HPN 2020 Sept

HOSPITAL PROFESSIONAL NEWS IRELAND

HPN September 2020 Issue 76 HOSPITALPROFESSIONALNEWS.IE

Ireland’s Dedicated Hospital Professional Publication

IN THIS ISSUE:

DRIVEN TO FULFIL THE PROMISE OF BIOSIMILARS— THE PFIZER WAY The Pfizer Promise is simple: To help you provide patients with more treatment options while delivering a portfolio of potentially cost saving oncology biosimilars.1-3

Breadth of offerings Pfizer has a portfolio of oncology biosimilars on the market, including both cancer therapies and supportive care products, to give patients more treatment options.2,3

Quality focused Pfizer oncology biosimilars are all produced to meet the same high-quality standards as Pfizer's other biologics—using the same robust protocols for monitoring quality throughout every stage of the manufacturing process.4

Manufacturing and supply experience Pfizer leverages more than 30 years of state-of-the-art manufacturing and supply-chain experience in biologics to reliably deliver biosimilars to patients.4,5

References: 1. IMS Institute for Healthcare Informatics. Delivering on the Potential of Biosimilar Medicines: The Role of Functioning Competitive Markets. Parsippany, NJ: IMS; March 2016. 2. Drugs.com. How many biosimilars have been approved in the United States? https://www.drugs.com/medical-answers/many-biosimilars-approved-united-states-3463281/. Updated December 8, 2019.

Accessed July 2020. 3. McGowan S, Jesse M. Biosimilars Pipeline Report. AmerisourceBergen. https:/www.amerisourcebergen.com/-/ media/assets/amerisourcebergen/biosimilars-pipeline-report_0420_v3.pdf?la=en&hash=1071304C7B66ED62628201B8268C0B633 627CB6B. Updated May 1, 2020. Accessed July 2020. 4. Data on file. Pfizer Inc., New York, NY. 5. Pfizer. Heritage in Biologics. https:// www.iononline.com/SiteRepository/Biosimilar/Pfizer/Pfizer-Heritage-in-Biologics_25Oct19. July 2016. Accessed July 2020.

PP-BIO-IRL-0085

All rights reserved.

July 2020

News: Impact of Consultant vacancies evident Page 4 Report: Medicines for Ireland on Lessons from Covid-19 Page 8 Perspectives: Pharmacists on the frontline Page 12 Feature: Changing landscape of secondary cardiovascular prevention in Stroke Page 16 CPD: MS – Now a treatable condition?

Page 23 Educational: Increased breast cancer risk in obesity Page 32

A new option in HIV-1

Make Doravirine a Part of Every Day DELSTRIGO® (100 mg doravirine/300 mg lamivudine/300 mg tenofovir disoproxil fumarate, equivalent to 245 mg of tenofovir disoproxil) is indicated for the treatment of adults infected with HIV-1 without past or present evidence of resistance to the NNRTI class, lamivudine, or tenofovir.1 PIFELTRO® (doravirine) is indicated, in combination with other antiretroviral medicinal products, for the treatment of adults infected with HIV-1 without past or present evidence of resistance to the NNRTI class.2 This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information.

Healthcare professionals are asked to report any suspected adverse reactions.

See section 4.8 of the SPC for how to report adverse reactions.

ABRIDGED PRODUCT INFORMATION Refer to Summary of Product Characteristics before prescribing. PRESENTATION Pifeltro: film-coated tablet containing 100 mg doravirine. Delstrigo: film-coated tablet containing 100 mg doravirine, 300 mg lamivudine and 300 mg tenofovir disoproxil fumarate, equivalent to 245 mg of tenofovir disoproxil. INDICATIONS Pifeltro: For use in combination with other antiretrovirals, for the treatment of HIV-1 without past or present evidence of resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI). Delstrigo: For the treatment of HIV-1 without past or present evidence of resistance to NNRTIs, lamivudine or tenofovir. DOSAGE AND ADMINISTRATION Therapy should be initiated by a physician experienced in HIV infection management.

Pifeltro: One 100 mg tablet once daily. Delstrigo: One 100/300/245 mg tablet once daily. Pifeltro and Delstrigo: If co-administered with rifabutin or other moderate CYP3A inducers, increase doravirine dose to 100 mg twice daily (12 hours apart). Pifeltro: Elderly: No dose adjustment necessary. Renal impairment: No dose adjustment necessary. Hepatic impairment: mild to moderate: no dosage adjustment required; severe: use with caution. Delstrigo: Elderly: Special care advised. Renal impairment: estimated creatinine clearance (CrCl) ≥ 50 mL/min: no dose adjustment necessary; estimated CrCl <50 mL/min: not recommended. Hepatic impairment: mild to moderate: no adjustment required; severe hepatic: use with caution. CONTRAINDICATIONS Hypersensitivity to the active substance or excipients Co-administration with strong CYP3A inducers. PRECAUTIONS AND WARNINGS A residual risk of sexual transmission of HIV-1 cannot be excluded and precautions should be taken in accordance with national guidelines. Use with CYP3A inducers may reduce the exposure of doravirine. Autoimmune disorders (such as autoimmune hepatitis) and immune reactivation syndrome have been reported in patients treated with combination antiretroviral therapy which may require investigation and treatment. Contains lactose monohydrate. Delstrigo: Post-treatment exacerbation of HBV (including hepatic decompensation and liver failure) have been reported in patients co-infected with HIV-1 and HBV following discontinuation of lamivudine or tenofovir disproxil. Monitor patients co-infected with HIV-1 and HBV after discontinuation of Delstrigo and if appropriate initiate anti-HBV therapy. Renal impairment, including acute renal failure and Fanconi syndrome have been reported with tenofovir disoproxil. Assess estimated CrCl prior to initiation and during therapy. In patients at risk of renal dysfunction, serum phosphorus, urine glucose, and urine protein should also be assessed. Discontinue therapy if estimated CrCl declines below 50 mL/min. Avoid with concurrent or recent use of nephrotoxic medicinal products (e.g. high-dose or multiple NSAIDs). Evaluation of renal function is recommended for persistent or worsening bone pain, pain in extremities, fractures, and/or muscular pain or weakness. Assessment of bone mineral density should be considered for patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Hypophosphatemia and osteomalacia secondary to proximal renal tubulopathy should be considered in patients at risk of renal dysfunction who present with persistent or worsening bone or muscle symptoms. Doravirine/lamivudine/tenofovir disoproxil must not be co-administered with other medicinal products containing lamivudine, tenofovir disoproxil, or tenofovir alafenamide or with adefovir dipivoxil. Doravirine/lamivu-

dine/tenofovir disoproxil should not be administered with doravirine unless needed for dose adjustment (e.g. co-administered with rifabutin). Drug interactions: Refer to SmPC for full information on drug interactions. Pifeltro and Delstrigo: Doravirine is metabolized primarily by CYP3A. Do not co-administer with strong CYP3A enzyme inducers. If co-administration with rifabutin or other moderate CYP3A inducers cannot be avoided, increase doravirine dose to 100 mg twice daily (taken 12 hours apart). Use with caution when co-administering doravirine with medicinal products that are sensitive CYP3A substrates that have a narrow therapeutic window (e.g., midazolam, tacrolimus and sirolimus). Delstrigo: Do not administer with other antiretroviral medicinal products. Co-administration of doravirine/lamivudine/tenofovir disoproxil with medicinal products that reduce renal function or compete for active tubular secretion may increase serum concentrations of lamivudine. Co-administration of doravirine/lamivudine/tenofovir disoproxil with medicinal products that reduce renal function or compete for active tubular secretion via OAT1, OAT3 or MRP4 may increase serum concentrations of tenofovir. Avoid with concurrent or recent use of nephrotoxic medicinal products. Pregnancy and Lactation: Pifeltro and Delstrigo: Avoid use during pregnancy. An Antiretroviral Pregnancy Registry has been established. Breastfeeding is not recommended.

SIDE EFFECTS Refer to SmPC for complete information on side-effects.Pifeltro and Delstrigo: Common: abnormal dreams, insomnia, headache, dizziness, somnolence, nausea, diarrhoea, abdominal pain, flatulence, vomiting, rash, fatigue alanine aminotransferase increased. Uncommon: hypophosphataemia, nightmare, depression, suicidal ideation, paraesthesia, asthenia. Rare: hypomagnesaemia, blood creatine phosphokinase increased. Delstrigo: Common: cough, nasal symptoms, alopecia, muscle disorders, fever. Uncommon: neutropenia, anaemia, thrombocytopenia, pancreatitis, rhabdomyolysis, proximal renal tubulopathy (including Fanconi syndrome), aspartate aminotransferase increased. Rare: lactic acidosis, hepatitis, angioedema, myopathy, acute renal failure, renal failure, acute tubular necrosis, nephritis (including acute interstitial) and nephrogenic diabetes insipidus. Very Rare: pure red cell aplasia, peripheral neuropathy (or paraesthesia). PACKAGE QUANTITIES Bottle of 30 tablets. Legal Category: POM. Marketing Authorisation numbers: Pifeltro: EU/1/18/1332/001, Delstrigo: EU/1/18/1333/001. Marketing Authorisation Holder: Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands. Date of revision: September 2019. © Merck Sharp & Dohme Ireland (Human Health) Limited 2019.

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. Date of Preparation: June 2020. IB/0007/0008.

References: 1. DELSTRIGO Summary of Product Characteristics, December 2019. 2. PIFELTRO Summary of Product Characteristics, November 2019.

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)

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

IE-DOV-00016

PIFELTRO® ▼ (Doravirine) DELSTRIGO® ▼ (Doravirine/Lamivudine/Tenofovir disproxil fumarate)

3

September Issue Issue 76

Contents

Foreword

Biosimilar prescribing by Pharmacists could save millions P6

Editor As Hospital Professional News was going to press, the government announced new restrictions to combat coronavirus.

They came into effect immediately and remain in place until September 13th.

Lessons learned from Covid-19 – Policy paper by Medicines for Ireland P8 Hospital pharmacist Neassa Judge answers call to the frontline P14

The President of the Irish Medical Organisation (IMO) has said that these measures are necessary to respond to the increasing Covid-19 case numbers which have emerged in recent weeks but also issued a warning.

4

Consultant capacity severely impacting waiting lists P32

Dr McGarry said that the vast majority of people have responded to the Covid-19 crisis amazingly well. “There has been a lot of criticism but most people deserve nothing but credit for how they have responded to this crisis since March and we need to tap into that spirit again now for the coming weeks.”

The latest developments in HIV management and treatment P37

8

REGULARS Feature: Are you keeping up with secondary cardiovascular prevention in stroke? P16

Turn to page 5 for more details.

CPD: MS – A treatable condition? P23

Everyone’s plans for 2020 were thrown into doubt and chaos when Covid-19 hit Ireland. One local hospital pharmacist made the most of the situation however, and signed up to the HSE’s ‘Be on Call for Ireland’ campaign.

14

Feature: Ophthalmology consult service audit P28

Neassa Judge was eager to help in any way she could. On page 14, she gives readers an insight into the work she carried out as a pharmacist with Midlands Regional Hospital in Tullamore, supporting the pharmacy team there, who were under pressure due to the pandemic.

Educational: Breast cancer and the link to obesity P32 32

Clinical Profiles P44 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.

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.

PUBLISHER IPN Communications Ireland Ltd Clifton House, Lower Fitzwilliam Street, Dublin 2 | (01) 669 0562 GROUP DIRECTOR Natalie Maginnis n-maginnis@btconnect.com

However he also warned that the outlook for the health services in the coming months remained challenging with long waiting lists, an ongoing recruitment crisis and an exhausted workforce; “Health services staff have been battling this crisis now for six months and are exhausted.”

BUSINESS & SALES MANAGER Siobhan Buchanan-Johnston siobhan@hospitalprofessionalnews.ie

SALES & MARKETING EXECUTIVE Amy Evans | amy@ipn.ie EDITORIAL editorial@hospitalprofessionalnews.ie

ACCOUNTS Rachel Wilson cs.ipn@btconnect.com CONTRIBUTORS

To Neassa, this was hugely worthwhile, both personally and professionally.

Our Report for this issue looks at a recent policy paper published

by Medicines for Europe/Medicines for Ireland. This examined ‘lessons learned from Covid-19’ for the pharmaceutical industry. Chair of MFI David Delaney says, “This document sets out a range of important national and European policy recommendations that illustrate the important role of the EU in relation to the supply of medicines and medical devices. This further illustrates the importance for Ireland of a pan-European response to many of the issues that have arisen due to the Covid-19 pandemic.”

The report, with comment from MFI members starts on page 8.

Enjoy the issue.

Neassa Judge, MPSI Barry O'Sullivan, MPSI Dr Darragh T. O'Sullivan MB BCh, Dr Paul Cotter MB BCh MPhil MD Dr Sally Ann Lynch | Tara Clark Dr Laura Kennelly Professor Niall Turbridy

DESIGN DIRECTOR Ian Stoddart Design HOSPITALPROFESSIONALNEWS.IE

@HospitalProNews HospitalProfessionalNews

HOSPITAL PROFESSIONAL NEWS IRELAND Ireland’s Dedicated Hospital Professional Publication HOSPITALPROFESSIONALNEWS.IE | HPN • SEPTEMBER 2020

4 News Impact of unfilled hospital consultant vacancies evident The Irish Hospital Consultants Association (IHCA) has highlighted the plight of thousands of people who have been added to acute hospital waiting lists since the start of 2020.

63,679 people have now been added to various National Treatment Purchase Fund (NTPF) lists in 2020, as the latest waiting list figures (for July 2020) show:  832,443 people on some form of NTPF waiting list in July, an increase of 15,727 (1.9%) in one month and 63,679 (8.3%) since the start of the year;  601,362 outpatients nationally are waiting to be seen by a consultant, an increase of 16,963 (2.9%) on June's figures and 47,928 (8.7%) during 2020;  80,283 now wating for inpatient/ day case treatment, an increase of 13,720 (20.6%) since the start of 2020.

The latest figures show significant increases across numerous treatment areas for outpatient and inpatient/day case waiting lists since the start of the year, notably in: The above NTPF data represents

Specialty

No. people added to Outpatient and Inpatient/Day Case waiting list in 2020

% increase in 2020

ENT (Otolaryngology)

4,757

6.9%

General Surgery

10,740

25.7%

Gynaecology

2,814

8.8%

Ophthalmology

3,191

6.5%

Orthopaedics

9,260

12.4%

Urology

4,009

10.4%

an overall increase of 34,771 people on outpatient and inpatients/day case waiting lists in these specialties in the past seven months. This accounts for 56% of the overall increase (+61,648) since the start of the year.

For example, Ireland has only a third of the number of Consultant Urologists posts filled when compared to New Zealand, or only 15% of the number in Denmark (both countries have similar populations to Ireland).** This is despite urology waiting lists growing by 10.4% since the beginning of 2020.

“The increasing number of people waiting to see consultants or have treatment has overall increased month-on-month, as a result not only of the coronavirus but also due to persistent consultant shortages and a lack of capacity in the system. Our health service capacity deficits can and should be addressed immediately. The Minister for Health's previous commitment to address the consultant recruitment and retention crisis, and to get more specialists back working in our acute hospitals is key to reducing waiting lists. But it requires the Minister for Health and the government to end as promised the discrimination since 2012 against new consultants.”

Consultants warn that these 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 the health system.

Ireland already has 41% fewer medical specialists on a population basis than the EU average, and a third to a half the number in some specialties.*

Dr Donal O'Hanlon, President, IHCA, says, "While the fact that waiting lists are continuing to rise comes as no surprise, we cannot become complacent. The reality is we shouldn't accept this situation and we don't need to either.

Decisive action must be taken now to prevent a winter like no other.

Appraisal system being examined at Medical Council Dr Rita Doyle, President, Irish Medical Council

Council is examining a number of international models.

A longer cycle of maintenance of professional competence with an appraisal system is being developed by the Medical Council.

Ms Jantze Cotter, the Council’s Director of Professional Development and Research, said

a new model would place greater focus on reflective practice. The Council is also developing an appraisal system, but Ms Cotter indicated it would not necessarily be akin to the revalidation model at the General Medical Council in the UK. She said the

SEPTEMBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

A three-year rather than annual cycle may be adopted, according to Ms Cotter, who also confirmed the Council’s longer-term aim to implement a licensing system. Meanwhile, a number of postgraduate training bodies have advocated for increased flexibility in the model of maintaining professional competence. Prof Sean Tierney, Dean of Professional Practice and Development, RCSI, said the College would welcome

“some flexibility introduced into the credit system so that doctors who are exceeding their requirements in some categories and meeting the overall requirements could use their excess in other categories to ‘compensate’ for other areas”.

The RCSI would also endorse further development of the audit requirements and support to expand the range of national audits provided by the National Office of Clinical Audit, in addition to more HSE resourcing for local audits. Prof Michael Griffin, Chair of the professional competence scheme committee at the College of Anaesthesiologists of Ireland (CAI), said the College favours the model “being less rigid in its categories and more supportive of doctors selecting relevant educational activities proportionate to their stage of career”. CAI CEO Mr Martin McCormack also emphasised the importance of more protected time for doctors to engage in educational activities.

News

5

Ongoing Recruitment Crisis and Exhausted workforce IMO President Dr McGarry

The President of the Irish Medical Organisation (IMO) has said that the new restrictions announced by the Government as Hospital Professional News was going to press, are necessary to respond to the increasing Covid-19 case numbers which have emerged in recent weeks.

Dr McGarry said that the situation required a strong response and welcomed the announcement of the new measures by the Government.

Dr McGarry said that the vast majority of people have responded to the Covid-19 crisis amazingly well. “There has been a lot of criticism but most people deserve nothing but credit for how they have responded to this crisis since March and we need to tap into that spirit again now for the coming weeks.”

However he also warned that the outlook for the health services in the coming months remained challenging with long waiting lists, an ongoing recruitment crisis and an exhausted workforce; “Health services staff have been battling this crisis now for six months and are exhausted.”

“There are a number of issues that need to be addressed as a matter of urgency, such as the ongoing consultant pay disparity of 30+%, the need to grant consultant status to public health specialists and the need to support GPs through what will be a very busy winter.”

The message from the Taoiseach was grave as we went to press.

“We are at another critical moment,” Micheál Martin said.

“If we want to limit the number

of people who get seriously ill or die because of the virus. We need to follow these public health measures.

closed doors, the limiting of indoor and outdoor gatherings and asking older people to limit their interactions to a small network.

“We can’t go back. If we falter now every sacrifice we’ve made to date will be for nought.”

Accompanying this stark warning from the Taoiseach was a series of new measures aimed at curbing the spread of Covid-19 in Ireland.

At the weekend, acting chief medical officer Dr Ronan Glynn said we’ve seen multiple clusters and rising numbers of cases in many parts of the country and described this as “deeply concerning”.

They include sports events and matches reverting to behind

“The virus is still out there and has not gone away,” he said.

MSD enter agreement with Takeda MSD has entered into an agreement for the acquisition of the Dunboyne manufacturing facility of Takeda Dunboyne Biologics Limited, a subsidiary of Takeda Pharmaceutical Company Limited, it was announced last month.

Subject to completion activities, including the engagement with the employees based at the site and final due diligence steps, the agreement will see the state-of-the-art, flexible manufacturing facility acquired as a going concern. Takeda will now embark upon a consultation period with approximately 200 employees of the Dunboyne site and the process is expected to conclude by mid-September.

Thomas Wozniewski, Takeda Global Manufacturing & Supply Officer, said, “We are pleased to announce the divestment of the Dunboyne Biologics plant to MSD who will retain all of our existing Dunboyne employees. In MSD, we believe we have found the most suitable buyer for the Dunboyne facility, offering a great perspective for our Dunboyne team.”

Sanat Chattopadhyay, Executive Vice President & President, Manufacturing Division, MSD, added, “This facility will further expand our footprint in Ireland and support commercialisation of our existing and future pipeline of biologics products. The talent of the team in Dunboyne was a determining factor in our decision to acquire this facility and we look forward to welcoming our new colleagues to the broader MSD Ireland network, building on the progress they have made to date and, together, realising the potential of this facility for the benefit of patients in Ireland and globally.”

HOSPITALPROFESSIONALNEWS.IE | HPN • SEPTEMBER 2020

6 News Pharmacists prescribing Biosimilars could save Millions Pharmacists have called on the Minister for Health Stephen Donnelly TD to change legislation to allow them substitute expensive biological medicines for more cost-effective biosimilars.

In 2017 the Department of Health held a public consultation on a National Biosimilar Medicines Policy, and IPU proposals showed ¤370 million in potential savings were possible if action was taken.

Nearly three years later, there has been no action and those savings have not been made.

Eoghan Hanly, Vice-President of the Irish Pharmacy Union said allowing pharmacists to substitute biological medicines for biosimilars “is the fastest and most effective way to ensure a rapid and meaningful increase

in the use of biosimilars, which could save the Irish State hundreds of millions of euro”.

Commenting on the recently updated Guide to Biosimilars for Healthcare Professionals from the Health Products Regulatory Authority (HPRA), Mr Hanly called it a “massive own goal for the health service that we are not availing of hundreds of millions in potential savings”.

Mr Hanly said, “The finances of the health service have never been in great shape and the ongoing pandemic will only make that worse. Analysis done for the IPU three years ago identified clear savings of hundreds of millions of euro but we are not able to use that money to support people in our health service today,

because that opportunity was wasted. Will we be back here again saying the same thing in another three years?”

Mr Hanly continued, “There are no clinically meaningful differences between a biosimilar and reference biological medicine and increased use of biosimilars would result in significant savings.

Despite this, uptake has been extremely low in Ireland, with biosimilars representing less than 10% of the market share, which is far below the EU average.

In 2013 pharmacists began facilitating Government policy on the use of generic medication.

Consequently, the use of generic medicines in Ireland increased from 17% to over 40%, generating a total of ¤1.145

billion in savings for the State.

As the experience of generic substitution demonstrated, allowing community pharmacists to substitute is the fastest and most effective way to ensure a rapid and meaningful increase in the usage of biosimilars.

“An amendment to the Health (Pricing and Supply of Medical Goods) Act 2013 would allow pharmacists to substitute a biological reference product with a biosimilar, and the IPU is now calling on Minister Stephen Donnelly to legislate for this. Every week that the Government fails to implement this proposal is costing roughly ¤2 million in potential savings foregone”, concluded Mr Hanly.

Abstract submission for EAHP’s 25th Congress Those hospital pharmacists considering to submit an abstract to the upcoming Congress of the European Association of Hospital Pharmacists (EAHP) can now start their preparation. Abstract submissions are now open between 1st August and 15th October 2020 for hospital pharmacists, other healthcare professionals and interested scientists.

The 25th Anniversary Congress of EAHP will be held in Vienna, Austria from 24th and 26th of March 2021.

Different seminars, workshops and keynotes will be organised around the theme: “Hospital Pharmacy 5.0 – the future of patient care”.

Abstract authors are reminded to carefully read and comply with the guidelines presented on EAHP's website which outline the review process, provide guidance to those submitting abstracts for the first time and list tips on avoiding abstract rejection. Submissions of abstracts from all disciplines of hospital pharmacy or related areas are encouraged, provided that they can be linked to one of the 44 European Statements of Hospital Pharmacy.

Questions concerning the abstract submission process can be addressed to abstract@eahp.eu. The best abstracts/posters, with regards to aspects like originality, scientific quality and practical applicability, will be awarded with 3 prizes amounting to 750 euro, 500 euro and 250 euro.

Irish researchers to lead ¤3m study Researchers at RCSI University of Medicine and Health Sciences are leading a new ¤3m study to investigate the real-world effects of the newest cystic fibrosis medications as they become available for people with CF. The research will look at how a new triple combination cystic fibrosis drug, Kaftrio, will affect people in their day to day lives, rather than in controlled clinical trial conditions. Kaftrio (known as TriKafta in the US) is a successor to Orkambi.

The project, called RECOVER, has been awarded ¤2.85m from Cystic Fibrosis Foundation (US), ¤112 thousand from Cystic Fibrosis Trust (UK) and ¤100 thousand from Cystic Fibrosis Ireland.

“Our study will allow us to discover in detail how this powerful new treatment affects the health and everyday lives of people with

Professor Paul McNally RCSI RECOVER

cystic fibrosis, to understand why different people might respond differently to the drug and to gain insight into how this treatment might affect the very significant treatment burden that people with cystic fibrosis currently endure,” said Professor Paul McNally, Associate Professor of Paediatrics at RCSI, Respiratory Consultant in Children's Health Ireland and lead researcher on the RECOVER study.

“Clinical trials occur under very controlled conditions and exclude many sick people with cystic fibrosis. 'Real-world' studies, such as RECOVER, are essential to confirm the trial findings and examine in-depth effects on the everyday lives all people with cystic fibrosis.”

SEPTEMBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

DON’T WAIT UNTIL OSTEOPOROSIS STRIKES AGAIN Rebuild bone before it breaks again—with Movymia®1

MOVYMIA®: THE NEW TERIPARATIDE BIOSIMILAR FROM CLONMEL HEALTHCARE

RELIABLE: Movymia®’s quality, safety and efficacy is highly similar to its reference product1,2,* EFFECTIVE: Anabolic MoA effectively rebuilds bone through the stimulation of osteoblasts1,3 AFFORDABLE: Allows more eligible patients to benefit due to its cost advantage4,5 RE-USABLE: One high quality reuseable pen for the entire treatment period1 MOVYMIA 20 MICROGRAMS/80 MICROLITERS SOLUTION FOR INJECTION Each dose of 80 microliters contains 20 micrograms of teriparatide. One cartridge of 2.4 ml of solution contains 600 micrograms of teriparatide (corresponding to 250 micrograms per ml).

Presentation: Glass cartridge. Indications: Movymia is indicated in adults. Treatment of osteoporosis in postmenopausal women and men at increased risk of fracture. In postmenopausal women, a significant reduction in the incidence of vertebral and non-vertebral fractures but not hip fractures has been demonstrated. Treatment of osteoporosis associated with sustained systemic glucocorticoid therapy in women and men at increased risk for fracture. Dosage: The recommended dose is 20 micrograms administered once daily. Patients should receive calcium and vitamin D supplements if dietary intake is inadequate. The maximum total duration of treatment is 24 months. The 24 month course should not be repeated over a patient’s lifetime. Following cessation of teriparatide therapy, patients may be continued on other osteoporosis therapies. Teriparatide must not be used in severe renal impairment. Use with caution in moderate renal impairment and impaired hepatic function. Teriparatide should not be used in paediatric patients (less than 18 years), or young adults with open epiphyses.

Method of administration: Movymia should be administered once daily by subcutaneous injection in the thigh or abdomen. It should be administered exclusively with the Movymia Pen reusable, multidose medicine delivery system and the injection needles which are listed as compatible in the instructions provided with the pen. The pen and injection needles are not included with Movymia. However, for treatment initiation a cartridge and pen pack should be used. Movymia must not be used with any other pen. Patients must be trained to use the proper injection techniques. Contraindications: Hypersensitivity to the active substance or excipients. Pregnancy and Breast-feeding. Pre-existing hypercalcaemia, severe renal impairment, metabolic bone diseases other than primary osteoporosis or glucocorticoid-induced osteoporosis, unexplained elevations of alkaline phosphatase, prior external beam or implant radiation therapy to the skeleton, patients with skeletal malignancies or bone metastases. Warnings and precautions: In normocalcaemic patients, slight and transient elevations of serum calcium concentrations have been observed following teriparatide injection. Serum calcium concentrations reach a maximum between 4 and 6 hours and return to baseline by 16 to 24 hours after each dose of teriparatide.

Therefore, if blood samples for serum calcium measurements are taken, this should be done at least 16 hours after the most recent teriparatide injection. Routine calcium monitoring during therapy is not required. Teriparatide may cause small increases in urinary calcium excretion, but the incidence of hypercalciuria did not differ from that in the placebo-treated patients in clinical trials. Teriparatide should be used with caution in patients with active or recent urolithiasis because of the potential to exacerbate this condition. In short-term clinical studies with teriparatide, isolated episodes of transient orthostatic hypotension were observed. Typically, an event began within 4 hours of dosing and spontaneously resolved within a few minutes to a few hours. When transient orthostatic hypotension occurred, it happened within the first several doses, was relieved by placing subjects in a reclining position, and did not preclude continued treatment. Caution should be exercised in patients with moderate renal impairment. Experience in the younger adult population, including premenopausal women, is limited. Treatment should only be initiated if the benefit clearly outweighs risks in this population. Women of childbearing potential should use effective methods of contraception during use of teriparatide. If pregnancy occurs, teriparatide should be discontinued. The recommended treatment time of 24 months should not be exceeded. Contains sodium. Interactions: Digoxin, digitalis. Fertility, pregnancy and lactation: Women of childbearing potential should use effective methods of contraception during use of teriparatide. If pregnancy occurs, Movymia should be discontinued. Movymia is contraindicated for use during pregnancy and breast-feeding.

The effect of teriparatide on human foetal development has not been studied. The potential risk for humans is unknown. Driving and operation of machinery: Teriparatide has no or negligible influence on the ability to drive and use machines. Transient, orthostatic hypotension or dizziness was observed in some patients. These patients should refrain from driving or the use of machines until symptoms have subsided. Undesirable effects: Nausea, pain in limb, headache, dizziness. Refer to Summary of Product Characteristics for other adverse effects. Pack size: 1. Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie. Marketing authorisation holder: STADA Arzneimittel AG, Stadastrasse 2-18, 61118 Bad Vilbel, German. Marketing authorisation number: EU/1/16/1161/001-003. Medicinal product subject to medical prescription. Date last revised: July 2019.

1. Movymia® SmPC. 2. Movymia® EPAR – public assessment report, available at: https://www.ema.europa.eu/documents/assessment-report/movymia-epar-public-assessment-report_en.pdf 3. Brixen KT et al. Basic Clin Pharmacol Toxicol. 200494(6):260–70. 4. Lyman GH et al. N Engl J Med. 2018378(21):2036–2044. 5. Janjigian YY et al. Future Oncol. 201814(23):2403–2414.* Forsteo®

October 2019. 2019/ADV/TER/122H

8 Report

Lessons learned for the Future • Government pandemic planning should exempt medicine manufacturing and logistics from lockdowns.

• Avoiding shortages during a pandemic requires industry coordination, demands visibility and close cooperation between governments/regulators and industry for regulatory flexibility.

• EU and national coordination to ensure equitable supply of medicines is important for industry. Hoarding and other restrictions undermine our ability to supply patients in need.”

Off-Patent Industry

After several months of crisis, Medicines for Ireland has compiled a new report which looks at some of the key lessons learned from Covid-19 for the future of pharmaceutical policy in Europe.

As the supplier of the majority of medicines in Ireland to both the HSE and to patients directly, Medicines for Ireland (MFI) members are a critical and central stakeholder in the Irish health service.

The COVID-19 outbreak in Europe has catalysed some long-standing issues in the functioning of pharmaceutical policy, as well as the impact this can have on patient access and hospital and pharmacy supply.

The global Covid-19 outbreak lead to an acute shortage of essential supplies, including personal protective equipment, diagnostics, and medicines. During the crisis the EU Commission formally called on the pharmaceutical industry to increase production capacity for all medicines for which there is an increased demand as a result of Covid-19, and in particular for those for which there is a risk of supply shortages.

In this context, Medicines for Ireland has worked pro-actively with Government, regulators and key policy makers to ensure round the clock continuity of supply in Ireland. Medicines for Ireland continues to work directly with the Department of Health and

the Health Products Regulatory Authority (HPRA) as well as the HSE, EU Commission and all relevant EU institutions to ensure a solution focused approach is taken to secure a stable supply of medicines to the Irish market.

