exception due to possible recurrence or even rebound of disease activity (challenging situations arise, for example, in the context of pregnancy, lactation, or surgery).

More attention is now being paid to disease activity in relation to age, effects of therapy relating to age, and phenomena of immune senescence versus immunocompetence in old age. Roughly, the inflammatory activity and the effect of immunotherapy, especially the influence on progression, decrease with age. When weighing the therapeutic goals and benefit-risk profile, considering disease activity becomes more important, especially at a higher age (> 50). We generally recommend that MS patients who are stable on a given DMT, receive clinical and/or radiological monitoring, and are without any safety or tolerability issues, should continue therapy. Discontinuing or pausing treatment is associated with the risk of recurrence of disease activity and/or progression, depending on the mechanism of action. Discontinuing or pausing treatment at a patient’s explicit request (without planned follow-up therapy) may be done if adhering to clear guidelines for clinical and imaging monitoring. The DGN guideline positions itself very clearly towards the discontinuation of diseasemodifying therapy in the long term

and strongly recommends this possibility after 5 years. From the point of view of the MSTCG, this recommendation is not feasible considering the available data and can even create risks for some patients. Discontinuation or pausing of therapy at the explicit request of the patient (without a planned follow-up therapy) can take place under clear conditions for clinical and imaging monitoring but is by no means the rule. Corresponding discontinuation studies have only just been initiated internationally. On the other hand, there are clear epidemiological data on a possible “re-activation” in the sense of disease progression at any time, as well as data on a re-activation or rebound after discontinuation of immunomodulatory drugs. In addition, increased disease activity (rebound) may occur after discontinuation of natalizumab or S1P receptor modulators. In this line of critique, from the point of view of the MSTCG, the DGN guideline balances medication safety for the patient higher than modern options for long-term disease stabilization. Several studies and reports describe the further development of MS and clinical and paraclinical disease activity after discontinuing DMT. The course after discontinuation depends on various factors such as disease severity in the individual patient, disease duration, comorbidities, and the type of DMT. While pulsed immunotherapies tend to stabilize disease over the longer term, maintenance therapies suggest a more rapid return of disease activity after cessation. The therapy sequence is also essential.14, 15 In addition, there are immunopathogenic factors (genetics, environment, lifestyle). Another factor to consider is differences in wash-out periods, i.e., the times between discontinuation of a substance and initiation of follow-up treatment (typically from one to six months). Special consideration in this context is given to drugs that affect leukocyte migration.16, 17 For them, in addition to the expected recurrence of disease activity due to discontinuation, various reports describe a rebound, meaning a return of disease activity to a level exceeding that before the start of therapy. Although numerous studies describe this effect for fingolimod and natalizumab, rebound does not occur in every individual after discontinuing these therapies. However, an

appropriate follow-up treatment should always be administered after fingolimod and natalizumab to prevent the potential recurrence of disease activity. Hence, discontinuation or suspension of a medication for the therapy of (highly) active MS, either based on suboptimal efficacy or safety concerns, must be accompanied by a clear follow-up concept. The following factors should be considered when selecting a follow-up medication: 1.) disease activity (clinical and MRI): the higher the disease activity, the larger the need for immediate initiation of a new therapy; 2.) disease severity; 3.) half-life as well as biological activity of the previous medication (differentiation between socalled maintenance therapies (natalizumab, S1P receptor modulators, partly ocrelizumab) and pulsed therapies, (alemtuzumab, cladribine, partly ocrelizumab)); 4.) the risk of “carry-over” PML should be reduced as much as possible, and clinical, MRI, and liquid diagnostic parameters (detection of HPyV-2 [JCV] DNA by PCR) should be used to determine the baseline or pre-conversion status. The risk of recurrence of disease activity or rebound (especially after leukocyte migration therapies such as natalizumab or S1P receptor modulators) should be considered and can be expected 2–6 months after discontinuation of these agents. For SPMS, uncertainties may arise further down the line when patients with initially active disease have been treated and no longer have relapses. Various experts, including the authors of the North American guideline, recommend discontinuing therapy when there is pure progression without relapse. However, it is unclear whether the DMT suppresses relapse activity despite not affecting progression, meaning that patients would continue to benefit from the relapse rate reduction provided by DMT. If therapy is discontinued in SPMS patients, close monitoring of subsequential inflammatory activity is essential. Article Citation: Wiendl, H., Gold, R., Zipp, F. et al. Multiple sclerosis therapy consensus group (MSTCG): answers to the discussion questions. Neurol. Res. Pract. 3, 44 (2021). https://doi.org/10.1186/s42466021-00140-1 References available on request

Lead your patients to stronger bones with Prolia®

1-4

10 YEAR DATA 5S

Osteoporosis is a serious ongoing condition and ongoing treatment is required.6,7,8,9*

* Prolia® should not be stopped without considering alternative treatment in order to prevent rapid bone mineral density loss and a potential rebound in vertebral fracture risk.6 PROLIA® (denosumab) Brief Prescribing Information Please refer to the Summary of Product Characteristics (SmPC) before prescribing Prolia. Pharmaceutical Form: Pre-filled syringe with automatic needle guard containing 60 mg of denosumab in 1 ml solution for injection for single use only. Contains sorbitol (E420). Indication: Treatment of osteoporosis in postmenopausal women at increased risk of fractures. Dosage and Administration: 60 mg Prolia administered as a subcutaneous injection once every 6 months. Patients must be supplemented with calcium and vitamin D. No dosage adjustment required in patients with renal impairment. Not recommended in paediatric patients under 18 years of age. Give Prolia patients the package leaflet and patient reminder card. Re-evaluate the need for continued treatment periodically based on the benefits and potential risks of denosumab on an individual patient basis, particularly after 5 or more years of use. Contraindications: Hypocalcaemia or hypersensitivity to the active substance or to any of the product excipients. Special Warnings and Precautions: Traceability: Clearly record the name and batch number of administered product to improve traceability of biological products. Hypocalcaemia: Identify patients at risk for hypocalcaemia. Hypocalcaemia must be corrected by adequate intake of calcium and vitamin D before initiation of therapy. Clinical monitoring of calcium levels is recommended before each dose and, in patients predisposed to hypocalcaemia, within 2 weeks after the initial dose. Measure calcium levels if suspected symptoms of hypocalcaemia occur. Renal Impairment: Patients with severe renal impairment (creatinine clearance < 30 ml/min) or receiving dialysis are at greater risk of developing hypocalcaemia. Skin infections: Patients receiving Prolia may develop skin infections (predominantly cellulitis) requiring hospitalisation and if symptoms develop then they should contact a health care professional immediately. Osteonecrosis of the jaw (ONJ): ONJ has been reported rarely with Prolia 60 mg every 6 months. Delay treatment in patients with unhealed open soft tissue lesions in the mouth. A dental examination with preventative dentistry and an individual benefit:risk assessment is recommended prior to treatment with Prolia in patients with concomitant risk factors. Refer to the SmPC for risk factors for ONJ. Patients should be encouraged to maintain good oral hygiene, receive routine dental check-ups and immediately report oral symptoms during treatment with Prolia. While on treatment, invasive dental procedures should be performed only after careful consideration and avoided in close proximity to Prolia administration. The management plan of patients who develop ONJ should be set up in close collaboration between the treating physician and a dentist or oral surgeon with expertise in ONJ. Osteonecrosis of the external auditory canal: Osteonecrosis of the external auditory canal has been reported with Prolia. Refer to the SmPC for risk factors. Atypical femoral fracture (AFF): AFF has been reported in patients receiving Prolia. Discontinuation of Prolia therapy in patients suspected to have AFF should be considered pending evaluation of the patient based on an individual benefit risk assessment. Long-term antiresorptive treatment: Longterm antiresorptive treatment may contribute to an increased risk for adverse outcomes such as ONJ and AFF due to significant suppression of bone remodelling. Concomitant medication: Patients being treated with Prolia should not be treated concomitantly with other denosumab containing medicinal products. Warnings for Excipients: Patients with rare hereditary problems of fructose intolerance should not use Prolia. Dry natural rubber: The needle cover of the pre-filled syringe contains dry natural rubber (a derivative of latex) which may cause allergic reactions. Interactions: Prolia did not affect the pharmacokinetics of midazolam, which is metabolized by cytochrome P450

Amgen Ireland 21 Northwood Court, Santry, Dublin 9, Ireland.

3A4 (CYP3A4). There are no clinical data on the co-administration of denosumab and hormone replacement therapy (HRT), however the potential for pharmacodynamic interactions would be considered low. Pharmacokinetics and pharmacodynamics of Prolia were not altered by previous alendronate therapy. Fertility, pregnancy and lactation: There are no adequate data on the use of Prolia in pregnant women and it is not recommended for use in these patients. It is unknown whether denosumab is excreted in human milk. A risk/benefit decision should be made in patients who are breast feeding. Animal studies have indicated that the absence of RANKL during pregnancy may interfere with maturation of the mammary gland leading to impaired lactation post-partum. No data are available on the effect of Prolia on human fertility. Undesirable Effects: The following adverse reactions have been reported: Very common (≥ 1/10) pain in extremity, musculoskeletal pain (including severe cases). Common (≥ 1/100 to < 1/10) urinary tract infection, upper respiratory tract infection, sciatica, constipation, abdominal discomfort, rash, alopecia and eczema. Uncommon (≥ 1/1000 to < 1/100): Cellulitis, ear infection and lichenoid drug eruptions. Rare (≥ 1/10,000 to < 1/1,000): Osteonecrosis of the jaw, hypocalcaemia (including severe symptomatic hypocalcaemia and fatal cases), atypical femoral fractures, and hypersensitivity (including rash, urticaria, facial swelling, erythema and anaphylactic reactions). Very rare (< 1/10,000): Hypersensitivity vasculitis. Please consult the Summary of Product Characteristics for a full description of undesirable effects. Pharmaceutical Precautions: Prolia must not be mixed with other medicinal products. Store at 2°C to 8°C (in a refrigerator). Prolia may be exposed to room temperature (up to 25°C) for a maximum single period of up to 30 days in its original container. Once removed from the refrigerator Prolia must be used within this 30 day period. Do not freeze. Keep in outer carton to protect from light. Legal Category: POM. Presentation and Marketing Authorisation Number: Prolia 60 mg: Pack of 1 pre-filled syringe with automatic needle guard; EU/1/10/618/003. Price in Republic of Ireland is available on request. Marketing Authorisation Holder: Amgen Europe B.V., Minervum 7061, NL-4817 ZK Breda, The Netherlands. Further information is available from Amgen Ireland Limited, 21 Northwood Court, Santry, Dublin DO9 TX31. Prolia is a registered trademark of Amgen Inc. Date of PI preparation: October 2020 (Ref: IE-PRO-0920-00003) 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. References: 1. Prolia® [denosumab], Summary of Product Characteristics. 2. Cummings SR et al, N. Eng. J Med 2009;361:756-765. 3. Holzer G et al, J Bone Miner Res 2009;24(3):468-74. 4. Poole K et al; J Bone Miner Res 012; 27 (suppl1):S44 abstract 1122. 5. Bone HG, et al; Lancet Diabetes Endocrinol. 2017;5:513-23;3-23. 6. Tsourdi E, et al. Bone. 2017;105:11–7. 7. Hernlund E, et al. Arch Osteoporos. 2013;8:136; 8. Kanis JA, et al. Osteoporos Int. 2019;30:3–44; 9. Brown JBMR 2013 Vol28 pp746-752.

24 Osteoarthritis

The need for a Model of Care for Osteoarthritis in Primary Care in Ireland Written by Dr Helen French, Senior Lecturer, School of Physiotherapy, RCSI & Dr Joice Cunningham, Postdoctoral Research Fellow, School of Physiotherapy, RCSI Synopsis - Osteoarthritis (OA) places a substantial burden on individuals and societies, and represents a global challenge to healthcare services. International guidelines recommend education, exercise and weight management as first-line treatments for OA. However, in practice, uptake of guidelinebased non-surgical care is suboptimal. While clinical guidelines provide recommendations regarding best practice, for the most part they fail to address how to operationalise these recommendations into clinical practice. A Model of Care (MoC) is a framework, pathway or strategy that drives the translation of evidence into clinical practice by outlining the optimal manner in which condition specific care should be delivered to consumers within a local health system. The ENACt (ManagemENt of OsteoArthritis in primary Care in Ireland) project aims to develop a primary care-based MoC for OA in Ireland, which will be informed by best evidence and iterative consultation with key stakeholders including service users and service providers. This Health Research Board funded project is being conducted by a research team based in RCSI led by principal investigator Dr. Helen French. This article will describe the stages of the ENACt project and the planned development process for the MoC.

Dr Helen French, Senior Lecturer, School of Physiotherapy, RCSI

Dr Joice Cunningham, Postdoctoral Research Fellow, School of Physiotherapy, RCSI

Osteoarthritis (OA) is the most common joint disease in Ireland, affecting approximately 400,000 people. It is one of the leading causes of pain and physical disability. The number of people with OA in Ireland and internationally is growing, with an estimated half of those aged over 65 years diagnosed with OA. An aging population leads to higher prevalence of agerelated chronic conditions, which results in a greater burden on healthcare services1. Long-term pain and disability associated with age-related musculoskeletal conditions such as OA can result in restricted activities of daily living, reduced physical activity, decreased active involvement in society and healthy working life expectancy, and increased risk of other non-communicable diseases2-5. Whilst aging is an important contributing factor to the development of OA, it should not be considered a disease of “wear and tear”. OA is now seen as a low-grade inflammation disease6, affecting all tissues of the joint, involving cartilage degradation, bone remodelling, osteophytes, and synovitis7. While the mechanisms responsible for OA are multifactorial, the age-related

shift in the immune response to a more pro-inflammatory state, also referred to as ‘inflammaging’, is thought to play a role in the development and progression of OA8. Furthermore, increasing levels of obesity superimposed on aging increases chronic lowgrade inflammation. The demand for joint replacement surgery is projected to continue to grow, quadrupling by 20309, leading to concerns regarding capacity to meet future demands10. Therefore, the personal and economic burden of OA is substantial and set to continue to increase. With increasing healthcare utilisation and costs, the global health and socioeconomic impact of OA is currently unsustainable and constitutes a major worldwide challenge11, 12. At present, there is an over-emphasis on surgical and pharmacological interventions, despite evidence supporting conservative treatments such as exercise, weight loss and education. Public health interventions are required to address the existing overuse of inappropriate and low-value care and provide equitable access to cost-effective, evidence-based, management (high-value care)13.

OCTOBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

The GP is generally the first port of call for people seeking care for OA in Ireland and acts as a "gatekeeper" to the wider health system, such as hospitals and specialist clinics. Sláintecare, which is the first largescale attempt to reform the health service, recognises that the Irish health service is currently over hospital-centric and sets out a vision to move services into community and primary care. The ENACt project aligns with this vision. Currently there is no Model of Care (MoC) for OA in primary care in Ireland. Despite the already considerable and escalating societal, economic and personal burden of OA, it is frequently overlooked in national and global strategic plans for chronic disease management, with prioritisation given to other non-communicable diseases such as heart disease, diabetes, chronic obstructive pulmonary disease and mental health problems13. OA does not feature alongside other chronic diseases such as asthma and diabetes in chronic disease management programmes or strategies https:// www.hse.ie/eng/about/who/ gmscontracts/2019agreement/ chronic-disease-managementprogramme/. Therefore, the aim of the ENACt project is to develop a MoC for OA in primary care in Ireland to deliver best practice care nationwide. This research, to be conducted in three work packages, aims to determine current primary care management of OA in Ireland, and to develop a MoC focusing on core interventions (education, exercise and weight loss) over a 4-year period (October 2020-October 2024). The project will comprise three phases: • Work Package 1 will involve identifying current management of OA. This will include i) a scoping review to establish

evidence for primary care-based MoCs for OA internationally ii) a qualitative systematic review to establish the barriers and facilitators to implementation of OA management programmes (OAMPs) iii) qualitative interviews to investigate current management of OA in Ireland. Interviews will involve service providers including; general practitioners (GPs) and other primary care clinicians such as physiotherapists and nurses, as well as service users, i.e., individuals with OA and iv) secondary analysis of data from the Irish Longitudinal Study of Aging (TILDA) to investigate the utilisation of drugs for OA over an 8-year period. • Work Package 2 will involve the development of the primary care-based MoC for OA in Ireland by triangulating Work Package 1 findings, using behaviour change frameworks to identify the most appropriate components of the MoC. Key constructs will be mapped onto theoretical construct domains, to further map to behaviour change techniques (BCTs), which will be used to further develop components of the MoC. The affordability, practicability, effectiveness, acceptability, side-effects/safety and equity (APEASE) criteria will be used to ensure it can be realistically delivered. • Work Package 3 will involve the MoC being delivered to individuals with OA at three GP practices, followed by acceptability testing of the model. This will be done through qualitative interviews with service providers (i.e., GPs and other primary care clinicians) and service users (i.e., individuals with OA) involved in this process to ascertain its acceptability.

The profound effect of impaired musculoskeletal health on healthy aging, characterised by morbidity and mortality, has been recognized by the World Health Organisation. ‘Care as usual’ traditional OA management approaches often result in varying treatments, evidencepractice gaps and fragmented and delayed treatment due to waiting lists and over-demand. Therefore, a ‘paradigm shift’ in OA management is urgently required

to promote evidence-informed OA management, which addresses the underutilisation of core recommended treatments and over-reliance on pharmacological agents and surgery. The ENACt project will develop a MoC tailored specifically to the Irish healthcare system, with the ultimate goal of implementing and evaluating this MoC on a largescale national level. References available on request

News

Representing Patients with Axial Spondyloarthritis Arthritis Ireland has joined the Axial Spondyloarthritis International Federation (ASIF), an international membership organisation representing 50 patient associations around the world.

a global perspective of the impact of diagnostic delay and the factors that contribute to it. It also identifies opportunities for overcoming the delay, drawing on different examples of best practice from around the world.

ASIF works to increase awareness and knowledge of axial spondyloarthritis (axSpA), a range of chronic inflammatory conditions that primarily affect the spine and sacroiliac joints.

Arthritis Ireland is the national patient organisation and health research charity representing the one million people living with arthritis in Ireland.

A report published by ASIF last month highlights that there is on average a seven-year delay in achieving a confirmed diagnosis, which can result in irreversible damage. The Delay to Diagnosis report sets out for the first time

According to Gráinne O’Leary, Chief Executive of Arthritis Ireland, “Axial spondyloarthritis is a very challenging condition in terms of its impact on people’s lives. However, the situation is exacerbated by low levels of awareness and understanding

of the condition, with early symptoms frequently attributed to general back pain. “Becoming a member of ASIF will benefit people living with axSpA in this country and is a positive step for Arthritis Ireland. We look forward to working together with international colleagues to raise awareness of the condition and to address the many difficulties that exist around achieving a timely diagnosis,” Ms O’Leary stated. AxSpA places a huge physical impact and psychological stress on patients, which can disrupt every aspect of their life and its quality, including mobility, sleep, work and relationships. Symptoms frequently begin when

the person is in their twenties. AxSpA encompasses radiographic (ankylosing spondylitis or AS) and non-radiographic (nr-axSpA) forms. It is also associated with a wide range of comorbidities, including cardiovascular disease, diabetes, renal disease, inflammatory bowel disease, enthesitis and uveitis. Two-thirds (64%) of people with axSpA experience depression. It is estimated that axial spondylorarthritis affects 3 to 7 people per 1,000 – although international estimates vary considerably. This translates to potentially 15,000-33,000 people living with axSpA in Ireland.

HOSPITALPROFESSIONALNEWS.IE | HPN • OCTOBER - 2021

News 27 New ‘one-stop-shop’ Gynaecological Cancer Platform A new first-of-its-kind platform for Ireland providing relevant, reliable and evidence-based information for people affected by cervical cancer was launched to mark World Gynaecological Oncology Awareness Day (GO Day) on Monday September 20. The ThisIsGo.ie platform offers a one-stop-shop for helpful resources and advice on cervical cancer as part of the first phase of its development, including over 130 different articles, videos and audio content covering every stage of cancer diagnosis, treatment, and life with and after cancer.

Gynaecological Oncologist Professor Donal Brennan

The platform has been codeveloped by the Irish Cancer Society through its Women’s Health Initiative and support researchers and clinicians in UCD, in close collaboration with women and families directly affected by cervical cancer, and supported by Pfizer.

Gynaecological Oncologist Prof Donal Brennan, whose team developed the platform, said, “Over the last three years Irish people have become aware of the terrible impact a cervical cancer diagnosis can have on women and their families. We hope that ThisIsGo. ie will provide a safe and accurate repository of information that will empower women with cervical cancer to understand the disease and complications associated with treatment.

ThisIsGo.ie offers a personalised experience tailored to the stage and needs of individual users, including a specific section for partners of women who have or have had cervical cancer. It contains evidence-based information on everything from the stages of cervical cancer and a step-by-step guide for what to expect from treatment, to important parts of the journey that may often be overlooked including simple tips on preparing for hospital, and talking to children about cancer.

“This platform provides a very necessary resource for women who often struggle to access all the supports they need during what can be short and intermittent hospital visits. By taking a holistic approach it provides access to information on a wide range of subjects ranging from cancer diagnosis and treatment to emotional and physical wellbeing, practical and financial advice as well as dealing with long term side-effects of treatment such as lymphoedema, bowel, bladder and sexual dysfunction.”

“In Ireland, in our #DareToAsk campaign we are encouraging patients to ask their doctors those questions they have been too shy or afraid to ask,” says Sharon O’Toole, Trinity College Dublin and co-ordinator of the World GO Day activities on behalf of the Irish Network for Gynaecological Oncology, which will be launching a special podcast in conjunction with the “the Answers for Cancers podcast” team on World GO Day

to answer many of these questions that have been collated from patients, and it will also be featured on the ThisIsGo.ie platform. Over 1400 gynaecological cancers are diagnosed in Ireland annually (NCRI 2020 Annual Report), representing over 12% of female cancers. This year's message for World GO Day is simple: Information is power, but communication is the solution!

ESMO 2021 Multiple Myeloma Study Among patients with multiple myeloma (MM), higher amylase levels are linked with more advanced disease as well as inferior survival, according to research presented at the European Society of Medical Oncology (ESMO) Congress 2021. Elevated amylase in Multiple myeloma (MM) was first described in 1988. It has been postulated that translocation of chromosome 1, where the amylase gene is situated is responsible for the ectopic production from the malignant plasma cells. Previous case reports have shown that patients with hyperamylasemia in MM are associated with extensive bone disease, rapid progression and shorter survival. The study was conducted to

ascertain the degree of elevated amylase in MM patients. Methods It was conducted as a single institutional study. In newly diagnosed or relapsed cases of MM, serum amylase levels were determined. The study included patients with normal lipase and creatine clearance and without any evidence of intestinal obstruction or perforation. Patients with amylase value > 100 U/L were designated to have “elevated amylase level” in the study. Statistical analysis done using SPSS version 20. Results Out of 58 patients with MM, 29.3 % were found to have elevated

serum amylase levels and the mean value was 130±69 U/L. The median age of patients was 65 years. The male to female ratio was 1.9: 1. There was no statistically significant association between age, gender, type of heavy chain class, light chain or high-risk cytogenetics. Among the patients with ISS stage I, II and III, 20.8%, 31.3%, and 41.2% were noted to have elevated amylase levels. A statistically significant association was noted between the presence of extramedullary disease (EMD) and elevated amylase level (p-value 0.028). Higher mortality at 29.4% and shorter mean survival of 30.2±3.3 months was noted in those patients with elevated amylase level in comparison to 17%

mortality and mean survival of 51.7±4.9 months in those with normal amylase level. The study authors state, “Patients with MM associated with elevated amylase levels were more likely to be diagnosed with advanced ISS stage, higher mortality and shorter survival. A significant association was noted between elevated amylase level and EMD. The limitations of the study were small sample size.” Reference Panthula C, Jose WM, Krishnan S. The utility of serum amylase as a clinical marker in patients with multiple myeloma. Paper presented at: European Society for Medical Oncology (ESMO) 2021 Congress; September 16-21, 2021. Abstract 847P.

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28 Pain

Chronic Pain: A Neuroimmune Phenomenon Written by Professor Connail McCrory MB BCH BAO LRCP&SI FCAI FIPP FPMCAI MD Clinical Professor, School of Medicine, Trinity College Dublin Honorary Consultant, St. James Hospital, Dublin

Chronic adult pain is a common problem affecting about 19% of the European population with 61% of these people being unable to work normally resulting in absenteeism, decrease productivity and early retirement with associated negative social and economic impacts and increased demands on healthcare provision. Whilst acute pain is adaptive and protective and usually attributable to a precipitating event chronic pain is not and there is as yet no physiological benefits attributable to chronic pain. Acute pain is generally responsive to anti-inflammatory medication supplemented if necessary with a short courseof opioid medication.

the relationship between pain and the immune system and pain is one of the four cardinal signs of inflammation. Depression, anxiety, sleep disturbance and hyperalgesia are commonly problematic in patients with chronic pain. It is now believed that the neuronal interface which results in these responses includes T cells, macrophages, glial cells

This is not however the case with chronic pain. Chronic neuropathic pain (CNP) in particular is notoriously difficult to treat and is the main reason for attendance at pain clinics. The factors which affect the transition from acute adaptive pain to chronic maladaptive pain are poorly understood and are an area of investigation because of the high prevalence of chronic pain in society. It has been noted that patient suffering from chronic pain express symptoms and demonstrate signs of sickness behavior. Sickness or pain related behavior relates to the interaction between the patient and environment, similar to what is seen in patients who have an acute infection on board. This observation has led to the realization that pain chronicity is probably a central immunemediated phenomenon. Ongoing research has further identified

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and secreted neuropeptides. The nervous system and immune system share a common language mediated at least in part by neuropeptides, (cytokines, chemokines and neurotrophins). Bidirectional communication becomes maladaptive leading to enhanced pain signaling and chronicity. Whilst there has always been a debate about whether pain chronicity is driven by peripheral stimulation or is solely a central effect it is now quite clear that activation of the dorsal root ganglion and dorsal horn of the spinal cord are central to the development of pain chronicity. Chronic pain occurs when automatic spontaneous nonstimulated sensory unpleasant phenomenon are experience by the patient.1 Neuropathic pain may be caused by lesion of the somatosensory system and is estimated to be a chronic problem in 7-8% of the general population in Europe. Access to the central nervous system in humans for the purposes of research is ethically challenging and traditionally

difficult to perform. There has been much development in the field of neuroimaging however this has its limitations in terms of regular clinical application. Chronic neuropathic pain (CNP) remains the greatest clinical challenge. Diagnosis is still heavily dependent on clinical assessment. A multitude of questionnaires are available to help clinicians diagnose CNP but many of these are quite labour-intensive to apply. The DN4 and LANNS Questionnaires are probably the simplest and easiest to use. Laboratory testing such as nerve conduction studies and sensory evoked potentials, laser evoked potentials, punch biopsy, which can quantify Aδ and C fibres, measuring density of intraepidermal nerve fibres and quantitative sensory testing are time-consuming and expensive. The search for an easy to measure inexpensive biomarker continues. The management of CNP relates to both interventional / surgical therapies such as pulsing the dorsal root ganglion and spinal cord stimulation which require

29 group which were not medicated with opioids.6 The quoted studies are referenced at the end of this article for those who wish to explore this topic further. Amitriptyline and opioids are commonly employed therapies which have significant neuroimmune effects. The amitriptyline work demonstrates the effect is not just related to neuropeptide metabolism but also has a direct effect on T-cell expression and the receptors on the surface of T cells and the neuropeptide secreted from these cells. The opioid study demonstrates that opioid prescription has a major effect on central neuropeptide and protein biosynthesis in humans. The fact that both these drugs have an effect on immune function supports the concept that CNP is a neuroimmune phenomenon.

hospital attendance including a visit to the operating theatre with anaesthesia and are expensive to carry out. With the high number of patients suffering from CNP it is simply not practical or within the healthcare budget to provide these expensive therapies to all patients. Doctors are left with medication as the easiest to obtain therapeutic option however effectiveness is limited by relatively poor efficacy and deleterious side-effects. Number needed to treat (NNT) versus number needed to harm (NNH) ratios are humbling. Two of the most commonly used drug classes are the tricyclic antidepressants and opioids.2 As these drugs do seem to have benefit in patients with CNP their mode of action centrally must explain at least in part the pathophysiology of CNP. Chronic post-surgical pain (CPSP) is disabling and can result in significant physical and economic morbidity for the patient. CNP is the commonest cause of CPSP and may affect up to 40% of patients having surgery depending upon the site and type of surgery. Thoracic surgery in particular is associated with CPSP. Poor acute pain control in the immediate postoperative setting has been associated with the development of chronic pain but the aetiology is more complex than this. We investigated the effect of thoracic surgery on human cerebrospinal fluid (CSF) neuropeptides and found that despite adequate acute pain

control significant central CSF pro-inflammatory neuropeptide biosynthesis occurred in vivo in patients having a thoracotomy.3 This was associated with the development of CPSP. Amitriptyline is probably seen as the most effective drug in the management of neuropathic pain. We examined the effect of amitriptyline on T-cell phenotype and function on human peripheral blood mononuclear cells. This was achieved by Annexin V / propidium staining, flow cytometry and Elisa examination. Levels of secreted cytokines, chemokines and neurotrophins were measured. The results showed that there was no increase in T-cell death however the type of T-cell present was altered by amitriptyline. The frequency of naïve T cells was significantly lowered after amitriptyline and nortriptyline therapy. The effect of interferongamma on CD AT cells was also reduced. Interestingly natural killer T cells are significantly higher following treatment with nortriptyline. Amitriptyline lowered the levels of interleukin 16 and tumour necrosis factor.4 Amitriptyline is a modulator of both phenotype and function of T cells. Further examination of cerebrospinal fluid (CSF) in patients who responded well to amitriptyline demonstrated a reduction in pro inflammatory pathways of neuronal glial communication and evidence of a neurotrophic effects.5 Opioid medication has been used extensively to treat acute, chronic and cancer pain. It is effective in the management of acute

and cancer pain however opioid medication in the management of chronic pain is a very contentious issue. This is well delineated in the CDC report 2016. Opioid related phenomena include sedation, tolerance, euphoria, reward, addiction, analgesia, depression, hyperalgesia and death. There is growing evidence that central signaling maybe responsible at least in part for these phenomenon. Crosstalk between glia, immune cells and neurons, which we refer to as the neurommune interface, occurs by messengers which include cytokines, chemokines, neurotrophins and neuropeptides. Changes in the dynamic of these messengers may be caused by opioid therapy. There remains debate about whether opioids are truly immunosuppressive. In vivo human opioid mural uniform ecology has remained largely unexplored. The effect of opioid therapy on expression of proteomic and neuropeptide constituents of (CSF) will provide greater insight into the pure mechanisms of action in vivo. We examined human CSF in patients with CNP medication with opioid (predominantly oxycodone) versus patients with CNP not medicated with opioids using mass spectrometry. 432 proteins were found to be increased in baseline CSF in the patients receiving opioids versus those not receiving opioids. The 10 most differentially increased proteins included somatostatin. In addition 47 neuropeptides demonstrated decreased expression in the group receiving opioids versus the

Again constant surveillance must be provided by both the prescribing doctor and dispensing pharmacist when these therapies are employed because affects on human central peptide and protein biosynthesis in vivo are quite extensive. References (1) Neuroimmunity and Chronic Pain British Journal of Anaesthesia Education 2018 (12): 377-383 J Royds, CMcCrory (2) European Journal of Neurology 2010 17 1113-1123 European Federation of neuroscience guidelines on the pharmacological treatment of neuropathic pain: 2010 revision Attal et al (3) Central and systemic inflammatory response to thoracotomy – potential implications for acute and chronic postsurgical pain. Journal of Neuroimmunology 2015;285:147-49 RM Talbot, KF McCarthy, C McCrory (4) An investigation into the modulation of T-cell phenotypes by amitriptyline and nortriptyline European Neuropsychopharmacology 2020,31,131-144 Royds J, Conroy MJ,Dunne MR, McCrory C, Lysaght J (5) Examination and characterization of the effect of amitriptyline therapy for chronic neuropathic pain on your peptide and propionic constituents of human cerebrospinal fluid. Brain Behaviour & Immunity – Health 10 (2021) 100184 J Royds,H Cassidy, M Conroy, M Dunne, J Lysaght, C McCrory (6) An investigation into Proteomic Constituents of Cerbrospinal Fluid in patients with chronic neuropathic pain medicated with opioids-a pilot study. J Neuroimmune Pharmacology 2021;16(3): 634-650 Royds J, Conroy MJ, Dunne MR, Cassidy H, Matallanas D, Lysaght J, McCrory C

HOSPITALPROFESSIONALNEWS.IE | HPN • OCTOBER - 2021

30 News Value Added Medicines Report Medicines for Ireland have recently 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 their sister organisation, Medicines for Europe. The report outlines a range of important national and European policy recommendations that illustrate the important role that Value Added Medicines (VAMs)

play in a wide range of benefits for patients and Healthcare Professionals – from ensuring better adherence and compliance, to keeping healthcare costs down by reducing the need for patients to be moved to expensive next line therapies. The current Irish environment, and structure of reimbursement, does not allow the Irish government to harness these benefits, potentially saving costs and increasing patient care. Says the organisation,

“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. “That’s why all of us at Medicines for Ireland and within the Value Added Medicines Committee, welcome the opportunity to engage with key stakeholders on

this important topic, and to begin the discussions around what a fitfor-purpose regulatory framework for VAMs may look like for Ireland. What’s clear is that we need a system that rewards innovation with appropriate incentives, whilst recognising the potential long-term value and savings that VAMs can bring to the State.” The November issue of Hospital Professional News will carry details of the report in full.

Fundraising For You at University Hospitals Limerick Pictured are some of the staff at University Hospitals Limerick who recently bid farewell and best wishes to frontline workers before they headed off on a two-day cycle to Dublin, as part of a fundraiser, icu4u.ie Frontline medical staff throughout the Republic of Ireland and Northern Ireland cycled to the Memorial Gardens at Islandbridge in Dublin in September, to remember those who have lost their lives to Covid-19. They aim to raise ¤150,000 for those impacted by the secondary challenges of the pandemic through 4 chosen charity partners: • ALONE (supporting older people) • Aware (mental health supports) • Aware NI (depression supports in Northern Ireland) • Breakthrough Cancer Research (new treatments for poor prognosis and difficult to treat cancers). The ICU4U event saw small teams of ICU doctors, nurses, paramedics, ambulance drivers, other healthcare staff and Gardai depart from each of the six nationwide University Hospitals in Cork, Belfast, Galway, Limerick, Sligo and Waterford on 2-3 September, with midway points in Dundalk, Athlone, Portlaoise and Kilkenny.

Interoperability is Key says Pharmacy Federation Digital transformation of health care may allow for more inclusive, equitable and ethical use of healthcare resources, can improve health outcomes and reduce healthcare costs, and is often more environmentally friendly, the International Pharmaceutical Federation (FIP) said in a new Statement of Policy, which was adopted by the FIP Council.

solutions cannot be achieved without the implementation of interoperability, which must be a prerequisite for any digital technology development, and this includes the use of internationally recognised interoperability standards, terminology and taxonomy, the federation has stated.

However, the full potential of digital and technology-enabled

“We expect the impact of digital advances, such as predictive

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and personalised medicine, facial recognition, natural language processing and augmented reality, to gain even greater significance.

needs a confident, capable, agile and digitally enabled pharmaceutical workforce, the federation said.

We must be prepared to tackle the challenges to usher pharmacy into its digitally supported future,” said Jacqueline Surugue, chair, FIP Technology Forum. Furthermore, in order to leverage the potential of digital health into a sustainable pharmacy ecosystem, the world

Its new policy statement makes a number of specific recommendations to academic institutions, government and policymakers, FIP member organisations and pharmacists in order to support digital transformation.

CERVICAL CANCER

New Treatments: Offering Future Hope for Locally Advanced and Metastatic Cervical Cancer Written by Dr Hailey Carroll1, Dr Dearbhaile Collins1 Department of Medical Oncology, Cork University Hospital1

benefit6. However, this study failed to show survival advantage, and thus chemoradiation remains the standard of care for these locally advanced cancers.

Dr Hailey Carroll, Medical Oncology Specialist Registrar, Cork University Hospital

Dr Dearbhaile Collins, Consultant Medical Oncologist, Cork University Hospital

Background

cervical cancer continues to be the deadliest gynaecological malignancy worldwide. Until the early 1990s, the treatment of cervical cancer evolved primarily around radiotherapy alone3. Over the last 30 years, the development of multi-modality combination regimens and novel anticancer agents has improved these patients' outcomes, particularly those with recurrent, advanced, or metastatic disease, for whom survival remains poor. Despite these advances, the median survival of patients with metastatic stage IV disease is only between one to two years.