Chair of Medicines for Ireland, David Delaney, told Hospital Professional News, ““Medicines for Ireland (MFI) is the Irish pharmaceutical trade association and the supplier of the majority of medicines in Ireland to the HSE and patients directly. ‘Lessons Learned from Covid-19’ has been produced in conjunction with our sister organisation, Medicines for Europe.

“This document sets out a range of important national and European policy recommendations that illustrate the important role of the EU in relation to the supply of medicines and medical devices.

This further illustrates the importance for Ireland of a panEuropean response to many of the issues that have arisen due to the Covid-19 pandemic.

“The Covid-19 pandemic surge has brought unprecedented challenges to the pharmaceutical

David Delaney, Chair, Medicines for Ireland

SEPTEMBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

industry in Ireland and our members have responded to this challenge to ensure the supply of medicines to the patients who need them the most. It is worth noting that in manufacturing medicines in Ireland to supply to patients throughout the globe, MFI continue to support thousands of jobs throughout Ireland, through our significant role in maintaining Ireland’s ¤40bn annual pharmaceutical exports.”

“There are a range of lessons learned that Medicines for Ireland have highlighted. They include: • Contingency plans are critical and should be integrated into the planning of all medicine manufacturers.

The off-patent medicines industry mobilised all efforts to ensure medicines continued to be developed, transported and supplied, in collaboration with the European Institutions, throughout the crisis. Our industry notably massively scaled up production and put in place cooperation mechanisms to tackle the colossal surge in demand for medicine.

Lessons learned • Manufacturing contingency plans enabled a dramatic increase in supply during COVID-19.

• Government pandemic planning should exempt medicine manufacturing and logistics from lockdowns and other control measures.

• Avoiding shortages during a pandemic requires industry coordination, demand visibility and close cooperation between governments/regulators and industry for regulatory flexibility.

9 Paul Neill, Director, Generic Products, Ireland, Teva says, “The Covid-19 pandemic was hugely challenging for everyone, but I’m proud of the way Teva and the wider pharmaceutical industry responded. As one of the largest suppliers of medicines to the State, we recognised early on during the Covid-19 crisis that we had a responsibility to make sure we kept medicines moving for the patients that rely on us. Our number one priority was making sure that patients continued to have access to the medicines that they rely on, which is why we worked hard to maintain supplies of our products to pharmacies across Ireland.

“We also donated a consignment of more than 100,000 pots of Sudocrem® to the HSE, these were distributed to Healthcare staff across the entire HSE infrastructure - our small way of saying ‘thank you’ to all the healthcare professionals keeping the country safe during the pandemic.

“As the Medicines for Ireland report shows, avoiding shortages during a pandemic requires industry co-ordination and close cooperation between the State and the pharmaceutical industry. There are important lessons to be learnt, and we look forward to having discussions with the HSE and the new coalition government to explore ways we can continue to work together in the future to ensure a robust and stable supply of medicines to the Irish market continues.”

• EU and national coordination to ensure equitable supply of medicines is important for industry. Hoarding and other restrictions undermine our ability to supply patients in need.

• Disruptions to global supply chains did not cause any critical shortages during COVID-19 because Europe has a robust medicines and API manufacturing sector. The sector should be strengthened to increase Europe's manufacturing competitiveness and resilience.

• Repurposing of medicines was essential in securing treatment options in a crisis.

A fit for purpose regulatory and market framework is needed to encourage future repurposing developments.

Improving pandemic preparedness Although health systems adapted to the influx of COVID19 patients, both the European Union (EU) and Member States were slow to prepare for the outbreak including enacting effective control measures such as testing and contact tracing. This happened despite the WHO warning early on that there was a risk of COVID-19 spreading beyond Asia. Member States also adopted different and poorly coordinated measures which increased the difficulties to track and monitor the outbreak.

Panic also set in regarding ICU medicine supplies which led many countries to hoard medicines at the expense of European solidarity and the efficient delivery of medicines to patients in need.

Paul Neill, Director, Generic Products, Ireland, Teva

Recommendations:

This shows the need for an EU pandemic preparedness plan, which should integrate lessons learned from previous epidemics (SARS or H1N1) as well as COVID-19. An EU pandemic preparedness plan should address country coordination of confinement measures, including border closures and travel restrictions. The fragmentation in these measures in the early stages of COVID-19 led to major internal market disruptions, which challenged the manufacturing, packaging, testing and distribution of urgently needed medicines.

The recognition of pharmaceutical manufacturing as essential production was critical for our industry response to the surge in demand for medicines brought on by COVID-19. Medicines for Europe members successfully

• Maintain the integrity of the internal market so that critical manufacturing and logistics for medicine supply can continue during a health crisis.

• Develop an EU epidemic/ pandemic preparedness plan to be implemented, where appropriate, for future communicable disease risks, led by the European Commission, with input from industry, with the technical support of the European Medicines Agency (EMA), European Centre for Disease Control (ECDC), and in coordination with Member States. Industry input would cover supply chain risks and how to plan for sudden demand surges, including logistical challenges requiring support.

• Share best practices between EU countries on how to best treat patients during a pandemic.

• Foresee measures to ensure continuity of treatment for all patients during a pandemic, as well as continuing screening and diagnostic procedures.

This is important to avoid disease worsening for chronically ill patients.

Padraic O’Brien is Associate Director Commercial with Accord Healthcare Ireland and is Vice-Chair of Medicines for Ireland. He told Hospital Professional News, “We are all aware that Frontline workers, clinicians, care workers and support staff are the heroes of Coronovirus; however generic suppliers like Accord Healthcare have played a vital role in ensuring these key professionals have the medicines available to do their job.

Recognise the public health role of off-patent medicines in future industrial and pharmaceutical strategies

“In a market often fixated by high-profile high-cost drugs, the role of the generic medicines sector can be under-appreciated. However, its performance during the pandemic illustrates its importance and ability to respond to a series of challenges that threatened to derail the provision of healthcare.

“While the sector experienced unprecedented demand on medicines coupled with unparalleled logistical challenges, and work place interruptions, it was evident that these challenges were surmounted as a consequence of the collaborative solution focused approach of manufacturers, wholesalers, pharmacists, and regulatory authorities. Our shared experience of the pandemic to date has educated us all, and it has highlighted the necessity that the industry must be pandemic-ready at all times.

“Supply chain resilience from the industry coupled with regulatory flexibility from the HPRA ensured patients received the medicines they needed on time.”

implemented contingency production plans that reduced supply chain risks and enabled them to scale up production output during the outbreak. In some cases, border closures and heavy-handed state interventions undermined supply capabilities and limited industry efforts.

Commission efforts and outreach to tackle these challenges were important to move medicines to where they were needed. A more rapid and coordinated approach to medicine demand and supply planning at Member State and European level would also reduce panic in hospitals and Member States that led to a lot of hoarding within and across countries to the detriment of equitable access to medicine.

Padraic O’Brien, Associate Director Commercial, Accord Healthcare Ireland

The pandemic showcased the essential role that offpatent medicines play in a large public health crisis, as the majority of medicine needs were covered by our industry. For example, in Germany, 97% of the medicines needed for Covid19 had a generic medicine option available on the market. Our industry was also able to massively scale up supply to meet the large-scale demand surge for medicines used in

HOSPITALPROFESSIONALNEWS.IE | HPN • SEPTEMBER 2020

10 Report on medicines procurement most economically advantageous tender (MEAT) criteria. An important step would also be to define “investment in manufacturing security of supply” as a tax credit under EU state aid law.

Supply chain resilience was challenged during COVID-19 by restrictions on exports from India and China but also by restrictions inside the EU by some member states. While it would be unrealistic to manufacture everything in the EU, steps can be taken to strengthen our manufacturing base in Europe. A new medicines trade policy agenda focused on regulatory cooperation and convergence could also reduce the risk of future trade disruptions in the global supply chain.

Covid19. This Covid19 experience typifies the central role of our industry in public health.

Recommendations: • Future pharmaceutical or industrial policy strategies should take the following elements into consideration: • The generic, biosimilar and value added medicines industry is vital for public health in terms of access and sustainability. The crisis notably underlined the value of maintaining a strong medicines manufacturing sector that was able to adapt to a major global supply chain disruption and a massive demand surge to serve European patients.

• Looking forward, policies should be adopted to stimulate investments in:  a resilient and diversified manufacturing chain including a strong medicine manufacturing sector in Europe. This will improve rapid production scaleup together with an efficient and flexible regulatory framework to respond to demand surges. o sustainable policies that encourage companies to have resilient supply chains with mature quality, safety, environmental and supply chain reliability. o better planning and commitment from Member States on equitable access to medicines based on solidarity.

• To increase strategic autonomy in medicines production, the EU should adopt an industrial strategy to strengthen the

resilience and competitiveness of the manufacturing chain in Europe. The strategy should introduce resilience criteria in procurement, reimbursement and state aid policies and better integrate API in the regulation of medicines. An EU Recovery Fund should provide investment in key value chains crucial for our future resilience, such as the medicines sector. In this context, the EU Green Deal and Digital Transformation can help to boost resilience.

• Measures to stimulate investments in R&D need to be targeted and focused, with clear objectives to be achieved and factor in competition and equitable access policies.

Building resilient supply chains The pandemic had a dramatic impact on demand surges that in some cases doubled or tripled relative to the normal annual consumption of medicines. Clearly no medicine stockpile could have covered these massive demand surges. Therefore, a key lesson of this crisis is the need to support the expansion of existing manufacturing capacity in finished dosage form and active pharmaceutical ingredient (API) during a crisis. This could be achieved with reform of market policies, implementing security of supply into national medicines procurement and purchasing policies, starting with the longawaited Commission guidelines

In the EU, several Member States have put in policies to ensure medicines supply for their own populations. Most national measures targeted parallel exports of medicines due to concerns that speculation could undermine supply.

Since 2013, the use of generic medicines and biosimilars have provided savings of ¤1.6bn to the Irish state. There is further potential to save much more and the members of Medicines for Ireland will continue to work with Government on behalf of patients and their families to ensure a sustained supply for patients in Ireland.

Medicines for Ireland members include: Accord Healthcare, Clonmel Healthcare, Consilient Health, Fannin, Fresenius-Kabi, Mylan, Nasal Medical, Pinewood, Rowa and Teva.

Martin Gallagher, Director of Marketing and Business Development said; Throughout 2018/2019 when planning ahead for 2020, our main concerns were around Brexit and it’s impact on the supply of medicines in Ireland.

The company was working to ensure that we had sufficient stocks to maintain a stable market and continue to grow our business. At that point, we never envisaged a world where frontline workers would take such risks on our behalf, for which we owe them enormous levels of gratitude, where our population would be in lockdown, where the normal way of visiting your GP, hospital or pharmacist would change so dramatically. As a company, when the unprecedented catastrophic crisis of Covid-19 hit, it was extraordinary to see the response of staff and the company aligning itself with the demands placed by the behaviour in the Pharma market, particularly through the month of March.

As one of the largest suppliers of finished packed medicines in Ireland we managed to maintain continuity of supply to our patients, which was achieved by altering work practices so as to align ourselves with the pharmacists and other HCPs. There are key lessons to be learned from this crisis; contingency planning for the unforeseen, open lines of communication with our stakeholders and prioritising agility in the workplace.

SEPTEMBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

Martin Gallagher, Director of Marketing and Business Development, Clonmel

12 News

Student Pharmacists’ experiences of the COVID-19 pandemic Intern Pharmacist Edel Burton and Senior Pharmacist Barry O’Sullivan discuss the impact of Covid 19 on intern placement

fellow Healthcare Professionals, better than we currently provide.

We should always seek to be better at everything we do. Our patients deserve that.

The APPEL placement programme can be a potentially stressful time, away from their peers and familiar surrounds in University; student pharmacists must develop their skills quickly. Adding to this were two significant changes in the planned experiential learning program for Edel. A change in placement provider and a global pandemic were certainly not in the placement training plan drawn up for Edel.

Intern Pharmacist Edel Burton discusses below, the impact of Covid-19 on learning. The APPEL Experiential Learning Placement Programme is a period of discovery, development and decisions. The Pharmacy Class of 2020 will forever be known as the first student pharmacists of the 5-year integrated Masters Programme. I never thought we would also be known as the student pharmacists of the 2020 COVID-19 pandemic.

I started my journey as a student pharmacist on 6th January this year. My experiential learning placement was a split placement between the Mater Private Cork, and McCauley’s Pharmacy, Mahon Point, Cork. This placement was unique, as the pharmacy serviced the Mater Private Cork. Thus I had the benefit of experiencing both the community and hospital settings on a weekly basis.

Queues down the shop and out the door, constant requests for hand sanitizer and worried patients seeking reassurance epitomized the effects of COVID-19 on community pharmacy for me. As a student pharmacist, I strove to follow the example of my Pharmacist colleagues, remaining professional and offering reliably sourced information and advice.

It was a time when I had to rely on every skill, behaviour and

competency I had learned during my pharmacy education. A time when I had to deliver care, empathy and understanding as always, but at a distance.

As of 30th March 2020 the Mater Private Cork opened its own Pharmacy Department. So, my experience of COVID-19 is now only from a hospital perspective. I now wear scrubs and a mask each day on placement, I am in different locations to some of my Pharmacy colleagues and I avoid restricted areas of the hospital. I no longer interact with patients, I fill out a COVID-19 screening form each morning upon entering the hospital and have been trained in the donning and doffing of Personal Protective Equipment.

A lot has changed in how we practice in the last few weeks.

However the Core Competency Framework hasn’t changed, the Code of Conduct hasn’t changed, and my passion for pharmacy certainly hasn’t changed. Patientcentred care is still at the root of pharmacy. As my Senior Preceptor has taught me well; circumstances might change and you might have to adapt your processes, but the rationale, logic and goal behind them remains constant.

The hospital’s patient profile has changed. Pre-COVID it was an acute hospital, with a high turnover, mainly caring for surgical

SEPTEMBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

and cardiac in-patients. Now the Mater Private Cork is accepting patients with a range of conditions, requiring longer term care. That has affected the medications we keep and increased our transfers from other hospitals. I am trained in Basic Life Support, have worked with the Nursing Department to put together folders on critical care medicines for each ward, and am currently completing an online course in Critical Care Medications.

Some elements of my daily routine have been removed and replaced by other tasks, due to the current situation. This is a challenging time for our country and the world we live in. As a student pharmacist it is a challenge, but also a privilege to be able to work in this climate. I have truly seen that regardless of the situation, the health, wellbeing and safety of the patient is always our primary focus.

Preceptor Perspective As a Senior Preceptor, I believe our duty of care to oversee the professional development of the student pharmacist extends past the hours allocated and indeed past the experiential learning time with them. Senior Preceptors need to ensure we are fostering the next generation of Pharmacists to deliver a level of patient care and interdisciplinary support to our

Like her peers, Edel, has been a crucial asset as the pharmacy profession tooled up for whatever COVID-19 may bring. Apart, but together, in their efforts.

During this time of flux and uncertainty, the Pharmacy Department of the Mater Private Cork was born. The transition period saw a lot of planning and an innumerable amount of tasks to be carried out to ensure turbulence between the end of the external contract and commencement of the internal function was kept to a minimum. Edel was central to all this.

Additional to CPD cycles, core competencies and associated study, it was prudent to add one more item to Edel’s daily workload.

We called it her decompression time. Defined down time each day after work where she sets aside the notes and tends to her own well-being. Simple things like a family walk or Zoom with friends can very useful in dissolving the stress of COVID-19, PPE, infection control protocols and so on.

In some ways the current crop of student pharmacists are getting a learning experience far more complex than they could have foreseen at the outset, apart but together, they should be proud of their efforts.

Barry O'Sullivan MPSI MBA Senior Pharmacist, Pharmacy Department, Mater Private Hospital, Cork

FOR YOURSELF, WOULD YOU CONSIDER

BOTH EFFICACY AND SAFETY?

Choose both efficacy and safety with ELIQUIS®

ELIQUIS is a factor Xa inhibitor that offers superior risk reduction in stroke and systemic embolism, with significantly less major bleeding vs. warfarin in non-valvular AF patients.1,* • Superiority demonstrated on stroke / systemic embolism vs. warfarin 1 • Superiority demonstrated on major bleeding vs. warfarin 1 ELIQUIS® (apixaban) 2.5 mg & 5 mg Film-coated Tablets Prescribing Information Consult Summary of Product Characteristics (SmPC) before prescribing PRESENTATION: Film-coated tablets; 5 mg and 2.5 mg apixaban. INDICATION: Prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF) with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA), age ≥ 75 years, hypertension, diabetes mellitus or symptomatic heart failure (NYHA Class ≥ II). Treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE), and prevention of recurrent DVT and PE in adults (see Special warnings and precautions for information on haemodynamically unstable PE patients). Prevention of venous thromboembolic events (VTE) in adults who have undergone elective hip or knee replacement surgery (2.5 mg only). DOSAGE AND ADMINISTRATION: Oral. Taken with water, with or without food. Prevention of stroke and systemic embolism in patients with NVAF: The recommended dose is 5 mg twice a day. In patients who meet at least two of the following criteria: serum creatinine ≥ 1.5 mg/dL (133 micromole/l), age ≥ 80 years, or body weight ≤ 60 kg the recommended dose is Eliquis, 2.5 mg twice daily. Patients with severe renal impairment (creatinine clearance 15-29 ml/min) should receive Eliquis 2.5 mg twice daily. Therapy should be continued long term. Treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt): The recommended dose for the treatment of acute DVT and treatment of PE is 10 mg twice daily for the first 7 days followed by 5 mg twice daily. As per available medical guidelines, short duration of treatment (at least 3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation). The recommended dose for the prevention of recurrent DVT and PE is 2.5 mg twice daily. When prevention of recurrent DVT and PE is indicated, the 2.5 mg twice daily dose should be initiated following completion of 6 months of treatment with Eliquis 5 mg twice daily or with another anticoagulant. The duration of overall therapy should be individualised after careful assessment of the treatment benefit against the risk for bleeding. Prevention of VTE (VTEp): elective hip or knee replacement surgery: The recommended dose is 2.5 mg twice a day. The initial dose should be taken 12 to 24 hours after surgery. Hip replacement surgery, the recommended duration of treatment is 32 to 38 days. Knee replacement surgery, the recommended duration of treatment is 10 to 14 days. Missed Dose for All Indications: If a dose is missed, Eliquis should be taken immediately and then continue with twice daily dose as before. Switching: switching treatment from parenteral anticoagulants to Eliquis (and vice versa) can be done at the next scheduled dose. These medicinal products should not be administered simultaneously. Switching treatment from VKA therapy to Eliquis: warfarin or other VKA therapy should be discontinued and Eliquis started when the international normalized ratio (INR) is < 2. Switching treatment from Eliquis to VKA therapy: administration of Eliquis should be continued for at least 2 days after beginning VKA therapy. After 2 days of co- administration of Eliquis with VKA therapy, an INR should be obtained prior to next scheduled dose of Eliquis. Co-administration of Eliquis and VKA therapy should be continued until the INR is ≥2. Renal impairment: No dose adjustment in mild or moderate renal impairment. Eliquis is to be used with caution in severe renal impairment (creatinine clearance 15-29 mL/min) as there may be an increased risk of bleeding. For the prevention of stroke and systemic embolism in patients with NVAF and severe renal impairment, patients should receive the lower dose of Eliquis 2.5 mg twice daily. Patients with NVAF and serum creatinine ≥ 1.5 mg/dL (133 micromole/L) associated with age ≥ 80 years or body weight ≤ 60 kg should also receive the lower dose of Eliquis 2.5 mg twice daily for stroke/systemic embolism prevention. In patients with creatinine clearance < 15 mL/min, or in patients undergoing dialysis, there is no clinical experience therefore Eliquis is not recommended. Hepatic impairment: Contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Not recommended in patients with severe hepatic impairment. Use with caution in patients with mild or moderate hepatic impairment (Child Pugh A or B). No dose adjustment is required in patients with mild or moderate hepatic impairment. Use with caution in patients with elevated liver enzymes (ALT/AST >2 x ULN) or total bilirubin ≥ 1.5 x ULN. Prior to initiating Eliquis, liver function testing should be performed. Catheter ablation (NVAF): Patients can continue Eliquis use while undergoing catheter ablation. Cardioversion (NVAF): Eliquis can be initiated or continued in NVAF patients who may require cardioversion. See SmPC for further details. Patients with NVAF and acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI): There is limited experience of treatment with apixaban at the recommended dose for NVAF patients when used in combination with antiplatelet agents in patients with ACS and/or undergoing PCI after haemostasis is achieved. See SmPC for further details Paediatric population: Eliquis is not recommended in children and adolescents below the age of 18. CONTRAINDICATIONS: Hypersensitivity to active substance or to excipients, active clinically significant bleeding, hepatic disease associated with coagulopathy and clinically relevant bleeding risk, lesion or condition if considered a significant risk factor for major bleeding, see SmPC for further details. Concomitant treatment with any other anticoagulant agent except under specific circumstances of switching anticoagulant therapy or when unfractionated heparin (UFH) is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation, see SmPC for further details. WARNINGS AND PRECAUTIONS: Haemorrhage risk: Carefully observe for signs of bleeding. Use with caution in conditions with increased risk of haemorrhage. Discontinue administration if severe haemorrhage occurs. An agent to reverse the anti-factor Xa activity of apixaban is available. For information on reversal and managing bleeding, see SmPC for further details. Interaction with other medicinal products affecting haemostasis: Concomitant treatment with any other anticoagulant is contraindicated (see contraindications). Concomitant use of Eliquis with antiplatelet agents increases the risk of bleeding. Care with concomitant SSRIs, SNRIs or NSAIDs, including GPIIb/IIIa receptor antagonists, dipyridamole, dextran or sulfinpyrazone) or thrombolytic agents. As such agents increase the bleeding risk, co-administration of these products with Eliquis is not recommended. See SmPC for further details. Due to an increased bleeding risk, concomitant treatment with any other anticoagulants is contraindicated, except under specific circumstances of switching anticoagulant therapy, when UFH is given at doses necessary to maintain an open central venous or arterial catheter or when UFH is given during catheter ablation for atrial fibrillation. Administration of activated charcoal reduces Eliquis exposure. Also see contraindications and special warnings and precautions section; Consult SmPC (contraindications, special warnings and precautions and drug interactions) for full details on interactions. PREGNANCY AND LACTATION: Pregnancy: Not recommended. Breastfeeding: Discontinue breastfeeding or discontinue Eliquis therapy. UNDESIRABLE EFFECTS: Increased risk of occult or overt bleeding from any tissue or organ, which may result in post haemorrhagic anaemia. The signs, symptoms, and severity will vary according to the location and degree or extent of the bleeding. Frequencies: common (≥ 100/1 to < 10/1); uncommon (≥ 1,000/1 to < 100/1); rare (≥ 10,000/1 to < 1,000/1); very rare (< 1/10,000); not known (cannot be estimated from the available data) Prevention of VTE in adult patients who have undergone elective hip or knee replacement surgery (VTEp): Common: anaemia, haemorrhage, haematoma, nausea, contusion. Uncommon: thrombocytopenia; Hypotension (including procedural hypotension); specific haemorrhage such as gastrointestinal, epistaxis, abnormal vaginal, urogenital, post procedural, incision site, operative; haematochezia.

Liver function test abnormal Rare :hypersensitivity, allergic oedema and anaphylaxis; specific haemorrhage such as eye (including conjunctival), gingival, rectal, muscle; haemoptysis. Prevention of stroke and systemic embolism in adult patients with NVAF, with one or more risk factors (NVAF): Common: anaemia, nausea, specific haemorrhage such as eye (including conjunctival), gastrointestinal, rectal; haemorrhage, haematoma, epistaxis, gingival bleeding, haematuria, contusion, hypotension acetylsalicylic acid. Following surgery, other platelet aggregation inhibitors are not recommended concomitantly with Eliquis.

In patients with atrial fibrillation and conditions that warrant mono or dual antiplatelet therapy, a careful assessment of the potential benefits against the potential risks should be made before combining this therapy with Eliquis. A clinical trial enrolled patients with atrial fibrillation with ACS and/or undergoing PCI and a planned treatment period with a P2Y12 inhibitor, with or without ASA, and oral anticoagulant (either apixaban or VKA) for 6 months. Concomitant use of ASA increased the risk of ISTH (International Society on Thrombosis and Hemostasis) major or CRNM (Clinically Relevant Non-Major) bleeding in apixaban-treated subjects. See SmPC for further details Use of thrombolytic agents for the treatment of acute ischemic stroke: Limited experience. Patients with prosthetic heart valves: safety and efficacy of Eliquis have not been studied in patients with prosthetic heart valves, with or without atrial fibrillation.

Therefore, the use of Eliquis is not recommended in this setting. Patients with antiphospholipid syndrome: Direct acting Oral Anticoagulants (DOACs), including Eliquis, are not recommended for patients with a history of thrombosis who are diagnosed with antiphospholipid syndrome (see SmPC for further details).

Surgery and invasive procedures: Discontinue at least 48 hours prior to elective surgery or invasive procedures with a moderate or high risk of bleeding. Discontinue at least 24 hours prior to elective surgery or invasive procedures with a low risk of bleeding. If surgery or invasive procedures cannot be delayed, appropriate caution should be exercised, taking into consideration an increased risk of bleeding. Eliquis should be restarted after the invasive procedure or surgical intervention as soon as possible provided the clinical situation allows and adequate haemostasis has been established. For patients undergoing catheter ablation for atrial fibrillation, Eliquis treatment does not need to be interrupted. Temporary discontinuation: Discontinuing anticoagulants, including Eliquis, for active bleeding, elective surgery, or invasive procedures places patients at an increased risk of thrombosis. Lapses in therapy should be avoided and if anticoagulation with Eliquis must be temporarily discontinued for any reason, therapy should be restarted as soon as possible. Spinal/epidural anaesthesia or puncture: Patients treated with antithrombotic agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal haematoma which can result in long- term or permanent paralysis. The risk of these events may be increased by the post- operative use of indwelling epidural catheters or the concomitant use of medicinal products affecting haemostasis. Indwelling epidural or intrathecal catheters must be removed at least 5 hours prior to the first dose of Eliquis. The risk may also be increased by traumatic or repeated epidural or spinal puncture. Patients are to be frequently monitored for signs and symptoms of neurological impairment (e.g., numbness or weakness of the legs, bowel or bladder dysfunction). If neurological compromise is noted, urgent diagnosis and treatment is necessary. Prior to neuraxial intervention the physician should consider the potential benefit versus the risk in anticoagulated patients or in patients to be anticoagulated for thromboprophylaxis. There is no clinical experience with the use of Eliquis with indwelling intrathecal or epidural catheters. See SmPC for further details. Haemodynamically unstable PE patients or patients who require thrombolysis or pulmonary embolectomy: Eliquis is not recommended as an alternative to unfractionated heparin in patients with pulmonary embolism who are haemodynamically unstable or may receive thrombolysis or pulmonary embolectomy since the safety and efficacy of Eliquis have not been established. Patients with active cancer: efficacy and safety of Eliquis in the treatment of DVT, treatment of PE and prevention of recurrent DVT and PE (VTEt) in patients with active cancer have not been established. Renal impairment: see dosage and administration section. Elderly patients: increasing age may increase haemorrhagic risk. Also, the co-administration of Eliquis with ASA in elderly patients should be used cautiously because of a potentially higher bleeding risk. Body weight: low body weight (< 60 kg) may increase haemorrhagic risk. Hepatic impairment: see dosage and administration section. Interaction with Inhibitors of CYP3A4 and P-gp: Not recommended with strong inhibitors of both CYP3A4 and P-gp These medicinal products may increase Eliquis exposure by 2-fold or greater in the presence of additional factors that increase Eliquis exposure (e.g. severe renal impairment) see SmPC for further details. Interaction with Inducers of CYP3A4 and P-gp: Eliquis should not be used for the treatment of DVT and PE in patients receiving concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp since efficacy may be compromised. Concomitant systemic treatment with strong inducers of both CYP3A4 and P-gp, Eliquis should be used with caution for the prevention of VTE in elective hip or knee replacement surgery, for the prevention of stroke and systemic embolism in patients with NVAF and for the prevention of recurrent DVT and PE, though no dose adjustment for Eliquis is required during concomitant therapy with such medicinal products. Hip fracture surgery: Eliquis has not been studied in clinical trials in patients undergoing hip fracture surgery. Therefore, it is not recommended in these patients. Laboratory parameters: Clotting tests (PT, INR, and aPTT) are affected by the mechanism of action of apixaban. Changes observed at the expected therapeutic dose are small and subject to a high degree of variability, see SmPC for further details. Information about excipients: Eliquis contains lactose. Patients with galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take Eliquis. DRUG INTERACTIONS: Eliquis should be used with caution when co-administered with SSRIs/SNRIs, NSAIDs, ASA and/or P2Y12 inhibitors because these medicinal products typically increase the bleeding risk. There is limited experience of co-administration with other platelet aggregation inhibitors (such as (including procedural hypotension); Gamma-glutamyltransferase increased. Uncommon: hypersensitivity, allergic oedema and anaphylaxis; specific haemorrhage such as brain, intracranial, intraspinal, intra-abdominal, abnormal vaginal, urogenital, mouth, haemorrhoidal, traumatic, post procedural, incision site; haemoptysis, haematochezia, thrombocytopenia, Liver function test abnormal. Rare: specific haemorrhage such as respiratory tract, retroperitoneal. Treatment of DVT and PE, and prevention of recurrent DVT and PE (VTEt): Common: anaemia, nausea, skin rash, haemorrhage, haematoma, epistaxis; specific haemorrhage such as mouth, gastrointestinal, rectal; gingival bleeding, haematuria, abnormal vaginal, urogenital, contusion, gamma-glutamyltransferase increased, alanine aminotransferase increased; thrombocytopenia. Uncommon: Hypersensitivity, allergic oedema and Anaphylaxis, specific haemorrhage such as eye (including conjunctival), haemorrhoidal, traumatic, post procedural, incision site; haemoptysis, muscle, haematochezia, Liver function test abnormal. Rare: specific haemorrhage such as brain, intracranial, intraspinal, respiratory tract. Refer to SmPC for all other adverse events, including other types of haemorrhage. LEGAL CATEGORY: POM. MARKETING AUTHORISATION NUMBER: EU/1/11/691/002-3, EU/1/11/691/008, EU/1/11/691/014 PACKAGE QUANTITIES: Carton of 20 film-coated tablets 2.5 mg, 60 film-coated tablets 2.5 mg, 56 film-coated tablets 5 mg, 28 film- coated tablets 5 mg. MARKETING AUTHORISATION HOLDER: Bristol-Myers Squibb/Pfizer EEIG LOCAL REPRESENTATIVE IN IRELAND: Bristol-Myers Squibb Pharmaceuticals uc, Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland.. Tel: 01 483 3625 DATE OF LAST REVISION: March 2020 ADDITIONAL INFORMATION AVAILABLE ON REQUEST Mercury Internal Ref. no: 432IE2002206-01

Adverse events should be reported. Reporting forms and information can be found at: Ireland - via HPRA Pharmacovigilance at www.hpra.ie Adverse events should also be reported to Bristol Myers Squibb via medical.information@bms.com or 1 800 749 749 (Ireland)

*with one or more risk factors, such as prior stroke or transient ischaemic attack (TIA); age≥ 75 years; hypertension; diabetes mellitus; symptomatic heart failure (NYHA Class ≥ II) AF = Atrial Fibrillation. Reference: 1. Granger CB et al. N Engl J Med 2011; 365: 981–992.

Date of approval: June 2020 Job code: PP-ELI-EUR-1046; PP-ELI-IRL-0418 www.eliquis.ie

14 Perspectives Answering Ireland’s call - Pharmacists on the Frontlines Pharmacist, Neassa Judge, MPSI

Hospital Pharmacist Neassa Judge, MPSI recently signed up to the ‘Be on Call for Ireland’ initiative. Here, she give Hospital Professional News readers an overview of her experience.