Cervical cancer is the 2nd most common malignancy and the 3rd leading cause of cancer deaths in females globally1. In Ireland, between 250-300 women are diagnosed with cervical cancer each year. Between 70-90% of cervical cancers are due to underlying chronic infection from high-risk subtypes of human papillomavirus (HPV), which is a sexually transmitted, and therefore, largely preventable disease2. The development of vaccinations against HPV has introduced an effective form of primary prevention against the development of cervical cancer. Cervical cancer screening programmes, which use cytology either in isolation or in conjunction with HPV testing, to identify pre-malignant highgrade dysplasia and carcinoma in situ (CIN) of cervical cancer and is an effective form of secondary prevention. Cervical cancer is globally recognized as a disease that most commonly affects marginalized populations, particularly women from a lower socioeconomic background, with the highest incidence and mortality in countries where women cannot access interventions available in developed countries. Thus,

Current Standard of Care Approximately 44% of patients diagnosed with cervical cancer present with early-stage disease localized to the cervix, a further 36% of patients present with locally advanced disease involving regional lymph nodes and surrounding tissues, and a smaller 16% of patients present with de novo metastatic disease4. For very early-stage disease, surgery remains the best option for cure. While recent technological advances saw a move towards minimally invasive and robotassisted surgeries, recent data from the LACC trial suggests a

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small but statistically significant increase in cancer recurrence in patients who underwent minimally invasive rather than traditional open surgery5. The LACC study reported a 99% 3-year overall survival after open surgery versus 93.8% after minimally invasive surgery. Since its publication, multiple retrospective and extensive cohort studies have been published, at times with conflicting findings. Ongoing prospective trials such as ROCC (NCT04831580), RACC (NCT03719547), MITOR (NCT04999696) and the LAUNCH studies (NCT04929769, NCT04939831) aim to collect further essential data in this cohort. In the 1990s, the benefit of concomitant chemotherapy and radiation for patients with unresectable but non-metastatic disease was demonstrated by multiple phase III trials, leading to the current gold standard of cisplatin-based chemotherapy in addition to external beam radiation followed by internal brachytherapy. ASCO 2021 saw the results presented of the OUTBACK trial, which sought to assess whether chemotherapy after concurrent chemoradiation could offer a further survival

In the recurrent or metastatic population, or patients with disease not amenable to curative treatment, GOG-204 was a significant phase III, randomized control trial that set out to identify the superior chemotherapy regimen. Four platinum doublet combinations were compared (cisplatin-gemcitabine, cisplatinvinorelbine, cisplatin-topotecan, and cisplatin-paclitaxel). This study found that combination cisplatinpaclitaxel showed the highest response rate (29%), median progression-free survival (PFS, 5.8 months), and median overall survival (OS, 12.8 months), which, in addition to favourable efficacy and toxicity, established a new standard of care in 20097. The next step forward in treatment options was five years later. The phase III trial GOG-240 investigated the role of bevacizumab, an anti-angiogenic antibody that targets vascular endothelial growth factor (VEGF) in addition to the established combination of cisplatin-paclitaxel in patients with previously treated, recurrent disease. This study demonstrated an improved median overall survival of 3.7 months by the addition of bevacizumab to chemotherapy. However, a significantly higher number of patients developed grade 3 gastrointestinal or genitourinary fistulas in the bevacizumab group (6% vs 0%, p=0.002), which remains a consideration for oncologists considering the addition of bevacizumab in these patients, who, by the nature of their disease, have tumours prone to fistulation8. Immunotherapy The advent and success of immunotherapy in multiple tumour types has led to an interest in its role in patients with cervical cancer. Virally driven cancers, such as cervical cancer and its association with HPV, have a number of behavioural, immunological and pathological

33 findings that suggest they may be more sensitive to reactivation of the immune system as a cancer treatment strategy. The most common form of immunotherapy are monoclonal antibody immune checkpoint inhibitors, which act against against various receptors, for example, programmed cell death 1 (PD-1), programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte antigen (CTLA-4). KEYNOTE-158, a phase II basket trial, looked at the efficacy and safety of single-agent pembrolizumab, a monoclonal antibody directed against PD-1, in patients with cervical cancer that had progressed after at least one prior chemotherapy9. These patients received 200mg every three weeks for two years or until cancer progression or unacceptable toxicity. The primary endpoint was the overall tumour

Anti-angiogenic agents

Immunotherapy compounds

PARP inhibitors

Novel drug class

response rate (ORR). The latest updates from this trial presented at the Society of Gynecological Oncology (SGO) annual meeting in 2021 reported an ORR of 14.3%. In the 82 patients who had biopsy specimens that expressed PD-L1 the ORR was 17.1% (range 9.727.0), whereas those with tumours that did not express PD-L1 (n=15) had no responses to the immune checkpoint inhibitor10. Also reported at SGO 2021, the EMPOWER-Cervical 1 trial, reported the first survival benefit with another PD-1 inhibitor, cemiplimab. This multicentre, phase III administered cemiplimab at a dose of 350mg three weekly versus investigator's choice chemotherapy (pemetrexed, topotecan, irinotecan, gemcitabine, or vinorelbine) in patients who had the progressive

or metastatic disease after first-line platinum-based chemotherapy11. At the interim analysis, all endpoints, including OS, PFS and ORR, favoured cemiplimab over chemotherapy, regardless of histology or PD-L1 expression. Median OS in the cemiplimab group was statistically improved at 12.0 months compared to 8.5 months in the chemotherapy cohort (HR 0.69). Other single-agent immune checkpoint inhibitors are also being explored in metastatic cervical cancer, such as the PD-1 inhibitors bastilimab and camrelizumab. One trial exploring the former agent is the BRAVA trial, which is in the process of opening in Ireland through Cancer Trials Ireland over the coming months

Novel compound

In combination with

Niraparib Niraparib

Concurrent radiotherapy Dostarlimab (immune checkpoint inhibitor) Bevacizumab (antiangiogenic agent) Pembrolizumab (immune checkpoint inhibitor) Cediranib (antiangiogenic agent) Radiation Atezolizumab (immune checkpoint inhibitor) Tislelizumab (immune checkpoint inhibitor) Alone

Rucaparib Olaparib Olaparib Talazoparib +/- tiragolumab (novel anti-TIGIT antibody) +/- ociperlimab (novel anti-TIGIT antibody) AK104 (bispecific anti-PD1 and anti-CTLA-4) AK104 (bispecific anti-PD1 and anti-CTLA-4) Apatinib Axitinib Cediranib Lenvatinib Cabozantinib

Chemotherapy Camrelizumab (immune checkpoint inhibitor) Avelumab (immune checkpoint inhibitor) Olapaib (PARP inhibitor) Pembrolizumab (immune checkpoint inhibitor) Pembrolizumab (immune checkpoint inhibitor)

(NCT04943627). However, the general developmental direction for these agents in cervical cancer is rapidly moving to investigating their use earlier in the disease course and in combination with other agents. Current ongoing studies such as KEYNOTE-826 (NCT03635567), FERMATA (NCT03912415) and BEATcc (NCT03556839) are exploring various immune checkpoint inhibitors in combination with platinum-doublet chemotherapy as first-line treatment for recurrent or metastatic cervical cancer. Many

Table 1

Trial name, NCT reference (www.clinicaltrials.gov) NIVX, NCT03644342 STAR, NCT04068753 NCT03476798 NCT04641728; NCT04483544 NCT04487587 NCT03968406 SKYSCRAPER-04, NCT04300647 NCT04693234 NCT0486870; NCT04380805 NCT04982237 NCT04974944; NCT03816553 NCT03826589 NCT04487587 NCT04865887 NCT04230954

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CERVICAL CANCER

of these studies have recently closed to recruitment, and the initial results are expected in the next year or two. In earlier stages, including locally advanced cervical cancer, immune checkpoint inhibitors are being trialled in combination with concurrent chemoradiation. The international KEYNOTE-A18/ENGOTcx11 is open to recruitment here in Ireland through Cancer Trials Ireland and Irish patients suitable for combined chemoradiotherapy should be considered for this randomized clinical trial (NCT04221945). Other immune checkpoint inhibitors are also being tested in a similar setting and cancer stage including durvalumab (NCT03830866), dostarlimab (ATOMICC; NCT03833479) and atezolizumab (NCT03738228) Another method of targeting the immune system in advanced disease involved vaccination for patients with established HPVpositive cervical cancer. Multiple vaccines are in development such as a therapeutic DNA vaccine, GX-118E (tirvalimogene teraplsmid), and BVAC-C, a B-cell and monocyte based vaccine transfected with recombinant HPV E6/E7. HPV-directed vaccines continue to be explored alone and in combination with the immune checkpoint inhibitors and results from these exciting clinical trials

are awaited (NCT04800978, NCT03444376, NCT02866006, NCT04096911). In addition, these vaccines are being tested with concurrent chemoradiation in locally advanced cervical cancer (NCT04580771). Novel Treatments Tisotumab vedotin (TV) is an investigational antibody-drug conjugate (ADC) that is directed towards tissue factor (TF) receptor-expressing cells and, upon binding, releases a potent chemotherapeutic compound, monomethyl auristatin E (MMAE) intracellularly. It is currently being tested alone and combined with other agents in relapsed or metastatic cervical cancer12, 13. Following phase I data showing promising efficacy in heavily pretreated cervical cancer patients, the phase II, open-label, single-arm, study innovaTV 204/ GOG 3023/ENGOTcx6 reported initial data from 101 evaluable pre-treated patients. The confirmed ORR was 24% (95% confidence interval (CI) 16–33), with 7% complete responses and 17% partial responses14. Adverse events of special interest include bleeding, neuropathy and ocular toxicities, including conjunctivitis and keratitis. The use of TV in advanced cervical cancer continues to be explored. Cancer Trials Ireland has been included

in many of the international TV studies including ENGOTcx8/ innovaTV205 of TV in combination with bevacizumab, pembrolizumab or carboplatin (NCT03786081)15 and ENGOTcx12/innovaTV301 (NCT04697628), the phase III randomized clinical trial of single agent TV versus investigator choice chemotherapy in cervical cancer patients that is due to open here imminently. Another new treatment option under investigation for patients with pretreated cervical cancer is bintrasfusp alfa. This bifunctional fusion protein comprises a TGF-βRII (TGF-β trap) fused to a human anti-PD-L1 monoclonal antibody. Pooled data from phase I (NCT02517398) and II (NCT03427411) studies looking at patients with advanced cervical cancer not previously treated with immunotherapy suggests that treatment with bintrafusp alfa has promising clinical activity and a tolerable safety profile in these patients16. Ongoing studies will afford further data on efficacy and toxicity with this novel agent in cervical cancer (NCT04246489, NCT04708470, NCT04551950). A brief summary of some of the agents currently being explored in locally advanced and metastatic cervical cancer both alone and with other compounds are listed in Table 1. They include the PARP inhibitors (oral compounds that target the DNA damage

repair pathway) and other anti-angiogenic agents such as apatinib, lenvatinib, cediranib and axitinib, often in combination with immune checkpoint inhibitors. Summary Advances in primary prevention of cervical cancer with the development of HPV vaccination and improved secondary prevention via screening programmes has led to a decreased incidence of cervical cancer, particularly in developed countries. The global health agenda strives to improve access to screening and vaccination in low-income countries, where cervical cancer rates are highest, and access to these effective strategies are limited. Despite advances in screening programmes and vaccine prevention programmes, cervical cancer, in particular unresectable disease, remains a devastating diagnosis. The more advanced the disease, the more modest the survival advantages with systemic anticancer treatment. Nevertheless, the past few years has seen a rapid development of novel agents in this cancer type, including immunotherapy, targeted therapy and antibody drug conjugates. These have ushered new treatment options and hope to patients with cervical cancer. In addition, further research on combination strategies and optimization of the sequence of different available treatments has also and will continue to benefit patients. As the study results of many of the cancer clinical trials noted above emerge, there is a tangible belief that we will start to see better cure rates for early-stage disease and improved overall survival and quality of life for those with incurable, metastatic late-stage disease. References available on request

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CONGENITAL HEART DISEASE

Prenatal Screening for Congenital Heart Disease in Ireland Congenital heart disease (CHD) refers to a structural abnormality within the heart, its walls, valves, great arteries or veins which is present at birth . A leading cause of congenital malformation-related infant mortality, CHD is also the most common organ-specific birth defect, with a worldwide incidence of 3-8 cases per 1,000 live births.1 While the most common structural cardiac abnormality, isolated small ventricular septal defects, are generally well-tolerated and are detected when an echocardiographic examination is performed to evaluate a cardiac murmur in the newborn period, other cardiac abnormalities confer particular risk to the newborn as early as the first few minutes of life. Specifically, the most critical congenital heart disease results in an inability to maintain adequate circulation without patency of the ductus arteriosus being maintained. Fetal cardiac anatomy that results in a situation whereby neonatal oxygenation will be compromised without the ductus arteriosus connection is therefore termed ‘duct-dependent congenital heart disease’.

4 chamber axial view of fetal heart ultrasound image at 20 weeks

Written by Ms Fiona Cody, Specialist obstetric sonographer/ Radiographer and PhD scholar, RCSI Rotunda Hospital. Professor Fionnuala Breathnach, Associate Professor Obstetrics and Gynaecology, Maternal Fetal Medicine Specialist, RCSI Rotunda Hospital.

Examples include single-ventricle conditions (resulting in hypoplastic left heart disease or hypoplastic right heart disease), Tetralogy of Fallot with pulmonary atresia and Transposition of the great arteries. Prenatal detection of such abnormalities is critically important, and enables the implementation of a perinatal care plan that may include in-utero transfer to a tertiary-care facility, multidisciplinary coordination of a planned delivery and timely administration of prostaglandin E1 (PGE1) to maintain ductal patency and thereby maintain

adequate oxygenation in advance of definitive cardiac intervention. Prenatal detection of ductdependent congenital heart disease confers survival advantage for these babies. This article will explore the contemporary system for prenatal detection of congenital heart disease in Ireland, the efforts that are being made to optimise access for all patients to highquality prenatal diagnosis services and to perinatal care pathways that are aimed at ensuring the best achievable outcome where a baby is born with severe congenital heart disease.

Prenatal Detection: The Mid-trimester Ultrasound A mid-trimester fetal anatomy ultrasound scan at 20-22 weeks’ gestational age, performed by a sonographer with expertise in fetal ultrasound, is necessary to confirm normality of the fetal cardiac structures. At a minimum, acquisition of five standard sonographic views (4-chamber view, left ventricular outflow tract, right ventricular outflow tract, 3-Vessel/ tracheal view and the abdominal situs view) are considered by

HOSPITALPROFESSIONALNEWS.IE | HPN • OCTOBER - 2021

CONGENITAL HEART DISEASE 5 Axial views for optimal fetal heart screening

if a standardised approach to acquiring the standard five cardiac views is not adopted.3,4 Prenatal Referral Pathway: When a cardiac anomaly is suspected or identified by the obstetric sonographer, a referral is made to a Fetal Medicine specialist where a more detailed fetal echocardiogram is performed in addition to a comprehensive ultrasound examination for extracardiac abnormalities or for features that may conform to a genetic syndrome. Accurate and timely prenatal diagnosis is critically dependent on access to fetal medicine and fetal cardiology expertise, which may be more readily available in some maternity settings than others. In Ireland, the existence of a single national Paediatric Cardiac centre, located in Dublin, renders the importance of prenatal diagnosis more pertinent in centres remote from Dublin than those cases detected in the capital. Such is the nature of critical/duct-dependent cardiac lesions that unanticipated cases delivered remote from Dublin shoulder a greater risk for mortality or severe morbidity than those cases detected after birth in Dublin centres, owing to the advantage of geographic proximity to the Cardiac Centre for Dublin cases. Prenatal Screening: Beyond ‘High-risk’ versus ‘Low-risk’:

Abbreviations: LV = Left ventricle RV = Right ventricle LA = left atrium RA = Right atrium Ao = Aorta D.aorta/DAo = decending aorta Tr = trachea St = stomach Fo = foramen ovale PV = Pulmonary veins sp = spine li = liver MPA = main pulmonary artery RPA = right pulmonary artery LPA = left pulmonary artery SVC = superior venae cavae IVC = Inferior venae cavae DA = ductus arteriosis ISUOG (International society for Ultrasound in obstetrics and Gynaecology)2 and other professional bodies to represent the required standard for prenatal exclusion of critical congenital heart disease. Successful acquisition of these views in the ‘thumbnail’-sized fetal heart at 18-22 weeks’ gestation is rendered particularly challenging by virtue of

the complexity of cardiac anatomy, its motion (the fetal heart rate ranges between 120 and 160 beats per minute in the mid-trimester), by fetal movement and position. Furthermore, maternal factors such as obesity or abdominal scarring, in addition to operator skill and experience and institutional approach to prenatal diagnosis can all impact prenatal detection

OCTOBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

of CHD. Where congenital heart disease occurs in the context of additional extracardiac structural abnormalities or genetic abnormalities, the sonographer is alerted to a heightened requirement for surveillance of the fetal cardiac structures. In contrast, isolated CHD in an otherwise normal fetus may be more easily missed,

In 2016 in Ireland, congenital heart disease accounted for 13.2% of infant mortality due to congenital malformation and 90% of affected babies were born to mothers with no identifiable risk factors that would be considered to render them ‘high risk’ for CHD.3,4 The national prenatal detection rate for critical CHD was 58%. Despite the availability and advances in pre-natal ultrasound screening in the developed world, prenatal detection rates remain highly variable and deserve close attention as the survival benefits of prenatal detection of major cardiac abnormalities are well-established.5,6 Prenatal diagnosis allows for planned timing of delivery, determination of optimal mode and location of delivery and facilitates early neonatal strategies to maintain ductal patency which may help mitigate against the known associations between CHD and

S U S P E C T AT T R - C M ( T R A N S T H Y R E T I N A M Y L O I D C A R D I O M YO PAT H Y )

A L I F E - T H R E AT E N I N G D I S E A S E T H AT C A N G O U N D E T E C T E D Life-threatening, underrecognized, and underdiagnosed, ATTR-CM is a rare condition found in mostly older patients in which misfolded transthyretin proteins deposit in the heart.1-7 It is vital to recognize the diagnostic clues so you can identify this disease.

C O N S I D E R T H E F O L L O W I N G C L I N I C A L C L U E S , E S P E C I A L LY I N C O M B I N AT I O N , T O R A I S E S U S P I C I O N F O R AT T R - C M A N D T H E N E E D F O R F U R T H E R T E S T I N G

HFpEF INTOLERANCE DISCORDANCE DIAGNOSIS ECHO NERVOUS SYSTEM heart failure with preserved ejection fraction in patients typically over 60 years old5-7

to standard heart failure therapies (ACEi, ARBs, and beta blockers)8-10 between QRS voltage and left ventricular (LV) wall thickness11-13

of carpal tunnel syndrome or lumbar spinal stenosis3,8,14-20

showing increased LV wall thickness6,13,16,21,22

—autonomic nervous system dysfunction-including gastrointestinal complaints or unexplained weight loss6,16,23,24

L E A R N H O W T O R E C O G N I Z E T H E C L U E S O F AT T R - C M AT :

SUSPECTANDDETECT.IE

References 1. Sipe JD, Benson MD, Buxbaum JN, et al. Amyloid fibril proteins and amyloidosis: chemical identification and clinical classification International Society of Amyloidosis 2016 Nomenclature Guidelines. Amyloid. 2016;23(4):209-213. 2. Maurer MS, Elliott P, Comenzo R, Semigran M, Rapezzi C. Addressing common questions encountered in the diagnosis and management of cardiac amyloidosis. Circulation. 2017;135(14):1357-1377. 3. Connors LH, Sam F, Skinner M, et al. Heart failure due to age-related cardiac amyloid disease associated with wild-type transthyretin: a prospective, observational cohort study. Circulation. 2016;133(3):282-290. 4. Pinney JH, Whelan CJ, Petrie A, et al. Senile systemic amyloidosis: clinical features at presentation and outcome. J Am Heart Assoc. 2013;2(2):e000098. 5. Mohammed SF, Mirzoyev SA, Edwards WD, et al. Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction. JACC Heart Fail. 2014;2(2):113-122. 6. Maurer MS, Hanna M, Grogan M, et al. Genotype and phenotype of transthyretin cardiac amyloidosis: THAOS (Transthyretin Amyloid Outcome Survey). J Am Coll Cardiol. 2016;68(2):161-172. 7. González-López E, Gallego-Delgado M, Guzzo-Merello G, et al. Wild-type transthyretin amyloidosis as a cause of heart failure with preserved ejection fraction. Eur Heart J. 2015;36(38):2585-2594. 8. Narotsky DL, Castano A, Weinsaft JW, Bokhari S, Maurer MS. Wild-type transthyretin cardiac amyloidosis: novel insights from advanced imaging. Can J Cardiol. 2016;32(9):1166.e1-1166.e10. 9. Brunjes DL, Castano A, Clemons A, Rubin J, Maurer MS. Transthyretin cardiac amyloidosis in older Americans. J Card Fail. 2016;22(12):996-1003. 10. Castaño A, Drach BM, Judge D, Maurer MS. Natural history and therapy of TTR-cardiac amyloidosis: emerging disease-modifying therapies from organ transplantation to stabilizer and silencer drugs. Heart Fail Rev. 2015;20(2):163-178. 11. Carroll JD, Gaasch WH, McAdam KP. Amyloid cardiomyopathy: characterization by a distinctive voltage/mass relation. Am J Cardiol. 1982;49:9-13. 12. Cyrille NB, Goldsmith J, Alvarez J, Maurer MS. Prevalence and prognostic significance of low QRS voltage among the three main types of cardiac amyloidosis. Am J Cardiol. 2014;114(7):1089-1093. 13. Quarta CC, Solomon D, Uraizee I, et al. Left ventricular structure and function in transthyretin-related versus light-chain cardiac amyloidosis. Circulation. 2014;129(18):1840-1849. 14. Connors LH, Prokaeva T, Lim A, et al. Cardiac amyloidosis in African Americans: Comparison of clinical and laboratory features of transthyretin V122I amyloidosis and immunoglobulin light chain amyloidosis. Am Heart J. 2009;158(4):607-614. 15. Nakagawa M, Sekijima Y, Yazaki M, et al. Carpal tunnel syndrome: a common initial symptom of systemic wild-type ATTR (ATTRwt) amyloidosis. Amyloid. 2016;23(1):58-63. 16. Rapezzi C, Merlini G, Quarta CC, et al. Systemic cardiac amyloidoses: disease profiles and clinical courses of the 3 main types. Circulation. 2009;120(13):1203-1212. 17. Sperry BW, Reyes BA, Ikram A, et al. Tenosynovial and cardiac amyloidosis in patients undergoing carpal tunnel release. J Am Coll Cardiol. 2018;72(17): 2040-2050. 18. Westermark P, Westermark GT, Suhr OB, Berg S. Transthyretin-derived amyloidosis: probably a common cause of lumbar spinal stenosis. Ups J Med Sci. 2014;119(3):223-228. 19. Yanagisawa A, Ueda M, Sueyoshi T, et al. Amyloid deposits derived from transthyretin in the ligamentum flavum as related to lumbar spinal canal stenosis. Mod Pathol. 2015;28(2):201-207. 20. Sueyoshi T, Ueda M, Jono H, et al. Wild-type transthyretin-derived amyloidosis in various ligaments and tendons. Hum Pathol. 2011;42(9):1259-1264. 21. Phelan D, Collier P, Thavendiranathan P, et al. Relative apical sparing of longitudinal strain using two-dimensional speckle-tracking echocardiography is both sensitive and specific for the diagnosis of cardiac amyloidosis. Heart. 2012;98(19):1442-1448. 22. Ternacle J, Bodez D, Guellich A, et al. Causes and consequences of longitudinal LV dysfunction assessed by 2D strain echocardiography in cardiac amyloidosis. JACC Cardiovasc Imaging. 2016;9(2):126-138. 23. Coelho T, Maurer MS, Suhr OB. THAOS - The Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis. Curr Med Res Opin. 2013;29(1):63-76. 24. Swiecicki PL, Zhen DB, Mauermann ML, et al. Hereditary ATTR amyloidosis: a single-institution experience with 266 patients. Amyloid. 2015;22(2):123-131.

The health information contained in this ad is provided for educational purposes only. Date of Preparation: February 2021 GCMA code: PP-RDP-IRL-0105

CONGENITAL HEART DISEASE

5 D fetal echocardiography, 9 rendered heart views acquired with a Samsung WS80A ultrasound machine

childhood neurodevelopmental delay.7 Careful prenatal evaluation of congenital heart disease can help inform the appropriateness of aggressive neonatal resuscitation or of palliative perinatal care. Early diagnosis may lead to parents making the very difficult decision to terminate the pregnancy in cases where the diagnosis is known to confer a fatal outcome.4 A large international study demonstrated an average detection rate of 50% across 18 centres worldwide where anomaly scans were routinely performed. This varied in accordance with differing screening policies, pregnancy termination laws and levels of scanning expertise, from a prenatal detection rate of 13% in Slovak republic to 87% in Northern France.8 In Ireland in 2016 detection rates were 71% (58/80) in hospitals offering a midtrimester anatomy scan compared to 29% (9/31) in hospitals offering a limited anatomy scan service. A ten-fold increase in the one-year mortality rate of those diagnosed postnatally was observed as well as an increased rate of admission to PICU there was also an increased requirement for pre-operative mechanical ventilation among those cases of CHD born without a prenatal diagnosis, compared to those babies born in the setting of an anticipated duct-dependent cardiac abnormality.4 A sharp increase in detection rates is apparent where fetal anatomy scanning is introduced universally, as occurred in the Netherlands after 2007.9 In 2017, five of the 19 maternity units in Ireland offered no fetal anomaly scan, 7/19 offered anomaly scans to a select group of patients and the remaining 7/19 units offered a mid-trimester fetal anatomy scan to all patients.10 Ireland’s ongoing National Maternity Strategy, published in 2017, emphasises the need to develop a plan to ensure equity of access to a fetal anomaly scan for all pregnancies.11 ‘Missed’ Diagnoses: A study in the Netherlands in 2021 demonstrated that the principle reason for missed CHD at the mid-trimester anatomy scan was poor quality fetal cardiac

imaging. Those sonographers who performed fewer examinations per year also had higher rates of missed pathology. Even when 4 standard images were obtained, 50% of major cardiac anomalies were missed at the anatomy scan. The Dutch study reported a lack of recognition of the pathology by the sonographers and a lack of adaptational skills to obtain the correct images.12 Improving education levels and targeted fetal echocardiography training can improve detection rates to up to 80% according to the study. Following a targeted training project in the Rotunda Hospital between 2010 and 2012 in addition to investment in ultrasound equipment the prenatal detection rate for major CHD at the hospital increased from 31%-91%.13 Prenatal Screening: The Status Quo: A 2021 national survey of fetal sonographers conducted by our group, indicates that some maternity units remain in need of support to improve prenatal cardiac screening services. Eighteen of the 19 maternity units now offer a mid-trimester anatomy scan at 18-22 weeks’ gestation to all patients, with the remaining unit is striving to do so in the near future. However, not all units

OCTOBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

consider pre-specified cardiac views essential for completion of the anatomy scan. Eight maternity units in Ireland have Subspecialist Fetal Medicine consultant expertise on staff , while the remaining 11 units have care pathways in place to facilitate patient referral to a tertiary care centre. Implementation of national fetal cardiac screening consensus approach is the subject of ongoing work by our research group. Advancing Technologies: In theory, 5D fetal echocardiography offers the potential to create an operatorindependent automated approach to examination of the fetal heart. It encompasses the capacity to obtain a cardiac volume in a manner that minimises operatordependence. 5D software technology allows interrogation of a Spatiotemporal Image Correlation (STIC) volume data sets using Fetal intelligent navigation Echocardiography (FINE) which automatically generates nine standard fetal echocardiography views simultaneously. However, these features may be more suited to sonographer/ cardiology experts using the system for a more detailed analysis.

The potential for this technology to enable remote volume acquisition, whereby the sonographer is trained to obtain a volume using an ultrasound software package and the images then viewed by a fetal echocardiography team elsewhere. This approach may reduce the need for tertiary referral and is the subject of ongoing research. From a training perspective, virtual reality ultrasound tools may enable navigation of the normal fetal heart and many of the complex abnormalities without the requirement for patient involvement. Conclusion: Improving the prenatal detection rate of congenital heart disease in Ireland by clearly establishing a national protocol for prenatal cardiac imaging is the ultimate goal of an implementation science project being led by RCSI. With input from experts in prenatal diagnosis and fetal cardiology and incorporating evidence-based international strategies, we aim to implement a consensus-based screening strategy. A national programme for targeted training in fetal echocardiography should render this goal achievable. References available on request

BACTERIAL VAGINOSIS

Management and Treatment of Bacterial Vaginosis Introduction Normal vaginal flora consists of lactobacilli, transient or commensal anaerobic and aerobic bacteria, and Candida species. The normal pH value of the vaginal flora is 3.8-4.4, however this does differ between ethnicities1. Bacterial vaginosis (BV) is a common vaginal infection caused by an imbalance in the types of bacteria in the vagina, with an increase in concentration of anaerobic micro-organisms (such as Gardnerella vaginalis, Prevotella species, Mycoplasma hominis, and Mobiluncus species), a loss of lactobacilli, and an increase in vaginal pH to above 4.5 and up to 6.02,3. BV is not a sexually transmitted infection (STI), however having unprotected sex or having concurrent STIs increases the risk of developing BV3. The prevalence of BV differs depending on ethnicity and is more prevalent in Afro Caribbean women (45-55%) than in Caucasian women (5-15%)4. The presence of BV during pregnancy varies according to ethnicity and how often a population is screened3. There are a number of factors which increase the risk of developing BV; unprotected sex, recent change in sexual partner, use of douches, deodorant and vaginal washes, menstruation, presence of semen in the vagina, copper intrauterine device, ethnicity, previous BV, and smoking3. Factors that can reduce the risk of developing BV include the use of hormonal contraception, consistent condom use, circumcised partner3 and smoking cessation. BV is associated with several obstetric and gynaecological complications including late miscarriage, pre-term labour and delivery, pre-term premature rupture of membranes, spontaneous abortion, postpartum endometritis, post-surgical infections, and subclinical pelvic inflammatory disease3. There is evidence that BV increases the risk of HIV acquisition and this is possibly due to changes in vaginal flora that occur with BV5. Clinical features Symptoms6, 3 • Offensive fishy smelling vaginal discharge

• BV is not associated with soreness, itching or irritation • Many women (approximately 50%) are asymptomatic

Written by Louise Delany, Antimicrobial Pharmacist, The National Maternity Hospital Dublin

Signs6,3 • Thin, white, homogenous discharge, coating the walls of the vagina and vestibule • BV is not usually associated with signs of inflammation Diagnosis There are two main approaches to diagnosing BV6. 1. Amsel’s criteria At least three of the four following criteria are present for the diagnosis of BV to be confirmed:

or shampoo in the bath6. Patients should also be counselled on smoking cessation and safe sex practices to reduce instances of BV. Goals of treatment include relief of symptoms, reduction in postoperative infection, and reduction of STIs.

Management

Without treatment, BV resolves spontaneously in up to onethird of non-pregnant and one-half of pregnant individuals. Non-pregnant women who are symptomatic or those undergoing gynaecological procedures or surgeries that involve the vagina should be offered treatment. Non-pregnant women with asymptomatic BV do not usually require treatment. Screening for BV is not recommended as part of regular antenatal care3, however if a pregnant woman is incidentally found to have asymptomatic BV, the woman’s obstetrician should be consulted as to whether treatment is appropriate3. Pregnant women diagnosed with BV who are symptomatic should be treated.

Patients diagnosed with BV should be advised to avoid contributing factors including vaginal douching, use of shower gel in the genital area, and use of antiseptic agents

Current management of BV is oral metronidazole, oral clindamycin or intravaginal clindamycin2. Oral metronidazole is usually well tolerated and a relatively

• Thin, white, homogenous discharge • Clue cells on wet mount microscopy • pH of vaginal fluid >4.5 • Release of fishy odour after adding 10% potassium hydroxide to wet mount 2. Gram-staining vaginal smear and evaluating with the Hay/Ison7 criteria or the Nugent8 criteria. All patients who have symptoms of BV should have a test for chlamydia and gonorrhoea, to exclude other causes of their symptoms.

inexpensive treatment option, whereas the use of clindamycin is more expensive in both oral or topical preparation. Clinical trials using probiotics for the treatment of BV have not yielded sufficient evidence of efficacy as treatment options for BV6. If symptoms persist or recur after initial treatment, adherence to treatment should be checked, the diagnosis of BV should be reconsidered and exposure to contributing factors should be reviewed. A referral to GU services may be required for patients with recurrent BV or if other diagnoses are a possibility. References available upon request

Drug Metronidazole

Dose 400mg PO every 12 hours

Or Clindamycin 2% cream

Duration Prescribing considerations/ advice 5-7 days Avoid alcohol during treatment with metronidazole and up to 48 hours after course has completed [9] Drug interactions of note: warfarin, acenocoumarol, ciclosporin, lithium, phenobarbital, phenytoin [9]

5g applicatorful inserted intravaginally at night

7 nights

Or Clindamycin

Clindamycin cream can damage latex condoms/ diaphragms[9] and use of these as contraception should be avoided during treatment and for 72 hours afterwards.

300mg PO every 12 hours

7 days

Consider risk factors for Clostridium difficile before prescribing PO clindamycin

HOSPITALPROFESSIONALNEWS.IE | HPN • OCTOBER - 2021

BREAST CANCER

Hormone Profiling to Improve Survival Rates for Breast Cancer Dr Marie McIlroy, Lecturer, Endocrine Oncology Research, Department of Surgery, RCSI University of Medicine and Health Sciences

A study by RCSI University of Medicine and Health Sciences has provided greater insight into the role that hormones play in the development of breast cancer in patients. The novel findings could enhance the treatment for breast cancer, assisting clinicians in optimising individual patient care and improving overall survival rates for patients. The study entitled 'Steroid Ligands, the Forgotten Triggers of Nuclear Receptor Action; Implications for Acquired Resistance to Endocrine Therapy', is published in Clinical Cancer Research.

deeper understanding as to how breast cancer cells are affected by different hormones and why patients respond differently to hormone therapy. The study found that hormone profiles before and after treatment play a significant role in the success of the therapy. This finding opens the door to further studies in larger patient cohorts to improve success rates associated with breast cancer treatment. Signalling Molecules

According to the WHO, 2.3 million women were diagnosed with breast cancer in 2020. Excluding skin cancer, breast cancer is the most common cancer in women in Ireland. 3,600 women every year in Ireland are diagnosed with breast cancer and the majority of these receive hormone therapy.

“Hormones are powerful signalling molecules that play important roles in helping our bodies function normally and respond to the world around us. For over 100 years we have known that oestrogens play a role in making breast cancers grow and many of the common drugs prescribed to treat it are to reduce the amount these hormones or to block their action. Unfortunately, not all patients will respond to these drugs and we need a better way to determine response to this type of therapy,” said Dr Marie McIlroy, the study’s senior author and Lecturer, Endocrine Oncology Research, Department of Surgery, RCSI.

Patients can respond differently to hormone therapy with some having a more positive response than others. This study analysed patients’ hormone profiles to provide researchers with a

“By looking at each individual person’s tumour hormone levels we get a better idea of the differences between people who respond well to hormone treatment and those who do not,

The hormone oestrogen has been proven to have an impact on breast cancer development and there is strong evidence that other hormones such as androgens may also play a role.

OCTOBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

potentially enabling us to make more informed decisions on treatment options for patients.” Funded by the Beaumont Cancer Research and Development Trust, the study was carried out by researchers from the RCSI in collaboration with the Applied Bioinformatics of Cancer, Institute of Genetics and Cancer, University of Edinburgh Cancer Research Centre; Manchester University, NHS Foundation Trust; Department of Pathology, Beaumont Hospital, Dublin; and Charles University, Pilsen, Czech Republic. Discussion Elevated androgens associate with both hormone receptor–positive and hormone receptor–negative breast cancers; highlighting the uncertainty around the pro-tumorigenic potential of steroids in the absence of their recognized receptors32. Moreover, there is strong epidemiologic evidence inferring that estrogens may not be the only steroid drivers of breast cancer33–35. We have previously shown that the androgenic steroid environment that results from AI therapy in breast cancers induces AR-mediated gene changes associated with poor response to conventional estrogen/ERtargeting therapies7, 36. The data presented here highlight the importance of fully elucidating the

role that circulating sex-steroid precursors and subsequent activation of the receptor is exerting on breast tumor survival in the setting of anti-estrogen therapy failure. While the concept of bioavailable androgens driving endocrine resistance is not new32, 37, 38, this is the first study to show dynamic changes in steroid levels on treatment using sensitive mass spectrometry quantification of estrogen and androgens. In this study, we have revisited AR IHC and breast cancer risk and applied a more stringent (IHC >75%) cut-off point17. The uncertainty surrounding AR as a prognostic and/or predictive factor in the setting of endocrine-treated breast cancer was addressed by a recent analysis of the BIG 1-98 trial data39. The authors determined that AR protein expression (IHC >1% scored positive) is not prognostic in the setting of hormone receptor–positive, postmenopausal breast cancer. They did, however, observe in patients assigned to letrozole monotherapy that AR expression associated nonsignificantly with poorer disease-free interval (HR = 1.52). This trend toward reduced disease-free interval in an AI-treated cohort is mirrored in our own study. Here we have shown elevated AR protein denotes a survival advantage that cannot be attributed to conventional subtyping (ER+), nor is it associated with favorable response to endocrine therapy. AI-Resistance In our previous studies, we developed AI-resistant cell models cultured in 4AD to recapitulate the inhibition of estrogen synthesis. Transcriptional changes associated with 4AD exposure were also determined to strongly associate with poor response to AI therapy. While 4AD is not a potent androgen, it has been shown to be the most abundant intratumoural steroid in both breast cancer and castrateresistant prostate cancer tissue. To look at this clinically, we screened a cohort of ER+, postmenopausal breast cancer

Scan QR Code to learn more about TRAZIMERA®

BUILDING ONTO THE CLINICAL EXPERIENCE OF TRASTUZUMAB WITH PFIZER1 2

TRAZIMERA® is a biosimilar of trastuzumab Prescribing Information TRAZIMERA ® ▼ (trastuzumab) powder for concentrate for solution for infusion Please refer to the full Summary of Product Characteristics (SmPC) before prescribing. Presentation: Vial containing 150 mg or 420 mg of trastuzumab powder for concentrate for solution for infusion. Indications: See SmPC for full details. HER2 positive metastatic breast cancer (MBC) as monotherapy for patients who have received at least two chemotherapy regimens and failed hormonal therapy (if applicable). In combination with paclitaxel, docetaxel or an aromatase inhibitor in appropriate patients. HER2 positive early breast cancer (EBC) following surgery, chemotherapy and radiotherapy (if applicable). Following adjuvant chemotherapy with doxorubicin and cyclophosphamide, in combination with paclitaxel or docetaxel. In combination with adjuvant chemotherapy consisting of docetaxel and carboplatin. In combination with neoadjuvant chemotherapy followed by adjuvant trastuzumab therapy, for locally advanced (including inflammatory) disease or tumours > 2 cm in diameter. HER2 positive metastatic gastric cancer (MGC) in combination with capecitabine or 5-fluorouracil and cisplatin in patients who have not received prior anti-cancer treatment for metastatic disease. Dosage and administration: See SmPC for full details. Prior HER2 testing is mandatory. To be initiated by a physician experienced in the administration of cytotoxic chemotherapy and administered by a healthcare professional, by intravenous infusion only. Ensure that the drug prepared and administered is Trazimera (trastuzumab) and not Kadcyla (trastuzumab emtansine). MBC or EBC. Three-weekly schedule. Loading dose of 8 mg/kg. Maintenance dose of 6 mg/kg at three-weekly intervals beginning three weeks after the loading dose. Weekly schedule. Loading dose of 4 mg/kg. Maintenance dose of 2 mg/kg beginning one week after the loading dose. See SmPC for details of chemotherapy combination dosing. MGC. Loading dose of 8 mg/kg. Maintenance dose of 6 mg/kg at threeweekly intervals beginning three weeks after the loading dose. Treat patients with MBC or MGC until progression of disease. Treat patients with EBC for 1 year or until disease recurrence, whichever occurs first. No reductions in the dose of trastuzumab were made during clinical trials. Monitor patients during periods of reversible, chemotherapy-induced myelosuppression. See SmPC for details of administration if left ventricular ejection fraction drops or doses are missed. Initial loading dose should be administered as a 90-minute intravenous infusion by a healthcare provider prepared to manage anaphylaxis and an emergency kit should be available. Observe patients for at least six hours after the start of the first infusion and two hours after the start of subsequent infusions for infusion-related symptoms. If the initial loading dose was well tolerated, subsequent doses can be administered as a 30-minute infusion. Contraindications: Hypersensitivity to trastuzumab, murine proteins, or excipients. Severe dyspnoea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy. Warnings and precautions: See SmPC for full details. Record name and batch number of administered product. HER2 testing must be performed in a specialised laboratory with adequate validation of testing procedures. No clinical trial data are available on re-treatment of patients with previous exposure to trastuzumab in the adjuvant setting. Cardiac dysfunction. Perform baseline cardiac assessment and, as a minimum, repeat every 3 months during treatment and every 6 months following discontinuation of treatment until 24 months from the last administration. A careful risk-benefit assessment should be made before deciding to treat with Trazimera. See SmPC for further details of monitoring and management of cardiac function. Infusion-related reactions (IRRs) and hypersensitivity. Serious IRRs have been reported. Pre-medication may be used to reduce risk of occurrence of these events. See SmPC for further details. Pulmonary events. Severe pulmonary events have been reported. These events have occasionally been fatal. Patients experiencing dyspnoea at rest due to complications of advanced malignancy and comorbidities may be at increased risk and should not be treated with trastuzumab. See SmPC for further details. Interactions. Clinically significant interactions with the concomitant medicinal products used in clinical trials have not been observed. See SmPC for further details. Pregnancy and lactation.

Women of childbearing potential should use effective contraception during treatment and for 7 months afterwards. Trastuzumab should be avoided during pregnancy unless the potential benefit for the mother outweighs the potential risk to the foetus. Women should not breast-feed during treatment and for 7 months after the last dose. Undesirable effects: Amongst the most serious and/or common adverse reactions reported in trastuzumab usage (intravenous and subcutaneous formulations) to date are cardiac dysfunction, infusion-related reactions, haematotoxicity (in particular neutropenia), infections and pulmonary adverse reactions. See SmPC for further details. Very common (≥1/10). Infection, nasopharyngitis, febrile neutropenia, anaemia, neutropenia, white blood cell count decreased/leukopenia, thrombocytopenia, weight decreased/weight loss, anorexia, insomnia, tremor, dizziness, headache, paraesthesia, dysgeusia, conjunctivitis, lacrimation increased, blood pressure decreased/increased, heart beat irregular, cardiac flutter, ejection fraction decreased, hot flush, dyspnoea, cough, epistaxis, rhinorrhoea, diarrhoea, vomiting, nausea, lip swelling, abdominal pain, dyspepsia, constipation, stomatitis, erythema, rash, swelling face, alopecia, nail disorder, palmar-plantar erythrodysaesthesia syndrome, arthralgia, muscle tightness, myalgia, asthenia, chest pain, chills, fatigue, influenza-like symptoms, infusion related reaction, pain, pyrexia, mucosal inflammation, peripheral oedema. Common (≥1/100 to <1/10). Neutropenic sepsis, cystitis, influenza, sinusitis, skin infection, rhinitis, upper respiratory tract infection, urinary tract infection, pharyngitis, hypersensitivity, anxiety, depression, peripheral neuropathy, hypertonia, somnolence, dry eye, cardiac failure (congestive), supraventricular tachyarrhythmia, cardiomyopathy, palpitation, hypotension, vasodilatation, pneumonia, asthma, lung disorder, pleural effusion, haemorrhoids, dry mouth, hepatocellular injury, hepatitis, liver tenderness, acne, dry skin, ecchymosis, hyperhydrosis, maculopapular rash, pruritus, onychoclasis, dermatitis, arthritis, back pain, bone pain, muscle spasms, neck pain, pain in extremity, renal disorder, breast inflammation/ mastitis, malaise, oedema, contusion. Uncommon (≥1/1,000 to <1/100). Deafness, pericardial effusion, wheezing, pneumonitis, urticaria. Rare (≥1/10,000 to <1/1,000). Anaphylactic reaction, anaphylactic shock, jaundice. Incidence not known. Neoplasm / malignant neoplasm progression, hypoprothrombinaemia, immune thrombocytopenia, tumour lysis syndrome, hyperkalaemia, papilloedema, retinal haemorrhage, cardiogenic shock, gallop rhythm, pulmonary fibrosis, respiratory distress, respiratory failure, lung infiltration, acute pulmonary oedema, acute respiratory distress syndrome, bronchospasm, hypoxia, oxygen saturation decreased, laryngeal oedema, orthopnoea, pulmonary oedema, interstitial lung disease, angioedema, glomerulonephritis membranous, glomerulonephropathy, renal failure, oligohydramnios, renal hypoplasia, pulmonary hypoplasia. Legal category: Product subject to prescription which may not be renewed (A): S1A Marketing Authorisation Number(s): 150 mg: EU/1/18/1295/001; 420 mg: EU/1/18/1295/002 Marketing Authorisation Holder: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium. Date of revision: March 2021. Version: bTR 5_0 ▼ 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. 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 + 353 1 4676500.

References: 1. Trazimera® (trastuzumab) Summary of Product Characteristics. 2. European Medicines Agency. Trazimera® EPAR summary for the public https://www.ema.europa.eu/en/medicines/human/EPAR/trazimera Accessed August 2021.

PP-TAS-IRL-0033 | Date of Preparation: August 2021

T 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.

ORE

investigatedinpatientsreceivnghighdosechemotherapy.Thismedicnalproductshould filgrastim.Ifaseriousalergicreactionoc urs,ap ropriatetherapyshouldbeadminster d, s y r i n g e o r p r e fi l e d s y r i n g e i n j e c t o r w i t h o n e a l c o h o l s w a b , i n a b l i s t e r d p a c k a g i n g . Pelgraz® PFI Patient Support App not be used to increase the dose of cytotoxic hemotherapy beyond established dose with close patient folow-up over several days. Stevens-Johnson syndrome (SJS), which Ma r k e t i n g A u t h o r i s a t i o n N u m b e r s : P r e fi l e d s y r i n g e : E U / 1 / 1 8 / 1 3 1 3 / 0 1 , P r e regimens. Pulmonary adverse reactions, in particular intersti al pneumonia, have be n canbelife-threateni gorfatal,hasbe nreportedrarelyinas ociationwithpegfilgrastim fi l e d i n j e c t o r : E U / 1 / 1 8 / 1 3 1 3 / 0 2 . Ma r k e t i n g A u t h o r i s a t i o n H o l d e r ( M A H ) : A c o r d reported after G-CSF adminstration. Patients with a recent history of pulmonary treatment.IfthepatienthasdevelopedSJSwiththeuseofpegfilgrastim,treatmentmust infiltrates or pneumonia may be at higher isk. The onset of pulmonary signs uch as not be restarted at any time. As with al therapeutic proteins, ther is a potential for Healthcare S.LU, World Trade Center, Mol de Barcelona, s/n, Edifici Est, 6a planta,5 cough,fever,and yspnoeainas ociationwithradiol gicalsignsofpulmonaryinfiltrates, immunogenicty.Ratesofgenerationofantibodiesagainstpegfilgrastimisgeneralylow. Barcelona, 08039 Spain. Legal Category: POM. Ful prescribng information including and deterioration in pulmonary function along with increased neutrophil count may be Bindingantibodiesdo c urasexpectedwithal biol gics;however,theyhavenotbe n the SmPC is available on request from Ac ord Healthcare Ireland Ltd, Euro House, Lit le preliminary signs of adult respiratory distres syndrome (ARDS). In such circumstances as ociatedwithneutralisngactivtyatpresent.Aorti shasbe nreportedafterfilgrastim Island, Co. Cork, Tel: 021-4619040 or www.ac ord-healthcare.ie/products. Adverse pegfilgrastim should be discontinued at the discretion of the physican and the orpegfilgrastimadminstrationinhealthysubjectsandincancerpatients.Thesymptoms reactionscanbereportedtoMedicalInformationatAc ordHealthcareLtd.via ap ropriatetreatmentgiven.Glomerulonephritshasbe nreportedinpatientsreceivng experienced included fever, abdominal pain, malaise, back pain and increased E-mail: medinfo@ac ord-healthcare.com orTel:+44(0)1271385257. ofGenerationofAPI: May2021.IE-01426 inflammatorymarkers(e.g C-reactiveproteinandWBCcount).Inmostcasesaorti swas DateCompliance fiConfi lgrastimandpegfilgrastim.Generaldence, y,glomerulonephritsresolvedafterdosereductionConvenience, The Pelgraz® PFI App is designed to support patients self-administering Pelgraz® PFI at home

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Always administe r Pelgraz® exactly as your doctor has told you to. The following instruction s should act as a helpful remin der but if you are der, unsure 1 about anything you should check with your docto doct r or pharmacist.

session Last chemotherapy

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Self-inject supprration or t tool

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Pre-Filled Injector One Dose for ANC Recovery

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

www.ac ord-healthcare.ie www.accord-healthcare.ie

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

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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 hould be reported. Reporting forms and information can be found on the HPRA website (www.hpra.ie), or by e-mail ng medsafety@hpra.ie. Adverse events hould also be reported to Medical Information via email; medinfo@ac ord-healthcare.com or tel:0 4 (0) 1271 385257 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

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sera. The data showed 4AD to be higher in the recurrent population with lower 4AD associated with increasing age only in the patients who responded to endocrine therapy.

AR and ER signaling pathways based on primary breast tumor gene expression analysis using Philips Oncosignal platform. While activity of signaling pathways for both steroid receptors were As ligand bioavailability may evident, this analysis showed have major consequences for a preponderance of AR signal response to endocrine therapy, transduction pathway activity this prompted us to characterize over that of ER in patients who the steroid landscape in a recurred on AI therapy. Further cohort of AI-responsive and analysis of an independent AI-nonresponsive breast cancers. AI-treated clinical cohort showed Evidence that combining steroid ect while active ER gene 10 9 serum data to standard clinical Self-injthat t or pp su markers diminished, breast pathology in breast cancer risk e Sever cancer–specific AR signaling prediction has some precedence markers were increased or with a recent nested were static. case–control study showing improved discrimination for Of note, 4AD-associated gene estrogen receptor–positive changes showed increased disease. In our study, we found expression in acquired AI that we could detect changes in resistance versus dormant circulating androgens in patients tumors, indicating that tumors whose breast cancers recurred with plentiful steroid precursors while on AI therapy. may adapt to long-term alteration AR is reported to block the tumorigenic potential of ER, it therefore makes sense that ER+/AR+ tumors do better and this is widely reported in clinical meta-analysis, and which we too also show. However, under AI treatment, the survival advantage is diminished, perhaps because AR is no longer acting in opposition to active ER signaling. To investigate whether this is the case, we evaluated

of the steroid environment. These findings are in line with the recently published, phase II clinical trial, which showed that patients with high levels of AR mRNA and low levels ESR1 mRNA derived significant benefit from the combination of enzalutamide and exemestane. A possible explanation for this data is that diminished genomic activation of both ER and AR may be more permissive of noncanonical pathways.

Benefit of Therapeutic Agents The reduced production of potent sex steroids, accompanied by a surfeit of weak precursor steroids in aging adults provides rationale for the benefit of therapeutic agents that drive genomic nuclear receptor activity. Despite breast cancer subtype classification being based on the fairly ubiquitous presence of hormone receptors (ER, PR); the presence of ligands are somewhat overlooked. The relevance of age-related endocrine changes in driving transcriptomic and proteomic alterations in breast cancer has recently garnered attention, particularly with regards the robustness of biomarker assessment platforms such as OncotypeDX. This is a burgeoning area of research and it is clear that inclusion of the patient endocrine landscape may enhance robustness in the application of biomarker-based algorithms. In the past few years, there has been a shift toward LC/MS-MS detection of steroids with unparalleled specificity and sensitivity.

patient steroid levels and evaluate the relevance of these to patient response on endocrine therapy. This study assessed systemic steroid levels, as although intratumoural steroid levels would be very informative the former is more clinically feasible. A limitation of this study is the small sample size; however, this was mitigated by age, steroid receptor, grade, and treatment matching of clinical samples. With precision oncology moving into mainstream clinical decision making, this study highlights the value of layering multiple components of the steroid tumor microenvironment. Steroid receptors, their ligands and signal transduction pathway activity profiling should all be factored in determining optimal treatments for hormone receptor–positive, postmenopausal breast cancer. Our study very importantly shows that it is possible to quantitatively detect circulating steroids in patient serum while on therapy. References available upon request

This has revolutionized our capacity to quantify individual

HOSPITALPROFESSIONALNEWS.IE | HPN • OCTOBER - 2021

BREAST CANCER RESEARCH

Inhibitor drug ‘primes’ the body to better respond to anti-cancer treatment “There may be a role for this combination of therapies in breast cancers” Dr Dearbhaile Collins, Consultant Medical Oncologist, Cork University Hospital

immunotherapy in solid tumors that traditionally are nonresponsive to checkpoint inhibition therapy.

Combining a histone deacetylase inhibitor drug with immunotherapy agents is safe, and may benefit some patients with advanced cancers that have not responded to traditional therapy, according to results of a phase 1 clinical trial involving University College Cork (UCC) and US researchers. During the study, 33 patients with advanced solid tumors received the histone deacetylase inhibitor drug entinostat for two weeks. Then, some patients received the immunotherapy agent nivolumab, a checkpoint inhibitor, in combination with the entinostat, while others received both nivolumab and a second checkpoint inhibitor agent, ipilimumab, after the initial dosing with entinostat. Senior study author Professor Roisin M. Connolly, M.B.B.Ch., M.D., chair in cancer research at University College Cork (UCC) and Cork University Hospital and adjunct professor at Johns Hopkins worked with colleagues in the Johns Hopkins Kimmel Cancer Center, Bloomberg~Kimmel Institute for Cancer Immunotherapy and several other centers including University of Pittsburgh Cancer Institute, Yale Cancer Center and City of Hope in Los Angeles, which participated in study enrollment, and the University of Southern California, which collaborated on analysis of the data. Checkpoint inhibitors, such as nivolumab and ipilimumab, release important “brakes” that permit the immune system to fight the cancer

cells. The epigenetic inhibitor drug entinostat has been shown in preclinical models and laboratory studies (which led to this current clinical trial) to drive changes in the chemical environment of cells to make them more amenable to immunotherapy, says Vered Stearns, M.D., director of the Women’s Malignancies Disease Group at the Johns Hopkins Kimmel Cancer Center. The authors found that the objective response rate, or percentage of patients whose cancer responded to therapy, was 16%. One patient with triple-negative breast cancer had a complete response, meaning a total shrinkage of the cancer. Because the cancer types included in the study are not felt to have high response rates to immune checkpoint therapy, these preliminary results are very promising. Treatment-related adverse events were mostly low grade, and included fatigue, nausea, anemia and diarrhea. These results were published online in the June 16 issue of Clinical Cancer Research. Safe and tolerable combination of therapies Study co-author Evanthia T. Roussos Torres, M.D., Ph.D., an adjunct professor at Johns Hopkins and assistant professor of medicine at the University of Southern California’s Norris Comprehensive Cancer Center in Los Angeles, says the entinostat functioned as an immune systempriming agent prior to using

OCTOBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

“One of the major findings of our study is that this is a safe and tolerable combination of therapies,” she says. “There aren’t very many trials investigating dual immune checkpoint inhibition in combination with other novel therapeutics. We determined a safe, tolerable dose with this combination that had very few adverse effects. That is significant.” Combination therapy helped increase immune cells that directly kill cancer cell The researchers collected blood and tumor samples from the 33 patients before and after the two weeks of entinostat to assess the impact of the entinostat on the immune system, and also after the addition of the immune checkpoint agents to evaluate the effect of each of the treatments on the immune environment. The study team found a significant increase in the ratio of CD8/FoxP3 gene expression in tumors following checkpoint inhibitor treatment but not after entinostat treatment alone. This suggests that the combination therapy helped increase both cytotoxic immune system T cells — immune cells that directly kill cancer cell — as well as decrease immune system T regulatory cells — immune cells that modulate the immune response — which equaled a stronger immune response, Roussos Torres says. The median age of participants was 60, most (91%) were female, 30% had breast cancer (the main tumor type studied) and the median number of prior regimens tried for their disease was 3.5. The median progression-free survival, or time until disease progression or death, was 6.1 months, and median overall survival was 10.6 months. Stable disease, considered the best response, was observed in 44% of participants. Clinical benefit rate, or the percentage of patients who

achieved stable disease, or partial or complete response, was 60%. May be a role for this combination of therapies in breast cancers The most robust increases in CD8/FoxP3 ratio were observed in two patients with HR-positive breast cancer who experienced a partial response and stable disease. Three additional patients who experienced stable disease had adenocarcinoma, a cancer of glandular tissue. The complete response in a patient with breast cancer “is a promise that there may be a role for this combination of therapies in breast cancers,” says senior study author Roisin M. Connolly, M.B.B.Ch., M.D., an adjunct professor at Johns Hopkins and chair in cancer research at University College Cork and Cork University Hospital in Ireland. “Immunotherapy hasn’t been as big a blockbuster to date in advanced breast cancer as in other cancers, such as lung cancers or melanoma. This study paves the way for novel combination therapies that have the potential to improve response rates to immune checkpoint inhibitors in traditionally less-responsive tumor types.” This drug combination is being investigated further in a group of 24 patients with HER2-negative breast cancer as part of the same NCI-sponsored clinical trial. “We are excited to have completed accrual to these ongoing studies in advanced HER2-negative breast cancer, and expect to report on these findings later this year,” says Stearns. Study co-authors were Christine Rafie, Chenguang Wang, David Lim, Melinda Downs, Molly Geare, Leslie Anforth, Michelle A. Rudek, Qingfeng Zhu, Sepideh Besharati, Ashley CiminoMathews, Robert A. Anders, Vered Stearns, and Elizabeth M. Jaffee of Johns Hopkins. Other authors contributing to the study were from the University of Miami Miller School of Medicine; the University of Pittsburgh Cancer Institute; Yale Cancer Center; City of Hope, Duarte, California; the National Cancer Institute; and the NIH Clinical Center.

In treating a broad range of women with HR+/HER2- mBC:1

CONFIDENCE

BUILT ON STRENGTH STRENGTH FROM… Powerful clinical efficacy1 Real-world experience2 Patient-reported outcomes3 Established safety profile1 One scheduled monitoring provision1 One capsule, Once daily1 Indications: IBRANCE® is indicated for the treatment of HR+/HER2- locally advanced or mBC:1 • In combination with an AI • In combination with fulvestrant in women who have received prior ET • In pre- or peri-menopausal women, the ET should be combined with an LHRH agonist For more information visit www.pfizerpro.ie/product/ibrance IBRANCE® (PALBOCICLIB) PRESCRIBING INFORMATION: Please refer to the Summary of Product Characteristics (SmPC) before prescribing IBRANCE 75 mg, 100 mg or 125 mg hard capsules. Presentation: Hard capsules containing 75 mg, 100 mg or 125 mg palbociclib. Indications: Treatment of hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) negative locally advanced or metastatic breast cancer: in combination with an aromatase inhibitor; or in combination with fulvestrant in women who have received prior endocrine therapy. In pre- or perimenopausal women, the endocrine therapy should be combined with a luteinizing hormone releasing hormone (LHRH) agonist. Dosage: Therapy should be initiated and supervised by a physician experienced in the administration of anti-cancer medicinal products. The recommended dose is 125 mg of palbociclib once daily for 21 consecutive days followed by 7 days off treatment (Schedule 3/1) to comprise a complete cycle of 28 days. When coadministered with palbociclib, the aromatase inhibitor should be administered according to the dose schedule reported in the SmPC. Treatment of pre/perimenopausal women with the combination of palbociclib plus letrozole should always be combined with an LHRH agonist (see SmPC section 4.4). Capsules should be swallowed (should not be chewed, crushed, or opened prior to swallowing). They should be taken with food, preferably a meal to ensure consistent palbociclib exposure (see SmPC section 5.2). Palbociclib should not be taken with grapefruit or grapefruit juice (see SmPC section 4.5). Dose modification of IBRANCE is recommended based on individual safety and tolerability. Management of some adverse reactions may require temporary dose interruptions/delays, and/or dose reductions, or permanent discontinuation. For dose reduction guidelines for management of adverse reactions, haematologic and non-haematologic toxicities, refer to SmPC section 4.2. IBRANCE should be permanently discontinued in patients with severe interstitial lung disease (ILD)/pneumonitis. For patients who experience a maximum of Grade 1 or 2 neutropenia in the first 6 cycles, complete blood counts for subsequent cycles should be monitored every 3 months, prior to the beginning of a cycle and as clinically indicated. No dose adjustments of IBRANCE are required for patients with mild or moderate hepatic impairment (Child-Pugh classes A and B). For patients with severe hepatic impairment (Child-Pugh class C), the recommended dose of IBRANCE is 75 mg once daily on Schedule 3/1 (see SmPC section 5.2). No dose adjustments of IBRANCE are required for patients with mild, moderate or severe renal impairment (creatinine clearance [CrCl] ≥15 mL/min) (see SmPC section 5.2). No dose adjustment of IBRANCE is necessary in patients ≥65 years of age (see section 5.2). Contraindications: Hypersensitivity to the active substance or to any of the excipients (see SmPC section 6.1), use of preparations containing St. John’s Wort

(see SmPC section 4.5). Warnings and Precautions: Ovarian ablation or suppression with an LHRH agonist is mandatory when pre/ perimenopausal women are administered IBRANCE in combination with an aromatase inhibitor, due to the mechanism of action of aromatase inhibitors. Palbociclib in combination with fulvestrant in pre/perimenopausal women has only been studied in combination with an LHRH agonist. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia. Appropriate monitoring should be performed (see SmPC sections 4.2 and 4.8). Severe, life-threatening, or fatal ILD and/or pneumonitis can occur in patients treated with cyclin dependent kinase 4/6 (CDK4/6) inhibitors, including IBRANCE when taken in combination with endocrine therapy. Across clinical studies (PALOMA-1, PALOMA-2, PALOMA-3), 1.4% of IBRANCE-treated patients had ILD/ pneumonitis of any grade, 0.1% had Grade 3, and no Grade 4 or fatal cases were reported. Additional cases of ILD/pneumonitis have been observed in the post-marketing setting, with fatalities reported. Patients should be monitored for pulmonary symptoms and IBRANCE treatment should be immediately interrupted in patients suspected to have developed ILD/pneumonitis, see SmPC section 4.2, 4.4 and 4.8. Since IBRANCE has myelosuppressive properties, it may predispose patients to infections. Infections have been reported at a higher rate in patients treated with IBRANCE in randomised clinical studies compared to patients treated in the respective comparator arm. Grade 3 and Grade 4 infections occurred respectively in 5.6% and 0.9% of patients treated with IBRANCE in any combination (see SmPC section 4.8). Patients should be monitored for signs and symptoms of infection and treated as medically appropriate (see SmPC section 4.2). Physicians should inform patients to promptly report any episodes of fever. Strong inhibitors of CYP3A4 may lead to increased toxicity (see SmPC section 4.5). Avoid concomitant use of strong CYP3A inhibitors during treatment with palbociclib. Coadministration should only be considered after careful evaluation of the potential benefits and risks. If coadministration with a strong CYP3A inhibitor is unavoidable, reduce the IBRANCE dose to 75 mg once daily. When the strong inhibitor is discontinued, the dose of IBRANCE should be increased (after 3–5 halflives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor (see SmPC section 4.5). Coadministration of CYP3A inducers may lead to decreased palbociclib exposure and consequently a risk for lack of efficacy. Therefore, concomitant use of palbociclib with strong CYP3A4 inducers should be avoided. No dose adjustments are required for coadministration of palbociclib with moderate CYP3A inducers (see SmPC section 4.5). Women of childbearing potential or their male partners must use a highly effective method

of contraception while taking IBRANCE (see SmPC section 4.6). IBRANCE contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product. Drug Interactions: The concomitant use of strong CYP3A inhibitors including, but not limited to: clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, saquinavir, telaprevir, telithromycin, voriconazole, and grapefruit or grapefruit juice, should be avoided (see sections 4.2 and 4.4). No dose adjustments are needed for mild and moderate CYP3A inhibitors. The concomitant use of strong CYP3A inducers including, but not limited to: carbamazepine, enzalutamide, phenytoin, rifampin, and St. John’s Wort should be avoided (see SmPC sections 4.3 and 4.4). No dose adjustments are required for moderate CYP3A inducers. The dose of sensitive CYP3A substrates with a narrow therapeutic index (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus) may need to be reduced when coadministered with IBRANCE as IBRANCE may increase their exposure. Based on in vitro data, palbociclib is predicted to inhibit intestinal P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) mediated transport. Therefore, administration of palbociclib with medicinal products that are substrates of P-gp (e.g., digoxin, dabigatran, colchicine, pravastatin) or BCRP (e.g., rosuvastatin, sulfasalazine) may increase their therapeutic effect and adverse reactions. Based on in vitro data, palbociclib may inhibit the uptake transporter organic cationic transporter OCT1 and then may increase the exposure of medical product substrates of this transporter (e.g., metformin). Pregnancy & Lactation: Females of childbearing potential who are receiving this medicinal product, or their male partners should use adequate contraceptive methods (e.g., doublebarrier contraception) during therapy and for at least 3 weeks or 14 weeks after completing therapy for females and males, respectively (see SmPC section 4.5). There are no or limited amount of data from the use of palbociclib in pregnant women. Studies in animals have shown reproductive toxicity (see SmPC section 5.3). IBRANCE is not recommended during pregnancy and in women of childbearing potential not using contraception. Based on male reproductive organ findings (seminiferous tubule degeneration in testis, epididymal hypospermia, lower sperm motility and density, and decreased prostate secretion) in nonclinical safety studies, male fertility may be compromised by treatment with palbociclib (see SmPC section 5.3). Thus, men may consider sperm preservation prior to beginning therapy with IBRANCE. Driving and Operating Machinery: IBRANCE may cause fatigue and patients should exercise caution when driving

PP-IBR-IRL-0429 | Date of preparation: July 2021

or using machines. Side Effects: The most common (≥20%) adverse reactions of any grade reported in patients receiving palbociclib in randomised clinical studies were neutropenia, infections, leukopenia, fatigue, nausea, stomatitis, anaemia, diarrhoea, alopecia, and thrombocytopenia. The most common (≥2%) Grade ≥3 adverse reactions of palbociclib were neutropenia, leukopenia, anaemia, fatigue, infections, alanine aminotransferase (ALT) increased and aspartate aminotransferase (AST) increased. Dose reductions or dose modifications due to any adverse reaction occurred in 38.4% of patients receiving IBRANCE in randomised clinical studies regardless of the combination. Very common adverse events (>1/10) are neutropenia, infections, leukopenia, fatigue, anaemia, asthenia, pyrexia, nausea, stomatitis, alopecia, diarrhoea, thrombocytopenia, vomiting, rash, decreased appetite, dry skin, AST increased, ALT increased and aspartate aminotransferase (AST) increased. Commonly reported adverse events (>1/100 to <1/10), are, dysgeusia, epistaxis, ILD/pneumonitis, lacrimation increased, vision blurred, dry eye, febrile neutropenia. Refer to SmPC for further information on side effects. Refer to section 4.8 of the SmPC for further information on side effects, including description of selected adverse reactions. Legal Category: S1A. Marketing Authorisation Numbers: EU/1/16/1147/001 – 75 mg (21 capsules); EU/1/16/1147/003 – 100 mg (21 capsules); EU/1/16/1147/005 – 125 mg (21 capsules). 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.

Last revised: 07/2021 Ref: IB 9_0 References: 1. IBRANCE® Summary of Product Characteristics. 2. Taylor-Stokes G, et al. Breast. 2019;43:22-27. 3. Rugo HS,et al. Ann Oncol. 2018;29(4):888-894. AI = aromatase inhibitor; ET = endocrine therapy; HR+/HER2- = hormone receptor-positive, human epidermal growth factor receptor 2-negative; LHRH = luteinising hormone releasing hormone; mBC = metastatic breast cancer; SmPC = summary of product characteristics.

6/10

patients alive at 5 years 1,2

62.5% overall survival (0S) at 5 years with ALECENSA vs 45.5% with crizotinib * 1,2

Difference (95% CI): -17.0% (-33.5 to -2.5) Clinically meaningful improvement in OS ALEX Phase III trial: Global, multicentre, randomised, open-label trial comparing efficacy and safety between ALECTINIB and crizotinib in treatment-naïve patients with stage IIIB/IV ALK+ NSCLC (n=303)1-3

ALECENSA first line in ALK+ non-small cell lung cancer Indication: ALECENSA as monotherapy is indicated for the first-line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC).4 Data cut-off: 29 November 2019.1,2 *OS data remain immature.1,2 ALK: anaplastic lymphoma kinase. NSCLC: non-small cell lung cancer. OS: overall survival. References: 1. Mok T et al. Annals of Oncology 2020. DOI: https://doi.org/10.1016/j.annonc.2020.04.478. 2. Peters S et al. Poster 9518. Presented at ASCO Annual Meeting 29-31 May 2020. 3. Peters S et al. Alectinib versus Crizotinib in Untreated ALK-Positive Non–Small-Cell Lung Cancer. N Engl J Med 2017; 377:829-38. 4. ALECENSA SmPC 03 April 2020, available at www.medicines.ie. Date of item: November 2020. M-IE-00000403 ABRIDGED PRESCRIBING INFORMATION (API) For full prescribing information refer to the Summary of Product Characteristics [SmPC].

▼ (alectinib) 150 mg hard capsules (Each hard capsule contains alectinib hydrochloride equivalent to 150 mg alectinib).

Alecensa®

▼ This medicine 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 box below for details on how to report. Indications: As monotherapy for the first line treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). As monotherapy for the treatment of adult patients with ALK-positive NSCLC previously treated with crizotinib. Dosage and Administration: Treatment initiated and supervised by a physician experienced in the use of anticancer medicinal products. Validated ALK assay is necessary for the selection of ALK-positive NSCLC patients. Establish ALK-positive NSCLC status prior to initiation of Alecensa therapy. Recommended dose of Alecensa is 600 mg (four 150mg capsules) taken twice daily with food (total daily dose of 1200 mg). Patients with underlying severe hepatic impairment (Child-Pugh C) should receive a starting dose of 450 mg taken twice daily with food (total daily dose of 900 mg). Hard capsules to be swallowed whole, not to be opened or dissolved. Continue treatment until disease progression or unacceptable toxicity. If a planned dose is missed, make up that dose unless the next dose is due within 6 hours. Do not take 2 doses at the same time. If vomiting occurs after taking a dose, take the next dose at the scheduled time. When dose adjustment is necessary, reduce in steps of 150 mg twice daily based on tolerability. Refer to SmPC for dose modification advice. For all patients with hepatic impairment, appropriate monitoring is advised. No available data on patients over 80 years. No available data on children and adolescents <18 years or on patients with body weight above 130 kg. Contraindications: Hypersensitivity to alectinib or to any of the excipients. Special Warnings and Precautions: Interstitial lung disease (ILD)/pneumonitis: Cases of ILD/pneumonitis have been reported in Alecensa clinical trials. Monitor for pulmonary symptoms indicative of pneumonitis. Immediately interrupt in patients diagnosed with ILD/pneumonitis and permanently discontinue if no other potential causes of ILD/pneumonitis have been identified, refer to SmPC. Hepatotoxicity: AST, ALT (>5 x ULN) and bilirubin elevations (>3 x ULN) occurred in Alecensa pivotal clinical trials. The majority of these occurred during the first 3 months of treatment. Monitor AST, ALT and bilirubin at baseline, and then every 2 weeks during the first 3 months of treatment. Thereafter monitoring should be performed periodically, with more frequent monitoring in patients who develop aminotransferase and bilirubin elevations. Treatment should be withheld and resumed at a reduced dose, or permanently discontinued, refer to SmPC. Severe myalgia and creatine phosphokinase (CPK) elevation: Myalgia and musculoskeletal pain was reported in patients in pivotal trials, including Grade 3 events. Patients should be advised to report any unexplained muscle pain, tenderness, or weakness. CPK levels should be assessed every two weeks for the first month of treatment and as clinically indicated in patients reporting symptoms. Based on the severity of the CPK elevation, Alecensa should be withheld, then resumed at the same dose or dose reduced, refer to SmPC. Bradycardia: Symptomatic bradycardia can occur. Monitor heart rate and blood pressure as clinically indicated. Evaluate concomitant medicinal products known to cause bradycardia, as well as anti-hypertensive medicinal products if patients experience symptomatic bradycardia or life-threatening events. Symptomatic bradycardia can be managed with treatment interruption, dose reduction. If life-threatening, permanently discontinue if no contributing concomitant medicinal product is identified or upon recurrence. Gastrointestinal perforation: Cases of gastrointestinal perforations have been reported

in patients at increased risk (e.g., history of diverticulitis, metastases to the gastrointestinal tract, concomitant use of medicinal product with a recognized risk of gastrointestinal perforation) treated with Alecensa. Consider discontinuation of Alecensa in patients who develop gastrointestinal perforation. Inform patients of the signs and symptoms of gastrointestinal perforations and advise them to consult their HCP rapidly in case of occurrence. Photosensitivity: Photosensitivity has been reported. Avoid prolonged sun exposure during treatment and for at least 7 days after discontinuation. Advise to protect against sunburn. Women of child-bearing potential: Alecensa may cause foetal harm during pregnancy. Female patients of child bearing potential receiving Alecensa must use highly effective contraceptive methods during treatment and for at least 3 months following the last dose. Lactose intolerance: Patients with rare hereditary problems of galactose intolerance, congenital lactase deficiency or glucose-galactose malabsorption should not take Alecensa. Sodium content: Alecensa contains 48 mg sodium per daily dose (1200 mg), equivalent to 2.4% of the WHO recommended maximum daily intake of 2 g sodium for an adult. Interactions: Avoid grapefruit juice, grapefruit and Seville oranges. No dose adjustments are required when Alecensa is co-administered with CYP3A inducers, CYP3A inhibitors, CYP3A substrates, proton pump inhibitors or other medicinal products which raise gastric pH. Appropriate monitoring is recommended for patients taking concomitant strong CYP3A inducers, strong CYP3A inhibitors, P-gp substrates, BCRP substrates. The effectiveness of concomitant administration of oral contraceptives may be reduced. Refer to SmPC. Fertility, Pregnancy and Lactation: Advise women of childbearing potential to avoid pregnancy during treatment. See Special Warnings and Precautions. Patients should be advised to report a pregnancy while taking Alecensa or during the 3 months following the last dose of Alecensa and should be advised of the potential harm to the foetus. Reproductive toxicity observed in animals. Do not breast-feed while taking Alecensa. Refer to SmPC. Effects on ability to drive and use machines: Exercise caution when driving or operating machines. Undesirable Effects: Safety evaluated in 405 patients in phase II and III clinical trials. Most common ADRs were constipation (35%), oedema (30%) and myalgia (28%). Very common: anaemia, constipation, nausea, diarrhoea, vomiting, increased bilirubin, increased AST, increased ALT, rash, myalgia, increased blood creatine phosphokinase, oedema, weight increased. Common: Dysgeusia, vision disorders, bradycardia, stomatitis, increased alkaline phosphatase, photosensitivity, blood creatinine increased, acute kidney injury. Uncommon: Severe interstitial lung disease (ILD)/pneumonitis, drug-induced liver injury. Refer to Alecensa SmPC for a full list of adverse reactions. See SmPC section 4.8 for instructions on reporting Suspected Adverse Reactions. Legal Category: Product subject to prescription which may not be renewed (A). Presentation and Marketing Authorization Number: 224 (4 packs of 56) hard capsules (EU/1/16/1169/001). Marketing Authorisation Holder: Roche Registration GmbH, Emil-Barell-Strasse 1, 79639 Grenzach-Wyhlen, Germany. Alecensa® is a registered trade mark. Further information is available from Roche Products (Ireland) Limited, 3004 Lake Drive, Citywest, Naas Road, Dublin 24. Telephone: (01) 4690700. Fax: (01) 4690791. Date of API Preparation: April 2020.

▼ This medicine 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 event, please report it to: The Drug Surveillance Centre Roche Products (Ireland) Limited Telephone: (01) 4690700 Fax: (01) 4690793 Email: ireland.drug_surveillance_centre@roche.com

Alternatively, suspected adverse reactions should be reported to: HPRA Pharmacovigilance The Health Products Regulatory Authority (HPRA) Telephone: (01) 6764971 Fax: (01) 6762517 Website: www.hpra.ie Email: medsafety@hpra.ie

Alecensa® Summary of Product Characteristics [SmPC] is available on www.medicines.ie. API (IE/ALEC/0217/0003(5) based on Alecensa SmPC dated 03rd April 2020.

POLYCYSTIC OVARY SYNDROME

Polycystic Ovary Syndrome Written by Dr David Crosby, and Dr Laurentina Schaler, National Maternity Hospital, Dublin Clinical presentation and management Common clinical presentations of PCOS are outlined in Table 2. Management of patients with PCOS is complex and requires a multidisciplinary approach involving gynaecology, endocrinology, reproductive medicine, dermatology, dieticians, psychology, nursing and other allied healthcare professionals. Management of PCOS can adopt a conservative, medical or surgical approach based on the presentation and the patient’s wishes.