Like many others, my plans for 2020 were thrown out the window when the COVID-19 pandemic hit.

Watching the news of Italy was harrowing, and as a healthcare professional I knew I wanted to stay in Ireland to help our health service during the unprecedented times ahead. I first heard about the HSE’s ‘Be On Call for Ireland’ initiative on the radio and immediately signed up online, eager to help in any way I could.

A few weeks later I was contacted and asked to start a pharmacist role in Midlands Regional Hospital Tullamore (MRHT) to support the pharmacy team there, who were under pressure due to the pandemic.

Working in a hospital pharmacy was a first for me. I qualified as a pharmacist back in 2016 and have worked across multiple community pharmacies and with a large pharmaceutical company in Dublin since. Moving into a hospital environment for the first time, especially during a global pandemic, was a daunting experience. However, to the

credit of the pharmacy team in MRHT, it was so worthwhile both professionally and personally.

The pharmacy team in MRHT are an incredibly supportive team and I learned so much during my time there. Despite being an extremely challenging and emotive time, there was such a great team spirit and I was inspired by how agile and hard-working the team were. Along with getting used to increased hygiene measures and the correct donning of PPE, my main learnings heading into a hospital environment were: 1) I had a lot of learning to do! Working in community pharmacy you rarely come across IV antibiotics doses, therapeutic drug monitoring requirements or IV fluid management so there were a number of areas that required upskilling/further education when starting in the hospital.

It was great to see increased availability of free online learning modules during the pandemic and there was a wealth of educational courses available online to upskill. I found the ASHP’s Critical Care pharmacy course particularly useful.

2) Access to patient information allows pharmacists to make more clinically significant

SEPTEMBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

interventions. Working in a community setting you rarely have access to a patient’s medical history, let alone their bloods to calculate hepatic or renal function. Having access to this information makes a huge difference in your clinical conversations and ability to optimise medication therapy.

3) There’s still some work to do on raising awareness on the role of the pharmacist. I think the COVID-19 pandemic has emphasised the importance of working together as multidisciplinary teams, sharing experience and knowledge to enhance patient care. One of the biggest challenges faced during the pandemic was the lack of clinical guidelines or experience on how to treat patients and this required a real team effort. No one profession could tackle it on their own. We all had to try to keep abreast with new clinical developments and information on COVID-19 coming out daily. I believe this has helped raise awareness on the value pharmacists add to the multidisciplinary team.

Pharmacists, as medication experts, have an important role to play on the frontlines, offering advice and information, and helping to optimise medication therapy.

"Despite being an extremely challenging and emotive time, there was such a great team spirit and I was inspired by how agile and hard-working the team were" 4) Sourcing and ensuring adequate supply of medicines are critical tasks faced during this pandemic, in the midst of national and international shortages. These shortages aren’t a new phenomenon, however there has been a significant worsening in recent times due to the pandemic and bulk-buying of medicines.

Pharmacists have an extremely important role to play in managing these shortages and obtaining alternatives.

Reflecting on my experience in the hospital, it was such a great learning and I feel grateful to have had the opportunity. I hope more pharmacists do get the opportunity to gain experience in the hospital environment and I hope to see it become an obligatory placement during the undergraduate degree, similar to other countries. Both community and hospital pharmacists can learn a huge amount from each other and I believe more information sharing between roles will bring our profession a lot further.

02-07-2017

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16 Stroke

Let's get straight to the POINT7, are you keeping up with the changing landscape of secondary cardiovascular prevention in stroke?

Dr. Darragh T. O'Sullivan MB BCh, Dr. Paul Cotter MB BCh MPhil MD

A 74 year-old lady is BIBA, after waking with a new, right sided leg and arm weakness. Her NIHSS is deemed to be 3. The CT brain is unremarkable. The CT angiogram shows no large vessel occlusion. She was not on anti-thrombotics. What course of action would you pursue?

A. Give 300mg Aspirin, then admit to stroke unit for stroke work up B. Thrombolyse (Once contraindications ruled out), and discuss Thrombectomy with the nearest referral service C. Give 300mg of Aspirin and clopidogrel (clopidogrel to continue for 3 months). Then, admit to stroke unit for stroke work up D. Urgent echo to assess for possible source, and call the on call consultant

I have to admit that I find secondary prevention in stroke challenging. One of the major reasons being that there is currently a dizzying pace of research in this sector, and the resultant evolution of antithrombotic treatments, is one that can be mind boggling. Stroke management is like a minefield, but one where they move the mines every couple of years to prevent familiarity. I graduated less than a handful of years ago, and already, my notes on this topic are redundant. I enjoy keeping up with evidence and reading about trials that change management, but it can be difficult to erase previous knowledge as new research comes to light. With that in mind, I was keen to try and summarise recent information, raise some awareness, and hopefully provide some transparency, to the increasingly opaque window of best management following stroke.

It is frequently stated that it takes an average of seventeen years for research to reach clinical practice.

This time lag has been estimated by authors such as Grant et al1, and Balas and Boren2. Such convergence around an 'average' time lag of seventeen years does hide complexities found in

policy and practice3. However, I maintain a cautious optimism that modern technology has somewhat compressed this number since the writing of these articles (most recent in 2011). It is also mutually beneficial to believe that we will have a grasp on this year's clinical practice breakthroughs before 2037. Before we look into the recent research, I feel it most pertinent to cast an eye back to one of the cornerstones of current management. It is twenty three years since the release of two groundbreaking trials, that proved the efficacy and safety of aspirin in secondary prevention of stroke the international stroke trial (IST)4, and the chinese acute stroke trial (CAST)5. These were trials that involved almost 40,000 patients between them.

• The IST demonstrated that aspirin-allocated patients had significantly fewer recurrent ischaemic strokes within fourteen days of stroke onset, with no significant excess of haemorrhagic strokes, meaning a significant reduction in overall death or nonfatal stroke4.

• The CAST demonstrated a significant proportional reduction in mortality during the four

SEPTEMBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

week treatment period, as well as a significant reduction in recurrent ischaemic stroke. It also demonstrated an absolute difference in death or dependency, in favour of aspirin, which fell short. Thus, the die was CAST (pun intended). Ever since these trials, anti-platelet agents have become a focal point for research in stroke. History lesson aside, let's move forward to recent times.

A vastly changed landscape, but one where the thrombosishaemorrhage spectrum continues to be coerced into surrender.

There are several recent trials worthy of mention, and rather than simply break them down, I have created a quiz in the form of a multiple choice questionnaire (MCQ) associated with clinical vignettes. This was done with a view to putting the clinical practice-changing points into a hypothetical scenario, and explaining the associated evidence afterwards. After all, as with many crafts, we learn most from our mistakes. Some of the notable recent trials such as CHANCE, POINT, NAVIGATE ESUS, and RESTART have formed the basis for the questions. If you would like to avoid the spoilers, then now is the time to run through the MCQ, before reading onwards.

2. A 82 year old lady presents following an episode of Left sided weakness, which lasted 30 minutes. CT Head is unremarkable. This is deemed to have been a TIA. She s hypertensive and has type 2 diabetes. How would you manage this on admission?

A. Start aspirin with a loading dose, and a plan to switch to clopidogrel after 2 weeks. Investigate for a cause and optimise risk factors (BP and diabetes) B. Start aspirin and clopidogrel, with loading doses. Plan to continue DAPT at maintenance doses for 3 months, before stopping aspirin. Investigate for a cause and optimise risk factors C. Progress to CT angiography before commencing anti-platelets.

Arrange investigations for cause, and optimise risk factors D. Await consultation review on the post take round, before addressing anti-platelet strategy 3. An 80 year old gentleman presents following an episode of slurred speech, and facial droop, which lasted 15 minutes.

He has recently had a full work up for TIAs, which revealed a 50% right carotid stenosis. He was commenced on clopidogrel at that time. He is also known to have hypertension. What would your plan be?

A: Reassure that all investigations have been performed, refer him for carotid assessment by a vascular surgeon, and arrange and ambulatory blood pressure monitor

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Confidence, Convenience, Compliance Abbreviated Prescribing Information Please refer to the Summary of Product Characteristics (SmPC) before prescribing Pelgraz▼(pegfilgrastim) 6 mg solution for injection in pre-filled injector.

Presentation: Each 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 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. Granulocyte-colony 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

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reduction or withdrawal of filgrastim and pegfilgrastim. Urinalysis monitoring is recommended. Capillary leak syndrome has been reported after G-CSF administration and is characterised by hypotension, hypoalbuminaemia, oedema and haemoconcentration. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care. Generally asymptomatic cases of splenomegaly and cases of splenic rupture, including some fatal cases, have been reported following administration of pegfilgrastim. Spleen size should be carefully monitored (e.g. clinical examination, ultrasound). A diagnosis of splenic rupture should be considered in patients reporting left upper abdominal pain or shoulder tip pain. Treatment with pegfilgrastim alone does not preclude thrombocytopenia and anaemia because full dose myelosuppressive chemotherapy is maintained on the prescribed schedule.

Regular monitoring of platelet count and haematocrit is recommended. Special care should be taken when administering single or combination chemotherapeutic medicinal products which are known to cause severe thrombocytopenia. 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 x 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 x 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 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

Oncology & Haematology

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. This medicinal product contains 50 mg sorbitol in each unit volume, which is equivalent to 30 mg per 6 mg dose. Pelgraz contains less than 1 mmol (23 mg) sodium 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: Sickle cell crisis, capillary leak syndrome, glomerulonephritis, hypersensitivity reactions (including angioedema, dyspnoea, anaphylaxis), splenic rupture (including some fatal cases), Sweet’s syndrome (acute febrile 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 injector with one alcohol swab, in a blistered packaging. Marketing Authorisation Number: 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-UK Ltd. via E-mail: medinfo@accord-healthcare.com or Tel: +44(0)1271385257.

Date of Generation of API December 2019. IE-01454

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

May 2020. IE-01429

18 Stroke B: Add aspirin, for 3 months, and continue clopidogrel. Refer to the vascular surgeons for assessment, and book an ambulatory blood pressure monitor.

C: Admit for a repeat full work up, switch his anti-platelet agent to aspirin, and optimise blood pressure D: Switch his anti-platelet agent to an anticoagulant, optimise blood pressure and refer to the vascular surgeons 4. A 72 year old gentleman presents with acute onset of vertigo, and unilateral limb ataxia. His NIHSS is 5. CT shows nil acute. MRI reveals a cerebellar infarct. He had been on aspirin due to IHD. He has a stroke work up. His LDL is 3.2 and his BP has averaged 154/92 throughout admission. What would you do?

A: Focus on the risk factors, by reducing LDL to 2.3 and blood pressure to 140/90 B: Add clopidogrel, continuing DAPT for 3 months. Reduce LDL to 1.8 and blood pressure to 140/90 C: Focus on risk factors by reducing LDL to 1.8, and blood pressure down to at least 140/90.

Consider a switch of aspirin to clopidogrel after 2 weeks D: Commence a PSK9 inhibitor, and address blood pressure 5. A 69 year old lady presents with right sided weakness, homonymous hemianopia, and sensory loss. CT angiography shows a large vessel occlusion. She is transferred for thrombectomy (outside thrombolysis window). She returns after successful clot retrieval, and you admit her in the stroke unit. She was not on anti-thrombotics. What is your approach?

A: Commence aspirin, with a loading dose, and book post-stroke investigations B: Commence dual anti-platelet agents with loading doses, and book post-stroke investigations C: Book post-stroke investigations, and await repeat CT head before making a decision regarding antiplatelet agents D: Book post-stroke investigations, make patient nil by mouth, and await swallow assessment before making a decision on anti-platelet agents 6. A 72 year old gentleman, who had a STEMI with PCI 3 weeks ago, now presents with slurred speech, and right sided weakness. He is not for thrombolysis or thrombectomy. On a repeat CT the next day, a modest amount of haemorrhage is noted in the area of his stroke. He had been on DAPT since the time of his MI.

What would you do?

A: Hold the anti-platelets, and book for a repeat CT to assess the evolution of haemorrhage B: Continue the aspirin but hold the second anti-platelet agent, and plan for an interval CT to assess evolution C: Continue DAPT, as the risk of stent thrombosis poses the greatest risk, and plan to repeat the CT D: Switch to prophylactic LMWH, and book a repeat CT scan 7. A 75 year old lady, with poorly-controlled hypertension, presents following a collapse, with confusion, dysarthria and headache. CT confirms an intracerebral haemorrhage. She had been taking aspirin, which was started during a spell of unstable angina. What would you do with her aspirin?

A: Hold the aspirin for at least 24 hours, but with a plan to restart it again during the first week of her admission, provided she remains stable clinically and radiologically B: Stop the aspirin, as the risk of haemorrhage now outweighs the benefit associated C: Perform interval CT scans until the haemorrhage has resolved, then review the patient to discuss risk and benefit of recommencing treatment D: Continue the aspirin, with close monitoring of the patient 8. A 77 year old gentleman presents with a left brachiofacial weakness, and left sided neglect.

CT angiography shows a right branch MCA occlusion. He is admitted for a stroke work up.

No cause is identified, so it is classified as an embolic stroke of unknown significance (ESUS).

With what regimen would you send him home?

A: A dingle antiplatelet agent, as we have not identified an indication for anticoagulation B: A DOAC, as atrial fibrillation is the most common cause of embolic stroke (even if it was not picked up on 48 hours of telemetry) C: Continue to investigate, by referring for a loop recorder, with a single anti-platelet agent being employed as treatment D: Dual anti-platelet agents for 3 months, followed by a single agent indefinitely 9. Finally, how good is aspirin in acute stroke? (Based on a study in a Chinese population, in the 1990s) A: 12% proportional risk reduction of death or non-fatal stroke, in the 4 weeks following initial stroke B: 1.1% absolute reduction in death or dependency at discharge C: Reduction of recurrent ischaemic stroke in the 4 weeks after initial stroke, by 0.5% D: All of the above

SEPTEMBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

There is an established trend whereby treatments found to be successful in myocardial infarction then undergo trials as a treatment in stroke. Simply put, there is common ground in the treatment principles. In fact, the CAST directly referred to the effectiveness of aspirin in myocardial infarction, in it's very first sentence, in the article published in the Lancet. This was the driver for the CAST. Later, another Chinese trial, called ''Clopidogrel with aspirin in acute minor stroke or transient ischaemic attack (CHANCE)'' was released in 2013. It concluded that among patients with transient ischaemic attack (TIA) or minor stroke, the combination of clopidogrel and aspirin was superior to aspirin alone for the first ninety days, without increasing the risk of haemorrhage6. This was progress, but could the same be applied to a medical brand that adopts a more western approach, and in a non-asian population. Cue the 2018 trial called ''clopidogrel and aspirin in acute ischaemic stroke and high risk TIA (POINT)''.

This trial took place across ten countries including North America, Europe, New Zealand, and Australia. This provided the conclusive evidence that dual therapy with clopidogrel and aspirin leads to less ischaemic events, at the expense of a small increase in haemorrhagic events7.

As a practitioner, what do I need to take into practice from these trials? I often find that after I read an impressive trial, I take note of the result, but can forget to break down the qualifying criteria. I would like to elaborate.

Firstly, it should be noted that Clopidogrel was given at a loading dose of 600mg, before following on with maintenance doses of 75mg. Meanwhile, Aspirin was more loosely controlled with initial dosing allowed to range from 50mg to 325mg (due to international dosing differences). Both agents were to be commenced ''as soon as possible''. Beyond pharmacology, they qualified stroke as minor, and the TIAs as high risk. They defined a minor stroke as a National institute of health stroke scale (NIHSS) score of no more than 3.

Meanwhile, a high-risk TIA, was considered to be a TIA with an ABCD2 score of at least 4. One could assume that they deduced haemorrhage risk to be too high above an NIHSS of 3, and similarly, haemorrhage risk to outweigh benefit below an ABCD2 score of less than 4. Finally, this treatment should continue for three months, before de-escalation to a single anti-platelet agent. This

pair of trials were the key points required for questions one to three of the MCQ. Moving on from anti-platelet therapy, what about the role of anticoagulation? We know that atrial fibrillation is the most common cause of embolic stroke, and if we identify this arrhythmia during a stroke work up, we treat with anticoagulation. However, embolic strokes of undetermined significance (ESUS) represent 20% of embolic strokes, which prompted a trial known as the NAVIGATE ESUS trial8, published in 2018. This investigated whether anticoagulation with Rivaroxaban would result in a lower risk of recurrent stroke than aspirin, in the context of an embolic stroke, with no identified cause. There was a simple answer here - no, it was not. Patients had a higher risk of bleeding without any added benefit over aspirin. A second similar trial, called RE-SPECT ESUS9, attempted a similar model using Dabigatran, and yielded similar results. Thus, antiplatelet agents remain the standard of care in ESUS. This trial formed the basis for question eight in the MCQ. By now, we've addressed some of the recent developments in stroke secondary prevention, all of which, involve anti-thrombotic strategies. However, as we apply these strategies, and steepen the workload required for thrombosis, haemorrhage becomes a more prominent feature of treatment.

Once we encounter a major haemorrhagic event, what then tips the scales of risk-benefit.

Thanks to our neighbours across the Irish sea, we have some robust evidence to hang our hat on, namely, the RESTART trial10. They looked at patients on anticoagulation or anti-platelet treatments for the prevention of occlusive vascular disease, who experienced an intracerebral haemorrhage (ICH). As part of the inclusion criteria, these patients had to survive, and have had their preventative medication stopped.

They then either restarted anti-platelet therapy (at a median of seventy six days) or stopped their treatment. Unsurprisingly, they found that the restart group had less ischaemic stroke, and less major occlusive vascular events. However, rather surprisingly, they found that the restart group also had lower rates of haemorrhage. All results fell short of significance, with the primary outcome of recurrent symptomatic spontaneous ICH occurred in 4% of the restart group versus 9% of the stop group (p=0.057)9. This trial should certainly provide confidence in our

RESPIRATORY OBESITY

ELDERLY

CARDIAC

WHEN CONTROL OF NMB REVERSAL IS WHAT MATTERS

BRIDION INDICATIONS • Reversal of rocuronium (ROC) or vecuronium (VEC) induced neuromuscular block (NMB) in adults.

• For routine reversal of ROC-induced block in children and adolescents aged 2 to 17 years.1 investigated in patients receiving ROC or VEC in the ICU setting. Do not use sugammadex to reverse block induced by nonsteroidal blockers such as succinylcholine or benzylisoquinolinium compounds, or steroidal blockers other than ROC or VEC. Conditions associated with prolonged circulation time such as cardiovascular disease, old age, or oedematous state may cause longer recovery times. Be prepared for possible drug hypersensitivity reactions. This medicinal product contains up to 9.7 mg sodium per ml, equivalent to 0.5 % of the WHO recommended maximum daily intake of 2 g sodium for an adult. OVERDOSE No dose related adverse events nor serious adverse events were reported. Sugammadex can be removed using haemodialysis with a high flux filter. INTERACTIONS Toremifene and fusidic acid may displace rocuronium or vecuronium from sugammadex and delay recovery (no clinically relevant capturing interactions are expected). Interaction of sugammadex with hormonal contraceptives may lead to a decrease in progesterone exposure equivalent to one missed daily dose of oral contraceptive (no displacement interactions are expected). In general sugammadex does not interfere with laboratory tests, with the possible exception of the serum progesterone assay where interference is observed at sugammadex plasma concentrations of 100 μg/ml plasma. In a study doses of 4 mg/kg and 16 mg/kg sugammadex resulted in maximum mean prolongations of the activated partial thromboplastin time by 17 and 22% respectively and prothrombin time by 11% and 22% respectively. These were of short duration (≤ 30 minutes). In in vitro experiments pharmacodynamic interaction was noted with vitamin K antagonists, unfractionated heparin, low molecular weight heparinoids, rivaroxaban and dabigatran. PREGNANCY AND LACTATION Pregnancy and Lactation: Caution in pregnant women. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from sugammadex therapy, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman. The effects on human fertility have not been investigated. SIDE EFFECTS Refer to SmPC for complete information on side effects. Common (≥ 1/100 to < 1/10): Anaesthetic complications including movement of limbs or body or coughing during anaesthesia, grimacing, or suckling on the endotracheal tube, airway complication of anaesthesia, procedural hypertension and procedural complication. Uncommon (≥ 1/1,000 to < 1/100): Hypersensitivity reactions, including anaphylaxis, have occurred in some patients and volunteers. Other less common and rarely reported side effects are listed in the SmPC. In clinical studies with subjects treated with rocuronium or vecuronium, where sugammadex was administered using a dose labelled for the depth of neuromuscular blockade, an incidence of 0.2% was observed for recurrence of neuromuscular blockade as based on neuromuscular monitoring or clinical evidence. The use of lower than recommended doses may lead to an increased risk of recurrence of neuromuscular blockade after initial reversal and is not recommended. HANDLING See SmPC for details of compatability with infusion solutions. Physical incompatibility has been reported with verapamil, ondansetron and ranitidine. PACKAGE QUANTITIES 10 vials of 2 ml, 10 vials of 5 ml.

LEGAL CATEGORY POM. Marketing Authorisation Numbers EU/1/08/466/001-002. Marketing Authorisation Holder Merck Sharp & Dohme B.V., Waarderweg 39, 2031 BN Haarlem, The Netherlands. Date of review of prescribing information: April 2020. © Merck Sharp and Dohme B.V., 2020. All rights reserved. Further information is available on request from: MSD, Red Oak North, South County Business Park, Leopardstown, Dublin 18 or from www.medicines.ie. Date of preparation: July 2020. EMEA/H/C/000885/II/0036.

Reference: 1. Bridion SPC April 2020

PREDICTABLE. COMPLETE. RAPID.

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: 01-299 8700)

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

IE-XBR-00032

BRIDION® 100 MG/ML SOLUTION FOR INJECTION (Sugammadex) ABRIDGED PRODUCT INFORMATION Refer to Summary of Product Characteristics (SmPC) before prescribing. PRESENTATION Vials of 200mg (2 ml) or 500mg (5 ml). INDICATIONS Reversal of rocuronium (ROC) or vecuronium (VEC) induced neuromuscular (NM) block in adults. For routine reversal of ROC-induced block in children and adolescents aged 2 to 17 years. DOSAGE AND ADMINISTRATION I.V. as a single bolus injection administered rapidly (within 10 seconds), into an existing I.V. line, by/under the supervision of an anaesthetist. Use appropriate technique to monitor recovery of NM block. Dose depends on the level of block to be reversed, not the anaesthetic regimen. Adults: Routine reversal following ROC- or VEC-induced block: • 4 mg/kg if recovery has reached at least 1-2 post-tetanic counts (PTC). Median recovery time (T4/T1 = 0.9) ≅ 3 minutes. • 2 mg/kg if recovery has occurred up to at least T2 following ROC- or VEC-induced block. Median recovery time (T4/T1 = 0.9) ≅ 2 minutes. Median recovery time (T4/T1= 0.9) is slightly faster with ROC- than VEC-induced block. Immediate reversal of ROC-induced block: 16 mg/kg. Median recovery time (T4/T1 = 0.9) ≅ 1.5 minutes when 16 mg/kg is given 3 minutes after a bolus dose of 1.2 mg/kg ROC. Not recommended for immediate reversal of VEC-induced block.

Re-administration of sugammadex: For post-operative recurrence of block after an initial dose of 2 mg/kg or 4 mg/kg, repeat dose of 4 mg/kg is recommended. Following a second dose of sugammadex, monitor the patient closely to ascertain sustained return of neuromuscular function. Re-administration of ROC or VEC after sugammadex: Up to 4 mg/kg Sugammadex a waiting time of 5 minutes for re-use of 1.2 mg/kg ROC; 4 hours waiting time for re-use of 0.6 mg/kg ROC or 0.1 mg/kg VEC. With ROC onset of NM block may be prolonged and duration of NM block may shortened. After immediate reversal, 16 mg/kg sugammadex, a waiting time of 24 hours is recommended. See SPC for patients with mild or moderate renal impairment. Special populations: Renal impairment: For mild and moderate renal impairment use adult dose. Not recommended in severe renal impairment (including patients requiring dialysis). Elderly: Use adult dose although recovery times are slower. Obese: In obese patients, including morbidly obese patients (body mass index ≥ 40 kg/m2), adult dose based on actual body weight. Hepatic impairment: Caution in patients with severe hepatic impairment, or impairment with coagulopathy. Children and adolescents (2-17 years): 2 mg/kg for routine reversal of ROC-induced block at T2. Not recommended in other routine reversal situations. Not recommended for Immediate reversal. May be diluted for accuracy of dose. Term newborn infants and infants: Not recommended. CONTRA-INDICATIONS Hypersensitivity to sugammadex or to any excipients. PRECAUTIONS AND WARNINGS Ventilatory support is mandatory for patients until adequate spontaneous respiration is restored following reversal of block. Should block reoccur following extubation, adequate ventilation should be provided. The use of lower than recommended doses may lead to an increased risk of neuromuscular blockade after an initial reversal and is not recommended. Caution should be exercised when considering the use of sugammadex in patients receiving anticoagulation for a pre-existing or co-morbid condition. An increased risk of bleeding cannot be excluded in patients with hereditary vitamin K dependent clotting factor deficiencies; with pre-existing coagulopathies; on coumarin derivatives and at an INR above 3.5; using coagulants who receive a dose of 16mg/ kg sugammadex. If re-administration of ROC or VEC is required in patients with mild or moderate renal impairment after routine sugammadex reversal a waiting time for re-use of 0.6 mg/kg ROC or 0.1 mg/kg VEC should be 24 hours. If a shorter waiting time is required, the ROC dose for a new NM blockade should be 1.2 mg/kg within 30 minutes after Sugammadex administration. For re-administration of ROC or VEC after immediate reversal a waiting time of 24 hours is recommended. If neuromuscular block is required before the recommended waiting time has passed, a nonsteroidal neuromuscular blocking agent should be used. The use in patients with severe renal impairment is not recommended including those requiring dialysis. If neuromuscular block is reversed, while anaesthesia is continued, additional doses of anaesthetic and/or opioid should be given as clinically indicated. Marked bradycardia with cardiac arrest have been observed within minutes after administration, closely monitor patients for hemodynamic changes during and after reversal. Treat with anti-cholinergic agents such as atropine if clinically significant bradycardia observed. Sugammadex has not been

20 Stroke ability to turn to a patient, and say, yes, you should restart treatment at a later stage.

using dual anti-platelet therapy.

These include the SAMMPRIS12, CARESSS13, and CLAIR14 trials.

The MCQ comprised questions based on the trials above, along with a number of questions on fundamental stroke care. It was an exercise to test some colleagues, but also to find out if recent trials have made their way into practice. As of writing, a sample of twenty eight had taken the MCQ, comprising a majority of medical senior house officers, along with a few registrars and interns. Let's have a look at the answers:

• Question four was included for two reasons. Firstly, for those aware of the POINT, this question was there to highlight that an NIHSS above three is an exclusion criterion for it's application.

Secondly, this question was there to break up the questions based on recent research, and focus on established standards of care. The main point here is that identifying and aggresively addressing risk factors is paramount. Beyond that, this patient should remain on a single antiplatelet agent.

Hence, the answer is C, which accounted for 50% of the vote.

Peculiarly, 46% opted for dual anti-platelet therapy.

• Question one was a vignette which puts the POINT into practice. This patient has an NIHSS of three, which is on the upper limit of the criterion set out in their study. This question was put in with the intent of highlighting that minor stroke, based on most recent evidence, should now be managed with a three month course of dual antiplatelets. The answer is C. The answers returned by those partaking had an almost 2:1 split, with 32% answering correct, and 68% choosing to administer 300mg aspirin (answer A).

• Question two was another vignette which embodied a clinical scenario designed to bring the POINT into practice. This lady had a TIA, with a couple of risk factors added to her presentation, which were there to highlight that this was a high risk TIA, with an ABCD2 score of 6, and an associated 90-day stroke risk of 17.8%11. The answer here was B, opting to start dual anti-platelet therapy for a three month period.

18% got this question correct, suggesting that knowledge of this trial is not widespread. 61% opted to load with aspirin, with the rest opting to wait for further investigations, or consultant input.

• Question three was a third and final vignette, used to demonstrate a change in clinical practice relating to the POINT. Patients with recurrent TIAs are a vulnerable group that can be overlooked, as they are already on treatment, and have had their work up. Again, this is a high risk TIA, with an ABCD2 score of 4, meaning a 9.8% 90-day stroke risk. This patient should also have been commenced on dual antiplatelet therapy for three months i.e.

Answer B. This was answered correctly by 39%, which was the leading answer, although no option got less than 14%. Moreover, in the context of carotid stenosis, there are actually several other trials, which I have not addressed, which have shown a benefit in

• Question five was to delineate practice around antiplatelet use post thrombectomy. This one is slightly unfair, as definitive evidence is lacking. What seems to be common practice is to await the 24 hour repeat CT before commencing aspirin. However, one study looked at patients who were treated with antithrombotics before thrombectomy, and showed reduced intracerebral haemorrhage and mortality favouring the group treated with antithrombotics15.

39% chose to administer the aspirin here, while 35% chose to await the CT. I'll leave this one open.

• Question six is one that relates to evidence from the field of cardiology. This patient is on dual antiplatelet therapy following PCI, and has a modest haemorrhagic transformation. The answer here is to continue the current regimen i.e.

Answer C. If clopidogrel is stopped before the one year mark in a patient who has had a drug-eluting stent placed, there is a 30-fold increase in stent thrombosis.

If clopidogrel is stopped in the first month, >25% suffer stent thrombosis, which carries a 25-40% mortality rate caused by the resultant acute myocardial infarction16. 18% chose option C, while answer B received the most votes at 46%, opting to hold the second anti-platelet agent and re-scan.

• Question seven was an attempt to create a scenario pertaining to the RESTART. This lady has had an intracerebral haemorrhage. The RESTART had several sub groups based on when treatment was recommenced, with patients having similar treatment effect when started early, versus when started late. It suggested that further studies should be performed to assess benefit of

SEPTEMBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

early commencement of therapy, as the results suggested that the risk of recurrence of ICH is low10. The only available answer where the aspirin was stopped and then definitively restarted was answer A, making this the correct choice, based on current evidence.

This accounted for 36% of the partaking opinion.

2020];369:11-19. Available from: http:// www.nejm.org/doi/full/10.1056/NEJMoa1215340

• Question eight was a working example of a case relevant to the aforementioned NAVIGATE ESUS. This patient has had an ESUS. The take home point being that anticoagulation is not superior to aspirin as a preventative. Given the presentation, the NIHSS has to be >3, so dual anti-platelet therapy is also ruled out. This means that C is the correct answer, which consumed 68% of the voting.

8. Hart R, Sharma M, Mundl H, Kasner S. Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source. New England Journal of Medicine [Internet]. 2018;379(10):986-987.

Available from: https://www.nejm.org/ doi/full/10.1056/nejmoa1802686

• Finally, question nine. This contains some of the findings from the CAST, which laid the foundations for decades of research to follow. The correct answer was D, which was chosen by 82%.

I would like to thank all those who could spare their time to contribute to the quiz. It is an interesting, if small, insight into where we are with current practice.

I hope you have taken a nugget or two of information that can be assimilated into your practice.

In the meantime, the research will continue at a thunderous pace, and we will continue to lag behind, but hopefully by less than seventeen years!

References: 1. Grant J, Green L, Mason B. Basic research and health: a reassessment of the scientific basis for the support of biomedical science. Research Evaluation. 2003;12(3):217-224.

2. Balas E, Boren S. Managing Clinical Knowledge for Health Care Improvement. Yearbook of Medical Informatics.

2000;09(01):65-70.