Introduction Polycystic Ovary Syndrome, or PCOS, is the most common endocrinopathy in women of reproductive age. There can often be a delay in definitive diagnosis due to significant variation in phenotypic presentation. The incidence of PCOS in women of reproductive age is estimated to be between 8 and 13% depending on the population studied. The prevalence in Ireland is 128 per 100,000 women of reproductive age. There is marked variation across Europe, with a prevalence ranging from 34 to 461 in 100,000 women of reproductive age in recently published data1. This variation can be explained by the differences in diagnostic

criteria used, the heterogenous nature of the condition and the difference in the number of cases diagnosed in a region. Additionally, certain ethnic groups, including South Asian and Australian Aboriginal populations have a higher incidence of PCOS2. Although there have been no definitive monogenic causes of PCOS identified to date, it is hypothesised that PCOS may be polygenic in nature, with almost 50% of female first degree relatives of women with PCOS also affected3. Diagnosis The Rotterdam Criteria, defined by the European Society of Human Reproduction and Embryology (ESHRE) and the American Society

Table 1: Rotterdam Criteria (2003) for diagnosis of PCOS* 1. Ovulatory dysfunction 2. Polycystic ovaries on ultrasound (≥12 follicles 29mm per ovary and/or a volume >10ml)** 3. Clinical or biochemical hyperandrogenism *A minimum of 2 out of 3 criteria are required for a diagnosis of PCOS

following the exclusion of phenotypically androgen excess *A minimum of 2 out of 3 criteriasimilar are required for adisorders such as congenital adrenal hyperplasia, androgen-secreting tumours, Cushing diagnosis of PCOS following the exclusion of syndrome, thyroid dysfunction, and hyperprolactinemia ** Using transvaginal phenotypically similar excess of disorders such as ultrasound transducers with a androgen frequency bandwidth ≥ 8MHz, the threshold for polycystic ovarian morphology shouldandrogen-secreting be on either ovary, a follicle number congenital adrenal hyperplasia, per ovary ofCushing ≥20 and/or syndrome, an ovarian volume ≥ 10ml, ensuring no corpora tumours, thyroid dysfunction, and lutea, cysts or dominant follicles are present hyperprolactinemia ** Using transvaginal ultrasound transducers with a frequency bandwidth of ≥ 8MHz, the threshold for OCTOBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE polycystic ovarian morphology should be on either ovary, a

for Reproductive Medicine (ASRM) in 2003, continue to be widely utilised internationally for the diagnosis of PCOS in women of reproductive age. A minimum of two criteria are required to make the diagnosis, after the exclusion of other aetiologies (Table 1). These aetiologies include thyroid disease, hyperprolactinemia, Cushing syndrome, androgen secreting tumours or congenital adrenal hyperplasia. It has been suggested that the diagnosis of PCOS should be approached with caution during puberty as symptoms, which are often transitional during this time, can be mistaken for PCOS and in some cases lead to an overdiagnosis. As a result, it has been recommended that ultrasonographic assessment should not be included in the diagnostic criteria for up to eight years following menarche. Rather, adolescents with symptoms and signs suggestive of PCOS should be followed up and reassessed to establish progression of symptoms before making a definitive diagnosis4.

Lifestyle modifications, including regular physical exercise and dietary optimisation, form the basis of the initial management and can help achieve optimal body mass index (BMI), regulate hormonal imbalances, and improve quality of life5-7. Counselling can play an extremely important role in the management of women with PCOS. Other conservative measures include cosmetic treatments for hirsutism. Hormonal treatment with a combined oral contraceptive pill (COCP) is recommended to regulate hormonal imbalances and thus regulate menstrual cycles and improve hirsutism. When commencing hormonal therapy, phenotypic features of PCOS, which may be a relative or absolute contraindication to treatment with these modalities, should be taken into consideration. Some international guidelines recommend that in cases where lifestyle and the COCP have failed to achieve an adequate response or in women with high risk of metabolic disease, consideration can be given to the addition of Metformin4. However, there is conflicting evidence that the use of Metformin in PCOS confers any long term benefit8. The negative effects on the quality of life for women who suffer with PCOS can often be underestimated. Symptoms

Table 2: Common clinical presentations of PCOS • Acne

• Alopecia

• Hirsutism

• Irregular menstrual cycles

• Infertility

• Increased body mass index

• Mood disturbance

• Pelvic pain

Figure 1 : Typical sonographic appearance of a polycystic ovary with multiple peripheral follicles.

Figure 1 : Typical sonographic appearance of a polycystic ovary with multiple peripheral follicles 3.

Balen AH. Polycystic Ovary Syndrome (PCOS). TheObstetrician and Gynaecologist. 2017.

Teede HJ, Misso ML, Boyle JA, Garad RM, McAllister V, Downes L, et al. Translation and implementation of the Australian-led PCOS guideline: clinical summary and translation resources from the International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. Medical Journal of Australia. 2018;209:S3-S8.

Huber-Buchholz M-M, Carey D, Norman R. Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. The Journal of Clinical Endocrinology & Metabolism. 1999;84(4):1470-4.

Moran LJ, Noakes M, Clifton PM, Tomlinson L, Norman RJ. Dietary composition in restoring reproductive and metabolic physiology in overweight women with polycystic ovary syndrome. The Journal of Clinical Endocrinology & Metabolism. 2003;88(2):812-9.

Thomson RL, Buckley JD, Lim SS, Noakes M, Clifton PM, Norman RJ, et al. Lifestyle management improves quality of life and depression in overweight and obese women with polycystic ovary syndrome. Fertility and sterility. 2010;94(5):1812-6.

A multidisciplinary, individualised approach to care can provide optimisation of women’s health and prevent short and long term complications including type II diabetes, cardiovascular disease, endometrial cancer and infertility in women with PCOS.

RCOG. Long-term consequences of polycystic ovary syndrome. 2014.

Dokras A, Stener-Victorin E, Yildiz BO, Li R, Ottey S, Shah D, et al. Androgen Excess-Polycystic Ovary Syndrome Society: position statement on depression, anxiety, quality of life, and eating disorders in polycystic ovary syndrome. Fertility and sterility. 2018;109(5):888-99.

Further Reading:

10. Balen AH, Anderson RA, Policy, BFS PCot. Impact of obesity on female reproductive health: British fertility society, policy and practice guidelines. Human Fertility. 2007;10(4):195-206.

circumference, dyslipidaemia and hypertension. It is recommended that these risk factors be screened for, assessed and monitored on an ongoing basis in this population.

such as hirsutism, obesity and acne can lead to unnecessary embarrassment and suffering and these should be addressed and managed, where possible. Healthcare professionals must Symptoms & Management be cognisant of the symptoms of anxiety and depression that women with PCOS may present with and where needed, onward referral for further management should be employed9.

is unsuccessful, a second line approach is laparoscopic ovarian drilling or puncture. Women with PCOS may have ovaries with a thick outer layer. Ovarian drilling works by breaking through the thick outer surface and lowering the amount of testosterone made by the ovaries. This procedure can result in ovulation in up to 50% of women that were unresponsive to initial therapy.

PCOS and infertility

Body mass index can also affect ovarian function and therefore contribute to infertility. Fertility treatment is challenging in women with higher body mass indices and monitoring of ovarian response with ultrasound can be limited as a result. Complications and adverse outcomes in those with higher body mass indices are however, not just limited to fertility treatments. The incidence of pregnancy complications such miscarriage and congenital anomalies are also increased in women in the obese category. The British Fertility Society have recommended that fertility treatment should be deferred until a BMI under 35 kg/m2 is achieved, and that in women where treatment is less time sensitive, a BMI of less than 30 kg/m2 is preferable10.

PCOS is found to be the cause of anovulatory cycles in 80-90% of women with menstrual irregularities and is also a common diagnosis seen in approximately a third of couples attending fertility clinics3. Once again, a multimodal approach is necessary, including lifestyle and diet adjustments for those with higher body mass indices, possibly followed by ovulation induction once other causes of infertility have been excluded. Prior to embarking on fertility treatment in women with PCOS, optimisation of health should be achieved. Women should be advised to take folic acid at a dose of 400mcg daily. In women who are obese (BMI ≥ 30kg/m2), 5mg of folic acid supplementation should be recommended daily. A comprehensive infertility workup should be performed prior to fertility treatment. Investigations to assess ovarian reserve, confirm tubal patency and assess semen analysis if applicable should also be considered prior to fertility treatment to guide the most appropriate individualised management. One management approach is ovulation induction. This can be achieved through oral agents, including selective oestrogen receptor modulators or aromatase inhibitors, or subcutaneous gonadotropins. Initially, all cycles of ovulation induction should be monitored with ultrasonographic follicular tracking. Women with polycystic ovaries are at a higher risk of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy, and therefore may require even closer monitoring during ovulation induction. If ovulation induction treatment

Long term prognosis Although data on long term outcomes in women with PCOS are conflicting, symptoms associated with PCOS such as obesity, dyslipidaemia and anovulation may result in long term complications including type II diabetes, cardiovascular disease and endometrial hyperplasia. The prevalence of gestational diabetes, impaired glucose tolerance and type II diabetes have been found to be significantly increased in women with PCOS11,12. International guidelines suggest that glycaemic control should be assessed at diagnosis in this population and one to three yearly thereafter4. Although an increased risk of cardiovascular disease in women with PCOS has not been quantified to date, women with PCOS often carry additional risk factors for cardiovascular disease such as increased BMI, increased waist

analysis. Human reproduction. 2016;31(12):2841-55.

Although the relative incidence still remains low, women with PCOS have a two to six-fold increased risk of endometrial cancer13. It is crucial for women with amenorrhea to shed their endometrium at least every three months in order to reduce the risk of endometrial hyperplasia, a precancerous condition which can lead to endometrial cancer over time. This occurs as a result of chronic exposure to oestrogen that is unopposed by progesterone. Healthcare professionals need to be aware of this increased risk and have a low threshold for investigation of abnormal uterine bleeding in women with PCOS. Conclusion Polycystic Ovary Syndrome is a common condition in women of reproductive age. It is often undiagnosed due to its heterogenous phenotype. Early recognition is crucial to allow appropriate management of symptoms and sequelae, which can have major implications on a woman’s quality of life.

•

HSE PCOS Overview: https:// www2.hse.ie/conditions/polycysticovary-syndrome/ • EInternational evidence-based guideline for the assessment and management of polycystic ovary syndrome (PCOS) S : https://www. eshre.eu/Guidelines-and-Legal/ Guidelines/Polycystic-OvarySyndrome • RCOG Patient Information Leaflet PCOS : https://www.rcog.org.uk/en/ patients/patient-leaflets/polycysticovary-syndrome-pcos-what-itmeans-for-your-long-term-health/ References: 1.

Miazgowski T, Martopullo I, Widecka J, Miazgowski B, Brodowska A. National and regional trends in the prevalence of polycystic ovary syndrome since 1990 within Europe: the modeled estimates from the Global Burden of Disease Study 2016. Archives of Medical Science: AMS. 2021;17(2):343. Bozdag G, Mumusoglu S, Zengin D, Karabulut E, Yildiz BO. The prevalence and phenotypic features of polycystic ovary syndrome: a systematic review and meta-

11. Rubin KH, Glintborg D, Nybo M, Abrahamsen B, Andersen M. Development and risk factors of type 2 diabetes in a nationwide population of women with polycystic ovary syndrome. The Journal of Clinical Endocrinology & Metabolism. 2017;102(10):3848-57. 12. Moran LJ, Misso ML, Wild RA, Norman RJ. Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. Human reproduction update. 2010;16(4):347-63. 13. Charalampakis V, Tahrani AA, Helmy A, Gupta JK, Singhal R. Polycystic ovary syndrome and endometrial hyperplasia: an overview of the role of bariatric surgery in female fertility. European Journal of Obstetrics & Gynecology and Reproductive Biology. 2016;207:220-6.

HOSPITALPROFESSIONALNEWS.IE | HPN • OCTOBER - 2021

PERINATAL MENTAL HEALTH

Perinatal Mental Health During Covid-19: A Delicate Balance Written by Dr Laura McHugh, Psychologist in Clinical Training, NUI Galway

During pregnancy, women experience both physiological and psychological changes which can place them at risk of developing mental health difficulties1. Mental health difficulties during pregnancy are related to adverse outcomes for both mother and infant. For the infant, maternal anxiety and depression are associated with a shorter gestational period, low birth weight and adverse neurodevelopmental outcomes2, as well as reduced postpartum bonding3. For mothers who experience mental health difficulties during pregnancy, impacted sleep, conflict with partners, feelings of worry, and loss of a sense of self are described by women4, as well as impacted parent-infant bonding3. The addition of the Coronavirus (SARS-CoV2) (Covid-19) pandemic to the period of pregnancy may potentially increase the risk of mental health difficulties for women during this time5. Restrictions on the presence of partners during antenatal appointments and the period of labour have been put in place to varied extents across hospital groups6. Remote consultations with healthcare staff, social distancing and home isolation have also been introduced across Ireland. The rationale for all of these restrictions being to prevent the spread of infection of the Covid-19 virus,

and minimize exposure for vulnerable groups such as expectant mothers7. These preventative measures in response to the Covid-19 pandemic may have unintended consequences for the mental health of women during pregnancy5. The public health measure in response to Covid-19 mean that the typical ‘right of passage’ experiences for women during pregnancy, such as a therapeutic connection with healthcare providers, social interaction with other pregnant women, and celebrations amongst friends and family may not be accessible to women6. The causes of stress and worry that have been identified by pregnant women during the

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51 pandemic include fear of catching or spreading Covid-19, changes to the organisation of perinatal care, online consultations with healthcare staff, and not having a partner present during birth8. Continued experiences of dailystressors for women has been related to adverse mental health

outcomes during the period of pregancy9. During the pandemic, studies have been carried out across the globe to explore the mental health of pregnant women. These studies have been carried out in Italy10, the United States11, China12 and across Europe, inclusive of Ireland13. These studies indicate a significant prevalence of anxiety and depression in pregnant women during the Covid-19

pandemic8. Studies which surveyed expectant mothers before the pandemic and during the pandemic found pregnant mothers during the pandemic were more likely to experience clinical levels of anxiety and depression than the mothers who were surveyed before the pandemic14. Research observing this uptrend of mental health difficulties among expectant mothers during Covid-19 have highlighted the need to monitor the mental health status of pregnant women at this time13. Social support is protective against mental health difficulties for pregnant women, particularly for first-time mothers15. The availability of emotional and practical supports from friends and family during pregnancy is associated with lower levels of emotional distress for women16. Women consider access to social ‘safety nets’, in the form of connections with others and partner support, as key to reducing feelings of isolation during pregnancy17. The availability of these ‘safety nets’ are a continued challenge for women during the pandemic. Continued spousal support during the period of labour is also of particular importance. Cochrane reviews summarising research in this area have indicted the importance of continued spousal support during labour18. Spousal support serves the function of helping to communicate preferences to a health worker, support in decision-making, and providing encouragement, reassurance, and physical comfort during labour18. The presence of continuous one-to-one support for women during labour was related to shorter labours, lower rates of caesarean births, lower rates of intrapartum analgesia, positive feelings about the birth experience and lower rates of depressive symptomology post-birth18. Conversely, low support during labour and birth is a risk factor for the development of postnatal post-traumatic stress disorder (PTSD)19. To this end, the World Health Organization (WHO) guidance recommends the presence of a companion of the woman's choice during labour and childbirth, to improve labour outcomes and women's satisfaction with services20.

However, women may not only be vulnerable in terms of mental health during pregnancy, but may also be vulnerable medically. During pregnancy, the immune system is partially supressed, making women more vulnerable to viral infections21. The risks to both mother and infant medically due to Covid-19 are still being understood21. Synthesis of the possible implications of Covid-19 infection for pregnant women note the limited number of case reports to draw upon, with small and diverse samples making generalisations challenging22. However, some data has suggested that if infected with Covid-19, pregnant women experience more severe illness, are more likely to experience pre-term births and increased neonatal mortality22,23. Research considering these findings, and comparing the pathogenic potential of Covid-19 to other members of the coronavirus family, such as Middle East respiratory syndrome (MERS-CoV), recommend that pregnant women are considered high-risk and the implementation of protective steps to monitor and prevent infection21. The mental health needs of pregnant women have been overshadowed by other pressing issues in healthcare settings during the Covid-19 pandemic5. Research during the pandemic has demonstrated an uptrend in perinatal mental health difficulties for women. Fear of the spread of Covid-19, changes to perinatal care, online consultations, and not having a partner present during birth are ongoing stressors for women during pregnancy. However, the availably of practical and emotional support from loved ones during pregnancy, and continuous one-to-one support during labour, are protective against mental health difficulties and related to positive outcomes during labour and post birth. The need for focus on the mental health of pregnant women during the pandemic, and to proactively develop strategies to monitor and protect against mental health difficulties for women has been a central recommendation of research5. References available on request

HOSPITALPROFESSIONALNEWS.IE | HPN • OCTOBER - 2021

INCONTINENCE

Therapeutic Management of Stress Urinary Incontinence Written by Linda Kelly RCSN RN and RM(H Dip), RMP, Advanced Midwife Prescriber in Urodynamics and Women’s Health at The National Maternity Hospital, Holles Street - David Fitzgerald MPharm MSc (Clinical Pharmacy) MPSI, Chief Pharmacist at The National Maternity Hospital, Holles Street

Non-Pharmacological Management

Epidemiology and Risk Factors The International Continence Society (ICS) defines urinary incontinence (UI) as “the complaint of any involuntary leakage of urine”. UI can be categorised into:

Women attending with SUI should be advised that nonpharmacological treatment options are the first line of management. Such treatments can improve symptoms but may not cure them. These options include; 1. Lifestyle changes: o Keeping fluid intake to 1500ml-2000mls daily,

1. Stress Urinary incontinence (SUI) - involuntary leakage on effort or exertion or on sneezing or coughing

o Regular voiding (6-8 times daily),

2. Urge Urinary incontinenceinvoluntary leakage accompanied by or immediately preceded by urgency

o Reducing weight,

3. Mixed Urinary IncontinenceInvoluntary leakage associated with urgency and also exertion, effort, sneezing or coughing1 UI is a major clinical problem and can have a profound effect on a woman’s quality of life and activities of daily living. It can be physically debilitating and socially isolating which in turn can lead to loss of self-confidence, feelings of helplessness and in some cases depression and anxiety. SUI is the most common type of urinary incontinence in women2. The exact incidence of SUI in Ireland is unknown although various sources suggest that it could affect as many as 1 in 3 women. In 2018 it was estimated that there were 164 million individuals worldwide affected by SUI. The exact pathophysiology of SUI is unknown although it is agreed that lack of urethral support, poor pelvic floor muscle tone, urethral sphincter damage and urethral hypermobility all play a part to varying degrees. Leakage of urine occurs when the pressure in the bladder exceeds the closure pressure of the urethra. This commonly happens during physical activity such as exercise or on coughing, sneezing or laughing1. Risk factors for developing SUI include age, obesity, smoking, parity, vaginal delivery, hysterectomy, depression, IBS, sleep apnoea and neurological disorders3.

o Caffeine avoidance,

o Avoiding lifting heavy objects, o Avoiding/managing constipation, o Stopping smoking, o Doing lower impact exercises 2. Pelvic floor physiotherapy with a women’s health physiotherapist to help optimise the pelvic floor function. 3. Continence pessaries and vaginal/urethral support devices e.g. Contiform® pessary, Diveen® applicator - these are single use or reusable devices which are inserted into the vagina to provide support to the urethra and help reduce leakage of urine. 4. Containment products; some women prefer to use good quality containment products such as the EVB shorts etc. If using containment products it is important to ensure good perineal and personal hygiene to prevent skin breakdown.

anatomical factors involved in the pathogenesis of SUI. The development of medications to treat SUI has been slow. Pharmacological management of SUI aims to increase tone in the urethral muscles. Several medications may contribute to increased urethral tone, but lack of efficacy and/or adverse effects have limited their use in practice (see table 1)4.

If non-pharmacological treatments do not improve symptoms women should be referred to an appropriate healthcare provider to discuss. Medications are usually considered as adjunctive therapy, since it is difficult to pharmacologically treat the

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Table 1

Pelvic floor disorders are more common after menopause. Hence, oestrogen therapy may be of use in treatment of SUI in post-menopausal women with oestrogen deficiency8. Metaanalyses rated the evidence for efficacy of oestrogen in treating incontinence as low but well tolerated9,10. Current guidelines suggest the use of oestrogen as an adjunct therapy only9. A Cochrane review found the route of administration to be important. A worsening of incontinence was reported with systemic administration compared to an improvement using topical administration11.

In 2004, the combined serotonin and noradrenaline reuptake inhibitor (SNRI) Duloxetine, was licensed in Europe as adjunctive therapy for SUI. Originally licensed as an anti-depressant, Duloxetine acts by increasing the contractile activity in the urethral sphincter5. A Cochrane analysis of nine randomised controlled trials (RCT) s comparing Duloxetine to placebo reported the rate of subjective “cure” using 40mg twice daily to be higher than placebo (10.8% vs 7.7%; 95% confidence interval 1.02 – 1.98; p = 0.04). The estimated absolute size of effect was three more patients cured Future Treatments out of every 100 treated. Nausea Management of SUI is primarily was the most common adverse through non-pharmacological event with an incidence of 23 to treatment and lifestyle 25% and was the main reason for changes. There is an urgent discontinuation6. UK guidelines development of new recommend Written byoffering LindaDuloxetine Kelly RCSN RNneed andfor RM(H Dip), RMP, Advanced M pharmacological therapies for as a non-routine, second-line SUI that are safe, efficacious andHolles Str and Women’s Health at The National Maternity Hospital, treatment for women with SUI well tolerated. who would prefer pharmacological MSc (Clinical Pharmacy) MPSI, Chief Pharmacist at The National Ma to surgical treatment or are not Useful resources suitable for surgical treatment7. www.continence.ie | www.evb.ie Despite its established efficacy in www.ics.org | www.iuga.org phase III trials, the Food and Drug www.iccp | www.iaun.ie Administration (FDA) in the United www.oab.ie | www.hse.ie/continence States did not grant a license for References available on request treatment of SUI due to concerns

Table 1

Medication

5. Surgical options Pharmacological Management

over increased risk of suicide attempts in women prescribed this medication for this indication.

Duloxetine Imipramine Clenbuterol Methoxamine Midodrine Ephedrine Norephedrine (phenylpropanolamine) Oestrogen

Level of evidence 1 3 3 2 2 3 3

Grade of Recommendation B D C D C D D

SJÖGREN’S SYNDROME

Changing the Focus of Practice – The Patient Perspective of Sjögren’s Syndrome Contributing authors:

Deirdre Collins - Sjögren’s Syndrome Patient Advocate, co-organiser of the Inaugural Information Webinar for Sjögren’s Syndrome Patients in Ireland

Sjögren's Syndrome is a chronic autoimmune disease, which predominately affects women (9:1). In Sjögren’s, the specialized secretary glands that produce saliva and ocular tears become infiltrated with lymphocytes, leading to inflammatory fibrosis and their ultimate destruction. This leads to a pathognomonic sicca complex of dry eye (keratoconjunctivitis sicca) and dry mouth (xerostomia). Additionally, some patients can develop systemic complications such as fatigue, joint and muscle pain, skin rashes, pulmonary complications and beyond, with symptoms ranging from mild to severe. At present, there is no way to predict which patients will go on to develop extra-glandular complications. Treatment options are reactive and limited, and the disease can have a significant impact on patients’ quality of life. There are two forms of Sjögren’s Syndrome, primary and secondary. Primary Sjögren's Syndrome occurs by itself without any other illness. Secondary Sjögren's Syndrome develops in a person who has another autoimmune condition, such as rheumatoid arthritis or systemic lupus erythematosus.

Dr Emily Greenan, MB, BCh and BAO, HDipTeaching - patients will go on to develop extra-glandular complications. present, there is no way to (LCM) predict which Clinical tutor, RCSI University of Treatment options are reactive and limited, and the disease canKerin, have a significant impact(Psych) on patients’ Medicine and Health Sciences and Lorna B.A, H.Dip and Department of Ophthalmology Royal MCAT (RMIT Melbourne) Manager quality of life. Victoria Eye and Ear Hospital. PhD of Patient and Public Involvement candidate School of Pharmacy and (PPI) in Research, Royal College of There are two forms of Sjögren’s Syndrome, primary and secondary. Primary Sjögren's Syndrome Biomolecular Sciences (PBS). Surgeons Ireland (RCSI) University Co-founder co-Chair of Secondary Sjögren's of Medicine Health Sciences. occurs by itself and without any other illness. Syndromeand develops in a person who has Women in Vision and Eye Research Founder of Love Knowledge another autoimmune condition, such as rheumatoid arthritis or systemic lupus erythematosus. (WVER) Ireland Research Consultancy

Dr Joan Ní Gabhann-Dromgoole, PhD, BSc (Hons) PG Dip MedEd - Lecturer in Ophthalmology and Immunology, School of Pharmacy and Biomolecular Sciences (PBS), RCSI University of Medicine and Health Sciences. Scientific lead of the Ocular Immunology Research Group (OIRG) and co-founder and co-Chair of Women in Vision and Eye Research (WVER) Ireland

with Sjögren’s had abnormal levels of certain microRNA molecules that control ocular inflammation. This suggested that changes in the amounts of these regulators could be causing the increased production of inflammationtriggering messenger molecules from our immune cells ultimately leading to the dry eye disease suffered by Sjögren’s Syndrome patients.

Figure 1:1:Outlines the epidemiology of Sjögren’sof Syndrome Figure Outlines the epidemiology Sjögren’s Syndrome

The Ocular Immunology Research Group (OIRG) in The Royal College of Surgeons (RCSI) has been involved in research in dry eye disease for over 10 years. Our research group has a special interest in ocular conditions associated with autoimmunity and inflammation like Sjögren's Syndrome. The aim of our research is to increase the understanding about what is leading to the uncontrolled inflammation that is seen on the ocular surface in Sjögren’s Syndrome. We believe that by increasing our understanding through research

we could help find ways to control this, and this will potentially lead to improved diagnosis and better treatment options. In trying to understand what is happening at the ocular surface we have begun to look at a network of regulators which control all of the processes within our cells. These regulators or controllers are small pieces of genetic material termed ‘microRNAs’. We compared eye samples from patients with Sjögren’s Syndrome to samples from healthy individuals and found that those

In cells grown in the laboratory, we can manipulate these signals to halt or stop the damage caused to the eye by the cells of the immune system. This information also has the potential to help diagnose patients and make new, targeted drugs to treat the disease. This research is the first step toward a potential new treatment, and much more pre-clinical testing is needed before we can develop it into a therapy that is ready for patients. However, it provides the opportunity to possibly treat the root cause of the disease rather than just the symptoms. In addition to our molecular studies the OIRG have also investigated the quality of life of individuals with Sjögren’s Syndrome. During the course of these investigations, our research group became

HOSPITALPROFESSIONALNEWS.IE | HPN • OCTOBER - 2021

SJÖGREN’S SYNDROME

acutely aware that those affected by Sjögren’s Syndrome were an underrepresented group, who experience significant delays in diagnosis, mismanagement and a lack of supports. Currently there is currently no charity or support group specifically dedicated to Sjögren’s in Ireland. The lack of charity and support group means that our research group could not directly inform individuals with Sjögren’s Syndrome about our research, nor could we have their input into the research questions we ask. This led the co-founders of the Women in Vision and Eye Research Ireland (WVER), Dr Joan Ní GabhannDromgoole and Dr Emily Greenan, to organise a webinar on Worlds Sjögren’s Day, July 23rd 2021 that aimed to increase awareness and help support patients in becoming their own advocates. We wanted to organise an event that provided holistic information pertaining to the diagnosis and management of Sjögren’s rather than focusing on one organ or part of the body. We also designed an online survey, which sought to determine how COVID-19 had affected these patients. Given the diverse range of Sjögren’s symptoms spanning across a multitude of organ systems we brought together the expertise from a range of medical professionals who are involved in the care and management of Sjögren’s patients e.g. ophthalmology, pharmacy, rheumatology, research, general practice, dermatology and dentistry. We were very fortunate that all the expert invited speakers gave so freely of their time and expertise in addition to having support from Théa Pharmaceuticals, who provided the online platform for the webinar. Additionally, to increase the relevance and impact of this event we reached out to individuals with Sjögren’s Syndrome and asked them to help organise the event. By joining the organising team, we hoped that patient representation would tailor the event to more accurately reflect the needs of patients. Dorothy Kennedy acted as a Patient Advocate and agreed to share her journey with a journalist from the Irish Independent that featured in the papers weekly health supplement. Her story while personal, had elements that would resonate with Sjögren’s patients. There is much that is unknown regarding Sjögren’s disease pathology, equally the impact of this condition on patients’ lives

can be diminished or poorly understood. Articles such as these where individuals publicly share their experiences are invaluable as a means to raise awareness among broader audiences At its core this event was patient focused, thus we were privileged that Deirdre Collins, a second Sjögren’s Patient Advocate not only contributed to the event organization but shared also her experience of being diagnosed and living with Sjögren’s as an expert speaker at the webinar. Having suffered with symptoms since childhood, patient advocate, Deirdre Collins went through years of pain and discomfort as doctors tried to figure out what was wrong with her and explains her lived experience with having Sjögren’s Syndrome. “I was diagnosed with Sjögren’s Syndrome four years ago, following twenty years of symptoms. Starting with dry eye in my early teens, I developed severe headaches, fatigue, brain fog, and aches and pains in my later teens. My twenties were marked by severe dry eye, joint pain, digestive issues, and profound fatigue. Dry mouth, slow gastric motility, and small fibre neuropathy became apparent in my thirties. “Sjögren’s Syndrome has a serious impact on nearly every aspect of my life. I had to give up my career as the traditional office environment was exacerbating my symptoms to the point where I was seriously struggling to work. Lighting, air conditioning, and constant computer work caused my eyes to become very dry, painful, and blurred. The joint pain in my hands made it difficult to type. Not every work environment can accommodate those with chronic illness. “One of the greatest challenges is having Sjögren’s Syndrome while being a parent. There have been days where I have been unable to carry my daughter or lift her in and out of her cot. It is difficult to provide for an energetic toddler while suffering from debilitating fatigue and pain. The resulting guilt

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and frustration at my limitations has had a significant impact on my mental health as a new mother. “From a patient perspective, treatment for Sjögren’s Syndrome is a series of trials and errors. I’m currently taking Plaquenil, Mercaptopurine, Lyrica, ibuprofen, omeprazole, a variety of drops for dry eye and lozenges, sprays and gels for dry mouth and nose. Even with all these medications, I still suffer from pain and fatigue every day. “One of the challenges of getting a Sjögren’s Syndrome diagnosis is the variety and fluctuation of symptoms. Not all symptoms may be active when a patient visits their GP. It is important that when a patient visits a GP about a current symptom, that the GP opens a conversation and explores what other symptoms the patient may be experiencing. Often with chronic illness, more minor complaints can be tolerated and not perceived as important enough to mention. Or, symptoms may be sporadic, and a patient can forget to mention them when focused on the reason for the GP visit. “With Sjögren’s Syndrome, there is a focus on dry eye and mouth as factors of diagnosis. My first symptom was dry eye. However, the symptoms of dry mouth were never described to me. I have thick saliva, and difficulty eating certain foods. I get jaw pain from salivary glands that is not constant. Asking a patient if they have dry mouth, without describing the symptoms, can lead to a missed diagnosis. “Fatigue can appear similar to depression. It is vital that if there is accompanying pain, other possibilities such as Sjögren’s need to be explored. Anti-depressants can exacerbate dryness and this is something that should be considered. “Not all patients with Sjögren’s will have a positive blood test. A lip biopsy should be considered if a patient has symptoms that indicate Sjögren’s Syndrome. If a GP is unsure, patients should be referred to an ophthalmologist and a rheumatologist to confirm diagnosis.

“I have been referred to A&E several times by my GP for pain and other symptoms. During these trips, as well as during my pregnancy, I never encountered a nurse or midwife that had heard of Sjögren’s Syndrome. A patient, in pain and under stress, explaining their medical condition to medical professionals is far from optimal. “A lack of understanding about Sjögren’s Syndrome has been a constant issue for me as a patient. So I was delighted to be approached by Dr Joan Ní Gabhann-Dromgoole and Dr Emily Greenan to take part in the Sjögren’s Patient Information webinar. It offered me an opportunity to share my story as a patient, and to be part of an event that brought Sjögren’s patients together. It was a wonderful experience to see so many experts talking about Sjögren’s with genuine passion for making things better for those living with the condition. It offered a genuine hope that there are doctors and scientists who truly understand Sjögren’s and that improvement in treatments can be made. The patient centric approach was refreshing and was hugely appreciated by those attending. “Following the webinar, I have been contacted by a significant number of fellow Sjögren’s patients who have had similar journeys to diagnosis as I have. With similar frustrations at the reduction of Sjögren’s to simply dry eye and dry mouth. There is huge demand amongst those living with this condition for more research, greater education of medical professionals about the realities of Sjögren’s, and a need for a patient support organization to be a voice and community for those living with this poorly understood illness. Patients want to be involved with research. We want to help in any way we can to further the understanding of something that affects us so profoundly. The webinar has been a catalyst for highlighting the need for more awareness of Sjögren’s Syndrome”. Figure 2: Word cloud illustrating data collected from the online webinar depicting the symptoms that most bother patients with Sjögren’s Syndrome

55 Patient feedback for the webinar has been overwhelmingly positive. The inclusion of the range of specialists provided a central hub of information and expertise, and was seen a real success of the event. As the webinar was recorded individuals could re-watch the event, so no key nuggets of information were lost. Furthermore, all participants and attendees were able to share comments and questions in the online platform chat box and time was allocated for speakers to address live patient queries. The patient information leaflet prepared by Dr Joan Ní GabhannDromgoole and Dr Emily Greenan containing contributions from expert speakers has also been reported to a valuable resource. We have also found that there is a genuine interest and eagerness among patients to be involved in research at various level – outreach, participation and actively involved in determining the research questions. Overall, patient advocates and survey respondents have helped identify areas of Sjögren’s care and management where there are gaps (Figure 3). Acting on these gaps or unmet needs in collaboration with patients will ultimately lead to better health outcomes, improved services, physician and public education.

Being actively involved in Public Patient Involvement (PPI) and embedding it from the very inception of this event has ensured that the event did address patients, specifically in terms of the specialists represented at the event and providing opportunities to start a support organization. Lorna Kerin, Manager of PPI in RCSI explains the concept of PPI and the mutual benefits it can have for both research and patients.