3. Morris Z, Wooding S, Grant J. The answer is 17 years, what is the question: understanding time lags in translational research. Journal of the Royal Society of Medicine. 2011;104(12):510520.

4. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19 435 patients with acute ischaemic stroke. The Lancet.

1997;349(9065):1569-1581 5. Chen Z. CAST: randomised placebo-controlled trial of early aspirin use in 20 000 patients with acute ischaemic stroke. The Lancet.

1997;349(9066):1641-1649.

6. Wang Y, Wang Y, Zhao X. Clopidogrel with Aspirin in Acute Minor Stroke or Transient Ischemic Attack.

New England journal of medicine [Internet]. 2013 [cited 6 August

7. Johnston S, Easton J, Farrant M, Barsan W, Conwit R, Elm J et al.

Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA. New England Journal of Medicine [Internet].

2018 [cited 6 August 2020];379(3):215225. Available from: https://www.nejm. org/doi/full/10.1056/nejmoa1800410

9. Diener H, Sacco R, Easton J, Granger C, Bernstein R. Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined source. New England Journal of Medicine [Internet]. 2020 [cited 7 August 2020];(380):1906-1917.

Available from: https://www.nejm.org/ doi/full/10.1056/NEJMoa1813959 10. Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): A randomised, openlabel trial. The Lancet [Internet]. 2019 [cited 6 August 2020];393(10191):26132623. Available from: https://www. thelancet.com/journals/lancet/article/ PIIS0140-6736(19)30840-2/fulltext 11. ABCD² Score for TIA - MDCalc [Internet]. Mdcalc.com. 2020 [cited 6 August 2020]. Available from: https:// www.mdcalc.com/abcd2-scoretia#evidence 12. Turan TN, Nizam A, Lynn MJ, Egan BM, Le NA, Lopes-Virella MF, et al. Relationship between risk factor control and vascular events in the SAMMPRIS trial. Neurology. 2017;88(4):379–385. doi: 10.1212/WNL.0000000000003534.

13. Markus HS, Droste DW, Kaps M, Larrue V, Lees K, Siebler M, et al. Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using Doppler embolic signal detection: the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial. Circulation. 2005;111(17):2233–2240. doi: 10.1161/01.CIR.0000163561.90680.1C. 14. Wong KS, Chen C, Fu J, Chang HM, Suwanwela NC, Huang YN, et al.

Clopidogrel plus aspirin versus aspirin alone for reducing embolisation in patients with acute symptomatic cerebral or carotid artery stenosis (CLAIR study): a randomised, open-label, blinded-endpoint trial. Lancet Neurol.

2010;9(5):489–497. doi: 10.1016/ S1474-4422(10)70060-0 15. Pandhi A, Tsivgoulis G, Krishnan R, Ishfaq MF, Singh S, Hoit D, et al.

Antiplatelet pretreatment and outcomes following mechanical thrombectomy for emergent large vessel occlusion strokes. J Neurointerv Surg.

2018;10:828–833. doi:10.1136/neurintsurg-2017-013532 16. Weaver J. Caution: Maintain Anti-platelet therapy in patients with coronary artery stents. Anaesthesia Progress. 2007. Winter; 54(4):161-162. doi:10.2344/00033006(2007)54[161:CMATIP]2.0.CO;2

News 21 AXIS announces details of its Virtual Market Access Masterclass September 18th and 23rd 2020 AXIS Consulting has announced details of its forthcoming Market Access Masterclass which this year takes place as a virtual meeting held over two separate days, September 18th and 23rd 2020 from 9am-12.15pm.

The AXIS Market Access Masterclass will review the reimbursement process for Orphan and Oncology medicines as well as submissions to BeNeLuxA. This not to be missed event will integrate key insights from over 21 years of experience in Market Access in Ireland with important, relevant perspectives from a number of high-profile guest speakers.

Announcing the event Brenda Dooley, CEO, AXIS Consulting said, “This masterclass is an excellent opportunity to gain an in-depth, up to date understanding of the Irish reimbursement process. We will also be advising on how to avoid common submission pitfalls and we will share case studies on successful reimbursement applications in Ireland.

Full details on our excellent speaker line up will be announced next week.”

Recognised as the leading knowledge broker on the Irish reimbursement pathway for many

Brenda Dooley, Chief Executive Officer, AXIS Consulting years with over 75+ completed submissions to the Irish authorities, AXIS Consulting provides a range of services to support reimbursement submissions in Ireland including local expert elicitation, systematic literature reviews, health technology assessments and evidence generation.

Previous masterclass participants have attested to the valuable insights and highquality content delivered. “The AXIS team knew the Irish Market Access Landscape inside out – this is an essential masterclass to attend & I would thoroughly recommend it to other industry colleagues.” (Participant, AXIS Masterclass, March 2020).

The fee for attendance at the Market Access Masterclass on September 18th - 23rd is ¤495 inclusive of VAT. Bookings can now be made directly at www.axisconsulting.ie.

AXIS Consulting is an Irish company formed in 2012 with registered offices in Baggot Street, Dublin and directly employs a team of health economists and statisticians with plans to expand the team further in the months ahead.

HOSPITALPROFESSIONALNEWS.IE | HPN • SEPTEMBER 2020

22 News Hospital deliver over 36,000 virtual outpatient consultations Clinical teams at Galway University Hospitals have delivered over 36,000 virtual outpatient consultations since the beginning of the COVID-19 pandemic.

Dr Yvonne Smyth, Consultant Cardiologist at University Hospital Galway says, “The cardiology outpatient service in University Hospital Galway is an extremely busy one; we see 9,500 patients each year. Prior to the onset on COVID-19 this involved up to seven clinics per week, with up to 50 patients attending each clinic. From the middle of March this year, as the rate of COVID-19 in Ireland rapidly increased, it quickly became clear that it would not be possible to run our cardiology outpatient clinics as we traditionally had. In addition to the unacceptable risk of having large numbers of patients waiting in close proximity, we were also very conscious of the profile of our cardiology patients, many of whom were older and had other underlying health conditions that made it necessary for them to cocoon. Some of our patients require the support of a family

member or friend to physically attend their appointment, further increasing the number of people at the clinic.

“All of these issues made it particularly important for us to quickly find an alternative way of delivering our outpatient cardiology service. We began initially with telephone consultations and later included video consults; to date we have delivered 3,800 virtual cardiology outpatient appointments. All of our patients adapted quickly to the technology and found the opportunity to link with us, despite COVID-19, very reassuring.

“Of course, if we felt at any time that a patient needed to be seen in person, we made arrangements to do that and all the necessary infection prevention and control measures were taken. Our outpatient cardiac diagnostic service has resumed and patients attend in person for cardiac investigations including ECHO and stress testing.

“It is also important to note that emergency cardiology continued

Dr Yvonne Smyth, Consultant Cardiologist, University Hospital Galway 24/7 throughout this period and we continue to urge patients not to delay seeking medical

help if they experience chest pain or other symptoms of a heart attack.”

PMI – VOICE OF PHARMA SERIES The newest series from the Pharmaceutical Managers’ Institute will give 3 industry experts 120 minutes to discuss a particular topic including the opportunity for attendees to pose questions to the panel. The PMI will be hosting these sessions online initially in line with Covid19 policy to protect their members.

The first session takes place on September 10th, where speakers will be discussing how “How Innovation is Disrupting the Delivery of Healthcare” – this was particularly highlighted during the Covid19 pandemic this year with increased collaboration between Stakeholders and the entire healthcare industry.

Speakers include Professor Derek O’Keeffe, Consultant Endocrinologist at University Hospital Galway and Professor of Medical Device Technology at NUI Galway; Professor Martin Curley, Director of the Digital Academy & Open Innovation, HSE and Dr Frank O’Donnell, Public Sector Lead, Microsoft.

For further information visit https://www.thepmi.com/events/voices-of-pharma-series/

Bon Secours Golf Society The Bon Secours Hospital Tralee golf society enjoyed their first 3 ball scramble of the year which was held in Ballyheigue Castle Golf Club on Saturday the 25th of June.

• 1st prize winners: Kathleen Finnegan/Kathryn Walsh/ Tim Walsh/Brendan Walsh.

• 2nd prize winners: Conor Clifford/James Baily/ Damian Whyte.

• 3rd prize winners: Gerry Redican/Sean O’ Connell/ Olivia Fitzgerald

SEPTEMBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

CPD 68: MS - NOW A TREATABLE CONDITION? Continuing Professional Development

CPD

23

AUTHORS: Dr. Laura Kennelly - Neurology SHO in St. Vincent’s University Hospital Professor Niall Tubridy - Consultant Neurologist in St. Vincent’s University Hospital

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

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

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

If the answer is yes, I should identify any knowledge gaps in the clinical area.

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

Have I identified further learning needs?

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.

MS - Now A Treatable Condition?

Multiple sclerosis (MS) is a chronic, likely immune-mediated disease of the central nervous system (CNS), affecting both the brain and spinal cord. It is a complex neurodegenerative disease, characterised by the presence of inflammation, axonal degeneration and multifocal, demyelinating plaques. For many patients it ultimately results in high levels of functional impairment and disability as the disease progresses, with 50% of patients requiring assistance with walking within 15 years.1 Although there is no national register it is estimated that there are 9000

Although MS can present at any age, it most typically presents in adults aged 20-40 years. Women are more frequently affected than men by at least a 2:1 ratio.

Individuals of Northern European descent have also been found to be more likely to be affected than other ethnicities.3 The clinical presentation of MS is extremely variable. Commonly, patients initially present following a subacute neurological occurrence affecting the CNS, known as a

RRMS

PPMS

SPMS

Time

Fig 1: Types of MS https://www.nationalmssociety.org/ What-is-MS/Types-of-MS

people in Ireland and 2.5 million people worldwide, living with this condition.2

clinically isolated syndrome (CIS).

It is the first clinical presentation of a disease that shows characteristics of inflammatory demyelination, that may or may not progress to a diagnosis of MS.4 Clinical presentations are many and varied, depending on the area of the brain affected.

They may include upper and lower limb dysfunction, visual disturbances, balance and coordination problems, spasticity, altered sensation, abnormal speech, swallowing disorders, fatigue, bladder and bowel problems, sexual dysfunction, cognitive issues and emotional disturbances.5 Optic neuritis (inflammation of the optic nerve),

Presentation:

Disability

Disability

Multiple sclerosis (MS) is a complex neurodegenerative disease of the central nervous system (CNS), affecting both the brain and spinal cord. For many patients, it may ultimately still result in high levels of functional impairment and disability as the disease progresses. However, fantastic developments have been made in a once untreatable condition.

In this article, we offer a background to MS and explore some of the treatment options now available.

Introduction:

Disability

60 Second Summary

Relapse

Time Active (relapse or new MRI activity) with progression

RRMS

Time

Active without worsening

Not active without progression (stable)

Active (relapse or new MRI activity) with progression

Worsening (incomplete recovery from release)

Not active with progression

Active (relapse or MRI activity) without progression

Stable without activity

Active without progression

New MRI activity

New MRI activity

Not active with progression Not active without progression (stable) New MRI activity

HOSPITALPROFESSIONALNEWS.IE | HPN • SEPTEMBER 2020

Fig 2: Current DMT’s in MS

24

Fig 2: Current DMT’s in MS

CPD 68: MS - NOW A TREATABLE CONDITION? Drug: Drug:

Fig 2: Current DMT’s in MS

1st Line

2nd Line 3rd Line

Beta interferons (Ia/Ib), glatiramer acetate, dimethyl fumarate Beta interferons (Ia/Ib), glatiramer acetate, dimethyl fumarate Natalizumab, ocralizumab, rituximab, fingolimod, cladribine Natalizumab, ocralizumab, rituximab, fingolimod, cladribine Alemtuzumab

3rd Line

Alemtuzumab

1st Line 2nd Line

Uhthoff's phenomenon (worsening of MS symptoms with a rise in body temperature, for example, following exercise) and Lhermitte's phenomenon (an electric-shock like sensation down the spine or limbs on neck flexion) are characteristic of MS. Clinical signs and symptoms may have resolved by the time they are seen by a medical professional, resulting in a normal neurological examination.

This highlights the importance of taking a thorough and detailed medical history. However, a CIS (without corresponding radiological or CSF findings) is not enough to make a diagnosis of MS, as per the Revised McDonald Criteria, as it does not fulfil the criteria of lesions disseminated in time (DIT).

Pathology and risk factors: Inflammatory changes of the CNS are the primary causes of damage in MS. Genetic and environmental factors, including exposure to infectious agents, are thought to influence susceptibility.6,7 Environmental factors such as lack of sunlight exposure/vitamin D, cigarette smoking and exposure to infectious agents (EBV, HHV 6) are all thought to be associated with an increased risk of developing MS. Observational studies have suggested that the level of serum vitamin D can influence the risk of developing MS and modify disease activity in MS patients.

MS patients who smoke cigarettes have also been shown to have higher rates of disease activity, faster rates of brain atrophy and a greater overall disability burden.

Smoking has also been associated with limiting the effectiveness of disease modifying drugs and can increase the risk of developing co-morbidities. As such, smoking cessation and vitamin D supplementation (2000 iu/day) are recommended for all patients with MS.8,9,10

Classification: MS can be classified into four different phenotypes as described by the International Advisory Committee on Clinical Trials of MS - clinically isolated syndrome, relapsing remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS). The majority (85%) of patients are diagnosed with relapsing remitting multiple sclerosis (RRMS), which is characterised by clearly defined episodes of new or worsened symptoms (relapse), followed by intervals of partial or complete recovery (remission). It can be further classified as being active (with relapses and/or evidence of new findings on MRI) or not active, as well as worsening (increasing disability following a relapse) or not worsening. Secondary progressive multiple sclerosis (SPMS) follows an initial relapsingremitting course in which relapse is not followed by complete recovery and there is gradual accumulation in disability as a result of worsening neurologic function. As with RRMS, it can be classified as either active or inactive as well as ‘with progression’ (disability increased over time, with or without relapses or new MRI activity) or ‘without progression’.

Primary progressive MS (PPMS) features worsening neurological function and therefore disability from the onset of symptoms.

It does not feature episodes of relapse or remission.11 Although not an official classification of MS, radiologically isolated syndrome (RIS) has been used to classify patients with lesions on MRI consistent with MS. These patients may have neurological signs or symptoms not typical of MS and have MRI scans for another reason (e.g. post head trauma). These individuals

SEPTEMBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

may or may not go on to develop MS but close monitoring of neurological signs and symptoms is recommended. One third (34%) of patients with an RIS have been found to develop a first acute clinical event consistent with a clinically isolated syndrome of MS within 5 years.12 Diagnosis: The differential diagnoses to consider include neuromyelitis optica (anti-aquaporin 4), myelin oligodendrocyte glycoprotein related demyelination (anti-MOG), Sjogren’s syndrome (anti-Ro, anti-La), sarcoidosis (serum ACE), systemic lupus erythematous (ANA) and Lyme disease (Borrelia burgdorferi), all of which may present with symptoms similar to MS. The diagnostic criteria for MS are the Revised McDonald Criteria, most recently updated in 2017.13 They consist of a combination of clinical, para-clinical and radiological features, intended to gather evidence data consistent with the disease, while out ruling other potential causes not consistent with MS.3 The criteria support diagnosis on the basis of clinical and radiological evidence (spatial and temporal dispersion of MRI lesions), meaning that many people previously considered to have a first clinical episode (known as clinically isolated syndrome or CIS) can now be diagnosed with MS following an MRI. A diagnosis of MS requires that lesions are ‘disseminated in time and space’.

This refers to the occurrence of at least 2 episodes of neurological dysfunction reflecting distinct sites of CNS damage that cannot be explained by any other mechanisms.14 MRI scans show high sensitivity for detection of focal white matter lesions in the CNS and specifically for lesions disseminated in time and space.

MS lesions are generally best appreciated on T2-weighted (T2W)

and fluid-attenuated inversion recovery (FLAIR) sequences.

Dissemination in space is fulfilled by the presence of 1 or more T2 hyper-intense lesions characteristic of MS in 2 of 4 characteristic anatomic locations (periventricular, pericallosal, juxtacortical or infratentorial).

Dissemination in time can be demonstrated by a new T2 hyper- intense or gadolinium (Gd) enhancing lesion when compared to an initial baseline MRI scan or simultaneous presence of Gd enhancing and Gd non-enhancing lesions at follow-up MRI examination.

Dawson’s fingers are a relatively specific radiological sign for MS. They consist of periventricular demyelinating plaques found perpendicular to the corpus callosum. The diagnosis of MS can be further reinforced by other paraclinical data. This includes the presence of prolonged visual evoked response latency and cerebrospinal fluid (CSF) analysis for the presence of unmatched oligoclonal IgG bands.15 Management: The management of MS is complex and evolving and should be approached with a biopsychosocial framework in mind. The principle management strategy is three-fold.

1. Symptomatic treatment 2. Acute relapse management 3. Disease modifying treatment (DMT) Appropriate management aims to reduce the frequency and severity of relapses, slow the progression of the disease and manage symptoms, in order to maximise a patient's quality of life. Interventions should aim to alleviate the symptoms while also minimising the risk of side effects from the medical management of

Fig 3: MS lesions on MRI: Sagittal FLAIR

25 Fig 3: MS lesions on MRI: Sagittal FLAIR

Dawson's Fingers Juxtacortical lesion

MS. A multimodal, interdisciplinary approach is imperative for the most effective management of patients with MS on an inpatient, outpatient and community basis.

A major factor to consider when establishing a management plan is the patient's level of impairment as assessed by the Expanded Disability Status Scale (EDSS).

Specialist nurses, occupational therapists, physiotherapists, speech and language therapists, neuropsychologists, pharmacists, dieticians, medical social workers, neurorehabilitation physicians and psychiatrists all imperative for holistic patient care. This is particularly true of patients with advanced MS, who’s need for assistance in many activities of daily living (ADL’s) is greater and increasingly more complex. The main goal is to support patients to control their symptoms, preserve their functional ability and ultimately maximise their independence and quality of life.

Symptomatic management can be achieved via pharmacological and non-pharmacological means.

This could include management of a patient's pain, spasticity, bladder and bowel dysfunction, fatigue, swallow, vision, sexual dysfunction, cognition and neuropsychiatric symptoms among others The management of an acute relapse of MS most commonly involves the use of high dose corticosteroids (1g methylprednisolone for 3-5 days).

High dose steroids have been shown to decrease recovery time from acute attacks but do not alter the progression of the disease.8

Recent trials have shown noninferiority of oral vs intravenous high dose methylprednisolone.

Alternatives, such as IVIG and plasma exchange should be considered for patients who are not suitable candidates for corticosteroid therapy or if the relapse is particularly aggressive.16 Disease modifying treatments (DMT’s) are licensed for use in Ireland particularly for people with Relapsing Remitting Multiple Sclerosis. The overall aim of DMT’s is to reduce the number and severity of relapses, and hopefully delay the progression of functional disability and slow the speed at which it happens. Efficacy, route of administration and side effect profile varies among products. The decision to commence a DMT is often guided by the frequency of clinical relapses, MRI radiological activity and disability level.

More effective treatments tend to have more serious potential side effects. These side effects can range minor (mild allergic reactions) to major (Progressive Multifocal Leukoencephalopathy [PML]). DMT’s are commonly used in an ‘escalation’ manner, starting with less efficacious but potentially safer therapy, moving up the treatment ladder if there is treatment failure (clinical relapses or new lesions on MRI). Alternatively, an induction method can be used, where drugs with high efficacy are used earlier in the course of the disease, to potentially prevent functional decline. Current advice is to start treatment early, before the development of significant disability, in order to optimise

long term outcomes. The decision to switch between agents is dependent on both clinical and radiological criteria.17 DMT’s are generally broadly divided into 3 categories, based on their decrease in the annualised relapse rate (ARR). First line DMT’s (beta interferons (Ia/Ib), glatiramer acetate, dimethyl fumarate) are associated with a reduction in ARR of 30-40%, while second line DMT’s (natalizumab, fingolimod, cladribine, ocralizumab and rituximab) are associated with a reduction, on average, of 5070%. Third line options such as alemtuzumab are associated with a 60-70% decrease in relapse rate. Data from prospective observational studies suggest that the use of DMT’s is associated with a reduced risk of conversion to secondary progressive MS, particularly with fingolimod, alemtuzumab or natalizumab, compared with no DMT use.18 Careful consideration is necessary when choosing the most appropriate treatment for a patient, balancing efficacy with side effect profile. Interferon beta products (Avonex, Rebif, Betaferon) are the most common first line DMT's with glatiramer acetate (Copaxone) and dimethylfumarate (Tecfidera) other popular options. Second line options include natalizumab (Tysabari), fingolimod (Gilenya), ocrelizumab (Ocrevus) and rituximab (Rituxan).

Natalizumab is a popular and effective choice for patients with active relapsing and remitting MS. It is a monoclonal antibody directed against α4 integrin and

limits the entry of mononuclear cells into the central nervous system. In clinical trials, it has been shown to reduce the progression of the disabling effects of MS by approximately half and decreased the number of MS relapses by two thirds (66%).19 The recommended treatment schedule is 300mg IV infusions at 4-6 week intervals.

All patients are screening for JC virus (JCV) antibodies prior to commencing on natalizumab, due to the potential risk of developing natalizumab-associated PML, which can lead to severe disability or death. The estimated incidence of PML in anti-JCV antibody negative patients is 1/10,000.20 In JCV positive patients, the risk of developing PML is also dependent on immunosuppressant drugs taken in the past, the length of time taking natalizumab (risk increases if patient has been taking Tysabari for >24 months) and the patients JCV antibody titre. Patients who had anti–JCV antibody titres >1.5 units, had taken immunosuppressants before the initiation of natalizumab therapy, and had received 25 to 48 months of natalizumab treatment had the highest estimated risk to 11.1/1000.21 To reduce this risk of natalizumab associated PML, retrospective studies have shown that switching to extended interval dosing (EID) from standard interval dosing (SID) is associated with clinically and statistically significantly lower PML risk, without loss of effectiveness. In practice, this means increasing the gap between natalizumab infusions from four to six weeks.22 PML has also been associated with ocrelizumab, rituximab,

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26

CPD 68: MS - NOW A TREATABLE CONDITION? 8. Doshi, A. and Chataway, J., 2017. Multiple sclerosis, a treatable disease. Clinical Medicine, 17(6), pp.530-536.

9. Sintzel, M., Rametta, M. and Reder, A., 2017. Vitamin D and Multiple Sclerosis: A Comprehensive Review. Neurology and Therapy, 7(1), pp.59-85.

10. Rosso, M. and Chitnis, T., 2020.

Association Between Cigarette Smoking and Multiple Sclerosis.

JAMA Neurology, 77(2), p.245.

11. National Multiple Sclerosis Society. 2020. Types Of MS. [online] Available at: <https://www.nationalmssociety. org/What-is-MS/Types-of-MS> [Accessed 30 July 2020].

dimethyl fumarate and fingolimod, but the risk is primarily an issue with natalizumab treatment.23 Such is the efficacy of modern DMT’s, disease remission has become an increasingly attainable target in MS treatment. The phrase No Evidence of Disease Activity (NEDA), has been used to describe same, using both clinical and radiological parameters (without evidence of relapses, disability progression or new T2 lesions on MRI). Guidelines for MRI protocols used to monitor patients in clinical practice have recommended the use of brain T2-weighted MRI, which reveals subclinical active (new and enlarging) lesions.24 Although not currently offered in Ireland, autologous haematopoietic stem cell transplantation (AHSCT) is a treatment option that may be offered to a very select group of patients in certain UK centres.

Irish patients may be referred should they fulfil certain strict criteria. These patients often have a very aggressive form of MS or a refractory to at least 2 DMT’s.

Follow up: Regular MRI scanning (6 months to 1 year) for those on DMT or people with relapsing remitting MS who are not receiving a DMT is advisable. If new MRI activity is seen, then treatment should be escalated or initiated if not already started. Suboptimal responses to treatment should prompt further discussion about changes in treatment regime.25 Conclusion: MS is a complex neurodegenerative condition.

Remarkable developments have been made in a once untreatable condition. Although

there is currently no cure, there are multiple treatment options now available and many more in development for the future.

References: 1. Ebers, G., 2020. The Natural History Of Multiple Sclerosis: A Geographically Based Study: 8: Familial Multiple Sclerosis.

2. Ms-society.ie. 2020. [online] Available at: <https://www.mssociety.ie/sites/default/files/2019-06/ MS%20Ireland%20-%20 Societal%20Cost%20of%20MS%20 in%20Ireland%202015cc.pdf> [Accessed 30 July 2020].

3. DiPiro, J., Talbert, R., Yee, G., Matzke, G., Wells, B., Posey, L., Streetman, D. and Streetman, D., 2009. Book Review: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition. Annals of Pharmacotherapy, 43(2), pp.395-395.

4. Miller, D., Barkhof, F., Montalban, X., Thompson, A. and Filippi, M., 2005. Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis. The Lancet Neurology, 4(5), pp.281-288.

5. Msif.org. 2020. [online] Available at: <https://www.msif.org/wpcontent/uploads/2014/09/Global_ economic_impact_of_MS.pdf> [Accessed 30 July 2020].

6. Loma, I. and Heyman, R., 2011.

Multiple Sclerosis: Pathogenesis and Treatment. Current Neuropharmacology, 9(3), pp.409-416.

7. Barcellos, L., Oksenberg, J., Begovich, A., Martin, E., Schmidt, S., Vittinghoff, E., Goodin, D., Pelletier, D., Lincoln, R., Bucher, P., Swerdlin, A., Pericak-Vance, M., Haines, J. and Hauser, S., 2003. HLA-DR2 Dose Effect on Susceptibility to Multiple Sclerosis and Influence on Disease Course. The American Journal of Human Genetics, 72(3), pp.710-716.

SEPTEMBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

12. Okuda, D., Siva, A., Kantarci, O., Inglese, M., Katz, I., Tutuncu, M., Keegan, B., Donlon, S., Hua, L., Vidal-Jordana, A., Montalban, X., Rovira, A., Tintoré, M., Amato, M., Brochet, B., de Seze, J., Brassat, D., Vermersch, P., De Stefano, N., Sormani, M., Pelletier, D. and Lebrun, C., 2014. Radiologically Isolated Syndrome: 5-Year Risk for an Initial Clinical Event. PLoS ONE, 9(3), p.e90509.

13. Carroll, W., 2018. 2017 McDonald MS diagnostic criteria: Evidencebased revisions. Multiple Sclerosis Journal, 24(2), pp.92-95.

14. Goldenberg, Marvin M. “Multiple sclerosis review.”

P & T : a peer-reviewed journal for formulary management vol. 37,3 (2012): 175-84.

15. Giorgio, A. and De Stefano, N., 2018. Effective Utilization of MRI in the Diagnosis and Management of Multiple Sclerosis. Neurologic Clinics, 36(1), pp.27-34.

16. Le Page, E., Veillard, D., Laplaud, D., Hamonic, S., Wardi, R., Lebrun, C., Zagnoli, F., Wiertlewski, S., Deburghgraeve, V., Coustans, M. and Edan, G., 2015. Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial.

The Lancet, 386(9997), pp.974-981.

17. Scolding, N., Barnes, D., Cader, S., Chataway, J., Chaudhuri, A., Coles, A., Giovannoni, G., Miller, D., Rashid, W., Schmierer, K., Shehu, A., Silber, E., Young, C. and Zajicek, J., 2015. Association of British Neurologists: revised (2015) guidelines for prescribing diseasemodifying treatments in multiple sclerosis. Practical Neurology, 15(4), pp.273-279.

18. Brown, J., Coles, A., Horakova, D., Havrdova, E., Izquierdo, G., Prat, A., Girard, M., Duquette, P., Trojano, M., Lugaresi, A., Bergamaschi, R., Grammond, P., Alroughani, R.,

Hupperts, R., McCombe, P., Van Pesch, V., Sola, P., Ferraro, D., Grand'Maison, F., Terzi, M., LechnerScott, J., Flechter, S., Slee, M., Shaygannejad, V., Pucci, E., Granella, F., Jokubaitis, V., Willis, M., Rice, C., Scolding, N., Wilkins, A., Pearson, O., Ziemssen, T., Hutchinson, M., Harding, K., Jones, J., McGuigan, C., Butzkueven, H., Kalincik, T. and Robertson, N., 2019. Association of Initial Disease-Modifying Therapy With Later Conversion to Secondary Progressive Multiple Sclerosis.

JAMA, 321(2), p.175.

19. Ms-society.ie. 2020. [online] Available at: <https://www.mssociety.ie/sites/default/files/2019-06/ MS%20Ireland%20Tysabri%20 Information%20Sheet%20-%20 Feb%202015.pdf> [Accessed 30 July 2020].

20. Tysabrihcp.com. 2020.

Monitoring For PML Symptoms While On TYSABRI® (Natalizumab). [online] Available at: <https://www. tysabrihcp.com/en_us/home/ efficacy-safety/pml-risk.html> [Accessed 30 July 2020].

21. Bloomgren, G., Richman, S., Hotermans, C., Subramanyam, M., Goelz, S., Natarajan, A., Lee, S., Plavina, T., Scanlon, J., Sandrock, A. and Bozic, C., 2012. Risk of Natalizumab-Associated Progressive Multifocal Leukoencephalopathy.

New England Journal of Medicine, 366(20), pp.1870-1880.

22. Ryerson, L., Foley, J., Chang, I., Kister, I., Cutter, G., Metzger, R., Goldberg, J., Li, X., Riddle, E., Smirnakis, K., Kasliwal, R., Ren, Z., Hotermans, C., Ho, P. and Campbell, N., 2019. Risk of natalizumabassociated PML in patients with MS is reduced with extended interval dosing. Neurology, pp.10.1212/ WNL.0000000000008243.

23. Ho, P., Koendgen, H., Campbell, N., Haddock, B., Richman, S. and Chang, I., 2017. Risk of natalizumabassociated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: a retrospective analysis of data from four clinical studies. The Lancet Neurology, 16(11), pp.925-933.

24. Agiela, M., 2014. Effect of natalizumab on clinical/radiological disease activity and EDSS of relapsing remitting multiple sclerosis patients. Multiple Sclerosis and Related Disorders, 3(6), p.755.

25. Traboulsee A, Simon JH, Stone L, et al. Revised Recommendations of the Consortium of MS Centers Task Force for a Standardized MRI Protocol and Clinical Guidelines for the Diagnosis and Follow-Up of Multiple Sclerosis. AJNR Am J Neuroradiol. 2016;37(3):394-401. doi:10.3174/ajnr.A4539

Latanoprost 50 micrograms/ml + Timolol 5 mg/ml eye drops, solution in single-dose container

The first PRESERVATIVE-FREE

Latanoprost/Timolol fixed combination

• Non-inferior IOP reduction to BAK-preserved latanoprost/timolol fixed combination1 • Superior tolerability to BAK-preserved latanoprost/timolol fixed combination1 • The next option in the treatment pathway for Monopost® patients • The next option for preserved latanoprost/ timolol intolerance

Fixapost 50 micrograms/ml + 5 mg/ml eye drops, solution in single-dose container. Please refer to Summary of Product Characteristics (SmPC) before prescribing. Additional information available on request. Presentation and active ingredients: Box of 6 sachets (30 pack) each containing 5 single-dose containers (LDPE) containing 0.2 ml of eye drops. 1 ml eye drops solution contains 50 micrograms of latanoprost, 5 mg of timolol and 50 mg of macrogolglycerol hydroxystearate 40 (castor oil polyoxyl hydrogenated). Indication: Reduction of intraocular pressure (IOP) in adult and elderly patients with open angle glaucoma and ocular hypertension who are insufficiently responsive to topical beta-blockers or prostaglandin analogues. Posology and Method of Administration: Adults (including the elderly): One drop in the affected eye(s) once daily. Do not exceed this dose. Use immediately after opening the single-dose container and discard any remaining contents after use. Remove contact lenses before instillation and reinsert after 15 minutes. Punctal occlusion for two minutes immediately after instillation can reduce possible systemic absorption. Paediatric population: No data are available. Administer topical ophthalmic medicines at least five minutes apart. Contra-indications: Known hypersensitivity to any ingredient. Reactive airway disease including bronchial asthma or history of bronchial asthma, severe chronic obstructive pulmonary disease. Sinus bradycardia, sick sinus syndrome, sino-atrial block, second- or third-degree atrioventricular block not controlled with pace-maker, overt cardiac failure, cardiogenic shock. Warnings and Precautions: Cardiac disorders: Therapy with beta-blockers in patients with cardiovascular diseases (e.g. coronary heart disease, Prinzmetal’s angina and cardiac failure) and hypotension should be critically assessed and consider therapy with other active substances. Watch patients with cardiovascular diseases for signs of deterioration and for adverse reactions. Due to the negative effect on conduction time, only give beta-blockers with caution to patients with first degree heart block.

Cardiac reactions and, rarely, death in association with cardiac failures have been reported following timolol administration. Vascular disorders: Treat with caution in patients with severe peripheral circulatory disturbance/disorders (severe forms of Raynaud’s disease or Raynaud’s syndrome). Respiratory disorders: Respiratory reactions, including death due to bronchospasm in patients with asthma have been reported following administration of some ophthalmic beta-blockers. Use FIXAPOST with caution in patients with mild/moderate chronic obstructive pulmonary disease (COPD), and only if the benefit outweighs the risk. Hypoglycaemia/diabetes: Beta-blockers may mask the signs and symptoms of acute hypoglycaemia so use with caution in patients subject to spontaneous hypoglycaemia or in patients with labile diabetes. Hyperthyroidism: Beta-blockers may mask the signs of hyperthyroidism. Corneal diseases: Ophthalmic beta-blockers may induce dryness of eyes. Use with caution in patients with corneal diseases. Other beta-blockers: Effect on intra-ocular pressure or of systemic beta-blockade may be potentiated when timolol is given to patients already receiving a systemic beta-blocking agent. Closely observe the response of these patients. Concomitant therapy: Timolol may interact with other drugs. Other prostaglandin analogues: Concomitant use of two or more prostaglandins, prostaglandin analogues, or prostaglandin derivatives is not recommended. Anaphylactic reactions: While taking beta-blockers, patients with a history of atopy or of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge with such allergens and unresponsive to the usual doses of adrenaline used to treat anaphylactic reactions. Choroidal detachment: Has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide) after filtration procedures. Surgical anaesthesia: Beta-blocking ophthalmic preparations may block systemic beta-agonist effects e.g. of adrenaline. Inform the anaesthetist when the patient is receiving timolol. Iris pigmentation changes: Latanoprost may gradually change eye colour by increasing the amount of brown pigment in the iris, predominantly in patients with mixed coloured irides, i.e. green-brown, yellow-brown or blue/grey-brown. The change has only rarely been seen in patients with homogeneously blue, grey, green or brown eyes. Change in iris colour occurs slowly and has not been associated with any symptom or pathological changes. The resultant colour change may be permanent. Neither naevi nor freckles of the iris have been affected by the treatment. Examine patients regularly and consider stopping treatment if increased iris pigmentation ensues. Before treatment is instituted patients should be informed of the possibility of a change in eye colour. Unilateral treatment can result in permanent heterochromia. Eyelid and eyelash changes: Eyelid skin darkening, which may be reversible, has been reported. Latanoprost may gradually change eyelashes and vellus hair in the treated eye; these changes include increased length, thickness, pigmentation, and number of lashes or hairs, and misdirected growth of eyelashes, and are reversible when treatment is discontinued. Glaucoma: There is no documented experience with latanoprost in inflammatory, neovascular or chronic angle closure glaucoma, in open angle glaucoma of pseudophakic patients, in pigmentary glaucoma or in acute attacks of closed angle glaucoma. Latanoprost has no or little effect on the pupil. Use FIXAPOST with caution in these conditions. Herpetic keratitis: Use with caution in patients with a history of herpetic keratitis and avoid in cases of active herpes simplex keratitis and in patients with a history of recurrent herpetic keratitis specifically associated with prostaglandin analogues. Macular oedema: Macular oedema, including cystoid macular oedema, has been reported during treatment with latanoprost, mainly in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular oedema. Use FIXAPOST with caution in these patients. Excipients: FIXAPOST contains macrogolglycerol hydroxystearate (castor oil polyoxyl hydrogenated) which may cause skin reactions. Pregnancy: Do not use FIXAPOST during pregnancy. Lactation: Do not use or stop breast feeding. Fertility: No effect on fertility in animal studies. Driving and Using Machines: Minor influence. Do not drive or use machines until vision is clear. Interactions: Please refer to Summary of Product Characteristics (SmPC) Undesirable Effects: FIXAPOST is absorbed systemically and the same types of cardiovascular, pulmonary and other adverse reactions as seen with systemic beta-adrenergic blocking agents may occur. Incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. Most latanoprost ocular adverse events are generally transient and occur on dose administration. For timolol, the most serious adverse reactions are systemic in nature, including bradycardia, arrhythmia, congestive heart failure, bronchospasm and allergic reactions. Treatment related adverse reactions seen in clinical trials with the combined latanoprost/timolol preserved reference product are: Very common: Iris hyperpigmentation. Common: eye pain, eye irritation (including stinging, burning, itching, foreign body sensation). Uncommon: Corneal disorders, conjunctivitis, blepharitis, eye hyperaemia, vision blurred, lacrimation increased, headache, rash, pruritus. Please refer to Summary of Product Characteristics (SmPC) for active-specific adverse reactions. Overdose: No data are available in humans. Symptoms of systemic timolol overdose are: bradycardia, hypotension, bronchospasm and cardiac arrest. Symptomatic and supportive treatment in case of systemic symptoms or accidental oral ingestion. Timolol does not dialyse readily. Adverse events should be reported. Reporting forms and information can be found at http://www.hpra.ie Legal Category: POM. PA Number: PA 1107/014/001. MA Holder: LABORATOIRES THEA, 12 RUE LOUIS BLERIOT, 63017 CLERMONT-FERRAND CEDEX 2, France Date of Preparation: August 2020. Item code: TP20027 -IE-FIXAPOST API- V1

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 EVENT SHOULD BE REPORTED TO THEAPAMEXLTD. 094 925 0290 OR MEDICAL INFORMATION ON +44 345 521 1290

TheaPamex Ltd. 14 Moneen Business Park, Castlebar, Co. Mayo. Ireland Phone: 094 925 0290 Website: www.theapharma.ie

References: 1-Aptel, F. et al. Journal of Glaucoma. 2019; 28(6):498–506

TP/20/031 FIXAPOST ADVERT V1

let’s open our eyes

28 Ophthalmology

Ophthalmology Consult Service Audit Title: An audit of the current process and structure of the inpatient ophthalmology consult service; analysing outcomes with a view to implementing change in service provision.

Purpose: A quality improvement process that seeks to improve inpatient care through systematic review of ophthalmology consults received from other clinical specialties in Sligo University Hospital during the period November 2019 – January 2020.

Methods: A retrospective analysis of the requested inpatient ophthalmology consults. Patient data was collected using the software Medisoft to identify patient demographics, the referral source, indication and outcome.

Results: There were sixty-one ophthalmology reviews for inpatients during the chosen three month time period, mostly “new” patients to the ophthalmology service (78.7%, n=48). The source of referral was predominantly from the general medical or acute assessment team (57.4%, n=35).

The reason for referral was a “decrease in vision” (26.2%, n=16), and not specified in a significant percentage (13.1%, n=8). Visual acuity was not performed by the referring team in any scenario. Visual acuity of 6/9 best-corrected visual acuity (BCVA, Snellen) or better was achieved in most patients once examined (68.75%, n=22). Only one-fifth of patients had acute symptoms (hours-days) (21.3%, n=13), the remainder had either an unspecified or weeks/months duration of symptoms. Thirty-seven percent of referrals had a ‘grossly normal eye exam’, and most patients were discharged from ophthalmology services without follow-up arranged (34.4%, n=21).

Introduction: Receiving a request for an Ophthalmology review is a common event, which results in inpatients being reviewed in our Eye Casualty area. Inpatients differ from our other casualty patients; by virtue of being an inpatient they commonly have a variety of active medical issues; including limited mobility or cognition, which we need to be aware of prior to review. A porter or nurse may be required to assist. They may arrive to our department fasting, reveal unknown infection control issues or have to leave for imaging, interventions or medications. Risks to other patients in the department include delays to treatment, increased waiting times and exposure to healthcare associated infections. Currently there is no hospital-wide guideline for referral.

Presently, the method of referral is that the on-duty doctor for any ophthalmic emergencies receives a call from another specialty; the patient is informally discussed and if deemed appropriate advised when to come to the department for review. There is no formal method of referral and no documentation of the referral process. There is no patient triage or scheduling system for when they are to be seen.

Communication to the referring team is via the notes written in their medical chart. We propose a change in methodology to ensure an appropriate streamlined service. This would include a short questionnaire including basic pertinent details of the patient; their location, the contact details of team, a brief history and relevant findings as well as any mobility, cognitive or infection

control issues. This would allow triage and appropriate treatment for both urgent and non-urgent cases, as well as a streamlined, safe service for the remainder of the eye casualty department and staff.

symptoms, outcome of consult and diagnosis. Visions were taken as those performed by our eye department on the day of review, not by the referring team.

Methods:

There were sixty-one ophthalmology reviews for inpatients during the chosen three month time period. The mean age of inpatient was 56.44 ±22.57 (Range 2-87). More men were seen than women (52.5%, n=32 versus 47.5%, n=29).

Most patients were unknown previously to our ophthalmology service (78.7%, n=48). The source of referral commonly from the general medical teams or acute assessment team (57.4%, n=35), another 8.2% (n=5) from oncology and 3.3% (n=2) from neurology teams. Ear, nose and throat (ENT) and paediatric teams accounted for 8.2% (n=5) respectively and general surgical team had only one referral (1.6%). (Figure 1) The commonest reason for referral was

Inpatient consults seen by the ophthalmology casualty department during a three month period (1st November 2019 to 31st January 2020) was chosen as a representative sample. The Medisoft database was utilised to retrospectively collate the data. Any notes resulting from the consult are documented in the patients file/chart as well as our Medisoft system. Medisoft alone was utilised for the purpose of this review. The following details were noted: age, gender, whether the patient was known to ophthalmology services, referring hospital team, referral indication, laterality of symptoms if applicable, vision, duration of

Fig. 1 Source of referral

SEPTEMBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

Fig. 1 Source of referral

Results:

a decrease in vision (26.2%, n=16) followed by headaches (13.1%, n=8). Cellulitis/dacrocystitis was the indication in four patients (6.6%), all of whom were referred by the ENT team. Less common reasons for referral included photophobia, dizziness, absent red reflex, acute stroke and nonaccidental injury (each 1.6%, n=1). Of note, there was no clearly documented reason for referral in 13.1% of patients (n=8). (Figure 2) Visual acuity was not documented in all cases (100%, n=61). When documented by our eye casualty department, best-corrected visual acuity (in the eye of concern) was 6/9 or better in most patients (68.8%, n=22). (Figure 3) Duration of symptoms was not specified in 44.3% of cases (n=27).

One fifth of patients noted acute symptoms in the recent hours or days (21.3%, n=13), the rest of the patients noted symptoms for “weeks” (19.7%, n=12) or even “months” (14.8%, n=9). (Figure 4)

Fig. 1 Source of referral

29 Fig. 2 Clinical indication for inpatient referral

Fig. 3 Best-corrected visual acuity (BCVA) of the referred patient

Fig. 2 Clinical indication for inpatient referral

Fig. 3 Best-corrected visual acuity (BCVA) of the referred patient

Fig 4 Duration of symptoms

Fig. 3 Best-corrected visual acuity (BCVA) of the referred patient

Fig 4 Duration of symptoms

HOSPITALPROFESSIONALNEWS.IE | HPN • SEPTEMBER 2020

30 Ophthalmology Most patients were discharged from ophthalmology services without follow-up arranged (31.1%, n=19), a further two patients (3.3%, n=2) were discharged but treatment commenced (topical lubricants).

Thirteen percent received daily inpatient ophthalmology review (n=8), half of which (n=4) were under ENT for orbital cellulitis or dacrocystitis. (Figure 5) Over a third of patients (37%, n=17) with a diagnosis documented were deemed to have a “grossly normal eye exam”. (Figure 6) Recommendations for Change 1. Need for documentation by the ophthalmology team The doctor covering the eye casualty receives phone-referrals for patients, occasionally in person by another hospital doctor.

Presently there is no formal documentation of when the referral is received and we cannot extract any data of the duration of time between referral made and patient seen.

Action proposed: Date of referral, referring team/consultant and contact details need to be noted.

The ophthalmology doctor needs to triage the patient appropriately and advise when that patient should be seen.

Fig 5 Outcome of ophthalmology consultation

Fig 5 Outcome of ophthalmology consultation

Fig 5 Outcome of ophthalmology consultation

2. Need for documentation by the referring team

The doctor requesting the referral should provide basic information regarding the patient: reason for referral, clinical query, a brief history and examination findings, including visual acuity. Practical information regarding the mobility and infectious status of the patient would allow a streamlined review and opportunity to address logistical issues prior to the patient arriving to the eye department.

Action proposed: User-friendly questionnaire available to referring team for pertinent patient details.

Conclusion: The COVID-19 pandemic has reminded us that each interaction with a patient is not without risk; going forward we must promote vigilant infection control measures.

Improvement in the referral process will ensure a streamlined patient journey. We suggest Fig 6 Diagnosis implementing a formal referral process for urgent ophthalmology consults. This change is required to maximise patient safety; avoid unnecessary time spent in the ophthalmology department as Fig 6 Diagnosis well as delays to our other casualty patients.

SEPTEMBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

Fig 6 Diagnosis

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32 News Hospital Capacity Pressures Continue Dr Michael Boyle, Rotunda Hospital

space, consultants warn that the risk of transmission of infection will remain dangerously high.

Capacity issues in Ireland’s neonatal services are further compounded by severe consultant shortages.

As Covid-19 backlog persists, preterm and newborn babies could become latest casualties of Ireland’s acute hospital capacity pressures, it has been claimed.

and that neonatal cots were being placed too close together, increasing the risk of crossinfection between infants in these units.

According to the recent Health Information and Quality Authority’s (HIQA) “Overview Report on the National Standards for Safer Better Maternity Services” published in February 2020, approximately 10% of newborns are admitted to neonatal units every year, the majority of which are struggling to deliver the required levels of care.

However, the Irish Hospital Consultants Association says that these isolation facilities are now critical for managing care for infants and parents in a Covid-19 environment in line with international guidelines.

The report showed that four neonatal units did not have adequate isolation facilities,

Infants of Covid-19-infected or Covid-19-suspected mothers should initially be isolated if they require admission to a neonatal unit. However, without adequate investment to create the additional

HIQA found that none of the specialist maternity hospitals (the National Maternity Hospital (Holles Street), Rotunda Hospital, Coombe Woman & Infants University Hospital, and Cork University Maternity Hospital) had achieved the recommended levels of staffing, meaning that the nation’s specialist facilities are falling below the required levels. Difficulties and delays in recruitment is a key issue that Department of Health confirms is impacting the implementation of Maternity Policy in Ireland.

The medical staffing requirements are also at odds with HSE figures, which suggest that only 37 of the approved 41 permanent consultant neonatology posts in public hospitals are filled on a permanent basis.

A recent HSE report on medical specialist staffing further confirms the gravity of the current and projected consultant recruitment and retention crisis: Ireland has the lowest number of consultant paediatricians on a population basis (5.4 per 100,000) compared

with England, Scotland, Australia, and New Zealand.

The report also projects a 78% increase in the demand for consultant paediatricians and neonatologists by 2028, meaning an extra 199 consultants will need to be added to the current headcount of 255 in less than eight years.

Speaking in a video interview released by the IHCA as part of its #CareCantWait campaign, consultant neonatologist Dr Michael Boyle of the Rotunda Hospital said, “Having a baby is one of the most momentous experiences of anybody’s life, and if you add a huge stressor like giving birth at 25 weeks into that, it’s full of uncertainty and worry.

“There are significant challenges as I would see it from my perspective such as access to intensive care beds. We would occasionally find that we are unable to accept a referral from another hospital because we don’t have the space or the staff to care for them and that is an awful position to be in.

“We are firefighting, we’re dealing with the issues as they present on the day. It’s a challenge to improve a service when you can’t focus on the longer-term elements that you’d like to develop.”

Increased breast cancer risk in obesity linked to fat cell chemicals Obesity increases the release of tumour-promoting molecules from fat tissue and is associated with an increased risk of breast cancer, according to a study published in Endocrine-Related Cancer.

The study found that fat tissue from people with obesity released increased amounts of extracellular vesicles (EV’s) enriched in harmful and inflammatory molecules into the blood stream, which can alter breast cancer cells to become more aggressive and invasive. These findings suggest that substances released from fat tissue may increase tumour malignancy that could lead to new therapeutic targets and improved cancer treatments.

Obesity is a global, public health problem with rapidly increasing rates that has been linked to increased risk of breast cancer.

Breast cancer is the most common cancer among women and despite the well-known association between obesity and increased breast cancer risk, few studies have evaluated the role of fat tissue. Fat tissue is known to release inflammatory molecules that can increase the risk of diabetes, cardiovascular disease and cancer. They also produce EV’s that carry inflammatory molecules and other substances, including enzymes and molecules that are involved in cell-to-cell communication. More of these vesicles are released from the fat tissue of people with obesity. A better understanding of how the contents of EV’s may affect cancer cells could help explain the link between obesity and a poor cancer prognosis.

Professor Christina Barja-Fidalgo and her group, from State University of Rio de Janeiro,

SEPTEMBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

analysed the effects of the fat tissue-derived EV’s on breast cancer cells. Fat tissue was obtained from obese patients who had undergone weight-loss surgery, and from lean people undergoing plastic surgery. These tissues were incubated in culture for 24 hours and the amount and type of substances secreted from both were compared. The analysis showed that the fat tissue from obese patients secreted higher amounts of inflammatory molecules and also produced a greater number of small vesicles, which may increase breast cancer risk.

These findings demonstrate how obesity can induce alterations in fat tissue function, which may explain how obesity contributes to increased breast cancer risk, as well as why obese women are more likely to have a worse prognosis.

“When the extracellular vesicles carrying inflammatory molecules interact with breast cancer cells, we see they are able to modify their behaviour, so that they become more aggressive with increased capacity to invade other tissues.”

Professor Barja-Fidalgo explains.

Professor Barja-Fidalgo now plans to investigate the characteristics and specific contents of extracellular vesicles released by fat tissue, to determine the main molecules associated with obesityinduced alterations in tumour cells and their modes of action.

Professor Barja-Fidalgo adds: “Identifying these harmful fat tissue secretions in the blood of obese patients could be a new parameter to be monitored, as an indicator of cancer progress. Understanding the content of the vesicles released by fat tissue during obesity may provide new therapeutic targets and improve cancer treatment.”

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). It should be taken with food, preferably a meal to ensure consistent palbociclib exposure (see SmPC section 5.2).

Palbociclib should not be taken with grapefruit or grapefruit juice (see SmPC section 4.5). Dose modification of IBRANCE is recommended based on individual safety and tolerability. Management of some adverse reactions may require temporary dose interruptions/delays, and/or dose reductions, or permanent discontinuation. For dose reduction guidelines for management of adverse reactions, haematologic and non-haematologic toxicities, refer to SmPC section 4.2. Permanently discontinue IBRANCE 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 trials (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 postmarketing setting, with fatalities reported. Monitor patients for pulmonary symptoms and interrupt IBRANCE treatment immediately 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, increase the IBRANCE dose (after 3–5 half-lives of the inhibitor) to the dose used prior to the initiation of the strong CYP3A inhibitor (see SmPC section 4.5). Coadministration of CYP3A inducers may lead to decreased palbociclib exposure and consequently a risk for lack of efficacy. Therefore, concomitant use of palbociclib with strong CYP3A4 inducers should be avoided. No dose adjustments are required for coadministration of palbociclib with moderate CYP3A inducers (see SmPC section 4.5). Women of childbearing potential or their male partners must use a highly effective method of contraception while taking IBRANCE (see SmPC section 4.6).

IBRANCE contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption

should not take this medicine. 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 Pglycoprotein (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., double-barrier contraception) during therapy and for at least 3 weeks or 14 weeks after completing therapy for females and males, respectively (see SmPC section 4.5). There are no or limited amount of data from the use of palbociclib in pregnant women. Studies in animals have shown reproductive toxicity (see SmPC section 5.3). IBRANCE is not recommended during pregnancy and in women of childbearing potential not using contraception. Based on male reproductive organ findings (seminiferous tubule degeneration in testis, epididymal hypospermia, lower sperm motility and density, and decreased prostate secretion) in nonclinical safety studies, male fertility may be compromised by treatment with palbociclib (see SmPC section 5.3). Thus, men may consider sperm preservation prior to beginning therapy with IBRANCE. Driving and operating machinery: IBRANCE may cause fatigue and patients should exercise caution when driving or using machines. Side Effects: The most common (≥20%) adverse reactions of any grade reported in patients receiving palbociclib in randomised clinical studies were neutropenia, infections, leukopenia, fatigue, nausea, stomatitis, anaemia, diarrhoea, alopecia, and thrombocytopenia. The most common (≥2%)

PP-IBR-IRL-0323 | Date of preparation: July 2020

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 – 75mg (21 capsules); EU/1/16/1147/003 – 100mg (21 capsules) EU/1/16/1147/005 – 125mg (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. ▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 of the SmPC for how to report adverse reactions.

Last revised: 06/2020 Ref: IB 8_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.

34 Feature National Newborn Screening for cystic fibrosis in the Republic of Ireland: genetic data from the first 6.5 years Sally Ann Lynch and Tara Clark | Department of Clinical Genetics, CHI @ Crumlin At the time, homozygosity In the first 6.5 years a total of for the c.1521_1523delCTT 5053 newborns (1.16% of total (p.(Phe508del)) and either births) were screened with a 38 heterozygosity or homozygosity CFTR mutation panel, 170 affected for the c.1652G>A (p.(Gly551Asp)) cases, 320 unaffected carriers, 32 meant a child was eligible for the CF screening positive inconclusive new CFTR modulator therapy diagnosis (CFSPID) were identified. & the authors indicated 70% There was one case of classic of affected patients would be CF that was not picked up, a eligible.1 In fact, in this fast moving case with co-morbidities and world, just over 3 weeks after this rare mutations not on the 38 publication, on the 26th of June CFTR mutation panel. Indeed, the European Medical Agency the steering group had predicted (EMA) granted a licence for Kaftrio that up to 0.8 affected CF cases (elexacaftor /tezacaftor/ivacaftor) would be missed per annum by previously known as Trikafta. the screening programme which Kaftrio is a successor to Orkambi. would equate to 5 cases for the This is the first triple combination time period involved. The team therapy for the treatment of are confident that they have The steering group, set up to cystic fibrosis in patients aged complete ascertainment of false oversee implementation and National Newborn Screening for negative cystic fibrosis the should Republic of12 Ireland: genetic data years and older who arefrom cases asinthese planning prior to launch of homozygous or heterozygous for have presented clinically since the the first 6.5 years NBS, designed testing strategy the common c.1521_1523delCTT study period end date (Dec 2017). parameters that would, they (p.(Phe508del)) mutation in the Professor Philip Farrell, in an Sally Ann Lynch and Tara Clark envisaged, maximize identification cystic fibrosis transmembrane editorial3 reviewing Sasaki’s paper of affected classic CF cases whilst conductance regulator (CFTR) quoted “The metrics reported minimizing detection of unaffected Department of Clinical Genetics, CHIfrom @ Crumlin gene. The HSE have already the Republic of Ireland (ROI) carriers, see figure 1. As with all negotiated a funding agreement programme are the best ever screening programmes, the aim with the drug company Vertex so it achieved with regard to sensitivity is to identify as many cases as hoped the drug will be available 1 and positive predictive value (PPV) possible with minimal number of years (July 2011-Dec 2017) Sasaki & colleagues recently published findings from the first 6.5 is in Ireland from Autumn 2020. at 99.4 and 84.1%, respectively." false negatives and false positives; of Newborn screening (NBS) for cystic fibrosis in the Republic of Ireland (online publication The screening has therefore been complete ascertainment is rarely If one re-visits Sasakis data1, one successful has common achieved the date 01/06/2020). fibrosis (CF) is theand most life-limiting autosomal recessive possible.

The resultsCystic presented can see that this means that a initial committee aims. CF as the benefits of early in Sasaki’s showfor thatCF was disease in publication Ireland. NBS setsteering up to identify classical further 25% of affected patients, the predictions of the steering diagnosis are evident and well established in this cohort. are At the time, Ireland withthe theRepublic approval ofofKaftrio, willhas The advances in treatment group have been born out and the be eligible for CFTR of modulator game this field and the world’s incidence of CF at 1changing in 1353inand an estimated carrier frequency 1 in 192. screening hashighest been successful. therapy taking the total number the treatments which have been The steering group, set up to oversee implementation and planningofprior to patients launch of NBS, eligible to 95% of the developed only work on specific The term “pathogenic variant” is designed testing terminology strategy parameters that would, envisaged, maximize identification of affected cohort. mutation classes. they The most now the preferred for common mutation identified in the a diseaseclassic causingCF DNAcases change affected whilst minimizing detection of unaffected carriers, see figure 1. As The NBS programme noted study was c.1521_1523delCTT but in this article we have used the with all screening programmes, the aim is to identify as many casesa as possible minimal higher numberwith of affected (p.(Phe508del)) followed by old-fashioned term mutation as it newborns withpossible. c.1652G>AThe number of used falseinnegatives positives; complete ascertainment is rarely 1 c.1652G>A (p.(Gly551Asp)). is still often relation to and CF. false (p.(Gly551Asp)) previously results presented in Sasaki’s publication show that the predictions of the steeringthan group have quoted figures4,5 with an been born out and the screening has been successful. The term “pathogenic variant” is now allele frequency of 8.2%.

Thethe preferred terminology for a disease DNA change but in this article we have used the oldFigure 1 The CF Newborn Screen Pathwaycausing in Republic of Ireland Sasaki & colleagues1 recently published findings from the first 6.5 years (July 2011-Dec 2017) of Newborn screening (NBS) for cystic fibrosis in the Republic of Ireland (online publication date 01/06/2020). Cystic fibrosis (CF) is the most common life-limiting autosomal recessive disease in Ireland. NBS for CF was set up to identify classical CF as the benefits of early diagnosis are evident and well established in this cohort. At the time, the Republic of Ireland has the world’s highest incidence of CF at 1 in 1353 and an estimated carrier frequency of 1 in 19.2

fashioned term mutation as it is still often used in relation to CF.

Department of Health used English laboratory incidence data for this specific mutation in their agreement to purchase Ivacaftor which is currently quoted as 5.2%.6 This mutation is much more common in Ireland and indeed this trend is also noted in Scotland which has a frequency of 10.6%.6 This confirms the importance of using local laboratory testing data when negotiating access to new therapies as the incidence of specific mutation will vary between populations. Sasaki also reported a revised incidence & carrier frequency for CF in Ireland, with an incidence now of 1 in 2570 and a carrier frequency of 1 in 25.

This reflects the ethnic diversity of our population.

On a positive note, it is tempting to believe that the term “life-limiting” may no longer be applicable to CF if the early results from these new drugs are born out.

References 1. E Sasaki, M Kostocenko, N Lang , T Clark, M Rogers, R Muldowney, O Walsh, L O'Grady, G Edge, A Ward, B Linnane, I Borovickova , DE Barton, SA Lynch. Eur J Hum Genet 2020 Jun 1.doi: 10.1038/ s41431-020-0661-5.

2. P Farrell, S Joffe, L Foley, G J Canny, P Mayne, M Rosenberg.

Diagnosis of cystic fibrosis in the Republic of Ireland: epidemiology and costs Ir Med J 2007 Sep;100(8):557-60. PMID: 17955689 3. PM Farrell. Setting a new standard in cystic fibrosis newborn screening illustrates controversial issues as new data emerge. Eur J Hum Genet (2020). https://doi. org/10.1038/s41431-020-06904. ECFS patient registry annual data report. 2017. https://www.ecfs. eu/sites/default/files/generalcontent-images/working-groups/ ecfspatient-registry/ECFSPR_ Report2017_v1.3.pdf.

5. US Cystic Fibrosis Foundation National Registry annual report.

2017 https://www.cff.org/ Research/Researcher-Resources/ Patient-Registry/2017-PatientRegistry-Annual-Data-Report.pdf.

Figure 1 The CF Newborn Screen Pathway in Republic of Ireland SEPTEMBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

In the first 6.5 years a total of 5053 newborns (1.16%) of total births) were screened with a 38

6. UK Cystic Fibrosis Registry Annual Data Report. 2018. https:// www.cysticfibrosis.org.uk/~/ media/documents/the-work-wedo/uk-cf-registry/2018-registryannual-data-report.ashx?la=en

Break the cycle of chronic pain PALEXIA® SR Tablets are indicated for the management of severe chronic pain in adults, which can be adequately managed only with opioid analgesics1

PALEXIA SR® Prolonged Release Tablets Prescribing Information. Refer to the Summary of Product Characteristics (SmPC) before prescribing. Presentation: 50 mg (white), 100 mg (pale yellow), 150 mg (pale pink), 200 mg (pale orange) and 250 mg (brownish red) prolonged-release tablets contain 50 mg, 100 mg, 150 mg, 200 mg and 250 mg of tapentadol (as hydrochloride) respectively. Indication: Palexia SR is indicated for the management of severe chronic pain in adults, which can be adequately managed only with opioid analgesics. Dosage and method of administration: Individualise according to severity of pain, the previous treatment experience and the ability to monitor the patient. Swallowed whole with sufficient liquid, not divided or chewed, with or without food. The tablet shell may not be completely digested and eliminated / seen in the patient’s stool which has no clinical significance as the active substance will have already been absorbed. Initial dose 50 mg twice a day. Switching from other opioids may require higher initial doses. Titrate in increments of 50 mg twice a day every 3 days for adequate pain control. Total daily doses greater than 500 mg not recommended. Discontinuation of treatment: Taper dose gradually to prevent withdrawal symptoms. Renal/hepatic impairment: Not recommended in patients with severe cases. Caution and dose adjustments with moderate hepatic impairment. Elderly: May need dose adjustments. Children below 18 years: Not recommended. Contraindications: Hypersensitivity to ingredients, suspected or having paralytic ileus, acute intoxication with alcohol, hypnotics, centrally acting analgesics or psychotropics. Not for use when mu-opioid receptor agonists are contraindicated (e.g. significant respiratory depression, acute or severe bronchial asthma or hypercapnia). Special warnings and precautions: Abuse and addiction potential of Palexia should be considered where there is increased risk of misuse, abuse, addiction or diversion. All patients should be carefully monitored for signs of abuse and addiction. Concomitant use with sedating medicinal products such as benzodiazepines or related substances may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedating medicinal products should be reserved for patients for whom alternative treatment options are not possible. If used concomitantly, reduction of dose of one or both agents should be considered and the duration of the concomitant treatment should be as short as possible. The patients should be followed closely for signs and symptoms of respiratory depression and sedation.