Diagnosis

Physician education

Effective therapies

“Public Patient Involvement is the development of active research partnerships to involve people with experience of living with, or caring for someone affected by, a healthcare condition (‘patients’) and healthcare stakeholders such as clinicians or policy makers or health service providers (‘public’) in a research process that is relevant to patient and public needs. “PPI is a highly inclusive, collaborative approach to research as it involves patients, carers and public stakeholders advising at particular points during or throughout the research process as members of the research team. The role of patients, carers and public stakeholders in PPI in research is that of ‘experts by experience’, as their unique experiential perspective on a healthcare condition, research or service is invaluable to researchers seeking to design research that is genuinely relevant, meaningful and useful to the patient population. “It is important to note that involvement in PPI in research is significantly different to research participation (being a research participant or subject in a research study) and is also different from research engagement (engaging in outreach to communicate research). Lorna explains the benefits of PPI to both the people with experiences of health conditions as well as clinicians and researchers. “PPI allows those affected by health conditions to access to the latest research, to increase their knowledge of the disease and how to alleviate symptoms. It also provides for an opportunity for patients to support research and ensure that it is targeted to their needs as well as improving research dissemination among

patient groups. Furthermore, it involves service users and carers in improving the quality of services and making services more responsive to the needs of the individuals who use them”. The benefits of PPI to researchers has been elucidated in the literature. Systematic reviews have identified its impact on clinical trials recruitment and retention (Crocker, 2018), on biomedical and health services (Shipee 2015) and on researchers and communities (Brett 2012; 2014). Further examples where PPI contributors supported the development of international research recommendations (Gerlag et al., 2012); the development of patient questionnaires (Stack et al., 2015) and patient-initiated research to determine why people with symptoms of rheumatoid arthritis delay seeking help (Tiwana et al., 2015). “Real life examples of patients with Sjögren's Syndrome making a difference through partnership with researchers included The Glasgow Patient Involvement in Rheumatology Research (PIRR) where patients participated on clinical trial steering groups. Both The North East Sjögren's Syndrome Association (NESSA) in The Newcastle Public Involvement in Musculoskeletal Services (PIMS) created forums for researchers and the service users/carers to engage with each other about current research projects, discuss future projects and feedback results to existing patient groups”. Lorna Kerin also presented at the webinar, and explained what, where and how involvement can take place in the research cycle to shape research including: Codeveloping grant applications; Co-

design of ‘study procedures’ (how/when/who will be invited to be part of the research); Developing research materials (e.g. patient information leaflets; ethics consent forms); Communicating research findings via patient networks and support groups; Co-writing of research findings in press releases, conference presentations, journal papers etc. “Involving PPI in the webinar ensured that event invited patient recommendations for research priorities, offered people the opportunity to become involved in future PPI in research, as well as providing latest research evidence and clinical treatment options from a range of specialists on their healthcare condition”. Overall, the Sjögren’s webinar was highly successful, and an event that we hope will become an annual occurrence with a rotating range of specialists. The outcome of this event is that the Patient Advocate, Deirdre Collins, and Lead Researchers, Dr Joan Ní Gabhann-Dromgoole and Dr Emily Greenan now have a pool of informed and enthusiastic people with lived experience of Sjögren’s Syndrome who have expressed their interest in contributing to setting up a patient charity, to contributing to PPI in Research initiatives so they can influence research questions, studies and dissemination, or to participating in research studies to support greater scientific understanding of Sjögren’s Syndrome. The value of these future PPI research partnerships means that for the first time in Ireland, people with lived experience of Sjögren’s Syndrome and their families will have a patient-led, researcher supported space to collaborate with researchers with scientific expertise and with clinicians who provide medical care to dynamically shape research to meaningfully improve the quality of healthcare available. This event may be a model to stimulate PPI interest and partnerships that other researchers and PPI advocates might consider. Over the coming year, we hope that a patient network will be established and a support organisation formed that will provides information and support for individuals with Sjögren’s Syndrome. Figure 3: Bar chart illustrating what areas individuals with Sjögren’s Syndrome feels need the most attention to improve their medical care

HOSPITALPROFESSIONALNEWS.IE | HPN • OCTOBER - 2021

OVARIAN CANCER

Ovarian cancer a silent killer Written by Dr Amina Javaid and Mr Waseem Kamran

Most patients respond well to the Imaging tests may include pelvic first-line chemotherapy, achieving and abdominal ultrasound, complete response, however, computed tomography (CT), or some will develop recurrence. magnetic resonance imaging For patients with residual disease (MRI). The heterogeneity of < 1 cm, the risk for recurrence these tumors makes treatment is estimated at 60–70%; for difficult. Different histological women with large-volume residual types of epithelial ovarian cancer disease, the risk is estimated at have distinct cellular origin, 80–85%. diverse mutational spectrum, and thus, different prognosis. The patients with complete The standard treatment for response are kept under clinical ovarian cancer is maximal and biochemical follow up for cytoreductive surgical surgery at least 5 years. Increasing followed by the platinum-based level of CA125 can be an early Dr Amina Javaid Mr Waseem Kamran chemotherapy. Standard surgical symptom of recurrence, however, staging consists of peritoneal if not accompanied by clinical washings, total hysterectomy, and symptoms, second line treatment Dr Amina Javaid, Mr Waseem Kamran bilateral salpingo-oophorectomy, is not recommended. Delay of inspection of all abdominal treatment, until clinical symptoms is the most second Ovarian Ovarian cancer iscancer the second organs and peritoneal surfaces, occur, does not worsen the most common and the most common and the most lethal gynaecologic sampling of suspicious areas for survival. There is also ongoing lethal malignancy malignancy ingynaecologic the western world. It most biopsy, total omentectomy, and debate whether neoadjuvant in the western world. It most para-aortic lymphadenectomy. commonly occurs between fifth and sixth chemotherapy (giving 3 cycles of commonly occurs between the After completing surgical staging, decade of lifeand butsixth can decade occur inofyounger or chemotherapy prior to surgery) fifth life the International Federation of and interval debulking surgery older agebut group as well. The lifetime can occur in younger or risk Gynaecology and Obstetrics may be superior to the massive of developing ovarian cancer is The older age groups as well. (FIGO) staging system for ovarian primary debulking surgery in lifetime1.4 riskpercent of developing ovarian approximately in a woman cancer is applied to determine advanced ovarian cancer. This cancer is approximately 1.4 with ovaries. the patient management and approach is related with higher percent in a woman with ovaries. prognosis. Primary debulking mortality and morbidity while CommonCommon risk factors increasing risk include factors include surgery consists of complete primary debulking surgery may increasing age,menarche, nulliparity,late early age, nulliparity, early macroscopic tumour removal lead to earlier recurrence and menarche, late menopause, menopause, family history of ovarian, which might involve splenectomy, shorter survival. In our current history of ovarian, carrier breast, of diaphragmatic resection, liver breast, orfamily endometrial (uterine), practice, we discuss all cases or endometrial (uterine), carrier resection, intestinal resection of ovarian cancer at our gynae a geneticofabnormality called a genetic abnormality called or any other abdominal organ multidisciplinary meetings and a BRCA1a or BRCA2 mutation or Lynch BRCA1 or BRCA2 mutation resection if needed to achieve go ahead with most appropriate syndrome nonpolyposis or (hereditary Lynch syndrome (hereditary Fig.1 En bloc resection of ovarian cancer complete cytoreduction. approach after taking into colorectal cancer [HNPCC]. Patients with nonpolyposis colorectal cancer Fig.1 En bloc resection of Microscopic analysis should account whole clinical picture. [HNPCC].are Patients with genetic genetic mutation diagnosed with the ovarian cancer aim to define the histological Despite the high response rate mutation are diagnosed with type of the Imaging tumor, including disease at an early stage. Protective factors include previous pregnancies, to initial treatment, majority of step in the evaluation. tests may include pelvic and abdominal thebreast disease at an early stage. grading. High-grade/low-grade history of feeding, oral contraceptives use, insertion of an intrauterine ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI). Protective factors include previous occur between 50-65 years of for scale is currently used, except device and tubal ligation. There is lack of clinical or biochemical methods pregnancies, history of breast The heterogeneity of these tumors makes treatment difficult. Different for endometrioid ovarian cancer Germ cell as tumours account screening and early of thisuse, disease.age. It was named silent killer Fig.2 Involvement of bowel with feeding, oraldiagnosis contraceptives whereof a three-grade scale is cancer have histological types epithelial ovarian distinct cellular origin, for 5% and occur in women less because insertion approximately 75% of cases are diagnosed at an advanced stage of metastatic ovarian cancer of an intrauterine device used (G1, G2 or G3) Staging than 20 years of age. Common diverse spectrum, and thus, different prognosis. disease due nonspecific symptoms, early stagesinclude of the disease are mutational and to tubal ligation. There is lackwhile of assessment is done according to symptoms abdominal clinical or biochemical methods of the potentially curable. Epithelial carcinoma ovaries, fallopian tubes, FIGOfor recommendations. pain, abdominal distention, The and standardcurrent treatment ovarian cancer for screening and similar. early diagnosis Major prognostic factors peritoneum are clinically Evidence suggests these increased diseases have a nausea, that anorexia, is maximal cytoreductive surgical surgery of this disease. It was named as associated with improved size tubes or bloating, common pathogenesis and may be initiated inabdominal the fallopian as sticky silent killer because approximately followed by the platinum-based outcomes include younger weight loss, early satiety, urinary lesions. 75% Mostofofcases ovarian cancer cases are epithelial, which accounts for 85-90% are diagnosed at age, low volume of residual frequency, or urgency, diarrhoea chemotherapy. Standard surgical staging of all diagnosed ovarian tumors and occur between 50-65 years of age. Germ an advanced stage of disease disease, good performance or constipation. Dyspnoea is consists of peritoneal washings, total cell tumours account for 5% and occur in women less than 20 years of age. due to nonspecific symptoms, status and serous histology. occasionally present due to a hysterectomy, andsurgery, bilateral salpingowhile early stages of the disease After patients are pleural effusion. Another acute Commonaresymptoms include abdominal pain, abdominal distention, nausea, potentially curable. Epithelial oophorectomy, inspection of all abdominal treated with chemotherapy. presentation can be bowel anorexia,carcinoma increasedofabdominal size or bloating, weight loss, early satiety, the ovaries, First line chemotherapy involvesof obstruction in advanced disease. organs and peritoneal surfaces, sampling urinary frequency, or urgency, diarrhoea or constipation. Dyspnoeamay is occur fallopian tubes, and peritoneum intravenous platinum/taxane Sometimes symptoms suspicious areas for biopsy, total are clinically occasionally present similar. due to aEvidence pleural effusion.inAnother acute presentation many patients even at early can be regimes, every 3 weeks for six omentectomy, and para-aortic suggests that these diseases have cycles. Patients with stage FIGO stages symptoms of the disease. bowel obstruction in advanced disease. Sometimes may Once occur in a common and Stage IA/IB and with grade 1 and ovarian cancer is suspected lymphadenectomy. After completing many patients evenpathogenesis at early stages of may the disease. Once ovarian cancer is be initiated in the fallopian tubes 2 tumors, no further treatment is based on symptoms and/or an surgical staging, the International suspected based on symptoms and/or an abnormal physical examination, as sticky lesions. Most of ovarian required. Treatment outcome is abnormal physical examination, imagingcancer tests ofcases the abdomen and pelvis are usually recommended as an initial Federation Gynaecology and Obstetrics are epithelial, after the completion imaging tests of the abdomen and ofassessed (FIGO) staging systemchemotherapy for ovarian cancer which accounts for 85-90% of all of first-line by pelvis are usually recommended as an initial step in the evaluation. diagnosed ovarian tumors and imaging results is applied to determine the (mostly patientCT scan).

Ovarian cancer a silent killer

management and prognosis.

OCTOBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

Fig.2 Involvement of bowel with metastatic ovarian cancer

Primary debulking surgery consists of complete macroscopic tumour removal which might involve splenectomy,

e patients will develop recurrence. A major option for the treatment of recurrent ovarian cancer is chemotherapy. An important prognostic factor is the time from the end of the previous treatment known as treatment-free interval. Among relapsed disease patients, mortality is high. The time to relapse is also used as a determinant of tumor sensitivity to platinum. Tumors are categorized as:

ied

e is Fig.3 Fig.3Involvement Involvement of of bowel bowel with with metastatic metastaticovarian ovariancancer cancer her y (giving 3 cycles of chemotherapy prior to surgery) gery may be superior to the massive primary nced ovarian cancer. This approach is related with idity while primary debulking surgery may lead to rter survival. In our current practice, we discuss all our gynae multidisciplinary meetings and go ahead roach after taking into account whole clinical picture.

• Platinum refractory—when tumor progresses during first-line treatment • Platinum resistant— recurrence within 6 months after completion of first-line treatment • Partially sensitive—recurrence within 6–12 months • Highly sensitive recurrence after more than 12 months Chemotherapy

is the mainstay of treatment for recurrent ovarian cancer with surgery having a role in platinum sensitive patients. New drugs are mostly directed against molecular targets cancer cells proliferation pathways, tumor growth and escape from immune surveillance and death signals. These include anti-angiogenic factors, inhibitors of growth factor signalling, polyADP-ribose polymerase (PARP) inhibitors, or folate receptor inhibitors. These new agents and therapeutic approaches are not shown to be curative for ovarian cancer but may lead to the delay of recurrence or stabilization of the disease.

Women’s Health: News

SFI Future Innovator Prize

A project at University College rate to initial treatment, majorityProfessor of patients will UCD Patricia Maguire, Dublin addressing the significant School of Biomolecular and challenge of diagnosing r option for the treatment of recurrent ovarian Biomedical Science, cancer Dr Paulina preeclamptic toxaemia (PET), one of the world’s deadliest pregnancy complications, has been awarded a SFI Future Innovator Prize.

Szklanna, Professor Mary Higgins and Professor Fionnuala Ní Áinle, UCD School of Medicine

actor AI_PREMie is the time from the end of the previous uses cutting-edge biomedical, clinical and machinerelapsed disease patients, ment-free interval. Among learning techniques to analyse a e to relapse is ofalso usedsignals as a determinant of tumor combination biomarker and clinically relevant maternal umorsdata, aretocategorized as: provide a straightforward assessment of pregnancies at risk of PET complications, thereby helping to prevent unnecessary adverse outcomes for mothers and babies. PET is a serious complication affecting one in every 10 pregnancies, and annually kills 50,000 mothers and 500,000 babies worldwide. The AI_PREMie team led by Professor Patricia Maguire, UCD School of Biomolecular and Biomedical Science, includes Dr Paulina Szklanna, and Professor Mary Higgins and Professor Fionnuala Ní Áinle, UCD School of Medicine. Minister for Further and Higher Education, Research, Innovation and Science, Simon Harris TD, together with Minister of State for Overseas Development and Diaspora, Colm Brophy TD, awarded the project a SFI Future

Innovator Prize of ¤500,000 under the Artificial Intelligence (AI) for Societal Good Challenge.

their babies, priority goals under the UN SDGs.”

“The AI_PREMie project team and I are absolutely delighted and honoured to receive this special prize in recognition of our new AI-powered risk stratification platform for preeclampsia,” said Professor Maguire.

Adding, “It has been an honour to work with such an incredible interdisciplinary team collaborating with all three Dublin maternity hospitals, and SFI’s innovative challenge-based funding process has really enabled us to further this important project to reality."

“Advancing both foetal and women’s health is of paramount importance and developing these tools will place Ireland at the global forefront in preventing unnecessary adverse outcomes for mothers and

The biomarkers which can be used to diagnose preeclampsia risk were discovered using a novel noninvasive blood-based diagnostics platform (PALADIN) developed by Professor Maguire.

Earlier this year she and her team were awarded with the 2021 NovaUCD Invention of the Year Award for this discovery. Professor Mark Ferguson, Director General, Science Foundation Ireland and Chief Scientific Adviser to the Government of Ireland said, “I would like to extend my congratulations to the runners up, Prof Patricia Maguire and the AI_PREMie team, for the important work they are doing in advancing foetal health and women’s health with their state-of-the-art diagnostic application.”

HOSPITALPROFESSIONALNEWS.IE | HPN • OCTOBER - 2021

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

VISION & EYE HEALTH

Increasing the Visibility of Women – An initiative by the Women in Vision and Eye Research Ireland Contributing authors: Dr Emily Greenan, MB, BCh and BAO, HDipTeaching (LCM) and Dr Joan Ní Gabhann-Dromgoole, PhD, BSc (Hons) PG Dip MedEd Dr Emily Greenan, MB, BCh and BAO, HDipTeaching (LCM) Clinical tutor, RCSI University of Medicine and Health Sciences and Department of Ophthalmology Royal Victoria Eye and Ear Hospital. PhD candidate School of Pharmacy and Biomolecular Sciences (PBS). Co-founder and co-Chair of Women in Vision and Eye Research (WVER) Ireland

Gender disparity between men and women has been brought to light recently, highlighting inequalities within the fields of medicine and academia. Achieving equality within these professions is beneficial not only to women but for medicine, research and patients as a whole. Diversity in fields of practice ensures a variety of thought, innovation, with stronger teams and ensures better outcomes for all. It has been noted that women in academic and clinical medicine face significant professional challenges. While women are increasingly entering the field a number of barriers have been identified that result in gender disparity. Women are less likely to be recognised as experts and leaders, with fewer women speaking at national medical conferences, receiving prestigious awards, being promoted or holding leadership roles. A study undertaken to determine whether gender differences in individual National Institutes of Health (NIH) awards and in funding totals exist in ophthalmology found that that men were awarded higher awards and funding when compared to their female colleagues. Furthermore, it has

Dr Joan Ní Gabhann-Dromgoole, PhD, BSc (Hons) PG Dip MedEd Lecturer in Ophthalmology and Immunology, School of Pharmacy and Biomolecular Sciences (PBS), RCSI University of Medicine and Health Sciences. Scientific lead of the Ocular Immunology Research Group (OIRG) and co-founder and co-Chair of Women in Vision and Eye Research (WVER) Ireland

been noted that reviewers hold women applicants to higher evaluation standards. Among the most frequently noted obstacles to women’s career success are challenges managing the demands of work and family. Women with children publish less than men with children, suggesting that family demands impact women differently. This was highlighted during the COVID 19 pandemic during which first authorship among women declined by 23%.

Overall, these differences may have consequences for the professional success of women in their fields of work. The Women in Vision and Eye Research Ireland (WVER) network aims to support the Royal College of Surgeons (RCSI) and the Royal Victoria Eye and Ear Hospital (RVEEH) strategies in relation to reputation enhancement, forming collaborations in addition to strategies that focus on reducing gender disparity.

Women are under-represented as authors of research papers in many scientific areas, particularly in senior authorship positions. Women also have smaller professional networks, smaller audiences, and a narrower reach on virtual platforms which are increasingly essential for dissemination, thus negatively impacting on citation counts. Despite recognition that current global and national healthcare challenges have shown the requirement for novel approaches that are dependent of on a diverse range of leaders, women professional continue to be under-represented.

To achieve this the WVER network aligns with best practice from industry and the university sector and incorporates key strategies aimed at addressing the barriers faced by women in academic and clinical medicine. Specifically to redress the gender disparity experienced by women in academic and clinical medicine the WVER annual conference provides a platform that recognising and supporting the excellence of women in eye care and research. The annual conference promotes women speakers, amplifying women’s profiles, thus enhancing reputation, providing recognition of expertise and excellence. The committee

and the annual conference will also provide access to national and international networks. In a recent study Ayyala et al. found that ‘”women, for the most, part lacked the career accelerator provided by sponsors leveraging power to advance their protégés/ ées’ careers’’. This can be detrimental to career progression, as sponsorship in addition to mentorship, is now recognised as a critical factor for successful career advancement. It has been reported that although women require the supports afforded by sponsorship opportunities, they are less likely to seek them out. A further study investigated men’s invisible advantage in STEM by comparing mentoring and sponsorship in four higher education institutions in Bulgaria, Denmark, Ireland and Turkey. While the mentorship received by women focussed on reassurance, men’s mentorship was more likely to be career focussed. Furthermore, men were more likely to receive sponsorship from their PhD supervisors in contrast to women and have working relationships with senior academics, resulting in

HOSPITALPROFESSIONALNEWS.IE | HPN • OCTOBER - 2021

TREAHALOSE • Protects proteins and lipids from denaturation2 • Renews cellular materials by inducing autophagy210

Break the vicious cycle of Dry Eye Disease with Théa APOPTOSIS

TREAHALOSE • Protects cells from desiccation11

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Relieve the symptoms of Dry Eye Disease with Thealoz Duo2 APOPTOSIS

HYPOTONIC • Restores the osmotic balance4

PRESERVATIVE - FREE • Avoids further cell damage2 TREAHALOSE • Protects proteins and lipids from denaturation2 • Renews cellular materials by inducing autophagy2

TREAHALOSE • Protects cells from desiccation1 Zoftacot® 3.35mg/ml eye drops, solution in single-dose container. Please refer to the Summary of Product Characteristics for full prescribing information. Additional information is available on request. Active Ingredients: Hydrocortisone sodium phosphate. Presentation: 3 sachets each containing 10 single-dose units of 0.4ml. A single-dose container contains enough to treat both eyes. Indications(s): Treatment of mild non-infectious allergic or inflammatory conjunctival disease. Posology and method of administration: Adults & the Elderly: 2 drops 2-4 times per day in the affected eye. Treatment will generally vary from a few days up to a maximum of 14 days. Consider gradual tapering off down to one drop every other day to avoid relapse. Children: safety and efficacy is not established. Contraindications: Hypersensitivity to active substance or excipients. Ocular hypertension including that caused by known glucocorticosteroids. Herpes simplex and other corneal viral infections at acute stage of ulceration, unless combined with specific therapeutic agents. Conjunctivitis with ulcerative keratitis even at the initial stage. Ocular tuberculosis, ocular mycosis, acute ocular purulent infection, purulent conjunctivitis, and purulent blepharitis, stye and herpes infection that may be masked or aggravated by anti-inflammatory drugs. Warnings and precautions: Red eye: Do not prescribe for undiagnosed red eye. Ocular hypertension & cataracts: Monitor patients at regular intervals during treatment – prolonged use of corticosteroids has been shown to cause ocular hypertensions especially for patients with previous IOP increase induced by steroids, and also cataract formation especially in children and the elderly. In children the ocular hypertensive response can happen more often, frequently and severely than in adults. Immuno suppression: Use of corticosteroids can result in opportunistic ocular infections due to delay or suppression or healing delay; and to the masking of symptoms. Viral keratitis: Not recommended but may be used if required only with a combined antiviral treatment and under close supervision. Perforations and thinning of cornea / sclera: Thinning of cornea and sclera (caused by diseases) may increase risk of perforations with use of topical steroids. Suspect a fungal infection with corneal ulcerations where a steroid has been used for a long time. Remove contact

lenses when using Zoftacot. With blurred vision or other visual disturbances, consider referring patients for evaluating possible causes which may include cataract, glaucoma or rare diseases like central serous chorioretinopathy (CSR). Zoftacot contains phosphates. Children: Long-term continuous corticosteroid therapy may produce adrenal suppression. Pregnancy: Not recommended unless clearly necessary. Lactation: Risk to newborns/infants cannot be excluded. It is unknown if Zoftacot is excreted in human milk. Driving & using machines: Temporary blurred vision or other visual disturbances may affect ability to drive or use machines. Wait until vision clears before driving or operating machinery. Undesirable effects: Mild and transient burning and stinging immediately after instillation. Unseen with hydrocortisone, but have been observed with other topical corticosteroids: allergic and hypersensitivity reactions, delayed wound healing, posterior capsular cataract, opportunistic infections, herpes simplex infection, fungal infection, glaucoma, mydriasis, ptosis, corticosteroid induced uveitis, changes in corneal thickness, crystalline keratopathy, blurred vision. Very rarely, corneal calcification in patients with significantly damaged corneas. Prolonged use of corticosteroids has shown to cause ocular hypertension, especially with pre-existing or family history of increased IOP, and cataract formation. Children / elderly are more susceptible to IOP rise. Diabetics are more prone to sub capsular cataracts following topical steroids. In diseases causing thinning of the cornea, topical steroids could lead to perforation. Adverse events should be reported. Reporting forms and information can be found at http://www.hpra.ie. Overdose: Rinse with sterile water. Discontinue treatment where prolonged overdosage causes ocular hypertension. Symptoms from accidental ingestion are unknown, however, consider gastric lavage or emesis. Legal category: POM. PA Number: PA1107/13/1. PA Holder: Laboratoires THEA, 12 rue Louis Blériot, 63017 Clermont-Ferrand Cedex 2, France. Date of preparation: May 2019. Item Code: TP/19/033/Zoftacot API/V1.

References 1) L. Jones et al. The Ocular Surface 15 (2017) 575-628 2) Chiambaretta, F. et al. Eur J Ophthalmol 2017; 27(1): 1-9

3) Jones et al. TFOS DEWS II Management and Therapy Report. Ocular Surface 2017;15:575-628. 4) Ricker et al Trehalose maintains phase separation in an air dry-binary lipid mixture. Biophys J.2003; 84:3045-3051

ADVERSE EVENTS SHOULD BE REPORTED. REPORTING FORMS AND INFORMATION CAN BE FOUND AT WWW.HPRA.IE/HOMEPAGE/ MEDICINES/SAFETY-INFORMATION/REPORTING-SUSPECTED-SIDE-EFFECTS. ADVERSE EVENTS SHOULD ALSO BE REPORTED TO THEAPAMEX LIMITED 094 9250290 OR MEDICAL INFORMATION ON +44 345 521 1290

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VISION & EYE HEALTH mentorship possibilities. It was suggested that domestic responsibilities may account for the limited access women had to these networks, particularly in Ireland and Turkey. Female sponsors were noted to be lacking or entirely absent, potentially resulting from a lack of female representation at more senior levels. The WVER committee therefore aims to create a supporting and mentoring network that encourages career

development by championing the talents of its members. This will enhance and facilitate women’s leadership and career aspirations within fields’ of academia, research and clinical medicine. While women are gaining numeric representation in academia and at the entry level stages of medical education, the absence of women in high raking positions within this field limits exposure to role models. This can have negative

effects on women’s professional aspirations, self-perceptions, and stereotypes leading to a paucity of women reaching positons of leadership. The WVER committee aims to tackle this by providing additional events that will foster the visibility of professional women. Furthermore, at our annual conference we will be presenting The Dr Kathleen Lynn Award. Aside from being a highly skilled

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and dedicated physician, Dr Lynn was an ardent feminist, suffragette and a patriot. In her career as a doctor she led the way for women working in medicine in Ireland despite the barriers and restriction placed upon women in the professional at the time. Dr Lynn is an inspiration, as she did much to improve the lives of her patients through medicine and education. We look forward to presenting this medal in her name to an early stage career investigator who is making outstanding contributions to eye health and research at our inaugural conference. This conference will also feature both international and national female expert speakers who will present updates on innovation and recent scientific advancements pertaining to eye care, as well as rapid fire presentation sessions for early career clinicians and investigators. Our institutions need to continue to grow and innovate. The way to ensure this prosperity is to eliminate gender disparity. Diversity, equity, and inclusion will strengthen and benefit us and our respective fields.

APOPTOSIS

News: Ophthalmology

28th European Ophthalmology Congress Webinar The European Ophthalmology Congress is to be held during September 28-29, 2021 in Dublin. The Congress which is a one of a kind and worldwide blend of substantial and medium pharmaceutical, biotech and symptomatic or diagnostic organizations, leading universities and clinical research companies making the meeting an ideal stage to share understanding, encourage co-ordinated efforts crosswise over industry and the scholarly community, and assess rising advancements over the globe. Delegates have the opportunity to meet noteworthy Ophthalmologists, Optometrists Researchers and Clinicians from United Kingdom, The United States Of America, Rome, Japan, Germany, Switzerland, Ireland, Russia, Singapore, Dubai, Saudi Arabia, China, Turkey, Spain, Taiwan, Chicago, Korea, India, Australia and many more nations.

Ophthalmology 2021 includes international attendee workshops, lectures and symposia, including a designated registration area, a refreshment break and gala lunch. Ophthalmologist & Optometrist can join the EuroSciCon as an international member to receive discounts on registration. This presents an ideal opportunity to join leading experts and allied professionals from April 19-20, 2021 to keep up with the rapidly accelerating pace of change that is already having an impact on the field of Ophthalmology and will continue to in the future. The scientific program includes Keynote & Plenary talks, Video Presentations, Poster Presentations and E-Posters. Furthermore, oral communications of (post)doctoral junior scientists will be considered. It is the goal of the organizers to make this meeting an event of scientific excellence, attractive to both industrial and academic

scientists in Ophthalmology and its advancements. Sessions Sessions will cover pertinent areas such as Comprehensive Eye Care: At the point when an individual calls to make an eye appointment, the person ought to be set up to portray any present vision issues. What's more, patients ought to inquire as to whether the eye examination will influence their vision briefly and in the event that they will require somebody to drive them home. They may likewise need to get some information about the expense of the test, if their protection plan will take care of any of the expense, and how installment is taken care of. Smartphones and Eyestrain: As much as we rely upon our cell phones for survey and reacting to

messages, checking the climate, perusing feature news, and posting notices on Facebook, our cell phones might cause us some vision issues. Gazing at those minor screens can expedite a variety of eye issues, for example, obscured vision, migraines, sore eyes, cerebral pains, muscle strain and dry eye. Diabetic Retinopathy: Diabetic retinopathy happens when changes in blood glucose levels cause changes in retinal veins. Now and again, these vessels will swell up (macular oedema) and release liquid into the back of the eye. In different cases, unusual veins will develop on the outside of the retina. Except if treated, diabetic retinopathy can slowly turn out to be progressively genuine and advance from 'foundation retinopathy' to truly influencing vision and can prompt visual impairment.

HOSPITALPROFESSIONALNEWS.IE | HPN • OCTOBER - 2021

MENOPAUSE

Management of Menopause in Ireland Written by Dr Catherine Riordan, Women’s Health, Urology & Reproductive medicine. Dr Catherine Riordan has over 30 years experience in the fields of women’s health, reproductive medicine and urology, giving her a complementary skillset for menopause care and management. Catherine, MB, Bch BAO, FRCS is a graduate of University College Dublin and a Fellow of the Royal College of Surgeons, England. She is a member of the British menopause Society (BMS). And is a member of the North America Menopause Society (NAMS). Outside the Menopause Hub, Catherine runs a specialist fertility service at Bray Women's Health Centre, is part of the urology team at St Michael's Hospital and teaches anatomy at the Royal College of Surgeons in Ireland (RCSI).

including a progestogen is needed to prevent unopposed estrogen stimulation of the endometrium. Testosterone supplementation is sometimes also necessary for full symptom relief. Estrogen has multiple physiological functions across multiple systems.

In all areas of her practice, Catherine takes an holistic approach and believes that, while medication plays an important part, it is just one part of a multifactorial picture. This is particularly true of menopause.

Therefore, a lack of estrogen can cause multiple symptoms, the most common being: vasomotor symptoms (VMS) or hot flushes, poor sleep, low mood, poor memory, loss of concentration, loss of confidence, anxiety, panic attacks, joint pains, weight gain, urinary frequency and incontinence, recurrent UTIs, vaginal dryness and painful intercourse, loss of libido,

Menopause is the last menstrual period and happens on average, at age 51. In approximately 1% of women, Premature Ovarian Insufficiency (POI) occurs before the age of 40. Bilateral oophorectomy results in immediate surgical menopause. Menopause is something all women face eventually. 80% of women will suffer symptoms, 50% of these describing them as moderate to severe, 15% as severe. Symptoms can begin several years prior to actual menopause, a phase referred to as perimenopause, and can persist beyond 10 years in approximately 10% of women. The time of menopause, for most women, coincides with life events such as children leaving home, aging parents and an increasing awareness of one’s own mortality. The fall in hormones can make these stressors harder to cope with. Hormone Replacement Therapy (HRT) is recognised as the most effective treatment for menopause and primarily involves the restoration of estrogen levels for symptom relief. For women who have not had a hysterectomy, combined HRT

OCTOBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

pelvic organ prolapse. Other consequences of falling estrogen levels are loss of bone density, increase in atherosclerosis and an increased risk of diabetes. As highlighted earlier this year, when Joe Duffy ended up devoting his entire show to the subject for a week, women in menopause are all too often poorly treated by the medical profession. Symptoms are dismissed and minimised, put down to psychological issues, a normal part of aging and something to just be dealt with. Why might this be? It is at least in part due to the publication of the preliminary results of the US Women’s Health Initiative study in 2003. This study was initiated in 1991 to assess the use of oral conjugated equine estrogen (CEE) alone, CEE combined with the synthetic progestogen medroxyprogesterone acetate and placebo, for the treatment of asymptomatic women aged between 50 and 79, with an average age of 63. Most of them initiated HRT several years after menopause and had a high BMI. A higher incidence of stroke and an increased risk of cardiovascular events was reported in both treatment groups and a higher incidence of breast cancer in the combined HRT treatment

group. The resulting sensational headlines around the world led to a dramatic fall in the use of HRT for symptomatic women. Such headlines are very hard to come back from and, despite publication of clarification of these findings in 2007 and multiple other large studies since, there still remains a firm belief that HRT is dangerous. Further research has shown that the risks were overstated, largely due to the average age of the participants at initiation of treatment and the type of HRT used. What have we learned since? The Supposed Risks Cardiovascular Disease: Oral estrogen undergoes first-pass liver metabolism, the result of which is a prothrombotic effect on the coagulation cascade which increases the risk of venous thromboembolism (VTE) and ischaemic stroke. Transdermal estrogen does not undergo firstpass metabolism. Studies show no increased risk of stroke or VTE associated with doses of up to 50mcg of transdermal estradiol, either alone or combined with progestogens. Micronised progesterone has been shown to have a neutral effect on

vasculature and therefore a lower risk of VTE and cardiovascular disease than synthetic progestogens. Studies suggest a window of opportunity to reduce coronary heart disease by up to 50% if HRT is initiated before the age of 60 or within 10 years of menopause. The benefit is due to a significant reduction in the progression of atherosclerosis. This is not seen if HRT is initiated 10 years or more beyond menopause, when atherosclerosis is already established. In young healthy women, HRT reduces overall mortality by up to 40%. Breast cancer: Short term use of estrogen-alone HRT is unlikely to increase the risk of invasive breast cancer. Combined HRT is associated with a small increase in risk. For most women, the overall risk is low and should be taken in the context of the overall benefits of HRT. Between the ages of 50 and 59, over a five year period, 23 women in the UK can expect to develop breast cancer. Combined HRT may be associated with an extra 4, drinking 2 or more units of alcohol per day, an extra 5 and a BMI of over 30, an extra 24. The increased risk is durationdependent and falls to zero 5 years after cessation. Evidence suggests that micronised progesterone or dydrogesterone may be safer than

other progestogens, but further study is required to confirm this. For women with a higher baseline risk, such as those with a family or a personal history of breast cancer, the additional risk may not outweigh the benefits and they will need to be carefully assessed and counselled accordingly. The Benefits of HRT Central nervous system: The hallmark of menopause is vasomotor instability, resulting in hot flushes, affecting up to 80% of women. In 10-15% of women, these can be severe and disabling and occur multiple times during the day and night, disturbing dayto-day activities and disrupting sleep. HRT can improve low mood associated with menopause, due to both direct effects on the brain and indirect effects such as the improvement in sleep that comes with control of VMS and bladder issues. Genitourinary system: 50% of post menopausal women suffer from Genitourinary Syndrome of Menopause. Symptoms include urinary incontinence, bladder oversensitivity and recurrent UTIs. The incidence of pelvic organ prolapse increases, at least partly related to poor collagen support. Vaginal dryness, atrophic change and reduced moisture occur in up to 55% of women just 4 years post menopause, leading

to sexual difficulties. All of these issues respond well to low dose local estrogen treatment which is not absorbed systemically to any significant degree and is safe for almost all women into old age. A study in Sweden showed improved bladder control in older women and reduced need for nursing home admission following local estrogen treatment. Connective tissue and bone: Estrogen enhances bone formation and reduces bone resorption. Estrogen deficiency causes resorption to outstrip formation, resulting in a loss of bone density. Accelerated loss begins in perimenopause and, within the first 5 years post menopause, 20% - 30% of cancellous bone and 5%-10% of cortical bone can be lost, before the rate slows to 1-2% per year. Collagen loss shows a similar pattern.

this would traditionally include the SSRIs, SNRIs, Clonidine and Gabapentin. Promising agents under trial are oral hypothalamic kisspeptinneurokinin B (NKB) neuron antagonists which confer VMS control without the risks associated with HRT. Estetrol, an estrogen produced by the fetal liver and excreted in maternal urine, inhibits VMS and bone density loss with minimal effect on liver and breast tissue. It is already available in the form of an oral contraceptive pill and is under trial for use in menopause and perimenopause.

Conclusions

Selective Estrogen Receptor Modulators with antagonist effects on breast and endometrial tissue have a role. eg Ospemifene is available for the treatment of vulvovaginal symptoms and Bazedoxifene combined with CEE is under trial for use in women who cannot tolerate progestogens. The bottom line is that thousands of women suffer with symptoms of menopause which can have a significant detrimental impact on their wellbeing.

Under the age of 60, the benefits of HRT outweigh the risk for most women, particularly if transdermal estrogen is used. For those at higher risk, such as those with current or a past history of breast cancer, alternatives should be considered. For VMS control,

For most, there are safe forms of HRT which will give relief and, for many, transform their lives. For those with risk factors, there are plenty of alternatives and new agents on the horizon. There is no excuse for any of these women to go untreated.

Estrogen has been shown to inhibit damage to chondrocytes and estrogen deficiency appears to accelerate the progression of osteoarthritis.

HOSPITALPROFESSIONALNEWS.IE | HPN • OCTOBER - 2021

OTEZLA® can offer solutions to the challenges in this new environment

OTEZLA® has an established efficacy and safety profile for up to 5 years†1,2

No warnings regarding risk of serious infection2

No contraindications for concurrent use with live vaccination2

A short half-life of 9 hours

Minimise frequency of clinical appointments

Immunomodulatory mode of action2

No laboratory pre-screening, and no drug specific blood monitoring required2

Means that OTEZLA® is rapidly cleared from the body if administration needs to be stopped2

Confidence not compromise in immune response, down-regulation of proinflammatory cytokines and up-regulation of anti-inflammatory cytokines

Make OTEZLA® the positive choice for your psoriasis and psoriatic arthritis patients OTEZLA® (apremilast) 10mg, 20mg and 30mg film coated-tablets Brief Prescribing Information. Refer to the Summary of Product Characteristics (SPC) before prescribing. Further information is available upon request. Presentation: 10mg, 20mg and 30mg film coated-tablets. Indications: Psoriatic arthritis: OTEZLA, alone or in combination with Disease Modifying Antirheumatic Drugs (DMARDs), is indicated for the treatment of active psoriatic arthritis (PsA) in adult patients who have had an inadequate response or who have been intolerant to a prior DMARD therapy. Psoriasis: OTEZLA is indicated for the treatment of moderate to severe chronic plaque psoriasis in adult patients who failed to respond to or who have a contraindication to, or are intolerant to other systemic therapy including ciclosporine, methotrexate or psoralen and ultraviolet-A light (PUVA). Dosage and administration: Treatment with OTEZLA should be initiated by specialists experienced in the diagnosis and treatment of psoriasis or psoriatic arthritis. The recommended dose of OTEZLA is 30mg twice daily taken orally in the AM and PM, approximately 12 hours apart, with no food restrictions. The film-coated tablets should be swallowed whole. An initial dose titration is required per the following schedule: Day 1: 10mg in the AM; Day 2: 10mg in the AM and 10 mg in the PM; Day 3: 10mg in the AM and 20mg in the PM; Day 4: 20mg in the AM and 20mg in the PM; Day 5: 20mg in the AM and 30mg in the PM; Day 6 and thereafter: 30mg twice daily in the AM and PM. No re-titration is required after initial titration. If patients miss a dose, the next dose should be taken as soon as possible. If it is close to the time for their next dose, the missed dose should not be taken and the next dose should be taken at the regular time. Patients with severe renal impairment: The dose of OTEZLA should be reduced to 30mg once daily in patients with severe renal impairment (creatinine clearance of less than 30mL per minute estimated by the Cockcroft-Gault equation). For initial dose titration in this group, it is recommended that OTEZLA is titrated using only the AM doses and the PM doses be skipped. Paediatric population: The safety and efficacy of OTEZLA in children aged 0 to 17 years have not been established. No data is available. Contraindications: Hypersensitivity to the active substance(s) or to any of the excipients. OTEZLA is contraindicated in pregnancy. Pregnancy should be excluded before treatment can be initiated. Special warnings and precautions: Diarrhoea, nausea and vomiting: Severe diarrhoea, nausea, and vomiting associated with the use of OTEZLA have been reported. Most events occurred within the first few weeks of treatment. In some cases, patients were hospitalized. Patients 65 years of age or older may be at a higher risk of complications. Discontinuation of treatment may be necessary. Psychiatric disorders: OTEZLA is associated with an increased risk of psychiatric disorders such as insomnia and depression. Instances of suicidal ideation and behaviour, including suicide, have been observed in patients with or without history of depression. The risks and benefits of starting or continuing treatment with OTEZLA should be carefully assessed if patients report previous or existing psychiatric symptoms or if concomitant treatment with other medicinal products likely to cause psychiatric events is intended. Patients and caregivers should be instructed to notify the prescriber of any changes in behaviour or mood and of any suicidal ideation. If patients suffered from new or worsening psychiatric symptoms, or suicidal ideation or suicidal attempt is identified, it is recommended to discontinue treatment with OTEZLA. Severe renal impairment: See dosage and administration section. Underweight patients: OTEZLA may cause weight loss. Patients who are underweight at the start of treatment should have their body weight monitored regularly. In the event of unexplained and clinically significant weight loss, these patients should be evaluated by a medical practitioner and discontinuation of treatment should be considered. Lactose content: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product. Interactions: Co-administration of strong cytochrome P450 3A4 (CYP3A4) enzyme inducer, rifampicin, resulted in a reduction of systemic exposure of OTEZLA, which may result in a loss of efficacy of OTEZLA. Therefore, the use of strong CYP3A4 enzyme inducers (e.g. rifampicin, phenobarbital, carbamazepine,

phenytoin and St. John’s Wort) with OTEZLA is not recommended. In clinical studies, OTEZLA has been administered concomitantly with topical therapy (including corticosteroids, coal tar shampoo and salicylic acid scalp preparations) and UVB phototherapy. OTEZLA can be co-administered with a potent CYP3A4 inhibitor such as ketoconazole, as well as with methotrexate in psoriatic arthritis patients and with oral contraceptives. Pregnancy, lactation and fertility: Women of childbearing potential should use an effective method of contraception to prevent pregnancy during treatment. OTEZLA should not be used during breast-feeding. No fertility data is available in humans. Undesirable effects: Psychiatric disorders: In clinical studies and post-marketing experience, uncommon cases of suicidal ideation and behaviour, were reported, while completed suicide was reported post-marketing. The most commonly reported adverse reactions with OTEZLA in these indications are gastrointestinal (GI) disorders including diarrhoea (15.7%) and nausea (13.9%). These GI adverse reactions generally occurred within the first 2 weeks of treatment and usually resolved within 4 weeks. Adverse reactions reported in the psoriatic arthritis and/or psoriasis clinical trial programme and post marketing experience include: very common (≥ 1/10) diarrhoea*, nausea*; common (≥1/100 to <1/10) bronchitis, upper respiratory tract infection, nasopharyngitis*, decreased appetite*, insomnia, depression, migraine*, tension headache*, headache*, cough, vomiting*, dyspepsia, frequent bowel movements, upper abdominal pain*, gastroesophageal reflux disease, back pain*, fatigue; uncommon (≥1/1,000 to <1/100) hypersensitivity, suicidal ideation and behaviour, gastrointestinal haemorrhage, rash, urticaria, weight loss; not known (cannot be estimated from the available data) angioedema. *At least one of these adverse reactions was reported as serious. Please consult the SPC for a full description of undesirable events. Pharmaceutical Precautions: Do not store above 30°C. Legal category: POM. Presentation and Marketing Authorisation Numbers: Initiation pack containing 27 film coated tablets (4 x 10mg, 4 x 20mg, 19 x 30mg) - EU/1/14/981/001; 30mg film coated tablets in a pack size of 56 tablets - EU/1/14/981/002. Marketing Authorisation Holder: Amgen Europe B.V. Minervum 7061, 4817 ZK Breda, The Netherlands. Further information is available from Amgen Ireland Limited, 21 Northwood Court, Santry, Dublin D09 TX31. OTEZLA is a trademark owned or licensed by Amgen Inc., its subsidiaries, or affiliates. Date of preparation: April 2020 (Ref: IE-OTZ-2000019). Adverse reactions/events should be reported to the Health Products Regulatory Authority (HPRA) using the available methods via www.hpra.ie. Adverse events should also be reported to Amgen Limited on +44 (0)1223 436441. † Otezla met the primary endpoint of the pivotal trials in psoriasis: PASI-75 response vs placebo at 16 weeks. ESTEEM 1: 33.1% (N=562) vs 5.3% (N=282); ESTEEM 2: 28.8% (N=274) vs 5.8% (N=137), P<0.0001. OTEZLA met the primary endpoint of the pivotal trials in Psoriatic Arthritis: ACR 20 response vs placebo at 16 weeks. PALACE 1: 38% (N=168) vs 19% (N=168), P≤0.001. PALACE 2: 32% (N=162) vs 19% (N=159) P≤0.01; PALACE 3: 41% (N=167) vs 18% (N=169) P≤0.001.2 References: 1. Kavanaugh et al. Arthritis Research & Therapy 2019: 21;118. 2. OTEZLA (apremilast). Summary of Product Characteristics.