It is strongly recommended to inform patients and caregivers to be aware of these symptoms. At high doses or in mu-opioid receptor agonist sensitive patients, dose-related respiratory depression may occur. Caution and monitoring required with impaired respiratory function. Should not use in patients susceptible to intracranial effects of carbon dioxide retention (e.g. increased intracranial pressure, impaired consciousness or coma). Use with caution with head injury, brain tumors, moderate hepatic impairment, biliary tract disease including acute pancreatitis. Not recommended if history of or at risk of seizures. May increase the seizure risk in patients taking medicinal products that lower the seizure threshold. Not recommended in severe renal or hepatic impairment. Care should be taken when combining with mixed mu-opioid agonists/antagonists (e.g. pentazocine, nalbuphine) or partial mu-opioid agonists (e.g. buprenorphine). Should not use with hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption. Interactions: The concomitant use with sedating medicinal products such as benzodiazepines or other respiratory or CNS depressants (other opioids, antitussives or substitution treatments, barbiturates, antipsychotics, H1-antihistamines, alcohol) increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. When combined therapy with a respiratory or CNS depressant is contemplated, the reduction of dose of one or both agents should be considered and the duration of the concomitant use should be limited. Can induce convulsions and increase the potential for selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, antipsychotics and other medicinal products that lower the seizure threshold to cause convulsions. There have been reports of serotonin syndrome in a temporal connection with the therapeutic use of tapentadol in combination with serotoninergic medicinal products (e.g. SSIRs, SNRIs and tricyclic antidepressants). Use with strong inhibitors of uridine diphosphate transferase isoenzymes (involved in glucuronidation) may increase systemic exposure of Palexia SR. Caution if concomitant administration of strong enzyme inducing drugs (e.g. rifampicin, phenobarbital, St John’s Wort) starts or stops as this may lead to decreased efficacy or risk for adverse events, respectively. Avoid use in patients who have taken monoamine oxidase inhibitors (MAOIs) within the last 14 days, due to cardiovascular events. Pregnancy and lactation: Use in pregnancy only if the potential benefit justifies the potential risk to the foetus. Not recommended during and immediately before labour and delivery. Do not use during breast feeding. Driving and using machines: May have major effect on ability to drive and use machines, especially at the beginning or change in dosage, in connection with alcohol or tranquilisers. Undesirable effects: Very common (≥1/10): dizziness, somnolence, headache, nausea, constipation. Common (≥1/100, <1/10): decreased appetite, anxiety, depressed mood, sleep disorder, nervousness, restlessness, disturbance in attention, tremor, involuntary muscle contractions, flushing, dyspnoea, vomiting, diarrhoea, dyspepsia, pruritus, hyperhidrosis, rash, asthenia, fatigue, feeling of body temperature change, mucosal dryness, oedema. Other important undesirable effects observed in clinical trials and/or postmarketing: drug hypersensitivity, depressed level of consciousness, mental impairment, syncope (uncommon ≥1/1000, <1/100), impaired gastric emptying, respiratory depression, convulsion, angioedema, anaphylaxis and anaphylactic shock, drug dependence (rare ≥1/10,000, <1/1000), delirium (unknown). No evidence of increased risk of suicidal ideation or suicide with Palexia SR. Additional information is available on request.

Overdose: Seek specialist treatment (see SmPC). Legal classification: POM, CD (Schedule II). Marketing Authorisation numbers and pack sizes: 50 mg: PA 2242/12/4, 28 and 56 packs; 100 mg: PA 2242/12/5, 56 pack; 150 mg: PA 2242/12/6, 56 pack; 200 mg: PA 2242/12/7, 56 pack and 250 mg: PA 2242/12/8, 56 pack. Marketing Authorisation Holder: Grünenthal Pharma Ltd, 4045 Kingswood Road, Citywest Business Park, Citywest, Co. Dublin, Ireland. M-PLX-IE-12-19-0003. Date of Preparation: December 2019.

Reference: 1. Palexia SR Summary of Product Characteristics.

Date of Preparation: February 2020. M-PLX-IE-02-20-0004.

36 News

CPD Support Scheme Professor Oscar Traynor, RCSI

its eleventh year, is commissioned and funded by the HSE to facilitate NCHDs within the public health service, who are not on training schemes, to maintain their professional competence in line with Medical Council requirements and provides a structured means of achieving 20 external CPD credits.

The 2020/2021 Continuous Professional Development Support Scheme for non-consultant hospital doctors (NCHDs) working in the fields of surgery and emergency medicine, has just been announced.

This year’s programme offers a newly expanded choice of modules. Eligible NCHDs have until Wednesday, 30 September to enrol on the programme.

The programme, which is now in

For the 2020/21 course, RCSI will offer participants an expanded range of classes in surgical skills, emergency medicine, along with clinical audit, quality improvement orocesses, research and ethics, IT skills, personal development and a range of e-learning activities. All modules will be taking place in the National Surgical and Clinical Skills at RCSI’s state-of-the-art facility at 26 York Street.

Professor Oscar Traynor, Director, National Surgical Training Centre, RCSI, says, "The RCSI Continuous Professional Development Support Scheme (CPD-SS) assists NCHDs to satisfy their professional competence requirement. The programme provides highly relevant courses for emergency medicine and surgery NCHDs at both SHO and Registrar level, to maintain and enhance the skills and technical expertise needed in order to excel in their speciality."

The CPD-SS is open to NCHDs who are registered on the General Division or Supervised Division of the Register of Medical Practitioners maintained by the Medical Council. NCHDs must hold the 2010 NCHD contract and be working within the public health service. To successfully enrol on the CPD-SS applicants must have paid the annual Professional Competence Scheme (PCS) fee for 2020/2021.

New initiative offers fertility hope for childhood cancer patients A ground-breaking initiative by the Irish Cancer Society will give children being treated for cancer the best possible chance at starting a family of their own in later life.

Ireland currently lags behind other European countries in having no state-funded fertility preservation service for children and adolescents with a cancer diagnosis.

Over 200 children are diagnosed with cancer each year in Ireland, with the necessary treatment often damaging their fertility and impacting their chances of being able to have children in future.

The charity’s new Childhood Cancer Fertility Project delivered in association with Merrion Fertility Clinic will see hundreds of children, adolescents and young adults given a precious chance at future parenthood through

The Childhood Cancer Fertility Project is designed to be the forerunner for a new national fertility preservation programme on its completion.

Project Clinical Lead Prof Mary Wingfield said: “Loss of fertility is one of the less visible side effects of cancer treatment and it can have a devastating effect on survivors – on their quality of life, their mental health and their relationships.

The three-year project represents a ¤420,000 investment as part of the Society’s commitment to childhood cancers in its new fiveyear strategy.

“This funding grant will make such a difference to so many children, adolescents and their families, and I am so grateful to the Irish Cancer Society for enabling this service,” Prof Wingfield concluded.

the use of cutting-edge fertility preservation methods.

Introducing Altavita D3 50,000 iu soft capsules Consilient Health Ltd. is pleased to announce the launch of Altavita D3 50,000 iu (Colecalciferol) capsules for the treatment of vitamin D deficiency.

The recommended dose is one Altavita D3 50,000 iu weekly for 6 to 8 weeks for your patients with vitamin D deficiency (plasma 25(OH)D < 25 nmol/l).

Consilient Health continue to supply all presentations of Altavita D3 designed for your patient’s routine. These presentations include the 1,000 iu (daily prevention), 7,000 iu (weekly prevention) and 25,000 iu (monthly prevention).

The Altavita range is reimbursed under the General Medical and Drug Community Scheme.

For further information please visit altavita.ie or medicines.ie. Alternatively contact your local sales representative.

SEPTEMBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

HIV News 37

WHO: access to HIV medicines severely impacted by Covid-19 Seventy-three countries have warned that they are at risk of stock-outs of antiretroviral (ARV) medicines as a result of the COVID-19 pandemic, according to a new WHO survey conducted ahead of the International AIDS Society’s biannual conference. Twenty-four countries reported having either a critically low stock of ARVs or disruptions in the supply of these life-saving medicines.

Dr Meg Doherty, Director of the Department of Global HIV, Hepatitis and STI Programmes at WHO

The survey follows a modelling exercise convened by WHO and UNAIDS in May which forecasted that a six-month disruption in access to ARVs could lead to a doubling in AIDS-related deaths in sub-Saharan Africa in 2020 alone.

In 2019, an estimated 8.3 million people were benefiting from ARVs in the 24 countries now experiencing supply shortages.

This represents about one third (33%) of all people taking HIV treatment globally. While there is no cure for HIV, ARVs can control the virus and prevent onward sexual transmission to other people.

A failure of suppliers to deliver ARVs on time and a shut-down of land and air transport services, coupled with limited access to health services within countries as a result of the pandemic, were among the causes cited for the disruptions in the survey.

The findings of this survey are deeply concerning,” said Dr Tedros Adhanom Ghebreyesus, WHO Director-General. “Countries and their development partners must do all they can to ensure that people who need HIV treatment continue to access it. We cannot let the COVID-19 pandemic undo the hard-won gains in the global response to this disease.”

Stalled progress According to data released from UNAIDS and WHO, new HIV infections fell by 39% between 2000 and 2019. HIV-related deaths fell by 51% over the same time period, and some 15 million lives were saved through the use of antiretroviral therapy.

However, progress towards global targets is stalling. Over the last two years, the annual number of new HIV infections has plateaued at 1.7 million and there was only a modest reduction in HIV-related

death, from 730 000 in 2018 to 690 000 in 2019. Despite steady advances in scaling up treatment coverage – with more than 25 million people in need of ARVs receiving them in 2019 – key 2020 global targets will be missed.

HIV prevention and testing services are not reaching the groups that need them most.

Improved targeting of proven prevention and testing services will be critical to reinvigorate the global response to HIV. WHO guidance and country action Covid-19 risks exacerbating the situation. WHO recently developed guidance for countries on how to safely maintain access to essential health services during the pandemic, including for all people living with or affected by HIV. The guidance encourages countries to limit disruptions in access to HIV treatment through “multi-month dispensing,” a policy whereby medicines are prescribed for longer periods of time – up to six months. To date, 129 countries have adopted this policy.

Countries are also mitigating the impact of the disruptions by working to maintain flights and supply chains, engaging communities in the delivery of HIV medicines, and working with manufacturers to overcome logistics challenges.

New opportunities to treat HIV in young children At the IAS conference, WHO will

highlight how global progress in reducing HIV-related deaths can be accelerated by stepping up support and services for populations disproportionately impacted by the epidemic, including young children. In 2019, there were an estimated 95 000 HIV-related deaths and 150 000 new infections among children.

Only about half (53%) of children in need of antiretroviral therapy were receiving it. A lack of optimal medicines with suitable pediatric formulations has been a longstanding barrier to improving health outcomes for children living with HIV.

Programmes at WHO. “This will give us another new tool to reach children living with HIV and keep them alive and healthy.”

Last month, WHO welcomed a decision by the U.S. Food and Drug Administration to approve a new 5mg formulation of dolutegravir (DTG) for infants and children older than 4 weeks and weighing more than 3 kg.

This decision will ensure that all children have rapid access to an optimal drug that, to date, has only been available for adults, adolescents and older children.

WHO is committed to fasttracking the prequalification of DTG as a generic drug so that it can be used as soon as possible by countries to save lives.

WHO has released new guidelines for the diagnosis and management of histoplasmosis, among people living with HIV. Histoplasmosis is highly prevalent in the WHO Region of the Americas, where as many as 15 600 new cases and 4500 deaths are reported each year among people living with HIV. Many of these deaths could be prevented through timely diagnosis and treatment of the disease.

Through a collaboration of multiple partners, we are likely to see generic versions of dolutegravir for children by early 2021, allowing for a rapid reduction in the cost of this medicine,” said Dr Meg Doherty, Director of the Department of Global HIV, Hepatitis and STI

Tackling opportunistic infections Many HIV-related deaths result from infections that take advantage of an individual’s weakened immune system.

These include bacterial infections, such as tuberculosis, viral infections like hepatitis and Covid-19, parasitic infections such as toxoplasmosis and fungal infections, including histoplasmosis.

In recent years, the development of highly sensitive diagnostic tests has allowed for a rapid and accurate confirmation of histoplasmosis and earlier initiation of treatment. However, innovative diagnostics and optimal treatments for this disease are not yet widely available in resource-limited settings.

HOSPITALPROFESSIONALNEWS.IE | HPN • SEPTEMBER 2020

38 HIV News

Advancements in the Treatment of HIV The first-ever virtual edition of the world’s largest conference on HIV took place last month, with a focus on the links between HIV and the COVID-19 pandemic and recognition of global debates around racism.

Diagnosis of HIV in Ireland is increasing despite new initiatives to tackle the issue.

There were 476 new diagnoses of HIV last year, compared to 447 in the same time period during 2018.

Ireland ranks almost double the European average, with higher numbers than during the Aids epidemic in the 1980s and 1990s.

According to the HIV/Aids surveillance in Europe 2008-2017 data, rates increased by 10 per cent or more in countries in both 2008 and 2017 in only three countries; Iceland, Ireland and Malta.

The numbers of new diagnoses continue to rise, despite the initial stages of the PrEP (pre-exposure prophylaxis) HIV prevention programme being implemented by the Government after a review by the State’s health watchdog found the drug is highly effective at preventing HIV in people at substantial risk.

Almost 10,000 people have been diagnosed with HIV in Ireland since the early 1980s

As the 23rd International AIDS Conference (AIDS 2020: Virtual) drew to a close last month, Dr Carl Dieffenbach, Ph.D., Director of the Division of AIDS at NIH’s National Institute of Allergy and Infectious Diseases (NIAID), highlighted some important HIV research developments. Among the topics he discussed were: • New NIH partnership announced around HIV broadly neutralizing antibodies. Dr. Dieffenbach noted that a new public-private partnership between NIH, IAVI, and other collaborators was announced at the conference yesterday, focused on development of broadly neutralizing antibodies (bNAbs), a type of antibody that can block many types of HIV from entering healthy cells in the laboratory.

Clinical studies evaluating bNAbs for HIV prevention and treatment are currently underway. Under the new partnership, the collaborators will pool their bNAb assets and expertise to expedite development of an accessible and affordable combination product specifically designed to be produced at scale, should bNAbs be shown to be efficacious for HIV prevention, and possibly for treatment.

• NIH’s role in the Ending the HIV Epidemic initiative.

Observing that Ending the HIV Epidemic: A Plan for America had been discussed during several AIDS 2020 sessions, Dr. Dieffenbach described NIH’s role in supporting the 10-year initiative to reduce new HIV transmissions by 90% by 2030. He highlighted NIH’s initial $11 million investment in implementation science research conducted by the NIHsupported Centers for AIDS Research and AIDS Research Centers in coordination with local partners in many of the 57 jurisdictions prioritized in phase 1 of the initiative. He also announced that NIH is continuing their support of that implementation science research for a second year.

Some of the projects funded in the first year will be extended and expanded, and there will be some new areas of emphasis.

One of those, he explained, is exploring how can we improve communication about preexposure prophylaxis (PrEP) to increase uptake among cisgender women.

• HIV research in the coming year. Dr. Dieffenbach remarked that in the next year, he hopes to see findings from HPTN 084, the NIH-sponsored study of long-acting injectable cabotegravir among cisgender women. This is the companion study to HPTN 083, one of the studies he discussed earlier this week, which found that longacting injectable cabotegravir is even more effective in preventing HIV than daily oral Truvada among cisgender men who have sex with men and transgender women who have sex with men. Another area of activity he is looking ahead to in the coming year is new research on gene-based cures for both sickle cell disease and HIV being performed as part of a new collaboration with the Bill & Melinda Gates Foundation.

Recent Developments Given the significant improvement in HIV management by ART, today’s research mainly aims at developing antiretroviral medicines with long-lasting effects. Unlike currently available drugs with daily dosing, the future

Dr Carl Dieffenbach

SEPTEMBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

long-lasting drugs are expected to have weekly, monthly, or even less frequent dosing.

Although no vaccine is still available to prevent HIV infection, the development of therapeutic vaccines that can be given to already infected people is going on. By stimulating the immune system, these vaccines will prepare the body to gain control over HIV infection for a prolonged period.

Also, the development of new drugs for the usual daily ART is going on. Some drugs that are under investigation include nucleoside reverse transcriptase translocation inhibitors (inhibit HIV reverse transcriptase and prevent DNA synthesis) and maturation inhibitors (halt viral maturation by targeting HIV lifecycle).

Moreover, drugs that bind to viral surface protein (gp120) to inhibit virus-mediated immune cell infection, as well as drugs that inhibit capsid (protein shell to cover viral genome) formation are under investigation.

Sugar-based signature identifies T cells where HIV hides despite antiretroviral therapy Scientists at The Wistar Institute may have discovered a new way of identifying and targeting hidden HIV viral reservoirs during treatment with antiretroviral therapy (ART).

These findings were published in Cell Reports and may have translational implications for improving the long-term care of HIV positive people.

ART has dramatically increased the health and life expectancy of HIV-infected individuals, suppressing virus replication in the host immune cells and stopping disease progression; however, low yet persistent amounts of virus remain in the blood and tissues despite therapy.

Virus persistency limits immune recovery and is associated with chronic levels of inflammation so that treated HIV-infected individuals have higher risk of developing a number of diseases.

This persistent infection stems from the ability of HIV to hide in a rare population of CD4 T cells. Finding new markers to identify the virus reservoir is of paramount importance to achieve HIV eradication.

“With recent advances that we are making in the fields of glycobiology and

POWER POWER POWER REIMAGINED REIMAGINED REIMAGINED AN INNOVATIVE NEW TREATMENT FOR YOUR PATIENTS LIVING WITH HIV AN INNOVATIVE NEW TREATMENT FOR ANYOUR INNOVATIVE NEW TREATMENT FOR PATIENTS LIVING WITH HIV YOUR PATIENTS DURABLE LIVING WITH HIV 1,2 POWERFUL, EFFICACY POWERFUL, DURABLE EFFICACY1,2 POWERFUL, DURABLE EFFICACY1,2 HIGH BARRIER TO RESISTANCE1,2 HIGH BARRIER TO RESISTANCE1,2 HIGH BARRIER TO RESISTANCE1,2

TDF, TAF AND ABC FREE1-3 TDF, TAF AND ABC FREE1-3 1-3 TAF AND ABC FREE GEMINI-1TDF, and GEMINI-2 96-week data in treatment-naïve patients: DOVATO 86.0% (n=716) vs DTG + TDF/FTC 89.5% (n=717) (Proportion of patients withdata HIV-1 <50 copies/mL) GEMINI-1 and GEMINI-2 96-week in RNA treatment-naïve patients: DOVATO 86.0% (n=716) vs DTG + TDF/FTC 89.5% (n=717) GEMINI-1 and GEMINI-2 96-week data in treatment-naïve patients: (Proportion of patients with HIV-1 RNA <50 copies/mL) DOVATO 86.0% (n=716) vs DTG + TDF/FTC 89.5% (n=717)

WHY USE 3 IF 2 IS ALL HE NEEDS? (Proportion of patients with HIV-1 RNA <50 copies/mL) WHY USE 3 IF 2 IS ALL HE NEEDS? WHY USE 3 IF 2for IS the ALL HE NEEDS? DOVATO is indicated treatment of HIV-1 in adults and DTG 50 mg + 3TC 300 mg used in the GEMINI studies.

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adolescents above 12 years weighing at least 40 kg, with no known or DOVATO is indicated for the treatment of HIV-1 in adults and suspected resistance to the integrase inhibitor class, or lamivudine. adolescents above 12 years weighing at least 40 kg, with no known or suspected resistance to the integrase inhibitor class, or lamivudine.

Abridged Prescribing Information Dovato (dolutegravir 50mg/lamivudine 300mg) tablets See Summary of Product Characteristics (SmPC) before prescribing.

Abridged Prescribing Information

Presentation: Film-coated tablet containing dolutegravir sodium equivalent to 50 mg about the potential risk of neural tube defects including consideration of effective Dovato (dolutegravir 50mg/lamivudine 300mg) tablets dolutegravir 300 mg lamivudine debossed with “SV-137” on one face. Indication: HIV-1 contraceptive measures. If a woman plans pregnancy, the benefits and the risks of continuing Abridgedand Prescribing Information See Summary of Product Characteristics before >40kg, prescribing. in adults & adolescents above 12 years of(SmPC) age weighing with no known or suspected treatment should be discussed with the patient. The safety and efficacy of a duel regime has Dovato (dolutegravir 50mg/lamivudine tablets resistance to theFilm-coated integrase inhibitor class, or300mg) lamivudine.

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Legal Category: POM A. Date of the website at www.hpra.ie. Adverse reactions can also be reported to the HPRA by calling monitoring. and lactation: fertility - no data; animal antacids fertility separation ifFertility, not taken at the same time food.Human Use Use with cladribine or emtricitabine not- preparation requires boosted PI orpregnancy increased dose ofwith dolutegravir. with Mg/Al-containing of API: July 2020. Code: PI-6305. Further information available from (01) 6764971.

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Use with calcium, multivitamins orofiron also requires dosage GlaxoSmithKline, 12should Riverwalk, Citywest, Campus, Dublin 24. Tel:Authority 01-4955000. using an Adverse Reaction Report Form obtained either from the HPRA or electronically via acting alcohols SmPC section unavoidable, consider moreorfrequent viral load separation if not(see taken at the same 4.5). time Ifwith food. Use with cladribine emtricitabine not the websiteevents at www.hpra.ie.

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Adverse events should alsoobtained be reported tofrom GlaxoSmithKline 1800 244 255. using an Adverse Reaction Report Form either HPRA or on electronically via studiesalcohols indicateJune no effects. childbearing potential (WOCBP) should be counselled acting (see SmPC Women section of 4.5).

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2020. the website at www.hpra.ie. Adverse reactions can also be reported to the HPRA by calling monitoring. Fertility, pregnancy and lactation: Human fertility - no data; animal fertility (01) 6764971. Adverse events should also be reported to GlaxoSmithKline on 1800 244 255. studies indicate no effects. childbearing (WOCBP) should be2.counselled References: 1. Cahn P et al.Women J AcquirofImmunde Deficpotential Syndr. 2020;83(3):310-318. van WYK J et al. Clin Infect Dis. 2020;ciz1243:1-10 3. DOVATO Summary of Product Characteristics. June 2020.

References: 1. Cahn P et al.isJ owned Acquir Immunde Deficto Syndr.

2020;83(3):310-318.

WYK J et al. Clin Infect Dis. 2020;ciz1243:1-10 3. DOVATO Summary of Product DOVATO by or licensed the ViiV Healthcare group2.ofvan companies.

Characteristics. June 2020.

Date of preparation: August 2020. PM-IE-DLL-ADVT-200002 ©2020 ViiV Healthcare group of companies or its licensor.

DOVATO is owned by or licensed to the ViiV Healthcare group of companies. ©2020 ViiV Healthcare group of companies or its licensor.

DOVATO is owned by or licensed to the ViiV Healthcare group of companies. ©2020 ViiV Healthcare group of companies or its licensor.

Date of preparation: August 2020. PM-IE-DLL-ADVT-200002 Date of preparation: August 2020. PM-IE-DLL-ADVT-200002

40 HIV News Dr Mohamed Abdel-Mohsen, Ph.D.

surface glycomic signature that can impact HIV persistence.”

For their studies, Abdel-Mohsen and colleagues used a primary cell model of HIV latency to characterize the cell-surface glycomes of HIV-infected cells.

They confirmed their results in CD4 cells directly isolated from HIV-infected individuals on ART. They identified a process called fucosylation as a feature of persistently infected T cells in which the viral genome is actively being transcribed. Fucosylation is the attachment of a sugar molecule called fucose to proteins present on the cell surface and is critical for T-cell activation.

Study for "HIV-1 cure" For eradication of HIV-1 infection, it is important to gain an in-depth understanding of the wide-ranging characteristics of HIV-1-infected cells in vivo.

glycoimmunology, it has become clear that the sugar molecules present on the surface of immune cells play a critical role in regulating their functions and fate,” said corresponding author Mohamed Abdel-Mohsen, Ph.D., assistant professor in

The Wistar Institute Vaccine & Immunotherapy Center. “However, the relevance of host cell-surface glycosylation in HIV persistence remained largely unexplored, making it a 'dark matter' in our understanding of HIV latency. For the first time, we described a cell-

Recently developed 'omics' analyses (*1) can be a powerful tool to identify the characteristics of HIV-1-infected cells. However, it should be noted that a large majority of the CD4+ T cells(*2) in infected individuals are uninfected, and therefore, the transcriptional profiles of "bulk" CD4+ T cells in vivo do not reflect those of "pure" HIV-1producing cells.

Multiomics analysis to comprehensively reveal the

features of HIV-1-infected cells in vivo In this study, the research group used a human hematopoietic stem cell-transplanted humanized mouse model that maintains human leukopoiesis under relatively stable immunological conditions in vivo and a replication-competent reporter HIV-1, and used four recently developed techniques to investigate viral genomics and transcriptomics.

According to the research group, this study consisted of the four following analyses: First, droplet digital PCR revealed the presence of potential reservoirs in infected humanized mice. Second, ligation mediated PCR showed the preference of HIV-1 to integrate into open chromatin regions, as suggested by the association of the epigenetic modifications of integration sites with viral production. Third, digital RNAsequencing quantified the absolute copy number of viral transcripts in the HIV-1-producing cells in vivo and further identified the differentially expressed genes between virus-infected and uninfected cells. Finally, singlecell RNA-sequencing revealed and characterized the heterogeneity of the HIV-1-producing cells in vivo.

Associate Professor Sato emphasized “To our knowledge, this study is the first investigation to describe multiple aspects of HIV-1-producing cells and also the first comprehensive investigation of the characteristics of HIV-1-infected cells in vivo.”

Ireland on track to eradicate hepatitis C by 2030 World Hepatitis Day recently took place (Tuesday 28th July), and the HSE National Hepatitis C Treatment Programme has highighted the new advancements in treatment for hepatitis C and is encouraging people who think they may have been at risk to get tested.

Previously, many people’s experience of hepatitis C treatment included weekly injections over a year with side effects that mimic the symptoms of the flu – with less than a 50% chance of being cured.

Now, Hepatitis C treatment has been transformed by new, extremely effective, tablet-only medicines with minimal side effects. These new medicines, known as direct-acting antivirals (or DAAs) are very effective drugs,

curing hepatitis C in more than 95% of cases.

The HSE is committed to promoting widespread access to new and highly effective DAAs. Under the clinical leadership of Professor Aiden McCormick, the HSE National Hepatitis C Treatment Programme aims to provide everyone in Ireland infected with hepatitis C access to free DAA medicines. To date, over 5,000 patients in Ireland have been treated with highly effective DAA's for hepatitis C. Current data suggests that Ireland has reached the 2020 targets and is on track to achieve the 2030 WHO elimination targets.

On World Hepatitis Day, the HSE appealed to those who are

SEPTEMBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

undiagnosed in Ireland, who may be anxious or hesitant about getting tested or treated, to come forward.

can be cured with a short course of easy-to-take tablets, and that anyone who has ever been at risk should get tested.”

Professor Aiden McCormick, HSE Clinical Lead for the HSE National Hepatitis C Treatment Programme says, “For people with hepatitis C, the outlook has never been better.

Our treatment programme provides free access to direct acting antiviral (DAA) tablets. DAA tablets are the safest and most effective medicines for treating hepatitis C. They’re highly effective at curing hepatitis C in more than 95 per cent of people. Traditional hepatitis C treatments came with a long list of side effects and were neither as quick nor as effective as these new drugs. We must keep getting the message out that hepatitis C

Marie O’Grady, Programme Manager, HSE National Hepatitis C Treatment Programme, adds, “Over 5,000 patients in Ireland have been treated with highly effective, direct acting antiviral drugs (DAA's) for hepatitis C. It’s vital that we maintain this momentum to reach the 2030 WHO target of making hepatitis C a rare disease by 2030.

With highly effective treatments available through the HSE, there is no reason for anyone to be living with Hepatitis C. We need to urgently find those still living with an undiagnosed infection and support them to access treatment.”

News 41 Study shows latest on Heart Disease in Women This September, the Irish Heart Foundation is launching a campaign to strike before stroke hits as it marks the beginning of a month-long awareness campaign supported by the HSE and focused, for the first time, on stroke prevention among men and women over 40.

Research shows that stroke can strike at any age as 2,000 working age people are now affected annually by the disease in Ireland.

60% of over 45s in Ireland have high blood pressure which is a major risk for stroke. Medical Director of Irish Heart, Dr Angie Brown says, “Stroke is a serious medical emergency mostly associated with older age but the reality is that people of working age are now accounting for one in four of all strokes in Ireland and this is growing rapidly in spite of Ireland’s ageing population.

Preventable risk factors such as high blood pressure and smoking are significant contributors, as well as unhealthy eating and a sedentary lifestyle.

“This September at Irish Heart we want to provoke a younger age group into action that prevention starts now. People in their 40’s often don’t understand their own

level of risk nor would they think that a blood pressure check is relevant to them. Yet 60% of over 45s in Ireland have high blood pressure which is a major risk for stroke. In particular we’re talking to men because they account for almost three-quarters of strokes across the younger age categories and a blood pressure check is a useful indicator of risk.”

Women and Heart Disease According to latest research, women in their 30s and 40s with a common condition affecting how the ovaries work are more likely to get heart disease. That’s the finding of a study published in the European Journal of Preventive Cardiology, a journal of the European Society of Cardiology (ESC).1 “Polycystic ovary syndrome isn’t a life sentence – there are many ways to stay heart healthy,” said study author Dr. Clare Oliver-Williams of the University of Cambridge, UK. “Small changes add up, like eating more fruits and vegetables and doing more exercise.”

It is estimated that 6–20% of women of reproductive age have polycystic ovary syndrome

(PCOS).2 Features of the condition include multiple cysts (fluid-filled sacs) on the ovaries, irregular periods, excess body hair or hair loss from the head due to high levels of male hormones, and difficulty becoming pregnant.

Women with PCOS are more likely to be overweight or obese, have diabetes, and have high blood pressure – all risk factors for heart disease and stroke.

This study examined whether this risky profile translates into a greater likelihood of developing cardiovascular disease – and, for the first time, whether that persists across the lifespan. Dr. Oliver-Williams explained: “Some PCOS symptoms are only present during the reproductive years, so it’s possible that the raised chance of heart disease might disappear later in life.”

The study included 60,574 women receiving treatment to help them get pregnant, such as in vitro fertilisation (IVF), from 1994 to 2015. Of those, 6,149 (10.2%) had PCOS. The researchers used medical records to follow the women for nine years. During that period, 2,925 (4.8%) women developed cardiovascular disease.

Overall, women with PCOS were at 19% higher risk of developing cardiovascular disease than women who did not have PCOS. When divided into age groups, women with PCOS aged 50 and over did not have a higher risk of developing cardiovascular risk compared to their peers without PCOS. Women in their 30s and 40s with PCOS were at greater risk of cardiovascular disease compared to those without PCOS. The evidence in those under 30 was less clear; this is likely because there were insufficient women of that age in the dataset to identify the risk.

Oliver-Williams C, Vassard D, Pinborg A, Schmidt L. Risk of cardiovascular disease for women with polycystic ovary syndrome: results from a national Danish registry cohort study. Eur J Prev Cardiol. 2020. doi:10.1177/2047487320939674.

1

Jayasena CN, Franks S. The Management of Patients With Polycystic Ovary Syndrome. Nat Rev Endocrinol. 2014;10:624–636.

2

Irish Cardiac Society/Mayo Clinic Meeting 2020 Cardiology on the Green 2020 has been postponed and will now take place from April 15th - 17th 2021 in the RCPI Dublin.

Enquiries to bdalton@irishheart.ie Aimed at consultant cardiologists, cardiology trainees and allied healthcare professionals, Cardiology on the Green 2019 brought together expertise from both sides of the Atlantic across all cardiac subspecialties through an innovative and interactive programme over three days.



Pfizer Announces Availability of XELJANZ®

Pfizer Healthcare Ireland has announced the availability of XELJANZ® (tofacitinib citrate) 11mg prolonged-release tablets for the once-daily treatment of moderate to severe rheumatoid arthritis (RA) in combination with methotrexate in patients who have had an inadequate response or intolerance to methotrexate or other DMARDs. Commenting on the announcement, Michael Stewart, I&I Lead Ireland, Pfizer Healthcare Ireland said; “Pfizer continues to be an innovator in inflammation and immunology. The introduction of XELJANZ 11mg once daily tablets provides physicians with another treatment option for rheumatoid arthritis patients who may prefer an oral once-daily treatment. Xeljanz also has a close connection here in Ireland as it is manufactured in our Ringaskiddy site in Cork.”

HOSPITALPROFESSIONALNEWS.IE | HPN • SEPTEMBER 2020

42 News Dr Tomás Ryan wins 2020 Lister Institute Research Prize Dr Tomás Ryan, Associate Professor in Trinity’s School of Biochemistry and Immunology and the Trinity College Institute of Neuroscience (TCIN)

Dr Tomás Ryan has been awarded a highly prestigious 2020 Lister Institute Research Prize, becoming the first scientist in an Irish institution to secure the Lister Institute Preventive Medicine Prize Fellowship.

He will use the prize to pursue research into memory “engrams” to better understand if – and how – we may retrieve misplaced infant memories in adults.

Infantile amnesia is a focus of his work, which is the loss of memories formed in early

childhood (prior to 2–4 years).

Though infantile amnesia is likely the cost of crucial cognitive developmental processes, it is also a constraint on learning during early life. This research is focused on understanding the neurobiology of this form of apparent memory loss.

Dr Ryan said, “It’s an honour and privilege to receive this prestigious award. The freedom to pursue blue skies, fundamental research is at the core of the scientific enterprise, and is the starting point for all societal benefits in medicine, education, and industry.

The support of the Lister Institute of Preventive Medicine will directly enhance the autonomy and

impact of my research team. I look forward to working with the Lister Institute to contribute to the scientific community in Ireland and the UK.” Dr Ryan is an Associate Professor in Trinity’s School of Biochemistry and Immunology and the Trinity College Institute of Neuroscience (TCIN). He is also Principal Investigator of a European Research Council-funded team that was established at Trinity in 2017, and is Chair of the European FENS-Kavli Network of Excellence.

He has regularly featured in the media in recent months as an expert on aspects of COVID-19 in Ireland and associated government policies.

New Study on Allergies A new research study from RCSI University of Medicine and Health Sciences and CHI Temple Street will examine if Ireland’s COVID-19 restrictions will result in an increase in allergies in infants born since March.

Led by clinician scientists at RCSI’s Department of Paediatrics and CHI Temple Street, the study will investigate whether the lower rates of viral infections and improved air quality which resulted from the lockdown are going to make allergic conditions more or less common in children born to families who have

experienced social distancing and isolation. Identifying non-acute consequences of COVID-19 is now a global research priority.

Professor of Paediatrics at RCSI University of Medicine and Health Sciences Jonathan Hourihane, who is leading the study, said, “The lockdown presents a unique scientific opportunity to examine the early origins of often lifelong diseases, issues that constitute a major health and social burden in Ireland and other developed countries.”

Allergic diseases like eczema, asthma, hay fever and food allergy

have become more common over the last 30 years. This is thought to result from decreased exposure to infections, due to smaller family sizes, the introduction of effective immunisations against the most serious infections and community focus on hygiene. This is called the ‘Hygiene Hypothesis’. Air quality, which has also worsened in Ireland and in other industrialised nations over the last 30 years, also affects allergic conditions.

Professor Hourihane continued, “Ireland’s COVID-19 lockdown appears to have reduced the amount of other viral infections,

which typically circulate in the community. We have seen less than half the usual number of attendances at paediatric emergency departments and rates of seasonal influenza and other late spring upper respiratory viruses seemed much lower than usual during this time.”

The study will involve 1,000 infants born in Ireland between March and May 2020. Parents of children born in that time window in the Rotunda Hospital Dublin and The Coombe Women and Infants University Hospital will be invited by letter to participate.

Galway Professor among expert Task Force NUI Galway Professor of Medical Device Technology and Consultant Physician University Hospital Galway, Professor Derek O’Keeffe, is among a 60-person expert task force organised by the team at the Harvard Motion Analysis Laboratory at Spaulding Rehabilitation Hospital to examine the role of mobile health (mHealth) technologies in the COVID-19 pandemic.

The study, ‘Can mHealth Technology Help Mitigate the Effects of the COVID-19 Pandemic?’ was published in the IEEE Open Journal of Engineering in Medicine and Biology today (Wednesday, 12 August).

Professor O’Keeffe said: "The alarming growth of COVID-19

cases has highlighted the shortcomings of healthcare systems, governmental policies, and wider societal issues.

Therefore in this important research work we have developed a framework to rapidly assess digital health solutions to help the public, patients and clinicians to deal with this pandemic.

Clinically we have divided our findings into the distinct domains of preventative, acute and recovery care. Our approach gives authorities an evidence based toolbox to implement state of the art remote patient and frontline worker vital sign monitoring solutions. In addition we outline the ideal criteria and examples of both occupational and general public contact tracing solutions,

SEPTEMBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

such as the recent HSE COVID-19 Tracker App." The Task Force paper concluded that Smartphone applications enabling self-reports and wearable sensors enabling physiological data collection could be used to monitor clinical personnel and detect early signs of an outbreak in the hospital/healthcare settings.

They also reported similarly, in the community, early detection of COVID-19 cases could be achieved by building upon prior studies which showed that by using wearable sensors to capture resting heart rate and sleep duration it is possible to predict influenza-like illness rates as well as COVID-19 epidemic trends.

Professor Derek O’Keeffe

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Treatment beyond 8 we ks hould not be continued if no clincal malignancy, including lymphomas and leukaemia, in al patientssupported Examine al patients, way" hepatosplenic T-cel lymphoma). Serious haematol gical, neurol gical and autoim une Ankylosing spondylits (AS), adults: For sever active AS with inadequate response to response in that ime. Uveits, adults: For non-infectious intermediate, posterior and patients, treated with Tumour Necrosi Factor (TNF) antagonist .the conventionaltherapy.Dosage:Mia, ahas dults:40mgsinRHEUMATOID g54, ledoseEOW.Treatmentbeyond12we ks panuveits with inadequate response to corticosteroids, in patients in ne d of especialy those with a medical history of extensive im unosup res ant or PUVA reactions have also be n reported. These include ra e reports of pancytopenia, aplastic shouldbereconsider difnocARTHRITIS lincalresponseinthat ime.Axialspondyloarthritswithout corticosteroid-sparing, or in whom corticosteroid treatment is inap ropriate. Dosage: 80 treatment, for non-melanoma skin cancer prior to and uring treatment; caution in COPD anaemia, central and peripheral demyelinating events and reports of lupus, lupus-related radiographicevidenceofAS(nr-axSpA),adults:Forsever nr-axSpAwithobjectivesignsof mgintialdoseatWe k0,folowedby40mgEOWfromWe k1.Treatmentcanbeintiated patients, and in patients with increased risk for malignancy due to heavy smoking. conditons and Stevens-Johnson syndrome. Other les com on and ra ely reported inflam ation(el vatedCRPand/orMRI),andaninadequateresponseto rintoleranceto in combination with corticosteroids and/or with other non-biol gic im unomodulatory Considerthepotentialriskwiththecombinationofazathioprineor6-mercaptopurineand adverse reactions are listed in the SmPC. Legal Category: POM. Marketing Authorisation nonsteroidalanti-nflam atorydrugs.Dosage:40mgsingledoseEOW.Treatmentbeyond agents. Concomitant corticosteroids may be taper d in ac ordance with clincal practice adalimumab (hepatosplenic T-cel ymphoma has oc ur ed). Risk of hepatosplenic T-cel Holder: Fresenius Kabi Deutschland GmbH, Else-Kröner-Straße 1, 61352 Bad Homburg 12 we ks hould be reconsider d if no clincal response in that ime. Psoriatic arthrits starting two we ks after intiating treatment with Idacio. Evaluate on a yearly basi the lymphoma can ot be xcluded. Caution in patients with a history of malignancy. Risk of v.d Höhe,Germany.Marketingauthorisation umbers:EU/1 9/1356/0 1,EU/1 9/1356/0 2, (PsA), adults: For active and progres ive PsA with inadequate response to DMARDs. benefit and risk of continued long-term treatment. Paediatric Uveits, 2 years and above: developing dysplasia or col n cancer is unknown. Patients with UC with increased risk of EU/1 9/1356/0 3 Package size and cost: UK / ROI - Idacio 40mg/0.8ml vial x 1: £316.93 / Reduces rate of progres ion of peripheral joint damage on X-ray in polyarticular For chronic non-infectious anterior uveits with inadequate response to r intolerance to dysplasia or col n carcinoma, or history of dysplasia or col n carcinoma, to be scre ned €309.31, Idacio 40mg/0.8ml pre-filed syringe x 2: £63 .86 / €618.63, Idacio 40mg/0.8ml sym etricalsubtypesofthediseaseandimprovesphysicalfunction.Dosage:40mgsingle conventional therapy, or in whom conventional therapy is inap ropriate. Dosage: < 30 kg: fordysplasiabeforetreatmentandthroughoutdiseasecourse.Haematol gicalreactions: pre-filed pen x 2: £63 .86 / €618.63 Further information: available from Fresenius Kabi doseEOW.Treatmentbeyond12we ks houldbereconsider difnoclincalresponseinthat 20mgdoseEOWincombinationwithMTX.Optional40mg(forpatients<30kg)or80mg Adverse vents of the haematol gical system reported with adalimumab. Patients hould Ltd., Cestrian Court, Eastgate Way, Manor Park, Runcorn, Cheshire, WA7 1NT. Tel +4 time.Psoriasi ,adults:Formoderatetosever chronicplaquepsoriasi incandi atesfor (for patients ≥ 30 kg) loading dose one we k prior to start of maintenance therapy. No se kim ediatemedicalat entionifsignsandsymptomsofblo d yscrasiasdevelopwhile (0)192853 53 Dateofprepar tionofPI:April2020 01/API/ DACIO/FKUK-IRL systemictherapy.Dosage:80mgintialdoseatWe k0,folowedby40mgEOWfromWe k clincaldat inuseofloadingdose<6yearsofage(se SmPC).If≥30kg:40mgdoseEOW on treatment. Vac inations: Patients may receive concur ent vac inations, except for live Adverse vents hould be reported.

1. Treatment beyond 16 we ks hould be reconsider d if no clincal response in that ime in combination with MTX. Evaluate on a yearly basi the benefit and risk of continued vac ines. Bring paediatric patients up to date with al im unisations prior to intiating Reporting forms and information can be found at: yel owcard.mhra.gov.uk (ref rtoSmPC).PaediatricPlaquePsoriasi ,4yearsandabove:Forsever chronicplaque long-term treatment. Idacio may be available in other strengths and/or presenta ions Idacio treatment. Congestive heart failure: Se contraindications. Caution is advised with w w.hpra.ie/homepage/about-us/report-an-is ue psoriasi with inadequate response to or if topical therapy and phot herapies are depending on the indivdual treatment ne ds. Contraindications: Hypersensitvity to the mild heart failure (NYHA clas I/ I). Discontinue treatment if new or worseni g symptoms Adverse vents hould also be reported to Fresenius Kabi Ltd. inap ropriate.Dosage:15kgto<30kg:20mgdoseintialyfolowedby20mgEOWstarting activesubstanceortoanyexcipents(se SmPC);Activetuberculosi (TB)orothersever ofcongestiveheartfailure.Autoim uneproces es:Autoim uneantibodiesmayformwith Cestrian Court, Eastgate Way, Manor Park, Runcorn, Cheshire, WA7 1NT onewe kafterintialdose.If≥30kg:40mgdoseintialyfolowedby40mgEOWstarting infections uch as epsi and op ortunistic infections; Moderate to sever heart failure Idacio. Stop treatment if development of a lupus-like syndrome with positve antibodies T e l + 4 ( 0 ) 1 9 2 8 5 3 5 3 one we k after intial dose. Treatment beyond 16 we ks hould be reconsider d if no (NYHAclas I /IV).Warni gsandprecautions:Clearlyrecordthenameandbatchnumber against double-stranded DNA. Surgery: Consider the long half-life of Idacio for plan ed ®

® is an adalimumab biosimilar, is approved for the same indications as the IDACIO®IDACIO is an adalimumab biosimilar, whichwhich is approved for use in the same conditions as the reference product, including the treatment of moderately to severely Crohn’s biologicbiologic reference product, including the treatment of moderate to severe, activeactive rheumatoid 1, 2 1, 2 and ulcerative colitis in adult Patientsaprescribed IDACIO can access Patients prescribed IDACIO canpatients. access KabiCare, web-based resource developed arthritisdisease KabiCare, a web-based resource developed with a holistic approach to patient support. with a holistic approach to patient support.

The indications for IDACIO inIDACIO adults include, with methotrexate, the treatment of moderate to and severe, The indications for include in thecombination treatment of moderately to severely active Crohn’s disease active rheumatoid thewho response to DMARDs* has been inadequate and also the treatment severe, active ulcerativearthritis colitis inwhen adults have had inadequate response to conventional therapies or whoof are intolerant 1 IDACIO can be given as monotherapy and progressive rheumatoid arthritis without previous methotrexate treatment. to or have contraindications to such therapies.1 Before prescribing IDACIO please consult 1the Summary of Before prescribing in case ofProduct intolerance to methotrexate, or when continued methotrexate treatment is inappropriate.

Characteristics. Patients prescribed IDACIO should receive a patient alert card. For more information IDACIO please Product Characteristics.

Patients prescribed IDACIO should receive a patient aboutconsult IDACIOthe andSummary KabiCare,ofplease contact your local Fresenius Kabi representative. alert card. For more information about IDACIO and KabiCare, please contact your local Fresenius Kabi representative.

References: References: 1. IDACIO Summary of Product Characteristics. Fresenius Kabi Ltd. 2. Humira Abbvie 1. IDACIO 40mg solution Summary for injectionofinProduct pre-filledCharacteristics. syringe and pre-filled pen.Ltd. Summary of Product Characteristics. Fresenius Kabi Deutschland GmbH. 2. Humira 40mg solution for injection in pre-filled syringe and pre-filled pen. Summary of Product Characteristics. AbbVie Deutschland GmbH & Co. KG. KabiCare is funded and developed by Fresenius Kabi. *DMARDs =IDACIO disease-modifying anti-rheumatic drugs, includingofmethotrexate and KabiCare are registered trademarks Fresenius Kabi.

KabiCare is funded and developed by Fresenius Kabi. IDACIO and KabiCare are registered trademarks of Fresenius Kabi.

Abbreviated Prescribing Information. Consult the Summary of Product Characteristics for full information. Additional information is available on request.

Idacio (adalimumab) 40 mg  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 below for how to report adverse reactions.

Idacio 40 mg solution for injection in pre-filled syringe Idacio 40 mg solution for injection in pre-filled pen Idacio 40 mg solution for injection in vial for paediatric use Presentation and method of administration: Each single dose 0.8 ml pre-filled syringe, 0.8 ml pre-filled pen or 0.8 ml vial contains 40 mg of adalimumab for subcutaneous injection.

Indications and Dosage: Please refer to SmPC for full information. Idacio treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of conditions for which Idacio is indicated. Ophthalmologists are advised to consult with an appropriate specialist before initiation of treatment with Idacio. Patients treated with Idacio should be given a patient alert card. After proper training in injection technique, patients may self-inject with Idacio if their physician determines that it is appropriate and with medical follow-up as necessary. During treatment with Idacio, other concomitant therapies (e.g., corticosteroids and/or immunomodulatory agents) should be optimised. Rheumatoid arthritis (RA), adults: In combination with methotrexate (MTX) for moderate to severe, active RA with inadequate response to disease-modifying antirheumatic drugs (DMARDs) including MTX. In combination with MTX for severe, active and progressive RA when not previously treated with MTX. Can be given as monotherapy if intolerance to or when continued treatment with MTX is inappropriate. Reduces rate of progression of joint damage on X-ray and improves physical function, in combination with MTX. Dosage:40 mg single dose every other week (EOW). Concomitant MTX should be continued. In monotherapy, patients may require 40 mg every week or 80 mg EOW if they experience a decrease in clinical response. Treatment beyond 12 weeks should be reconsidered if no clinical response in that time. Consider need for dose interruption, e.g. before surgery or if serious infection occurs. Reintroduction after 70 days or longer of discontinuation gave same magnitudes of clinical response and similar safety profile as before dose interruption. Polyarticular juvenile idiopathic arthritis (pJIA), paediatrics 2 years and above: In combination with MTX for active pJIA with inadequate response to one or more DMARDs. Can be given as monotherapy if intolerance to or when continued treatment with MTX is inappropriate. Dosage: 10 kg to < 30 kg 20 mg single dose EOW. If ≥ 30 kg: 40 mg single dose EOW. Treatment beyond 12 weeks should be reconsidered if no clinical response in that time. Enthesitis-related arthritis (ERA), paediatrics 6 years and above: For active ERA with inadequate response to or intolerance to conventional therapy.

Dosage: 15 kg to < 30 kg: 20 mg single dose EOW. If ≥ 30 kg: 40 mg single dose EOW. Ankylosing spondylitis (AS), adults: For severe active AS with inadequate response to conventional therapy. Dosage: adults: 40 mg single dose EOW. Treatment beyond 12 weeks should be reconsidered if no clinical response in that time. Axial spondyloarthritis without radiographic evidence of AS (nr-axSpA), adults: For severe nr-axSpA with objective signs of inflammation (elevated CRP and/or MRI), and an inadequate response to or intolerance to nonsteroidal anti-inflammatory drugs. Dosage: 40 mg single dose EOW. Treatment beyond 12 weeks should be reconsidered if no clinical response in that time. Psoriatic arthritis (PsA), adults: For active and progressive PsA with inadequate response to DMARDs. Reduces rate of progression of peripheral joint damage on X-ray in polyarticular symmetrical subtypes of the disease and improves physical function. Dosage: 40 mg single dose EOW. Treatment beyond 12 weeks should be reconsidered if no clinical response in that time. Psoriasis, adults: For moderate to severe chronic plaque psoriasis in candidates for systemic therapy. Dosage: 80 mg initial dose at Week 0, followed by 40 mg EOW from Week 1. Treatment beyond 16 weeks should be reconsidered if no clinical response in that time (refer to SmPC). Paediatric Plaque Psoriasis, 4 years and above: For severe chronic plaque psoriasis with inadequate response to or if topical therapy and phototherapies are inappropriate. Dosage: 15 kg to < 30 kg: 20 mg dose initially followed by 20 mg EOW starting one week after initial dose. If ≥ 30 kg: 40 mg dose initially followed by 40 mg EOW starting one week after initial dose. Treatment beyond 16 weeks should be reconsidered if no

clinical response in that time. Hidradenitis suppurativa (HS), adults and adolescents from 12 years and above: For active moderate to severe HS (acne inversa) with inadequate response to conventional systemic HS therapy. Dosage: HS, adults: 160 mg dose initially at Day 1, followed by 80 mg two weeks later at Day 15. Two weeks later (Day 29) continue with a dose of 40 mg every week or 80 mg EOW.HS, adolescents 12 years and above ≥ 30 kg: 80 mg initial dose at Week 0, followed by 40 mg EOW from Week 1. If there is inadequate response to 40 mg EOW, an increase in dosage to 40 mg every week or 80 mg EOW may be considered. Antibiotics may be continued if necessary. Concomitant topical antiseptic wash on HS lesions is recommended to be used on a daily basis. Treatment beyond 12 weeks should be reconsidered if no improvement in that time. Reintroduction of Idacio after treatment interruption as appropriate. Evaluate periodically the benefit and risk of continued long-term treatment. Crohn’s disease (CD), adults: For moderately to severely active CD with no response despite a full and adequate course of, intolerance to or contraindication for a corticosteroid and/or an immunosuppressant therapy. Dosage: Induction: 80 mg dose at Week 0, followed by 40 mg at Week 2. For a more rapid response: 160 mg at Week 0, followed by 80 mg at Week 2; risk of adverse events higher during rapid induction. Maintenance: 40 mg dose EOW. During maintenance, corticosteroids may be tapered in accordance with clinical guidelines. If decrease in clinical response, can increase dosage to 40 mg every week or 80 mg EOW. Patients with no response by Week 4 may benefit from continued maintenance therapy to Week 12. Treatment beyond 12 weeks should be reconsidered if no clinical response in that time. Paediatric Crohn’s disease (CD), 6 years and above: For moderately to severely active CD with inadequate response to, intolerance to or contraindication for conventional therapy including primary nutrition therapy and a corticosteroid and/or an immunomodulator. Dosage: < 40 kg: Induction: 40 mg dose at Week 0, followed by 20 mg at Week 2. For a more rapid response: 80 mg at Week 0, followed by 40 mg at Week 2; risk of adverse events higher during rapid induction.

Maintenance: 20 mg dose EOW from week 4. If insufficient response, consider an increase in dosing frequency to 20 mg every week. If ≥ 40 kg: Induction: 80 mg dose at Week 0, followed by 40 mg at Week 2. For a more rapid response: 160 mg dose at Week 0, followed by 80 mg at Week 2; risk of adverse events higher during rapid induction. Maintenance: 40 mg dose EOW from week 4. If insufficient response, consider an increase in dosage to 40 mg every week or 80 mg EOW. Treatment beyond 12 weeks should be reconsidered if no clinical response in that time. Ulcerative colitis (UC), adults: For moderately to severely active UC with inadequate response to, intolerance to or contraindication for conventional therapy including corticosteroids and 6-mercaptopurine (6-MP) or azathioprine (AZA).

Dosage: Induction: 160 mg dose at Week 0, followed by 80 mg at Week 2. Maintenance: 40 mg dose EOW. During maintenance, corticosteroids may be tapered in accordance with clinical guidelines. If insufficient response, consider an increase in dosage to 40 mg every week or 80 mg EOW. Treatment beyond 8 weeks should not be continued if no clinical response in that time. Uveitis, adults: For non-infectious intermediate, posterior and panuveitis with inadequate response to corticosteroids, in patients in need of corticosteroid-sparing, or in whom corticosteroid treatment is inappropriate. Dosage: 80 mg initial dose at Week 0, followed by 40 mg EOW from Week 1. Treatment can be initiated in combination with corticosteroids and/or with other non-biologic immunomodulatory agents. Concomitant corticosteroids may be tapered in accordance with clinical practice starting two weeks after initiating treatment with Idacio. Evaluate on a yearly basis the benefit and risk of continued long-term treatment. Paediatric Uveitis, 2 years and above: For chronic non-infectious anterior uveitis with inadequate response to or intolerance to conventional therapy, or in whom conventional therapy is inappropriate. Dosage: < 30 kg: 20 mg dose EOW in combination with MTX. Optional 40 mg (for patients < 30 kg) or 80 mg (for patients ≥ 30 kg) loading dose one week prior to start of maintenance therapy. No clinical data in use of loading dose < 6 years of age (see SmPC). If ≥ 30 kg: 40 mg dose EOW in combination with MTX. Evaluate on a yearly basis the benefit and risk of continued long-term treatment. Idacio may be available in other strengths and/or presentations depending on the individual treatment needs. Contraindications: Hypersensitivity to the active substance or to any excipients (see SmPC); Active tuberculosis (TB) or other severe infections such as sepsis and opportunistic infections; Moderate to severe heart failure (NYHA class III/IV). Warnings and precautions: Clearly record the name and batch number

of administered product to improve traceability of biological products. Infections: Patients taking TNF-antagonists are more susceptible to serious infections. Impaired lung function may increase the risk for developing infections. Monitor for infections, including TB, before, during and for at least 4 months after treatment. Treatment with Idacio should not be initiated in patients with active infections including chronic or localised infections until infections are controlled. In patients who have been exposed to tuberculosis and patients who have travelled in areas of high risk of tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis, the risk and benefits of treatment with Idacio should be considered prior to initiating therapy. Evaluate new infections during treatment and monitor closely. Stop treatment if new serious infection or sepsis and treat appropriately. Exercise caution in patients with a history of recurring infections or who are predisposed to infections, including the use of concomitant immunosuppressive medications. Serious infections: Serious infections, including those associated with hospitalisation or death, were reported in patients receiving treatment. TB: Consult SmPC for details. Reactivation and new onset TB, both pulmonary and extra-pulmonary (disseminated), were reported. Screen all patients before therapy initiation for active or inactive (latent) TB. Appropriate screening tests (i.e. tuberculin skin test and chest X-ray) should be performed in all patients. If latent TB is suspected, consult physician with appropriate expertise and follow local treatment recommendations for prophylaxis prior to initiation of Idacio. Despite prophylaxis, TB reactivation has occurred on adalimumab. If active TB is diagnosed, do not initiate Idacio treatment. Other opportunistic infections: Opportunistic infections were observed in patients receiving adalimumab. Stop treatment in patients with signs and symptoms of such infections. Consult with physician with appropriate expertise for diagnosis and administration of empiric antifungal therapy in these patients. Hepatitis B reactivation: Reactivation of HBV has occurred in chronic carriers (surface antigen positive). Patients should be tested for HBV infection before initiating treatment. HBV carriers should consult a specialist physician and be closely monitored for reactivation of HBV infection throughout therapy and for several months following termination of treatment. If reactivation occurs, stop treatment and initiate appropriate antiviral and supportive treatment. Neurological events: Caution in patients with pre-existing or recent-onset central or peripheral nervous system demyelinating disorders. Discontinuation of treatment should be considered if any of these disorders develop. Neurologic evaluation should be performed in patients with non-infectious intermediate uveitis prior to initiation of treatment and regularly during treatment, to assess for pre-existing or developing central demyelinating disorders. Allergic reactions: Reports of serious allergic reactions including anaphylaxis received. For serious allergic or anaphylactic reaction, stop Idacio immediately and initiate appropriate therapy.

Malignancies and lymphoproliferative disorders: A possible risk has been reported of malignancy, including lymphomas and leukaemia, in all patients, including paediatric patients, treated with Tumour Necrosis Factor (TNF) antagonists. Examine all patients, especially those with a medical history of extensive immunosuppressant or PUVA treatment, for non-melanoma skin cancer prior to and during treatment; caution in COPD patients, and in patients with increased risk for malignancy due to heavy smoking.

Consider the potential risk with the combination of azathioprine or 6-mercaptopurine and adalimumab (hepatosplenic T-cell lymphoma has occurred). Risk of hepatosplenic T-cell lymphoma cannot be excluded. Caution in patients with a history of malignancy. Risk of developing dysplasia or colon cancer is unknown. Patients with UC with increased risk of dysplasia or colon carcinoma, or history of dysplasia or colon carcinoma, to be screened for dysplasia before treatment and throughout disease course. Haematological reactions: Adverse events of the haematological system reported with adalimumab. Patients should seek immediate medical attention if signs and symptoms of blood dyscrasias develop while on treatment. Vaccinations: Patients may receive concurrent vaccinations, except for live vaccines. Bring paediatric patients up to date with all immunisations prior to initiating Idacio treatment. Congestive heart failure: See contraindications. Caution is advised with mild heart failure (NYHA class I/II). Discontinue treatment if new or worsening symptoms of congestive heart failure. Autoimmune processes: Autoimmune antibodies may form with Idacio. Stop treatment if development of a lupus-like syndrome with positive antibodies against double-stranded DNA. Surgery: Consider the long half-life of Idacio for planned

Fresenius Kabi Ireland Unit 3B Fingal Bay Business Park,

Fresenius IrelandIreland Balbriggan,Kabi Co.Dublin, Unit 3B (0)1 Fingal Bay Business Park, T: +353 8413030 Balbrigga, F: +353 (0)1Co.Dublin, 8496949 Ireland T: +353 (0)1 8413030 www.fresenius-kabi.ie F: +353 8496949 Date of (0)1 preparation: July 2020 www.fresenius-kabi.ie Job code: BIO/IDACIO/011.20 Date of preparation: 2020 Additional information isJuly available on request Job code: BIO/IDACIO/010.20 Additional information is available on request

surgical procedures. Monitor closely for infections. Elderly patients: Serious infections were higher in patients over 65 years of age, some of which had a fatal outcome. Consider risk of infections in these patients. Interactions: Antibody formation was lower when adalimumab was given together with MTX in comparison with use as monotherapy.

Combination of Idacio with other biologic DMARDs (e.g. anakinra and abatacept) or other TNF-antagonists is not recommended. Fertility, pregnancy and lactation: Idacio should only be used during pregnancy if clearly needed. Women of childbearing age should consider the use of adequate contraception and continue its use for at least 5 months after the last treatment. No administration of live vaccines (e.g. BCG) to infants exposed to Idacio in utero for 5 months following mother’s last Idacio treatment during pregnancy.

Idacio can be used during breast-feeding. Adverse Reactions: Very common ≥ 1/10: Respiratory tract infections (including lower and upper respiratory tract infection, pneumonia, sinusitis, pharyngitis, nasopharyngitis and pneumonia herpes viral), leukopenia (including neutropenia and agranulocytosis), anaemia, lipids increased, headache, abdominal pain, nausea and vomiting, elevated liver enzymes, rash (including exfoliative rash), musculoskeletal pain, injection site reaction (including injection site erythema). Common ≥ 1/100 to < 1/10: Systemic infections (including sepsis, candidiasis and influenza), intestinal infections (including gastroenteritis viral), skin and soft tissue infections (including paronychia, cellulitis, impetigo, necrotising fasciitis and herpes zoster), ear infections, oral infections (including herpes simplex, oral herpes and tooth infections), reproductive tract infections (including vulvovaginal mycotic infection), urinary tract infections (including pyelonephritis), fungal infections, joint infections, skin cancer excluding melanoma (including basal cell carcinoma and squamous cell carcinoma), benign neoplasm, leucocytosis, thrombocytopenia, hypersensitivity, allergies (including seasonal allergy), hypokalaemia, uric acid increased, blood sodium abnormal, hypocalcaemia, hyperglycaemia, hypophosphatemia, dehydration, mood alterations (including depression), anxiety, insomnia, paraesthesias (including hypoesthesia), migraine, nerve root compression, visual impairment, conjunctivitis, blepharitis, eye swelling, vertigo, tachycardia, hypertension, flushing, haematoma, asthma, dyspnoea, cough, GI haemorrhage, dyspepsia, gastroesophageal reflux disease, sicca syndrome, worsening or new onset of psoriasis (including palmoplantar pustular psoriasis), urticaria, bruising (including purpura), dermatitis (including eczema), onychoclasis, hyperhidrosis, alopecia, pruritus, muscle spasms (including blood creatine phosphokinase increased), renal impairment, haematuria, chest pain, oedema, pyrexia, coagulation and bleeding disorders (including activated partial thromboplastin time prolonged), autoantibody test positive (including double stranded DNA antibody), blood lactate dehydrogenase increased, impaired healing. Serious, including fatal, adverse reactions have been reported including infections/sepsis, TB, opportunistic infections, allergic reactions (including anaphylaxis), HBV reactivation and malignancies (including leukaemia, lymphoma and hepatosplenic T-cell lymphoma). Serious haematological, neurological and autoimmune reactions have also been reported. These include rare reports of pancytopenia, aplastic anaemia, central and peripheral demyelinating events and reports of lupus, lupus-related conditions and Stevens-Johnson syndrome. Other less common and rarely reported adverse reactions are listed in the SmPC. Legal Category: POM. Marketing Authorisation Holder: Fresenius Kabi Deutschland GmbH, Else-Kröner-Straße 1, 61352 Bad Homburg v.d.Höhe, Germany. Marketing authorisation numbers: EU/1/19/1356/001, EU/1/19/1356/002, EU/1/19/1356/003 Package size and cost: UK / ROI - Idacio 40mg/0.8ml vial x 1: £316.93 / €309.31, Idacio 40mg/0.8ml pre-filled syringe x 2: £633.86 / €618.63, Idacio 40mg/0.8ml pre-filled pen x 2: £633.86 / €618.63 Further information: available from Fresenius Kabi Ltd., Cestrian Court, Eastgate Way, Manor Park, Runcorn, Cheshire, WA7 1NT. Tel +44 (0)1928 533 533 Date of preparation of PI: April 2020 001/API/IDACIO/FKUK-IRL Adverse events should be reported.