OSTEOPOROSIS

What Women Need to Know Osteoporosis is defined by the World Health Organization it as a degenerative bone disease characterized by low bone mass and microstructural deterioration of bone tissue which leads to bone fragility and increased risk of fractures (WHO, 1994). Postmenopausal females are the highest risk group for fractures, and the majority of which are preventable. Lack of exposure to estrogen, smoking, specific medications (glucocorticoids, PPIs, anticonvulsants, thiazolidinediones, aromatase inhibitors, antigoagulants, lithium) and certain medical conditions (hyperthyroidism, rheumatoid arthritis, malabsorption, cancer, hepatic/renal disease) are causative factors. It is the most common global metabolic bone disease, with the International Osteoporosis Foundation reporting that 1 in 3 women over 50, and 1 in 5 men will experience osteoporotic fractures in their lifetime and estimated to affect over 200 million people. In the US 10 million cases of osteoporosis are diagnosed, with an additional 44 million having low bone density.(National Osteoporosis Foundation ,2020). Data from the UK reports approximately

536,000 fragility fractures occurring annually as a result. Ireland’s climate plays a role in the development of osteoporosis, as the northerly latitude decreases exposure of UV light between October and March resulting in low levels of vitamin D. It is estimated that around 300,000 people living in Ireland have Osteoporosis, but only 15% are clinically diagnosed, and that 1 in 2 females over the age of 50 will develop an osteoporosis related fracture over their lifetime (Irish Osteoporosis society). Dual-energy x-ray absorptiometry (DEXA) is the gold standard for evaluation of Bone Mineral Density (BMD). Peripheral DEXA is used to measure BMD at the wrist; it may be most useful in identifying patients at very low fracture risk who require no further work up. DEXA of the femoral neck is the method of choice in those displaying a higher fracture risk. A T-score is calculated by comparing the BMD value with that of controls at their peak bone density, while a Z-Score is compared to an age-matched normal mean. World Health Organization criteria define a normal T-score value as within 1 standard deviation (SD) of the mean BMD value in a healthy

Written by Dr Conor Harrity, Medical Director, The Menopause Hub, Consultant Gynecologist at Beaumont & Rotunda Hospitals, Fertility Specialist at Repromed

young adult. Variations in these standards assist in diagnosis. - T-score of –1 to –2.5 SD indicates osteopenia (Low bone mass) - T-score of less than –2.5 SD in lumbar spine or femoral neck indicates osteoporosis (ISCD) - T-score of less than –2.5 SD with fragility fracture(s) indicates severe osteoporosis A DEXA scan should be performed for women aged >65 (Men >70). For postmenopausal women <65 (Men <70) it should be recommended only in the presence of additional risk factors such as low body weight, previous fracture, the use of high risk medication, or the presence of associated diseases. Rescreening intervals of 15 years are appropriate for women with normal BMD or mild osteopenia, but should be increased to 5 years with moderate osteopenia, or 1 year with advanced osteopenia. The Fracture risk assessment tool (FRAX) can be used as a prognostic marker. It calculates the 10 year fracture probability above that of a 65 year old Caucasian female without risk factors. The result can be used to assist when determining if BMD

measurement or active treatment may be necessary, however, the thresholds for drug treatment have not been proven to be effective for fracture prevention. A particularly useful role for this marker is to assist when deciding if a DEXA scan is needed for women aged 40-65. Treatment of low bone density includes a combination of dietary, lifestyle and medical interventions. Optimisation of calcium and vitamin D status are important first line interventions. Risk appropriate exercise and prevention of falls are also needed. For women of low to medium risk for osteoporotic fracture, the consideration of hormone replacent therapy in the decade following menopause can be considered. In these patients Oestrogen replacement has been suggested to lead to a higher improvement in BMD, and better quality bone than alendronate. For patients at high risk of fracture Anti-Resorptive treatment with bisphosphonates, Denosumab or SERMs are appropriate interventions. For very high-risk patients formation stimulating agents such as teripratide, abaloparatide or romosozumab (sclerostin antibody) can be considered, followed by an inhibitor of bone resorption. Unfortunately the benefit of oestrogen therapy on bone density is lost within a few months of stopping treatment. This is also seen with denosumab, raloxifene and teriparatide. After discontinuation of HRT in patients with significant osteopenia a short course of alendronate or zoledronate infusion may be considered.

HOSPITALPROFESSIONALNEWS.IE | HPN • OCTOBER - 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 phone3

For more information visit www.FreeStyleDiabetes.ie Images are for illustrative purposes only. Not actual patient or data. 1. Scanning the sensor does not require lancets. 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 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. 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-41796 v1.0 06/21.

CPD 79: DIABETIC KETOACIDOSIS Continuing Professional Development

AUTHOR: Cathy Naylor

CPD

Cathy Naylor is Chief II Pharmacist for Medicines Information and Education at University Hospital Waterford. She previously worked at The John Radcliffe Hospital, Oxford in various clinical posts; including Stroke, Neurosciences and Acute General Medicine. From 2016-2019 she was an Education Programme Director Pharmacist at the John Radcliffe managing pre-registration pharmacist training. She also worked as a Teacher Practitioner Pharmacist on the Pharmacy Undergraduate programme at the University of Reading and taught on the Non-Medical Prescribing course for nurses, midwives, therapeutic radiographers, paramedics and physiotherapists at Oxford Brookes University.

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?

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

Diabetic ketoacidosis (DKA) is a medical emergency, typified by a triad of diagnostic criteriaacidosis (venous pH < 7.3 and/or serum bicarbonate < 15 mmol/L), ketosis (plasma ketones > 3.0 or significant ketonuria- +2 or more on standard ketone sticks) and hyperglycaemia (blood glucose levels >11.0 or known diabetes mellitus). It primarily occurs in type 1 diabetes mellitus (T1DM), usually precipitated by factors such as: non-compliance with insulin; intercurrent illness; surgery; with drugs such as corticosteroids, atypical antipsychotics, thiazide diuretics; or with alcohol or cocaine use. DKA is frequently the first presentation for newonset diabetes. DKA can also occur in type 2 diabetes (T2DM), known as ketosis-prone T2DM. If not treated appropriately, DKA can be life-threatening and is the most common cause of diabetesrelated death in younger diabetic patients (paediatric patients and young adults up to aged 25), usually due to a cerebral oedema, a serious complication. Management of paediatric DKA in Ireland is guided by a HSE National Clinical Guideline (2018) as well as a number of recent international guidelines- BPSED (British Paediatric Society of Endocrinology and Diabetes) 2020 and ISPAD (International Society for Paediatric and Adolescent Diabetes), 2018. In patients aged 16-25, who come under adult services, cautious treatment is required to prevent cerebral oedema. There are a several clinical guidelines, governing treatment of DKA in adult patients such as those from the American Diabetes association, the Canadian Diabetes Association and the Joint British Diabetes Society (JBDS). There are points of difference amongst these guidelines that may cause inconsistencies amongst clinicians. The UK guidelines, initially written over a decade ago, but revised most recently in June 2021 will guide the treatment recommendations in this piece, which is aimed at hospital pharmacists and those governing clinical guidelines in Irish hospitals.

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

Diabetic Ketoacidosis in Adult Patients Introduction: Diabetic ketoacidosis (DKA) is a serious, life threatening emergency in patients with diabetes mellitus. DKA continues to be a common cause of hospital admission in type 1 diabetes mellitus (T1DM) and is the leading cause of mortality in young people with T1DM.1 DKA may be the first manifestation of T1DM in 25% of cases.2 DKA may also occur in patients with type 2 diabetes (T2DM), known as ketosis-prone T2DM, which is more common in those of Afro-carribean, Asian or Hispanic backgrounds.3 Euglycaemic DKA (euDKA)characterised by ketonaemia and acidosis- can occur in patients taking SGLT2 (Sodium-Glucose co-transporter 2 inhibitors)dapagiflozin, canagiflozin, empagiflozin. ertugliflozin and sotagliflozin. euDKA may also occur in pregnant patients; patients with prolonged starvation; patients who were partially treated with insulin prior to admission; or due to acute alcohol intake.3 Pathogenesis, clinical features and diagnosis DKA is caused by absolute or relative insulin deficiency, often coupled with increased concentration of counter-

regulatory hormones, such as cortisol, glucagon, catecholamines and growth hormone.2 This combination leads to hyperglycaemia, through failure of insulin-mediated cellular uptake of glucose. With the impairment of glucose uptake, an alternate energy source is provided by an increase in the formation of free fatty acids- acetoacetic acid and β hydroxybutyrate, which lower pH and cause metabolic acidosis. The free fatty acids are oxidised to ketones (ketogenesis)acetoacetic acid to acetone, which gives the characteristic fruity smelling breath associated with DKA. Glycogenolysis and gluconeogenesis in the liver further increase hyperglycaemia (see figure 1). Euglycaemic DKA, caused by SGLT2 inhibitors, is thought to occur as a result of their mechanism of action, reducing serum glucose primarily by increasing glucosuria in the kidney. They also appear to directly stimulate release of glucagon from the pancreas. The glucosuria leads to decreased sodium reabsorption in the kidney, which in turn, increases ketone body reabsorption. Lower plasma glucose suppresses insulin release and further increases glucagon release from the

pancreas. Increased glucagon-to insulin ratio results in increased lipolysis, fatty acid oxidation and ketone production by the liver.4 A picture of ketosis and acidosis arises, without the usual hyperglycaemia characteristic of DKA. This can lead to delays in diagnosing euDKA. As such, patients presenting to hospital unwell, who are taking an SGLT2 inhibitor, should have their ketones checked, and if raised, their pH checked also.2 The SGLT2 inhibitor should be stopped immediately and a HPRA Human Medicines Adverse Reaction Report completed. Whether the drugs can be restarted should be discussed with the diabetes team.5 DKA onset can be rapid- often within 24 hours and patients deteriorate quickly without treatment- coma or death can occur in 3-4 days.3 Precipitating factors include: infection; myocardial infarction; surgery; omission of insulin; new onset of diabetes; and certain drugs, such as corticosteroids, thiazides and second generation antipsychotics.2 In the case of T1DM, mistakenly omitting insulin in the context of illness with reduced oral intake is a common precipitant of DKA. Diabetes Ireland state that every patient and/or their carers should be given a verbal and written

CPD 79: DIABETIC KETOACIDOSIS Figure 1: Pathogenesis of DKA. Reproduced with Permission. Misra S and Oliver N. Diabetic ketoacidosis in adults. (2015) BMJ; 351.

mmol/L or a reading of +2 or more on standard urine sticks; and 3) Acidosis: a venous pH of <7.3 and/or a bicarbonate of <15 mmol/L. For a diagnosis of DKA all three criteria must be present. In euglycaemic DKA, blood glucose may be in normal range or only mildly raised.2 Severe DKA Management in a high dependency setting should be considered for patients with severe DKA (presence of any of the symptoms listed in table 1 below), pregnant patients, young patients (18-25 years) and patients with heart failure, renal failure or any other serious comorbidities.5

copy of individualised “sick day rules”, which reiterates how to prevent loss of control of their diabetes during periods of illness.6 Most importantly, for T1DM, this includes never stopping insulin, avoidance of dehydration, and increasing frequency of monitoring of blood glucose and ketones when unwell. Psychological issues associated with eating disorders and purposeful insulin omission, particularly in adolescent patients with T1DM, are well documented, occurring in up to 20% of recurrent DKA episodes in younger patients.3 Factors leading to insulin omission in this population include fear of weight gain, fear of hypoglycaemia, rebellion from authority and the stress of chronic disease.7 Cocaine use has also been associated with recurrent DKA.2,7 Patients with DKA can present with polyuria, polydipsia and weight loss. They may also have clinical features of underlying

Table 1. Symptoms of Severe DKA

infection, abdominal pain, nausea, vomiting, and drowsiness. Metabolic acidosis may induce compensatory hyperventilation (called Kussmaul respirations).5,7 According to the JBDS guidelines5,8 DKA is diagnosed based on a triad of criteria: 1) Diabetes- hyperglycaemia (blood glucose > 11.0 mmol/L) or a previous diagnosis of diabetes mellitus; 2) Ketonaemia or significant ketonuria- plasma ketones >3.0

Severe DKA is the most common cause of diabetes-related death in children and adolescents. Most DKA-related deaths occur due to cerebral oedema, which bears greater risk in paediatric patients and those aged 25 and under.5 For this reason, treatment of paediatric DKA differs from adult management. In Ireland, there is a National Clinical Practice Guideline for the management of paediatric DKA.9 The British Society for Paediatric Endocrinology and Diabetes (BPSED) have also published a recent clinical guideline (2020).10 Young patients who come under adult services (aged 16-25) may be treated using adult guidelines but should be closely monitored for signs of clinical oedema, such as headaches, altered consciousness (as measured by Glasgow Coma Score) and agitation/aggression.5

Management: Management of DKA has three important remits: 1) fluid replacement to address dehydration, hypovolaemia and potential shock; 2) replacement of insulin to reduce ketosis and treat hyperglycaemia; and 3) maintain potassium homeostasis. Fluid Replacement: In adult patients, the severity of dehydration can be assessed using pulse and blood pressure, taking age, gender and concomitant medication into account. Systolic blood pressures (SBP) below 90 mmHg on admission are likely to be caused by low circulating volume, but could be down to factors such as heart failure or sepsis.5 JBDS guidelines recommend initial fluid resuscitation to shocked patients (SBP 90 mmHg ) with 500mL bolus of 0.9% sodium chloride given over 10-15 minutes. If SBP remains below 90 mmHg, this should be repeated. Once SBP is above 90 mmHg, the fluids regimen outlined in table 2 below is recommended for an average adult, weighing 70kg. Caution is recommended in elderly, renal impairment, heart failure (CCF) and young or pregnant patients, where cerebral or pulmonary oedema could be a risk. Beyond the timescale outlined, further fluid therapy should be guided by fluid status.5 Once blood glucose has dropped to below 14 mmol/L, 10% glucose should be run alongside 0.9% sodium chloride.5 Electrolyte abnormalities are common in DKA, but potassium replacement, titrated to potassium levels as per table 2, is the most important. Patients may present with normal or elevated potassium on admission (due to insulin deficiency and hyperosmolality,

Severe DKA (indicated by the presence of any of the following): • • • • • • • • •

Ketones greater than 6 mmol/L Bicarbonate (HCO3-) below 5 mmol/L Venous pH below 7.1 Hypokalaemia on admission (potassium less than 3.5 mmol/L) Glasgow Coma Score (GCS) below 12 Systolic BP less than 90 mmHg Oxygen saturation below 92% (assuming normal baseline respiratory function) Heart rate above 100 or below 60 bpm Anion gap above 16 mmol/L {Anion gap = (Na+ + K+) – (Cl- + HCO3-)}

Table 1. Symptoms of Severe DKA

69 Table 2: Fluid replacement regime for Adult DKA patients

Fluid

Rate

0.9% Sodium Chloride 1L

Over 1 hour {given in first hour or when SBP>90 mmHg following fluid bolus(es)} Caution in elderly, CCF, renal failure, adolescence, Over 2 hours pregnancy (risk of cerebral and pulmonary oedema)

0.9% Sodium Chloride 1L +/- Potassium Chloride*

which drive potassium out of cells), but total body potassium is low due to osmotic diuresis and secondary hypoaldosteronism.3 Extracellular potassium levels can fall rapidly with insulin infusion, which stimulates cellular uptake of potassium; fluids, which have a dilutional effect; and correction of acidosis. Patient’s urine output should be monitored and potassium replacement should be cautious if the patient is oliguric.5 In-keeping with international safety warnings and the Irish Medicines Safety Network (ISMN) Best Practice Guidelines for the Safe Use of Intravenous Potassium in Irish Hospitals (2020), premixed bags of 0.9% sodium chloride with potassium chloride at concentrations of up to 40 mmol/L should be used where possible, with higher potassium concentrations only considered in critical care settings.11 The use of intravenous bicarbonate is not recommended routinely in DKA as it can paradoxically worsen acidosis and increase the risk of hypokalaemia and cerebral oedema. In addition to potential harmful effects, there is little evidence of benefit. Bicarbonate infusions should only be considered by senior level clinicians, if pH <7 and ideally, in a critical care setting.2,3,5 Fluid replacement in paediatric patients: Whilst this CPD deals with DKA in adults, it is worth mentioning that management of DKA differs in paediatric patients, where volume restoration is gradual to avoid cerebral oedema. The current HSE National Clinical Guideline9 recommends 10 mL/kg of 0.9% NaCl over 30 minutes, repeated if necessary to treat shock. BPSED10 recommend that patients who are not shocked receive 10 mL/kg of 0.9% NaCl over 60 minutes, while shocked patients are given 20 mL/ kg 0.9% NaCl over 15 minutes, followed by up to two boluses of 10 mL/kg. Thereafter BPSED recommend inotropes should be considered. Subsequent fluids are carefully calculated based on weight and % dehydration and given slowly over 48 hours with careful monitoring to avoid cerebral oedema. For patients aged 16-18 treated under adult services, the adult treatment

0.9% Sodium Chloride 1L +/- Potassium Chloride*

Over 2 hours 

0.9% Sodium Chloride 1L +/- Potassium Chloride*

Over 4 hours

0.9% Sodium Chloride 1L +/- Potassium Chloride*

Over 4 hours

0.9% Sodium Chloride 1L +/- Potassium Chloride*

Over 6 hours

 



K+ >5.5- nil, recheck potassium levels in 2 hours K+ 3.5-5.5 - 40mmol/L potassium chloride K+ <3.5- Urgent senior medical review. Higher concentrations of potassium may be required Caution if patient anuric

Table 2: Fluid replacement regime for Adult DKA patients

guidelines should be used to avoid mistakes due to staff unfamiliarity with the paediatric treatment regimens. Those admitted to a paediatric ward should be treated using paediatric clinical guidance. As stated above, patients aged 16-25 under adult services should be closely monitored for cerebral oedema. Insulin Therapy: Once fluids have been initiated, insulin replacement can commence, ideally via a second peripheral access line.5 The American Diabetes Association (ADA)12 and JBDS now both recommend a fixed

rate intravenous insulin infusion (FRIII), rather than a variable rate insulin infusion (VRIII, previously known by the ambiguous term “sliding scale”). It is now recognised that blood glucose levels are a poor marker for serum ketosis and altering insulin rate based on glucose levels may lead to inadequate resolution of ketoacidosis. The disadvantage with using FRIII is that blood glucose must be measured hourly to avoid hypoglycaemia and 10% glucose infusion must be started once serum blood glucose <14 mmol/L. The FRIII is continued until resolution of ketosis, defined by pH>7.3 and capillary ketones<0.6mmol/L. In addition

Patient weight (kg) Insulin dose (units/hour) when blood glucose >14 mmol/L (0.1 units/kg/hour) 40-49 4 50-59 5 60-69 6 70-79 7 80-89 8 90-99 9 100-109 10 110-119 11 120-129 12 130-139 13 140-150 14 >150 15 (initial doses >15 units should only be under specialist supervision) Table 3: Fixed rate intravenous insulin infusion. (JBDS, 2021) 5

to starting glucose 10% alongside the insulin infusion, the 2021 JBDS guidelines also recommend considering de-escalation of the insulin dose from 0.1 to 0.05 units/ kg/hour once blood glucose <14 mmol/L. This recommendation is due to significant rates of hypoglycaemia (27.6%) and hypokalaemia (67%) reported on the national audit of a previous version of the guideline.5 FRIII is given via an infusion pump. It is made up of 50 units of

Table 3: Fixed rate intravenous insulin infusion. (JBDS, 2021) 5

De-escalated insulin dose (units/hour) when blood glucose <14 mmol/L (0.05 units/kg/hour) 2 2.5 3 3.5 4 4.5 5 5.5 6 6.5 7 7.5

CPD 79: DIABETIC KETOACIDOSIS

Summary of Recommendations for treating DKA in adult patients Intravenous fluids Shock (SBP < 90 mmHg)- give 500mL 0.9% NaCl over 15-20 minutes SBP still <90 mmHg, repeat if necessary Not shocked

Insulin

0.9% NaCl 1L Over 1 hour 0.9% NaCl 1L Over 2 hours (+/- KCl 40 mmol) 0.9% NaCl 1L Over 2 hours (+/- KCl 40 mmol) 0.9% NaCl 1L Over 4 hours (+/- KCl 40 mmol) 0.9% NaCl 1L Over 4 hours (+/- KCl 40 mmol) 0.9% NaCl 1L Over 6 hours (+/- KCl 40 mmol) Additional fluids to be based on clinical assessment Potassium replacement if [K+] 3.5-5.5 mmol/L (aim [K+] 4-5.5 mmol/L) If < 3.5 mmol/L higher concentrations of potassium may be required (consider critical care). > 5.5 mmol/L omit and monitor hourly. Start glucose 10% 500mL over 4 hours when blood glucose <14 mmol/L (run concurrently with 0.9% NaCl) Dilute 50 units human soluble insulin (Actrapid® or Humulin S ®) in 50mL NaCl 0.9% Start a FRIII at a rate of 0.1 units/kg. Continue long-acting/human insulin analogues Aims: Reduction of ketones by 0.5 mmol/hour, reduction of blood glucose by 3 mmol/hour and increase in bicarbonate by 3 mmol/hour If ketones and blood glucose not dropping sufficiently, check insulin infusion pump, cannula and lines, before increasing by 1 unit/hour Continue FRIII until ketones < 0.6mmol/L and pH >7.3 Once blood glucose <14 mmol/L, consider reducing insulin dose to 0.05 units/kg/hour If patient eating and drinking, start subcutaneous insulin If not eating and drinking, switch to VRIII When switching from IV insulin (FRIII or VRIII) to subcutaneous, give subcutaneous dose 30-60 minutes prior to stopping infusion and with a meal.

human soluble insulin (Actrapid® or Humulin S®) made up to 50mL with 0.9% sodium chloride. JBDS, unlike ADA, do not recommend an initial priming dose of insulin. See table 3 for JBDS recommended FRIII dosing. They state doses in excess of 15 units per hour should be discussed with the diabetes inpatient team. JBDS recommend hourly monitoring of blood glucose and ketones. Venous pH, bicarbonate and serum potassium should be checked at 60 minutes, 2 hours and 2 hourly thereafter or until transition to subcutaneous insulin.5

The treatment targets with FRIII are to reduce blood ketones by 0.5 mmol/L/hour; reduce blood glucose by 3.0 mmol/L/hour (whilst avoiding hypoglycaemia), increase bicarbonate by 3.0 mmol/L/hour and maintain potassium between 4.0 and 5.5 mmol/L. If these targets are not being achieved, the the pump, connections and line patency should be checked before consideration given to increasing the infusion rate by 1 unit/hour increments until the required response is attained. Continuation of basal insulin JBDS guidelines recommend

basal insulin is continued in patients who were taking prior to admission, at their pre-admission dose and time. They state that continuation of long acting basal subcutaneous insulin analogues (Levemir®, Lantus®, Toujeo® and Tresiba®) provides background insulin when the IV insulin is discontinued, avoiding rebound hyperglycaemia. Short acting insulin, mixed analogues and oral hypoglycaemic agents should be held with IV insulin infusion. JBDS recommendations5,8 also state that human analogues (Insulatard®, Humulin I®, Insuman Basal) may also be continued on the basis

that there is not much difference between the onset of action and duration of actions of human basal insulin compared with the long acting analogues, however this has not yet been investigated in quality trials, so is at the discretion of the unit treating the patient. In patients who were not taking basal insulin prior to DKA admission (e.g. those newly diagnosed with T1DM), the initiation of a long acting analogue is recommended at a dose of 0.25 units/kg given once a day. This is based on one small randomised controlled trial which showed that initiating a long acting analogue (e.g. Lantus® or Levemir®) alongside FRIII may reduce the incidence of rebound hyperglycemia when the insulin infusion is discontinued, without increasing the risk of hypoglycemia.13 Resolution of symptoms: Once DKA is resolved (pH >7.3 and ketones 0.6 mmol/L) and patient is eating and drinking, they can be switched back to their usual subcutaneous insulin regime. Urine ketones can persist and should not delay transfer to subcutaneous insulin in the context of overall clinical recovery. If their HbA1C suggests a poor level of control, their insulin regime should be reviewed by a specialist diabetes team.5 If patients are not eating and drinking, they can be switched to a variable rate intravenous insulin infusion (VRIII, previously known as a sliding scale). When switching to subcutaneous insulin, the short acting analogue should be given 30-60 minutes prior to stopping intravenous insulin infusion (FRIII or VRIII), and alongside a meal.5,8 Insulin naïve patients should ideally be seen by a specialist diabetes team, who would advise on a suitable insulin regime as there are a number of factors which may affect their insulin sensitivity, such as age, weight and degree of glycaemic control. An initial total daily dose of insulin of approximately 0.5-0.75 units/ kg may be used. For a basal-bolus regime, 50% should be given as long-acting basal insulin with the evening meal and the remainder as a short-acting analogue, divided equally across the morning, lunchtime and evening meals.14 Close monitoring of blood sugar and ketones is required. References on request

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

72 News

Redefining Diabetes Remission Irish Society for Clinical Nutrition and Metabolism (IrSPEN) spokesperson, and expert group member Professor Carel le Roux

identified when blood sugar levels return to below the level indicative of diabetes (HbA1c <48mmol/mol), continue for at least 3 months, and without the use of medications.” He added that testing to determine long-term maintenance of a remission should be done at least yearly, together with the routine testing for potential complications.

In light of increasing numbers of patients achieving diabetes remission – the American Diabetes Association convened an international, multidisciplinary expert group to review medical guidelines and definitions.

A new international report has recognised the major progress in treating type 2 diabetes – and prompted a new medical definition of ‘diabetes remission’.

Irish Society for Clinical Nutrition and Metabolism (IrSPEN) spokesperson, and expert group member, Professor Carel le Roux said the report of the group launched this week has agreed that: “the term remission be used rather than cure, that this be

IrSPEN spokesperson and UCD Chair of Surgery at St Vincent’s University Hospital Professor Helen Heneghan said a return to normal sugar levels in patients with typical type 2 diabetes can now be attained by several therapies, which is very positive for patients. “Language around diabetes definition is critical and there is a need for the accuracy which this medical consensus report has provided. “However, the frequency of sustained improvement, its likely duration, and its effect on subsequent medical outcomes

remain unclear for now – but research underway here in Ireland will help answer these questions.” The international expert group also included representatives from the European Association for the Study of Diabetes, Diabetes UK, the Endocrine Society and the Diabetes Surgery Summit. IrSPEN spokesperson and bariatric surgeon at St Vincent’s Private Hospital Mr Dimitri Pournaras added that although bariatric surgery was the first to show that remission of diabetes was possible, “the future for people living with type 2 diabetes has never been brighter given our ability to now combine nutritional therapies, pharmacotherapies and surgical therapies”. Professor le Roux concluded by saying that treatments for type 2 diabetes have transformed in recent years as different therapies been shown to normalize blood sugar in certain people.

Switch On and Speed Up Tendon Healing Researchers at CÚRAM, the SFI Research Centre for Medical Devices based at NUI Galway, have shown how the simple act of walking can power an implantable stimulator device to speed up treatment of musculoskeletal diseases. The research establishes the engineering foundations for a new range of stimulator devices that enable control of musculoskeletal tissue regeneration to treat tendon

damage and disease and sports injuries, without the use of drugs or external stimulation. The study investigated whether electrical therapy, coupled with exercise, would show promise in treating tendon disease or ruptures. It showed that tendon cell function and repair can be controlled through electrical stimulation from an implantable device which is powered by body movement.

Dr Marc Fernandez, who carried out the principal research of the study at CÚRAM, said: “Successful treatment of tendon damage and disease represents a critical medical challenge. “Our discovery shows that an electrical charge is produced in the treatment target area - the damaged or injured tendon - when the implanted device is stretched during walking. The potential gamechanger here is like a power

switch in a cell - the electrical stimulus turns on tendon-specific regenerative processes in the damaged tendon.” The stimulator device uses a fabric like mesh - known as a piezoelectric material - that produces electricity when stretched or put under mechanical pressure. It is made using a scaffold of nano-fibres which are one-thousandth of the thickness of a human hair.

New Guidelines on IBS The British Society of Gastroenterology has published updated guidelines for the management of Irritable Bowel Syndrome (IBS) in which probiotics may prove effective for general symptoms and abdominal pain linked to the condition. Gastroenterology experts, writing in publication ‘Gut’ recommend the use of probiotics as a first-line treatment, although they stopped short of recommending a specific species or strain. “Irritable bowel syndrome (IBS) remains one of the most common gastrointestinal disorders seen by clinicians in both primary and secondary care,” say the authors. “Since publication of the last British Society of Gastroenterology (BSG) guideline in 2007, substantial advances have been made in understanding its complex pathophysiology, resulting in its re-classification as a disorder of gut-brain interaction, rather than a functional gastrointestinal disorder. Moreover, there has been a considerable amount of new evidence published concerning the diagnosis, investigation and management of IBS. “IBS is a multifactorial disorder of gut-brain interaction, and the evidence summarised here underlines the importance of effective communication, making a positive diagnosis, and instituting appropriate, evidence-based non-pharmacological and pharmaological therapies according to predominant symptoms, global patient assessment and patient choice, in order to improve both symptoms and quality of life within a biopsychosocial framework. This guideline has also highlighted emerging new therapeutic options for IBS and priority areas for ongoing research,” they conclude.

OCTOBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

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Contains a unique combination of two clinically researched researched synergetic strains. individual strains with two different modes of action both targeting key mechanisms in IBS Calcium: Contributes to the normal function of digestive enzymes Pantothenic Acid, Vitamin B6: Contribute to the reduction of tiredness and fatigue.

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74 News

Budget 2022: Critical Moment for Mental Health Professor Anne Doherty, Consultant Liaison Psychiatrist and Chair of the IHCA Psychiatry Committee

“The combination of gaping mental health capacity deficits with significantly increased demand for treatment of mental illnesses impacted by Covid-19 is stretching our acute services to breaking point” Hospital consultants are calling on Government to set funding for Ireland’s mental health services at realistic levels, as the impact of Covid-19 continues to expose the decades-long detrimental effects of severe deficits across the service.

the equivalent 2009 expenditure level, given the population growth since then, the current mental health budget is actually ¤2,000 per 1,000 population below the spend 13 years ago.

alternative placement for those with severe and enduring mental illness, who often have inappropriately long acute inpatient stays due to the lack of suitable step-down facilities.

Commenting on the launch of its Mental Health Pre-Budget 2022 Submission, the Irish Hospital Consultants Association (IHCA) says that there is now an opportunity to ensure that the mental health services are able to provide for ongoing increasing demand.

At 5.4% of the overall health budget, the mental health budget in 2021 is also half the level of spending compared with other European neighbours and is low by international standards. Germany, the Netherlands and Sweden all spend approximately 11% of government health spending on mental health, with France allocating 13%.

However, there was a stark warning that providing psychiatric care to patients while living alongside Covid has and will continue to present significant challenges because of the overwhelming capacity deficits that have existed for more than a decade.

For Budget 2022, the IHCA urges the Government to increase capital expenditure for Ireland’s mental health services and for its allocation to be expedited to address the physical infrastructure deficits that have resulted from more than a decade of capital cuts and underinvestment.

Consultants say that the provision of an additional 28 acute psychiatric beds as outlined in the HSE’s National Service Plan 2021, while welcome, will not address the enormous shortfall in our psychiatric bed capacity, which reduced by 68% between 2004 and 2019. They estimate that an immediate increase of at least 300 acute adult psychiatric inpatient beds is required to meet recommended levels.

With record numbers of people on waiting lists to be assessed and treated by a hospital consultant, as well as unprecedented numbers of patients presenting to Emergency Departments for mental healthcare, the IHCA says that targeted funding, beds and staffing is required now to deliver timely access to quality care for all patients.

Immediate Capacity

Funding Inadequacies

Yet more than 1 in 8 inpatients spend six months or longer in an acute mental health bed, highlighting the lack of a suitable

While the 2021 Mental Health Budget of ¤1,114.1m is 9% above

With bed shortages and long waiting lists, the acute hospital system continues to feel the strain. Ireland has the third lowest number of inpatient psychiatric care beds in the EU, at just 32.69 per 100,000 inhabitants - this is half the EU27 average of 73.12 beds per 100,000.

OCTOBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

In light of the pandemic and the challenges of infection control, the fact that the majority of mental health units are in dormitory style format is also a concern. The IHCA recommends a greater number of single occupancy rooms made available to reduce the risk of not just Covid-19, but any viral or contagious infection spreading between vulnerable patients. Consultant Staffing At a time where some Emergency Departments are witnessing 8-fold increases in the number of patients presenting with mental health crises – especially among young people – the IHCA says it is unacceptable that more than 1 in 5 approved Consultant Psychiatry posts are vacant or

filled on a temporary basis across the country. The Association has long pointed to the ongoing salary inequity (applied since 2012) as the root cause of Ireland’s Consultant Psychiatrist recruitment and retention crisis, calling on Minister for Health Stephen Donnelly to deliver on his ‘unambiguous commitment’ to remedy the discrimination against consultants who have taken up contracts since 2012 and for future appointees. Consultant vacancies are contributing to persistent and damaging waiting lists for treatment which are likely to worsen over the coming months with the impact of the pandemic hitting all areas of the health service, especially mental health. First signs are already showing increased presentations of patients in crisis at Emergency Departments, which are often chaotic environments and not an appropriate setting for treating those who are acutely mentally unwell for a prolonged period of time. Commenting on the submission, Professor Anne Doherty, Consultant Liaison Psychiatrist and Chair of the IHCA Psychiatry Committee says, “The pandemic has completely exposed the cracks across our public hospital system, including in our mental health services. The combination of gaping mental health capacity deficits with significantly increased demand for treatment of mental illnesses impacted by Covid-19 is stretching our acute services to breaking point. It has focused our attention on the urgent need to dedicate specific funding and resources to mental health, anticipating the wider impact of the pandemic on our population. “We are at a pivotal moment and decision-making around this Budget is critical. It provides an opportunity to get it right, making a huge difference for our mental health patients. “The solution is obvious: we must open the necessary level of beds and recruit the required number of Consultant Psychiatrists - and quickly. Government action now will prevent the current pandemic healthcare crisis drawing out for the rest of the decade and impacting on the nation’s mental health for years to come.”

Enabling people with depression to feel, think and do better1

Brintellix is indicated for the treatment of major depressive episodes in adults1 Brintellix® (vortioxetine) film-coated tablets Prescribing information: Please refer to the full Summary of Product Characteristics (SPC) before prescribing, particularly in relation to side effects, precautions and contraindications. Presentation: Tablets containing 5, 10, 15 or 20mg vortioxetine. Indication: Treatment of major depressive episodes in adults. Dosage: 10mg once daily. May be increased to a maximum 20mg daily or reduced to 5mg if necessary. After symptoms resolve, treatment recommended for at least 6 months. Can be taken with or without food. Elderly (≥65 years): Initial dosage is 5mg once daily. Caution advised if using doses above 10mg daily. Children (7-11 years): Not recommended. Adolescents (12-17 years): Not recommended in major depressive disorder; efficacy not established. Cytochrome P450 inhibitors and inducers: Consider a dose reduction of vortioxetine if a strong CYP2D6 inhibitor is added. Consider a dose adjustment if a broad CYP450 inducer is added to treatment. Renal or hepatic impairment: No dose adjustment; subpopulations are vulnerable and data on the use of Brintellix are limited. Contraindications: Hypersensitivity to the active substance or excipients. Concomitant use with non-selective, monoamine oxidase inhibitors (MAOIs) or selective MAO-A inhibitors (e.g. moclobemide). Fertility, pregnancy and lactation: Limited data; should only be administered to pregnant women if the expected benefits outweigh the potential risk to the foetus. Animal studies showed reproductive toxicity. Use of SSRIs in pregnancy, particularly in late pregnancy, may increase the risk of persistent pulmonary hypertension in the newborn (PPHN). Potential risk of postpartum haemorrhage following exposure to an SSRI or SNRI within the month prior to birth. Excreted into human milk, risk to the breastfeeding child cannot be excluded. Animal data showed no effect on fertility, sperm quality or mating performance. Human case reports with some SSRIs have shown that an effect on sperm quality is reversible. Impact on human fertility has not been observed. Please refer to SPC for more detail. Warnings & Precautions: Closely supervise patients, especially those at high risk for suicide-related behaviours during first few weeks of treatment and during dose changes. Use with caution in patients: at risk of hyponatraemia; with a history of mania/hypomania; aggression/agitation; undergoing ECT; with unstable epilepsy (discontinue if seizures begin for the first time or increase in frequency); with bleeding tendencies/disorders, taking anticoagulants or medicines affecting platelet function; in patients on lithium or tryptophan; with increased intraocular pressure, or those at risk of acute narrow angle glaucoma. Monitor patients for appearance of serotonin syndrome or neuroleptic malignant syndrome and discontinue if occurs. Patients may experience feelings of aggression, anger, agitation and irritability. Patients/caregivers should seek medical advice if such behaviour emerges or aggravates. SSRIs/SNRIs may increase the risk of postpartum haemorrhage. Brintellix tablets contain sodium (<1mmol/tablet). Drug interactions: Alcoholic drinks not advisable. Vortioxetine is extensively metabolised in the liver. Potential for interactions with: MAOIs, MAO-A and MAO-B inhibitors; serotonergic medicines; St John’s wort; products which may lower the seizure threshold, e.g. antidepressants, neuroleptics, mefloquine or bupropion. Lower dose may be considered if strong CYP2D6 inhibitor is added to treatment depending on patient response, these effects may be greater in patients who are poor metabolisers of CYP2D6. Dose adjustment may be considered if a broad cytochrome P450 inducer is added to treatment. Reports of false positive results in urine enzyme immunoassays for methadone in patients taking vortioxetine.

Exercise caution in interpreting positive drug screen results. Effects on ability to drive and operate machines: No or negligible influence, dizziness has been reported; use caution at the start of treatment or when the dose is changed. Adverse events: Most common adverse reaction is nausea, usually mild or moderate, transient and occurs within first two weeks of treatment. The following have been reported in clinical trials and during post-marketing use: Very common (≥1/10 patients): nausea. Common (≥1/100 to <1/10): abnormal dreams, dizziness, diarrhoea, constipation, vomiting, pruritus, including generalised pruritus. Uncommon (≥1/1,000 to <1/100): flushing, night sweats. Rare (≥1/10,000 to <1/1,000): mydriasis (which may lead to acute narrow- angle glaucoma). Not known: anaphylactic reaction, hyponatraemia, insomnia, agitation, aggression, serotonin syndrome, haemorrhage (including contusion, ecchymosis, epistaxis, gastrointestinal or vaginal bleeding), angioedema, urticaria, rash. Sexual dysfunction: 20mg dose was associated with increase in sexual dysfunction. Class effect: Studies in patients ≥50 years of age, show an increased risk of bone fractures in patients receiving SSRIs and TCAs. Not known if relevant to vortioxetine. Paediatrics: Higher incidences reported in adolescents for abdominal pain-related events and suicidal ideation. Prescribers should consult the full SPC in relation to other side effects. Overdose: Management consisting of treating clinical symptoms and relevant monitoring. Legal category: POM, for non-renewable supply. Brintellix Tablets, blisters of: 5mg (EU/1/13/891/002) 28 tablets. 10mg (EU/1/13/891/010) 28 tablets. 15mg (EU/1/13/891/019) 28 tablets. 20mg (EU/1/13/891/028) 28 tablets. Further information available from: Lundbeck Ireland Ltd, 4045 Kingswood Road, Citywest Business Park, Co. Dublin. Tel: 01 468 9800. Date of last revision of PI: November 2020. Reference: IE-BRIN-0254. Brintellix® is a Registered Trade Mark. Job number: IE-BRIN-0261 Date of preparation: March 2021

Reference: 1. Brintellix Summary of Product Characteristics. Available at https://www.medicines.ie/medicines/brintellix-10-mg-film-coated-tablets-34817/smpc Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie. Adverse events should also be reported to Lundbeck on: 01 468 9800 Email: SafetyLuIreland@lundbeck.com

76 Deep Vein Thrombosis

Blood Clots (VTE) - The #1 Cause of Preventable Death In Our Hospitals Written by Dr Barry Kevane, Consultant Haematologist, Mater Misericordiae University Hospital, Dublin/ Ann Marie O'Neill, Thrombosis Patient & Founder of Thrombosis Ireland

Dr Barry Kevane, Consultant Haematologist, Mater Misericordiae University Hospital, Dublin

Ann Marie O'Neill, Thrombosis Patient & Founder of Thrombosis Ireland

Venous thromboembolism (VTE), which comprises of deep vein thrombosis (DVT) and pulmonary embolism (PE), is an incredibly common but frequently overlooked source of cardiovascular morbidity and mortality1, 2. Epidemiological data has consistently demonstrated that VTE is the third leading cause of cardiovascular death worldwide (after myocardial infarction and stroke)3. Survivors of VTE frequently experience life-altering chronic illness. However, it is also now clear that the majority of VTE events are likely to be preventable (particularly those which arise in association with hospital admission)4. Consequently, efforts to promote awareness of VTE risk and to implement strategies directed at improving prevention of VTE must be prioritised at national and local level.

In recent decades we have seen rapid advances in VTE care, including improvements in diagnostic technologies as well as therapeutic options. With these advances, analyses of global trends in VTE-related mortality suggest that progress in improving patient outcomes is being made5. However, notwithstanding these incremental improvements in care, VTE remains a potentially devastating diagnosis which can be immediately fatal in severe cases and which requires expert clinical management in order to mitigate the risk of mortality and chronic morbidity3. With the emergence of the COVID-19 pandemic and the associated thrombotic risk, patients and clinicians have been presented with new unprecedented challenges6, 7. In the field of thrombosis, we have seen ground-breaking research being undertaken nationally and internationally, with patient-centred

OCTOBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

clinical studies providing new avenues for treatment as well as presenting new paradigms for our understanding of the role of VTE and coagulation activation in systemic disease8, 9.

This conference has been approved for 11 credits from the RCPI. There are three main sections of the conference. (1) Main Conference, (2) Nursing Session and (3) Patient Session.

World Thrombosis Day is recognised on 13th October. It focuses attention on the often overlooked and misunderstood condition of thrombosis/VTE. World Thrombosis Day takes place every year on the birthday of Rudolf Virchow, who was the pioneer in the pathophysiology of thrombosis. A German physician, pathologist, biologist and anthropologist, Virchow developed the concept of ‘thrombosis’ and advanced understanding of this condition. Over a century ago, Rudolf Virchow described 3 factors that are critically important in the development of venous thrombosis. (1) venous stasis, (2) activation of blood coagulation, and (3) vein damage. These factors have come to be known as the Virchow triad.

Attendance is free and you can register and see all programs at https://www.vtedublin.org/ VTE: A MAJOR GLOBAL AND NATIONAL BURDEN

Every Year numerous events and campaigns are organised around World Thrombosis Day to raise awareness and save lives.

VTE occurs at a frequency of approximately 1 per 1000 adults per year1, 10. VTE can happen to anyone at any age but it is strongly associated with increasing age and among individuals aged over 85 years, the incidence of VTE rises to 5-6 per 1000 per annum. Approximately two-thirds of VTE events present as DVT of the lower limbs with approximately one-third of cases presenting as pulmonary embolism (although the majority of individuals with PE will have evidence of concomitant DVT and vice versa). A small number of individuals with venous thrombosis present with blood clots at more unusual sites, including the cerebral veins and within the splanchnic circulation10.

As part of the World Thrombosis Day 2021 initiative, the VTE Dublin 2021 International Conference (in partnership with Thrombosis Ireland) will bring together some of the leading international experts in the field of VTE. Together with patient representatives supported by Thrombosis Ireland, the invited international faculty will discuss advances in the field of thrombosis with a particular emphasis on topics which have been identified as priorities by patients and their advocates, including cancerassociated VTE and thrombosis associated with COVID-19.

The majority of VTE-related deaths are likely as a result of PE and recent data suggest that PE accounts for approx. 7 deaths per 100,000 individuals per annum5, 11. Untreated PE is thought to have a mortality rate approaching 30%. With advances in diagnostic and therapeutic strategies PE-related mortality appears to be decreasing, but even among patients who receive treatment, rates of early mortality may still be in excess of 10% in certain high-risk sub-groups3. It is likely that many PE-related deaths occur suddenly or among

COMBINING POWER AND CONFIDENCE AGAINST LDL-C* IN THE TREATMENT OF

HYPERCHOLESTEROLAEMIA

Rosuvastatin + Ezetimibe

20 mg/10 mg

10 mg/10 mg

Rosuvastatin + Ezetimibe

40 mg/10 mg

Suvezen is indicated for substitution therapy in adult patients who are adequately controlled with rosuvastatin and ezetimibe given concurrently at the same dose level as in the fixed combination, but as separate products, as adjunct to diet for treatment of primary hypercholesterolaemia (heterozygous familial and nonfamilial) or homozygous familial hypercholesterolaemia1 Prescribing Information: Suvezen (rosuvastatin/ ezetimibe) film-coated tablets Please refer to the Summary of Product Characteristics (SmPC) for full prescribing details. Presentations: Suvezen 10mg/10mg, 20mg/10mg and 40mg/10mg: Each film-coated tablet contains 10mg; 20mg or 40mg of rosuvastatin (as rosuvastatin calcium) respectively, and 10mg ezetimibe. Indication: Suvezen is indicated for substitution therapy in adult patients who are adequately controlled with rosuvastatin and ezetimibe given concurrently at the same dose level as in the fixed combination, but as separate products, as adjunct to diet for treatment of primary hypercholesterolaemia (heterozygous familial and non-familial) or homozygous familial hypercholesterolaemia. Dosage and Administration: The patient should be on and continue, an appropriate lipid-lowering diet, during treatment with Suvezen. Suvezen is not suitable for initial therapy. Treatment initiation or dose adjustment, if necessary, should only be done with the monocomponents and after setting the appropriate doses the switch to the fixed dose combination of the appropriate strength is possible. Patient should use the strength corresponding to their previous treatment. The recommended dose is one Suvezen tablet daily. To be administered at any time of the day, with or without food. The tablet should be swallowed whole with a drink of water. If co-administered with bile acid sequestrant (BAS), administration of Suvezen should occur either ≥2 hours before or ≥4 hours after administration of a BAS. Special populations: Paediatric (<18 years): Safety and efficacy has not been established. Elderly (>70 years): Starting dose of 5 mg rosuvastatin is recommended. The combination is not suitable for initial therapy. Hepatic impairment: Mild: No dosage adjustment is required. Moderate/Severe: Treatment with Suvezen is not recommended. Renal impairment: Mild: No dose adjustment is necessary. Moderate (creatinine clearance <60 ml/min): The recommended start dose is rosuvastatin 5mg. Race: The recommended start dose is rosuvastatin 5 mg for patients of Asian ancestry due to increased systemic exposure. The fixed dose combination is not suitable for initial therapy. Monocomponent preparations should be used to start the treatment or to modify the dose. Suvezen 40 mg/10 mg tablets are contraindicated in these patients. Genetic polymorphisms: In patients who are known to have specific types of genetic polymorphisms that can lead to increased rosuvastatin exposure, a lower daily dose of Suvezen is recommended. Dosage in patients with pre-disposing factors to myopathy: The recommended start dose is rosuvastatin 5mg in patients with pre-disposing factors to myopathy. Suvezen 40 mg/10 mg tablets are contraindicated in some of these patients. Concomitant therapy: The risk of myopathy (including rhabdomyolysis) is increased when Suvezen is administered concomitantly with certain medicinal products that may increase the plasma concentration of rosuvastatin (e.g. ciclosporin and certain protease inhibitors including combinations of ritonavir with atazanavir, lopinavir, and/or tipranavir). Whenever possible, alternative medications should be considered, and, if necessary, consider temporarily discontinuing Suvezen therapy. In situations where coadministration of these medicinal products with Suvezen is unavoidable, the benefit and the risk of concurrent treatment and rosuvastatin dosing adjustments should be carefully considered. Contraindications: Hypersensitivity to the active substances or excipients. Pregnancy, breast-feeding and in women of childbearing potential not using appropriate contraceptive measures. Active liver disease or any serum transaminase elevations which are unexplained, persistent or exceeding 3x the upper limit of normal (ULN). Severe renal impairment (creatinine clearance <30ml/min); myopathy or receiving concomitant ciclosporin. 40mg/10mg dose contraindicated in patients with pre-disposing factors for myopathy/rhabdomyolysis; such factors include: Moderate renal impairment (creatinine clearance <60ml/min), hypothyroidism, personal or family history of hereditary muscular disorders, previous history of muscular toxicity with another HMG-CoA reductase inhibitor or fibrate, alcohol abuse, situations where an increase in plasma levels of rosuvastatin may occur, Asian patients, concomitant use of fibrates. Precautions and Warnings: Skeletal muscle effects: have been reported in rosuvastatin-treated patients with all doses and in particular with doses >20mg. As with other HMG-CoA reductase inhibitors, reporting rate for rhabdomyolysis is associated with use at doses >40mg. Post-marketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported. If myopathy is suspected based on muscle symptoms or is confirmed by a creatine phosphokinase (CPK) level, Suvezen and any of these other agents that the patient is taking concomitantly should be immediately discontinued. All patients starting therapy with Suvezen should be advised of the risk of myopathy and told to report promptly any unexplained muscle pain, tenderness or weakness, particularly if associated with malaise or fever. Creatine kinase (CK) measurement: CK should not be measured following strenuous exercise or in the presence of a plausible alternative cause of CK increase. If CK levels are significantly elevated at baseline (>5x ULN) a confirmatory test should be carried out within 5 – 7 days. If the repeat test confirms a baseline CK >5x ULN, treatment should not be started. Patients with pre-disposing factors for myopathy/ rhabdomyolysis: Caution should be exercised in these patients. Risk: benefit of treatment should be considered and clinical monitoring is recommended. CK levels should be measured in these patients. Therapy should be discontinued if CK levels are markedly elevated (>5x ULN) or if muscular symptoms are severe and cause daily discomfort. If symptoms resolve and CK levels return to normal, then consideration should be given to reintroducing treatment at the lowest dose. Immune-mediated necrotising myopathy (IMNM): Clinically characterised by proximal muscle weakness and elevated serum CK, has been reported very rarely during or after treatment with statins, including rosuvastatin, despite discontinuation of statin treatment. In clinical trials an increase in the incidence of myositis and myopathy has been seen in patients receiving other HMG-CoA reductase inhibitors together with fibric acid derivatives. Suvezen should not be used in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g. sepsis, hypotension, major surgery, trauma, severe metabolic, endocrine and electrolyte disorders; or uncontrolled seizures). Liver effects: In controlled co-administration trials in patients receiving ezetimibe with statin, consecutive transaminase elevations ≥3x ULN have been observed. It is recommended that liver function tests be carried out prior to, and 3 months following, the initiation of treatment. Rosuvastatin should be discontinued or the dose reduced if the level of serum transaminases is >3x ULN. The reporting rate for serious events is higher at the 40mg dose. In patients with secondary hypercholesterolaemia caused by hypothyroidism or nephrotic syndrome, the underlying disease should be treated prior to initiating therapy with rosuvastatin. Liver disease and alcohol: As with other HMG-CoA reductase inhibitors, rosuvastatin should be used with caution in patients who consume

Single-pill combination of rosuvastatin and ezetimibe available in 3 doses**

excessive quantities of alcohol and/or have a history of liver disease. Renal effects: Proteinuria has been observed in patients treated with higher doses of rosuvastatin and was transient or intermittent in most cases. Proteinuria has not been shown to be predictive of acute or progressive renal disease. An assessment of renal function should be considered during routine follow-up of patients treated with a dose of 40mg. Diabetes mellitus: Some evidence suggests that statins raise blood glucose and in some patients, at high risk of future diabetes, may produce a level of hyperglycaemia where formal diabetes care is appropriate. This risk, however, is outweighed by the reduction in vascular risk with statins and therefore should not be a reason for stopping statin treatment. Patients at risk (fasting glucose 5.6 – 6.9mmol/l, BMI >30kg/m2, raised triglycerides, hypertension) should be monitored both clinically and biochemically according to national guidelines. Interstitial lung disease: Exceptional cases have been reported with some statins, especially with long term therapy. Presenting features can include dyspnoea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If it is suspected, statin therapy should be discontinued. Protease inhibitors: Increased systemic exposure to rosuvastatin has been observed in subjects receiving rosuvastatin concomitantly with various protease inhibitors in combination with ritonavir. Consideration should be given both to the benefit of lipid lowering by use of Suvezen in HIV patients receiving protease inhibitors and the potential for increased rosuvastatin plasma concentrations when initiating and up titrating rosuvastatin doses in patients treated with protease inhibitors. The concomitant use with certain protease inhibitors is not recommended unless the dose of rosuvastatin is adjusted. Fibrates: The safety and efficacy of ezetimibe administered with fibrates have not been established. If cholelithiasis is suspected in a patient receiving Suvezen and fenofibrate, gallbladder investigations are indicated and therapy should be discontinued. Anticoagulants: If Suvezen is added to warfarin, another coumarin anticoagulant, or fluindione, the International Normalised Ratio (INR) should be appropriately monitored. Fusidic acid: Suvezen must not be co-administered with systemic formulations of fusidic acid or within 7 days of stopping fusidic acid treatment. In patients where the use of systemic fusidic acid is considered essential, statin treatment should be discontinued throughout the duration of fusidic acid treatment. There have been reports of rhabdomyolysis (including some fatalities) in patients receiving fusidic acid and statins in combination. The patient should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain or tenderness. Statin therapy may be re-introduced seven days after the last dose of fusidic acid. In exceptional circumstances, where prolonged systemic fusidic acid is needed, e.g., for the treatment of severe infections, the need for co-administration of Suvezen and fusidic acid should only be considered on a case by case basis and under close medical supervision. Suvezen contains lactose monohydrate and sodium: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine. This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’. Interactions: Contraindicated combinations: Ciclosporin. Not-recommended combinations: Fibrates and other lipid-lowering products, protease inhibitors, transporter protein inhibitors and fusidic acid. Other possible interactions: Cytochrome P450 enzymes, antacids, colestyramine, anticoagulants, Vitamin K antagonists, erythromycin, oral contraceptive/hormone replacement therapy. When co-administering rosuvastatin with other medicinal products known to increase exposure to rosuvastatin, doses should be adjusted (see SmPC for full details). The maximum daily dose should be adjusted so that the expected rosuvastatin exposure would not likely exceed that of a 40mg daily dose of rosuvastatin taken without interacting medicinal products. Fertility, Pregnancy and Breastfeeding: No clinical data are available on the use of ezetimibe during pregnancy. Potential risk from inhibition of HMG-CoA reductase outweighs the advantage of treatment during pregnancy. If a patient becomes pregnant during use of Suvezen, treatment should be discontinued immediately. Animal studies have shown excretion of medicinal product through breast milk. However, there are no data in humans. No clinical trial data on the effects of fertility in humans. Adverse Reactions: Adverse drug reactions previously reported with one of the individual components (ezetimibe or rosuvastatin) may be potential undesirable effects with Suvezen. Common (≥1/100 to <1/10): diabetes mellitus, headache, dizziness, constipation, nausea, abdominal pain, diarrhoea, flatulence, myalgia, ALT and/or AST increased, asthenia and fatigue. Uncommon (≥1/1,000 to <1/100): decreased appetite, paraesthesia, hot flush, hypertension, cough, dyspepsia, gastroesophageal reflux disease, nausea, dry mouth, gastritis, pruritus, rash, urticaria, arthralgia, muscle spasms, neck pain, back pain, muscular weakness, pain in extremity, ALT and/or AST increased, blood CPK increased, gamma-glutamyltransferase increased, liver function test abnormal, chest pain, pain, asthenia, oedema peripheral. Rare (≥1/10,000 to <1/1,000): thrombocytopenia, hypersensitivity reactions including angioedema, pancreatitis, increased hepatic transaminases, myopathy (including myositis), rhabdomyolysis, lupus-like syndrome and muscle rupture. Very rare (<1/10,000): polyneuropathy, memory loss, jaundice, hepatitis, arthralgia, haematuria, gynaecomastia. Not known: thrombocytopenia, hypersensitivity (including rash, urticaria, anaphylaxis and angioedema), depression, peripheral neuropathy, sleep disturbances (including insomnia and nightmares), dizziness, paraesthesia, cough, dyspnoea, diarrhoea, pancreatitis, constipation, hepatitis, cholelithiasis, cholecystitis, Stevens Johnson syndrome, erythema multiforme, immune-mediated necrotising myopathy, tendon disorders (sometimes complicated by rupture), myalgia, myopathy/rhabdomyolysis, oedema, asthenia. See SmPC for full details on adverse reactions. Legal Category: POM. Marketing Authorisation Numbers: 10mg/10mg: PA0540/193/001; 20mg/10mg: PA0540/193/002; 40mg/10mg: PA0540/193/003. Marketing Authorisation Holder: Sanofi-Aventis Ireland Ltd. T/A SANOFI, Citywest Business Campus, Dublin 24, Ireland. Further information is available from: Sanofi, 18 Riverwalk, Citywest Business Campus, Dublin 24 or contact IEmedinfo@sanofi.com Date of Preparation: December 2020.

Reference: 1. Suvezen Summary of Product Characteristics * LDL-C: Low-density lipoprotein Cholesterol ** Suvezen is available in 3 doses in Ireland. Suvezen 10mg/10mg, 20mg/10mg and 40mg/10mg: Each film-coated tablet contains 10mg; 20mg or 40mg of rosuvastatin (as rosuvastatin calcium) respectively, and 10mg ezetimibe.

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

MAT-IE-2101261 (v1.0) – August 2021

78 Deep Vein Thrombosis care. Recent clinical studies suggest that oral anticoagulants should be considered in the primary prevention of thrombosis in patients receiving chemotherapy (which further increases thrombosis risk), particularly in high-risk subgroups of patients with cancer16, 17. Ensuring patients with cancer are counselled as to their risk of thrombosis (and issued with a Thrombosis Alert Card) should also be considered as an important part of any discussion relating to cancer and cancer therapy. Despite advances in the treatment of CAT, affected patients continue to have high-rates of thrombosis recurrence as well as high-rates of anticoagulant-associated bleeding (in contrast to the general population). Further clinical and translational research is required to optimise the prevention and treatment of thrombosis in this particularly high-risk and challenging patient group.

individuals who did not receive a timely diagnosis (based on postmortem studies), an observation which highlights the importance of raising awareness of VTE risk and ensuring access to diagnostic pathways to all patients.

sub-optimal. These observations have prompted the World Health Organisation and other bodies, to recognise HA-VTE as being a leading cause of preventable death associated with hospital admission4, 13.

RISK FACTORS FOR VTE

In Ireland, the HSE have recently prioritised the development of strategies for the prevention of HA-VTE in Irish hospitals. Initiatives have included the publication of a collaborative report (Preventing Blood Clots in Hospitals) incorporating clinical practice guidelines mandating that formal VTE risk assessment should be carried out on all patients admitted to hospital14. As part of this initiative, the HSE have also launched the ‘Thrombosis Alert Card’, as a tool for educating patients and healthcare providers regarding the risk factors for VTE as well as the associated signs and symptoms. The HSE have recommended that all patients admitted to Irish Hospitals should receive this alert card and supplies were issued to all Irish hospitals in 2020.

Hospital-acquired VTE The majority of all VTE events occur in association with admission to hospital (where patients are often unwell with acute medical illness and are often exposed to major provoking factors such as major surgery, prolonged immobilisation etc.)1, 10, 12. The risk of VTE which is conferred by hospital admission likely persists for weeks following discharge and consequently, hospital acquired thrombosis is defined as a VTE occurring either during admission or within 90 days of discharge. Hospital acquired VTE (HA-VTE) can be prevented in the majority of cases4, 13. This can be achieved through the systematic application of VTE risk assessment and prevention protocols for all patients admitted to hospital. In the UK (and in other regions) a systematic approach to VTE risk assessment, where high-risk individuals were identified using validated risk assessment tools and then prescribed pharmacological thromboprophylaxis, was shown to significantly reduce VTE-related. However, adherence to such protocols tends to be

Thrombosis Ireland insist that every Patient has the right to this information in order to protect themselves, particularly during the 90 days after discharge from hospital when they are still at increased risk of getting a blood clot. Venous thromboembolism (VTE) is preventable in many cases. It is also very treatable but potentially fatal if not diagnosed on time.

OCTOBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

Signs and Symptoms of a blood clot • Swelling or pain in the leg or arm • Warmth or redness in the leg or arm • Shortness of breath or rapid breathing • Chest pain (particularly when breathing deeply) • Coughing or coughing up blood If you have one or more of these symptoms, you may have a blood clot and need urgent treatment. For more information go to www.thrombosis.ie Cancer-associated VTE Cancer is a major risk factor for venous thrombosis. Patients with cancer have a risk of VTE which is up to 7-times higher than that seen in the general population. It is estimated that up to 20% of patients with cancer will experience a VTE event at some point over the course of their disease10, 15. Moreover, a concurrent diagnosis of a VTE event in a patient with cancer has major implications for duration of survival (in contrast to cancer patients without VTE) and a VTE event is up to 5-times more likely to be fatal in an individual with cancer in contrast to a VTE patient without a concurrent cancer diagnosis15. Prevention of cancer-associated thrombosis (CAT) is a critical, but frequently overlooked, component of cancer

1 in 5 of your cancer patients will experience a blood clot. Awareness of their risk, knowledge of the signs and symptoms of a blood clot and understanding that they need to get medical attention fast if they suspect a clot is crucially important. It is potentially lifesaving information. Hormonal factors and VTE-risk Hormonal factors (including pregnancy and the use of exogenous oestrogen preparations) are frequently implicated in the occurrence of VTE events3. Pregnancy increases the risk of VTE approximately 5-fold from baseline, however for the majority of women, the absolute risk of VTE remains low. For women who have additional co-existing risk factors for VTE, such as a family history of VTE or certain medical comorbidities, additional measures may be required to reduce the risk of a potentially devastating pregnancy-associated VTE18. Depending on the risk profile of the individual woman, decisions to commence antenatal or postnatal thromboprophylaxis may be made. Although, fortunately, the rate of pregnancy-associated VTE is low overall, clinicians must be vigilant as VTE remains the leading cause of direct maternal mortality in the developed world. Specific VTE risk assessment tools and clinical practice guidelines have been developed for this purpose. The use of certain hormonal contraceptives and postmenopausal hormone replacement therapies have been shown to confer an increased thrombosis risk in the region of approximately 3-5 fold from baseline18.

Clexane Safety Syringe designed to protect against needle stick injuries

Needle completely covered by the protection shield immediately after the injection

Automatic release of the safety mechanism when the plunger is fully depressed

Prescribing Information: Clexane® (enoxaparin sodium) & Clexane® Forte Solution for Injection in pre-filled syringes Please refer to the Summary of Product Characteristics (SmPC) before prescribing. Presentations: Clexane® single dose pre-filled syringes containing either: 2,000 IU (20mg) enoxaparin sodium in 0.2ml, 4,000 IU (40mg) enoxaparin sodium in 0.4ml, 6,000 IU (60mg) enoxaparin sodium in 0.6ml, 8,000 IU (80mg) enoxaparin sodium in 0.8ml or 10,000 IU (100mg) enoxaparin sodium in 1ml. Clexane® Forte single dose pre-filled syringes containing either: 12,000 IU (120mg) enoxaparin sodium in 0.8ml or 15,000 IU (150mg) enoxaparin sodium in 1ml. Indications: In adults for: prophylaxis of venous thromboembolic disease in moderate and high risk surgical patients, in particular those undergoing orthopaedic or general surgery including cancer surgery; prophylaxis of venous thromboembolic disease in medical patients with an acute illness (such as acute heart failure, respiratory insufficiency, severe infections or rheumatic diseases) and reduced mobility at increased risk of venous thromboembolism (VTE); treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), excluding PE likely to require thrombolytic therapy or surgery; prevention of thrombus formation in extracorporeal circulation during haemodialysis; treatment of unstable angina and non ST-segment elevation myocardial infarction (NSTEMI), in combination with oral acetylsalicylic acid; treatment of acute ST-segment elevation myocardial infarction (STEMI) including patients to be managed medically or with subsequent percutaneous coronary intervention (PCI). Dosage & Administration: Each pre-filled syringe is for single use only. Prophylaxis of VTE in Surgical Patients: With moderate risk of thromboembolism, recommended dose of enoxaparin sodium is 2,000 IU (20mg) once daily by subcutaneous (SC) injection. Initiation 2hrs before surgery was proven effective and safe in moderate risk surgery. Treatment should be maintained for at least 7-10 days whatever the recovery status (e.g. mobility) and should be continued until the patient no longer has significantly reduced mobility. In patients at high risk of thromboembolism, the recommended dose of enoxaparin sodium is 4,000 IU (40mg) once daily by SC injection preferably started 12hrs before surgery. Need for earlier than 12hrs enoxaparin sodium preoperative prophylactic initiation (e.g. high-risk patient waiting for a deferred orthopaedic surgery), the last injection should be administered no later than 12hrs prior to surgery and resumed 12hrs after surgery. For patients undergoing major orthopaedic surgery an extended thromboprophylaxis up to 5 weeks is recommended. For patients with high risk of VTE undergoing abdominal or pelvic surgery for cancer, extended thromboprophylaxis up to 4 weeks is recommended. Prophylaxis of VTE in Medical Patients: Recommended dose of enoxaparin sodium is 4,000 IU (40mg) once daily by SC injection. Treatment with enoxaparin sodium is prescribed for at least 6-14 days. Benefit is not established for treatment longer than 14 days. Treatment of DVT/PE: 150 IU/kg (1.5mg/kg) administered SC once daily should be used in uncomplicated patients with low risk of VTE recurrence. 100 IU/kg (1mg/kg) twice daily should be used in all other patients such as those with obesity, symptomatic PE, cancer, recurrent VTE or proximal (vena iliaca) thrombosis. The regimen should be selected based on individual assessment including evaluation of the thromboembolic risk and risk of bleeding. Enoxaparin sodium treatment is prescribed for an average period of 10 days. Oral anticoagulant therapy should be initiated when appropriate. Treatment of Acute Coronary Syndromes: For treatment of unstable angina and NSTEMI, the recommended dose of enoxaparin sodium is 100 IU/kg (1mg/kg) every 12hrs by SC injection administered in combination with antiplatelet therapy. Treatment should be for a minimum of 2 days and until clinical stabilization (usual duration 2 to 8 days). Acetylsalicylic acid recommended for all patients without contraindications at an initial oral loading dose of 150–300mg (in acetylsalicylic acid-naive patients) and a maintenance dose of 75–325mg/day long-term. For treatment of acute STEMI, recommended dose of enoxaparin sodium is a single intravenous (IV) bolus of 3,000 IU (30mg) plus a 100 IU/kg (1mg/kg) SC dose followed by 100 IU/kg (1mg/kg) administered SC every 12hrs (maximum 10,000 IU (100mg) for each of the first 2 SC doses). Appropriate antiplatelet therapy such as oral acetylsalicylic acid (75mg to 325mg once daily) should be administered concomitantly unless contraindicated. Recommended duration of treatment is 8 days or until hospital discharge. When administered in conjunction with a thrombolytic (fibrin specific or non-fibrin specific), enoxaparin sodium should be given between 15 minutes before and 30 minutes after the start of fibrinolytic therapy. For patients managed with PCI, if the last dose of enoxaparin sodium SC was given less than 8hrs before balloon inflation, no additional dosing needed. If the last SC administration was given more than 8hrs before balloon inflation, an IV bolus of 30 IU/kg (0.3mg/kg) enoxaparin sodium should be

+ m 700

D E T A 1 TRE E ID W D L R WO

administered. During haemodialysis: 100 IU/kg (1mg/kg) enoxaparin sodium introduced into arterial line of the circuit at beginning of dialysis. This dose is usually sufficient for a 4-hour session. If fibrin rings are found, e.g. after a longer session, a further 50 to 100 IU/kg (0.5 to 1mg/kg) may be given. In patients with high risk of haemorrhage reduce the dose to 50 IU/kg (0.5mg/kg) (double vascular access) or 75 IU/kg (0.75mg/kg) (single vascular access). Special Populations: Elderly ≥75 years of age: For treatment of acute STEMI, an initial IV bolus must not be used. Initiate dosing with 75 IU/kg (0.75mg/kg) SC every 12hrs (maximum 7,500 IU (75mg) for each of the first 2 SC doses only, followed by 75 IU/kg (0.75mg/kg) SC dosing for the remaining doses). Paediatric: Safety and efficacy not established. Renal impairment: Dosage adjustment required for patients with severe renal impairment (creatinine clearance 15-30 mL/ min). Not recommended for patients with end stage renal disease (creatinine clearance <15 mL/ min. Hepatic Impairment: Limited data in this population therefore caution should be used. Contraindications: Hypersensitivity to enoxaparin sodium, heparin or its derivatives, including low molecular weight heparins (LMWH) or any of the excipients. Recent (<100 days) history of immune mediated heparin-induced thrombocytopenia (HIT) or in the presence of circulating antibodies. Active clinically significant bleeding and conditions with a high risk of haemorrhage, including recent haemorrhagic stroke, gastrointestinal ulcer, presence of malignant neoplasm at high risk of bleeding, recent brain, spinal or ophthalmic surgery, known/ suspected oesophageal varices, arteriovenous malformations, vascular aneurysms/ major intraspinal/ intracerebral vascular abnormalities. Spinal/ epidural/ loco-regional anaesthesia when enoxaparin sodium is used for treatment in the previous 24hrs. Warnings and Precautions: Do not use interchangeably (unit for unit) with other LMWHs. History of HIT (>100 days) without circulating antibodies: Use with extreme caution in these patients and only after careful benefit-risk assessment and non-heparin alternative treatments are considered. Monitoring of platelet counts: There is a risk of antibody-mediated HIT, which is higher in postoperative patients and mainly after cardiac surgery and in patients with cancer. It is recommended that the platelet counts be measured before the initiation of therapy with enoxaparin sodium and then regularly thereafter during the treatment; or if clinical symptoms suggestive of HIT are experienced. Patients must be aware of the symptoms and told to inform their primary care physician if experienced. If a confirmed significant decrease of the platelet count is observed (30-50% of the initial value), enoxaparin sodium treatment must be immediately discontinued, and the patient switched to another non-heparin anticoagulant alternative treatment. Haemorrhage: Use with caution in conditions with increased potential for bleeding (e.g. impaired haemostasis, history of peptic ulcer, recent ischemic stroke, severe arterial hypertension, recent diabetic retinopathy, neuro- or ophthalmologic surgery, concomitant use of medications affecting haemostasis). Laboratory tests: Increases in activated partial thromboplastin time (aPTT) and activated clotting time (ACT) may occur at higher doses but not linearly correlated with increasing enoxaparin sodium antithrombotic activity. Spinal/epidural anaesthesia or lumbar puncture: must not be performed within 24hrs of administration of therapeutic doses of enoxaparin sodium; placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of enoxaparin sodium is low. Skin necrosis and cutaneous vasculitis: have been reported with LMWHs and should lead to prompt treatment discontinuation. Percutaneous coronary revascularization procedures: To minimize the risk of bleeding following the vascular instrumentation during the treatment of unstable angina, NSTEMI and acute STEMI, adhere precisely to the intervals recommended between enoxaparin sodium injection doses. It is important to achieve haemostasis at the puncture site after PCI. In case a closure device is used, the sheath can be removed immediately. If a manual compression method is used, sheath should be removed 6 hours after the last IV/SC enoxaparin sodium injection. If the treatment with enoxaparin sodium is to be continued, the next scheduled dose should be given no sooner than 6 to 8 hours after sheath removal. The site of the procedure should be observed for signs of bleeding or hematoma formation. Acute infective endocarditis: Use of heparin is usually not recommended in patients with this condition. Mechanical prosthetic heart valves: Enoxaparin sodium has not been adequately studied for thromboprophylaxis in patients (including in pregnancy) with mechanical prosthetic heart valves. Elderly patients (especially >80 years old): may be at increased risk of bleeding complications at therapeutic doses. Hepatic impairment: Enoxaparin sodium should be used with caution in these patients. In patients with liver cirrhosis dose adjustment based on monitoring of anti-Xa levels is unreliable and not recommended. Renal impairment: There is

an increased risk of bleeding for these patients therefore careful clinical monitoring is advised and biological monitoring by anti-Xa activity measurement might be considered. Enoxaparin sodium is not recommended for patients with end stage renal disease. In patients with severe renal impairment (creatinine clearance 15-30 mL/min) a dosage adjustment is recommended for therapeutic and prophylactic dosage ranges. Low body weight patients: are at increased risk of bleeding at prophylactic and treatment dose ranges. Obese patients: are at higher risk for thromboembolism however there is no consensus for dose adjustment; these patients should be observed carefully. Hyperkalaemia: Heparins can suppress adrenal secretion of aldosterone leading to hyperkalaemia, particularly in patients such as those with diabetes mellitus, chronic renal failure, pre-existing metabolic acidosis, taking medicinal products known to increase potassium; plasma potassium should be monitored regularly especially in patients at risk. Traceability: In order to improve the LMWH traceability, it is recommended that health care professionals record the trade name and batch number of the administered product in the patient file. Sodium: For patients receiving doses >210mg/day, this medicine contains >24mg sodium, equivalent to 1.2% of the recommended maximum daily intake of sodium for an adult. Pregnancy and Lactation: Enoxaparin sodium should be used during pregnancy only if the physician has established a clear need. Pregnant women receiving enoxaparin sodium should be carefully monitored for evidence of bleeding or excessive anticoagulation and should be warned of the haemorrhagic risk. If an epidural anaesthesia is planned, it is recommended to withdraw treatment before. Enoxaparin sodium can be used during breastfeeding. Interactions: Not Recommended: Systemic salicylates, acetylsalicylic acid at anti-inflammatory doses, and NSAIDs including ketorolac. Other thrombolytics and anticoagulants. Caution: Platelet aggregation inhibitors including acetylsalicylic acid used at anti-aggregant dose (cardioprotection), clopidogrel, ticlopidine, and glycoprotein IIb/IIIa antagonists indicated in acute coronary syndrome due to the risk of bleeding, Dextran 40. Systemic glucocorticoids. Medicinal products increasing potassium levels. Adverse Reactions: Very Common: Hepatic enzyme increases (mainly transaminases >3 times the upper limit of normality). Common: Haemorrhage, haemorrhagic anaemia, thrombocytopenia, thrombocytosis, allergic reaction, headache, urticaria, pruritus, erythema, injection site haematoma / pain / other reaction (such as oedema, haemorrhage, hypersensitivity, inflammation, mass, pain, or reaction). Uncommon: Hepatocellular liver injury, bullous dermatitis, local irritation, skin necrosis at injection site. Rare: Eosinophilia, cases of immuno-allergic thrombocytopenia with thrombosis (in some cases thrombosis was complicated by organ infarction or limb ischaemia), anaphylactic/anaphylactoid reactions including shock, spinal/neuraxial haematoma resulting in varying degrees of neurologic injuries including long-term or permanent paralysis, cholestatic liver injury, alopecia, cutaneous vasculitis, skin necrosis, injection site nodules, osteoporosis following therapy >3 months, hyperkalaemia. Please refer to the SPCs for full details. Legal Category: POM. Marketing Authorisation (MA) Numbers: Clexane 2,000IU: PA540/97/4; Clexane 4,000IU: PA540/97/5; Clexane 6,000 IU: PA540/97/6; Clexane 8,000 IU: PA540/97/7; Clexane 10,000 IU: PA540/97/1; Clexane Forte 12,000 IU: PA540/97/8; Clexane Forte 15,000 IU: PA540/97/2. MA Holder and further information is available on request from: Sanofi Ireland Ltd., 18 Riverwalk, Citywest Business Campus, Dublin 24 or contact IEmedinfo@sanofi.com Tel: 01 403 5600. Date of Preparation: May 2020. Adverse events should be reported. Reporting forms and information can be found at: www.hpra.ie; E-mail: medsafety@hpra.ie Adverse events can also be reported to Sanofi Ireland Ltd. Tel: 01 403 5600. Alternatively, send via Email to IEPharmacovigilance@sanofi.com Reference: 1. Data on File – Clexane IMS Data. MAT-IE-2000431 (v2.0). Date of preparation: October 2020. Clexane (enoxaparin) SPC available at www.medicines.ie

80 Deep Vein Thrombosis Counselling women with regards to the risk of thrombosis is crucial (particularly for women with significant VTE risk factors), while also giving due regard to the clear benefits associated with access to these products from a reproductive health perspective19, 20. Blood Clots are the No.1 cause of direct maternal death in our Maternity Hospitals. COVID-19 associated thrombosis Since the emergence of the COVID-19 pandemic, it became apparent that this infection was associated with increased coagulation activation (which appears to contribute to disease severity) and an increased risk of thrombosis. The risk of VTE appears highest among patients admitted to hospital with COVID-19 and in particular, among those who require intensive care-level support7. A number of international clinical trials are ongoing currently which are aiming to determine the optimal approach to thrombosis prevention

and management in COVID-19. Interestingly, recent data from two such trials (including the RAPID COVID COAG trial, for which the Mater Hospital in Dublin was the sole European recruitment site), demonstrated that escalated doses of heparin may reduce the risk of death associated with COVID-19 and reduce the risk of progression to severe disease8, 9. Data from further clinical and translational studies in this area are eagerly awaited. THE INTERNATIONAL VTE DUBLIN 2021 CONFERENCE & Thrombosis Ireland VTE Exemplar Awards On the 7th-8th of October 2021, the 6th annual international VTE Dublin Conference will take place. This year the conference will be entirely virtual, and registration will be free of charge. This conference was first held in 2015, organised by Professor Fionnuala Ní Áinle, Consultant Haematologist, Mater hospital and Dr Tomás Breslin, Consultant in Emergency Medicine, Mater Hospital, Dublin.