Reporting forms and information can be found at: yellowcard.mhra.gov.uk www.hpra.ie/homepage/about-us/report-an-issue Adverse events should also be reported to Fresenius Kabi Ltd. Cestrian Court, Eastgate Way, Manor Park, Runcorn, Cheshire, WA7 1NT Tel +44 (0)1928 533 533

44 Clinical R&D ACCORD HEALTHCARE LAUNCH INNOVATIVE PATIENT FOCUSED APP Following on from the successful launch of its patient-activated, pre-filled injector (PFI) to deliver pegfilgrastim (Pelgraz® ), Accord Healthcare are delivering another first, with the launch of their Pelgraz® support app in Ireland.



The app is designed specifically for patients who have been prescribed Pelgraz® PFI. “We appreciate that patients undergoing treatment for cancer can feel like they have very little control over their illness and we believe it is important to give patients back some sense of control. We have therefore developed our app to help give patients the confidence to self-administer their treatment from the convenience of their own home, while offering them the peace of mind that they are complying with their prescribed treatment regimen”, says Mr Tony Hynds, Managing Director, Accord Healthcare Ireland Ltd. The app supports patients to administer their medication at the correct time and in the correct way. It also provides relevant educational content and the ability to track side-effects along with highlighting how to report any sideeffects. The app allows a patient to set a reminder to administer their treatment, based on when their last chemotherapy session took place and when the clinician indicated to use the product.

Once the reminder is opened, the app automatically presents the administration instructions, which includes an animated video and step-by-step instructions.

The symptom tracker allows patients to log their side-effects and symptoms post-chemotherapy and track them over a given period, providing the patient with the tools and information to have an in-depth conversation at their subsequent meeting with their healthcare professional should they wish.

The ethos behind Accord’s Pelgraz® PFI launch is to give patients the confidence to administer pegfilgrastim from the comfort of their own home.

With pegfilgrastim administered at least 24 hours after cytotoxic chemotherapy, patients will often have to return to hospital or await a visit from a home care nurse to administer pegfilgrastim.

“Evidence shows that travelling to and attending hospital visits are one of the major contributing factors that negatively impact the quality of life for people living with cancer. Reducing the number of times that a patient must visit the clinic or hospital, at a time when they are living with the side-effects of chemotherapy and

when their immune systems are compromised, must be a priority for patients and their healthcare team. Being able to offer the option of spending more time at home during chemotherapy treatment is something I know patients genuinely welcome and also means that the clinic could potentially make more effective use of nurse resources.” said Prof Hartmut Link, Professor of Medicine, external faculty at University Medical Centre, Hannover, Germany.

Patients prescribed Pelgraz® can download the support app from the Apple App store and Google Play.

LATEST CLINICAL RESEARCH EVALUATING VASCEPA® (ICOSAPENT ETHYL) Amarin Corporation plc have announced that new data that add to the growing body of knowledge on VASCEPA® (icosapent ethyl) in patients at risk for major adverse cardiovascular events will be presented at ESC Congress 2020, the annual meeting of the European Society of Cardiology (ESC), being held virtually from August 29 - September 1, 2020.

These new findings will be presented in one Late-Breaking Science presentation and four rapid fire abstract and e-poster presentations from a variety of academic collaborators based on research or analyses supported by Amarin.

"Cardiovascular disease is an ever-increasing global challenge commanding both attention and action," said Craig Granowitz, M.D., Ph.D., Amarin's senior vice president and chief medical officer.

"Often devastating, cardiovascular disease demands new research to increase our understanding of how to address residual cardiovascular risk. Several scheduled presentations at ESC provide new data on VASCEPA and its potential to address heart health in at-risk patients."

Featured Amarin-supported abstracts to be presented at ESC Congress 2020 include: Late-Breaking Science Presentation • Session: Late-Breaking Science in Lipids "Effect of Icosapent Ethyl on Progression of Coronary Atherosclerosis in Patients with Elevated Triglycerides on Statin Therapy: Final results of the EVAPORATE Study" – presented on behalf of all authors by Matthew Budoff, M.D., The Lundquist Institute – August 29, 8:50-9:20 a.m. CEST (Central European Summer Time) Rapid Fire Abstracts and e-Poster Presentations

SEPTEMBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

• Session: Rapid Fire Abstracts "REDUCE-IT: Accumulation of Data Across Prespecified Interim Analyses to Final Results" – presented on behalf of all authors

by Brian Olshansky, M.D., University of Iowa – Available from August 30 • Session: Rapid Fire Abstracts "REDUCE-IT: Total Ischemic Events Reduced Across the Full Range of Baseline LDL Cholesterol and Other Key Subgroups" – presented on behalf of all authors by Deepak L. Bhatt, M.D., M.P.H., Brigham and Women's Hospital – Available from August 30 • Session: Rapid Fire Abstracts "Are the Results of Clinical Trials Relevant in The Real World?

The Applicability of REDUCE-IT to the FAST-MI Registry." – presented on behalf of all authors by Jean Ferrières, M.D., M.Sc., FESC, Toulouse Rangueil University Hospital – Available from August 30 • Session: e-Poster "REDUCE-IT: Outcomes by Baseline Statin Type" – presented on behalf of all authors by Deepak L. Bhatt, M.D., M.P.H., Brigham and Women's Hospital – Available from August 28 Additional REDUCE-IT® and icosapent ethyl (EPA)-related topics will be presented at ESC Congress 2020 and can be found at https:// www.escardio.org/Congresses-&Events/ESC-Congress.

Tiziana Life Sciences plc Announces Closing of $57.25 Million Offering Tiziana Life Sciences plc, a biotechnology company focused on innovative therapeutics for oncology, inflammation and infectious diseases, has announced the closing of its registered direct offering (the "Offering") of American Depositary Shares ("ADSs") on the NASDAQ Global Market. As announced on 3 August 2020, Tiziana issued 11,009,615 ADSs (representing 22,019,230 new ordinary shares of nominal value £0.03 each in the capital of the Company ("Ordinary Shares")) at a price of $5.20 per ADS raising gross proceeds of approximately $57.25 million (before deducting placement agent fees and offering expenses). Each ADS offered represents two (2) Ordinary Shares. All ADSs sold in the Offering were offered by the Company. The number of Ordinary Shares represented by ADSs comprised in the Offering were within existing shareholder authorities.

ThinkEquity, a division of Fordham Financial Management, Inc., acted as the sole placement agent manager for the Offering.

Tiziana intends to use the net proceeds received from this Offering (i) to advance the clinical development of Foralumab, (ii) to initiate a trial in HCC patients with Milciclib, (iii) to expedite clinical development of TZLS-501 for coronavirus COVID-19, and for working capital and other general corporate purposes. Tiziana's Ordinary Shares are admitted to trading on AIM, a market of the London Stock Exchange plc ("AIM"), under the symbol "TILS".

The ADSs are listed for trading on the Nasdaq Global Market under the symbol "TLSA".

This Offering was being made pursuant to a registration statement on Form F-3, as amended (File No. 333-236013), previously filed with the U.S. Securities and Exchange Commission (the "SEC"), which became effective on February 6, 2020.

This press release shall not constitute an offer to sell or the solicitation of an offer to buy any of the securities described herein, nor shall there be any sale of these securities in any state or jurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of any such state or jurisdiction. A final prospectus supplement and accompanying base prospectus relating to this offering have been filed with the SEC and are available at the SEC's website at http:// www.sec.gov.

Copies of the final prospectus supplement and accompanying prospectus relating to the offering may be obtained from ThinkEquity, a division of Fordham Financial Management, Inc., 17 State Street, 22nd Floor, New York, New York 10004, by telephone at (877) 4363673, by email at prospectus@ think-equity.com. Electronic copies of the final prospectus supplement and accompanying prospectus will also be available on the SEC's website at http://www.sec.gov.

Total Voting Rights In conformity with DTR 5.6.1, the Company notifies that as at the date of this announcement, it has a single class of shares in issue being Ordinary Shares and that following the issue of the Ordinary Shares to be issued in the Offering, the total number of Ordinary Shares in issue is 190,559,823 There are no Ordinary Shares held in treasury. Each Ordinary Share entitles the holder to a single vote at general meetings of the Company.

The figure of 190,559,823 Ordinary Shares may be used by shareholders (and others with notification obligations) as the denominator for the calculations by

Clinical R&D 45 which they will determine whether they are required to notify their interest in, or a change to their interest in, the Company under the Financial Conduct Authority's Disclosure Guidance and Transparency Rules.

The person who arranged for the release of this announcement on behalf of the Company was Keeren Shah, Chief Financial Officer of Tiziana.

SANOFI TO ACQUIRE PRINCIPIA BIOPHARMA Sanofi and Principia Biopharma Inc. a late-stage biopharmaceutical company focused on developing treatments for immune-mediated diseases, entered into a definitive agreement under which Sanofi will acquire all of the outstanding shares of Principia for $100 per share in cash, which represents an aggregate equity value of approximately $3.68 billion (on a fully diluted basis). The Sanofi and Principia Boards of Directors unanimously approved the transaction.

Principia's Bruton tyrosine kinase (BTK) inhibitors add to Sanofi's efforts to accelerate and build a portfolio of the next generation of transformative treatments for autoimmune diseases. BTK is present in the signaling pathways of key innate and adaptive cell types of the immune system. Being able to block or disrupt these signaling processes can help in stopping inflammation and tissue destruction related to autoimmune diseases and target some of the underlying pathophysiology.

• BTK inhibitor '168: In a Phase 2b study in patients with multiple sclerosis, '168 reduced Gdenhancing T1 hyperintense lesions by 85% compared to placebo.

In June, Sanofi announced the first multiple sclerosis patient was enrolled in the Phase 3 program for the BTK inhibitor, comprising four pivotal clinical trials across the disease spectrum. The Principia acquisition will provide an opportunity to expand the development program to evaluate indications beyond central nervous system diseases.

• Rilzabrutinib: This oral BTK inhibitor is currently being evaluated in a Phase 3 program for patients with moderate to severe pemphigus, a rare, debilitating autoimmune disease that causes blistering of the skin and mucous membranes. A Phase 3 program for immune thrombocytopenia, a disease that causes high risk for bleeding events, is expected to be initiated by the end of 2020, assuming no COVID-19 related impact. The company also has an ongoing Phase 2 program for IgG4related diseases, which is driven by chronic inflammation, immune

cell infiltration, and fibrosis within organs that can lead to severe morbidity.

• PRN473 Topical: This BTK inhibitor is a topical agent currently in Phase 1 trials and is being developed for immune-mediated diseases that could benefit from localized application to the skin.

The Principia BTK inhibitor franchise is based on its proprietary Tailored Covalency® platform that has generated potential best-in-class clinical candidates. The platform allows the design of both reversible covalent and irreversible covalent small molecule inhibitors that are more selective with less off-target effects. The optimized target residence time has potential to deliver a desired efficacy with a stronger safety profile.

In 2017, Sanofi formed a collaboration with Principia under which Principia granted Sanofi an exclusive, worldwide license to develop and commercialize BTK inhibitor '168 in multiple sclerosis and other central nervous system diseases.

GENMAB ANNOUNCES EUROPEAN MYELOMA NETWORK AND JANSSEN ACHIEVE POSITIVE TOPLINE RESULTS Genmab A/S (Nasdaq: GMAB) has announced that the European Myeloma Network (EMN) in collaboration with Janssen Research & Development, LLC (Janssen) reported positive results from the Phase 3 APOLLO (MMY3013) study of the subcutaneous (SC) formulation of daratumumab in combination with pomalidomide and dexamethasone (Pd) versus Pd alone as treatment for patients with relapsed or refractory multiple myeloma who have previously been treated with lenalidomide (an immunomodulatory drug) and a proteasome inhibitor (PI). The study met the primary endpoint of improving progression-free survival (PFS). Overall, the safety profile of daratumumab SC in combination with Pd was consistent with the safety profile for each therapy separately.

"We are pleased with these positive results for daratumumab, administered as a subcutaneous formulation, in combination with pomalidomide and dexamethasone. The corresponding intravenous regimen was previously approved by the U.S. FDA based on the Phase1 single-arm EQUULEUS study," said Jan van de Winkel, Ph.D., Chief Executive Officer of Genmab.

Janssen Biotech, Inc., which obtained an exclusive worldwide license to develop, manufacture

and commercialize daratumumab from Genmab in 2012, intends to discuss the data with health authorities in preparation for regulatory submissions and plans to submit the data for presentation at an upcoming medical conference.

The APOLLO study was designed to confirm the results from the Phase 1 EQUULEUS (MMY1001) study, which investigated intravenous (IV) daratumumab plus Pd in the same indication.

In June 2017, the U.S. Food and Drug Administration (U.S. FDA) approved the use of DARZALEX in combination with Pd for the treatment of patients with multiple myeloma who have received at least two prior therapies including lenalidomide and a PI based on the results of the EQUULEUS study.

EUROPEAN COMMISSION CALL FOR DATA ON PROSTAGLANDINS AND THEIR ANALOGUES USED IN COSMETIC PRODUCTS The European Commission has issued a call for data on the safety of prostaglandins and their analogues as cosmetic ingredients in the framework of Regulation (EC) 1223/2009.

The Commission has concerns about the use of such ingredients in cosmetic products. Several countries have recorded serious undesirable effects caused by the use of cosmetic products containing prostaglandins and/or its analogues for eyelash growth.

The Commission will mandate the EU Scientific Committee for the Safety of Consumers (SCCS) to assess the safety of the abovementioned cosmetic ingredients. In preparation, interested parties have been invited to submit relevant scientific information on the safety of prostaglandins and their analogues.

More information in relation to requirements for submission of data and the background of this topic, as well as a non-exhaustive list of the ingredients in question, can be found on the European Commission website.

The last date for submission of relevant information to the European Commission is 21 October 2020.

Sanofi and GSK in advanced discussions to supply up to 300 million doses of COVID-19 vaccine Sanofi and GSK are in advanced discussions, with the European Commission (EC) for the supply of up to 300 million doses of a COVID-19 vaccine. The vaccine candidate developed by Sanofi in partnership with GSK, is based on the recombinant protein-based

technology used by Sanofi to produce an influenza vaccine, and GSK's established adjuvant technology. The doses would be manufactured in European countries including France, Belgium, Germany and Italy. This marks a key milestone in protecting and serving the European population against COVID-19.

"Today's announcement helps to ensure that millions of Europeans will have access to a potential vaccine protecting against COVID-19, once proven safe and effective. It has been our steadfast commitment to provide a vaccine that is affordable and accessible to everyone, and we are grateful to the European Commission for their ongoing engagement and shared support of this effort," said Thomas Triomphe, Executive Vice President and Global Head of Sanofi Pasteur.

"Together with GSK, we are working relentlessly to develop and produce a vaccine to address this global health crisis."

Roger Connor, President of GSK Vaccines added "GSK is proud to be working in partnership with Sanofi to make this vaccine available as soon as possible in Europe. Both companies have significant R&D and manufacturing capability in Europe and are already working hard to scale up production across our networks.

This announcement from the EC supports our ongoing efforts" Sanofi is leading the clinical development and registration of the COVID-19 vaccine and expects a Phase 1/ 2 study to start in September, followed by a Phase 3 study by the end of 2020. If data are positive, regulatory approval could be achieved by the first half of 2021. In parallel, Sanofi and GSK are scaling up manufacturing of the antigen and adjuvant to produce up to one billion doses per year overall.

Sanofi and GSK are committed to making the vaccine available globally Sanofi and GSK recently signed agreements with the United States where they have longstanding partnerships with the Biomedical Advanced Research and Development Authority, and also with the UK Government. The partners plan to provide a significant portion of total worldwide available supply capacity in 2021/22 to the global initiative "Access to COVID-19 Tools (ACT) Accelerator," a global collaboration of leaders of governments, global health organizations, businesses and philanthropies to accelerate development, production, and equitable access to COVID-19 tests, treatments, and vaccines.

HOSPITALPROFESSIONALNEWS.IE | HPN • SEPTEMBER 2020

46 Clinical R&D TESTOSTERONE-CONTAINING MEDICINAL PRODUCTS – CAUTION IN PATIENTS WITH THROMBOPHILIA OR RISK FACTORS FOR VENOUS THROMBOEMBOLISM (VTE)

Testarzon, Testim, Testogel, and Tostran. Further details on testosterone-containing medicines are available at www.hpra.ie and www.ema.europa.eu.

Following a recent periodic review of oral, topical, and injectable testosterone-containing medicinal products*, the European Medicines Agency’s (EMA) Pharmacovigilance Risk Assessment Committee (PRAC) has recommended an update to the product information for testosterone-containing medicinal products. These products are licensed in Ireland as testosterone replacement therapy for male hypogonadism. Based on a review of the literature, and in particular data from studies by Glueck et al. the PRAC considered that the existing warning in the product information (Summary of Product Characteristics (SmPC) and Package Leaflet (PL)) regarding clotting disorders should be amended to highlight the need for caution in patients with risk factors for venous thromboembolism (VTE). Similarly, a warning will be included to indicate that in patients with thrombophilia, cases of VTE have been reported, including some in those on anticoagulant treatment. Therefore, continuing testosterone treatment after a first thrombotic event in patients with thrombophilia should be carefully evaluated, and in the case of treatment continuation, further measures should be taken to minimise the individual VTE risk.

Moreover, the PRAC considered it pertinent to specify risk factors for VTE in the Package Leaflet and additionally to include signs and symptoms of thrombosis in order to highlight these for patients.

INTRAVACC'S CANDIDATE RSV VACCINE DEMONSTRATES SAFETY IN PHASE I TRIAL

Advice to Healthcare Professionals • Topical, oral and injectable testosterone-containing medicinal products should be used with caution in patients with risk factors for venous thromboembolism (VTE).

• In patients with thrombophilia, cases of VTE have been reported, including some in those on anticoagulant treatment.

Continuing testosterone treatment in patients with thrombophilia requires careful evaluation after a first thrombotic event and implementation of measures to minimise the individual VTE risk. *Testosterone-containing medicines licensed in Ireland include Androgel, Nebido, Restandol Testocaps,

Intravacc, a global leader in translational research and development of viral and bacterial vaccines, has announced the publication in the medical journal Vaccine, of a clinical phase I study with its candidate Respiratory Syncytial Virus (RSV) vaccine.

The vaccine showed excellent induction of immunogenicity after nasal administration to healthy adult volunteers (18-50 years).

In addition, the Live Attenuated Vaccine (LAV), constructed with reverse genetics, appears to be safe and well-tolerated. Intravacc is currently orienting on a suitable partner for further joint clinical development of this vaccine in a large pediatric setting.

A pediatric vaccine against RSV would not only prevent morbidity and mortality in infants and young children but could also reduce transmission to the elderly. The RS virus is the most common cold virus in children under the age of five and poses a serious threat to the elderly as well. Many biotech and pharmaceutical companies have been developing an RSV vaccine since the 1960s, but to this day no vaccine emerged out of this. An estimated 120,000 children worldwide still die of the virus every year, especially in developing countries.

The conducted trial was a randomized, placebo-controlled phase I study with a first administration in humans of a live attenuated RSV virus without the G (adhesion) protein to evaluate safety, tolerability, excretion and immunogenicity. In preclinical studies, RSV∆G showed decreased host cell binding and infectivity. Intranasal immunization of laboratory animals with the RSV∆G vaccine protected against replication of wild-type RSV, without aggravating the disease.

An RSV lacking the G-protein is expected to be attenuated, but still able to elicit an effective immune response due to the presence of the surface protein F as the major antigen site and residual infectivity. Using reverse genetics, Intravacc constructed a Live Attenuated Vaccine against RSV from which the coding sequence for the attachment

SEPTEMBER 2020 • HPN | HOSPITALPROFESSIONALNEWS.IE

protein (G) was removed from the RSV genome (RSVΔG).

Live attenuated vaccines can be administered intranasally, mimicking the natural route of infection and thereby stimulating both local mucosal and systemic immunity.

Volunteers received one dose of vaccine intranasally, the control group a placebo. The side effects were mild and comparable to the placebo group. No measurable amounts of vaccine were excreted after administration, indicating sufficient attenuation of the vaccine.

Since almost everyone is infected with the RSV almost every year, adults have a fairly high background immunity. That makes it difficult to evaluate efficacy in this group. Measured antibody levels were comparable before and after immunization and between vaccine and placebo groups. In a subsequent study it must be demonstrated whether the vaccine is immunogenic to children.

TIZIANA GRANTED A PATENT ON METHODS AND USE OF ANTI-CD3 MONOCLONAL ANTIBODIES FOR TREATMENT OF CROHN'S DISEASE Tiziana Life Sciences plc, a biotechnology company focused on innovative therapeutics for oncology, inflammation and infectious diseases, has announced that the United States Patent and Trademark Office ("USPTO") has granted a patent on use and methods of treatment of Crohn's disease with Foralumab, its proprietary fully human monoclonal antibody, and all other anti-CD3 monoclonal antibodies (mAb). The CD3 (cluster of differentiation 3) is a protein complex on T-cells, which is important for the regulation of the immune system. The patent will be published by the USPTO on 1 September, 2020 as Patent No. 10,759,858. Recently, Tiziana also announced the issuance of the first-ever patent on oral administration of anti-CD3 mAbs for treatment of human diseases (Patent No. 10,688,186). The grant of this additional compositionof-matter and use patent further strengthens the Company's intellectual property, consisting of proprietary technologies on oral and nasal administration of Foralumab and other anti-CD3 mAbs for the treatment of human diseases.

Tiziana previously reported the

successful completion of a Phase 1 trial utilizing oral administration of Foralumab on 9 January, 2020, which was designed to evaluate its safety and tolerability in healthy subjects. The trial was conducted at Brigham and Women's Hospital, Harvard Medical School, Boston, Mass., and indicated that oral administration of Foralumab was well-tolerated up to a 5 mg dose (https://www.tizianalifesciences. com/news-item?s=2020-0109-tiziana-reports-phase-1clinical-data-demonstrating-oraltreatment-with-foralumab-a-fullyhuman-anti-cd3-monoclonalantibody-is-well-tolerated-inhealthy-volunteers). The Company plans to move forward with a phase 2 trial in the 4th quarter of 2020 with orally administered Foralumab for the evaluation of moderate-to-severe patients with Crohn's Disease.

Dr. Kunwar Shailubhai, CEO & CSO of Tiziana Lifesciences, commented, "We are delighted that this key patent on composition-of-matter and use for treatment of Crohn's Disease is granted. We are very excited about the continued development of the oral administration of Foralumab for the treatment of Crohn's disease because this alternative route of administration seems to minimize toxicity and we believe it would maximize clinical activity by acting topically in the gut to inhibit inflammation."

Additionally, Tiziana previously reported the successful completion of a Phase 1 study evaluating safety and analysis of biomarkers for clinical activity of nasally administered stabilized solution of Foralumab on 28 November, 2018 (https:// www.tizianalifesciences.com/ news-item?s=2018-11-28tiziana-announces-initiation-ofphase-1-clinical-trial-with-nasaladministration-of-foralumab-afully-human-anti-cluster-definition3-monoclonal-antibody-anti-cd3mab-in-healthy-volunteers).

Additionally, a Phase 2 trial in patients with progressive multiple sclerosis will commence in the 4th quarter. Importantly, in both clinical studies, the severe toxicities commonly associated with intravenous administration of anti-CD3 mAbs were not observed with oral or nasal administration of Foralumab.

The person who arranged for the release of this announcement on behalf of the Company was Dr. Kunwar Shailubhai, CEO & CSO of Tiziana.

NEW

BUILDING ONTO THE CLINICAL EXPERIENCE OF BEVACIZUMAB WITH PFIZER1 ZIRABEV® is an EMA licensed biosimilar of bevacizumab

2

ZIRABEV® ▼ 25 mg/ml concentrate for solution for infusion (bevacizumab) ABBREVIATED PRESCRIBING INFORMATION - IE Please refer to the full Summary of Product Characteristics (SmPC) before prescribing. Presentation: Vial containing 100 mg or 400 mg of bevacizumab concentrate for solution for infusion (bevacizumab is a recombinant humanised monoclonal antibody produced by DNA technology in Chinese Hamster Ovary cells). Administration: Intravenous (IV) infusion only under the supervision of a physician experienced in the use of antineoplastic medicinal products. If first (over 90 mins) and second (over 60 mins) infusions are well tolerated, all subsequent infusions may be administered over 30 mins. Dose reductions not recommended. If indicated, therapy should be stopped or temporarily suspended. Indications and dosage: 1) Zirabev (5 or 10 mg/kg every 2 weeks or 7.5 or 15 mg/kg every 3 weeks) in combination with fluoropyrimidine-based chemotherapy is indicated for treatment of adult patients with metastatic carcinoma of the colon or rectum. 2) Zirabev (10mg/kg every 2 weeks or 15mg/kg every 3 weeks) in combination with paclitaxel is indicated for first-line treatment of adult patients with metastatic breast cancer. 3) Zirabev 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 Zirabev in combination with capecitabine. 4) Zirabev (7.5 or 15 mg/kg every 3 weeks), in addition to platinum- based chemotherapy (for up to 6 cycles, then Zirabev monotherapy), 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) Zirabev (10 mg/kg every 2 weeks) in combination with interferon alfa-2a is indicated for first line treatment of adult patients with advanced and/or metastatic renal cell cancer. 6) Zirabev (15 mg/kg every 3 weeks), in combination with carboplatin and paclitaxel (for up to 6 cycles followed by Zirabev monotherapy until disease progression, a maximum of 15 months or until unacceptable toxicity, whichever occurs earlier) 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. 7) Zirabev (15 mg/kg every 3 weeks), in combination with carboplatin and gemcitabine (6 to 10 cycles, followed by Zirabev monotherapy) or in combination with carboplatin and paclitaxel (6 to 8 cycles, followed by Zirabev monotherapy), 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. 8) Zirabev (10 mg/kg every 2 weeks) in combination with topotecan (given weekly), 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. If topotecan is administered every 3 weeks, the Zirabev dose is 15 mg/kg every 3 weeks. 9) Zirabev (15 mg/kg every 3 weeks), 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. Elderly patients: Dosage adjustments are not required in elderly patients. Hepatic impairment & renal impairment: The safety and efficacy have not been studied in patients with hepatic or renal impairment. Paediatric patients: Not indicated. Contra-indications: Hypersensitivity to the active substance or to any of the excipients. Hypersensitivity to Chinese Hamster Ovary (CHO) cell products or other recombinant human or humanised antibodies.

Pregnancy. Pregnancy and lactation: Women of childbearing potential have to use effective contraception during (and up to 6 months after) treatment. Bevacizumab is contraindicated in pregnancy. Women must discontinue breast-feeding during therapy and not breastfeed for at least six months following the last dose of bevacizumab. Warnings and precautions: Traceability: Zirabev is a biological

medicine; clearly record the trade name and batch number in the patient file. There is an increased risk of developing the following serious conditions (see SmPC for full guidance on patient risk factors and when to discontinue or withhold Zirabev): Gastrointestinal (GI) perforations and fistulae, GI-vaginal fistulae, Non-GI fistulae, wound healing complications, hypertension, aneurysms and artery dissections, posterior reversible encephalopathy syndrome (PRES), proteinuria, arterial thromboembolism, venous thromboembolism, haemorrhage, pulmonary haemorrhage/haemoptysis, congestive heart failure, neutropenia and infections, hypersensitivity reactions/ infusion reactions, osteonecrosis of the jaw. Zirabev is not formulated for intravitreal use. Unapproved intravitreal use has led to serious ocular adverse reactions including permanent blindness as well as systemic adverse effects including non-ocular haemorrhages and arterial thromboembolic reactions. As bevacizumab may cause ovarian failure, discuss fertility preservation strategies with women of child-bearing potential prior to starting treatment. Side-effects: The overall safety profile of bevacizumab is based on data from over 5,700 patients with various malignancies, predominantly treated with bevacizumab in combination with chemotherapy in clinical trials.

The most serious adverse reactions were: gastrointestinal perforations; haemorrhage, including pulmonary haemorrhage/haemoptysis, which is more common in non-small cell lung cancer patients: arterial thromboembolism. The most frequently observed adverse reactions across clinical trials in patients receiving bevacizumab were hypertension, fatigue or asthenia, diarrhoea and abdominal pain. Very common (> 1/10) side effects were: febrile neutropenia, leucopenia, neutropenia, thrombocytopenia, anorexia, hypomagnesaemia, hyponatraemia, peripheral sensory neuropathy, dysarthria, headache, dysgeusia, eye disorder, lacrimation increased, hypertension, thrombo-embolism (venous), dyspnoea, rhinitis, epistaxis, cough, rectal haemorrhage, stomatitis, constipation, diarrhoea, nausea, vomiting, abdominal pain, wound healing complications, exfoliative dermatitis, dry skin, skin discoloration, arthralgia, myalgia, proteinuria, ovarian failure, asthenia, fatigue, pyrexia, pain, mucosal inflammation, weight decreased. Common (≥1/100 to <1/10) reported side-effects were: sepsis, abscess, cellulitis, infection, urinary tract infection, anaemia, lymphopenia, hypersensitivity, infusion reactions, dehydration, cerebrovascular accident, syncope, somnolence, congestive heart failure, supraventricular tachycardia, thromboembolism (arterial), haemorrhage, deep vein thrombosis, pulmonary haemorrhage/haemoptysis, pulmonary embolism, hypoxia, dysphoniaa, gastrointestinal perforation, intestinal perforation, ileus, intestinal obstruction, recto-vaginal fistulae, gastrointestinal disorder, proctalgia, palmar-plantar erythro-dysaesthesia syndrome, fistula, muscular weakness, back pain, , pelvic pain and lethargy,.

The following severe side effects (frequency not known) have also been reported: necrotising fasciitis, hypersensitivity, infusion reactions, posterior reversible encephalopathy syndrome, hypertensive encephalopathy, aneurysms and artery dissections, renal thrombotic microangiopathy, pulmonary hypertension, nasal septum perforation, GI ulcer and perforation, rectal haemorrhage, gallbladder perforation, osteonecrosis of the jaw, non-mandibular osteonecrosis, ovarian failure, foetal abnormalities. See SmPC for full details on all other side effects. Driving and operating machinery: 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. Legal category: POM, S1A. Marketing Authorisation Number: EU/1/18/1344/001, EU/1/18/1344/002. Marketing Authorisation Holder: Pfizer Europe MA EEIG, Boulevard de la Plaine 17, 1050 Bruxelles, Belgium. Last revised: 05/2020. Ref: bZR 2_0. For further information on this medicine please contact: Pfizer Medical Information on 1800 633 363 or at EUMEDINFO@Pfizer.com. For queries regarding product availability please contact: Pfizer Healthcare Ireland, Pfizer Building 9, Riverwalk, National Digital Park, Citywest Business Campus, Dublin 24 + 353 1 467 6500.

References: 1. ZIRABEV® (bevacizumab) Summary of Product Characteristics. 2. European Medicines Agency. ZIRABEV® EPAR summary for the public. https://www.ema.europa.eu/en/medicines/human/EPAR/zirabev . Accessed July 2020.

Abbreviations: EMA = European Medicines Agency.

PP-BVC-IRL-0030 | Date of Preparation: July 2020

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.