Each year, international leaders in the field of VTE have been invited to discuss advances in the field of VTE and related specialities. This year, the organising committee are proud to welcome global experts in the field of cancer-associated thrombosis, COVID-19, TTP and other areas VTE. Reflecting the patient-centred focus of the conference, each lecture will be accompanied by a brief patient video, outlining their personal experience of the condition being discussed. The winners of the inaugural Thrombosis Ireland VTE Exemplar awards will also be announced at this year’s conference. These awards will highlight achievements in healthcare & research settings in a number of key areas and celebrate outstanding work in improving VTE Patient Safety through risk assessment, education, information, quality improvements and research. We have many nominations for individuals, teams, hospitals and hospital groups around the country and look forward to presenting awards to all category winners at VTEDUB21.

Nominations are closed for this year but we look forward to your nominations in 2022. FUTURE DIRECTIONS Major advances have been made in the field of VTE in recent years. The development of risk prediction models, sophisticated diagnostic technologies and novel therapeutic agents have provided clinicians with opportunities to improve outcomes for affected patients. However significant challenges remain. In particular, awareness of the magnitude of VTE risk associated with hospital admission as well as other high-risk scenarios such as active cancer and traumatic injury remains low. Moreover, VTE risk assessment tools and VTE prevention protocols are under-utilised in Irish hospitals. Further engagement between organisations such as Thrombosis Ireland, VTE Ireland and the HSE with clinicians and representative bodies will be crucial in optimising VTE care and streamlining clinical pathways into the future. References available on request

News

Blood Clotting may be Root Cause of Long COVID Professor James O’Donnell, Director of the Irish Centre for Vascular Biology, RCSI and Consultant Haematologist in the National Coagulation Centre in St James's Hospital, Dublin

New evidence shows that patients with Long COVID syndrome continue to have higher measures of blood clotting, which may help explain their persistent symptoms, such as reduced physical fitness and fatigue. The study, led by researchers from RCSI University of Medicine and Health Sciences, is published in the Journal of Thrombosis and Haemostasis.

Previous work by the same group studied the dangerous clotting observed in patients with severe acute COVID-19. However, far less is known about Long COVID syndrome, where symptoms can last weeks to months after the initial infection has resolved and is estimated to affect millions of people worldwide. The researchers examined 50 patients with symptoms of Long

OCTOBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

COVID syndrome to better understand if abnormal blood clotting is involved. They discovered that clotting markers were significantly elevated in the blood of patients with Long COVID syndrome compared with healthy controls. These clotting markers were higher in patients who required hospitalisation with their initial COVID-19 infection, but they also found that even those who were able to manage their illness at home still had persistently high clotting markers. The researchers observed that higher clotting was directly related to other symptoms of Long COVID syndrome, such as reduced physical fitness and fatigue. Even though markers of inflammation had all returned to normal levels, this increased clotting potential was still present in Long COVID patients. “Because clotting markers were elevated while inflammation markers had returned to normal, our results suggest that the clotting system may be involved in the root cause of Long COVID syndrome,” said Dr Helen Fogarty, the study’s lead author, ICAT

Fellow and PhD student at the Irish Centre for Vascular Biology in the RCSI School of Pharmacy and Biomolecular Sciences. This work was funded by the Welcome Trust, the Health Research Board (HRB) Irish Clinical Academic Training (ICAT) programme as well as the HRB-funded Irish COVID-19 Vasculopathy Study (ICVS). The work was also supported by a philanthropic grant from the 3M Foundation to RCSI University of Medicine and Health Sciences in support of COVID-19 research. “Understanding the root cause of a disease is the first step toward developing effective treatments,” said Professor James O’Donnell, Director of the Irish Centre for Vascular Biology, RCSI and Consultant Haematologist in the National Coagulation Centre in St James's Hospital, Dublin. “Millions of people are already dealing with the symptoms of Long COVID syndrome, and more people will develop Long COVID as the infections among the unvaccinated continue to occur. It is imperative that we continue to study this condition and develop effective treatments.”

Clinical R&D 81 MICHALA FISCHER-HANSEN TO JOIN THE BOARD OF ABACUS MEDICINE Abacus Medicine A/S is again strengthening its Board of Directors as Michala FischerHansen will join as a new member. She is nominated by the two main shareholders in Abacus Medicine, which are Wagner Family Holding and Chr. Augustinus Fabrikker. Michala Fischer-Hansen is currently Executive Vice President at Falck, where she is also a member of the Executive Management. “With Michala Fischer-Hansen’s international profile, a great understanding of our industry and her experience with commercial effectiveness, marketing, pharma economics and market access, she is the right profile to contribute to the Abacus Medicine Group’s continued growth,” says Flemming Wagner, CEO and founder of Abacus Medicine. Before joining Falck in 2019, Michala Fischer-Hansen had a 19-year commercial career at Novo Nordisk, i.a. as VP and General Manager for Novo Nordisk operations in Australia and New Zealand. Earlier, Michala also served as Corporate Vice President heading up the commercial global rollout of a new insulin portfolio of brands and Senior Director of Marketing Effectiveness at Novo Nordisk Inc. in the US. Michala Fischer-Hansen has previously served as Vice Chairman of the Board of the World Diabetes Foundation as well as previous elected member of the Board of Medicines Australia. Abacus Medicine A/S will invite all shareholders to an extraordinary general meeting as soon as possible. With the addition of Michala Fischer-Hansen, the Board of Directors of Abacus Medicine A/S will consist of Niels Smedegaard (Chairman), Anders K. Bønding, Michala Fischer-Hansen, Jens Albert Harsaae, Mark Johnston, Troels Peter Troelsen, and Flemming Wagner. ALZECURE'S ALZHEIMER'S PROJECT RECEIVES APPROVAL TO START NEXT CLINICAL PHASE I STUDY WITH ACD856 AlzeCure Pharma AB (publ) (FN STO: ALZCUR), a pharmaceutical company that develops a broad portfolio of candidate drugs for diseases affecting the central

nervous system, with projects in both Alzheimer's disease and pain, has announced that the company has received approval from the regulatory authorities in Sweden to begin the next clinical phase I study (multiple ascending dose, MAD) with the candidate drug ACD856 focused on Alzheimer's disease. The MAD Phase I study is AlzeCure's third clinical study with ACD856, the lead candidate drug within the company's NeuroRestore platform. ACD856 is being developed as a symptomrelieving treatment for disease states where the cognitive ability is impaired, such as in Alzheimer's disease. The primary study goal is to evaluate ACD856's tolerability and safety after repeated dosing, as well as to examine early signals on brain activity. The substances in the NeuroRestore platform stimulate several important signaling pathways in the brain, which, among other things, leads to improved cognition. Preclinical studies have shown that AlzeCure's candidate drugs strengthen the communication between nerve cells and improve cognitive ability including memory functions. "I'm very pleased that we have all regulatory approvals in place to be able to start the next study with ACD856. This means we will be able to start the MAD study during the fall, which is in line with our previously communicated goals," said Johan Sandin, CSO at AlzeCure Pharma. "This is a statement of strength that shows that AlzeCure continues to deliver according to plan," said Martin Jönsson, CEO of AlzeCure Pharma AB. "Diseases with cognitive disorders, and especially Alzheimer's disease, are areas with high need of new, more effective treatments and I am very much looking forward to the continued development of this important candidate drug." DUPIXENT® (DUPILUMAB) PIVOTAL TRIAL MEETS ALL PRIMARY AND SECONDARY ENDPOINTS A pivotal Phase 3 trial evaluating Dupixent® (dupilumab) for the treatment of children aged 6 months to 5 years with moderateto-severe atopic dermatitis, a chronic type 2 inflammatory disease, met its primary and all secondary endpoints. The data show adding Dupixent to standard of care topical corticosteroids (TCS) significantly reduced

overall disease severity and improved skin clearance, itch, and health-related quality of life measures at 16 weeks compared to TCS alone. Dupixent is the first biologic medicine to show positive results in this young population and remains the only approved biologic medicine in patients 6 years and older with uncontrolled moderate-to-severe atopic dermatitis. The data reinforce the wellestablished efficacy and safety profile of Dupixent in other age groups including a lower observed rate of skin infection in the Dupixent group compared with placebo. During the 16week treatment period Dupixent patients were 50% less likely to experience a skin infection (12% Dupixent, 24% placebo), and the total number of infections was nearly 70% lower (11 Dupixent, 34 placebo). These results add to the extensive LIBERTY AD clinical program – the largest Phase 3 clinical trial program in atopic dermatitis involving approximately 3,500 children, adolescents, and adults to date. Atopic dermatitis is a chronic type 2 inflammatory disease, with the age of onset younger than 5 years in 85-90% of patients. The debilitating symptoms that infants and young children with moderate-to-severe atopic dermatitis experience often continue through adulthood and include intense, persistent itch and skin lesions that can cover much of the body, resulting in skin dryness, cracking, redness or darkening, crusting and oozing – along with increased risk of skin infections. Moderate-to-severe atopic dermatitis significantly impacts the life of a young child, their parents and caregivers, including their mood, sleep patterns, and quality of life. In addition, the underlying type 2 inflammation involved in atopic dermatitis can contribute to the development of other atopic diseases, like asthma, that may also appear throughout a person's life. Patients received Dupixent every four weeks (200 mg or 300 mg, based on body weight) plus TCS or TCS alone (placebo). The primary endpoints assessed the proportion of patients achieving an Investigator's Global Assessment (IGA) score of 0 (clear) or 1 (almost clear) and 75% improvement in Eczema Area and Severity Index (EASI-75). The prespecified primary analysis showed that at 16 weeks patients treated with Dupixent:

• 28% achieved clear or almostclear skin compared to 4% with placebo (p=<0.0001), the primary endpoint. • 53% achieved 75% or greater overall disease improvement from baseline compared to 11% with placebo (p=<0.0001), the co-primary endpoint outside of the U.S. • 70% average improvement from baseline in EASI compared to 20% improvement with placebo (p=<0.0001). • 49% average improvement from baseline in itch compared to 2% improvement in placebo (p<0.0001). • Significantly improved measures of observed patient outcomes (including sleep, skin pain and health-related quality of life), as well as caregiver-reported health-related quality of life. The trial demonstrated similar safety results to the known safety profile of Dupixent in atopic dermatitis. For the 16-week treatment period, overall rates of adverse events (AEs) were 64% for Dupixent and 74% for placebo. Most common AEs and AEs of special interest included nasopharyngitis (8% Dupixent, 9% placebo), upper respiratory tract infection (6% Dupixent, 8% placebo) and conjunctivitis (5% Dupixent, 0% placebo), herpes viral infections (6% Dupixent, 5% placebo) and injection site reactions (2% Dupixent, 3% placebo). ORION CORPORATION AND ALLIGATOR BIOSCIENCE ANNOUNCE IMMUNOONCOLOGY RESEARCH COLLABORATION AND LICENSE AGREEMENT Orion Corporation and Alligator Bioscience (Nasdaq Stockholm: ATORX) have announced that they have entered into a research collaboration and license agreement to discover and develop together new bispecific antibody cancer therapeutics. The research collaboration is focused on the discovery of novel bispecific antibodies directed towards immuno-oncology targets selected by Orion. The agreement covers an option to develop three bispecific antibodies. The agreement calls for Alligator Bioscience to employ its proprietary phage display libraries and RUBY™ bispecific platform to develop immuno-oncology product candidates based on design criteria identified by Orion. During the research period of the

HOSPITALPROFESSIONALNEWS.IE | HPN • OCTOBER - 2021

82 Clinical R&D collaboration, Alligator Bioscience will receive an upfront payment and research support payments. Should Orion trigger its option to continue development and commercialization of the product candidates, Alligator Bioscience would be eligible for development, approval and sales milestone payments for all three projects in addition to royalties. Outi Vaarala, Senior Vice President, R&D, Orion, said: "We are particularly pleased with this collaboration with Alligator Bioscience to develop new immuno-oncology treatments mobilizing the immune system to eliminate cancer cells. Bispecific antibodies provide as a tool many advantages for the next generation immuno-oncology treatments with improved efficacy, particularly in the cancer patients who do not respond to the present available therapeutics." "We are excited to enter into this collaborative research program which combines Alligator Bioscience's expertise in antibody discovery and immuno-oncology development with Orion's insights into novel immuno-oncology approaches," said Søren Bregenholt, CEO of Alligator Bioscience. Bregenholt continued, "This agreement validates that Alligator Bioscience's extensive range of phage display libraries and our RUBY bispecific platform offer a solid foundation to identify and develop high quality first-in-class therapeutic antibodies with excellent manufacturability characteristics." SKIN CELLS FROM FRONTOTEMPORAL DEMENTIA PATIENTS MAY PROVE USEFUL IN REVEALING DISEASE MECHANISMS AND IN BIOMARKER AND DRUG RESEARCH A new study from the University of Eastern Finland suggests that skin fibroblasts from frontotemporal dementia patients may be useful in investigating underlying disease mechanisms as well as in biomarker and drug research. Frontotemporal dementia (FTD) is the second most common cause of dementia in the working age population. The most common genetic cause of FTD is the C9orf72 hexanucleotide repeat expansion. This expansion is exceptionally common in Finnish FTD patients. Currently, there are no efficient therapies for FTD, it is challenging to diagnose, and the disease mechanisms remain largely unclear.

The new study explored whether skin cells from FTD patients, obtained through skin biopsy performed at Kuopio University Hospital, show specific cell pathological hallmarks or functional alterations compared to healthy individuals, which could promote better understanding of molecular mechanisms of FTD and be useful in the discovery of novel biomarkers or in testing drug effects. Both C9orf72 repeat expansion carriers and patients with sporadic FTD, for whom the underlying cause of disease is unknown, were included in the study.

ATP-mediated energy production by the cells' power plants, the mitochondria, were measured. Because the defective energy metabolism and the changes in p62 vesicles were detected in both sporadic and C9orf72 expansion-carrying patients, these pathological alterations may represent common pathological changes in FTD patients regardless of their genetic background.

Cell pathological changes related to the C9orf72 repeat expansion have not been widely described in other cells than neurons so far. In the present study, skin fibroblasts of FTD patients carrying the C9orf72 expansion were found to contain pathological RNA foci in the nuclei, which were derived from the expanded repeat sequence. These findings indicate that skin fibroblasts of carriers of the C9orf72 expansion partially show similar pathological changes to those found in the brain. Thus, patient skin cell cultures may possess potential, for example, as platforms for testing drug effects when screening compounds that could prevent formation of the abnormal RNA foci and the subsequent pathological dipeptide repeat (DPR) proteins derived from these abnormal RNAs.

In the Haapasalo Lab, FTD patient-derived skin cells have also been utilised to generate iPSCs and further differentiated to different types of brain cells, such as neurons and microglia. Examination of these cells is currently ongoing.

The brains of FTD patients typically also show other pathological protein inclusions. The present study showed that in the skin fibroblasts of both sporadic and C9orf72 expansioncarrying FTD patients, there were substantially more and larger p62 protein-containing vesicles than in the healthy control fibroblasts. Accumulation of p62 could be a sign of defective ability of the cells to degrade proteins, but defects in the function of the main cellular protein degradation routes, the proteasomes or autophagosomes, were not detected in this study. On the other hand, the present findings raise the question whether the increased number and size of p62 vesicles in skin fibroblasts could be utilised as disease biomarkers in the diagnostics of FTD.

Research article: Leskelä S*, Hoffmann D*, Rostalski H, Huber N, Wittrahm R, Hartikainen P, Korhonen V, Leinonen V, Hiltunen M, Solje M, Remes AM, Haapasalo A. FTLD Patient– Derived Fibroblasts Show Defective Mitochondrial Function and Accumulation of p62. Mol Neurobiol

The current study also revealed that skin fibroblasts from both sporadic and C9orf72 expansion-carrying FTD patients displayed a significantly weaker energy metabolism. These changes were detected in assays where the basal respiration and

OCTOBER - 2021 • HPN | HOSPITALPROFESSIONALNEWS.IE

The changes observed in the skin fibroblasts are partially similar to those observed in the brain of FTD patients.

The study, published in Molecular Neurobiology, is part of the research activities of the FinFTD Research Network bringing together Finnish basic and clinical FTD researchers. The research, aiming at clarifying disease pathomechanisms and identifying novel biomarker or therapeutic targets using FTD patientderived skin and neuronal cells, is supported by the FiNeFTD consortium grant from the Academy of Finland to Annakaisa Haapasalo and Prof. Anne Remes from the University of Oulu.

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ERLEADA® (APALUTAMIDE) APPROVED FOR REIMBURSEMENT IN IRELAND FOR ADULT MEN WITH NON-METASTATIC CASTRATION-RESISTANT PROSTATE CANCER WHO ARE AT HIGH RISK OF DEVELOPING METASTATIC DISEASE The Janssen Pharmaceutical Companies of Johnson & Johnson today announced that ERLEADA® (apalutamide), a next generation oral androgen receptor inhibitor, has been granted reimbursement in Ireland for the treatment of adult men with non-metastatic castrationresistant prostate cancer (nmCRPC) who are at high risk of developing metastatic disease.

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Data from the pivotal Phase 3 SPARTAN study undertaken ahead of approval, assessed the efficacy and safety of apalutamide plus androgen deprivation therapy (ADT) versus placebo plus ADT in patients with nmCRPC who had a rapidly rising prostate specific antigen (PSA) level despite receiving continuous ADT. Findings from the study showed that apalutamide plus ADT, significantly reduced the risk of developing distant metastasis or death (metastasis free survival [MFS]) by 72 percent, compared to placebo in combination with ADT (HR = 0.28; 95% CI, 0.230.35; P < 0.001). The median MFS was improved by over two years (40.5 months vs. 16.2 months) in patients with nmCRPC whose PSA is rapidly rising.1 “Delaying the development of metastases is a key goal in the treatment of prostate cancer. Once cancer spreads, it can become less responsive to treatment and can worsen the patient’s prognosis,” said Professor John McCaffrey, Consultant Medical Oncologist at the Mater Misericordiae University Hospital, Dublin. “The availability of apalutamide, which can increase time without metastases is a welcome development in the treatment of patients with prostate cancer.” “We are delighted with today’s announcement of the reimbursement of apalutamide, and we are pleased that we can now offer patients with high risk non-metastatic castrationresistant prostate cancer a new treatment option,” said Dr Bríd Seoighe, Head of Medical Affairs, Janssen Science Ireland UC. “At Janssen we believe that bringing medicines to patients at earlier stages of disease is vital to the patients living with the disease and their families.” The most common Grade 3/4 treatment-emergent adverse events in the SPARTAN study were hypertension (14.3 percent vs. 11.8 percent), rash (5.2 percent vs. 0.3 percent), fall (1.7 percent vs. 0.8 percent) and fracture (2.7 percent vs. 0.8 percent). Treatment discontinuation due to adverse events was 11 percent in the apalutamide arm compared to 7 percent in the placebo arm. Rates of serious adverse events were similar in the apalutamide in combination with ADT arm versus placebo in combination with ADT arm (25 percent vs. 23 percent respectively).

Clinical R&D 83 Employee benefits will be more important to our industry than ever before! Attracting and retaining employees has become a huge challenge to the pharmaceutical and healthcare industry. Many employers do not have the budget available to increase salaries or pay for private healthcare for everyone to encourage people back into the sector. We spoke with Mia Shepherd of HSF health plan, a health cash plan operating in Ireland since 1949 to understand why many of their customers describe them as the “best kept secret” and how they are supporting employees and employers after such a period of change. Mia explained that HSF health plan, is well established and have been working alongside employers in Ireland since 1949, partnering with organisations such as; HSE, Boots and Adrian Dunne. Mia explained that employees quickly attribute a value to having HSF health plan, as they are able to claim for costs, such as dental check-ups, hygienist visits, eye tests, glasses, contact lenses, GP appointments and prescriptions putting money back in their pockets for these everyday healthcare costs.

From an employer perspective, we know many people will be working with a restricted or even no budget for supporting their employees physical and emotional wellbeing. An advantage here is that HSF health plan’s health cash plans can be offered as a voluntary benefit at no cost to the employer (but at a discounted rate for the employee) or as an employer funded benefit, starting ¤2.37 per week for a family plan. Many employers will highlight these plans within their recruitment material, with family or single person cover available this benefit can become available to their family increasing the appeal to those seeking to have cover for them too. “Many employees will be amongst those on what are now in many circumstances long waiting lists for consultations, scans or tests causing anxiety and in some cases delaying any treatment which might be necessary. HSF health plan’s policyholders have been able to use their policy to claim for the costs of medical tests privately (a GP referral isn’t required by HSF health plan), empowering them access these often costly medical expenses and providing them with peace of

mind. We know that many people in the healthcare industry work here from abroad and would travel abroad to access this treatment, causing disruption and possibly even putting them in a position where they do no return to work for the employer afterwards. “Also included within our health plans or purchased as a standalone service are video and telephone consultations with GP’s, Counselling and Emotional Wellbeing support and a telephone legal advice service, ensuring that people can easily access help 24 hours a day. “We have partnered with many organisations within the Healthcare Sector, and being able to provide a telephone number to a group of employees to contact the counselling service has been invaluable to some of the HR Practitioners we work with. For employees, being able to schedule appointments around shifts and their own commitments is important and decreases disruption to the business there may be otherwise. “We also know that employers are keen to demonstrate that they partner with the right

organisations. HSF health plan is the trading company of the charity The Hospital Saturday Fund. In 2020 The Hospital Saturday Fund made grants totalling ¤1.8m to charities in Ireland and the UK. More information can be found on their website The Hospital Saturday Fund. “All profits made by HSF health plan are channelled to The Hospital Saturday Fund. This allows us to support medicallyassociated charities and individuals in the form of grants. “All those who join HSF health plan, just by belonging, are making a contribution to the important work of the charity, not something which usually happens when an insurance policy is taken out.” Paul Jackson, Chief Executive, The Hospital Saturday Fund.” A short video can be reviewed at https://vimeo. com/552812633/529020478d For more information about HSF health plans, please contact Mia Shepherd, National Sales Manager, Ireland on 00353 8776 90732 or via email: mia.shepherd@hsf.ie

Clonmel Healthcare add Medithyme Cough Syrup to their portfolio of products for Cough and Cold Clonmel Healthcare is delighted to announce the launch of Medithyme Cough Syrup; a traditional herbal medicinal product containing thyme liquid extract, which can be used as an aid to facilitate coughing up phlegm (expectorant) in productive cough* associated with cold. Medithyme is a traditional herbal medicinal product. Medithyme is:  Sugar free  Suitable for vegans  Gluten free The recommended dose is: Children from 12 years and adults: 15 ml, 4 times per day. Shelf life of 5 years; Use within 6 months of opening. Available in 180ml bottle. A copy of the summary of product characteristics is available upon request. Please contact Clonmel Healthcare on 01-6204000 if you require any additional information. *Medithyme Cough Syrup is a traditional herbal medicinal product, for use in case of productive cough associated with cold, exclusively based on longstanding use. For supply through general sale. TR 126/319/001. TR Holder: Clonmel Healthcare Ltd., Clonmel, Co. Tipperary. Date prepared: August 2021. 2021/ADV/MED/083H.

HOSPITALPROFESSIONALNEWS.IE | HPN • OCTOBER - 2021

When treating adult patients with gBRCA-mutated HR+/HER2or triple-negative locally advanced or metastatic breast cancer1

e r o m m e Give th NOW YOU CAN

TALZENNA is a proven alternative to chemotherapy* that provides patients with greater eﬃcacy in a convenient, once-daily oral dose1 LONGER MEDIAN PROGRESSION-FREE SURVIVAL (PFS) TALZENNA significantly prolonged median PFS vs chemotherapy: 8.6 months vs 5.6 months (HR=0.54 [95% CI: 0.41-0.71]; P<0.0001)1

DOUBLED OBJECTIVE RESPONSE RATE (ORR) ORR for TALZENNA was 62.6% (95% CI: 55.8-69.0) vs 27.2% (95% CI: 19.3-36.3) with chemotherapy (OR=4.99 [95% CI: 2.93-8.83]; P<0.0001)1†‡

CONVENIENT DOSING TALZENNA provides convenient, once-daily oral dosing, with or without food1

Indication: TALZENNA is indicated as monotherapy for the treatment of adult patients with germline BRCA1/2-mutations, who have HER2-negative locally advanced or metastatic breast cancer. Patients should have been previously treated with an anthracycline and/or taxane in the (neo)adjuvant, locally advanced or metastatic setting unless patients were not suitable for these treatments (see section 5.1 of full SmPC). Patients with hormone receptor (HR)positive breast cancer should have been treated with a prior endocrine-based therapy, or be considered unsuitable for endocrine-based therapy. CI=confidence interval; gBRCA=germline breast cancer susceptibility gene; HER2-=human epidermal growth factor receptor 2 negative; HR=hazard ratio; HR+=hormone receptor-positive; OR=odds ratio; RECIST=Response Evaluation Criteria in Solid Tumors.

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. Talzenna®▼0.25 mg and 1 mg hard capsules IE Prescribing Information: Before prescribing Talzenna (talazoparib) please refer to the full Summary of Product Characteristics (SmPC). Presentation: Each 0.25 mg hard capsule contains talazoparib tosylate equivalent to 0.25 mg talazoparib. Each 1 mg hard capsule contains talazoparib tosylate equivalent to 1 mg talazoparib. Indications: Talzenna is indicated as monotherapy for the treatment of adult patients with germline BRCA1/2-mutations, who have HER2-negative locally advanced or metastatic breast cancer. Patients should have been previously treated with an anthracycline and/or a taxane in the (neo)adjuvant, locally advanced or metastatic setting unless patients were not suitable for these treatments. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine-based therapy, or be considered unsuitable for endocrine-based therapy. Dosage and Administration: Treatment should be initiated and supervised by a physician experienced in the use of anticancer medicinal products. Patients should be selected for the treatment of breast cancer with Talzenna based on the presence of deleterious or suspected deleterious germline BRCA mutations determined by an experienced laboratory using a validated test method. Genetic counselling for patients with BRCA mutations should be performed according to local regulations, as applicable. The recommended dose is 1 mg talazoparib once daily. Patients should be treated until disease progression or unacceptable toxicity occurs. Complete blood count should be obtained prior to starting Talzenna therapy and monitored monthly and as clinically indicated. To manage adverse drug reactions, interruption of treatment or dose reduction based on severity and clinical presentation should be considered (see SmPC section 4.2). Special populations: Hepatic impairment: See SmPC section 4.2. No dose adjustment is required for patients with mild, moderate or severe hepatic impairment. Renal impairment: See SmPC section 4.2. No dose adjustment is required for patients with mild renal impairment. For patients with moderate renal impairment, the recommended starting dose of Talzenna is 0.75 mg once daily. For patients with severe renal impairment, the recommended starting dose of Talzenna is 0.5 mg once daily. Talzenna has not been studied in patients with CrCL < 15 mL/min or patients requiring haemodialysis. Elderly: No dose adjustment is necessary in elderly (≥ 65 years of age) patients. Paediatric population: The safety and efficacy of Talzenna in children and adolescents < 18 years of age have not been established. Method of administration: Talzenna is for oral use. To avoid contact with the capsule content, the capsules should be swallowed whole, and must not be opened or dissolved. They can be taken with or without food (See SmPC section 5.2). Contraindications: Hypersensitivity to the active substance or to any of the excipients. Breast-feeding. Special Warnings and Precautions: Myelosuppression: Myelosuppression consisting of anaemia, leucopenia/ neutropenia, and/or thrombocytopenia, have been reported in patients treated with talazoparib (see section 4.8). Talazoparib should not be started until patients have recovered from haematological toxicity caused by previous therapy (≤ Grade 1). Precautions should be taken to routinely monitor haematology parameters and signs and symptoms associated with anaemia, leucopenia/neutropenia, and/or thrombocytopenia in patients receiving talazoparib. If such events occur, dose modifications (reduction or interruption) are recommended. Supportive care with or without blood and/or platelet transfusions and/or administration of colony stimulating factors may be used as appropriate. Myelodysplastic

PP-TAL-IRL-0038 Date of Preparation September 2021

* † ‡

Capecitabine, eribulin, gemcitabine, or vinorelbine. Conducted in the intent-to-treat population with measurable disease at baseline. Per RECIST v1.1, confirmation of response was not required.1 ORR is the proportion of patients who have a partial or complete response to treatment.

Reference: 1. TALZENNA Summary of Product Characteristics.

syndrome/Acute myeloid leukaemia: Myelodysplastic syndrome/Acute Myeloid Leukaemia (MDS/AML) have been reported in patients who received poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors, including talazoparib. Overall, MDS/AML has been reported in 2 out of 584 (0.3%) solid tumour patients treated with talazoparib in clinical studies. Potential contributing factors for the development of MDS/AML include previous platinum-containing chemotherapy, other DNA damaging agents or radiotherapy. Complete blood counts should be obtained at baseline and monitored monthly for signs of haematologic toxicity during treatment. If MDS/AML is confirmed, talazoparib should be discontinued. Contraception in women of childbearing potential: Talazoparib was clastogenic in an in vitro chromosomal aberration assay in human peripheral blood lymphocytes and in an in vivo bone marrow micronucleus assay in rats but not mutagenic in Ames assay (see section 5.3), and may cause foetal harm when administered to a pregnant woman. Pregnant women should be advised of the potential risk to the foetus (see section 4.6). Women of childbearing potential should not become pregnant while receiving Talzenna and should not be pregnant at the beginning of treatment. A pregnancy test should be performed on all women of childbearing potential prior to treatment. A highly effective method of contraception is required for female patients during treatment with Talzenna, and for at least 7 months after completing therapy. Since the use of hormonal contraception is not recommended in patients with breast cancer, two non-hormonal and complementary contraception methods should be used. Male patients with female partners of reproductive potential or pregnant partners should be advised to use effective contraception (even after vasectomy), during treatment with Talzenna and for at least 4 months after the final dose. Interactions: Talazoparib is a substrate for drug transporters P-gp and Breast Cancer Resistance Protein (BCRP) and it is mainly eliminated by renal clearance as unchanged compound. Concomitant treatment with inhibitors of P-glycoprotein (P-gp): Strong inhibitors of P-gp may lead to increased talazoparib exposure. Concomitant use of strong P-gp inhibitors (including but not limited to amiodarone, carvedilol, clarithromycin, cobicistat, darunavir, dronedarone, erythromycin, indinavir, itraconazole, ketoconazole, lapatinib, lopinavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir, telaprevir, tipranavir, and verapamil) during treatment with talazoparib should be avoided. Co-administration should only be considered after careful evaluation of the potential benefits and risks. If co-administration with a strong P-gp inhibitor is unavoidable, the Talzenna dose should be reduced to 0.75 mg once daily. When the strong P-gp inhibitor is discontinued, the Talzenna dose should be increased (after 3-5 half-lives of the P-gp inhibitor) to the dose used prior to the initiation of the strong P-gp inhibitor. No talazoparib dose adjustments are required when co administered with rifampin. However, the effect of other P-gp inducers on talazoparib exposure has not been studied. Other P-gp inducers (including but not limited to carbamazepine, phenytoin, and St. John’s wort) may decrease talazoparib exposure. BCRP inhibitors: The effect of BCRP inhibitors on PK of talazoparib has not been studied in vivo. Co-administration of talazoparib with BCRP inhibitors may increase talazoparib exposure. Concomitant use of strong BCRP inhibitors (including but not limited to curcumin and cyclosporine) should be avoided. If co administration of strong BCRP inhibitors cannot be avoided, patient should be monitored for potential increased adverse reactions. Effect of acid-reducing agents: Population PK analysis indicates that co-administration of acid-reducing agents including proton pump inhibitors and histamine receptor 2 antagonists (H2RA), or other acid reducing agents had no significant impact on the absorption of talazoparib. Systemic hormonal contraception: Drug-drug interaction studies between talazoparib and oral contraceptives have not been conducted. Fertility, pregnancy and lactation: Fertility:

There is no information on fertility in patients. Based on non-clinical findings in testes (partially reversible) and ovary (reversible), Talzenna may impair fertility in males of reproductive potential. Women of childbearing potential should not become pregnant while receiving Talzenna and should not be pregnant at the beginning of treatment. A pregnancy test should be performed on all women of childbearing potential prior to treatment. Women of childbearing potential must use highly effective forms of contraception prior to starting treatment with talazoparib, during treatment, and for 7 months after stopping treatment with talazoparib. Since the use of hormonal contraception is not recommended in patients with breast cancer, two non-hormonal and complementary contraception methods should be used. Male patients with female partners of reproductive potential or pregnant partners should be advised to use effective contraception (even after vasectomy) during treatment with Talzenna, and for at least 4 months after the final. Pregnancy: There are no data from the use of Talzenna in pregnant women. Studies in animals have shown embryo foetal toxicity. Talzenna may cause foetal harm when administered to a pregnant woman. Talzenna is not recommended during pregnancy or for women of childbearing potential not using contraception. Breast-feeding: It is unknown whether talazoparib is excreted in human breast milk. A risk to breast-fed children cannot be excluded and therefore breast-feeding is not recommended during treatment with Talzenna and for at least 1 month after the final dose. Undesirable Effects: The overall safety profile of Talzenna is based on pooled data from 494 patients who received talazoparib at 1 mg daily in clinical studies for solid tumours, including 286 patients from a randomised Phase 3 study with germline BRCA-mutated (gBRCAm), HER2-negative locally advanced or metastatic breast cancer and 83 patients from a nonrandomised Phase 2 study in patients with germline BRCA-mutated locally advanced or metastatic breast cancer. The most common (≥ 25%) adverse reactions in patients receiving talazoparib in these clinical studies were fatigue (57.1%), anaemia (49.6%), nausea (44.3%), neutropenia (30.2%), thrombocytopenia (29.6%), and headache (26.5%). The most common (≥ 10%) Grade ≥ 3 adverse reactions of talazoparib were anaemia (35.2%), neutropenia (17.4%), and thrombocytopenia (16.8%). Dose modifications (dose reductions or dose interruptions) due to any adverse reaction occurred in 62.3% of patients receiving Talzenna. The most common adverse reactions leading to dose modifications were anaemia (33.0%), neutropenia (15.8%), and thrombocytopenia (13.4%). Permanent discontinuation due to an adverse reaction occurred in 3.6% of patients receiving Talzenna. The median duration of exposure was 5.4 months (range 0.03-61.1). Very common adverse reactions (>1/10) are Thrombocytopenia, Anaemia, Neutropenia, Leucopenia, Decreased appetite, Dizziness, Headache, Vomiting, Diarrhoea, Nausea, Abdominal pain, Alopecia and Fatigue. Commonly reported adverse reactions (>1/100 to <1/10), are Lymphopenia, Dysgeusia, Stomatitis and Dyspepsia. Refer to SmPC section 4.8 for further information on side effects. Legal Category: Product subject to prescription which may not be renewed (A): S1A. Marketing Authorisation Number: Talzenna 0.25 mg hard capsules – EU/1/19/1377/001-004; Talzenna 1 mg hard capsules – EU/1/19/1377/005-006. 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 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 + 353 1 4676500. Date of Preparation: 05/2021 Ref: TE 2_0

▼This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get to HPRA Pharmcoviglance, Earlsfort Terrace, Dublin 2, IRL. Tel: +353 1 676 4971, Fax: +353 1 676 2517, Website: www.hpra.ie, E-mail: medsafety@hpra.ie

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